abstracts - 31. Deutscher Krebskongress 2014

Transcrição

Oncol Res Treat
37(suppl 1) VI–145 (2014)
37 | S1 | 14
print
online
ISSN 2296–5270
e-ISSN 2296–5262
e-ISBN 978-3-318-02610-8
Formerly
Band 37,
Supplement 1,
Februar 2014
31. Deutscher Krebskongress
ABSTRACTS
Berlin, 19.–22. Februar 2014
KON – ntelligente Konzepte
in der Onkologie
Herausgeber Michael Hallek, Köln
S. Karger
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Band 37, Supplement 1, Februar 2014
Offizielles Organ von
DGHO– Deutsche Gesellschaft für Hämatologie und Medizinische Onkologie
ÖGHO– Österreichische Gesellschaft für Hämatologie & Medizinische Onkologie
DFaG – Deutsche Fatigue Gesellschaft
AIO – Arbeitsgemeinschaft Internistische Onkologie in der Deutschen Krebsgesellschaft e.V.
Mitglied der Deutschen Krebsgesellschaft e.V.
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Band 37,
Supplement 1,
Februar 2014
31. Deutscher Krebskongress
KON – ntelligente Konzepte
in der Onkologie
Berlin, 19.–22. Februar 2014
ABSTRACTS
Herausgeber Michael Hallek, Köln
Basel · Freiburg · Paris · London · New York · Chennai · New Delhi ·
Bangkok · Beijing · Shanghai · Tokyo · Kuala Lumpur · Singapore · Sydney
Oncol Res Treat 2014;37(suppl 1):IV
Programmkomitee
Albers, P. (Düsseldorf ), Bartsch, H.H. (Freiburg), Baumann, F. (Köln), Becker, J. (Graz),
Bergmann, L. (Frankfurt/M), Bokemeyer, C. (Hamburg), Bruns, J. (Berlin), Büttner, R. (Köln),
Cursiefen, C. (Köln), Dietel, M. (Berlin), Dietz, A. (Leipzig), Domagk, K. (Hamburg),
Dunst, J. (Lübeck), Eggert, A. (Berlin), Engers, R. (Düsseldorf ), Enghofer, E. (Leverkusen),
Fehm, T. (Düsseldorf ), Feyer, P. (Berlin), Fietkau, R. (Erlangen), Graeven, U.
(Mönchengladbach), Gschwend, J. (München), Gutzmer, R. (Hannover), Hallek, M. (Köln),
Hartmann, J. (Kiel), Hasch, G. (Darmstadt), Hegewisch-Becker. (Hamburg), Helbig, U.
(Berlin), Hochhaus, A. (Jena), Hölscher, A. (Köln), Hübner, J. (Berlin), Issels, R. (München),
Jackisch, C. (Offenbach), Katalinic, A. (Lübeck), Kerschgens, C. (Berlin), Kleeberg, U.
(Hamburg), Klinkhammer-Schalke, M. (Regensburg), Kohlhuber, F. (Bonn), Kotzerke, J.
(Dresden), Krege, S. (Krefeld), Kusch, M. (Köln), Lang, H. (Mainz), Lordick, F. (Leipzig),
Mallmann, P. (Köln), Meier, K. (Soltau), Nettekoven, G. (Bonn), Neugebauer, E. (Witten),
Ortmann, O. (Regensburg), Paradies, K. (Hamburg), Pfaff, H. (Köln), Reif, K. (Bochum),
Retz, M. (München), Riemann, J.F. (Ludwigshafen), Röcken, C. (Kiel), Rüffer, J.U. (Köln),
Schadendorf, D. (Essen), Schirren, J. (Wiesbaden), Schlag, P. (Berlin), Schmidberger, H.
(Mainz), Schmutzler, R. (Köln), Singer, S. (Mainz), Souchon, R. (Tübingen), Stadler, R.
(Minden), Steiner, T. (Erfurt), Stummer, W. (Münster), Sturm, D. (Chemnitz), Thomas, M.
(Heidelberg), Thomas, R. (Köln), van, Oorschot. (Würzburg), Voltz, R. (Köln), vom, Hagen, U.
(Berlin), Wallwiener, D. (Tübingen), Walther, J. (Heidelberg), Walter, S. (Bonn), Weisse, I.
(Stuttgart), Wiedenmann, B. (Berlin), Wiegel, T. (Ulm), Wiestler, O. (Heidelberg),
Wittekind, C. (Leipzig), Wolf, J. (Köln), Zander, T. (Köln)
Gutachter
lbers, P. (Düsseldorf ), Albus, C. (Köln), Arnold, D. (Freiburg), Bahra, M. (Berlin),
A
Bamberg, M. (Tübingen), Beckmann, M.W. (Erlangen), Benzing, T. (Köln), Berdel, W.E.
(Münster), Berthold, F. (Köln), Beuth, J. (Köln), Biersack, H.J. (Bonn), Bloch, W. (Köln),
Bokemeyer, C. (Hamburg), Bootz, F. (Bonn), Brossart, P. (Bonn), Brüning, J. (Köln),
Budach, W. (Düsseldorf ), Cornely, O. (Köln), Debatin, K.M. (Ulm), Deckert, M. (Köln),
Domagk, K. (Stadt), Emons, G. (Göttingen), Engenhart-Cabillic, R. (Marburg), Engers, R.
(Neuss), Feyer, P. (Berlin), Fietkau, R. (Erlangen), Frank, K. (Köln), Friedel, G. (Gerlingen),
Gabbert, H. (Düsseldorf ), Gathof, B. (Köln), Geiser, F. (Bonn), Graeven, U.
(Mönchengladbach), Harbeck, N. (München), Hartmann, G. (Bonn), Hegewisch-Becker, S.
(Hamburg), Hellmich, M. (Köln), Henne-Bruns, D. (Ulm), Herden, J. (Köln), Herschbach, P.
(München), Hertenstein, B. (Bremen), Heukamp, L. (Köln), Höffken, K. (Jena),
Hohenberger, W. (Erlangen), Hölscher, A. (Köln), Hopt, U.T. (Freiburg), Howaldt, H.P.
(Gießen), Hübner, J. (Berlin), Jonat, W. (Kiel), Kalff, J. (Bonn), Keller, M. (Heidelberg),
Kiechle, M. (München), Klaschik, E. (Alfter), Klingebiel, T. (Frankfurt/M.), Koch, U.
(Hamburg), Kortmann, R.D. (Leipzig), Krieg, T. (Köln), Kuhn, W. (Bonn), Lang, H. (Mainz),
Lehmacher, W. (Köln), Liekweg, A. (Köln), Lutz, M. (Saarbrücken), Maintz, D. (Köln),
Mallmann, P. (Köln), Malter, W. (Köln), Meier, K. (Soltau), Meyer, H.J. (Berlin), Molls, M.
(München), Müller, S. (Bonn), Perner, S. (Bonn), Possinger, K. (Egling), Radbruch, L. (Bonn),
Reif, K. (Bochum), Reinacher-Schick, A. (Bochum), Riemann, J.F. (Ludwigshafen), Rödel, C.
(Frankfurt/M.), Scheid, C. (Stadt), Scheulen, M. (Essen), Schild, H. (Bonn), Schirren, J.
(Wiesbaden), Schlegel, U. (Bochum), Schmidt-Wolf, I. (Bonn), Schmoll, H.J. (Halle/S.),
Schmutzler, R. (Köln), Schuler, M. (Essen), Schulz, R.J. (Köln), Schütte, W. (Halle/S.),
Seehofer, D. (Berlin), Seufferlein, T. (Ulm), Sterner-Kock, A. (Köln), Stürzl, M. (Erlangen),
Stuschke, M. (Essen), Tannapfel, A. (Bochum), Thiel, E. (Berlin), Thomas, R. (Köln), Trümper, L.
(Göttingen), Ukena, D. (Bremen), Unger, C. (Freiburg), Vanhoefer, U. (Hamburg), Vatter, H.
(Bonn), Voltz, R. (Köln), vom, Hagen, U. (Berlin), Wahl, G. (Bonn), Wahlers, T. (Köln),
Wallwiener, D. (Tübingen), Weis, J. (Freiburg), Welt, A, (Essen), Wenz, F, (Mannheim),
Wiestler, O, (Heidelberg), Wittekind, C, (Leipzig), Zander, T, (Köln)
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Inhalt
Oncol Res Treat 2014;37(suppl 1):V
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Antiangiogenic or Antimetastatic Agents
1
Biomarkers
2
Breast Cancer – Adjuvant Therapy
10
Breast Cancer – Local-Regional Therapy
15
Breast Cancer – Metastatic Breast Cancer
17
Cancer Prevention 21
Cell Cycle, Apoptosis, Angiogenesis
22
Cell-Based Therapy 23
Central Nervous System Tumors
24
Clinical Trial Design
27
Developmental Therapeutics: Immunotherapy
29
Developmental Therapeutics: Molecular Therapeutics
31
Economy 32
Epidemiology 33
Functional Imaging 38
Gastrointestinal (Colorectal) Cancer (including liver metastases)
39
Gastrointestinal (Noncolorectal) Cancer 50
Gastrointestinal Stromal Tumors 57
Genitourinary Cancer including Prostate Cancer
58
Gynecologic Cancer
65
Head and Neck Cancer
76
Health Services Research
79
Leukemia, Myelodysplasia, and Transplantation
84
Lung Cancer – Adjuvant Therapy
86
Lung Cancer – Local-Regional Therapy
86
Lung Cancer – Metastatic Lung Cancer
87
Lymphoma and Plasma Cell Disorders
92
Miscellaneous
92
Molecular Pathology
95
Molecular Targets
96
Oncological Pharmacy
100
Paediatric Cancer
101
Palliative Care
101
Patient Care
102
Phase I Studies
105
Psychooncology
106
Quality-of-Life Management
111
Radiation Biology
114
Inhalt
Oncol Res Treat 2014;37(suppl 1):VI
Sarcoma
115
Skin Cancer including Melanoma
118
Stem Cells in Cancer
119
Supportive Care
120
Surgical Oncology
124
Tumor and Cell Biology
127
Tyrosine Kinase Inhibitors
131
Pflegerische Beiträge
132
Autorenindex
134
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II
Inhalt
Index
Abstracts
Oncol Res Treat 2014;37(suppl 1):1–133
Antiangiogenic or Antimetastatic Agents
ID 285
Dimethylfumarate suppresses prostate cancer cell
proliferation and fortifies chemotherapeutic action
I. Hrgovic1, E. Valesky1, R. Rustemeyer1, T. Hailemariam-Jahn1,
F. Roos2, A. Pinter1, R. Kaufmann1, M. Meissner1
Universitätsklinik Frankfurt, Klinik für Dermatologie, Venerologie und
Allergologie, Frankfurt, Deutschland
2
Universitätsklinik Mainz, Klinik für Urologie, Mainz, Deutschland
1
Recent evidence suggests, that Dimethylfumarate (DMF), known as a
highly potent anti-psoriatic agent, might have anti-tumorigenic properties. To analyze, the effects of DMF on prostate carcinoma cell lines, we
first performed cytotoxicity assays with the androgen dependent cell line
LNCAP and the androgen independent cell line PC-3. No LDH release
could be demonstrated. In further analysis we could show, that DMF suppresses prostate carcinoma cell proliferation in a concentration dependent
manner. These effect could be paralleled with reduced prostate specific
antigen (PSA) expression. In functional tumor invasion assays we could
demonstrate that DMF treatment reduces prostate cancer cell invasion
almost as effective as the first-line chemotherapeutic Docetaxel. To examine whether these effects are conveyed by apoptotic mechanisms we
performed apoptosis assays. There was no significant apoptosis induced
by DMF in both cell lines. Therefore, we performed cell cycle analysis.
DMF induced an G0/G1 arrest in both prostate carcinoma cell lines. Interestingly, in LNCAP DMF induced p53, p21 and p27 whereas in PC-3,
which harbors a p53 mutation, only p21 and p27 were induced. In further experiments, possible additive effects of DMF treatment combined
with Docetaxel, were evaluated. Here, it could be demonstrated, that the
combination of both agents is more effective than the chemotherapeutic
agent alone.
These data provide first evidence, that DMF inhibits prostate cancer proliferation by reinduction of important cell cycle inhibitors. The combination of Docetaxel and DMF provides additive anti-cancer effects. Hence,
DMF might be an interesting agent in the treatment of prostate cancer and
is worth for further in vivo analysis.
ID 424
2-Methoxyestradiol impairs lymphangiogenesis through
G2/M cell cycle arrest and apoptosis
I. Hrgovic, M. Doll, A. Pinter, S. Kippenberger, E. Valesky,
R. Kaufmann, M. Meissner
Klinikum der Johann Wolfgang Goethe-Universität, Klinik für Dermatologie,
Venerologie und Allergologie, Frankfurt am Main, Deutschland
Question: Lymphangiogenesis is a crucial step in the progression of
cancer. Formation of new lymphatic vessels provides an additional route
for tumor cells to metastasize. Therefore, inhibiting lymphangiogenesis
represents an interesting target in cancer therapy. 2-Methoxyestradiol
(2-ME) is a physiological metabolite of estradiol with low cytotoxicity.
As 2-ME promotes anti-angiogenic effects on endothelial cells, we hypothesized that 2-ME may have impact on lymphangiogenesis.
Methods: Human lymphatic endothelial cells (LEC) were cultured in vitro and treated with or without 2-ME. Effects of 2-ME on proliferation,
cell cycle progress and apoptosis were analyzed mainly by Bromdesoxy-
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uridin assay, flow cytometry and immunoblotting. In vitro angiogenesis
was investigated using the Matrigel tube formation assay.
Results: We found that 2-ME inhibited cell proliferation in a concentration-dependent manner. Furthermore, we demonstrate that 2-ME induced
both G2/M arrest and apoptosis in LEC. Cell cycle arrest was accompanied by up-regulation of p53 and p21, as well as down-regulation of
Cyclin B1, Cdc25c and cdc2. In addition, 2-ME induced apoptosis by
cytochrome c release, activating Caspase-9, -7, and -3 and cleavage of
poly-(ADP-ribose) polymerase and up-regulation of the pro-apoptotic
Protein Bim, whereas cleavage of Caspase 8 was unaffected by higher
concentrations of 2-ME. Moreover, 2-ME induced in a time-dependent
manner an activation of ERK1/2 and JNK in LEC. Inhibition of JNK- and
ERK1/2-pathway reduced 2-ME-induced apoptosis of LEC. In further
analysis, we could demonstrate an inhibition of the formation of capillary
like structures by 2-ME treatment.
Conclusion: Our results demonstrated that 2-ME has distinct anti-lymphangiogenic effects by arresting cell cycle in G2/M phase and activating
the intrinsic apoptotic pathway.
ID 426
HDAC inhibitors decreases lymphangiogenesis by
inducing apoptosis and cell cycle arrest via
p53/p21-dependent pathways
I. Hrgovic, M. Doll, A. Pinter, S. Kippenberger, E. Valesky,
R. Kaufmann, M. Meissner
Klinikum der Johann Wolfgang Goethe-Universität, Klinik für Dermatologie,
Venerologie und Allergologie, Frankfurt am Main, Deutschland
Question: Lymphangiogenesis is a crucial step in the progression of cancer. Formation of new lymphatic vessels provides an additional route for
tumor cells to metastasize. Therefore, inhibiting lymphangiogenesis represents an interesting target in cancer therapy. Recent evidence suggests
that histone deacetylase inhibitors (HDACi) may mediate part of their
antitumor effects by interfering with angiogenesis. We therefore examined the potential impact of three different HDACi, trichostatin A (TSA),
sodium butyrate (NaB) and valproic acid (VPA) on cell proliferation in
primary human lymphatic endothelial cells (LEC).
Methods: Human lymphatic endothelial cells (LEC) were cultured in
vitro and treated with or without HDACi. Effects of HDACi on proliferation, cell cycle progress and apoptosis were analyzed mainly by
BrdU-Assay, flow cytometry and immunoblotting.
Results: HDACi inhibited cell proliferation in a concentration-dependent
manner. We found that TSA induced G0/G1 arrest in LEC. Cell cycle arrest
was accompanied by up-regulation of p53 and p21. Moreover, we found
that p21 mRNA was significantly up-regulated by TSA, while the protein
and mRNA half-life remains largely unaffected. The promoter activity of
p21 was enhanced by TSA indicating a transcriptional mechanism. Subsequent EMSA analyses showed increased constitutive Sp1/3-dependent
DNA binding in response to HDAC inhibition. We demonstrated that p53
was required for TSA induced p21 expression. Interestingly, siRNA-mediated p21 depletion reduced the antiproliferative effects of TSA in LEC.
In addition, TSA induced apoptosis by cytochrome c release, activating
Caspase-9/-7 and down-regulating the anti-apoptotic proteins cIAP-1/-2.
Conclusion: In conclusion, we demonstrate that HDACi have distinct anti-lymphangiogenic effects by activating the intrinsic apoptotic pathway
and cell cycle arrest via p53/p21-dependent pathways.
Inhalt
Index
Biomarkers
ID 017
Osteopontin, vascular endothelial growth factor and
carbonic anhydrase 9 as potential biomarkers in the
radiochemotherapy of non small-cell lung cancer
C. Ostheimer1, M. Bache1, A. Güttler1, M. Kotzsch2,
D. Vordermark1
Martin-Luther-Universität Halle-Wittenberg, Klinik für Strahlentherapie,
Halle, Deutschland
2
Technische Universität Dresden, Institut für Pathologie, Dresden,
Deutschland
1
Background: Prognosis and therapeutic outcome of advanced stage non
small-cell lung cancer (NSCLC) remains poor and combined radiochemotherapy often is the definite treatment. However, hypoxic radioresistance
limits the response to radiotherapy. This prospective study evaluated the
inter-relationship and prognostic quality of hypoxia-related proteins in
NSCLC patients treated by radiochemotherapy.
Material and Methods: Pre-treatment osteopontin (OPN), vascular endothelial growth factor (VEGF) and carbonic anhydrase 9 (CA 9) plasma
levels were determined by ELISA in 55 NSCLC (M0) patients. Treatment
consisted of a 66-Gy curative-intended radiotherapy ± chemotherapy.
Biomarker correlation, association with clinicopathological parameters
and the prognostic value of a biomarker combination was assessed.
Results: All biomarkers linearly correlated and were linked to different clinical parameters including weight loss (OPN), gross tumor volume (VEGF)
and T stage (CA 9). Single marker plasma levels of OPN (p = 0.03), VEGF
(p = 0.02) and CA 9 (p = 0.04) significantly predicted overall survival. Biomarker combination correlated additively with prognosis and increased the
risk of death by a factor 2. The effect was most pronounced with the triple
combination OPN/VEGF/CA 9, yielding a 6-fold risk of death (p = 0.009).
Combined plasma levels of OPN/VEGF/CA 9 were independent predictors
of survival in a multivariate analysis (p = 0.03).
Conclusions: These results suggest that a biomarker co-detection augments the prognostic value of single markers. The studied proteins should
be considered for a hypoxic biomarker profile which might help identifying patients with hypoxic and radioresistant tumors.
ID 050
Comparison of the prognostic significance of
immunoglobulin kappa C, CD4 and CD8 in node-negative
breast cancer
M. Schmidt1, B. Hellwig2, I. Sicking1,2, M. Battista1, S. Gebhard1,
A. Lebrecht1, M. Gehrmann3, R. Wirtz3,4, G. Hoffmann1,
C. Solbach1, J. Rahnenführer1,2, J. Hengstler1,2,5
Universitätsmedizin Mainz, Frauenklinik, Mainz, Deutschland
Technische Universität, Institut für Statistik, Dortmund, Deutschland
3
Bayer GmbH, Leverkusen, Deutschland
4
Stratifyer, Köln, Deutschland
5
Technische Universität, Leibniz Research Centre for Working Environment and Human Factors (IfADo), Dortmund, Deutschland
1
2
Background: The prognostic significance of tumor-infiltrating lymphocytes in breast cancer is well accepted. We compared the prognostic relevance of immunoglobulin kappa C (IGKC), CD4 and CD8 in node-negative breast cancer using mRNA expression.
Methods: Microarray based gene-expression data for IGKC (214669_x_
at), CD4 (203547_at) and CD8 (205758_at) were analyzed in four previously published cohorts (Mainz, Rotterdam, Transbig, Yu) of node-negative breast cancer patients not treated with adjuvant therapy (n = 824).
The prognostic significance for metastasis-free survival (MFS) was compared using a likelihood-ratio-test in the whole cohort as well as in different molecular subtypes (luminal A, luminal B, basal-like, HER2+).
Results: IGKC (p < 0.001) had the strongest independent association
with MFS in the whole cohort of node-negative breast cancer patients.
2
CD4 (p < 0.05) and CD8 (p < 0.05) showed only a significant association
with MFS in univariate analysis. In luminal A breast cancer, neither IGKC
nor CD4 nor CD8 were associated with MFS. In luminal B tumors, only
IGKC retained independent prognostic significance (p < 0.001). IGKC
showed univariate significance in basal-like breast cancer (p < 0.05) and
retained the significance when included in the model as second variable
after CD4. In HER2+ breast cancer, IGKC (p < 0.001) as well as CD4
(p < 0.05) and CD8 (p < 0.05) displayed univariate significance but only
IGKC maintained independent relevance (p < 0.05).
Conclusion: IGKC as marker of the humoral immune system showed the
strongest association with MFS in node-negative breast cancer as compared to CD4 or CD8. There were marked differences in the prognostic
relevance between different molecular breast cancer subtypes.
ID 079
Immunological parameters as predictive and prognostic
biomarkers for chemoradioimmunotherapy of patients
with pancreatic adenocarcinoma
A. Bazhin, J. Werner, S. Karakhanova
Chirurgische Uniklinik Heidelberg, Heidelberg, Deutschland
Pancreatic adenocarcinoma (PDAC) has a particularly poor prognosis
with a median survival of 6 months. Nowadays the standard treatment
today is surgical resection and subsequent adjuvant chemotherapy. This is
possible in about 20% of all patients, and results in a median survival of
over 20 months. Chemoradioimmunotherapy of patients with pancreatic
adenocarcinoma (CapRitrial) did not show benefit of interferon-α adding
to 5-fluorouracil based treatment protocol. However, the clinical outcome
represented the best ever reported survival for patients with resected pancreatic cancer in adjuvant setting. The aim of the present work was to
identify immunological parameters in a group of patients treated with
chemoradioimmunotherapy, which could be useful for predictive and/
or prognostic purpose.Here we provide evidence that high lymphocyte
number before the therapy correlates positive with better disease-free and
overall survivals. An increase in effector cytotoxic T cells or a high increase in effector memory CD8+ T cells after interferon-α injection have a
positive correlation with the patients’ outcome during the therapy. Moreover a decrease in CD4 cells expressing immunosuppressive molecule
CD152 is associated with better disease-free survival. Thus, tmmunological parameters, identified in this trial as possible surrogate blood markers,
may be of interest and importance in context of the personalized medicine
for improvement of PDAC patients’ treatment, after a validation in a prospective setting.
ID 085
WTZ-Tumorprofil – A preemptive biomarker profiling
program in relation to personalized clinical drug
development at a large German Comprehensive Cancer
Center: Two years’ experience.
M. Wiesweg1, S. Ting2, H. Reis2, K. Worm2, S. Kasper1, S. Bauer1,
T.C. Gauler1, A. Welt1, H. Richly1, M. Tewes1, J. Meiler1,
J. Hense1, W.E. Eberhardt1, C. Derks1, D. Cortes-Incio1,
S. Skottky2, J. Wohlschläger2, F. Breitenbücher1, L. Freitag3,
G. Stamatis3, K.W. Schmid2, M. Schuler1,3
Universität Duisburg-Essen, Westdeutsches Tumorzentrum, Innere Klinik
(Tumorforschung), Essen, Deutschland
2
Universität Duisburg-Essen, Westdeutsches Tumorzentrum, Institut für
Pathologie und Neuropathologie, Essen, Deutschland
3
Universität Duisburg-Essen, Westdeutsches Lungenzentrum, Ruhrlandklinik, Essen, Deutschland
1
Background: Biomarker-guided treatment of metastatic lung cancer,
GIST or melanoma has set unprecedented examples for effective targeted
therapies. Multiple investigational drugs are explored in patient populations defined by specific biomarkers of low prevalence, demanding a
novel process of patient identification for early clinical trials. Here we
Abstracts
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describe a biomarker program linked to the standard diagnostic algorithm
which has been initiated at the West German Cancer Center, one of 12
German Oncology Centers of Excellence.
Methods: In addition to standard diagnostic procedures, profiling is offered to all patients with advanced lung or colorectal cancer, who meet
generic study inclusion criteria. Biomarkers comprise oncogenic ‘driver’
mutations (KRAS, NRAS, EGFR, BRAF, PIK3CA, DDR2), gene amplifications and translocations (HER2, ALK, FGFR, PIK3CA, ROS1),
and PTEN loss, following prespecified algorithms. The clinical course of
‘profiled’ patients is closely monitored offering trial participation whenever applicable.
Results: 410 patients (301 NSCLC, 109 CRC) have been profiled in 20
months. The most prevalent biomarkers were KRAS mutations (29%)
for adeno NSCLC, FGFR1 amplification (25%) for squamous NSCLC,
and KRAS (38%) and BRAF (6%) mutations for CRC. 21 patients have
entered biomarker-guided clinical trials, while therapeutic decisions for
approved drugs were guided in 68 patients.
Conclusion: Preemptive biomarker profiling was established as part of the
diagnostic algorithm of a large Comprehensive Cancer Center, enabling the
prospective identification of patients eligible for biomarker-guided trials.
High patient numbers and substantial investments are mandatory.
ID 094
The detection of excision repair cross-complementing
rodent repair deficiency, complementation group
1-positive circulating tumor cells in the blood of ovarian
cancer patients as a predictive biomarker for
platinum-resistance
J.D. Kuhlmann1, P. Wimberger1, A. Bankfalvi2, T. Keller3,
S. Schöler2, B. Aktas4, P. Buderath4, S. Hauch5, R. Kimmig4,
S. Kasimir-Bauer4
Universitätsklinikum Dresden, Klinik für Frauenheilkunde und Geburtshilfe, Dresden, Deutschland
2
Universitätsklinikum Essen, Institut für Pathologie und Neuropathologie,
Essen, Deutschland
3
Acomed Statistics, Leipzig, Deutschland
4
Universitätsklinikum Essen, Klinik für Frauenheilkunde und Geburtshilfe,
Essen, Deutschland
5
Adnagen AG, Langenhagen, Deutschland
1
Platinum-resistance constitutes one of the most recognized clinical challenges for ovarian cancer. Primary tumor-based ERCC1-detection by immunhistochemistry was recently shown to be inaccurate for the prediction
of platinum-resistance. Considering our previous finding that circulating
tumor cells (CTC) in the blood of ovarian cancer patients are prognostically significant and hypothesizing that negative prognostic impact of
CTC may arise from a cellular phenotype, being associated with platinum-resistance, we now inquired, whether ERCC1-expression in CTC
may be a suitable biomarker for stratifying response to platinum-based
chemotherapy. In total, 245 patients were studied. The presence of CTC
was analyzed by immunomagnetic CTC-enrichment, targeting the epithelial epitopes GA 73.3 (EpCAM) and MUC-1, followed by multiplex
RT-PCR to detect the transcripts GA733-2 (EpCAM), MUC-1 and Ca
125, including ERCC1 in a separate approach. ERCC1-expression in the
primary tumor was assessed by immunhistochemistry (antibody 8F1). At
primary diagnosis ERCC1+CTC were observed in 8% of patients and associated with decreased progression-free survival (PFS) and overall survival (OS) (p = 0.037, p = 0.035, respectively). Moreover, multivariate
analysis revealed ERCC1+CTC to be an independent predictor for a poor
PFS (p = 0.007). Most interestingly, the presence of ERCC1+CTC at primary diagnosis was an independent predictor for platinum-resistance (p <
0.007), whereas ERCC1-expression in corresponding primary tumor tissue predicted neither platinum-resistance, nor prognosis. This is the first
report, suggesting a blood-based assay for predicting platinum-resistance
at primary diagnosis of ovarian cancer.
Abstracts
ID 099
Validation of plasma proneurotensin as a novel biomarker
for the prediction of incident breast cancer
O. Melander1, M. Belting2, P. Almgren1, J. Manjer1, B. Hedblad1,
G. Engström1, J. Struck3, U. Kilger3, P. Nilsson1, A. Bergmann3,
M. Orho-Melander 1
Skåne University Hospital, Malm, Clinical Research Center, Ent 72,
bldg 91, floor 12, Malmö, Schweden
2
Lund University, Section of Oncology, Lund, Schweden
3
Sphingotec GmbH, Hennigsdorf, Deutschland
1
Context: Experimental settings have indicated that Neurotensin regulates
both satiety and breast cancer growth. In a first study (Malmö Diet and
Cancer Study) increasing fasting plasma Proneurotensin 1-117, a stable
peptide derived from the same precursor as Neurotensin, was significantly associated with the development of breast cancer.
Objective: To validate in an independent second study the initial finding
of proneurotensin being a risk prediction marker for the development of
breast cancer.
Design, Setting, and Participants: The Malmö Preventive Project
(MPP) is a general population study and comprised 18,200 subjects at
the timepoint of first re-examination (2002–2006). Of these subjects 1569
women including all women of the entire re-examination cohort who
developed breast cancer until 2012 were randomly selected for baseline
plasma proneurotensin assessment. The mean age of the women at baseline was 70.0±4.4 years, and all women were free from breast cancer at
baseline.
Proneurotensin was measured in samples from these fasting women and
related to the risk of later breast cancer development, which had occurred
until 2012 (130 incident breast cancer events), using multivariate Cox
proportional hazards models.
Results: In the women of the MPP study, Proneurotensin (hazard ratio
[HR] per SD increment of log-transformed proneurotensin) was related to incident breast cancer (130 events; HR, 2.07; 95% CI, 1.77–2.42;
P < .001; adjusted for age, BMI and smoking). This Hazard ratio was even
stronger than initially observed in the Malmö Diet and Cancer Study (123
events; HR, 1.44; 95% CI, 1.21–1.71; P < .001). The women investigated
in the MPP study were about 10 years (mean) older than in the Malmö
Diet and Cancer Study.
Conclusion: Proneurotensin has been validated in a second cohort as a
novel risk stratification marker for the development of breast cancer.
ID 100
A biomarker based detection and characterization of
carcinomas exploiting two fundamental biophysical
mechanisms in mammalian cells
M. Grimm1, P. Teriete2, S. Schmitt3, T. Biegner4, A. Stenzl5,
J. Hennenlotter5, H.-J. Muhs6, A. Munz1, T. Nadtotschi1, K. König7,
J. Sänger8, O. Feyen9, H. Hofmann9, S. Reinert1, J.F. Coy9
University Hospital Tuebingen, Department of Oral and Maxillofacial
Surgery, Tuebingen, Deutschland
2
Cancer Research Center, Sanford-Burnham Medical Research Institute,
La Jolla, CA, USA, Vereinigte Staaten von Amerika
3
University Hospital Heidelberg, German Cancer Research Center (DKFZ)
Flow Cytometry Core Facility, Heidelberg, Deutschland
4
University Hospital Tuebingen, Department of Pathology, Tuebingen,
Deutschland
5
University Hospital Tuebingen, Department of Urology, Tuebingen,
Deutschland
6
Clemenshospital Muenster, Department of Gynecology, Muenster, Deutschland
7
University Hospital Tuebingen, Department of Anaesthesiology and Intensive Care Medicine, Tuebingen, Deutschland
8
Institute of Pathology, Bad Berka, Deutschland
9
TAVARLIN AG, Pfungstadt, Deutschland
1
Background: Biomarkers allowing the characterization of malignancy
and therapy response of oral squamous cell carcinomas (OSCC) or other
types of carcinomas are still outstanding. The biochemical suicide mole-
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cule endonuclease DNaseX (DNaseI-like 1) has been used to identify the
Apo10 protein epitope that marks tumour cells with abnormal apoptosis
and proliferation. The transketolase-like protein 1 (TKTL1) represents
the enzymatic basis for an anaerobic glucose metabolism even in the presence of oxygen (aerobic glycolysis/Warburg effect), which is concomitant
with a more malignant phenotype due to invasive growth/metastasis and
resistance to radical and apoptosis inducing therapies.
Methods: Expression of Apo10 and TKTL1 was analysed retrospectively
in OSCC specimen (n = 161) by immunohistochemistry. Both markers
represent independent markers for poor survival. Furthermore Apo10 and
TKTL1 have been used prospectively EDIM-blood test in patients with
OSCC (n = 50), breast cancer (n = 48), prostate cancer (n = 115), and
blood donors/controls (n = 74).
Results: Positive Apo10 and TKTL1 expression were associated with
recurrence of the tumor. Multivariate analysis demonstrated Apo10 and
TKTL1 expression as an independent prognostic factor for reduced tumor-specific survival. Apo10+/TKTL1+ subgroup showed the worst disease-free survival rate in OSCC.
EDIM-Apo10 and EDIM-TKTL1 blood tests allowed a sensitive and specific detection of patients with OSCC, breast cancer and prostate cancer
before surgery and in after care. A combined score of Apo10+/TKTL1+
led to a sensitivity of 95.8% and a specificity of 97.3% for the detection
of carcinomas independent of the tumor entity.
Conclusions: The combined detection of two independent fundamental
biophysical processes by the two biomarkers Apo10 and TKTL1 allow a
sensitive and specific detection of neoplasia in a noninvasive and cost-effective way.
ID 101
Plasma Pro-Enkephalin, a stable peptide of the precursor
to the endogenous opioid Enkephalin, predicts breast
cancer risk
O. Melander1, M. Orho-Melander1, P. Almgren1, J. Manjer1,
B. Hedblad1, G. Engström1, J. Struck2, P. Nilsson1, A. Bergmann2,
M. Belting1
Skåne University Hospital, Malm, Clinical Research Center, Ent 72,
bldg 91, floor 12, Malmö, Schweden
2
1
Context: Opioid peptides may negatively regulate carcinogenesis and the
growth of breast tumors by various mechanisms. Little is known about
their role in the development of breast cancer in humans. Pro-Enkephalin
A 119-159 (pro-ENK), a peptide derived from the same precursor as Enkephalin, has been developed as a reliable surrogate plasma marker for
the unstable Enkephalin.
Objective: To test if fasting plasma levels of pro-ENK are associated
with development of incident breast cancer.
Design, Setting, and Participants: We measured pro-ENK in fasting
plasma from 2554 women (mean age 58±5.9 years) of the population
based Malmö Diet and Cancer Study (MDCS) free from breast cancer prior to the baseline exam in 1991–1994. pro-ENK was related to first breast
cancer events (n = 154) during a median of 14.8 years of follow-up. For
replication, we related pro-ENK to risk of later breast cancer development (130 incident events) in an independent sample from the Malmö
Preventive Project (MPP) consisting of 1569 women (mean age 70.0±4.4
years), all free from breast cancer at baseline.
Results: In the MDCS, pro-ENK was inversely related to risk of incident breast cancer [HR 0.76 (0.65–0.89), P = 0.001)]. Women belonging
to quartiles 3, 2 and 1 compared to women belonging to the 4th quartile of
plasma pro-ENK had hazard ratios of 1.32 (0.75–2.30), 2.05 (1.23–3.42)
and 2.58 (1.56–4.25) (P < 0.001). In the MPP, the odds ratio was 0.63
(0.52–0.75) (P<0.001). As compared to women belonging to the 4th quartile of plasma pro-ENK, women belonging to quartiles 3, 2 and 1 had
odds ratios for breast cancer of 2.45 (1.23–4.88), 2.93 (1.49–5.74) and
4.79 (2.51–9.12) (P<0.001).
4
Conclusion: In two large general population studies low fasting plasma
concentration of pro-ENK is strongly associated with increased risk of
future breast cancer development in middle aged and post-menopausal
women.
ID 163
Specific miRNA signatures characterize distant
metastases of clear cell renal cell carcinoma at different
sites
J. Heinzelmann1,2, U. Wickmann2, S. Baumgart1,2, F. Stolzenbach1,
R. Schneeweiss1, M. Gajda3, M. Stöckle1, K. Junker1
Universitätsklinikum des Saarlandes, Klinik für Urologie, Homburg,
Deutschland
2
Universitätsklinikum Jena, Klinik für Urologie, Jena, Deutschland
3
Universitätsklinikum Jena, Institut für Pathologie, Jena, Deutschland
1
Background: miRNAs are regulators of gene expression in tumorigenesis and progression. To identify miRNAs associated with metastases miRNA expression in distant metastases was compared to primary ccRCC.
Material and Methods: Total RNA of 27 primary ccRCC samples and
25 distant metastases (lung, bone and brain) was isolated from formalin-fixed paraffin-embedded (FFPE) samples Microarray analyses were
performed for a global miRNA expression profiling. Results were validated by qPCR.
Results: We identified 9 miRNAs (including miR-30c and miR-126) with
a similar expression in metastatic primary ccRCC and distant metastases from different metastatic sites compared to non-metastatic primary
ccRCC. 11 miRNAs (including miR-10b and miR-204) were differently
expressed in distant metastases compared to primary ccRCC. Furthermore, each metastatic site is characterized by a specific miRNA signature. Results were verified on selected miRNAs using qPCR. Ongoing in
vitro studies are investigating the functional role of miRNAs in metastatic
processes of ccRCC.
Discussion: These data suggest that miRNAs play an important role
in metastatic processes of ccRCC. Furthermore, our results regarding
different metastatic sites suggest to two important statements: Specific
miRNAs characterize distant metastases in general. On the other hand,
miRNA expression is associated with specific conditions at different metastatic sites. Thus, the data presented in this study give the base for a
better understanding of the involvement of miRNAs as regulators of metastasis which opens new possibilities for new targeted therapy options.
ID 177
A new diagnostic test for monitoring of breast cancer
patients
A.-R. Rotmann
Praxis für Gynäkologie, Rodgau-Nieder-Roden, Deutschland
Background: Impaired glucose metabolism and elevated blood glucose
levels have been linked with increased cancer risk and cancer mortality.
New therapies have been established addressing new targets controlling
glucose metabolism in breast cancer patients.
Recently it has been shown that the detection of the biomarker transketolase-like-1 (TKTL1) in monocytes allows the detection of upregulated
glucose metabolism in cancer patients. The epitope detection in monocytes (EDIM) has been established as a new technology for a non-invasive biomarker based detection and characterization of tumors as well as
early detection of recurrence and/or metastasis. The biomarker Apo10 is
highly specifically expressed in tumor cells irrespective of the tumor entity and is accumulated in due to blocked apoptosis. Thus, the combined
use of the biomarkers Apo10 and TKTL1 offers the possibility to detect
abnormal cell proliferation and up-regulated glucose metabolism, indicating neoplasias and the degree of malignancy.
This new technology also could be used to identify breast cancer patients
that will benefit from existing and new therapeutic approaches. Just re-
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cently the mTOR inhibitor everolimus has been approved and Metformin
has been shown to reduce the incidence of invasive breast cancer.
Methods: In a routine gynecological practice we use the test for early
detection, for monitoring of patients during treatment and in aftercare.
Conclusion: Our data from more than 100 patients with breast cancer for
a period up to 4 years are promising results worth to be further validated.
This new diagnostic test could be a useful tool to identify and monitor
cancer patients and the use of new therapies.
ID 182
Expression of progesterone receptor membrane
component 1 (PGRMC1) in tissues of breast cancer
patients
I. Wurster1, C. Meisner1, H. Seeger2, U. Vogel3, H. Schneck4,
C. Blassl4, S. Schultz4, T. Fehm4, H. Neubauer4
University of Tuebingen, Institute for Clinical Epidemiology and Applied
Biometry, Tuebingen, Deutschland
2
University of Tuebingen, Department of Obstetrics and Gynaecology,
Tuebingen, Deutschland
3
University of Tuebingen, Institute of Pathology, Tuebingen, Deutschland
4
Heinrich Heine University of Duesseldorf, Department of Obstetrics and
Gynaecology, Duesseldorf, Deutschland
1
Objectives: Progesterone receptor membrane component 1 (PGRMC1)
may be important in tumorigenesis and may thus increase the risk for developing breast cancer under certain circumstances e.g. during hormone
therapy. The main purpose of this study was to investigate the expression
of PGRMC1 in benign and malignant tissues of breast cancer patients.
Methods: Matching ‘baseline’ tissue biopsies of 69 breast cancer patients
undergoing pre-surgery therapy were analyzed by immunohistochemistry
for expression levels of PGRMC1 and its phosphorylated version at serine 180 (pPGRMC1). Associations with clinicopathological parameters,
e.g. tumour grading and receptor expression, and patient’s characteristics
such as the patient’s age were calculated.
Results: PGRMC1 and pPGRMC1 are expressed in breast cancer tissue as well as in connective tissue and are co-expressed with estrogen
receptors, but not with progesterone receptor. Every breats cancer specimen showed expression of PGRMC1 and pPGRMC1 with a very strong
expression in the cytoplasm of tumour cells. A much weaker signal was
detected in connective tissue surrounding the actual carcinoma tissue (p
< 0.001). No correlation was observed forthe expression of PGRMC1
and pPGRMC1 with histopathological status, menopausal status, tumour
grading or the patient’s age. However, the expression of PGRMC1 and
pPGRMC1 appears to be correlated with the expression of certain hormone receptors, especially in the age group of 60–69 years. Stratification
for age revealed that pPGRMC1 is significantly higher expressed in elderly patients > 70 years than in the age groups 50–59 and 60–69 years.
Conclusion: PGRMC1 is highly expressed in breast tumour tissues and
thus may play a decisive role in breast cancer development. Further studies are necessary to reveal how PGRMC1 may be involved in breast carcinogenesis probably triggered by hormone therapy.
ID 183
Medroxyprogesterone acetate-driven increase in breast
cancer risk might be mediated via cross-talk with
growth factors in the presence of progesterone receptor
membrane component-1
H. Neubauer1, H. Seeger2, H. Schneck1, A. Mueck2, T. Fehm1
possible carcinogenic effect of MPA remains unclear so far. Progesterone
receptor membrane component-1 (PGRMC1) may be important in tumorigenesis and thus may increase breast cancer risk. We investigated the
influence of MPA alone and in combination with growth factors on breast
cancer cells overexpressing PGRMC1.
Methods: MCF-7 cells were stably transfected with PGRMC1 expression plasmid (WT-12 cells). Cells transfected only with the vector were
used as control cells (EVC-cells). Medroxyprogesterone acetate (MPA),
norethisterone (NET) and progesterone (P) were tested alone and in combination with a mixture of growth factors. Cell proliferation was measured by MTT assay.
Results: The growth factor mixture (GF) was able to induce cell proliferation in both cell types, however, the effect was much higher in the WT12 cells. In WT-12 cells both MPA and NET alone significantly increased
cell proliferation with values of 40% and 97%, respectively. Progesterone, however, had no effect. In combination with GF MPA significantly further enhanced cell proliferation as compared to the effect of MPA
alone and GF alone in both cell lines. NET showed no further increase as
compared to NET alone and P had no effect.
Conclusions: We could demonstrate a significant proliferative effect
of MPA when combined with high concentrations of growth factors.
This effect was more pronounced in breast cancer cells overexpressing
PGRMC1. These results may be of clinical relevance since in the combined WHI trial an increased breast cancer risk was found during treatment with conjugated equine estrogens plus MPA.
ID 190
Analysing the mutational status of PIK3CA in circulating
tumor cells from metastatic breast cancer patients
F. Meier-Stiegen1, H. Schneck1, C. Blassl1, R. Pedro Neves2,
W. Janni3, T. Fehm1, H. Neubauer1
Universitäts-Frauenklinik Düsseldorf, Forschungslabor Life Science Center, Düsseldorf, Deutschland
2
Heinrich-Heine Universität Düsseldorf, Düsseldorf, Deutschland
3
Universitäts-Frauenklinik Ulm, Ulm, Deutschland
1
The frequently altered phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway is involved in the regulation of cellular processes required
for breast carcinogenesis. The aim of the project was to develop a method
to identify hotspot mutations in the PIK3CA gene in circulating tumor
cells (CTCs) of metastatic breast cancer (metBC) patients.
From 44 enrolled CTC-positive metBC patients a total number of 57 peripheral blood samples were analysed by CellSearch. Genomic DNA of
enriched CTCs was isolated, amplified and analyzed for PIK3CA mutations in exons 9 and 20 which lead to E542K, E545K or H1047R amino
acid changes and result in increased PI3K activity. The mutations were
detected by using SNaPshot-methodology comprising PCR amplification
and single nucleotide primer extension.
SNaPshot analysis was established using genomic DNA from different
breast cancer cell lines and then successfully transferred to investigate
blood samples and single cells. Overall, twelve hotspot mutations in either exon 9/E545K (6/12, 50%) or exon 20/H1047R (6/12, 50%) could be
determined within 9 out of 57 (15.8%) blood samples from 7 out of 44
(15.9%) patients; CTC counts ranged from 1 to 9748.
PIK3CA variants E542K, E545G and E545A were not detected. Analysing the PIK3CA genotype of CTCs has clinical relevance with respect to
drug resistance, e.g. against HER2-targeted therapy. The herein described
approach including SNaPshot technology provides a simple method to
characterize hotspot mutations within CTCs.
2
University of Tuebingen, Department of Obstetrics and Gynaecology,
Tuebingen, Deutschland
1
Background: The WHI trial suggests an increase of breast cancer in postmenopausal women probably according to the progestogenic compound,
i.e. medroxyprogesterone acetate (MPA). However, the mechanism for a
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ID 195
CTCtrap – Circulating Tumor Cells TheRapeutic
APheresis: A novel biotechnology enabling personalized
therapy for all cancer patients
N. Kasprowicz1, F. Farace2, G. Attard3, B. Rack4, C. Vizler5,
R. Zamarchi6, M. Scholz7, A. Aaspõllu8, A. Ventola9,
L. Terstappen10, T. Fehm1
2
Institut de Cancérologie Gustave Roussy, Villejuif, Frankreich
3
Institute of Cancer Research, Großbritannien
4
Ludwig-Maximilians University München, Munich, Deutschland
5
Biological Research Centre – Hungarian Academy of Science (BRC),
Ungarn
6
Oncology Institute of Veneto IRCCS, Italien
7
LEUKOCARE AG, Munich, Deutschland
8
Asper Biotech Ltd, Estland
9
Aquamarijn Micro Filtration BV, The Netherlands
10
Twente University, Medical Cell Biophysics, Faculty of Science and
Technology, The Netherlands
1
Chemotherapy is slowly being supplemented by a new generation of
drugs that recognize specific targets in or on cancer cells and has proven
to be more effective with markedly fewer side effects. As a consequence
renewed tumor analysis is required to redefine the optimal treatment regiment. However a biopsy can frequently not be obtained without risk and
or discomfort to the patient. Circulating tumor cells (CTC) may circumvent this problem. CTC refer to cells that detach from a primary tumor or
metastatic site, circulate in the peripheral blood and may form metastasis.
CTC represent a ‘liquid biopsy’ that can be used to tailor treatment for
individual patients. CTC are however rare and can only be obtained for
further characterization in a small fraction of patients.
In the CTCtrap consortium universities, research institutions and SMEs
are linked in a common effort, starting from the simple, but innovative
view of using Therapeutic Apheresis (TA), as a way to collect CTC from
peripheral blood in cancer patients.
A new TA column will be developed to capture CTC and then reintroduce
the blood devoid of tumor cells back into the body with the promise to
obtain CTC in all patients at risk for recurrence or diagnosed with metastatic disease. The molecular characterization of these CTC is expected to
gather new knowledge on metastasis’ mechanism, provide a risk assessment and the optimal therapy choice during the course of the disease of
cancer patients. The new knowledge on CTC heterogeneity within cancer
type and within individuals will allow for the tuning of CTCapheresis to
specific cancer types. Prospective pilot studies will be setup to investigate
the feasibility of the CTCapheresis in the clinic and their potential therapeutic benefit.
Success of CTCapheresis will lead to a radical change in the diagnosis
and treatment of solid tumors.
ID 228
Plasma Pro-Enkephalin adds value to Proneurotensin for
the risk prediction of incident breast cancer
O. Melander1, M. Orho-Melander1, P. Almgren1, J. Manjer1,
B. Hedblad1, G. Engström1, J. Struck2, P. Nilsson1, A. Bergmann2,
M. Belting3
Skåne University Hospital, Malm, Clinical Research Center, Malmö,
Schweden
2
3
Lund University, Section of Oncology, Malmö, Schweden
1
Context: Neurotensin regulates breast cancer growth, and plasma Proneurotensin 1-117 (pro-NT), a stable peptide derived from the Neurotensin precursor, is associated with the development of breast cancer. Enkephalin may negatively regulate carcinogenesis and the growth of breast
tumors and can be assessed in plasma by measuring a stable surrogate
marker, Pro-Enkephalin A 119-159 (pro-ENK).
6
Objective: To test if plasma levels of pro-ENK add value to pro-NT for
the risk prediction of incident breast cancer.
Design, Setting, and Participants: We measured pro-ENK and pro-NT
in fasting plasma from 1929 women (mean age 58±5.9 years) of the population based Malmö Diet and Cancer Study (MDCS) free from breast cancer prior to the baseline exam. We used Cox proportional hazards models
to relate pro-ENK and pro-NT to first breast cancer events (n = 123) within 15 years of follow-up.
Results: Pro-ENK: Women belonging to quartiles 3, 2 and 1 of pro-ENK
compared to those of quartile 4 had HRs for breast cancer of 1.41 (0.74–
2.69), 2.3 (1.27–4.14) and 3.19 (1.82–5.62).
Pro-NT: As compared to women belonging to the 1st quartile of pro-NT,
women belonging to quartiles 2, 3 and 4 of pro-NT had HRs for breast
cancer of 1.24 (0.69–2.24), 1.61 (0.92–2.82) and 2.37 (1.4–4.01).
Adding pro-ENK to pro-NT provided added predictive value (p < 0.0001),
and HR for women with pro-ENK in the 1st quartile and pro-NT in the
4th quartile (high risk group) were 4.17 (2.48–7.03) as compared to women with pro-ENK in quartiles 2–4 and pro-NT in quartiles 1–3 (low risk
group). Women with one of the biomarkers in high risk still had a slightly
increased risk (HR 1.71 (1.16–2.52)) as compared to the low risk group.
Conclusion: Biomarker based risk prediction for the development of
breast cancer is significantly improved, when plasma pro-ENK is added
to pro-NT.
ID 260
Analysis of hypoxia-associated miRNA in oral squamous
cell carcinoma
M. Kappler1, J. Kotrba1, U. Pabst1, H. Wichmann1, S. Rot1,
M. Bache2, H. Taubert3, A.W. Eckert1
Martin-Luther-Universität Halle-Wittenberg, Universitätsklinik und Poliklinik für Mund-, Kiefer- und Plastische Gesichtschirurgie, Halle (Saale),
Deutschland
2
Martin-Luther-University Halle-Wittenberg, Department of Radiation Oncology, Halle (Saale), Deutschland
3
Friedrich Alexander University Erlangen, Department of Molecular Urology, Erlangen, Deutschland
1
Introduction: Tumor hypoxia plays a pivotal role in tumor progression.
Hypoxic tumors are more insensible to radiation or chemotherapy. The
identification of hypoxic tumors can improve the overall and disease free
survival of oral squamous cell carcinoma [OSCC] patients. Micro RNA
[miRNA] are a class of small non-coding mRNA´s. Out of more than
1600 miRNA´s only miRNA 210 has been described as hypoxia-related
in OSCC. The aim of the present investigation was to analyze tumor-specific and hypoxia-related miRNA in OSCC and to compare with the expression level of Hypoxia-inducible factor 1 α [HIF-1 α].
Materials and Methods: All expression profiles were performed at 4
commercially available OSCC cell lines [XF354, Cal33, SAS and FaDu].
All cell lines were incubated under normoxic (21% oxygen) and hypoxic
conditions (1% oxygen) over 24 hours. The total amount of HIF-1α protein was analyzed by real time protein managing system. Cell lines were
investigated by deep sequencing and specific real-time PCR for each cell
line in detail after cultivating under different oxygen pressures.
Results: MiRNA 210 was upregulated in all 4 cell lines under hypoxic
conditions in comparision to normoxia. We found a 3-fold increase of
miRNA 210 (p < 0,001). Two other miRNA (miRNA 193, p = 0,012 and
miRNA 34, p = 0,07) were also hypoxia-associated in OSCC cell lines
with marginal significance.
Conclusion: To our knowledge, this is the first investigation detecting
miRNA 193 and miRNA 34 as hypoxia-related miRNA in OSCC. We
hypothesize, that OSCC tissues have a unique and specific miRNA profile
pattern. The detection of hypoxia-related miRNA may help to stratify the
therpeutical options in OSCC.
Abstracts
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ID 263
Circulating microRNAs to monitor preoperative CRT in
rectal cancer patients
A. Azizian1, J. Salendo1, P. Jo1, M. Grade1, H. Wolff2, M. Ghadimi1,
J. Gaedcke1
Universitätsmedizin Göttingen, Allgemein-, Viszeral- und Kinderchirurgie,
Göttingen, Deutschland
2
Universitätsmedizin Göttingen, Strahlentherapie, Göttingen, Deutschland
1
Aim: Preoperative chemoradiotherapy (CRT) is the standard treatment
for locally advanced rectal cancer. However tumorresponse is heterogenous. An early estimation of response during CRT is desirable as it could
enable a modification of therapy at an early stage. To this day there is no
reliable biomarker to monitor therapy response. MicroRNAs represent
master regulators of gene expression and may therefore contribute to the
diversity of response to CRT.
The purpose of this investigation is the evaluation of microRNAs as biomarkers for response monitoring during CRT in patients with locally advanced rectal cancer.
Methods: In preliminary work five microRNAs (miR-17, miR-18b,
miR-20a, miR-31 and miR-193a_3p) were identified as being differently
expressed prior to preoperative CRT compared to healthy controls. MicroRNAs were analyzed in the plasma of patients (n = 43) with locally
advanced rectal cancer at four time points, namely: prior to-, during-, and
after the CRT, and after the surgical resection. Isolation was carried out
using Qiagen RNeasy mini kit columns after adding C. elegans miRNA
mimics as spike-ins. Expression levels between these time points were
compared and correlated to clinical parameters.
Results: miR-31 was excluded due to Ct values beyond 40. The remaining miRNAs showed different expression levels over the time period. The
reduction of the expression of miR-18b and miR-20a during CRT correlated significantly with a negative postoperative nodal state (p < 0,05).
Conclusion: Circulating microRNAs illustrate the potential to monitor
the response to CRT in patients with locally advanced rectal cancer. The
development of their expression could predict the nodal state of patients
even before surgery. Further genome-wide analyses in a larger patient
cohort is necessary.
ID 272
DNA Methylation Biomarkers SHOX2 and SEPT9 in Blood
for Monitoring Disease Progression in Cancer Patients
D. Dietrich1, A. Schröck2, A. Leisse1, F. Bootz2, G. Kristiansen1
Institut für Pathologie, Uniklinikum Bonn, Bonn, Deutschland
Klinik und Poliklinik für Hals-, Nasen-, und Ohrenkrankheiten, Uniklinikum
Bonn, Bonn, Deutschland
1
2
Diagnostic tests for monitoring the course of malignant diseases are of
tremendous value for personalized treatment decisions. The identification
of patients who are at increased risk for recurrence might allow subjecting
them to an adjuvant treatment, i.e. radio- or chemotherapy. Free-circulating tumor DNA in blood holds great potential to detect postoperative
residual tumor and occurrence of local and distant metastases. This study
aimed to develop and validate a non-invasive biomarker test, to help monitoring the course of patients suffering from head and neck squamous cell
carcinomas (HNSCC). Samples from 55 HNSCC patients (cases) were
obtained from patients who underwent clinical work-up for confirmed
HNSCC at the University Hospital Bonn, Department of Otolaryngology,
Head and Neck Surgery, University Hospital Bonn. 61 patients (controls)
who underwent clinical work-up for suspected HNSCC without any evidence of presence of any malignancy. The HNSCC patients were followed
up for up to one year. A sensitive and accurate qPCR assay was used to
quantify methylation levels of the methylation biomarkers SHOX2 and
SEPT9 in plasma. Increased copy numbers of free circulating methylated
SHOX2 and SEPT9 were found in plasma from patients with HNSCC as
compared to patients without malignant diseases. A significant decrease
of biomarker level was found 4–10 days after tumor resection. Disease
Abstracts
recurrence and survival was associated with an increase of SHOX2 and
SEPT9 methylation in blood during follow-up. This assay may be used to
monitor the disease progression in HNSCC patients and therefore identify
patients which might benefit from adjuvant therapy.
ID 274
Diagnostic and Prognostic Value of SHOX2 and SEPT9
DNA Methylation and Cytology in Benign, Paramalignant,
and Malignant Pleural Effusions
M. Jung, D. Dietrich, G. Kristiansen
Institut für Pathologie, Uniklinikum Bonn, Bonn, Deutschland
Pleural effusions (PE) are a common clinical problem. The discrimination between benign (BPE), malignant (MPE) and paramalignant (PPE)
pleural effusions is highly important to trigger the appropriate patients’
treatment. Cytology is the gold standard for diagnosing malignant pleural
effusions. However, its sensitivity is limited due to the sometimes low
abundance of tumor cells and the challenging assessment of cell morphology in cytological samples. This study aimed to develop and validate
a diagnostic test, which allows for the highly specific detection of malignant cells in pleural effusions based on the DNA methylation biomarkers
SHOX2 and SEPT9. A quantitative real-time PCR assay was developed
which enabled the accurate and sensitive detection of SHOX2 and SEPT9
in PEs In a case control study comprising of 114 patients (58 cases, 56
controls) PEs were analyzed by means of cytology and DNA methylation
biomarkers. Cytological analysis as well as SHOX2 and SEPT9 methylation resulted in 100% specificity. The combined analysis of cytology and
DNA methylation resulted in an increase of 71% positively classified PEs
from cancer patients as compared to cytological analysis alone. Furthermore, DNA methylation analysis in PEs allowed predicting the overall
survival in cancer patients (Kaplan-Meier analysis, p = 0.041 (SHOX2),
p = 0.007 (SEPT9)). The developed test may be used as a diagnostic and
prognostic adjunct to existing clinical and cytopathological investigations
in patients with PEs of unclear etiology.
ID 294
Assessment of breast volume changes during human
pregnancy using a threedimensional surface assessment
technique in the prospective CGATE study
S.M. Jud1, L. Haeberle1, M.O. Schneider1, J. von Wilucki1,
A. Hein1, M.C. Koch1, I. Linde1, C.M. Bayer1, F. Faschingbauer1,
E. Raabe1, U. Dammer1, R. Schulz-Wendtland2, M.W. Beckmann1,
P.A. Fasching 1
Universitäts-Frauenklinik Erlangen, Erlangen, Deutschland
Universität Erlangen, Radiologisches Institut – Gynäkologische Radiologie, Erlangen, Deutschland
1
2
Objectives: Pregnancies and breastfeeding are two important protective
factorsconcerning breast cancer risk, especially in younger age.Molecular
effect are rarely known.The aim of the present study was todocument
changes in breast volume during pregnancy prospectively.
Methods: In the prospective Clinical Gravidity Association Trial and
Evaluation (CGATE) programme, pregnant women were followed up
prospectively from gestational week 12 to birth. Three-dimensional
breast surface imaging andsubsequent volume assessments were performed. Factors influencing breast volumeat the end of the pregnancy
were assessed using linear regression models.
Results: 106 women were prospectivley followed from early pregnancy
to birth. Breast volumes averaged 420 ml at the start of pregnancy and
516 ml at the end of pregnancy. The first, second and third quartiles of
the volume increase were 41, 95, and 135 ml, respectively. Breast size
increased on average by 96 ml, regardless of the initial breast volume.
Conclusions: Breast volume measurementduring pregnancyusing
3D-technique is feasible. Breast volume increases during pregnancy, but
not all womens’ breastsrespond to pregnancy in the same way. Breast
7
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Index
volume changes during pregnancy arean interesting phenotype that can be
easily assessed in further studies to examinebreast cancer risk.
ID 307
Ki-67 is a prognostic factor in breast cancer patients –
findings of a large population-based cohort of a cancer
registry
E.C. Inwald1, M. Klinkhammer-Schalke2, F. Hofstädter3,
F. Zeman4, M. Koller4, M. Gerstenhauer2, O. Ortmann1
Lehrstuhl für Frauenheilkunde und Geburtshilfe der Universität Regensburg am Caritas-Krankenhaus St. Josef, Regensburg, Deutschland
2
Tumorzentrum Regensburg, An-Institut der Universität Regensburg,
Regensburg, Deutschland
3
Institut für Pathologie, Universität Regensburg, Regensburg, Deutschland
4
Zentrum für Klinische Studien, Universität Regensburg, Regensburg,
Deutschland
1
Introduction: Beside the conventional established histopathological parameters the assessment of proliferation is an emerging field regarding
treatment decisions in breast cancer patients. In this respect, the proliferation marker Ki-67 is intensely discussed. The intention of this population-based study was to evaluate routine use and value of Ki-67 as a prognostic parameter, and to analyze associations between Ki-67 and common
histopathological and outcome parameters in routine clinical setting.
Methods: This study included data from the clinical cancer registry
Regensburg (Bavaria, Germany). Patients with primary, non-metastatic
(M0), not neo-adjuvant treated breast cancer were considered. Within the
total data pool of 4,692 patients who had been diagnosed between 2005
and 2011, in 3,658 (78%) cases Ki-67 was routinely determined.
Results: Ki-67 expression was associated with all common histopathological factors (P < 0.001). Regarding survival analyses, Ki-67 was
classified into five categories (reference category Ki-67 ≤15%) due to
a non-linear relationship to overall survival (OS). In multivariable analyses, Ki-67 was identified as an independent prognostic parameter both
for disease-free survival (DFS) (Ki-67>45%, P = 0.001) and OS (Ki-67:
26–35%, P = 0.017; Ki-67: 36–45%, P = 0.011; Ki-67>45%, P = 0.002)
in breast cancer patients. The 5-year DFS (OS) rate was 86.7% (89.3%) in
patients with Ki-67 ≤15% in comparison with 75.8% (82.8%) in patients
with a Ki-67 value >45%.
Conclusion: The current study was able to demonstrate that Ki-67 is already widely applied in routine clinical work. Ki-67 is associated with
conventional histopathological parameters and, even more important, is
an independent prognostic parameter for DFS and OS in breast cancer
patients.
ID 327
Detection and clinical relevance of hematogenous tumor
cell dissemination in patients with ductal carcinoma in
situ
N. Krawczyk1, M. Banys2, I. Gruber3, A. Hartkopf3, D. Wallwiener3,
A. Staebler4, S. Becker5, T. Fehm1,5
Universität, Frauenklinik, Düsseldorf, Deutschland
Marienkrankenhaus, Frauenklinik, Hamburg, Deutschland
3
Universität, Frauenklinik, Tübingen, Deutschland
4
Universität, Pathologie, Tübingen, Deutschland
5
Universität, Frauenklinik, Frankfurt, Deutschland
1
2
Background: Hematogenous tumor cell dissemination is considered a
crucial step in systemic disease progression and predicts reduced clinical
outcome in breast cancer patients. Only invasive cancers are assumed to
shed tumor cells into the bloodstream and infiltrate lymph nodes. However, recent studies have revealed that disseminated tumor cells (DTCs)
may be detected in the bone marrow of patients with preinvasive lesions,
i.e. in ductal carcinoma in situ (DCIS). The purpose of this analysis was
to examine the incidence and clinical value of DTC detection in DCIS
patients.
8
Methods: 404 patients treated for DCIS at the University Hospital Tuebingen, Germany between 2003 and 2012 were included into this analysis. Bone marrow (BM) aspirates were analyzed by immunocytochemistry (pancytokeratin antibody A45-B/B3) according to the ISHAGE
evaluation criteria. Sentinel nodes were analyzed in 316 of these patients
by extensive step sectioning and hematoxylin-eosin staining.
Results: In 63 of 404 patients (16%) DTCs could be detected. No correlation was observed between BM status and tumor size, grading, histology
or Van Nuys prognostic index. In two cases metastatic spread into lymph
nodes was observed; isolated tumor cells in a sentinel node were found in
one patient. A median follow up of 45 months (range: 3–131 months) was
obtained for 356 patients. The differences in overall survival (OS) and
disease-free survival (DFS) calculated by log-rank test were not statistically significant (OS: p = 0.088, DFS: p = 0.982).
Conclusions: Tumor cell dissemination may be detected in patients diagnosed with DCIS. Whether these cells disseminate from real preinvasive
mammary lesions or represent the earliest step of microinvasion, remains
unclear. A longer follow-up may be necessary to accurately assess clinical
value of these cells in DCIS patients.
ID 363
The importance of MACC1 in colon cancer stem cells and
adult stem cell signaling
M. Hardt1,2, C. Lemos1, D. Schumacher3, C. Regenbrecht3,
E. Heiden4, U. Stein1,2
Max-Delbrück-Centrum für Molekulare Medizin, AG Prof. Dr. Ulrike Stein,
Berlin, Deutschland
2
Charite Universitätsmedizin Berlin, Experimental and Clinical Research
Center, Berlin, Deutschland
3
Charite Universitätsmedizin Berlin, Institut für Pathologie, Berlin, Deutschland
4
Charite Comprehensive Cancer Center, Berlin, Deutschland
1
The gene MACC1 (Metastasis-Associated in Colon Cancer 1) has been
affirmed as a biomarker for metastasis in colorectal cancer (CRC). Only a
subset of cells within a tumor is endowed with the potential to propagate
the latter and concomitantly drives metastasis. Following this cancer stem
cell hypothesis, MACC1’s role at the level of the stem cell is of crucial
importance and investigated herein.
We seek to analyze the expression of MACC1 directly in the stem cell
population of CRC patient material, cell lines as well as mouse models
available in our lab. For this purpose, primary cultures of patient-derived
organoids are currently being expanded to allow for efficient fluorescent-activated cell sorting. Likewise, the intestinal stem cell populations
of wild type and mouse models with engineered MACC1 expression will
be assessed. At the cell line level, we could already show that the sorting
of SW620 cells via CD44 enables differential enrichment of the intestinal
stem cell marker Lgr5 together with MACC1.
In parallel, we aim to elucidate MACC1’s role in stem cell signaling. Of
note, we found that MACC1 levels modulate the expression of Oct4 in
CRC cell lines. Overexpression of MACC1 in CaCo2 and SW480 cells
was related to an increase in Oct4 mRNA and protein expression. Consistently, knockdown of MACC1 in CaCo2 and SW620 cells resulted in
decreased levels of Oct4.
In conclusion, we provide here the first molecular link between MACC1
and stem cells. Additional studies will help clarify the nature of the
MACC1 and Oct4 interaction and its functional relevance. The finding
that the expression of MACC1 is indeed focused in cancer stem cells
might further increase its prognostic value and accentuate the importance
of MACC1 in carcinogenesis.
Abstracts
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ID 412
Detection of somatic mutations by next-generation
sequencing in a clinical setting
C. Schroeder1,2, M. Sturm1, S. Junker1, M. Bitzer3, N. Malek3,
B. Sipos4, H.-G. Rammensee5, O. Rieß1,2, P. Bauer1,2
Institute of Medical Genetics and Applied Genomics, Tübingen, Deutschland
2
Genes and Therapy, Tübingen, Deutschland
3
University Hospital Tübingen, Department of Internal Medicine I, Tübingen, Deutschland
4
University Hospital Tübingen, Department of Pathology, Tübingen,
Deutschland
5
Institute for Cell Biology, Department of Immunology, Tübingen, Deutschland
1
Next-generation-sequencing (NGS) is a key technology for high-throughput identification of genomic biomarkers that are of prognostic or therapeutic relevance. An increasing number of biomarkers, either of prognostic or therapeutic relevance, are reported by case reports and clinical
trials. To face these developments, we founded an interdisciplinary clinical-oncogenetic tumor board at our hospital to coordinate sequencing
efforts and discuss sequencing results. Specialists involved in this process are pathologists, geneticists and oncologists. Currently, we offer two
cancer gene panels (48 genes hotspot panel, 182 genes complete coding
sequence) and exome/transcriptome sequencing to selected patients. Up
to now, we analyzed 43 tumor samples with our hotspot panel and a total of 11 samples with our 182 cancer gene panel. The analysis included
both FFPE material and native tumor tissue from different cancer entities.
Our analysis workflow is automated and variants are tracked by our inhouse database. We were able to identify mutations in common cancer
genes like KRAS, TP53, CTNNB1, PIK3CA and ERBB2. Each variant
was validated to be somatic (comparison to reference sample, e.g. blood)
and confirmed by a second independent sequencing method (e.g. Sanger
sequencing). Medical reports were generated within four weeks summarizing variants and current literature. Our data suggest that detection of
somatic mutations can be highly automated and standardized. Though,
clinical interpretation of the majority of somatic mutations remains challenging and functional studies are needed for translation of somatic mutations into therapeutic decisions.
ID 435
Changes in the level of plasma microRNAs in rectal
cancer patients
J. Salendo
Universitätsmedizin Göttingen, Klinik für Allgemein Chirurgie, Göttingen,
Deutschland
Background: The identification of response in locally advanced rectal
cancer (RC) to a 5-FU based chemoradiotherapy (CRT) is a crucial step
towards an individualization of the therapy. Recently, the impact of microRNAs (miRNAs) on progression or resistance in cancer has been described. Although their expression changes in patients´ blood has recently
been described in different cancer types data in rectal cancer are scarce.
Materials/Methods: miRNAs were extracted from patient and healthy
control plasma. The 30 differentially regulated miRNAs were retrieved
from the comparison of rectal cancer and normal tissue based on miRNA
microarray analyses. They were analysed in a first plasma set materials of
RC patients and gender matched- healthy controls. Furthermore, a subset
of miRNAs was further analysed in plasma of 178 individuals, inclusive
the expressions before and after the treatment.
Results: Eight miRNAs were chosen for further analyses. Subsequently,
in the analysis using larger cohort three miRNAs could be further confirmed. Interestingly, all miRNAs that were overexpressed in tumor tend
to have lower expressions in the plasma of RC patients than healthy patients. Comparing pre- and post-therapeutical expressions of patients that
underwent neoadjuvant CRT all miRNAs were significantly differentially
expressed.
Abstracts
Conclusion: Our study demonstrated changes on the level of circulating miRNA between RC and healthy patients. Furthermore we identified
miRNAs responsive to the neoadjuvant CRT, highlighting the potential
of plasma miRNA to observe the response in RC patients. The impact of
the level changes after treatment on prognosis will be shown in a comprehensive approach.
ID 455
Run-in phase of prospective WSG ADAPT HR+/HER2- trial
demonstrates feasibility of early endocrine sensitivity
prediction by Recurrence Score and conventional
parameters in clinical routine.
N. Harbeck1, O. Gluz2,3, D. Hofmann2, H.H. Kreipe4, M. Christgen4,
C. Svedman5, S. Shak5, S. Kümmel6, B. Nuding7, N. Rezai8,
H. Forstbauer9, R. Würstlein2,10, R.E. Kates2, U. Nitz2,3
Universitätsfrauenklinik Großhadern, Brustzentrum der LMU München,
München, Deutschland
2
Westdeutsche Studiengruppe GmbH, Mönchengladbach, Deutschland
3
Ev. Bethesda Krankenhaus, Brustzentrum Niederrhein, Mönchengladbach, Deutschland
4
Medizinische Hochschule Hannover, Institut für Pathologie, Hannover,
Deutschland
5
Genomic Health, Inc., Redwood City, Deutschland
6
Kliniken Essen-Mitte, Klinik für Senologie/Brustzentrum, Essen,
Deutschland
7
Ev. Krankenhaus Bergisch Gladbach, Brustzentrum, Bergisch Gladbach,
Deutschland
8
Luisenkrankenhaus Düsseldorf, Brustzentrum, Düsseldorf, Deutschland
9
Praxisnetzwerk Troisdorf, Hämatologie/Intern. Onkologie, Troisdorf,
Deutschland
10
1
Background: Endocrine sensitivity by proliferation response to shortterm preoperative endocrine therapy (ET) is currently not included in adjuvant chemotherapy (CTx) decisions in early breast cancer (eBC).
Methods: The ADAPT HR+/HER2- trial includes N0-1 eBC patients
(pts) being candidates for adjuvant CTx; it aims to spare CTx by combining genomic assessment by Oncotype DX and endocrine sensitivity
testing. Pts receive 3-week preoperative ET: aromatase inhibitors (AI) or
tamoxifen. Pts with low (0–11) Recurrence Score (RS) or intermediate
RS (12–25) and ET response (central Ki-67post<10%) are recommended
to forego adjuvant CTx («low-risk»).
Results: By 9/2013, 564 pts (median age 54y) from 33 study sites were
enrolled. At 1st pre-planned analysis (5/2013; n = 246): RSlow 21.6%,
RSintermediate 57.7%, RShigh 20.7%; respective risk group responders
(Ki‑67post <10%): 84.1%, 73.9%, 40.0% (p < 0.001 comparing low/intermediate vs. high). Median Ki‑67 level drop (percentage of pre-treatment
value) was 25% in pre- (n = 101) vs. 75% in postmenopausal pts (n = 115)
(p < 0.001); median drop by RS group was similar: low 61%, intermediate 53%, high 56% (p = 0.81). Ki-67pre, endocrine regimen/menopausal
status, and RS were independent predictors for Ki‑67post.
Conclusions: The ADAPT Run-In Phase confirms design estimates of
RS and proliferation response to induction ET with >70% ET responders
with intermediate genomic risk who could potentially be spared CTx. It
indicates feasibility of combining static and dynamic biomarker assessment for individualized therapy in eBC. Survival non-inferiority of intermediate RS/responders vs. low RS pts (active control) will be tested in
the ADAPT main phase.
9
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Breast Cancer – Adjuvant Therapy
ID 078
Endoxifen and fulvestrant regulate gene expression of
estrogen receptor alpha and its co-activators DEADbox5
and 17
M. Hirschfeld , V. Neumann , M. Jäger , T. Erbes , E. Stickeler
1
1
1
1
1
Universitätsfrauenklinik Freiburg, Molekulare Onkologie, Freiburg,
Deutschland
1
Background: Application of anti-estrogens remains a standard therapy
in ERα -positive breast cancer. Endoxifen acts as a selective receptor
down-modulator of ERα function, while fulvestrant acts as a selective
receptor down-regulator via an increased ERα inhibition and degradation. RNA helicases p68 (DDX5) and p72 (DDX17) act as co-activators
of ERα. DDX17 expression correlates with decreased Her2/neu levels,
extended relapse-free periods, and an increase in overall survival rates. In
contrast, DDX5 expression is associated with increased Her2/neu levels
and higher tumor grading, but not correlated with relapse-free or overall
survival. This study aimed for the investigation of potential regulatory
effects of the anti-estrogens on the expression of ERα, DDX5 and 17.
Methods: In vitro application of endoxifen and fulvestrant.
Results: Both drugs created a significant decrease of mRNA and protein
expression levels of all target genes. DDX5 and 17 expression levels generally decreased, whereat endoxifen treatment triggered a stronger effect
than fulvestrant. While both ERα antagonists caused a uniform decrease
in ERα protein levels, DDX protein levels were differentially affected.
Fulvestrant triggered a uniform downregulation of DDX5 and 17. In contrast, endoxifen stimulation resulted in an up-regulation of DDX5 and 17
protein. Conclusion: Both ERα antagonists show regulatory effects on
ERα, DDX5 and 17 expression. The in vitro data might explain individual therapeutic efficacy or the occurrence of resistance against endocrine
therapy dependent on cellular context. The elucidation of DDX status
might serve as a useful prognostic tool to estimate efficacy of anti-estrogen treatment in breast cancer therapy.
ID 110
Chemotherapy in breast cancer patients – predictors of
non-adherence to guidelines
L. Schwentner1, A. Wöckel1, R. Van Ewijk2, W. Janni1,
R. Kreienberg1, M. Blettner2, S. Singer1,2
1
2
Universität Ulm, Frauenheilkunde und Geburtshilfe, Ulm, Deutschland
Universität Mainz, IMBEI, Mainz, Deutschland
Background: Guideline (GL) adherence in breast cancer is a significant
survival predictor. We investigate what patient-related and physician-related factors predict guideline non-adherence.
Methods: 642 primary breast cancer patients were followed from hospital admission till systemic treatment beginning. Multi-disciplinary
tumorboard chemotherapy (CT) decisions were documented. Patients
completed the Patient Health Questionnaire for psychiatric comorbidities, EORTC Quality of Life (QoL) core questionnaire and questions on
specific fears of receiving CT. Somatic comorbidity was assessed by ASA
score. Potential predictors of a) treatment decision and b) GL non-adherence were tested in multivariate logistic regressions.
Results: GL indicated no CT in 8.5% of cases. Tumorboards suggested CT-administration in 49.8%. Reasons for GL deviations were rarely
given. 84.5% of patients agreed with CT-decisions. Reasons for patient
non-agreement were fear and cost-benefit unbalance. Actual patient treatment was GL-conform in 98.1%: there were 12 cases of under- and 0
of over-treatment. 20.5% of patients had somatic and 21.6% psychiatric
comorbidity. 65% reported being very afraid of CT.
Tumorboards less often prescribed CT to patients >75 years (OR 0.4),
with somatic comorbidities (OR 0.5) or high fear (0.6). Actual treatment
more often deviated from GL for >75 years (OR 0.3) and poor QoL (OR
10
0.7). Neither tumorboard decisions nor actual treatment correlated with
education or psychiatric comorbidity.
Conclusions: Age, somatic comorbidity, fears regarding CT and QoL are
related to CT-decisions.
ID 114
Vaginal estriol-lactobacilli combination (Gynoflor®)
therapy and sexual quality of life in breast cancer patients
on aromatase inhibitors with atrophic vaginitis
M. Mögele1, S. Buchholz1, A. Lintermans2, G. Bellen3,
V. Prasauskas4, O. Ortmann1, P. Grob4, P. Neven2, G. Donders5
Lehrstuhl für Frauenheilkunde und Geburtshilfe der Universität Regensburg am Caritas Krankenhaus St. Josef, Regensburg, Deutschland
2
University Hospital Gasthuisberg Leuven, Belgium, Leuven, Belgium,
Belgien
3
Femicare vzw, Clinical Research for Women, Tienen, Belgium, Belgien
4
Medinova AG, Zurich, Switzerland, Zurich, Deutschland
5
University Antwerp, Belgium, Antwerp, Belgien
1
Besides the pharmacology parameters this clinical study investigated also
effect on sexual domain of QOL during the treatment of BC survivors
on AI with vaginal ultra-low-dose estriol-lactobacilli combination tablets
Gynoflor®.
This was an open label bicentric clinical study in 16 postmenopausal BC
survivors on AIs suffering from vaginal atrophy induced sexual disorders.
Clinical vaginal atrophy symptoms were assessed by scoring with an
11-point estimation scale (0 = not at all, 10 = worst imaginable feeling).
Sexuality parameters of QOL and medication compliance were recorded
in patient’s diary. Recruited women underwent an initial treatment for 4
weeks (1 vaginal tablet daily) followed by maintenance therapy (3 vaginal tablets weekly) for 8 weeks.
Vaginal dryness continuously improved from a median of score 8 at entry to score 4 at the end of initial therapy, and median score 2 at the end
of maintenance therapy. Previous normal sexual activity before the BC
diagnosis reported 14 (88%) women. During the BC treatment with AIs
this number was dramatically decreased, at study entry – only 3 (19%) of
women were sexually active, whereas at the end of the study already 7
(31%) women reported sexual intercourse. The FSSEI demonstrated clear
trend for improvement of main domains of sexual QOL (desire, arousal,
orgasm and satisfaction), whereas the statistically significant result due to
a small number of subjects were seen only for few parameters.
Local vaginal ultra-low-dose estriol-lactobacilli therapy (Gynoflor®) in
postmenopausal breast cancer (BC) survivors on aromatase inhibitors
(AIs) with atrophic vaginitis is a safe treatment (presented earlier) with a
positive impact on the sexual domain of quality of life (QOL).
ID 153
Guideline Adherence in the Therapy of Young Mothers
with Breast Cancer in Germany
D. Fischer1, M. Hedderich1, A. Heinrich2, K. Baumann1, A. Rody1,
A. Waldmann3
Uni Lübeck, Frauenklinik, Lübeck, Deutschland
UKE, Hamburg, Deutschland
Uni Lübeck, Institut für Sozialmedizin und Epidemiologie (ISE), Lübeck,
Deutschland
1
2
3
Background and Objective: The aim of the study is to analyse the
guideline adherence in the treatment of young breast cancer patients in
an adjuvant setting.
Materials and Methods: A retrospective study analyzed the treatment of
1053 young mothers first diagnosed between 2002 and 2011 with primary
breast cancer according to the AGO guideline adherence. The patients
participated in a resident mother-child program and were compared to
age-heterogeneous cohorts.
Results: The median age of the young cohort was 39 years. Their tumors
were significantly higher in stage and grading than the older group (51%
Abstracts
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vs. 44% >T1 stage, 47% vs. 36% N+, 45% vs. 29% G3). The biology of
the tumors was significantly worse. Therefore young patients got a significantly more aggressive therapy than older women. The percentage of
guideline adherence for the therapeutic modalities for BCT, mastectomy,
axillary dissection, hormone therapy, chemotherapy and antibody therapy
was >95% in the young patients. However, chemotherapy results differ
significantly in comparison to the older group.
Conclusion: Young breast cancer patients participating in a resident
mother-child program are diagnosed in a worse stage and their carcinomas are more aggressive. Their treatment shows a high level of AGO
guideline adherence. It remains unclear to what extent the guideline adherence improves overall survival and disease free survival in this group.
ID 176
Long-term results of trastuzumab in the adjuvant
treatment of breast cancer, with focus on elderly patients
P. Dall1, G. Lenzen2, T. Göhler3, G. Feisel-Schwickeradi4, T. Koch5,
V. Heilmann6, C. Schindler7, J. Wilke8, H. Tesch9, J. Selbach10,
J. Eggert11, A. Hinke12
Städt. Klinikum, Frauenklinik, Lüneburg, Deutschland
Practice, Osnabrück, Deutschland
3
Practice, Dresden, Deutschland
4
Klinikum Kassel, Kassel, Deutschland
5
Klinikum Nürnberg Nord, Frauenklinik, Nürnberg, Deutschland
6
Practice, Günzburg, Deutschland
7
Practice, Leipzig, Deutschland
8
Practice, Fürth, Deutschland
9
Onkologie Bethanien, Frankfurt, Deutschland
10
Practice, Duisburg, Deutschland
11
Practice, Moers, Deutschland
12
WiSP, Langenfeld, Deutschland
1
2
Trastuzumab (T) is a standard treatment in patients (pts) with HER2+
early breast cancer in addition to (neo)adjuvant chemotherapy (CT). This
German prospective observation study examined the generalizability of
the results from pivotal randomized studies, with the focus on benefits
and risks for elderly patients (EP) in the present analysis.
4027 pts were enrolled from 2006 to 2012, unselected regarding age or
concomitant/sequential adjuvant CT. Among 3940 evaluable pts, 1013
were EP ≥ 65 years (y) of age (26%). This contrasts to the pivotal studies,
with only 6% beyond 65 y in the NSABP/NCCTG studies. More than half
of the pts had pT≥2, with EP more often presenting with a larger tumor
(56 vs. 48%, p < .0001). As expected, performance status was more impaired in EP (ECOG 0: 53 vs 65%, p < .0001). 94% received CT, 78% as
adjuvant, 14% as neoadjuvant treatment (in EP only 8%). The proportion
without any (neo)adjuvant CT was higher in EP (8 vs. 5%). T was stopped
prematurely more often in EP (11 vs 8%, p = .014).
After up to a maximum follow-up of 8 y, 370 relapses were reported so
far. Recurrence-free survival is 94.7, 89.8 and 82.9% after 2, 3 and 5 y,
respectively, in EP only slightly lower with 93.9, 89.3 and 81.6%, not
statistically significant (p = .18, HR = 1.17, 95% CI 0.93–1.47). In the EP
subgroup the incidence of cardiac events of all grades was only slightly
increased (4.6 vs. 3.9% overall).
The maturing follow-up data confirm the beneficial results from the
randomized studies. Moreover, the data show that a similar anti-tumor
efficiency can be achieved in EP, and suggest that minor age-related differences detected with respect to adjuvant treatment duration, aggressiveness and toxicity do not impair the long-term outcome.
Abstracts
ID 249
Suitable patients for IORT at the Interdisciplinary Breast
Cancer Center Mannheim
D. Astor1, E. Sperk1, A. Keller1, G. Welzel1, A. Gerhardt2,
M. Sütterlin2, F. Wenz1
Medical Center Mannheim, University of Heidelberg, Department of Radiation Oncology, Mannheim, Deutschland
2
Medical Center Mannheim, University of Heidelberg, Department of Obstetrics and Gynecology, Mannheim, Deutschland
1
Background: Recommendations for suitable patients for intraoperative
radiotherapy (IORT) alone are available from the ESTRO (European Society for Radiotherapy and Oncology) and ASTRO (American Society
for Radiation Oncology). Several TARGIT (TARGeted Intraoperative
radiotherapy) trials under guidance of the Interdisciplinary Breast Cancer Center Mannheim (TARGIT E ‘elderly’, TARGIT C ‘consolidation’,
TARGIT BQR ‘boost quality registry’) also include patients with other
characteristics.
Methods: Between 01/03 and 12/09, 1505 cases were treated. Complete
data sets for age, stage (T, N, M), histology, hormone receptor status and
metastasis were available in 1108 cases. Recommendations are as follows: ESTRO: >50 years, invasive ductal carcinoma/other favourable
histology (IDC), T1-2 ( ≥ 3cm), N0, any hormone receptor status, M0;
ASTRO: ≥60 years, IDC, T1-2 ( ≥ 2cm), N0, M0; TARGIT E: ≥70 years,
IDC, T1, N0, any hormone receptor status, M0; TARGIT C: ≥50 years,
IDC, T1-2 ( ≥ 2cm), N0, positive hormone receptor status, M0; TARGIT
BQR: every age, every histology, T1-2 ( ≥ 3.5cm), any hormone receptor
status, N0/+, M0/+.
Results: Out of the 1108 available cases, 379 cases (34.2%) are suitable
for IORT regarding the ESTRO and 175 (15.8%) regarding the ASTRO
recommendations. 82 (7.4%) patients were suitable for the TARGIT E
trial, 258 (23.3%) for TARGIT C and 671 (60.6%) for TARGIT BQR.
Conclusion: The TARGIT E and C inclusion criteria for IORT alone are
more conservative than the ESTRO recommendations. Nearly two thirds
of the treated patients could be allocated to an IORT boost.
ID 262
The prognostic relevance of disseminated tumor cells
in primary breast cancer patients – results from a large
single-center study
A. Hartkopf, T. Fehm, M. Wallwiener, M. Hahn, D. Wallwiener,
S. Becker, E. Solomayer, F.-A. Taran
Universität Tübingen, Tübingen, Deutschland
Background: The presence of disseminated tumor cells (DTC) in the
bone marrow (BM) of primary breast cancer (PBC) patients is associated
with a worsened prognosis. This is the largest single-center study that
determines the impact of DTC on disease free (DFS) and overall survival.
Methods: BM aspirates were collected from patients that underwent
surgery for PBC at Tuebingen University Hospital, Germany, between
01/2001 and 01/2013. DTC were identified by immunocytochemistry
(pancytokeratin antibody A45/B3) and cytomorphology. The DTC-status
was compared to other prognostic factors by use of the chi-squared test
and survival was analyzed in an univariate (log-rank test) and multivariate analysis (cox regression).
Results: 3,141 patients were available for this retrospective analysis. Of
these 803 (26%) were DTC-positive. DTC-positivity was associated with
larger tumors (p < 0.001), positive lymph nodes (p = 0.001), ER-negative
(p = 0.022) and PR-negative (p < 0.001) patients. DTC-positive patients
were at an increased risk of death (median OS of DTC- vs. DTC+ patients: n. r. (not reached) vs. 115 (95% CI: 113–118) months, p = 0.004)
and disease relapse (median DFS was n. r. in either groups, p < 0.001).
Independent factors for OS / DFS were DTC-status, menopausal-status,
tumor size, nodal-status, ER-status and PR-status / DTC-status, tumor
size, nodal-status and ER-status.
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Conclusion: This study confirms the strong and independent prognostic value of DTC-determination in primary breast cancer patients. The
DTC-status might help to identify patients that are at an increased risk
of death or disease relapse and thus in need for an aggressive adjuvant
treatment.
ID 280
Radiation-induced modulation in the distribution of
lymphocytes in breast cancer patients
E.K. Sage1, M. Sedelmayr1, M. Gehrmann1, C. Bayer1,
D. Schilling1, M.N. Duma1, T.E. Schmid1, H. Geinitz2, G. Multhoff1
Klinikum rechts der Isar der TU München, Klinik und Poliklinik für Strahlentherapie und Radiologische Onkologie, München, Deutschland
2
Krankenhaus der Barmherzigen Schwestern, Radio-Onkologie, Linz,
Deutschland
1
ID 270
Application of integrative medicine by postmenopausal
breast cancer patients in the PreFace Phase IV study – a
prospective, longitudinal trial
C.C. Hack1, M.W. Beckmann1, A. Hein1, C.M. Bayer1, C. Rauh1,
K. Almstedt1, N.B.M. Hüttner1, W. Janni2, T. Fehm3, N. Maass4,
A. Rody5, N. Fersis6, D. Wallwiener7, J. Hübner8, P.A. Fasching1,9
Frauenklinik University Hospital Erlangen, Department of Gynecology and
Obstetrics, Erlangen, Deutschland
2
University Hospital Ulm, Department of Gynecology and Obstetrics, Ulm,
Deutschland
3
University Hospital Düsseldorf, Department of Gynecology and Obstetrics, Düsseldorf, Deutschland
4
University Hospital Aachen, Department of Gynecology and Obstetrics,
Aachen, Deutschland
5
University Hospital Schleswig-Holstein, Campus Lübeck, Department of
Gynecology and Obstetrics, Lübeck, Deutschland
6
Hospital Chemnitz, Department of Gynecology and Obstetrics, Chemnitz,
Deutschland
7
University Hospital Tübingen, Department of Gynecology and Obstetrics,
Tübingen, Deutschland
8
German Cancer Society, Berlin, Deutschland
9
University of California at Los Angeles, David Geffen School of Medicine,
Department of Medicine, Division of Hematology/Oncology, Los Angeles,
CA, USA
1
Aim: It is known, that a relevant number of breast cancer patients applies
integrative medicine in addition to conventional cancer therapy. In particular modern cancer therapies as aromatase inhibitors are associated with
considerable adverse effects like ostealgia and arthralgia, what could trigger above all the application of integrative medicine to alleviate the pain.
Aim of this presented trial is the registration of the usage of integrative
medicine in the adjuvant therapy status during the course of treatment.
Methods: The PreFace Study is a Phase IV Study, where postmenopausal
and hormone-receptor-positive breast cancer patients are medicated with
the aromatase inhibitor Letrozol. As part of a patient diary all patients
have been asked to document which integrative medicine has been applied at the time before Letrozol therapy (month 0), at month 6 and at
month 12 after start of therapy. For this purpose the PRIO questionnaire
was used.
Results: 2491 patients of 3524 in all gave particulars to the application
of integrative medicine within the total study. Respectively 50%, 54%
and 53% of the patients have stated to use actively integrative medicine
at month 0, 6 and 12. Before start of therapy the motivation at 44% of the
users was the promotion of cancer healing and at 61% the improvement
of quality of life. During the course of the PreFace study this motivation dwindled significantly. The most frequently documented methods
at start of therapy was nutritional supplement (22%), intake of vitamins
(21%) and the devotions (19%). Mistletoe therapy was only mentioned
from 3–4% of the patients. The frequency of usage of the most integrative
methods did not change during the observation period.
Conclusion: Integrative medicine is still frequently used by breast cancer
patients. Some methods such as the mistletoe therapy are conducted today
only in rare cases from postmenopausal breast cancer patients.
12
Background: Mounting evidence indicates that radiotherapy has a modulating impact on the immune system. We examined immune cells in peripheral blood of breast cancer patients with or without chemotherapy
(ChT) before radiotherapy (RT) with respect to percentual distribution.
Methods: Blood samples of 40 patients with breast cancer were collected
before, at 30 Gy and at the end of RT, as well as six weeks and six months
after RT. Eight of these patients received adjuvant chemotherapy before
RT. Five healthy volunteers were used as control. Lymphocyte subpopulations were analysed by flow-cytometry.
Results: Our results show that ChT affects the lymphocytes’ count
more than RT. Particularly B cells are impacted by ChT. Compared to
the control (12.8 ± 1.1%) the number of B cells is reduced significantly
to 0.8 ± 0.2% by ChT. There was a partial recovery during RT. Regarding patients with RT only, a significant decrease in B cell count from
11.8 ± 0.8% before RT to 8.0 ± 0.7% at the end of RT was observed. Six
months after RT the percentage of B cells almost reaches control level
(11.0 ± 0.6%). The fraction of Natural killer cells was elevated after ChT
(15.8 ± 2.7%) and decreased to normal levels (9.3 ± 1.4%) at the end of
RT. During RT there was a transient increase in the amount of regulatory
T cells of 14 ± 2% of the initial level, which was more pronounced without previous ChT (43 ± 3%).
Conclusion: Our results indicate that B and T cells are differently sensible to RT and ChT. There are also differences in the recovery time of
immune cells after chemo- and radiotherapy. A clearer understanding of
the impact of radiation and chemotherapeutic agents on immune cells and
activation markers could lead towards new innovative therapy concepts
combining RT and ChT with immunotherapy.
ID 305
Effects of estriol on growth, gene expression and
estrogen response element activation in human breast
cancer cell lines
C. Lattrich, M. Diller, S. Schüler, S. Buchholz, O. Treeck,
O. Ortmann
Lehrstuhl für Frauenheilkunde und Geburtshilfe der Universität Regensburg am Caritas-Krankenhaus St. Josef, Regensburg, Deutschland
Introduction: Local application of estradiol (E2) to treat vulvovaginal atrophy in postmenopausal breast cancer patients receiving aromatase inhibitors is known to elevate serum estradiol levels and thereby might counteract
breast cancer therapy. Thus, vaginal application of estriol (E3) has been
recommended for these patients. However, it is unclear to what extent E3
stimulates breast cancer cell growth. In this study, we examined the effect
of E3 on growth and gene expression of two human breast cancer cell lines.
Methods: We used an established in vitro cell culture assay and compared
the effect of E2 and E3 on growth of the estrogen receptor alpha-positive
breast cancer cell lines MCF-7 and T-47D testing a wide range of hormone
concentrations of 10-12 to 10-7 M. E3 effects on gene expression were examined by means of reporter gene assays, RT-qPCR and Western blot analysis.
Results: E3 acted as a potent estrogen and exerted a mitogenic effect on
T-47D and MCF-7 cells at concentrations of 10-9 M (288 pg/ml) and higher.
With regard to activation of an estrogen response element (ERE) in breast
cancer cells, effects of E3 were visible at 10-10 M. The same concentrations
of E3 activated expression of the estrogen-responsive gene PR and of the
proliferation genes cyclin A2, cyclin B1, Ki-67, c-myc and b-myb, providing
molecular mechanisms underlying the observed growth increase.
Abstracts
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Conclusions: Like E2, low levels of E3 were able to trigger an robust
estrogenic response in breast cancer cells. Thus, E3 treatment for postmenopausal breast cancer patients with vulvovaginal atrophy has to be
indicated with caution.
SEPTEMBRA – a pilot study to detect and analyze
circulating tumor cells in breast cancer patients
had no impact on further outcome (p > 0,05). Statistically significant impact
factors for the whole cohort were application of endocrine therapy on local
recurrence-free survival (p = 0,026), age > 60 at time of occurence of contralateral breast cancer (p = 0,009) and stage (p < 0,001) on metastasis-free
survival, and stage (p < 0,001) on overall survival.
Conclusions: Patients with synchronous or metachronous bilateral
breast cancer do not differ regarding further outcome. However, age at
occurence of contralateral breast cancer has strong impact on metastasis-free survival.
N.S. Kasprowicz1, E. Honisch1, S. Mohrmann1, J. Fischer2,
D. Niederacher1, N.H. Stoecklein3, T.N. Fehm1
ID 400
ID 332
Universitätsklinikum, Frauenklinik, Düsseldorf, Deutschland
2
Universitätsklinikum, Institut für Transplantationsdiagnostik und Zelltherapeutika, Düsseldorf, Deutschland
3
Universitätsklinikum, Klinik für Allgemein-, Viszeral- und Kinderchirurgie,
Düsseldorf, Deutschland
1
Background: Circulating tumor cells (CTC) are promising biomarkers
for diagnosis and systemic therapy in breast, colon and prostate cancer.
However, their low detection rates – especially in non-metastatic patients
– limit currently their clinical use. Leukapheresis may provide a method
to increase CTC yields by analyzing an increased blood volume.
Methods: To evaluate leukapheresis in non-metastastic breast cancer
(BC) patients, we initiated a prospective pilot-study, SEPTEMBRA. Before and after primary surgery of BC, the patients underwent diagnostic
leukapheresis (DLA). Simultaneously, 7.5 ml of peripheral blood was
drawn to be analyzed by the current gold-standard, the CellSearch-System® (Veridex, USA). We compared DLA products with peripheral blood
samples regarding prevalence and quantity of CTC. Statistical analysis
was performed with exact Fisher-test and Mann-Withney-U-test. P-value
of <0.05 was regarded as significant.
Results: So far, we have included 6 patients with non-metastatic breast
cancer. Analysis was performed on 21 peripheral blood samples and 11
DLA products. Analysis shows a significant higher prevalence of CTC
in DLA products than in the peripheral blood samples (82% versus 19%
p < 0.001). Furthermore, the number of CTCs was higher in DLA products (median 5, range 0–20 vs. median 0, range 0–3; p < 0,001).
Conclusion: Our results suggest that leukapheresis (DLA) seems to be able
to increase both CTC detection rate as well as CTC yields. Thus we believe
that leukapheresis will help to exploit the full clinical potential of CTC as
biomarkers for diagnosis and systemic therapy. In the future, we plan to extend this study to metastatic patients and those with neoadjuvant treatment.
ID 390
Bilateral breast cancer: Risk factors with impact on
clinical outcome
A. Meyer1,2, A. Köhler2, R. Hermann2,3, H. Christiansen2
Gemeinschaftspraxis für Strahlentherapie, Hildesheim, Deutschland
2
Medizinische Hochschule Hannover, Klinik für Strahlentherapie, Hannover, Deutschland
3
Zentrum für Strahlentherapie und Radioonkologie, Westerstede, Deutschland
1
Introduction: Unilateral breast cancer patients have a 2–3 fold increased
risk of the development of contralateral breast cancer. Little is known
about the prognostic outlook after treatment of second primary cancer.
Patients and Methods: 331 pat. with bilateral metachronous or synchronous breast cancer were treated with radiotherapy of the breast or the
thoracic wall between 01/1998 and 12/2008. Median follow-up was 74
months. Synchronous bilateral breast cancer was defined as occurence of
second contralateral tumour within 6 months of diagnosis of first tumor.
Results: Further outcome after 2 and 5 years regarding overall survival was
82% and 66%, local recurrence-free survival 83% and 73% and metastasis-free survival 77% and 60%. Synchronous or metachronous occurence
of contralaeteral breast cancer had no impact on further outcome regarding
the above mentioned end points (p > 0,05). In patients with metachronous
contralateral breast cancer the interval between the two breast cancer events
Abstracts
Impact of adjuvant treatment decisions for survival
outcomes in very elderly breast cancer patients (≥75
years)
J. Bonacker, A. Stachs, S. Hartmann, J. Stubert, M. Dieterich,
B. Gerber, T. Reimer
Universität Rostock, Gynäkologie, Rostock, Deutschland
Background: The optimal management of adjuvant breast cancer in very
elderly women is controversial. The lack of data from clinical trials reduces
the value of published guidelines. The aim of our study was to evaluate the
impact of prognostic factors and therapeutic applications on survival.
Methods: This unicentric study included 452 breast cancer patients aged
≥75 years who received adjuvant therapy between 2000 and 2009. Reported treatment modalities were categorized as optimal or suboptimal
standard. Factors with impact on survival (disease-free [DFS], breast cancer-specific [BCSS], and overall survival [OS]) were identified by logrank test and Cox regression.
Results: Among 452 patients, 37 women (8.2%) refused any surgery. The
rates of suboptimal standard treatment were higher for endocrine (12.8%),
systemic (30.8%), and radiation therapy (18.8%). Using log-rank test
standard radiotherapy, hormone receptor status, grading, tumor size, and
nodal status were significantly related with DFS. The corresponding factors with an impact on BCSS were: standard endocrine therapy, hormone
receptor, HER2, and nodal status. Age was significantly associated with
OS. Various treatment modalities and prognostic factors maintained their
statistical impact on OS. The multivariate analysis will be presented at
the DKK 2014.
Conclusions: Among this selected cohort, 46.7% of patients were treated
with suboptimal standard. The general acceptance of published guidelines
showed only a marginal effect on BCSS. However, standard radiation
(DFS) and endocrine therapy (BCSS) revealed a significant impact on
survival outcomes. Both should be considered in treatment decisions with
respect to patient’s health status.
ID 437
Pathological complete response rates in patients with
BRCA1/2-associated breast cancer after neoadjuvant
chemotherapy
L. Richters1,2, K. Rhiem1, B. Wappenschmidt1, M. Kiechle3,
R. Schmutzler1
Universitätsklinkum Köln, Zentrum für Familiären Brust- und Eierstockkrebs, Köln, Deutschland
2
Universitätsklinikum Köln, Klinik und Poliklinik für Gynäkologie und Geburtshilfe, Köln, Deutschland
3
Frauenklinik rechts der Isar, München, Deutschland
1
Purpose: As shown in previous studies, hereditary breast cancer responds differently to diverse chemotherapeutics. Therefore the present
paper investigates retrospectively the rate of pathological complete response (pCR: ypT0 ypN0) and overall response (ORR) in Patients with
BRCA1/2-associated breast cancer after differing neoadjuvant regimens.
Methods: 135 cases of BRCA1/2-associated breast cancer (BRCA1:
n = 101; BRCA2: n = 34) treated with neoadjuvant chemotherapy could
be identified in our collective between 1996 and 2013. Mainly inva-
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sive-ductal (n = 119), triple-negative (n = 75) and high grade (G3, n = 94)
carcinomas were described.
Regimens containing anthracyclines (A; n = 9), A and taxans (T) (n = 101),
A and T in combination with Platin (P) (N=19) and T with P were compared.
Because of their her2/neu-status trastuzumab was applicated in 9 cases,
in context of clinical studies bevazizumab (n = 5), lapatinib (n = 1) and
sorafenib (n = 1) were administered.
Results: Overall 51.1% (n = 135; BRCA1: 55.5%; BRCA2: 38.2%) of the
cases showed a pCR, the ORR was 94.6%. After a treatment containing P
and A pCR was achieved in 68.8% (n = 16, ORR: 100%), therapies without
P containing T and A (n = 74) showed a pCR-rate of 52.7% (ORR: 94.4%).
Conclusions: BRCA-associated breast cancers show high ORR and pCR
rates. Highest rates can be observed after therapies with platin and anthracyclines in BRCA1-mutation carriers. These results coincide with preliminary data.
More extensive analyses are required to evaluate the response rates of
hereditary breast cancers after different regimens and their correlation to
progression-free and overall survival. Through this an optimized therapy
for these high risk patients might be enabled in future.
ID 449
Prevalence of circulating tumor cells (CTCs) after
adjuvant chemotherapy with or without anthracyclines in
patients with HER2-negative early breast cancer (EBC)
F. Schochter1, U. Andergassen2, J.K. Neugebauer2, T.W. Friedl1,
A. Pestka2, J.K. Jückstock2, B. Jäger1, J.C. Salmen1, P.G. Hepp3,
G. Heinrich4, O. Camara5, T. Decker6, A. Ober7, T.N. Fehm3,
K. Pantel8, P.A. Fasching9, A. Schneeweiss10, M.W. Beckmann9,
W. Janni1, B.K. Rack2
University of Ulm, Department of Obstetrics and Gynecology, Ulm,
Deutschland
2
Ludwig-Maximilians-University, Department of Obstetrics and Gynecology,
Munich, Germany, Deutschland
3
Heinrich Heine University, Department of Obstetrics and Gynecology,
Duesseldorf, Deutschland
4
Medical Office of Gynecology, Fürstenwalde, Deutschland
5
Jena University Hospital, Department of Obstetrics and Gynecology,
Jena, Deutschland
6
Medical Office of Oncology, Ravensburg, Deutschland
7
St. Vincenz Hospital, Limburg, Deutschland
8
University Medical Center Hamburg-Eppendorf, Institute of Tumor Biology,
Hamburg, Deutschland
9
University Erlangen, Department of Obstetrics and Gynecology, Erlangen,
Deutschland
10
National Center for Tumor Diseases, Heidelberg, Deutschland
1
Background: Based on data suggesting a limited benefit of anthracycline-based chemotherapy in HER2-negative early breast cancer (EBC),
the SUCCESS C study randomly assigned patients with EBC to a chemotherapy regimen with or without anthracyclines. Given the demonstrated
prognostic value of circulating tumor cells (CTCs) in EBC, we compared
CTC prevalence after chemotherapy between both treatment arms.
Methods: The SUCCESS C trial was a randomized, open-label, Phase III
study comparing disease-free survival (DFS) in patients with HER2-negative EBC treated with either 3 cycles of epirubicin, 5-fluorouracil and
cyclophosphamide followed by 3 cycles of Docetaxel (FEC-DOC), or 6
cycles of an anthracycline-free regimen with docetaxel and cyclophosphamide (DOC-C). The CTC status at chemotherapy cycle 6 was evaluated using the FDA-approved CellSearch -system (Veridex, USA).
Results: CTCs were found in 221 of 1766 patients (12.5%; median 1,
range 1–18 CTCs). One CTC was detected in 123 (55.7%), two CTCs in
54 (24.4%), three to five CTCs in 37 (16.7%), and more than five CTCs
in 7 (3.2%) of these patients. CTC prevalence after chemotherapy did
not differ significantly between the two treatment arms (Chi-square test,
p = 0.18). CTCs were detected in 11.5% (103 out of 897; median = 1,
range 1–18) of patients treated with anthracycline-containing chemotherapy and in 13.6% (118 out of 869; median = 1, range 1–8) of patients
treated with anthracycline-free chemotherapy.
14
Conclusions: The comparable prevalence of CTCs after chemotherapy
indicates that anthracycline-free chemotherapy may not be inferior to
anthracycline-containing chemotherapy in HER2-negative EBC. This,
however, has to be confirmed by survival analyses.
ID 454
Quality of life of Young Mothers with Breast Cancer in
Germany
K. Baumann1, B. Wedel1, C. Benz-Jansen1, A. Waldmann1,
A. Rody1, D. Fischer1
Universtitätsklinikum Schleswig-Holstein, Campus Lübeck, Klinik für
Frauenheilkunde und Geburtshilfe,Universitäres Brustzentrum, Lübeck,
Deutschland
1
Background and Objective: Aim of the study is to analyse the health-related quality of life in young breast cancer patients in comparison to an
age-heterogenous breast cancer cohort and to a young general population.
Prevalence markers for a reduced quality of life were identified.
Materials and Methods: A retrospective study analyzed quality of life
of 517 young mothers (at least 1 child < 12 yrs) first diagnosed between
2006 and 2011 with primary breast cancer. The patients participated in a
resident mother-child program. The standardized questionnaire focused
on medical, clinical and social data and especially on quality of life (EORTC QLQ-C30, -BR23).
Results: The median age of the young cohort was 39 years. Inability to
work, being unemployed and a higher body mass index were predictors
for a globaly reduced quality of life. Unanticipated treatment and clinical
issues did not affect quality of life. Young breast cancer patients compared to the older breast cancer cohort showed a reduced quality of life
regarding social, emotional and cognitive functioning. In contrast to this
physical and sexual functions and stress by hair loss were significant better tolerated by the younger patients. Compared to the young general population the patients showed a serious reduced quality of life.
Conclusion: Young breast cancer patients with children under the age
of 12 should be carefully observed because of their high risk of reduced
quality of life. Our results may lead to the development of interventional
procedures to enhance quality of life in the vulnerable group of young
breast cancer patients.
ID 456
Febrile neutropenia (FN) and infections under adjuvant
chemotherapy of breast cancer with 6 x TC vs. 4 x EC –
4 x Doc: Toxicity data of the WSG planB trial
O. Gluz1, D. Hofmann1, R. Von Schumann 1,2, R. Kates1,
M. Clemens3, M. Salem 4, T. Reimer5, B. Liedtke6, B. Aktas7,
A. Stefek8, A. Pollmanns9, F. Lorenz-Salehi 10, C. Uleer11,
P. Krabisch12, D. Augustin13, N. Harbeck1,14, U. Nitz1,2
Westdeutsche Studiengruppe GmbH, Mönchengladbach, Deutschland
Ev. Bethesda Krankenhaus, Brustzentrum Niederrhein, Mönchengladbach, Deutschland
3
Klinikum Mutterhaus der Borromäerinnen, Hämatologie/Onkologie, Trier,
Deutschland
4
Universitätsfrauenklinik Köln, Brustzentrum Köln/Frechen, Köln, Deutschland
5
Klinikum Südstadt, Fachambulanz für Onkologie, Rostock, Deutschland
6
Ev. Krankenhaus Bergisch Gladbach, Brustzentrum, Bergisch Gladbach,
Deutschland
7
Universitätsfrauenklinikum Essen, Essen, Deutschland
8
Johanniter Frauenklinik, Gynäkologie, Stendal, Deutschland
9
Ev. Krankenhaus Oberhausen, Brustzentrum, Oberhausen, Deutschland
10
Dr. Horst-Schmidt Kliniken, Wiesbaden, Deutschland
11
Gemeinschaftspraxis, Hildesheim, Deutschland
12
Klinikum Chemnitz, Frauenklinik, Chemnitz, Deutschland
13
Klinikum Deggendorf, Mammazentrum Ostbayern, Deggendorf, Deutschland
14
1
2
Abstracts
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Index
Background: FN and infections are the main causes of advanced grade
morbity/mortality in adjuvant therapy of BC. Heterogeneous data for
TC are available: 3.3–6.6% with G-CSF support and up to 50% without
G-CSF prophylaxis. The advantage of primary G-CSF prophylaxis (PP)
is therefore uncertain.
Methods: Within in the planB trial HER2- high risk patients with pN0/+
BC were randomized to anthracycline-free schedule (6 × T75C600) vs. 4 ×
E90C600 – 4 × Doc100. PP was recommended in patients with age ≥ 65 and/
or concomitant diseases. Toxicity was documented at every cycle, graded
accorded to CTC 3.0 criteria and compared according to Chi-square test.
Results: Out of 2449 randomized patients (TC/EC-Doc: 1222/1227), data
of 1930 patients (TC/EC-Doc: 982/948; age > 65 years 180/184) with ≥ 1
adverse event were analyzed. FN was observed in 92 patients (TC/EC-Doc:
48 (4.9%)/44 (4.7%), n.s.; age ≥65 years TC/EC-Doc: 6.7%/4.3%, n.s.).
PP was documented within the first cycle at the following rates: TC/ECDoc 11.4%/3.3%, p < 0.01. FN in the first cycle (n = 1680): TC/EC-Doc:
2.3%/0.7%, p = 0.004; with PP 1%/0%; without PP: 2.9%/0.9%, p = 0.003)
Infections grade 3–5 (n = 110) where documented in 105 patients (TC/
EC-Doc: 68 (6.6%)/37 (3.9%), p = 0.003).
Deaths: TC: 5 (4 × infections, especially gastrointestinal infections, 1 pulmonary embolism). EC-Doc: 1 (infection); p = 0.1.
Discussion: Despite more frequent PP TC causes significantly more severe infections, FN at the first cycle, and more therapy-related mortality
than EC-Doc (n.s.). Nevertheless, the FN rate is lower than published
data for TC. It is recommended to add PP to risk groups (gastrointestinal
risks, older patients).
Breast Cancer – Local-Regional Therapy
ID 161
Application ofreirradiation and hyperthermia in recurrent
breast cancer: Long-term results and technological
opportunities.
G. van Rhoon, M. Linthorst, A. van Geel, M. Baaijens,
J. van der Zee
Erasmus MC Cancer Institute, Radiotherapy, Rotterdam, Niederlande
Introduction: Reirradiation combined with hyperthermia is an effective
treatment for recurrent breast cancer. Here we report long-term results of
patients treated since 1992.
Materials and Methods: 198 patients with subclinical and 250 with irresectable disease were treated, including 36 patients with tissue transfers.
All patients were treated with 8 fractions of 4 Gy twice weekly, and 8
(until 1996) or 4 one-hour hyperthermia treatments applied after radiotherapy. Approximately half of the patients received radiotherapy in another institute.
Results: In subclinical disease the 3- and 5-year local control (LC) was
83% and 78%. In patients with irresectable disease complete response
was 70% and 3- and 5-year LC was 40% and 39%. 5- and 10-year overall
survival was 60 and 36% for subclinical disease, and 18 and 10% for
irresectable disease. Both LC and toxicity in patients with tissue transfers
were similar to those in the other patients. Superficially measured temperatures >43° were associated with more hyperthermia toxicity.
Patients irradiated elsewhere had a better LC than patients irradiated in
the Erasmus MC. For patients with gross disease, the radiating institute
was the only significant factor influencing LC in multivariate analysis.
At the same time, patients with subclinical disease irradiated elsewhere
had significantly less late grade 3–4 toxicity (7% at 5 years) than patients
irradiated in Erasmus MC (15%).
Conclusions: These results again show that reirradiation with hyperthermia is worthwhile. Patients with tissue transfers can be treated safely. The
better results in patients irradiated elsewhere was unexpected. Hyperthermia toxicity may be decreased when superficially measured temperatures
are kept below 43 °C.
Abstracts
ID 251
Cosmetic Differences after Hypofractionated &
Normofractionated Intensity Modulated Radiotherapy in
Breast Cancer Patients: An Interim Analysis of the Phase
II KOSIMA-Trial (ARO 2010-3)
A.Y. Aboumadian1,2, O. Aldabbas1, M. Polednik1, G. Welzel1,
F. Wenz1
Universitätsmedizin Mannheim, Heidelberg Universität, Klinik für Strahlentherapie und Radioonkologie, Mannheim, Deutschland
2
Cairo University, Department of Clinical Oncology, Cairo, Egypt
1
Purpose: We aim to compare the cosmetic outcome and treatment side
effects between a hypofractionated (HF) and a normofractionated (NF)
radiotherapy schedules after breast conserving surgery.
Methods: Early breast cancer patients >60 years were stratified in two
arms, right sided cases to 40/2.67 Gy and left sided to 50/2 Gy using a
tangential intensity modulated radiotherapy (tIMRT) technique. A boost
dose of 16/2 Gy was added to patients <70 years. Planning was performed
according to strict dosimetric limits. CTC-AE v3 & LENT-SOMA scaled
side effects were prospectively documented. Here, we report on early
adverse effects at 1 and 6 weeks after end of RT for the first serial 96
patients.
Results: Minor differences were present in average breast size (1170 cc
vs. 1105 cc) and number of patients receiving a boost (54% vs. 50%) for
HF and NF arms respectively. Median age was similar with 69 years.
Planning quality was preserved in both groups. The peak incidence of
acute G2-dermatitis at 1 week was similar in both arms with 10.4%. At 6
weeks only maximum of G1-dermatitis in 16 and 18% was still observed.
Hyperpigmentation was persistent during the first 6 weeks with max. G2
hyperpigmentation of 4.1% vs. 10.4%. Breast edema reached a peak at 1
week and tended to be less incident in the HF arm with G1+2 edema in
22.9% vs. 31.2% in the NF arm. Breast retraction was evident in around
10% of patients at baseline. At 6 weeks it increased to 18.7% in the HF
group vs. 25% in the NF group. No grade 3 or 4 adverse effects were observed in all previously mentioned outcome points. At week 6, G3 breast
pain was observed in 1 patient in each arm with G2 pain being 10.4% and
6.3% which were close to baseline values.
Conclusion: Minimal acute adverse effects are associated with breast
IMRT. In the early post therapeutic phase, the hypofractionated treatment
schedule seemed to be better tolerated and caused relatively less cosmetic
changes.
ID 373
Single center experiences with intraoperative
radiotherapy as a boost during oncoplastic breastconserving surgery
W. Malter1,2, V. Kirn1, R. Bongartz2, R. Semrau2, B. Markiefka3,
P. Mallmann1, S. Krämer1
Uniklinik Köln, Brustzentrum der Frauenklinik, Köln, Deutschland
Uniklinik Köln, ³Klinik und Poliklinik für Strahlentherapie, Köln, Deutschland
3
Uniklinik Köln, Zentrum für Pathologie, Köln, Deutschland
1
2
Background: Breast-conserving surgery (BCS) is performed in an oncoplastic approach with tumor-specific immediate reconstruction of the partial mastectomy defect. In the attempt to further improve local outcome
in breast-conserving therapy we introduced intraoperative radiotherapy
(IORT) with low-kilovoltage X-rays as a boost during oncoplastic BCS
followed by EBRT.
Material and Methods: Between February 2010 and July 2012, a total of
149 patients were treated with IORT as a boost during primary oncoplastic breast-conserving surgery, followed by whole-breast radiotherapy. After mobilisation of glandular tissue the segmental resection borders were
narrowed to the applicator using purse-string sutures. Resection defects
were definitely reconstructed after IORT-boost using the predefined oncoplastic principles to achieve optimal esthetic results after BCS.
15
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Results: Median age was 58 (range 36–86) years. There were T1 and
T2 tumours in 117 and 29 patients, respectively, and N0, N1 and N2 disease in 111, 26, and 12 patients, respectively. The used radiation applicator-sizes ranged between 25 and 40 mm in 79% of the patients. The mean
radiation time was 21 (range 18–32) minutes. IORT boost radiotherapy
was combined with oncoplastic principles for partial mastectomy reconstruction: glandular rotation (n = 109), dermoglandular rotation (n = 29),
tumoradapted reduction mammoplasty (n = 11).
Conclusion: IORT as a tumour bed boost with low-kilovoltage x-rays is
clinically applicable with low toxicity and complication rates. The method supports the close interdisciplinarity between radiation therapy and
breast surgery and can be combined with oncoplastic principles in BCS.
ID 378
Targeted breast surgery – classification of oncoplastic
techniques
S. Krämer, W. Malter, N. Lange, C. Fridrich, P. Mallmann
Background: Most patients presenting with breast cancer are treated by
breast-conserving therapy (BCT). Some of these patients present with
poor cosmetic results after surgery. To avoid partial defects after BCT a
wide spectrum of reconstructive techniques have been published during
the last years – a concept termed oncoplastic breast surgery. To improve
clinical utility of oncoplastic breast-conserving surgery we developed a
classification of oncoplastic techniques with standardization of indications and surgical performance.
Material and Methods: We prospectively defined five major principles in oncoplastic breast surgery based on the localization, size of the
segmental resection defect, size of the breast and the necessity for skin
resection during breast-conserving therapy. These major principles are:
BCT-glandular rotation, BCT-dermoglandular rotation, BCT-tumoradapted reduction mammoplasty, BCT-thoracoepigastric flap, BCT-latissimus
dorsi flap.
Results: Between November 2008 and November 2011 we performed
952 breast-conserving operations in 913 patients. For reconstruction of
the partial resection defect during segmental resection the defined five
oncoplastic principles were used as follows: glandular rotation (n = 549;
58%), dermoglandular rotation (n = 149; 16%), tumoradapted reduction
mammoplasty (n = 135; 14%), thoracoepigastric flap (n = 27; 3%) and
latissimus dorsi flap (n = 92; 9%). Partial mastectomy defects could be
reconstructed during BCT with these five oncoplastic principles in 97%.
The cosmetic results were good or excellent in 95%.
Conclusion: The use of five defined oncoplastic principles allows the
reconstruction of segmental resection defects during breast-conserving
therapy with highest clinical applicability and results in favourable esthetic outcomes. This approach might be useful in extending the indications
for breast-conserving therapy.
ID 383
Intraoperativeassessment of macroscopic instantaneous
sections to prevent re-resection in IORT patients
W. Malter1, S. Kapteina1, F. Thangarajah1, B. Markiefka2,
R. Bongartz3, R. Semrau3, M. Hellmich4, S. Krämer1, P. Mallmann1
Uniklinik Köln, Zentrum für Pathologie, Köln, Deutschland
3
Uniklinik Köln, Klinik und Poliklinik für Strahlentherapie, Köln, Deutschland
4
Universität Köln, Inst. of Medical Statistics, Informatics and Epidemiology,
Köln, Deutschland
1
2
Objective: Local breast-conserving surgery combined with intraoperative (boost) radiotherapy of early breast cancer is becoming a new standard in local therapy during the last years. To get the applicated full dose
of IORT translated into an increased local control it is important to reduce
16
the re-resection rate as low as possible after IORT-boost and to achieve
tumor-free resection margins before whole-breast irradiation.
Methods: Between 2/2010 and 12/2012 intaoperative boost irradiation
was performed after breast-conserving surgery of breast cancer using the
INTRABEAM System, Carl Zeiss Surgical, Oberkochen, Germany; 20
Gy, 50 KV x-ray). Breast-conserving surgery was performed in an oncoplastic-targeted concept with segmentally formed resection specimens,
which was published elsewhere in combination with IORT. The resected
specimens were then analyzed by an experienced pathologist with macroscopically analysis to reveal tumor-free resection margins or close margin
situations with targeted re-resectioning before IORT.
Results: In 141 patients (pts.) intraoperative boost irradiation was performed. In 13% a re-excision (after IORT-boost) was performed to
achieve tumor-free resection margins. In 19 out of 22 pts. (NPV 86,4%;
95% CI 66,7 to 95,3%) the final tumor-free margins were as expected
during macroscopically section assessment. In 99 out of 119 pts. (PPV
83,2%; 95% CI 75,5 to 88,8%) the intraoperative margin-assessment of
the pathologist revealed correctly tumor-free resection margins during
macroscopically analysis of the resected specimens.
Conclusion: The macroscopic instantaneous section analysis of resection
margins during breast-conserving surgery is a reliable and precise method
to estimate tumor-free margins before IORT (boost) irradiation. An experienced breast pathologist is able to do these margin examinations fast and
economically based.
ID 395
Updates from the TARGIT A trial for the German centers:
Local recurrence and survival
E. Sperk1, J. Vaidya2, M. Bulsara3, M. Sütterlin4, B. Ataseven5,
S. Pigorsch6, P. Feyer7, J.U. Blohmer8, M. Kaufmann9, C. Rödel10,
K. Friese11, C. Belka12, E.-F. Solomayer13, J. Fleckenstein14,
T.-W. Park-Simon15, M. Bremer16, D. Joseph17, J. Tobias18,
M. Baum18, F. Wenz1
Universitätsmedizin Mannheim, Strahlentherapie und Radioonkologie,
Mannheim, Deutschland
2
University College London, Breast Surgery, London, Großbritannien
3
The University of Western Australia, School of Population Health, Perth,
Australien
4
Universitätsmedizin Mannheim, Universitätsfrauenklinik, Mannheim,
Deutschland
5
Kliniken Essen-Mitte, Department of Gynecology and Gynecologic Oncology, Essen, Deutschland
6
Klinikum rechts der Isar Klinik, Poliklinik für Strahlentherapie und Radiologische Onkologie, München, Deutschland
7
Vivantes Kliniken Berlin-Neukölln, Klinik für Strahlentherapie und Nuklearmedizin, Berlin, Deutschland
8
St. Gertrauden-Krankenhaus, Frauenklinik, Berlin, Deutschland
9
Universitätsklinikum Frankfurt, Universitätsfrauenklinik, Frankfurt,
Deutschland
10
Universitätsklinikum Frankfurt, Klinik für Strahlentherapie, Frankfurt,
Deutschland
11
Klinikum der Universität LMU München, Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe, München, Deutschland
12
Klinikum der Universität LMU München, Klinik und Poliklinik für Strahlentherapie und Radioonkologie, München, Deutschland
13
Universitätsklinikum des Saarlandes, Klinik für Frauenheilkunde, Geburtshilfe und Reproduktionsmedizin, Homburg, Deutschland
14
Universitätsklinikum des Saarlandes, Klinik für Strahlentherapie und
Radioonkologie, Homburg, Deutschland
15
Medizinische Hochschule Hannover, Klinik für Frauenheilkunde und
Geburtshilfe Gynäkologische Onkologie, Hannover, Deutschland
16
Medizinische Hochschule Hannover, Strahlentherapie und Spezielle
Onkologie, Hannover, Deutschland
17
Sir Charles Gairdner Hospital, Department of Radiation Oncology,
Nedlans, Australien
18
University College London, Department of Oncology, London, Großbritannien
1
Purpose: Updated results from the randomized TARGIT A trial with
3451 patients were presented at the San Antonio Breast Cancer Sympo-
Abstracts
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Index
sium in 2012. Now the German cohort of patients was analyzed regarding
local recurrence and survival. The German cohort was supposed to be
more homogeneous than the international cohort (age, treatment, smaller
tumours < 2 cm).
Methods: 734 patients were randomized either to the TARGIT group
(n = 366), where after breast conserving surgergy (BCS) an IORT was
added (20 Gy) during the same procedure. External beam radiotherapy
(EBRT, 46–50 Gy) was added per protocol if high risk factors (lymphovascular invasion, positive lymph nodes or resection margins, extensive
intraductal component, T2) were present. Or patients were randomized
to the EBRT group (n = 368), where BCS was followed by EBRT as a
standard procedure (56 Gy to the whole breast). Kaplan Meier estimates
(5 years) were performed for local relapse and overall survival.
Results: After 5 years, 4 local recurrences as primary endpoint were seen
in the TARGIT group and 1 in the EBRT group, p = 0.19. As secondary
endpoint 6 deaths (3 breast cancer deaths, 3 non breast cancer deaths)
were seen in the TARGIT group and 12 deaths (5 breast cancer deaths,
7 non breast cancer deaths) in EBRT group, p = 0.01. Significantly less
non breast cancer deaths were reported after IORT compared to the EBRT
group, p = 0.04. No difference could be seen for breast cancer deaths,
p = 0.45.
Conclusion: Patients treated within the TARGIT A trial in Germany have
excellent 5 year outcomes regarding local control and overall survival. A
significantly better overall survival was seen in the TARGIT group.
Breast Cancer – Metastatic Breast Cancer
ID 016
HER1, HER2, HER3 and HER4 – clinicopathologic
analysis of matched pairs of primary and cerebral
metastatic breast cancer
C. Bachmann1, G. Brockhoff2, E. Grischke1, A. Staebler3,
J. Schittenhelm4, D. Wallwiener1
Universitätsfrauenklinik Tübingen, Tübingen, Deutschland
Universität, Frauenklinik, Regensburg, Deutschland
3
Universität, Pathologie, Tübingen, Deutschland
4
Universität, Neuropathologie, Tübingen, Deutschland
1
2
Background and Aim: HER2 overexpression is a prognostic and predictive factor for development of CNS metastases (BM) in primary breast
cancer. Studies have shown that the immunophenotype of distant breast
cancer metastases may be different from that of primary tumour, leading
to inappropriate choice of systemic treatment. A number of studies have
demonstrated that HER3 overexpression is associated with poor prognosis and HER4 is more related with a favourable prognosis in breast
cancer. Aim is to study if there is receptor change for ER/PR and HER1–4
status in matched pairs of BM and primary.
Methods: 24 consecutive patients with surgical resected BM of breast
cancer were enrolled. All patients were treated at the Department of Gynecology, University Tübingen, Germany and got first diagnosis of primary breast cancer between 2001 and 2008. Matched pair analysis of
primary and BM were performed with IHC staining for ER/PR/HER1–4.
HER2 in situ hybridization was done in cases of IHCconversion or IHC
showed 2+.
Results: Her2 positive breast cancer patients had higher risk getting BM
(52%: Her2 positive) compared to Her2 negative patients. There was almost 100% coincidence of HER2 status in BM and primary and a high
discordance for ER/PR status. In almost all cases BM showed loss of receptor positivity (ER/PR). The comparison of HER1/3/4 status of primary
and BM showed inhomogeneous results.
Conclusion: The HER1–4 status of primary and BM showed inhomogenous results. The impact of Her3/4 expression on prognosis has to be investigated in larger studies. Definite conclusions for HER3/4 expression
could not yet be drawn.
Abstracts
ID 067
Serial Enumeration of Circulating Tumor Cells Predicts
Treatment Response and Prognosis in Metastatic Breast
Cancer
M. Wallwiener1, A.D. Hartkopf2, C. Modugno1, S. Riethdorf3,
J. Nees1, D. Madhavan4, S. Schott1, C. Domschke1, I. Baccelli1,4,
B. Burwinkel4, F. Marmé1, J. Heil1, C. Sohn1, K. Pantel3,
A. Trumpp4, A. Schneeweiss1,5
Uni-Frauenklinik Heidelberg, Heidelberg, Deutschland
Uni-Frauenklinik Tübingen, Tübingen, Deutschland
3
Universität Hamburg-Eppendorf, Hamburg-Eppendorf, Deutschland
4
DKFZ, Heidelberg, Deutschland
5
NCT, Heidelberg, Deutschland
1
2
Purpose: To prospectively assess circulating tumor cell (CTC) status at
baseline (CTCBL) and after one cycle of a new line of systemic therapy
(CTC1C) and changes from CTCBL to CTC1C (CTC kinetics, CTCKIN) for
their utility in predicting response, progression-free (PFS) and overall
survival (OS) in metastatic breast cancer (MBC).
Experimental Design: CTCBL and CTC1C status was determined as negative or positive for < 5 or ≥ 5 CTC/7.5 ml blood using CellSearch™ (Veridex). CTCKIN was categorized as favorable (CTC1C negative) or unfavorable (CTC1C positive). Tumor response was assessed every 2–3 months
using the Response Evaluation Criteria in Solid Tumors (RECIST). CTC
status and kinetics were tested statistically for correlation with outcome.
Results: 126/366 (34%) patients enrolled were CTCBL+, and 56/191
(29%) were CTC1C+. Median PFS and OS (months) were significantly
reduced in CTCBL+ vs CTCBL− patients (PFS 4.5 [95% confidence interval 3.6–6.0] vs 7.7 [6.1–9.1]; OS 13.9 [9.7–18.9] vs 33.4 [33.4-not available (na)]), and for CTC1C+ vs CTC1C− patients (PFS 4.1 [3.5–6.1] vs 8.2
[6.7–10.2]; OS 13.1 [7.0–23.9] vs 31.8 [28.2-na]. Unfavorable CTCKIN
was significantly associated with progressive disease. Multivariate Cox
regression analysis revealed CTCBL+ and ≥3rd-line therapy as independent prognostic factors for shorter PFS, and CTCBL+, bone-plus-visceral/
local metastases, and triple-negative receptor status for shorter OS.
Conclusions: CTCBL, CTC1C, and CTCKIN are predictive of outcome in
MBC. Serial CTC enumeration is a useful tool to tailor systemic treatment in MBC.
ID 068
The prognostic impact of circulating tumor cells in
subtypesof metastatic breast cancer
M. Wallwiener1, A.D. Hartkopf2, I. Baccelli3, S. Riethdorf4,
S. Schott1, K. Pantel4, F. Marme5, C. Sohn1, F. Schütz1,
A. Trumpp3, B. Rack6, B. Aktas7, E.-F. Solomayer8, V. Müller4,
W. Janni9, A. Schneeweiss5, T.N. Fehm10
Uni-Frauenklinik Heidelberg, Heidelberg, Deutschland
Universitäts-Frauenklinik, Tübingen, Deutschland
3
DKFZ, HI-STEM, Heidelberg, Deutschland
4
Universität Hamburg-Eppendorf, Hamburg-Eppendorf, Deutschland
5
NCT Heidelberg, Heidelberg, Deutschland
6
LMU München, München, Deutschland
7
Universität Essen, Essen, Deutschland
8
Universität Homburg, Homburg, Deutschland
9
Universität Ulm, Ulm, Deutschland
10
Universität Düsseldorf, Düsseldorf, Deutschland
1
2
The detection of circulating tumor cells (CTCs) in the peripheral blood
of metastatic breast cancer (MBC) patients is an independent marker
of prognosis. This large prospective multicenter study aimed to assess
the impact of CTCs on overall survival (OS) and progression free survival (PFS) in patients with predefined molecular subgroups of MBC.
To this end, 468 MBC patients were divided into three subgroups based
on immunohistochemical staining of the primary tumor: (1) hormone
receptor-positive/HER2-negative (HorR+/HER2-), (2) HER2-positive
(HER2+), and (3) HorR-negative/HER2-negative (HorR-/HER2-) patients. CTC status (≥5 CTCs/7.5 ml blood (CTC-positive)) was deter-
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mined using the CellCearch/ system before patients started a new line
of therapy. At baseline, 205 (42%) patients were CTC-positive.On multivariate analysis, CTC-positivity was an independent prognostic factor
for shorter PFS and OS. In HorR+/HER2- patients, median PFS [95%
CI] of CTC-negative versus CTC-positive patients was 8.60 [5.93–11.27]
versus 4.33 [3.29–5.38] months (pHER2+ patients 7.60 [5.40–9.79] versus 6.60 [4.20–9.00] months (p = 0.477) and in HorR-/HER2- patients
5.83 [5.09–6.78] versus 3.05 [1.81–4.29] months (pversus 18.07 [11.10–
25.05] months (p = 0.001) in the HER2+ subgroup, and not reached versus 8.57 [4.07–13.07] months in the HorR-/HER2- subgroup (p = 0.001).
In conclusion, our results strongly confirm the independent prognostic
value of CTC enumeration in MBC patients. In contrast to recent reports,
there was no association between primary tumor-based molecular subgroups and the impact of CTC status on OS. Hence, CTC status may help
to identify patients who require aggressive therapy, especially among
those with triple-negative MBC.
ID 120
Baseline results from ACT-FASTER, a prospective cohort
study exploring treatmentpatterns with fulvestrant
and exemestane in postmenopausal patients with
advancedhormone-receptor positive breast cancer under
real-life conditions in Germany
D. Bauerschlag, N. Maass, W. Greiner, K. Possinger, H. Tesch,
S. Zaun, P. Klein, H. Ostermann
Uniklinik RWTH Aachen, Gynäkologie, Aachen, Deutschland
Introduction: Fulvestrant (FUL) is a selective estrogen receptor
down-regulator forpostmenopausal (PMP) women with advanced ER+
breast cancer (ABC) after tamoxifen. Atpresent, there is no definitive recommendation on endocrine therapy (ET) sequencing in ABC. ACT-FASTER aims to generate data on use of FUL 500 mg and exemestane (EXE)
under real-life conditions with a focus on different treatment lines.
Methods: This is a prospective non-interventional cohort study
(NCT01171417) in PMP women with HR+ ABC on treatment with FUL
500 mg (1st, 2nd, 3rd line) or EXE. The two coprimary objectives are: For
pts on FUL, to compare the time to progression (TTP) as a function of line
of treatment (1st / 2nd / 3rd line); for all pts, real-life data on epidemiology and management, incl. tumour characteristics, co-morbidities and
treatments received. Secondary endpoints include outcome parameters
(TTP, CBR, OS) and healthcare resource use.
Results: Across 115 centers, 493 evaluable pts were enrolled. Mean age
was 67.4 years; 85.4% had WHO PS 0-1; 72% had concomitant diseases;
99% were ER+; 87% PgR+. 72% had a recurrence after early disease
(EBC). In these, primary therapy for EBC included surgery (97%), radiation (71%) and adjuvant systemic therapy (95%). On study, 87% of pts
received FUL for ABC (42%, 37% and 21% as 1st, 2nd and 3rd-line),
and 13% EXE. 73% of pts had received prior treatment for ABC. ET
(62%) was the most frequent prior therapy for ABC; disease progression the most common reason for changing therapy (64%). Conclusions:
ACT-FASTER aims to generate real-life information on ET of PMP patients with ER+ ABC. Consistent with current standards of care, ET was
the most frequently used therapy for patients with ER+ ABC prior to initiation of FUL or EXE.
ID 130
Metastatic breast cancer: Improving survival in routine
care by targeted therapies
Methods: Retrospective analysis of all patients with metastatic breast
cancer who were treated between 06/1995 and 06/2013. Relevant clinical
data were transferred from clinical files into a database and analysed statistically using SPSS and SURVSOFT.
Results: 716 female patients with a median age of 61 years (31–93) (time
of metastasis) were analysed. 80% were postmenopausal, 21% suffered
from primary metastatic disease. Sites of metastases were distributed as
follows: 47% visceral, 36% bone, 9% lymph nodes, 4% CNS and 4% others. Mean number of metastatic sites was 1.4 (1–4). Median overall survival was 34 months (0–301+), disease specific survival was 36.8 months.
Overall survival was significantly correlated with the sites of metastases,
number of involved organs, disease-free survival since initial diagnosis
and hormone receptor status. Patients with a hormone receptor positive
tumour had a median overall survival of 37 months (0–277+) compared
to patients with a triple negative tumour, who showed a median overall
survival of 13 months (0–116+). Patients with a HER2-positive tumour
had a median overall survival of 35 months (0–301+).
Conclusions: Survival of patients with metastatic breast cancer with hormone receptor or HER2-positive tumours can be extended significantly
by the sequential use of targeted therapies in routine care.
ID 135
The conditional knockdown of bone sialoprotein reveals
modulation of genes inversely related to breast cancer
skeletal metastasis
M. Kovacheva1, S. Berger2, M. Berger1
DKFZ, Toxicology and Chemotherapy, Heidelberg, Deutschland
Central Institute of Mental Health, Department of Molecular Biology,
1
2
Bone metastasis is a serious complication in breast cancer patients and
renders the disease virtually incurable. Bone sialoprotein (BSP) is thought
to play an important role in lytic skeletal lesions, though the underlying
mechanisms are not clear. We established MDA-MB-231 cell subclones
with conditional (doxycycline dependent) miRNA mediated inhibition
of BSP production. In these cells tetracycline-dependant transactivator
(tTA) stimulates the simultaneous expression of a specific miRNA, of
RFP and firefly luciferase.
Following 6 days of miRNA expression, BSP concentrations were decreased by 22–86% in the respective cell clones. The function of the
genes introduced was investigated by fluorescent microscopy and FACS
analyses. BSP knockdown was associated with rounded cells and cell
fragments as signs of apoptosis.
In order to understand the molecular mechanism triggered by diminished
BSP levels, which induce apoptosis, an expression profiling analysis was
performed and selected proteins confirmed by western blot. A decrease in
BSP concentrations for 6 days led to a modulation of 1.3% of all genes,
implicating a specific effect of BSP knockdown. Both, ATF3 and CHOP
mRNA levels were elevated more than 5fold, and the corresponding protein levels by 2.4fold and more. The increased expression of these transcription factors was associated with cleavage of caspases 8, 9, 3, 7 and
of PARP.
In conclusion, these data indicate that BSP knockdown causes specific
cellular responses associated with ER stress and activation of intrinsic
and extrinsic apoptotic pathways. They also confirm the relevance of BSP
in breast cancer skeletal metastasis and render the protein a promising
target in the clinical treatment of these patients.
R. Weide1, S. Feiten2, V. Friesenhahn2, J. Heymanns1,
K. Kleboth2, J. Thomalla1, C. van Roye1, H. Köppler1
Praxisklinik für Hämatologie und Onkologie Koblenz, Koblenz, Deutschland
Institut für Versorgungsforschung in der Onkologie, Koblenz, Deutschland
1
2
Objectives: Evaluation of routine care in unselected patients with metastatic breast cancer who were treated in an oncology group practice.
18
Abstracts
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ID 136
Preemptive tumor profiling for biomarker-stratified early
clinical drug development in metastatic breast cancer
patients
A. Welt1, S. Kasper1, M. Tewes1, B. Aktas2, O. Hoffmann2,
M. Wiesweg1, S. Ting3, H. Reis3, K. Worm3, H. Richly1, J. Hense1,
M.R. Palmer4, B.H. Lee4, J. Wendling1, J. Kossow1,
M.E. Scheulen1, C. Lehnerdt1, M. Kohl1, C. Derks1, S. Slottky3,
U. Haus5, K. Schmid3, R. Kimmig2, M. Schuler1,6
Westdeutsches Tumorzentrum, Universitätsklinikum Essen, Innere Klinik
2
Westdeutsches Tumorzentrum, Universitätsklinikum, Klinik für Frauenheilkunde u. Geburtshilfe, Essen, Deutschland
3
Westdeutsches Tumorzentrum, Universitätsklinikum, Institut für Pathologie, Essen, Deutschland
4
Novartis Instituts for Biomedical Resaerch, Cambridge, MA, USA
5
Novartis Pharma, Nürnberg, Deutschland
6
German Cancer Consortium (DKTK), Heidelberg, Deutschland
1
Introduction: Multiple drug candidates have been developed to modulate molecular targets in breast cancer (BC) besides hormone receptors
and Her2 which may associate with specific biomarker profiles. Exploratory biomarkers are increasingly incorporated in early clinical trials.
This demands a new process of patient selection. Here we describe the
implementation of preemptive, multiplexed biomarker profiling linked to
standard diagnostic algorithms for metastatic BC patients treated at the
West German Cancer Center.
Methods: Profiling for experimental biomarkers was prospectively offered to patients with metastatic BC who met generic clinical trial inclusion criteria. Formalin-fixed, paraffin-embedded tumor samples were
retrieved and studied for potentially ‘actionable’ biomarkers related to
active clinical trials by immunohistochemistry, amplicon sequencing, and
in-situ hybridization. The clinical course of ‘profiled’ patients was monitored to offer trial participation whenever applicable.
Results: We report results from the first 131 patients enrolled in this program. PIK3CA mutations (23%) and amplifications (2%), loss of PTEN
expression (13%), and FGFR1 amplifications (8%) were detected next to
established biomarkers such as estrogen (67%) and progesterone receptor
expression (52%), and HER2 overexpression or amplification (23%). So
far 16 ‘profiled’ patients (12%) have been enrolled in biomarker-stratified
early clinical trials.
Conclusion: Preemptive biomarker profiling can be integrated into the
diagnostic algorithm of a large Comprehensive Cancer Center. Extensive
administrative efforts are required to successfully enroll ‘profiled’ patients in ‘stratified’ early clinical trials.
ID 271
microRNA miR-142-3p inhibits breast cancer cell
invasiveness by interfering with WASL / N-WASP- and
ITGAV-dependent cytoskeletal function
A. Schwickert1, E. Weghake1, K. Brüggemann1, A. Engbers1,
J. Seggewiß2, B. Kemper3, C. Stock4, C. Riethmüller5, L. Kiesel1,
M. Götte1
Universitätsklinikum Münster, Klinik für Frauenheilkunde und Geburtshilfe,
Münster, Deutschland
2
University of Münster, IFG, IZKF, Münster, Deutschland
3
University of Münster, Center for Biomedical Optics and Photonics, Münster, Deutschland
4
University of Münster, Institut of Physiology II, Münster, Deutschland
5
Center for Nanotechnology, Serend-ip GmbH, Münster, Deutschland
1
Aim of Study: MicroRNAs are pivotal post-transcriptional regulators of
gene expression. Their differential regulation plays an important role in
tumorigenesis and cancer progression. miR-142-3p has been found to be
dysregulated in several breast cancer subtypes. We aimed at investigating
a potential role for miR-142-3p in breast cancer cell invasiveness.
Abstracts
Methods: MDA-MB-231, MDA-MB-468 and MCF-7 cell lines were
transiently transfected with control or miR-142-3p precursors or antimiR-inhibitors. Target gene expression was monitored by Affymetriy
gene array, qPCR, Western blotting and 3’UTR luciferase assay. Cell
behaviour was monitored by Matrigel invasion assay. Cell morphology
was investigated by confocal immunofluorescence microscopy, nanoscale
atomic force microscopy and digital holographic microscopy.
Results: miR-142-3p upregulation reduced matrigel invasiveness and
lead to reduced expression of WASL, Integrin-αV, RAC1, CFL2, ROCK2,
IL6ST, KLF4,PGRMC2 and ADCY9. Microscopyrevealed a restructuring
of the intracellular actin cytoskeleton as well as a reduction in cell volume
and size. A more cortical actin distribution as well as a loss of invadopodia were observed in cells overexpressing miR-142-3p. siRNA-mediated
depletion of WASL and ITGAV resulted in a significant reduction of cellular invesiveness, highlighting the contribution of these factors to the
miRNA-dependent invasion phenotype.
Conclusions: Our data identify WASL and ITGAV as novel invasion-associated targets of miR-142-3p in breast cancer. With its tumor suppressive
potential, miR-142-3p is a promising candidate for future approaches of
miRNA-based anti-metastatic cancer therapy.
ID 403
Preclinicale evaluation of 5-FdU-Alendornat, a new
antimetabolite-bisphosphonate against bone metastasis
in a breast cancer mice model
S. Schott1, R. Towers2, S. Tiwari32, A.- C. Rambow3, P. Kneissl3,
C. Busch4, C. Glüer2, C. Sohn1, W. Jonat3, C. Schem3
Universitätsfrauenklnik Heidelberg, Heidelberg, Deutschland
Universitätsklinikum Schleswig-Holstein, Campus Kiel, Klinik für diagnostische Radiologie, Sektion für Molekulares Imaging (MOIN CC), Kiel,
Deutschland
3
Universitätsklinikum Schleswig-Holstein, Campus Kiel, Klinik für Gynäkologie und Geburtshilfe, Klinik für Gynäkologie und Geburtshilfe, Kiel,
Deutschland
4
Universitätsklinikum, Dermatologie, Tübingen, Deutschland
1
2
Bone metastasis occurs among 80% of progressed breast cancer patients
with limited therapeutic options. In order to optimize the therapeutic
strategies for bone metastasis the antimetaboilte 5-FdU was chemically
linked to the bisphosphonate alendronate (ale). The obtained 5-FdU-alendronate-conjugate (5-FdU-Ale) enables a bone targeting. The conjugated
BSP-part attaches to the bone matrix. The molecule accumulates and locally metabolises. First in vivo data are presented.
Material, Methods: The embryotoxicity of 5-FdU-Ale was evaluated in
comparison to ale in the chicken embryo assay at concentrations from
0.01 to 500 mM, incubatied for 72 h.
The maximum tolerable dose (MTD) was evaluated in analogue to the
NCI acute toxicology determination protocol. In each group, 3 BalbC
mice obtained either 200, 100, 50 or 25 mg/kg 5-FdU-Ale i.p.
An in vivo mice model, established for bone metastasis, provided fist in
vivo data on 5-FdU-Ale in comparison to PBS controls. The mice received 5-FdU-Ale (200 mg/kg) q7d for 5 weeks. A longitudinal follow-Up
was performed with the NightOWL LB983; Berthold, weekly. The Bioluminescence of the tumors allowed comparison of the number and size.
Additionally the bone mineral density and bone volume/tissue ratio was
evaluated with the micro-animal CT scan vivaCT40, Sanco Medical. Side
effects were monitored by mice appearance and weight loss.
Results: In comparison to ale, that was toxic to all chic embryos with 100
mM after 24 h, the 5-FdU-Ale was toxic with 500 mM. The MTD was
not reached with 200 mg/kg. The 5-FdU-Ale group showed significant
smaller metastases as well as generally less manifestations in comparison
to the controls. The weight loss was significant lower in the therapy than
in the control group
Further studies are recommended.
19
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ID 413
Clinical utility of the CellSearchTM system to predict
radiologically confirmed failure of systemic therapy
in patients with metastatic breast cancer: A singleinstitution experience
C.M. Kurbacher1, J.A. Kurbacher1, S. Dexel2, U. Schween2,
J. Lepique1, R. Reichelt2
Medizinisches Zentrum Bonn-Friedensplatz, Zentrum für Gynäkologie und
Geburtshilfe, Bonn, Deutschland
2
L.a.n.c.e. mbH, Bonn, Deutschland
1
Background: The occurrence of circulating tumor cells (CTC) in the
peripheral blood of patients (pts) with metastatic breast cancer (MBC)
determined by the CellSearchTM system (CSS) is now widely recognized
as an adverse prognostic factor. We hereby report on our single-institution
experience with the routine use of CSS to monitor pts on systemic treatment (Tx) due to MBC.
Methods: A total of 35 pts with MBC were included in this non-interventional study. Systemic Tx was as follows: chemotherapy (CTx), n = 8;
endocrine Tx (HTx), n = 9; targeted Tx (TTx), n = 1; multimodal combinations of either CTx or HTx and TTx (MTx), n = 17. Baseline investigations including both CTC determination by CCS and the appropriate
radiologic technique were performed immediately prior to start of Tx. A
second CTC count was scheduled 6 weeks later. For all CTC counts, a
value of > 5 CTCs per 7.5 mL venous blood was considered pathological.
The first radiologic tumor reevaluation was performed 12 weeks after Tx
initiation and repeated every 12 weeks in cases that did not show clear
evidence of disease progression (PD).
Results: All pts with radiological PD showed either increasing (n = 12)
or decreasing, but non-normalized CTC values (n = 3) Four of these pts
had moderately increasing CTC counts within the normal range. In pts
lacking radiological evidence of PD, remained normal in 12 cases, normalized in 6 cases and decreased without normalization in another 2 instances. Thus, the positive predictive value (PPV) for the CCS for Tx
failure was 73.3% with a negative predictive value (NPV) of 90%. Hence,
the overall predictive accuracy for radiological Tx failure was 82.9%.
Conclusions: Serial CTC counts are able to predict radiological failure of
systemic therapy for MBC. Further propspective trials in this setting are
thus extremely justified.
ID 421
Eribulin 1,23 mg/m² an d1/8 q3w als Therapieoption beim
fortgeschrittenen metastasierten Mammakarzinom in der
Klinischen Anwendung
D. Benndorf, E. Solomayer, I. Juhasz-Böss
Universitätsklinikum des Saarlandes, Gynäkologie, Homburg, Deutschland
Fragestellung: Beim fortgeschrittenen metastasierten Mammakarzinom
sind nach mehreren Vortherapien die Therapieoptionen zum Teil begrenzt. Seit der Zulassung von Eribulin besteht eine neue Therapieoption.
Die klinischen Erfahrungen mit Eribulin sind noch unzureichend. Daher
werteten wir unser Patientenkollektiv bezüglich Einsatz und Verträglichkeit von Eribulin aus.
Methode: Retrospektive Untersuchung aller Patientinnen an der UFK
Homburg die bis heute Eribulin 1,23 mg/m² an d1/8 q3w in der Therapie des metastasierten Mammakarzinoms erhalten haben.Ausgewertet
wurden der onkologische Verlauf sowie die Eribulin bedingte Verträglichkeit bzw. aufgetretene Nebenwirkungen.
Ergebnisse: Insgesamt n = 14 Patientinnen erhielten im Beobachtungszeitraum Eribulin. Eribulin wurde durchschnittlich im metastasierten Stadium als 3,92 Therapielinie (Range 1–7)sowie in der Gesamttherapie als 6,42 Therapielinie eingesetzt (Range 4–9). Die durchschnittliche
Therapiedauer beträgt zum aktuellen Beobachtungszeitpunkt 4,5 Zyklen
(Range 1–20 Zyklen) bzw. 3,78 Monate (Range 1–20 Monate). 9 Patientinnen erhalten zum Datum der Auswertung immer noch die Medikation.
20
Als Nebenwirkung wurden angegeben: Leukopenie mit Unterbrechung
der Therapie um 1 Woche (1), periphere Polyneuropathie Grad 1 (3×),
Fatigue (2×), Hautausschlag perioral ohne weitere Nebenwirkung (1x)
sowie milde Übelkeit (2×).
Schlussfolgerung: Eribulin ist beim fortgeschrittenen metastasierten
Mammakarzinom eine effektive und gut verträgliche Therapieoption.
Selbst in der fortgeschrittenen Therapielinie kann der Progress über mehrere Monate bis >1,5 Jahr vermieden werden.
ID 425
Macrophage-capping protein (CapG) as a putative
oncogen is overexpressed in invasive breast carcinoma
cells
M. Neumann, R.P. Neves, S. Schulz, H. Neubauer, M. Fleisch,
T. Fehm, D. Niederacher
Universitäts-Frauenklinik Düsseldorf, Molekulargenetisches Labor, Düsseldorf, Deutschland
Objective: The aim of this work was to study the correlation between
CapG expression level and clinico-pathological parameter in breast cancer as well as functional characterization of CapG and analysis of CapGtranscriptome in mamma carcinoma cell lines to understand the pathogenic mechanism of CapG up-regulation.
Material and Methods: CapG expression level in breast cancer tissue
and MaCa-cells were analyzed by qRT-PCR. CapG knockdown was performed using siRNA and stable CapG overexpression was achieved by
retroviral vector based transfection. Invasiveness was analysed using the
BioCoat™Matrigel™ based invasion assay. Subcellular localization and
CapG-protein leve was analyzed by immunoblotting. Microarray expression profiling was performed to identify CapG associated candidate genes
and analyzed by gene ontology tools. Co-immunoprecipitation was performed for identification of CapG interacting proteins.
Results: CapG over-expression was detected in 28% of breast cancer tissues and significantly associates with metastasis-status (M1) and
ER-status (ER-negative) (both p ≤ 0.05). Invasiveness of MaCa-cell lines
correlated with CapG-expression level and CapG knockdown or over-expression decrease or increase invasiveness, respectively. Moreover, CapG
nuclear-localization was observed in high invasive MaCa- cell lines or
after overexpression in CapG transfectants.. Analyzing CapG-transcriptome and co-immunoprecipitation experiments revealed new CapG associated candidate genes / interacting proteins, which might help to understand the role of CapG in the process of metastasis.
Conclusion: The results suggest that CapG plays a role in invasiveness
and dissemination of breast cancer cells.
ID 430
Plakoglobin is a highly significant prognostic factor in
breast cancer
E. Mahnke1, I. Fuchs2, G. Schaller3, I. Adamietz4, H. Bühler5
Waldkrankenhaus, Frauenklinik, Berlin, Deutschland
Zentrum für Pränataldiagnostik und Humangenetik, Berlin, Deutschland
3
Breast Care Institute, München, Deutschland
4
Universitätsklinikum Marienhospital, Klinik für Strahlentherapie und Radio-Onkologie, Herne, Deutschland
5
Universitätsklinikum Marienhospital, Institut für Molekulare Onkologie,
Strahlenbiologie und Experimentelle Strahlentherapie, Herne, Deutschland
1
2
Background: The prognosis for breast cancer patients is mainly affected by spreading of the malignant cells. A crucial step in metastasis is
the dissociation of cancer cells from the epithelial network. The loss of
cellular adhesion proteins in the course of an EMT (epithelial-mesenchymal-transition) is a prerequisite in this context. Well studied is the role
of E-cadherin in prognosis but very little is known about plakoglobin,
although this protein is exclusively part of both adhesion structures, adherens junctions and desmosomes.
Abstracts
Inhalt
Index
Methods: In a retrospective study on 96 breast cancer patients the expression of plakoglobin was determined immunohistochemically and
correlated with the outcome of the patients after a period of 16 years. In
addition, the plakoglobin expression was detected in 7 human breast cancer cell lines and correlated with the invasiveness of the cells.
Results: Plakoglobin was found to be a valid prognostic marker with
p < 0.008 in log-rank tests. In the positive cohort 72% of the patients
were still alive after 16 years in contrast to 43% in the negative group.
Surprisingly the prognosis was most favorable, with only 28% deceased,
if plakoglobin was located in the nucleus of the cells (p < 0.0002). In-vitro experiments revealed a close correlation of high plakoglobin with low
invasiveness of the cells.
Conclusions: Plakoglobin appeared as a highly significant prognostic
factor in breast cancer that probably could spare positive patients a stressful cytostatic therapy. The favorable influence of nuclear localization
might be due to a competitive displacement of beta-catenin, a malignant
transcription factor in the wnt pathway.
ID 442
Overall survival in advanced breast cancer is associated
with the type of 1st line treatment but not with an objective
response to this treatment
A. Regierer1, R. Wolters2, I. Novopashenny2, A. Weigel1,
J. Fischer1, M. Constantinidou1, J. Eucker1, K. Possinger1,
M. Wischnewsky2
Charité, Onkologie, Berlin, Deutschland
2
Universität Bremen, Mathematik u. Informatik, Bremen, Deutschland
1
Introduction: Patient’s expectations to cancer treatment include a high
response rate. However, we have previously shown that the type of response to 1st line therapy in advanced breast cancer is not associated with
overall survival (OS). Here we analyze the type of 1st line treatment and
correlate it with the type of response.
Methods: Our clinical cancer registry includes the data of 934 patients
with metastatic breast cancer. The influence of the type of response of
the 1st line therapy on OS was analyzed. Response was categorized as
objective response (OR, comprising of complete and partial response), no
change (NC) and progressive disease (PD). The types of 1st line treatment
were categorized as endocrine treatment (ET), mono chemotherapy (monoCT), and poly chemotherapy (polyCT).
Results: The type of response differs significantly with the type of 1st
line treatment. ET resulted in only 15% OR and 49% NC, monoCT in
26% OR and 38% NC, and polyCT in 41% OR and 27% NC. However,
this does not translate into a survival benefit, as pat. receiving ET have
a significantly longer OS than pat. receiving chemotherapy (CT) (ET vs.
monoCT HR 1.45, 95% CI (1.06–2.00), p = 0.021; ET vs. polyCT HR
1.67, 95% CI (1.36–2.05), p < 0.001).
Conclusions: Although ET has significantly lower OR-rates it is significantly associated with a longer OS in advanced breast cancer. Therefore,
we underline the fact that the type of response to 1st line treatment is not
relevant for survival.
Cancer Prevention
ID 198
20 years of primary skin cancer prevention in Gremany:
Expieriences and results
M.P. Anders, K. Choudhury, B. Volkmer, R. Greinert,
E.W. Breitbart
idence that skin cancer is sun-induced. To reduce both the burden of skin
cancer and the exposure to ultraviolet radiation (UVR), primary preventive activities are important to generate an impact on people’s health behavior. Since 1989 the Association of Dermatological Prevention (ADP)
therefore developed target group specific interventions. Awareness and
multilevel educational campaigns and interdisciplinary workshops were
conducted nationwide for over 20 years.
Methods: To evaluate the primary preventive activities the ADP conducted seven population-based, cross-sectional surveys. Data collections
were carried out from 1989 to 2011. The main focus of the surveys was
the UVR related behavior like changes in sun protection behaviors and
sunbed use. Further outcomes evaluated intermediate steps in the communication process like knowledge.
Results: The proportion of interviewees who used sunscreen when they
stayed in the sun increased from 34.6% in 1989 to 47.1% in 1993, then
decreased again to 45.5% in 2002. 0.6% used sun protection factor higher
than 19 in 1989, but in 2002 this proportion increased to 34.9%. Sunbed
use in the last 12 month increased from 1989 (12.9% of interviewees) to
28.1% in 2009, but then declined to 10.4% in 2011.
Conclusion: UVR related preventive behavior has improved over the last
two decades and the use of sunscreen has been established in the population. Indoor tanning had increased enormously in the late 1990s and in the
2000s, but since 2011 it declined. Simultaneously knowledge about skin
cancer and skin cancer risk factors has been increased in the population.
ID 276
Breast Cancer in young women after radiation therapy
of Hodgkin disease in childhood and adolescence –
individual therapeutic strategies
K. Rhiem1, N. Herold1, R. Bongartz2, G. Schellong3,
R. Schmutzler1
Zentrum für Familiären Brust- und Eierstockkrebs, Köln, Deutschland
Universitätsklinikum, Klinik und Poliklinik für Strahlentherapie, Köln,
Deutschland
3
Universitätsklinikum, Klinik für Kinderheilkunde – Hämatologie und Onkologie, Münster, Deutschland
1
2
Children with Hodgkin disease (HD) showed an over 90% survival rate
after effective combined treatment with radio- and chemotherapy but
were burdened with a high number of relevant late effects. Secondary
breast cancer is the most frequently diagnosed secondary malignancy in
young women after supradiaphragmal radiation therapy of HD in childhood and adolescence. Longitudinal follow-up data (HD-78-HD90 between 1978 and 1995) analysed by a working group on HD-therapy associated late effects of the Society of Pediatric Oncology and Hematology
(GPOH) identified a 24fold increase of breast cancer in women between
25 and 45 y after HD radiotherapy during puberty compared to age-adjusted women of the general population. The median time of breast cancer
diagnosis was 20.7 years after HD therapy between the ages of 9 and 16
years. Due to these data a structured breast cancer screening program
was established in cooperation with the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC). Two women´s decisions on
therapeutic strategies after their early breast cancer diagnosis within the
screening program illustrate the scope of alternatives: The first patient (39
y, stage pT1b, pN0, HR+, Her2-, G2) underwent BCT and intraoperative
radiotherapy. The second patient (39 y, stage pT1c, pN0, HR+, Her2, G2)
underwent bilateral (semi-)prophylactic mastectomy with primary heterologous reconstruction. The data and cases demonstrate 1. the necessity
to include women after HD radiotherapy during puberty into the structured screening program, 2. the variety of individual therapeutic strategies
based on the support of a multidisciplinary team.
Association of Dermatological Prevention, Hamburg, Deutschland
Background: The burden of skin cancer has been increasing over the last
decades worldwide in the light-skinned population. There is mounting ev-
Abstracts
21
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ID 380
Are men twice as careless regarding oncological risks as
women?
I. Belova
Ernst Moritz Arndt Universität Greifswald, Lehrstuhl für Allgemeine
Betriebswirtschaftslehre und Gesundheitsmanagement, Greifswald,
Deutschland
Cell Cycle, Apoptosis, Angiogenesis
ID 169
The BH3-only protein BimL overrides Bcl-2-mediated
apoptosis resistance in melanoma cells
M. Plötz, B. Gillissen, S.-A. Quast, A. Berger, P.T. Daniel
Introduction: In order to make screening programs successful, they should
appeal to the population. This, it is important to check whether there are
differences beetween men and women regarding health awareness.
Methods: Using skin cancer – which is the most common cancer – this
study aims at finding out which gender in Germany and Russia reacts
more sensitively to signs of the disease.
For the German sample, the participation rates of men and women in the pilot screening project in Schleswig-Holstein from 2003/2004 are compared.
In Russia, detection rates of new cases of non-melanoma skin cancers
(NMSC) are compared in the year 2008 in Moscow in women and men.
They represent the ratio (proportion) of incidence (ASR/World) without
screening checkups compared to the incidence (ASR/World) in medical facilities of the Kremlin, which practise a screening program with
100%-participation rate at ca. 70,000 people. This reflect the health
awareness of Muscovites.
Results: In Schleswig-Holstein, 2.6 times fewer men than women took
part in the screening (10.4 vs. 27.2% (1)).
In Moscow, suspected cases of skin cancer, men visited a physician 1.8
times less than women. (The new NMSC detection rates were 10% and
32% accordingly (2)).
Conclusions: In both countries, men are negligent with regard to their oncological risks. Education campaigns (at least with respect to skin cancer)
should thus be be aimed at the male gender in the first place.
Charité, Berlin, Deutschland
Literature:
1. Katalinic A, et al.: Does skin cancer screening save lives? Cancer 2012; Vol.
118, Issue 21: 5395–5402.
2. Belova I: Comparison of the effectiveness of German and Russian health
care management using the example of skin cancer. PhD thesis, University of
Greifswald.
V. Bucan, A.-L. Gratzke, K. Reimers, P.M. Vogt
ID 453
First experiences with the GS Junior 454 in molecular
genetic analysis of patients with hereditary breast and
ovarian cancer at the Center of Familial Breast and
Ovarian Cancer, Cologne
B. Blümcke, A. Baasner, J. Hauke, B. Wappenschmidt,
E. Hahnen, R. Schmutzler
Uniklinik, Zentrum für familiären Brust- und Eierstockkrebs, Köln, Deutschland
Mutations in BRCA1 and BRCA2 are linked to the development of hereditary breast and ovarian cancer. In 2012, 74,500 women and 600 men got
breast cancer and 7,200 women got ovarian cancer in Germany, while a
hereditary predisposition is suspected in about 10% of these cases. Family history and age of onset are the most important inclusion criteria for
genetic testing. Since August 2012, we have analysed 237 index patients
with hereditary breast and/or ovarian cancer using the GS Junior 454
(Roche) and the BRCA kit (BRCA MasterTM Dx kit, Multiplicom). The
BRCA1/2 genes contain many homopolymer stretches of at least 6 bp
in length. Since these stretches are difficult to detect with the GS Junior
454 platform, we additionally employed a homopolymer assay fragment
analysis (BRCA HP, Multiplicom), which allows rapid detection of small
insertions/deletions in approximately 30 of these coding homopolymer
stretches in BRCA1/2. In this cohort, 36 out of 237 index patients were
tested positive for pathogenic BRCA1/2 mutations. Of those, 10 individuals show disease-causing alterations located in homopolymer stretches
that were easily detected by homopolymer assay pre-screening. Thus, our
results warrant homopolymer pre-screening prior to costly next generation sequencing analyses.
22
Melanoma cells are characterized by apoptosis deficiency coinciding with
reduced expression of the proapoptotic Bcl-2 protein Bim. An adenoviral
vector was constructed with the BimL cDNA controlled by an inducible
promoter. Highly efficient apoptosis induction and abrogated cell proliferation was seen in melanoma cells upon BimL overexpression. Loss of
mitochondrial membrane potential, release of mitochondrial apoptogenic
factors and caspase-9 processing indicated the activation of mitochondrial apoptosis pathways. BimL activated both Bax and Bak, as shown
by siRNA knockdown and activation-specific antibodies. Of note, BimL
overrode the apoptosis blockade by Bcl-2 overexpression or by Bax/
Bak single knockdown. The high efficacy correlated to BimL interaction
with all antiapoptotic Bcl-2 family members in melanoma cells, shown
by co-immunoprecipitation analyses for Bcl-2, Bcl-xL, Mcl-1 and Bcl-w.
Thus, BimL reveals an outstanding proapoptotic potential in melanoma
cells, and strategies for its re-expression appear of interest. These have
been reported for B-Raf inhibitors, and their efficacy may be partly attributed to BimL.
ID 193
Using the antiapoptotic protein LFG for sensitizing breast
cancer cells to chemotherapy
Medizinische Hochschule Hannover, Plastische Hand und Wiederherstellungschirurgie, Hannover, Deutschland
Introduction: Lifeguard (LFG) is an anti-apoptotic protein that inhibits
programmed cell death mediated by Fas in tumour cells. The exact mechanism of action and the molecular function from LFG in the carcinogenesis of human breast cells is not clear. But the expression of LFG mRNA
correlates with LEF-1 transcription factor activity. Here we investigated
impact of LFG suppression on the cell apoptosis.
Methods: RT-PCR and Western blot were used to investigate LFG expression after down regulation by siRNA transfection. To investigate the
activation of caspase-3/7 in the breast cancer cells we using the Apo-One
Homogeneous Caspase-3/7 Assay.
Results: In the present study corroborates the essential role of LFG as
well as its regulatory mechanisms and moreover demonstrates here for
the first time sensitisation of breast cancer cells to chemotherapeutics,
caused by LFG gene suppression. Our results indicate a pivotal role of
LFG in the regulation of apoptosis in MCF-7 breast cancer cells.
Conclusion: In prospective, our results have to be tested in context with
other resistant types of cancer plus different chemotherapeutics and finally proved in preclinical in vivo experiments.
ID 287
Dimethylfumarate impairs lymphangiogenesis by cell
cycle arrest
E. Valesky, I. Hrgovic, M. Doll, R. Kaufmann, M. Meissner
Universitätsklinik Frankfurt, Klinik für Dermatologie, Venerologie und Allergologie, Frankfurt, Deutschland
Recent evidence suggests, that Dimethylfumarate (DMF), known as a
highly potent anti-psoriatic agent, might have anti-tumorigenic properties. In addition, it could be recently demonstrated that DMF has anti-angiogenic properties by suppression of VEGFR-2. We hypothesized
that DMF might also have anti-lymphangiogenic qualities. To prove this
Abstracts
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assumption, we first performed cytotoxicity assays with primary human
lymphendothelial cells (LEC). No relevant LDH release could be demonstrated. In further analysis we could show, that DMF suppresses LEC
proliferation in a concentration- and time-dependent manner. In functional analysis we could demonstrate a reduced migration rate as well as an
inhibition of the formation of capillary like structures. To further elucidate wether this anti-lymphangiogenic action is conveyed by an apoptotic
mechanism we studied the amount of apoptotic nucleosomes and the activity of caspase 3/7. There was no significant apoptosis induced by DMF.
Therefore, we performed cell cycle analysis demonstrating a pronounced
G1 cell cycle arrest. The further evaluation of important cell cycle regulator proteins revealed an increase in p21 and p27 and a suppression
of cyclin D1 and A protein expression. Interestingly, the superordinated
regulator of p21, the tumor suppressor gene product p53, was induced and
phosphorylated by DMF treatment. To further analyse the regulation of
p21 we examined it´s mRNA expression. Here we could demonstrate an
increase of p21 mRNA expression. This transcriptional way of regulation
was enforced by a posttransscriptional and posttranslational mechanism.
In conclusion, our results provide for the first time evidence, that DMF
has distinct anti-lymphangiogenic effects.
ID 349
Die Effekte des AT1-Blockers Telmisartan in humanen
Kolonkarzinomzellen
L.D. Lee, J. Gröne, H. Seeliger, M.E. Kreis
Charité – Universitätsmedizin Berlin, Campus Benjamin Franklin, Chirurgische Klinik I, Berlin, Deutschland
Fragestellung: Telmisartan ist ein AT1-Blocker mit partiellem PPARgamma Agonismus. PPARgamma Aktivierung in Kolonkarzinomzellen
inhibiert Zellproliferation und induziert Apoptose. Unsere Studie untersuchte somit mögliche antiproliferative und apoptotische Effekte von
Telmisartan in humanen Kolonkarzinomzellen via partieller PPARgamma-Aktivierung.
Methoden: Zelllinien HT-29, SW-480, SW-620. Positivkontrolle Pioglitazon, Telmisartan, Negativkontrolle Vehikel DMSO, PPARgamma
Blocker GW9662. Konzentrationen 0,2-5,0µM. Inkubationszeit 24 h.
Bestimmung Zellviabilität mittels MTT-Assay und des antiproliferativen Effekts mittels Neubauer Zählkammer. Die mRNA-Regulation von
PPARgamma und Cystatin A mittels qRT-PCR. Apopostoseinduktion
mittels Caspase-3/7-Assay. Statistische Analyse SPSS Version 19 IBM,
p < 0,05.
Ergebnisse: Der antiproliferative Effekt von Telmisartan war signifikant
(p < 0,05) in therapeutischen Serumkonzentrationen. GW9662 blockiert den Effekt von Pioglitazon, aber nicht von Telmisartan. In SW-480
und SW-620 ist die Reduktion der Zellviabilität durch Telmisartan und
GW9662 signifikant größer. Der apoptotische Effekt gleicht Pioglitazone.
GW9662 zeigt hier keinen Effekt. PPARgamma mRNA wird erwartungsgemäß durch Telmisartan signifikant herunterreguliert (negative Feedback) und Cystatin A hochreguliert.
Schlussfolgerung: Telmisartan zeigt eindeutig signifikante Effekte in Inhibition der Zellproliferation, Reduktion der Zellviabilität und Induktion
der Apoptose in HT-29, SW-480 und SW-620. Die Effekte sind annähernd
des PPARgamma Vollagonisten Pioglitazon und teilweise stärker, insbesondere in Anwesenheit vom PPARgamma Blocker GW9662. Die Effekte lassen sich somit nicht allein durch den bekannten partiellen PPARgamma Agonismus von Telmisartan erklären.
Abstracts
ID 379
Novel apoptosis inducers overcome IAP-mediated
resistance of the renal cell carcinoma cell line ClearCa-2
J. Stevens1, E. Carosati2, G.M. Randazzo2, R. Mannhold1,
L.D. Horsch1, A. Schneider1, S. Heikaus1, G. Cruciani2,
H.E. Gabbert1, C. Mahotka1
Universitätsklinikum Düsseldorf, Institut für Pathologie, Düsseldorf,
Deutschland
2
University of Perugia, Chemometrics and Cheminformatics, Perugia,
Italien
1
Objectives: Deregulation of apoptosis plays an important role in carcinogenesis, tumor progression, and resistance to chemotherapy. IAPs (inhibitor of apoptosis proteins) as main regulators of apoptosis are potent
caspase inhibitors, which are regulated by smac. To explore their relevance for the induction of apoptosis in the drug- and TRAIL-resistant
renal cell carcinoma (RCC) cell line clearCa-2 (clear cell type), we analysed 31 novel hit candidates selected by virtual screening.
Methods: ligand-based virtual screening, RNAi-method, nucleofection,
DNA-cloning, Western blotting, proliferation assays, flow cytometry.
Results: 1. Endogenous XIAP-expression is different in the TRAIL-sensitive clearCa-6 (low XIAP levels) and TRAIL-resistant clearCa-2 (high
XIAP levels) cell line. 2. The XIAP expression level correlates with the
sensitivity to TRAIL, whereas a high level of XIAP induces resistance in
clearCa-2. 3. Knocking down the endogenous XIAP-expression by RNAi,
the resistant cell line clearCa-2 can be sensitised by TRAIL treatment. 4.
In contrast, first XIAP overexpression experiments in a TRAIL-sensitive
cell line clearCa-6 show that XIAP might also be responsible for TRAIL
resistance. 5. Test compounds LBPS-1, -3, and -5 induce apoptosis by
(re-)activation of caspases in the resistant cell line ClearCa-2.
Conclusions: The obtained results indicate that IAPs – especially XIAP –
are essential regulators of apoptosis in renal cell carcinoma and contribute
to the resistance to TRAIL-induced cell death. The novel chemotypes,
discovered by virtual screening, are able to induce cell death in highly
resistant RCC cell line ClearCa-2. These findings may contribute to new
therapy options for RCCs.
Cell-Based Therapy
ID 086
Tumor-derived adenosine enhances generation and
suppressive functions of human adaptive regulatory T
cells
M. Mandapathil, E.K. Jackson, S. Lang, J.A. Werner, T. Whiteside
Philipps-Universität Marburg, Klinik für Hals-Nasen-Ohrenheilkunde,
Marburg, Deutschland
Objectives: Adaptive regulatory T cells (Tr1) are induced in the periphery upon by environmental stimuli. In cancer patients, their frequency in
the peripheral blood and local tumor tissue is increased. Expression of
the ectonucleotidase CD73 and adenosine production by the tumor may
influence Tr1 generation and their immunosuppressive activity.
Methods: Tr1 were generated in a previously established co-culture in
vitro system of sorted peripheral blood CD4+CD25neg T cells with autologous immature dendritic cells (iDC) and irradiated adenosine-producing
CD73+ MDA-MB231 or non-producing CD73neg MCF-7 breast cancer
cell lines (TU). Expression of ectonucleotidases and other surface markers on Tr1 was determined by multicolor flow cytometry. Tr1-mediated
suppression of proliferation was evaluated in CFSE-based assays. Luciferase-based ATP-detection assays and mass spectrometry were used
to measure ATP hydrolysis and adenosine levels, respectively. Cytokine
levels were measured by ELISA or Luminex. CD73 expression on tumor
cells or T cells in TU tissues was assessed by immunofluorescence.
23
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Results: CD73+ TU induced higher numbers of Tr1 cells than CD73neg
TU (p < 0.01). Tr1TUCD73+ hydrolyzed more exogenous ATP, produced
more adenosine and mediated higher suppression than Tr1TUCD73neg (all at
p < 0.05). ARL67156, an ectonucleotidase inhibitor, and ZM241385, A2A
receptor antagonist, reduced suppression of responder cell proliferation
mediated by Tr1TUCD73+ cells (p < 0.01). Basal-like breast cancer (BrCa)
cells expressing higher levels of ectonucleotidases induced more Tr1 than
less aggressive luminal-like BrCa.
Conclusion: Tumors producing adenosine (CD73+TU) create a microenvironment favoring the induction of Tr1 which express CD39 and CD73,
mediate enzymatic ATP breakdown to adenosine and are thus in part responsible for suppression of anti-tumor immunity.
Central Nervous System Tumors
ID 024
mTOR-inihibition and interruption of PI3K/Akt signaling
leads to proliferation inhibition and induces apoptosis
with defective autophagy in human meningioma cells
J. Walter, A.S. Krombholz, S. Grube, D. Freitag, C. Ewald,
R. Kalff
Universitätsklinikum Jena, Klinik für Neurochirurgie, Jena, Deutschland
Objective: The PI3K/Akt pathway and its effector mTOR play an important role in regulation of cell growth and have recently been evaluated
as a target for the treatment of gliomas. But to date little is known about
mTOR in more benign intracranial tumor like meningiomas. This study
aims to elucidate the role of the pro-survival PI3K/Akt/mTOR pathway in
the proliferation of human meningiomas, and to assess the use of mTOR
inhibitors as therapeutic agents.
Methods: MTT and BrdU assays of primary human meningioma cell
cultures and permanent meningioma cell lines were used to investigate
the viability and proliferation inhibitory effects of the mTOR inhibitors
Everolimus and Temsirolimus. Apoptosis analysis proceeded by detecting cleavage of caspase-3 and PARP, whereas autophagy was analyzed
by detection of cleaved LC3B-II. The levels of proteins were probed
by Western blotting. Furthermore, nuclear fragmentation analysis after
mTOR-inhibition was conducted by immunofluorescence.
Results: Inhibition of mTOR by Everolimus and Temsirolimus led to a
significant reduction of viability as well as inhibition of proliferation of
human meningioma cells in a time and concentration dependent manner.
There was no relevant difference of efficacy of mTOR inhibition concerning primary cell cultures and permanent cell lines. mTOR inhibition in
meningioma cells induced apoptosis in a caspase-PARP-dependent manner. Apoptosis was accompanied by defective autophagy, proven by the
detection of cleaved LC3B-II.
Conclusions: The ability of Everolimus and Temsirolimus to abrogate
phos-mTOR activation and by this to interrupt PI3K/Akt signalling in
human meningiomas, leading to proliferation inhibition and induction of
apoptosis, warrants mTOR to be investigated as a potent target in anti-meningioma therapy.
ID 025
Multi tyrosin kinase inhibition in the treatment of human
gliomas
J. Walter, D. Freitag, S. Grube, C. Ewald, R. Kalff
Universitätsklinikum Jena, Klinik für Neurochirurgie, Jena, Deutschland
Objective: Axitinib, a multi receptor tyrosine kinase (RTK) receptor
inhibitor, specifically targets VEGFRs, PDGFRs and c-Kit. It`s the aim
to investigate the effects of axitinib on glioma cell growth in a ex vivo
organotypic brain slice cultures of gliomas, primary glioma cell cultures
and glioma cell lines.
24
Methods: Organotypic brain slice cultures of gliomas, treated with Axitinib, allowed quantification of invasion, proliferation and angiogenesis
by staining the treated samples for CD31, GFAP, EMA, Iba1, Ki67, and
cleaved Caspase 3 as well as PAS and HE. MTT / BrdU assays of primary glioma cultures and permanent cell lines were used to investigate
viability and proliferation inhibitory effects of axitinib. Apoptosis analysis proceeded by detecting cleaved caspase-3 and PARP. Autophagy was
analyzed by detection of cleaved LC3B-II. Protein levels were probed by
Western blotting.
Results: Multi RTK inhibition by axitinib led to a decrease in number of
proliferative cells and an increase of apoptotic cells as well as necrotic areas in organotypic glioma slice cultures. In primary cell cultures axitinib
led to a significant reduction of viability and inhibition of proliferation.
There was no difference of efficacy of RTK inhibition concerning primary cell cultures and cell lines. RTK kinase inhibition induced apoptosis in
a caspase-dependent manner in gliomas. Apoptosis was accompanied by
defective autophagy, demonstrated by the detection of cleaved LC3B-II.
Conclusions: Axitinib effectively inhibits tumor progression in an organotypic ex vivo model of human gliomas. Furthermore multi tyrosin
kinase inhibition by axitinib leads to proliferation and viability inhibition
in gliomas, as well as to an induction of apoptosis in those tumors. These
results suggest that axitinib could constitute a therapeutic alternative for
the treatment of human gliomas.
ID 098
The treatment of newly diagnosed glioblastoma with
cilengitide does not alter patterns of progression
G. Eisele1, A. Wick2, A.-C. Eisele1, P. Clement3, J. Tonn4,
G. Tabatabai5, A. Ochsenbein6, U. Schlegel7, B. Neyns8, D. Krex9,
M. Simon10, G. Nikkhah11,12, M. Picard13, R. Stupp14, W. Wick15,
M. Weller1
University Hospital Zurich, Department of Neurology, Zurich, Schweiz
University Hospital Heidelberg, Department of Neurooncology, Heidelberg, Deutschland
3
KU Leuven, Department of Oncology, Leuven, Belgien
4
LMU Munich, Department of Neurosurgery, Munich, Deutschland
5
University Hospital Tubingen, Department of General Neurology, Tubingen, Deutschland
6
University Hospital Bern, Department of Oncology, Bern, Schweiz
7
University Hospital Bochum, Department of Neurology, Bochum, Deutschland
8
UZ Brussels, Department of Medical Oncology, Brussels, Belgien
9
TU Dresden, Department of Neurosurgery, Dresden, Deutschland
10
University Hospital Bonn, Department of Neurosurgery, Bonn, Deutschland
11
University Hospital Freiburg, Department of Neurosurgery, Freiburg,
Deutschland
12
University Hospital Erlangen, Stereotactic and Functional Neurosurgery,
Erlangen, Deutschland
13
Merck Serono, Darmstadt, Deutschland
14
University of Lausanne, Multidisciplinary Oncology Department, Lausanne, Schweiz
15
German Cancer Research Center, Clinical Cooperation Unit Neurooncology, Heidelberg, Deutschland
1
2
Most current efforts to improve the outcome in newly diagnosed glioblastoma focus on the addition of anti-angiogenic agents to the standard of
care of concomitant chemoradiotherapy with temozolomide. Preclinical
data as well as anecdotal clinical observations indicate that anti-angiogenic treatment may result in altered patterns of tumor progression. We
have previously developed an analysis tool using MRIcro software to explore whether comparable groups of patients differ in their patterns of
progression. The integrin antagonist cilengitide has been explored in a
phase 2 trial as an adjunct to standard of care in newly diagnosed glioblastoma. We analyzed patterns of progression on MRI in 21 patients enrolled
in this trial. Thirty patients from the experimental treatment arm of the
EORTC/NCIC 26981 trial served as a reference. Analysis of recurrence
pattern revealed neither a difference in the size of the recurrent tumor nor
in the distance of the recurrences from the preoperative tumor location
Abstracts
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between groups. Overall frequencies of distant recurrences were 20%
in the reference group and 19% (4/21 patients) in the cilengitide group.
Compared with standard chemoradiotherapy alone, the addition of cilengitide did not alter patterns of progression. This analysis does not support concerns that cilengitide may induce a more aggressive phenotype
at progression, however it also provides no evidence for an anti-invasive
activity of cilengitide.
and ADAM17 specific inhibitors. Soluble ULBP2 levels in GSC culture
supernatants were reduced upon blockade of ADAM10 and ADAM17,
underscoring the view that these proteases cleave ULBP2 from the surface of GSC. Subsequently, the impairment of ADAM10 and ADAM17
led to enhanced immune recognition of GSC by natural killer cells and
enhanced secretion of interferon-γ by these immune effector cells. Therefore, ADAM10 and ADAM17 constitute suitable targets to boost an immune response against GSC.
ID 184
Allele-specific real-time RT-PCR for the detection of
IDH1 mutations in gliomas: Mutant and wildtype IDH1
are upregulated in human gliomas whereas systemic
treatment and tumor relapse do not change IDH1 gene
expression
L. Dreher, M. Perrech, G. Röhn, R. Goldbrunner, M. Timmer
IDH1 mutations (IDH1mut) occur in more than 70% of WHO grade II
and III gliomas and secondary glioblastomas (GBM). The most frequent
mutation leads to a specific amino acid change at codon 132. The diagnostic of this mutation is so far based on DNA sequencing and immunohistochemistry (IHC), methods limited in terms of sensitivity and ease
of use. Recently, measuring the IDH1mut level by real time PCR was
introduced as alternative method.
A total of 71 tumor samples were obtained intraoperatively from glioma
patients. The samples were divided into 7 subgroups (control brain tissue, diffuse glioma, anaplastic glioma, secondary glioblastoma +/– chemotherapy (CTx), primary glioblastoma +/– CTx). Tumor samples were
snap frozen and processed for sectioning, RNA and protein isolation. The
quantitative expression of IDH1 mRNA was assessed using real-time
PCR with specific primers for IDH1mut and -wt; protein expression was
verified by Western Blot analysis and IHC.
Allele-specific quantitative PCR does work in larger patient cohorts and
seems to be an easy and ~10 times more sensitive method for IDH1mut
evaluation compared to the ones used so far. Most astrocytomas and sec.
GBM bear the mutation (con. 0.13 to 0.2) whereas most prim. GBM do
not. The difference between control tissue, prim. GBM and astrocytomas/
sec. GBM was highly significant (p = 0.003). Radio- and/or CTx do also
not alter the IDH1mut expression.
This assay is able to analyze 100 samples simultaneously in ~1 hour. Recurrent disease and radio-CTx do not alter the general IDH1 status. In
summary, this method is highly sensitive, cost-effective and timesaving
and may therefore play an important role in IDH1mut analysis in the future.
ID 213
ADAM10 and ADAM17 contribute to the immune evasive
phenotype of glioblastoma stem cells
F. Wolpert , I. Tritschler , A. Steinle , M. Weller , G. Eisele
1
2
1
INTRAGO – Intraoperative Radiotherapy for Glioblastoma
– a phase I/II study
F.A. Giordano1, S. Brehmer2, F. Schneider1, S. Clausen1,
G. Welzel1, M. Seitz-Rosenhagen2, P. Schmiedek2,
Y. Abo-Madyan1,3, F. Wenz1
Universitätsmedizin Mannheim, Medizinische Fakultät Mannheim der
Universität Heidelberg, Klinik für Strahlentherapie und Radioonkologie,
2
Universitätsmedizin Mannheim, Medizinische Fakultät Mannheim der
Universität Heidelberg, Neurochirurgische Klinik, Mannheim, Deutschland
3
Department of Clinical Oncology and Nuclear Medicine (NEMROCK),
Cairo University, Kairo, Ägypten
1
Uniklinik Köln, Allgemeine Neurochirurgie, Köln, Deutschland
1
ID 248
1
Universitätsspital Zürich, Klinik für Neurologie, Zürich, Schweiz
Goethe-Universität Frankfurt am Main, Institut für Molekulare Medizin,
Frankfurt am Main, Deutschland
1
Glioblastoma multiforme (GBM), the most common primary malignant
brain tumor, is still associated with a poor prognosis. Despite surgical
resection and radiochemotherapy, most tumors recur locally and even a
broad variety of salvage therapies (including re-resection, re-irradiation
or molecular therapies) can rarely prevent subsequent clinical deterioration with lethal complications.
One possible underlying cause of the high rate of local recurrences may
be that even after fluorescence- and neuronavigation-guided tumor resection, microscopically persistent tumor cells can rapidly re-colonize until
radiochemotherapy is initiated. We therefore hypothesize that intraoperative radiotherapy (IORT) may arrest or eradicate persistent tumor cells
and thereby bridge the therapeutical gap between surgery and radiochemotherapy.
A novel approach to achieve high degrees of target volume coverage even
in complexly shaped tumor cavities might be the use of spherically irradiating sources, such as provided with applicators of the Intrabeam-system
(Carl Zeiss Meditec, Oberkochen). We therefore designed a phase I/II
dose escalation study termed ‘INTRAGO – INTraoperative RAdiotherapy for GliOblastoma’, which is presented here. Within the study, we will
apply spherical IORT after gross tumor resection of primary supratentorial GBMs in patients ≥ 50 years of age with a Karnofsky index of at least
50%. Primary end points are feasibility and definition of the maximum
tolerated dose which shall be evaluated in a classical 3+3 design. Secondary end points are efficiency and impact on survival and on quality of life.
ID 320
microRNAs in acquired chemoresistance of malignant
gliomas
2
C. Happold1, N. Stojceva1, G. Schechtmann2, G. Reifenberger2,
M. Weller1
The treatment of glioblastoma remains a challenge in neuro-oncology.
In recent years, glioblastoma stem cells (GSC) have been identified as
a putative target for immunotherapy of glioblastoma. However, an immune inhibitory phenotype of GSC might counteract immunotherapeutic
approaches.
The family of a disintegrin and metalloproteinases (ADAM) are involved
in the maintenance of themalignant phenotype of glioblastomas. Here, we
investigated a possible role of ADAM proteases in the immune evasion of
GSC. ADAM10 and ADAM17 were expressed in a panel of GSC lines.
The cell surface expression of UL-16 binding protein (ULBP) 2, a ligand
for the activating immunoreceptor NKG2D, was enhanced upon blocking ADAM10 and ADAM17 using small interfering RNA or ADAM10
1
Abstracts
UniversitätsSpital Zürich,Klinik für Neurologie, Labor für Molekulare Neuro-Onkologie, Zürich, Schweiz
2
Heinrich-Heine-Universität Düsseldorf, Institut für Neuropathologie, Düsseldorf, Deutschland
Glioblastomas are the most malignant primary brain tumors. Despite
multimodal therapy including surgery, irradiation and chemotherapy, the
median survival of remains in the range of 12 months on a population
level. Even patients with tumors with a methylated O6-methylguanine
DNA methyltransferase (MGMT) promotor, which derive most benefit
from standard chemoradiotherapy using temozolomide (TMZ/RT→TMZ), are prone to progress as a result of acquired resistance. Here, we
investigate whether selected microRNAs (miRNAs), short, noncoding,
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single-stranded RNA molecules involved in the post-transcriptional regulation of gene expression, play a role in the development of acquired
resistance in human glioma cell lines. We have generated glioma cell lines
with acquired TMZ resistance by repetitive TMZ exposure and verified
the stable resistance phenotype by clonogenic growth assays. Next, we
performed miRNA expression chip arrays on both parental and resistant
cell lines and identified several deregulated miRNAs in a comparative
analysis. We validated the selected miRNA by PCR and explored their
impact on the development of resistance pattern in functional assays. We
demonstrate that miRNA can sustain resistance phenotypes in parental
cell lines, therefore representing new investigative targets for future experimental approaches to overcome acquired resistance.
ID 324
CD317 Immunotoxin Therapy for Glioblastoma
D. Gramatzki1,2, M. Peipp3, K. Frei4, M. Staudinger3,
M. Gramatzki3, M. Weller1,2
University Hospital Zurich, Laboratory for Molecular Neuro-Oncology,
Department of Neurology, Zurich, Schweiz
2
University of Zurich, Neuroscience Center Zurich, Zurich, Schweiz
3
Christian-Albrechts-University of Kiel, Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine, Kiel, Deutschland
4
University Hospital Zurich, Department of Neurosurgery, Zurich, Schweiz
1
Targeted immunotoxins are recombinant molecules, consisting of a specific antibody fragment coupled to a protein toxin. In the present proposal, we aim at targeting the cell surface antigen CD317, also known as
HM1.24 protein. This antigen is preferentially found on mature cells of
B-lineage such as multiple myeloma cells, but was recently found to be
overexpressed on some solid cancer types too.
Analysis of the glioblastoma database of the Cancer Genome Atlas network demonstrates, that CD317 mRNA levels are up-regulated in human
glioblastoma in vivo. Interestingly, enhanced CD317 expression significantly correlates with a reduced probability of survival in this patient
group. CD317 protein expression levels, analyzed by immunohistochemistry analysis on a tissue micro array demonstrate, that this protein
is up-regulated in human glioblastoma. Moreover, CD317 protein level
correlates directly with the malignant phenotype of gliomas. CD317 is
expressed heterogeneously in human glioma- initiating and human longterm glioma cell lines on mRNA and protein levels in vitro. The immunotoxin HM1.24-ETA’ is a fusion protein of a humanized, CD317 specific
single-chain Fv fragment combined with a truncated version of Pseudomonas exotoxin A. This immunoconjugate induces acute cytotoxicity in
CD317-positive glioblastoma cells in a concentration-dependent manner.
Target cell cytotoxicity in the human glioma cells in vitro occurred via
caspase 3 activity, underlining apoptosis as the mode of cell death induced
by HM1.24-ETA’. Interestingly, interferon-β induces CD317 mRNA and
protein levels on the cell surface of glioblastoma cells and therefore enhances the cytotoxic effect of HM1.24-ETA’ in vitro.
These results underline, that HM1.24-ETA’ may have the potential to provide a novel approach of immunotherapy for glioblastoma patients.
ID 351
Sphingosine kinase isoforms and receptors S1PR1,
2, 3 and 5 and their inhibitor Fingolimod in human
glioblastomas
K. Malgorzata1, M. Ocker2, D. Neureiter3, K. Quint2, H. Strik4
Universität Gießen, Neurochirurgie, Gießen, Deutschland
Universität Marburg, Chirurgische Forschung, Marburg, Deutschland
3
Universität Salzburg, Pathologie, Salzburg, Österreich
4
Universität Marburg, Neurologie, Marburg, Deutschland
1
2
Here, the expression of SphKs and their receptors was investigated in
human glioblastoma samples and the effect of Fingolimod, a pharmacological SphK1 inhibitor, on human glioma cell lines was tested.
Methods: Samples from 59 primary (n = 35), recurrent (n = 18) and secondary (n = 6) glioblastomas were analyzed using quantitative real-time
PCR and immunohistochemistry for SphK1 and 2 and S1PR1, 2, 3 and 5.
Expression was correlated with patient survival. The effect of Fingolimod
on A172, G28 and U118 glioma cell growth was tested with the xCELLigence system (Roche Molecular Diagnostics), measuring impedance as a
surrogate marker for proliferation and toxicity. Effects on cell cycle and
death were tested with flow cytometry.
Results: as compared to normal brain, SphK2, S1PR1 and 5 were significantly upregulated in glioma tissue. In recurrent glioblastomas, S1PR2, 3,
and 5 were significantly lower than in untreated primary tumors. Expression in secondary gliomas was not significantly different from controls.
Impedance was reduced in a dose-dependent manner at concentrations
> 5 µM in G28 and A172 and > 10 µM in U87, respectively. Flow cytometry showed that 10 µM Fingolimod induced a significant increase in
sub-diploid events in U87 (78.9 ± 6.0%), G28 (36.4 ± 6.1%) and A172
cells (20.3 ± 1.7%).
Conclusion: Sphingosine kinases and their receptors are highly expressed
in human gliomas. SPK inhibition with Fingolimod exerts a strong influence on the glioma cell cycle and inhibits efficiently glioma cell growth.
This indicates that SphKs and their receptors are promising targets to treat
malignant gliomas.
ID 406
miRNA fingerprints in the blood as prognostic biomarkers
in PCNSL patients
P. Roth1, A. Keller2, J. Hoheisel3, P. Codo1, A. Bauer3, C. Backes2,
P. Leidinger2, E. Meese2, E. Thiel4, A. Korfel4, M. Weller1
UniversitätsSpital Zürich, Klinik für Neurologie, Zürich, Schweiz
Universität des Saarlands, Homburg, Deutschland
3
DKFZ, Heidelberg, Deutschland
4
Charite, Berlin, Deutschland
1
2
Primary CNS lymphoma (PCNSL) is an uncommon variant of extranodal non-Hodgkin lymphoma. Higher age and low Karnofsky Performance
Status (KPS) are associated with reduced overall survival (OS). microRNA (miRNA) are small RNA molecules involved in the posttranscriptional gene regulation. They may also be useful as blood-derived biomarkers
in various tumor entities. Here, we aimed at characterizing miRNA expression profiles in the blood of PCNSL short- (STS) and long-term survivors (LTS) to determine their potential as novel prognostic markers. All
blood samples were obtained at the time of enrolment in the G-PCNSLSG1 trial, a large randomized phase III study which assessed the role of
consolidating whole brain radiation therapy (WBRT) in PCNSL patients.
We examined 2 cohorts of 20 patients with STS patients having a median
OS of 3 months compared to 55 months for the LTS group. Both cohorts
were balanced for median age and KPS: 64 years and 70% for STS compared to 62 years and 70% for LTS. miRNA was extracted from blood
samples and analyzed using Next Generation Sequencing. The biostatistical analysis revealed a differential regulation of several miRNAs in the 2
cohorts. An in silico enrichment analysis demonstrated that 9 deregulated
miRNAs are known to be onco-miRNAs representing a significant enrichment for these markers (p < 0.001). Real-time PCR was used to confirm the differential regulation of the most promising candidate miRNAs
as well as novel short RNA molecules with putative miRNA function not
known before. Based on these results, blood-derived miRNA patterns
warrant further exploration as prognostic biomarkers in PCNSL patients.
Objective: Sphingosine-1-phosphate (S1P), the corresponding kinases
SphK1 and 2 and receptors S1PR1, 2, 3, and 5 are involved in cell survival, growth, migration and angiogenesis. Previous studies demonstrated
that the expression of SphK1 influenced survival of glioblastoma patients.
26
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ID 433
Validation of reference genes for quantitative real-time
polymerase chain reaction in surgical specimens of
human meningiomas
F. Rapp1, S. Grube, D. Freitag, R. Kalff, J. Walter
Universitätsklinikum Jena, AG Neuroonkologie, Jena, Deutschland
In meningiomas quantitative real-time reverse transcriptase polymerase
chain reaction can be used as a sensitive technique for accurate quantitative analysis of specific gene expression levels. To compare mRNA
transcripts across different tumor samples, various appropriate reference
genes are required to be selected for internal standardisation. So far, such
a validation of candidate reference genes of surgical specimens of meningiomas varying in WHO grades has not yet been reported.
At first, total RNA was extracted from eight surgical specimens of different human meningiomas of all three WHO grades, before beeing transcripted into cDNA for providing the starting material for the following
qPCR. Eight candidate reference genes (B2M, GAPDH, HPRT, HMBS,
YWHAZ, UBC, TBP, SDHA) have been chosen for beeing qantitatively
measured by running every single one of them with each of the eight
cDNA samples. Afterwards, using BestKeeper software, the different
expression levels of these reference genes were analyzed and ranked according to the criteria of standard deviation, correlation coefficient, p-Value and the Power of HKG (regression analysis of housekeeping genes
versus BestKeeper).
The final results identify GAPDH, HPRT and YWHAZ as the three genes
showing the highest expression stability wherefore they are the optimal
ones for normalisation of target genes in a larger panel of meningioma
specimens.
ID 440
Validation of Reference Genes for qPCR in Human
Glioblastoma Tissue
T. Goettig1,2, A. Vestergaard1,2
1
2
Friedrich-Schiller-Universität Jena, Neurochirurgie, Jena, Deutschland
Universität, Neurochirurgie, Jena, Deutschland
Objective: Our study targets specific tumor signaling pathways in human
glioblastoma, which might be of importance for cell proliferation and inducing apoptosis.
For the quantitative analysis of the gene expressions by qPCR, we evaluated the best matching reference genes (housekeeping genes) among
B2M, GAPDH, HMBS, HPRT, SDHA, TBP, UBC and YWHAZ.
Methods: To identify suitable reference genes in human glioblastoma
tissue in quantitative RT-PCR we isolated the required RNA surgically obtained cryoconserved human glioblastoma tissue specimina. We
chose samples with a RNA-concentration >100 ng/µl to synthesize the
cDNA through Reverse-Transcriptase-PCR to optimize the amount of
cDNA-product.
The eight formally mentioned reference genes were then each tested on
13 various randomly chosen patient cDNA samples.
Results: While especially the B2M melting analysis showed unspecific products and was therefore excluded of the BestKeeper analysis,
YWHAZ, HMBS and HPRT stood out with the best coefficient of correlation (p = 0,001), standard deviation and power of HKG, implying the
highest stability.
Conclusions: We found YWHAZ, HMBS and HPRT as the most stable
reference genes. As a result they are used for the expression analysis of
specific target genes for cell proliferation on a larger population of glioblastoma samples.
Abstracts
Clinical Trial Design
ID 003
Randomized controlled study for the prevention of
peritoneal carcinosis in gastric carcinoma
D. Zieker, S. Müller, I. Königsrainer, S. Beckert, A. Königsrainer,
J. Glatzle
Uni Tübingen, Allgemeine Chirurgie, Tübingen, Deutschland
Gastric carcinoma is one of the world’s most prevalent tumors. In more
than 30% of these tumors the disease spreads to the peritoneum. This is
known as peritoneal carcinomatosis (PC) and is associated with a five-year
survival rate of less than 2%. The current therapy regime for gastric carcinomas includes a diagnostic laparoscopy with peritoneal wash cytology
before commencement of neoadjuvant treatment in order to exclude PC.
Patients with PC are deemed incurable and given palliative chemotherapy.
Patients with no PC are considered treatable and undergo neoadjuvant chemotherapy according to medical guidelines with subsequent gastrectomy.
Problematic is the finding of a small number of tumor cells in the peritoneal
wash. Patients in whom laparoscopically performed wash cytology shows
free tumor cells in the peritoneal cavity have a 40% greater increased risk
developing PC within one year as compared with patients without tumor
cells in the peritoneal wash cytology. Such high-risk patients should in addition to a gastrectomy additionally undergo intraperitoneal chemotherapy
(HIPEC) in order to remove as far as possible all free tumor cells and micrometastases and thus reduce the risk of relapse and peritoneal carcinosis.
The study is an open-label, monocenter randomized phase II trial. The primary endpoint of this study is the peritoneal carcinosis free 5 year survival.
Secondary endpoints are the overall survival, disease-free survival, and incidence of adverse events. The sample size was 20 for each group, determined with a significance level of 0.05, power of 0.80, and a drop out rate
of a 10% for a risk reduction of developing peritoneal carcinosis by 50%.
The aims of this study are, firstly, to reduce the risk of developing PC
by performing a gastrectomy with HIPEC and, secondly, to improve relapse-free survival and overall survival. The study is already approved by
the German Federal Institute for Drugs and Medical Devices as well as by
the Ethics Committee of the University of Tübingen. The study was also
already initiated by monitoring (EudraCT-Nr.: 2011-004405-25 / Studycode: HIPEC_Stomach, ClinicalTrials.gov Identifier: NCT01683864).
ID 034
Individualised communication skills training for
randomised clinical trials in oncology. Final results of a
RCT
A. Wünsch1, M. deFigueiredo2, T. Gölz3, G. Ihorst4, H. Bertz5,
K. Fritzsche2
Klinikum rechts der Isar, Psychosomatische Medizin und Psychotherapie,
Sektion Psychosoziale Onkologie, München, Deutschland
2
Universitätsklinikum Freiburg, Psychosomatische Medizin und Psychotherapie, Freiburg, Deutschland
3
Universitätsklinikum Freiburg, Zentrum für Kinder- und Jugendmedizin,
Freiburg, Deutschland
4
Universitätsklinikum Freiburg, Studienzentrum, Freiburg, Deutschland
5
Universitätsklinikum Freiburg, Innere Medizin I, Freiburg, Deutschland
1
Background: One of the hardest communication tasks for physicians is
to disclose information about randomized clinical trials (RCT). Physicians have to address complex information, consider ethical and legal aspects, so patients can come to a free and uncoercive decision. Communication Skills Training (CST) was developed to train physicians in this task
and was evaluated in a randomized controlled trial. (1) Can CST improve
communication skills conveying key information about clinical trials?(2)
Can this training improve the feeling of competence of participants? (3)
Do improved consultations need more time?
Methods: This CST is based upon individual learning goals of participating physicians derived from video assessment. These learning goals were
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used in role play with actor-patients in CST to train each physician. For
evaluation, 40 physicians were randomly assigned to training or waiting
control group. Training success was evaluated by blinded rater using a
specific checklist to evaluate video-recorded standardized consultations
with actor-patients. Feeling of competence was assessed by a questionnaire. Time of consultations was metered post-hoc.
Results: (1) Results show significant improvements in content specific
communication skills of trained physicians. (2) Feeling of competence
improved significantly. (3) Time did not increase significantly in better
rated consultations.
Conslusion: The developed CST is the first CST, which can show improvements in communication skills conveying key information about
clinical trials evaluated in a randomized controlled design. It integrates
ethical standards, patient-orientation and is time efficient. It can prepare
physicians in this difficult task effectively.
ID 323
Factors associated with clinical trial enrollment among
female with gynaecological cancer
R. Mavrova, J. Radosa, J. Stroeder, D. Herr, E.-F. Solomayer,
I. Juhasz-Böss
Uniklinik Homburg/Saar, Gynäkologie, Homburg, Deutschland
Purpose: Only few women with gynaecological cancer participate in
cancer clinical trials nationwide. Advances in cancer treatment are in part
the result of patient involvement in such trials. There is a need to identify
the barriers interfering patient accrual.
Methods: This study was conducted at the Department for Gynaecology
and Obstetrics at the Saarland University Hospital, Germany to investigate
factors influencing the participation and enrollment in clinical trials among
women with a recently diagnosed gynaecological cancer during 6 months.
Patients were educated and offered to participate in the provided study or to
receive the standard therapy according to the guidelines for their cancer entity. We analyzed the age of the patient, the stage of the disease, the clinical
trial design and subjective reasons for participation or not.
Results: 23 patients were offered participation and 14 patients (61%)
were enrolled. Our collective consists of women with breast cancer
(70%), ovarian cancer (26%) and endometrial cancer (4%). The mean age
was 58 years (range 40-72). Analyzed were four different clinical trial
designs: neoadjuvant trials (30%), adjuvant trials (22%), no intervention
studies (35%) and studies for patients with metastasis (13%). Women
were not offered trials because of ineligibility (33%), difficulties getting
to the hospital because of long drive distances (56%) and patient refusal (11%). Women participate in trials because of better medical support
(7%), the possibility of new drugs (57%), no other therapeutical alternatives (14%) and to help further generations (21%).
Conclusions: Studies should be offered in more even small institutions to
increase participation and enrollment in cancer clinical trials.
ID 369
The Treat CTC trial – a new approach targeting circulating
tumor cells (CTC) in early breast cancer (EBC)
B. Rack1, C. Messina2, S. Litiere2, C. Dittrich3, D. Mavroudis4,
A. Kong5, W. Janni6, J. Koch1, C. Sotiriou7, J.-Y. Pierga8,
M. Piccart7, M. Ignatiadis7
Ludwig-Maximilians-Universität, München, Deutschland
European Organization for Research and Treatment of Cancer (EORTC)
Headquarters, Brussels, Belgien
3
LBI-ACR VIEnna, Kaiser Franz Josef-Spital, Vienna, Oesterreich
4
University General Hospital Heraklion, Crete, Griechenland
5
Oxford University Hospitals NHS Trust – Churchill Hospital, Oxford,
Großbritannien
6
Department of Gynaecology and Obstetrics, Universitätsklinikum Ulm,
Ulm, Deutschland
7
Department of Medical Oncology, Institut Jules Bordet, Université Libre de
Bruxelles, Brussels, Belgien
8
Department of Medical Oncology, Institut Curie, Paris, Frankreich
1
2
28
Background: The presence of CTC is associated with an impaired prognosis in MBC and EBC. Therefore, patients with persisting CTC after
(neo)adjuvant chemotherapy might benefit from additional systemic
treatment.
Recent data have reinforced the hypothesis that trastuzumab can eliminate tumor cells by antibody dependent cell cytotoxicity (ADCC) and that
the benefit may be associated with targeting cancer stem cells in a HER2
independent model (Ithimakin 2013). Trastuzumab eliminated CTC, irrespective of the HER2 status of the primary tumor and CTC and this was
associated with reduced relapses (Georgoulias 2012).
Trial Design: Treat CTC trial is a European randomized phase II trial,
sponsored by the EORTC and run under the BIG umbrella. It will assess
the efficacy of trastuzumab in eliminating CTC after the completion of
(neo)adjuvant chemotherapy and surgery in patients with HER-2-negative EBC. Eligible patients will be randomized to either 6 cycles of trastuzumab or observation.It is estimated that 2175 women will be registered
to include 174 patients eligible for randomization.
Main Eligibility criteria:
- Adequately excised HER2-negative EBC
- Evidence of CTC detection using the CellSearch technology after completion of (neo)adjuvant chemotherapy
- Completion of adjuvant chemotherapy for node-positive disease or neoadjuvant chemotherapy with residual invasive disease in breast or lymph
nodes
- Histological Grade > 1 and primary tumor size > 1 cm
Perspectives: Given the prognostic relevance of CTC in BC, the Treat
CTC trial will be the first multi-center, randomized trial in which CTC
are used to guide treatment decisions in EBC. The results of this trial will
help to clarify the clinical utility of CTCs in early disease.
ID 429
Capecitabine and bevacizumab with radiotherapy
as first-line maintenance treatment for patients with
oligometastatic colorectal cancer – clinical case report
and presentation of an interdisciplinary trial (OLGA trial)
A. Stein1, N. Andratschke2, J. Dunst3, J. Quidde1,
M. Guckenberger4, R. Hofheinz5, G. Hildebrandt2, C. Roedel6,
A. Vogel7, F. Wenz8, C. Petersen9, D. Arnold10
Universitätsklinikum Hamburg-Eppendorf, Universitäres Cancer Center
Hamburg II. Medizinische Klinik und Poliklinik, Hamburg, Deutschland
2
Universitätsmedizin Rostock, Klinik und Poliklinik für Strahlentherapie,
Rostock, Deutschland
3
Universitätsklinikum Schleswig-Holstein, Klinik für Strahlentherapie, Kiel/
Lübeck, Deutschland
4
Universitätsklinikum Würzburg, Klinik und Poliklinik für Strahlentherapie,
Würzburg, Deutschland
5
Universitätsmedizin Mannheim, III. Medizinische Klinik, Mannheim,
Deutschland
6
Universitätsklinikum Frankfurt, Klinik für Strahlentherapie und Onkologie,
Frankfurt, Deutschland
7
Medizinische Hochschule Hannover, Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Hannover, Deutschland
8
Universitätsmedizin Mannheim, Klinik für Strahlentherapie und Radioonkologie, Mannheim, Deutschland
9
Universitätsklinikum Hamburg-Eppendorf, Klinik für Strahlentherapie und
Radioonkologie, Hamburg, Deutschland
10
Klinik fuer Tumorbiologie, Freiburg, Deutschland
1
Background: Metastatic colorectal cancer (MCRC) often present with
oligometastatic disease. Currently available highly active standard treatment regimens enable tumour response or disease control in most patients, thus raising the question of further management. Secondary resection and/or ablation, e.g. by surgery or radiofrequency, may contribute to
long-term survival and even cure, or at least allow a relevant chemotherapy free interval. These approaches are often limited by anatomical site,
invasiveness and morbidity of the respective procedure. Radiotherapy is
an already established treatment approach in localized (colo)rectal cancer potentially enabling non-invasive local ablation with low toxicity to
nearly every site of the body. Combining chemoradiation with an antian-
Abstracts
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Index
giogenic agent (e.g. bevacizumab) has a strong biological rationale, and
studies consistently show an increase in radiosensitivity.
Methods/Design: This multicentre, single arm phase II trial conducted
in Germany evaluates the role of chemoradiation with capecitabine and
bevacizumab in 72 patients with oligometastatic colorectal carcinoma
(up to 5 lesions/3 sites) neither being progressive nor resectable after 3-6
months of induction chemotherapy. The primary objective is to evaluate the efficacy of chemoradiation; primary endpoint is progression free
survival rate at 12 months. Secondary objectives include efficacy, safety
and tolerability. The trial is approved and registered EudraCT Nr: 2011005296-16.
Conclusion: The OLGA trial is designed to evaluate the benefits and
limitations of chemoradiation with capecitabine and bevacizumab in the
treatment of oligometastatic CRC.
ID 450
DETECT IV – a multicenter, single arm, phase II study
evaluating the efficacy of Everolimus in combination
with endocrine therapy in patients with HER2-negative,
hormone-receptor positive metastatic breast cancer and
exclusively HER2-negative circulating tumor cells (CTCs)
C. Melcher1, F. Schochter2, S. Albrecht2, C. Hagenbeck1,
T.W. Friedl2, B. Jäger2, B.K. Rack3, V. Müller4, P.A. Fasching5,
W. Janni2, T.N. Fehm3
2
Deutschland
3
4
University Medical Center Hamburg-Eppendorf, Department of Tumor
Biology, Hamburg, Deutschland
5
Deutschland
1
Background: Several studies have indicated that determining prevalence
and number of circulating tumor cells (CTCs) at various time points
during treatment is an effective tool for assessing treatment efficacy in
metastatic breast cancer (MBC). However, even if the prognostic value
of CTCs in MBC is well understood, the role of both CTC prevalence
and CTC phenotype in predicting treatment response needs further investigation.
Specific Aims/Trial Design: DETECT IV is a prospective, multicenter,
open-label, single arm phase II study aimed at postmenopausal patients
with hormone-receptor positive, HER2-negative MBC and exclusively
HER2-negative CTCs. The primary objective of the trial is to estimate
the clinical efficacy of the mTOR inhibitor everolimus in combination
with endocrine therapy as assessed by progression-free survival (PFS).
Additional research on CTC dynamics and characteristics will provide a
better understanding of the prognostic and predictive value of CTCs and
is one step towards a more personalized therapy for MBC.
Eligibility Criteria: Postmenopausal female patients with hormone-receptor positive, HER2-negative MBC and exclusively HER2-negative
CTCs having an indication for endocrine therapy will be included.
Methods/Target Accrual: DETECT IV will start in October 2013 and
aims at recruiting 400 patients. It is estimated that 2000 patients with
HER2-negative MBC have to be screened for the presence of exclusively
HER2-negative CTCs. The primary endpoint PFS will be assessed using
the Kaplan-Meier method. Prevalence and number of CTCs at various
time points will be determined using the FDA-approved CellSearch System (Veridex, USA).
Abstracts
ID 451
DETECT III – a multicenter, randomized, phase III trial
to assess efficacy of lapatinib in patients with HER2negative metastatic breast cancer and HER2-positive
circulating tumor cells (CTCs)
S. Albrecht1, F. Schochter1, C. Melcher2, C. Hagenbeck2,
T.W. Friedl1, B. Jäger1, B.K. Rack3, V. Müller4, P.A. Fasching5,
W. Janni1, T.N. Fehm3
Deutschland
2
3
4
University Medical Center Hamburg-Eppendorf, Department of Tumor
Biology, Hamburg, Deutschland
5
Deutschland
1
Background: The recently reported discordance of the HER2 status between primary tumor and circulating tumor cells (CTCs) in metastatic
breast cancer (MBC) may be an important factor affecting the response
to HER2-targeted treatments. Therefore, it is important to determine if
therapy based on the HER2 status of CTCs offers a clinical benefit for
patients.
Specific Aims / Trial Design: DETECT III is a prospective, multicenter,
open-label, two-arm, phase-III study for patients with HER2-negative
MBC. Patients with HER2-positve CTCs are randomized to standard
therapy with or without additional HER2-targeted treatment with Lapatinib. The primary objective of the DETECT III trial is to estimate the
clinical efficacy of the HER2-targeted therapy monitored by the disappearance of CTCs after treatment. This-study is the first phase III clinical
trial where treatment is based on phenotypic characteristics of CTCs. It
may lead to a new strategy for the treatment of MBC.
Eligibility Criteria: In DETECT III patients with HER2-negative MBC,
HER2-positive circulating tumor cells (CTC) and indication for anti-cancer treatment will be included.
Methods / Target Accrual: The DETECT III – trial started February
2012 and aims at recruiting 120 patients overall. Prevalence and number
of CTCs at various time points as well as the HER2 status of CTCs are
determined using the FDA-approved CellSearch System (Veridex, USA).
So far (August 2013), 585 patients have been screened and 383 (65.3%)
were positive for CTCs. At least one HER2-positive CTC was found in
71 (18.6%) patients.
Developmental Therapeutics: Immunotherapy
ID 080
Two immune faces of pancreatic adenocarcinoma:
Possible implication for immunotherapy
S. Karakhanova, J. Werner, A. Bazhin
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive
human neoplasms, having extremely poor prognosis with a five-year survival rate of <1% and a median survival of 6 months. In contrast to other
malignancies, pancreatic cancer is highly resistant to chemotherapy and
targeted therapy. Therefore, new treatment options are urgently needed
to improve the survival of patients with PDAC. Based on our data showing that patients with higher CD8+ T cell tumour infiltration exhibited
prolonged overall and disease-free survival compared to patients with
lower or without CD8+ T cell tumour infiltration, we suggested that immunotherapy could be a promising treatment option for PDAC. However,
clinical data from theCapRitrial (chemoradioimmunotherapy with interferon-α (IFN)) did not point to an improved efficiency of chemoradiation
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combined with IFN as compared to chemoradiotherapy alone, suggesting
an important role of the immune suppression induced by PDAC and/or
unspecific immune stimulation. In support of this hypothesis, we found
that the PDAC patients and experimental mice had an increased number of regulatory T cells (Treg) and myeloid-derived suppressor cells
(MDSC). These results allowed us to conclude that PDAC provokes not
only an anti-tumour immune response, but also strong immune suppression. Thus, we supposed that new immunotherapeutical strategies should
involve not only stimulation of the immune system of PDAC patients, but
also exert control over the tumour immune suppressive milieu.
ID 156
Outpatient treatment of malignant pleural effusions
due to metastatic breast and ovarian carcinoma by
intrapleural catumaxomab instillation
C.M. Kurbacher, O. Horn, C. Schweitzer, N. Nymbach, S. Herz,
G. Wessling, J. Lepique, J.A. Kurbacher
Background: Malignant pleural effusion (PE) is among the late sequelae
of metastatic epithelial tumors including metastatic breast cancer (MBC)
or recurrent ovarian carcinoma (ROC). Recently, pleurodesis with talc
is considered standard of care for the treatment of PE. However, this
therapy routinely routinely requires hospitalization and admission to an
intensive-care unit. The trifunctional monoclonal antibody catumaxomab (CATU), is approved for the treatment of malignant ascites due to
epithelial cell adhesion molecule (EpCAM)-positive tumors. We hereby
report on our single-institution experiences of local PE treatment with
CATU-instillations in an outpatient setting in pts with MBC and ROC.
Methods: A total of 7 patients (pts) with PE (MBC, n = 5; ROC, n = 2)
were treated with intrapleural (IPL) CATU instillation. In 6 pts, CATU
was given as a single-shot with 50 µg. In one MBC patient, CATU was
repeatedly administered via an intrapleural (IPL) catheter according to the
intraperitonal (IP) schedule (10, 20, 50, 100 µg) over a 14 d period. Two
pts were treated with a second CATU-instillation at 50 µg. All patients
received antipyretics and antiemetics according to the recommendations
for IP CATU (metamizole or paracetamole).
Results: IPL CATU was generally well tolerated. Side-effects, including
fever, dyspnea, hypotonia, and fatigue, never exceeded CTCAE G2. In 2
pts, re-puncture and second CATU-instillation had been necessary. Three
pts of are still alive never after 500, 93 and 90 d. No patient required local
treatment related to PE after CATU.
Conclusion: IPL CATU instillation is a reasonable and low-toxic alternative to established treatments for malignant PE due to MBC or ROC.
IPL CATU is generally well tolerated and allows for clinical routine PE
treatment in outpatients. Larger-scaled prospective trials in this setting are
therefore strongly recommended.
ID 216
Impact of CTLA-4 antibodies Tremelimumab and
Ipilimumab on the human immune system. Results of
an ex vivo human melanoma model with the oncolytic
parvovirus H-1 or cytotoxic drugs
K. Goepfert, L. Wittmann, M. Linnig, B. Heinrich, P. Galle,
M. Moehler
antigen 4) antibodies (AB) Tremelimumab (Treme) and Ipilimumab (Ipi)
may additionally strengthen DC maturation.
Human Sk29Mel melanoma cells expressed CTLA-4 on cell surface. In
immature DCs (iDC) coculture with H-1PV infected or cytotoxic drugs
pretreated Sk29Mel tumor cell lysates (TCL) induced maturation of iDCs
shown by increased expression of CD80, CD83 and CD86. Treme and
Ipi did not negatively affect this DC maturation. Using ELISA, coculture
experiments with H-1PV infected TCLs additionally increased cytokine
production (IL-6, IFNγ, IL-12 and TNFα). The addition of Ipi or Treme
did not further strengthened DC maturation. Furthermore, we analysed
these DC TCL cocultures with regulatory T cells (Tregs) to overcome the
negative Tregs effects on DC maturation by anti-CTLA-4 AB. Here, both
Treme and Ipi significantly increased IL-6 and decreased TGF-ß.
H-1PV or cytotoxic drug induced cell killing strengthened immunogenicity of melanoma tumor cell lysates. Tremelimumab and Ipilimumab
additionally blocked Tregs favouring a pro-inflammatory milieu and reinforced T-cell activation. This combination of active enhancement of tumor immunogenicity and concomitant blockade of the CTLA-4 silencing
process by tumor cells and Tregs is therapeutically promising
ID 335
Clinical analysis supports a significant role in tumor
progression of the PD-1/PD-L1 pathway in colorectal
cancer
T. Grimmig1, R. Mönch1, C.-T. Germer2, A.M. Waaga-Gasser1,
M. Gasser2
Universitätsklinikum Würzburg, Chirurgische Klinik I, Molekulare OnkoImmunologie, Würzburg, Deutschland
2
Universitätsklinikum Würzburg, Chirurgische Klinik I, Würzburg, Deutschland
1
Background: The programmed death-1/programmed death ligand (PD1/PD-L) pathway in T cell activation has been shown to play an important
role in tumor evasion from host immunity. While recent evidence from
first clinical data points to beneficial effects of PD-1/PD-L1/L2-inhibitory
intervention strategies in several clinical cancers its relevance in colorectal cancer (CRC) remains unclear.
Methods: We investigated expression levels of PD-1, PD-L1, PD-L2,
CD4, CD8 and Foxp3 in tumors from patients with CRC (n = 116 with
completed 5-year survival) by immunohistochemistry and RT-qPCR. Obtained data were analyzed for their prognostic significance with respect
to outcome analysis.
Results: T cell infiltration was observed in 90.5% of the tumors, with
58% of the patients demonstrating PD-1-positive T cells in their tumors. Patients who developed PD-1-positive T cell infiltration showed
increased PD-L1-expression within their tumors than PD-1-T cell negative individuals. Ligand expression (PD-L1/PD-L2) in the cancer tissues combined with dense PD-1-positive T cell infiltration was associated
with poor prognosis in affected patients (p < 0.001). Multivariate analysis demonstrated that PD-L expression in the tumors was an independent
prognostic factor in CRC.
Conclusion: The presented results from clinical tumors suggest for the
first time for CRC that negative signaling of infiltrating PD-1-positive T
cells through PD-L1 expression within the tumor is promoting tumor progression through downregulation of anti-tumor immunity. In conclusion,
this study demonstrates the importance of strategies inhibiting negative
PD-1/PD-L1 signaling in CRC.
Universitätsmedizin Mainz, Mainz, Deutschland
Tumor-directed and immune-stimulating therapies are of special interest
in cancer treatment. We analysed the impact of the oncolytic parvovirus H-1 and cytotoxic drugs like temozolomide, fotemustine, dacarbacine and combination of paclitaxel and carboplatin to trigger melanoma
cell death and its immunogenicity to induce human dendritic cell (DC).
Maturation.. Adding of anti-CTLA-4 (cytotoxic T-lymphocyte-associated
30
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ID 346
Tumor infiltrating B-cells in primary cutaneous T-cell
lymphoma correlate with disease progression and might
represent a novel target for immunotherapy
S. Theurich1,2, M. Schlaak3, H. Steguweit2, L.C. Heukamp4,
K. Wennhold2, P. Kurschat3, A. Shimabukuro-Vornhagen1,2,
H. Schlösser2, U. Holtick1,2, M. Hallek1, R. Stadler5,
M. von Bergwelt-Baildon1,2
Uniklinik Köln, Klinik I für Innere Medizin, Hämatologie und Onkologie,
Köln, Deutschland
2
Uniklinik Köln, Klinik I für Innere Medizin, Labor für Interventionelle Immunologie, Köln, Deutschland
3
Uniklinik Köln, Klinik für Dermatologie, CIO, Hauttumorzentrum, Köln,
Deutschland
4
Uniklinik Köln, Institut für Pathologie, Köln, Deutschland
5
Johannes Wessling Klinikum, Klinik für Dermatologie, Minden, Deutschland
1
B cells have been recently described to mediate tumor biology but so far
their role as a tumor promoting or tumor repressing lymphocyte population
remains controversial. Mycosis fungoides (MF) and other primary cutaneous T-cell lymphomas (CTCL) are characterized by an indolent course in
early stages. However, advanced stage MF (≥ EORTC Stage IIB) and the
follicular MF subtype (FMF) as well as Sézary syndrome (SS) show a more
aggressive pattern with a median survival of less than two years. The pathogenesis of these more aggressive courses is still incompletely understood.
With regard to a potential role of tumor associated B cells in CTCL,
we systematically analyzed the B-cell infiltrate in tumor samples
of 33 CTCL patients and correlated these data with the stage, subtype and clinical course. Non-malignant T-cell mediated skin disease (psoriasis, ekzema) samples (n 
= 
10) served as controls.
Advanced stage MF, FMF and SS samples contained significantly increased numbers of infiltrating B cells per lymphoma infiltrate. Moreover, time to progression showed a significant inverse relationship with
the density of the B-cell infiltrate.
Based on our results, we hypothesized that infiltrating B cells might be
a therapeutic target in CTCL. In a 77-year old patient suffering from advanced stage FMF with a significant B-cell infiltration and progression after standard treatments, intralesional B-cell depletion with the anti-CD20
monoclonal antibody rituximab resulted in a sustained complete local
tumor regression.
In summary, we present first evidence for the potential tumor promoting
role of CTCL associated B cells which warrants further study as a potential therapeutic strategy. ID 408
Beyond cytotoxicity: Implications for immune mediated
mechanisms of action of brentuximab vedotin treatment
in CD30+ lymphomas
S. Theurich1,2, P. Müller3, K. Martin3, S. Savic4, G. Terszowski3,
D. Lardinois5, M. Schlaak6, R. Stadler7, H.-M. Kvasnicka8,
G. Spagnoli5, S. Dirnhofer4, D.E. Speiser9,
M. von Bergwelt-Baildon1,2, A. Zippelius3,10
Uniklinik Köln, Klinik I für Innere Medizin, Hämatologie und Onkologie,
Köln, Deutschland
2
Uniklinik Köln, Klinik I für Innere Medizin, Labor für Interventionelle Immunologie, Köln, Deutschland
3
University Hospital Basel, Cancer Immunology & Biology, Department of
Biomedicine, Basel, Schweiz
4
University Hospital Basel, Institute of Pathology, Basel, Schweiz
5
University Hospital Basel, Department of Surgery, Basel, Schweiz
6
Uniklinik Köln, Klinik für Dermatologie, CIO, Hauttumorzentrum, Köln,
Deutschland
7
Johannes Wessling Klinikum, Klinik für Dermatologie, Minden, Deutschland
8
University of Frankfurt, Senckenberg Institute of Pathology, Frankfurt
(a.M.), Deutschland
9
University of Lausanne, Ludwig Center for Cancer Research, Lausanne,
Schweiz
10
University Hospital Basel, Department of Medical Oncology, Basel, Schweiz
1
Abstracts
The expression of CD30 is a characteristic feature of distinct nodal or
cutaneous lymphomas. Since the clinical approval of brentuximab vedotin (BV), a monoclonal anti-CD30 antibody-drug-conjugate, targeted
therapy of CD30+ lymphomas is possible and has revealed impressive
efficacy even in heavily pretreated patients. While the CD30-mediated
cytotoxicity of BV has so far been regarded as the main way of action, we
hereby provide evidence for BV induced changes of the immune response
as a further, powerful therapeutic mechanism.
In patients suffering from CD30+ lymphomas (Hodgkin lymphoma,
CD30+ cutaneous lymphoma), BV treatment remodeled the local and systemic immune reaction towards an enhanced anti-lymphoma response.
This could be demonstrated via the induction of circulating lymphoma
specific T cells and also by an increased infiltration of CD8+ cytotoxic
T cells in the tumor microenvironment. In parallel, inhibitory immune
cells such as regulatory FoxP3+ T-cell numbers were decreased after BV
treatment. We were able to show such BV induced immune responses
in patients with relapsed disease following allogeneic stem cell transplantation but also in a non-transplant setting. Furthermore, in a murine
model, elucidation of the underlying mechanisms of action revealed that
the cytotoxic component of BV, monomethyl auristatin E (a derivate of
dolastatin), is able to induce antigen-uptake, maturation and increased
lymph-node migration of dendritic cells. This in turn enhances sustained
anti-tumor immune responses.
In summary, we present data of a novel mechanism of action of brentuximab vedotin beyond simple cytotoxicity. This provides a rationale for
clinical treatment regimens combining dolastatin-based therapies, such as
brentuximab vedotin, with immune-based therapies.
(ST, PM, KM and MBB, AZ contributed equally.)
Developmental Therapeutics:
Molecular Therapeutics
ID 112
High throughput parallel amplicon sequencing of
common driver mutations from FFPE lung cancer
samples in molecular pathological routine diagnostics for
a regional health care provider network
K. König1,2, M. Peifer2,3, M. Bos2, L. Nogova2,
S. Merkelbach-Bruse1, K. Stamm4, T. Henkel4, R. Thomas2,3,
J. Wolf2, R. Büttner1,2, L. Heukamp1,2
Universitätsklinikum Köln, Institut für Pathologie, Köln, Deutschland
Universitätsklinikum Köln, Lung Cancer Group Cologne, Köln, Deutschland
3
Universität zu Köln, Department of Translational Genomics, Köln,
Deutschland
4
targos gmbh, Kassel, Deutschland
1
2
Background: Treatment paradigms for non-small-cell lung cancer (NSCLC) have shifted from one based only on histology to one that incorporates molecular subtypes involving particular genetic alterations such
as activating mutations in EGFR or translocations of ALK. The list of
therapeutically targetable lesions is rapidly increasing. Analysis of these
potential targets is becoming a challenge in terms of work load, tissue
availability as well as cost.
Within the Network Genomic Medicine Lung Cancer (NGM), a regional
molecular screening network of the Center for Integrated Oncology Köln
Bonn, we aimed to improve on the sequential analysis of a set of 9 target
amplicons by Sanger sequencing using bench top ultra-deep parallel sequencing platforms.
Methods: We established a multiplex PCR to amplify up to 640 lung
cancer relevant target regions from at least 20 ng of FFPE derived tumor DNA. The amplicon libraries were ligated to adapters encompassing medical identifier sequences that allowed multiplexing of up to 48
patients. The resulting libraries were sequenced on a benchtop Illumina
31
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platform (MiSeq). Mutations identified by parallel sequencing were confirmed by Sanger sequencing.
Results: 330 patients were analyzed both by traditional single PCR based
Sanger sequencing. We found that the NGS approach worked reliably,
was less prone to sequencing analysis errors and that the time needed to
complete the mutation screening was significantly reduced to 7 working
days from previously 21 days. A total of at least 300ng of DNA was needed to complete the analysis of 9 amplicons by Sanger sequencing compared to 20 to 100ng of DNA needed for up to 640 amplicons analyzed
by parallel sequencing.
ID 255
EL102 – a new strategy for targeting hypoxia-driven
cancer
A. Maderer1, K. Göpfert1, D. Sauvigny1, M. Linnig1, J.D. Lewis 2,
P.R. Galle1, M. Möhler1
1
2
Universitätsmedizin Mainz, Mainz, Deutschland
ELARA Pharmaceuticals, Heidelberg, Deutschland
EL102, a novel toluidine sulphonamide, is an orally available small molecule inhibitor of HIF1a induced hypoxic signaling pathways. It is a dual-inhibitor of apoptosis and angiogenesis and positively tested for prostate cancer and multiple myeloma. EL102 inhibits directly the androgen
-, progesterone -, adenosine 3A receptor and tubulin.
We screened one melanoma, 5 gastric and 6 colorectal cancer cell lines by
RT-PCR for these target structures. Multiple viability, cell cycle and apoptosis assays were performed in four selected human colon cancer cell lines
(HT-29, HCT-116, Caco-2, SW480) with different expression profiles. We
analysed single incubation of EL102 and combination with cytotoxic drugs.
Additionally, intracellular signalling pathways especially Hif1a, VEGF and
cell cycle associated proteins were analysed by Western blotting.
The melanoma cell line expressed all, colorectal only a few and the gastric cancer cell lines at most one target structure of EL102. The substance
showed clear anti-proliferative and pro-apoptotic effects in the analysed
colorectal cancer cell lines in nM range. The effects depended on the
availability of the target structures. EL102 induced a G2 shift and showed
additive apoptotic effects when combined with irinotecan. Furthermore,
Hif1a and VEGF-A were clear down regulated in 3 of the colorectal cancer cell lines.
EL102 is an innovative new treatment strategy in normoxic and also hypoxic tumor cell environments in different indications. The experiments
argue for a high potency of this substance to complement standard therapy and to overcome possible tumour resistance mechanisms.
ID 414
SORAVE: Sorafenib and everolimus for patients with
solid tumors and with KRAS mutated NSCLC – results of
a phase I study
L. Nogova1, C. Mattonet2, M. Gardizi2, M. Scheffler2, M. Bos2,
C. Wömpner2, K. Töpelt2, L. Heukamp2, A. Suleiman2,
S. Frechen2, F. Sörgel3, U. Fuhr2, R. Schnell4, I. Katay4,
D. Behringer5, T. Geist6, B. Kaminski7, M. Eichstaedt8,
D. Tummes9, R. Büttner2, J. Wolf2
Universität Köln, Köln, Deutschland
Uniklinik Köln, Köln, Deutschland
3
Institut für Biomedizinische und Pharmazeutische Forschung, Nürnberg,
Deutschland
4
Praxis Internistischer Onkologie und Hämatologie, Köln, Deutschland
5
Augusta Kliniken, Bochum, Deutschland
6
Pneumologische Praxis, Düsseldorf, Deutschland
7
Krankenhaus Bethanien, Solingen, Deutschland
8
MVZ, St. Marienhospital, Düren, Deutschland
9
Onkologische Schwerpunktpraxis, Aachen, Deutschland
1
2
Background: Inhibition of signaling pathways interfering with cell proliferation and angiogenesis may increase anti-tumor efficacy. Sorafenib as
32
well as mTOR inhibitors showed preliminary activity in KRAS mutated
NSCLC.
Methods: In the dose escalation part, patients with relapsed solid tumors
were treated with escalating doses of everolimus from 2.5 to 10.0 mg
daily p.o. in a 14 days run-in phase followed by the combination with a
fixed dose of sorafenib 400 mg bid p.o. The extension phase is currently
recruiting patients with KRAS mutated NSCLC. Pharmacokinetic (PK)
analyses are performed during run-in and during the combination. Treatment outcome is validated with CT scans on day 57.
Results: In the dose escalation part, 19 patients were recruited. The dose
limiting toxicity (DLT) was not reached. At everolimus dose level of 10
mg/day, increased rates of grade 3 thrombocytopenia, leukocytopenia and
anaemia occurred after the DLT interval of 29 days. Based on these observations, the dose level of 7.5 mg/day everolimus in combination with
400 mg sorafenib bid was defined as a maximal tolerated dose. The best
treatment outcome on day 57 was stable disease in 11 patients. Median
PFS and OS were 3.7 and 5.5 months, respectively.
The extension phase in KRAS mutated NSCLC is currently ongoing.
Nine patients have been recruited so far. The CT response at day 57 compared to the baseline of four evaluable patients is ranging from –22% to
+5% in the sum of the longest diameter of all targeted lesions.
Conclusion: Treatment of patients with relapsed solid tumors with the
combination of 7.5 mg everolimus p.o. daily and 400 mg sorafenib p.o.
bid is safe and feasible. Current results of an extension phase in KRAS
mutated NSCLC patients show preliminary clinical activity in this patient
group with an unfavorable prognosis.
Economy
ID 090
Estimating Site Costs Prior to Conducting Clinical Trials –
a Study Site Budgeting Tool
D. Arenz1, B. Hero1,2,3, B.F. Eichhorst3,4, M. Langer1,4, L. Pester1,3,4,
J. von Tresckow3,4, M.J.G. Vehreschild4, O.A. Cornely1,3,4,5
Universität zu Köln, Zentrum für Klinische Studien, Köln, Deutschland
Universitätsklinikum Köln, Klinik für Kinder- und Jugendmedizin, Köln,
Deutschland
3
Centrum für Integrierte Onkologie Köln Bonn, Köln Bonn, Deutschland
4
Universitätsklinikum Köln, Klinik I für Innere Medizin, Köln, Deutschland
5
Universität zu Köln, Exzellenzcluster CECAD, Köln, Deutschland
1
2
Objectives: Conducting clinical trials is costly and time-consuming. Underestimating required resources slows enrollment and lowers data quality. We aimed to develop a tool for calculating trial fees prior to initiating
a clinical trial.
Methods: To develop this tool, trial staff from sites at the University of
Cologne, Germany formed a task group. Tasks within a clinical trial were
itemized into single activities and basic time expenditures were assigned.
Hourly rates for different occupation groups involved were derived from
total labor costs. Results were used to design a cost calculation tool. Using round robin tests, study coordinators calculated time expenditures
based on the same study protocol and case report forms to validate the
tool. In addition, study coordinators of one site calculated time expenditure of all trials initiated and tracked time prospectively over a period of
12 months to assess the predictive value of the tool.
Results: The study site budgeting tool (STUDGET) determines hours of
work and calculates the hourly rates of staff, totalizing them to fees required. The tool is web-based and available via studget.clinicalsite.org.
By improving accuracy of STUDGET in round robin tests, we achieved
a median deviation of € 371.59 (range € 43.58 – € 1,152.08) in calculated
case payments (reference € 1,671.97). Comparison of predicted and actual hours showed a correlation of 105% median (range 18–228%). Outliers
were due to unforeseeable changes in trial execution.
Conclusion: We developed the web-based tool STUDGET allowing trial
sites to determine the case fee needed to conduct a clinical trial.
Abstracts
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ID 150
Is the care for women with a hereditary risk for breast
and ovarian cancer fundable at all? – Health-economic
analysis of genetic testing intensified early cancer
detection and prophylactic surgery from the perspective
of the health care system and the health care provider
L. Brunel-Geuder1, P.A. Fasching1, M.R. Bani1, C.R. Löhberg1,
S.M. Jud1, M.G. Schrauder1, K. Geisler1, S. Wagner2, J. Hoyer3,
A. Reis3, E. Wenkel4, R. Schulz-Wendtland4, M.W. Beckmann1,
M. P. Lux1
Frauenklinik,Universitätsklinikum Erlangen, Universitäts-Brustzentrum
Franken, Erlangen, Deutschland
2
Frauenklinik,Universitätsklinikum Erlangen, Kaufmännische Direktion,
Dezernat 6, Erlangen, Deutschland
3
Humangenetisches Institut, Universitätsklinikum Erlangen, Universitäts-Brustzentrum Franken, Erlangen, Deutschland
4
Radiologisches Institut,Universitätsklinikum Erlangen, Universitäts-Brustzentrum Franken, Erlangen, Deutschland
1
Objective: 10–15% of all breast and ovarian cancer cases have a hereditary origin. It is essential to identify high-risk families to offer genetic
testing and intensified care. The question is whether these procedures are
refundable in the actual health care (HC) system.
Methods: This health economic evaluation considered the process from
initial consultation, genetic testing up intensified screening and prophylactic surgery. The analysis is based on the interdisciplinary consultations
for high-risk patients at the University Breast Center Franconia (370 consultations, 71 patients with BRCA mutation).
Results: Long-term HC resources can be saved regarding genetic testing
and prophylactic procedures, e.g. savings of 239,539.52 €, if prophylactic
mastectomy is performed in all mutation carriers of this collective. However, some parts of the care are underfunded for the HC provider, e.g.
intensified screening with a loss of -466.08 €/patient/year or prophylactic
mastectomy with primary reconstruction by allografts with a deficit of
-3.504.09 €.
Considering the gain of additional life years each prophylactic procedure
is cost- effective for the HC system. Regarding the perspective of the HC
provider, adnexectomy and prophylactic mastectomy costs 83.29 € per
gained life year (-949.35 € in combination with primary reconstruction
by allografts) – cost-effective for the society but in deficit for the HC
provider.
Conclusion: The care for high-risk families is cost-effective. In the longterm monetary resources can be saved. This does not apply to the HC provider as several prophylactic options lead to a financial deficit. Therefore
specialized care centers need additional charges if they care for numerous
high-risk families.
ID 462
Performance-based cost allocation in a Comprehensive
Cancer Center
J.-P. Glossmann1, M. Kron1, A. Bernschein1, B. Funke2,
P. Görgen2, I. Schmidt-Wolf2, M. Hallek1, J. Wolf1
Universitätsklinikum Köln, Centrum für Integrierte Onkologie, Köln,
Deutschland
2
Universitätsklinikum Bonn, Centrum für Integrierte Onkologie, Bonn,
Deutschland
1
limited existing financial resources such as the grants for «Onkologische
Spitzenzentren» by the German Cancer Aid.
Methods: Diagnosis Related Groups (DRGs) are used to allocate
CCC-specific overhead costs to the departments which benefit from the
structures. Annual cancer-specific revenues for each department are identified by selecting DRGs with a cancer diagnosis. A margin is calculated
by subtracting the revenues of a baseline year for each department. A
positive value indicates a growth in cancer-related revenues and results in
an additional fee added to a base fee of 5000.00 Euro.
Results: In 2012 a total of 444,240.00 Euro (Köln: 344,240.00 Euro,
Bonn: 100,000.00 Euro) was invested in the CIO Köln Bonn by 52 departments (Köln: 25 departments, Bonn: 27). The sum per department
ranged from 5000.00 Euros to 79,960.37 Euros.
Conclusion: To our knowledge this is the first performance-based internal cost-allocating model in a German CCC. Ultimately, overhead costs
for CCCs should be reimbursed by statutory health insurances.
Epidemiology
ID 037
Update on incidence of amino-bisphosphonate
associated osteonecrosis of the jaw
Y. Begus-Nahrmann1, P. Kästner1, C. Walter2
Konzept Pharma Service GmbH, Freden (Leine), Deutschland
Universitätsmedizin der Johannes-Gutenberg-Universität Mainz, Klinik für
Mund-Kiefer-Gesichtschirurgie, Mainz, Deutschland
1
2
Background: Osteonecrosis of the jaw (ONJ) is a frequent adverse effect
for doses of amino-bisphosphonates (aBP) used in metastatic settings.
Comparing incidence rates from recent reports to the last review 2009
provide details, whether preventive measures to minimize the ONJ risk
could be transferred to daily practice.
M&M: To identify current ONJ incidence rates (2009 to date) a PubMed
literature research was performed using the search terms: ‘bisphosphonate’, ‘osteonecrosis’, ‘incidence’, ‘prevalence’ and ‘denosumab’. Articles were screened for incidence rates. Further articles from the references were included.
Results: 26 articles reported interpretable incidences of ONJ. The average incidences for breast cancer patients were 6% (0.6–20.8%), for multiple myeloma 6.3% (1.3–15.6%), for prostate cancer 6.7% (1–18.3%).
Compared to the incidence reported 2009, a difference of +1.4%, –1.3%
and –3.6% is detected. ONJ incidences are significantly influenced by
range of aBP administration and dramatically potentiated by combination
with chemotherapeutics. Denosumab was also reviewed for the incidence
of ONJ. The incidences for breast cancer were 2%, prostate cancer 3.5%
(2–5%), and multiple myeloma patients 1.5% (1.1–1.83%).
Conclusion: No remarkable changes for the incidence of aBP associated
ONJ are observed for breast and multiple myeloma patients. For prostate cancer the incidence is reduced but still relevant. Denosumab shows
low but considerable ONJ incidence, yet more long-term studies will be
essential. Beside the awareness of ONJ risk due to aBP treatment and
prevention measures data from the last years demonstrate that ONJ is still
a present issue.
Introduction: Statutory health insurances, politicians and patient advocacy groups in Germany call for high-end cancer care provided by Comprehensive Cancer Centers (CCCs). CCCs such as the Center for Integrated Oncology Köln Bonn (CIO Köln Bonn) maintain a cancer-specific
infrastructure such as patient navigators, a clinical cancer registry, quality
management, psycho-oncological support and a tissue bank. However,
little progress has been made in re-financing the additional financial burden related to these structures.
Aim: To develop and implement an internal, performance-based cost-allocating system to bridge the financial gap of growing overhead costs and
Abstracts
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ID 044
Socio-economic deprivation and cancer survival in
Germany
L. Jansen1, A. Eberle2, K. Emrich3, A. Gondos1, B. Holleczek4,
H. Kajüter5, W. Maier6, A. Nennecke7, R. Pritzkuleit8, H. Brenner1,9
Deutsches Krebsforschungszentrum (DKFZ), Abteilung für klinische Epidemiologie und Alternsforschung, Heidelberg, Deutschland
2
Leibniz-Institut für Präventionsforschung und Epidemiologie – BIPS
GmbH, Bremen, Deutschland
3
Johannes Gutenberg Universität Mainz, Krebsregister Rheinland-Pfalz,
Instituts für Medizinische Biometrie, Epidemiologie und Informatik (IMBEI),
Mainz, Deutschland
4
Krebsregister Saarland, Saarbrücken, Deutschland
5
Krebsregister Nordrhein-Westfalen, Münster, Deutschland
6
Helmholtz Zentrum München, Deutsches Forschungszentrum für
Gesundheit und Umwelt (GmbH), Institut für Gesundheitsökonomie und
Management im Gesundheitswesen, Neuherberg, Deutschland
7
Behörde für Gesundheit und Verbraucherschutz, Hamburgisches Krebsregister, Hamburg, Deutschland
8
Universität Lübeck, Institut für Krebsepidemiologie, Lübeck, Deutschland
9
Deutsches Konsortium für Translationale Krebsforschung (DKTK), Heidelberg, Deutschland
1
Background: While socio-economic inequalities in cancer survival have
been demonstrated both within and between countries, evidence on the
variation of inequalities over time past diagnosis is sparse. Furthermore,
no comprehensive analysis of socio-economic differences in cancer survival in Germany has been conducted. Our study aimed to analyze in
detail variations in cancer survival for patients diagnosed with one of the
25 most common cancer sites in 1997–2006 in Germany.
Methods: Data from 10 population-based cancer registries in Germany
(covering 32 million inhabitants) were combined. Patients were assigned
a socio-economic status according to the district of residence at diagnosis. Period analysis was used to derive age-standardized relative survival
within 5 years from diagnosis for 2002–2006 for each deprivation quintile
in Germany. Relative survival of patients living in the most deprived districts was compared to survival of patients living in all other districts by
model-based period analysis.
Results: For 21 of 25 cancer sites, 5-year relative survival was lower
in the most deprived districts than in all other districts combined. The
median relative excess risk of death over the 25 cancer sites decreased
from 1.24 in the first three months to 1.16 in the following nine months
to 1.08 in the following four years. Inequalities persisted after adjustment
for stage.
Conclusion: The observed major regional socio-economic inequalities
indicate a potential for improving cancer care and survival in Germany.
As inequalities were largest in the first months and persisted after adjustment for stage, differential quality of medical care should be considered
as reason for inequalities.
ID 072
FungiscopeTM – Global Emerging Fungal Infection
Registry
K. Wahlers1, M.J.G. Vehreschild1, A. Hamprecht2, S. de Hoog3,
J. Vehreschild1, O.A. Cornely1
Uniklinik Köln, Klinik I für Innere Medizin, Köln, Deutschland
Uniklinik Köln, Institut für Medizinische Mikrobiologie, Immunologie und
Hygiene, Köln, Deutschland
3
CBS Fungal Biodiversity Centre, Utrecht, Niederlande
lecular evidence of IFD. Data collected include demographics, underlying
conditions, immunosuppressive medication, clinical signs and symptoms,
sites of infection, diagnostic tests, pathogen identification, antifungal
treatment, surgical procedures, response to treatment, and survival.
Results: To date, 340 cases have been captured. Mucorales (n = 146;
43%), Fusarium spp. (n = 55; 16%), yeasts (n = 48; 14%), and Dematiaceae (n = 34; 10%) are the most frequently registered pathogens. Chemotherapy or allogeneic stem cell transplantation were the predominant risk
factors (n = 225; 66%), followed by diabetes (n = 67; 20%), intensive care
(n = 74; 22%), and chronic renal disease (n = 33; 10%). Sites of infection
included lung (n = 160; 47%), followed by blood stream (n = 71; 21%),
paranasal sinuses (n = 57; 17%), and deep soft tissue (n = 54; 16%). Favorable outcome was found in 174 (51%) patients. All-cause-mortality
and mortality attributable to IFD was 45% and 34%, respectively.
Conclusion: We documented a broad biological diversity of IFD across
Europe, Asia and the Americas. Patients with malignancies are at particular risk. Mortality is high. Further investigators are cordially invited to
contribute to FungiscopeTM.
ID 121
Possible Process and Quality Assessment for FullElectronic Cancer Registries
S. Friedrich1, S. Hermann1, M. Ketterer2, N. Becker3
Deutsches Krebsforschungszentrum, Epidemiologisches Krebsregister
Baden-Württemberg, Heidelberg, Deutschland
2
IT-Choice Software AG, Karlsruhe, Deutschland
3
Deutsches Krebsforschungszentrum, Heidelberg, Deutschland
1
Completely electronic data transfer to population-based cancer registries
– as realized in the Federal State Cancer Registry of Baden-Württemberg
(KRBW) – may be an efficient alternative to paper-based reporting. It
facilitates reporting for physicians and plausibility control immediately
at time of data transmission. Data can be made available rapidly for users
of the registry.
On the other hand, advantages regarding time gain and data quality
at time of reporting may be lost by internal data processing if it is too
time-consuming and e.g. gaps in data being obvious for hand-working
data managers slip through an automatic processing. Thus, indicators for
velocity of data processing and outcome quality are needed.
In the KRBW reported data enter into the «Vertrauensstelle» (VS), pass
to the «Klinische Landesregisterstelle» (KLR) and then on to the Epidemiological Cancer Registry (EKR). A simple indicator for velocity is the
mean time span between data entry in the VS and availability for users
from the EKR. Data can be manually consistency-checked in the KLR
which may increase data quality but also increases processing time. The
proportion of detected inconsistencies in the checked data may be another indicator for efficient internal data processing. Completeness of the
individual records is a particular issue of clinical cancer registries as the
KRBW is. Automatic checks triggering a reminder system for callbacks
with the reporting physicians are (a) no reports on treatment more than
3 months after diagnosis, (b) no after-care reports more than 6 months
after last information on treatment, (c) no vital status information within
the past 12 months. The presentations will provide further indicators and
details with exemplary evaluations.
1
2
Background: The relevance of emerging invasive fungal diseases (IFD)
is increasing. FungiscopeTM is a global registry for emerging IFD with
contributors from >20 countries. The objective is to broaden knowledge
on epidemiology, determine clinical patterns, describe and improve diagnostic procedures and therapeutic regimens, and to exchange of clinical
isolates among contributors.
Methods: Fungiscope™ uses web-based data capture via www.fungiscope.net. Case enrollment requires cultural, histological, antigen or mo-
34
ID 131
Interim results from the German randomized lung
screening trial LUSI
A. Eigentopf1, N. Becker1, E. Motsch1, M.-L. Groß1
DKFZ Heidelberg, Epidemiologie von Krebserkrankungen, Heidelberg,
Deutschland
1
In 2011, first results of the USA lung screening trial (NLST) were published indicating a 20% reduction of lung cancer with multi-slice-CT
(MSCT). However, since important questions cannot be resolved by this
Abstracts
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Index
trial (e.g. magnitude of overdiagnosis), parallel running European trials
which share a different study design have been continued and are o ngoing.
The German Lung Cancer Screening Intervention Trial (LUSI) is a component of these European studies. Currently, the first three screening
rounds are completed and all participants are undergoing the fourth or
fifth round of screening / observation or finished already screening and
are under follow-up observation.
For basic characteristics of the German trial the most recent data will
be presented. A crucial issue is e.g. compliance which is with currently
92% excellent. Contamination in the control group is extremely low. The
detection rate in the screening rounds 2–5 is with about 0.5% within the
expected range and comparable to the other European studies. Overall, 52
lung cancer cases were identified so far and 81 participants died from any
cause. The distribution of overall mortality in the both study arms is an
important quality indicator for a balanced randomization and can be presented at time of the congress for about 3 years of mortality observation
after randomization.
With power calculations based on the observed lung cancer incidence in
the European trials, it will be estimated at which time a final evaluation
will be reasonable.
ID 140
Also, first degree relatives of CRC patients have an increased CRC risk.
It is our goal to create population based data on familial CRC risk in a
German population.
Concept: Incident CRC cases in Upper Bavaria are collected and their
family trees constructed. The Patient’s relatives are documented by name,
address and date of birth, but without health related information. Cancer
history is added to a family by a record linkage procedure combining
members of the family trees with cancer histories in the Munich Cancer
Registry (MCR). A specific data protection concept guarantees anonymity for families and their cancer histories. Prevalence of familial CRC risk
in upper Bavaria and the posterior probability of a family to carry CRC
risk can be inferred from the anonymous data. Strength of simple familial
CRC risk detection tools can also be assessed.
Experience: Per year, 141 clinical departments and 24 oncological practices report about 1300 incident CRC cases (below 70 years) to the MCR.
During the first year, we recruited 456 patients in 27 clinical departments
and 6 oncological practices and contacted 1600 relatives. Participation
of relatives is reluctant in spite different information sources (leaflet, call
center, internet) on the study purpose. Record linkage creates an anonymous collection of CRC family histories. 37 families with a CRC patient
below the age of 50 are recorded. They are recruited into a psycho-oncological substudy.
«Cancer in Germany» 2013 – Current Epidemiological
Cancer Statistics
Acknowledgement: The study is sponsored by the BMFSFJ and supported by the
Felix-Burda Stiftung and the Netzwerk gegen Darmkrebs.
B. Barnes, U. Wolf, J. Haberland, J. Bertz, S. Dahm,
K. Kraywinkel
ID 179
Robert Koch-Institut, Zentrum für Krebsregisterdaten, Berlin, Deutschland
We present here the latest statistics from the ninth Edition of the report
«Cancer in Germany», published in 2013 by the German Centre for Cancer Registry Data (ZfKD) at the Robert Koch Institute (RKI) and the Association of Population-based Cancer Registries in Germany (GEKID).
This report includes nationwide analyses of incident cancer cases through
the year 2010. The data for this report were transferred to the ZfKD in
anonymised form by all German population-based cancer registries. As in
previous years, cancer incidence and mortality are presented by age and
sex. Current trends are analysed and put into international context. Additional focus is placed on prevalence, five-year survival and tumour extent
(T-stage) at diagnosis. The spectrum of presented localisations was expanded again to include mesothelioma and vulvar cancers, among others.
For the year 2010, the RKI estimates that 477,300 cases of invasive cancer were newly diagnosed. The annual number of incident cases increased
by approximately 16% among men and 11% among women from 2001
to 2010. As with previous estimates, the most common cancer sites were
the prostate among men, with 65,800 cases, and the breast among women, with 70,300 cases. These were followed by colorectal cancers among
women and lung cancers among men.
The ZfKD may provide, upon application, the verified dataset from the
population-based cancer registries to third parties for analyses. Furthermore, the Homepage of the ZfKD has been expanded to include an interactive database.
Anmerkung: Die Krebsregisterdaten wurden auf Vollzähligkeit geprüft und endgültig ausgewertet. Die Ergebnisse im zweiten Absatz wurden demensprechend
aktualisiert.
ID 155
Strengthening and protecting families – how to handle
the familial colorectal cancer risk. A prospective
observational study – concept, structure, and first
experience
Internationally agreed lymphoma classification: Different
applications lead to strongly different incidence figures
K.-H. Adzersen1, S. Friedrich1, N. Becker2
Deutsches Krebsforschungszentrum, Epidemiologisches Krebsregister
Baden-Württemberg, Heidelberg, Deutschland
2
1
After decades of competing and incommensurable lymphoma classifications, the WHO classification of 2001 for ‘Tumours of Haematopoietic
and Lymphoid Tissues’ was the first internationally agreed classification
for this important and complex group of malignancies. It promised internationally comparable incidence figures and e.g. the potential to pool
epidemiologic data from different countries for common evaluations.
However, looking into details of the practical use of the WHO classification reveals partially substantial differences leading to strongly different
incidence figures.
We used the data of the Federal State Cancer Registry of Baden-Württemberg from the years 2010 and 2011 and applied three different variants of
usage of the classification for computing incidence figures: (a) the original WHO classification, renewed in 2008, (b) the European Network of
Cancer Registries (ENCR), Haemacare 2009, and (c) the grouping of RKI
(Robert Koch Institute) using the International Classification of Diseases
10th revision 2010 (ICD-10-GM).
The WHO classification comprises 56 specific NHL morphologies, the
ENCR 51 and the RKI grouping ICD-10 (2010) 28, leading to 3912 NHL
cases (WHO), 3509 (ENCR) and 2792 (RKI), respectively.
Lymphomas belong to the cancer sites for which long-lasting upwards
trends in incidence have been observed. For a reliable description of future trends and the analysis of their determinants, a common disease definition is indispensible. The currently existing strong differences in the
application of internationally agreed standards require urgently consensus
arrangements at least among the cancer registries to ascertain comparability.
U. Mansmann, G. Wölke, J. Engel, J. Stausberg
LMU München, IBE, München, Deutschland
Background: Lynch defines patients with familial colorectal cancer
(CRC) risk as those with two or more first- or second-degree relatives
(or both) with CRC. They make up about 20 percent of all CRC patients.
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ID 225
On the way towards an ‘Evidence Based Cancer
Registration Software’ for Clinical Cancer Registries
and Organ Centers – an experience report of the
Comprehensive Cancer Center Ulm
W. Voigt1, P. Kuhn1, E. Kuhn2
Universitätsklinikum Ulm, CCCU Comprehensive Cancer Center Ulm,
Ulm, Deutschland
2
Fachochschule Trier, Wirtschaftsinformatik, Trier, Deutschland
Conclusion: The number of patients with bisphosphonate-associated osteonecrosis of the jaws has increased in the recent years despite preventive measures that have been implemented and which were not able to reduce the overall number of osteonecroses. Reasons might be an increased
alertness regarding the disease so that more necroses are being diagnosed
and that more bisphosphonates hav e been prescribed.
1
Issue: In context of the «Nationaler Krebsplan», an initiative of the German government, the cancer registries play an important role in the field
of quality assurance, to improve the cancer patient care. The directives of
the registries are data reduction and economy. The problem is, to find an
adequate software to register the data needed as prescribed.
Methods: In developing our registration program within a group of
14 clinics [1], we tried to follow the rules of Evidence based Medicine
(EBM). EBM means, the diagnostic or therapeutic measurement has to
be proofed by scientific methods. How can you prove the evidence of a
program? The evidence can be proved 1.) by the contentedness of the users 2.) by the quality of the software (functional, user friendly, only basic
data needed, economical, correctness of data), and 3.) by application (by
taking part in national benchmarking, in the certification process of the
organ centers and by fulfilling the requirements of the national and state
registries.
Results: To 1: this is shown by a survey of the user group, to 2: this is
shown by the way, the system has been designed and is continually enhanced to 3: this is shown by benchmarking samples on the «Deutscher
Krebskongress» and by the number of certifications of the Organ centers
Conclusion: Our model: ‘CREDOS user group’ is very close to the requirements of EBM. It supports the requirements of the data registration
in the best possible way and enables the registries to generate data, which
help to control and ensure the best treatment for our cancer patients. Nevertheless the quality of a cancer register depends on the quality of the
documentaries (knowledge, experience and most important of all: motivation)
[1]www.ccc-ulm.delast entry: 14.9.2013.
ID 236
Bisphosphonate associated osteonecrosis of the jaws,
osteoradionecrosis and osteomyelitis
C. Walter1, K. Sagheb1, J. Bitzer1, R. Rahimi-Nedjat1, K.J. Taylor2
1
2
Universität Mainz, MKG-Chirurgie, Mainz, Deutschland
Universität, IMBEI, Mainz, Deutschland
Introduction: Several reasons can lead to osteonecrosis of the jaws. In
addition to medication such as bisphosphonates, osteonecrosis can be
caused by radiation therapy or local factors. The aim of this study was
to analyse the distribution of osteonecrosis of the jaws in patients being treated in an oral and maxillofacial surgical department and to detect
changes in the distribution by comparing the latest data with an earlier
study.
Material and Methods: All patients with either osteonecrosis of osteomyelitis treated from April 2005 until July 2012 were analysed. In case
of recurrence of the disease or synchronous presence of several affected
areas, the patient was only counted once. The results were compared to
a similar study performed with patients treated from January 2000 until
April 2005.
Results: In 45% bisphosphonates were responsible for the osteonecroses.
Odontogenic or surgically-induced osteonecroses were present in 32%.
17% had an osteoradionecrosis; in 4% a trauma was the reason for the
necroses, and in another 4% no reason was obvious. From 2000 to 2005
only 10% of all necroses were caused by bisphosphonates. Aside from
bisphosphonate-associated osteonecrosis, all other reasons did not change
their frequency between the two studies.
36
ID 252
Krebsregisterdokumentation im Praxisalltag
A. Matzdorff1, F. Kowalski1, T. Muche1, A. Fuchs1, C. Stegmaier2
Caritasklinikum Saarbrücken, Klinik f. Hämatologie/Onkologie, Saarbrücken, Deutschland
2
Epidemiologisches Krebsregister Saarland, Saarbrücken, Deutschland
1
Einleitung: Im April ist das Gesetz zur Krebsfrüherkennung und zur
Qualitätssicherung durch klinische Krebsregister in Kraft gesetzt worden.
Die Arbeitsgemeinschaft Deutscher Tumorzentren (ADT) hat dafür einen
einheitlichen onkologischen Basisdatensatz entwickelt.
Fragestellung: Wie hoch ist der Zeitaufwand bei der Anwendung des
ADT-Basisdatensatzes und welche Probleme ergeben sich in der klinischen Praxis?
Methode: Für 20 aufeinanderfolgende Patienten einer hämato-onkologischen Kliniksambulanz eines Tages wurde der Basisdatensatz erhoben.
Ergebnisse: Der Zeitaufwand betrug 50 min pro Fall (Durchsicht der
Papierakte, der Eintragungen im KIS, ggf. Rückfragen beim Arzt). Probleme ergaben sich bei (Auswahl):
–– Unterschiedliche ICD-10 und TNM-Klassifikationen in Berichten verschiedener Institutionen. Fehlen der ICD-O.
–– Fehlende Histologie (z.B. multimorbide Patienten, die für eine tumorspezifische Therapie nicht in Frage kommen).
–– Patienten, die an verschiedenen, z.T. räumlich oder zeitlich weit auseinanderliegenden Orten behandelt werden.
–– Patienten mit mischzelligen Tumoren oder mit mehreren gleichzeitig
behandelten Tumoren.
–– Erfassung von neuen Wirkstoffen (Tyrosinkinasehemmern).
–– Problematische Fragen des ADT Fragebogens: ob von Leitlinien abgewichen wurde, ob ein Tumorkonferenzbeschluss vorgelegen hat.
Schlussfolgerung: Der ADT-Basisdokumentationsbogen erfasst Daten,
die über die Vorgaben der Onkologie-Vereinbarung und die Empfehlungen der Fachgruppen (z.B. Grundsatzpapier der DGHO „Onkologische
Zentren») hinausgehen und in Arztberichten nicht abgebildet werden. Der
Zeitaufwand für die Basisdokumentation ist erheblich .
ID 258
The Risk of Developing Subsequent Primary Tumour
among Adult Patients with Leukaemia and Lymphoma in
Germany
N. Baras1,2, S. Dahm1, J. Haberland1, K. Kraywinkel1
Robert-Koch Institute, German Centre for Cancer Registry Data, Berlin,
Deutschland
2
Charité – Universitätsmedizin, Berlin, Deutschland
1
Background: Survivors of lymphoma and leukaemia have been reportedly shown to be at increased risk for developing other primary malignancies.
Methods: We used the national German cancer registry database pooled
from 14 population-based cancer registries to calculate the incidence of
subsequent tumours among patients with first primary Hodgkin lymphoma (HL, C81), Non-Hodgkin lymphoma (NHL, C82–C85), multiple myeloma (MM, C90) and leukaemia (C91–C95) diagnosed between 1970
and 2010. The ratio of the observed and the expected numbers of subsequent tumours (standardized incidence ratio, SIR) was evaluated using
the population-based incidence rates.
Results: A total of 209,429 cases were diagnosed with lymphoma and
leukaemia, and were followed for 2,982,409 person-years between 1970
and 2010. Among these cases, 11,680 (6%) subsequent tumours, 10,022
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of which were solid tumours (C00–C75) were observed in both sexes.
The overall risk of subsequent tumours at any site was significantly elevated after HL (SIR = 2.33, CI: 2.17–2.50), NHL (SIR = 1.51, CI: 1.47–
1.55), and leukaemia (SIR = 1.45, CI: 1.40–1.50). There was a very slight
increase in the overall risk after MM (SIR = 1.11, CI: 1.06–1.17). The risk
of developing a solid tumour was significantly increased between 7% (CI:
2–13%) after MM and 80% (CI: 65–95%) after HL. We found consistently increased risks for the following solid subsequent tumours after HL,
NHL and Leukaemia: oropharynx, stomach, colon and rectum, lung, skin
melanoma, and kidney. Significant excess risks for subsequent cancers of
the thyroid and female breast were only found after HL and NHL.
Conclusion: Despite somewhat limited follow-up time for some registries, the pooled German data showed an increased risk of developing
subsequent malignancies for leukaemia and lymphoma patients compared
to the general population which is consistent with other population-based
studies.
ID 283
Breast cancer survival in Germany – a population-based
high resolution study from Saarland
B. Holleczek1,2, L. Jansen2, H. Brenner2
Saarland Cancer Registry, Saarbrücken, Deutschland
Division of Clinical Epidemiology and Aging Research, German Cancer
Research Center, Heidelberg, Deutschland
implementation of the program and could be seen as a necessary condition for a screening related reduction of breast cancer mortality several
years later.
Methods: We analyzed data of nine German population based cancer registries which covered 13of 16 federal states and one district for the time
period 2002–2010. We calculated age standardized stage specific incidence rates for the age groups 30 to 49, 50 to 69 and 70 years and older.
Results: Following a temporary increase, the pooled incidence rate of
advanced breast cancer (UICC II–IV) in the target population reached
its pre-mammography level in 2010, while the incidence rate of early
breast cancer (UICC I) in 2010 was still more than 40% higher compared
to the years 2002–2004. In the district of Muenster, where the program
was implemented until 2006, the rate of advanced stage tumors was 8%
lower in 2010 compared to the initial rate. For older and younger women a slight increase of advanced breast cancer incidence could be observed. The completeness of stage information improved especially for
the screening age group.
Conclusions: The time trends of stage specific incidence rates so far
seem to follow the expected course: far more early stage tumors are being
detected than before implementation of screening, while there are first
indications that the rates of advanced breast cancer incidence might be
reduced about 5 years after implementation of the program.
1
2
Background: Population-based survival studies of breast cancer patients
are commonly restricted to age- and stage-specific analyses. This study
from Germany aimed at extending available population-based survival
data on further prognostic cancer characteristics such as tumor grade, hormone receptor status and human epidermal growth factor receptor type 2
(HER2/neu) expression.
Material and Methods: Data from the population-based Saarland Cancer Registry including female patients diagnosed with invasive breast
cancer between 2000 and 2009 were included. Period analysis methodology and regression modelling were used to obtain estimates of 5-year
relative survival and tumor related excess risks in 2005–2009.
Results: Overall age standardized 5-year relative survival was 83%. In
addition to age and stage, tumor grade and hormone receptor status were
independent predictors of 5-year relative survival. Detailed analyses by
age, stage, morphology, tumor grade, hormone receptor status and HER2/
neu expression consistently revealed lower survival of patients with high
grade, hormone receptor negative or HER2/neu positive cancers and patients aged 70 years or older.
Conclusion: This high resolution study extends available population-based survival data of breast cancer patients. Particular efforts
should be made to overcome the persisting large survival deficits, which
were observed for elderly patients in all clinical subgroups.
Reference
Holleczek B, Jansen L, Brenner H (2013) Breast Cancer Survival in Germany:
A Population-Based High Resolution Study from Saarland. PLoS ONE 8(7):
e70680.
ID 317
Time trends of stage specific incidence rates of invasive
breast cancer over the first years of the German
Mammography Screening Program
K. Kraywinkel1, U. Batzler2, A. Katalinic3
1
2
3
Krebsregister NRW, Münster, Deutschland
Universität Lübeck, Institut für Krebsepidemiologie, Lübeck, Deutschland
Background: The German Mammography Screening Program has been
introduced between 2005 and 2009 for all women between 50 and 69
years of age. An important parameter for the assessment of its effectiveness is the incidence of advanced malignant breast tumors in the target
population. A decrease of this rate would be expected at some point after
Abstracts
ID 382
Volume of screening colonoscopy increases detection
rate of non-advanced adenoma but not of advanced
adenoma
N. Zwink1, C. Stock2, M. Hoffmeister1, B. Birkner3,4, H. Brenner1
German Cancer Research Center (DKFZ), Division of Clinical Epidemiology and Aging Research, Heidelberg, Deutschland
2
Institute of Medical Biometry and Informatics (IMBI), Department of Medical Biometry, Heidelberg, Deutschland
3
Gastroenterology Practice, Munich, Deutschland
4
Bavarian Association of Statutory Health Insurance Physicians, Munich,
Deutschland
1
Background & Aims: Adenoma detection rates (ADR) have been suggested as an indicator of the quality of screening colonoscopy. The aim
of this study was to assess the inter-physician variation in ADR in routine
practice in the German healthcare system.
Design: Cohort study.
Setting: Quality assurance program of the Bavarian Association of Statutory Health Insurance Physicians («Qualitätsmaßnahme Koloskopie»),Germany.
Patients: Individuals aged ≥55 years who underwent screening colonoscopy between 2007 and 2009.
Main Outcome Measurements: Variation in ADR (95% confidence intervals [CI]) per physician and year. Physicians were grouped according
to the number of screening colonoscopies per year (≤50, 50–99, 100–199,
≥200 colonoscopies).
Results: In total, 203,363 individuals (mean age 64 years, 55.2% women)
underwent screening colonoscopy between 2007 and 2009 in Bavaria,
Germany. Screening colonoscopies were performed by 509 physicians.
Detection rate of any adenoma (including non-advanced and advanced
adenoma) ranged from 21.0% (95% CI 20.0–22.1%) to 26.2% (95% CI
24.9–27.5%), of non-advanced adenoma from 13.0% (95% CI 12.4–
13.7%) to 17.7% (95% CI 16.8–18.6%) and of colorectal cancer from
0.8% (95% CI 0.8–0.8%) to 1.2% (95% CI 1.1–1.3%) in the group of
physicians with less than 50 to at least 200 screening colonoscopies per
year, respectively. Detection rate of advanced adenoma did not increase
with increasing colonoscopy rate per physician and varied between 8.0%
(95% CI 7.6–8.4%) and 9.1% (95% CI 8.7–9.6%).
Conclusions: The overall ADR as an indicator of the quality of screening colonoscopy must be treated with caution. Stratification showed the
volume of screening colonoscopies to be related to the detection rate of
non-advanced adenomas only but not of advanced neoplasms.
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ID 444
Clinical Practice of Gastric Cancer Diagnosis and
Treatment in Upper Franconia: Potential and Pitfalls of
Cancer Registration
D. Salomo1,2, D. Eckert2, T. Maisel1,2, A. Kiani1,2
1
2
Klinikum Bayreuth GmbH, Medizinische Klinik IV, Bayreuth, Deutschland
Tumorzentrum Oberfranken e.V., Bayreuth, Deutschland
In several regions of Germany, population-based epidemiological cancer
registries have been established, that have the task to register and analyze
the incidence, regional distribution and mortality of all tumor entities.
In bavaria, for example, six regional cancer registries cover more than
95% of all cancer cases. The quality of the registry data depends on the
information provided by the reporting physician, and the accuracy of the
data is largely unknown. In addition, epidemiological cancer registries
do not contain detailed clinical information about the disease. The aim
of the current study was to retrospectively analyze the completeness and
accuracy of a given data set of an epidemiological cancer registry, and to
supplement this data by specific enquiry with clinical information.
All 222 patients diagnosed in 2007 with gastric cancer and registered in
the epidemiological cancer registry of upper franconia were analyzed. A
questionnaire was developed, in which all clinically relevant modalities
of gastric cancer diagnosis and treatment were addressed. The registry
data was analyzed before and after the questionnaire was sent to the treating physicians.
Before the enquiry, the epidemiological data necessary to assess tumor
prognosis was incomplete. For example, information about the UICC
stage was lacking in 30%, but could be obtained by enquiry in 95% of the
patients. Clinical data was scarce, but could be complemented to a great
extent by enquiry. Information about the practice of cancer treatment in
upper franconia was obtained.
Clinical registries will be important tools to analyze the practice of cancer
treatment on a population basis, but the quality of the data must be verified in order to obtain reliable information.
ID 446
Elderly cancer patients want information but no
participation in onco-surgical treatment decisions.
Observational study in two tertiary university hospitals.
M. Schmidt, B. Neuner, F. Degel, C. Spies
Charité Universitaetsmedizin Berlin, Klinik für Anästhesiologie m. S. operative Intensivmedizin, Berlin, Deutschland
Introduction: The relationship between physician and patients has undergone important changes. Emancipation of patients has led to real
partnership in medical decision-making.Objectives: To evaluate elderly
(>65 years) onco-surgical patients desire for autonomy and information
in clinical decision making.
Methods: Between February 2010 and September 2012 and after ethical
committee approval and written informed consent the study was conducted in 2 tertiary university hospitals in Germany. Included patients
were older than 65 years and were scheduled for abdominal onco-surgery.
The need for information and involvement were evaluated using the Autonomy Preference Index (API) before surgery. Basic demographic data
included age, gender, cancer site, marital status and educational level.
Multivariate analysis was done by linear regression analysis.
Results: Overall 658 patients (mean age 71.8 years, 68.4% males) were
included. Cancer sites were prostate cancers (38.8%), ovarian cancers
(13.7%), cancers of the genitourinary tract (16%), upper gastrointestinary
tract (21.1%) and colorectal cancers (10.5%). Sixty-seven per cent of the
patients were married, 10% were widowed, 9% were divorced and 6%
lived alone. One third (32%) of the patients had 12 to 13 years of education. The mean API for participation (DPMS) score was 39 (SD 5.1)
whereas the API for information showed a ceiling effect. In multivariate analysis adjusted for age, marital status, educational level and cancer
site, only gender (female vs male, p = 0.004, CI 95% -10,22 – -1.92) was
38
found to be an independent predictor for need of information and participation. Conclusion: The majority of elderly onco-surgical patients want
to be informed about their disease and their treatment. The desire for participation in treatment decisions is low. Women want to be more actively
involved in treatment decisions than men.
Functional Imaging
ID 054
Assessment of therapy effects in lymphoma patients
at end-of-treatment using volume perfusion computed
tomography (VPCT)
M. Horger, C.D. Claussen, R. Syha
Eberhard-Karls-Universität Tuebingen, Radiologische Diagnostik, Tübingen, Deutschland
Purpose: To determine the diagnostic benefit of using volume perfusion
computed tomography (VPCT) at end-of-treatment for response assessment in lymphoma patients.
Materials and Methods: 75 patients with different lymphoma subtypes
were prospectively enrolled. The local ethics board approved this study.
50/75 patients presented residual masses at end-of-treatment. 26/50 patients underwent VPCT both at baseline and at end-of-treatment; 24/50
patients only had end-of-treatment-VPCT studies.
We measured each time size of the main lymphoma mass, its blood
flow(BF), blood volume(BV) and k-trans, and calculated ratios, their sensitivity/ specificity/negative(NPV) and positive predictive values(PPV).
For patients undergoing VPCT only at end-of-treatment, a cut-off threshold between responders and non-responders was calculated. CT-imaging
obtained >12 months afterwards was used for validation.
Results: For patients undergoing VPCT, both at baseline and end-oftreatment, the paired t-test revealed a significant reduction in size (p <
0.001), BF(p < 0.001), and k-trans (p < 0.001) for responders. For non-responders, only reduction in size (p = 0.0125) proved significant, but misleading. In aggressive lymphomas changes in all parameters proved significant. Identification of non-response in patients undergoing VPCT only
at end-of-treatment was reached only for BF (p < 0.001) at a BF value
of 18.51 (sensitivity 92.86%, specificity 72,73%, accuracy 84%, positive
predictive value 81,25%, negative predictive value 88.89%). Baseline
perfusion parameters alone did not predict response.
Discussion: VPCT seems adequate for assessment of lymphoma response
at end-of-treatment and for prediction of progression free survival.
ID 417
High specificity of Positron Emission Mammography
(PEM) in diagnosis of breast cancer
F.H.H. Müller1, M. Hentschel2, A. Müller1, J. Farahati3
Praxis für Radiologie und Nuklearmedizin, Nuklearmedizin, Ludwigshafen, Deutschland
2
Univerisität, Nuklearmedizin, Bern, Schweiz
3
Elisabeth Krankenhaus, Nuklearmedizin, Dorsten, Deutschland
1
Aim: How is the diagnostic performance of PEM, a HR-PET with intrinsic resolution of 1.6 mm and similar diagnostic sensitivity and higher
specificity in detection of breast cancer (B-Ca), compared to other diagnostic features?
Methods: PEM was performed in 119 lesions with suspicious breast lesions 90 min after i.v. application of 3.5 MBq F-18-FDG per KG body
weight. A ROI marked the target lesion, measured by the maximum PEM
uptake value (PUVmax) and was correlated with a corresponding non-target ROI in the contra lateral healthy breast determining the target/non-target ratio. Two independent readers analysed images of all 119 lesions and
compared the results to histopathology (11 PEM-Biopsies/8 Breast-Cancers) later. The group analyses for all malignant, benign, corresponding
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non-target lesions and the mean target/non-target ratio were calculated by
paired Student t-Test.
Results: 22 out of 119 lesions were malignant. Mean of PUVmax was
measured 4.3±2,7 in malignant lesions and 1.1±0.4 for the contra-lateral
healthy breast (p = 0.001). The mean target/non-target ratio in patients
with B-Ca of 3.7 ± 1.5 was significantly higher compared to benign lesions 1.1 ± 0.4 (p = 0.001).
Considering a PUVmax >1.9, PEM was true-positive in all 22 cancers
resulting in a sensitivity of 100%, specificity of 97%, PPV of 88% and
NPV of 100%.
Detecting of B-Ca by PEM was at it´s best observed with a PUVmax cutoff level of ≥1.9 combined with a target/non-target ratio of ≥1.4.
Conclusion: PEM can detect breast cancer with high accuracy using
PUVmax as well as target/non-target ratio even with high specificity. A
higher rate of examinations improves the accuracy of results compared to
other diagnostic features.
Gastrointestinal (Colorectal) Cancer
(including liver metastases)
ID 006
Population Pharmacokinetics Analysis of Regorafenib
and its active Metabolites from the Phase III CORRECT
study of metastatic colorectal cancer
M. Karthaus1, Z. Jirakova Trnkova2, A. Grothey3, A. Sobrero4,
S. Siena5, A. Falcone6, M. Ychou7, Y. Humblet8, O. Bouché9,
L. Mineur10, C. Barone11, A. Adenis12, J. Tabernero13, T. Yoshino14,
H.J. Lenz15, F. Cihon16, S. Reif2, D. Laurent2, K. Diefenbach17,
E. van Cutsem18
Städtisches Klinikum München, Klinikum Harlaching, München, Deutschland
2
Bayer Healthcare, Berlin, Deutschland
3
Mayo Clinic, Division of Medical Oncology, Rochester, Vereinigte Staaten
Von Amerika
4
San Martino Hospital, Genua, Italien
5
Ospedale Niguarda Ca‘ Granda, Mailand, Italien
6
Istituto Toscano Tumori, Pisa, Italien
7
CRLC Val d‘Aurelle, Montpellier, Frankreich
8
St. Luc University Hospital, Brüssel, Belgien
9
Centre Hospitalier Universitaire Robert Debrét, Reims, Frankreich
10
Institut Saint-Catherine, Avignon, Frankreich
11
Universita Cattolica des S.Cuore, Roma, Italien
12
Centre Oscar Lambret, Lille, Frankreich
13
Vall d‘Hebron University Hospital, Barcelona, Spanien
14
National Cancer Center Hospital East, Kashiwa-City, Japan
15
University of Southern California Norris Comprehensive Cancer Center,
Los Angeles, Vereinigte Staaten Von Amerika
16
Bayer HealthCare Pharmaceuticals, Montville, Vereinigte Staaten Von
Amerika
17
Bayer Pharma AG, Berlin, Deutschland
18
Leuven Cancer Institute, Leuven, Belgien
1
Background: The aim of this study was to develop a population pharmacokinetics (PK) model for Regorafenib (REG) and its two active metabolites M-2 and M-5, and to use this model for evaluation of covariate
effects in the phase III CORRECT study.
Methods: A population PK model for REG, M-2, and M-5 was developed with NONMEM, based on PK data from a phase I dose-escalation
study. Subsequently, this model was applied to the sparsely sampled
CORRECT study, by systematically estimating one or more parameters,
while fixing the remaining parameters, until the best model was obtained.
A model-based covariate analysis was performed to explore the impact of
patient demographics and baseline parameters on drug exposure in CORRECT. PK data from 67 densely sampled pts (study 11650) and from 381
sparsely sampled pts (CORRECT)were used.
Abstracts
Results: PK of REG, M-2, and M-5 were described by a 2-compartmental
model. Derived PK parameter estimates were used to calculate the individual exposure (Cavmd) of REG, M-2, and M-5 in CORRECT. Overall,
a moderate to high variability in the REG PK was observed in CORRECT, with a coefficient of variance of clearance of 44% and even higher
variability in exposure to M-2 and M-5. Covariate analysis of CORRECT
showed that higher bilirubin levels at baseline were associated with
higher individual exposure of REG and M-2. Higher body weight was
associated with lower exposure of M-2 and M-5, and exposure of M-5
was higher in women than in men. The magnitude of observed covariate
effects was small compared with the overall high variability in exposure.
Conclusion: The combined population PK model adequately described
the PK profiles of REG and its two active metabolites M-2 and M-5, in
the phase I and in the phase III study. The effects of the covariates tested
in population PK analysis of the CORRECT data were not considered
clinically relevant in light of the overall high variability in exposure.
ID 007
Regorafenib dose modifications in patients with
metastatic colorectal cancer in the phase III CORRECT
study
M. Karthaus1, A. Falcone2, E. van Cutsem3, A. Sobrero4,
S. Siena5, M. Ychou6, H.J. Lenz7, T. Yoshino8, F. Cihon9,
A. Wagner10, A. Grothey11
Städtisches Klinikum München, Klinikum Harlaching, München, Deutschland
2
3
4
5
6
7
8
9
Amerika
10
11
Von Amerika
1
Background: CORRECT (NCT01103323) was a randomized, double-blind, placebo-controlled, phase III study that evaluated regorafenib
(REG) in patients (pts) with metastatic colorectal cancer (mCRC) that had
progressed on standard therapy. REG-treated pts showed a clinically significant improvement in overall and progression-free survival vs placebo
(P). Adverse events (AEs), such as hand-foot skin reaction (HFSR), could
be managed with dose interruptions or reductions.
Methods: The CORRECT study randomized pts to receive REG 160
mg or P once daily for weeks 1–3 of each 4-week cycle. AEs could be
managed with interruption or a reduction in treatment dose by 40 mg.
In addition, the study protocol provided specific dose modification recommendations for HFSR, hypertension and liver function abnormalities.
Results: 753 pts (500 REG, 253 P) received at least one dose of treatment
(median 2 cycles in each group, mean 3.3 cycles of regorafenib, 2.3 cycles of placebo). Dose modifications were reported in 76% of REG-treated pts and 38% of P recipients. The most common AEs requiring dose
reduction were HFSR (18% of REG-treated pts vs 0.4% of P recipients),
diarrhea (4% vs 0%), hypertension (3% vs 0.4%), fatigue (3% vs 2%), and
rash/desquamation (3% vs 0%). The most common AEs requiring dose
interruption were HFSR (19% vs 0%), fatigue (6% vs 2%), diarrhea (6%
vs 1%), rash/desquamation (5% vs 0%), and hypertension (3% vs 0.4%).
AEs leading to permanent discontinuation were reported in 18% and 13%
of pts in the REG and P groups, respectively.
Conclusion: Although significantly more REG-treated pts than P recipients had dose modifications due to AEs, the difference in the incidence of
permanent treatment discontinuation was relatively small. This suggests
that dose modifications are effective for managing AEs, and allow pts to
continue REG treatment.
39
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Index
ID 008
A. Stein1, S. Siena2, A. Grothey3, A. Sobrero4, A. Falcone5,
M. Ychou6, H.J. Lenz7, T. Yoshino8, F. Cihon9, V. Pawar9,
E. van Cutsem10
Hubertus Wald Tumorzentrum, II.Medizinische Klinik und Poliklinik, UKE,
2
Ospedale Niguarda Ca’ Granda, Mailand, Italien
3
Von Amerika
4
5
6
CRLC Val d’Aurelle, Montpellier, Frankreich
7
8
9
Amerika
10
1
Background: In the phase III CORRECT trial, regorafenib (REG)
showed signif. improvement in OS and PFS vs placebo (P) in patients
(pts) with mCRC whose disease had progressed on standard therapies.
We examined the impact of REG efficacy and tolerability on quality of
life (QoL).
Methods: CORRECT was an international multicenter, randomized, placebo-controlled trial sponsored by Bayer HealthCare. Adults with mCRC
progressing after all standard therapies were randomized 2:1 to receive
REG 160 mg (n = 505) or P (n = 255) once daily for the first 3 weeks
of each 4-week cycle. Prespecified QoL analyses were undertaken using the EORTC QLQ-C30 and EQ-5D. QoL outcomes were expressed
as time-adjusted area under the curve (AUC) to allow descriptive evaluations of QoL in the REG and P groups across the entire treatment period.
Individual domains were compared using descriptive statistics.
Results: Overall, changes in QoL were similar in the REG and P groups:
difference in least-squares (LS) mean time-adjusted AUC of EORTC
QLQ-C30 score: –1.19 (95% confidence interval [CI] –3.13 to 0.75);
differences in LS mean time-adjusted AUC for EQ-5D index and visual
analog scale (VAS) scores: 0.00 (95% CI –0.03 to 0.03) and –1.21 (–3.04
to 0.61), resp. Changes from baseline did not differ between Reg and P on
most of the 6 domains assessed in the EORTC QLQ-C30. Change from
baseline on the role functioning scale was similar overall in both groups,
although scores appear to differ between REG and P at cycles 3 and 4 for
the diarrhea subscale and at cycle 4 for the social functioning subscale.
Conclusion: No substantial differences in overall change in QoL were
seen between REG-treated pts and P recipients. Role functioning may be
impaired by AEs, but remained similar in both groups; management of
AEs with dose modifications may improve role functioning and diarrhea
in REG-treated pts.
ID 009
Time to health status deterioration in regorafenib-treated
patients with metastatic colorectal cancer (mCRC): a
post-hoc analysis of the phase III CORRECT study
A. Stein1, V. Pawar2, A. Grothey3, A. Sobrero4, S. Siena5,
A. Falcone6, M. Ychou7, H.J. Lenz8, T. Yoshino9, A. Wagner10,
E. van Cutsem11
Hubertus Wald Tumorzentrum, II.Medizinische Klinik und Poliklinik, UKE,
2
Amerika
3
Mayo Clinic, Rochester, Vereinigte Staaten Von Amerika
4
5
6
7
1
40
9
10
11
8
Effects of regorafenib therapy on health-related quality
of life in patients with metastatic colorectal cancer in the
phase III CORRECT study
Background: The phase III CORRECT study was a randomized, double-blind, placebo-controlled study. The study showed that regorafenib
(REG) improved OS and PFS in pts with mCRC refractory to standard
therapy. This post-hoc analysis assessed time to deterioration (TTD) of
health status in CORRECT.
Methods: Pts with mCRC progressing after all standard therapies were
randomized to receive REG 160 mg (n = 505) or placebo (P; n = 255)
once daily for weeks 1–3 of each 4-week cycle. TTD was analysed using
three definitions of deterioration: a 3-component composite of ≥10 point
reduction in EORTC QLQ-C30 global health status (GHS) score, disease
progression, or death; a 2-component composite of ≥10 point reduction in
GHS score or death; and ≥10 point reduction in GHS score alone. Additional analyses assessed these endpoints using physical functioning (PF)
score in place of GHS.
Results: REG was associated with significantly longer TTD vs P when
assessed with the GHS-based 3-component endpoint (hazard ratio [HR]
0.77; 95% confidence interval [CI] 0.65–0.91; pvs P using the 2-component composite and GHS only definitions (HR 0.91; 95% CI 0.75–1.09;
p = 0.35 and HR 0.96; 95% CI 0.77–1.20; p = 0.80, respectively). Results
for analyses performed with the PF-based endpoints were consistent with
those for GHS, with HRs for the 3-component, 2-component, and PF-only endpoints of 0.74; 0.62–0.88.
Conclusion:REG is associated with a significantly longer median TTD
than P when deterioration is measured using a 3-component composite
endpoint, but not when deterioration is measured using a 2-component
endpoint or GHS alone. This suggests that deterioration in health status in
this patient group is driven by disease progression, not by quality of life.
The 1 and 2-component analyses should be interpreted with caution due
to high patient censoring.
ID 045
Stage-specific associations between beta blocker use
and prognosis after colorectal cancer
L. Jansen1, M. Hoffmeister1, V. Arndt1, J. Chang-Claude2,
H. Brenner1,3
Deutsches Krebsforschungszentrum (DKFZ), Abteilung für klinische
Epidemiologie und Alternsforschung, Heidelberg, Deutschland
2
Deutsches Krebsforschungszentrum (DKFZ), Abteilung Krebsepidemiologie, Heidelberg, Deutschland
3
Deutsches Konsortium für Translationale Krebsforschung (DKTK), Heidelberg, Deutschland
1
Background: Recent observational studies have suggested that use of
beta blockers might be associated with better prognosis among patients
with various cancer sites. As evidence is limited for colorectal cancer, we
investigated the association of beta blocker use and prognosis in a large
population-based cohort of colorectal cancer patients.
Methods: Between 2003 and 2007, information on beta blocker use at
diagnosis and potential confounders was collected by personal interviews
for 1,975 colorectal cancer patients. Vital status, cause of death, and
recurrence status were assessed during a median follow-up time of 5.0
years. The associations of beta blocker use and overall, colorectal cancer
specific, and recurrence-free survival were estimated by Cox proportional
hazard regression. In addition, beta blocker subgroup, site, and stage-specific analyses were performed.
Results: After adjustment for covariates including socio-demographic,
cancer-related and lifestyle factors as well as comorbidity and medications, no significant association between beta blocker use at diagnosis and
prognosis was observed for all stages combined. However, in stage-specific analyses beta blocker use was associated with longer overall survival (hazard ratio: 0.50, 95% confidence interval: (0.33–0.78), p = 0.0023)
and CRC specific survival (0.47 (0.30–0.75), p = 0.0017) in stage IV pa-
Abstracts
Inhalt
Index
tients. For these patients, median overall survival was 18 (38 versus 20
months) and colorectal cancer specific survival was 17 months longer (37
versus 20 months) for beta blocker users than for non-users.
Conclusion: Our results suggest that beta blocker use might be associated
with longer survival in stage IV colorectal cancer patients.
ID 056
The prognostic inhomogeneity of ypT3 in mid and low
rectal carcinomas after neoadjuvant chemoradiotherapy
S. Merkel1, K. Weber1, V. Schellerer1, J. Göhl1, R. Fietkau2,
A. Agaimy3, W. Hohenberger1, P. Hermanek1
Universtätsklinikum Erlangen, Chirurgische Klinik, Erlangen, Deutschland
Universitätsklinikum Erlangen, Strahlenklinik, Erlangen, Deutschland
3
Universitätsklinikum Erlangen, Pathologisches Institut, Erlangen,
Deutschland
1
2
Introduction: In 2001, we demonstrated the prognostic differences between pT3 rectal carcinomas with invasion into the perirectal fat up to
5 mm (pT3a) and those with more than 5 mm (pT3b) in patients with
surgery alone. pT3a carcinomas had a significant lower rate of locoregional recurrences and a superior cancer-related survival (similar to pT2)
compared to pT3b carcinomas (similar to pT4). Now we analysed the
prognostic impact of the subdivision of ypT3 carcinomas after neoadjuvant chemoradiation (nCRT).
Methods Data from 300 consecutive patients with nCRT and curative
resection of a rectal carcinoma (<12 cm) between 1995 and 2007 were
analysed. In the category ypT3 a subdivision was performed based on
the maximal tumour invasion beyond the outer border of the muscularis
propria: ypT3a ≤5 mm (n = 81), ypT3b >5 mm (n = 43).
Results: Significant differences between ypT3a and ypT3b were found in
locoregional recurrences (5-year rate 6.5% vs 17.5%; p = 0.049), distant
metastases (20.1% vs 41.1%; p = 0.002), disease-free (72.8% vs 46.5%;
p = 0.001), observed (79.0% vs 74.4%; p = 0.036) and cancer-related
survival (81.3% vs 74.4%, p = 0.007). ypT3a behaved more similarly to
ypT2, while ypT3b behaved more similarly to ypT4. Apart from locoregional recurrences this could be confirmed for ypN0 carcinomas. The
ypT3 subclassification was identified as an independent prognostic factor
for disease-free, observed and cancer-related survival. The ypN category
had no prognostic impact in ypT3 carcinomas.
Conclusion: In ypT3 rectal carcinoma, the proposed subclassification is
superior to ypN classification in predicting prognoses. Further validation
is recommended prior to inclusion of the T3 subclassification into the
official TNM staging system.
ID 088
A lymph node count <12 has no prognostic impact in
colorectal cancers when lymph node examination follows
current quality standards
H. Bläker1, B. Hildebrandt2, H. Riess2, M. von Winterfeld1,
B. Ingold-Heppner1, W. Roth3, M. Kloor3, P. Schirmacher3,
M. Dietel1, S. Tao4, L. Jansen4, J. Chang-Claude5, A. Ulrich6,
H. Brenner4, M. Hoffmeister4
Charite Universitätsmedizin, Institut für Pathologie, Berlin, Deutschland
Charite Universitätsmedizin, Abteilung Onkologie, Berlin, Deutschland
3
Universität Heidelberg, Institut für Pathologie, Heidelberg, Deutschland
4
Deutsches Krebsforschungszentrum, Abteilung Klinische Epidemiologie
und Alternsforschung, Heidelberg, Deutschland
5
Deutsches Krebsforschungszentrum, Abteilung Krebsepidemiologie,
Heidelberg, Deutschland
6
Universitätsklinik Heidelberg, Chirurgische Klinik, Heidelberg, Deutschland
1
2
Purpose: Previous studies on colorectal cancers report an association of a
low lymph node yield with adverse outcome. The quality of lymph examination in the studied cohorts, however, was lower than current standards.
Improvement of lymph node examination may influence the prognostic
impact of a low lymph node count. Thus, we investigated the prognostic
Abstracts
impact of a lymph node count <12 in cohort of cancers diagnosed according to current quality standards.
Patients and Methods: Colorectal cancers from 1899 patients enrolled
into a population based study were investigated. Cancers were diagnosed
between 2003 and 2007 and included 441 stage I, 588 stage II, 610 stage
III, and 260 stage IV cases. The prognostic impact of a lymph node count
<12 was analysed.
Results: A lymph node count <12 was more common in patients with
cancers of low tumor stage, low T-category, and left sided location
(p < 0.0001, each). After a median follow-up time of 4.9 years, no impact of a lymph node count <12 on overall, cancer specific, or disease
free survival was observed (adjusted hazard ratios 1.04-1.06). Compared
to studies reporting an adverse prognostic impact of a low lymph node
count, adherence to the 12 lymph node minimum was significantly higher
in the present study (79%).
Conclusions: This is the first study to investigate the prognostic impact of
lymph node count <12 in a cohort of colorectal cancers in which almost
80% of cases were diagnosed compliant with the 12 node minimum. Our
study does not reveal an association of <12 investigated lymph nodes
with adverse outcome for any tumor stage, questioning integration of a
low lymph number as a risk factor in stage II disease.
ID 089
The colorectal carcinoma – treatment research and
treatment reality in oncology practices
F. Strohbach1,2, R. Göttel3, H.-W. Tessen2,4
Onkologische Schwerpunktpraxis Berlin, Berlin, Deutschland
Projektgruppe Internistische Onkologie (PIO), Goslar, Deutschland
3
rgb Onkologisches Management GmbH, Sarstedt, Deutschland
4
Onkologische Schwerpunktpraxis Goslar, Goslar, Deutschland
1
2
Approach: Which share does a continuous, systematic case documentation and evaluation contribute to treatment research?
Methods: Data from oncology practices from 2003 to 2013 (PIO), analysis of the ONCOReg. index, 7,142 histories of diseases in 118 oncology
practices from 15 federal states.
Results: Pat. in UICC-state I: 220 (3%), II: 929 (13%), III: 3,214 (45%),
IV: 2,685 (38%), n/a: 94 (1%)
Gender: m: 4,285 (60%), f: 2,857 (40%)
Age: median 66 (18–92) years
Primary Surgery.: 6,626 (93%) pat.
Adjuvant Ctx: 3,813 (53.4%) pat., 2,580 (68%) of which with Oxaliplatin, 607 (24%) of which > 70 years, 50 (19%) in UICC-state II.
Palliative Ctx: 4,655 pat. had spread metastasis.
A resection of metastasis was performed on 750 (16%) of the patients.
4,613 (99%) of the patients received a 1st-line ctx, 3,079 (66%) a 2ndline, 1,589 (34%) a 3rd-line, 723 (16%) a 4th-line (max. 9 lines), 3,342
(72%) an antibody.
Survival: 2,853 (40%) of the patients have died, loss of contact to 827
(12%) of them.
Monitoring period of adjuvant ctx >/= 3 years: 1,189 (31%).
After adjuvant ctx: DFS: 37.9 mths. 3-year OS: 80% all therapies; Oxaliplatin-based therapies 81%, </= 70 years 89%; >70 years 79%; UICC
II 87%.
After palliative ctx: PFS: 1st/2nd-line 9.4/6.2 mths. OS: 1st/2nd-line
24.3/14.9 mths.
OS from initial metastasis: 27.4 mths.; with/without antibody 28.7/23.0
mths.
With/without resection of metastasis 49.5/24.8 mths.
Conclusion: The data collected over a long period of time depict very
precisely the reality of treatment in oncology practices in Germany. The
evaluation presented contributes an important share to the complex of
treatment research and answers a series of patient-related questions. Further evaluations will be presented regularly.
41
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ID 093
Potential role of new MSI-target gene AGO2 in German
Lynch syndrome patients
B. Majchrzak1, K. Schulmann2, C. Bernhardt2, A. Maghnouj1,
W. Schmiegel2, S. A. Hahn1
Ruhr Universität Bochum, Molekulare Gastroenterologische Onkologie,
Bochum, Deutschland
2
Universitätsklinikum Knappschaftskrankenhaus Bochum Langendreer,
Bochum, Deutschland
1
Lynch syndrome (LS) is the most common form of inherited colorectal
cancer (CRC), accounting for approximately 5% of all CRC cases. This
autosomal dominant genetic disorder is characterized by germline mutations in one of the mismatch repair genes (MSH2, MLH1, PMS2, MSH6).
Especially genes containing microsatellite sequences are particularly susceptible for increased rates of mutations resulting in microsatellite instability (MSI).
MSI-H LS tumours are commonly known to display a unique microRNA profile, whose reasons can be manifold and are not yet sufficiently
understood. Evidence suggests that enzymes belonging to the RNAi machinery themselves might be targets of genetic disruption due to MSI.
Recent studies showed that among the miRNA regulation-related factors
harboring microsatellite tracts in their coding sequences, TRBP, AGO2
and XPO5 showed frameshift mutations due to MSI-H CRC-tumours,
therefore being new MSI-target genes. However, limited data is available
about the frequency of these mutations especially in LS patients.
Here we thoroughly analyzed microsatellite repeats of AGO2, TRBP and
XPO5 in 25 primary MSI-H LS tumour samples using high resolution
PAA gels and single clone capillary sequencing. We were able to confirm
AGO2 frameshift mutations in 4% of the tested LS samples. A functional
assay revealed a distinct loss of functionality of the mutated form resulting from the frameshift mutation. Overall, our results support AGO2 as
a MSI-target gene in this German HNPCC population. Further analysis
using TALEN- induced mutation models might reveal a potential role of
these mutations in LS patients.
ID 095
Growth of intrahepatic colorectal tumors after liver
resections in mice
V. Nißler1, H. Brandt1, A. Liebl2, A. Perrakis1, V. Schellerer1,
W. Hohenberger1, C. Becker3, M. Stürzl2, R. Croner1
Chirurgische Klinik des Universitätsklinikums Erlangen, Erlangen,
Deutschland
2
Abteilung für Molekulare und Experimentelle Chirurgie (AMEC)/ Division
of Molecular and Experimental Surgery (AMEC), Erlangen, Deutschland
3
Medizinische Klinik I, Kussmaul Campus für Medizinische Forschung
Universitätsklinikum Erlangen, Erlangen, Deutschland
1
Introduction: The high incidence of tumor recurrence after resection of
liver metastases remains an unsolved problem. In colorectal carcinomas
(CRC) 30–50% of the patients develop recurrent tumors after a complete
resection of liver metastases. If the tendency to relapse and the intrahepatic tumor growth are influenced by hepatic proliferation mediators after
liver resection remains unclear.
Material and Methods: In athymic nude-foxn1nu/nu mice MC38 tumor
cells were either injected subcutaneously (SC) or intrahepatically (IH).
Subsequently, either a single laparotomy (LAP SC, LAP-IH) or a 1/3 liver resection (LR1/3-SC, LR1/3-IH) or a 2/3 liver resection (LR2/3-SC,
LR2/3-IH) was performed. In each group, 10 animals were examined for
14 days. Tumor size, tumor proliferation and liver regeneration (liver hypertrophy-index) were quantified.
Results: After 14 days, almost complete regeneration of the remaining liver following 1/3 or 2/3 liver resections (liver hypertrophy-index;
LR1/3-SC, LR1/3-IH: 1,06; LR2/3-SC, LR2/3-IH: 0,8) was observed.
After single laparotomy the average weight of intrahepatic tumors was
330 mg (range: 10–1534 mg). The mean tumor weight of intrahepatic
tumors was 660 mg (range: 76–1873 mg) after 1/3 LR. vs 960 mg (range:
42
189–3030 mg) after 2/3 LR (p < 0.05). After 1/3 LR, tumor size was 166
mm2 (range: 51–399 mm2) vs. 199 mm2 (range: 71–406 mm2) after 2/3 LR
(p < 0.05), and 113 mm2 (range: 15–290 mm2 ) after laparotomy alone.
The subcutaneous tumors showed no differences in tumor size and volume after LR or SC.
Conclusion: Minor and major hepatic resections lead to an activation of
tumor growth within the remaining liver. There is no systemic effect on
extrahepatic tumors. The influence of hepatic regeneration mechanisms
on intrahepatic tumor progress requires further molecular analyzes.
ID 113
Phase II study in metastatic colorectal cancer patients
treated with pharmacokinetically (PK) dose adjusted
weekly or biweekly 5-fluorouracil (5-FU) regimes
K. Link1, T. Bertsch2, K. Weigang-Köhler1, L. Müller3, Y.-D. Ko4,
O. Stoetzer5, V. Kunzmann6, I. Suttmann7, M. Roessler8,
B. Moritz8, S. Salamone9, U. Sonnenschein10, M. Wilhelm1
Klinikum Nürnberg Nord, Med. Klinik 5, Nürnberg, Deutschland
Klinikum Nürnberg Nord, Institut für Klinische Chemie, Nürnberg,
Deutschland
3
Onkologische Schwerpunktpraxis, Leer, Deutschland
4
Evangelische Kliniken Bonn, Hämatologie/Onkologie, Bonn, Deutschland
5
Hämato-Onkologische Gemeinschaftspraxis, München, Deutschland
6
Universitätsklinikum Würzburg, Med. Klinik II, Würzburg, Deutschland
7
Klinikum Dritter Orden, Klinik für Innere Medizin I, München, Deutschland
8
CESAR, A-Wien, Deutschland
9
Saladax Biomedical, USA, Deutschland
10
Saladax Biomedical, CH-Oberwil, Deutschland
1
2
Patients and Methods: In this currently ongoing study (CESAR C-II009), patients with metastatic colorectal cancer received first- or second
line treatment with infusional 5-FU (AIO-regimen, FUFOX, mFOLFOX6) +/- Oxaliplatin, Bevacizumab or Cetuximab. The dose of the first
application of 5-FU was calculated according to BSA. Plasma concentrations of 5-FU were measured by the MyCare™ 5-FU immunoassay,
18 hours after start of the infusion, when steady state concentrations had
been reached. If the 5-FU plasma concentration was not within the target
AUC range of 20–30 mg x h/L and/or toxicity occurred, the subsequent
dose was adjusted according to an appointed algorithm. Measurements of
the 5-FU plasma concentration were repeated for the following 5 applications of chemotherapy.
Conclusions: So far 48 patients from 6 study sites in Germany have
been included in this trial. AUC-guided dose adjustment of 5-FU seems
to be feasible and is showing promising results in the patients treated so
far. Notable is a strong dose increase which could be achieved in some
patients, which was well tolerated, resulting in an impressive tumor response. Preliminary results and corresponding PK-data will be presented
at the meeting.
ID 115
Individual variations in the rate of hyperthermia induced
apoptosis and necrosis
S. Winkler, P. Hoppe, M. Haderlein, R. Fietkau, L. Distel
Strahlenklinik / Universität Erlangen-Nürnberg, Erlangen, Deutschland
Objective: Individualization of cancer therapy is referred to as the key
technology of the future. Aim of the study was to evaluate whether there
are hyperthermia specific individual differences in cancer patients. The
induction of apoptosis and necrosis after in vitro hyperthermia was used
to analyze interindividual differences.
Methods: The study collective consists of 101 head and neck and rectal cancer patients and 20 healthy individuals. Lymphocytes were isolated by density gradient centrifugation and then treated with 42 or 43 degrees C hyperthermia for 1 h. 48h later lymphocytes were stained with Annexin V-FITC
and 7AAD and analyzed by flow cytometry. Lymphocyte subgroups were
additionally immunostained with anti CD4 and CD8 antibodies.
Abstracts
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Index
Results: At 42 degrees C and after subtracting the apoptosis rate of the
untreated samples the apoptosis rate of the CD8 positive cells of the control group isn’t significantly different from the patient’s group. However,
the necrosis rate of the patient’s group is significantly higher (p < 0.001)
compared to the healthy individual’s group. At 43 degrees C the latter
finding is the same (p < 0.001) while there is a lower apoptosis rate of
CD8 positive cells of the cancer patients group compared to the healthy
individuals group (p = 0.02). In the cancer patients group there are distinct interindividual differences.
Conclusion: There are distinct hyperthermia induced differences between
healthy individuals and cancer patients and additionally there are clear
interindividual differences. It indicates that there may be interindividual
differences in response to hyperthermia on cancer cells and normal tissue.
ID 126
Updated Overall Survival (OS) analysis of novel predictive
KRAS/NRAS mutations beyond KRAS exon 2 in PEAK:
A 1st-line phase 2 study of FOLFOX6 plus panitumumab
(pmab) or bevacizumab (bev) in metastatic colorectal
cancer (mCRC)
M. Karthaus1, L. Schwartzberg2, F. Rivera3, G. Fasola4,
J.-L. Canon5, H. Yu6, K. Oliner6, W. Go6
Städtisches Klinikum München GmbH – Klinikum Neuperlach, Munich,
Deutschland
2
The West Clinic, Memphis, Vereinigte Staaten Von Amerika
3
Hospital Universitario Marques de Valdecilla, Santander, Spanien
4
University Hospital S. Maria della Misericordia, Udine, Italien
5
Grand Hôpital de Charleroi, Charleroi, Belgien
6
Amgen Inc., Thousand Oaks, Vereinigte Staaten Von Amerika
1
ID 125
Targeted therapies of two different braf mutated cell lines
and the establishment of a 3D tumor model on the basis
of a decellularized intestinal matrix
Aim: A prospective secondary analysis of PEAK showed trends towards
improved PFS and OS in wild-type (WT) RAS (exons 2, 3, 4 of KRAS/
NRAS) mCRC treated with FOLFOX6 +pmab vs +bev. We report updated
OS and PFS data.
Methods: All 285 randomised intent-to-treat pts (ITT) were assessed WT
KRAS exon 2. This analysis assessed FOLFOX6 +pmab vs +bev in WT
RAS mCRC, which was determined by mutational analyses of KRAS exon
2, 3, 4 and NRAS exon 2, 3, 4.
Result: The table shows PFS and OS results according to RAS mutational
status: ITT; WT RAS; or KRAS exon 2 WT and ‘other’ RAS mutation
(MT).
Conclusion: In the ITT population (WT exon 2 KRAS), HR for OS favored FOLFOX6 +pmab vs +bev. In WT RAS pts (WT exons 2, 3, 4
KRAS/NRAS), HR for both PFS and OS favored FOLFOX6 +pmab vs
+bev. Additional RAS mutations beyond KRAS exon 2 appear predictive
for pmab effect.
F. Baur, S. Sieber, G. Dandekar, S. Nietzer, H. Walles
Universitätsklinikum Würzburg, Lehrstuhl für Tissue Engineering & Regenerative Medizin, Würzburg, Deutschland
The heterogeneity of colorectal carcinomas (CRCs) is an obstacle in the
development of drugs and the prediction of clinical outcome. Vemurafenib
is a potent inhibitor of BRAF in braf mutant melanomas but shows response rates of just 5% in braf mutant CRCs (Corcoran et al. 2012). It has
been reported that the inhibition of BRAF increases the phosphorylation
of the epidermal growth factor receptor (EGFR) via a feedback loop in
CRC cell lines (Prahallad et al. 2012). Thus we tested combination therapies with vemurafenib and the EGFR inhibitor gefitinib as well as the
effect of accessory tipifarnib, a farnesyl transferase inhibitor, to block the
Pi3K/Akt/mTOR pathway. We used different combinations of all three
inhibitors in two cell lines (HROC24, HROC87) carrying a braf mutation
(V600E) but differing in other mutations (Maletzki et al. 2012).
Vemurafenib mono-treatment decreased the cell number in HROC24 but
not in HROC87 cells, whereas gefitinib alone showed a cell number decreasing effect only in HROC87. The combination of two or three drugs
was more efficient than the respective mono-therapy in HROC87 but not
in HROC24 cells. This leads to the conclusion that the determination of a
single genetic lesion is not always sufficient to choose the most effective
therapy. In general, it is reported that 3D tumor models are more resistant
to chemotherapies than 2D cell culture models and that they show more
reliable results in drug testing (Stratmann et al. 2013). For this reason, we
established a 3D model on a decellularized intestinal matrix to compare
the effect of the drugs on cell number, proliferation and apoptosis of common 2D cell culture with our 3D cell culture models.
ID 129
Colon carcinoma in the elderly: What is different?
V. Schellerer1, M. Langheinrich1, K. Weber1, J. Göhl1, R. Croner1,
W. Hohenberger1, S. Merkel1
Friedrich-Alexander-Universität, Allgmein- und Visceralchirurgie, Erlangen, Deutschland
1
Introduction: Colorectal carcinoma is one of the leading cancers in
western countries and the number of elderly patients is rising. While the
incidence of rectum carcinomas decreases the number of colon cancers
increases. Target of the following article was to evaluate the preoperative
characteristics, the surgical procedure, the post-operative complications
and prognosis related to age.
Table of ID 126
Population
WT KRAS exon 2 (ITT)
PFS
OS
WT RAS (exons 2, 3, 4
KRAS / NRAS)
PFS
OS
WT exon 2 KRAS +
MT exons 3/4 KRAS or MT
exons 2,3, 4 NRAS
PFS
OS
NR = not reached
Abstracts
FOLFOX6 +pmab
Patients, N
Median months
(events, n)
(95% CI)
FOLFOX6 +bev
Patients, N
Median months
(events, n)
(95% CI)
HR (95% CI)
Descr. p-value
142
(100)
(52)
10.9 (9.7–12.8)
34.2 (26.6-NR*)
143
(108)
(78)
10.1 (9.0–12.0)
24.3 (21.0–29.2)
0.84 (0.64–1.11)
0.62 (0.44–0.89)
0.224
0.009
88
(57)
(30)
13.0 (10.9–15.1)
41.3 (28.8–41.3)
82
(66)
(40)
10.1 (9.0–12.7)
28.9 (23.9–31.3)
0.66 (0.46–0.95)
0.63 (0.39–1.02)
0.025
0.058
24
(22)
(10)
8.4 (6.5–10.7)
27.0 (15.1-NR)
27
(23)
(21)
8.8 (7.3–11.2)
16.6 (13.3–21.6)
1.13 (0.63–2.05)
0.41 (0.19–0.87)
0.683
0.020
43
Inhalt
Index
Methods: We included all patients receiving a resection for a colon carcinoma between 1995 and 2007 (n = 1268). Patients were divided by age as
follows: less than 65 years (n = 526), between 65 and 79 years (n = 587)
and older than 80 years (n = 155).
Results: In patients >80 years we found significantly more women, a
higher ASA classification, more emergency presentations and a higher
incidence of preoperative and postoperative complications (p < 0.001).
In extended resections, the number of examined regional lymph nodes
was significantly lower (p < 0.001), whereas no differences were found
comparing the number of positive nodes. Comparison of pathological
stages revealed no differences. However, in patients >80 years less stage
IV carcinomas were treated curatively (R0; p = 0.088). After R0 resection
and exclusion of postoperative deaths, the observed 5-year survival rate
of older patients was significantly lower (p < 0.001): < 65 years 84.4%,
65–79 years 74.4%, > 80 years 53.2%. The 5-year cancer-related survival
rates were similar (p = 0.484): <65 years 89.3%, 65–79 years 85.1%, >80
years 89.4%.
Conclusion: Older patients present with higher complication rates according to their preexisting health status. Only approximately 10% of the
patients >80 years with curative resection die within 5-years due to their
colon carcinoma.
mor cells has been associated with protumoral activity; however, its role
in nontumoral cells during tumour development remains elusive. Tumor
invasion and metastasis share many similarities with leukocyte trafficking, which is critically regulated by chemokines and their receptors. In
this study we aimed to assess the role of CCR1 in colon cancer cell lines.
CCR1 expresion was determined in five human (SW480, SW 620, HT29,
LS174T and Caco) and one rat (CC531) colon cancer cell lines. We silenced CCR1 expression by RNA interference (RNAi) and then examined
the effects of CCR1 gene knockdown on biological properties of the colorectal cancer cell lines by in vitro functional tests.
We found that CCR1 was expressed in four of these cell lines (HT29,
SW620, CC531 and SW480). After siRNA exposure the concentration
of CCR1 was reduced by 78–99% after 24 to 72 hours. With regard to
functional tests, CCR1 knockdown had only a minor effect on cell proliferation (10 to 20%), except for CC531 cells in which the proliferation was
reduced by 80% after 24 hours. The siRNA treatment reduced also the
ability of cells to produce small and large colonies by 10 to 80%.
These findings suggest that the expression of CCR1 favours cell proliferation as well as colony formation of colorectal cancer cells in vitro. Future
experiments will focus on the influence of CCR1 in colorectal cancer cell
lines growing in vivo.
ID 143
ID 206
Inhibition and blockage of CCR5: A possible therapeutic
option for colorectal cancer
A. Pervaiz, M.R. Berger, H. Adwan
Molecular mechanisms of receptor tyrosine kinase
inhibition in colorectal cancer cells and indications for
therapeutical options
DKFZ, Heidelberg University, Toxicology and Chemotherapy Unit, Heidelberg, Deutschland
R. Oberthür1, S. Kaulfuß1, J. Meyer1, H. Seemann1, R. Dressel2,
M. Rave-Fränk3, J.-G. Scharf4, P. Burfeind1
The C-C chemokine receptor type 5 (CCR5 or CD195) is predominantly
expressed on T cells, macrophages, dendritic cells and microglia. CCR5
is a major receptor for HIV entry and is found on tumor cells in primary and metastatic colorectal cancer. We aimed at evaluating the role of
CCR5 in colorectal cancer. To that purpose we used CCR5 knockdown by
RNAi methodology and blockade by maraviroc for alterations in biological properties of SW480 and SW620 colorectal cancer cell lines in vitro.
Methods included implantation of rat colorectal CC531 cancer cells in the
rat liver and expression profile studies by mRNA micro-array analysis,
transient knockdown of CCR5 in SW480 and SW620 cells confirmed by
RT and qPCR, and study of functional effects of CCR5 knockdown and
blockade on SW480 and SW620 cells by proliferation, migration, colony
formation and scratch assays.
Implanted colorectal CC531 cancer cells exhibited 20x higher expression
in the rat liver for the initial 3 days and came back to normal level after
week 4. Exposure to siCCR5 reduced the expression of CCR5 mRNA
after 24–72 h by maximally ~70 and ~75% for SW480 and SW620 cells
after 48 hr. Significant declines in proliferation and migration of SW480
and SW620 cells were found after knockdown and blockade of CCR5 by
siRNA and maraviroc as well as moderate reductions in clonogenicity and
the ability to cover scatched area.
In conclusion, high expression of CCR5 contributes to enhanced proliferation and migration, while colonization and wound healing abilities of
colorectal cancer cell lines are diminished. Controlling the expressional
level and development of antagonists for CCR5 could be a future therapeutic option for the treatment of colorectal cancer.
1
ID 145
CCR1 Chemokine effect on colorectal cancer
I. Akram, H. Adwan, M.R. Berger
DKFZ, Chemotherapy and Texocology, Heidelberg, Deutschland
Chemokines are small molecular weight proteins, which mainly function
as chemoattractant cytokines for leukocyte migration. Chemokine receptors (CCRs) are important co-stimlatory molecules associated with various diseases. Expression of the CC chemokine receptor 1 (CCR1) by tu-
44
Universitätsmedizin Göttingen, Institut für Humangenetik, Göttingen,
Deutschland
2
Universitätsmedizin Göttingen, Zelluläre und Molekulare Immunologie,
3
Universitätsmedizin Göttingen, Strahlentherapie und Radioonkologie,
4
HELIOS Klinikum Erfurt, Gastroenterologie & Hepatologie, Erfurt,
Deutschland
Colorectal cancer (CRC) is a leading cause of cancer deaths worldwide.
Receptor tyrosine kinases (RTKs) are known to be key players in the development of CRC. Recently, we could show that inhibition of the RTKs
insulin-like growth factor-I receptor (IGF-IR) and epidermal growth factor receptor (EGFR) in CRC cells results in decreased proliferation and
induction of apoptosis. Furthermore, CRC cells display higher sensitisation to 5-FU based radiochemotherapy (RCT) when both RTKs were
inhibited simultaneously. To identify the molecular mechanisms underlying this sensitisation we analysed DNA repair mechanisms, apoptosis and cell cycle distribution. Phospho-H2AX staining as a marker for
DNA double strand breaks reveals impairment of DNA repair after single
inhibitor treatments 24 h after RCT in CRC cells and even more pronounced effects after dual inhibition of IGF-IR and EGFR. Simultaneous
inhibition of IGF-IR and EGFR reduces phosphorylation and therefore
the anti-apoptotic potential of AKT. In addition, DLD-1 cells showed a
cell cycle arrest in G2 phase when treated with erlotinib (anti-EGFR) or
erlotinib and NVP-AEW541 (anti-IGF-IR) simultaneously in addition to
RCT after 24 h, whereas induction of apoptosis was observed in Caco-2
and SW837 cells 24 h after RCT. In vivo studies using the SW837 xenograft model demonstrated reduced tumour weight and volume after simultaneous RTK inhibition. Furthermore, we could show that IGF-IR and
EGFR form heterodimers in a ligand-dependent manner. Taken together,
these results indicate that IGF-IR and EGFR play important roles in the
resistance of CRC to neoadjuvant RCT and that simultaneous treatment
of RCT resistant CRC with a combination of RTK inhibitors can circumvent these problems.
Abstracts
Inhalt
Index
ID 254
Characterization of tumor associated b cells in colorectal
cancer
H.A. Schlößer1, A. Shimabukuro-Vornhagen2, P. Scherwitz3,
T. Koslowsky4, S. Eidt5, D.L. Stippel1, M.S. von Bergwelt-Baildon2
University Hospital, Department of General, Visceral and Cancer Surgery,
Cologne, Deutschland
2
University Hospital Cologne, Department I of Internal Medicine, Cologne,
Deutschland
3
Marien Hospital, Department of Surgery, Brühl, Deutschland
4
St. Elisabeth Hospital, Department of Surgery, Cologne, Deutschland
5
St. Elisabeth Hospital, Insitute of Pathology, Cologne, Deutschland
1
Introduction: A precise understanding of the mechanisms by which human immune cell subsets affect tumor biology will be critical for a successful treatment of cancer with immunotherapeutic approaches. Little is
known about the role that B cells play in cancer pathophysiology. Recent
evidence suggests that B lymphocytes can both promote and inhibit the
development and progression of tumors. Whether B cells support or hinder tumor growth seems to depend on a variety of factors such as tumor
entity, timing, and composition of the B cell subsets.
Materials and Methods: In this study we characterized B cell subsets
in tumor, metastases, mucosa and peripheral blood of 51 patients with
a diagnosis of colorectal cancer. Naive-, virgin naive-, virgin activated-,
activated-, memory- and regulatory B cells were identified by 10 color
flow cytometry. PBMCs of ten age matched healthy donors were analyzed
as controls.
Results: A significant amount of B cells could be identified in 28 analyzed
tumor samples and the percentage of B cells within tumor samples was
higher than in peripheral blood of CRC patients (6.8 vs. 4.9%). Tumor
associated B cells are highly activated and of a more mature phenotype
than in mucosa or peripheral blood. PBMCs of colorectal cancer patients
contain a significantly higher percentage of memory B cells than PBMCs
of age matched healthy controls (19.7 vs 8.2%). CD24high CD38high B
cells as a regulatory B cell subset are increased in the tumor of advanced
stage disease (1.7 vs. 0.6%).
Conclusion: B cells can be identified in CRC tissue and show a highly
activated phenotype suggestive for a specific response. On the other hand
we could identify an increase of transitional B cells in advanced stage
disease as a possible mechanism of immune ecape
ID 268
S100A4-RAGE interaction triggers MAPK/ERK and
hypoxia signaling in human colorectal cancer cells
M. Dahlmann1, A. Okhrimenko1, P. Marcinkowski1, M. Osterland2,
P. Herrmann2, J. Smith1, C.W. Heizmann3, P.M. Schlag2,4,
U. Stein2
Max-Delbrück-Centrum Berlin, Translationale Onkologie solider Tumore,
Berlin, Deutschland
2
Experimental and Clinical Research Center, Translationale Onkologie
solider Tumore, Berlin, Deutschland
3
University Children‘s Hospital, Clinical Chemistry and Biochemistry,
Zürich, Schweiz
4
Charité Universitätsklinikum, Charité Comprehensive Cancer Center,
Berlin, Deutschland
1
Colorectal cancer is one of the most common cancer diseases worldwide,
with high mortality if patients develop distant metastases. S100A4 is an
acknowledged as prognostic biomarker and inducer for colorectal cancer
metastasis. Besides exerting intracellular functions, S100A4 is also secreted into the tumor microenvironment and can initiate cellular responses, leading to cancer progression. One of its extracellular interaction partners is the receptor for advanced glycation end products (RAGE).
The impact of the S100A4-RAGE interaction for cell motility and metastasis formation in colorectal cancer was not elucidated so far. We demonstrate here the direct interaction of S100A4 and RAGE in colorectal cancer cell lines leading to hyperactivation of ERK and hypoxia signaling
Abstracts
pathways. The increase in cellular motility upon S100A4 treatment was
reversed with the use of RAGE antagonists.
In patient primary colorectal tumors of stages I, II and III high RAGE
expression correlates with reduced overall as well as metastasis-free
survival rates. Therefore, the employment of RAGE as a biomarker can
improve the prognosis for colorectal cancer. Therapeutic approaches
targeting RAGE or intervening in RAGE dependent signaling early in
tumor progression might represent alternative strategies restricting the
S100A4-induced metastasis in colorectal cancer.
ID 293
Survival benefit in colorectal cancer – an analysis of a
population-based clinical cancer registry
A. Schlesinger-Raab1, R. Eckel1, G. Schubert-Fritschle1,
D. Hölzel2, J. Engel1
Institut für Epidemiologie, Biometrie und Medizinische Datenverarbeitung,
Tumorregister München, München, Deutschland
2
1
Objective: The study aim was to evaluate improvement in survival of
colorectal cancer over a time period of 20 years.
Methods: About 41,000 patients’ diagnoses with colorectal cancer between 1990 and 2010 in the catchment area of the Munich Cancer Registry (population 4.6 million) were evaluated.
Distributions of patient and tumour characteristics as well as overall (OS)
and relative survival (RS) were analysed in regard to time period of initial
diagnosis.
Results: Demographic ageing were observed over time with an average
increase of age at diagnosis of about three years and an increase in the
proportion of patients ≥70 and ≥80 years (e.g. ≥80 years from 18 to 26%
in colon and from 11 to 18% in rectal cancer). These older cohorts had a
worse prognosis.
The 5-year RS for colon cancer remained stable over time (from 65.9 to
66.6%) and only minor differences were observed for rectal cancer (from
62.7 to 64.3%).
However, after stratification by age, metastases at diagnosis, and UICC
stage, benefits could be seen clearly in patients < 70 with initial diagnosis
of M0 (5-year RS increased from 80.9 to 87.4% for colon and from 75.3
to 84.6% for rectal cancer) as well as in patients with UICC stage III in
colon cancer (from 58.3 to 72.9%) and UICC stages II and III in rectal
cancer (stage II from 78.6 to 83.7%, stage III from 51.3 to 71.4%).
Survival improvement for patients with M1 at diagnosis was lower and
only observed for patients < 70 years of age.
Conclusion: Survival benefits are superposed by the effect of demographic ageing. In colon cancer, especially for patients < 70 years with
M0 at diagnosis or UICC stage III, and in rectal cancer particularly in
patients < 70 years with M0 at diagnosis and UICC stage II/III survival
improvements were observed.
ID 296
KRAS mutation heterogeneity in rectal cancer after
preoperative chemoradiotherapy
P. Jo1, J. Salendo1, J. Kitz2, L.C. Conradi1, A. Azizian1, H.A. Wolff3,
M. Grade1, P. Ströbel2, M. Ghadimi1, J. Gaedcke1
UMG, Allgemein-, Viszeral- und Kinderchirurgie, Göttingen, Deutschland
UMG, Pathologie, Göttingen, Deutschland
3
UMG, Strahlentherapie und Radioonkologie, Göttingen, Deutschland
1
2
Introduction: Anti-EGFR targeted therapy is of increasing importance
and prior KRAS mutation testing is mandatory. In colon cancer a certain
degree of KRAS mutation heterogeneity has been reported. For rectal
cancer patients treated preoperatively by chemoradiotherapy (CRT) it
remains to be analyzed if the pre- and posttherapeutic KRAS status is
comparable.
Aims: Therefore, tumor tissue from 47 patients was analyzed comprising
114 preoperative biopsies and 85 tissue blocks from resected specimens.
45
Inhalt
Index
Intratumoral KRAS heterogeneity was assesed in pretherapeutical biopsies of 34 (mean 3.0 biopsies/patient) and resected specimens of 12 patients (mean 4.2 tissue blocks/ patient).
Methods: Primer extension method was used to assess the KRAS mutation status for Codons 12, 13, 61, and 146.
Results: Comparison of pre- and posttherapeutic KRAS mutation status
revealed a discrepancy in 6 of 47 patients (12.8%). Intratumoral KRAS
heterogeneity in pretherapeutical biopsies was found in only one patient
showing wild type and G12V mutation, respectively. In the residual a
KRAS mutation and wildtype was found side-by-side in six patients
(50%).
Conclusion: Taken together, KRAS mutation heterogeneity in posttherapeutical tumor is not negliable. Depending on the degree of residual tumor the assessment of the mutation status should be performed on more
than one tumor tissue block.
ID 298
Different bidirectional HIPEC regimens after CRS in
patients with peritoneal matastasis from colorectal
cancer
G. Glockzin1, M. Gerken2, S.A. Lang1, P. Piso3, H.J. Schlitt1
Universitätsklinikum Regensburg, Klinik und Poliklinik für Chirurgie,
2
Universität Regensburg, Tumorzentrum, Regensburg, Deutschland
3
Krankenhaus Barmherzige Brüder Regensburg, Allgemein- und Viszeralchirurgie, Regensburg, Deutschland
1
Introduction: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) might be an effective additive treatment
option within an multidisciplinary therapeutic regimen for patients with
peritoneal metastasis arising from colorectal cancer. Nevertheless, multiple HIPEC regimens with different drug combinations and concentrations
are used.
Patients and Methods: 32 consecutive patients with colorectal peritoneal metastasis that underwent CRS with complete macroscopic cytoreduction (CC-0/1) and bidirectional HIPEC have been analyzed regarding
morbidity mortality and 3-year survival. Twenty patients received oxaliplatin-based and twelve patients received irinotecan-based HIPEC.
Results: Morbidity rates were not significantly diffrent between the OX
group and the IRI group (p = 1.000). The morbidity rate was 0% in both
groups. 3-year survival rates were 65.0% in the OX group vs. 41.7% in
the IRI group, respectively (p = 0.295).
Conclusion: The morbidity and toxicity rates of bidirectional irinotecan-based and oxaliplatin-based HIPEC are comparable. Based on the
not significant difference regarding 3-year and median survival oxaliplatin-based HIPEC might be preferred. Prospective randomized trials are
needed to determine the optimal HIPEC regimen.
ID 299
A pipeline for generating patient-derived 3D cell cultures
and their application for individualized, targeted
therapeutic regimens.
D. Schumacher1, K. Boehnke2, M. Lange3, C. Davies1,
U. Keilholz4, J. Haybäck5, J. Velasco2, M.-L. Yaspo6, H. Lehrach6,
D. Henderson3, R. Schäfer1,4, C. Regenbrecht1
Charité Universitätsmedizin Berlin – Institut für Pathologie CCM, Molekulare Tumorpathologie, Berlin, Deutschland
2
Eli Lilly, Madrid, Spanien
3
4
Charité Comprehensive Cancer Center, Berlin, Deutschland
5
Medizinische Universität Graz, Institut für Pathologie, Graz, Oesterreich
6
Max Planck Institute for Molecular Genetics, Berlin, Deutschland
1
Colon cancer is the 3rd most common type of cancer and the 4th leading
cause of cancer-related deaths worldwide. Though early diagnosis and
molecular characterization (COSMIC, TCGA) have improved signifi-
46
cantly during the last years, rapid and cost-effective means to address
molecular genotyping and therapeutic options are still in high demand.
An ever growing inflow of data from whole-genome and exome sequencing studies into the community of colon cancer researchers continues to
increase the number of potentially harmful genomic alterations, thereby
pinpointing to putative novel targets for anti-cancer drugs, and yet, drug
development and approval is naturally not able to keep up with these discoveries.
Here, we present an experimental pipeline starting from 3D cell cultures
of patient-derived colon cancer cells. 3D cell cultures are increasingly
recognized as suitable models for basic and translational research, preserving an in-vivo like architecture, preventing tumor cells from differentiating, allowing the investigation of intra-tumor heterogeneity and cancer
stem cell like sub-populations, while at the same time observing effects
like hypoxia within the growing in-vitro tumor mass.
We then use these cell cultures for cost-efficient benchtop sequencing
of selected clinically relevant oncogenes and tumor suppressors, complemented by automated drug screenings aiming to increase therapeutic
response when compared to standard therapy.
With an overall growth-rate of more than 60%, our strategy allowed for
almost 50% of samples to be processed within 3 weeks upon reception.
Sequencing, drug screening and IHC based QC took less than 3 weeks,
allowing for an evidence-based treatment decision within 6 weeks after
surgery.
ID 312
Interaction of the CXC-chemokines SDF-1 and I-TAC in
the regulation of tumor angiogenesis of colorectal cancer
O. Kollmar1, K. Rupertus2, J. Sinistra3, M. Menger3
Universitätsmedizin Göttingen, Klinik für Allgemein-, Viszeral- und Kinderchirurgie, Göttingen, Deutschland
2
Universität Tübingen, Department of Hematology, Oncology and Immunology, Tübingen, Deutschland
3
University of Saarland, Institute for Clinical and Experimental Surgery,
Homburg/Saar, Deutschland
1
Background: The chemokine SDF-1 has a decisive role in tumor progression by mediating pro-angiogenic and pro-metastatic effects through its
receptor CXCR4. The SDF-1 pathway is connected with another chemokine, I-TAC, through its second receptor CXCR7. I-TAC also binds to the
CXCR3 receptor. I-TAC function in tumor angiogenesis is likely receptor
dependent because CXCR3 predominantly mediates angiostatic signals
whereas CXCR7 mediated signaling is rather angiogenic. We therefore
studied the interaction of SDF-1 and I-TAC in an in vivo model of colorectal cancer metastasis.
Material and Methods: GFP-transfected CT26.WT colorectal cancer
cells were implanted into the dorsal skinfold chamber of syngeneic BALB/c mice. The animals received either peritumoral application of I-TAC
or intraperitoneal injections with neutralizing antibodies against I-TAC,
SDF-1 or both. Tumor growth characteristics, angiogenesis, cell migration, invasive tumor growth, tumor cell proliferation and apoptosis were
studied by intravital fluorescence microscopy and immunohistochemistry
during an observation period of 14 days.
Results: Local exposure to I-TAC significantly stimulated tumor growth
compared to controls and enhanced invasive growth characteristics without affecting tumor angiogenesis and tumor cell migration. Neither I-TAC
nor SDF-1-blockade had a significant impact on tumor growth and angiogenesis, whereas the combined neutralization of I-TAC and SDF-1 almost
completely abrogated tumor vessel formation. As a consequence, tumor
growth and invasive growth characteristics were reduced compared to the
other groups.
Conclusion: The results of the present study underline the interaction of
SDF-1 and I-TAC during tumor angiogenesis. The combined blockade of
both signaling pathways may provide a strong anti-angiogenic approach
for anti-tumor therapy.
Abstracts
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Index
ID 326
Efficacy of palliative chemotherapy in elderly patients
with metastatic colorectal cancer – a retrospective
analysis of a single center experience
D. Biesenbaum, M. Kind, J. Rüssel, H.-J. Schmoll
Universitätsklinikum Halle (Saale), Klinik für Innere Medizin IV – Onkologie/Hämatologie, Halle, Deutschland
Background: Generally well tolerated combination chemotherapies
(CTs) are available for patients (pts) with metastatic colorectal cancer
(mCRC) that considerably increase survival. However, the reality outside
clinical trials is commonly characterized by an unselected population of
elderly patients with a lower performance status and a higher comorbidity. Few data are available in elderly pts, although the incidence rate is
more than 15 times higher in individuals 50 years and older.
Methods: We reviewed the files of 98 pts with mCRC from 2007 to 2012
who received CT in our department. We predefined 3 groups with cut-off
ages (COAs) at 65, 70, and 75 to compare younger (Y) with older (O) pts.
Progression free survival (PFS) and overall survival (OS) were estimated
by Kaplan-Meier analysis from the first day of 1st line CT. The p-value
was calculated by log-rank test.
Results: We detected a significant difference in OS between Y and O at
the COA of 75 (p = 0.005). The median age of O75 was 79 years. 25%
presented with an ECOG performance status >1. The median OS was 8.4
months with a median PFS of 6.9 months. The population of Y75 presented with an ECOG >1 only in 4% and showed a median OS of 21.2 months
with a median PFS of 10.5 months. There was no difference in PFS by
comparison (p = 0,824).
Conclusion: Just at the COA of 75 there is a significant difference between O75 und Y75 concerning OS but there is no significant difference
in PFS although Y75 presented with a better performance status. Even if
the study is limited by its retrospective nature, this real life data supports
the assumption that pts with mCRC up to 75 years benefit from chemotherapy in a likewise extent.
ID 331
Impact of KRAS signaling on MACC1 expression in
colorectal cancer cells
K. Ilm1, W. Kemmner2, S. Shirasawa3, T. Sasazuki 3, U. Stein2
Max-Delbrück-Center for Molecular Medicine, Berlin, Deutschland
Experimental and Clinical Research Center, Berlin, Deutschland
3
Fukuoka University, Department of Cell Biology Faculty of Medicine,
Fukuoka, Deutschland
1
2
MACC1 was identified as a prognostic marker for the identification of
colorectal cancer (CRC) patients at high risk for metastasis. Tumors,
staged I, II, and III, which developed metachronous metastases, showed
significantly higher MACC1 expression levels compared to non-metastasizing tumors. Apart from its role in transcriptional activation of c-Met,
the regulation of MACC1 itself is poorly understood. Experimental evidence indicates that MAPK signaling regulates MACC1 expression. Our
studies aim at the impact of KRAS on regulation of MACC1 expression
and MACC1-associated metastasis in CRC. Thus, RNAi strategies were
used to analyze the impact of KRAS signaling on MACC1 in several
CRC cell lines with different KRAS mutation status. Further, we compared HCT116 cells harboring the activating KRAS G13D mutation with
the HCT116-derived cell line Hkh-2 lacking the mutated KRAS allele.
Interestingly, transient knock-down of G13D mutated KRAS increases
MACC1 expression in HCT116 cells. Similarly, knock-out of the mutated
KRAS allele through gene targeting in these cells increases MACC1 promoter activity as well as MACC1 mRNA and protein expression. Modulation of the endogenous MACC1 expression has no impact on KRAS expression. Additionally, tumor samples from CRC patients were analyzed
concerning KRAS mutation in codon 12 and 13 and MACC1 expression.
Interestingly, patients with KRAS mutation in codon 13 showed a significantly decreased metastasis-free survival compared to patients with
Abstracts
wild type KRAS. Taken together, MACC1 expression levels and KRAS
mutations in codon 13 contribute to the identification of patients at high
risk for metastasis formation and for the prediction of metastasis-free survival.
ID 344
Inhibition of tumor growth of colorectal liver metastases
after trans-arterial chemoembolization using different
chemoembolisats in a rat model
C. Ziemann1, J. Sperling2, M. Malter3, K. Keller3, J. Roller1,
S. Dold1, O. Kollmar2, M. Laschke3, M. Glanemann1, M. Menger3
Universitätsklinikum des Saarlandes, Homburg, Allgemeine Chirurgie,
Viszeral-, Gefäß- und Kinderchirurgie, Homburg, Deutschland
2
Universitätsmedizin Göttingen, Allgemein-, Viszeral- und Kinderchirurgie,
3
Universität des Saarlandes, Institut für Klinisch-experimentelle Chirurgie,
Homburg, Deutschland
1
Introduction: The transarterial chemoembolization (TACE) of the liver
is an established method for liver metastases and primary hepatocellular
carcinoma. However, there are no comparative studies on the effectiveness of various chemoembolisats. Therefore, in the present study we have
examined the influence of 3 different chemoembolisats on the growth of
colorectal liver metastases in a rat model.
Material und Methods: 32 Wistar albino Glaxo from Rijswijk (WAG /
Rij) rats were randomized into 4 groups and received a subcapsular implantation of 5 × 105 colorectal tumor cells (CC531) in the left liver lobe.
A TACE were performed in all groups via the gastroduodenal artery on
day 8th. The animals received in accordance to the experimental protocol
Embocept S® (20–70 μm), Lipiodol Ultra Fluid® or DC Bead® (70–150
μm). Animals of the control group received only saline. The tumor size
was measured on day 8th and 11th by using a three-dimensional 40 MHz
ultrasound device. On day 11th the tumor and liver tissue were taken for
histological and immunohistochemical analyzes.
Results: Animals of the control group showed at day 11th a tumor volume
of ~ 160% compared to day 8th. The administration of Lipiodol Ultra Fluid® did not significantly influence (140%) the tumor growth. In contrast,
tumor growth from day 8th to day 11th was completely inhibited (100%)
by Embocept S® and DC Beads®. Immunohistochemical analysis of the
tumors showed significantly more necrotic areas after administration of
Embocept S® and DC Bead®. The proliferation rate of the tumor cells in
the various groups showed no differences between all groups.
Conclusion: Our study shows that a TACE of Embocept S® and DC
Bead® can inhibite the growth of colorectal liver metastases completely
in the given time period. The inhibition of the tumor growth seems to be
caused by increased tumor cell necrosis.
ID 345
Surgical quality following rectal cancer surgery without
neoadjuvant chemoradiation in patients selected by
preoperative magnetic resonance imaging – preliminary
results of the OCUM Study.
M. Kreis, J. Strassburg, R. Ruppert, H. Ptok, C. Maurer,
T. Junginger, S. Merkel, P. Hermanek
Charité Universitätsmedizin Berlin, Klinik für Allgemein-, Viszeral- und
Gefäßchirurgie, Campus Benjamin Franklin, Berlin, Deutschland
Introduction: Neoadjuvant chemoradiation adds functional impairment
to patients undergoing total mesorectal excision (TME). Surgical quality is of paramount importance to achieve low local recurrence rates in
patients operated without neoadjuvant chemoradiation when a negative
circumferential margin was shown by preoperative magnetic resonance
imaging (MRI). We aimed to determine surgical quality in a prospective
multicenter cohort study (OCUM) in patients selected by MRI for surgery
without neoadjuvant chemoradiation.
47
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Index
Methods: Quality of TME was assessed in three categories for 282 patients from 12 hospitals enrolled for surgery without neoadjuvant chemoradiation (Nagtegaal et al. 2005, Quirke and Morris 2007). Tumor perforation, local tumor cell dissemination and number of lymph nodes were
assessed. Further, negative predictive value of MRI for histopathological
involvement of the circumferential margin was determined.
Results: In patients undergoing TME the muscularis propria plane (category III) was reached in 1/282 patients (0,4%). Intraoperative tumor cell
dissemination was observed in 3/282 patients (1,1%). Total number of
lymph nodes was 25 (median, range 10–79) and 79/282 patients had positive lymph nodes (28%). The number of 12 lymph nodes recommended
by UICC was not reached in one patient. Preoperative MRI correctly predicted a negative circumferential margin involvement as determined by
histopathological workup in 98,9% of patients.
Conclusions: Excellent results in terms of surgical quality are possible
justifying surgery without pretreatment in patients with MRI-negative
circumferental margin tumors. This concept may help to avoid additional
functional impairment and reduced quality of life following neoadjuvant
chemoradiation in selected patients.
ID 364
Status quo of the endurance performance capacity and
physical strength of patients with esophageal and gastric
cancer
C.T.H. Baltin1, P. Zimmer2, E. Bollschweiler1, A. Hölscher1,
W. Bloch2, F. Baumann2
Universitätsklinik Köln, Allgemein-, Viszeral- und Tumorchirurgie, Köln,
Deutschland
2
Institut für Kreislaufforschung und Sportmedizin, Deutsche Sporthochschule Köln, Abteilung molekulare und zelluläre Sportmedizin, Köln,
Deutschland
1
Introduction: Exercise therapy or sport therapy for cancer patients aims
to improve the quality of life. For patients with esophageal and gastric
cancer there are hardly any studies that have analyzed the holistic effects
of sport therapy. In order to perform a sport-specific therapeutic intervention for these patients, a diagnosis of endurance performance capacity and
physical strength is necessary. The present study aims to quantify for the
first time the endurance performance capacity and physical strength for
these patients using reproducible measurements.
Methods: In a prospective cross-sectional study a total of 30 inpatients
(median age 55 years, minimum 27 years, maximum 76 years, 80% men)
with esophageal or gastric cancer were analyzed preoperatively from May
to September 2013 with respect to their physical performance capacity.
The endurance performance capacity was evaluated using the maximum
oxygen uptake (VO2max). The maximum physical strength of patients
was determined using the ‘8-repetition-maximum’ (8RM) test on a leg
extension and bench press machine.
Results: The mean relative VO2max of esophageal and gastric cancer patients of the sample is 22.4 ml/min/kg (SD 5.21). Compared to the reference values of the American Heart Association, the endurence performace
capacity is classified as ‘sufficient’. Mean results of leg extension and
bench press machine testing of patients are 36.3 kg (SD 14.6), respectively, 39.4 kg (SD 16.3) and, therefore, significantly lower compared to the
reference values for
healthy subjects of the general population.
Conclusion: Preoperative training programs should be conceived with
regard to the revealed performance deficits of patients with esophageal
and gastric cancer. In this way, the potential outcome of overall treatment
could be increased including the quality of life of these patients.
48
ID 372
Individualized Stereotactic Body Radiotherapy (SBRT) in
Liver Metastases of CRC Patients – only Rank 3rd after
Surgery and Interventional Radiology?
I. Ernst1, C. Moustakis1, F. Büther2, B. Greve1, S. Scobioala1,
U. Haverkamp1, H.T. Eich1
Universitätsklinikum Münster, Radioonkologie – Strahlentherapie, Münster, Deutschland
2
European Institute for Molecular Imaging (EIMI), Münster, Deutschland
1
Purpose/Objective(s): Stereotactic body radiotherapy (SBRT) allows
efficient and safe treatment for patients suffered from liver tumors or
metastases. Nevertheless other local ablative methods like surgery or interventional radiology techniques tend to be of higher account in interdisciplinary decisions. Aim of this study is to evaluate free breathing liver
SBRT by using 4 D list mode PET/CT based PTV for Tomotherapy and
Linac with regard to local control, toxicity, and patient acceptance.
Materials/Methods: 175 patients (p) suffered by CRC and 1 to 4 liver
metastases were enrolled. Planning procedure encompassed contrast enhanced MRI and 4 D list mode PET/CT. All patients underwent SBRT
with prescribed radiation dose to the 65% enclosing isodose. Normally,
3 × 12.5 Gy were delivered. Tumors close to stomach or small bowel
received 7.0 Gy in 5 fractions. Clinical history, laboratory findings, early
and late toxicity scores including quality of life scores, PET/CT, and MRI
were gathered before SBRT, at the 6-week follow-up visit and then at
3-month, 6-month, 9-month, 12-month, 18-month, 24-month, 30-months,
and 36- months follow-ups.
Results: All patients tolerated planning procedure and SBRT very well.
No early or late toxicity ≥ °2 (CTCAE v.3.0) was reported. The application time was 2 to 49 min (mean 11.8 min). Local control is 98.3%, mean
observation time 25.3 months.
Conclusions: 4 D list mode PET/CT allows valid acquisition of tumor
movements for free breathing SBRT with high tumor control rate. Low
toxicity and short application time using Tomotherapy® or Linac lead to
high patient acceptance. Therefore SBRT should be rated high in interdisciplinary decisions for therapy of patients with liver metastases.
ID 388
IntraPeritoneale Druck-AerosolChemotherapie (PIPAC)
mit oxaliplatin beim kolorektalen Karzinom mit
fortgeschrittener Peritonealkarzinose: Erste klinische
Ergebnisse
M. Reymond1, U. Giger-Pabst1, W. Solaß1, D. Strumberg1,2,
J. Zieren1
Ruhr-Universität Bochum, Marienhospital Herne, Klinik für Chirurgie,
HERNE, Deutschland
2
Ruhr-Universität Bochum, Klinik für Onko-Hämatologie, Herne, Deutschland
1
Einleitung: Wir berichten über die ersten Ergebnisse der PIPAC bei Patienten mit Peritonealkarzionose (PK) und kolorektalem Karzinom (KRK).
Material und Methoden: Seit 8.2012 wurden 34 PIPAC bei 19 Pat. mit
PK and KRK durchgeführt (zugelassene Heilversuche). Bis auf 2 hatten
alle Pat. eine systemische Chemotherapie erhalten. Kein Patient hatte Organmetastasen. Bei keinem Pat. war eine CRS und HIPEC indiziert. Das
mittlere Alter war 59 ± 13 Jahren. Karnofsky war 83 ± 20%. Mittleres
PCI war 18 ± 12. Das Follow-up erfolgte bis 4.9.2013 oder bis zum Tod.
Das Tumoransprechen wurde makroskopisch (PCI) und histologisch begutachtet. Es wurde oxaliplatin 92 mg/m2 bei 12 mmHg und 37 °C für
30 min appliziert.
Ergebnisse: In 2/19 Fällen war kein Zugang möglich. Es kam zu einer
intraoperativen Komplikation (Darmläsion beim Zugang). Mittlere Operationszeit (PIPAC allein) betrug 86 Minuten. Die PIPAC konnte bei 10
Patienten wiederholt werden. Zwei Patienten hatten kombinierte CRS
und PIPAC, davon entwickelte 1 Patient eine Magenperforation mit Peritonitis. Vier sonstige Nebenwirkungen CTCAE > 2 wurden registriert
Abstracts
Inhalt
Index
(1x abdominelle Schmerzen, 3x Erbrechen). Es gab keine Krankenhausmortalität. Von den 10 Patienten mit wiederholter PIPAC, 4 zeigten eine
komplette intraperitoneale Remission (CR), 3 hochgradige regressive histologische Veränderungen (PR), 1 eine stabile Krankheit (SD). Vierzehn
Patienten leben. Das aktuarielle Überleben nach 271 Tagen ist 69,9%, das
mediane Überleben wurde nach 9 Monaten noch nicht erreicht.
Schlussfolgerung: Diese ersten, preliminären Ergebnisse sind positiv.
Die PIPAC mit oxaliplatin kann eine Tumorregression bei fortgeschrittener PK eines KRK induzieren, die Clinical Benefit Rate (CBR) ist 8/10.
PIPAC wird gut vertragen wenn nicht mit CRS kombiniert.
ID 411
10 Jahre Chirurgie des Rektumkarzinoms –
Daten aus prospektiven klinisch-systematischen
Beobachtungsstudien
H. Ptok1,2, A. Mundt3,2, F. Meyer4,2, H. Lippert4,2, I. Gastinger2
Carl-Thiem-Klinikum, Chirurgische Klinik, Cottbus, Deutschland
Otto-von-Guericke-Universität, AN-Institut für Qualitätssicherung in der
operativen Medizin, Magdeburg, Deutschland
3
Carl-Thiem-Klinikum, Klinik für Anästhesiologie und Intensivmedizin,
Cottbus, Deutschland
4
Universitätsklinikum Magdeburg A.ö.R., Klinik für Allgemein-, Viszeralund Gefäßchirurgie, Magdeburg, Deutschland
1
2
Die Behandlung des Rektumkarzinoms hat sich in den letzten 2 Dekaden
deutlich gewandelt. Durch konsequenten Einsatz neoadjuvanter Therapieverfahren und Anwendung der totalen mesorektalen Exzision beim tief
sitzenden Rektumkarzinom konnte die lokale Tumorkontrolle signifikant
gebessert werden. Mit der vorliegenden Analyse sollen die Umsetzung
der multimodalen Therapie beim Rektumkarzinom unter den Bedingungen der Routineversorgung sowie die erreichten Ergebnisse über einen
10-Jahres-Zeitraum untersucht werden.
Methode: Es wurden die Daten der prospektiven multizentrischen Beobachtungsstudie „Qualitätssicherung – Rektumkarzinom» der Jahre 2000
bis 2010 ausgewertet. N = 33 724 Patienten wurden erfasst. Die Resektionsrate betrug 95,2%. Die Rate kurativer Resektionen betrug 84,2%.
Ergebnisse: Die postoperative Gesamtmorbidität und Letalität zeigten keine Änderung im Verlauf der Beobachtung. Der Anteil neoadjuvant behandelter Patienten mit kurativer Resektion stieg von 5,6% (2000) auf 40,5%
(2010). Die TME-Rate stieg bei tiefsitzenden Karzinomen von 75,2%
(2000) auf 95,3% (2010). Für Patienten, die in den Jahren 2000/2001 kurativ reseziert wurden, lag die 5-Jahres-Lokalrezidivrate bei 11,7%, während
diese für in den Jahren 2005/2006 resezierte Patienten bei 4,6% lag (p <
0,001). Eine Verbesserung des Gesamtüberlebens zeigte sich nicht.
Schlussfolgerung: Bei gleichbleibender Gesamtmorbidität und Letalität hat der zunehmende Einsatz neoadjuvanter Behandlungen und die
Etablierung der TME in der flächendeckenden Routineversorgung von
Patienten mit Rektumkarzinomen zu einer signifikanten Verbesserung
der lokalen Tumorkontrolle geführt, ohne dass ein Einfluss auf das Gesamtüberleben der Patienten nachweisbar ist.
ID 427
Pulmonary Metastasectomy for Colorectal Cancer:
Lymph Node Metastases and Factors affecting Long-term
survival
S. Bölükbas1, S. Sponholz1, N. Kudelin1, M. Eberlein2, J. Schirren1
HSK Wiesbaden, Klinik für Thoraxchirurgie, Wiesbaden, Deutschland
Carver College of Medicine, University of Iowa, Division of Pulmonary,
Critical Care and Occupational Medicine, Iowa, Vereinigte Staaten von
Amerika
1
2
Objective: To investigate the role of lymph node metastases and longterm outcome in patients undergoing pulmonary metastasectomy and systematic lymph node dissection of colorectal cancer.
Methods: Retrospective review of 165 patients with colorectal cancer undergoing pulmonary metastasectomy and systematic lymph node dissec-
Abstracts
tion with curative intent from 1999–2009. Chi-square tests, Kaplan-Meier
analyses, log-rank test and Cox regression analyses were used to estimate
survival and to determine prognosticators of survival and lymph node
metastases.
Results: Lymph node metastases (prevalence 22.4% in the present cohort)
were more often detected in case of rectal cancer, anatomic resections
for pulmonary metastasectomy and multiple metastases, respectively.
Median survival for all patients was 64 months. Lymph node metastases
were associated with inferior but promising survival (44 vs. 78 months,
P=0.03). Survival advantage was seen in the univariate analyses in case of
disease-free intervall ≥36 months, colon cancer, response to pre-metastasectomy chemotherapy and single pulmonary metastasis.Combined liver
and lung resections had no significant impact on survival.Rectal cancer
and response or stable disease to pre-metastasectomy chemotherapy were
independent significant prognosticators.
Conclusions: Lymph node metastases are associated with inferior but
promising long-term survival. Systematic lymph node dissection should
be recommended due to high prevalence of lymph node metastases in
case of rectal cancer, required anatomic resections and multiple metastases. Rectal cancer and response to pre-metastasectomy chemotherapy are
independent prognosticators for long-term survival.
ID 428
Locoregional application of temsirolimus is effective to
inhibit tumor growth of CC531 colorectal liver metastases
even after stimulation by hepatectomy or portal branch
ligation
J. Sperling1, C. Ziemann2, A. Gittler2, A. Benz-Weißer3,
M.D. Menger3, O. Kollmar1
2
Universitätsklinik des Saarlandes, Homburg/Saar, Deutschland
3
Universitätsklinik des Saarlandes, Institut für Klinisch-Experimentelle
Chirurgie, Homburg/Saar, Deutschland
1
Background: Temsirolimus (Te) is an effective antitumor agent for the
treatment of various solid tumors when given systemically. However,
locoregional application has the potential to increase antitumor effects
compared to systemic administration. Herein we studied whether a hepatic-arterial infusion (HAI) of Te is effective to inhibit tumor growth of
colorectal rat liver metastases.
Methods: WAG/Rij rats (n = 36) were randomized to 6 groups and underwent subcapsular implantation of CC531 cancer cells in the left liver
lobe with or without performing a 70% liver resection (Phx) or a portal
branch ligation (PBL). Ten days later animals received either a HAI of Te
(TEM, Phx-TEM, PBL-TEM) or, when serving as controls, of a comparable amount of saline solution (Sham, Phx-Sham, PBL-Sham). Tumor
growth was determined on day 10 and 13 by threedimensional ultrasound.
On day 13 tissue was taken for histological and immunohistochemical
analysis.
Results: From day 10 to day 13 controls showed an increased tumor
growth, most pronounced after Phx (Phx-Sham: +63.17±9.91%). In contrast, HAI of Te results in an almost complete inhibition of tumor growth
(TEM: +0.47±7.68%). Of interest, after Phx and PBL tumor growth was
even significantly reduced by HAI of Te (Phx-TEM: –8.26±13.13%,
PBL-TEM: –1.08±4.69%). Immunohistochemistry revealed an increased
cleaved caspase-3 activity together with a significant reduction of PECAM-1 positive cells after HAI of Te.
Conclusion: HAI of Te is effective to inhibit tumor growth of CC531 colorectal rat liver metastases even if growth stimulating procedures like Phx
or PBL were performed previously. Tumor growth Inhibition is provided
by increased tumor cell apoptosis and decreased tumor vascularisation.
49
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Gastrointestinal (Noncolorectal) Cancer
ID 027
Metastatic Pancreatic Cancer Patients May Benefit
from Stop and Go Treatment Strategies (Induction and
Reinduction) with FOLFIRINOX: A Case Report
F.K. Tauchert, M. Ruppert, E. Jäger
Krankenhaus Nordwest, Klinik für Onkologie, Frankfurt am Main, Deutschland
Background: Metastatic pancreatic cancer is a lethal disease with limited treatment options. We give an account on a patient, who benefits of
multiple reinductions of his therapy according to FOLFIRINOX-regime.
Case report: Fifty-five years old patient with metastatic pancreatic cancer (lung- & liver metastases) with a progressive disease after four month
firstline-therapy with Gemcitabin started secondline treatment according
to the FOLFIRINOX-regime in January 2011. CT-scan after 5 and 8 cycles showed partial response. Due to personal reasons, he ended chemotherapy after 8 cycles in May 2011. Next ct-scan in august 2011 showed
progression of liver metastases. Chemotherapy according to FOLFIRINOX-regime was re-induced. CT-scan after another five cycles of chemotherapy in October 2011 revealed shrinkage of the liver-metastases
again. Again, the patient stopped treatment due to personal reasons again,
resulting in a progressive disease in February 2012. FOLFIRINOX was
applied for the third time. In May 2012 after four cycles of chemotherapy
ct-scans showed a stable disease.
Conclusion: With FOLFIRINOX as a highly active regimen, stop and go
strategies may become of clinical interest in metastatic pancreatic cancer.
This case provides a rational for a clinical trail.
ID 038
Sex Hormone Binding Globulin Is Deregulated in
Aggressive Hepatocellular Carcinoma and Predicts Early
Tumor Recurrence
F. Weber1, N. Wellenberg1, M. Ahrens2, S. Swoboda1, M. Trippler3,
B. Sitek2, A. Hoffmann4, H. Meyer2, H. Baba5, M. Eisenacher2,
J. Schlaak3, A. Paul1
Medizinische Fakultät, Universität Duisburg-Essen, Klinik für Allgemein-,
Viszeral- und Transplantationschirurgie,, Essen, Deutschland
2
Ruhr Universität Bochum, Medizinisches Proteom Center Ruhr, Bochum,
Deutschland
3
Medizinische Fakultät, Universität Duisburg-Essen, Klinik für Gastroenterologie und Hepatologie, Essen, Deutschland
4
Medizinische Fakultät, Universität Duisburg-Essen, Klinik für Innere Medizin – Tumorforschung, Essen, Deutschland
5
Medizinische Fakultät, Universität Dusiburg-Essen, Institut für Pathologie,
Essen, Deutschland
1
Introduction: Curative surgical intervention for HCC is hindered by the
high rate of tumor recurrence. Prognostic markers can help to tailor therapeutic management. Due to organ shortage this is especially important in
the setting of liver transplantation.
Methods: We utilized high density gene expression platforms in order
to elucidate the molecular signature of HCC. Molecular markers were
further validated in a third independant set of in total 61 patients with
HCC by RT-PCR. SHBG (Sex hormone-binding globulin) expression
was normalized and correlated to clinical data. In vitro studies are beeing
conducted to elucidate the functional properties utilizting siRNA knockdown and gene transfection experiments.
Results: SHBG is signicicantly downregulated in HCC showing a poor
prognosis (relative expression 0.14 vs 0.94, p = 0.01). Furthemore, the
median overall survival and tumor free survival for patients with low
SHBG expression was 49 and 23 months, respectively. This was significantly shorter when compared to those with high SHBG expression (76
and 59 months, p < 0.015). The SHBG deregulation was not associated
with other variables. Functional studies correlated SHBG expression with
50
altered cell migration but did not show any effect on cell cycle or proliferation.
Conclusion: We show that the deregulation of SHBG is associated with
early tumor recurrence as well as poor overall survival in patients with
HCC. This holds true independantly of gender, underlying hepatopathy
and type of surgical intervention. Our extensive validation underline the
potential clinical implication to identify high risk HCC patients and provides evidence to elucidate SHBG as a traget for adjuvant therapies.
ID 049
Outcome of somatostatin-receptor targeted PRRT with
177Lu-octreotate in advanced pancreatic neuroendocrine
tumors G1-2
S. Ezziddin1, F. Khalaf1, M. Vanezi1, T. Haslerud1, K. Mayer2,
H. Ahmadzadehfar1, W. Willinek3, H.-J. Biersack1, A. Sabet1
Uniklinik Bonn, Nuklearmedizin, Bonn, Deutschland
Uniklinik Bonn, Med. Klinik III, Bonn, Deutschland
3
Uniklinik Bonn, Radiologie, Bonn, Deutschland
1
2
Purpose: The clinical benefit of peptide receptor radionuclide therapy
(PRRT) has not been fully outlined for pancreatic neuroendocrine tumors
(P-NET). This study analyses standardized PRRT with 177Lu-octreotate
in a well-characterized patient population of advanced P-NET G1-2.
Methods: Retrospective assessment of n = 68 P-NET patients with inoperable metastatic disease consecutively treated with 177Lu-octreotate
(4 intended cycles at 3 monthly intervals; mean activity per cycle, 8.0
GBq). 46 patients (67.6%) had documented morphologic tumor progression within treatment; PRRT was the first-line systemic therapy in 35 patients (51.5%). Assessment of response, toxicity and survival according
to previous work.
Results: Median follow-up was 58 months (95% CI, 47-69). Reversible
hematotoxicity (≥ grade 3) occurred in 4 patients (5.9%). No significant
nephrotoxicity (≥ grade 3) was observed; the mean relative change per
year of the glomerular filtration rate was –2±21%. Treatment response
consisted of PR in 41 (60.3%), MR in 8 (11.8%), SD in 9 (13.2%), and
PD in 10 (14.7%) patients. Median progression-free survival (PFS) and
overall survival (OS) were 34 (95% CI, 26–42) and 53 months (95%
CI, 46–60), respectively. G1 grading was associated with increased PFS
(p = 0.04) and OS (p = 0.044) on multivariate analysis. Other variables
with significant contribution to OS were reduced performance status (Karnofsky score ≤70%; p = 0.007), high hepatic tumor burden (≥25% liver
volume; p = 0.017), and elevated plasma NSE (>15 ng/ml; p = 0.035).
Conclusion: PRRT seems to be highly effective in advanced P-NET G1-2
yielding very promising response rates and survival outcomes. Independent predictors of survival are the proliferation index, patient’s performance status, tumor burden and the baseline plasma NSE level.
ID 074
Correlation of histopathological Response with Prognosis
for perioperative Chemotherapy with Epirubicin, Cisplatin
and 5-FU (ECF) for resectable gastro-esophageal
Adenocarcinoma.
C. Treese1, D. Bichev2, M. von Winterfeld3, S. Daum1,
P. Thuß-Patience2
Charité Berlin, Campus Benjamin Franklin, Medizinische Klinik I für Gastroenterologie, Infektiologie und Rheumatologie, Berlin, Deutschland
2
Charité, Campus Virchow Klinikum, Medizinische Klinik mit Schwerpunkt
Hämatologie, Onkologie und Tumorimmunologie, Berlin, Deutschland
3
Charité, Campus Mitte, Institut für Pathologie, Berlin, Deutschland
1
Background: Perioperative chemotherapy with ECF-like regimes is the
recommended treatment in Europe in patients with adenocarcinoma of the
gastro-esophageal junction/stomach (AGE/GaCa) stage UICC II and III.
However, only limited data exist on histological response and relevance
for prognosis. Here we report our experience administering this regimen
concerning clinical and histological outcome.
Abstracts
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Index
Methods: In this retrospective analysis all patients, treated from 09/2004
to 09/2008 with AGE/GaCa who received preoperative chemotherapy
with ECF were included. Cisplatin and 5-FU were substituted with oxaliplatin or capecitabine when indicated. Histologic response was assessed
using Becker score.
Results: 79 patients were analysed with a median follow up of 41 months.
Median age was 64 years, 56 pts were male. Surgery including D2 lymph
node dissection was performed on 70 pts. So far 38 pts (54.3%) had tumor
recurrence and 40 pts (57.1%) died, 30 (42.9%) of them tumor related.
Median overall survival was 25 mths (CI 95% 9.0–40.9) and the median
event free survival was 14 mths (CI 95% 2.6–25.3). Cumulative survival
at one year was 74.0% and 42,5% at three years follow up. Histological
response to chemotherapy: complete:10 pts, near complete: 3 pts, partial:
21 pts, no response 27 pts. 3-year survival of complete responders was
84.6%, of partial- 42% and non-responders 28%.
Conclusion: Our results show complete histological remission in 12.7%
of the intent to treat group, a similar range as seen with taxane based
regimens. These patients had a significantly better 3-year overall survival
(84.6%) than patients with lower remission rates. A randomised phase III
trial comparing ECF to a taxane based regimen is being conducted.
ID 092
Outcome of patients (pts) with advanced
pancreaticobiliary cancers treated with sequential
chemotherapies at the West German Cancer Center (WTZ)
S. Kasper1, A. Abendroth1, M. Abramczyk1, R. Noureddine1,
A. Paul2, G. Gerken3, K.W. Schmid4, P. Markus5, J. Meiler1,
M. Wiesweg1, G. Kaiser2, A. Dechene3, M. Schuler1
Westdeutsches Tumorzentrum, Universitätsklinik Essen, Innere Klinik
2
Westdeutsches Tumorzentrum, Universitätsklinik Essen, Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Essen, Deutschland
3
Westdeutsches Tumorzentrum, Universitätsklinik Essen, Klinik für Gastroenterologie und Hepatologie, Essen, Deutschland
4
Westdeutsches Tumorzentrum, Universitätsklinik Essen, Institut für Pathologie und Neuropathologie, Essen, Deutschland
5
Elisabeth Krankenhaus Essen, Klinik für Allgemein-, Viszeral- und Unfallchirurgie, Essen, Deutschland
1
Introduction: The prognosis of pts with advanced pancreaticobiliary
cancers (PBC) is still dismal with median survival rates below 1 year. Recently, aggressive multiagent therapy (FOLFIRINOX) was found superior over gemcitabine in pancreatic cancer. However, sequential therapies
may provide disease control with less toxicity. To obtain a benchmark for
future trials we have analyzed the outcome of PBS pts treated at the WTZ,
one of 12 Oncology Centers of Excellence in Germany.
Methods: The outcomes of 450 pts with advanced or metastatic PBC cancers treated at the WTZ were studied. Response rates (ORR), disease-free
survival (DFS) and overall survival (OS) was analyzed in relation to pts
characteristics and treatments.
Results: The majority of pts had metastatic disease (74.8%). Curative
or palliative surgery was performed in 33.6% pts, which was followed
by adjuvant/additive chemotherapy in most cases. First line therapy consisted of gemcitabine (38.4%), platinum combinations (38.0%) or others.
ORR was 23.7%, with significantly higher ORR in pts receiving platinum combintaions (31.2% vs. 15.6%, p = 0.015 χ-square). Median PFS
was 5 months (interquartile range 2–9) without significant difference in
both groups. Second (65.6%) and 3rd line (38.9%) therapies were given
to a large proportion of patients. Median OS of the entire population was
11 months (interquartile range 5–19), and 10 months (4–18) in pts with
metastatic disease.
Conclusion: The outcome of unselected pts with advanced PBC treated at the WTZ compares favourably with recently reported results from
FOLFIRINOX-type chemotherapy protocols. Prospective comparison to
sequentially administered two-agent regimens is warranted in the palliative setting.
Abstracts
ID 141
Identifying of new genetic factors that are involved in the
ability of PDAC clones to grow in the rat liver
H. Adwan, K. Kadhim, M.R. Berger
Introduction: 60% of all patients with pancreatic ductal adenocarcinoma
(PDAC) are diagnosed initially with advanced disease. Furthermore, two
thirds of the remaining 40% will develop liver metastasis within the next
three years. In order to improve early diagnosis of PDAC patients, we
aimed at Identifying new genes and miRNA species that are linked to the
origin and metastasis of that disease.
Methods: Initially, 50 clones were isolated from the ASML rat PDAC
mother cell line by FACS.
These clones were tested for their cellular properties (proliferation, migration and colony formation) and thereafter, 20 clones were chosen for
additional investigation in vivo.
To that purpose, the clones were tested for their ability to grow in rat liver
by injecting 4 million cells from each clone into the portal vein of 5 BDX
rats, respectively.
The most promising 10 clones were further selected to compare growth
ability with the respective gene expression by using micro-array analysis.
Results: From the 20 clones tested, only 6 were able to grow aggressively and consistently in the rat liver. Another 8 clones were able to grow
weakly or moderately and the remaining 6 clones were not able to grow
in the rat liver.
The chip-array analysis demonstrated that some 500 genes and 100 miRNA species were found to be associated with the ability of the clones to
grow in the liver.
Conclusions and Perspectives: Genetic factors seem to be involved in
the ability of PDAC clones to grow in the rat liver. The characterization
of these factors may help identifying new diagnostic tool.
ID 160
Impact of objective response and overall survival in
patients with inoperable or metastatic gastric and
esophagogastric junction (EGJ) cancer: Landmark
analysis of 10 year data from first-line clinical trials
T.A. Bolt1, C. Pauligk1, D. Werner1, F. Mayer2, R. Hofheinz3,
H. Nils4, K. Luley5, H. Schmalenberg6, M. Egger7, S.-E. Al-Batran1
Krankenhaus Norwest, Institut für klinisch-onkologische Forschung,
Frankfurt, Deutschland
2
University Medical Center, Tübingen, Deutschland
3
University Medical Center, Department of Hematology and Medical Oncology, Mannheim, Deutschland
4
Klinikum Wolfsburg, Wolfsburg, Deutschland
5
Universitätsklinikum Lübeck, Lübeck, Deutschland
6
Universitätstumorcentrum Jena, Jena, Deutschland
7
Ortenau Klinikum, Lahr-Ettenheim, Deutschland
1
Background: The aim of the study is to determine whether the achievement of an objective response to 1st linechemotherapy is prognostic of
patient’s outcome in gastric/EGJ adenocarcinoma.
Method: Individual patient (pts) data from prospective 1st line trials conducted by a single study group were used. Response data, pts’ characteristics, type of chemotherapy and overall survival (OS) data were analyzed.
Responses were evaluated according to WHO criteria in all trials and
landmark analysis conducted.
Results: Response rates were complete (CR) in 3.1%, partial (PR) in
37.7%, stable disease (SD) in 33.8% and progressive disease (PD) in
15.4% pts (9.9% were not evaluable). Overall response rate (OR= CR +
PR) was 40.8%.
Median OS in pts with CR vs. PR vs. SD vs. PD were 28.9 vs. 14.8 vs.
10.8 vs. 5.2 months, respectively; p = 2.6 x 10-42. OR also strongly predicted OS (16.7 vs. 8.6 months in pts with vs. no OR; p = 9.0 × 10-14).
Landmark studies were established with landmarks set on 2 and 4 months.
Median OS at landmark point 2 months in pts with CR vs. PR vs. SD vs.
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PD were 17.3 vs. 14.5 vs. 11.1 vs. 5.4 months, respectively; p = 3,7 ×
10-12. Pts with OR vs. no OR had a median OS of 14.7 vs. 10.9 months,
p = 0.0001.
Median OS at landmark point 4 months in pts with CR vs. PR vs. SD vs.
PD were 23.9 vs. 14.8 vs. 11.8 vs. 7.7 months, respectively; p = 1.2 ×
10-10. Pts with OR vs. no OR had a median OS of 16.1 vs. 11.1 months,
p = 7.0 × 10-6.
OR remained the strongest predictor of OS in the multivariate analysis
(p = 6.3 × 10-7) followed by the presence of peripheral LN as the only site
of metastasis (p = 8.2 × 10-5) and ECOG (p = 0.002).
Conclusion: The achievement of an objective response is the strongest
predictor of survival in pts with gastric and EGJ cancer and could serve
as surrogate marker if validated.
ID 174
A novel method combining gene and protein platforms
on one slide for the detection of HER2 in gastric cancer:
Final results
D. Werner1, A. Battmann2, K. Steinmetz1, T. Jones3, T. Lamb4,
M. Martinez4, S.-E. Al-Batran1
Institut für Klinisch-Onkologische Forschung, Krankenhaus Nordwest
GmbH, Frankfurt/Main, Deutschland
2
Institut für Pathologie am Krankenhaus Nordwest, Frankfurt/Main,
Deutschland
3
Roche Pharma, Penzberg, Deutschland
4
Ventana/Roche Tissue Diagnostics, Tucson, Vereinigte Staaten Von
Amerika
1
Background: Evaluation of gene amplification and/or protein overexpression of HER2 in gastric cancer (GC) is a prerequisite to establish an
adequate treatment strategy. GC are heterogeneous, separate evaluations
lead to uncertainties in localizing distinct clones and are time consuming.
The aim of the study was to evaluate the feasibility of gene-protein platform (GP) in comparison to single staining methods.
Methods: Immunohistochemistry (IHC) plus silver in situ hybridization
(SISH) and the new GP method for HER2 were performed in randomly
collected 100 cases of GC. Evaluation was performed by two observers
(ob), in discrepant cases a third ob was consulted to make a decision by
consensus. Results of IHC/SISH were compared with GP staining. Rüschoff criteria were applied. Tumors showing HER2 expression (exp) 3+
or amplification were considered HER2 positive.
Results: 96/100 samples were eligible. Amplification was observed in
14.6% by both, SISH and GP. 70.8% by IHC and GP had no exp (0) and
10.4%/11.5% (IHC vs. GP) had weak (1+) exp. Moderate exp (2+) was
observed in 9.4% by IHC and 7.3% by GP. Rate of overexpression (3+)
was similar in IHC (9.4%) and GP (10.4%). There were complete concordances (100%;κ=1) in assessment of cases with score 0 and amplified tumors. High concordance are shown in score 1+ (98.96%;κ=0.95) and 3+
(96.88%;κ=0.83) cases. Concordance in cases with score 2+ was found
in 95.83% (κ=0.73) of observations. After third observation, there were
5 discordant cases with most discrepancies in assessment of IHC 2+/3+.
Conclusions: GP has been tested for first time in GC. Results showed that
this platform can be a feasible alternative to single methods. Discrepancies in cases with score 2+ expression are a result of ob variability.
ID 181
E- and P-selectin are essential for peritoneal
carcinomatosis in a xenograft model of human pancreatic
adenocarcinoma
D. Wicklein1, F. Gebauer2, J. Salamon3, J.R. Izbicki2,
U. Schumacher1
E- and P-selectins expressed on the luminal surface of mesodermally derived endothelial cells play a crucial role in the formation of haematogenous metastases in a number of malignancies. As peritoneal mesothelial
cells are also derived form the mesoderm, we hypothesized that selectins
are also of importance in peritoneal tumor spread.
Immunohistochemistry was used to identify selectin expression on normal human peritoneum and isolated mesothelial cells. E- and P-selectin
interactions with human pancreatic adenocarcinoma cells were investigated in dynamic flow assays and flow cytometry, the latter was also used
to determine the main selectin ligands on pancreatic adenocarcinoma cell
lines PaCa 5061, BxPC-3 and PaCa 5072 and selectin expression on human mesothelial cells. All cell lines were xenografted into the peritoneum
of E- and P-selectin-deficient pfp/rag2 mice and selectin wild-type controls. Peritoneal carcinomatosis was quantified using MR imaging or a
scoring system.
E- and P-selectin were constitutively expressed on human mesothelial
and endothelial cells in the peritoneum. PaCa 5061 and BxPC-3 cells interacted with E- and P-selectins in dynamic flow assays and flow cytometry with CA19-9 (Sialyl Lewis a) being the main E-selectin ligand. For
xenografted PaCa 5061 and BxPC-3 cells, peritoneal metastasis was significantly reduced in E- and P-selectin double knockout mice compared
with wild-type pfp/rag2 animals. In contrast, PaCa 5072 cells were almost
devoid of selectin binding sites and no intraperitoneal tumor growth was
observed.
Interactions of tumor cells with peritoneal selectins play an important role
in the peritoneal spread of pancreatic adenocarcinoma.
ID 186
Adding docetaxel to cisplatin based therapy represents
a beneficial option for gastric cancer patients in the
perioperative situation
C. Ilmberger1, K. von Dehn-Rotfelser1, J. Schirra2, M. Joka3,
K.-W. Jauch3, B. Mayer1,3
SpheroTec, Martinsried, Deutschland
Klinikum der Universität München, Medizinische Klinik und Poliklinik II,
3
Klinikum der Universität München, Chirurgische Klinik und Poliklinik,
1
2
5-FU, cisplatin and docetaxel (FCD) is approved for the palliative treatment of gastric cancer and has been reported to have a shorter remission
time compared to other perioperative treatment options. Thus, FCD might
represent a treatment option in the perioperative situation. Its therapeutic
efficacy was investigated using multicellular tumor spheroids (MCTS)
derived from patient tumor material, which have been shown to imitate
the original tumor regarding tumor architecture, cellular composition, tumor microenvironment and therapeutic response.
Tumor biopsies of 10 gastric cancer patients were processed for the culture of MCTS. After 48 h following the formation, these microtumors
were treated with FCD, as well as the drug combinations recommended
in the perioperative situation, namely 5-FU plus cisplatin (FC) and 5-FU
plus oxaliplatin (FO) with or without epirubicin (FCE and FOE, respectively). Therapeutic response was assessed by metabolic inhibition determined using the ATP assay, 48 h after treatment.
The addition of epirubicin significantly increased the therapeutic response
compared to the double combinations FC and FO in 83% of the samples
(p < 0,001). In comparison, FCD was significantly more effective than
FCE in 50% of the cases (p = 0,001) and showed the strongest metabolic
inhibition in 29% of the samples (p = 0,002).
Considering efficacy and the short remission time after chemotherapy
FCD seems superior to FCE and should be considered for the perioperative treatment of gastric cancer.
Universitätsklinikum Hamburg-Eppendorf, Anatomie und Experimentelle
Morphologie, Hamburg, Deutschland
2
Universitätsklinikum Hamburg-Eppendorf, Allgemein-, Viszeral und Thoraxchirurgie, Hamburg, Deutschland
3
Universitätsklinikum Hamburg-Eppendorf, Radiologie, Hamburg, Deutschland
1
52
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ID 199
Presence of circulating tumor cells with stem
cell characteristics predicts response to SIRT in
hepatocellular carcinoma
I. Nel1, H.A. Baba2, A. Höwner1, F. Weber3, B. Sitek4,
M. Eisenacher4, H.E. Meyer4, G. Gerken5, J.F. Schlaak5,
A.C. Hoffmann1
Universitätsklinikum Essen, Innere Klinik (Tumorforschung), Essen,
Deutschland
2
Universitätsklinikum Essen, Institur für Pathologie und Neuropathologie,
Essen, Deutschland
3
Universitätsklinikum Essen, Allgemein-,Viszeral- und Transplantationschirurgie, Essen, Deutschland
4
Ruhr Universität Bochum, Medizinisches Proteomcenter, Bochum,
Deutschland
5
Universitätsklinikum Essen, Klinik für Gastroenterologie und Hepatologie,
Essen, Deutschland
1
Background and Aims: As we recently reported, different circulating
tumor cell (CTC) populations are identifiable in the peripheral blood of
patients with HCC (Nel et al., Transl Oncol, 2013). We now investigated
circulating epithelial and stem cell-like cells and whether their distribution during treatment courses is associated with clinical characteristics.
Methods: Before and after SIRT, mononuclear cells and non-hematopoietic cells were isolated from peripheral venous blood using density
gradient centrifugation. Cell suspensions were spun onto glass slides.
CTC presence was verified by immunofluorescence staining against panCK (epithelial), N-cadherin (mesenchymal), CD133 (stem-cell-like);
counterstaining with CD45 (hematopoietic) and hemalm (nucleus; bright
field). CTC and hematopoietic cells were enumerated and individual cell
type profiles were analyzed and correlated to therapeutic outcome in 10
patients with either disease control or progressive disease.
Results: Mann-Whitney test revealed that CK+ cells (p = 0.01) and
CD133+ cells (p = 0.12) before and after SIRT, respectively, differed
significantly between patients with disease control and progression. The
number of CD133+ cells and the ratio CD133+/CK+ cells (prior SIRT)
was each split into low and high counting groups at the 50th percentile,
respectively. All patients with low counts were combined into one factor
(LowCD133). In a backward linear multivariate regression model LowCD133(p = 0.02) and AFP (p = 0.03) were the only factors in this patient
cohort showing a significant independent correlation to progression.
Conclusions: These results underline that examining individual CTC
composition upfront to and during local-ablative therapy of patients with
HCC might be used to predict outcome and therefore individualize treatment decisions. Analysis of stem-cell related markers might enhance the
predictive power.
69 (34.5%) patients had 25(OH)D3 levels below 10 ng/ml and were classified as insufficient, 76 patients (38%) had levels between 10 and 20 ng/
ml (deficient) and 55 (27.5%) patients had levels above 20 ng/ml. 25(OH)
D3 levels differed significantly between Child Pugh stages and showed a
negative correlation with the MELD score. Patients with decompensated liver disease had significantly lowered 25(OH)D3 levels. There were
significant differences between stages of HCC according to the BCLC
staging system and CLIP score. Patients with severe 25(OH)D3 deficiency
had a significantly shorter OS (HR 2.631, (CI) 1.354–5.113, P = 0.004).
In a multivariate Cox regression model 25(OH)D3 levels < 10 ng/ml and a
CLIP score > 2 were independently associated with shorter OS.
Conclusion: 25(OH)D3 serum levels differ between HCC stages and
correlate with the severity of liver insufficiency. Furthermore, 25(OH)
D3 levels below 10 ng/ml were associated with a higher mortality risk in
univariate and multivariate analyses.
ID 256
Extended cholecystectomy as the essential prognostic
factor in T1b-T3 incidental gallbladder carcinoma –
results of the German Registry
T. Goetze, V. Paolucci
Ketteler-Krankenhaus, Klinik für Chirurgie, Offenbach, Deutschland
Background: The immediate radical re-resection (IRR) after simple
cholecystectomy in incidental gallbladder carcinoma (IGBC) is debated
in the literature. The German S3-Guidelines recommend IRR in T2 and
more advanced stages. Current literature recommends more extensive
surgery already in T1b-tumors.
Methods: For data analysis, the German Registry was used.
Results: To date more than 900 cases of IGBC have been analyzed. In
20% of patients with T1a-tumor there was an IRR. In 40% of 109 patients
with T1b-tumor there was an IRR. There is a significant survival benefit
for re-resected T1b patients. There is also a significant survival benefit for
the 215 T2-tumors respectively the 75 T3-patients with IRR compared to
the 441 T2-tumors respectively 207 T3-tumors without IRR. Comparison
of liver resection techniques shows good results for the wedge- resection
technique in T1b- and T2-carcinomas. For T3-carcinomas more radical
techniques show better results. Less than 50% of T2-3 tumors in the registry have had re- resection.
Conclusions: IRR should be highly recommended in patients with T1b
and more advanced IGBC`s. Wedge- resection technique is an attractive
procedures for T1b- and T2-IGBC`s due to their lower invasiveness in
spite oncological adequacy.
ID 319
ID 232
Severe 25-hydroxyvitamin D deficiency identifies HCC
patients with a poor prognosis
F. Finkelmeier1, V. Köberle1, J. Bojunga1, B. Kronenberger1,
S. Zeuzem1, J. Trojan1, A. Piiper1, O. Waidmann1
Medizinische Klinik 1, Schwerpunkt Gastroenterologie und Hepatologie,
1
Progression and therapy efficacy of liver cancer is
determined by macronutrient composition
I. Rudolph1, A. Kettelhake1, G. Mastrobuoni2, S. Kempa2,
T. Cramer1
1
2
Charite, Gastroenterologie und Hepatologie, Berlin, Deutschland
MDC, BISMB, Berlin, Deutschland
Objective: Vitamin D is involved in many biological functions. It has
been identified as prognostic factor in malignant and non-malignant diseases. However, the role of vitamin D in HCC as a prognostic factor remains inconclusive.
Methods: From February 2009 to July 2013, 200 patients with the diagnosis of HCC were consecutively enrolled into the present prospective
cohort study. 25-hydroxyvitamin levels were quantified by radioimmunoassay from serum samples obtained at the day of study inclusion. Patients
were followed until death or last contact. The primary end point was overall survival (OS).
Results: The mean follow-up was 322 days. 19 patients underwent liver
transplantation and 60 (30%) patients died within the observation time.
Primary liver cancer (Hepatocellular Carcinoma (HCC)) is characterized
by rising incidence and robust therapy resistance. Prognosis of inoperable
patients is poor within a range of a few months. Detailed molecular and
biochemical analysis of HCC pathogenesis is of pivotal importance to
identify and develop new therapy targets. The pronounced dependence
of cancer on glucose uptake and metabolism together with the association of HCC with the metabolic syndrome led us to hypothesize a role of
diet (specifically, macronutrient composition) in HCC pathogenesis. We
fed mice harbouring a liver-specific expression of the SV40 large T oncogene (ASV-B mice) carbohydrate-restricted chow (12% carbohydrates
compared to 50% in standard chow) and noted several striking effects
on tumor biology. ASV-B mice are characterized by an age-dependent
adenoma-carcinoma sequence: Adenomas at 12, multiple HCCs around
Abstracts
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16 weeks. When low carbohydrate chow (LCC) was started at 14 weeks,
adenoma progression to HCC was significantly inhibited (tumor load was
reduced from 68% in controls to 35% under LCC). Interestingly, combined treatment with LCC and the glycolysis inhibitor 2-deoxy-glucose
(2-DG) further aggravated this effect to 20% tumor load. Initiation of
LCC after HCC development (around 17 weeks) resulted in massive
tumor regression with microscopic appearance of necrotic tumor areas.
MS-based proteomics and metabolomics is currently being applied to deconstruct the molecular nature of this effect. Taken together, our results
support a critical role of macronutrient composition, especially carbohydrate content, for both HCC prevention and therapy. As low carbohydrate
diets have been safely used for almost a century, clinical application of
these results seems feasible.
ID 322
An integrated systems medicine approach to deconstruct
the metabolism of Hepatocellular Carcinoma
A. Kettelhake1, G. Mastrobuoni2, C. Bielow2, I. Rudolph1,
O. Demidova1, M. Pietzke2, S. Kempa2, T. Cramer1
Charite, Gastroenterologie und Hepatologie, Berlin, Deutschland
2
MDC, BISMB, Berlin, Deutschland
1
Hepatocellular carcinoma (HCC) is one of the most common tumor types
in the world with constantly rising incidence in industrialized countries.
Therapeutic options are limited since HCCs are robustly resistant to
conventional treatment. Detailed characterization of the molecular and
biochemical pathogenesis of HCC is required to identify novel targets
for therapy and prevention. Metabolic alterations represent a hallmark
of cancer. In previous work, we and others could show that inhibiting
glycolysis or glucose uptake results in significant reduction of HCC malignancy in vitro and in vivo, arguing for a causal role of certain metabolic
pathways for HCC pathogenesis. The aim of our study is to characterize
«translatable» aspects of HCC pathogenesis via a systems medicine approach integrating proteomic and metabolomic data. We performed an
in-depth characterization of a murine HCC model (liver-specific expression of the oncogene SV40 large T) and respective benign liver tissue of
the proteome and the metabolome via modern mass spectrometry-based
methodology. Shotgun proteomics highlighted differentially expressed
enzyme isoforms with high glucose affinity. Metabolome studies showed
distinct changes in the abundance of glycolytic and TCA cycle intermediates. Interestingly, we could not find experimental evidence supporting
a role of the Warburg effect (high glucose uptake and fermentation to
lactate) in this HCC model system. To get new insights in the complex
metabolic reprogramming and metabolic dependencies of human HCC,
we started to perform similar ‘omics’-analyses of human tissues. We will
outline the potential relevance of our findings for improved stratification
of HCC patients as well as surveillance of patients at-risk (chronic viral
hepatitis, NASH, liver cirrhosis) for developing HCC.
ID 342
Single measurement of hemoglobin predicts outcome of
HCC patients
F. Finkelmeier1, D. Bettinger2, V. Köberle1, M. Schultheiß2,
B. Kronenberger1, A. Piiper1, O. Waidmann1
Medizinische Klinik 1, Schwerpunkt Gastroenterologie und Hepatologie,
2
Universtitätsklinik Freiburg, Medizinische Klinik 2, Freiburg, Deutschland
1
Objective: Cancer related anemia is a common complication in nearly all
types of cancer. However, the prognostic potential of hemoglobin has not yet
been investigated in patients with hepatocellular carcinoma (HCC). Therefore we performed prospective cohort study in two independent cohorts investigating the relation of Hemoglobin (Hb) levels and overall survival (OS).
Methods: From February 2009 to March 2013, 199 patients with confirmed HCC were consecutively enrolled into the present prospective
cohort study. Patient characteristics, treatment, and outcome was entered
54
into a prospectively conducted database. Blood samples were obtained
at the day of study inclusion. Patients were followed until death or last
contact. The primary end point was overall survival (OS).
Results: The mean follow-up time was 323 + 342 days. 18 patients underwent liver transplantation and 57 (28.6%) patients died within the observation time. The mean Hb level was 12.3 +/–2.1 g/dl. Hb levels significantly differed between Child Pugh stages and showed a negative correlation
with the MELD score. There were significant differences between stages of
HCC according to the BCLC staging system. Patients with Hb level ≤ 13
g/dl had a significantly shorter OS (hazard ratio (HR) 2.422, (CI) 1.357–
4.322, P = 0.003). In a multivariate Cox regression model low Hb levels (≤
13 g/dl) and high CRP levels (> 0.5 mg/dl) were independently associated
with higher mortality. In a second, independent cohort of 87 patients Hb
level ≤ 13 g/dl were also associated with a shorter OS.
Conclusion: We were able to show that anemia correlates with the prognosis of HCC patients and could be considered as an easy accessible additional risk factor for mortality.
ID 355
In vivo RNAi screen for new tumor suppressor genes in
Hepatocellular Carcinoma.
F. Heinzmann1, T.-W. Kang1, A. Hohmeyer1, P. Schirmacher2,
R. Geffers3, T. Longerich2, L. Zender1
University Hospital Tuebingen, Division of Translational Gastrointestinal
Oncology, Tuebingen, Deutschland
2
University Hospital Heidelberg, Institute for Pathology, Heidelberg,
Deutschland
3
Helmholtz – Centre for Infection Research, Genom Analytics, Braunschweig, Deutschland
1
The protooncogene c-Myc is a tightly regulated transcription factor in normal cells and deregulated c-Myc plays a significant role in the development of human cancers and is overexpressed in a wide range of human
tumors like in human hepatocellular carcinoma (HCC) (50%). Hepatocellular carcinoma constitutes the third most common cause of cancer related
death worldwide, a fact that is also largely attributed to the lack of effective
treatment options. The multikinase inhibitor Sorafenib represents the first
systemic treatment resulting in 2.8 month prolonged survival highlighting
the need of a better understanding of the molecular mechanisms of hepatocarcinogenesis that should ultimately lead to the development of new treatment strategies. Short hairpin RNAs capable of stably suppressing gene
function by RNA interference (RNAi) can mimic tumor-suppressor-gene
loss in mice allowing us to analyze passenger and driver mutations in
HCC development. Here we used a novel in vivo RNAi screening platform to directly identify new tumor suppressor genes in a c-Myc driven
HCC mouse model. Proof of principle experiments using positive control
shRNAs against established tumor suppressor genes such as PTEN showed
that our screening setup can identify potent tumor suppressor genes in this
model. A focused shRNA library targeting the mouse orthologs of genes
deleted in human hepatocellular carcinoma was then co-delivered with
c-Myc into p53 heterozygous mouse livers. Genomic DNA was isolated
from outgrown tumors and scoring shRNAs were identified via PCR amplification and deep sequencing of the shRNA cassette. Our screen identified
several new tumor suppressor candidates that will be presented. Some of
these were already functionally validated and mechanistically characterized
regarding their role in hepatocarcinogenesis.
ID 377
Individualized Stereotactic Body Radiotherapy (SBRT)
by Linac or Tomotherapy for Patients suffered from
inoperable CCC / Klatskin Tumours
I. Ernst1, C. Moustakis2, F. Büther1, B. Greve2, S. Scobioala2,
U. Haverkamp2, H.T. Eich2
European Institute for Molecular Imaging (EIMI), Münster, Deutschland
Universitätsklinikum Münster, Radioonkologie – Strahlentherapie, Münster, Deutschland
1
2
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Purpose/Objective(s): Stereotactic body radiotherapy (SBRT) allows
efficient and safe treatment for patients suffered from liver tumors or metastases. Aim of this study is to evaluate free breathing liver SBRT for
inoperable patients suffered from histologically proven CCC with regard
to local control, toxicity, and patient acceptance.
Materials/Methods: 34 patients (p) were enrolled. Planning procedure
encompassed contrast enhanced MRI and 4 D list mode PET/CT. Planning target volume contained gross tumor volume, 2 mm set-up margin
and safety margins based on 4 D list mode PET detected motion. All patients underwent SBRT with prescribed radiation dose to the 65% enclosing isodose. Normally, 3 × 12.5 Gy were delivered. Tumors close to
stomach or small bowel received 7.0 Gy in 5 fractions. All patients received prophylactic antiemetic medication one hour before starting SBRT
and got proton pump inhibitors for six months starting with first SBRT.
Clinical history, laboratory findings, early and late toxicity scores including quality of life scores, PET/CT, and MRI were gathered before SBRT,
at the 6-week follow-up visit and then at 3-month, 6-month, 9-month,
12-month, 18-month, 24-month, 30-months, and 36- months follow-ups.
Results: All patients tolerated planning procedure and SBRT very well.
No early or late toxicity ≥ °2 (CTCAE v.3.0) was reported. Local control
is 100%. Mean overall survival is 22.3 months. Patients died on distant
metastases, no patient died on local progress.
Conclusions: 4 D list mode PET/CT allows valid acquisition of tumor
movements for free breathing SBRT with high tumor control rate. Therefore SBRT should be rated high for patients with inoperable CCC. Further
interdisciplinary protocols have to be discussed to reduce distant metastases.
ID 391
Synergistic effects of Hyperthermia with Taurolidine
(TRD) in malignant tumor cells – in vitro study of
pancreatic and colon cancer cell lines
M. Buchholz, A. Flier, A. Chromik, W. Uhl
St.Josefs Hospital, Allgemein und Viszeralchirurgie, Bochum, Deutschland
Interrogation: The originally anti-infective agent Taurolidine (TRD) has
been shown to have anti-neoplastic properties in vitro and in vivo. In this
study we investigated whether a combination of TRD with hyperthermia
would have a synergistic anti-neoplastic effect in malignant human cell
lines derived from pancreatic cancer (AsPC-1, BxPC-3, HPAF II and
MiaPaca-2).
Methods: All cancer cell lines were incubated with Taurolidine in two
different concentrations 100 and 500 µmol/l). We incubated the cells at a
temperature of 40,5 °C for 24h. In another experiment we incubated the
cells for 2h or 4h before or after addition of TRD at 42 °C . The anti-neoplastic activity of Taurolidine in combination with hyperthermia was
quantified by MTT-assay (cytotoxicity) and flowcytometric FACS-analysis with propidiumiodide and Annexin V (apoptosis induction).
Results: In MTT-assay, Taurolidine in combination with hyperthermia
revealed a significant higher cytotoxic effect than Taurolidine alone in
BxPC-3 and HPAF II pancreatic cancer cell lines – starting with a concentration of 500 µmol/l. FACS analysis was also characterized by a significant higher necrotic response to TRD in combination with hyperthermia
than TRD alone in BxPC-3 and AsPC-1 cells. However, the combination
of TRD and hyperthermia did not show a significant synergistic effect in
all four pancreatic cancer celllines, especially in MiaPaca-2 cells.
Conclusions: It could be demonstrated for the first time, that Taurolidine
in combination with hyperthermia provides a higher anti-neoplastic effect
in some pancreatic cancer cell lines. Therefore our findings suggest that
the combination therapy exerted synergistic anti-neoplastic effects, providing a potential new perspective for clinical tumor therapy.
Abstracts
ID 392
Erste Klinische Ergebnisse der IntraPeritonealen
Druck-Aerosolchemotherapie (PIPAC) bei Patienten
mit Magenkarzinom und fortgeschrittener
Peritonealkarzinose
U. Giger-Pabst1, W. Solaß1, D. Strumberg2, J. Zieren1,
M. Reymond1
HERNE, Deutschland
2
1
Einleitung: Die „Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC)» ist ein minimal-invasives Verfahren und verbessert die lokoregionäre Chemotherapeutika-Aufnahme. Es werden die ersten Ergebnisse der
PIPAC bei Patienten mit PC und GC vorgestellt.
Material und Methoden: Seit 11.2011 wurden 38 PIPAC bei 21 Pat. mit
GC and PC durchgeführt (zugelassene Heilversuche). Karnofsky war 77
± 23%. PCI war 18 ± 11. 5 Pat. hatten weitere Metastasen. 15 Pat. hatten
Chemotherapie erhalten und 13 waren voroperiert. Alter lag bei 50 ± 13
J.. FU erfolgte bis 17.6.2013 oder bis zum Tod. Tumoransprechen wurde
makroskopisch (PCI) und histologisch begutachtet.
Ergebnisse: Operationszeit war 90 ± 19 Minuten. Es kam zu zwei Darmläsionen beim Zugang, bei 1 Pat. war kein Zugang möglich. PIPAC wurde
bei 11 Pat. im 6-wöchigen Intervall wiederholt. 2 Patienten (beide ASA
IV, Karnofsky 40%, refraktärer Aszites) verstarben im Krankenhaus. Eine
Nebenwirkung CTCAE 2 wurde registriert (GPT Erhöhung). Von den 11
Patienten mit wiederholter PIPAC-Applikation, 3 zeigten eine komplette
intraperitoneale Remission, 5 hochgradige regressive histologische Veränderungen und 3 eine stabile Krankheit. 14 Patienten leben, 7 sind gestorben (davon 4 mit weiteren Metastasen). Das aktuarielle Überleben
nach 1 Jahr war 68,5% bei den Patienten mit isolierter Peritonealkarzinose, das mediane Überleben bei den Metastasenpatienten war 3,5 Monate.
Schlussfolgerung: In dieser ersten, kleinen Patientengruppe haben 3/4
Pat von der PIPAC profitiert. Die Überlebensdaten sind ermutigend.
PIPAC wird gut vertragen, aber nicht bei dekompensiertem Aszitis.
Die Effizienz der PIPAC wird jetzt unter Studienbedingungen evaluiert
(NCT01854255).
ID 394
Anti-neoplastic effects of a new derivative of Taurultam
(NDTRLT) in malignant tumor cells – in vitro study of
pancreatic cancer cell lines
M. Buchholz1, A. Flier1, S. Hahn2, R.W. Pfirrmann3, A. Chromik1,
W. Uhl1
St.Josefs Hospital, Allgemein und Viszeralchirurgie, Bochum, Deutschland
Ruhr Universität, Molekulare Gastroenterologische Forschung, Bochum,
Deutschland
3
Weggis, Luzern, Schweiz
1
2
Interrogation: Taurolidine is a substance with anti-neoplastic activity
against many tumor cells. The anti-proliferative and cell death inducing
capacity of Taurolidine as been contributed to several metabolities like
Taurultam (TRLT). In this study we analyzed a new derivative of Taurultam (NDTRLT) in malignant human pancreatic cancer cell lines in vitro.
Additionally, synergistic anti-neoplastic effects of NDTRLT with hyperthermia were determined.
Methods: All cancer cell lines were incubated with NDTRLT, a new
derivate of TRLT, in increasing concentrations for 6, 12, 24 and 48 h.
The anti-neoplastic activity of NDTRLT was quantified by MTT-assay,
BrdU-assay and flowcytometric FACS-analysis with propidiumiodide
and Annexin V. The effects of a combination therapy with hyperthermia
were analyzed by MTT-assay applying 200 and 1000 µmol/l NDTRLT at
different hyperthermic temperatures (40.5 and 42 °).
Results: In MTT-, BrdU- and real-time cell analyzer-assays, NDTRLT
revealed a significant cytotoxic and anti-proliferative effect on all pancreatic cancer cell lines starting with a concentration of 200 µmol/l and
55
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Index
a maximum effect at 1500 µmol/l. FACS analysis was characterized by a
significant and strong apoptotic response upon stimulation by NDTRLT.
Furthermore, combination therapy of the new derivative and hyperthermia showed a synergistic effect in pancreatic cancer cell lines.
Conclusions: It could be demonstrated for the first time, that NDTRLT, the
new derivative of TRLT, provides anti-neoplastic effects in pancreatic cancer
cell lines – operating with different mechanisms e.g. inhibition of proliferation, direct cell toxicity and induction of apoptosis. The anti-neoplastic effects
of NDTRLT are significantly higher compared to TRLT alone. As a result,
the new agent NDTRLT offers a promising potential for anti-tumor therapy.
ID 409
Langzeitüberleben von Kardiakarzinomen im Vergleich zu
distalen Magenkarzinomen – Multizentrische Ergebnisse
der Deutschen Magenkarzinomstudie 2
R. Steinert1,2, I. Gastinger2, K. Ridwelski2,3, H. Ptok2,4, S. Wolff2,5,
F. Meyer2,5, R. Otto2, H. Lippert2,5
St.-Josefs-Krankenhaus Salzkotten, Klinik für Allgemein- und Viszeralchirurgie, Salzkotten, Deutschland
2
An-Institut für Qualitätssicherung in der operativen MedizingGmbH an der
Otto-von-Guericke-Universität, Magdeburg, Deutschland
3
Klinikum Magdeburg gGmbH, Klinik für Allgemein- und Viszeralchirurgie,
Magdeburg, Deutschland
4
Carl-Thiem-Klinikum, Chirurgische Klinik, Cottbus, Deutschland
5
Universitätsklinikum Magdeburg A.ö.R., Klinik für Allgemein-, Viszeralund Gefäßchirurgie, Magdeburg, Deutschland
1
Hintergrund: Multizentrische Daten der Versorgungsforschung sollen
die aktuelle Behandlungssituation von Magenkarzinomen zeigen. Adenokarzinome des ösophagogastralen Übergangs scheinen dabei eine eigene
Entität darzustellen.
Methode: Im Rahmen der prospektiven multizentrischen Beobachtungsstudie QCGC 2 erfolgte die Datenerhebung im Zeitraum vom 01.01.2007
bis 31.12.2009. Die proximalen Magenkarzinome wurden für die vorliegende Untersuchung separiert. Es wurde eine vergleichende Auswertung
des erfassten onkologischen Langzeitergebnisses vorgenommen.
Ergebnisse: In 141 Kliniken wurden 2.897 Patienten mit der Diagnose
Magenkarzinom stationär aufgenommen und 2.788 (96,2%) operativ behandelt. Hinsichtlich der Tumorlokalisation fanden sich 544 Karzinome
des ösophagogastralen Überganges, welche in 108 (76,6%) der 141 Kliniken operiert wurden.
Die Adenokarzinome des ösophagogastralen Überganges zeigten stadienunabhängig ein signifikant kürzeres medianes Überleben (25 Monate) als die distalen Karzinome des Magens (38 Monate). Auch die 5-JÜR
sind mit 33,1% für die AEG-Patienten deutlich schlechter gegenüber
41,4% für Patienten mit einem distalen Magenkarzinom. Im Vergleich der
einzelnen Tumorstadien war ein signifikant schlechteres 5-Jahresüberleben (p < 0,001) schon im UICC-Stad. II (46,3% Vs. 50%) und besonders
gravierend in den Stadien UICC III (0% versus 22%) und UICC IV (7,4%
versus 12%) nachweisbar.
Schlussfolgerung: Die flächendeckenden Ergebnisse nach Behandlung
der Magenkarzinome können trotz multimodaler Verfahren nicht zufriedenstellen. Kardiakarzinome sind prognostisch signifikant schlechter.
Eine Zentralisierung dieser Patienten erscheint sinnvoll.
ID 443
Cytoreductive surgery for pancreatic cancer may improve
overall outcome of gemcitabine-based chemotherapy.
U. Pelzer1, M. Bahra2, F. Klein2, G. Puhl2, T. Denecke3, M. Sinn1,
J. Stieler1, B. Dörken1, P. Neuhaus2, H. Riess1
Charité – Universitätsmedizin Berlin, Centrum für Tumormedizin, Berlin,
Deutschland
2
Charité – Universitätsmedizin Berlin, Klinik für Allgemein-, Visceral- und
Transplantationschirurgie, Berlin, Deutschland
3
Charité – Universitätsmedizin Berlin, Abteilung für Radiologie, Berlin,
Deutschland
1
56
Introduction: Pancreaticoduodenectomy, as well as distal and total pancreatectomy are considered as surgical standard procedures of pancreatic
adenocarcinoma. Improvements in expertise lowered the mortality rates
under 5%. Most patients present with an advanced stage of disease at the
time of diagnosis, sometimes isochronal at time of resection. In high volume centers a more aggressive surgical approach developed to enhance
the overall outcome.
Methods: We identified patients with palliative surgery from our prospective documented single center data base. Definition for non curative
surgery was R2,- or M1-stage. These patients were matched with regards
to gender, age and pretherapeutic performance status to patients with primary gemcitabine-based chemotherapy in the same period. Patient data
were analysed for postoperative morbidity/mortality, begin of palliative
chemotherapy and serum markers. Postoperative morbidity was classified
according to Clavien Classification.
Results: 45 out of 460 resected patients meet the predefined criteria.
38/45 patients underwent pancreatic head resection, 30 patients pylorus-preserving pancreaticoduodenectomy, 8 patients classic Kausch-Whipple procedure, 7 patients underwent total pancreatectomy. Mean
length of hospital stay was 23.2 days. Median survival was 10,2 months
with initial cytoreductive pancreatic resection vs. 7,4 months without surgery (p = 0.009). The 1-year survival was 38%, 2-year survival was 11%
in the resection cohort vs. 18% and 2% without cytoreductive resection.
Conclusion: This analysis demonstrates the impact and potentials of
specified surgery options of a high volume center, we may have the option
of individual survival prolongation due to cytoreductive surgery cancer
treatment.
ID 457
Gemcitabine and the monoclonal antibody nimotuzumab
versus gemcitabine and placebo for the treatment
of chemotherapy-naïve patients (pts) with advanced
pancreatic cancer (PC): A multicentre, randomized phase
IIb/ IIIa study
D. Strumberg1, B. Schultheis1, M.P. Ebert2, J. Siveke2,
A. Kerkhoff3, W. Berdel3, R. Hofheinz4, D.M. Behringer5,
W.E. Schmidt6, E. Goker7, S. De Dosso8, M. Kneba9, S. Yalcin10,
F. Overkamp11, F. Schlegel12, M. Dommach13, R. Rohrberg14,
T. Steinmetz15, D. Reuter16, F. Bach16
Marienhospital Herne, Hämatologie/ Onkologie, Herne, Deutschland
Klinikum rechts der Isar TU München, München, Deutschland
3
University Hospital Münster, Münster, Deutschland
4
University Medical Centre Mannheim, Department of Hematology and
Medical Oncology, Mannheim, Deutschland
5
Augusta-Kranken-Anstalt, Bochum, Deutschland
6
St. Josef Hospital, Med. Klinik I, Bochum, Deutschland
7
Ege University Medical School, Izmir, Deutschland
8
Oncology Institute of Southern Switzerland, Bellinzona, Schweiz
9
University Medical Center Schleswig-Holstein, Department of Medicine,
Kiel, Deutschland
10
Hacettepe University Hospital, Ankara, Tuerkei
11
Medical Practice for Oncology and Hematology, Recklinghausen,
Deutschland
12
St. Antonius Hospital, Eschweiler, Deutschland
13
Sana-Kliniken, Medizinisches Versorgungszentrum Onkologie, Düsseldorf, Deutschland
14
Gemeinschaftspraxis und Tagesklinik fuer Haematologie, Onkologie und
Gastroenterologie, Halle, Deutschland
15
Group Practice Hematology/Oncology Cologne, Cologne, Deutschland
16
Oncoscience AG, Wedel, Deutschland
1
2
Background: For the majority of pts with metastatic PC, gemcitabine
(gem) remains the mainstay of palliative treatment, although its modest
impact on survival and disease progression. However, FOLFIRINOX significantly increases survival, but its use is limited to selected patients, due
its high toxicity. This study was aimed to investigate the effect of adding
nimotuzumab (nimo), an anti-EGFR monoclonal antibody, to first-line
gem in PC.
Abstracts
Inhalt
Index
Patients and Methods: Pts with locally-advanced or metastatic PC were
randomly assigned to receive gem: 1000 mg/m2/ 30-min iv once weekly
(d1, 8, 15; q28) and nimo: fixed dose of 400 mg once weekly as a 30-min
infusion, or placebo, until progression or unacceptable toxicity. Primary
endpoint was overall survival (OS).
Results: Between 9/2007- 10/2011 a total of 192 pts were randomised
(average age 63.6 ±10 years; 60% male; 69% ECOG PS 0), and 186 were
evaluable at the ITT analysis.
One-year OS was 19.5% with gem+placebo and 34.4% with gem+nimo
(HR=0.69; p = 0.034). Median OS and PFS were 6.0 mo in the gem+placebo group, vs. 8.7 mo in gem+nimo (HR=0.83; p = 0.21), and 3.7 vs.
5.4 mo, respectively (HR=0.73; p = 0.06). One-year PFS was 9.5% for
gem+placebo, compared with 21.5% for gem+nimo (HR=0.71; p = 0.05).
Significantly, in pts ≥ 62 years (60% of the population), median OS and
PFS were 5.2 mo in the gem+placebo group vs. 8.8 mo in gem+nimo
(HR=0.66; p = 0.034), and 3.2 in gem+placebo vs. 5.5 mo in gem+nimo
group, respectively (HR=0.55; p = 0.0096). Nimo was safe and well tolerated, and no grade 3/4 toxicities were observed.
Conclusion: This randomized study clearly showed that nimo in combination with gem is safe and well tolerated. The 1-year survival rate is
significantly improved. Especially pts ≥ 62 years seem to benefit.
Gastrointestinal Stromal Tumors
ID 010
Results from a phase III trial (GRID) evaluating
regorafenib (REG) in metastatic gastrointestinal stromal
tumour (GIST): Subgroup analysis of outcomes based on
pretreatment characteristics
P. Reichardt1, H. Joensuu2, P.G. Casali3, Y.-K. Kang4, J.-Y. Blay5,
P. Rutkowski6, H. Gelderblom7, P. Hohenberger8, M.G. Leahy9,
M. von Mehren10, G. Badalamenti11, M.E. Blackstein12,
A. Le Cesne13, P. Schoffski14, R.G. Maki15, J.-M. Xu16, T. Nishida17,
C. Kappeler18, I. Kuss18, G.D. Demetri19
Helios-Klinikum Berlin-Buch, Sarkomzentrum Berlin-Brandenburg, Berlin,
Deutschland
2
Helsinki University Central Hospital, Helsinki, Finland
3
Fondazione IRCCS Istituto Nazionale dei Tumori, Mailand, Italien
4
Asan Medical Center, Seoul, Korea, Republik
5
Centre Léon Bérard, Lyon, Frankreich
6
Maria Sklodkowska-Curie Memorial Cancer Center, Warschau, Polen
7
Leiden University Medical Center, Leiden, Niederlande
8
Universitätsklinikum Mannheim, Klinik für Chirurgie, Mannheim, Deutschland
9
The Christie Hospital NHS Foundation Trust, Manchester, Großbritannien
10
Fox Chase Cancer Center, Philadelphia, Vereinigte Staaten Von Amerika
11
University of Palermo, Medical Oncology Division, Palermo, Italien
12
Mount Sinai Hospital, Toronto, Kanada
13
Institut Gustave Roussy, Villejuif, Frankreich
14
KU Leuven and Leuven Hospitals, Leuven, Belgien
15
Mount Sinai School of Medicine, New York, Vereinigte Staaten Von
Amerika
16
Academy of Military Medical Science, Cancer Center, Beijing, China
17
Osaka Police Hospital, Osaka, Japan
18
19
Dana-Farber Cancer Institute, Boston, Vereinigte Staaten Von Amerika
1
Background: REG, an oral receptor kinase inhibitor with activity against
KIT, PDGFR, VEGFR, FGFRs, and other oncologic targets, demonstrated significant improvement in progression-free survival (PFS) over placebo (PL) in a phase III study (GRID) of patients (pts) with advanced
GIST following failure of at least imatinib (IM) and sunitinib (SU). To
understand the impact of pts’ baseline characteristics on outcome, we performed an exploratory analysis of REG effects across pt subgroups based
on sex, age, and mitotic index of primary GIST tissue, as well as duration
and number of lines of previous therapies.
Abstracts
Methods: Adult pts with metastatic GIST (n = 199) progressing after at
least IM and SU were randomized 2:1 to receive oral REG 160 mg or PL
once daily for the first 3 weeks of each 4-week cycle. Subgroup analysis of centrally assessed PFS was performed, based on sex, age (<65, 65
years), mitotic index of primary GIST (<5, 5 to <10, 10 mits/50 hpf), duration of IM and SU treatment (<6, 6 to <18, 18 months), and number of
prior anticancer treatment lines (2 or 3). Mitotic index data on primaries
were available for 119 patients.
Results: REG demonstrated improvement in PFS vs PL in all analysed subgroups, i.e. according to sex, age (<65/≥65 yrs), duration of prior IM and SU
(<6, ≥6 to <18, ≥ 18 mos), resp. with HR well below 0.50 for REG vs PL.
Conclusions: REG had substantial efficacy in all patient subgroups included in this analysis.
Clinical trial information: NCT01271712.
ID 011
Mutational analysis of plasma DNA from patients (pts)
in the phase III GRID study of regorafenib (REG) versus
placebo (PL) in tyrosine kinase inhibitor (TKI)-refractory
GIST: Correlating genotype with clinical outcomes
P. Reichardt1, G.D. Demetri2, M. Jeffers3, Y.-K. Kang4, J.-Y. Blay5,
P. Rutkowski6, H. Gelderblom7, P. Hohenberger8, M.G. Leahy9,
M. von Mehren10, H. Joensuu11, G. Badalamenti12,
M.E. Blackstein13, A. Le Cesne14, P. Schoffski15, R.G. Maki16,
J.-M. Xu17, T. Nishida18, I. Kuss19, P.G. Casali20
Deutschland
2
3
Amerika
4
5
6
7
8
9
The Christie Hospital NHS Foundation Trust, Manchester, Großbritannien
10
Fox Chase Cancer Center, Philadelphia, Vereinigte Staaten Von Amerika
11
Helsinki University Central Hospital, Helsinki, Finland
12
University of Palermo, Medical Oncology Division, Palermo, Italien
13
Mount Sinai Hospital, Toronto, Kanada
14
15
KU Leuven and Leuven Hospitals, Leuven, Belgien
16
Mount Sinai School of Medicine, New York, Vereinigte Staaten Von Amerika
17
Academy of Military Medical Science, Cancer Center, Beijing, China
18
Osaka Police Hospital, Osaka, Japan
19
20
1
Background: The phase III GRID study showed that REG provides a
significant improvement in PFS compared with PL in pts with advanced
gastrointestinal stromal tumors (GIST) following failure of at least imatinib (IM) and sunitinib (SU; HR 0.27).
Methods: DNA was isolated from both archival tumor tissue (n = 102)
and plasma at baseline (n = 163) and analyzed for mutations via Sanger
sequencing (tissue) or BEAMing (plasma).
Results: Mutational frequencies for tumor tissue samples were: KIT,
66%; PDGFRA, 3%; KRAS, 1%; BRAF, 0%. For plasma, frequencies
were: KIT, 58%; PDGFRA, 1%; KRAS, 1 out of 2 samples, BRAF, 0%.
Detection of primary KIT mutations showed 84% concordance between
tissue and plasma. Secondary KIT mutations were more commonly detected in plasma (47%) than in tissue (12%). Subgroup analysis based on
mutational status showed an improved PFS in REG-treated pts vs PL in
all subgroups by both central and local review of imaging studies. The
presence of a secondary KIT mutation in plasma was associated with
shorter PFS in pts receiving PL (HR 1.82, p = 0.05). Pts with a KIT-exon
9 mutation received IM for a shorter period of time, and SU for a longer
period of time, relative to other GIST genotypes. Pts with a PDGFRA mutation showed variable clinical responses, while 1/1 KRAS-mutant GIST
did not respond well to IM, SU, or REG.
57
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Conclusions: KIT mutational status correlated to IM and SU treatment
duration. While consistent with prior reports using tissue sampling, this
validates the utility of plasma-based circulating DNA analysis of target
oncogenes. Secondary KIT mutations appear to have a negative prognostic impact in GIST, while the clinical benefit of REG vs PL was not influenced by KIT mutational status.
ID 012
Health-related quality of life (HRQoL) of patients with
advanced gastrointestinal stromal tumors (GIST) treated
with regorafenib (REG) vs placebo (P) in the phase III
GRID trial
S. Bauer1, J. Chang2, P.G. Casali3, P. Reichardt4, Y.-K. Kang5,
J.-Y. Blay6, Y. Wu2, D. Odom7, I. Kuss8, G.D. Demetri9
Deutschland
2
Amerika
3
4
Deutschland
5
6
7
RTI Health Solutions, Research Triangle Park, Vereinigte Staaten Von
Amerika
8
9
1
Background: The GRID trial demonstrated significant improvement in
PFS for REG vs P in pts with metastatic GIST after progression on at least
imatinib and sunitinib. Exploratory analyses were conducted to assess the
effect of treatment on HRQoL.
Methods: The HRQoL analyses were selected a priori based on clinical
relevance; the global health status/QoL (QL) and the physical functioning
(PF) scales of the EORTC QLQ-C30 questionnaire were used. A linear
mixed-effects model was used to examine the treatment effect on HRQoL
and trends over time, assuming that missing data were missing at random.
Pattern-mixture models were applied to assess the treatment effect while
accounting for potentially informative missing data. Time-to-deterioration
(TTD) of HRQoL and responder analyses were conducted to determine the
treatment effect based on timing and proportion of patients reaching a minimal important difference (MID) change in QL/PF (≥10 points).
Results: The QL and PF changes over time were numerically similar
between REG and P based on the linear mixed-effects model. The pattern-mixture models grouped patients based on timing of last HRQoL assessment ( P (QL: 6.5 vs 4.0; PF 8.0 vs 4.0 weeks, respectively). Median
TTD was comparable between treatments after removing disease progression from the definition. The responder analyses showed that a similar
proportion of patients achieved an improvement in MID in REG vs P
(QL: 26.2% vs 25.4%; PF: 18.0% vs 15.3%, respectively).
Conclusion: The findings of this exploratory analysis demonstrate that
HRQoL is similar for REG and P groups, indicating that REG prolongs
PFS vs P while maintaining at least comparable HRQoL.
ID 013
Time course of adverse events in the phase III GRID study
of regorafenib in patients with metastatic gastrointestinal
stromal tumors (GIST)
S. Bauer1, J.-Y. Blay2, P.G. Casali3, P. Reichardt4, Y.-K. Kang5,
P. Rutkowski6, H. Gelderblom7, P. Hohenberger8, C. Kappeler9,
I. Kuss9, G.D. Demetri10
Deutschland
2
3
4
Deutschland
1
58
7
8
9
10
5
6
Background: Regorafenib (REG), has demonstrated significant improvement in PFS vs placebo (HR 0.27)
Methods: Adults with metastatic GIST after treatment with imatinib and
sunitinib were randomized 2:1 to receive oral REG 160 mg or matching P
once daily for the first 3 weeks of each 4-week cycle. Treatment-emergent
AEs and biochemical abnormalities were assessed at each cycle.
Results: The safety population comprised 198 patients (pts): REG
n = 132; P n = 66. The median treatment duration was 22.9 weeks (range:
9.3–50.9) in the REG group and 7.0 weeks (5.1–25.9) in the P group.
Treatment-emergent AEs of any grade occurred in all of the REG pts and
92% of P pts, at grade 1/2 in 24% and 53%, respectively, at grade 3 in
64% and 29%, respectively, and at grade 4 in 7% and 6%, respectively. AE-related deaths occurred in seven REG and four P pts. The most
frequent AEs occurring in REG pts were hypertension (59%), hand-foot
skin reaction (HFSR) (57%), fatigue (50%), diarrhea (47%), and oral mucositis (41%). The incidence of all of these AEs peaked in cycle 1 and
tapered to relatively stable lower incidence rates over later cycles. AEs
led to dose modification in 72% of REG pts and in 26% of P recipients.
The proportion of planned REG dose actually administered decreased between cycles 1 and 4 (89% of planned dose received in cycle 1 and 77%
of planned dose received in cycle 4), and dose intensity was relatively
stable in subsequent cycles (planned dose received remained above 72%).
Conclusion: In the GRID trial, the incidence of the most common AEs in
the REG group peaked early during treatment, and was manageable with
dose modification so that lower levels of AEs occurred in later treatment
cycles, with no evidence of cumulative toxicity. Few pts (6% REG, 8% P)
required discontinuation from study due to AEs.
Genitourinary Cancer including Prostate Cancer
ID 036
Pain analyses from the phase 3 randomized ALSYMPCA
study with radium-223 dichloride (Ra-223) in castrationresistant prostate cancer (CRPC) patients with bone
metastases
A.J. Schrader1, S. Nilsson2, O. Sartor3, O. Bruland4, F. Fang5,
A.-K. Aksnes6, C. Parker7
Universitätsklinikum Ulm, Klinik für Urologie, Ulm, Deutschland
Karolinska University Hospital, Stockholm, Schweden
3
Tulane Cancer Center, New Orleans, Vereinigte Staaten Von Amerika
4
University of Oslo, The Norwegian Radium, Hospital, Oslo, Norwegen
5
Bayer HealthCare, Montville, Vereinigte Staaten Von Amerika
6
Algeta ASA, Oslo, Norwegen
7
The Royal Marsden NHS Foundation Trust, Sutton, Großbritannien
1
2
Background: Bone metastases (mets), present in > 90% of patients (pts)
with CRPC, may cause severe pain. In a phase 2 dose-response study
with a single injection of Ra-223, pain response was seen in up to 71%
of CRPC pts with painful bone mets (Nilsson 2012). In the phase 3 ALSYMPCA study, which included 921 CRPC pts with bone mets randomized 2:1 to receive 6 injections of Ra-223 (50 kBq/kg IV) q4wk or
matching placebo (Pbo) (Ra-223, n = 614; placebo, n = 307), Ra-223
significantly improved overall survival vs Pbo (median 14.9 vs 11.3 mo;
HR = 0.695) and was well tolerated. Post hoc analyses of pain parameters
in ALSYMPCA are presented.
Methods: A Cox model was used to analyze time to initial opioid use
and time to EBRT. Pts with no opioids at baseline were included in the
pain analyses and all pts in the analysis for time to EBRT. Concomitant
Abstracts
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Index
opioids were recorded from first study drug injection to 12 weeks after
last injection.
Results: Baseline pain was similar between the treatment groups based
on WHO pain ladder. Time to EBRT was significantly longer with Ra-223
vs Pbo (HR = 0.670; 95% CI, 0.525–0.854). Despite a longer observation
time, fewer Ra-223 pts (50%) than Pbo (62%) reported bone pain as an
AE. At baseline, 269 Ra-223 pts and 139 Pbo did not use opioids. Median
time to initial opioid use was significantly longer in the Ra-223 group,
with a risk reduction of 38%, compared to Pbo (HR = 0.621; 95% CI,
0.456–0.846). Fewer Ra-223 pts (36%) than Pbo (50%) required opioids.
The QOL pain score indicated reduced pain for Ra-223 pts relative to
Pbo at week 16 (P = 0.001). Ra-223 pts had significant pain reduction vs.
baseline at weeks 16 (P P = 0.001).
Conclusions: These results provide consistent evidence that Ra-223 reduces pain and opioid use in CRPC pts with bone mets.
ID 039
Efficacy and safety of radium-223 dichloride (Ra-223) in
castration-resistant prostate cancer (CRPC) patients with
bone metastases who had prior or no-prior docetaxel in
the phase 3 ALSYMPCA trial
F. König1, N.J. Vogelzang2, S.I. Helle3, D.C. Johannessen4,
J.M. O’Sullivan5, J. Garcia-Vargas6, C.G. O’Bryan Tear7,
M. Shan6, C. Parker8
Outpatient clinic of Urology, Berlin, Deutschland
Comprehensive Cancer Center of Nevada, Las Vegas, Vereinigte Staaten
Von Amerika
3
Haukeland University Hospital, Bergen, Norwegen
4
Ulleval University Hospital, Oslo, Norwegen
5
Queens University, Centre for Cancer Research and Cell Biology, Belfast,
Irland
6
7
Algeta ASA, Oslo, Deutschland
8
The Royal Marsden NHS Foundation Trust and Institute of Cancer, Sutton, Großbritannien
1
2
Background: Ra-223, a first-in-class α-emitter, significantly improved
median overall survival (OS) at the interim analysis and confirmed at the
updated analysis by 3.6 mo vs placebo (Pbo) in CRPC patients (pts) with
bone metastases (mets) receiving best standard of care (BSoC) in the ALSYMPCA study (HR = 0.695; 95% CI, 0.581–0.832; P = 0.00007), and
had a highly favorable safety profile in the updated ALSYMPCA analysis
(Parker et al. ASCO 2012). This predefined subgroup analysis assessed
efficacy and safety of Ra-223 in pts who had prior (pD) or no-prior (npD)
Docetaxel (D).
Methods: Eligible pts had progressive, symptomatic CRPC with ≥ 2
bone mets; had no known visceral mets; were receiving BSoC; and had
received pD, or were unfit for or declined D (npD). Pts were randomized
2:1 to 6 injections of Ra-223 (50 kBq/kg IV) q4wk or matching Pbo and
stratified by prior D use, baseline alkaline phosphatase level, and current
bisphosphonate use. Survival data were compared using a log-rank test.
Results: 395/921 (43%) randomized pts had npD (Ra-223, n = 262; Pbo,
n = 133); 526/921 (57%) received pD (Ra-223, n = 352; Pbo, n = 174).
Median ages were 74 y (npD) and 69 y (pD). In pts with npD, median OS was 16.1 mo in the Ra-223 group vs 11.5 mo in the Pbo group
(HR = 0.745; 95% CI, 0.562–0.987; P = 0.039). In pts with pD, median
OS was 14.4 mo vs 11.3 mo in the Ra-223 and Pbo groups, respectively
(HR = 0.710; 95% CI, 0.565–0.891; P = 0.003). Overall, there was a low
incidence of myelosuppression. Incidences of neutropenia and thrombocytopenia were higher in pts with pD vs pts with npD.
Conclusions: Ra-223 significantly prolonged OS and had a highly favorable safety profile in CRPC pts with bone mets, regardless of whether
they had pD or npD. pD pts had a slightly increased rate of grade 3 and 4
bone marrow suppression with Ra-223.
Abstracts
ID 047
Hematologic safety of Ra-223 dichloride (Ra-223) in
castration-resistant prostate cancer (CRPC) patients with
bone metastases from the phase 3 ALSYMPCA trial
A. Strauss1, C. Parker2, J. Garcia-Vargas3, C.G. O‘Bryan-Tear4,
F. Fang3, N.J. Vogelzang5
University Hospital Göttingen, Göttingen, Deutschland
The Royal Marden NHS Foundation Trust, Sutton, Großbritannien
3
4
5
Von Amerika
1
2
Background: Updated ALSYMPCA analysis: Ra-223 signif. improved
OS by 3.6 mo vs placebo (Pbo) in 921 CRPC pts with BM (HR=0.695;
95% CI, 0.581-0.832; P=0.00007) and had a highly favorable safety profile. The hematologic safety profile and results from a post hoc analysis
assessing prognostic factors for changes in hematologic parameters are
presented.
Methods: Pts were randomized 2:1 to 6 injections of Ra-223 (50 kBq/
kg IV) q4wk or matching Pbo and stratified by prior docetaxel (D) use,
total alkaline phosphatase (tALP), and current bisphosphonate use. Multivariate regression analysis was performed to explore the relationshipof
6 baseline factors with maximum % change of hematologic parameters
from baseline up to 24 wk on treatment (tx).
Results: The updated analysis included 901 pts (safety population; Ra223, n = 600; Pbo, n = 301). Overall grade 3/4 AEs were similar between
Ra-223 and Pbo groups (neutropenia: 2% vs 1%; thrombocytopenia: 6%
vs 2%; anemia: 13% vs 13%). Tx with Ra-223 + prior D use extent of
disease >6 BM, tALP ≥220 U/L, but not current bisphosphonate use, were
associated with decreases from baseline in hemoglobin (Hb), neutrophils,
or platelets; prior EBRT to bone for pain was associated with an increase.
Conclusions: Overall, there was a low risk for hematologic AEs with
Ra-223 tx in CRPC pts with BM. The strongest prognostic factors for
decreases in neutrophils and platelets were Ra-223 tx + prior D use. Baseline tALP was a strong predictor of decrease in Hb.
ID 057
Updated survivl, Qulity of life (QOL), and safety Dta of
Radium-223 Chloride (Ra-223) in patients with Castrationresistant Prostate Cancer (CRPC) with Bone Metastases
from the phase 3 double-blind, randomized, multinational
study (ALSYMPCA)
T. Steuber1, C. Parker2, R.E. Coleman3, S. Nilsson4,
N. Volgelzang5, A.J. Lloyd6, K. Staudacher7, R. van Gool8,
A.O. Sartor9
Martini-Klinik am UKE GmbH, Hamburg, Deutschland
The Royal Marden NHS Foundation Trust, Academic Urology, Sutton,
Großbritannien
3
Weston Park Hospital, Academic Unit of Clinical Oncology, Sheffield,
Großbritannien
4
Karolinska University Hospital, Radiumhemmet, Stockholm, Schweden
5
Von Amerika
6
Oxford Outcomes, Patient Reported Outcomes, Oxford, Großbritannien
7
8
Bayer HealthCare, Montville, Deutschland
9
Tulane Cancer Center, Department of Medicine and Urology, New Orleans, Vereinigte Staaten Von Amerika
1
2
Introduction: Ra-223 is a first-in-class alpha-emitter pharmaceutical that
targets bone metastases with high-energy, very short range (<100 μm)
alpha-particles. In the interim analysis (IA) of ALSYMPCA, which compared Ra-223 and placebo (Pbo) in CRPC patients (pts) with bone metastases receiving best standard of care, Ra-223 improved overall survival
(OS), with a 30.5% reduction in risk of death (HR.695). Updated survival,
QOL, and safety data are reported.
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Methods: Eligible pts previously received or refused docetaxel, or were
docetaxel ineligible, and were randomized 2:1 to receive Ra-223 (50 kBq/
kg IV) or Pbo every 4 weeks x 6. After the IA, an updated analysis of all
enrolled pts prior to crossover assessed effects of Ra-223 on the primary
(OS, using a stratified log-rank test) and secondary (eg, skeletal-related
events [SREs], QOL, and safety) endpoints. QOL was assessed with the
Functional Assessment of Cancer Therapy-Prostate (FACT-P) and EuroQoL (EQ-5D) instruments.
Results: The updated analysis data for 921 pts (Ra-223, n = 614; Pbo,
n = 307) will be presented. Median OS benefit for Ra-223 was 3.6 mos
(HR 0.695). Time to first SRE was 6 mos longer with Ra-223. At week
16, Ra-223 pts reported significantly greater well-being (physical, emotional, functional, prostate cancer score, and total score) (FACT-P) and
significantly better QOL (EQ-5D) compared to Pbo pts. The incidence
of myelosuppression with Ra-223 was low: 2.2% grade 3/4 neutropenia;
6.3% grade 3/4 thrombocytopenia.
Conclusions: The ALSYMPCA updated analysis substantiates that Ra223 is an effective therapy that significantly improves OS and time to first
SRE, with a highly favorable safety profile, in CRPC pts with bone mets.
Ra-223 showed significantly better preservation of QOL, with improved
functioning and well-being, compared to Pbo.
ID 064
Safety of cytotoxic chemotherapy following Radium-223
Chloride (Ra-223) therapy in the phase 3 alsympca study
in patients with Castration-resistant Prostate Cancer
(CRPC) with Bone Metastases
P. Strölin1, O. Sartor2, R.E. Coleman3, S. Nilsson4, N. Vogelzang5,
A. Cross6, C.G. O’Bryan Tear7, K. Staudacher8,
J.E. Garcia Vargas8, J. Zou8, C. Parker9
Martini-Klinik am UKE GmbH, Hamburg, Deutschland
Tulane Cancer Center, Department of Medicine: Section of Hematology
& Medical Oncology and Department of Urology, New Orleans, Vereinigte
Staaten Von Amerika
3
Weston Park Hospital, Academic Unit of Clinical Oncology, Sheffield,
Großbritannien
4
Karolinska University Hospital, Radiumhemmet, Stockholm, Schweden
5
Comprehensive Cancer Center Nevada, Developmental Therapeutics,
Las Vegas, Vereinigte Staaten Von Amerika
6
PharmaNet, Biostatistics, Hemel Hempstead, Vereinigte Staaten Von
Amerika
7
8
Bayer HealthCare Pharmaceuticals, Montville, Kanada
9
The Royal Marsden NHS Foundation Trust, Academic Urology, Sutton,
Großbritannien
1
2
Introduction: Ra-223 is a first-in-class alpha-emitter pharmaceutical that
targets bone metastases with high-energy, extremely short range (<100
μm) alpha-particles. ALSYMPCA compared efficacy and safety of Ra223 vs placebo (Pbo) in CRPC patients ( pts) with bone metastases receiving best standard of care. In the updated analysis of all 921 randomized
pts (Ra-223, 614; Pbo, 307) prior to Pbo crossover, the median overall
survival (OS) benefit for Ra-223 was 3.6 months (hazard ratio 0.695) and
the incidence of myelosuppression was low. The use of cytotoxic chemotherapy (Chemo) after completion of study treatment was evaluated.
Methods: The cohort for this analysis consisted of all pts who received
Chemo after completion of Ra-223 or Pbo. Chemo agents were identified,
and length of time from last injection of study drug to start of Chemo and
its duration calculated. Available hematology data were reviewed, and
post hoc analysis of survival conducted.
Results: The proportion of pts receiving subsequent Chemo was 90/614
(15%) in the Ra-223 group and 54/307 (18%) in the Pbo group. Docetaxel
(n = 102), mitoxantrone (n = 23), and cyclophosphamide (n = 19) were
the most commonly used. Duration of Chemo and available docetaxel
dosage data were similar in both groups. Median time to Chemo was 2
weeks longer following Ra-223. Median OS from start of Chemo was
15.6 mos and 14.6 mos in the Ra-223 and Pbo groups, respectively
60
(P = .6930). Number of deaths and causality during and 30 days post Chemo andlimited available hematologic data were similar in both groups.
Conclusions: Patients were able to receive Chemo following Ra-223 and
have a similar safety profile and outcome as for Chemo following Pbo.
No toxic deaths occurred. Prospective studies to evaluate Chemo following Ra-223 are warranted.
ID 065
Erectile dysfunction one year after a (first) hospitalization
for prostate cancer – results of a survey of health
insurance beneficiaries
E.M. Bitzer, S. Neusser, C. Lorenz, T. Grobe
Pädagogische Hochschule Freiburg, Public Health & Health Education,
Background: Due to demographic changes hospitalizations associated
with prostate cancer increased from 1994 to 2010 by 40%. The therapeutic options may cause harm. Little is known on the frequency of erectile
dysfunction (ED) and factors associated with the occurrence in routine
health care .
Methods: We conducted a survey on 1.165 beneficiaries (up to 75 years
of age) hospitalized for prostate cancer (ICD C61) in 2010 without prior
hospitalizations for ICD C61 in the years 2005 to 2009. ED was assessed
with the German version of the EORTC Prostate Specific Module (PSM).
Patient reports were obtained one year after discharge and linked with
insurance hospital claims data . The ED-scale ranges from 0 to 100 with
larger values representing higher impairment. We estimated the probability of reporting maximal ED impairment via multiple logistic regression.
Result: Questionnaires of 825 men (mean age 67.6 yrs., 80% treated with
radical prostatectomy) were available for analyses (response 70.8%). The
mean score of the EORTC-PSM-Subscale ED was 89.9. Compared to
men aged 71–75 yrs the odds for ED are reduced in men 40–60 years
(OR 0.35, 95%-CI 0.2–0.64) and 61 to 65 years of age (OR 0.53 95%CI 0.40–10.89). Further ED-protective factors are nerve-sparing surgical
technique (OR 0.30 95%-CI 0.20–0.47), no-operation (OR 0.26 95%-CI
0.14–0.48), and Brachytherapy (OR 0.25 95%-CI 0.11–0.57). Co-morbidity, self reported post-operative complications, radiation, and hormonal treatment increased the likelihood of ED. The C-value of the model
was 0,75.
Conclusion: ED is a common sequelae of surgical and non-surgical treatment approaches in routine health care.
ID 106
Comparing epidemiological data from the United States
and Germany reveals different treatment habits for lowrisk prostate cancer
J. Huber1, B. Hager1, B. Keck2, M. Fröhner1, M. Wirth1,
K. Kraywinkel3
Universitätsklinikum Carl Gustav Carus an der TU Dresden, Klinik und
Poliklinik für Urologie, Dresden, Deutschland
2
Universitätsklinikum Erlangen, Klinik für Urologie, Erlangen, Deutschland
3
1
Introduction: For low-risk prostate cancer recent guideline updates considerably strengthened defensive treatment strategies. Aim of the study
was to analyze changes in primary treatment over time and across different healthcare systems.
Methods: We compared ‘Surveillance Epidemiology and End Results’ data (USA) with reports from four German federal epidemiological cancer registries (Eastern Germany, Bavaria, Rhineland-Palatinate,
Schleswig-Holstein), both from 2004 to 2010. We excluded metastatic
disease and patients older than 79 years. Thereof, we identified 88,829
(USA) and 27,003 (Germany) patients with low-risk according to the
2013 EAU guidelines.
Results: Referred to all age groups the use of defensive treatment strategies including hormonal therapy has increased from 23.7% to 37.9%
Abstracts
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Index
in the USA and from 26.5% to 30.2% in Germany from 2004 to 2010.
In Germany this proportion was fairly stable until 2009 and increased in
2010. In contrast, there was a continuous increase in the USA. Treatment
habits for active therapy are rather stable over time in each country, but
they differ largely across healthcare systems. Exemplary, in 2010 radical prostatectomy was applied more frequently in Germany (46.4% vs.
17.9%) and radiotherapy was dominant in the USA (43.4% vs. 20.4%).
Conclusion: For low-risk disease defensive treatment strategies are becoming more frequently applied. This trend is more continuous in the
USA. Partly habits for active treatment appear system dependent, because
the observed differences are not sufficiently explicable by diverging
adoption of scientific evidence or varying patient preferences.
ID 122
Is a fatal family history of prostate cancer a prognostic
factor for survival?
K. Herkommer1, E. Donel1, J. Gschwend1, M. Kron2
Klinikum rechts der Isar der TU München, Urologische Klinik und Poliklinik, München, Deutschland
2
Universität Ulm, Institut für Biometrie und Medizinische Statistik, Ulm,
Deutschland
1
zu
rü
ck
ge
zo
ge
n
Purpose: InGermany 20% of all prostate cancer patients have a positive
family history. These patients often worry about having a worse outcome
or having a higher risk of dying of prostate cancer. The aim of this study
was to determine the impact of a fatal family history (FH) on survival of
prostate cancer patients after radical prostatectomy inGermany.
Material and Methods: 2883 patients after radical prostatectomy with at
least one first-degree relative with pc of the nationwide database familial
pc inGermany were stratified according to family history (fatal vs. nonfatal). Fatal FH was defined as patients who had at least one first-degree
relative and/or one second-degree relative who died of pc. Biochemical
progression free survival (BPFS), overall survival (OS) and cancer specific survival (CSS) for each epidemiological feature were analyzed according to the method of Kaplan and Meier and subgroups were compared in a
proportional hazard regression calculating hazard ratio (HR) and p-value.
Results: In the subgroup with fatal pc we observed less organ confined
tumors (60.6% vs. 67.1%), higher rates of male to male transmission
(66.9% vs. 54.4%), more hereditary patients (53.2% vs. 18.6%), more
patients with more than 2 affected relatives (67.3% vs. 25.9%) and an
earlier age of onset (median age of diagnosis 62.5 yr vs. 63.6 yr). Survival was comparable in the fatal subgroup and the nonfatal subgroup:
BPFS HR=0.96 (p = 0.695), OS HR=1.13 (p = 0.506), CSS HR=0.92
(p = 0.788).
Conclusion: Survival was not remarkably different in familial patients
with fatal family history compared to those with non-fatal FH. Now we
can calm down our patients after radical prostatectomy because our findings suggest that a fatal family history is not associated with worse clinical outcome or poorer survival.
ID 134
Changes in prognostic and therapeutic parameters in
prostate cancer from an epidemiological view over 20
years
M. Dörr, A. Schlesinger-Raab, G. Schubert-Fritschle, J. Engel
Tumorregister München (TRM), München, Deutschland
Objective: The aim of this analysis was to examine changes in prognosis
and treatment of prostate cancer patients over the last 20 years, and to
evaluate their impact on survival.
Patients and Methods: 36,008 prostate cancer patients diagnosed between 1990 and 2010 and living in the catchment area of the Munich
Cancer Registry (Upper Bavaria and in part Lower Bavaria, population
4.6 million) were analysed.
Results: Pretherapeutic PSA testing increased dramatically in the early
1990’s. A shift from capsule exceeding tumours to capsule limited tu-
Abstracts
mours also took place especially in the 1990s. In the early 1990s nearly
10% of the diagnosed tumours were stage T4, approximately 35% T3,
23% T2, and circa 13% T1. By 2010 only about 3% of the diagnosed
tumours were stage T4, 15% T3, 40% T2 and 23% T1.
Concurrently, initial therapeutic strategies changed noticeably over the
last 20 years. Radical prostatectomy increased continuously, from 20%
to almost 50% of all initial treatments. Hormone therapy developed oppositely, with initial hormone therapy as the most selected treatment until
1994 and then continuously decreased from 55% in 1990 to 18% in 2010.
Radiation therapy and transurethral resection of the prostate slightly increased from about 5 to 10%.
Over the observed time period, 5- and 10-year relative survival improved
from 92 to 97% and from 86 to 92%, respectively.
Conclusion: We interpret the small rise in prostate cancer survival rates
over the last 20 years, along with the dramatic reversal in tumour staging toward more prognostically favourable T-categories, and noticeable
changes in initial therapy strategies as a consequence of overdiagnosis
due to the introduction of PSA tests as well as a result of more initial
radical prostatectomies.
ID 142
Management of low risk Prostate Cancer, Preliminary
Results of HAROW
L. Weißbach1, D. Schnell1, B. Häussler2
1
2
Stiftung Männergesundheit, Berlin, Deutschland
IGES, Berlin, Deutschland
Five treatment options were offered to men with low risk carcinoma of the
prostate (T ≤2, PSA ≤10 ng/ml, Gleason 6, positive cores ≤2, PSA-density
<0,2 ng/ml 2): Hormonal treatment, Active Surveillance (AS), Radiotherapy (RT), Operation (RP), and Watchful Waiting (WW). The AS arm is
of special interest. The study aims at evaluation of therapeutic strategies
regarding tumor biology and feasibility of AS.
Methods: From 07-2008 to 07-2013, 3.185 men were entered in a 5-arm
prospective non-randomized trial. AS was carried out by 249 urologists
in private practice. Surveillance included quarterly PSA, digital rectal
examination (DRE) and yearly rebiopsy. If increasing growth at DRE,
fast rising PSA, increasing tumor volume and aggressiveness indicated
progression, AS was abandoned and conventional therapy initiated. QL
and patients’ assessment of medical performance were investigated by
questionnaire.
Results: 53% of men chose RP, 12% RT, 7% hormonal treatment, 4%
WW, 13% other. 467/3185 (15%) men favored AS. 72/467 AS patients
required therapeutic intervention: 42 had progression, 30 other various
reasons. Preliminary results: to date, none of the AS patients (median follow up 2 years) died of PCA, 3 men died of other causes; none has systemic progression. So far 98.7% survive. QL and assessment of doctors’
performance was good.
Conclusions: Patients’ AS acceptance was higher than expected (15% vs.
8-10% in international comparison). Attendant urologists adapted quickly
to, and showed increasing acceptance of AS. Feasibility of AS was rated
high by doctors and patients.
Sponsored by GAZPROM Germania.
ID 159
Efficacy of a specialized rehabilitation program on
physical strength and mental power after radical
prostatectomy
D.-H. Zermann, M. Heydenreich
Vogtland-Klinik Bad Elster, Urologie/ Onkologie/ Nephrologie, Bad Elster,
Deutschland
Introduction: Specialized rehabilitation programs allow an early social
and occupational reintegration of patients after prostate cancer surgery.
Aim of this prospective study was an evaluation of the efficacy of a complex training program on functional, physical and mental parameters.
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Methods: 60 patients after prostate surgery were evaluated. All patients
completed a 3-week-rehabilitation program including an 1-hour-pad-test,
a 6-minutes-walk-test and evaluation of quality of life (FACT-G, FACT-P,
FACIT-Fatigue).
Results: The following results (pre-post-comparison) were obtained:
–– significant reduction of urinary incontinence (38.2 g to 23 g/1-hour
pad test)
–– significant increase of 6-minute walk distance – Ø 57.15 m
–– significant improvement of quality of life (FACT-G: 83.2 to 87.5;
–– FACT-P: 31.05 to 33.25; FACIT-Fatigue von 41.7 to 43.9 points).
Conclusion: A specialized rehabilitation program after prostate cancer
surgery allows a significant improvement of functional deficits, physical
and mental health. Therefore a rehabilitation program should be offered
to all prostate cancer patients.
ID 200
Leupaxin acts on cell adhesion and cytoskeletal
remodeling and influences integrin expression in prostate
cancer cells
S. Dierks, S. von Hardenberg, L. Hartmund, P. Burfeind,
S. Kaulfuß
Institut für Humangenetik, Tumorgenetik, Göttingen, Deutschland
Prostate cancer still is the most common cancer type and third leading
cause of cancer-related deaths in Germany. Recently, we could identify the focal adhesion protein leupaxin (LPXN) to be overexpressed in
approximately 20% of prostate carcinomas (PCa) and that this overexpression leads to the progression of PCa. Knockdown of LPXN in PC-3
and DU-145 cells resulted in reduced adhesion, migration and invasion.
To identify candidate proteins that could mediate the LPXN-induced cytoskeletal changes necessary for adhesion and migration, we performed
a Yeast-two-Hybrid screen and identified the actin stabilizing protein
Caldesmon (CaD) as a putative interaction partner of LPXN. Using
proximity ligation assays (PLA) we could show that during migration
of PCa cells LPXN interacts with CaD and more interestingly with its
phosphorylated form which detaches from actin leading to highly dynamic cytoskeletal structures. Further investigations involving PLA and
inhibitor experiments revealed the extracellular signal-regulated kinase
(ERK) to be responsible for CaD phosphorylation. Here we report a possible mechanism for cytoskeletal rearrangement during migration and
invasion of PCa cells involving LPXN as an adapter molecule that regulates CaD-phosphorylation through ERK. In addition to cytoskeletal rearrangements, we observed changes in integrin expression and increased
radio-sensitivity of PCa cells after LPXN knockdown. These findings
could be linked to the alterations in adhesion and the response to radiotherapy of PCa cells.
ID 264
Functional outcomes and their impact on long-term
quality of life after open retropubic radical prostectomy
B. Löppenberg, C. von Bodman, M. Brock, F. Roghmann,
J. Palisaar, J. Noldus
Results: Between 2003 and 2008, 2373 patients had RP with nerve-sparing (NS) in 56.5% (n = 1341). Return-rate of the questionnaires was
58.3% (n = 1383), representing the study cohort. Median follow-up (FU)
was 61 months. Mean age at surgery and FU was 63.6±6.4 and 69.2±6.3
years, respectively. Biochemical recurrence (BCR) occurred in 16.7%
(n = 231) of the patients and 2.2% (n = 51) died. The mean GHS was
71.3±20.7. In the ICIQ 28% (n = 386) scored 0 indicating continence
and 10.2% (n = 141) scored ≥11 indicating severe incontinence, the
GHS was 78±19.3 and 54.9±21.4, respectively. No pads were used by
69.1% (n = 955) patients and 17.9% (n = 247) used ≥2 pads, the GHS
was 74.7±19.9 and 58.5±20.4. Of patients with NS 23.3% (n = 189) and
39.8% (n = 322) had no erectile dysfunction according to IIEF-5 and
EHS, GHS was 81.6±17.1 and 78.8±16.9, respectively. Patients with
BCR had a GHS of 66.8±21.8 as compared to 72.3±20.4 without.
Conclusions: The long-term HQL after RP for PCA is diminished severely by incontinence and to a lesser effect by erectile dysfunction and BCR.
ID 281
Presence of high-risk human papillomavirus DNA
is associated with nuclear expression of p16INK4a,
noninvasive growth pattern and favourable cancerspecific survival in penile squamous cell carcinoma
J. Steinestel1, A. Al Ghazal1, M. Schrader1, A. J. Schrader1,
P. Möller2, K. Steinestel2,3
Universität Ulm, Abt. Urologie, Ulm, Deutschland
Universität Ulm, Institut für Pathologie, Ulm, Deutschland
3
Institut für Radiobiologie, München, Deutschland
1
2
Up to 50% of penile squamous cell carcinomas (pSCC) develop against
the background of high-risk human papillomavirus (HR-HPV) infection.
Whether HPV-triggered carcinogenesis in pSCC has an impact on tumour
aggressiveness or cancer-specific survival, however, is still subject to research. In 60 tissue specimens from 58 patients with surgically treated
pSCC, we performed p16INK4a immunohistochemistry and DNA extraction
followed by HPV subtyping using a PCR-based approach. We found that
88% of tumours showed a keratinizing growth pattern; HR-HPV DNA
was detected in 29%, while p16INK4a staining was observed in 59% of
samples. Overall sensitivity and specificity of p16INK4a to predict presence
of HR-HPV DNA was 100% and 59%, respectively; taking into account
only intense nuclear p16INK4a staining improved specificity to 80%. Both
approaches correlated significantly with presence of HR-HPV DNA in
the samples (p < 0.001). Expression of p16INK4a or presence of HR-HPV
DNA was inversely associated with pSCC tumour invasion (p = 0.004
and p = 0.016), but did not correlate with nodal involvement or distant
metastasis. Presence of HR-HPV but not histologic grade or p16INK4a
positivity predicted slightly better cancer-specific survival (p = 0.118 vs.
p = 0.283 and 0.493, respectively). Our results confirm intense nuclear
staining for p16INK4a, rather than a certain growth pattern, to be a good
predictor for presence of high-risk HPV DNA in pSCC. Furthermore, we
show for the first time that HPV-triggered pSCCs seem to be associated
with less aggressive local behavior, and that presence of HR-HPV DNA
is a better predictor of cancer-specific survival compared to histologic
differentiation and p16INK4a positivity.
Ruhr Universität, Urologische Klinik, Bochum, Deutschland
Background: Patients who underwent radical prostatectomy (RP) for
prostate-cancer (PCA) have excellent long-term survival. Functional results are important, as adverse outcomes may have a detrimental effect
on health-related quality of life (HQL). We report long-term functional
outcomes and their influence on HQL after RP.
Methods: Men treated with RP for PCA at an academic center received
a set of questionnaires (International consultation on incontinence questionnaire (ICIQ), International index of erectile function (IIEF-5), Erection hardness score (EHS)), to assess functional outcomes five years after
RP. The results were correlated with the global-health score (GHS) of the
EORTC QLQ-C30 to assess the impact on HQL.
62
ID 284
Oncological outcome and complications after radical
nephrectomy in patients with renal cell carcinoma and
tumor thrombus of the inferior vena cava
C. Piper, D. Pfister, A. Thissen, D. Porres, A. Heidenreich,
C. Piper
RWTH Uniklinik Aachen, Klinik für Urologie, Aachen, Deutschland
Introduction: Radical nephrectomy represents the only curative treatment approach in patients with RCC and TT-IVC. It was the aim of our
retrospective analysis to analyse (1) the oncological results, (2) periop-
Abstracts
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Index
erative morbidity and (3) role of adjuvant therapy following RN in these
patients.
Patients and Methods: 205 patients with RCC and TT-IVC were identified in a data bank. The mean age was 65 (42–76) years. 58 (28.3%)
patients had a level I thrombus, 79 (38.5%), 47 (22.9%), and 21 (10.2%)
patients exhbited a level II, III & IV thrombi. 170 (82.9%) patients were
without evidence of metastases at time of RN (group 1), 21 (10.2%) had
retroperitoneal (group 2), and 14 (6.8%) visceral metastases (group 3)
and were treated with MTKI postoperatively. ECOG Performance Status
was 0-1 in all patients. Progression-free (PFS), overall (OS) and cancer
specific (CSS) survival was analysed. Postoperative complications were
classified according to the Clavien classification.
Results: Perioperative complications developed in 21%: 13.2% Clavien Grad I-III and 7.3% Grad IV complications, perioperative mortality
was 0%. Relapses developed in 62 (30.2%) patients independend on the
thrombus level. The mean PFS was 45.8, 12.4, and 0.4 months in groups
1, 2, and 3 (p = 0.0004), resp. The mean CSS was 74.1, 35.5, and 21.7
months in groups 1, 2 and 3 (p = 0.0014), resp.. Postoperative MTKI were
without evidence on PFS and CSS. 5-year CSS was 56%, 25% and 15%
in groups 1, 2, and 3. (p = 0.003), resp.
Summary: RN with thrombectomy results in good long-term survival
if patients do not exhibit systemic metastases. Complete resection of locoregional lymph node metastases and/or visceral metastases results in a
long-term survival of only 20%. Adjuvant MTKI do not seem to have a
positive effect on long-term outcome.
ID 286
Management of growing teratoma syndrome (GTS):
Aachen university experience
A. Thissen, D. Pfister, C. Piper, D. Porres, A. Heidenreich
Background: GTS is rare constituting only about 2% of all testis cancer patients. GTS is defined as an enlarging metastatic mass during systemic chemotherapy for advanced nonseminomatous germ cell tumours
(NSGCT) despite decreasing serum tumor markers. Complete surgical
resection is mandatory to achieve a favourable outcome. We report on our
single center experience in the management of GTS.
Methods: Postchemotherapeutic retroperitoneal lymph node dissection
(PCRPLND) was performed in 162 pts. with advanced NSGCT. 14 pts.
(4.9%) fulfilled the criteria of a GTS: enlarging metastatic mass in the
retroperitoneum or visceral organs during systemic chemotherapy with
normalized or regredient tumour markers. In all cases complete radical
bilateral PCRPLND including the resection of adjacent visceral and vascular structures was performed.
Results: Median patient age was 24.5 (18–52) years. All patients exhibited NSGCT with a good or intermediate prognosis according to IGCCCG;
10 and 4 patients presented with clinical stage IIC and III, resp. Median
tumour diameter at time of surgery was 6.5 (3.0–35) cm. Tumour markers
were normalized in 12/14 patients and plateauted in 2/14 patients. Tumour masses were localized in the retroperitoneum in 12 pts.; 2 patients
had additional pulmonary metastases. Median time from chemotherapy to
surgery was 4.8 (1.5–26.5) months 4 pts. required resection of the inferior
vena cava or abdominal aorta; adjunctive nephrectomy was performed in
3 pts. After a median follow-up of 4.2 years 2 pts. developed recurrent
disease; the remainder are alive without evidence of disease.
Conclusions: GTS is a rare phenomenom among pts. with advanced NSGCT and necessitates complete surgical resection of all masses with curative intention. Due to the complex surgery, treatment should be performed
at specialized centres.
Abstracts
ID 311
National Second-Opinion Project of the German Testicular
Cancer Group (GCTSG): Improving Quality of Care for
Testicular Cancer Patients
F. Zengerling1, M. Hartmann2, A. Heidenreich3, S. Krege4,
P. Albers5, A. Karl6, J. Bedke7, W. Wagner8, M. Retz9,
L. Weißbach10, S. Kliesch11, K.-P. Dieckmann12, H.U. Schmelz13,
M. Kuczyk14, E. Winter15, T. Pottek16, A.J. Schrader1, M. Schrader1
Universitätsklinikum Ulm, Klinik für Urologie, Ulm, Deutschland
Universitätsklinikum Hamburg-Eppendorf, Klinik für Urologie, Hamburg,
Deutschland
3
RWTH Aachen, Klinik für Urologie, Aachen, Deutschland
4
Alexianer Krefeld, Klinik für Urologie, Krefeld, Deutschland
5
Universitätsklinikum Düsseldorf, Klinik für Urologie, Düsseldorf, Deutschland
6
Universität München, Klinik für Urologie, München, Deutschland
7
Universitätsklinikum Tübingen, Klinik für Urologie, Tübingen, Deutschland
8
Bundeswehrkrankenhaus Hamburg, Klinik für Urologie, Hamburg,
Deutschland
9
Klinikum Rechts der Isar, Technische Universität München, Klinik für
Urologie, München, Deutschland
10
Stiftung Männergesundheit, Berlin, Deutschland
11
Universität Münster, Zentrum für Reproduktionsmedizin und Andrologie –
Klinische Andrologie, Münster, Deutschland
12
Albertinenkrankenhaus, Klinik für Urologie, Hamburg, Deutschland
13
Bundeswehrkrankenhaus Koblenz, Klinik für Urologie, Koblenz, Deutschland
14
Medizinische Hochschule Hannover, Klinik für Urologie, Hannover,
Deutschland
15
HELIOS Klinik Schwerin, Klinik für Urologie, Schwerin, Deutschland
16
Asklepios Westklinikum, Klinik für Urologie, Hamburg, Deutschland
1
2
Background: The treatment of testicular germ cell tumors is subject to
constant change. In order to meet this challenge, numerous national and
international guidelines have been published since the 1990s. Since 2006,
the National Second-Opinion Project of the German Testicular Cancer
Group (GCTSG) aims to improve the implementation of guidelines as
well as the quality of care for testicular cancer patients.
Methods: Before determining their therapy, participating urologists could
communicate with the second-opinion center (SOC), which is formed by
more than 30 urologists from the German-speaking area. Via an internet
based platform therapy-relevant data were sent to the SOC by the participating urologists, allowing the SOC to give an individual treatment recommendation. Primary end points of the study were congruence between
first and second opinion, treatment changes based on the second opinion,
and relapse-free 2-year survival.
Results: A previous analysis in 2011, which included 927 cases, showed a
high rate of discrepant first and second opinions of about 40%, which significantly increased in advanced tumor stages (clinical stage ≥IIa: 52.3% vs.
Conclusion: Guidelines for the treatment of germ cell tumors are inadequately implemented, particularly in advanced tumor stages. Every fifth
second opinion implied a relevant change in the scope of therapy. SOCs
are a viable tool for the improvement of cancer care in Germany.
ID 313
Surgical Management of Testicular Cancer Patients with
Complex Postchemotherapy Residual Masses: Aachen
University Experience
A. Heidenreich, A. Thissen, C. Piper, D. Porres, D. Pfister
Background: Postchemotherapy retroperitoneal lymphadenectomy (PCRPLND) represents the treatment of choice in patients with residual
masses following systemic chemotherapy for advanced testicular nonseminomas (NS). Involvement of major retroperitoneal vessels or thoracic/lumbar spine is rare and challenging but needs complete resection for
curative intent. We report on our single centre experience in the management of such complex cases.
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Patients and Methods: PCRPLND was performed in 162 pts. with
advanced NS and normalized/plateauing tumour markers. A total of 13
patients required adjunctive skeletal and vascular surgery to the lumbar
spine and the aorta/inferior vena cava in conjunction with a full bilateral
radical PC-RPLND
Results: Median patient age was 24.5 (18–52) years. All patients were of
intermediate or poor prognosis according to IGCCCG. Median tumour
diameter at time of surgery was 18.6 (9.0–35) cm. In 5 patients 1-2 metastatic lumbar vertebral bodies were completely resected, stabilized and
replaced. In 6 patients the infrahilar aorta/inferior vena cava was replaced
by a graft. In 2 patients complete resection of the common iliac arteries
and veins with graft replacement was performed. In addition, retrocrural lymph nodes had to be resected in 5 patients and 3 patients required
adjunctive nephrectomy. After a median follow-up of 2.5 years 1 patient
developed recurrent disease.
Conclusions: Few patients with advanced NS need complex surgery in
an interdisciplinary setting with good functional and oncological outcome. Even the presence of vertebral metastases should not restrain the
surgeon to perform PC-RPLND. Due to the complexity, treatment should
be performed at specialized centres.
ID 354
Oncological efficacy and toxicity of Docetaxel and
Prednison in the management of patients with castration
resistant prostate cancer: Single centre experience
A.K. Thissen, D. Pfister, D. Porres, C. Piper, A. Heidenreich
Uniklinikum Aachen, Urlogie, Aachen, Deutschland
Docetaxel is the recommended first line therapy for metastatic CRPC.
Data on therapeutic effectiveness and side effects are basically not available from the real-world population of patients. We report on our experience with DOC/Pred of non-selected CRPC patients treated in a tertial
referral centre.
The charts of 109 patients with metastatic, progressive CRPC were retrospectively reviewed and the following parameter were recorded besides
patient characteristics: duration and type of androgen deprivation prior to
DOC, PSA↓>30%, PSA↓>50%, PFS and OS, treatment associated side
effects, mean number of cycles, dose reduction, dose delay, frequency
and duration of hospitalisation due to side effects.
The mean age was 63.9 (47–83) years, mean PSA was 338.8 (1.0–7728)
ng/ml. Mean duration of ADT was 231.3 (12–924) weeks and 59.7% of
pts received LHRH monotherapy. PSA responses with PSA↓>30% and
PSA↓>50% were observed in 56% and 45%, resp. Mean PFS was 184
(97–1367) days, mean OS was 605 (72–2018) days. Grad 3/4 toxicities
developed in 67% with neutropenia (41.6%) and anemia (19.4%) as the
most common side effects. 5.9% experienced neutropenic fever. 77.5%
had to be hospitalised for the management of infections (34.7%), surgical or interventional procedures due to local progression (29.1%), or
cardiovascular complications (15.2%). Mean duration of hospital stay
was 17.3 (2–190) days and a mean of 2.04 (1–10) hospital admissions
were necessary.
Treatment with DOC/Pred results in oncologically equivalent results
when compared to the TAX327 trial. Due to the unselected cohort of patients, treatment associated side effects and cancer associated complications occur significantly more often as in the TAX327 study. These data
have to anticipated by treating uro-oncologists, patients have to be informed and followed accordingly.
64
ID 367
Reduction of planning target volume margins for prostate
cancer radiotherapy on helical tomotherapy using
implanted fiducial markers and daily image-guidance
S. Drozdz, M. Schwedas, T.G. Wendt
Universitätsklinikum Jena, Klinik für Strahlentherapie und Radioonkologie,
Jena, Deutschland
Purpose: Internal organ motion (prostate, rectum, bladder) and the daily
set up error can lead to a geographic miss of the target volume. These uncertainties are generally handled by a safty margin. The aim of this study
is to evaluate the appropriate margin for prostate cancer radiotherapy on
helical tomotherapy using fiducial markers and daily image-guidance.
Methods & Materials: The study included 20 patients diagnosed with
locally advanced prostate cancer radically treated with a 6 MV helical
tomotherapy up to a dose of 74 Gy. Three implanted fiducial markers
were used to determine interfractional prostate movement and the daily
set up error. For each patient a mega-voltage computed tomography scans
(MVCT) were acquired prior to the daily treatment. The difference between fiducial marker matching and bony anatomy matching were quantified. From its deviation the margin was calculated based on the van Herk
formula.
Results: The safty margin can be reduced with image-guidance and fiducial markers. The calculated difference between the set up error of the
online matching of markers and of the offline matching of the bony anatomy is 2, 3 and 2 mm in LR, SI, AP direction. It means, based on the van
Herk formula, a margin reduction of 5, 7 and 5 mm (LR, SI, AP) when
using marker matching. The greater margin reduction in the SI-direction
is caused by poor resolution in the SI-direction in the MVCT scans. But
there should be an intrafractional prostate motion considered which is a
limiting factor on margin reduction, as shown in our former study.
Conclusions: Using fiducial-based image-guidance is the best way of
correctly identifying the position of the target. It improves dose coverage
of the target volume, significant determination of planning margins and
reduces doses in the organs at risk.
ID 371
C-acetate PET/CT imaging for detection of recurrent
disease following radical prostatectomy in patients with
prostate cancer
11
V. Müller-Mattheis1, H. Hautzel1,2, M. Fahlbusch1, P. Albers1
1
2
Heinrich-Heine-Universität, Urologische Klinik, Düsseldorf, Deutschland
Institut für Medizin, Forschungszentrum, Jülich, Deutschland
Background: Patients showing rising PSA levels after definitive local
therapy of prostate carcinoma often present a diagnostic dilemma, because
a local recurrence or metastatic lymph node lesions would be amenable to
additional local therapy. The effectiveness of 11C-acetate PET (AC-PET)
matched with corresponding CT scans was evaluated.
Methods: 103 patients with adenocarcinoma of the prostate were enrolled
in this study because of rising PSA values following radical prostatectomy [RP] (n = 97) or radiotherapy [RT] ( n = 6). 11C-acetate whole-body
PET images were obtained. Additionally, a CT scan from the neck to the
pelvic floor was performed. An image overlay of corresponding CT and
PET scans was done. By using attenuation corrected PET data, standardized uptake value (SUV) was calculated, cut-off 2.
Results: Out of 103 patients n =  42 were AC-PET positive. PSA level in 16
of this subset was between 0.5 and 1.45 ng/mL (mean value 1.14 ng/mL), in
16 patients between 2.7 and 9.01 ng/mL, and 7 patients had a PSA distribution between 13.4 and 30.5 ng/mL, respectively. In 16/42 AC-PET positive
patients hypermetabolic lymph node lesions were found, histopathologically confirmed in 10/16 cases. In the remaining 6, unspecific inflammatory
tissue alterations were identified. In 9 patients with corresponding AC-PET
and CT scans RT of detected lymphnode lesions was performed followed
by decreasing PSA level. 23/42 patients were treated with either hormone
manipulation (21/23) or chemotherapy (2/23). Combining the patients hav-
Abstracts
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Index
ing undergone surgery and RT (n = 25), there were 19/25 true positive in
terms of AC-PET, in 13/25 PSA level was <2.0 ng/mL.
Conclusions: Although AC-PET seems to be a promising tool in the detection of recurrent prostate cancer even with PSA levels <2 ng/mL, false
positive patients with a different metabolism marked by 11C-acetate decrease the specifity of the approach.
ID 405
Urothelial cell and lung cancer: An epidemiologic and
clinical analysis of their coincidence
B. Keck1, B. Wullich1, J. Giedl2, B. Walter3, K. Kraywinkel4,
S. Dahm4, S. Pahernik5, M. Hohenfellner5, S. Petsch6, S.J. Klug7,
V. Novotny8, M. Wirth8, J. Huber8
University Hospital, Department of Urology, Erlangen, Deutschland
University Hospital, Department of Pathology, Erlangen, Deutschland
3
Hospital Altötting, Department of Urology, Altötting, Deutschland
4
Robert Koch Institute, Centre for Cancer Registry Data, Berlin, Deutschland
5
University of Heidelberg, Department of Urology, Heidelberg, Deutschland
6
Tumor Centre at the University Erlangen-Nueremberg, Erlangen,
Deutschland
7
University Cancer Centre University Hospital «Carl Gustav Carus», Tumor
Epidemiology and Outcome Research, Dresden, Deutschland
8
University Hospital «Carl Gustav Carus», Department of Urology, Dresden, Deutschland
1
2
Objective: As tobacco smoking is a common risk factor of urothelial
carcinoma (UC) and lung cancer (LC) we set up a clinical and epidemiological analysis to study the clinical significance of LC in UC patients.
Material and Methods: We analyzed 6029 UC patients of a multicentre
cohort (university hospitals Erlangen, Dresden, and Heidelberg) as for
their coincidence of UC and LC. We identified 145 patient and analyzed
epidemiological and clinical data using Student’s t-test.
Results: There were 145/6029 patients with a coincidence of UC and
LC. That represents 2.4% of all patients and is in line with the population-based incidence of 2.5% (3509/142210) derived from the German
national registry. Of these 145 patients 89% were male and 11% female.
The median age at diagnosis was 66.5±9.3 years. 53.1% of the patients
suffered from UC first, 27.6% presented with LC first, and 17.2% suffered from synchronously diagnosed diseases. Moreover, there was no
difference of synchronous and metachronous disease regarding the median age at diagnosis of the first malignancy. The median interval until the
diagnosis of the secondary cancer was 3.6±2.5 years for primary LC and
5.0±4.4 years for primary UC (p = 0.03). 61.4% (89/145) of the patients
died during follow-up. Of these 12.4% died from UC and 71.9% from LC.
15.7% died from another cause. Patients who suffered from synchronous
disease survived much shorter (1.3 vs. 6.1 years, p < 0.001).
Conclusion: The incidence of LC in UC patients is higher than it is expected in a healthy population and affects mainly male patients. Thereby
LC defines the patients’ prognosis. Patients who develop synchronous
malignancies may harbor distinct molecular aberrations causing their
poor prognosis.
ID 423
Methods: 18 pts with biopsy proven, completely resectable PCA, minimal bone metastases (≤ 3 hot spots on bone scan), absence of visceral or
extensive lymph node metastases were included in the pilot study. All pts
underwent neoadjuvant ADT with LHRH analogues for 6 months. If the
PSA decreased to < 0.4 ng/ml and bone lesions disappeared on control
scan, pts were considered suitable for extended RP followed by 2 years
adjuvant ADT.
Results: Mean age was 61 (42–69) years, mean PSA was 96.3 (72–139)
ng/ml and 0.29 (0–0.39) ng/ml at recruitment and at 6 months. Mean
number of bone lesions was 1.9 (1–3). All lesions disappeared after 6
months of ADT. Pathohistology revealed pT2c in 4 (22.2%), pT3a and
pT3b in 3 (16.7%) and 11 (61.11%) pts. 7 (38.9%) pts and 3 (16.7%)
pts had lymph node metastases or positive surgical margins (PSM). PSM
were treated with adjuvant radiation therapy ad 66.6Gy. No Clavien grade
3–5 complications occurred. The mean follow-up is 29 (3–52) months, 3
(16.7%) pts relapsed. The remainder is without evidence of disease.
Conclusions: CRP is feasible in well selected men with low volume bone
metastases who respond well to neoadjuvant ADT. These men have a life
expectancy of 7 years. CRP reduces the risk of local complications. CRP
might be a new treatment option in the multimodality management of
PCA and minimal metastatic disease.
Gynecologic Cancer
ID 082
Entscheidungsfindung im Kontext einer familiärer
Disposition für Brust- und Eierstockkrebs
Positionen des BRCA-Netzwerk – Hilfe bei fam. Brustund Eierstockkrebs und Erfahrungen aus der Beratung
betroffener Familien durch selbst Betroffene
A. Hahne
BRCA-Netzwerk – Hilfe bei fam. Brust- und Eierstockkrebs e.V., Königswinter, Deutschland
Einleitung: das BRCA-Netwzerk – Hilfe bei fam. Brust- und Eierstockkrebs hat sich 2008 gegründet. Es bietet Austausch und Informationen für
Familien mit einer bekannten oder vermuteteten genetischen Veranlagung
für Brust- und Eierstockkrebs. Seit Gründung wurden bundesweit 20
Gesprächskreise gegründet, die lokale Anlaufstelle sind. darüber hinaus
berät das BRCA-Netzwerk online und via Telefon. Verständlich Informationen sowie Ansprechpartner sind über die Website www.brca-netzwerk.
de niedrigschwellig abzurufen.
Fragestellung: Der Stellenwert von Selbsthilfe und Patienteninitiative
im Entscheidungsfindungsprozess für oder gegen eine Gensequenzierung,
für oder gegen prophyl. Maßnahmen (Mastektomie / Ovariektomie).
Methode: Einzelfallbeschreibung aus der Selbsthilfearbeit.
Ergebnisse: Selbsthilfe als Part der Entscheidungsfindung ist eine
notwendige Ergänzung der medizinischen und psychosozialen Versorgungsstrukturen.
Schlussfolgerung: Weiterentwicklung und Finanzierung von Selbsthilfestrukturen.
Cytoreductive Radical Prostatectomy (CRP) in Patients
with Prostate Cancer (PCA) and Low Volume osseous
Metastases
ID 103
C. Piper, D. Pfister, D. Porres, T. van Erps, A. Heidenreich
C. Gründker, E. Schmidt, M. Haase, G. Emons
Uniklinik Aachen, Urologie, Aachen, Deutschland
Universitätsmedizin Göttingen, Klinik für Gynäkologie und Geburtshilfe,
Background: Androgen deprivation (ADT) represents the standard treatment in men with PCA and bone metastases. RP is usually ignored due to
the common view that the biology of the disease is attributed to preexisting metastases. Recently, it has been shown that potentially lethal cancers
persist even after neoadjuvant ADT and chemotherapy. We explored the
outcome of patients with PCA and low volume skeletal metastases who
were subjected to ADT and CRP.
Abstracts
Role of SDF-1 in endometrial cancer metastasis
The crosstalk between metastatic cancer cells and target sites is critical
to the development and progression of metastases. Disruption of this interaction will allow us to design mechanism-based effective and specific
therapeutic interventions for metastases. We have established a coculture
system of cells derived from different tumor entities and MG63 human
osteoblast-like cells to analyze tumor cell invasion. We have shown that
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Index
ovarian, endometrial and breast cancer cell invasion was dramatically increased when cocultured with MG63 cells. Using this model we examine
tumor cell invasion on cellular as well as molecular level.
In the present study we have analyzed whether stromal derived factor-1
(SDF-1) is responsible for human endometrial cancer cell invasion and
whether Kisspeptin-10 (KP-10) treatment affects SDF-1-induced invasion of endometrial cancer cells.
Endometrial cancer cell invasion was significantly increased when cocultured with MG63 cells. Treatment with KP-10 significantly reduced the
invasiveness of endometrial cancer cells. During coculture SDF-1 protein expression of MG63 cells was significantly increased. The MG63
coculture-induced increase of endometrial cancer cell invasion could be
blocked by anti-SDF-1 antibodies. Treatment of endometrial cancer cells
in monoculture (without MG63) with SDF-1α, SDF-1β or the combination of both isoforms resulted in a significant increase of endometrial cancer cell invasion. The SDF-1-induced increase of endometrial cancer cell
invasion was significantly reduced after treatment with KP-10.
Our findings suggest that SDF-1 plays a major role in endometrial cancer
invasion. SDF-1-induced invasion can be inhibited by KP-10 treatment.
ID 104
Inhibition of GPR30 by estriol successfully prevents
growth stimulation of triple-negative breast cancer cells
by 17β-estradiol
However, there are limitations in the adherence and application of guideline changes.
Objectives: To evaluate the awareness of modern antiemetic guidelines
(GL) and their practical use in pts receiving anthracycline plus cyclophosphamide (AC)-containing chemotherapy. ASCO recommends prophylaxis with 5-HT3-receptorantagonist (RA), Neurokinin1-RA and dexamethasone.
Methods: 49 practices used the ODM Quasi® GYN system for the documentation of data on institutions, patients, knowledge and application of
antiemetic GL. Antiemetic treatment was documented in 250 breast cancer pts who received cycle 1 and 3 of AC chemotherapy (80% adjuvant,
20% neoadjuvant).
Results: Awareness of antiemetic GL: AGO* 76%, ASCO 82%, NCCN
31%, MASCC 22%; application of GL: AGO 57%, ASCO 53%, MASCC
12%, NCCN 8%, none (2%). 94% were aware of the change of the emetic
group of AC in the ASCO GL. Active use of triple drug antiemesis: 84%,
planned use: 12%, no use: 4%.
Antiemetic treatment documentation in 246 pts: Cycle 1: 82 (33%) received the triple drug schedule according to GL, 113 (46%) a combination of 5HT3-RA and DEX. Cycle 3: triple: 35%, 5HT3-RA +Dex: 44%.
4 pts were lost to follow up.
Conclusions: Only 33% of pts received the triple combination according
to GL in the first cycle of AC, 35% in the third cycle.
* AGO- German Working Group of Gynecologic Oncology.
R. Girgert, C. Gründker, G. Emons
Clinical success of therapy in triple-negative breast cancer (TNBC) is still
poor and urgently awaits improvement. The majority of TNBC express
the membrane bound estrogen receptor GPR30. As proof of principle
we recently showed that a knock-down of GPR30 expression prevents
growth stimulation of TNBC cell lines by 17β-estradiol and 4-hydroxytamoxifen.
Cells of TNBC cell lines were treated with 10-4 M estriol, an antagonist to GPR30 and activation of c-Src and EGF-receptor was assessed
using Western blots. Expression of c-fos, cyclin D1 and aromatase was
quantified by RT-PCR. Gα-specific signaling of GPR30 was analyzed by
CREB-phosphorylation on Western-blots and electrophoretic mobility
shift assay.
Activity of Src kinase was increased by 10-8 M estradiol and 10-4M estriol treatment clearly lowered p-src induction. Transactivation of the
EGF-receptor was increased by 17β-estradiol and estriol completely
prevented EGF-receptor transactivation. Subsequently, 17β-estradiol increased c-fos-, cyclin D1- and aromatase- expression. Estriol prevented
this mRNA induction in all three tested cell lines. Inhibition of GPR30
with 10-4 M estriol completely abolished activation of all these signaling
pathways responsible for the enhancement of cell proliferation by 17β-estradiol. 10-8 M 17β-estradiol enhanced proliferation of all three TNBC
cell lines whereas cotreatment with 10-4 M estriol kept cell number up to
20% under control level.
Though TNBC does not express ERα it is sensitive to estrogen stimulation and the blockade of the estrogen receptor GPR30, a pharmacological
inhibition of GPR30 by specific small molecular inhibitors might become
a promising targeted therapy of TNBC in the future.
ID 146
How Office Based Gyneco-Oncologists in Germany
Apply Antiemetic Guidelines in Patients Receiving ACContaining (Neo) Adjuvant Chemotherapy
J. Schilling, H.-J. Hindenburg
BNGO e.V., Neuenhagen b. Berlin, Deutschland
ID 157
Bevacizumab-based therapy in patients with intensively
pretreated epithelial and other Mullerian tract
carcuinomas: A single institution experience
C.M. Kurbacher1, W. Nagel2, S. Herz1, G. Wessling1, J. Lepique1,
J.A. Kurbacher1
2
Medizinisches Zentrum Bonn-Friedensplatz, Praxis für Urologie, Bonn,
Deutschland
1
Background: We hereby report on our single-institution experience with
bevacizumab (Bev)-based therapy (Tx) in patients (pts) with heavily pretreated recurrent Mullerian tract carcinomas (MTC) including ovarian
(C), fallopian tube (FTC), peritoneal papillary-serous (PPSC), and type II
endometrial carcinoma (EC-II).
Methods: 78 pts (OC, n = 69; FTC, n = 2; EC-II, n = 4; PPSC, n = 3)
were included in this retrospective study with 45 pts (57.7%) being platinum-resistant. Pts had received a median of 4 (range 1-10) prior chemotherapies (CTx). Tx was was given as Bev monotherapy (group A, n = 
19), Bev+metronomic CTx (group B, n = 38), and Bev+conventionally
dosed CTx (Group C, n = 21). Bev was administered at either 10 mg/
kg q2w or 15 mg/kg q3w. Adverse effects were classified according to
CTCAE 4.0. TTP was calculated from the start of Bev until progression,
OS was calculated from the start of Bev until death or loss to follow up.
Results: Most common adverse effects were hypertension, proteinuria,
headache, infection, epistaxis, and subileus. Hypertension was limiting
in only case, as were renal toxicity, subileus, and infection. Median TTP
was 29.9 wks and median OS was 55.1 wks with no significant difference
between platinum-resistant and -sensitive pts. In regard to both TTP and
OS, there was a non-significant trend favoring group A (36.0/66.4 wks)
and B (29.9/61.6 wks) vs group C (20.3/36.0 wks).
Conclusion: Bev based Tx was active and generally well tolerated in this
hard-to-treat population of pts with recurrent MTC. Both TTP and OS
were equal or even superior to any conventional Ctx used in this setting.
Clinical Platinum-resistance did not predict a worse clinical outcome. We
conclude that, Bev should be preferably given either as single agent or
alongside with metronomic CTx in pts with intensively pretreated MTCs.
Introduction: Supportive care guidelines are an important instrument to
maintain quality of treatment and quality of life in cancer patients (pts).
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ID 164
Changes in the Progesterone-, Estrogen-, HER2/neureceptor status and the proliferation marker Ki-67 in
metastasized breast cancer: Discordance rates and time
to progression in brain metastasis
M. Timmer, C. Cramer, G. Röhn, R. Goldbrunner
Estrogen receptor (ER), progesterone receptor (PgR), human EGF receptor 2 (Her2), and Ki-67 are important predictive and prognostic markers
for making effective treatment decisions. Out of 90 patients with breast
cancer brain metastasis in our tumor tissue bank from 2001 to 2012, there
were 23 consecutive patients from whom both, the primary lesion and the
brain metastasis were operated in our hospital. The lesions were resected
and ER, PgR, Her2 and Ki-67 were evaluated by immunostaining and
molecular technique.
The median age of the patient cohort was 56±9 years at first diagnosis. At
that time 85% of the patients who developed a brain metastasis later on
already had lymph node involvement. The Ki-67 proliferation index increased significantly from a mean of 21% at primary tumor site to 60% at
relapse (p < 0.001). Most patients developed one single brain metastasis
at diagnosis (74%), but 26% had multiple brain metastasis. The localisation of the filiae was mainly either the cerebellum (39%) or fronto-temporal (43.5%). The hormone receptor positive rate from the primary tumor
to recurrence decreased from 43% to 17% and from 43% to 26% for ER
and PgR, respectively. On the other hand, the rates of Her2+ tumors increased from 45% to 86%. 22% of all cases were triple negative.
ER and PgR decreased while Her2 and Ki-67 increased due to relapse.
Interestingly, there was a doubling of Her2+ cases in the relapse situation.
These findings could get important for making effective treatment in the
era of targeted therapies.
ID 167
E- and P-selectin determine peritoneal spread of ovarian
cancer in a xenograft model
C. Schröder1, D. Wicklein1, T. Streichert2, C. Bartmann3, J. Dietl3,
K. Milde-Langosch4, U. Schumacher1
Universitätsklinikum Hamburg-Eppendorf, IAEM, Hamburg, Deutschland
Universitätsklinikum Hamburg Eppendorf, Institut für Klinische Chemie,
3
Universitätsklinikum Würzburg, Gynäkologie, Würzburg, Deutschland
4
Universitätsklinikum Hamburg Eppendorf, Gynäkologie, Hamburg,
Deutschland
1
2
Background: Ovarian cancer is the seventh most common cause of cancer death in women world-wide. The high mortality is caused both by
the late detection and the early intra-peritoneal spread, a process that is
in general scarcely appreciated. However, recent progress in the understanding of the peritoneal spread of pancreatic cancer indicated that Eand P-selectin carbohydrate ligand interactions play a decisive role in the
intra-abdominal spread of this neoplasm.
Methods: Two human ovarian carcinoma cell lines (SKOV3 and OVCAR3) were xenografted into the peritoneal cavity of E- and P-selectin-deficient scid mice and wild-type controls. Kaplan-Meier curves were
prepared for the survival analysis and engrafted tumours were used for
RNA isolation and for transcriptome analysis. The results of selected
genes were validated by FACS and immunohistochemistry.
Results: Both xenografted SKOV3 and OVCAR3 cells engrafted significantly less in E- and P-selectin-deficient scid mice compared to wild type
scid mice (days versus days). Kaplan-Meier analysis showed that a significantly (p = 0.0001) higher overall survival was linked to the loss of Eand P-selectin. Affymetrix cDNA microarray data of the engrafted tumours
indicate an up-regulation of adhesion molecules of the leukocyte cascade.
Conclusion: The engraftment of tumour cells in the peritoneal cavity significantly depends on their adhesion to the mesothelium mediated by selectins and other cell adhesion molecules of the leukocyte adhesion cascade.
Abstracts
ID 180
Vulvar cancer on the rise. A German population based
cancer registry study using pooled data at the Centre for
Cancer Registry Data at Robert Koch-Institute (ZFKD)
N. Buttmann, K. Kraywinkel
RKI, ZfKD, Berlin, Deutschland
Objectives: A substantial increase of invasive vulvar cancer in younger
women over the past three decades has been described in a retrospective
analysis of medical records in Western-Central Germany. Cancer of the
vulva in younger women has etiologically been linked to HPV, preceded
by histologically corresponding intraepithelial lesions. We aimed to provide recent trends on the vulvar cancer burden in Germany, using population based cancer registry data.
Methods: We accessed the data of twelve German cancer registries which
provided data for the period from 1999 to 2010. ICD-10 and morphology
codes in ICD-O-3 were used to select site and histologic types. The annual percentage change has been calculated on age adjusted rates with a
joinpoint regression model.
Results: The annual incidence of invasive carcinoma of the vulva nearly
doubled in the past decade. Age standardized incidence rates annually increased by 6.3% from 2.7 per 100,000 women in 1999 to 5.0 per 100,000
women in 2010. The largest rise was observed among younger women
(30–49 years). Mortality rates also slightly increased by 3.4% per year.
A tendency towards higher relative proportions of squamous cell carcinoma (SCC) and an increase of clitoral tumors was seen. The fraction of
cases detected at small tumor size (restricted to vulva/perineum) slightly
increased, from 67.6% to 74.4% while larger tumors proportionally remained stable.
Conclusion: Compared to internationally available data, Germany witnessed substantially higher rates of invasive vulvar cancer over the past
decade, accompanied by an increase in mortality. Several risk factors as
HPV infection, smoking and immunosuppression might have contributed
to this development.
ID 185
Differentielle Expression von Transkripten
und mikroRNAs während der Progression des
Mammakarzinoms
S. Schultz1, H. Neubauer1, H. Bartsch2, K. Sotlar2,
K. Petat-Dutter2, M. Bonin3, S. Poths3, M. Walter3, O. Riess3,
D. Wallwiener4, T. Fehm1
2
Institut für Pathologie, München, Deutschland
3
Institut für medizinische Genetik, Microarray Facility, Tübingen, Deutschland
4
Universitäts-Frauenklinik Tübingen, Tübingen, Deutschland
1
Die Analyse molekularer Mechanismen beim Übergang vom duktalen in
situ Karzinom (DCIS) der Brust zum invasiven duktalen Karzinom (IDC)
trägt zum Verstehen der Vorgänge der Tumorprogression bei.
Die Ziele dieses Projektes sind die Identifizierung und Validierung von
Transkripten und miRNAs, die (1) zwischen DCIS und IDC differentiell
exprimiert sind und die (2) aggressive DCIS mit hohem Potential für invasives Wachstum detektieren.
Es wurden 15 FFPE-Mammakarzinomproben mit reinem DCIS ohne invasive Komponente selektiert, sowie 15 FFPE-Proben mit DCIS/IDC-Komponenten. Die Gewebeschnitte wurden durch einen Pathologen charakterisiert und die Tumorzellen mittels Lasermikrodissektion isoliert, die
Gesamt-RNA extrahiert, und auf Microarray-Plattformen hybridisiert und
bioinformatisch analysiert. Die Expression ausgewählter Transkripte/miRNAs wurde mittels qRT-PCR in unabhängigen Gewebeproben validiert.
Zwischen reinen DCIS und DCIS aus invasiven Mammakarzinomen sind
2117 Transkripte und 24 miRNAs differentiell exprimiert (P<0.05); zwischen DCIS und IDC sind es 1748 Transkripte und 33 miRNAs (P<0.05).
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In der qRT-PCR bestätigt sich ein kontinuierlicher Expressionsanstieg
von MMP11 und COL10A1 von reinen DCIS über DCIS der invasiven
Mammakarzinome zum IDC. Hsa-miR-214 und hsa-miR-199a-5p sind
im Vergleich zum DCIS im IDC hochreguliert. Auch hier konnte ein kontinuierlicher Expressionsanstieg beobachtet werden.
Mit MMP11, COL10A1 und hsa-miR-199a-5p konnten mögliche prognostische Marker identifiziert und validiert werden, die zum Verstehen
der biologischen Mechanismen der Tumorprogression beitragen, und die
darüber hinaus DCIS mit einem hohen Potential für invasives Wachstum
charakterisieren können.
ID 187
Hsa-miR-199a-5p is functionally relevant in progression
from ductal carcinoma in situ to invasive breast tumours
S. Schultz1, H. Neubauer1, H. Bartsch2, K. Sotlar2,
K. Petat-Dutter2, M. Bonin3, S. Poths3, M. Walter3, O. Riess3,
D. Wallwiener4, T. Fehm4
2
Institut für Pathologie, München, Deutschland
3
Institut für medizinische Genetik, Microarray Facility, Tübingen, Deutschland
4
Universitäts-Frauenklinik Tübingen, Tübingen, Deutschland
1
A fundamental and clinically important step during the breast tumourigenesis is the transition from ductal carcinoma in situ (DCIS) to invasive
ductal carcinoma (IDC). At this point, cancer cells gain the potential to
spread and metastasize. Since the molecular characteristics of this step
still remain poorly understood an improved knowledge of the transition
from pre-invasive to invasive breast cancer will pave the way for novel
preventative and therapeutic strategies.
We analyzed miRNA expression profiles in 15 matched pairs of DCIS and
IDC areas isolated by laser capture microdissection (LCM) from formalin
fixed and paraffin embedded (FFPE) breast cancer tissues using Illumina
miRNA BeadChip microarray platform. Differential expression of two
candidate miRNAs – hsa-miR-199a-5p and hsa-miR-214 – was further
investigated by quantitative RT-PCR in additional independent samples
from 25 breast cancer patients. Invasion assays were performed in combination with knock down of hsa-miR-199a-5p.
In total, matched pair microarray analysis revealed 33 significantly differentially expressed miRNAs (P<0.05). Expression of hsa-miR-199a-5p is
upregulated in IDC according to our microarray data – a result which we
were able to validate by qRT-PCR in independent samples. Knock down
of hsa-miR-199a-5p in invasive MDA-MB-231 and TMX2-28 breast
cancer cells using a specific inhibitor significantly reduced invasiveness
by approx. 73% and 71%, respectively (both P<0.05).
We identified candidate progression miRNAs which are differentially expressed between DCIS and IDC using LCM and microarray analysis on
FFPE breast cancer tissues. Hsa-miR-199a-5p could be validated in an
independent sample cohort, is influencing in vitro cell invasiveness and
may therefore be a potential drugable regulator of tumour progression and
invasion in breast cancer.
ID 197
Increased detection of glandular lesions of the cervix
uteri by using Pap smears
U. Hahlbohm, C. Noble-Pyott, G. Richter
Institut Dr. Richter, Zytologie, Hameln, Deutschland
Aims: The aim is to assess glandular lesions with more certainty using
conventional Pap smears. They are dedicated with PAP group III in the
Münchener NomenklaturII in German- speaking areas and in Englishspeaking areas according to Bethesda AGUS. In already existing publications about this theme the finding rate of glandular lesions is described as
<10%. On the basis of the criteria here applied the finding rate of glandular lesions in cytological smears should be increased.
68
Methods: During microscopic inspection a particular polarization deficiency of cells exists, which let the cell picture appear strong bizarre
disorderly, coupled with the known malignant criteria and a ball-like
three dimensional cell group formation this can be classified. A single cell
capture however is not sufficient for appraisal of glandular atypia. The
relevance of the naked cell nucleus should be observed. A familiar tumor
diatheses cannot be found here.
Results: In 2009 and 2010 in a total number of 145,986 Pap smears the
PAP group III was given 108 times (=0.07%). This equals a patient number of 108 women. The histological clarification could be asserted in 27
cases with the following distribution:
Adenocarcinoma of the Cervix uteri : 6 = 22.2%, Adenocarcinoma of the
Endometrium: 1 = 3.7%, AIS: 4 = 14.8%, ECIN II: 1 = 3.7%, ECIN I:
2 = 7.4%, Squamous cell carcinoma: 1 = 3.7%, CIS: 2 = 7.4%, CIN III:
1 = 3.7%, CIN II: 3 = 11.1%, CIN I: 4 = 14.8%, negative: 2 = 7.4%
Conclusions: The established results show a finding rate of 23% for lesions. Thereby an increase of 131% compared with the already existing
finding rate of <10% is obtained. This can express the heightened sensitivity of glandular lesions in cytological smears using the above mentioned malignancy criteria.
ID 222
Progression-free survival in patients in with advanced
ovarian cancer defined by GCIG criteria vs. RECIST
criteria: Analysis of the secondary endpoint of the AGOOvar16 trial
S. Mahner1, C. Jackisch2, J. Sehouli3, J. Rau4, B. Schmalfeldt5,
A. Belau6, B. Richter7, G. Emons8, T.-W. Park-Simon9,
H.-J. Lueck10, A. Burges11, T. Fehm12, G. Feisel-Schwickardi13,
M. Clemens14, A. du Bois15
University Medical Center Hamburg-Eppendorf, Hamburg, Deutschland
Klinikum Offenbach, Offenbach, Deutschland
Charite Campus Virchow, Berlin, Deutschland
4
KKS, Marburg, Deutschland
5
Technische Universität, München, Deutschland
6
Unversität Greifswald, Greifswald, Deutschland
7
Frauenklinik, Radebeul, Deutschland
8
Universitätsfrauenklinik Götingen, Göttingen, Deutschland
9
MHH, Hannover, Deutschland
10
Frauenarztpraxis, Hannover, Deutschland
11
Klinikum Grosshadern, München, Deutschland
12
Universitätsfrauenklinik Tübingen, Tübingen, Deutschland
13
Klinikum Kassel, Kassel, Deutschland
14
Klinikum Trier, Trier, Deutschland
15
Kliniken Essen Mitte, Klinik für Gynäkologie und Gynäkologische Onkologie, Essen, Deutschland
1
2
3
Background: AGO-OVAR16 is a randomized, double-blind trial of pazopanib as maintenance therapy in patients with advanced epithelial ovarian cancer (AEOC).
Methods: Patients with AEOC (N=940) were randomly assigned 1:1 to
receive pazopanib 800 mg once daily or placebo for up to 24 months.
Primary endpoint was investigator-assessed progression-free survival
(PFS) by RECIST v1.0. A secondary endpoint was PFS by Gynecologic
Cancer InterGroup ‘GCIG’ criteria, based on radiology and tumor-marker
CA-125.
Results: By RECIST criteria there were 273 progression and 195 censoring events in the placebo arm, 237 progression and 235 censoring events
in the pazopanib arm (investigator review). By GCIG criteria, there were
290 progression events in the placebo arm (213 per RECIST and 77 per
CA-125) and 255 progression events in the pazopanib arm (184 per RECIST and 71 per CA-125). Using RECIST criteria, pazopanib increased
PFS compared to placebo by investigator review (HR=0.77; 95% CI: 0.640.91; P=0.0021; median 17.9 vs 12.3 months). Analyses by GCIG were
consistent (HR=0.79; 95% CI: 0.67–0.93; P=0.0047; median 16.8 vs 11.9
months). The proportion of patients with CA-125 progression as the first
progression event was nearly identical between both arms (16% and 15%).
For subjects with both CA-125 and RECIST PD (~10%), the time interval
Abstracts
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from CA-125 progression to RECIST progression was also well balanced
between the placebo and pazopanib arms (mean 2.6 vs 2.8 months).
Conclusions: Maintenance therapy with pazopanib provided a significant
PFS benefit in patients with advanced epithelial ovarian cancer, irrespective of the applied diagnostic criteria. Recurrent disease was diagnosed by
GCIG criteria approximately 2.5 months earlier than RECIST.
ID 230
Effect of Estrogen Receptor β Agonists on proliferation
and gene expression of ovarian cancer cells
S. Schüler, C. Lattrich, J. Häring, O. Treeck, O. Ortmann
Universitätsfrauenklinik Regensburg am Caritas-Krankenhaus St. Josef,
Lehrstuhl für Gynäkologie und Geburtshilfe, Regensburg, Deutschland
Introduction: Estrogen receptor (ER) b has been reported to affect ovarian carcinogenesis. We examined the effects of four ERβ agonists on proliferation and gene expression of OVCAR3 and OAW-42 cells.
Methods: OVAR3 and OAW-42 ovarian cancer cells were treated with the
ERβ agonists ERB-041, WAY200070, Liquiritigenin and 3β-Adiol (10 mM
each) and cell growth was measured by means of the Cell Titer Blue Assay
(Promega). Proliferation was also examined after knockdown of ERβ using
specific siRNA. Additionally, transcriptome analyses were performed with
these cell lines after treatment with ERB-041, WAY200070 and Liquiritigenin by means of Affymetrix GeneChip arrays.
Results: After treatment of OVCAR3 and OAW-42 cells with the ERβ
agonists, all of these drugs were observed to significantly decrease proliferation in both cell lines even at a low concentration of 10 nM. Maximum effects were induced by Liquiritigenin, which inhibited growth of
OVCAR3 cells down to 68.8% after 5 days of treatment, and ERB-041
suppressing proliferation of the same cell line by about 30%. In OAW-42
cells, the agonist WAY200070 induced maximum effects and inhibited
cell growth down to 73.2%, whereas ERB-041 decreased proliferation
down to 75.6% after 5 days of treatment. On the other hand, knockdown
of ERβ with specific siRNA increased cell growth of OVCAR3 cells by
45%. Transcriptome analyses revealed a set of genes regulated after addition of ERb agonists. EPCAM gene, known to be upregulated in ovarian
cancer, was 2.2-fold downregulated after treatment in OAW42 cells.
Conclusion: In conclusion, the observed growth-inhibitory effects of all
ERβ agonists on ovarian cancer cell lines in vitro encourage further studies to test its possible use in the clinical setting.
ID 231
Influence of the postoperative residual tumor on the
outcome of therapy with pazopanib in ovarian cancer
(OC): A subgroup analysis of an international intergroup
trial (AGO-OVAR16)
M. Gropp-Meier1, B. Schmalfeld2, A. Belau3, J. Rau4, B. Richter5,
G. Emons6, P. Hillemanns7, H.-J. Lück8, A. Burges9, T. Fehm10,
P. Harter11, P. Wimberger12, K. Baumann13, C. Kurzeder14,
U. Canzler15, W. Meier16, L.C. Hanker17, S. Mahner18, J. Kosse19,
J. Sehouli20, M. Sütterlin21, A. Zorr22, A. du Bois23
Krankenhaus St. Elisabeth, Frauenklinik, Ravensburg, Deutschland
2
Klinikum rechts der Isar der Technischen Universität, Frauen- und Poliklinik, München, Deutschland
3
Universitätsklinikum Greifswald der Ernst-Moritz-Arndt Universität, Klinik
und Poliklinik für Frauenheilkunde und Geburtshilfe, Greifswald, Deutschland
4
KKS Marburg, Marburg, Deutschland
5
Elblandkliniken Meißen-Radebeul GmbH & Co KG, Frauenklinik, Radebeul, Deutschland
6
Georg-August Universität Göttingen, Gynäkologie und Geburtshilfe,
7
Medizinische Hochschule Hannover, Frauenklinik, Hannover, Deutschland
8
Gynäkologisch-onkologische Praxis, Hannover, Deutschland
9
Klinikum der Universität, Campus Großhadern, Klinik und Poliklinik für
Frauenheilkunde und Geburtshilfe, München, Deutschland
10
Universitätsklinikum Tübingen, Universitätsfrauenklink, Tübingen, Deutschland
1
Abstracts
HSK Dr. Horst-Schmidt-Klinik, Klinik für Gynäkologie und Gynäkologische Onkologie, Wiesbaden, Deutschland
12
Essen, Deutschland
13
Universitätsklinikum Gießen und Marburg GmbH Standort Marburg,
Klinik für Gynäkologie, gynäkologische Endokrinologie und Onkologie,
14
Universitätsklinikum Ulm, Universitätsfrauenklink, Ulm, Deutschland
15
Universitätsklinikum Carl Gustav Carus, Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe, Dresden, Deutschland
16
Evangelisches Krankenhaus, Frauenklinik, Düsseldorf, Deutschland
17
Klinikum der J.W. Goethe Universität, Zentrum für Frauenheilkunde und
Geburtshilfe, Frankfurt, Deutschland
18
Universitätsklinikum Hamburg-Eppendorf, Klinik und Poliklinik für Gynäkologie, Hamburg, Deutschland
19
Klinikum Offenbach GmbH, Klinik für Gynäkologie und Geburtshilfe,
Offenbach, Deutschland
20
Charité, Campus Virchow Klinikum, Frauenklinik, Berlin, Deutschland
21
Universitätsklinikum Mannheim, Frauenklink, Mannheim, Deutschland
22
Klinikum Lippe-Detmold, Frauenklinik Lippe, Lippe, Deutschland
23
Klinikum Essen-Mitte, Klinik für Gynäkologische Onkologie, Essen,
Deutschland
11
Despite of aggressive primary therapy prognosis of OC is still pure. VEGF/
PDGF seem to play a major role in the pathogenesis of the disease. Improvement of progression free survival (PFS) has already been reached by
the incorporation of an VEGF antibody. Pazopanib is an orally administered
tyrosine kinase inhibitor targeting ATP binding sites of VEGFR, PDGFR
and c-kit receptors. We examined the influence of the postoperative residual
tumor (PRT) on the response to maintenance therapy with Pazopanib.
From 06/2009 until 08/2010 a total of 940 patients with OC FIGO II –
IV have been randomized in the AGO-OVAR16 trial. Patients without
progressive disease and a measurable tumor < 2cm after primary therapy
were randomized and received either Pazopanib 800 mg daily (n = 472)
or placebo (n = 468) for up to 24 months.
Patient characteristics (PS, FIGO stage, histology, PRT, chemotherapy,
best response to initial therapy, time to randomization) were well balanced between the two arms. In the pazopanib group 265 (56%) patients
had no PRT and 282 (60%) in the placebo group respectively. The median
PFS of the primary ITT analysis was 17,9 months in the pazopanib group
and 12,3 months in the placebo group (HR=0.77; 95% CI: 0.64; 0.91).
This effect was shown consistently between the arms in the subgroup
analyses of FIGO II or III & tumor size ≤ 1 cm with a HR=0.82 (95% CI:
0.65; 1.03) as well as in the subgroup of FIGO III & tumor size > 1 cm
with HR=0.78 (95% CI: 0.56; 1.09). In the subgroup with PRT > 0 cm
the effect of Pazopanib was lightly more pronounced with HR=0.69 (95%
CI: 0.54; 0.9). Additional subgroup analyses regarding differential effects
with respect to tumor size will be presented.
Pazopanib maintenance therapy shows a clinical benefit over different
subpopulations.
ID 234
Role of IGF1 in primary ovarian cancer – a study of the
OVCAD European Consortium
I. Rohr1, E.I. Braicu1, R. Zeilinger2, N. Concin3, R. Richter1,
M. Heinrich4, S. Mahner5, T. Van Gorp6, F. Trillsch5,
D. Cacsire Castillo-Tong 2, R. Chekerov1, J. Sehouli1
Charite Berlin, Gynäkologie, Berlin, Deutschland
Medizinische Universität, Wien, Oesterreich
Medizinische Universität, Innsbruck, Oesterreich
4
Alice Salomon Hochschule, Berlin, Deutschland
5
Universitätsklinikum Hamburg Eppendorf, Hamburg, Deutschland
6
Division of Gynaecological Oncology, Maastricht, Niederlande
1
2
3
Objective: IGF 1 is a hormone that has a direct affect on cellular proliferation and also in a number of cancers. Aim of our study was to analyze
the impact of IGF1 circulatory levels on patients with primary ovarian
cancer.
Methods: In the FP6 European Multicentric Project ‘OVCAD’, 275 consecutive patients with primary EOC were enrolled. Patients were eligible
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if radical cytoreductive surgery was performed and platinum-based chemotherapy was applied. Samples of plasma and ascites were collected
before or during surgery.
Results: Increased plasma IGF 1 levels were more frequently found in
low-grade serous and non-serous carcinoma (p = 0,0047) than in highgrade ovarian cancers. No significant correlations with other clinicopathological factors such as FIGO stage, residual tumor mass, age at initial
diagnosis, histology or CA 125, have been found. No association between
IGF1 expression and BMI was observed.
Conclusions: IGF1 seems to be overexpressed in patients with low grade
serous ovarian cancer patients. A significant impact on overall survival
in this patient subgroup couldn’t be found due to low number of patents.
Further studies are needed to elucidate the role of IGF1 in the pathogenesis of low grade ovarian cancer and to possibly further evaluate the impact
of IGF1 targeted therapy. The presented data suggests that increased IGF
1 expression occurs rather in well-differentiated serous and non-serous
ovarian cancer.
ID 243
Uterine Cancer: Intraoperative cytology during
endoscopic surgery
A. Gittler, S. Takacz, R. Mavrova, S. Baum, E.F. Solomayer,
I. Juhasz-Böss
Universität des Saarlandes, Gynäkologie, Homburg, Deutschland
Introduction: The laparoscopic treatment of uterine cancer is an oncologically safe treatment option in early stage carcinoma. However, there
still is no information whether surgery can lead to an intraperitoneal tumor
cell dissemination. The aim of our study was to investigate the peritoneal
cytology at the beginning and at the end of laparoskopic operations.
Method of Application: A prospective study of intraperitoneal cytology
at the beginning and at the end of laparoscopic surgery of patients suffering from cervical and endometrial cancer with stage I and II grade cancer.
Results: A first evaluation of the data of 31 patients ( 20 endometrial
cancer and 11 cervical cancer) is available. At the beginning of the operation only one patient showed a positive cytology. None of the patients
had a tumor cell dissemination during surgery. All patients were free of
recurrence at the time of data analysis.
Conclusion: During laparoscopic surgery of earlier stages of cervical Cancer and endometrial cancer no conversion of cytology can be detected, which
proves that laparoscopic surgery is a safe option of oncologic therapie.
ID 244
AGO Vulva CaRE-1 multicenter study – adjuvant
radio(chemo)therapy in vulvar cancer
P. Hillemanns1, L. Wölber2, J. Jückstock3, P. Neuser4, F. Hilpert5,
P. Harter6, N. De Gregorio7, A. Hasenburg8, J. Sehouli9,
A. Habermann10, S.T. Fürst3, H.-G. Strauß11, K. Baumann12,
F. Thiel13, A. Mustea14, W. Meier15, A. Du Bois6, P. Wimberger16,
L. Hanker17, B. Schmalfeldt18, U. Canzler19, T. Fehm20, A. Luyten21,
M. Hellriegel22, J. Kosse23, C. Heiss24, P. Hantschmann25,
P. Mallmann26, B. Tanner27, J. Pfisterer28, B. Richter29,
C. Petersen30, S. Mahner2
Geburtshilfe, Hannover, Deutschland
2
Universitätsklinikum Hamburg-Eppendorf, Hamburg, Deutschland
3
LMU München, München, Deutschland
4
KKS Marburg, Marburg, Deutschland
5
Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel, Deutschland
6
Kliniken Essen-Mitte, Essen, Deutschland
7
Universitätsklinikum Ulm, Ulm, Deutschland
8
Universitätsklinikum Freiburg, Freiburg, Deutschland
9
Charité, Campus Virchow Klinikum, Berlin, Deutschland
10
Universitätsklinikum Magdeburg, Magdeburg, Deutschland
11
Universitätsklinikum Halle/S., Halle, Deutschland
12
Universitätsklinikum Gießen u. Marburg, Marburg, Deutschland
1
70
Universität Erlangen, Erlangen, Deutschland
Universitätsklinikum Greifswald, Greifswald, Deutschland
15
Evangelisches Krankenhaus, Düsseldorf, Deutschland
16
Universitätsklinikum Essen, Essen, Deutschland
17
Klinikum der J.W. Goethe-Universität, Frankfurt, Deutschland
18
Klinikum rechts der Isar, München, Deutschland
19
Universitätsklinikum, Dresden, Deutschland
20
Universitätsklinikum, Tübingen, Deutschland
21
Klinikum, Wolfsburg, Deutschland
22
Georg-August-Universität, Göttingen, Deutschland
23
Klinikum, Offenbach, Deutschland
24
Klinik am Eichert, Göppingen, Deutschland
25
Kreisklinik, Altötting, Deutschland
26
Klinikum der Universität, Köln, Deutschland
27
Oberhavel Klinikum, Oranienburg, Deutschland
28
Städtisches Klinikum, Solingen, Deutschland
29
Elblandkliniken, Meißen-Radebeul, Deutschland
30
UKE, Hamburg, Deutschland
13
14
Aim: This study evaluates the impact of postoperative radio(chemo)therapy (RT/CTX) in patients with lymph-node positive vulvar carcinoma
compared to surgery alone.
Methods: Patients with primary squamous-cell vulvar cancer treated at
29 gynecologic cancer centers in Germany between 1998 and 2008 were
included in a centralized database and analyzed retrospectively.
Results: 1618 patients were documented with a median follow-up of 38.8
months (T1b 35.9%, T2 50.6%, T3 9.9% and T4 1.9%). 30.6% had lymph
node metastases (N+) with a median progression-free survival (PFS) of
15.9 months and overall survival (OS) of 46.9 months, compared to 99.1
and 208.8 months for N- patients, resp.
34.8% had 1 N+, 20.6% 2 N+, 12.5% 3 N+ and 17.6% >3 N+. 254
(51.3%) of N+ patients underwent adjuvant RT/CTX with a longer median PFS and OS compared to N+ pats. without adjuvant treatment [PFS:
18.5 vs. 12.0 months, p = 0.0003, HR 0.63 (95% CI: 0.50–0.81); OS:
111.6 vs. 37.1 months, p = 0.029, HR 0.71 (95% CI: 0.52–0.97)]. This effect remained consistent in multivariate analysis adjusted for age, ECOG,
UICC-stage, grade, invasion depth, number of N+ (PFS: HR 0.57, 95%
CI: 0.43–0.74, p < 0.0001; OS: HR=0.61, 95% CI: 0.43–0.86, p = 0.005).
However, in subgroup analyses statistical significance favoring adjuvant
therapy was only reached in patients with 2 or more LN metastases.
Conclusions: This large multicenter study in vulvar cancer shows that
prognosis of node-positive patients was improved with adjuvant radiotherapy but still remains poor compared to the outcome of node-negative
patients. A substantial benefit of adjuvant therapy can be seen in patients
with 2 or more positive lymph nodes. The AGO CaRE-1 study may provide the basis for a prospective trial investigating the role of adjuvant
radio(chemo)therapy in vulvar cancer.
ID 250
Prognostic impact of the time interval between primary
and re-staging surgery in patients with borderline ovarian
tumours (BOT): An analysis of the Arbeitsgemeinschaft
Gynaekologische Onkologie (AGO) Study Group
F. Trillsch1, S. Mahner1, J.D. Rützel1, E. Vettorazzi2, A. Reuß3,
P. Hillemanns4, L. Hanker5, A. Hasenburg6, H.-G. Strauß7,
M. Hellriegel8, P. Wimberger9, B. Klaus10, M.-D. Keyver-Paik11,
U. Canzler12, K. Wollschlaeger13, D. Forner14, J. Pfisterer15,
W. Schröder16, K. Münstedt17, B. Richter18, C. Fotopoulou19,
B. Schmalfeldt20, A. Burges21, T. Fehm22, W. Meier23,
N. Ewald-Riegler24, N. De Gregorio25, F. Hilpert26, A. Du Bois27
Universitätsklinikum Hamburg-Eppendorf, Klinik für Gynäkologie und
Gynäkologische Onkologie, Hamburg, Deutschland
2
Universitätsklinikum Hamburg-Eppendorf, Institut für Medizinische Biometrie und Epidemiologie, Hamburg, Deutschland
3
Philipps-Universität Marburg, Koordinierungszentrum für Klinische Studien, Marburg, Deutschland
4
Medizinische Hochschule Hannover, Frauenklinik, Hannover, Deutschland
5
Klinikum der J.W. Goethe-Universität, Zentrum für Frauenheilkunde u.
Geburtshilfe, Frankfurt/M., Deutschland
1
Abstracts
Inhalt
Index
Universitätsklinikum Freiburg, Frauenklinik, Freiburg, Deutschland
Universitätsklinikum Halle/S., Universitätsklinik und Poliklinik für Gynäkologie, Halle/S., Deutschland
8
Georg-August-Universität Göttingen, Gynäkologie und Geburtshilfe,
9
Essen, Deutschland
10
Universitätsklinikum Gießen u. Marburg GmbH, Klinik für Gynäkologie,
Gyn. Endokrinologie und Onkologie, Marburg, Deutschland
11
Rheinische Friedrich-Wilhelms-Universität, Universitäts-Frauenklinik,
Bonn, Deutschland
12
Universitätsklinikum Carl Gustav Carus, Klinik u. Poliklinik für Frauenheilkunde u. Geburtshilfe, Dresden, Deutschland
13
Universitätsklinikum Magdeburg, Universitäts-Frauenklinik, Magdeburg,
Deutschland
14
Sana-Klinikum Remscheid, Klinik für Frauenheilkunde und Geburtsmedizin, Remscheid, Deutschland
15
Städtisches Klinikum Solingen gGmbH, Klinik für Gynäkologie und Geburtshilfe, Solingen, Deutschland
16
GYNAEKOLOGICUM Bremen, Bremen, Deutschland
17
Universitätsklinikum Gießen, Zentrum für Frauenheilkunde u. Geburtshilfe, Gießen, Deutschland
18
Elblandkliniken Meißen-Radebeul GmbH & Co. KG, Frauenklinik, Radebeul, Deutschland
19
Charité, Campus Virchow Klinikum, Frauenklinik, Berlin, Deutschland
20
Klinikum rechts der Isar der Technischen Universität, Frauen- und Poliklinik, München, Deutschland
21
Klinikum der Universität München, Campus Großhadern, Klinik u. Poliklinik für Frauenheilkunde u. Geburtshilfe, München, Deutschland
22
Universitätsklinikum Tübingen, Universtitätsfrauenklinik, Tübingen,
Deutschland
23
24
HSK, Dr. Horst Schmidt Klinik GmbH, Klinik für Gynäkologie u. gynäkologische Onkologie, Wiesbaden, Deutschland
25
Universitätsklinikum Ulm, Frauenklinik, Ulm, Deutschland
26
Universitätsklinikum Schleswig-Holstein, Campus Kiel, Klinik für Gynäkologie und Geburtshilfe, Kiel, Deutschland
27
Kliniken Essen-Mitte, Klinik für Gynäkologische Onkologie, Essen,
Deutschland
6
7
Background: Primary surgery for BOT often results in incomplete surgical staging. Hence, re-staging procedures are indicated but little is known
about the impact of the time interval between primary and re-staging surgery on prognosis.
Methods: Clinical parameters of 950 BOT patients treated between 1998
and 2008 in 24 German centers were investigated with prospective reference pathology and follow-up. Prognostic significance of the time interval was assessed by cox regression models. Time interval was then
categorized in ≤30days vs. >30days and compared regarding patient characteristics.
Results: Of 560 patients incompletely staged in primary surgery 308
patients with distinct information on surgical timing underwent re-staging procedures (55.0%). A significant increase of recurrence risk could
be confirmed for patients undergoing restaging after >30days opposed
to ≤30days (HR 2.43; p = 0.04) in univariate analysis. Rates for fertility-sparing surgery in primary treatment (28.6% vs. 16.1%, p = 0.009)
and for uni- or bilateral cystectomy (15.0% vs. 5.0%, p = 0.003) were
significantly higher in patients with time interval >30days. In multivariate
analysis prognostic significance regarding PFS could be confirmed for the
time interval and FIGO stage but not for fertility-preservation.
Conclusions: A longer time interval between primary and re-staging surgery in BOT patients was associated with increased risk for recurrence.
Since fertility-preservative procedures requiring more time for informed
consent were more frequently observed in patients with longer time interval this supports current efforts to establish a short-termed centralized
diagnosis of BOT in reference pathology.
Abstracts
ID 273
GPER-1 acts as a tumor suppressor in ovarian cancer
L. Seiz1, T. Ignatov2, S. Modl2,3, C. Weißenborn2,3, A. Zenclussen3,
S. Dan Costa2, O. Ortmann1, A. Ignatov1,2
Department of Obstetrics and Gynecology, University Medical Center
Regensburg, Regensburg, Germany., Deutschland
2
Department of Obstetrics and Gynecology, University Clinic, Magdeburg,
Germany., Deutschland
3
Department of Experimental Obstetrics and Gynecology, University Clinic,
Magdeburg, Germany., Deutschland
1
Background: It is known that the new membrane-bound estrogen receptor GPER-1 acts suppressive in breast cancer cells and its expression decreases during disease progression. This study was conducted to evaluate
the GPER-1 expression in ovarian cancer and its correlation with progression. Its function was tested in vitro in ovarian cancer cells.
Patients and Methods: GPER-1 expression was analyzed by immunohistochemistry in 35 benign ovarian tumors, 35 tumors of low-malignant
potential and in 124 ovarian cancers. GPER-1 expression was correlated
to the prospectively evaluated disease-free survival of ovarian cancer patients. We also tested GPER-1 expression in ovarian cancer cells and the
effect of GPER-1 stimulation on cell growth.
Results: GPER-1 expression was significantly lower in ovarian cancer
tissue than in benign and low-malignant ovarian tumors. GPER-1 expression was observed in 83.1% of malignant tumors and was higher in early
stage cancers and tumors with high histological differentiation. GPER-1
expression was associated with favourable clinical outcome. The difference in 2-year disease-free survival by GPER-1 expression was significant, 28.6% for GPER-1 negative and 59.2% for GPER-1 positive cases
(p = 0.002). GPER-1 expression was observed in SKOV-3 and OVCAR-3
ovarian cancer cell lines. G-1, a selective GPER-1 agonist, suppressed
proliferation of the two cell types via inhibition of cell cycle progression in G2/M phase and stimulation of caspase-dependent apoptosis. The
blockade in G2/M phase was associated with increased expression of cyclin B1 and Cdc2 and phosphorylation of histone 3.
Conclusion: GPER-1 emerges as a new tumor suppressor with unsuspected therapeutic potential for ovarian cancer.
ID 303
Sexual activity and function in patients with
gynecological malignancies after completed treatment
D. Grimm1, A. Hasenburg2, L. Steinsiek1, F. Trillsch1, S. Mayer2,
S. Eltrop2, S. Mahner1, L. Woelber1
University Medical Center Hamburg-Eppendorf, Department of Gynecology and Gynecologic Oncology, Hamburg, Deutschland
2
University Hospital Freiburg, Department of Gynecology, Freiburg,
Deutschland
1
Background: Sexual activity (SA) and function (SF) after completion of
treatment are central for quality of life (QoL) in women affected by gynecological cancers. Aim of this study was to analyse the SA, SF and QoL of
women with primary cervical-, endometrial- or vulvar cancer compared
to patients with breast cancer.
Methods: In a multicenter cross-sectional study, women, aged 18–70
years, were surveyed at least 12 months after completion of primary
therapy for cervical-, endometrial- or vulvar cancer. A cohort of breast
cancer patients served as control. Data was collected through validated
questionnaires.
Results: Patients in the gynecological cancer group (GCG) (n = 77) and
the breast cancer group (BCG) (n = 186) were of similar age (median 55
vs. 56.5 years) and menopausal status (90.5% vs. 88.6%). 41.3% of the
patients in the GCG were sexually active and 45.8% in the BCG. The most
common reason for sexual inactivity in the GCG was «the-presence-of-a
physical-problem» (40.9% vs. 37.8%) whereas in the BCG «low-interestin-sex» was most common (44.9% vs. 34.1%). Overall, there was a better
SF in the GCG with a trend towards higher sexual satisfaction (p = 0.09),
significantly more pleasure (p = 0.02) and less discomfort during inter-
71
Inhalt
Index
course (p = 0.03). QoL and overall health were not significantly different
between the two groups (EORTC-QLQ-C30 score 68.25 vs. 67.50) and
comparable to populations without cancer.
Conclusion: The high number of sexually inactive women indicates that
women suffer from persistent functional problems after therapy of gynecological malignancies. However, women who regain sexual activity
after completed treatment have a very good overall SF.
ID 328
Berlin Tumor Center implemented Online Registry
for Patients with Borderline Tumors of the Ovary – a
Prospective Evaluation
L. Kretzschmar , R. Chekerov , A. Jagota , M. Abou-Dakn ,
S. Braun4, A. Ebert5, E. Keil6, C. Kronenberg7, B. Müller8,
C. Olbrich9, J. Potenberg10, S. Rothe11, J.-P. Scharf12, U. Torsten13,
U. Ulrich14, J. Sehouli1
1
1
2
3
Charité -Universitätmedizin Berlin, Berlin, Deutschland
Tumor Centrum Berlin, Berlin, Deutschland
3
Sankt Joseph Krankenhaus, Berlin, Deutschland
4
Sankt Gertrauden Krankenhaus, Berlin, Deutschland
5
Vivantes Humboldt-Klinikum, Berlin, Deutschland
6
Park-Klinikum Weißensee, Berlin, Deutschland
7
Vivantes Auguste-Viktoria Klinikum, Berlin, Deutschland
8
Vivantes Klinikum Hellersdorf, Berlin, Deutschland
9
DRK Kliniken Westend, Berlin, Deutschland
10
Evangelisches Waldkrankenhaus Spandau, Berlin, Deutschland
11
Helios Klinikum Berlin Buch, Berlin, Deutschland
12
Sana Klinikum Lichtenberg, Berlin, Deutschland
13
Vivantes Klinikum Neukölln, Berlin, Deutschland
14
Martin Luther Krankenhaus, Berlin, Deutschland
1
2
BOT are a rare, usually coincidental diagnose, commonly found after surgery for suspect ovarian tumors. Due to the limited amount of data the
Coordinating Tumor Center of Berlin established an online-based platform allowing the participating clinics in Berlin to register patients with
BOT and their clinical information. Results of the first four years after
implementation shall be presented.
Beginning 2010 all thirteen participating gynaecological departments of
Berlin have been entering their anonymised patient data concerning age,
fertility, date of diagnoses, surgical procedures, histopathology, adjuvant
therapy and follow-up data.
To date 232 patients have been registered in BOT. The median age was
47 years. Histology showed most patients having serous type tumors
(52%) followed by mucinous intestinal (16%), serous-papillary (15%)
and mucinous endocervical (13%), with 25% presenting peritoneal implants of which 15% were of invasive nature (absolute 4%). The majority
of patients presented FIGO I (79%).Every patient was treated surgically,
with an average of 2 surgeries/person, 60% laparoscopically; the most
common surgical procedures besides USO being omentectomy, cytology,
peritoneal biopsy, BSO, hysterectomy and appendectomy.
The online BOT Registry is the first prospective collection of clinical
data for patients with BOT in Germany. The current data shows that the
average patient treated for BOT is young, with serous histopathology and
early stage disease. BOT Registry proves to be a feasible and well-accepted tool for common data collection within the departments of gynecology
of Berlin clinics and can be considered representative and a valuable tool
for further clinical and epidemiological study projects.
ID 329
Outcome parameters in node-negative vulvar cancer – a
subset analysis of the AGO CaRE-1 study
L. Wölber1, J. Jueckstock2, F. Hilpert3, P. Neuser4, P. Harter5,
N. De Gregorio6, S. Iborra7, J. Sehouli8, A. Habermann9,
P. Hillemanns10, S. Fürst11, H.-G. Strauss12, K.H. Baumann13,
F. Thiel14, A. Mustea15, W. Meier16, A. Du Bois5, P. Wimberger17,
L.C. Hanker18, B. Schmalfeldt19, U. Canzler20, T. Fehm21,
A. Luyten22, M. Hellriegel23, J. Kosse24, C. Heiss25,
P. Hantschmann26, P. Mallmann27, B. Tanner28, J. Pfisterer29,
B. Richter30, L.-F. Griebel1, S. Mahner1
Universitätsklinikum Hamburg-Eppendorf, Klinik für Gynäkologie und
gynäkologische Onkologie, Hamburg, Deutschland
2
Klinikum Universität München Campus Innenstadt, Klinik und Poliklinik für
Frauenheilkunde und Geburtshilfe, München, Deutschland
3
Universitätsklinikum Schleswig-Holstein, Klinik für Gynäkologie und Geburtshilfe, Kiel, Deutschland
4
Philipps-Universität, Koordinierungszentrum für Klinische Studien, Marburg, Deutschland
5
Kliniken Essen Mitte, Klinik für Gynäkologie und gynäkologische Onkologie, Essen, Deutschland
6
Universitätsklinikum Ulm, Klinik für Frauenheilkunde und Geburtshilfe,
Ulm, Deutschland
7
Universitätsklinikum Freiburg, Klinik für Gynäkologie, Freiburg, Deutschland
8
Charite Universitätsmedizin Berlin Campus Virchow, Klinik Für Gynäkologie, Berlin, Deutschland
9
Universitätsklinikum Magdeburg, Universitätsfrauenklinik, Magdeburg,
Deutschland
10
Geburtshilfe, Hannover, Deutschland
11
Universitätsfrauenklinik München – Großhadern, München, Deutschland
12
Universitätsklinikum Halle, Klinik und Poliklinik für Gynäkologie, Halle,
Deutschland
13
Philipps Universität Marburg, Klinik für Gynäkologie, gyn. Endokrino- und
Onkologie, Marburg, Deutschland
14
Universitätsklinikum Erlangen, Frauenklinik, Erlangen, Deutschland
15
Universitätsfrauenklinik Greifswald, Greifswald, Deutschland
16
Evangelisches Krankenhaus, Klinik für Gynäkologie, Düsseldorf,
Deutschland
17
Essen, Deutschland
18
Universitätsklinikum Frankfurt, Klinik für Gynäkologie, Frankfurt,
Deutschland
19
Technische Universität München, Frauenklinik und Poliklinik, München,
Deutschland
20
Uniklinikum Dresden, Klinik für Frauenheilkunde und Geburtshilfe, Dresden, Deutschland
21
Universitätsklinikum Tübingen, Universitäts-Frauenklinik, Tübingen,
Deutschland
22
Klinikum Wolfsburg, Frauenklinik, Wolfsburg, Deutschland
23
24
Sana Klinikum Offenbach, Klinik für Gynäkologie und Geburtshilfe, Offenbach, Deutschland
25
Klinik am Eichert, Frauenklinik, Göppingen, Deutschland
26
Kreiskliniken Altöttingen-Burghausen, Abteilung für Gynäkologie und
Geburtshilfe, Altötting, Deutschland
27
Uniklinik Köln, Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe,
Kölln, Deutschland
28
Oberhavel Kliniken – Klinik Oranienburg, Frauenklinik, Oranienburg,
Deutschland
29
Städtisches Klinikum Solingen, Klinik für Frauenheilkunde und Geburtshilfe, Solingen, Deutschland
30
Elblandkliniken, Klinik für Frauenheilkunde und Geburtshilfe, Radebeul,
Deutschland
1
Aim: To identify possible prognostic factors in node-negative vulvar cancer.
Methods: The AGO CaRE-1 study was designed as retrospective survey
of treatment patterns and prognostic factors in vulvar cancer. Pts with
primary vulvar cancer stage ≥1b treated at 29 German gynecologic cancer
centers 1998-2008 were included in a centralized database.
Results: Of the 1618 pts documented, 702 were node negative (pN0)
after surgical staging and received no additional treatment despite sur-
72
Abstracts
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Index
gery. Median age of these pts was 66 yrs (21–94). 380 (54.1%) had pT1b,
300 (42.7%) pT2, 22 (3.1%) pT3 tumors. Median tumor size was 20 mm
(1-345) and depth of invasion 4 mm (0.75–60). 634 (90.3%) pts had an
R0 resection with a minimal margin of 5 mm (1–33); there were 23 R1
(3.3%) and 45 (6.4%) Rx resections. 622 pts (88.6%) received a full groin
dissection and 80 pts (11.4%) a sentinel node procedure only. Median follow-up was 42.5 months. 145 pts (20.7%) developed disease recurrence
(thereof 95 (65.5%) at the vulva only) after a median of 17.5 months.
82 pts (11.7%) died. To assess potential prognostic factors, multivariate
analyses were performed including age, stage, tumor size, invasion depth,
tumor grade, resection margin, and mode of groin dissection [sentinel
vs. full]) showing age as the only consistent prognostic factor for recurrence-free and overall survival.
Conclusions: Even in the large patient cohort of the AGO-CaRE database with more than 700 node-negative pts it was not possible to identify
reliable clinicopathologic prognostic factors for node-negative disease.
Identification of new markers will be necessary to select high risk pts for
adjuvant treatment.
analyses of symptomatic pts included only those with a baseline score ≥
15 (sufficient to show ≥15-point improvement). Mixed-model repeated
measures (MMRM) analysis was used to compare Qs from all time points
until PD/death.
Results: Qs were available at baseline from 89% of 361 randomized pts
and at wk 8/9 from 81% and 68% of pts in the BEV-CT or CT arm, respectively. More BEV-CT than CT pts had a ≥15% improvement in the
OV28 abdo/GI symptom subscale at wk 8/9 (21.9% vs 9.3%, 12.7% difference [95% CI 4.4–20.9]; p = 0.002). The sensitivity analysis showed
a 13.3% difference [95% CI 4.5–22.1] and the subgroup analysis of 233
symptomatic pts a 16.9% difference (95% CI 6.1–27.6) favoring BEVCT (29.6% vs 12.7%). MMRM analysis also favored BEV-CT (6.4-point
difference [95% CI 1.28–11.6]). More BEV-CT than CT pts had a ≥15%
improvement in FOSI score at wk 8/9 (12.2% vs 3.1%, 9.0% difference
[95% CI 2.9–15.2]).
Conclusions: Adding BEV to CT improved patient-reported abdo/GI
symptoms in platinum-resistant OC.
ID 347
ID 337
Health-related quality of life (HRQoL) results from the
AURELIA trial evaluating bevacizumab (BEV) plus
chemotherapy (CT) for platinum-resistant recurrent
ovarian cancer (OC)
F. Hilpert1, P. Wimberger2, J. Sehouli3, A. Reuss4, P. Harter5,
R. Hils6, N. De Gregorio7, H.-J. Lück8, B. Gerber9, T. Fehm10,
L. Hanker11, C. Uleer12, A. Burges13, J. Kosse14, M. Thill15,
M. Beckmann16, J.-P. Scharf17, W. Meier18, G. Gebauer19,
E. Pujade-Lauraine20
UKSH Campus Kiel, Klinik für Gynäkologie und Geburtshilfe, Kiel,
Deutschland
2
Universitätsklinikum Carl Gustav Carus, Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe, Dresden, Deutschland
3
Charité, Klinik für Gynäkologie, Berlin, Deutschland
4
Philipps-Universität, KKS, Marburg, Deutschland
5
Kliniken Essen-Mitte, Gynäkologie und Gynäkologische Onkologie,
Essen, Deutschland
6
HSK, Gynäkologie und Gynäkologische Onkologie, Wiesbaden, Deutschland
7
Universitätsklinikum, Frauenheilkunde und Geburtshilfe, Ulm, Deutschland
8
Gynäkologisch-Onkologische Schwerpunktpraxis, Hannover, Deutschland
9
Klinikum Südstadt, Universitätsfrauenklinik, Rostock, Deutschland
10
Universitätsklinikum, Frauenklinik, Düsseldorf, Deutschland
11
UKSH Campus, Klinik für Frauenheilkunde und Geburtshilfe, Lübeck,
Deutschland
12
Frauenärzte am Bahnhofsplatz, Hildesheim, Deutschland
13
LMU Campus Grosshadern, Frauenklinik, München, Deutschland
14
Sana Klinikum, Gynäkologie und Geburtshilfe, Offenbach, Deutschland
15
Agaplesion Markus Krankenhaus, Klinik für Gynäkologie und Geburtshilfe, Frankfurt am Main, Deutschland
16
Universitätsklinikum, Frauenklinik, Erlangen, Deutschland
17
Sana Klinikum, Frauenklinik, Berlin-Lichtenberg, Deutschland
18
19
Marienkrankenhaus, Frauenklinik, Hamburg, Deutschland
20
Hôpital Hôtel-Dieu, Paris, Frankreich
1
Background: Adding BEV to CT significantly improved PFS in platinum-resistant OC in the phase III AURELIA trial. HRQoL was a key
secondary aim of AURELIA.
Methods: Patients (pts) with OC were assigned to receive monochemotherapy (peg-lip doxorubicin, topotecan, or weekly paclitaxel) and than
randomized to CT ± BEV. HRQoL was assessed at baseline and every
2 or 3 cycles until PD using the EORTC OC Module (OV28) and FOSI.
The primary HRQoL endpoint was an absolute improvement of ≥15% on
the 100-point OV28 subscale for abdominal (abdo)/GI symptoms at wk
8/9. Pts with missing questionnaires (Qs) were included and considered
not to have improved. A sensitivity analysis excluded pts with Qs missing
for reasons other than PD/death or switch from CT to BEV. Subgroup
Abstracts
Folate Receptor Alpha (FRA) expression in endometrial
cancer (EC)
P. Kosian1, E. Somers2, D.J. O’Shannessy2, M. Nassir1,
C. Fotopoulou1, R. Chekerov1, J. Sehouli1, E.I. Braicu1
Charité – Universitätsmedizin Berlin, Department of Gynecology, Berlin,
Deutschland
2
Morphotec, Exton, Vereinigte Staaten Von Amerika
1
Background: Folate receptor alpha (FOLR1/FRA) is expressed in a high
percentage of serous ovarian, endometrial, lung and breast cancers but
expression in normal tissues is restricted to the apical surfaces of a limited subset of polarized epithelial cells. Therefore, FRA is an interesting
candidate for new targeted therapies. The aim of the present study was
to evaluate the expression of FRA in endometrial cancer and evaluate its
relationship to clinical and histopathological parameters.
Methods: Immunohistochemistry with MAb 26B3 was performed on
paraffin -embedded tissues from 113 primary endometrial cancer patients.
A positive result was defined as membrane staining of ≥5% of tumor cells.
Further, staining was calculated using the M-score, a semi-quantitative algorithm which incorporates both intensity and percentage tumor staining.
Results: An endometrioid subtype was present in 75.9% of the cohort and
FRA IHC was positive in 91.7% of the cohort. Significantly higher FRA
expression was observed in G3 compared to G1 (p = 0.042) and in serous
papillary compared to endometroid endometrial cancer (p = 0.005). Oestrogen receptor negativity correlated with a high folate receptor expression (p = 0,033). M-score cut-off value of 35% was a significant prognostic factor for overall survival (p = 0.014).
Conclusion: This study that FRA overexpressed in high risk EC tumors,
correlating with poor overall survival. Therefore there might be a benefit from FRA targeted diagnostics and therapeutics. Further multi-centre
studies are warranted.
ID 352
Endometriosis as a risk factor for Ovarian or Endometrial
Cancer – results of a hospital based case control study
S. Burghaus1, L. Häberle1, M.G. Schrauder1, K. Heusinger1,
K. Beckmann1, F. Thiel1, A. Hein1, D. Wachter1,2, A. Hartmann2,
M.W. Beckmann1, P.A. Fasching1, S.P. Renner1
1
2
Universitätsklinikum Erlangen, Frauenklinik, Erlangen, Deutschland
Universitätsklinikum Erlangen, Pathologie, Erlangen, Deutschland
Background: There is no screening program for ovarian or endometrial
cancer. One reason for that could be the relatively low incidence with
subsequently low positive predictive values for tests with low specifity.
One way to address the problem could be the utilization of risk factors to
define sub-populations with a higher incidence. Recently, there were hints
that endometriosis could be a risk factor for ovarian cancer.
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Methods: We conducted a hospital based case control analysis. Cases
were patients with endometrial or ovarian cancer who participated in
studies aiming at risk assessment for these diseases. Controls were women who were invited by newspaper advertisement. A total of 289 cases
and 1016 controls were included. Two logistic regression models were
used, one with the predictors age, number of pregnancies and previous oral contraceptive (OC) use and another one including additionally
whether the patient was diagnosed with endometriosis. Both models were
compared with the likelihood ratio test.
Results: Endometriosis was present in 21 controls (2.1%) and 14 cases (4.8%). Relevant predictors for case control status were previous OC
use (OR=0.41; 95%CI: 0.30–0.55) and endometriosis (OR=2.53; 95%CI:
1.23–5.21). The prediction model that included endometriosis was slightly better (p = 0.01, likelihood ratio test) than the model without endometriosis (AUC=0.67 vs. AUC=0.66).
Conclusion: In our case control study endometriosis could be described
as a risk factor for endometrial or ovarian cancer. Studies addressing this
question are rare and the implementation into a clinical prediction model
would demand a predise characterization of the risk factor endometriosis.
For this purpose we initiated a multicentric cohort study (www.myendometriosis.org).
Material und Methoden: In einer prospektiven Fallstudie wurden Cisplatin 7,5 mg/m2 und Doxorubicin 2,5 mg/m2 bei 12 mmHg und 37 °C für
30 min intraabdominell mittels PIPAC appliziert. Das Tumoransprechen
wurde mittels histologischer Tumorregression in der Biopsie und Peritonealkarzinose-Index (PCI) in der Video-Laparoskopie beurteilt.
Ergebnisse: Bei 18 Patientinnen wurden insgesamt 34 PIPAC-Prozeduren durchgeführt, in 8 Fällen in Kombination mit zytoreduktiver Chirurgie (CRS). Es gab keine perioperative Mortalität. Es traten 5 Nebenwirkungen ≥ 2 Grad WHO auf, davon 3 im Zusammenhang mit CRS. Das
mediane Follow-Up betrug 192 Tage (min. 13, max. 639). Das kumulative Überleben nach 400 Tagen war 62% und das mittlere Überleben 442
Tage. Bei 8 Patientinnen wurde die PIPAC im Intervall von 28-42 Tagen
wiederholt appliziert und in 6 dieser Fälle konnte ein objektives Tumoransprechen beurteilt werden (komplette Remission: 1; partielle Remission: 2; stabile Krankheit: 3). In einer multivariaten Analyse mit PIPAC,
Alter, Serum CA-125 und Vorkommen von Aszites konnte die PIPAC die
objektive Tumorantwort auf die Therapie unabhängig vorhersagen.
Schlussfolgerung: Die Wirksamkeit der PIPAC bei Patientinnen mit rezidivierendem, Platin-resistentem Ovarialkarzinom konnte in dieser ersten,
kleinen Fallserie nachgewiesen werden und wird zurzeit in einer klinischen Studien untersucht (NCT01809379)
ID 368
ID 416
A rare case of isolated subcutaneous implantation of a
borderline ovarian tumor
M. Banys, B. Yeganeh, R. Langenberg, G. Gebauer
Marienkrankenhaus Hamburg, Frauenklinik, Hamburg, Deutschland
Laparoscopy-related subcutaneous tumor implantations of gynecological malignancies are considered rare. We report the case of a 46-year-old
woman who presented with an isolated metastasis of a borderline ovarian
tumor in the abdominal wall. The patient presented with an asymptomatic
cyst with papillary excrescences in her right ovary, measuring 28 × 25
mm. CA125 was 38.7 U/ml. Patient’s concomitant diseases at time of
presentation were obesity, hypothyreosis and arterial hypertension. The
patient had a history of previous two laparoscopies (ectopic pregnancy
1990, sterilization 1996) and one vaginal birth. We conducted laparoscopic right adnexectomy; histopathological workup of the right ovary
revealed mucinous papillary borderline tumor. Consequently, nine days
later the patient underwent explorative median laparotomy with hysterectomy, left adnexectomy, omentectomy and appendectomy. No intraperitoneal implants were found. Further exploration revealed a cystic-solid
structure (5 × 5 cm) in the subcutaneous fat tissue above the fascia with no
contact to intraperitoneal cavity. The structure was resected; histopathological examination confirmed the diagnosis of a non-invasive implant of
a papillary borderline tumor. Possibly, tumor cells were displaced during
previous laparoscopies (the last one fourteen years prior to presentation).
ID 384
Wirksamkeit der intraperitonealen DruckAerosolchemotherapie (PIPAC) mit Cisplatin und
Doxorubicin bei rezidivierendem, Platin-resistentem
Ovarialkarzinom: Preliminäre klinische Ergebnisse.
W. Solaß1, I. Celik2, B. Bürkle2, U. Pabst1, D. Strumberg3,
J. Zieren1, M. Reymond1, C. Tempfer2
HERNE, Deutschland
2
Ruhr-Universität Bochum, Frauenklinik, Herne, Deutschland
3
1
Einleitung: Prüfung der Wirksamkeit und der Verträglichkeit der intraperitonealen Druckaerosolchemotherapie (PIPAC) bei Patientinnen mit
rezidivierendem, Platin-resistentem Ovarialkarzinom und Peritonealkarzinose.
74
AGO-OVAR 12: A Randomized Placebo-controlled GCIG/
ENGOT-Intergroup Phase III trial of standard frontline
chemotherapy +/- Nintedanib for advanced ovarian cancer
P. Harter1, R. Kimmig2, N. de Gregorio3, A. Reuss4, J. Pfisterer5,
D. Cibula6, F. Hilpert7, W. Meier8, L.C. Hanker9, U. Canzler10,
J. Sehouli11, K. Baumann12, A. Burges13, M. Gropp-Meier14,
A. Hasenburg15, A. Belau16, T. Fehm17, J. Kosse18, S. Mahner19,
B. Schmalfeldt20, F. Marme21, B. Richter22, U. Herwig23,
C. Liebrich24, B. Gerber25, J. Potenberg26, P. Krabisch27, M. Thill28,
M. Merger29, A. du Bois1
Kliniken Essen-Mitte, Essen, Deutschland
Universitätsklinikum, Essen, Deutschland
3
Universitätsklinikum, Ulm, Deutschland
4
5
Zentrum f. Gyn. Onkologie, Kiel, Deutschland
6
Universitätsklinikum, Prag, Tschechische Republik
7
Universitätsklinikum, Kiel, Deutschland
8
Ev. Krankenhaus, Düsseldorf, Deutschland
9
Universitätsklinikum, Frankfurt, Deutschland
10
Universitätsklinikum, Dresden, Deutschland
11
Charite, Campus Virchow, Berlin, Deutschland
12
Universitätsklinikum, Marburg, Deutschland
13
Klinikum der Universität München-Großhadern, München, Deutschland
14
Onkologie, Ravensburg, Deutschland
15
Universitätsklinikum, Freiburg, Deutschland
16
Universitätsklinikum, Greifswald, Deutschland
17
Universitätsklinikum, Tübingen, Deutschland
18
Sana Klinikum, Offenbach, Deutschland
19
Universitätsklinikum, Hamburg, Deutschland
20
Klinikum rechts der Isar, München, Deutschland
21
NCT, Heidelberg, Deutschland
22
Elblandkliniken Meißen-Radebeul, Radebeul, Deutschland
23
Albertinen Krankenhaus, Hamburg, Deutschland
24
Klinikum, Wolfsburg, Deutschland
25
Universitätsklinikum, Rostock, Deutschland
26
Ev. Waldkrankenhaus Spandau, Berlin, Deutschland
27
Klinikum, Chemnitz, Deutschland
28
Universitätsklinikum, Lübeck, Deutschland
29
Böhringer Ingelheim Pharma, Biberach, Deutschland
1
2
Background: Angiogenesis plays an established role as target in the
treatment of ovarian cancer(OC). Nintedanib(N), an oral inhibitor of
VEGFR, PDGFR, and FGFR, has shown activity in OC in phase II trials.
Methods: Pts with FIGO IIB-IV OC and upfront debulking surgery
were randomized 2:1 to N 200 mg bid + Carboplatin (C AUC5 or 6) and
Paclitaxel (T 175 mg/m2), or placebo (Pl) + TCq21. Primary endpoint
Abstracts
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Index
was investigator assessed PFS, analysis of stratification factors were preplanned.
Results: 1,366 patients were recruited 12/2009–7/2011 by 9 study groups;
911 TC+N and 455 received TC+Pl. Overall, 39% had a very high risk
with FIGO III and residuals >1cm or FIGO IV while 61% had FIGO III
and residuals ≤1cm or FIGO II (283 in TC-Pl, 556 in TC+N). After 752
observed events, PFS was significantly longer with N+TC than Pl+TC
(median 17.3 vs 16.6 months; HR 0.84; 95% CI: 0.72–0.98; p = 0.0239).
Post-hoc analysis of pre-defined subgroups showed a higher benefit in
patients of the low risk subgroup: median PFS 20.8 vs 27.1 months; HR
0.74 (0.61–0.91). OS data are still immature. Increased adverse events
(at least +10% difference G3-5 in TC+N) included thrombocytopenia
(+11.3%), ALT/AST increase (+13.3%), Diarrhea (+19.6%).
Conclusion: Nintedanib in combination with TC significantly prolongs
PFS in first-line OC; its impact was highest in pts with low post-OP tumor
burden. Nintedanib appears to be a valuable treatment option in advanced
OC, however, further studies should focus on patient selection and optimization of tolerability.
ID 419
Epigenetic silencing of KBTBD12, a member of the kelch
protein family, is involved in invasiveness of breast
cancer cells
E. Honisch1, C. Melcher1, L. Brandi1, C. Wiek2, H. Hanenberg2,
T. Fehm1, D. Niederacher1
Universitäts-Frauenklinik Düsseldorf, Molekulargenetisches Labor, Düsseldorf, Deutschland
2
Universitätsklinikum Düsseldorf, Hals-Nasen-Ohren-Klinik, Düsseldorf,
Deutschland
1
A growing number of breast cancer risk associated SNPs are identified by
genome wide association studies. However, causative genes and mechanisms behind the associations remain largely unknown. During validation
of known risk loci from the CGEMS project in BRCA negative familial
or genetically enriched cases from Germany, a variant in KBTBD12, a
member of the kelch repeat family of proteins could be identified. The
aim of this study was to initially characterize this so far undefined gene.
RNA expression was analyzed by quantitative real-time PCR. Methylation of a promoter associated CpG island was measured by direct bisulfite
sequencing and methylation specific PCR. Mutation analyses were conducted by dHPLC and Sanger sequencing. Breast carcinoma cell lines
were stably transfected by retroviral transfection. Migration and invasion
capabilities were determined by monolayer wound healing assay and
matrigel invasion assay respectively.
KBTBD12 mRNA expression was significantly downregulated in breast
carcinoma cell lines and tissues compared to normal tissues (tumor flanking and reduction mammoplasties). Reduced expression was associated
with promoter methylation and restored by cell line exposure to a demethylating agent. Germ line mutation analyses of 71 BRCA negative
high risk breast cancer patients showed no clearly pathogenic sequence
alterations. Metastatic breast cancer cell line MDA-MB-231 transfected
to express KBTBD12 showed significantly reduced migratory and invasive potential in vitro. Subcellular fractionation as well as microscopic
analyses suggests an association of KBTBD12 protein with the endoplasmic reticulum.
Our findings raise the possibility of KBTBD12 as a breast tumor suppressor gene.
Abstracts
ID 432
Results of an international Intregroup randomized phase
III trial of pazopanib versus placebo (AGO-OVAR16).
Subgroup Analysis of toxicity and clinical outcome in the
Asian and Non-Asian population
J. Sehouli1, P. Harter2, P. Wimberger3, J. Rau4, K. Baumann5,
C. Kurzeder6, U. Canzler7, W. Meier8, L.C. Hanker9, S. Mahner10,
P. Krabisch11, W.W. Reiter12, B. Aminossadati4, A. du Bois13
Charité Universitätsmedizin, Campus Virchow Klinikum, Frauenklinik,
Berlin, Deutschland
2
Dr. Horst-Schmidt-Klinik,, Klinik für Gynäkologie und Gynäkologische
Onkologie,, Wiesbaden, Deutschland
3
Universitätsklinikum Essen,, Klinik für Frauenheilkunde und Geburtshilfe,,
Essen, Deutschland
4
5
Universitätsklinikum Gießen und Marburg, Gyn. Endokrinologie und
Onkologie,, Marburg, Deutschland
6
Universitätsklinikum Ulm,, Universitätsfraeunklinik, Ulm, Deutschland
7
Universitätsklinikum Carl Gustav Carus ,, Klinik u. Poliklinik für Frauenheilkunde u. Geburtshilfe, Dresden, Deutschland
8
Evangelisches Krankenhaus, Fraeunklinik, Düsseldorf, Deutschland
9
Klinikum der J.W. Goethe-Universität,, Zentrum für Frauenheilkunde u.
Geburtshilfe, Frankfurt. M., Deutschland
10
Universitätsklinikum Hamburg-Eppendorf, Klinik und Poliklinik für Gynäkologie, Hamburg, Deutschland
11
Klinikum Chemnitz, Frauenklinik, Chemnitz, Deutschland
12
Schwerpunkt-Praxis;, Viersen, Deutschland
13
Kliniken Essen Mitte, Klinik für Gynäkologische Onkologie, Essen,
Deutschland
1
Pazopanib is an oral, multikinase inhibitor of VEGFR-1-3, PDGFR-α/β,
and c-Kit. This international study evaluated the efficacy, safety, and tolerability of pazopanib maintenance therapy in patients (pts) who have not
progressed after 1-line chemotherapy for AEOC.
Methods: Pts with histologically confirmed AEOC, FIGO IIb-IV, and no
evidence of progression after 1st-line therapy were randomized 1:1 to receive 800 mg pazopanib once daily or placebo for up to 24 months (mo).
Primary endpoint was PFS by RECIST. Within this study 373 Non-Asia
and 104 Asia pts were included and is the basis for this subgroup analysis.
Results: The global results of the study (n = 940) were presented at
ASCO 2013. Pts in the pazopanib arm had a prolonged PFS vs placebo (HR = 0.766; 95% CI: 0.64–0.91; p = 0.0021; medians 17.9 vs 12.3
mo, respectively). In the present subgroup analysis there were significant differences between Asian and Non-Asian population.For Asian and
Non-Asia pts, dose reduction occurred in 75% vs. 53%, respectively.
Non-Asian pts in the Pazopanib arm had a prolonged PFS vs. placebo
(HR = 0.694; 95% CI: 0.57–0.84; p =0.0001; medians 17.8 vs 11.9 mo,
respectively). Within Asian population no significant improvement of the
PFS in the pazopanib arm vs, placebo arm was found (HR= 1.164; 95%
CI: 0.782–1.734, p = 0.4528; medians 18.0 vs 23.9 mo, respectively). In
non-Asian pts the incidence of neutropenia (6% vs. 24%), thrombocytopenia (1% vs. 8%), palmar plantar-erythrodysaesthesia (1% vs. 5%),
hypertension (30% vs. 35%) was lower compared to Asian pts. Diarrhoe
(9% vs 4%), liver related toxicity (10% vs. 6%) and asthenia (3% vs. 1%)
were more often encounterd in Asian vs. non-Asian pts, respectively.
Conclusions: This study describes significant differences of the tolerability and toxicity and the clinical outcome between Asian and Non-Asian
AEOC pts. Further clinical trials should address this relevant topic.
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Head and Neck Cancer
ID 051
Primary surgery versus primary surgery followed by
adjuvant radiotherapy in patients with pT1/T2 pN1 oral
squamous cell carcinoma – results of an international
multicenter study
M. Kreppel1, M. Amit2, J. Zöller1, M. Scheer1,3, S. Patel4, Z. Gil2
University of Cologne, Department for Oral and Maxillofacial Plastic Surgery, Cologne, Deutschland
2
Rambam Medical Center, Rappaport School of Medicine, the Technion,
Israel Institute of technology, Haifa, Department of Otolaryngology, Haifa,
Israel
3
Mühlenkreiskliniken Minden, Department for Oral and Maxillofacial Plastic
Surgery, Minden, Deutschland
4
Memorial Sloan Kettering Cancer Center, NY, NY, Head and Neck Surgery, New York, Vereinigte Staaten Von Amerika
1
Background: In patients with advanced stage oral squamous cell carcinoma (OSCC), adjuvant radiotherapy (RT) leads to improved survival and locoregional control rates. For small tumors (pT1 & pT2) with a
small solitary ipsilateral cervical lymph node metastasis however, there
is no definite recommendation whether an adjuvant RT should be carried
out in comparison to a solely surgical treatment.
Methods: 216 patients with OSCC of histologically proven pT1/T2 pN1 status were included in this international multicenter study. Further inclusion
criteria were clear resection margins, the absence of lymphangiosis carcinomatosa and extracapsular spread. Overall survival (OS) and locoregional control (LRC) were determined by using the Kaplan-Meier method. Prognostic
factors were analyzed by the log rank test and the Cox regression.
Results: Mean and median follow up were 54.5 and 55 months respectively. 61 patients received a surgical treatment while adjuvant RT was
administered in 155 patients after surgery. Patients receiving adjuvant RT
showed a significantly higher 5-year OS rate than patients treated with
surgery only. (70% vs. 42%, p = 0.001). In multivariate analysis, only
adjuvant RT (p = 0.001) and age (p = 0.015) had a significant impact on
OS. LRC-rate after 5 years was also significantly better for patients, who
were treated with adjuvant RT (80% vs. 46%, p < 0.001)
Conclusion: Adjuvant RT in patients with small OSCC and pN1-status
seems to be beneficial for survival and locoregional control in comparison
to a solely surgical treatment.
ID 097
Impact of human papilloma virus infection on the
response of head and neck cancers (HNSCC) to antiepidermal growth factor receptor (EGFR) antibody
therapy*
T.C. Gauler1, M. Pogorzelski1, S. Ting2, F. Breitenbuecher1,
I. Vossebein1, S. Hoffarth1, S. Lang3, C. Bergmann3,
J. Abu Jawad4, J. Markowetz1, K.W. Schmid2, M. Schuler1,
S. Kasper1
Westdeutsches Tumorzentrum, Universitätsklinik Essen, Innere Klinik
2
Westdeutsches Tumorzentrum, Universitätsklinik Essen, Institut für Pathologie und Neuropathologie, Essen, Deutschland
3
Westdeutsches Tumorzentrum, Universitätsklinik Essen, Klinik für Hals-,
Nasen-, Ohrenheilkunde, Essen, Deutschland
4
Westdeutsches Tumorzentrum, Universitätsklinik Essen, Klinik für Strahlentherapie, Essen, Deutschland
1
Introduction: The monoclonal antibody cetuximab targeting the EGFR
has clinical activity in patients with advanced or metastatic HNSCC. Up
to 40% of HNSCC are associated with HPV infection. The functional association of HPV status with the cetuximab response in HNSCC remains
to be defined.
Methods: Formalin-fixed, paraffin-embedded tumor samples from 69
cetuximab-treated patients with recurrent or metastatic HNSCC were
76
probed for p16INK4a expression, an established biomarker of HPV infection.
Response rates, progression-free survival (PFS) and overall survival (OS)
were analyzed in relation to p16INK4a status. The impact of cetuximab on
apoptosis and proliferation in vitro and tumor growth in mice was studied
in HNSCC cell lines with defined HPV status, and in cetuximab-sensitive
cancer cell lines stably expressing HPV oncogenes E6 and E7.
Results: p16INK4a expression was detected in tumor samples from 18.8%
of HNSCC patients with preponderance of oropharyngeal cancers (33%).
Response rates (45.5% vs. 45.5%) and median PFS (97 vs. 92 days) following cetuximab-based therapy were similar in patients with p16INK4a
-positive and -negative tumors. As expected, OS was numerically longer
in the p16INK4a-positive group. Heterologous expression of HPV E6 or E7
or HPV status was shown to have no significant impact on response to
cetuximab in vitro. Cetuximab effectively inhibited growth of E6- and
E7-expressing tumors grafted in NOD/SCID mice.
Conclusions: HPV infection does not impact on the efficacy of cetuximab in HNSCC. Anti-EGFR antibody treatment should be applied independently of HPV status.
*Supported by grants from the DKH (110099 to M.P.) and an Oncology Center of
Excellence grant of the DKH to the West German Cancer Center.
ID 109
Mental disorders and psychosocial support during the
first year after total laryngectomy
J. Keszte1, H. Danker2, A. Dietz3, E.F. Meister4, F. Pabst5,
H.-J. Vogel6, S. Singer7
Universität Leipzig, Medizinische Psychologie und Medizinische Soziologie, Leipzig, Deutschland
2
Universitätsklinikum Leipzig, Klinik und Poliklinik für Psychosomatische
Medizin und Psychotherapie, Leipzig, Deutschland
3
Universitätsklinikum Leipzig, Klinik und Poliklinik für Hals-, Nasen-, Ohrenheilkunde, Leipzig, Deutschland
4
Städtisches Klinikum St. Georg, Klinik für Hals-, Nasen-, Ohrenheilkunde mit Belegabteilung für Mund-, Kiefer- und Gesichtschirurgie, Leipzig,
Deutschland
5
Städtisches Klinikum, Klinik für Hals-Nasen-Ohrenheilkunde, Kopf- und
Hals-Chirurgie, Plastische Operationen, Dresden Friedrichstadt, Deutschland
6
Elblandkliniken, Klinik für HNO-Heilkunde, Kopf- und Halschirurgie, Riesa,
Deutschland
7
Universität Mainz, Institut für Medizinische Biometrie, Epidemiologie und
Informatik, Mainz, Deutschland
1
Objectives: To assess the frequency of mental disorders and the use of
psychosocial services in laryngectomized patients during the first year
after surgery.
Methods: Multi-center prospective study including six structured interviews. Data regarding psychiatric comorbidity,three months (t3) and one
year after total laryngectomy (TLE) (t4) is reported in this paper.
Results: Mental disorders were diagnosed in 25% of the patients at t3 and
in 22% of the patients at t4. 6% of the patients developed a mental disorder between t3 and t4. In general male and female patients suffered from
mental disorders with equal frequency (t3: 23% vs. 37%; p = 0.26; t2:
22% vs. 21%; p = 1.00). Women suffered more often than men from posttraumatic stress disorder at t3 (p = 0.01) and generalized anxiety disorder
at t4 (p = 0.01). Of the patients who had acquired no voice until t4 80%
suffered from alcohol dependence (p = 0.01). There were no differences
between men and women in receiving any kind of counselling (p = 0.79)
or psychotherapy/psychiatric treatment (p = 0.47). Of those patients diagnosed with any mental disorder at t3, 7% had received psychotherapy
by t4. None of the patients diagnosed with alcohol dependence received
psychotherapy or psychiatric treatment.
Conclusions: Mental disorders occur in laryngectomees as frequently in
men as they do in women. TLE patients who were mentally ill did not receive enough psychotherapeutic or psychiatric support. Since mental health
seems to be related to successful voice restoration, future research should
develop and evaluate special psychosocial supportive programs for laryngeal cancer patients, especially regarding alcohol dependence treatment.
Abstracts
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Index
ID 111
Reirradiation and Cetuximab in Patients with Locally
Recurrent and Unresectable Head and Neck Cancer – Is
there any Impact on Survival? – Final Results from Single
Institution and Literature Review
D. Milanovic, A.L. Grosu, M. Henke
Universitätsklinikum Freiburg, Klinik für Strahlenheilkunde, Freiburg,
Deutschland
Background: Chemotherapy with epidermal growth factor receptor
(EGFR) inhibition is established as palliative management in patients
with recurrent, unresectable and previously irradiated head and neck
cancer (HNC). In this retrospective, monocentric study we analysed feasibility, toxicity, and outcome of Re-RT (reirradiation) and with EGFR
blockade with cetuximab.
Methods: Between June 2008 and June 2011, we reirradiated (50.4–66.6
Gy) 24 patients with histologically proven HNC, who had been previously treated with external beam radiotherapy (RT). In 23 cases, histology
was squamous cell carcinoma (SCC), while 1 patient was diagnosed with
high grade mucoepidermoid carcinoma (MEC). Cetuximab was given
initially at 400 mg/m2 two days before Re-RT and weekly (250 mg/m2)
thereafter. 21 patients completed Re-RT (50.4–66.6 Gy) and received
cetuximab as prescribed. Grade 3 acute side effects were documented for
dermatitis (35%), dysphagia (30%), acneiform rash (30%) and mucositis
(15%). Two patients are still alive – one with MEC 61 months after finishing treatment without signs of clinical or radiological progress and one
with SCC 43 months after finishing treatment. A multivariable analysis
using the Cox regression model showed significant positive impact of
acneiform rash while a period from first radiation to Re-RT longer than
120 months negatively influenced patients survival.
Conclusion: Re-RT with concurrent cetuximab was feasible at acceptable toxicity. Similar results were reported from other groups using same
regime. Given comparable survival rates, for patients reirradiated only
or for patients administered cisplatin based regimes with cetuximab we
suggest to sequentially apply these modalities.
ID 119
Simultaneous cytoplasmic and nuclear protein
expression of MAGE-A family and NY-ESO-1 cancer-testis
antigens represents an independent marker for poor
survival in head & neck cancer
S. Laban1,2, D. Atanackovic2, T. Lütkens2, C.-J. Busch2,
M. Freytag2, T.K. Hoffmann1, A. Knuth3, G. Sauter2, R. Knecht2,
A. Münscher2, T.S. Clauditz2
Universitätsklinik Ulm, HNO, Ulm, Deutschland
Universitätsklinikum Hamburg Eppendorf, Hamburg, Deutschland
3
Hamad Medical Corporation Qatar, National Center for Cancer Care &
Research, Doha, Qatar
1
2
Background: Despite enormous efforts, the prognosis of head and neck
squamous cell carcinoma (HNSCC) patients is still poor. The identification of immunotherapeutic targets, especially for patients at high risk of
death, is needed. The expression of cancer-testis antigens (CTA) has been
linked to poor prognosis in other cancer types, however, their prognostic
value in HNSCC is unclear, because only small cohorts have been examined regarding CTA protein expression.
Methods: A tissue micro array built of tumor samples from 453 HNSCC
patients was evaluated for the expression of CTA proteins using immunohistochemistry. Frequency of expression and the subcellular expression
pattern (nuclear, cytoplasmic, or both) was recorded.
Results: Protein expression of at least one CTA was detected in 47.5%
of patients. Positivity for MAGE-A family CTA, MAGE-C family CTA,
and NY-ESO-1 was found in approximately 30%, 7%, and 4% of tumors,
respectively. CTA protein expression, but most remarkably the expression
pattern had a strong impact on the prognosis. Median overall survival
(OS) of patients with (1) simultaneous cytoplasmic and nuclear expres-
Abstracts
sion compared to (2) either cytoplasmic or nuclear expression and (3)
negative patients was 23.0 vs. 109.0 vs. 102.5 months, for pan-MAGE
(≤0.0001), 46.6 vs. 50.0 vs. 109.0 for MAGE-A3/A4 (p = 0.0074), and
13.3 vs. 50.0 vs. 100.2 months for NY-ESO-1 (p = 0.0019). By multivariate analysis these factors were confirmed as independent markers for
poor survival.
Conclusions: The expression of MAGE-A family members or NY-ESO-1
identifies a patient subgroup with a high risk of death. Immunotherapeutic strategies targeting these CTA may improve the outcome of HNSCC
patients.
ID 133
Trends in incidence rates of oral and pharyngeal cancer
in Germany
K. Hertrampf1, J. Wiltfang1, R. Pritzkuleit2, A. Katalinic3,
H.-J. Wenz4, A. Waldmann3
Klinik für Mund-, Kiefer- und Gesichtschirurgie, Universitätsklinikum
Schleswig-Holstein, Campus Kiel, Kiel, Deutschland
2
Institut für Krebsepidemiologie, Universität, Lübeck, Deutschland
3
Institut für Sozialmedizin und Epidemiologie, Universität, Lübeck,
Deutschland
4
Klinik für Prothetik, Propädeutik und Werkstoffkunde, Universitätsklinikum
Schleswig-Holstein, Campus Kiel, Kiel, Deutschland
1
Background: Oral and pharyngeal cancer is still a serious health problem
in Germany. Since 2000, the incidence rates have increased from 10,000
to 13, 000 newly diagnosed cases per year. The aim of this evaluation is
to describe epidemiologic trends of this tumour in Germany, focusing on
incidence rates according to age and gender.
Methods: Incidence rates for oral and pharyngeal cancers (ICD-10 C00–
C14) for the period 2003–2010 by age, gender, and sub-sites (C00–C06,
C07–C08, C09–C14) was retrieved from the Association of Epidemiological Cancer Registries in Germany.
Results: In 2010, a total of 13,244 oral and pharyngeal tumours were
newly diagnosed. From 2003-2010, the incidence rates of oral and pharyngeal tumours in women increased slightly from 5.3 to 5.8/100 000
(ASR [E]), while incidence rates in men decreased from 19.9 to 19.1/100
000 (ASR [E]). An incidence peak was observed in the age group 60-64
years in men, whereas the incidence rates in women showed not such a
marked peak. A detailed analysis by gender and sub-sites reveals interesting differences. The German data did not show an increasing trend of
developing oral and pharyngeal cancer in younger people compared to
data from other European countries. With regards to the different subsites, incidences of the oral cavity (C00–C06) rank highest in women and
showed a slight incidence increase over the observation period. In men,
incidence rates of pharyngeal cancer showed a slight decrease and the
other sub-sites remained quite constant.
Conclusions: The population-based data forGermany showed interesting
differences in the trends for incidence rates for both genders and revealed
noticeable differences to European neighbours.
ID 212
Detection of circulating tumor cell sub-populations in
patients with head and neck squamous cell carcinoma
(HNSCC)
P. Hassenkamp1, I. Nel2, P. Weller1, P. Dountsop3, G. Lehnerdt1,
A.-C. Hoffmann2
Universitätsklinikum Essen, Universitäts-Hals-Nasen-Ohrenklinik, Essen,
Deutschland
2
Deutschland
3
HNO-Klinik, Evangelisches Krankenhaus, Düsseldorf, Deutschland
1
Background: Circulating tumor cells (CTC) could serve as a ‘liquid biopsy’ for individualizing and monitoring treatment in patients with solid
tumors. Standardized approaches with currently available techniques are
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challenged by the cellular heterogeneity of CTC as reported recently by
our group (Nel et al., Transl Oncol 2013). We assessed which non-hematopoietic cell types are identifiable in the peripheral blood of patients with
HNSCC and their distribution before and after resection.
Methods:Blood was drawn from HNSCC patients (n = 7) before, during
and after resection.Mononuclear cells (PBMNC) and CTC were isolated using density gradient centrifugation and spun onto glass slides. CTC
presence was verified by multi-immunofluorescence staining against
pan-cytokeratin (CK; epithelial), N-cadherin (mesenchymal); CD133
(stem-cell), CD45 (hematopoietic) and DAPI (nucleus). CTC and hematopoietic cells were enumerated and individual cell type profiles were
analyzed.
Results: We detected cells with epithelial properties like CK+/CD45-,
mesenchymal features such as CK-/CD45-/NCad+ and CK+/CD45-/
NCad+. We also observed cells with stem cell-like features: CK-/CD45-/
CD133+ and CK+/CD45-/CD133+. The total amount of CTC significantly decreased after surgery (p = 0.05). Prior to surgery the number of CK+,
CD133+ and NCad+ cells ranged from 2 to 37 (median 6), 1–14 (median 3) and 0–20 (median 3) CTC/1000 PBMNC. After resection the total
amount of CK+, CD133+ and NCad+ cells ranged from 0–5 (median 2.5),
0–6 (median 1) CTC and 0-2 (median 0.5), respectively.
Conclusions: Our data suggest that different CTC populations are identifiable in peripheral blood of HNSCC patients.Prospective evaluation of
recurrence rates in correlation with these distinct cell profiles seems to
be warranted.
ID 279
Human papillomavirus associated oral squamous
cell carcinoma: Is overall survival influenced by the
expression of cancer stem cell markers?
C. Götz1, E. Drecoll2, M. Straub2, P. Holm3, M. Kesting1,
K.D. Wolff1, A. Kolk1
TU München, Klinikum rechts der Isar, Mund-, Kiefer- und Gesichtschirurgie, München, Deutschland
2
TU München, Klinikum rechts der Isar, Pathologie, München, Deutschland
3
TU München, Klinikum rechts der Isar, Experimentelle Onkologie und
Therapieforschung, München, Deutschland
1
Introduction: 5-year-overall survival is quoted to be significant better in
human papillomavirus (hpv) associated oral squamous cell carcinomas
(oscc) than in oscc related to alcohol and tobacco consumption.
An explanation for these results could be that adjuvant chemotherapy and
radiation are resulting in higher response rates to oscc with hpv positive
carcinogenesis. On the other hand the hallmarks of cancer, including the
cancer stem cell (csc) theory could be different in hpv associated oscc.
In the past only few investigations were done in this field of molecular
oncology and were set into correlation to the clinical outcome of the patients.
To the detection of hpv infection it is mentioned that staining of p16
shows higher signals than other hpv correlated proteins are doing.
Methods: We analyzed the expression of the csc markers ALDH 1, CD
44 and Nanog with methods of IHC on a TMA. We did Western Blot on
tissues, which were extracted of hpv positive and negative oscc cell lines.
Furthermore we compared the results to hpv negative oscc cell lines. We
set the laboratory results into correlation with the overall survival of the
550 patients, on which the TMA is based.
Furthermore we detected hpv in IHC with two different molecular patterns, E7 and p16.
Results: The results showed significant difference between the expression oft the latter mentioned csc markers in hpv positive and negative
oscc. A reduced expression of these markers was found through IHC and
WB in hpv positive oscc. We used Spearman rank correlation and set the
p-value on <0.05.
Conclusion: According to the significant different results between hpv
positive and negative oscc we are showing that there is a need to do further research on this subject and to discuss the treatment of hpv postitive
oscc.
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ID 295
Flexible endoscopy for hyperspectral imaging
W. Laffers1, S. Westermann1, R. Martin2, B. Thies2, F. Bootz1,
A. Gerstner3
Universitätsklinikum Bonn, HNO, 53105, Deutschland
Universität Marburg, Institut für Geographie, Marburg, Deutschland
3
Städtisches Klinikum, HNO, Braunschweig, Deutschland
1
2
Background: Cancer of mucosal surfaces capable for detection by flexible endoscopy (head neck, gastrointestinal, genital, urologic) is the fast
majority of malignancies. Early diagnosis is essential for a better outcome
for patients but is still challenging. Hyperspectral imaging has been used
in remote earth sensing for decades e.g. for analysing and classifying the
surface of the earth. We modified hyperspectral imaging to be used for in
vivo flexible endoscopy in patients.
Method: We choose the larynx as an ideal representative test area. Patients underwent conventional microlaryngoscopies for diagnostic reasons. By using a tuneable monochromatic light source (PolyChrome V,
TillPhotonics, Gräfeling) with 10nm single-bands from 390 nm to 680
nm the mucosa of the larynx was illuminated stepwise. The total relexion was detected with a monochromatic CCD-camera (AxioCam, Zeiss,
Jena) synchronously. Image cubes were generated and analysed with idrisi® software.
Results: Hyperspectral imaging of the larynx was done in patients in accordance with the local ethics committee. Acquisition time was 30sec per
image cube. Areas of altered mucose, e.g. cancer, could be detected, in
particular without any additional information needed. In comparison to
microscopy or rigid endoscopy it was more difficult to find the accurate
focus depth for correct analysis.
Conclusion: Flexible endoscopy can be applied for hyperspectral imaging in patients in vivo. Its adoption to flexible endoscopes opens the entire area of endoscopy of mucosal surfaces for this technology. Spectral
profiles seem to differ according to different histological findings. Further
studies have to be performed to determine if hyperspectral imaging by
flexible endoscopy can be used for early detection of cancer.
ID 301
Radiosensitization of HPV Positive Head and Neck
Squamous Cell Carcinomas (HNSCC) by Chk1 Inhibition
C.-J. Busch1, M. Kriegs2, S. Laban1, S. Tribius3, R. Knecht1,
C. Petersen3, E. Dikomey2, T. Rieckmann2
Universitätsklinikum Hamburg-Eppendorf, HNO Abteilung, Hamburg,
Deutschland
2
Univesitätsklinikum Hamburg-Eppendorf, Labor für experimentelle Strahlenbiologie, Hamburg, Deutschland
3
Universitätsklinikum Hamburg-Eppendorf, Klinik für Strahlentherapie,
1
Purpose of the Study: Patients with HPV positive HNSCC show remarkably better survival rates than patients with HPV negative HNSCC
when treated with radiotherapy (RT) or radiochemotherapy (RCT). To reduce high-grade toxicities of standard cisplatin based RCT we are looking
for radiosensitizing substances in order to replace cisplatin. After ionizing
radiation (IR) HPV-positive HNSCC cell lines demonstrate a pronounced
and sustained G2-arrest which is likely a result of the higher amounts of
unrepaired DNA double strand breaks. We speculate that this arrest might
partly counteract the repair deficiency by providing the cells more time
for repair before entering mitosis.
Methods: To abrogate the G2 checkpoint we used PF-00477736 (PF), a
selective CHK1 kinase inhibitor. 5 HPV/p16INK4a-positive HNSCC cell
lines were treated by IR with and without PF. Chk1-activity and G2-arrest
were analyzed by western blotting and propidium iodide staining. The
impact of Chk1-inhibition on cell survival after irradiation was assessed
by colony formation assay.
Results: In all HPV/p16INK4a-positive HNSCC cell lines a pronounced
G2-arrest after 6 Gy IR could be observed. The G2-arrest was abrogated
sufficiently in all cell lines by PF in a dose dependent manner. An effec-
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tive dose was reached at 150 nm PF in 4 of 5 cell lines. On average, 150
nm PF in combination with IR showed significant radiosensitization in
colony formation assay.
Conclusion: The specific inhibition of checkpoint kinase 1 by PF results
in a significant radiosensitization of HPV/p16INK4a-positive HNSCC cell
lines in vitro. Our findings suggest that G2 checkpoint abrogation by PF
might be an alternative to cisplatin based RCT in HNSCC patients. A
validation of our data in xenograft models is planned.
ID 362
Extent of Fear of Recurrence (FoR) and its Associations
with Medical, Treatment-Related, Psychosocial and
Demographic Parameters in Cancer Patients after a
Partial Laryngectomy
A. Meyer1, M. Asen1, A. Dietz2, S. Singer3, J. Keszte1,
D. Wollbrück1
Universität Leipzig, Medizinische Psychologie und Medizinsche Soziologie, Leipzig, Deutschland
2
Universitätsklinikum Leipzig, Klinik für HNO-Heilkunde, Leipzig, Deutschland
3
Universitätmedizin Mainz, Epidemiologie und Informatik, Mainz, Deutschland
1
Objectives: Fear of Recurrence (FoR) is a common problem in patients
suffering from cancer. However, it is quite unknown in which extent patients who underwent a partial laryngectomy have FoR. The study examines the extent of FoR in this patient group and analysed the associations
between FoR and medical, treatment-related, psycho-social as well as
demographic parameters.
Methods: In a multicentre cross-sectional study, data was taken from
154 patients after partial laryngectomy. The data collection took place in
personal interviews and with standardized questionnaires (PA-F, HADS,
EORTC QLQ-H&N 35).
Results: The study participants had a low level of FoR (MW=6.67;
SD=2.43). FoR was higher in young patients (r = –0.265; p = 0.002)
and in users of medical rehabilitation programs (U=1480; p = 0.025).
The results of a multiple linear regression showed that patients who
thought smoking (r = 0.197; p = 0.029) or/and inner conflicts (r = 0.177;
p = 0.050) was/were the reason(s) for their cancer and who reported more
swallowing problems, had a significantly higher level of FoR (r = 0.496;
p < 0.001). Additionally, there was a negative correlation between the extent of FoR and the time which passed by since the last laryngeal surgery
(r = –0.322; p < 0.001).
Conclusions: Frequently occurring swallowing problems as well as internal causal attributions for the development of cancer as smoking and
inner conflicts increase the level of FoR in patients after a partial-laryngectomy. Since internal causal attribution may cause feelings of guilt a
psycho-oncological treatment can be indicated for patients with higher
levels of FoR. Since fear of recurrence is mainly found in younger individuals, this patient group is requiring more attention by physicians and
therapists.
ID 389
Neoadjuvant Docetaxel/Cisplatin/5-FU based
radiochemotherapy (RT-CT) increases pathologic
complete remissions and survival of patients with locally
advanced oral cavity carcinomas in comparison to RT-CT
with cisplatin alone followed by resection – a long term
observational study
M. Stuschke1, J. Abu Jawad1, W. Eberhardt2, S. Grehl1,
C. Pöttgen1, G. Arnold3, R. Pförtner4, T. Gauler2, C. Schmeling4,
C. Mohr4
Universitätsklinikum Essen, Strahlenklinik, Essen, Deutschland
Universitätsklinikum Essen, Innere Klinik / Tumorforschung, Essen,
Deutschland
3
Zentrum für Pathologie Essen Mitte, Essen, Deutschland
4
Kliniken Essen-Mitte, Mund-, Kiefer-, Gesichtschirurgie, Essen, Deutschland
1
2
Abstracts
Background: Neodjuvant RT-CT at moderate RT doses followed by resection of oral cavity carcinomas (OCC) allows the conduct of secondary
mandible reconstruction. Long term outcome is analysed in dependence
on the intensity of the neoadjuvant protocol.
Methods: Data from consecutive patients (pts) with locally advanced
OCC treated between 01/2003 and 06/2010 were analysed. Pts received
weekly Docetaxel/Cisplatin/5-FU over 5 weeks followed by RT (40 Gy,
5×2 Gy / week) and simultaneous Cisplatin at 15 mg/m2 and Docetaxel
at 10–20 mg/m2, twice weekly during weeks 1–3 of RT (TPF-RT). This
schedule was offered as a phase I/II trial. No high risk HPV16 genotype
was found in tumors form the pts of this trial. Pts with locally advanced
tumors not recruited into the TPF-RT trial, were offered P-RT (36 Gy,
5×2 Gy/w, simultaneous Cisplatin at 12.5 mg/m2, d1-5) before resection.
Multivariate analyses (MV) as well as propensity score weighting (PS)
were used to adjust for imbalances in prognostic factors between both
treatment groups.
Findings: 102 pts were treated and median follow-up was 80 (39-130) m.
TPF-RT pts had larger primary tumors than P-RT pts (p = 0.004). Overall
survival at 5 years was 80.4+7% and 64.3+6% in the TPF-RT and P-RT
groups, respectively (p = 0.027). MV (p = 0.02) and PS (p < 0.0001) revealed a marked reduction of hazard of death by a hazard ratio of 0.33
(0.13-0.84) or 0.25 (0.13-0.48) in the TPF-RT group. Crude rates of
pathologic complete responses (pCR) in TPF-RT and P-RT groups were
19/31 and 12 / 71 (PS odds ratio 9.2 (4.6-18.3, p < 0.0001). pCR was
associated with prognosis (p < 0.0001) and it captured the full treatment
effect on survival in MV and PS analyses.
Interpretation: This study demonstrates a markedly increased effect of
TPF-RT on pCR and survival of OCC patients.
Health Services Research
ID 014
Chemotherapy treatment patterns and outcomes in
platinum resistant ovarian cancer (PROC) patients – a
German database study
J. Schilling1, R. Shinde2, C. Thielecke3, H. Stiegler3, U. Plötner3,
T. Burke2, P. Kaskel4
Berufsverband der Niedergelassenen Gynaekologischen Onkologen in
Deutschland e.V., Berlin, Deutschland
2
MERCK & CO., INC., Global Health Outcomes, Whitehouse Station, NJ,
USA, Vereinigte Staaten Von Amerika
3
OnkoDataMed GmbH, Schöneiche b. Berlin, Deutschland
4
MSD SHARP & DOHME GMBH, Outcomes Research / HTA, Haar (Kreis
München), Deutschland
1
Background and Aims: Approx. 25% of advanced ovarian cancer
(AOC) patients (pts) suffer from relapse within 6 months (m) after end
of initial platinum based chemotherapy (PBC; platinum-resistant ovarian
cancer, PROC). PROC pts have an overall survival (OS) of ca. 12 m. The
aim of this study was to explore the real world practice pattern and survival in pts with PROC in the outpatient setting in Germany.
Methods: AOC pts treated with PBC aged-18+, diagnosed 1990-2012,
were included from a German database fed by community based gyneco-oncologists. Baseline data at the onset of platinum resistance and outcomes from subsequent therapy were recorded.
Results: 508 pts with AOC were identified. Of these, 480 initially received PBC, with response being refractory (progression while on therapy, N=11), resistant (N=20), partially sensitive (progression 6-12 m after
end of PBC, N=22), and complete sensitive (progression >12 m after
end of PBC, N=427). 190/480 pts received further chemotherapy (40%).
Mean age in PROC was 63.1 years with 13 pts diagnosed at stage IV. All
PROC pts received surgery cytoreduction. 15 / 20 PROC pts received up
to 4 lines of follow-up chemotherapy (total 26 lines; mean = 1.86 lines;
average 6.6 cycles each). The most common chemotherapies were topo-
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tecan (N=4), treosulfan (N=4) and PLD (N=2). The median OS for PROC
was 30 weeks.
Conclusion: As database is community based, many AOC pts were lost
over time as they may have transitioned to dedicated and specialized centers after disease advancement, rather than being treated in the outpatient
setting. Out of those treated, few were platinum resistant, and a significant
number of PROC pts received recommended chemotherapies; but still a
poor OS indicated high unmet medical needs in PROC.
ID 032
Patient Transition from Acute Care to Rehabilitation –
First results of a Survey of German Rehabilitation Clinics
(OPTIREHA)
H. Schmdit1, J. Abraham1, M. Landenberger1, P. Jahn1,2
Martin-Luther-University Halle-Wittenberg, Medical Faculty, Institute for
Health and Nursing Science, Halle Saale, Deutschland
2
Martin-Luther-University Halle-Wittenberg, University Hospital, Halle
Saale, Deutschland
1
Background: Rehabilitation for cancer patients aims to achieve better
reintegration, improvement of participation and quality of life. To reach
these objectives the management of patients’ transition from primary care
to rehabilitation should be tailored to meet patients’ individual needs and
abilities.
Objective: The aim of this study was to gain information about possible
problems and potential for optimization of patient transition from primary
care hospitals to rehabilitation clinics.
Method: This cross sectional observational study used a semi-structured
questionnaire to survey 138 German rehabilitation clinics for cancer patients.
Results: N=47 (34%) clinics answered the questionnaire. First results
suggest considerable potential for optimization of patient transition.
Three main problem areas were identified that might impair or complicate the rehabilitation process: 1. Inadequate flow of information regarding the clinical, psychosocial and cognitive condition of the patients can
delay the onset of important treatments thus impairing the rehabilitation
process. 2. Weak physical or cognitive condition of the patients, multimorbidity or special needs for medical care due to early dismissal can
lead to increased efforts or time demands. The achievement of set goals
for the rehabilitation might be impeded by these conditions. 3. Patients’
lack of information about aims and means of a rehabilitative treatment
and false expectations might reduce motivation and complicate adherence
to therapeutic measures.
Outlook: A pilot study to develop and test a modular assessment tool to
optimize information flow and patient transition will be performed. The
tool will be based on nurse routine documentation and ICF criteria.
ID 059
Off-Label Use – an unsolved problem in German
oncology
T. Langenbuch
Onkologie Volksdorf, Hamburg, Deutschland
Medical Doctors in Germany who use off-label drugs in their treatments
need to receive the public health insurances’ agreement to the bearing of
costs prior to treatment, to protect themselves from regress payments to
health insurances.
The numbers shown are taken from an oncologist’s practice between the
years 2005 and 2013. They reveal how time-consuming it is to apply for
and receive those agreements from the insurance companies, and also illustrate the retardation that occurs in the treatment of a cancer patient due
to the current situation with the insurances’ policies. The difficulties that
arise, both from the perspective of the patient and his/her relatives as well
as the doctor’s, will be highlighted, and alternative options to the present
procedure will be discussed.
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ID 061
Mortality after (first) hospitalization for colorectal
carcinoma
E.M. Bitzer, S. Neusser, T. Grobe
Pädagogische Hochschule Freiburg, Public Health & Health Education,
Background: The incidence of colorectal cancer (CRC) in Germany
is fairly stable. However population based mortality rates are declining
(CRC-mortality 2000–2010: –25%) and relative 5-year survival has increased from the 1980ies to 2000–2004 (45 vs. 60%). Do these developments translate into lower inpatient services utilization and what can be
said about mortality for CRC treated in hospital?
Methods: We used inpatient claims data and beneficiaries master data of
8.5 million German health insurance beneficiaries to calculate population
based rates of inpatient treatment for CRC (ICD C18–C20) for the years
2005 to 2012 (standardized for age and sex to the German population).
Using the life-tables method we analyzedthe 5-year mortality of those
beneficiaries who underwent inpatient treatment in a German hospital for
CRC in the year 2007 without preceding treatment in 2006.
Results: Between 2005 and 2012 we observed a decline in both the
rate of CRC associated hospitalizations (24.14/10,000 to 17.63/10,000,
–21%) and that of individuals affected by a CRC associated hospitalization (11.71/10,000 to 9.28/10,000, –27%). Compared to the (age and sex
matched) general population individuals with a CRC associated hospitalization in 2011 had a mortality almost 10times higher (26.3 vs. 2.8%).
Individuals with a CRC- hospitalization in 2011 (and no CRC-treatment
2006 to 2010) had 30-day mortality of 7.1% and a one-year mortality of 19.1%. Individuals with a CRC-hospitalization in 2007 without
CRC-treatmentin the preceding year had a 30-day mortality of 7.7%, oneyear mortality 20.5% and a five year mortality of 45.1%.
Conclusion: Declining CRC-Mortality is accompanied by declining
CRC-associated hospitalizations. CRC treated in hospital is still a highly
lethal disease.
ID 083
Workload and the physician-patient interaction – results
of the WIN ON-study
H. Pfaff1, N. Ernstmann1, S.E. Groß1, L. Ansmann1, T.D. Gloede1,
A. Nitzsche1, J. Jung1, M. Wirtz2, W. Baumann3, S. Osburg3,
M. Neumann4
IMVR, Köln, Deutschland
Pädagogische Hochschule Freiburg, Abteilung für Forschungsmethoden,
3
Winho, Köln, Deutschland
4
Universität Witten/Herdecke, Fakultät für Gesundheit, Department für
Humanmedizin, Witten/Herdecke, Deutschland
1
2
Background: The aim of the present study is to examine the association between private practice hematologists’ and oncologists’ (PPOs) job
stressors and its influence on the physician-patient interaction and patient
reported outcomes.
Methods: This study is part of the WIN ON (Working Conditions in
Oncology) project. All members of the Professional Organization of Office-Based Hematologists and Oncologists (BNHO) and additional PPOs
(n = 578) were invited to a mail survey. Out of 556 eligible oncologists,
N=157 sent back the completed questionnaire (response rate 28%). Patients with colorectal cancer being treated by these physicians are also
surveyed as part of a four-wave prospective study (N=169).
Results: The average workload is high with a median working time of
57 hours per week and a median number of patient consultations of 35
patients per day. About 50% of the PPOs report moderate symptoms of
emotional exhaustion (indication for burnout) and 18% report explicit
symptoms. In 85% interruptions during patient consultations occurred.
Disturbances during clinical encounters are correlated to patients’ fear
of cancer progression after the first consultation (r = 0.203; p ≤ 0.019).
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However, burnout-symptoms and patients’ fear of cancer progression are
not significantly correlated.
Discussion: In general, PPOs are exposed to high workload and often
show burnout-symptoms. Their workload, especially interruptions seem
to affect the physician-patient interaction. However the PPOs’ well-being
doesn’t seem to affect the physician-patient interaction. We aim to gain
deeper insights into this topic by combining physician and patient data
from the WIN ON-study and analyzing the data in multivariate regression
models.
Evaluation of process quality criteria for systemic therapy
in a clinical cancer registry
of cox regression models. Method of corrected group analysis derived
5-year survival curves.
Results: For analysis, 743 out of 877 (84.7%) patients were used. In total,
103 quality indicators were developed. Adherence index increased systematically from 15.1% (1996–97) to 35.2% (2003–04). 5-year survival
increased, but differences between time intervals were not significant.
More than three decisions divergent from guidelines are suspicious to
increase hazard ratios.
Conclusion: Service quality increased from a relative low level by factor
three despite of more and complex treatment options. Process improvements were not associated with systematic increases in outcomes. However, process related S3-guidelines remain relevant due to the suspicion
that a maximum of two consensual decisions against guidelines (e.g. tumorboards) may have the potential to develop protective effects.
A. Kimminger, W. Tretter, M. Wiedemann, G. Schubert-Fritschle,
J. Engel, D. Hölzel
ID 123
ID 084
Background: Systemic cancer therapy nowadays is characterized by individualization and increasing complexity. Little information, however,
exists about benefits and harms of guideline-oriented individualised therapies in routine health care. The aim of this project was to describe the
compliance and safety of individualised systemic therapy in the region of
the Munich Cancer Registry (MCR).
Methods: An efficient online documentation system was integrated
within a network for physicians and clinics facilitating documentation of
indication, dosage and treatment schedules of various prescribed pharmaceuticals, best response, and other quality criteria.
Results: The MCR registered treatment schedules for 1914 patients from
2008 to 2012 with 2753 disease courses. Adjuvant dosage was applied as
planned in 82.0% and as scheduled in 87.7% of all cases. For the following cancer entities, the percentages for fulfilled dosage and time schedule
were as follows: 92.9 and 87.1 (breast), 92.6 and 90.2 (lung), 66.7 and
84.0 (colon), 82.9 and 92.5 (rectum). The main reason for abandonment
of protocol was side effects (5.6%). The abandonment of adjuvant therapy
due to patient’s request was seldom (2.5%); cancer specific values were
1.4% (breast), 0.8% (lung), 2.5% (colon), and 3.4% (rectum).
n palliative care, percentages for applied dosage were almost comparable,
the fulfilled time scheduled, however, were clearly lower.
Conclusions: These first results about process quality criteria (dosage
and time schedule) show better realization than expected. Such analyses
demonstrate that the integration of specifications about systemic therapy in cancer registries delivers relevant information about individualised
therapy in routine care.
ID 105
Comparison of quality indicators, S3-guideline adherence
and 5-year survival between 1996–97 and 2003–04 of the
breast cancer network Regio in Hesse
C.O. Jacke1, M. Kalder2, U. Wagner2, U.-S. Albert2
Decision strategies of the multidisciplinary team for
cancer treatment
C. Wetzel, S. Seitz, O. Ortmann
Universität Regensburg, Klinik für Frauenheilkunde und Geburtshilfe,
Aim: This study investigates decision strategies of the ‘tumor board’, i.e.
the multidisciplinary team (MDT) in cancer care. Uncomplex and complex cases, i.e. cases with comorbidities, metastasis and recurrent disease,
were compared in the applied decision approaches.
Methods: Decision strategies used in the MDT case discussions for treatment recommendation of our gynecological cancer centre were assessed.
A standardised real time observation tool was used. Differences in the
frequency of strategies between uncomplex and complex cases were analysed using the Mann-Whitney-U-test.
Results: N=105 case discussions were assessed, N=65 uncomplex cases
and N=40 complex cases. Rule based decision making considering guidelines and clinical trials was applied as a decision strategy in 84.6% of the
uncomplex cases, which was significantly more frequently than in complex cases (52.2%; p < .01). In complex cases, the elimination-by-aspects
strategy and ‘if-then-rules’ were used significantly more often (in 15.0%
and 37.5%, respectively) than in uncomplex cases (in 1.5% and 7.7%,
p < .05 and p < .01, respectively).
Conclusions: The application of rule based decision strategies in the
MDT became evident, representing high quality decision approaches.
Guidelines are primarily available for uncomplex cases, whereas in complex cases a great diversity of individual aspects needs to be considered.
Hence, in complex cases clinicians apply alternative strategies, processing relevant information in a rational way. However, increasing the rate
of rule based decision strategies, explicit risk communication for transparency of strategy in all case discussions and establishing standards of
sophisticated MDT decision approaches would be desirable.
ID 147
Zentralinstitut für Seelische Gesundheit, AG Versorgungsforschung,
2
University Hospital Marburg Giessen, Location Marburg, Breast Center
Network Regio, Marburg, Deutschland
The variability of future cancer burden by tumour site
Background: In the last decade, breast cancer networks, tumorboards,
quality management programmes or S3-guidelines were developed to improve the effectiveness of breast cancer detection and treatment across
health care sectors. Aim of study was to assess these efforts from a temporal perspective (1996–97, 2003–04) for inpatient treatment only.
Methods: Breast cancer network Regio (Marburg-Biedenkopf) encompassed three hospitals in selected time intervals 1996–97 and 2003–04. In
total, 389 and 488 female patients with primary therapy of breast cancer
were recruited. Analysis referred to invasive carcinomas without metastasis, distinguishing between residential and non-residential patients. Time
interval specific quality indicators were extracted from clinical records
and aggregated to one adherence index which defined the group indicator
Background: Since the probability of a cancer diagnosis increases with
age, demographic changes will have a major influence on trends of cancer
incidence and prevalence. The resulting cancer burden on society can be
quantified by estimating future cancer cases.
Methods: Data from the Munich Cancer Registry (MCR) was used to show
the age distribution for the most frequently occurring tumour sites. Incidence rates were calculated and combined with data predicted by the Federal
Statistical Office to show the burden of cancer projected 40 years from now.
Results: In most tumour sites, the median age at diagnosis is older than
60, with a median age of 68.9 in men and 68.2 in women. Tumour sites
with the highest median age are bladder (men/women: 73.3 / 78.1) and
Abstracts
1
M. Rottmann, R. Eckel, D. Hölzel, G. Schubert-Fritschle, J. Engel
Tumorregister München (TRM), München, Deutschland
81
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stomach (71.4 / 77.5) for both men and women, and with a high median
age colorectal cancer (70.3 / 74.5). The total incidence rate for cancer is
535.0 per 100,000 in men and 499.2 per 100,000 in women, with rates
highest for prostate and breast cancer. In older age groups (≥ 70), incidence rates are considerably higher with 2321.8 per 100,000 in men and
1502.9 per 100,000 in women. By 2050, the largest increase of incident
cancer cases will be in tumour sites with a high median age at diagnosis
such as bladder (men/women: +71% / +50%), stomach (+53% / +46%),
or colorectal cancer (+43% / +37%), while tumour sites with a relatively
low median age such as in breast for women (+8%) or testis (-23%) for
men, will have a lower increase or even a decrease.
Conclusions: Due to demographic ageing, there will be notably different
changes in cancer incidence according to tumour type. Thus, as a result of
divergent effects, the resulting burden of cancer will be strongly dependent on cancer site.
ID 151
Medical Image Knowledge Extension Using Semantic
Networks, Ontologies and the Bayesian Theorem
M. Graf1, O. Nix2, W. Schlegel3, R. Floca1
DKFZ Heidelberg, Software Entwicklung für integrierte Diagnostik und
Therapie, Heidelberg, Deutschland
2
DKFZ Heidelberg, Qualitätsmanagement klinischer Forschung, Heidelberg, Deutschland
3
DKFZ Heidelberg, Medizinische Physik, Heidelberg, Deutschland
1
Medical images contain more information than their mere digital representations. «Radiological images contain a wealth of information, such as
anatomy and pathology, which is often not explicit and computationally
accessible» [1]. Data processing induces knowledge which is lost when
not linked to the same context, conversely meaning yet unprocessed data
which holds this semantic information can help to extract more knowledge later on. Through machine learning, software aided diagnosis and
therapy planning will become more tangible in near future.
Some effort was made to fight the lack of standardized image annotation
and markup, however, most of that work is currently at an early stage [2].
Previous studies target the annotation and information storage based on
ontologies. One, (AIM) aims at storing and querying the data in a schema
sufficient for data retrieval and automatic processing of annotations and
image markups [3].
In research cumulative image processing chains including cutting-edge
algorithms that are creating a vast number of information which is not
necessarily annotation or markup like. Therefore, we show a system that
comprises a generic and extensible information model to store arbitrary
semantic connections, adaptive by using Bayesian inference machine.
The proposed and in software implemented system presents in combination with medical image processing platforms and applied in three
research oriented software systems (e.g. differentiation of progressive
disease and pseudo progression of brain tumors), a contemporary, robust
environment for data storage, suspending current processes, and enhancing knowledge by triple tagging [4,5], Bayesian networks [6], and thus
probabilistic inference.
ID 226
Patient participation in multidisciplinary tumor
conferences in breast cancer care
L. Ansmann1, N. Ernstmann1, C. Kowalski1, R. Würstlein2,
M. Wirtz3, H. Pfaff1
Institut für Medizinsoziologie, Versorgungsforschung und Rehabilitationswissenschaft (IMVR) der Universität zu Köln, Köln, Deutschland
2
Klinikum der Universität München, Brustzentrum LMU, München,
Deutschland
3
Pädagogische Hochschule Freiburg, Institut für Psychologie, Freiburg,
Deutschland
1
82
Background: According to the Medical Association of Westphalia-Lippe, in breast cancer centers 95% of the patients should be discussed
in postoperative multidisciplinary tumor conferences (MTCs). By request
patients can take part in the MTC. There is evidence that MTCs improve
patient management and survival (Croke et al. 2012). So far, very few
studies investigate patient participation in MTCs (Choy et al. 2007). Our
study identifies which breast cancer patients are offered to take part in
MTCs and make use of the offer.
Methods: Survey data from 3856 patients in 86 breast cancer center hospitals in North Rhine-Westphalia from 2010 are analyzed. In regression
and multilevel models we analyze whether the offer to participate and the
actual participation in the MTC differs by patient characteristics.
Results: 14% of the patients were offered to participate. 58% of those
took part in the MTC. Patients with advanced staging and older age were
less frequently invited to take part. Patients treated with neoadjuvant
chemotherapy and with higher grading participated in the MTC more
frequently. Patients with mastectomy participated less frequently. Moreover, being offered to participate in the MTC is to 28% dependent on the
hospital. In addition, patients in MTCs reported higher involvement in
decision making.
Conclusion: The offer to participate in MTCs differs by the patient’s disease stage and age. Actual participation is more likely for patients with
complex disease status, since the presence and preferences of the patients
may help to make difficult decisions. Moreover, the results suggest that
patients in MTCs feel more involved in decision making. Further research
should focus on the benefits and feasibility of patient participation in
MTCs.
ID 259
Single Center Register (SCR) ‘Indolent hematological
malignancies’: Structure – results – perspectives
D. Kämpfe1, F. Killing2, W. Padur3
Praxis für Hämatologie und Onkologie, Lüdenscheid, Deutschland
Ärztenetz MK Süd, Lüdenscheid, Deutschland
3
Bürgeramt, Lüdenscheid, Deutschland
1
2
Issue: Public Health Researches are an expanding contemporary movement, which require innovative tools and methods. Our SCR gives a proposal.
Methods: Since July 2003 all patients with ensured indolent hematological malignancies ( lymphomas incl. CLL, cMPN incl. CML, MDS,
monoclonal gammopathies (mG) have been listed concerning all relevant
personal, clinical, paraclinical and therapeutical informations. Diagnoses
are enhedged by cooperation of hematologist, hematopathologist and other specialists corresponding to standard definitions (WHO, ELN). Data
are ascertained immediately and repeatedly at time of consultation assisted by IT. In cases of loss outcome data are completed by asking general
practitioners and Citizens Registration Office. Observation period is preplaned until 2023.
Results: Until July 2013 SCR includes (number of patients): CLL (233),
other indolent lymphomas (134), cMPN / CML (222), MDS (89) and mG
(397). Age and gender ratios, symptoms at time of referral, attendant diseases or seldom constellations are demonstrated exemplarily in CLL here
. Furthermore we can calculate prevalences of CLL and cMPN because
incidence of CLL corresponds with that of Northern Germany and is
similar to that of cMPN.
Conclusions: SCR’s bridge the gap between epidemiological registers
(widely unselected but data-restricted) and multicenter studies / registers
(medical datas more detailed but prospective selected patients). If unselected and carefully documented SCR’s may reflecte real life in diagnoses
and situations, which are seldom represented in universities and clinical
studies and help to estimate incidences and prevalences.
Abstracts
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Index
ID 267
The eHealth service CANKADO to overcome nonadherence during oral self-medication
T. Schinköthe1, N. Harbeck1,2, R. Würstlein1,2
1
2
Klinikum der Universität München, Brustzentrum, München, Deutschland
Klinikum der Universität München, CCC of LMU, München, Deutschland
25% of the cancer drugs, which are currently under development, are
intended for oral self-medication. This refers to the wishes of cancer patients, 54–89% of which prefer oral medication. However, the change
from intravenous administration to oral self-medication leads to a loss of
control of the physician in charge while the patient’s individual responsibility increases dramatically. A lack of therapy adherence is the main
problem. Depending on the tumor disease and therapy, up to 84% of all
patients are not adequately adherent.
CANKADO has been designed to support cancer patients during oral
self-medication. It’s intended to increase communication between stakeholders with a multi-channel-communication concept and based on findings of cognitive behavioral therapy. Adherence is supported via a gamification strategy. CANKADO’s approach focuses on those reasons that are
related to the patient or therapy itself. The system expands the range of care
services of the physician and provides the opportunity to interact apart from
personal meetings. In addition CANKADO offers the patients, physicians
and their assistants various support measures with separate accesses.
CANKADO‘s gamification concept is based on the principles of cognitive
behavioral therapy. CANKADO is meant to lead the patient from a lack
of adherence to adherence by using both the conventional elements of
cognitive behavioral therapy and playful elements. CANKADO provides
patient care by means of a combined system of computer application and
therapists where the physician in charge takes on the role of the therapist.
Taken together, CANKADO provides a complete new approach to overcome non-adherence, based on eHealth. CANKADO is a non-profit service.
ID 318
Evalution of vaccination status and knowledge of
vaccination prevention and infectious risk after
splenectomy
C. Lotze, B. Erdmann-Reusch
Klinik Bavaria, Kreischa, Deutschland
Introduction: Vaccination and education are recommended in published
guidelines for the prevention of infectious complications after splenectomy. These patients have a lifelong risk of post-splenectomy sepsis with
mortality ratesfrom 50–70%.
Methods: We examined the status of vaccinationand the knowledge on
vaccination prevention, infectious risks and health precautions of consecutive 116 splenectomy-patients in the rehabilitation clinic with a questionnaire since 2010. This is an actually update our study.
Results: Indications for splenectomy of the 116 patients in this analysis
included cancer surgery (76), haematological (11), post-trauma (15) and
other (14). The interview was performed for 62 patients within 3 months,
for 31 within 4 to 24 months and for 23 more than 24 months after the
splenectomy. To time of interview 45 patients (38.8%) were without
vaccinations. 64 patients (55.1%) received pneumococcal vaccine, 20
patients (17.2%) the haemophilus vaccine and 21 patients (18.1%) the
meningococcal vaccine. One of the patients received an antibiotic prophylaxis after splenectomy. 54 patients (46.5%) had knowledge of necessity of vaccination. 47 patients (40.5%) didn’t know about necessity
of vaccination. 61.2% of 116 patients didn’t know about infectious risk.
18.1% of 116 patients reported about minimal information about infectious risk and 16.4% were identified as having adequate knowledge about
infectious risk.
Conclusions: The patient awareness of infectious risk after splenectomy
and the vaccination prevention have to be substantially improved. Repetitively educational information through different healt professionals
is necessary.
Abstracts
ID 438
Reimbursement of special medical oncology outpatient
care. Cost accounting of transsectorally clinical pathways
as a model for a new fee system
I. Fackler-Schwalbe, E. Spaeth-Schwalbe
Medizinberatung Fackler-Schwalbe, Passau, Deutschland
Introduction: Special medical outpatient care was introduced in January
2012 in § 116 b SGB V, an amendment to the care structure law. Its focus
is on severe progressive forms of oncological diseases. Reimbursement is
made provisionally by EBM. In the mid- to long-term, a new medical fee
schedule is to be developed.
Methods: Following from the example of palliative colorectal cancer
treatment, transsectorally integrated clinical pathways will be developed.
Then, with the help of path cost accounting, together with marginal costing, they will be evaluated based on the cost of the care provided. Results
will be compared with the billing methods of the health insurance companies in accordance with EBM. Alternatively, profits may be calculated
based on the payment agreement for outpatient care laid down in § 116 b.
Results: Clinical pathways for outpatient therapy in oncology define process-oriented, standardized procedures; they demonstrate how time-consuming and staff-intensive care for cancer patients is, and they form the
basis for performance-based pay for special medical oncology outpatient
care using path cost accounting.
Conclusions: Cost accounting of transsectoral clinical pathways could
be a model for a new fee system of reimbursement in special medical
oncology outpatient care and thus serve as a basis for diagosis-related
groups (DRGs).
ID 459
Standard Operating Procedures help to implement
national guidelines by incorporating center specific
assets
B. Starbatty1, J.-P. Glossmann1, B. Funke2, M. Hallek1, J. Wolf1
Deutschland
2
Deutschland
1
Background: S3 guidelines are regarded as the standard in oncology
treatment. However, a 100% guideline adherence is not achieved and
might never be achieved due to various reasons. One reason might be the
lack of center specific infrastructure and clinical trial.
Methods: At our center – the Center for Integrated Oncology Köln Bonn
(CIO) – we use Standard Operating Procedures published in a web based
portal. These electronic documents are based on current national guidelines – including S3-guidelines when applicable – and are blended with
center-specific information. The SOPs are one main product of the work
of a group of specialists, the Interdisciplinary Oncological Project groups
(IOP).
Results: In the past years we have published a total of 23 SOPs while 6
additional SOPs are in preparation. The SOP-software’s strength is the
visualization and publication of processes. The CIO-specific information
includes:
– Links to our active clinical trials with inclusion and exclusion criteria
– Directions when to involve early intervention palliative care differentiated by tumor entity and stage
– An algorithm for identifying patients with need for psycho-oncological
services
– Directions when to present a patient at one of the numerous tumorboards.
Conclusion: We have successfully combined national guidelines with
local strengths. Furthermore, SOPs are available for some cancers where
national guidelines are still not available.
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Leukemia, Myelodysplasia, and Transplantation
ID 029
Multiple chloromas in a patient with acute myeloid
leukaemia: An interdisciplinary approach
U. Vehling-Kaiser1, T. Sternfeld2, L. Rieger3, P. Rexrodt4
Onkologisches und Palliativmedizinisches Netzwerk Landshut, Landshut,
Deutschland
2
Praxis für Innere Medizin, Landshut, Deutschland
3
Krankenhaus Landshut-Achdorf, Frauenklinik, Landshut, Deutschland
4
Radiologie Mühleninsel, Strahlentherapie, Landshut, Deutschland
1
We report the case of a 75 year old female patient who was diagnosed
10/2011 with MDS-related acute myeloid leukaemia. The patients
showed a good remission under the initial treatment with 5-azacytidine.
In 08/2012 the patient complaint about lower back pains when she was
walking. The MRT-scan showed multiple chloromas near the lumbar
spine and a menigeosis leukaemica was diagnosed. The local radiotherapy for the chloromas was effective and 5-azacytidine was continued. In
03/2013 patient’s sight was severely affected due to the development of
retrobulbar chloromas. Radiotherapy was successful again and 5-azacytidine continued to show a good remission in peripheral blood. In 05/2013
symptomatic chloromas developed in the bladder, vagina and both labia.
Chemotherapy was changed to 6-mercaptopurine and radiotherapy was
started again. Due the progressive disease the patient passed away on the
palliative ward 06/2013. The patient survived for about 20 months after
the diagnosis of acute leukaemia. Due to the interdisciplinary treatment of
the symptomatic chloromas the quality of life was relatively good allowing the patient to stay at home for most of the time.
ID 188
Follow-up of the non-interventional TARGET study
– efficacy and safety of nilotinib in routine clinical
management of CML patients (pts) failing prior therapy
F. Stegelmann1, J. Dengler2, P. Le Coutre3, M.C. Müller4,
A. Sauer5, U. Schwinger6, C. Losem7, W. Schneider-Kappus8,
S. Stern9, U. Vehling-Kaiser10, M. Meincke11, O. Frank12,
O.G. Ottmann13
Universitätklinikum, Klinik für Innere Medizin III, Ulm, Deutschland
Onkologische Schwerpunktpraxis, Heilbronn, Deutschland
3
Charité, Campus Virchow Klinikum, Berlin, Deutschland
4
Universitätsklinikum, III. Medizinische Klinik, Mannheim, Deutschland
5
MVZ für Blut- und Krebserkrankungen, Potsdam, Deutschland
6
Gemeinschaftspraxis, Stuttgart, Deutschland
7
Facharztzentrum, Neuss, Deutschland
8
Praxis für Hämatologie und Onkologie, Ulm, Deutschland
9
Praxisklinik für integrative Onkologie, Altötting, Deutschland
10
Tagesklinik, Landshut, Deutschland
11
Novartis Pharma GmbH, Onkologie, Altenholz, Deutschland
12
Novartis Pharma GmbH, Onkologie, Nürnberg, Deutschland
13
Universitätsklinikum, Medizinische Klinik II, Frankfurt, Deutschland
1
2
Introduction: Nilotinib is approved for the treatment of Ph+ CML patients in CP and AP with failure of prior therapy including imatinib (IM)
as well as for de novo Ph+ CML in CP.
Methods: Follow-up analysis of an observational study of nilotinib in 323
pts with Ph+ CML resistant to or intolerant of prior treatment within routine clinical management in 106 centres in Germany (01/2008-03/2013).
Results: 61.3% of the pts were older than 60 yrs and predominantly in
CP (99.1%). 96.3% of all pts were pretreated with IM (any dose). Further
medical pretreatment were chemotherapy (28.8%), IFN (21.4%), dasatinib (18.6%) and other unspecified drugs (13%). Treatment with nilotinib
was mostly due to resistance/intolerance against IM (47.4%/44.3%). Initial nilotinib dose was 800 mg/d in 64.1%. Nearly half of the pts were
treated in 2nd line. At study entry remission status was 61.6% in CHR,
22.9% in CCyR (missing data in 22.6%), 27.9%/8.4% in MMR/CMR.
These responses improved significantly under nilotinib reaching cumula-
84
tive incidences of CHR, MMR and CMR of 90.1%, 54.2% and 32.2%, respectively. Dose reduction/therapy interruption occurred in 26.6%/15.2%.
72.1% experienced at least one AE which was considered serious in
18.6%. Hematologic toxicity was observed in 15.2%, non-hematologic
toxicities occurred in 39.9% of pts. The most frequently reported AEs
were pruritus (12.1%), alopecia (7.4%) and rash (10.5%), fatigue (9.6%),
arthralgia (5.6%), dyspnoea (5.6%), nausea (6.5%) and upper abdominal
pain (5.3%) as well as headache (11.5%).
Conclusions: These data support the use of nilotinib as an efficacious
and safe drug for treatment of a broad population of CML pts with poor
response or intolerance to a prior therapy including IM.
ID 191
Interim analysis of the non-interventional MOMENT II
study – efficacy and safety of Nilotinib in routine clinical
management of newly diagnosed Ph+ CML patients in
chronic phase
A. Sauer1, B. Lathan2, K. Blumenstengel3, T. Gabrysiak4,
S. Tebbe5, M. Meincke6, O. Frank7, H. Tesch8
MVZ für Blut- und Krebserkrankungen, Potsdam, Deutschland
Gemeinschaftspraxis für Hämatologie & Onkologie, Dortmund, Deutschland
3
Gemeinschaftspraxis für Hämatologie & Onkologie, Eisenach, Deutschland
4
Onkologische Schwerpunktpraxis, Wolfsburg, Deutschland
5
Onkologische Praxis, Kassel, Deutschland
6
Novartis Pharma GmbH, Onkologie, Altenholz, Deutschland
7
Novartis Pharma GmbH, Onkologie, Nürnberg, Deutschland
8
Hämatologisch-Onkologische Gemeinschaftspraxis, Frankfurt am Main,
Deutschland
1
2
Introduction: As a potent and highly selective BCR-ABL inhibitor Nilotinib (NI) is approved for treatment of newly diagnosed Ph+ CML pts
in CP as well as for pts with Ph+ CML in CP and AP with failure to prior
therapy including imatinib.
Methods: Exploratory interim analysis of a non-interventional study of
NI in 85 pts with de novo Ph+ CML in CP within routine clinical management in 53 centres in Germany (08/2011–03/2013).
Results: All patients were newly diagnosed with a median age of 55 years
(range 20–89) and 58% were male. The median observation period was
175 days (range 7–537) with a median daily dose of 600 mg NI (range
300–800 mg). There were 9.4% of pts with one, 2.4% with more than
one interruption of therapy with a median of 13 days for the duration of
each interruption (range 2–34). At last visit 79.5% (of 73 pts with a hematologic examination) had a CHR, 86.7% (of 15 pts with a cytogenetic
examination) had a CCyR, 48.4% (of 51 pts with a molecular examination) had an MMR. In the subgroup of patients with molecular response
(n = 33) the median time to MMR or better was 168 days (range 60–393).
A premature study discontinuation took place in 11.8% of pts mostly due
to AEs/non-hematologic toxicity, in one case due to disease progression.
Altogether, 68.2% of pts experienced AEs. Hematologic toxicity was observed in 8.2% of pts, non-hematologic toxicities in 31.8% of pts. The
most frequently reported AEs were skin reactions, gastrointestinal symptoms (nausea 4.7%), dyspnoea (4.7%) as well as headache (4.7%). The
most frequent biochemical abnormalities were increases in blood bilirubin (8.2%), GGT (7.1%) and lipase (4.7%).
Conclusions: These data from routine clinical management support the
use of NI as an effective and safe drug for treatment of newly diagnosed
Ph+ CML pts in CP.
Abstracts
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ID 219
Screening supported by a central review allows a precise
selection of the population for maintenance therapy
within the CLLM1 trial of the German CLL Study Group
A. Westermann1, A. Fink1, A. Zey1, J.S. Wesselmann1, R. Busch2,
K. Fischer1, C. Wendtner3, K.-A. Kreuzer4, S. Stilgenbauer5,
S. Böttcher6, B. Eichhorst4, M. Hallek4
Deutsche CLL Studiengruppe, Uniklinik Köln. Innere Med. I, Köln,
Deutschland
2
Technische Universität München, Institut für Medizinische Statistik und
Epidemiologie, München, Deutschland
3
Krankenhaus München-Schwabing, Abt. Hämatologie/Onkologie, München, Deutschland
4
Uniklinik Köln, Med. I, Köln, Deutschland
5
Uniklinik Ulm, Innere Med. III, Ulm, Deutschland
6
Universitätsklinikum Schleswig-Holstein Campus Kiel, Med. II, Kiel,
Deutschland
1
Introduction: CLLM1 is a phase 3, randomized, placebo-controlled
study of the efficacy and safety of lenalidomide as maintenance therapy
for patients (pts) with chronic lymphocytic leukemia (CLL) following
firstline therapy. Physically fit pts with a high risk for early relapse as defined by the presence of minimal residual disease (MRD) levels of ≥10-2
or a combination of MRD levels of ≥10-4 to <10-2 with either an unmutated IGHV-status or TP53 aberrations are eligible. These high risk pts are
known to have not only a median progression free survival of less than 2
years but also a considerably shorter overall survival.
Methods: Screening procedures are implemented prior to randomization.
The central review covers the assessment of risk factors and a check of at
least 15 relevant inclusion/ exclusion criteria; in particular pts’ comorbidities, ECOG performance status, stage of disease and response to firstline
therapy. In addition blood samples are to be sent to the central laboratories for confirmation of CLL and to assess cytogenetic aberrations. After
firstline therapy MRD is analyzed centrally. A total of 200 Pts will be
randomized.
Results: Between July 2012 and September 2013 287 pts were registered.
63 (22%) failed to proceed to screening due to other B-cell lymphoma
(10/3.5%), pts’ decision (21/7.3%) and other reasons (32/11.1%). Non
response or death before randomization was observed with both 2/0.7%.
84 pts were screened after responding to therapy with FCR (49/ 58%), BR
(34/ 40%) or FC (1/1.1%). As expected 60 (71%) of them achieved MRD
negativity. 17 pts were randomized to receive study drug.
Conclusion: The Screening process supports the identification of eligible
high risk pts and prevents the inclusion of not eligible subjects.
ID 220
Establishment of a human 3D blood vessel model for
testing therapeutic agents such as tipifarnib in AML
H. Bersi, S. Nietzer, G. Dandekar, H. Walles
University Hospital Würzburg, Chair of Tissue Engineering and Regenerative Medicine, Würzburg, Deutschland
Amongst all types of leukemia, acute myeloid leukemia (AML) has the
worst prognosis. Even today, only 34% of under 60-year-old and 15% of
over 60-year-old patients show a long-lasting remission 4–5 years after
treatment (dgho aml guidelines 2013). Since there is a lack of sufficient
preclinical drug test systems correlating with clinical studies (Kola et al.
2004), our aim was to establish a more efficient preclinical three-dimensional (3D) blood vessel model to test anti-leukemic drugs. The 3D model
consists of human leukemia cells (non-adherent THP-1 cells, AML M5)
and human primary endothelial cells that grow as a monolayer on a decellularized intestinal scaffold. By using this model system, it is possible
to analyze the interaction of malignant cells and endothelial cells in a
more natural environment than in conventional cell culture. Moreover,
the influence of tested drugs on the endothelium can be investigated and
damaging effects can be monitored in our 3D model.
Abstracts
In our setting, we tested the efficacy of tipifarnib, a competitive farnesyltransferase inhibitor. Farnesyltransferase catalyzes prenylation of many
proteins involved in cell proliferation and survival (Weinberg 2013).
Tipifarnib shows anti-leukemic, dose-dependent effects on THP-1 in our
3D model. Increased induction of apoptosis in malignant THP-1 was observed by FACS analysis and potential damaging effects on endothelial
cells were assessed by immunhistological stainings. Based on our results,
it can be shown that our 3D model is a promising tool to investigate the
interactions of the therapeutic agent and malignant cells as well as its
influence on vasculature.
ID 500
Long Term Remissions After FCR Chemoimmunotherapy
In Patients With CLL
K. Fischer1, J. Bahlo1, A.-M. Fink1, R. Busch2, S. Boettcher6,
C. Maurer1, J. Mayer7, P. Dreger5, M. Kneba6, H. Döhner4,
C.-M. Wendtner3, S. Stilgenbauer4, M. Hallek1, B. Eichhorst1,
K.-A. Kreuzer1
Department I of Internal Medicine and Center of Integrated Oncology
Cologne-Bonn, University of Cologne, Cologne, Germany
2
Technical University, Institute for Medical Statistic and Epidemiology,
Munich, Germany
3
Department of Hematology, Oncology, Immunology, Palliative Care,
Infectious diseases and Tropical Medicine, Klinikum Schwabing, Munich,
Germany
4
Department III of Internal Medicine, University Hospital Ulm, Ulm,
Germany
5
Department V of Internal Medicine, University Hospital Heidelberg,
Heidelberg, Germany
6
Department II of Internal Medicine, University Hospital Schleswig-
Holstein, Kiel, Germany
7
Department of Hematology-Oncology, University Hospital Brno, Brno,
Czech Republic
1
Background: Chemoimmunotherapy with Fludarabine, cyclophosphamide (FC) and rituximab (R) is the standard therapy for physically fit
patients with previously untreated CLL (M Hallek, Lancet 2010). In this
report, we present data on long term safety and long term remissions after
FCR with particular emphasis on IGHVmutated patients.
Methods: In this prospective, randomized, open-label phase-III trial, 817
treatment-naïve patients with good physical fitness and CD20-positive
CLL received six courses of either FCR or FC. The primary endpoint was
progression-free survival (PFS). Secondary endpoints were response to
treatment, overall survival (OS), safety and survival times in biological
subgroups.
Results: At median follow-up of 5.9 years, median PFS was 57 and 33
months for the FCR and FC group (hazard ratio (HR), 0.6 (95% confidence interval (CI), 0.5–0.7), p < 0.001). Median OS was not reached
for the FCR group and 86 months for the FC group (HR, 0.7 (95% CI,
0.5–0.9), p = 0.001). In IGHVmutated patients, FCR increased PFS and OS
compared to FC (PFS HR, 0.5 (95% CI, 0.3–0.7), p < 0.001; OS HR 0.6
(95% CI, 0.3–1.1), p = 0.1, respectively, figure 1A, 1B) for all cytogenetic
subgroups except for deletion 17p. FCR induced an increase in prolonged
neutropenia during the first year after the end of treatment (16.6% versus
8.8% (p = 0.007)). Secondary malignancies including Richter`s transformation occurred in 13% in the FCR group and in 17% in the FC group
(p = 0.1).
Conclusions: FCR induced long term remissions in physically fit IGHV
mutated patients. This observation is clinically relevant with respect to
novel, targeted agents for CLL therapy that are currently being investigated and which not only have to show better tolerability and overall
response rates, but also similar long term efficacy.
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28%). Of note, overall 64% of the patients (carbo/vrb: 71%, cis/vrb: 44%)
completed combination therapy with the planned number of cycles.
Conclusions: The results of this retrospective study are in line with clinical trials of cis in combination with intravenous vrb and show that adjuvant chemotherapy of a platinum-based combination therapy with oral
vrb is effective. Carbo was better tolerated than cis resulting in superior
treatment compliance and comparable effectiveness.
Lung Cancer – Local-Regional Therapy
ID 203
Gut differenzierte Neuroendokrine Karzinome der Lunge
Figure 1A. Progression-free survival (PFS) in IGHV mutated/unmutated patients
(N = 622)
Figure 1B. Overall survival (OS) in IGHV mutated/unmutated patients (N = 622
Lung Cancer – Adjuvant Therapy
ID 116
Adjuvant treatment of completely resected stage IB-IIIA
non-small-cell lung cancer. A retrospective study with
cisplatin or carboplatin and oral vinorelbin
M. Serke
Lungenklinik Hemer, Pneumologie, Hemer, Deutschland
Es werden Patienten mit gut differenzierten intrathorakalen neuroendokrinen Tumoren (pulmonale Karzinoide) gezeigt. Beobachtet wurden
die Patienten in einer großen Lungenklinik., Beobachtungszeitraum vom
01.09.2008 bis 31.07.2013.
Material und Methode: In der Lungenklinik Hemer wurden gemäß Tumordokumentation 3485 Patienten mit gesichertem Lungenkarzinom behandelt. Hierunter fanden sich 90 Karzinoide. Alle Diagnosen wurden in der
Lungenklinik gestellt und alle Patienten waren unbehandelt. Zur Diagnostik
der neuroendokrinen Differenzierung wurden morphologische und histologische Kriterien angewandt. Die Betreuung erfolgte durch das Zentrum.
Ergebnisse: Karzinoide: 73 (81%) typische Karzinoide und 17 atypische
Karzinoide (19%), 64% der Pat. waren weiblich.
Typisches Karzinoid (TK): Wir beobachteten 73 Patienten mit typischem Karzinoid, mittl. Alter 64 Jahre, atypisches Karzinoid: mittleres
Alter: 60 Jahre, Die Patienten mit atypischem Karzinoid (N =17) waren
überwiegen weiblich (13 von 17) .
Therapie: Die meisten Patienten wurden operiert, bei 3 Pat. erfolgte bei
eingeschränkten funktionellen Reserven lediglich eine bronchoskopische
Tumorabtragung. Das Überleben war günstig: med. ÜL beim TC 1890
Tage, beim AC 1670 Tage.
Diskussion: Intrathorakale gut differenzierte Neuroendokrine Karzinome, Karzinoide gehören zu der Minderheit der prognostisch günstigen
intrapulmonalen Neubildungen. Das klinische Bild, Therapieverfahren
und Ergebnisse an 90 Patienten werden beschrieben.
ID 257
W. Engel-Riedel, F. Magnet, N. Alten, C. Ludwig, A. Bachinger,
E. Stoelben
CyberKnife Radiosurgery for lung tumors: Report of
clinical response and toxicity
Kliniken der Stadt Köln, Lungenklinik, Köln, Deutschland
S. Temming1, E. Stoelben2, R. Semrau1, M. Kocher1
Background: Adjuvant chemotherapy is implied for early stage NSCLC
after R0-resection. Most evidence-based data exist for combination of
cisplatin (cis) and vinorelbine (vrb). To analyze effectiveness and tolerability of platinum-based combination therapy with predominantly oral
vrb (Navelbine© Oral) we performed a retrospective study in our hospital.
Material and Methods: Data from 152 patients with R0-resected NSCLC (stage IB-IIIA) receiving adjuvant chemotherapy with cis or carbo
in combination with vrb between 03/2005 and 11/2011 were retrospectively analyzed. The primary endpoint was overall survival (OS), secondary endpoints progression-free survival (PFS) and toxicity.
Results: Patients were diagnosed with stage IB (35%), IIA (5%), IIB (38%)
or IIIA (22%) NSCLC. Vrb was predominantly administered orally (89%)
and most patients received carbo (74%).The estimated 5-year survival was
64% (cis/vrb: 65%, carbo/vrb: 64%) and PFS after five years was 60% (cis/
vrb: 63%, carbo/vrb: 59%). Toxicities mainly concerned the hematologic
system with 70% leukopenia (carbo/vrb: 74%), 32% thrombocytopenia
(carbo/vrb: 40%) 40% anemia, 28% neutropenia. The treatment caused
nausea and vomiting in 47% and 23% of the patients (cis/vrb: 59% and
1
86
2
Uniklinik Köln, Strahlentherapie, Köln, Deutschland
Köln Merheim Lungenklinik, Thoraxchirurgie, Köln, Deutschland
Objective: To report clinical efficacy and toxicity of fractionated CyberKnife radiosurgery for the treatment of inoperable lung tumors.
Methods: Between April 2012 and September 2013, 51 patients with
inoperable NSCLC Stadium I underwent CyberKnife radiosurgery. All
were highrisk patients and inoperable because of medical illness through
previous surgeries with lungfunction disorder, COPD, cardiovascular disease and age. The age range 55 to 87 years, with a median of 75 years. For
Tumor tracking during radiation we placed gold fiducials in 10 patients
or used the digital radiographic images of the tumor itself (X-sight Lung
Tracking System). The dose was delivered in 60 Gy (65–80% Isodose) in
3–8 fraction relative to size and the position of the tumor. 15 patients were
treated with 3× 20 Gy, 5 patients 3× 17 Gy (Monte-Carlo Algorithm), 18
patients 5× 12 Gy and 5 patients 8× 7.5 Gy. 5 patients were treated with
1× 25 Gy. Clinical, pulmonary and radiological evaluation was made after
six weeks, 3, 6, and 9 Month post CyberKnife radiosurgery.
Results: The overall survival after CyberKnife radiosurgery was 100%.
No patient relapsed locally. All tumors decreased in size or disappeared
Abstracts
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Index
after treatment. However regional recurrence or distant metastases occurred in 8 patients, from them 5 in lymphnodes, 2 in adrenal glands
and one in the contralateral lung. Acute toxicity like dyspnea, chestpain
were observed in 5 patients. Late toxicity like pneumonitis, esophageal or
bronchus fistula were not observed.
Conclusion: CyberKnife radiosurgery for Stage I NSCLC patients who
are medically inoperable because of COPD, cardiovascular disease and
age results in a favorable local control rate, quality of live with a low
incidence of toxicity.
Lung Cancer – Metastatic Lung Cancer
ID 022
Molecular screening in 915 lung cancer patients.
Monocentric results within the German Netzwerk
Genomische Medizin (NGM)
M. Serke, J. Wolf, R. Buettner, M. Bos, L. Heukamp, M. Gardizi
Lungenklinik Hemer, Pneumologie, Hemer, Deutschland
Material and Methods: Within the German Lung Cancer Genome screening project «Netzwerk Genomische Medizin (NGM)» Köln we analyzed
the test results of 915 lung cancer patients of our chest hospital in NRW/
Hemer. Tumor material of all available lung cancer patients was analyzed.
Results: 915 patients (pat.) of all tumour stages were analysed. Histology: 493 pat. (54%) with adenocarcinoma (AD), 250 pat. (27%) with
squamous-cell carcinoma (SQ), 54 pat. (6% ) NOS (non other specified),
73 pat. (8%) with small-cell lung cancer (SCLC), 27 pat. (3 %) with largecell carcinoma (LC), 18 pat. (2%) with other histologies.
Genomic Alterations: within all patients with non-small call lung cancer
(842 pat.) we identified 275 pat. (32.7%) with molecular alterations. In
the group of patients with non-SQ lung cancer we found molecular alterations in 233 pat. (49 = 8.3% EGFR-mutations, 10 =1.7% EML4/ALK
translocations, 13 (=1.7%) B-RAF mutations, 111 (=18.8%) K-RAS-mutations and others. Within the 249 pat. with SQ carcinoma 16% were FGFR1-positiv, within the SCLC patients 8% were FGFR1-positiv.
Discussion: A genome-based diagnosis of lung cancer within our large
screening project is feasable. In 10% of our patients with non-squamous
NSCLC treatable genomic changes may be recognized. We also identified
genetic changes in SQ-cell and SCLC lung cancer. The broad introduction
of such diagnostics will allow specific genomic driven therapeutic interventions with an improved survival of these patients.
(27%) with an UICC III, 172 (9%) UICC II and 141 (7%) UICC I. In 95
(5%) patients the stage was not determinable.
Results: A statistically significant change of relative 5-year survival rate
(5ysr) within the observation period cannot be determined. The 5ysr of
all registered patients is 18.5% (SE = 1.5). The average survival of all
patients is influenced by the high portion of late-diagnosed diseases with
already existing distant metastases. Primary metastatic patients show a
5ysr of 7.1% (SE = 1.5). The survival rate of patients with an UICC I-III
is 29.9% (SE = 2.5).
In case of a local finding, the survival rate increases to 48.3% (SE=5.3). If
regional lymph nodes are involved, the 5ysr decreases to 25.8% (SE=3.1).
Metastatic patients with an adenocarcinoma show a 5ysr of 7.8%
(SE=1.8). Whereas patients with a squamous-cell carcinoma show a survival rate of 3.7% (SE=2.7).
Conclusion: The analyzed registry data shows correlating survival times
of patients the ambulatory oncological care compared to literature data.
ID 102
A multi-center phase II study investigating the
combination of RAD001 (everolimus) with paclitaxel
and carboplatin in first line treatment of patients with
advanced Large Cell Lung Cancer with Neuroendocrine
Differentiation (LCNEC) – a case report
C. Schumann1, W. Engel-Riedel2, J. Kollmeier3, C. Grohé4,
J. von Pawel5, W. Eberhardt6, S. Gütz7, I. Nimmrich8, C. Weiß9,
M. Potzner9, M. Serke10, M. Thomas11
Universitätsklinikum Ulm, Klinik Innere Medizin II / Sektion Pneumologie,
Ulm, Deutschland
2
Kliniken der Stadt Köln, Lungenklinik Merheim, Köln, Deutschland
3
Helios Klinikum Emil von Behring, Klinik für Pneumologie, Berlin,
Deutschland
4
Evangelische Lungenklinik, Berlin, Deutschland
5
Asklepios Fachkliniken München Gauting, Gauting, Deutschland
6
Universitätsklinikum Essen, Westdeutsches Tumorzentrum, Essen,
Deutschland
7
Evangelisches Diakonissenkrankenhaus, Leipzig, Deutschland
8
Clinical Research i.A. Novartis Pharma GmbH, Berlin, Deutschland
9
Novartis Pharma GmbH, Nürnberg, Deutschland
10
Lungenklinik Hemer, Hemer, Deutschland
11
Universitätsklinik Heidelberg, Thoraxklinik, Heidelberg, Deutschland
1
Introduction: The non-small cell lung cancer (NSCLC) has its highest
mortality among men and is the third-most frequent cause of death among
women. Considering a medium relative 5-year survival rate of 15–18%
after the initial diagnosis, the prognosis is highly unfavorable. We will
demonstrate the reality of treatment in relation to the relative survival rate
in the period from 2003 to 2013.
Methods: The relative survival has been calculated applying periodical
analysis according to the method Ederer II.
At time of evaluation the registry contains 2,382 patients. Within the observation period a total of 1,985 patients with initial diagnosis has been
analyzed. 1,463 patients are male, 522 female. The registry contains
1,032 (52%) patients with primary metastatic NSCLC (UICC IV), 545
Introduction: Large cell neuroendocrine carcinoma of the lung (LCNEC) are rare. With current treatment options like platin derivates and/or
etoposide, patients have poor prognosis. Targeted therapies are discussed
as an approach to improve outcome of LCNEC. RAD001 (everolimus)
is an inhibitor of mTOR, a component of the PI3/AKT/mTOR pathway
known to be dysregulated in cancer, especially in neuroendocrine tumors
(NETs). RAD001 is approved for treatment of renal cell cancer, breast
cancer, and pancreatic NETs.
Methods: In the presented trial for advanced (stage IV) LCNEC patients,
daily RAD001 is combined with carboplatin and paclitaxel. Patients receive 4 cycles of combined treatment followed by RAD001 maintenance
therapy. The primary endpoint is the proportion of patients that are progression-free after 3 months. Main inclusion criteria are histologically
confirmed stage IV LCNEC, adequate bone marrow, renal, and liver
function. Main exclusion criteria are symptomatic CNS metastases, prior
treatment for advanced LCNEC, and any other severe medical condition.
Results: A case report of a 78-year old patient enrolled in this trial is
presented. The tumor revealed histologically NSCLC morphology of the
large-cell type and a clear CD56 staining as well as a proliferation rate of
more than 60% in Ki67 staining. The patient received 4 cycles of chemotherapy combined with RAD001 and subsequently RAD001 monotherapy for further 6 months. The tumor response was stable disease (SD) for
the first 3 months and partial response (PR) for the following 6 months.
Conclusions: These data show that a combined therapy of carboplatin
and paclitaxel with the mTOR inhibitor RAD001 might be a promising
approach for more efficient treatment of LCNEC patients.
Abstracts
ID 035
NSCLC-relative survival in the ambulatory oncological
care
H. Eschenburg1,2, S. Bartels3, H.-W. Tessen2,4
Onkologische Schwerpunktpraxis Güstrow, Güstrow, Deutschland
PIO (Projektgruppe Internistische Onkologie, Goslar, Deutschland
rgb Onkologisches Management GmbH, Sarstedt, Deutschland
4
Onkologische Schwerpunktpraxis Goslar, Goslar, Deutschland
1
2
3
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ID 108
ID 152
E. Celik, R. Semrau, S. Kunze, M. Kocher
D. Fecher, H. Walles, S. Nietzer, G. Dandekar
Uniklinik Köln, Strahlentherapie, Köln, Deutschland
Lehrstuhl für Tissue Engineering und Regenerative Medizin, Würzburg,
Deutschland
Cyberknife radiosurgery treatment for adrenal metastases
from lung cancer: A single-institution experience
Purpose: To present our initial institutional experience with robotic Cyberknife-based stereotactic radiotherapy in the treatment of adrenal gland
metastases in 5 consecutive lung cancer patients.
Methods and Materials: Between November 2012 and August 2013, 5 patients with solitary adrenal metastatic lesion received stereotactic body radiation therapy (SBRT). SBRT treatments were delivered with Cyberknife.
The median age of the patient population was 60.2 years (range, 47–82
years). In all of the patients, the prescription dose was 42 Gy in 7 fractions
(65% isodose, 6 Gy per fraction at the isocenter). All patients were clinically and radiologically evaluated with post-therapy clinical exams and
computed tomography. Response Evaluation Criteria in Solid Tumors (RECIST)-based tumor response was assessed to determine treatment outcome.
Results: At a median follow-up time of 6 months (range, 4–9 months) all
five patients were alive. Four of 5 lesions (80%) showed partial response
and one of 5 lesions (20%) progressed in the treated area. Overall, the
TMC rate at the first post-therapy exam after 4 months was 80%. Distant
control was 60%, and OS was 100%. No patient experienced grade 3
toxicity. The most common grade 1–2 acute toxicities were fatigue (60%)
and nausea (40%).
Conclusion: Hypofractionated robotic Cyberknife-based stereotactic radiotherapy in adrenal gland metastasis is a useful non-invasive treatment
option and feasible without significant acute toxicities, providing good
local control. Considering our experiences, these first results indicate that
radiotherapy in addition to systemic therapy may contribute to survival of
patients with adrenal metastases from lung cancer.
Establishment of a 3D Lung Tumor Model and Adjustment
to Lung Specific Conditions
Purpose: High mortality of lung cancer is often associated with tumor recurrences and distant metastases. One fundamental mechanism involved
in tumor cell invasion is the epithelial-to-mesenchymal transition (EMT).
To analyse this process, we generated a 3D lung tumor model.
Methods: A549 and HCC-827 cells were cultivated on decellularized
porcine small intestinal submucosa (SIS) segments and stimulated with
TGF-β1 at concentrations of 0.05, 0.5 and 5 ng/ml for 14 days. Immunohistology and real-time PCR were applied in order to find phenotypic
changes. The invasive potential was quantified by assessing the number
of single cells inside the SIS.
Results: Both cell types formed a cell layer on its apical side. While HCC827 exhibited a polarized expression of Mucin-1, E-cadherin and ß-catenin, A549 expressed these proteins diffusely. Stimulated with TGF-β1,
both cell types showed a concentration-dependent change in morphology,
gene expression and invasive behavior. While only 5–10% of single cells
were found inside the SIS under control conditions, treatment with 5 ng/
ml TGF-β1 led to an invasion of 35–50% of the cells. Additionally, the
expression of epithelial markers was lost, whereas the expression of mesenchymal markers was upregulated after TGF-β1 stimulation.
Conclusion: As a conclusion, our in vitro tumor model provides a polarised epithelial layer that exhibits upregulation of tumor relevant genes
and produces induction of EMT as well as invasion. It may help studying
these processes in greater detail and could be a tool for testing drug candidates targeting EMT and cell invasion.
ID 149
ID 204
Rationale for a generic targeted therapy multi‑drug
regimen for NSCLC stage IIIB/IV patients without
treatment options
Circulating tumor cell subgroups and outcome in patients
with non-small-cell-lung-cancer receiving platinum based
treatment
S. Langhammer
U. Jehn, I. Nel, M. Schuler, T. Gauler, A.-C. Hoffmann
life science consulting, Meerbusch, Deutschland
Deutschland
Despite more than 70 years of research concerning medication for cancer
treatment, the disease still remains one of the leading causes of mortality
worldwide. Many cancer types lead to death within a period of months to
years. The original class of chemotherapeutics is not selective for tumor
cells and often has limited efficacy, while treated patients suffer from adverse side‑effects. To date, the concept of tumor‑specific targeted therapy
drugs has not fulfilled its expectation to provide a key for a cure. Most
oncology trials are designed using a combination of chemotherapeutics
with targeted therapy drugs. However, these approaches have limited outcomes in most cancer indications.
Here a rationale to combine targeted therapy drugs for cancer treatment
based on observations of evolutionary principles of tumor development
and an HIV infection is presented. In both diseases, the mechanisms of
immune evasion and drug resistance can be compared to some extent.
However, only for HIV is a breakthrough treatment available, which is the
highly active antiretroviral therapy (HAART). The principles of HAART
and recent findings from cancer research were employed to construct a
hypothetical model for cancer treatment with a multi‑drug regimen of
targeted therapy drugs. As an example of this hypothesis, it is proposed
to combine already marketed targeted therapy drugs against VEGFRs,
EGFR, CXCR4 and COX2 in an oncology trial for NSCLC stage IIIB/IV
patients without further treatment options.
88
Backround: Circulating tumor cells (CTC) could serve as a ‘liquid biopsy’
for individualizing and monitoring treatment in patients with lung cancer
as recently shown by our group (Nel et al., Br J Cancer 2013). We assessed
which non-hematopoietic cell types are identifiable in the peripheral blood
of NSCLC patients and correlated those to clinical characteristics.
Methods: Mononuclear cells and CTC were isolated from peripheral venous blood of n = 45 patients with NSCLC receiving platinum-based therapy using density gradient centrifugation. Cell suspensions were spun onto
glass slides and further characterized by multi-immunofluorescence staining against cytokeratin (CK and EpCAM; epithelial), N-cadherin (mesenchymal); CD133 (stem-cell), CD45 (hematopoietic) and DAPI (nucleus).
Results: We detected cells with mesenchymal features such as N-cadherin+/CK-/CD45- and cells with epithelial properties like CK+/N-cadherin-/CD45-; CK+/EpCAM+/CD45- and cells with both characteristics like
CK+/N-cadherin+/CD45-. We also detected cells showing stem cell-like
features such as CD133+/CK-/CD45- and CD133+/CK+/CD45- cells.
Mann Whitney test revealed a significantly increased number of CD133+
cells in the presence of N-cadherin+ cells (p = 0.0004); Kaplan Meier test
indicated that the presence of N-cadherin+ cells was significantly associated to shortened PFS (5 vs. 9 months; p = 0.03; [HR]=2.63).
Conclusions: Our data suggest that different CTC populations are identifiable in peripheral blood and that these individual cell type profiles might
be used to predictoutcome to systemic therapies in lung cancer patients.
Abstracts
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ID 209
Final Results from REASON, a Registry for the
Epidemiologic and Scientific evaluation of EGFR
mutation status in newly diagnosed NSCLC patients
stage IIIB/IV in Germany
W. Schuette1, W. Eberhardt2, J.-M. Graf von der Schulenburg3,
M. Dietel4, P. Schirmacher5, S. Zaun6, U. Zirrgiebel7, M. Thomas8
Hospital Martha-Maria Halle-Dölau, Halle, Deutschland
University Hospital Essen, University Duisburg-Essen, Department of
Medical Oncology, Essen, Deutschland
3
Research Center Health-Economy, Leibnitz-University Hannover, Hannover, Deutschland
4
Pathological Institute Humboldt University Berlin, Berlin, Deutschland
5
Pathological Institute University Heidelberg, Heidelberg, Deutschland
6
AstraZeneca, Wedel, Deutschland
7
iOMEDICO AG, Freiburg, Deutschland
8
Internistische Onkologie der Thoraxtumoren, Thoraxklinik im Universitätsklinikum Heidelberg, Translational Lung Research Center Heidelberg
(TLRC-H), Member of the German Center for Lung Research (DZL),
1
2
Background: Somatic EGFR mutations (Mut) predict for sensitivity to
EGFR TKI in patients (pts) with advanced NSCLC. As most published
data originate from Asia, we aimed at generating data on EGFR Mut rates,
treatment and outcomes in Caucasians.
Methods: REASON is a non interventional study (NCT00997230) designed to collect data on EGFR Mut status, investigate association with
clinico-pathological features, treatment decisions and clinical outcome
for EGFR Mut+ pts with advanced NSCLC. Pts with planned EGFR Mut
testing were enrolled at 149 sites (85% hospitals). Primary objectives
were epidemiological data on EGFR Mut status and their correlation with
clinico-pathological features. As secondary aims, clinical outcome of pts
with EGFR Mut+ (PFS, OS), clinical management and pharmacoeconomic data will be evaluated for EGFR Mut+ pts.
Results: Of 4243 pts enrolled; 4200 are eligible. EGFR Muts were detected in 432 pts (Mut+ 10.3%); in 3593 pts (85.5%) no EGFR Mut was
found (Mut-); Mut status was not evaluable in 175 pts (4.2%). In multivariate analyses, the odds of Mut+ was higher in females vs males (OR,
SE: 1.85, 0.11), never smokers vs smokers (3.64, 0.11) and pts with adenocarcinoma (ADC) vs other histologies (2.94, 0.16). EGFR TKIs were
the most common 1st line treatment for EGFR Mut+ (57% vs 2% in Mut).
Platin doublets (79%) were the most common regimens in Mut- NSCLC.
Median PFS in Mut+ pts was 9.1 months (9.7 with TKI 1st line), OS 17.2
months. PFS was longer in women vs men, never smokers vs ever smokers, and ADC vs other histologies.
Conclusion: REASON provides the largest database on EGFR Mut in
Caucasians with newly diagnosed stage IIIB/IV NSCLC. Gender, smoking status and ADC histology were predictive factors for better PFS in
EGFR Mut+.
ID 233
Clinical activity of the ALK inhibitor LDK378 in advanced,
ALK-positive NSCLC
M. Thomas1, J. Wolf2, M. Schuler3, M. Goldwasser4, A. Boral4,
A.T. Shaw5
Thoracic Oncology Clinic for Thoracic Diseases, Department of Internal
Medicine, Heidelberg, Deutschland
2
Lung Cancer Group Cologne, Center for Integrated Oncology, University
Hospital Cologne, Cologne, Deutschland
3
West German Cancer Center, University Hospital Essen, Essen, Deutschland
4
Novartis Institutes for BioMedical Research, Inc, Cambridge, Vereinigte
Staaten Von Amerika
5
Massachusetts General Hospital Cancer Center, Boston, Vereinigte
Staaten Von Amerika
1
Methods: In this phase I study (NCT01283516), 130 pts with advanced
malignancies and a genetic alteration in ALK, including 122 with ALK-rearranged (ALK+) NSCLC (by FISH), were enrolled. LDK378 50-750 mg
was administered orally once daily (OD). All pts were assessed for PK,
response to therapy, and adverse events (AEs). In 19 CRZ-pretreated pts,
tumor biopsy was performed before LDK378 treatment to identify potential CRZ resistance mutations.
Results: As of October 19, 2012, 130 pts had been enrolled: 59 in dose escalation phase (where MTD of 750 mg OD was established); 71 pts in an
expanded cohort at the MTD. Among 114 NSCLC pts receiving LDK378
≥400 mg, the overall response rate (ORR) was 58% (95% CI, 48–67%).
In the subset of 79 CRZ-pretreated pts, the ORR was 57% (95% CI,
45–68%). Responses were observed in CRZ-pretreated pts with different
CRZ resistance mutations as well as in pts without detectable mutation
in the ALK gene other than the original rearrangement. Responses were
also seen in pts with untreated CNS metastases. Among NSCLC pts with
partial or complete response, median duration of response (DOR) was 8.2
months (95% CI, 6.9-NE), and 60.6% (95% CI, 34.9–78.8%) receiving
750 mg/day had a DOR of ≥6 months. In all 114 NSCLC pts, median PFS
was 8.6 months (95% CI, 5.7–9.9). The 3 most common AEs were nausea
(73%), diarrhea (72%), vomiting (58%). The most common Grade 3/4
AEs were ALT elevation (19%), AST elevation (10%), and diarrhea (8%).
Conclusions: These results suggest that potent ALK inhibition by
LDK378 represents a highly efficacious treatment strategy for ALK+ pts,
including those previously treated with CRZ.
ID 235
Validation of a three-dimensional human lung tumor test
system applied for the analysis of targeted treatment
effects on signaling pathway activation
C. Göttlich, D. Fecher, S. Nietzer, G. Dandekar, H. Walles
Universitätsklinikum Würzburg, Lehrstuhl für Tissue Engineering und
regenerative Medizin, Würzburg, Deutschland
Non small cell lung cancers (NSCLCs) are quite insensitive to chemotherapy. For this reason, it is very challenging to develop new therapies
different from common chemotherapy. In the present study, we introduced a three-dimensional (3D) human tumor model which was developed on the basis of a decellularised porcine jejunum using cell crowns to
fix the scaffold in 12-well plates. We used either a human cell line with an
activating epidermal growth factor receptor (EGFR) mutation (HCC827)
or EGFR wild-type cell lines (H441, A549) in order to simulate the approach of personalized medicine in the clinic where the mutation status
of the EGFR is tested prior to targeted therapy. To prove the robustness
of our models, we first tested the variance of five different cell crowns
of one trial and of three different trials. The variance of the tumor test
systems was low concerning cell number and overall morphology. Receptor tyrosine kinases (RTK) like EGFR play an important role in cancer
signaling pathways. To block EGFR activation, we treated the models
with the EGFR inhibitor gefitinib. RTK phosphorylation status was then
determined by using phosphor-RTK arrays (R&D) and results from 2D
and 3D cultures were compared. In 3D culture of HCC827 cells, not only
the EGFR but also hepatocyte growth factor receptor (HGFR) and ErbB2
were dephosphorylated after gefitinib treatment while in H441 and A549
cells, gefitinib treatment had no strong effect. This fits in with the clinic as
EGFR inhibitors have an effect only in patients with an EGFR mutation.
Thus our model is a promising tool to investigate the signaling pathways
involved here.
Background: LDK378 is a novel, more potent ALK TKI than crizotinib
(CRZ), with significant antitumor activity in preclinical models.
Abstracts
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ID 242
Safety profile of afatinib in first-line therapy of patients
with metastatic EGFR mutation-positive (M+) non-small
cell lung cancer (NSCLC): Comparative analysis of Asian
and non-Asian patients from two randomized trials
M. Schuler1, L.V. Sequist2, J.C. Yang 3, N. Yamamoto4,
K.J. O’Byrne5, T. Mok6, S.L. Geater 7, D. Massey8, S. Wind9,
D. O’Brien10, R. Lorence10, Y.-L. Wu11
University Hospital Essen, West German Cancer Center, Essen, Deutschland
2
Massachusetts General Hospital, Cancer Centre, Boston, Vereinigte
Staaten Von Amerika
3
National Taiwan University Hospital, Taipei, Taiwan
4
Shizuoka Cancer Center, Cancer Centre, Shizuoka, Japan
5
Princess Alexandra Hospital, Brisbane, Australien
6
The Chinese University of Hong Kong, Hong Kong, China
7
Prince of Songkla University, Songkla, Thailand
8
Boehringer Ingelheim Limited, Bracknell, Großbritannien
9
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Deutschland
10
Boehringer Ingelheim Pharmaceuticals, Ridgefield, Vereinigte Staaten
Von Amerika
11
Guangdong General Hospital, Guangzhou, China
1
Question: Afatinib – an oral, irreversible ErbB Family Blocker –
has superior efficacy to standard first-line chemotherapy in Asian
(LUX-Lung 6) and non-Asian patients (LUX-Lung 3) with metastatic EGFR M+ NSCLC. In both trials, median progression-free survival (independent review) on afatinib was 11 months and median
treatment duration 11–12 months. This analysis was conducted to
compare typical EGFR-mediated adverse events (AEs) between
Asian and non-Asian patients.
Methods: 239 (LUX-Lung 6) and 229 (LUX-Lung 3) patients received
afatinib 40 mg daily until progression or intolerable AEs. Dose could be
escalated to 50 mg, or reduced to 30 mg or 20 mg based on predefined
study criteria. Patients were grouped as Asian vs. non-Asian across both
trials. On-treatment AEs were monitored for up to 21 days post-treatment.
Results: 404 Asian and 64 non-Asian patients received afatinib. There
was no difference in afatinib trough concentrations in Asian vs. nonAsian patients; median treatment exposure was 359 vs. 261 days. All patients reported ≥1 AE. Most common drug-related AEs were EGFR-mediated: Diarrhoea (91.3% [9.7% Grade (G)3] vs. 93.8% [10.9% G3]) and
rash/acne (84.9% [15.6% ≥G3 including 1 G4] vs. 84.4% [14.1% G3]).
AEs leading to dose reduction were comparable between groups (44.6 vs.
43.8%). Drug-related AEs leading to discontinuation were slightly higher
in Asian vs. non-Asian patients (7.2 vs. 4.7%), but at a lower rate than
with chemotherapy (25.9%). Related interstitial lung disease-like events
occurred in 4 Asian patients (3 ≥G3) and no non-Asian patients.
Conclusions: Afatinib has a manageable safety profile in both Asian and
non-Asian patients and is suitable for long-term treatment of EGFR M+
NSCLC.
ID 340
Multimodal treatment of non-small lung cancer with
cerebral metastases
N. Kudelin, S. Bölükbas, J. Schirren
Dr. Horst Schmidt-Klinik Wiesbaden, Thoraxchirurgie, Wiesbaden,
Deutschland
Objective: The role of surgical treatment of lung cancer with cerebral
metastases remains controversial. The aim of this study was to determine
the long-term outcome and to identify potential prognostic factors in patients with cerebral metastatic non-small lung cancer (NSCLC).
Methods: The data of patients who underwent a resection of NSCLC
with brain metastases from January 1999 to December 2011 were investigated retrospectively at a single institution. Multimodal treatment included resection or radiation surgery of the brain metastases at first followed
90
by systematic chemotherapy and the surgical treatment of the lung cancer
at last. Survival, potential prognostic factors as well as morbidity and
mortality was investigated.
Results: 26 patients with brain metastases (18 males, 8 females) underwent a surgical resection of primary NSCLC. The mean age was 57.54
years. Morbidity and mortality rates were 15% and 0%, respectively.
Lobectomies were performed in 15 patients, pneumonectomy in 5 and
sleeve lobectomy in 6 patients, respectively. The brain metastases were
treated by resection, stereotactic radiotherapy or whole brain radiotherapy in several combinations. The 5-year survival rate was 24% (median
survival 25.7 months). There was no significant difference in patient’s
age, gender, histology of the primary tumor, number or treatment of the
brain metastases or the type of chemotherapy. The pneumonectomy for
resection of the primary NSCLC was associated with inferior survival
(15.0 vs. 26.6 months; p = 0.048).
Conclusions: Long-term survival is achievable in highly selected patients
with NSCLC and cerebral metastasis by multimodal treatment including
resection of the primary lung cancer. Pneumonectomy should be avoided.
ID 376
The Network Genomic Medicine: A prospective
comprehensive molecular screening network for
implementation of personalized lung cancer therapy
M. Bos1, M. Gardizi2, L.C. Heukamp3, S. Merkelbach-Bruse3,
H.-U. Schildhaus3, M. Scheffler2, L. Nogová2, C. Mattonet2,
M. Serke4, W.J. Randerath5, U. Gerigk6, T.H. Brümmendorf7,
S. Krüger8, J. Panse7, B. Kaminski5, M. Reiser9, R. Büttner3,
J. Wolf2
Universität Köln, Translationale Genomik, Köln, Deutschland
Uniklinik Köln, Medizinische Klinik I, Köln, Deutschland
3
Uniklinik Köln, Pathologisches Institut, Köln, Deutschland
4
5
Bethanienkrankenhaus, Klinik für Pneumologie und Allerologie, Solingen,
Deutschland
6
Malteser Krankenhaus, Klinik für Thoraxchirurgie, Bonn, Deutschland
7
Uniklinikum Aachen, Medizinische Klinik IV, Aachen, Deutschland
8
Florence Nightingale Krankenhaus, Klinik für Pneumologie und Allerologie, Düsseldorf, Deutschland
9
Pioh Köln, Onkologische Schwerpunktpraxis, Köln, Deutschland
1
2
Background: The potential of personalized medicine for improvement
of lung cancer patient outcome has been shown in advanced EGFR mutation- and ALK translocation positive NSCLC patients (pts) and numerous
targeted drugs for molecular defined subgroups are in clinical development. One of the major challenges now is the implementation of comprehensive molecular diagnostics and personalized therapy for all NSCLC
pts. regardless of where they are treated.
Methods: To increase the availability of molecular testing and subsequently personalized treatment options for NSCLC pts. in the catchement
area of the Center for Integrated Oncology Köln-Bonn, we established
the Network Genomic Medicine (NGM). NGM encompasses >40 health
care providers representing the full spectrum of lung cancer care. The
NGM headquarter is based at the University Hospital of Cologne. Within
NGM genetic and clinical data are analysed and pts. without approved
targeted treatment options are screened for recruitment into NGM-linked
personalized trials.
Results: We screened 5,145 lung cancer pts. from 01/2010 till 04/2013.
Genomic testing was feasible in 75% of samples. In AD we detected:
EGFR 13.8%;ALK 3.3%; KRAS 33.8%; BRAF 3.5%;PIK3CA 3.1%;
HER2 ampl. 3.6%; RET 4.7% and ROS1 5.1%. The frequencies of RET
and ROS1 are overestimated because of preselection of pan negative patients.In SCC we found a frequency of 21% for FGFR1 ampl. and 2.1%
for DDR2 mutations. Overall 40% of NSCLC pts. harboured a potentially
targetable molecular alteration and more than 40 pts. could be treated in
early personalized clinical trials.
Conclusion: We established one of the world´s largest platforms for comprehensive lung cancer genotyping. Our experiences underline that cen-
Abstracts
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Index
tral comprehensive molecular diagnostics is feasible in a large health care
provider network and allows implementation of personalized medicine in
routine clinical care of lung cancer pts.
ID 381
A retrospective analysis of overall survival of ALK
translocation – and of EGFR mutation positive NSCLC
patients treated with and without personalized therapy
M. Bos1,2, M. Gardizi3, L.C. Heukamp4, H.-U. Schildhaus4,
S. Merkelbach-Bruse4, L. Nogová3, M. Scheffler3, M. Serke5,
H. Schulz6, S. Krüger7, T.H. Brümmendorf8, J. Panse8,
S. Schmitz9, U. Gerigk10, W.J. Randerath11, Y.D. Ko12,
K. Kambartel13, A.-N. Hünerlitürkoglu14, R. Büttner4,14, J. Wolf3,14
Universität Köln, Translationale Genomik, Köln, Deutschland
Pioh Köln, Onkologische Schwerpunktpraxis, Köln, Deutschland
3
Uniklinik Köln, Medizinische Klinik I, Köln, Deutschland
4
Uniklinik Köln, Pathologisches Institut, Köln, Deutschland
5
6
Pioh Frechen, Onkologische Schwerpunktpraxis, Frechen, Deutschland
7
Florence Nightingale Krankenhaus, Klinik für Pneumologie und Allerologie, Düsseldorf, Deutschland
8
Uniklinikum Aachen, Medizinische Klinik IV, Aachen, Deutschland
9
Praxis am Sachsenring, Onkologische Schwerpunktpraxis, Köln, Deutschland
10
Malteser Krankenhaus, Klinik für Thoraxchirurgie, Bonn, Deutschland
11
Bethanienkrankenhaus, Klinik für Pneumologie und Allerologie, Solingen,
Deutschland
12
Evangelische Kliniken Bonn, Internistische Onkologie, Bonn, Deutschland
13
Bethanienkrankenhaus Moers, Lungenklinik Moers, Moers, Deutschland
14
Lukaskrankenhaus, Innere Medizin II, Neuss, Deutschland
1
2
Background: Erlotinib, gefitinib and crizotinib (C) have been approved
by the EMA for the treatment of advanced EGFR mutation positive
(EGFR M+) and ALK translocation positive (ALK +) NSCLC patients
(pts.), respectively. In randomized clinical trials for ALK + and EGFR
M+ pts. comparing chemotherapy (CTx) to TKI treatment so far no significant improvement in overall survival (OS) could be shown, based on
the high crossover rate of pts. initially treated in the CTx arm into the TKI
arm upon progression. Since prevention of crossover is obsolete due to
ethical reasons, registry data may gain in importance for investigating the
impact of new targeted drugs on OS.
Methods: Since 01/2010 EGFR sequencing and ALK FISH analysis for
lung AD was performed within the Network Genomic Medicine, a large
molecular screening network in the catchment area of the Center for Integrated Oncology Köln-Bonn as part of a broad genetic screening effort.
Clinical and follow-up data were extracted from medical records, directly
collected from physicians and pts.
Results: 44 ALK+ and 143 EGFR M+ pts. were analysed. The median
OS (mOS) of pts. with stage IIIb/IV was 14 months for ALK+ and 29
months for EGFR M+ pts. Both groups showed a significant difference
in mOS when separated by targeted treatment status. ALK+ pts. who received C had a mOS of 23 months and pts. who did not receive C had a
mOS of 8 months (p = 0.01). EGFR M+ pts. who received an EGFR TKI
had a mOS of 31 months and pts. who did not receive an EGFR TKI had
a mOS of 9 months (p < 0.001). There were no significant differences
with regard to treatment platinum-containing chemotherapy, age or sex
between groups.
Conclusion: Comparing EGFR+ and ALK+ pts. that only received CTx
to those treated with a specific tyrosine kinase inhibitor (TKI) showed
a significant improvement in OS. This confirms the predictive value of
ALK translocations and EGFR mutations for treatment with the respective TKIs.
Abstracts
ID 404
TRY: A phase II study to evaluate safety and efficacy
of combined trastuzumab and AUY922 in advanced
non-small-cell lung cancer (NSCLC) with HER2
overexpression or amplification or mutation.
L. Nogova1, M. Gardizi1, M. Bos1, M. Scheffler1, I. Papachristou2,
C. Wömpner1, L. Heukamp1, H.-U. Schildhaus3, U. Fuhr1, M. Sos1,
W. Eberhardt4, M. Wiesweg4, K.W. Schmid4, M. Schuler4,
R. Thomas2, R. Büttner1, J. Wolf1
Universität Köln, Köln, Deutschland
Uniklinik Göttingen, Göttingen, Deutschland
4
Uniklinik Essen, Essen, Deutschland
1
2
3
Background: HER2 amplifications and/or mutations are rare genetic alterations in NSCLC accounting for approximately 4%. Preliminary clinical
data suggested efficacy of trastuzumab in patients with HER2 IHC3+ status
or FISH positivity. The heat shock protein HSP90 is a molecular chaperone that modulates stability and/or transport of intracellular client proteins
including HER2. In breast cancer HSP90 inhibition has shown anticancer
activity in HER2-positive patients after trastuzumab failure. Here we are
investigating the efficacy of the combination of trastuzumab and the HSP90
inhibitor AUY922 in lung cancer patients with aberrant HER2.
Methods: This phase II study recruits metastatic NSCLC patients with
HER2overexpression (immunohistochemistry, DAKO-score 3+) or amplification (fluorescence in situ hybridization) or activating mutation after
at least one previous standard treatment. In the first part of the study,
patients are treated with trastuzumab only. CT scan is scheduled every 6
weeks during treatment. In case of disease progression, patients receive
the combination of trastuzumab and AUY922.
Results: The study was initiated this year and NSCLC patients are
screened within the Network of Genomic Medicine Lung Cancer on
HER2 overexpression, amplifications and mutations. Until now, we tested
720 tumor samples by FISH and 63 by genomic sequencing. We identified 55 patients with HER2 amplification, 34 with HER2 overexpression
(Dako score 3+) and 7 patients showed a mutation in the HER2 gene (1
exon 19; 6 exon 20).
Conclusion: HER2 overexpression, amplification or mutation is a rare
genetic alteration in NSCLC patients. Data on treatment with HER2 antibody trastuzumab and HSP90 inhibitor AUY922 will be presented.
ID 431
Clinical and Molecular Characteristics of Non-Small Cell
Lung Cancer Patients Harboring PIK3CA Mutations
M. Scheffler1, M. Gardizi2, M. Bos2, L. Heukamp3, K. König3,
M. Serke4, L. Nogova2, K. Töpelt2, E. Stoelben5, W. Engel-Riedel5,
W. Randerath6, B. Kaminsky6, J. Panse7, T. Zander1, R. Büttner3,
J. Wolf2
Uniklinik Köln, CIO Köln Bonn, Lung Cancer Group Cologne, Klinik I für
Innere Medizin, Köln, Deutschland
3
Uniklinik Köln, CIO Köln Bonn, Institut für Pathologie, Köln, Deutschland
4
Lungenklinik Hemer, Pneumologie, Thorakale Onkologie, Hemer,
Deutschland
5
6
Krankenhaus Bethanien, Klinik für Pneumologie und Allergologie, Zentrum für Schlaf- und Beatmungsmedizin, Solingen, Deutschland
7
Uniklinik Aachen, Euregionales comprehensive Cancer Center Aachen
(ECCA), Aachen, Deutschland
1
2
Purpose: Mutations of the PIK3CA gene have been frequently described
in non-small cell lung cancer (NSCLC), but limited data is available
about their biological relevance. This study was performed to characterize PIK3CA-mutated NSCLC clinically and genomically.
Patients and methods: Of 2047 patients presenting with NSCLC within
a timeframe of two years, 1144 (75.1% adenocarcinoma, 15.6% sqamous
cell carcinoma, 9.3% other histological subtypes) were screened for PIK-
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Index
3CA mutations. We identified 42 patients with PIK3CA mutations in exon
9 and exon 20 using dideoxy-sequencing and next-generation sequencing
(NGS). Clinical, pathological, and genetic characteristics of these patients
are described and compared with a control group of 211 patients with
comparable histological and clinical features features without PIK3CA
mutation.
Results: PIK3CA mutations occured in both genders (male/female ratio
3/2) in squamous-cell carcinoma (16/179, 8.9%) and in adenocarcinomas
(25/859, 2.9%) and were significantly associated with smoking. The most
common PIK3CA mutation was the exon 9 E545K mutation. Beside the
PIK3CA mutations, the majority of patients (59.5%) had additional oncogenic driver aberrations. Further, PIK3CA-mutated patients had significantly more often a history of cancer other than NSCLC in their history.
Conclusion: Within this dataset, which represents the largest cohort of
PIK3CA mutated NSCLC yet described, the need for comprehensive genetic analyses in order to define further pathway aberrations is obvious.
Nevertheless, PIK3CA mutations occur in a relatively high percentage of
squamous cell NSCLC and are at great number associated with a history
of cancer othe than NSCLC.
ID 439
MIMEB: A phase II trial to evaluate FDG-PET/FLT-PET and
DCE-MRI for early prediction of efficacy in patients with
advanced non-small cell lung cancer treated with erlotinib
and bevacizumab
M. Scheffler1, M. Bos1, M. Sos1, L. Nogova1, M. Gardizi1,
C. Mattonet1, I. Papachristou2, D. Kahraman3, C. Kobe3,
A. Lammertsma4, R. Boellaard4, T. Persigehl5, L. Heukamp6,
R. Büttner6, T. Elter5, K. Töpelt1, W. Engel-Riedel7, E. Stoelben7,
B. Neumaier8, M. Dietlein3, T. Zander5, J. Wolf1
2
Universität, Zentrum für Klinische Studien, Köln, Deutschland
3
Uniklinik Köln, CIO Köln Bonn, Institut für Nuklearmedizin, Köln, Deutschland
4
VU Amsterdam, Amsterdam, Deutschland
5
6
Uniklinik Köln, CIO Köln Bonn, Institut für Pathologie, Köln, Deutschland
7
8
Max-Planck-Institute for Neurological Research, Radiochemistry, Köln,
Deutschland
1
Background: Molecular imaging tools gain in importance for assessment
of efficacy in patients with advanced NSCLC treated with targeted therapy. We set up a prospective clinical trial in order to assess the predictive
value of early changes in FDG-PET, FLT-PET, and DCE-MRI during
therapy with erlotinib and bevacizumab in untreated patients with advanced non-squamous cell NSCLC and to identify a subgroup of patients
with clinical benefit from the combination therapy.
Methods: Patients with non-squamous NSCLC stage IV without prior
systemic therapy received at least six weeks of combined erlotinib and
bevacizumab. FLT and FDG-PET scans as well as DCE-MRI-scans were
performed at baseline, after one week of therapy and after six weeks of
therapy. Standard uptake values (SUVs) of the PET scans and vascularization parameters of the DCE-MRI scans were analyzed. Tumor specimens were analyzed in accordance with guidelines of a network screening
panel. The primary objective of this trial was to evaluate the accuracy
of FDG-/FLT-PET and DCE-MRI for early prediction of nonprogression
and PFS and its association with molecular markers.
Results: 40 patients were enrolled. Preliminary results regarding the predictive value of FDG-PET, FLT-PET and DCE-MRI in patients with advanced NSCLC treated first-line with erlotinib and bevacizumab as well
as the association with mutational status will be presented.
Conclusions/Perspective: Imaging-based predictive biomarkers to identify the subpopulation of patients with pronounced benefit of the combination of erlotinib with bevacizumab (FDG-, FLT- PET and DCE-MRI)
were successfully implemented in the treatment plan of a prospective
phase II trial.
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Lymphoma and Plasma Cell Disorders
ID 436
Nodal reactive and neoplastic proliferation of monocytoid
and marginal zone B cells: An immunoarchitectural and
molecular study highlighting the relevance of IRTA1 and
T-bet as positive markers.
R. Bob1, H. Stein1, B. Falini2
Pathodiagnostik Berlin, Referenzzentrum für Lymphom- und hämatopathologie, Berlin, Deutschland
2
University of Perugia, Ospedale S. Maria della Misericordia,, Institute of
Hematology, Perugia, Italien
1
Aims: Marginal zone B cells (MZCs) and monocytoid B cells (MBCs)
appear to be related lymphoid cells that take part in reactive and neoplastic marginal zone proliferations. These lesions are not yet well characterized, and the aim of this study was to find better diagnostic criteria
for them.
Methods and results: We analysed 60 nodal lesions with MBC and/or
MZC proliferation for their morphological, immunophenotypic, molecular genetic and IG gene rearrangement features. On the basis of the results
of the rearrangement assay and immunoglobulin light chain restriction,
the lesions were divided into reactive and neoplastic groups. Among the
neoplastic lesions, polymorphic and monomorphic subgroups emerged.
All reactive lesions had morphological features of the polymorphic subgroup. By immunohistochemistry, IRTA1 and/or T-bet expression was
found in all reactive lesions and in 90% of neoplastic lesions.
Conclusions: IRTA1 and T-bet are positive markers for the identification
of MZC/MBC proliferations, and thus for the diagnosis of nodal marginal
zone lymphoma (NMZL). Polymorphic and monomorphic subgroups of
NMZL could be distinguished. Most morphological and immunophenotypic patterns in reactive and neoplastic nodal expansions of MZCs and
MBCs overlapped. Therefore, PCR clonality assay of the immunoglobulin heavy and light chain gene loci is the most reliable method for their
differentiation.
Miscellaneous
ID 168
Potentials of Computer-aided Decision Support Systems
in Medicine
D. Andrzejewski1, I. Boersch1, T. Schrader1, P. Ledwon2,
N. Haeusler2, E. Beck1
Fachhochschule Brandenburg, Fachbereich Informatik und Medien,
Brandenburg, Deutschland
2
Städtisches Klinikum Brandenburg GmbH, Frauenheilkunde und Geburtshilfe, Brandenburg, Deutschland
1
Introduction: According to the principles of Evidence based medicine,
physicians’ decisions should be based on currently best available external. However, it is a well know phenomenon that in the overwhelming
majority decisions in medicine are made rather heuristic than based on
defined decision rules. This may be one of the reasons why only up to
70% of patients with breast cancer are treated in accordance with the national S3 Guideline. It is therefore tempting to speculate if this could be
improved by computer aided decision support systems.
Methods: For this pilot study, data sets of 165 patients of the Brandenburgisches Brustzentrum were analyzed concerning the decision categories
«adjuvant chemo- and/or hormonal therapy», applying methods of descriptive statistics (SPSS Version 19) and data mining. Tumor attributes
analyzed and most relevant for the above mentioned clinical decisions are
according to the S3 guideline: Patient’s age, menopausal status, hormone
receptor (HR) expression, HER-2/neu expression, TNM classification,
grading, and Nottingham Prognosis Index.
Abstracts
Inhalt
Index
Results: Whereas descriptive analysis showed clear cut correlations between some attributes and the aforementioned categories (e.g. HR expression and anti-hormonal therapy), most results were rather difficult
to interpret. E.g. concerning grading we found that 10/41 patients with
G1 tumors received adjuvant chemotherapy compared to 30/37 with G3
tumors. We then constructed a (still human readable) C4.5 decision tree to
predict physicians’ decisions resulting in a test error of 75%.
Conclusion: Using a limited number of tumor associated attributes already enables a good prognosis regarding the decision categories adjuvant chemo- and/or hormone therapy.
ID 178
Organ specific tumor conference for hepato-biliar
diseases – first results after 2 years
R. Kleinert1, R. Wahba1, D. Waldschmidt1,2, A. Hölscher1,2,
D. Stippel1,2
Universitätsklinikum Köln, Klinik für Allgemein-, Viszeral-, und Tumorchirurgie, Köln, Deutschland
2
Universitätsklinikum Köln, Klinik für Gastroenterolgie, Köln, Deutschland
1
Background: The established tumor conferences are nowadays often
supported by organ specific conferences. The requirements on these
meetings in particular on multidisciplinary are similar. The specific focus
promises a very efficient meeting as there is usually a smaller but even
more specialized expert round. Although the benefit of tumor conferences
is undisputable but there is little evidence about the measurable benefit
for the patient. However it may be characterized by the comparison of the
board recommendations with the therapies and specialized recommendations like inclusion in studies. Therefore it was our aim to test our tumor
conference for hepato- biliar diseases according to the criteria quoted
above.
Method: Retrospective analyses of the patients that were included in the
organ specific tumor conference between 09/2011 up to 09/2013.
Results: A total of 326 cases were discussed. Recommendations were
available in the intranet after 24 h. Recommendations were followed in
94%. Reasons for deviations were worsening of health status or rapid
progress. 6% were included in studies. 38% underwent surgery, interval
between recommendation and surgery was 10 days. 5% were telemedical
consultations over the internet. In 24% a combined therapy was recommended.
Conclusion: The potential of a hepato-biliar organ specific tumor lies in
discussion of specialized problems in close cooperation between oncologists, gastroenterologists and surgeons. The recommendations show a
high percentage of surgical therapies with high technical demands and
high amount of multimodal therapies.
ID 330
Characteristics, course and outcome of critically ill
patients with malignant diseases in a medical intensive
care unit in a community hospital with cancer center
K. Schulte1, M. Krakau1, P. Schellongowski2, A. Dormann1
Kliniken der Stadt Köln, Krankenhaus Holweide, Mediznische Klinik, Köln,
Deutschland
2
Medizinische Universität Wien, Universitätsklinik für Innere Medizin I,
Wien, Oesterreich
1
Purpose: Patients (pts.) with a malignant disease may require medical
critical care treatment due to the increasingly chronic courses of malignant illnesses. We report characteristics and outcomes of pts. with malignant conditions treated in the medical intensive care unit of a community
cancer center.
Methods: Characteristics, reasons for admission, interventions and outcomes of all pts. with active malignant diseases admitted to the medical
intensive care unit (MICU) of the Krankenhaus Holweide from 10/10 to
9/12 are reported retrospectively.
Abstracts
Results: Of 175 pts. (median age: 69.6 +/–10.8 years; female/male:
72/103; hematologic: n = 57 (32.6%); oncologic: n = 118 (67.4%)) 61
pts. (34.9%) had curative and 114 (65.1%) had palliative oncologic treatment options.
Reasons for admission were acute respiratory failure (n = 49; 28%), sepsis, acute renal failure (both n = 21; 12%) and bleeding (n = 18; 10.3%).
72 pts. (41%) received life saving interventions. Curative pts. had more
often a ‘fullcode’ status than palliative pts. (n = 57; 93.4% vs. n = 43;
37.7%; ≤0,0001) and were ventilated more often (n = 16; 26.2% vs.
n = 23; 20.2%; ≤0,01). The rates of catecholamine-therapy (n = 21;
34.5% vs. n = 31; 27.2%; p = 0,74), non-invasive ventilation (n = 12;
19.7% vs. n = 15; 13.2%; p = 0,28), and hemofiltration (n = 3; 4.9% vs.
n = 3; 2.6%; p = 0,42) did not differ significantly.
Survival was equal in palliative and curative pts. (ICU: 78,7/68.4%;
p = 0,16; hospital 68.9/ 57.0%; p = 0,15; 6-months 54.1/36.8%; p = 0,24).
Conclusion: Two thirds of the pts. admitted to the MICU had a palliative
oncological concept. Their treatment in the ICU did not differ from that
of curative pts.. There was no significant survival-difference at discharge
from MICU or hospital and at 6 months.
ID 356
The Freiburg Bio-Databanking combines automaticly
updated pathological and clinical information with
research data.
P. Bronsert1,2, F. Makowiec3, S. Schmid1, E. Stickeler4,
V. Drendel1, K. Aumann1, C. Jilg5, M. Werner1,2,6
Department für Pathologie, Institut für Klinische Pathologie, Freiburg,
Deutschland
2
Comprehenisve Cancer Center Freiburg, Tumorbank, Freiburg, Deutschland
3
Chirurgische Klinik der Universität Freiburg, Allgemein- und Viszeralchirurgie, Freiburg, Deutschland
4
Chirurgische Klinik der Universität Freiburg, Gynäkologie und gynäkologische Onkologie, Freiburg, Deutschland
5
Chirurgische Klinik der Universität Freiburg, Urologie, Freiburg, Deutschland
6
German Cancer Consortium (DKTK) and German Cancer Research
Center (DKFZ), Heidelberg, Deutschland
1
Aims: Biobanking in Comprehensive Cancer Centers aims to combine
pathologically well characterized and quality controlled tissue specimens with and correlating clinical data and follow-up of the patients.
Fundamental for functioning is a standardized acquisition of pathological
diagnosis of tumor tissue and the linkage to clinical data. To guarantee
sustainability, an automatical, flexible, expandable and restricted accessible database is needed, to link new generated research data to tissue
specimens. Certainly, strictly rules of admission, concerning patients data
privacy has to be ensured. Here we describe the development and the
features of our Biobank linked database
Material and Methods: The database was developed in MySQL 5.1, a
programming language designed for managing data in relational database
management systems on Windows XP Professional PC with the development environment Eclipse Hellios and the database development assistant
Toad for MySQL. It runs on a Suse Linux Enterprise server, a virtual
server at the central IT facility of the University of Freiburg. Furthermore
programs for data import from our intranet application for comprehensive tumor documentation called CARAT established for the entry of all
cancer data elements as well as from excel sheets were performed. Data
integrity is evaluated by random checks of patients by the IT officer and
a physician.
Results: We developed a flexible, expandable and restricted accessible
database on the fundament of open-source software. Clinical and research
data can be updated and/or changed either automatically or manually
from our facility and/or extern clinical partners. Patients personal data
are electronical protected according to current guide lines. Access for
pseudonymized clinic-pathological and research data is only admitted for
accredited persons.
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ID 366
Consortial Data- and Biobanking
P. Bronsert1,2, E. Stickeler3, K. Aumann1, S. Schmid1, T. Fehm4,
C. Röcken5, F. Fend6, C. Mundhenke 7, N. Aumann7, U. Vogel6,
A. Stäbler6, M. Werner1,2,8
Department für Pathologie, Institut für Klinische Pathologie, Freiburg,
Deutschland
2
Comprehenisve Cancer Center Freiburg, Tumorbank, Freiburg, Deutschland
3
Chirurgische Klinik der Universität Freiburg, Gynäkologie und gynäkologische Onkologie, Freiburg, Deutschland
4
Chirurgische Klinik der Universität Düsseldorf, Gynäkologie, Düsseldorf,
Deutschland
5
Department für Pathologie, Institut für Klinische Pathologie, Kiel, Deutschland
6
Department für Pathologie, Institut für Klinische Pathologie, Tübingen,
Deutschland
7
Chirurgische Klinik der Universität Kiel, Gynäkologie, Kiel, Deutschland
8
German Cancer Consortium (DKTK) and German Cancer Research
Center (DKFZ), Heidelberg, Deutschland
1
Aims: Essential for a consortial high quality tumor bank is a standardized
implementation of clinical and pathological information. By combining
three independent breast cancer biobanks from the University Hostpitals
Freiburg, Tübingen and Kiel, working procedures has to be synchronized,
harmonized and standard operating procedures (SOP) and datasets have
to be established. Furthermore, to ensure sustainability, an automatical
data transfer has to be implemented.
Material and Methods: All three facilities defined SOPs and established
Shared Resources Advisory. Datasets for pathological and clinical diagnoses were established. A periodically updating secured database with
an automated combination of all consortial data was programmed by an
experienced software engineer based on an open source and web accessible platform.
Results: Together from 2001 through 2013, the consortial breast cancer tissue bank contains 3900 fresh frozen, prospectively collected and
immunohistochemically classified breast cancer samples from all three
facilities. The median age is 61 years. Nearly half of the patients were
diagnosed with a ductal carcinoma in situ. The major pT category was
T1c, the most frequently pN category was pN0 followed by pN2, pN1 and
pN3 After written request, access for researchers to the consortial internet
accessible breast cancer database can be granted.
Conclusions: A well planed clinico-pathological and IT linked infrastructure is the fundament of a consortial database and the basic principle for
multicentric translational research. For testing and proving a successful
multicentric research approach, several national and international projects were initiated.
ID 458
8 years patient navigators in the interdisciplinary tumor
ambulance of CIO Köln Bonn – a role model for other
cancer centers?!
I. Bey1, B. Bergatt-Kuhl1, S. Arndt1, S. Treppner1, I. Schmidt-Wolf2,
M. Hallek1, J. Wolf1
Deutschland
2
Deutschland
1
Introduction: In 2005 the «Center for Integrated Oncology Köln Bonn»
has started to install patient navigators in the central interdisciplinary
tumor ambulance. Today these patient navigators («CIO-Lotsen») have
become a trade mark of the CIO. They are in the focus of the management
of cancer patients by ensuring the continuity of care. The patient navigator’s responsibility is to guide the patient through the complex process of
diagnostics and treatment. This unique concept of patient guidance has
quickly gained an excellent acceptance amongst our cancer patients. The
Patient Navigator
94
–– is the first and continuous contact for outpatients and their relatives
–– organizes appointments, reminds physicians and nurses about upcoming procedures
–– joins the patient in the interdisciplinary consultation hours
–– literally takes the patient by the hand and helps to make the multi pitstop process of medical diagnostics as convenient as possible
–– evaluates the possible inclusion into clinical trials with the medical
oncologist
–– inform and arrange supplementary services such as psycho-oncology,
palliative care, or physical excercise therapy
Currently, in Cologne there are 3 Patient Navigators, all certified nurses,
working in an office adjacent to the CIO outpatient unit. At the ambulance
in Bonn are 2 nurses on duty. The teams will be expanded continuously.
Aim: CIO Köln Bonn wants to present its successful navigator concept
to other german cancer centers very hands-on and comprehensively. The
goal is to supply decision-making-support and give advice and ideas to
develop own patient navigator models in their tumor anbulances..
Methods: PR and communication measures 2014: full-time event, information brochure, press work.
ID 461
A benchmark study of cancer patient outcome in two
Comprehensive Cancer Centers in the US and Germany
F. Kron1, J.P. Glossmann1, M. Lotze2, M. Barsoum 1, S. Winters2,
D. Normolle2, M. Boyiadzis2, M. Socinski2, A. Bernschein1,
I. Schmidt-Wolf3, B. Funke3, M. Meyer1, C. von Levetzow1,
S. Leitzke1, M. Hellmich1, C. Scheid1, K.-A. Kreuzer1,
A. Kostenko1, D. Waldschmidt1, L. Heukamp1, T. Zander1,
M. Scheffler1, M. Hallek1, J. Wolf1
Deutschland
2
University of Pittsburgh, Cancer Institute and Centers, Pittsburgh, Vereinigte Staaten Von Amerika
3
Deutschland
1
Introduction: International studies have shown significant differences in
population-based cancer survival. Those results have activated an ongoing health-policy debate on optimal cancer care.
Aim: Based on three high mortality cancers: lung cancer (C34), pancreatic cancer (C25) and acute myeloid leukemia (C92.00), we propose a
pilot comparative effectiveness study in two large Comprehensive Cancer
Centers (CCC) in the United States (University of Pittsburgh Cancer Institute) and Germany (Center for Integrated Oncology – Köln and Bonn,
CIO) to identify factors and reasons for inequalities in outcome, incidence, stage at presentation, and/or treatment regimens and cost.
Methods: The study population will include patients with primary tumors diagnosed and treated between 2009 and 2013. We will analyze
data retrospectively from the Clinical Cancer Registries of Cologne,
Bonn and Pittsburgh. Additionally we will complete our data by merging
special hospital management data with data from the federal cancer registry of North Rhine-Westphalia. We will develop hypotheses regarding
patient-related, institutional, health care and other factors that influence
early outcome. Data analysis contains statistical methods including Kaplan-Meier, Cox-Regression and other multivariate models.
Results:In a first step we have shown the technical feasibility of comparing complex cancer patient information from both sides of the Atlantic.
So far we have identified 723 lung cancer cases, 160 pancreatic cancers
and 192 leukemias at the CIO. Further we have assigned median survival of CIO lung cancer patients (age, stage, mutation and treatment with
platinum based chemotherapy). Pittsburgh data will be available by the
end of 2013.
Conclusion: Outcome research is a relatively new approach in improving
cancer care in Germany. This first transatlantic CCC benchmarking project will activate a variety of quality improvement initiatives.
Abstracts
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Molecular Pathology
ID 275
HS3ST2 modulates breast cancer cell invasiveness
and chemosensitivity via MAP kinase- and TCF7L2/
TCF4-dependent regulation of protease and cadherin
expression
A. Vijaya Kumar1, E. Salem Gassar1, D. Spillmann2, C. Hülsewig1,
L. Kiesel1, C. Stock3, G.W. Yip4, M. Götte1
2
Uppsala University, Department of Medical Biochemistry and Microbiology, Uppsala, Schweden
3
University of Münster, Institut of Physiology II, Münster, Deutschland
4
National University of Singapore, Department of Anatomy, Singapore,
Singapur
1
Aim of Study: HS3ST2, an enzyme mediating 3-O-sulfation of heparan
sulfate, is silenced by hyper-methylation in breast cancer. As heparan sulfate has an important co-receptor function for numerous signal transduction pathways, the phenotypical changes due to HS3ST2 re-expression
were investigated in vitro using high and low invasive breast cancer cell
lines.
Methods: MDA-MB-231 and MCF-7 cells were stably transfected with a
plasmid encoding HS3ST2, or a control vector. Cell behaviour was studied by chemosensitivity assay, matrigel invasion chamber and endothelial
transmigration assay. Molecular analysis was performed by Affymetrix
gene array screening, qPCR, Western blotting, Zymography and ratiometric pH measurements.
Results: HS3ST2-expressing MDA-MB-231 cells showed enhanced invasiveness and transendothelial migration. Expression of several matrix
metalloproteinases, cadherin-11, E-cadherin and CEACAM-1 was increased, while protease inhibitor expression was decreased. Low invasive
HS3ST2-over-expressing MCF-7 cells became even less invasive, with
no change in MMP activity. HS3ST2 increased HS-dependent basal and
FGF2-specific signaling through the constitutively active p44/42 MAPK
pathway in MDA-MB-231 cells. Increased MAPK activation was accompanied by upregulation of TCF7L2/TCF4. Dysregulation of TCF4-dependent ion transporters and increased cytosolic acidification were observed
in HS3ST2-expressing MDA-MB-231 cells, being a possible cause of
increased chemosensitivity towards doxorubicine and paclitaxel in these
cells.
Conlusions: This study provides the first in vitro evidence of the involvement of HS3ST2 in breast cancer cell invasion and chemosensitivity.
ID 277
Severe cancer phenotypes associated with CHEK2
mutations: More risk factors to be identified
K. Rhiem1, B. Wappenschmidt1, J. Hauke1, K. Klaschik1,
A. Baasner1, B. Blümcke1, A. Meindl2, E. Hahnen1, R. Schmutzler1
Zentrum für Familiären Brust- und Eierstockkrebs, Köln, Deutschland
Klinikum rechts der Isar, Klinik für Gynäkologie und Geburtshilfe, München, Deutschland
1
2
CHEK2 is an integral part of the BRCA1-associated genome surveillance
complex and monoallelic mutations were found in up to 5% of BRCA1/2
negative breast cancer (BC) and/or ovarian cancer (OC) families. Though
with varying frequencies, several studies confirmed the recurrent CHEK2
1100delC frameshift mutation as the most frequent in northern Europe.
The breast cancer risk for a female CHEK2 1100delC mutation carrier
increases up to 3fold, confirming CHEK2 as a moderately penetrant risk
gene. Meanwhile, the search for germline mutations in CHEK2 has been
implemented in a routine diagnostic setting, some laboratories focus on
recurrent CHEK2 mutations only via a non-quantitative MLPA assay. In
the course of a pilot study, we analyzed three CHEK2-positive families
with remarkably severe phenotypes. In the first family, the index patient
Abstracts
(bilateral BC, 29y, 32y) carried a CHEK2 1100delC frameshift. In the
second, the index patient (BC, 35y) carried a deletion of CHEK2 exon
9, and in the third family, the index patient (BC, 41y) carried a p.I157T
missense mutation associated with a 1,85fold increased risk only (95%
CI=1.51-2.26, p < 0.00001). We hypothesized that these CHEK2 alterations alone are not sufficient to cause the severe phenotypes (e.g. sarcoma) observed and searched for further exonic germline alterations by next
generation sequencing (NSG). Indeed, the first index patient carried the
CHEK2 1100delC frameshift mutation homozygously, the second shows
an additional ATM p.G2772R mutation previously described as disease
causing and the third patient additionally shows a known pathogenic alteration in a Fanconi anaemia gene. These data warrant i) the search for
further pathogenic alterations in CHEK2-positive families with unusually
severe phenotypes and potential impact for screening measures, ii) the
necessity to evaluate whether CHEK2 alterations occur in a homozygous
or heterozygous state.
ID 316
Development of the Cancer Genome Scanner (CAGE), a
single tube cancer assay for deep genomic analysis of
point mutations, insertions and deletions, copy number
alterations and gene fusions.
J. Heuckmann1, F. Leenders2, R. Thomas2
Blackfield AG, Köln, Deutschland
Universität Köln, Department of translational genomics, Köln, Deutschland
1
2
The discovery of activating EGFR mutations in NSCLC patients responding to the EGFR kinase inhibitors erlotinib and gefinitib changed
the landscape of personalized oncology dramatically. Today, several additional genomic alterations predicting responsiveness to certain targeted
drugs are known (e.g., KIT and BRAF mutations, ABL, ALK, ROS1 and
RET fusions, FGFR1 and HER2 amplifications etc.). However, due to the
genomic nature of these alterations, each of those is currently diagnosed
by an alteration specified assay, ranging from dideoxy amplicon sequencing to Fluorescence In Situ Hybridisation (FISH). Taking time and tumor
material consumption into account, analyzing the current spectrum of
mutations might not be feasible for all patients. Therefore, we developed
an all-in-one assay which allows the parallel detection of point mutations,
insertions and deletions, copy number alterations and gene fusions in a
broad spectrum of genes on a nucleotide to nucleotide resolution. Alterations in several of those clinically relevant genes are targetable with
currently approved drugs. Based on the targeted in-solution hybrid capture technology, followed by massively parallel sequencing, the Cancer
Genome Scanner (CAGE) allows a parallel, accurate and comprehensive
analysis of all genomic regions relevant for clinical oncology, even for
mutations occurring at low allele frequencies.
ID 452
RAD51C deletion screening identifies a recurrent gross
deletion in breast and ovarian cancer families
J. Hauke1, A. Becker1, G. Schnurbein1, G. Neidhardt1,
N. Weber-Lassalle1, B. Wappenschmidt1, E. Hahnen1, A. Meindl2,
R. Schmutzler1
Uniklinik, Zentrum für familiären Brust- und Eierstockkrebs, Köln,
Deutschland
2
Klinikum rechts der Isar, Frauenheilkunde und Geburtshilfe, München,
Deutschland
1
RAD51C is an integral part of the DNA double-strand repair through homologous recombination and monoallelic mutations were found in ~1.3%
of BRCA1/2 negative breast cancer (BC) and/or ovarian cancer (OC)
families. Though with varying frequencies, several studies confirmed the
occurrence of RAD51C mutations predominantly in BC and/or OC families, clearly establishing RAD51C as a cancer predisposing gene. There
is an ongoing debate whether pathogenic RAD51C alterations increase
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the relative risk (RR) for BC in addition to that for OC, which was estimated to be 5.88 (95% CI=2.91-11.88; P=7.65x10-7). Elucidating the
role of RAD51C in BC pathogenesis is hampered by the low frequency
of clearly truncating RAD51C mutations. In this study, we screened for
gross genomic alterations within the RAD51C gene in BRCA1/2-negative
familial BC index cases, 500 of which showing a BC only and 325 a BC/
OC family history. We identified a large heterozygous RAD51C deletion
encompassing the exons 5 to 9 in two independent families In the first,
remarkably a BC only family the mutation carrier was affected by early
onset and bilateral BC (33y, 39y). In the second, a BC/OC family, the
mutation was identified in dizygotic twins, one of which affected by early
onset BC (42y) and one by early onset OC (43y). The 36,637 base pair
(bp) deletion appears to be rare as we identified no further case in another
large cohort by junction fragment PCR (BC only: 1,011; BC/OC: 203).
The early onset of BC in both families, the occurrence of bilateral BC and
the triple-negative tumor phenotype resemble features closely associated
with hereditary BC and thus, the presence of a clearly truncating mutation
is supportive for a pathogenic role of RAD51C.
Molecular Targets
ID 052
Identification of mitochondrial and PI3K-Akt-mTOR
pathways as targets of naphtoquinones in cancer cells by
pharmacogenomics
B. Wiench1, Y.-R. Chen2, T. Eichhorn1, M. Paulsen3, R. Hamm1,
N.-S. Yang2, T. Efferth1
Johannes Gutenberg-Universität, Abteilung für Pharmazeutische Biologie,
Mainz, Deutschland
2
Agricultural Biotechnology Research Center, Taipei, Taiwan
3
Institut für Molekulare Biologie, Mainz, Deutschland
1
The development of drug resistance and severe side effects of current
cancer chemotherapy necessitates the development of novel anticancer
drugs with improved pharmacological features. Shikonin is a naphtoquinone derived from Lithospermum erythrorhizon, which is used for the
treatment of inflammatory and other diseases.
We analyzed shikonin in 15 cell lines, including multidrug-resistant cell
lines. Microarray profiling showed that shikonin affects cellular pathways
regulating cell cycle, mitochondrial function, reactive oxygen species
(ROS), and cytoskeleton formation. Uptake measurements of shikonin in
living cells using flow cytometry and confocal microscopy showed that
shikonin’s accumulation in mitochondria was associated with deregulation of cellular calcium and ROS levels followed by disturbed mitochondrial membrane potential, dysfunctional microtubules, cell cycle arrest
and apoptosis.
In addition to the targeting of mitochondria, we investigated the particular
sensitivity of shikonin towards leukemia cells. A «multi-omics» approach
using mRNA and miRNA microarrays as well as stable-isotope dimethyl
labeling for quantitative proteomics was applied. Bioinformatical integration of all data revealed that the PI3K-Akt-mTOR pathway was affected
by shikonin. Deregulations in this pathway are frequently associated with
cancerogenesis, especially in a wide range of hematological malignancies. Shikonin’s effect on the PI3K-Akt-mTOR pathway was validated by
the determination of decreased Akt phosphorylation and inhibition of the
IGF1R kinase activity after shikonin treatment. We conclude that inhibition of IGF1R-Akt-mTOR signaling represents a new cellular mechanism
of shikonin strengthening its potential for the treatment of hematological
malignancies.
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ID 073
Therapeutic targeting of a robust non-oncogene addiction
to PRKDC in DNA repair-defective tumors
L. Thelen, S. Chen, A. Riabinska, M. Daheim, M. Jokic,
R. Thomas, C. Reinhardt
University Hospital Cologne, Medical Clinic I, Köln, Deutschland
In response to DNA damage, cells activate a complex, kinase-based signaling network to arrest the cell cycle, initiate DNA repair, or, if the extend of
damage is beyond repair capacity, induce apoptotic cell death. ATM lies at
the heart of this signaling network, which is collectively referred to as the
DNA damage response (DDR). Disabling ATM mutations occur frequently
in various human tumor entities. Here we show that ATM-deficiency protects human and murine cancer cells from apoptosis induced by genotoxic
chemoptherapy. Using genetic and pharmacological approaches we demonstrate in vitro and in vivo that ATM-defective murine and human cells display a strong non-oncogene addiction to DNA-PKcs signaling. We further
show that this dependence of ATM-defective cells on DNA-PKcs offers a
window for therapeutic intervention. We show that pharmacological or genetic abrogation of DNA-PKcs in ATM-defective settings leads to the accumulation of DNA double-strand breaks and the subsequent CtIP-dependent
generation of large single-stranded DNA (ssDNA) repair intermediates.
These ssDNA structures trigger the activation of pro-apoptotic signaling
through the RPA/ATRIP/ATR/Chk1/p53/Puma axis, ultimately leading to
the apoptotic demise of ATM-defective cells exposed to DNA-PKcs inhibitors. Lastly, we demonstrate that DNA-PKcs inhibitors show remarkable
preclinical activity as single agents against ATM-defective lymphomas in
vivo. Together, our data implicate DNA-PKcs as a novel drug target for the
treatment of ATM-defective malignancies. In an extension of this work,
we performed a cell line-based screen with the aim to identify additional mutations that are associated with DNA-PKcs dependence. This screen
reveals that not only mutations in genes that are involved in homologous
recombination-based DNA repair, but also mutations in mismatch repair
genes produce DNA-PKcs dependnece.
ID 076
Novel alternatively spliced isoform of synuclein gamma
M. Hirschfeld, K. Schaal, M. Jäger, E. Stickeler
Deutschland
Introduction: Since Synuclein γ (SNCG) is found highly expressed in
advanced breast cancer it was initially described as breast-cancer specific gene (BCSG1). Clinical studies demonstrate the correlation of high
SNCG expression with advanced stages, metastasis and poor prognosis in
breast and ovarian carcinomas, i.e. reduced relapse-free and overall survival periods. In vitro analyses revealed a SNCG-dependent stimulation
of ligand-dependent transcriptional activity of ERα. So far, four mRNA
isoforms of SNCG were described, but only isoforms 1 and 2 code for
active proteins. For the first time, we analyzed expression levels of SNCG
mRNA isoforms in regard to hypoxia or acidosis, in vitro in endometrial
cancer cells. Methods: In vitro tests under hypoxic, acidic or control conditions with consecutive RNA and protein analysis.
Results: In comparison to the reference breast cancer cell line, endometrial
cancer cell lines displayed a general significantly reduced expression of
SNCG isoform 1, 2, 3 and 4. In contrast, a novel, shortened mRNA variant
of isoform 2 was identified in endometrial cancer cells. Hypoxia and acidosis triggered a marked up-regulation of the novel isoform 2 short, while
the expression of constitutive isoform 2 did not significantly change under
altered conditions. Immunohistochemistry and Western blot revealed a hypoxia- and acidosis- dependent increase in SNCG protein expression.
Conclusion: We hypothesize, that the novel SNCG isoform 2 short bears
a specific oncogenic potential in endometrial cancer, since it occurred
in elevated levels under typical epiphenomena of solid tumors in vitro.
Furthermore we postulate that this novel isoform is capable to code for a
biologically active protein isoform.
Abstracts
Inhalt
Index
ID 077
Endoxifen and hTra2-beta1 regulate estrogen receptor α
alternative splicing pattern in breast cancer cells
M. Hirschfeld, C. Zheng, M. Jäger, E. Stickeler
ID 173
Clostridium perfringens enterotoxin (CPE) gene therapy
for selective treatment of claudin-3- and -4 expressing
pancreatic tumors
Deutschland
J. Pahle1, D. Kobelt2, D. Behrens2, M. Rivera Markelova2,
J. Aumann1, W. Walther2,1
Background: Endoxifen acts as a selective estrogen receptor modulator by blocking ERα transcriptional activity. Alternatively spliced ERα
mRNA variants are present in normal and malignant breast tissues, possessing the potential for increased estrogen activities. Human Tra2-β1 is
a splicing factor regulating splicing processes in a sequence-specific and
concentration-dependent manner. hTra2-β1 intracellular localization may
vary during cancer progression or is changed by exogenic stimuli, e.g.
therapeutic drugs. Here we analyzed the potential impacts of endoxifen
and hTra2-β1 on ERα expression pattern and the effect of endoxifen on
hTra2-β splicing. Methods: In vitro tests under endoxifen and/or hTra2-β1
knock-down with consecutive analysis of mRNA and protein expression.
Results: Endoxifen induced a significant reduction of ERα protein expression. As a feedback effect, the ERα mRNA levels markedly increased.
Endoxifen treatment triggered a shift in ERα splicing toward the ERα Δ7
variant. hTra2-β1 knock-down created a similar impact on ERα splicing.
In addition, a novel isoform of hTra2-β1 occurred under endoxifen treatment. Interestingly, endoxifen also triggers an intracellular translocation
of hTra2-β1 characterized by decreased nuclear protein and increased accumulation in cytoplasm.
Conclusion: We hypothesize that endoxifen exerts a regulatory impact on
hTra2-β1 alternative mRNA splicing pattern and intracellular protein localization. hTra2-β1 is most likely involved in ERα-dependent regulation
of breast cancer by triggering aberrant ERα alternative splicing. ERα Δ7
might serve as an auspicious novel prognostic indicator for evaluation of
human breast cancer endocrine therapy efficacy.
1
ID 139
Potential early diagnosis of GI cancers by using a CPE
derivative specifically targeting CLDN-4
S. Bobersky , S. Hahn , N. Metzler-Nolte
1
2
1
Ruhr Universität Bochum, Anorganische Chemie I / Molekulare Gastroenterologische Onkologie, Bochum, Deutschland
2
Bochum, Deutschland
1
Among the gastrointestinal cancers, pancreatic ductal adenocarcinoma
(PDAC) is the most aggressive. Clinically, distinguishing between benign biliary structures and pancreatic masses and pancreatic cancer as
well as other periampullary malignancies is a challenge. Resectability is
present if the primary tumor has the «magic» size of 2–3 cm diameter and
no detectable metastasis. Detectability is flawed for all tumors below this
«magic» size. Tumors smaller than 1 cm are not traceable to date. The
focus here lies in using peptide-metal-bioconjugates to find novel binding partners for bioimaging gastrointestinal tumors, starting with PDAC,
because of the need for early detection of the disease. The Claudin-4
(CLDN-4) protein is one marker of ductal differentiation in pancreatic
tissue but, even in early lesions, the primary tumor and late metastasis
show a sufficient overexpression. CLDN-4 is an integral constituent of
tight junctions. Clostridium perfringens Enterotoxin’s C-terminal binding
sequence of 29 amino acids is supposedly adequate for targeting, binding
and sequential internalization of itself and its interacting binding partner:
CLDN-4. The primary focus lies in optimizing this binding sequence in
length as well as regarding its affinity to CLDN-4 leading to a medically
needed tool to detect even early lesions of GI cancers. Attaching a metal
complex feasible for PET imaging, this will become a diagnosis tool. By
combining other modules to the final binding sequence, even theranostic
tools can be possible.
Abstracts
Experimental and Clinical Research Center, Charité, Berlin, Deutschland
Max-Delbrück-Center for Molecular Medicine Berlin-Buch, Berlin, Deutschland
2
Bacterial toxins represent an effective therapeutic option for cancer therapy. Several studies showed their antitumoral potential. The Clostridium
perfringens Enterotoxin (CPE) is a pore forming toxin with a selective,
receptor dependent cytotoxicity. The transmembrane tight junction proteins claudin-3 and claudin-4 are known high-affine CPE receptors and
are often highly overexpressed in human epithelial tumors such as breast,
colon, ovarian and pancreatic cancer. CPE binding to its receptor triggers
formation of membrane pore complexes, which lead to cell death. Our approach aimed at evaluation of an efficient and selective cancer therapy of
claudin-3- and/or claudin-4-expressing pancreatic carcinoma by using a
non viral translation optimized CPE vector (optCPE) in vitro and in vivo.
We investigated the sensitivity of selected human pancreatic carcinoma
cell lines for treatment with recombinant CPE (recCPE) as well as by
optCPE gene transfer. Claudin-3 and -4 high expressing pancreas carcinoma lines showed high sensitivity towards recombinant, and transfected
CPE. Here an up to 100% toxicity was observed 72 h after gene transfer.
We demonstrated a correlation between CPE cytotoxicity and the level
of claudin-3 and/or -4 expression. The claudin-negative human control
cell line SkMel-5 did not show any sensitivity toward recombinant CPE
treatment or CPE gene transfer. The intratumoral in vivo gene transfer
of optCPE led to reduced tumor viability in Panc 9662 patient derived
xenograft bearing mice compared to the control group. This study shows
that CPE gene transfer is a promising and efficient option for a targeted
suicide gene therapy of claudin-3- and/or claudin-4-overexpressing pancreatic tumors in vitro and in vivo.
ID 217
K-Ras exon 2 mutations impact on regorafenib-activity in
an isogenic disease model of colorectal cancer
P. Camaj1, S. Primo1, V. Heinemann2, Y. Zhao1, Y. Wang1,
R. Laubender3, B. Schwarz2, C. Haertl1, S. Gamba1, C.J. Bruns1,
D.P. Modest2
Medizinische Faultät LMU München, Exp. Forschung: Chirurgie, München, Deutschland
2
Klinikum Großhadern, Medizinische Klinik III, München, Deutschland
3
Medizinische Fakultät LMU München, Institut für medizinische Infrometionsverarbeitung, Biometrie und Epidemiologie, München, Deutschland
1
Purpose: To investigate the impact of different KRAS mutations on treatment with the tyrosine kinase inhibitor regorafenib in SW48 colorectal
cancer cell line variants.
Materials and methods: Isogenic SW48 KRAS wt, G12A, G12C, G12D,
G12R, G12S, G12 V, and G13D cells were tested for the effect of regorafenib on B-RAF, ERK/ELK phosphorylation, cell cycle, and cytotoxicity.
Results: Compared to KRAS wt cells, all KRAS mutant variants were
associated with resistance to regorafenib treatment. In the MTT chemosensitivity assay, the grade of resistance was less pronounced in G13D
and highest in G12C, G12A, G12S and G12V mutant cells. The reduction
in B-RAF phosphorylation due to treatment with regorafenib was highest
in G12V and G13D mutant cells and lowest in G12C and G12R. The
mutant G12V exhibit strongest and mutant G12D weakest inhibition of
ERK-activation upon regorafenib treatment. ELK phosphorylation was
less decreased in all KRAS mutant variants with exception of G12D,
compared to KRAS wt cells following regorafenib treatment.
Conclusion: Our isogenic cell culture model suggests that KRAS mutations in SW48 colorectal cancer cells are linked to resistance to the multityrosine kinase inhibitor regorafenib. KRAS G13D mutant SW48 cells
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represented the KRAS subspecies with the lowest grade of resistance
and mutants G12C and G12A highest. Future studies will have to clarify
whether KRAS can be used to guide sunitinib treatment or – in general – a
treatment with a multityrosine kinase inhibitor in mCRC.
ID 246
Is there an association of Single-NucleotidePolymorphisms in the MDR1-gene with paclitaxel
sensitivity in human renal cell carcinoma?
P. Reinecke, N. Jallal, H.-E. Gabbert
Universitätsklinikum Düsseldorf, Institut für Pathologie, Düsseldorf,
Deutschland
Objective: Renal cell carcinomas (RCCs) are highly resistant to conventional chemotherapy. The Single-Nucleotide-Polymorphisms (SNPs)
in the MDR1-gene represent one possible drug resistance mechanisms.
Therefore to elucidate the response to antineoplastic agents we defined
the SNPs HAPLO and TAK in the MDR1-gene in a model with ‘intrinsic
paclitaxel resistance’ cell lines (chrompho-A and -B) and with ‘acquired
paclitaxel resistance’ cell lines (clearCa-21sens and clearCa-21res) before
and after exposure to paclitaxel.
Methods: MTT-assay, RT-PCR, DNA-sequencing.
Results: 1. In all cell lines P-glycoprotein (P-gp) was expressed on mRNA-level. 2. Furthermore the intrinsic resistance model showed an IC50
of 0.08 μM in the paclitaxel-sensitive chrompho-A and an IC50 of 387.5
μM in the paclitaxel-resistant chrompho-B after exposure to paclitaxel
whereas in the acquired model an IC50 of 0.38 μM in clearCa-21sens and
>1000 μM in clearCa-21res was detected by MTT-assay. 3. Defining the
SNPs HAPLO and TAK in the MDR1-gene in untreated cells of the intrinsic model both SNPs were observed in the paclitaxel-resistant cell
line chrompho-B by DNA sequencing. 4. In comparison the TAK-SNP
became evident in both cell lines of the acquired resistance model however the HAPLO-SNP only in the resistant cell line clearCa-21res. 5. After exposure to paclitaxel the HAPLO-SNP was detected in the cell line
clearCa-21sens.
Conclusion: Obviously our results indicate that there is an association of
SNPs in the MDR1-gene with paclitaxel sensitivity in human RCCs in a
model of ‘intrinsic’ and ‘acquired’ paclitaxel resistance. Thus further aims
should be to elucidate the mechanisms between SNPs in the MDR1-gene
and paclitaxel sensitivity in human RCCs.
ID 278
Syndecan-1 (CD138) modulates breast cancer stem
cell properties via regulation of IL-6-mediated STAT3
signaling
S.A. Ibrahim1, H. Hassan1, L. Vilardo2, H.T. Eich3, L. Kiesel4,
R. Reinbold2, B. Greve3, M. Götte4
University of Cairo, Department of Zoology, Faculty of Science, Giza,
Aegypten
2
ITB-CNR Segrate, Milan, Italien
3
Universitätsklinikum Münster, Department of Radiotherapy –Radiooncology, Münster, Deutschland
4
1
Aim of Study: Syndecan-1 (SDC1), a heparan sulfate proteoglycan, acts
as a coreceptor for growth factors and chemokines and is a molecular
marker associated with epithelial-mesenchymal transition during development and carcinogenesis. Resistance of SDC1-deficient mice to induced tumorigenesis has been linked to altered Wnt-responsive precursor
cell pools. Here, we analyze the molecular contribution of SDC1 to a
breast cancer stem cell phenotype in human breast cancer cells in vitro.
Methods: MDA-MB-231 and MCF-7 cells were transiently transfected
with SDC1 or control siRNA. Stemness-related parameters were analyzed by flow cytometry and sphere formation assays. Molecular analyses
were performed by PCR and Western blotting.
98
Results: Side population measurement by Hoechst dye exclusion and
ALDH1 activity revealed that SDC-1 knockdown reduced putative cancer stem cell pools by 60 and 27%, respectively, compared to controls.
Intriguingly, IL-6, its receptor sIL-6R, and the chemokine CCL20, implicated in regulating stemness-associated pathways, were downregulated
by >40% in Syndecan-1-silenced cells, which showed a dysregulated response to IL-6-induced epithelial-to-mesenchymal transition. Activation
of STAT-3 and NFkB transcription factors and expression the Wnt coreceptor LRP6, were reduced by >45% in SDC1-depleted cells compared
to controls. SDC1 siRNA reduced the formation of spheres and cysts in
MCF-7 cells grown in suspension culture.
Conclusion: As Syndecan-1 modulates the breast cancer stem cell phenotype via regulation of the IL-6/STAT3 and Wnt signaling pathways, it
emerges as a promising novel target for therapeutic approaches.
ID 321
Targeting STAT3 as a therapeutic strategy to sensitize
colorectal cancer to chemoradiotherapy
M. Grade1, M. Spitzner1, B. Roesler1, C. Bielfeld1, J. Gaedcke1,
H. Wolff2, T. Beissbarth3, J. Wienands4, M. Ghadimi1
2
Universitätsmedizin Göttingen, Klinik für Strahlentherapie und Radioonkologie, Göttingen, Deutschland
3
Universitätsmedizin Göttingen, Institut für Medizinische Statistik, Göttingen, Deutschland
4
Universitätsmedizin Göttingen, Institut für Zelluläre und Molekulare Immunologie, Göttingen, Deutschland
1
Problem: Increased activity of STAT3 is common in human malignancies, including colorectal cancers (CRC). We have recently reported that
STAT3 gene expression correlates with resistance to 5-FU-based chemoradiotherapy (CT/RT). This is of considerable clinical importance, because a large proportion of rectal cancers are resistant to preoperative
multimodal treatment.
Methods: To test whether STAT3 contributes to CT/RT-resistance,
STAT3 protein expression was measured in 12 CRC cell lines. STAT3
was inhibited in vitro in SW480 and SW837 using siRNA, shRNA, and
a small-molecule inhibitor (STATTIC). Silencing or inhibition of phosphorylation was confirmed using Western blot analysis and a luciferase
reporter assay. Following exposure to 3 µM of 5-FU and irradiation, sensitivity to CT/RT was assessed using standard colony formation assays.
Growth delay assay was used to determine the effect of STAT3 inhibition
on treatment sensitivity in vivo.
Results: STAT3 protein expression correlated positively with increasing
CT/RT-resistance. While STAT3 was not constitutively active, stimulation with IL-6 resulted in remarkably higher expression levels of phosphorylated STAT3 in CT/RT-resistant cell lines. A similar result was
observed when IL-6-induced expression of phosphorylated STAT3 was
determined after irradiation. RNAi- and STATTIC-mediated inhibition of
STAT3 resulted in significantly decreased clonogenic survival. In vivo,
STAT3 inhibition led to a profound CT/RT-sensitization in a subcutaneous xenograft model.
Conclusions: These results highlight a potential role of STAT3 in mediating CT/RT-resistance of CRC cells, and provide first proof of concept that
STAT3 represents a promising molecular target.
Abstracts
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Index
ID 333
CXCR4 over-expression is associated with Cisplatin
resistance in esophageal carcinoma
Y. Zhao1, Y. Wang1, L. Zhao1, S. Gros2, J. Mysliwietz3, J. Ellwart3,
H. Nieß1, C. Betzler4, K.-W. Jauch1, P. Nelson5, C. Bruns4
LMU Klinikum Grosshadern, Department of Surgery, München, Deutschland
University of Hamburg-Eppendorf, Department of Surgery, Hamburg,
Deutschland
3
Helmholtz Center for Environment and Health, Institute of Molecular
Immunology, München, Deutschland
4
Otto-von-Guericke University, Department of Surgery, Magdeburg,
Deutschland
5
LMU Medizinische Klinik und Policlinic IV, Clinical Biochemistry Group,
1
2
Introduction: CXC chemokine receptor 4 was found dys-regulated in
many different types of human cancers and generally correlate with poor
prognosis, metastasis, and resistance to chemotherapy. Limited data show
the influence of CXCR4 on esophageal carcinoma cells especially following chemotherapy with cisplatin.
Methods:CXCR4 was detected by FACs analysis in esophageal cell lines
OE19, OE21, OE33, PT1590, and LN1590. Corresponding cisplatin resistant cells were established following longterm selection under cisplatin
treatment and further confirmation by IC50 and ERCC1 expression. SDF-1α
and AMD3100 were used for stimulation or inhibition of CXCR4 in vitro.
A subcutanous tumor model of OE19 cell injection in Balb/c nude mice
was established, followed by treatment with cisplatin twice a week via i.p
injection. Tumors were collected for further molecular biology analysis.
Results: The esophageal cell lines OE19, PT1590, and LN1590 have detectable amount of CXCR4+ subpopulations as high as 2.8%±0.9, 0.7%±
0.9, and 1.0%±0.6, respectively. The OE19, PT1590, and LN1590 cisplatin resistant sublines displayed an increased IC50 value after 48h treatment
with cisplatin from 6.0±1.3 to 12.2±1.0, 1.4±0.7 to 9.1±0.7, and 1.4±0.6
to 7.2±0.6 ug/ml along with a significant overexpression of ERCC1. Interestingly, only OE19 and LN1590 cisplatin resistant cell lines showed
a significant enrichment of CXCR4+ cells (12.1%± 2.5 vs. 2.8%±0.9;
4.2%± 1.1 vs. 1.0%±0.6, pin vivo. The relative expression of CXCR4
will be further evaluated by realtime PCR and immunohistochemistry.
Conclusion:Overexpression of CXCR4 is significantly associated with
cisplatin-based chemotherapy resistance and might be a prognostic factor
in esophageal cancer. Inhibition of CXCR4 might be a strategy to address
chemoresistance of EAC cell lines.
ID 338
PDGF influences tumor proliferation like VEGF in colon
cancer
R. Mönch1, T. Grimmig1, V. Kannen2, M. Kim3, C.-T. Germer3,
M. Gasser3, A. M. Waaga-Gasser1
2
Universitätsklinikum Würzburg, Institut für Pharmakologie und Toxikologie, Würzburg, Deutschland
3
1
Background: The platelet derived growth factor (PDGF) and Vascular Endothelial Growth Factor (VEGF) are known to play a crucial role in different tumor entities. Involved in cell migration and proliferation of stromal
cells in cancer tissue they represent key targets in cancer therapy. The aim
of the study was to analyse the specific role of PDGF and VEGF stimulation on tumor cell proliferation and metabolism in colorectal cancer (CRC).
Methods: The human colon cancer cell line HT-29 and Caco-2 were cultured and stimulated with PDGF and VEGF in a time-dependent manner.
Whole cell extracts and RNA extracts were analyzed by Western Blot and
RT-q-PCR for PDGF- and VEGF receptors and for components of cellular metabolism. To discover effects of PDGF and VEGF on proliferation
MTS proliferation assays were performed.
Abstracts
Results: Western Blot analysis and RT-qPCR showed no relevant PDGF-receptor α and β expression in HT-29 cells but varying expression in Caco-2
cells. Stimulation with PDGF or VEGF resulted in increased proliferation
compared to untreated controls while simultaneous stimulation with both
growth factors did not result in intensified proliferation. Additionally, under
stimulation altered expression of various metabolic components was detected.
Conclusion: Our results demonstrate a promoting effect on tumor cell
proliferation of both growth factors PDGF and VEGF. Simultaneous stimulation did not show synergistic effects. PDGF in HT-29 cells resulted in
proliferation in the absence of PDGF receptors with changes in tumor
cell metabolism after stimulation. In conclusion, our data give evidence
for direct receptor/ligand signalling of PDGF not only on stromal cells
but also on colon cancer cells even in the absence of the PDGF receptor.
ID 358
Negative Selection In Vivo RNAi Screening Identifies a
Ribosomal Protein as a New Therapeutic Target in Liver
Cancer
M. Pesic1, K. Wolter1, T. Wuestefeld1, T.-W. Kang1, R. Chawla1,
R. Geffers2, F. Klawonn3, N. Malek4, P. Schirmacher5,
P.K. Premsrirut 6, T. Longerich5, L. Zender1
University Hospital Tuebingen, Division of Translational Gastrointestinal
Oncology, Dept. of Internal Medicine I, Tuebingen, Deutschland
2
Helmholtz Centre for Infection Research, Genome Analytics Group,
Braunschweig, Deutschland
3
Helmholtz Centre for Infection Research, Bioinformatics and Statistics,
Braunschweig, Deutschland
4
University Hospital Tuebingen, Internal Medicine I, Tuebingen, Deutschland
5
University Hospital Heidelberg, Institute for Pathology, Heidelberg, Deutschland
6
Mirimus, Inc., Cold Spring Harbor, New York, Vereinigte Staaten Von Amerika
1
Due to the lack of treatment options hepatocellular carcinoma (HCC) represents the third most frequent cause of cancer related death. The major
obstacle in HCC treatment is resistance to chemotherapy and new therapeutic targets, to overcome the treatment resistance, are urgently needed. We
devised a system that allows conducting negative selection in vivo RNAi
screens to identify new therapeutic target genes in murine HCCs. Multilocular invasive HCCs develop after short latency when oncogenic Nras is stably delivered into p19-/- mouse livers via transposable elements. As a proof
of principle that RNAi mediated knockdown of target genes can cause lethality of Nras driven HCCs, we showed that stable expression of shRNA
targeting a cell essential DNA replication protein 3 completely blocked
Nras driven tumorigenesis and that shRNA against Ras downstream target
B-Raf reduced the tumor burden of injected mice. To identify vulnerabilities of Nras driven murine HCCs that may be exploited as new therapeutic
targets, transposable elements co-expressing Nras and a focused shRNA
library were stably delivered into p19-/- mouse livers. The frequency of each
shRNA in the library before delivery into hepatocytes and after hepatocarcinogenesis was quantified via deep sequencing and a comparison of
obtained profiles identified hairpins against a ribosomal protein as top depleted. Functional validation experiments with different hairpins show that
knockdown of our candidate gene strongly suppress Nras driven tumorigenesis in p19-/- mice. Inhibition of expression of ribosomal candidate gene
via RNAi drives the murine hepatoma cells into irreversible cell cycle arrest
that has features of senescence. Interestingly, the cells upregulate cytokines
involved in activation of immune cells that mediate their clearance.
ID 359
Ipilimumab therapy seems to induce CD28 antibodies
with inhibitory effect on T cells of melanoma patients
C. Pföhler, K.-D. Preuss, E. Janssen, R. Koerner, C. Müller, T. Vogt
Universitätsklinikum des Saarlandes, Klinik für Dermatolgie, Homburg,
Deutschland
CD28 antibodies (abs) may have immunostimulatory effects by acting
as superagonists on the CD28 receptor of T cells followed by induction
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of T effector cells. On the other hand they may have immunosuppressive
effects by activating regulatory T cells or by blocking of the T cell receptor in its proper function. We constructed an ELISA assay to measure
CD28 abs in the serum of melanoma patients. We could show that 42/230
(18.3%) of all melanoma patients had CD28 serum antibodies while only
2/140 (1.4%) healthy blood donors were positive. In further experiments
we could show that CD28 abs of melanoma patients lead to reduced stimulation of Jurkat cells in vitro. This effect was titer-dependent as high
titers resulted in a stronger inhibition than a low titer. First prospective
investigations in a small group of patients receiving ipilimumab in stage
IV melanoma showed a seroconversion in about one fourth of the patients
meaning no prove of CD28 abs at the beginning of therapy followed by
production and detection of CD28 antibodies during therapy with ipilimumab. First analyses showed that titers of CD28 abs increased over time,
in some patients titers declined after stopping therapy with ipilimumab.
CD28 abs positive patients showed a progression of disease in all cases.
Further T cells assays are required to investigate the impact of CD28 abs
on T cells of melanoma patients. In addition we need to prove whether
ipilimumab therapy is able to induce the production of blocking CD28
abs. If our first observations can be confirmed discontinuation of ipilimumab therapy should critically be discussed after detection of CD28 abs.
Potentially, CD28 abs could serve as a relevant biomarker during immunotherapies with e.g. ipilimumab or anti-PD1 antibodies.
ID 375
Targeting mTORC2 component RICTOR impairs tumor
growth in an experimental pancreatic cancer model
K. Schmidt, C. Wagner, J. Redekopf, H.J. Schlitt, E.K. Geissler,
S. A. Lang
University of Regensburg, Surgery, Regensburg, Deutschland
Background: The serine/threonine kinase mTOR (mammalian target
of rapamycin) is active in two distinct complexes, called mTORC1 and
mTORC2. mTOR inhibitors that have recently gained increasing interest for the treatment of human pancreatic cancer, usually only affect
mTORC1. Since mTORC2 is a major regulator of Akt activity which in
turn plays a pivotal role in the development of human pancreatic cancer,
we assessed the effects of targeting RICTOR, an essential component of
mTORC2, on growth of pancreatic cancer cells.
Methods: The human pancreatic cancer cell line HPAF-II was stable
transfected with an shRNA plasmid targeting RICTOR including the respective control (Invitrogen). Knock-down was verified via Western blotting and/or PCR. In vitro effects of RICTOR inhibition on growth of cancer cells were assessed using MTT and cell count assays. Subsequently,
migration assays were employed to determine potential effects on cancer
cell motility. Tumor growth was finally evaluated in an orthotopic pancreatic cancer model in vivo.
Results: Stable transfection with the shRNA plasmid efficiently impaired
RICTOR expression in human pancreatic cancer cell line HPAF-II as
determined by Western blotting. In MTT assays, only minor effects on
growth of tumor cells were observed. In contrast, a significant inhibition of cancer cell motility was found upon RICTOR blockade in vitro
(≤0.05). In vivo, RICTOR knock-down led to significant impairment of
tumor growth as determined by final tumor weight (≤0.05). Moreover, the
incidence of liver and lymph node metastases was strongly reduced upon
RICTOR inhibition.
Conclusion: Inhibition of mTORC2 component RICTOR impairs tumor growth and metastases in vivo. Although the exact mechanism of
these effects remains to elucidated, therapies targeting RICTOR may be a
promising approach to improve current treatment concepts in pancreatic
cancer patients.
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Oncological Pharmacy
ID 237
Cumulative bisphosphonate dosages increase the risk
of bisphosphonate associated osteonecrosis of the
jaws – analysis of 67 patients with prostate cancer and
bisphosphonate therapy
C. Walter1, C. Engel1, C. Thomas2
1
2
Universität Mainz, Urologie, Mainz, Deutschland
Introduction: Bisphosphonates (BP) are associated with the occurrence
of osteonecrosis of the jaws (BP-ONJ). Nitrogen-containing bisphosphonates (N-BP) such as zoledronate and pamidronate are more often associated with BP-ONJ compared to non N-BPs such as clodronate. The aim of
this study was to analyze the effect of bisphosphonate treatment duration
on the likelihood of developing BP-ONJ.
Material and Methods: Patients from two cross-sectional studies performed in the Urologic Department at the University Medical Center of
the Johannes Gutenberg-University were analyzed regarding the duration of BP intake before a BP-ONJ developed.
Results: The studies were performed in 2011 and 2007. All together 67
patients had been treated due to prostate cancer; 10 of the 67 patients
had developed a BP-ONJ. There were no differences in between the two
groups. The average time of BP-intake was 18 (±14 standard deviation)
months for the entire group and 16±14 months for the patients without
and 27±11 months for the patients with BP-ONJ (p = 0,026).
Conclusion: The occurrence of BP-ONJ is correlated to the time of
BP-administration most probably due to the cumulative effect of the
N-BP. Similar side effects can be seen in patients receiving new medications such as antibodies against Rankl or tyrosine kinase inhibitors. In
cases where the primary disease allows it it might be feasible to either
reduce the frequency of BP administration or use medications that are less
often associated with osteonecrosis such as clodronate.
ID 289
Antineoplastic activity of alkylphosphocholines in cell
lines of B- and T-cell origin
Y. Ilieva1,2, S. Konstantinov1, M. Berger2
Medical University – Sofia, Department of Pharmacology, Pharmacotherapy and Toxicology, Bulgarien
2
DKFZ, Unit of Toxicology and Chemotherapy, Heidelberg, Deutschland
1
Miltefosine, perifosine and erufosine are representatives of the three
generations of alkylphosphocholines. Certain agents of this class of compounds have recently become known as inhibitors of AKT phosphorylation. Nevertheless, the differences in chain length, saturation of the carbon
chain, and position of the cis-double bond are associated with variations
in their mechanism of action, cytotoxicity, route of administration and
side effects. Initial investigations of their cytotoxicity in tumor derived
cell lines of B-cell and T-cell origin were performed by the MTT-dye
reduction assay. Our results showed a well pronounced dose – response
inhibition and the lowest observed IC50 values ranged from 2.2 µM for
perifosine (B cell lymphoma cell line DOHH-2, 48 h incubation) to 5.7
µM for erufosine (T cell lymphoma cell line HuT-78, 72 h incubation) and
to 8.8 µM for miltefosine (T cell lymphoma cell line HH, 48 h incubation). The lowest sensitivity to erufosine (IC50 = 108 µM, 24 h incubation)
and perifosine (IC50 = 92.0 µM, 24 h incubation) showed the B cell lymphoma cell line REH and the cell line DOHH-2 was the least sensitive to
miltefosine (IC50 = 44.4 µM, 24 h incubation). The mean IC50 values for
the three compounds were as follows: miltefosine - 21 µM, perifosine - 23
µM and erufosine - 50 µM. Compared to solid tumor derived cell lines,
like MCF-7 and MDA-MB-231 which show IC50 values of about 40 µM,
the variation in sensitivity to alkylphosphocholines between B- and T-cell
lymphoma derived cell lines is apparently greater. Future experiments
Abstracts
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Index
will therefore concentrate on the reason of this variation in sensitivity
including an analysis of the expression of apoptosis related genes and of
signaling pathways based on AKT.
ID 315
Oncology Competence Pharmacy – a German approach
to improve quality in oncology pharmacy
K. Meier1, K. Ohlinger2, S.-O. Nissen2, E.-M. Schöning2
Deutsche Gesellschaft für Onkologische Pharmazie, Hamburg, Deutschland
medac, Wedel, Deutschland
testine. Toxicology studies carried out in transgenic mice have shown that
i.v. injection of JO-1 is safe. In vivo studies have demonstrated that JO-1
remains active in the presence of anti-JO-1 antibodies. Taken together,
these findings offer preclinical proof of concept to employ JO-1 treatment
prior to mAb therapy or chemotherapy for cancer patients.
Paediatric Cancer
1
2
Introduction: Nowadays oral chemotherapy occurs more often in treatment of cancer patients. This demands a lot of knowledge regarding safe
handling of oral chemotherapy agents. Community pharmacy staff needs
special education and expert knowledge in order to counsel oncology
patients and for the communication with other healthcare professionals.
The same expert advice of high quality must be ensured regardless which
pharmacy staff member is providing the advice. Therefore every staff
member needs the same level of education. To ensure this standard we
developed the project ‘Oncology Competence Pharmacy’ (OCP).
Material and Method: German society of oncology pharmacy (DGOP) in
cooperation with medac developed the concept of OCP to verify the special
cytotoxic drug knowledge of pharmacy employees. The project is based on
an online tool for continuing education in oncology pharmacy. Therefore
every staff member gets an individual access to an e-learning online platform where he has to pass through different trainings provided as online
presentations and proof his educational success by a multiple choice test.
Currently 61 pharmacies with more than 700 members take part.
Results and Discussion: The online tool enables every staff member
to study whenever it is possible for the individual. Team studies are not
necessary so that the daily work flow is not impaired and everyone may
take the time he needs to gain qualifications in certain fields of oncology
pharmacy. The main target to ensure that every staff member has the same
level of education is locked by a multiple choice test.
Conclusion: The concept of OCP improves the quality in oncology pharmacy and helps oncology patients to find a specialized pharmacy.
ID 224
JO-1, an epithelial junction opener for the improvement of
cancer therapy
I. Beyer1, J. Persson2, H. Song2, H. Cao2, Q. Feng2, R. Yumul2,
R. van Rensburg 2, Z. Li2, C. Drescher2, A. Lieber2
Heinrich Heine Universitaet Duesseldorf, Frauenklinik, Duesseldorf,
Deutschland
2
University of Washington, Medical Genetics, Seattle, Vereinigte Staaten
Von Amerika
1
Epithelial cancers maintain intercellular junctions that link cancer cells together and prevent the penetration of therapeutics into the cancer. Several
studies demonstrated that the upregulation of epithelial junction proteins
correlated with increased resistance to therapy, e.g. monoclonal antibodies (mAb) and chemotherapeutics. One of the epithelial junction proteins
is desmoglein 2 (DSG2). Recently, we demonstrated that a group of human adenoviruses (Ad) use DSG2 as a primary attachment receptor for
the infection of cells. DSG2 is overexpressed in epithelial malignancies.
We have created a small recombinant protein derived from Ad serotype 3,
which binds to DSG2 and triggers transient opening of epithelial junctions.
We therefore named the protein JO-1 (junction opener -1). In several xenograft tumor models, we have shown that i.v. injection of JO-1 increased
the efficacy of mAb therapy. Many chemotherapy drugs are larger than
500 Da, the upper limit of molecules that are able to pass through tight
junctions. We have demonstrated that the therapeutic effects of several of
these drugs, including paclitaxel, nab-paclitaxel and liposomal doxorubicin are increased by co-therapy with JO-1. Furthermore, we have shown
that JO-1 leads to accumulation of drugs in the tumor. This resulted in the
decrease of chemotherapy-related toxicities to bone marrow, liver, and in-
Abstracts
ID 118
The Rehabilitation of Adolescents and Young Adults
(AYA): Co-operation between Pediatric and Adult
Oncologists results in a successful Transition – the Bad
Oexen Experience as a Model
K. A. Krauth1, V. König2
Klinik Bad Oexen, Pädiatrie/Kinderhämatologie und Onkologie, Bad
Oeynhausen, Deutschland
2
Klinik Bad Oexen, Onkologie, Bad Oeynhausen, Deutschland
1
Over the last decades the number of pediatric cancer patients reaching
adulthood has increased significantly. In order to ensure a good long-term
quality of life a successful transition from pediatric to adult oncology is
essential. How can the knowledge and experience of pediatric oncology
be successfully transferred into adult oncology?
While many former pediatric oncologic patients can lead a normal adult
life, a significant number of them must be regarded as chronically ill. So
far many of these patients, e.g. suffering from long-term sequelae of brain
or bone tumors and their treatments, are not adequately taken care of, as
soon as they leave pediatric oncology. Therefore, to ensure a smooth transition the combined efforts of pediatric and adult oncologists are needed
in order support the development of AYA units in oncologic centers.
More than 25 years of oncologic inpatient rehabilitation of adolescents
and young adults in Bad Oexen have proven that a team consisting of:
pediatric and adult oncologists, pediatric and adult nurses, physical therapists, ergotherapists, social workers, speech therapists and dietitians experienced in the treatment of adolescents and young adults ensure asuccessful rehabilitation in most patients. Adolescents and young adults are
rehabilitated in differentiated age groups ranging from 14 to 18 and 18 to
32 years. Close co-operation of pediatric and adult oncologists and their
teams leads to this success.
Thus the rehabilitation concept of the oncologic rehab center of Bad
Oexen/Bad Oeynhausen, Germany, represents a unique, innovative and
well-established model for the successful transition from pediatric to
adult oncology through close co-operation of pediatric and adult oncologists and their teams
Palliative Care
ID 026
The health insurance companies (HIC) practice of
accepting or reviewing prescriptions (PR) for specialized
outpatient palliative care service (SAPV) in Hesse
F.K. Tauchert1, M. Ruppert1, E. Jäger1
Krankenhaus Nordwest, Klinik für Onkologie, Frankfurt am Main, Deutschland
1
Background: SAPV in Hesse has been established in January 2010 to
provide professional care for patients in the last phase of life in their
homes. The increasing number of patients in SAPV lead to more reviewing of the prescriptions by the HIC. The Aim of this study was to explore
possible problems with prescriptions leading to reviews.
Methods: All SAPV-PR of our outpatient palliative care team in the period from april to June 2013 (n = 129) were analyzed for various factors
whether the HIC did a review or not.
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Results: The biggest HIC did 29.4% reviews vs. 5.3% for the rest
(p < 0.001). 2.0% of f1st-PR vs. 17.7% following-PR were reviewed
(p = 0.007). 7.7% of short-time-PR vs. 13.3% of long-time-PR were
reviewed (n.s.). 10.6% of PR for cancer-patients vs. 18.8% of PR for
non-cancer-patients were reviewed (n.s.)
Conclusions: The health insurance companies focus on reviewing following-PR. 93.3% of the reviews were initiated by only two HIC representing 30.2% of the patients. These findings should be verified by a
multicenter survey with a bigger sample to show whether this leads to
disadvantages for the patients.
ID 030
The mobile oncology service – a project for rural cancer
patients
U. Vehling-Kaiser , T. Sternfeld , F. Kaiser
1
2
1
Deutschland
2
1
Intravenous chemotherapies are more and more replaced by oral and
subcutaneous drugs. These therapies are more convenient as they can be
taken by the patients at home. Nevertheless side effects can occur and
therefore regular follow up examinations are mandatory. For severely
ill or otherwise handicapped patients in rural areas the transport to the
ambulatory cancer centre can be stressful and exhausting. Rural regions
are often characterised by long-distances, an insufficient public transport system and a low number of specialised cancer centres. To reduce
the frequency of necessary patients’ visits to the centre during an oral or
subcutaneous cancer therapy, a mobile oncology service (MOD: Mobiler
Onkologischer Dienst) was initiated. This service is offered to the described subgroup of handicapped or severely ill patients only. Doctor’s
assistants trained in the field of tumour therapy visit the patients on a regular basis. The compliance with the oral therapy is checked and patients
are asked and examined for side effects. Relevant changes are discussed
with the oncologist immediately. The MOD pilot project is sponsored by
the Bavarian State Ministry of the Environment and Public Health.
ID 170
Experience of a monoinstitution of a geriatric-oncology
department in treatment of advanced head and neck and
bronchogenic cancer
ID 266
Inhouse training of palliative medicine and its effects and
evaluation in a breast and gynecological center of a CCC:
Palliative treatment in clinical routine
R. Würstlein1,2, B. Haberland3,2, K. Ulbach1, K. Friese4,2,
V. Heinemann5,2, N. Harbeck1,2, C. Bausewein3,2
3
Klinikum der Universität München, Palliativmedizin, München, Deutschland
4
Klinikum der Universität München, Frauenheilkunde und Geburtshilfe,
5
Klinikum der Universität München, CCC, Med. Klinik III, München,
Deutschland
1
2
Background: Early integration of palliative medicine in the treatment
of oncological patient is highly recommended. Control of symptoms in
a metastasized stage is an immense interdisciplinary challenge for doctors and nurses. In cooperation with the clinic for palliative medicine a
training in the setting of a pilot scheme was developed. The focus was on
communication, control of symptoms and structures of treatment. The Inhouse trainining of palliative medicine in gynecological hospital (ITPG)
was evaluated by three questionnaires (before, directly after and three
month after the ITPG).
Results: Questions involved the motivation to participate, differences between the specialized groups and palliative care including the treatment
of complex symptoms. 78% of the participants had background in palliative care. Suggestions for improvement of the cooperation were seen in
the management of transferring and external specialists. Before ITPG 5%
of the participants assessed their skills in palliative care as not good, 32%
as very low, 42% as low, 11% as good and none as very good prepared.
After ITPG, 5% assessed their skills as low, 75% as good and 16% as
very good prepared.
Conclusion: The goal of ITPG is the improvement of personal skills and
the optimization of palliative care in the breast center and gynecological centers of cancer CCCLMU in cooperation with the clinic for palliative
medicine. The great acceptance to participate as an interdisciplinary team
in the ITPG induced an improved communication and amplified skills in
gynecological palliative care. A short and intensive advanced educational
training period shows an immense improvement of the participants’ skills
in palliative treatment. Therefore, the pilot scheme establishes the basis to
transfer this dynamic training of palliative medicine on other oncological
areas of the clinical center.
M. Schroeder1, F. Diab2, C. Noack3, U. Schäfer3
HELIOS Klinikum Duisburg, Medizinische Klinik 2 u. 7, Duisburg,
Deutschland
2
RNR an HELIOS St. Johannes Klinik, Duisburg, Deutschland
3
HELIOS Klinikum Duisburg, Medizinische Klink 7, Duisburg, Deutschland
1
Head and neck and bronchogenic cancer are most frequently diagnosed
in elderly pts with a rate of 60–80% in age more than 65 years. Therefore
cancer is in essential an old age cancer. Studies of old aged pts over 75
years don´t exist in theses tumorentities.
We report our experience with 34 pts with BC and H+N aged 70+ years
(median 76 years). All pts have been classified as incurable by an interdisciplinary tumor-board. Pretreatment investigation included geriatric
assessment, social evaluation, investigation of physical organ function,
comorbidities, comedication and reduction of functional status.
19 pts with H+N (f=9 / m=10) and 15 pts with BC (f=8 / m=7). All pts
suffered from deficit of 1 ADL and 1 iADL. 28/34 pts suffered from cognitive deficit. Treatment procedures will be reported in details. Survival
data are remarkable but not comparable with younger pts < 70 years.
Conclusion: Even geriatric multimorbid pts with H+N+BC have a profit
of a moderate antitumour therapy. Combined RX / CTX should be done
as hospitalized pts. Intensive supportive care has to be done. Remarkable
survival times are achievable, even more than 2 years. There is no standard therapy – individual treatment is necessary
102
Patient Care
ID 020
Patient satisfaction with oncologic care – an assessment
of the key sectors: Primary care physicians, specialist
physicians, hospitals and health insurance providers
C. Degen1,2, D. Möller2, C. Schlechter3
Deutsches Krankenhausinstitut, Universitäre Forschung und angewandte
Wissenschaft, Düsseldorf, Deutschland
2
Universität zu Köln, Seminar für Allgemeine BWL und Management im
Gesundheitswesen, Köln, Deutschland
3
megapharm GmbH, Herstellermanagement, Sankt Augustin, Deutschland
1
Objective: The following study examines the influencing factors on the satisfaction of oncologic patients with their primary care physician, specialist
physician, hospital and health insurance. Patient satisfaction with cross-sectoral collaboration is examined based on the satisfaction with these sectors.
Method: 12 specialist practices from 8 federal states participated in the
patient survey during the period 2011–2012. The satisfaction of 516 patients was investigated by multiple regression analysis.
Results: The results show that patients are content with cross-sectoral
collaboration if they are satisfied with their health insurance and specialist
Abstracts
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physician. For the satisfaction with the primary care physician and specialist physician, trust is perceived to be the most important influencing
factor. For hospitals, the most significant influencing factor is interest in
and time for patients. Regarding health insurance providing patients with
information leads to a greater degree of satisfaction.
Conclusion: Psychosocial factors are of key importance for patients’ perceptions of satisfaction with the different sectors. This contains factors
like to ‘putting confidence in physicians’ or ‘talking about patients’ fears’.
Oncologic care sectors should give more consideration to these factors
during patient care. A health insurance provider can take the role of a
competent point of contact, providing quality-assured information in the
context of oncologic diseases.
ID 041
Presentation and findings of a pilot project from the
«Bayerische Krebsgesellschaft» (BKG): «Special
consultation hour for patients suffering from cancerrelated fatigue»
I. Fischer1, D. Salzmann2, J.U. Rüffer3, J. Lennert2, S. Petsch4,
M. Besseler2
Institut für Tumor-Fatigue-Forschung, Emskirchen, Deutschland
Bayerische Krebsgesellschaft, München, Deutschland
3
Deutsche Fatigue Gesellschaft, Köln, Deutschland
4
Tumorzentrum der Universität Erlangen-Nürnberg, Erlangen, Deutschland
formation, and an algorithm illustrating the care process. Among others,
the effectiveness of the model is evaluated using the patient-reported outcome (PRO) version of the CTCAE criteria. The newly developed instrument was tested in a pilot study.
Results: Care modules were developed for medication review and interaction check, malnutrition, adherence and for the management of four
common adverse events: nausea/emesis, mucositis, fatigue, and pain.
They can be applied individually for each patient according to medication
and anticipated toxicity. In the pilot study 30 outpatients with solid tumors were surveyed. Results show that approximately 73% of the patients
suffered from severe or very severe toxicity according to PRO-CTCAE.
Fatigue was the most frequent adverse event (87%) followed by sleep
disorders (70%) and nausea (57%).
Outlook: The feasibility of the model is currently being evaluated in a
randomised two-arm interventional trial at the Johanniter-Hospital, Bonn.
About 50 patients are allocated either to the control group or to the intervention group. Endpoints of the study are the frequency and severity
of toxicity according to PRO-CTCAE and health-related quality of life.
Moreover, the acceptance of the model among health care professionals
and patients will be evaluated. The model is currently being adapted to
the conditions at the university hospital of Cologne.
1
2
Cancer-related fatigue (CRF) is defined as a persistent, subjective sense
of tiredness related to cancer or cancer treatment. It can significantly
impair normal physical and psychological functioning and -as a consequence of this- also every day life and quality of life. Although lots of
patients are affected and although evidence-based treatment options are
available, there is a lack of qualified counseling institutions inGermany.
As to date there is no ICD-code for cancer-related fatigue, the care-gap
most suitable can be closed by a nonprofit organization like the BKG.
Thus, together with the «Institut für Tumor-Fatigue-Forschung» the BKG
established in its psycho-social advice center in Nuremberg a free-of-cost
consultation hour for patients. It is comprised of diagnosis, individual
consultancy, education and the offer to take part in training courses, being
appropriate for patients with cancer-related fatigue and being orientated
on the current available evidence-based treatment options. This would
provide the first consultation for cancer-related fatigue of its kind under
the umbrella of the «Deutsche Krebsgesellschaft» (DKG).
The consultation hour is connected with a project in health services research. The intent of this research project is to identify the realistic need
for such a consultation hour and to evaluate their concept and their benefit. It is our aim initially to develop a consultation hour so that it could
be taken on by other consultation centers as needed. The project will be
performed in co-operation with the «Deutsche Fatigue Gesellschaft»
(DFaG) and the «Tumorzentrum der Universität Erlangen-Nürnberg».
The pilot project ends in December 2013; findings of the pilot phase will
be presented.
ID 171
Evaluation of a best-practice model for multiprofessional
cancer medication management
A. Wilmer1, A. Tasar2, K. Fleckenstein3, C. Hack3, H. Beck4,
A. Liekweg4, K. Ruberg2, Y.D. Ko3, U. Jaehde1
Universität Bonn, Klinische Pharmazie, Bonn, Deutschland
Kronen-Apotheke Marxen, Wesseling, Deutschland
3
Johanniter-Krankenhaus, Bonn, Deutschland
4
Uniklinik Köln, Apotheke der Uniklinik, Köln, Deutschland
ID 261
Ten years of successful oncologic quality assurance in
certified breast centres in Germany
S. Brucker1, M. Wallwiener2, M. Bamberg3, D. Wallwiener1,
C. Steering4
University Women’s Hospital, Tübingen, Deutschland
University Women’s Hospital, Heidelberg, Deutschland
3
University Medical Centre, Tübingen, Deutschland
4
Participating breast centres, Germany, Deutschland
1
2
Purpose: The German Society of Senology (DGS) and the German Cancer Society (DKG) developed and implemented a multimodal system on
the certification of breast centres. Aim was to establish a nationwide cooperation network between breast centres and an independent external
analysis institute to allow the proof of existing differences in quality of
care and the verifiability of quality assurance by an extensive benchmarking and thus to improve overall quality of care.
Methods: An own developed generic XML-based data set was used for
data collection from the hospitals and the annual analysis by an independent external benchmarking centre (Westdeutsches Brustcentrum
(WBC)). Annual conferences on the screening of the quality indicators
attended this process. By this the quality, structures, processes and results
should be assured in terms of the diagnosis and treatment of breast cancer.
Results: Overall 21 quality indicators (QIs) and sub-quality indicators
were developed. Three QIs have been abandoned, since they were stable
after a few years. 11 out of 14 QIs with defined DGK/DGS guidelines
could fulfill these by more than 90%, 6 were even over-fulfilled. Especially QIs on therapeutic recommendations, very important for the outcome
quality, could be crucially improved.
Conclusion: Specialization, guideline-concordant procedures as well
as certification and recertification of breast centres remain essential to
achieve further improvements in quality of breast cancer care and to stabilize and enhance the nationwide provision of high-quality breast cancer
care. Thereby national and international harmonization of the efforts has
to be pursued.
1
2
Objectives: This project aims at enhancing patient safety by structured
and standardized cancer care in a multiprofessional best-practice model.
Methods: The module-based model was developed in a multiprofessional quality circle to define ‘best practice’. All care modules include
evidence-based recommendations for supportive care, written patient in-
Abstracts
ID 265
What does it means, when my pathology report says...
I. Klempert, M. Dietel
Charité Universitätsmedizin Berlin, Institut für Pathologie, Berlin, Deutschland
Aims: Patients often have problems understanding the information given
in pathology reports. Inspired by Jonathan I. Epstein’s «The FAQ Ini-
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tiative Explaining Pathology Reports to Patients» (http://www.adasp.org/
FAQs/faqs.htm), we have started the development of an internetbased
free access platform, answering the most frequently asked question in
connection with pathology reports in German.
Methods: We used the existing contents of the website as a guideline and
translated the questions and answers into German. To provide a better orientation for patients, we designed a colour-coded layout. A brown background is used for fundamental knowledge, green stands for «healthy»,
red for «malignant» and yellow for everything in between. Additionally
we added new topics for example «cervix», based on often asked questions by patients in Germany.
Results: We have built a free access internet-based platform which provides useful and easy-to-understand information for uncertain patients,
but also for physicians and medical students. Additionally it is planed
to connect the pathology-platform to other similar platforms of different
medical disciplines such as surgery to provide a broader range of information.
Conclusions: The free access internet platform for uncertain patients,who
want to understand their pathology reports or find out more about pathology is a firm start, but it is necessary to update the website’s content regular and add new topics. We believe that our website offers a helpful and
fast assistance for unsettled patients.
ID 302
Cancer Survivorship – First experiences of the L.O.T.S.E.
– Project of the University Cancer Center Hamburg
(UCCH)
D. Becker, M. Trepel, C. Bokemeyer, G. Schilling
UKE, Universitäres Cancer Center, Hamburg, Deutschland
L.O.T.S.E. – Living Without Tumor – Strategies and Education is the
name of the newly established Cancer Survivor Program at the UCCH.
One part of this huge project is a special consultation, tailored towards
cancer survivors.
Between February and August 2013 we have seen a total of 75 patients.
Eighty-five percent were female, 15% male, with an average age of 62
and 63 years, respectively. The time since first diagnosis of a malignant
disease was 13.7 years for the female group and 8.9 years for the male
collective. Whereas different hematological and solid tumors were well
balanced in the male group, in the female group almost 60% had breast
cancer.
To learn more about the needs and concerns of these patients, we used a
short questionnaire (4-level Likert scale), asking about current psychosocial and physical burdens, as well as about supportive care needs.
The gravest psychosocial burdens reported by both genders concerned
fears -, which was followed by sorrows in the female group. The highest rated physical burdens the patients reported were pain, fatigue, sleep
disorders, polyneuropathic complaints, cognitive deficits, sexual dysfunctions and nausea.
The survey revealed that the highest supportive care needs, regardless
of gender, was to cope with uncertainty about the future, fears, physical
deficits and, a need for better information concerning the course of their
disease. The most important concern was the need for a permanent available contact person. Women also rated as high a need for support to better
cope with sadness and depression.
Our pilot study clearly shows a requirement to establish so called survivorship centers, which fill the current void of unmet care needs for this
rapidly growing group of patients.
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ID 304
Disabled oncological patients represent the main target
group for a sectoral-independent support through the
social service – evaluation of a survey at the University
Cancer Center Hamburg (UCCH)
S. Prange1, M. Frese2, C. Bokemeyer3, G. Schilling3
Universitätsklinikum Hamburg-Eppendorf, Patient Care Management,
Department of Social Work, Hamburg, Deutschland
2
Universitätsklinikum Hamburg-Eppendorf, Quality Management, Hamburg, Deutschland
3
Universitätsklinikum Hamburg-Eppendorf, Universitäres Cancer Center
Hamburg, Hamburg, Deutschland
1
In a representative survey of cancer patients in an in- and outpatient setting conducted at the UCCH between February and March 2013, a total
of 1624 patients were evaluated in respect to their satisfaction with the
social service and their further needs.
More than 60% of all participants stated to be of working-age. Twenty
percent of this subgroup was disabled at the time of the survey. Forty-five
percent of these patients never had contact with the social service.
In respect to both, physical as well as mental demands of work life in
general, the group of disabled patients voiced a low score of their ability
to work. Sixty-four percent considered themselves not employable within
the coming next two years and two-thirds did not believe to be able at all
to resume employment before retirement. Thirty percent planned to apply
for early retirement and 20% had already done so before taking part in
the survey.
The survey revealed that disabled patients were the group with the strongest needs for further social encouragement beyond the support they currently received. Only 36% reported satisfactory support after discharge.
In consideration of general demographic developments and regarding the
rapidly growing number of cancer survivors, participation in working life
is of great importance.
Achieving, improving or (re-)establishing the working capacity should
be the ultimate ambition for every patient in working-age after successful
cancer treatment. As all steps and interventions concerning return to work
are usually taken after completion of oncological treatment, social service
within a cancer center should be aligned to accompany disabled patients
independently of the sectors in an optimal way during their process of
vocational integration.
ID 343
Central Clinical Cancer Registry of Mecklenburg-West
Pomerania – concept and first experiences
S. Ulrike, C. Sell, P.H. Lahmann, W. Hoffmann
Institut für Community Medicine, Universitätsmedizin Greifswald, Zentrales
Klinisches Krebsregister M-V, Greifswald, Deutschland
Introduction: The Clinical Cancer Registry Law of Mecklenburg-West
Pomerania mandates that all physicians, dentists and pathologists involved in the diagnostic and treatment of cancer patients report information on diagnosis, treatment and disease progress to regional Clinical
Cancer Registries. The patients are asked to give informed consent to
the reporting and have the right to refuse further processing of their data.
The regional Cancer Registries should send the patients’ identifying data
to the so called «Treuhandstelle» (trusted third party) to obtain a pseudonym for each cancer patient. The de-identified clinical information and
information on reporting physicians and hospitals is sent to the Central
Clinical Cancer Registry. The Central Registry will perform a record linkage of the obtained information on each individual patient from the four
regional registries and different time periods.
Concept and First Real Life Experiences: We will present the concept
for implementing the Clinical Cancer Registry Law in Mecklenburg-West
Pomerania and report on experiences from the pilot test of the data exchange.
Abstracts
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The data of the four regional Cancer Registries in Mecklenburg-West
Pomerania will be linked and evaluated in the Central Registry to improve the oncological care. Based on the evaluations, tumour-specific
expert working groups will give feedback to the physicians and dentists
treating cancer patients about the quality of their treatment.
Conclusion: The internal process of quality assurance of clinical data on
cancer diagnosis, treatment and progression will lead to improved health
care for cancer patients in the state of Mecklenburg-West Pomerania.
ID 365
«Ohne geht’s nicht»: Evaluation einer
Radioonkologischen Pflegeberatungsambulanz
F. Papendorf1, M. Mascia2, H. John3, H. Christiansen3, I. Meyenburg-Altwarg2, B. Günther1
MH Hannover, Tumorzentrum, Hannover, Deutschland
MH Hannover, Geschäftsführung Pflege, Hannover, Deutschland
MH Hannover, Klinik für Strahlentherapie und Spezielle Onkologie, Hannover, Deutschland
1
2
3
Fragestellung: In der Klinik für Strahlentherapie und Spezielle Onkologie der Medizinischen Hochschule Hannover wurde im Jahre 2012 eine
Pflegeberatungsambulanz für ambulant bestrahlte Patienten etabliert.
Methoden:
Im Rahmen einer Evaluation wurden alle Beratungskontakte über einen
Zeitraum von 5 Monaten dokumentiert und ausgewertet.
Ergebnisse: In einer Zwischenauswertung konnten die Daten von 306
Patienten evaluiert werden. Eine Erstberatung dauerte durchschnittlich 30
Minuten. 31,4% der Patienten hatten das Angebot einer Folgeberatung in
Anspruch genommen – 21,9% dieser Patienten nahmen sogar mehr als
vier pflegerische Beratungen in Anspruch.
Diese Daten zum Beratungsaufwand können im Zusammenhang mit Angaben zu Diagnosen, Bestrahlungsintention, Beschwerdespektrum sowie
sozialen Parametern relevante Aussagen liefern. Beispielsweise wurden
für 24,6% der Patienten stärkere Beschwerden mit CTC-Grad >=3 dokumentiert, sowie für 23% Schmerzen mit WHO-Grad >=4. Patienten mit
Kopf-/Halstumoren oder gynäkologischem Tumor zeigten einen deutlich
erhöhten Beratungsbedarf.
In einer abschließenden, anonymen Befragung gaben über 80% der Patienten an, dass die Pflegeberatung zu einer Verminderung ihrer seelischen
und körperlichen Belastungen beigetragen habe. Fast alle Patienten fanden das Angebot hilfreich und würden es weiterempfehlen.
Schlussfolgerungen: Eine differenzierte Evaluation kann dazu beitragen,
Patientengruppen mit höherem Beratungsbedarf zu identifizieren, um das
Angebot zielgerichtet zu verbessern. Die hohe Zahl der auf freiwilliger
Basis durchgeführten Beratungsgespräche, die Häufigkeit auftretender
Beschwerden sowie das positive Feedback sollte dazu führen, dieses Angebot in die Routineversorgung zu übernehmen.
ID 460
How tumor board recommendations influence
patient care: Adherence to clinical decisions made in
multidisciplinary teams
A. Frangenberg, A. Bernschein, M. Gardizi, M. Meyer,
U. Schnittner, R. Hatwig, J. Wolf
Deutschland
Introduction: The Center for Integrated Oncology (CIO) Cologne Bonn
has started to implement a hospital-wide standardized, quality-oriented
auditing system to investigate adherence to interdisciplinary tumor board
(ITB) recommendations. First results of a pilot project at the University
Hospital of Cologne (UHC) are available.
Aim: The aim of the first evaluation project was to investigate the implementation of ITB recommendations to patient care in lung cancer (LC)
and colorectal cancer (CRC) patients with initial diagnosis in 2011 and to
identify causes of non-adherence in terms of a feedback-loop.
Abstracts
Methods: ITB records were retrospectively collected. Recommendations were compared with actually implemented therapies/diagnostics by
studying electronic patient files. Causes of non-adherence were identified.
Results: 108 ITB recommendations of 73 LC patients and 96 ITB recommendations of 58 CRC patients were analyzed. The recommendations
given by the ITB included for LC patients: 59% active antitumoral therapy (ATT), 18% further diagnostic procedures (DP), 8% ATT and further
DP, 6% clinical trials, 5% follow up, 4% other / for CRC patients: 62%
ATT, 18% no treatment, 14% ATT and further DP, 5% further DP, 1% other therapies. Regarding overall adherence, 82 of 108 (76%) respectively
82 of 96 (85%) recommendations were completely implemented. Causes
of non-adherence: course of disease made treatment-/diagnostic-change
necessary (35%), patient’s condition was worse/different than described
in the ITB (30%), patient refused the recommendation (25%), non-adherence due to the physician (10%).
Conclusion: Decisions made in multidisciplinary teams of experts have
a high potential of subsequently being realized and thereby influence patient care. What we do not know, however, is whether the implementation
of ITB recommendations in patient care is associated with better clinical
outcomes. Appropriate studies should follow.
Phase I Studies
ID 194
Phase I/II, open label, dose escalating study to
investigate safety, tolerability, and preliminary efficacy
of the trifunctional anti-HER2/neu x anti-CD3 antibody
ertumaxomab in patients with HER2/neu (1+/SISH
positive, 2+ and 3+) expressing solid tumors progressing
after standard therapy
N. Hänse1, M. Jäger2, D. Klunker3, W. Hozaeel1, M.-R. Rafiyan1,
D. Sorgius1, H. Lindhofer2,3, S.-E. Al-Batran1
Institut für Klinisch-Onkologische Forschung, Krankenhaus Nordwest,
Frankfurt/Main, Deutschland
2
TRION Pharma, München, Deutschland
3
TRION Pharma, Martinsried, Deutschland
1
Purpose: Ertumaxomab (ertu) is a bispecific, trifunctional antibody (ab)
targeting HER2/neu, CD3 and the Fcγ-receptors I, IIa, and III forming a
tri-cell complex between tumor cell, T cell and accessory cells. Patients
(pts) with HER2/neu expressing tumors progressing after standard therapy are treated to investigate safety, tolerability and preliminary efficacy.
Methods: In this ongoing investigator driven, non-randomized study,
ertu is applied i.v. in 2 cycles. Each cycle consists of 5 ascending doses
(10–500 µg) applied weekly within 28 days with a 21 day treatment-free
interval. If 2 pts experience a DLT at a given dose level, the MTD will
have been exceeded.
Results: So far 10 heavily pretreated pts (e.g. breast, rectal, gastric cancer) have been enrolled. 1 (10%) pt had a PR at end of study (EoS), 2
(20%) pts had a SD after the first cycle and a PD at EoS. 6 (60%) pts had
a PD after the first cycle and were not further treated. 1 (10%) pt had to be
replaced. So far, no therapy related SAE was detected and consequently
the MTD is not yet reached. All AEs (e.g. headache, fever, chills) were
transient and completely reversible. To date, single doses up to 300 µg
were well tolerated in this dose scheme (total dose up to 670 µg per cycle). All pts showed a transient decrease of the CD3+lymphocyte count
24 h after infusion. 3/5 analyzed pts developed an anti tumor immune response demonstrated by the induction of either anti-HER2/neu-abs (3/3)
or anti-EpCAM-abs (1/3).
Conclusions: In this study, doses up to 300µg can be safely administered
in an escalating dose scheme. First signs of efficacy with only mild and
reversible AEs warrant further increasing of dosing. The development of
anti-HER2/neu and anti-EpCAM abs suggests the promotion of an immunologic memory.
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Psychooncology
ID 004
Is there an influence of prostate cancer diagnosis on
distress and quality of life one year after biopsy?
A. Ihrig1, A. Brechtel1, L. Willmann1, H.-C. Friederich1, T. Kuru2,
J. Seidenader2, B. Hadaschik2, J. Huber2,3
University Hospital, National Center of Tumor Diseases, Section of Psychooncology, Heidelberg, Deutschland
2
University Hospital Heidelberg, Department of Urology, Heidelberg,
Deutschland
3
University Hospital «Carl Gustav Carus», Department of Urology, Dresden, Deutschland
1
Research Question: As a matter of course having cancer is supposed to
worsen quality of life (QoL). The aim of our study was to compare QoL
and distress in men with or without proven prostate cancer one year after
prostate biopsy.
Methods: At the University Hospital of Heidelberg 411 men (age 42–85
years) underwent transperineal MRI-fusion biopsy of the prostate to clarify the suspicion of prostate cancer. One year later patients received a
follow-up questionnaire via mail covering distress, QoL (EORTC-C30),
and the further course of treatment.
Results: The response rate was 78% and 295 questionnaires were analyzed. In 103 patients (35%) the biopsy result was benign, and in 192
(65%) prostate cancer was found. The majority decided for active treatment with radical prostatectomy (125) or radiotherapy (18) while 26
chose active surveillance.
QoL did not vary between patients with or without the diagnosis of prostate cancer. Counterintuitively, QoL was even slightly superior in the
prostate cancer group (EORTC 75 vs 74). Scores in both groups were
higher than normal in prostate cancer patients and the general population. The distress thermometer showed the same tendency (3.0 vs 3.2).
Only treatment related symptoms and social, role, and sexual functioning
showed poorer values in the prostate cancer group.
Conclusions: One year after the initial diagnosis of prostate cancer and
subsequent treatment QoL is not deteriorated. There might be a psychologic burden in the control group, because cancer suspicion can persist
despite a benign biopsy result. Since QoL was even superior to the general population, a paradoxical effect due to the diagnostic measures appears
to be likely.
ID 043
Electronic Psychooncological Screening of Cancer
Patients (ePOS): Diagnostics and Clinical Pathways
N. Schäffeler1,2, M. Wickert1,2, D. Wallwiener3,2, S. Zipfel1,2,
M. Teufel1,2
Universitätsklinikum Tübingen, Psychosomatische Medizin und Psychotherapie, Tübingen, Deutschland
2
Universitätsklinikum Tübingen, Südwestdeutsches Tumorzentrum (CCC),
3
Universitäts-Frauenklinik, Tübingen, Deutschland
Questionnaire-2» (PHQ-2), and «EORTC QLQ-C30» have been used.
Furthermore we asked the patients to indicate their subjective need.
Results: Out of N=245 patients who underwent the routine screening
n = 206 have been included in the study. There is no significant difference between computer- and paper-pencil-version in all instruments. The
maximal accordance of indications has been 88.5% (HADS depression
and PHQ-2), the minimal 36.6% (HADS depression and DT). There have
been small correlations between subjective need and screening indications.
Discussion: This study first reviews the accordance of 5 recommended
screening instruments which is quite low. They seem to focus on different aspects of distress in cancer patients. Nevertheless psychooncological
distress screening considering the subjective need seems to be a feasible
way to route psychooncological clinical pathways. Patients acceptance of
computer-based screening was high.
ID 046
Job related behavioral and experiential patterns of
employable cancer patients before and after inpatient
oncological rehabilitation
M. Reuss-Borst, E. Steckelberg
Rehaklinik Am Kurpark, Bad Kissingen, Deutschland
With an increasingly positive outlook for many tumor diseases as well as
general societal developments such as the increase in retirement age and
emerging lack of specialized workforce, the occupational reintegration of
cancer patients is becoming more important. The AVEM-questionnaire
provides an analysis of participants’ motivation to work, their resistance
to occupational stressors and their emotional states associated with the
working environment. Four coping patterns (cluster-analysis) are distinguished: High risk pattern A (high commitment, excessive demands
of oneself), high risk pattern B (‘burnout’, tendency to give up quickly,
low ability to deal with problems, no experiences of success), protection
pattern S (very low motivation and ambition to work, high ability to distance oneself from problems) as well as the pattern G, which is a healthy,
balanced and ambitious behavioral pattern in relation to the working environment.
A study with 136 cancer patients (70 female, 66 male) between the ages
of 19–60 years was conducted at the beginning and end of an inpatient
rehabilitation program which included an intensive psychosocial training.
A significant increase of patterns beneficial to health (G and S) and decrease of the high risk patterns (A and B) was found (F(2.6, 353.9) = 25.9,
p < 0.001, partial h2 = 0.16). In contrast to males (21.9%), females
(11.4%) had much less pattern G but a significantly higher amount of the
risk pattern B at the beginning of the rehabilitation (p = 0.002).
Working related themes should take a high priority in rehabilitation following a serious illness in order to assist the reintegration into the working environment as well as contribute to a long-term employability.
1
Background: About 1/3 of cancer patients develop distress related mental illnesses requiring treatment. Because of shortening inpatient treatment periods as well as brief personal resources psychooncology has to
face the challenge to reliably identify patients in need and offer prompt
treatment. Current S3-guidelines recommend a psychooncological routine screening as it is already required for certification of organ cancer
centres.
Methods: Patients with breast cancer have been randomly assigned to
a paper-pencil and a tablet-computer questionnaire. To evaluate the accordance of indication for psychooncological treatment the instruments
«Hornheider Screening Instrument» (HSI), «Distress Thermometer»
(DT), «Hospital Anxiety and Depression Scale» (HADS), «Patient Health
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ID 117
Psychooncology on the internet – chance or risk?
A. Winkel
Prosper-Hospital Recklinghausen, Klinik für Urologie, Recklinghausen,
Deutschland
Background: From the medical point of view, the internet is seen with
skepticism concerning the professional benefit. Nevertheless, new online-offers for psychooncological counseling arise on a regular basis.
Psychooncologic assistance demonstrably lessens fear, depression and
stress and helps to establish potent coping strategies. The chances of an
internet-based supervision consist of spatial independence, usefulness
without taking into consideration social standing, a high level of patient-held self-determination and lower influence of geographically disadvantageous locations, sense of shame and challenging family aspects.
Abstracts
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Methods: The web pagewww.projekt-koni.deaims at giving the opportunity for mutual exchange to children suffering from cancer as well as to
their relatives. Users of the website have the option to ask medical experts
questions. In a chat group accompanied by professionals a first contact
is arranged, initializing a continuative supervision without allowing inspection to other users. The questions asked to the psychooncologists are
inspected and evaluated.
Results: The analysis of the results in the frame of the web page directed
at patients suffering from cancer indicate the patients’ strong desire for
continuative supervision not in real life only, but also on the internet. Approximately 70% of the participants of the mentioned survey expressed a
strong wish for a chat supervised by a health professional.
Conclusion: The given data strongly suggests an immense usefulness of
psychooncologic supervision for selected target groups. A successful online supervision requires: an adequate ability to communicate in written
form and effortlessness concerning the handling of the internet.
ID 124
Psychooncological burden in tumor patients receiving
chemotherapy in an outpatient setting
K. Heinig1, A. Lück2, J. Wierecky3, U.-M. Mattner4, V. Schulz5,
H.-J. Hurtz6, F. Breuer7, F. Upleger8, M. Holländer9, B. Adhami10,
B. Otremba11, C. Kurbacher12, P. Schmidt-Rhode13,
P. Herschbach14, R. Reichelt15
SP Gynäkologische Onkologie, Spremberg, Deutschland
Zentrum für Urologie & Onkologie, Rostock, Deutschland
3
Gemeinschaftspraxis mit Schwerpunkt Onkologie & Hämatologie, Hamburg, Deutschland
4
Gynäkologische Praxisklinik, Hamburg-Harburg, Deutschland
5
Brustzentrum Kiel Mitte, Kiel, Deutschland
6
Gemeinschaftspraxis & Tagesklinik, Halle/Saale, Deutschland
7
PIOH, Frechen, Deutschland
8
Frauenarztpraxis am Klosterstern, Hamburg, Deutschland
9
Frauenärztliche Gemeinschaftspraxis, Pirmasens, Deutschland
10
Praxis Dr. Adhami, Erkelenz, Deutschland
11
Onkologische Praxis, Oldenburg, Deutschland
12
Fraunärztliche Gemeinschaftspraxis, Bonn, Deutschland
13
Frauenarztpraxis, Hamburg, Deutschland
14
Roman-Herzog Krebszentrum, München, Deutschland
15
Onkotrakt AG, Hamburg, Deutschland
1
2
Background. Cancer of any type is frequently associated with a psychooncological burden for the affected patients. However, the extent of
this burden often is not readily assessable, as many patients do not express their need for psychooncological counseling.
Materials and Methods. To assess the patients’ burden of disease, a
standardized self-rating questionnaire, termed FBK-R10 (Questionnaire
for Psycho-Oncological Burden of Cancer Patients, 10 items) was to be
answered by each patient at least once throughout the course of therapy.
Patients with a minimum of 1 item scoring 5 or 3 items scoring 4 were
referred to as most heavily burdened. A multidimensional burden was defined for patients not fulfilling these criteria but with a total score of >14.
Results. According to the FBK-R10, 43.7% (n = 652) of the male and
48.0% (n = 1,474) of the female patients suffered from psychooncological distress due to the disease. Merely 10.5% and 18.3% (male vs. female) out of these patients already received or expressed their wish to
receive psychooncological support. In contrast, 1 out of 4 patients with
psychooncological burden were unsure whether psychooncological support would be beneficial. Furthermore, 2.8% and 12.8% of the male and
female patients wanted to get in touch or already were in contact with a
patient support group.
Conclusions. Due to the high uncertainty concerning the demand for psychooncological support, the identification of burdened patients and timely
initiation of appropriate measures are of particular importance. In addition, long-term monitoring of patients is recommended. In this context,
the FBK-R10 has proven to be an appropriate instrument to identify the
need for psychooncological support in cancer patients.
Abstracts
ID 137
Sektorenübergreifende Psychosoziale Versorgung (PSV)
onkologischer Patienten im Rahmen des §116b SGB V
A. von Kries
HSK, Dr. Horst Schmidt Kliniken GmbH, Psycho-Onkologischer Dienst
(POD), Wiesbaden, Deutschland
Die vom Psycho-Onkologischen Dienst (POD) der HSK, Dr. Horst
Schmidt Kliniken GmbH Wiesbaden entwickelten praxistauglichen Versorgungsstrukturen und -abläufe und der notwendige Versorgungsumfang
werden vorgestellt.
Die Indikationsstellung wird beschrieben (Screening, Klinisches Urteil).
Die Dokumentation erfolgt edv-gestützt (ICD, OPS, EBM, Leistungsart
+ Umfang, mit wem und Inhalte. Dies ermöglicht die Analyse der Versorgungswirklichkeit (Statistiken).
Kooperationsverträge mit ärztlichen Praxen wurden gestaltet (patientennahe Versorgung, Interdisziplinarität).
Die Abrechnung erfolgt dierekt mit der GKV.
Fazit: In dem vorgegebenen Rahmen des bisherigen §116b SGB V ist eine
PSV umsetzbar. Die im neuen §116b SGB V geforderten Kooperationsverträge wurden schon umgesetzt. Die Auswertung der realen Versorgungszahlen ergab einen durchschnittlichen Versorgungsbedarf von 10–12 Sitzungen
á 50 Min pro Patient in 70–80% der Fälle ( N 200 / 2011). Die Angehörigen
sind in diesem Rahmen leider nicht eingebunden. Mit dieser PSV konnte die
nachstationäre Versorgungslücke geschlossen werden und die Wartezeit für
die ambulante Psychotherapie überbrückt werden. Zum Erhalt dieser PSV
im neuen §116b SGB V (spezialärztliche Versorgung) wurde mit der Fachgesellschaft PSO/DKG eine Stellungnahme an den G- BA verfasst.
ID 175
Dyadic communication and distress in cancer patients
and their caregivers
H. Sklenarova1, M. Haun1, A. Brechtel1, J. Huber2, M. Thomas3,
E. Winkler4, W. Herzog1, M. Hartmann1
Universitätsklinikum Heidelberg, Klinik für Allgemeine Innere Medizin und
Psychosomatik, Heidelberg, Deutschland
2
Universitätsklinikum Carl Gustav Carus an der Technischen Universität
Dresden, Klinik und Poliklinik für Urologie, Dresden, Deutschland
3
Thoraxklinik am Universitätsklinikum Heidelberg, Onkologie Innere Medizin, Heidelberg, Deutschland
4
Nationales Centrum für Tumorerkrankungen Heidelberg, Medizinische
Onkologie, Heidelberg, Deutschland
1
Problem: Establishing and maintaining open and coherent communication during the trajectory of a cancer disease constitutes a major challenge
for affected families. We examined how cancer patients’ disease-related
communication affects their own well-being and that of their relatives.
Methods: A cross-sectional survey on N = 189 pairs of cancer patients
from mixed cancer type and their closest caregivers was conducted at
the National Centre for Tumour Diseases in Heidelberg, Germany. To determine how patients communicate with caregivers or hospital staff, we
used the 5-item ‘Communication’ subscale of the Cancer Communication
Assessment Tool for Patients and Families (CCAT-PF). In addition, generalized anxiety and depression (GAD-2 and PHQ-2) as well as strain of
patients and their relatives were assessed (QSC-R10).
Results: Communication about the disease was not associated with
depression, neither for caregivers nor for patients. However, significant associations were found for caregiver’s communication score and
caregiver’s anxiety (GAD-2: r = .31 p < .001). In contrast, only modest
correlation coefficients were found for patient-specific communication
scores (GAD-2: r = .18; PHQ-2: r = .09; QSC-R10: r = .30).
Conclusion: These results demonstrate that patient’s degree of communication about the disease is related to dyadic affective adjustment, with
higher importance for the caregiver than for the patient. Therefore, targeting cancer-specific communication of the patient in psycho-oncological
interventions may help to improve emotional well-being not only of patients but especially also of caregivers.
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ID 205
How do nurses and physicians perceive age and need
oriented education of children of parents with cancer? An
explorative study at the university clinic in Munich
A. Beraldi1, S. Tari2, M. Erlbeck1, E. Hoster3, W. Hiddemann3,
P. Heußner1
Klinikum Großhadern, LMU, Psycho-Onkologie der Med III, München,
Deutschland
2
lebensmut e.V., München, Deutschland
3
Klinikum Großhadern, LMU, Med III, München, Deutschland
1
Background: Parents are often uncertain, if and how to talk about their
cancer disease to their children. The better all involved professionals are
informed about how to deal with children of parents with cancer the better
parents can be supported. The clinical experience however shows that
professionals too, are often uncertain and ambivalent regarding the children’s involvement in the disease management. The aim of the study was
to explore the perception, attitudes and cognitions of the different staff
members dealing with children (up to 21 years) of parents with a tumour.
The following questions were investigated:
- Which knowledge, perceptions, attitudes and cognitions regarding age
and need oriented education of children exist?
- How do doctors and nurses perceive the contact with children of cancer
patients in ordinary day in hospital?
Method: We conducted a cross sectional study with 1 time point. Data
collection was carried out from december 2012 until march 2013. Population consisted of nurses and physicians of the haematological clinic at the
university hospital Großhadern inMunich. A self-designed questionnaire
was administrated.
Results: 112 nurses and 65 physicians participated in the study. Return rate
was of 83%. Preliminary results show that over all attitudes concerning the
handling of children of cancer patients correspond to the recommendations
of the current literature. However there exists incertitude concerning specific situations (e.g. premorbid distress, age, severity of the illness).
78% of the sample show experiences in and 45% of them agree to be
distressed by handling with children of cancer parents.
Staff members that are parents are more distressed than participants without children, but would more frequently take the opportunity to talk to
children of cancer patients.
ID 207
Which questionnaire is most suitable for the detection of
depressive disorders in haemato-oncological patients?
Comparison between HADS, CES-D and PHQ-9.
A. Beraldi1, A. Baklayan1, E. Hoster2, W. Hiddemann2, P. Heußner1
Klinikum Großhadern, LMU, Psycho-Onkologie der Med III, München,
Deutschland
2
Klinikum Großhadern, LMU, Med III, München, Deutschland
1
Introduction: Depressive disorders often remain unrecognised in oncological patients (Ford et al., 1994, Mc Donald et al., 1999, Passik et al.,
1998, 2000). The aim of this study was to implement a diagnostic tool
that is suitable for the identification of depressive disorders in haemato-oncological patients. We therefore compared three questionnaires with
a gold standard to define which instrument allows the best to recognise a
depressive disorder in haemato-oncological patients.
Methods: We conducted a cross-sectional study with consecutive patient
accrual. The patients completed a questionnaire about socio-demographic
and medical information as well as the Hospital Anxiety and Depression
Scale (HADS-D, Zigmond & Snaith, 1983, Herrmann et al., 1995), the
9-item Patient Health Questionnaire (PHQ-9, Löwe et al., 2010) and the
Center for Epidemiologic Studies Depression Scale (CES-D) (Radloff,
1977, 1991). The Structured Clinical Interview for DSM-IV (SCID, Wittchen, Zaudig & Fydrich, 1997) served as gold standard.
Results: 128 patients were included. The SCID identified 11 cases with
a depressive disorder. The CES-D found 13 and the HADS-D found 17
108
depressive patients. The PHQ-9 found a depression in 8 cases. The sensitivity and specificity were as follows:
CES-D: 0.82 / 0.97, HADS-D: 0.82 / 0.93 and PHQ-9: 0.36/ 0.97. The areas under the curve (AUC) of the corresponding ROC-curves were significant (p < .001): CES-D = 0.965, HADS-D = 0.931 and PHQ-9 = 0.868.
Conclusion: The HADS-D and the CES-D showed the best sensitivity
and similar specificity and AUC-values. The diagnostic power of the
HADS-D and the CES-D was superior to the PHQ-9. Both seem to be
suitable to identify depressive disorders in haemato-oncological patients.
ID 214
How do long-term survivors of breast cancer remember
their course of illness 6–7 years after therapy onset?
Qualitative analysis of worst and positive experiences of
participants of a randomized trial
P. Lindberg1, M. Koller2, B. Steinger1, P. Netter3, W. Lorenz1,
M. Klinkhammer-Schalke1
Tumorzentrum Regensburg e.V., An-Institut der Universität Regensburg,
2
Zentrum für Klinische Studien, Universitätsklinikum Regensburg, Regensburg, Deutschland
3
Universität Gießen, Fachbereich Psychologie, Gießen, Deutschland
1
Background: Survivorship has become an important field in cancer research. But little is known about how breast cancer survivors remember
their course of disease.
Methods: A follow-up study with survivors, diagnosed with primary
breast cancer in 2004–2006, was conducted. 2×100 women were initially
part of a randomized trial with a quality of life diagnosis and therapy
pathway. More than 6 years after diagnosis, 166 survivors were asked by
questionnaire about their worst experience and positive aspects during
cancer (multiple answers possible). Qualitative data were categorized by
2 independent raters. Divergent cases were discussed with a third expert.
Results: 133 women with mean age of 64.2 years (SD = 10.8) and mean
time since surgery of 84.9 months (range 74–96) participated in follow-up
(response rate 80%). Qualitative questions were answered by 118 participants. As worst experience regarding breast cancer 38% reported psychological distress (e.g. fear of recurrence), followed by chemotherapy with
side-effects (25%), diagnosis (12%), mastectomy (8%), social burden
(7%), fact of having cancer (6%) and additional diseases (6%). Positive
aspects of illness were reported by 53% of survivors: 50% mentioned new
preferences in life (e.g. living more consciously, relaxed), followed by
social support (22%), favorable course of illness (15%), support by health
care staff (10%) and deep gratitude (9%).
Conclusion: Breast cancer survivors remembered psychological distress
and chemotherapy as most stressing during illness. Supportive interventions need to focus on these aspects. The fact, that the majority of women
also found some benefit in suffering from cancer needs to be communicated to newly diagnosed patients for better coping with disease.
ID 223
Effects of socioeconomic status on health-related quality
of life in prostate cancer patients
A. Ullrich1, H.M. Rath1, U. Otto2, C. Kerschgens3, M. Raida4,
C. Hagen-Aukamp5, U. Koch1, C. Bergelt1
Universitätsklinikum Hamburg-Eppendorf, Institut und Poliklinik für Medizinische Psychologie, Hamburg, Deutschland
2
Klinik Quellental, Bad Wildungen, Deutschland
3
Vivantes Rehabilitation, Berlin, Deutschland
4
HELIOS Klinik Bergisch-Land, Wuppertal, Deutschland
5
Niederrhein-Klinik, Korschenbroich, Deutschland
1
Objectives: This study aimed to investigate the effects of socioeconomic
status (SES) on health-related quality of life (HRQOL) in prostate cancer
patients who took part in a medical rehabilitation program.
Abstracts
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Methods: In this prospective multicenter study 837 patients completed the
quality of life questionnaire EORTC QLQ-C30 (15 domains) and its prostate cancer module PR25 (six domains) at the beginning (t1) and the end
(t2) of rehabilitation. To assess SES, we used a composite social class indicator on basis of education, occupation and income (Winkler Index). For
pre-post-comparisons of HRQOL in SES groups, ANCOVAS were modelled at t2-outcome with adjustment for differences among groups at t1.
Results: Patient’s mean age was 57 years and average time since diagnosis was 2.8 months. Twenty percent of patients were of lower, 53%
of middle and 27% of upper social class. After controlling for HRQOL
at t1, we found significant main effects of SES on HRQOL in 4 out of
6 functional and 6 out of 9 symptom scales of the QLQ-C30 (p-values
<.001–.012), and in all 4 symptom scales of the PR25 (p-values .004–
.040). Planned contrasts revealed that compared to lower class membership, upper class membership was accountable for significantly increased
HRQOL in 10 domains. In the domains of emotional functioning and
financial problems, both middle and upper class patients showed significantly better HRQOL.
Conclusions: There were substantial social differences in HRQOL at the
end of rehabilitation. Our results indicate HRQOL at t2 to be least favourable for patients of lower social class. To maximize health outcomes for this
patient group, special counselling from health care professionals and social
workers during rehabilitation might be helping, i.e. on financial issues.
eases of the kidney, the testes and the bladder, psychooncology is still
treated as a stepchild. Patients suffering from the named maladies encounter tremendous problems coping with the psychological aftermath.
Patients undergoing corporal changes due to their therapy (e.g. urostomy,
loss of a testicle, scars) face a high risk of suffering mentally.
Methods: Patients definitely contracted a cancerous disease and either
assigned a surgical therapy or a chemotherapeutic treatment obtain a distress-questionnaire prior to their inpatient-therapy in order to determine
their need for psychooncological supervision. According to their requirements, the patients already receive support by a psychooncologist during
their first hospital attendance. Following the medical intervention, the
patients were asked to answer the questionnaire anew.
Results: After two months of treatment, an average of 40 per cent of the
patients suffering from the diseases express a wish for psychooncological
supervision. 70 per cent of those patients were supported sufficiently by
a short intervention of not more than four or less consultations only. Following the psychoogological supervision, all patients declared to feel a
decrease concerning their distress.
Conclusion: Psychooncology is of high significance not only as additional therapy in breast, bowel and prostate cancer treatment, but also in
patients contracted with other cancerous urological diseases. Therefore,
further investigation of this topic in future is more than desirable.
ID 247
ID 239
Coping with medical information is related to nocebo
effects in patients with breast cancer
S. Heisig, M. Shedden Mora, Y. Nestoriuc
Universität Hamburg, Arbeitsbereich Klinische Psychologie und Psychotherapie, Hamburg, Deutschland
Introduction. Patients with cancer differ in coping with medical information. Informational coping styles have been shown to relate to psychological and physiological well-being. Unspecific side effects and the
nocebo phenomenon are influenced by psychological variables, but have
not been subject of research on informational coping styles. This study
aims to show that informational coping styles are associated with anxiety,
unspecific side effects and quality of life in patients with breast cancer.
Methods: Within a cross-sectional survey, n = 102 women with breast
cancer (mean age: 46.7±9.0, mean time since first diagnosis: 2.36±3.0
years), who were currently in medical treatment, were recruited through
the internet. Relations between informational coping styles (TMSI-D),
anxiety (HADS-D), future perspective, quality of life (EORTC-QLQ),
and unspecific side effects (GASE) were analyzed using a path analysis.
Results: Information seeking behavior was more frequent than avoiding
or distracting from information. Patients were more anxious than healthy
women. The path analysis showed that patients who were more anxious
reported more unspecific side effects and lower quality of life. Patients
who sought information and had a low future perspective were more anxious. Patients who avoided information showed less anxiety.
Discussion: Women with breast cancer who seek medical information
need special support because they tend to develop unspecific side effects
when being anxious. In clinical routine, often nonsufficient treatment information is given to patients with breast cancer, although most patients
seek information. Information provision should be adapted to individual
needs to prevent anxiousness and nocebo effects.
ID 245
Psychooncology in urology
A. Winkel, D. Kusche
Evaluation of the cancer consultation by the SachsenAnhalt Cancer Society
A.-T. Nietzschmann1, S. Weise2, D. Vordermark3,
Y. Paelecke-Habermann4
MLU Halle-Wittenberg, Klinik für Strahlentherapie, Halle (Saale), Deutschland
2
Sachsen-Anhaltische Krebsgesellschaft e.V., Halle (Saale), Deutschland
3
MLU Halle-Wittenberg, Universitätsklinik und Poliklinik für Strahlentherapie, Halle (Saale), Deutschland
4
Universität Würzburg, Psychologie, Würzburg, Deutschland
1
Background: The diagnosis cancer results in severe changes for those affected, including disease-related problems and crises. How well patients
handle the occuring psychosocial demands also depends on the professional und psychological help available. The Sachsen-Anhalt Cancer Society cares for patients and their families during the individual phases of
the disease with various information services and counseling. We aimed
to evaluate whether this counselling increases satisfaction with the level
of information.
Methods: Consulters of the Sachsen-Anhalt Cancer Society in the branch
Halle/Saale were interviewed from December 2010 to December 2012
before (t1) and after (t2) a consultation using a questionnaire on awareness about the disease, the treatment, the social and financial impact and
coping with every-day life (from «0» = no to «10» = very good). Statistical analysis was effects via t-test, Wilcoxon-test or sign-test for dependent
samples.
Results: 52 of 85 subjects approached participated in t1 and 42 of 85 in
t2 (response rates 61.1% and 49.4%). There was a significant increase in
satisfaction with the amount of information, the type of information, the
information being helpful so far, level of information about the cancer,
the treatment, the social and financial impact, and coping with every-day
life. Satisfaction with the comprehensibility of the information showed
no significant increase.
Summary: Counseling by the Sachsen-Anhalt Cancer Society led to an
increase in satisfaction with information on many aspects of cancer. This
could contribute to higher self-efficacy and thus to a better management
of the disease and higher quality of life.
Prosper-Hospital Recklinghausen, Klinik für Urologie, Recklinghausen,
Deutschland
Background: The value of psychooncological care is beyond controversy and therefore well-established, especially as additional therapy in
breast, bowel and prostate cancer treatment. Concerning cancerous dis-
Abstracts
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ID 308
Communication between nurses and patients in
oncology: Discrepancy between expectation and reality –
a single center study at a German university hospital
N. Birninger, F. Gieseler
University Hospital Schleswig-Holstein, Medical Department I, Lübeck,
Deutschland
Background: The appropriate communication with cancer patients is a
key factor in the quality of care. However, the implementation in daily
life often reveals a discrepancy between expectations and reality, as well
for doctors as for nurses. The intensification of workload combined with
consistently high standards is often portrayed as an ethical problem. Yet
there are very few studies that could be used as a basis for specific training
to improve this calamity and avoid burn-out situations. Here we present
first results of a study exploring the problems in communication between
doctors, patients and nurses at the UKSH Campus Lübeck.
Results: As part of the training for nursing in oncology 15 participants
(12 female, 3 male) were interviewed. The percentage of communication
within the triangle doctor-patient-nurse and the appraisal of the «actual situation» and a «should be» situation were asked. Actual situation:
nursing / patient 70%, physician / nursing 55%, physician / patient 56%.
Should be: nursing / patient 89%, physician / nursing 96%, physician /
patient 94%.
Conclusion: As assessed by the nurses for the actual situation, the low
values for physician / nursing communication (55%) and physician / patient communication (56%) are disturbing. The nursing staff often sees
himself as a mediator between doctor and patient – a role that they cannot cope in the current work situation. The goal of the ongoing study is
an improvement and coordination of education and training for doctors
and nurses with subsequent implementation and integration of knowledge
into the daily workflow. The goal is to improve the quality of care and
to reduce the ethical burden both for the nursing staff, as well as for the
doctors.
ID 314
Factors that influence posttraumatic growth following
breast cancer: A controlled study trial
Y. Gottschlik1, K. Brückner1, P. Erz1, L. Graf1, B. Leplow1,
C. Thomssen2, U. Berndt2
Martin-Luther-Universität, Psychologie, Halle-Wittenberg, Deutschland
Universitätsklinik und Poliklinik für Gynäkologie, Halle (Saale), Deutschland
1
ience» and «positive emotions» were significant predictors of PTG, accounting for 36% and 38% of PTG variance, respectively.
Conclusions: Positive emotions and resilience represent important indicators for PTG in breast cancer patients. Supportive psychological treatment strategies related to these two factors might be helpful for breast
cancer patients.
ID 334
The first results of targeted screening with a Distress
Thermometer and initiation of psycho-oncological care of
cancer patients.
M. Angerer-Shpilenya, A. Heidenreich
RWTH Uniklinikum Aachen, Urologie, Aachen, Deutschland
Introduction: Tumor disease has not only somatic but also psychological
impact on patients with complete change of life dimension. This resonates not only to the patients and their relatives, but also to the therapy.
A precise screening helps to determine the stress factor and to initiate an
psycho-social care.
Patients: 230 patients with various tumors got since 2011 in the Urological Clinic of Aachen Univ. Hospital screening using a Distress Thermometer (DT). 23 of the 40 questions of the DT depend on somatic complaints
of patients. The other 17 questions cover the psycho-social problems.
Results: 82 of the 230 patients reported to have a low stress level by
the tumor. 75 patients showed an average and 73 patients significantly
higher stress level. This means that 148 of the 230 patients need a psycho-oncological counseling and possibly even further treatment. The
most common entered symptoms were fears, nervousness, fatigue &
worry. Depending on the wishes of the patient the psycho-oncological
consultation was initiated. Only completing the DT helps the patient to
face their problems & worries and makes perhaps the first great step in
the perception of the disease. Since 1/2012 a new component was inserted
into the discharge reports of the tumor patients. This component contains
the recommendation, depending on the result of the DT, to start if necessary the professional psycho-oncological support. That gives the patients
a sense of security and a feeling not to fight alone against the disease.
Abstract: A targeted screening and an interdisciplinary, together with
psycho-oncologists, care to cancer patients support them and their families at all stages of the disease, helps to deal with the new life situation
and can possibly also increase the patient’s compliance and the therapeutic response.
2
Objectives: Psychological distress in cancer and its effect on anxiety and
depresssion has been assessed among several studies. Only recently researchers have begun to examine positive outcomes such as posttraumatic
growth (PTG) in cancer empirically. This study compared self-reported
PTG from women with breast cancer with those of an age- and education-matched control group and investigated the impact of personality
traits (resilience, optimism, self-efficacy) and positive emotions on PTG
in breast cancer survivors.
Methods: Participants were 64 breast cancer patients and 61 patients
with gynecological, not oncological surgery (control group). Patients
completed self-report measures of PTG, resilience, optimism, self-efficacy and positive emotions approximately six months after primary cancer
treatment. Sociodemographic and clinical characteristics from participants were recorded.
Results: Breast cancer patients showed a pattern of greater PTG compared to controls with respect to «relating to others» (t = 3.03, df = 123,
p < .01), «appreciation of life» (t = 3.48, df = 123, p < .01) and «personal
strength» (t = 2.54, df = 123, p < .05), respectively. «Resilience» (r = .60,
p < .01), «optimism» (r = .36, p < .01), «self-efficacy» (r = .49, p < .01)
and «positive emotions» (r = .61, p < .01) were positively correlated with
self-reported PTG levels in women with breast cancer. Moreover, «resil-
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ID 407
Psychosocial Factors Relating to the Decision Against or
in Favour for Prophylactic Surgery
K. Wassermann, K. Rhiem, R. Schmutzler
Uniklinik Köln, Zentrum f. Familiären Brust- und Eierstockkrebs, Köln,
Deutschland
BRCA-Mutations are related to an increased risk for breast and ovarian
cancer. The breast cancer risk ranges from 30-80% and can be reduced
to approx. 3% by prophylactic mastectomy. Therefore women with a
BRCA-mutation often deal with the question whether a prophylactic surgery or the intensified surveillance programme is a reasonable solution.
The decision does not only affect health, cancer incidence and survival,
but is entangled with everyday life. Data for side effects and the long term
outcome of a mastectomy are still poor.
To elucidate the psychological implications of such a decision we have
initiated a research project supported by the BMG (Bundesministerium
für Gesundheit). We offer psychological counselling and testing to mutation carriers in addition to the medical non-directive risk consulting. The
goal is to support a sustainable decision that considers all aspects of the
woman’s individual situation. The women get validated questionnaires
to analyse mental state, personality aspects and life events and are asked
about their decision process and the support needed.
Abstracts
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Preliminary Results: From 68 participants about 48% consider prophylactic mastectomy independent from their current health status and independent of their cancer risk situation. 28% of women with breast cancer
and 21% of the healthy women reveal increased anxiety scores (HADS
>8) before the medical consulting. 68% of the women with an increased
HADS-anxiety score tend to pMTX to reduce their fear.
After consultation 92% of women feel well informed (n = 39) and 85%
feel they can make a well-considered decision. 92% feel very satisfied/
satisfied with the support.
80% recommend other mutation carriers to undergo psychological counselling before making a decision.
Quality-of-Life Management
ID 028
Demands from patients completed primary treatment of
breast or gynaecological cancer
G. Sprossmann-Günther1, H.-R. Metelmann2, J. Potenberg1
Ev. Waldkrankenhaus, Oncological Centre, Berlin-Spandau, Deutschland
Universität Greifswald, Mund-Kiefer-Gesichtschirurgie, Greifswald,
Deutschland
1
2
Introduction: Completing primary treatment patients enter the follow-up
period. Technical procedures such as computer tomography, magnetic
resonance tomography or tumour markers could not improve the overall
survival. Patients often have symptoms caused by treatment or the disease
itself and wish to speak about their complaints.
Methods: To evaluate the wishes of the patients a specialized questionnaire was developed. Here questions were asked concerning the ideas suffering from breast or gynaecological cancer completed primary treatment.
Results: 150 questionnaires were distributed and 120 were returned (80%
response rate). 40% of patients got physiotherapy, 25% took advantage of
psychology and 17% asked for the pharmacists advice.
This support was needed in 55% occasionally and in 20% regularly. 40%
spoke not with the pharmacist over the entire prescription. Further points
of interest were drug interactions, adverse events and effects of the medicine. 39% of the patients said they would discontinue taking drugs if
adverse effects are occurring.
The majority could ask all the questions to the physician, but 24% of the
patients had not this opportunity. The cause for not asking was lacking of
privacy or trust.
The majority would like technical procedures such as computer tomography or magnetic resonance tomography and further laboratory tests. Further demands concerned more psychological support.
57% of the patients expect the covering of all expenses by the insurance
company, only 21% were ready to participate in the costs.
Conclusions: After completion of the primary treatment of breast or gynaecological cancer there is more demand for after-care including technical procedures and laboratory tests. Approximately 40% of patients will
discontinue the taking of cancer medicine if adverse events are occurring.
Health professionals are requested to offer more structured help in the
period of after-care.
ID 053
Normative data of the EORTC QLQ-C30 in Germany:
A population-based survey
Cancer (EORTC) Core Quality of Life Questionnaire (QLQ-C30), in a
random sample of the population of Northern Germany.
Methods: Population-based survey of a random sample of 10,000 persons
aged 16 years or older. The questionnaire addressed lifetime prevalence
of common diseases and QoL. Differences in QLQ-C30 scores (scored
according to standard procedures) of>10 points between subgroups were
considered as clinically relevant.
Results: The questionnaire was completed by 47%. Participants’ mean
age was 51.7 years (SD: 18.5 years); 57% were females. Missing data
across QLQ-C30 scales and items were sparse (min. 0.2%, max. 1.5%).
QoL varied by age and sex. Generally, men reported better functioning
and fewer symptoms than women. With increasing age function declined
and symptoms increased. Most frequently reported symptoms were fatigue, pain, and insomnia (Mean (SD): 31 (26), 28 (31), 28 (33)). Of all
4,684 respondents 27% did not report any disease; most frequently reported were hypertension (36%), hyperlipidemia (26%), and arthritis (30%).
Lifetime prevalence of depression was high (women: 16%; men: 11%).
Prevalence of at least one disease increased with age (16–19 years: 30%
vs. 85+ years: 91%), showing a significant impact on self-reported QoL.
Conclusion: Study participants are representative for the German general
population with regard to age, sex, and education. A high proportion of
participants reported depression which is also mirrored by the fatigue,
pain, and insomnia scores that are more than 10 points higher than in the
Schwarz and Hinz data (2001). This normative data should be used as
reference data when evaluating QoL in German cancer patients.
ID 096
Long term effects of the INOP-intervention on physical
activity and health following oncological rehabilitation
H. Kähnert1, A.-K. Exner1, B. Leibbrand2
Institut für Rehabilitationsforschung, Norderney, Abt. Bad Salzuflen, Bad
Salzuflen, Deutschland
2
Salzetalklinik, Abt. Onkologie, Bad Salzuflen, Deutschland
1
Background: A healthier lifestyle including regular physical activity (PA)
plays a major role in the rehabilitation of breast cancer patients. Although
oncological rehabilitation programs focus on a healthier lifestyle of their patients, long-term success is only modest. The study investigates the effectiveness of the INOP-intervention focusing on volitional strategies to change PA
and thus improve health-related quality of life (QL), functional capability in
workaday (FCW) as well as occupational (FCO) over 12 months.
Methods: Breast cancer patients (n = 386) who underwent a rehabilitation
were randomly assigned to the control (CG) or intervention group (IG) and
were interviewed at the beginning (t1), 6 (t3) and 12 month (t4) after discharge. While the CG received the usual care, the IG additionally received
the INOP-intervention. Analysis of covariance was applied to investigate
differences between CG and IG regarding the PA, QL, FCW and FCO.
Results: At the 12 month follow-up, level of PA in the IG was on average 120
min./week higher than in the CG (p < 0.05, d = 0.63). Moreover, from the primarily inactive participants 92% of the IG were exercising at t4, but only 60%
of the CG (p < 0.001, d = 0.37). During the 12 months after clinic discharge,
IG patients were also considerably less limited in their FCW (p < 0.001,
d = 0.44) and FCO (p < 0.05, d = 0.27) than CG patients. Furthermore, the
QL is noticeably more increased in IG than CG patients (p < 0.001, d = 0.53).
Conclusion: The study provides evidence that INOP is a useful intervention to enhance physical activity, quality of life and thus functional
capability of breast cancer patients at least 12 months after discharge. The
INOP-intervention is brief and can be implemented in a clinical setting
and post-rehabilitation support.
A. Waldmann1, D. Schubert1, A. Katalinic1,2
Universität zu Lübeck, Institut für Sozialmedizin und Epidemiologie,
Lübeck, Deutschland
2
Universität zu Lübeck, Institut für Krebsepidemiologie e.V., Lübeck,
Deutschland
1
Aims: Generating up-to-date normative data for quality of life (QoL), as
measured by the European Organization for Research and Treatment of
Abstracts
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ID 172
Quality of Patients’ Information – What Kind of
Information Is Looked for by Cancer Patients?
M. Liefold, G. Dathe, J. Wilhelm, T. Feustel, B. Wincheringer,
R. Grohs, M. Theuer, D. Wagner, E. Beck
Fachhochschule Brandenburg, Fachbereich Informatik und Medien,
Brandenburg, Deutschland
Introduction: Shared decision making is one of the central demands of
patients’ representatives. However, before decisions can be made, patients need all relevant information concerning the subjects under discussion. Besides the fact that information nowadays is readily available
via the internet, it is difficult for the average person to judge relevance,
validity and reliability of the provided information. Moreover it is still
unclear what kind of information is searched for by patients and to what
extend and granularity this information should be provided.
Methods: In order to get first impressions on patients’ needs regarding
information on malignant diseases, we asked the members of a local selfhelp sports group to formulate as many queries as possible dealing with
all their disease related concerns. We then choose a limited number of
these questions, discussed them within our group, searched for relevant
information available on the internet and prepared then short presentations. Finally these presentations were held and discussed with the members of the self-help group.
Results: More than two thirds of the patients questions (34/46) where
dealing with organizational or rather common «every day» problems.
Only 12 questions were related to disease specific topics (e.g. kind of
treatment, complementary methods). Most of the questions however,
where formulated in rather global forms and where thus not really answerable, which was one of the major topics discussed with the patients.
Granularity of the information should not be to detailed, no tables, graphs,
statistics or any technical terms are to be used.
Conclusion: In order to improve quality of information portals patients
should be invited to be members of the allocation teams.
ID 211
Novel care conception for cancer patients in Germany
ID 269
eHealth in modern patient-caregiver-communication:
Use of modern media in breast cancer patients and their
physicians
R. Würstlein1,2, T. Kirkovits1, C. Drewes1, I. Bauerfeind3,
U. Goldmann-Posch4, D. Schiltz1, N. Harbeck1,2, T. Schinköthe1
3
Tumorzentrum München, Projektgruppe Mammakarzinom, München,
Deutschland
4
mamazone, Augsburg, Deutschland
1
2
Introduction:Implementation of oral and s.c. medications for breast
cancer (BC) led to new challenges for patients and physicians regarding
optimal and continuous communication. New ways of communication,
including eHealth and web-based programs, may thus be useful. The
objective of our investigation is to evaluate actual use of internet and
modern media (e.g. smartphones) in BC patients and their healthcare professionals.
Methods: We designed questionnaires for patients and physicians and
analyze frequency and behavior of use of internet and modern media,
available equipment and opinions on future eHealth tools. Patients were
asked to answer the questionnaire before consultations and at a BC patient conference (mamazone). Health care specialists were asked to complete the questionnaire at several regional BC meetings.
Results: In an interim analysis 80% patients had been diagnosed with BC
at time of investigation, 29% with advanced stage. 89% of patients use
internet for health related issues. Even above age 70, more than the half
use internet for health related purposes. Among doctors, 98% use internet for medical issues. Implementation of potential future eHealth tools
would be highly accepted in both groups (f.e. registration of side effects
via electronic devices: patients 41.1%; physicians 71.2%).
Discussion: This survey shows a high rate of internet and modern media
use among BC physicians and their patients. In both groups, the additional possibility to regularly record side effects and manage them without
face to face meetings is favored. The routine use of modern media and
trust in new interactive communication tools may enable improvement in
doctor-patient-relationship, compliance and adherence in oncology.
T. Klose, M. Putzker
Sonnenschein Apotheke Koblenz, Koblenz, Deutschland
Subject: Diagnosis, therapy and monitoring of outpatients in Germany usually are performed at different locations with probably elevated
waiting periods each. Small cancer practices may lack actual scientific
knowledge. Supplying pharmacies do not employ a «Qualified Person»
according to § 15 of the German Drug Act in order to release medically
prescribed but non-approved effective components.
Methods: Five oncologists with high university reputation co-operate in
a day clinic in Koblenz/Rhineland-Palatinate (~ 3,000 patients per year;
> 30 types of cancer), added by a scientific investigation unit. The health
care center further includes a radiologic institute and a public pharmacy
certified to ISO 9001:2008 with a GMP-cleanroom at its disposal for the
production of cytostatic drugs and two «Qualified Persons» available.
Results: The patient profits from this comprehensive care conception.
Morning arrival via cab with outward and return journey being refunded
by the health insurance is followed by a medical check-up including a
hemogram and if necessary a radiological examination. Based upon these
data, the oncologist lays down the actual treatment. The pharmacy immediately produces the sterile solution (>10,000 individual formulations
anually) reaching the clinic by an in-house material lift. Venous infusion
of the patient is directly started and he is allowed to leave the clinic after
a few hours highly facilitating his independence and mobilty.
Conclusions: The novel care conception offers minimum stress for the
affected person, highest medico-pharmaceutical level of treatment, and
maximum cost saving for the health insurance company.
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ID 306
Younger cancer patients are much more affected in
quality of life than older patients
L. Distel1, W. Losensky1, S. Weiss1, R. Fietkau1, M. Weiling1
1
Strahlenklinik, Strahlenbiologie, Erlangen, Deutschland
Objective: Maintaining the quality of life during and after a cancer therapy is of great importance for a successful therapy outcome. The aim of
the study was to evaluate whether there are age related differences in a
cancer patients collective compared to the general German population*?
Methods: The study collective consists of 257 recruited patients and lead
to a total of 793 data sets. 44% of patients suffered from colorectal cancer
and 23% of patients from head and neck cancer. All patients were treated
with concurrent radiochemotherapy. The median age was 62 years with a
range of 24 to 86 years. Patients were classified into divisions of 10 years
age. The EORTC QLQ-C30 questionnaire was used and functional and
symptom scores were calculated. On average, each patient filled out 3.1
questionnaires.
Results: In the general German population functional scores decrease
with age and symptom scores increase with age. In contrary in the cancer
patients collective the functional score somewhat increase and the symptoms scores slightly decrease with age. Though in patients younger than
60 years there is a distinct difference between the German population
and cancer patients, while in patients older than 70 years there is only a
marginal difference.
Conclusion: Younger patients are much more affected in all quality of
life domains by a cancer therapy treatment than older patients. Older pa-
Abstracts
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ID 396
Cortical activity during exercise in B-Non-Hotgkinlymphoma (B-NHL) patients and healthy controls
T. Hülsdünker1, A. Mierau1, F. Baumann2, T. Elter3, M. Hallek3,
W. Bloch2, P. Zimmer2
Deutsche Sporthochschule Köln, Institut für Bewegungs- und Neurowissenschaft, Köln, Deutschland
2
Deutsche Sporthochschule Köln, Institut für Kreislaufforschung und
Sportmedizin, Abteilung für molekulare und zelluläre Sportmedizin, Köln,
Deutschland
3
Universitätsklinikum Köln, Med. Klinik 1, Köln, Deutschland
ID 401
Quality of life in Lynch Syndrome patients with colon
cancer is not impaired after extended (prophylactic)
colonic resection
C. Schneider1, R. Schneider2, G. Möslein1
1
2
HELIOS St. Josefs-Hospital, Chirurgie, Bochum, Deutschland
Universitätsklinik Marburg, Chirurgie, Marburg, Deutschland
Objectives: Lynch Syndrome (LS) is associated with a substantial risk
for metachronous cancers following segmental oncologic resection of the
initial cancer. The aim of this study was to compare the quality of life
(QoL) after segmental or extended colonic resection in patients with a
hereditary predisposition to colorectal cancer.
Design: QoL was assessed with EORTC QLQ-C30 and CR38 questionnaires. Patients were recruited from the German HNPCC Consortium,
the New Zealand Familial Gastrointestinal Cancer Registry and the database ofthe Hôpital Saint Antoine in Pariswith the following inclusion
criteria:Colonic resection for colon cancer; hereditary cancer according
to Amsterdam II Criteria and/or mismatchrepair deficient tumour;age at
operation < 60y; surgery >6 months before study; no ostomy.
Results: 51% of questionnaires were returned, 587 eligible (503 segmental, 84 extended). Patients with limited resections were significantly
younger at the time of surgery, whereas age at the time of survey was
comparable. Patients with subtotal colectomy, reporting more frequent
nocturnal bowel movements, demonstrated an improved outcome regarding fatigue/weakness, role functioning and constipation, but after adjustment for multiple testing, there was no significant difference.
Conclusion: This large, international study has demonstrated that when
compared with segmental resections, extended colonic resection is associated with an equivalent QoL. In view of the risk reduction for metachronous
cancers, patients with LS should undergo more extensive surgery at the time
of their primary colon cancer. This finding highlights the importance of preoperative diagnosis in patients with hereditary predisposition to cancer.
n
Aim: Does Quality of life assessment prior to the initial transarterial
chemoembolisation using the HCC-specific questionaire validated by the
EORTC help to improve patient selection for repetitive interventions?
Methods: Ouality of life (Qol) -assessment was performed in 66 patients
(14female/52male, median age: 66.4 years) undergoing initial transarterial chemoembolisation (TACE) for treatment of intermediate-stage hepatocellular carcinoma (HCC). Doxorubicin and cisplatin or mitomycin
were used as chemotherapeutic agents in combination with lipiodol. Qol
evaluation was performed before (66 patients: 100%) and 2 weeks after TACE (52 patients: 78.8%) as well as prior to the second TACE (26
patients: 39.4%). The combined questionnaire consists of 48 questions,
divided in 24 functional/symptom scales and single items. Global health
status scores at the individual timepoints were correlated to imaging parameters: 1) Sum of target lesion diameters 2) enhancement pattern of the
largest target lesion 3) RECIST tumor response.
Results: There was a significant correlation between Patients presenting
with large target lesion (TL) diameter (TL1 + TL2 > 6.1 cm) before 1st
TACE and low global health status one day before 2nd TACE (p < 0,01).
Enhancement pattern did also show a significant correlation to low global
health status before second TACE (p = 0,021). Tumor response (RECIST
1.1): 7.9% partial response, 84.6% stable disease, 11.5% progressive disease. RECIST tumor response did not show a significant correlation to
global health status.
Conclusion: Large Target Lesions as well as Target Lesions showing
heterogeneous enhancement pattern prior to the initial TACE do show
significant correlation to a low global health status one day before 2nd
TACE. These findings can help to decide about the continuation of TACE
treatment.
ge
Medizinische Hochschule Hannover, Institut für Diagnostische und Interventionelle Radiologie, Hannover, Deutschland
2
Medizinische Hochschule Hannover, Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Hannover, Deutschland
1
zo
D.B. Hasdemir1, M.W. Nordlohne1, H. Rosenthal1, N. Schweitzer2,
A. Vogel2, F. Wacker1, B.C. Meyer1, T. Rodt1
ge
Pre-treatment imaging parameters predicting low quality
of life after initial transarterial chemoembolisation in
treatment of intermediate-stage hepatocellular carcinoma
ck
ID 309
rü
*Schwarz R, Hinz A. Eur J Cancer 2001 37 1345.
locations during eyes-closed resting state as well as at the beginning, half
way through and at the end of exercise. Spectral power in the theta, alpha,
beta and gamma frequency bands was calculated in the frontal, central,
parietal and occipital regions of the cortex.
T-test for unpaired samples indicates lower occipital alpha power in the
B-NHL patients compared to controls during rest with eyes closed. Further, repeated measures analysis of variance revealed a group x time interaction for theta and alpha power during exercise. Both, theta and alpha
power increased from the beginning to the end of exercise in N-BHL
patients while there were no effects in the control group.
The results indicate a decreased arousal level in the course of exercise in
N-BHL patients represented by increased alpha and theta power values.
Increases in these frequency bands have further been proposed to be related to improved cognitive performance. Therefore, our results suggest that
physical activity might be beneficial for oncologic patients as reflected by
the positive effects on cortical activity.
zu
tients have probably developed strategies in their course of life to cope
better with the side effects and problems of a cancer therapy.
1
Cancer-related fatigue (CRF) is accompanied by reduced cognitive abilities and altered cortical activity suggesting an effect on the central nervous system. From many studies it is known that acute physical exercise
induces changes in the cortical state and positively affects cognitive performance even though, exclusively tested on healthy subjects. Therefore,
the aim of the present study was to investigate cortical activity during exercise in B-Non-Hodgkin-lymphoma (B-NHL) patients and age-matched
healthy controls.
16 subjects (9 B-NHL patients, 7 controls) exercised for 25min on a cycle
ergometer. Electroencephalography (EEG) was recorded from 16 scalp
Abstracts
ID 434
Physical Activity Navigator – successful example for
motivation in physical activity against cancer. 3-yearsresults of a project with exercise programs with in- and
outpatients from acute therapy to aftercare during the
chemotherapy and radiotherapy
S. Michelis1, M. Wöge2, F. Merten2, D. Nürnberg1
Onkologischer Schwerpunkt Brandenburg NW e.V., Neuruppin, Deutschland
2
OGD GmbH, Reha-Zentrum, Neuruppin, Deutschland
1
Presentation of a patient-centred care Project – called Physical Activity
Navigator. Hereby, are to describe the relevant interfaces for this care
pathway, show the stage specific methodology, and introduce the stake-
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holders. The foundation, «Leben mit Krebs» has enabled us to appoint
a sports therapist designing activity programs and coordinating physical
activities patients with cancer diagnosis. The Physical Activity Navigator
supports patients (1) in the Hospital, (2) in rehabilitation centre, and (3)
in special outpatient.
We have established a personalized sports therapy, offering patients in
our cancer wards to practice sports during primary treatment. The benefits of positive physical experience through individualized motor activity
are part of treatment concept during on-going inpatient chemotherapy
or radiotherapy. Following the hospitalization, we offer established outpatient exercise schemes for endurance training, adapted strength training, or gymnastics. These motor activity offers are recommended by our
ambulatory cancer healthcare centre. The rehabilitation Centre with its
specific possibilities for physical activity and sports links up all parts of
the program, from acute therapy to aftercare. In addition, we encourage
individual medical fitness training, advise recreational sports activities in
sport clubs, and introduce patients to an active daily living.
Results: We started the project Physical Activity Navigator in January
2011. A total of 280 in- and outpatients have been supervised in our program up to date. Currently, 30 outpatients per week are participating in
the special motor activity offers. We succeeded to integrate patients in
our care project, starting at the time of cancer diagnosis. This early intervention is the key to success of our physical activity pathway for cancer
patients.
Radiation Biology
ID 021
Individual differences in chromosomal aberrations in
a rectum cancer collective and cancer patients with
assumed increased radiosensitivity
A. Ellmann, B. Soppa, M. Haderlein, R. Fietkau, L. Distel
Strahlenklinik der Universität Erlangen-Nürnberg, Erlangen, Deutschland
Objective: The knowledge of patients’ individual radiosensitivity could
be the key to a more individual and specific therapy for cancer patients.
Side effects could be avoided from the healthy tissue and the tumour still
could be controlled. The aim was to identify sensitive individuals among
our collective.
Materials and Methods: Peripheral blood samples from 66 individuals
were analysed. The 57 rectum carcinoma patients got into this survey in
the context of a rectum carcinoma study, the other 9 patients got in due
to more intense side effects after a radiotherapeutic treatment. The blood
samples were parted, one half got irradiated with 2.0 Gy, the other half
served as unirradiated control. The chromosomes 1, 2 and 4 were painted
with the three colour FISH-painting technique to analyse chromosomal
aberations. These events were quantified as breaks per metaphase.
Results: The 66 individuals had a mean of 0.455 breaks per metaphase.
Gaussian fits were performed and breaks per metaphase in both collectives were found to be normally distributed. The 2.0 Gy sample corrected
for the 0 Gy control data showed that 5 individuals are above double
standard deviation range (0.716), 2 of them even above triple standard
deviation range (0.857).
Discussion: In this collective are 3% patients with a distinct increased
radiosensitivity and about 7% with increased radiosensitivity. Adopting
that malignant tissue has a corresponding sensitivity to radiation as normal tissue, single and total doses of radiation therapy should be adapted
to patient´s individual. Especially individuals with a low radiosensitivity
could benefit from a dose escalation and an increased tumour control rate.
114
ID 087
Flattening-filter-free intensity modulated breath-hold
image-guided SABR (Stereotactic ABlative Radiotherapy)
can be applied in a 15-min treatment slot
J. Boda-Heggemann1, S. Mai1, J. Fleckenstein1, K. Siebenlist1,
A. Simeonova1, M. Ehmann1, V. Steil1, F. Wenz1, F. Lohr1,
F. Stieler1
Universitätsmedizin Mannheim, Klinik für Strahlentherapie und Radioonkologie, Mannheim, Deutschland
1
Introduction: Hypofractionated image-guided stereotactic ablative radiotherapy (igSABR) in breath-hold is an effective non-invasive treatment modality for stage I-II NSCLC and lung metastases. In the past,
daily fraction duration with IMRT was >> 15 min. Flattening filters have
been used to compensate for variation in the integral fluence and were
integral parts of linear accelerators in the last decades. FFF (flattening-filter-free) mode reduces treatment duration by increasing dose rate. We
analyzed the impact on treatment slot time in the first cohort treated with
FFF breathhold igSABR.
Patients/ Methods: 9 PTVs of 8 patients have been treated with FFF
beams on a Versa HD linear accelerator (Elekta) with 60Gy in 12 or 5 Gy
single fraction doses in breath-hold with Active Breathing Coordinator
(ABC®, Elekta). IMRT plans for dMLC or VMAT delivery were generated with Monaco 3.3 (Elekta). Non-FFF breath-hold igSABR treatment
times were evaluated in a subgroup of 8 patients of previously published
patient populations. Total on-couch time, net treatment times and net
beam-on times were measured.
Results: One 12 Gy fraction of a non-FFF hypofractionated breath-hold
lung SABR had a fraction duration of 27±5 min. On-couch time for the
first fraction of FFF igSABR (including image guidance) was 15,77±8,58
min. Net treatment time (including beam-off free breathing phases)
was 7.3±4.8 min. Net beam on time was 4,56±0,50 min (dMLC) and
3,15±1,71 min (VMAT).
Conclusion: For lung SABR with VMAT or an 8 field IMRT using a
breath hold technique, FFF reduces beam-on time sufficiently to enable
each beam/VMAT sector to be delivered in a single breath hold, greatly
improving the duty cycle and consequently halving overall fraction time
from ~30 min to ~15 min, making this method available for more patients.
ID 192
Reduced side effects by proton microchannel irradiation
– study in a human skin model
T.E. Schmid1, S. Girst2, O. Zlobinskaya1, C. Greubel2, J. Seel2,
C. Siebenwirth2, C. Marx1, J. Wilkens1, G. Multhoff1, G. Dollinger2
Klinikum Rechts der Isar, TU München, Strahlentherapie und radiologische Onkologie, München, Deutschland
2
Universität der Bundeswehr München, Neubiberg, Deutschland
1
We propose a novel strategy to reduce the known side effects of radiotherapy by using proton microchannel irradiation. In order to prove the
hypothesis of reduced side effects in normal tissue through microchannel
proton irradiation, we report on a comparative study of microchannel and
broad beam irradiation of artificial skin tissue. 20 MeV protons were administered to human skin models (EpidermFTTM) in 10 to 180 µm wide
irradiation channels on a quadratic raster with distances of 500 to 1800
µm between each channel applying an average dose of 2 Gy. For comparison, other samples were irradiated homogeneously by protons at the
same average dose. Widened channels as in deeper lying tissues were investigated in skin tissues as well. Normal tissue viability was significantly
enhanced after microchannel proton irradiation compared to homogenous
irradiation (80 vs. 40% compared to unirradiated control. Levels of inflammatory markers, such as cytokines and chemokines, were significantly lower in the supernatant after microchannel irradiation than after
homogeneous irradiation. Furthermore, genetic damage as determined by
the measurement of micronuclei in keratinocytes was also significantly
reduced after microchannel irradiation compared to homogeneous irra-
Abstracts
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Index
diation (0.015–0.030 micronuclei per divided cell for microchannel vs.
0.070 ± 0.007 MN/divided cell for homogeneous irradiation). Our data
show that proton microchannel irradiation maintains cell viability while
significantly reducing inflammatory responses and genetic damage compared to homogenous irradiation, and thus might improve normal tissue
protection after radiation therapy. Supported by the DFG Cluster of Excellence: Munich-Centre for Advanced Photonics.
ID 397
The motility of irradiated glioblastoma cells is modulated
by the axon-guidance system Slit2/ROBO1
P. Nguemgo-Kouam1, I. Pisarenko1, B. Priesch-Grzeszkowiak1,
H. Bühler1, I. Adamietz2
2
1
Background: Glioblastoma is a highly invasive brain tumor with poor
prognosis. Recent data indicate that irradiation might enhance the motility of glioblastoma cells and thereby promote local recurrences. In this
study we investigated whether or not slit2/ROBO1 signaling has an impact on cellular migration following radio-therapy.
Methods: The experiments were performed on the human glioma cell
lines U87 and U373. Slit2 or ROBO1 over-expressing clones were established by transfection of the respective gene. The cells were irradiated
with 0, 0.5, 2, or 8 Gy photons. Expression of slit2 and ROBO1 was
determined by western blotting and qRT-PCR. The motility parameters
velocity, accumulated, and Euclidean distance were obtained by time-laps
videography.
Results: Wild type expression of slit2 was moderate in U373 and very
low in U87 cells. In contrast ROBO1 was high in U87 and low in U373
cells. The expression was markedly affected by irradiation, however differently in both cell lines. The migration of both cell lines was enhanced
after irradiation, particularly after low doses. After transfection the migration was reduced by 50% for all clones. Similar to the wild type cells irradiation enhanced the motility of both U373 clones slightly. In contrast the
motility of the U87 clones was decreased significantly after irradiation.
Conclusions: Slit2 and ROBO1 are differently expressed in glioblastoma
cells and can be influenced by irradiation. Slit2/ROBO1 are involved in
the cellular motility as shown by the transfected clones. Irradiation in the
range of a fractionated radio therapy enhances the migration of glioblastoma cells, however strengthened Slit2/ROBO1 signaling might counteract this potentially malignant side effect.
Sarcoma
ID 005
Outcome after local recurrence of soft tissue sarcoma: A
retrospective analysis of factors predictive of survival in
135 patients with local recurrent soft tissue sarcoma
A. Daigeler1, I. Zmarsly1, O. Goertz1, T. Hirsch1, H.-U. Steinau1,
M. Lehnhardt1, K. Harati1
Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil Bochum,
Klinik für Plastische Chirurgie und Schwerbrandverletzte, Handchirurgiezentrum, Operatives Referenzzentrum für Gliedmaßentumore, Bochum,
Deutschland
1
Aim: The aim of this study was to identify prognostic indicators of survival in patients with locally recurring soft tissue sarcoma (STS) through
a long-term follow-up at our institution.
Patients und Methods: We retrospectively assessed the relationship between post-recurrence survival (PRS) and factors related to demography,
disease and treatment in 135 patients who had experienced local recur-
Abstracts
rence after surgical treatment. The median follow-up time after initial recurrence was 12.3 years (95% confidence interval [CI]: 10.4–14.2).
Results: The 5-year estimate of the PRS rate was 53.1% (95% CI: 44.3–
61.2) for the entire series. In a univariate analysis, initial recurrence,
which occurred ≥2 years from primary diagnosis, was found to be a predictor of a better outcome (5-year PRS of 68.1%; 95% CI: 53.3–79.1)
compared with earlier recurrence (5-year PRS of 45.2%; 95% CI: 34.4–
55.5) (P=0.042). Synovial sarcoma and fibrosarcoma were associated
with a significantly worse post-recurrence outcome compared with other
STS histotypes. Patients with negative margins after the final surgery experienced improved survival compared with patients with positive margins (5-year survival: 46.7% [35.2–57.5] vs. 35.5% [23.4–47.8]; P=0.01).
In a multivariate analysis, the significant prognostic factors for PRS were
histologic grade, tumour site, the time to initial recurrence, the number of
recurrences and the surgical margin status attained at the last resection.
Schlussfolgerungen: Complete surgical resection with microscopically
clear margins is desirable in patients with local recurrent STS. However,
when the goal of achieving clear surgical margins would require major
functional impairment of the extremity, a radical surgical approach should
be weighed for the patient in each case.
ID 062
A non-comparative phase II study of dose intensive
chemotherapy with doxorubicin and ifosfamide followed
by high dose ICE consolidation with PBSCT in nonresectable, high grade, adult type soft tissue sarcomas
(STS)
J. Hartmann1, M. Horger2, T. Kluba3, A. Königsrainer4,
P. de Zwart5, C. Hann von Weyhern6, F. Eckert7, W. Budach8,
C. Bokemeyer9
Universitätsklinikum Schleswig-Holstein, Internistische Onkologie, Kiel,
Deutschland
2
Universitätsklinikum Tübingen, Diagnostische und Interventionelle Radiologie, Tübingen, Deutschland
3
Universitätsklinikum Tübingen, Orthopädie, Tübingen, Deutschland
4
Universitätsklinikum Tübingen, Allgemeine,Viszeral- und Transplantationschirurgie, Tübingen, Deutschland
5
BG Klinik, Unfall- und Wiederherstellungschirurgie, Tübingen, Deutschland
6
Klinikum München, Pathologie, München, Deutschland
7
Universitätsklinikum Tübingen, Radioonkologie, Tübingen, Deutschland
8
Universitätsklinikum Düsseldorf, Strahlentherapie und Radioonkologie,
Düsseldorf, Deutschland
9
9Universitätsklinikum Hamburg-Eppendorf, Onkologie, Hämatologie mit
der Sektion Pneumologie, Hamburg, Deutschland
1
Background: To determine the feasibility and effectivity of dose intensive induction chemotherapy (CTh) in patients (pts) with STS.
Methods: Treatment consisted of at least 2 cycles of DOX IFO. In responding and stable pts, this was followed by one cycle of HD-ICE), ETO
500 mg/m2, Carbo 500 mg/m2 and IFO 4 g/m2 (days –4 to –2, PBSC
support on day 0. Pts with a single distant metastasis deemed resectable
were allowed.
Results: 30 out of 631 consecutive pts, age 46 years (range, 21–62), were
included, 5 of whom had a single lung (4) or liver (1) metastasis. 29 pts
completed at least 2 cycles of DOX/IFO. While 16 pts (55%) remained
stable, 7 pts (24%) showed a PR, 1 pt (3%) a CR, and 5 pts (17%) progressed. HD-ICE was withheld because of PD in 5 pts, neurotoxicity in
6, insufficient PBSC mobilization, CR and refusal in 1 pt each. 16 pts received HD-ICE, which was associated with non-hematological grade III
toxicity including emesis, mucositis, fever, neurotoxicity, and transaminase level elevation. Two pts attained a PR after HD-ICE. 24 of 30 (80%)
pts underwent surgery, with complete resections in 19 pts (63% of all pts,
79% of the operated subgroup); however, 2 of whom required amputation. After a follow up period of 50 mos in surviving pts (range, 26–120)
5-yr DFS and OS rates were 39 and 48%, respectively. Pts with shrinking
STS becoming resectable after pretreatment had a markedly improved
DFS (median, 50 vs. 3.5 mos; HR: 7.2 (95% CI, 1.5–34.3), p < 0.01) and
survival (median, 73 vs. 9 mos; HR: 9.1 (95% CI 1.8–45.6), p < 0.007).
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Conclusions: Induction chemotherapy plus consolidation HD-ICE is
generally feasible, but is associated with significant neurotoxicity. The
advantage of HD-ICE over conventional dose CTh plus EBRT in non-resectable disease remains unproven.
ID 282
Population-based survival of adult patients with bone
cancer and soft tissue sarcoma – a comparison between
Germany and the United States
B. Holleczek1, L. Jansen2, C. Hamann3, A. Eberle4, K. Emrich5,
A. Gondos2, A. Katalinic6, H. Brenner2
Saarland Cancer Registry, Saarbrücken, Deutschland
Division of Clinical Epidemiology and Aging Research, German Cancer
Research Center, Heidelberg, Deutschland
3
Technical University Medical Center, Department of Orthopedics, Dresden, Deutschland
4
Cancer Registry of Bremen, Bremen, Deutschland
5
Cancer Registry of Rhineland-Palatinate, Mainz, Deutschland
6
Cancer Registry of Schleswig-Holstein, Lübeck, Deutschland
1
2
Background: Up-to-now, population-based survival studies of rare cancers from Germany were hampered by insufficient national coverage by
cancer registries. Using data from 11 German regions and US data from
the SEER program, this study aims at providing a detailed comparison of
survival of adult patients with bone cancer (BC) and soft and connective
tissue sarcoma (SCTS) in Germany and the US.
Methods: The analysis included 5526 patients with BC (ICD-10: C40+C41)
and 18,107 patients with SCTS (ICD-10: C47 and C49) over 15 years of
age at diagnosis with diagnosis and follow-up between 1997 and 2006 from
both countries. Five-year relative survival (RS) was derived overall and
according to age, sex, tumor site and morphology by period analysis.
Results: Overall age standardized 5-year RS of patients with BC and
SCTS was 54% and 60% in Germany and 63% and 66% in the US, respectively. Survival of sarcoma patients generally decreased with age.
Higher RS was observed for tumors of the limbs and the head region, but
survival was substantially lower for BC of the pelvic bones, and SCTS
of the trunk. BC patients with chondrosarcoma had highest survival, and
those with Ewing sarcoma had lowest survival. Among SCTS patients,
those with liposarcoma had highest survival, whereas survival was lowest
for those with rhabdomyosarcoma. For both BC and SCTS, analyses consistently revealed inferior survival of German patients.
Conclusions: Based on two large datasets, this population-based study
provided detailed survival data for patients with rare cancers from Germany and the US for the first time. It further revealed consistently lower
survival of these patients in Germany compared to the US that should be
further investigated.
ID 297
Hyperthermia combined with Trabectedin prolongs G2
cell cycle arrest and reduces cellular survival in human
tumor cells
D. Harnicek1, E. Kampmann2, A. Tanović3, A.S. Cardoso Martins1,
Y. Guo4, E. Gallmeier4, R. Kanaar4,5, K. Lauber6, T. Knösel7,
L. Lindner2, R. Issels2,1
Helmholtz Zentrum, München, Deutschland
Klinikum der LMU, Medizinische Klinik III, München, Deutschland
3
PharmaMar, Medical Affairs, Barcelona, Spanien
4
Klinikum der LMU, Medizinische Klnik II, München, Niederlande
5
Erasmus Medical Center, Department of Cell Biology & Genetics, Rotterdam, Niederlande
6
Klinikum der LMU, Institut für Strahlentherapie, München, Deutschland
7
Klinikum der LMU, Pathologisches Institut, München, Deutschland
1
2
py improves the treatment of patients with high-risk STS (Issels, Lancet
Oncol 2010). The rational for combining both treatments is that HT induces degradation of BRCA2 which is crucial for DSB-repair by Rad51
(Krawczyk, PNAS 2011).
Methods: Four different human cell lines were analyzed: osteosarcoma
(U2Os), liposarcoma (SW872), synovial sarcoma (SW982) and colorectal cancer (DLD1). For investigation of BRCA2 deficient cells, DLD1
mutant (-/-BRCA2) cells and siRNA knock-down were used. TR (0.5–4
nM) was applied for 3 h with 1.5 h HT (41.8°C and43°C). Cell cycle
arrest was analyzed by Nicoletti-staining and cytotoxicity was assessed
by clonogenic survival. Expression of BRCA2, the amount of γH2AX
positive DSB-repair-foci and recruitment of Rad51 were analyzed by immunostaining.
Results: Treatment with Tr enhanced G2 arrest and reduced clonogenic survival, both was significantly augmented by HT. After HT, BRCA2
expression was strongly reduced and recruitment of Rad 51 to DSBs was
diminished (41.8°C) or even abolished (43°C). Combined treatment increased the amount of DNA damaged cells. In BRCA2 deficient cells,
HT-dependent enhancement of TR toxicity in terms of G2 arrest and reduced survival was significantly reduced.
Conclusion: Treatment with TR and HT resulted in enhanced toxicity, which was accompanied by elevated DNA-damage and G2-arrest.
HT-mediated BRCA2-degradation and impairment of DSB-repair seem
to be related mechanisms.
ID 325
Uterine leiomyosarcomas: A single-center cohort with a
favorable outcome in advanced disease
E. Hartmann1, S. Buettner2, F. Menge1, P. Hohenberger1,
B. Kasper1
Universität Heidelberg, Mannheimer Fakultät, Interdisziplinäres Tumorzentrum, Mannheim, Deutschland
2
Universität Heidelberg, Mannheimer Fakultät, Abteilung für Medizinische Statistik, Biomathematik und Informationsverarbeitung, Mannheim,
Deutschland
1
This analysis examines treatment and survival characteristics of our cohort with advanced uterine leiomyosarcoma (uLMS).
Out of a series of 48 patients presenting with uterine sarcomas between
2007 and 2012, we analyzed all evaluable patients with uLMS, mainly
with locally recurrent or metastatic disease.
21 women were recorded with a median age of 47 years (range: 28–74) at
initial diagnosis. Hysterectomy had been previously performed for all patients. 57% (12/21) of the women presented with locally advanced uLMS
but limited to the uterus, whereas 43% (9/21) had already metastatic disease at initial diagnosis. In the first cohort, in 3 of 12 women, there was
no necessity for further treatment after hysterectomy; one patient received
adjuvant radiotherapy. However, 8 of 12 patients either developed metastases or never were tumor free (R1 resection) and subsequently presented
distant metastases. Surgical therapy (metastasectomy for solitary lesions,
multivisceral resection of local recurrence) was performed in 6 of 12 patients, chemotherapy in another 5 of 12 and radiotherapy in 4 of 12 patients. In the second cohort of patients with M1 disease the women were
treated with surgical therapy (5/9), chemotherapy (7/9) and radiotherapy
(3/9). 4 of 9 patients never reached remission; 5 of 9 patients experienced a limited period of response. The median relapse-free survival in
the cohort of 21 patients was 17 months (range, 2–57 months). The 5-year
survival rate was 60% and the median overall survival was 26 months
(range, 4–172 months).
Despite a negative patient selection in our cohort of advanced locally recurrent or metastatic uLMS, we observed a rather favorable outcome with
a median overall survival of 26 months and a 5-year survival rate of 60%.
Background: Trabectedin (TR) is approved in Europe for advanced
soft tissue sarcoma (STS) after failure of anthracyclines and ifosfamide.
Its cytotoxicity is associated with the induction of DNA double-strand
breaks (DSB). Regional hyperthermia (HT) combined with chemothera-
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Abstracts
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Index
ID 350
Impact of gender on efficacy of alkylating agents and
their acute toxicity in patients with standard risk localized
Ewing sarcomas (EWS-R1) in the EURO-Ewing99(EE99)-R1 trial
U. Dirksen1,2, H. van den Berg3,4, B. Brennan5, P. Marec Berard6,
R. Ladenstein7, I. Judson8, L. Hjorth9, J. Kruseova10, M.C. LeDeley11,
A. Ranft2,9, I. Lewis12, O. Oberlin13, A. Craft14, H. Jürgens1,2
Westfälische Wilhelms Universität Münster, Pädiatrische Hämatologie und
Onkologie, Münster, Deutschland
2
Universitätsklinikum Münster, Münster, Deutschland
3
Academic Medical Centre / University of Amsterdam, Amsterdam, Niederlande
4
- Emma Children Hospital AMC, Dept. of Paediatric Oncology, Amsterdam, Niederlande
5
University Hospital, Royal Manchester Children‘s Hospital, Manchester,
Großbritannien
6
Centre Berard, Institut d‘Hémato-Oncologie Pédiatrique, Frankreich
7
Universität Wien, St. Anna Kinderspital, Wien, Oesterreich
8
Royal Cancer Hospital, Institute of Cancer Research, London, Großbritannien
9
Clinical Sciences Lund University, Skåne University Hospital, Department
of Paediatrics, Schweden
10
University Prague, University Hospital Motol, Pediatric hematology and
Oncology, Prague, Tschechische Republik
11
Institut Gustave-Roussy, Service de Biostatistique et d‘Epidémiologie,
Paris, Frankreich
12
Alder Hey Children‘s NHS Foundation Trust, Liverpool, Großbritannien
13
Institute Gustave- Roussy, Hèmato-Oncologie Pédiatrique, Paris, Frankreich
14
Institute of Child Health, University of Newcastle upon Tyne, Newcastle
upon Tyne, Großbritannien
1
Background: Patients were randomized for cyclophosphamide vs. ifosfamide-based consolidation (VAC vs. VAI) in the Euro-EWING99-R1 trial.
Overall, the efficacy of the two agents was similar [PBC, 57, p710;2011).
Abstracts
Long-term outcome of desmoid tumors treated with highdose antiestrogen and NSAID therapy
C. Schneider1, D. Quast1, R. Schneider2, G. Möslein1
1
2
HELIOS St. Josefs-Hospital, Chirurgie, Bochum, Deutschland
Universitätsklinik Marburg, Chirurgie, Marburg, Deutschland
en
*Supported by Deutsche Krebshilfe and the BMBF.
ID 399
Introduction: Desmoid tumors are generally rare, but frequently occur
in patients with familial adenomatous polyposis (FAP) and are prone to
recurrence. The treatment is discussed controversely. We prospectively
evaluated the outcome of antiestrogens in combination with sulindac.
Material and Methods: Patients with symptomatic desmoids, either
spontanous or FAP-associated were treated with high-dose antiestrogen
and sulindac for more than 1 year. Development of disease was measured
via CT and/or MRI scan. Stable disease and tumor regression were regarded as response.
Results: 134 patients (64 spontaneous, 70 FAP-associated) with a mean
follow up of 7.1 years were included. Male:female ratio was 90:44 (p
< 0.5), the location was predominantly intraabdominal in FAP-patients
while spontaneous desmoids developed extraabdominal. FAP-patients
were significantly younger (39,7±13,6 y vs. 44,6±14,3 y).
The response rate was 85.1%, with 3 desmoid-associated deaths. Mean
time to response was 14.9 ± 9.1 months, only 1 recurrence occurred after
cessation of the medication and only 3 patients died from their desmoid.
No stop of the medication due to side effects was necessary.
Patients after surgical resection demonstrated a significantly higher rate
of progressive diseases (p =  0.03)
Conclusions: The treatment of desmoids with high- dose antiestrogens
and sulindac is characterized by a relatively long time to response, but a
high rate of success and low recurrences with excellent tolerance and very
low mortality, compared with other therapies.
og
The event free survival (EFS) in patients with relapsedEwingsarcoma
(ES) remains poor with a 5 year- EFS of 13%. We analysed the value of
high dose chemotherapy (HDtx) in relapsed ES and compared the most
frequently used high dose regimens versus no HDtx in terms of outcome.
Methods: Data from 239 patients with first relapse of ES registered from
2003–2009 into the ES relapse registry database of the German Society
of Pediatric Hematology and Oncology were analyzed. Outcome was
analyzed descriptively by event-free-survival (EFS) and overall-survival
(OS) controlled for risk factors by multivariate regression analysis.
Results:Amongst 73 pts who received HDtx; 15 received busulfan-melphalan (bu-mel), 38 treosulfan-melphalan (treo-mel) and 20 other regimens. Status prior to HDtx was remission in 25 pts, stable disease in 3 pts,
progressive disease in 1pt and not known in 15 pts. The 3- year overall
survival (3y-OAS) was 14% (SE= .03) in patients treated without HDtx,
47% (SE=.13) in patients treated with bu-mel and 48% (SE=.1) with treomel HDtx. The 3-yOAS in pts with early relapse was 6% (SE .02) without HDtx and 42 (SE= .14) or 31% (SE= .14) after bu-mel and treo-mel
HDTx, respectively. The 3-yOAS in pts with late relapse was 33% (SE
.08) without HDtx and 67 (SE= .27) or 67% (SE= .14) after bu-mel and
treo-mel respectively.
Conclusion: The results demonstrate a significant benefit from HDtx in
patients with relapsed ES. There was no significant difference between
the HDtx regimens in terms of outcome. Detailed analysis excluding the
patients who did not receive HDtx due to early progression and the impact
of different standard relapse regimen will be provided.
ez
Westfälische Wilhelms Universität Münster, Pädiatrische Hämatologie und
Onkologie, Münster, Deutschland
2
Universitätsklinikum Münster, Münster, Deutschland
1
kg
U. Dirksen1,2, S. Jabar2, A. Ranft2, H. Jürgens1,2, M. Rasper2
Based on the EE99R1 gender-stratified randomization, gender impact on
efficacy and acute toxicity was explored.
Methods: Gender impact on EFS and acute toxicity by course, switches
between treatment arms, and cumulative dose of alkylating agents was
evaluated in multivariable models on the intention-to-treat population,
including tests for heterogeneity of treatment effect due to gender.
Results: 856 patients (347 females) were randomized between 2000 and
2010: 425 VAI and 431 VAC. Overall EFS was not gender dependent.
(p = 0.33). Marginal variation was seen between treatment and gender
(p = 0.083): In males VAC exhibited poorer EFS than VAI, HR(VAC/
VAI) = 1.34 [0.96–1.86]. In females, VAC was slightly better than VAI,
HR = 0.83 [0.54–1.28]. Equivalently, males had poorer EFS than females
with VAC, HR(M/F) = 1.42 [0.97–2.08]. Results by gender were similar
with VAI, HR = 0.91 [0.62–1.33]. Severe hematological toxicity was more
frequent with VAC. Tubular renal impairment was more frequent with VAI.
Severe toxicity was more frequent in females, independent of the type of
toxicity, with no significant treatment-gender interaction. Thirty patients
switched from VAI to VAC (21 F, 9 M), mostly due to renal toxicity, and
3 from VAC to VAI (1 F, 2 M). A reduction of either alkylating agents` cumulative dose >20% was more frequent in females (15% vs. 9%, p = 0.01
Conclusions: Gender impact on EFS and acute toxicity from an alkylating agent requires further study. Effects of gender-dependent polymorphism/activity of metabolic enzymes (e.g. CYP2B6) of ifosfamide vs.
cyclophosphamide should be explored.
rü
c
The value of high dose chemotherapy in relapsed Ewing
sarcoma patients
zu
ID 336
ID 445
Risk stratification by number of metastatic sites in nonlocalized Ewing sarcomas*
A. Ranft, U. Dirksen, H. Jürgens
University Hospital, Pediatric Hematology and Oncology, Muenster,
Deutschland
Objective: The outcome variation in subgroups of Ewing sarcoma patients with metastases at initial diagnosis is high. A major current criterion
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is to stratify treatment according to the site of metastases, e.g., patients
with pulmonary disease only are distinguished from patients with other
metastatic sites. In this project outcome was analyzed according to the
number of metastatic sites.
Methods: Five-hundred Ewing sarcoma patients with metastases at diagnosis were analyzed. All patients were included in the GPOH Ewing sarcoma registry from 1998 to 2009 and received similar treatment strategies
with standard and/or high-dose chemotherapy. The median follow-up was
2.62 years (range 0.20–14). Outcome by event-free-survival (EFS) was
analyzed by univariate and multivariate analyses.
Results: 3y-EFS in patients with isolated pulmonary metastatic disease
was 0.46 (SE=.03; n = 268), compared to 0.27 (SE=.03; n = 232) in patients with dissemination to sites other than lung alone (R3) (p < .001). In
R3 patients, 3y-EFS with one metastatic site was 0.39 (SE=.07; n = 52),
compared to 0.28 (SE=.04; n = 120) with two, and 0.14 (SE=.05; n = 60)
with three or more metastatic sites (p < .001). In multivariate analysis, the
number of metastatic sites persisted as the major significant risk factor
(Hazard ratio (HR): 1.45 (2 vs. 1); 2.38 (>2 vs. 1); p < .001), whereas
the risk group affiliation did not (HR: 1.21; p = .302), even if the model
was controlled for treatment intensification with high-dose chemotherapy
(HR: 1.82-2.70; p < .001 vs. 1.63; p = .025; n = 432).
Conclusion: Stratification by virtue of the quantity of metastatic sites appears to discriminate for prognosis in non-localized Ewing sarcoma patients.
*Supported by Deutsche Krebshilfe.
TRAIL-induced apoptosis remained largely elusive. Here, sensitization of
melanoma cells for TRAIL by the PI3-kinase inhibitor wortmannin correlated to activation of mitochondrial apoptosis pathways. Apoptosis was
dependent on Bax and abrogated by Bcl-2 overexpression. The synergistic enhancement was explained by Bax activation through wortmannin,
which tightly correlated to characteristic Bax phosphorylation patterns.
Thus, wortmannin resulted in early reduction of the Bax-inactivating
phosphorylation at serine-184, whereas the Bax-activating phosphorylation at threonine-167 was enhanced. Proving the responsibility of the
pathway, comparable effects were obtained with an Akt inhibitor (MK2206). While suppressed phosphorylation of serine-184 may be attributed
to reduced Akt activity itself, the causes of enhanced threonine-167 phosphorylation were addressed here. Characteristically, production of ROS
was seen early in response to wortmannin and MK-2206. Providing the
link between ROS and Bax, we show that abrogated ROS production by
a-tocopherol or by NADPH oxidase 4 (NOX4) siRNA suppressed apoptosis and Bax activation. This correlated with reduced Bax phosphorylation at threonine-167. The data unravel a mechanism by which NOX4-dependent ROS production controls apoptosis via Bax phosphorylation. The
pathway may be considered for proapoptotic, anticancer strategies.
ID 154
Variationen zur Defektabdeckung durch regionäre Lappen
bei ambulanter Tumorchirurgie im Gesicht
L. Tischendorf
Skin Cancer including Melanoma
ID 018
RAF inhibition overcomes resistance to TRAIL-induced
apoptosis in melanoma cells
A. Berger, S.-A. Quast, P. Michael, N.-F. Kuhn, U. Trefzer, J. Eberle
Charité-Berlin, Klinik für Dermatologie, HTCC, Berlin, Deutschland
Mutated BRAF represents a critical oncogene in melanoma, and selective inhibitors have been approved for melanoma therapy. However, the
molecular consequences of RAF inhibition in melanoma cells remained
largely elusive. Here, we investigated the effects of the pan-RAF inhibitor L-779,450, which inhibited cell proliferation both in BRAF-mutated
and WT melanoma cell lines. It furthermore enhanced apoptosis in combination with the death ligand TRAIL (TNF-related apoptosis-inducing
ligand) and overcame TRAIL resistance in melanoma cells. Enhanced
apoptosis coincided with activation of mitochondrial pathways, seen by
loss of mitochondrial membrane potential and release of cytochrome c,
SMAC and AIF. Subsequently, caspases-9 and -3 were activated. Apoptosis induction by L-779,450/TRAIL was prevented by Bcl-2 overexpression and was dependent on Bax. Thus, activation of Bax by L-779,450
alone was demonstrated by Bax conformational changes, whereas Bak
was not activated. Furthermore, the BH3-only protein Bim was upregulated in response to L-779,450. The significant roles of Smac, Bax and Bim
in this setting were proven by si-RNA-mediated knockdown experiments.
L-779,450 also resulted in morphological changes indicating autophagy
confirmed by the autophagy marker LC3-II. The proapoptotic effects of
L-779,450 may explain the antitumor effects of RAF inhibition and may
be considered when evaluating RAF inhibitors for melanoma therapy.
ID 063
ROS-dependent phosphorylation of Bax by wortmannin
sensitizes melanoma cells for TRAIL-induced apoptosis
A. Quast, A. Berger, J. Eberle
Charité Universitätsmedizin, klinik für Dermatologie, HTCC, Berlin,
Deutschland
The pathways of reactive oxygen species (ROS)-mediated apoptosis induction, of Bax activation and the sensitization of tumor cells for
118
Praxis MKG Chirurgie, Halle, Deutschland
Die Spezifik ambulanter Operationen an der Gesichtshaut erfordert die
Auswahl geeigneter Methoden zur Defektdeckung, die onkologischen
und ästhetischen Ansprüchen genügen.
Wir stellen die Erfahrungen aus den Jahren 1993 bis 2013 an 1450 ambulanten Tumorbehandlungen in ihrem zeitlichen Wandel vor. Besprochen
werden Variationen, Vor- und Nachteile sowie eigene Modifikationen von
regionären Lappen:Transpositionslappen, Rotationslappen, Glabellalappen, Gleitlappen sowie Deckungen von Ober- und Unterlippendefekten.
Grenzen der ambulanten Chirurgie an der Gesichtshaut werden eher
durch Transportprobleme, Blutungsübel sowie Compliancefragen als
durch Tumorcharakteristika bestimmt.
ID 218
Systemic treatment of metastatic uveal melanoma – a
silver lining on the horizon?
H. Richly, M.E. Scheulen, M. Wiesweg, A. Abendroth, M. Schuler,
S. Bauer
Uniklinikum Essen, Tumorklinik, Essen, Deutschland
Background: Uveal melanoma (UM) is the most common ocular tumor
but accounts for only 0.1% of overall cancer mortality. Classical chemotherapeutic drugs, given systemically or as perfusion treatment, may delay progression but have a minor impact on the general course of disease.
Thus, clinical trials have been considered the standard of care in these
patients (pts). Recently, mutations in GNAQ/GNA have been shown to
affect most pts with metastastic uveal melanoma, that lead to activation
of protein kinase C (PKC) and the Raf/MEK/ERK signalling pathway.
We aim to present updates of ongoing clinical trials in order to facilitate
access to treatment for this rare disease.
Methods and Results: We have initiated three clinical trials that focus
on uveal melanoma or genetic pathways relevant for the disease. These
trials may have a major clinical impact for patients and trial design and
preliminary results (STREAM-trial) will be presented.
The STREAM trial is a multicenter randomized discontinuation, blinded,
placebo-controlled, phase II study of sorafenib in patients with chemonaïve metastatic uveal melanoma. To date, 60 patients have been enrolled
of whom 26 have entered randomization on day 56. The results of a
planned interims analysis of the STREAM trial will be presented.
Abstracts
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A phase I trial investigates the combination of a MEK-inhibitor (MEK162,
fix-dose) and a PKC-inhibitor (AEB071, escalating doses) in patients
with UM. A novel c-MET inhibitor (INC280) investigates clinical activity in c-MET-dependent solid tumors which has been found in up to 20%
of UM pts.
Conclusions: Novel insights into the genetic evolution of metastatic
uveal melanomas may trigger substantial therapeutic progress. Patients
should be directed towards clinical trials that inhibit these targets.
ID 447
Validation of a fresh-frozen tissue-based prognostic
gene signature in formalin-fixed, paraffin-embedded
melanomas
G. Brunner1, A. Heinecke2, L. Suter1, C. Berking3, H.-J. Schulze4,
J. Atzpodien5
Skin Cancer Center Hornheide-Münster, Cancer Research, Münster,
Deutschland
2
Westfälische Wilhelms University Münster, Medical Informatics and Bio
informatics, Münster, Deutschland
3
Maximilians University Munich, Dermatology and Allergology, Munich,
Deutschland
4
Skin Cancer Center Hornheide-Münster, Dermatology, Münster, Deutschland
5
Niels-Stensen-Kliniken, Oncology, Georgsmarienhütte, Deutschland
1
Current melanoma staging is limited in predicting outcome, and complementary molecular markers are not available for routine prognostic assessment.
We have recently identified a prognostic nine-gene signature expressed in
fresh-frozen primary cutaneous melanomas (training cohort n = 91; validation cohort n = 44). A signature-based risk score predicts patient survival independently of AJCC staging (multivariate analysis p = 0.0004; hazard ratio
3.8). The purpose of this study was to establish signature expression analysis
in formalin-fixed, paraffin-embedded (FFPE) melanomas.
From FFPE melanomas matching the training and validation cohorts of
the above study (n = 125), RNA was prepared and transcribed into cDNA.
Following cDNA pre-amplification, expression of the 9 signature genes, 2
additional candidate genes, and 3 housekeeping genes was quantified by
real-time PCR. Correlation of gene expression with overall survival was
evaluated using Cox regression analysis.
Expression of a signature of 8 genes was associated with overall survival in univariate analysis. A signature-based risk score predicted survival
independently of AJCC staging (multivariate analysis p = 0.0059, hazard ratio 3.09). The misclassification rates were 20% overall, 13.8% for
low risk, and 5.7% for double low-risk (combined with AJCC staging).
The risk score significantly refined conventional AJCC staging. Thus, the
fresh-frozen tissue based prognostic gene signature was successfully validated in FFPE melanomas.
Our quantitative prognostic score, based on FFPE melanomas, is complementary to AJCC in predicting outcome. This increases clinical applicability and allows retrospective assessment of melanomas. The score
identifies patients at low risk, not identified by AJCC staging, and defines
high-risk patients in need of adjuvant therapy.
Stem Cells in Cancer
ID 162
Evaluation of stem cell markers and different stemness
genes in glioblastoma cell lines
markers are still inadequate to specifically identify glioma stem cells.
Therefore, we aimed to investigate a set of key stemness – and progenitor
genes in established glioblastoma cell lines.
RNA was isolated from 5 cell lines: U87 as a commercially available
established glioblastoma cell line, Gl36 as a tumor derived primary glioblastoma cell line, human embryonic stem cells, neuronal progenitor cells
as positive control and fibroblasts as a negative control. After cDNA synthesis PCR was performed in order to investigate a set of stemness genes
(Nanog, Oct4, Klf4, Lin28 and cMyc) as well as neuronal progenitor
genes (Sox1, Pax6, Olig2, CD133). Protein expression was confirmed by
Western blot analysis and cell stainings.
A subset of stemness and progenitor genes is differentially expressed in
both investigated tumor cell lines. GI36 cells showed expression of Oct4,
Klf4, and Lin28, whereas Oct4 and Pax6 were identified in U87 cells.
Overall, Pax6 was the only detectable neuronal progenitor marker in both
tumor cell lines. Furthermore, cMyc was expressed in both tumor cell
lines, while neither of them showed any signs of CD133.
Our results show the expression of a subset of stemness and neuronal
progenitor genes in two glioblastoma cell lines. Interestingly, we found a
distinct expression pattern in an established glioblastoma cell line compared to a primary cell line, emphasizing the caution necessary when extrapolating results derived from established cell lines.
ID 208
Plasticity of CD133 and OCT4A-expressing melanoma
cells could account for treatment failure in malignant
melanomas
Y. Welte1, D. Behrens2, I. Fichtner2, R. Schäfer1,3,
C. Regenbrecht1,4
Institut für Pathologie/Charité – Universitätsmedizin Berlin, Berlin,
Deutschland
2
EPO Berlin-Buch GmbH, Berlin, Deutschland
3
German Cancer Consortium (DKTK) / DKFZ, Heidelberg, Deutschland
4
Comprehensive Cancer Center Charité, Berlin, Deutschland
1
Malignant melanoma is the most severe type of skin cancer. To study the
biology and clinical impact of melanoma stem cells, we have established
patient-specific cell lines and identified two distinct subpopulations of
cells that express CD133, which is correlated with asymmetric cell division and OCT4A the master regulator of pluripotency. An overlap of
both putative CSC populations was indicated by the overexpression of
OCT4A in the CD133+ subpopulation compared to CD133- melanoma
cells and vice versa.
We enriched CD133+ as well as OCT4A+ cells from the bulk and found
crucial pathways related to oncogenesis and stemness such as Wnt and
FGF/MAPK activated in the respective positive populations. In vivo experiments showed increased tumorigenic capabilities of CD133+ and OCT4A+ melanoma cells compared to their negative counterparts.
Analysis of the robustness of the CD133+ subpopulation revealed a plasticity of CD133+ and CD133- phenotypes. This plasticity may have tremendous implications for the therapeutic intervention in malignant melanomas. In vitro cytotoxicity assays with FGFR1- and PI3K-inhibitors
significantly increased the CD133+ melanoma subpopulation within 48 h.
Our results indicate small melanoma subpopulations with cancer stem
cell characteristics, which are neither statically nor hierarchically organized. Instead, a dynamic plasticity between both CSC and bulk tumor
populations exists, which facilitates rapid adaption to environmental
stress and could therefore substantially hamper a successful therapeutic
intervention.
L. Dreher1, M. Perrech1, G. Röhn1, R. Goldbrunner1, T. Saric1,
M. Timmer1
1
The cancer stem cell hypothesis postulates that a small population of cancer cells possess self-renewal characteristics and is responsible for initiating and maintaining tumour growth. The so far described stem cell
Abstracts
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ID 300
Characterization of colon cancer stem cells at the single
cell level for target identification in diagnosis and therapy
P. Malkomes1, N. Haetscher2,3, T. Oellerich3, T. Schroeder4,
K. Holzer1, H. Serve3, W.O. Bechstein1, M. Rieger2,3
Universitätsklinikum Frankfurt, Allgemein- und Viszeralchirurgie, Frankfurt,
Deutschland
2
Georg-Speyer-Haus, onkologische Forschung, Frankfurt, Deutschland
3
Universitätsklinikum Frankfurt, Hämatologie und Onkologie, Frankfurt,
Deutschland
4
Helmholtz Zentrum München, Stem Cell Dynamics Research Unit, Neuherberg, München, Deutschland
1
Introduction: Colorectal cancer is the second leading cause of cancer
related death in Germany. Current understanding suggests that colorectal
cancer is a stem cell-driven disease, in which only a small population of
cells, referred to as cancer stem cells (CSCs), are capable to initiate and
sustain tumor growth. Despite the description of some surface markers,
the identity of CSCs and thereby their biology remains largely undefined.
Our purpose is to identify CSCs by their distinct cell behavior in order to
detect new targets for a CSC-directed therapy.
Methods: We applied time-lapse microscopy and single cell tracking to
continuously study the behavior of individual colon cancer SW480 cells
and their progeny over many generations. Cell fates as division, death
or generation time were recorded in pedigrees and analyzed to identify
functionally different subpopulations. We prospectively purified these
subpopulations by FACS and performed proliferation and colonosphere
assays, in vivo transplantations as well as SILCAC-based proteomics.
Results: Continuous cell tracking enabled the link of surface marker expression with distinct cell behavior and thus the discrimination of functionally different subsets. Sorted subpopulations showed differences concerning proliferation and their stemness to form colonospheres and to initiate
tumor growth. Proteomics detected potential target proteins, which are now
functionally analyzed in cell lines and primary patient material.
Conclusion: Continuous single cell tracking yields new insights in individual cell behavior in heterogenous cell populations and provides great
potential in the identification of CSCs in colon cancer. Quantitative proteomics revealed new CSC-related targets.
was strongly reduced by 48% or by 73% in the presence of 1 µM or 10
µM ZOL respectively. The remaining cellular motility led to very little
change in distance, with cellular activity appearing more as a ‘stepping on
the spot’. A ZOL gradient dislocated the center of mass of migrating cells
towards lower concentrations.
Conclusions: The suppression of cancer stem cell motility could potentially contribute to the clinical benefits that recent studies have described
following the adjuvant administration of zoledronic acid in breast cancer.
Supportive Care
ID 031
Network kids – a support project for the children of
cancer affected families
U. Vehling-Kaiser1, M. Flieser-Hartl1,2, T. Sternfeld3, B. Betz1,
F. Kaiser1
Deutschland
2
Landshuter Kommunalunternehmen für Medizinische Versorgung, Landshut, Deutschland
3
1
Children are often psychologically and socially affected when a family
member, e.g. the parents, are diagnosed with cancer. The illness of parents can cause fears and depressions in children. Family and leisure time
activities can be severely affected by the treatment of one family member. Furthermore problems at school or at the apprenticeship can follow.
There are no established support programs for these children. Therefore
the «Netzwerkinder» project for the support of these affected families
was initiated. The project co-operates with local social workers, school
psychologists, child psychologist and cram schools. Leisure group activities as excursions and garden parties, private lessons and family weekends are organised and financed. Monetary support in selected situations
of acute misery due to the disease is offered.
ID 042
Physical Activity and Exercise after Treatment for
Childhood Cancer
ID 370
The motility of cultured breast cancer stem-like cells is
severely restricted by zoledronic acid.
S. Kesting1, M. Götte1, C. Winter2, D. Rosenbaum2, J. Boos1
C. Hoberg , P. Nguemgo-Kouam , A. Kochanneck , K. Fakhrian ,
H. Bühler1, I. Adamietz2
1
1
1
2
2
1
Background: Various effects on tumor cells have been described for
zoledronic acid (ZOL). However, only limited data exist regarding its influence on the motility of tumor cells. Since migration is a decisive step
in metastasis, we examined whether ZOL reduces the motility of tumor
cells, which may lead to less aggressive metastasis.
Methods: The hypothesis of tumor stem cells postulates that recurrences may occur from cancer stem cells rather than from ‘normal’, somatic
tumor cells. Therefore, we investigated the effects of ZOL on stem-like
progenitor cells obtained via the formation of spheroids from the human
breast cancer cell line MDA-MB 231. The motility parameters velocity,
accumulated and Euclidean distance were obtained by time-resolved videography. The effect of a ZOL gradient on the direction of migration was
determined in ibidi µ-slides.
Results: The videography showed that ZOL strongly reduced the migration of cancer stem cells. The cellular velocity was reduced by 61%
following exposure to 1 µM ZOL, and by 82% after exposure to 10 µM
ZOL. The accumulated distance traveled by the cells was reduced by 60%
or by 79% after exposure to 1 µM or 10 µM ZOL. The Euclidean distance
120
University Hospital of Muenster, Department of Pediatric Hematology and
Oncology, Muenster, Germany, Deutschland
2
University Hospital of Muenster, Movement Analysis Lab, Institute for
Experimental Musculoskeletal Medicine, Muenster, Germany, Deutschland
1
Background: It is not clear whether children and adolescents achieve
a satisfactory level of physical activity (PA) following cancer treatment
that matches reference values and whether patients return to physical education (PE) at school, club and leisure-time sports activities. This study
aimed at analyzing the status of integration into sport structures and assessing self-reported PA.
Method: A standardized questionnaire of the German Health Interview
and Examination Survey for Children and Adolescents (KiGGS) assessed
PA and exercise, supplemented by questions related to PE, specific aspects of disease and therapy. Applying this instrument enables comparison with a healthy reference population (n = 4529).
Results: 85 patients (13.5±3.7 years; 48 male) during maintenance therapy and aftercare of childhood cancer (4.6±3.6 years post-diagnosis)
were included. Overall, the status of PA and integration into club and
leisure-time sports activities was comparable to the reference population. However, 25% of the sample was exempted from PE at school. 21%
(KiGGS: 15%) met the PA recommendations in childhood (60 min/day).
Especially brain tumor patients showed a reduced level of PA. Both brain
and bone tumor patients revealed a status of integration below-average
and a high proportion of exemptions from PE.
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Conclusion: In general, the observed sample showed an adequate status
of integration into sport structures and a level of PA appropriate for their
age. However, this positive result should not mask problems occurring
in brain and bone tumor patients regarding their limited activity and insufficient integration. This emphasizes the need of individually-tailored
support and strategies for the promotion of a long-term active lifestyle.
ID 069
Different Doses of Micafungin for Prophylaxis of Invasive
Fungal Diseases: A Web-based Non-Interventional Trial in
Four Large University Hospitals in Germany
S. Heimann1, O.A. Cornely1, L. Meintker2, W. Heinz3,
T. Schroeder4, M. Vehreschild1, H. Wisplinghoff1,
M. von Bergwelt-Baildon1, J. Vehreschild1
University Hospital of Cologne, Cologne, Deutschland
University Hospital of Erlangen, Erlangen, Deutschland
University Hospital of Würzburg, Würzburg, Deutschland
4
University Hospital of Düsseldorf, Düsseldorf, Deutschland
1
2
3
Background: Treatment indications of new antifungals in clinical practice often deviate from the strict criteria used in controlled clinical trials.
Aim of this study was to describe customary prescription and treatment
strategies of micafungin (MIC).
Methods: A registry was set up on ClinicalSurveys.net and physicians
were invited to provide retrospective information on cases they had treated with MIC. Documentation comprised demographics, underlying disease, efficacy, safety, and tolerability of MIC.
Results: A total of 125 episodes of patients (PTS) hospitalized between
10/09 and 01/12 were documented, of which seven had to be excluded
due to incomplete documentation. The most common underlying disease
and risk factor was hematological malignancy (116, 98.3%) and antibiotic treatment > 3 days (115, 97.5%). Micafungin was administered as
prophylaxis (PPX) in 106 (89.9%) and for treatment of possible, probable
or proven IFD in 12 PTS (10.1%). In the group of antifungal PPX, mean
duration of MIC treatment was 22.8 days (d) (95% CI: 20.4–25.3); 53 of
the PTS (50%) received a dosage of 50mg, while the other 53 (50%) received 100mg/d. For the different doses, prophylactic outcome was rated
as success in 42 (79.2%) vs. 52 PTS (98.1%; p = 0.004); 55 PTS (51.9%)
were treated with posaconazole (POS) before initiation of MIC. Four PTS
(3.8%) developed a proven IFD while being treated with 50mg/d, compared to no PTS treated with 100mg/d. At the end of MIC PPX, 24 PTS
(22.6%) were switched to fluconazole, 63 PTS (59.4%) to POS.
Conclusions: Clinical effectiveness of MIC PPX in high risk PTS was
demonstrated. In most cases, MIC was part of a multi-modal antifungal
PPX strategy. Investigators reported better outcomes in PTS receiving
therapeutic doses of MIC for PPX.
ID 071
Factors that influence participation in physical activities
and exercise in pediatric cancer patients during
treatment: A qualitative study
M. Götte, S. Kesting, C. Winter2, D. Rosenbaum2, J. Boos
University Hospital of Muenster, 1Department of Pediatric Hematology and
Oncology, Muenster, Deutschland
2
Movement Analysis Lab, Institute for Experimental Musculoskeletal Medicine, Muenster, Deutschland
Purpose: Due to growing evidence about the value of exercise in pediatric cancer patients, the purpose of this study was to determine barriers and
motivations for physical activities during treatment.
Methods: This qualitative study included semi-structured guideline interviews, transcription and coding based on grounded theory with 40 pediatric
cancer patients (5.5 ± 2.3 months since diagnosis). Four major topics were
discussed: 1) values and beliefs, 2) barriers to exercise, 3) motivations to
exercise and 4) encouragement from parents and physicians. All participants
were treated at the Department of Pediatric Oncology in Muenster where a
supervised exercise program has been implemented for hospital stays.
Abstracts
Results: Patients reported mainly positive attitudes towards physical
activities during treatment and the local exercise program was desired
and valued as essential for engaging in exercise during in-patient stays.
Identified barriers included physical, psychological and organizational
aspects. Motivational aspects were based on improvements in physical
fitness and mental well-being. Parents’ behavior related to physical activities of their children differed between being supportive, inhibiting and inert. Few patients received information about exercise by their physicians.
Conclusions: Interventions that are aimed at maintaining physical activities during treatment and eliminating barriers to exercise are required
due to the patients´ positive attitudes and multiple motivations towards
exercise. These interventions need to be supervised and should include
health-counseling programs for patients, parents and physicians to underline the importance of physical activities in pediatric cancer patients.
ID 075
A multicenter cohort study on colonization and infection
with extended-spectrum beta-lactamase producing
Enterobacteriaceae (ESBL-E) in high-risk patients with
hematological malignancies
M.J.G. Vehreschild1, L. Peterson2, S. Schubert3, W. Vogel4,
S. Peter5, P. Schafhausen6, H. Rohde7, M. v. Lilienfeld-Toal8,
I. Bekeredjian-Ding9, O.A. Cornely1,10,11,12, H. Seifert13
Uniklinik Köln, Klinik I für Innere Medizine, Köln, Deutschland
University of Munich, Med. Klinik III, Munich, Deutschland
3
University of Munich, Max von Pettenkofer Institut, Munich, Deutschland
4
University Hospital Tübingen, Internal Medicine II, Tübingen, Deutschland
5
University of Tübingen, Institute of Medical Microbiology and Hygiene,
6
University Medical Center Hamburg-Eppendorf, Department of Oncology
and Hematology, Hubertus Wald Tumorzentrum, Hamburg, Deutschland
7
University Medical Center Hamburg-Eppendorf, Institute for Medical
Microbiology, Virology and Hygiene, Hamburg, Deutschland
8
Universitätsklinikum Bonn, Medizinische Klinik und Poliklinik I, Bonn,
Deutschland
9
Universitätsklinikum Bonn, Institut für Medizinische Mikrobiologie,
Immunologie und Parasitologie, Bonn, Deutschland
10
University of Cologne, Clinical Trials Center Cologne, ZKS Köln, BMBF
01KN1106, Cologne, Deutschland
11
University of Cologne, Center for Integrated Oncology CIO Köln/Bonn,
Cologne, Deutschland
12
University of Cologne, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Deutschland
13
University of Cologne, Institute for Medical Microbiology, Immunology
and Hygiene, Cologne, Deutschland
1
2
Introduction: Bloodstream infections (BSI) remain the leading cause of
mortality in patients with chemotherapy-induced neutropenia. The rate
and type of ESBL-E colonization, infection and transmission in German
cancer centers is largely unknown.
Methods: We performed a prospective, observational multicentre study
at five German university-based haematology departments. Participating
sites screened for intestinal ESBL-E colonization within 72h of admission. Additional samples were collected every 10 +/– 2 days and before
discharge from hospital. Two blood culture sets were drawn in case of
neutropenic fever. Anonymous data of all patients were entered into webbased electronic case report forms. Resistance gene amplification and
typing of isolates by rep-PCR or PFGE was performed to assess transmission between patients.
Results: Between Nov 2011 and Dec 2012, 736 hospitalizations of 496
patients were documented; 287 patients (57.9%) received intensive chemotherapy for acute leukemia, 108 (21.8%) autologous and 220 (44.4%)
allogeneic stem cell transplantation. Median duration of stay was 36.1d
(range 5-159d). ESBL-E was identified from screening samples (83.8%
E. coli and 13.2% K. pneumoniae) in 49/496 (9.9%; range by center:
5.9–22.6%) patients and 68/736 (9.2%) hospitalizations, and 7 (1.4%)
ESBL-E BSI were observed. The relative risk of BSI with ESBL-E was
13.1 in patients previously found to be colonized.
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Discussion: Even though BSI with ESBL-E is still rare in this high-risk
population, colonization rates are substantial and vary considerably between centers.
ID 148
Cardiorespiratory fitness in breast cancer patients
undergoing adjuvant therapy
O. Klassen1, M. Schmidt1,2, F. Scharhag-Rosenberger1,3,
M. Sorkin4, C. Ulrich1,5, A. Schneeweiss6, K. Potthoff7,
K. Steindorf1,2, J. Wiskemann1,3
German Cancer Research Center (DKFZ), National Center for Tumor
Diseases (NCT), Preventive Oncology, Heidelberg, Deutschland
2
German Cancer Research Center (DKFZ), Environmental Epidemiology,
3
University Hospital, Medical Oncology, Heidelberg, Deutschland
4
Yale University, Chronic Disease Epidemiology, New Haven, Vereinigte
Staaten Von Amerika
5
Fred Hutchinson Cancer Research Center, Cancer Prevention Program,
Seattle, Vereinigte Staaten von Amerika
6
University Hospital, Obstetrics and Gynecology, Heidelberg, Deutschland
7
University Hospital, Radiation Oncology, Heidelberg, Deutschland
# Shared last authorship.
1
Aim: To investigate cardiorespiratory fitness (CF) level in breast cancer
patients at different stages of adjuvant therapy.
Patients and Methods: Women with breast cancer, stage 0-III (n = 222),
were categorized according to their current treatment status (neo-adjuvant
chemotherapy (CT)/adjuvant CT/started CT/surgery only). Cardiopulmonary exercise testing was used to measure the patient’s CF. Maximal
oxygen uptake (VO2peak) was measured to represent cardiovascular and
pulmonary functions. Heart rate during exercise at 50 watts (HR50) was
assessed as a cardiocirculatory parameter and ventilatory threshold (VT)
was used as an indicator of O2 supply to muscle. Analysis of covariance
was used to investigate the determinates of CF.
Results: The mean age of our study population was 55±9 years. The
mean VO2peak was 20.6±6.7 ml/kg/min, mean VT 10.7±2.9 ml/min/kg and
mean HR50 112±16 beats/min. CT was significantly associated with decreased VO2peak, with significantly lower adjusted mean VO2peak among
patients post adjuvant CT compared to patients with no CT or just started
CT regime (all p < .01). Patients post adjuvant CT reached only 63% of
the VO2peak level expected for their age- and BMI-category (mean VO2peak
15.5±4.8 ml/kg/min). Similarly, HR50 was significantly associated, but
VT was not associated with treatment.
Conclusion: Breast cancer patients have marked impaired cardiopulmonary function during and after CT. Hereby, CT seems to impair CF by
influencing the oxygen delivery system rather than impacting metabolic
muscle function. However, the exact mechanisms need further investigations. Our results underline the need of exercise training in breast cancer
patients to counteract the loss of CF during the adjuvant therapy.
Physical activity is mentioned to be able to influence epigenetic modifications in various tissues including NK-cells. In the present study we try to
find out if physical activity induced epigenetic modifications also affect
NK-cells of cancer patients.
To investigate the influence of physical activity on epigenetic modifications in NK-cells, 8 female breast cancer patients in follow-up care perform endurance training for 5 months. Before and after the intervention,
blood is taken and NK-cells are isolated using magnetic beads. Changes
in global DNA metyhylation and histone acetylation (H4K5) are detected
by immunocytochemistry, followed by optic density analysis (ImmageJ).
Data collection will be finished in October. We expect a lower DNA methylation and a higher histone acetylation. Their impact on transcription is
oppositional and this result would promote a higher transcription. A higher level of transcription could enhance the NK-cell activity by increasing
the receptor density.
If we can show a change in epigenetic modifications by enhanced physical activity, a next step would be to investigate more precisely where
these changes are and how they influence the NK-cell activity in detail.
ID 238
Effect of bisphosphonates on vascular cells
A.M. Pabst1, T. Ziebart1, M. Ackermann2, M.A. Konerding2,
C. Walter1
1
2
Universität Mainz, Anatomie, Mainz, Deutschland
Introduction: Bisphosphonate-associated osteonecrosis of the jaw (BPONJ) can occur in long-term bisphosphonate treatment. In addition to
the impact the bone remodeling, bisphosphonates have a negative impact
on angiogenesis. In an in vivo study, the effects of bisphosphonates on
angiogenesis in a 3D Matrigel assay were analysed.
Material and Methods: Matrigel was injected into 6 to 8-week old female nude mice (n = 50). Five groups (n = 10) were treated either with
clodronate, ibandronate, pamidronate, zoledronate, or the carrier solution
as a control. Immunohistological stainings were performed to determine
the microvessel density (MVD), microvessel area (MVA), and microvessel size (MVS) in the Matrigel plugs after 3 weeks of treatment.
Results: MVD was decreased for all bisphosphonates tested (p each
<0.001). The nitrogen-containing bisphosphonates (N-BPs) had a stronger negative impact than the non-nitrogen containing (NN-BP) clodronate (control 166, clodronate 99, ibandronate 48, pamidronate 47, zoledronate 35 microvessels/mm2). Results for MVA were similar. Especially
ibandronate increased MVS compared to control group (p < 0.001).
Conclusion: Clodronate’s impact on MVD and MVA is less strong compared to the N-BPs, which might explain why no BP-ONJ occur after treatment with NN-BPs. Ibandronate increased MVS compared to all other bisphosphonates, which may be a compensation for reduced perfusion since
MVD and MVA were significantly decreased. This might be a possible explanation for the lower incidences of BP-ONJ after ibandronate treatment.
ID 221
Changes of epigenetic modifications in natural killer cells
of breast cancer patients in follow-up care by enhanced
physical activity
A. Schenk1, F. Baumann1, C. Koliamitra1, W. Bloch1,
F. Schollmayer1, J. Beulertz1, P. Zimmer1
Deutsche Sporthochschule Köln, Molekulare und zelluläre Sportmedizin,
Köln, Deutschland
1
Natural killer cells (NK-cells) are able to recognize and kill tumor cells.
With different germ-line encoded receptors, they recognize tumor cells
and kill them by promoting cell lysation and apoptosis. A higher expression of receptors on the surface of NK-cells could imply a higher sensitivity to target cells.
Besides genetically settings, gene expression is also based on epigenetic
modifications. Whereas DNA methylation seems to have a repressive effect
on transcription, histone acetylation seems to have activating potential.
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ID 253
Effects of a six-month sports therapy intervention for
childhood cancer patients: Preliminary results of the
ESCiMo Study.
V. Rustler1, F. Baumann1, W. Bloch1, A. Prokop2, J. Beulertz1
Deutsche Sporthochschule Köln, Institut für Kreislaufforschung und
Sportmedizin, Abteilung Molekulare und Zelluläre Sportmedizin, Köln,
Deutschland
2
Kliniken der Stadt Köln gGmbH, Kinderkrankenhaus Amsterdamer Straße, Klinik für Kinder- und Jugendmedizin, Pädiatrische Onkologie/Hämatologie, Köln, Deutschland
1
Background: Recently, several studies in pediatric oncology have
emerged finding positive effects of exercise programs on activity behavior, as well as different physiological and psychosocial outcome measures. However, research to date has mainly focused on ALL-patients
Abstracts
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Index
during medical treatment. Future research must therefore focus on cancer
diagnoses other than ALL, as well as on patients during survivorship.
Methods: The ESCiMo Study is a controlled trial, designed to evaluate
the effect of a group-based sports therapy program on motor performance
(primary outcome), quality of life and level of activity in a mixed childhood cancer population. Within a six-month period, childhood cancer
patients (post-inpatient medical treatment) aged 4–17 years will exercise
once a week for 60 minutes (intervention group). Healthy children in the
control group do not receive any specific sports therapy.
Results: Study recruitment started in May 2012. First findings suggest
that motor performance of participating childhood cancer patients may
improve substantially. Preliminary results regarding the effect of the exercise intervention on motor performance and quality of life in the IG
(n = 15) compared to the CG (n = 15) will be available at the time of the
congress.
Conclusion: The ESCiMo Study aims to explore the potential benefits
of a unique sports therapy program for a mixed childhood cancer population after cessation of their inpatient medical treatment. The results may
help to develop recommendations for exercise programs with childhood
cancer survivors and therefore improve the care structure in pediatric oncology.
ID 353
Evaluation of the impact of a three month resistance
training on fatigue and biomarkers of breast cancer
patients during chemotherapy
L. Gerland1, S. Frisse2, S. Latta3, W. Bloch1, N. Harbeck4,
F.T. Baumann1
Deutsche Sporthochschule Köln, Institut für Kreislaufforschung und Sportmedizin, Abt. für molekulare und zelluläre Sportmedizin, Köln, Deutschland
2
Unifrauenklinik, Brustzentrum, Köln, Deutschland
3
Frauenarztpraxis Latta, Brühl, Deutschland
4
Universität, Brustzentrum, München, Deutschland
1
ID 361
Evaluation of the physical demand of cancer patients
while cross-country skiing
K. Gutekunst1, L. Vogt1, K. Schmidt1, A. Bernardi1, E. Jäger2,
W. Banzer1
Goethe-Universität Frankfurt, Sportmedizin, Frankfurt am Main, Deutschland
Krankenhaus Nordwest, Frankfurt am Main, Deutschland
1
2
Leisure and adventure orientated journeys for cancer patients are increasingly promoted. Focusing on specific aerobic activities, some offers also
encourage patients to become physically active. However, there is lack
of objective data and evaluation. Therefore the present study monitored
objective and subjective parameters of the relative physical demand of
cancer patients during a one week cross-country skiing (CCS) excursion.
Thirteen cancer patients (63 ± 9.8 years; 9 ♀, 4 ♂) underwent baseline
(T0) cardiopulmonary exercise testing (treadmill) with continuous registration of oxygen uptake (VO2peak) and heart rate (HR). Subjective
mood state was assessed using the Profile of Mood States questionnaire
(POMS) at baseline, day 1 (T1) and day 3 (T2) of the excursion. HR was
monitored during the guided CCS sessions and perceived exertion (sRPE,
Borg scale 6-20) was recorded immediately afterwards. The individual
physical demand during CCS was categorized in reference to VO2peak
and corresponding HR intensities.
The average physical demand during CCS sessions (1.5±0.5h) was 13.1%
moderate, 65.7% vigorous and 17.3% near-maximal. Average sRPE was
12.3±1.5. Nonparametric testing (Friedman-test, post-hoc-comparisons)
revealed a reduction in the POMS subscale dejection from T0 to T2
(6.5±5.4 vs. 2.3±3.3; p = .015).
Considering the detected changes of dejection and the subjective perception of a moderate physical demand, CCS seems to be feasible for
cancer patients. However, due to the vigorous to near-maximal exercise
intensities in more than 80% of the sessions medical testing and exercise
counseling prior to participation is recommended.
Background: 80–96% of breast cancer patients suffer from cancer related
fatigue during acute therapy. Numerous studies showed positive effects of
exercise on CRF, but the number of studies implementing resistance training in rehabilitation is insufficient. Trials produced some evidence that
physical activity may result in beneficial changes in biomarkers in breast
cancer survivors. However, studies in this field are rare.
Goals: The study aims at analyzing the development of Fatigue and biomarkers of breast cancer patients executing resistance training during
chemotherapy.
Methods: The study was organized as a prospectively randomized and controlled preference study. 40 breast cancer patients in adjuvant chemotherapy were involved 6–12 weeks after surgery for 12 weeks: 20 probands each
were assigned to the intervention and control group. Resistance training
was executed twice per week for about 60 minutes, consisting of 7 routines
in 3 sets of 8–12 dynamic repetitions. Training was supervised. Subjective
intensity was controlled during exercise by modified RPE-scale, aiming at
local muscular exhaustion. The following parameters of both control and
intervention group were analyzed in the beginning, after 6 and after 12
weeks: Fatigue (MFI-Questionnaire), biomarkers.
Results: General (–10,6%) and physical Fatigue (–14,7%, p = 0,04)
could be lowered significantly in the IG whereas both increased in the CG
(GF=+6,2%, PF=+12,1%). The examination of all results is scheduled for
November 2013.
Discussion: General (n = 40) and therapy-matched (n = 27) results show
strong positive effects on GF and PF. Preliminary results suggest the integration of intense resistance training into the rehabilitation of mastocarcinoma patients.
ID 374
Abstracts
MeMa Study – exercise program for patients with
metastatic breast cancer
P. Wirtz1,2, P. Mallmann2,3, W. Malter2,3, W. Bloch1,2,
F.T. Baumann1,2
German Sports University Cologne, Institute of Cardiovascular Research
and Sports Medicine, Department of Molecular and Cellular Sports Medicine, Cologne, Deutschland
2
CIO Center for Integrated Oncology Cologne Bonn, Cologne, Deutschland
3
Gynecological Clinic of the University of Cologne, Breast Center, Cologne, Deutschland
1
Background: The importance of being physically active is known to reduce disease- and treatment-related side effects, as the fatigue syndrome,
and therefore positively influence quality of life in cancer patients. Recently, many studies have focused on the influence of physical activity
during and after medical treatment in breast cancer patients. These findings may lead to examine the feasibility and effects of an exercise program for patients with advanced breast cancer. The aim of the project is
to examine the influence of an exercise program on reduction of fatigue
syndrome in women with advanced breast cancer.
Methods: Twenty women with advanced breast cancer (age ≥ 18) in any
medical treatment take part in a 12 week supervised training intervention.
Patients with bone metastases affected more than 50% of bone density
are excluded. Participants exercise twice a week on medical exercise machines for 60 minutes or alternatively absolve twice a week a relaxation
training program for 45 minutes. Physical performance (spiroergometry),
muscle strength (h1RM), physical activity (GPAQ, KAS-O), anxiety and
depression (HADS), pain (BPI), quality of life (EORTC QLQ-C30, BR
23) and fatigue (MFI 20) are assessed before and after the intervention.
Perspective: Final outcomes about fatigue syndrome and the results of the
spiroergometry and the h1RM-test will be available at the time of the congress. Based on the results and conclusions of the study a program with
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larger sample size could be developed. Further studies should examine
possible effects of exercise programs on the progressions status and they
should improve supportive care for patients with advanced breast cancer.
ID 420
Perceived functional ability relates to laboratory and field
measures of exercise capacity in cancer patients
K. Schmidt, L. Vogt, C. Thiel, W. Banzer
Goethe-Universität, Abteilung Sportmedizin, Frankfurt, Deutschland
Although objective cardiopulmonary exercise testing (CPET) is considered as gold standard for exercise capacity evaluation, subjective instruments (e.g. self-rating scales) may be more economic to estimate fitness
in the everyday clinical setting. However, in cancer patients it is unknown
how such instruments relate to results derived from objective tests. Therefore this study in cancer patients compared a self-rating instrument to
assess perceived functional ability (PFA) with the gold standard in both,
laboratory and field exercise testing.
Methods: 50 cancer patients (57.4 ± 10.2 yrs.; during/after (56%/44%)
treatment) rated their PFA on a 13-point scale by estimating the walking/
running velocity they could keep up for 1.6 kilometers (4x400 m track).
Subjects also performed a CPET to assess peak oxygen consumption
(VO2peak) and a 6-minute walking test (6MWT) to determine 6MWT
distance (6MWD). PFA reproducibility was evaluated in a subsample
(n = 27) within 2-7 days.
Results: Participants’ VO2peak was 21.2 ± 4.8 ml·kg-1·min-1, mean 6MWD
594 ± 81m, and average PFA 6.9 ± 2.7 points. PFA was significantly correlated (p < .001) with VO2peak (r = .62) and 6MWD (r = .63). Grouped for
PFA estimated walking or running velocity (≤5; >5-7; >7 km·h-1) statistical testing revealed significant differences in VO2peak and 6MWD. The ICC
(2,1) for PFA test-retest reliability was .858 (95%CI: .713; .933) (p < .001).
Conclusions: The present findings revealed linear relationships between
PFA and VO2peak/6MWD which are almost comparable to the correlations
established between field and laboratory outcome measures. From subgroup analyses it emerged that different grades of PFA seem to be able to
distinguish between varying levels of exercise capacity.
Surgical Oncology
ID 227
Certification of biobanks: Adaption of the DIN EN ISO
9001:2008 norm to implement a quality management
system for the North German Tumorbank of Colorectal
Cancer.
M. Oberländer, R. Kaatz, J.K. Habermann
Universität zu Lübeck, Sektion für Translationale Chirurgische Onkologie
und Biomaterialbanken, Lübeck, Deutschland
Introduction: Standardization between biobanks is an essential factor
to guarantee high-quality human biospecimens for translational research
projects and clinical studies. So far, no international norm exists to promote common standards between biobanks. However, the DIN EN ISO
9001 norm is increasingly being adopted by biobanks in Europe since it
reflects many aspects of biobanking management and quality improvement.
Methods and Results: For the North German Tumorbank of Colorectal
Cancer (ColoNet) a quality management (QM-) system according to DIN
EN ISO 9001 was first implemented at the ColoNet site at the University Medical Center Lübeck. Here, the different biobanking steps (e.g.
patient’s recruitment, sample collection and processing) have been categorized into major «processes» which include associated Standard Operating Procedures (SOPs), form sheets and check lists. Over a period of 7
months, one study nurse, one research associate and one QM-consultant
124
were dedicated to create a QM-handbook which comprises the overall
quality criteria and aims that had been defined by the biobank and will
regularly be checked by internal and external audits. The implementation
of the QM-system resulted in certification in November 2011.
Summary: Preparing a biobank for certification according to DIN EN
ISO 9001 is possible within a 7 months’ time period if dedicated personal and funding is available. The certification has improved the overall
QM-performance assuring high-quality sampling and processing of biospecimens in Lübeck. This certification will further serve as basis for the
expansion of the QM-system to other ColoNet sites thus enabling highest
compatibility among all ColoNet sites.
ID 288
Kombination aus Schädeltrepanation und
Vakuumtherapie zur Granulationsinduktion bei großen
Skalpdefekten
E. Valesky, R. Kaufmann, M. Meissner
Universitätsklinik Frankfurt, Klinik für Dermatologie, Venerologie und Allergologie, Frankfurt, Deutschland
Große Skalpdefekte, die sämtliche Schichten einschließlich des Periosts
umfassen, stellen eine Herausforderung dar. Häufig bleiben nur sehr
aufwendige Lappenplastiken oder aber die freie Lappenplastik mit mikrovaskulärem Gefäßanschluss, um die Defekte zu verschließen. Diese
Operationen sind vielen Patienten aufgrund ihres hohen Alters, ihren
Begleiterkrankungen und Ihrer Prognose nicht zuzumuten. Eine einfach
durchzuführende Spalthauttransplantation ist aufgrund des fehlenden Periosts nicht möglich. Hier empfiehlt sich eine Trepanation der Tabula externa, um die gefäßführende Diploe zu eröffnen und eine Granulation zu
induzieren. Die Bildung des Granulationsgewebes kann sich jedoch über
viele Wochen bis Monate hinziehen. Die Gefahr des Austrocknens der
Trepanationslöcher besteht trotz regelmäßiger Verbandswechsel. Um den
Prozess wesentlich zu beschleunigen und ein Austrocknen zu verhindern,
kombinieren wir die Trepanation mit einer Vakuumtherapie. Am Beispiel
einer Patientin mit einem großen Angiosarkom des Capillitiums, wird
das Vorgehen beschrieben und dargestellt. Nach schnittrandkontrollierter Exzision des Tumors bis auf die Schädelkalotte, wurden im Bereich
des 15×17 cm großen Defekts, multiple Trepanationsbohrungen mit dem
Rosenbohrer angelegt. Direkt im Anschluss wurde eine Vakuumversiegelung durchgeführt. In 3 Wochen konnte ein flächiges Granulationsgewebe
über der Schädelkalotte erreicht und die Patientin erfolgreich Spalthaut
transplantiert werden. Die Kombination aus Trepanation und Vakuumtherapie stellt eine effektive Methode der Defektdeckung von großen, alle
Schichten umfassenden Skalpdefekten dar, bei denen ein Verschluß mittels Lappenplastiken nicht in Frage kommt.
ID 292
New aspects in the development of Bisphosphonaterelated jaw necorsis
W. Reich1, M.H.W. Lautner1, D. Wilhems1,2, A.W. Eckert1
Deutschland
2
Marti-Luther-University Halle-Wittenberg, Institute of Medical Microbiology, Halle (Saale), Deutschland
1
Introduction: Bisphosphonate-related osteonecrosis of the jaws
[BRONJ] is a serious side-effect of bisphosphonate treatment. The mechanism behind BRONJ remains unclear. In literature several origins are
suggested. An important role play presence of the teeth in the jaw, the
other lesions spontaneously develop due to dental prosthesis. Therefore
in this study 63 patients were analyzed retrospectively.
Materials and methods: A total of 63 patients with a clinical manifest
BRONJ were analyzed during 2005 and 2013. The following clinical and
histological parameters were collected to a database [SPSS 17.5]: primary
diagnosis, treatment and complications, kind of bisphosphonate adminis-
Abstracts
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Index
tration. Additionally, in 19 cases swabs were taken from acute BRONJ.
All microbiological material was collected under standardized conditions
(Stuart medium, transport within 4 hours to the laboratory).
Results: We found 84 clinical manifest BRONJ lesions. Most of them
were localized at the mandibular bone (n = 70), only 14 cases developed
at the maxilla. The mean time of bisphosphonate administration was
38 month. Most of them developed after tooth extraction or other dental surgical procedures. We found 95 different bacteria [4.3 strains per
specimen]. The predominant bacterial genera were: Streptococci (18x),
Neisseria (8x) and members of the family Enterobacteriaceae (7x). The
most frequent anaerobes were Prevotella (16x), Fusobacterium (14x) and
Peptostreptococcus (8x).
Discussion: The mean factors influencing a BRONJ are dental surgical
procedures and insufficient prosthetical rehabilitation. In our opinion, other
predictors should be suggested for the risk to develop BRONJ. The bacterial contamination is underestimated. As a consequence, an administration
with Bisphosphonates will induce a bony necrosis. But only the subsequent
bacterial contamination results in the typical clinical manifest BRONJ.
ID 357
Vascular anomalies in patients undergoing
retroperitoneal lymph node dissection
A.K. Thissen, D. Pfister, D. Porres, C. Piper, A. Heidenreich
Uniklinikum Aachen, Urlogie, Aachen, Deutschland
Anomalies of the renal vessels are clinically silent and might be depicted
during CT scanning of the abdomen for staging purposes of urological
malignancies. Awareness of these rare anomalies is crucial especially in
patients undergoing staging for germ cell tumors to avoid overstaging and
unnecessary therapy. We report on the incidence of renal vessel anomalies
of patients undergoing RPLND for testis cancer.
245 patients with testicular germ cell tumors underwent primary or secondary RPLND following inductive chemotherapy. Prior to RPLND, all
patients underwent abdominal staging by CT scans or by MRI in selected
cases. CT scans were reviewed with regard to the detection of vascular
anomalies of the vena cava inf., renal veins, renal arteries and iliac vessels. CT findings were correlated with intraoperative findings.
Overall, vascular anomalies were encountered in 39 patients (15.9%):
retroaortic left renal vein in 10 (4.1%), circumaortic left renal vein in 2
(0.8%), reduplication of the common iliac vein in 1 (0.4%), accessory
renal arteries in 14 (5.7%), thrombosis of the inferior vena cava in 12
(4.9%) patients with IIC disease. Anomalies of the renal vein were detected in 10/12 (83%), in 2 cases venous anomalies were falsely diagnosed as
lymph node disease in stage I NSGCT. All arterial anomalies were identified preoperatively. CT scan identified caval thrombosis in only 8 cases
(68%), 4 cases were identified by an additional MRI of the abdomen.
Vascular anomalies are frequently encountered in pts with RPLND for
testis cancer and have to be acknowledged during surgery even with negative imaging studies. Retroaortic renal veins represent a potential pitfall
of CT imaging resulting in unnecessary therapy; it should be considered
in pts with CT suspicious lymph nodes caudal to the renal hilus. IVC
thrombosis is associated with advanced disease and is best diagnosed by
MRI of the abdomen.
ID 387
Lung parenchyma sparing surgery – retrospective study
of laser segmental resection for pulmonary malignancies
A. Pereszlenyi, S. Eggeling, R.-L. Morgen, J. Strasburg,
S. Sklenar
Vivantes Lungenkrebszentrum, Thoraxchirurgie, Berlin, Deutschland
Objective: Is to prove the feasibility of laser segmental lung resection
for primary/secondary pulmonary tumors within the retrospective study.
Patients and Methods: Between 02/2009 and 08/2012, 31 patients (18
males, 13 females, mean age 69.7, range 54–85 yrs) underwent Laser
Abstracts
Segmental Resection (LSR) in our Clinic. The indications for LSR were:
non-small cell lung carcinoma (NSCLC) in 19 and pulmonary metastases
in 12 patients. The most detected histologic type of NSCLC was adenocarcinoma (n = 11), followed by squamous-cell (n = 6) and large-cell carcinoma (n = 2). The lung metastases of the colorectal-carcinoma (n = 8)
was the main indication for pulmonary metastasectomy. The metastases
of breast cancer (n = 2), melanoma and anal-carcinoma (one in each)
completed this indication group. All LSR were performed by the new Nd
YAG laser system of 1318 nm wavelength and up 120 W power output.
Results: No intraoperative mortality was recorded. The most common
complications after the LSR were prolonged air leakage in 5 and prolonged pleural effusion in 3 patients. Postoperative pneumonia occurred
in 3, atrial fibrillation in 2 pts. In none of these patients a bronchial stump
insufficiency/ fistula was recorded. Follow-up was completed for all patients with median of 15 Months (0.2–39 Mo). Survival was analyzed
according to Kaplan-Meier method with 10 Months 82.5%, 20 Mo 66.7%
and 30 Mo 48.2% overall survival.
Conclusion: Radical surgical resection is still the therapy of choice in
NSCLC treatment. However, laser segmental lung resection represents
an optimal treatment eventuality especially for those high risk patients in
whom the standard resection – lobectomy is not feasible or performable.
ID 393
Basal cell carcinoma of facial skin
A.W. Eckert, W. Reich, K. Scheller
Deutschland
Basal cell carcinoma is the most frequent human malignancy. Surgical
therapy is the common goldstandard. The classic surgical therapy is controversially discussed. A one-stage treatment is favorized by maxillofacial surgeons, whereas dermatologists suggest the two-stage approach
including micrographic surgery.
We evaluated the recurrence rates in facial skin basal cell carcinomas Based
on the clinical courses of more than 7 decades. We analyzed more than
1400 primary basal cell carcinomas and determined the risk to develop a
recurrence as a function of tumor size, histological subtype and R-status.
The recurrence rate of all primary basal cell carcinomas was 4%. The
predesinating factors for developing a recurrence were tumor localization, tumor size and histological subtype, respectively. Significant more
reccurences were observed in tumor diameters more than 14 mm. On
the other hand, also histological subtype had an influence. Solid forms
showed a recurrence of only 1.9%, whereas sclerodermiformic basal cell
carcinoma and metatypic subtype had an increased risk of 4.3 and 7.4%.
As a consequence, more than 97% of all primary basal cell carcinoma can
be treated by surgical removal without any recurrence. It was observed
that size, incomplete excision, deep margin involvement, the presence of
sclerodermiform or metatypic basal cell carcinoma related to an increase
in the probability of recurrence.The following safety distances for successful surgical resection should be considered: 5 mm to remove solid
types and 10 mm for surgical removal of sclerodermiformic/metatypic
basal cell carcinoma, large or recurrent tumors. We recommend the surgical removal of basal cell carcinoma and direct closure of the defect
instead of the more cost-effective micrographic surgery.
ID 398
Vaskuläre Dimension onkochirurgischer Interventionen
– repräsentative Fallbeispiele des ergänzenden
gefäßchirurgischren Managements
Z. Halloul1, A. Udelnow1, F. Meyer1
Universitätsklinikum Magdeburg A.ö.R., Arbeitsbereich Gefäßchirurgie,
Klinik für Allgemein-, Viszeral- und Gefäßchirurgie, Magdeburg, Deutschland
1
Einleitung: In der alltäglichen Praxis trifft jeder Chirurg immer wieder
auf vaskuläre Probleme, insbesondere im Rahmen ausgedehnter onkochi-
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rurgischer oder multiviszeraler Resektionen. Diese erfordern Kenntnisse
der speziellen und teils variablen Gefäßanatomie, der gefäßchirurgischen
Operationszugänge, aussichtsreicher operationstaktischer Vorgehensvarianten und der speziellen Gefäßersatzmöglichkeiten.
Patienten & Methode: Anhand exemplarischer Krankheitsbilder und
operativer Situationen werden operationstaktische Entscheidungen und
das gefäßchirurgisch- technische Vorgehen demonstriert.
Ergebnisse: Traumatische und iatrogene intraabdominelle Gefäßläsionen, spontane intra-abdominelle Blutungen, tumorassoziierte Gefäßinfiltration sowie perivaskuläre Infektionen gehören zu den häufigsten intraund perioperativen Konstellationen. In einem 4-Jahreszeitraum wurden
insgesamt 63 Tumor-assoziierte-Operationen durchgeführt (u.a. V. cava:
n = 16; Pfortader/Konfluenz: n = 12; A. mesenterica superior n = 2; A.
hepatica: n = 3; Truncus coeliacus: n = 2; Aorta/Beckenarterien: n = 7;
Halsgefäße: n = 4). Die Eingriffe verliefen gefäßchirurgisch weitestgehend komplikationsarm. Das Grundleiden bestimmte die Prognose.
Schlussfolgerungen: In Zentren mit multiviszeralen Rekonstruktionen
ist eine spezialisierte Gefäßchirurgie unabdingbar. Ein breites Spektrum
der interdisziplinären Zusammenarbeit bei der Operationsplanung und
Durchführung kann in indizierten Fällen die Resektabilität mit real erreichbarem R0-Status sichern und die Prognose verbessern helfen.
ID 402
Lung-sparing Radical Pleurectomy for Malignant Pleural
Mesothelioma: 11-year Single-Center Experience
S. Bölükbas1, M. Eberlein2, A. Fisseler-Eckhoff3, J. Schirren1
Amerika
3
HSK Wiesbaden, Institut für Pathologie und Zytologie, Wiesbaden,
Deutschland
1
2
Objective: To report our 11-year single center experience of malignant
pleural mesothelioma (MPM) treated with radical pleurectomy (RP) as
surgical arm within a multiimodality approach.
Methods: In a prospective, non-randomized study, all patients with histologically proven MPM, clinical stage cT1-3 cN0-2 and without prior
treatment for MPM were evaluated for multimodality therapy from 2002
to 2012: Lung-sparing RP followed by 4 cycles of Cisplatin/Pemetrexed.
Prophylactic radiation of the chest wall was only performed between
2002 and 2010.
Results: One-hundred-two out of 231 consecutive patients underwent RP.
84 out of 102 patients (82%) completed the therapy. Surgical morbidity and
mortality were 29.4% and 2.9%. Median survival and 5-year-survival were
26.3 months and 28%, respectively. Progression-free-survival was 13 Mo.
The sites of failure were locoregional in 44.1%, distant in 9.8% and both
in 13.7%, respectively. Macroscopic complete resection, T1/T2, N0, IMIG
stage I/II and age < 70 years were associated with significant prolonged survival in the univariate analyses. Non-epitheloid histology (p = 0.089) and tumor spread at the resected previous incision sites (p = 0.058) showed a trend
towards inferior survival. Histology, age ≥ 70 years, T3/T4, IMIG-stage III/
IV and tumor spread at the resected previous incision sites remained independent significant prognostic factors in the multivariate analysis.
Conclusions: Lung-sparing RP within a multimodality therapy concept is
associated with promising long-term survival. Tumor biology in terms of
type of histology, stage and tumor spread at the resected previous incision
sites are independent prognostic factors. Patients aged ≥ 70 years should
be selected very carefully for multimodality therapy.
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ID 410
En-Bloc Resection of pulmonary metastases with
infiltration of the spine
S. Bölükbas1, T. Dönges1, M. Eberlein2, J. Schirren1
Amerika
1
2
Objective: Pulmonary metastases from extrathoracic carcinoma with infiltration of the spine are very uncommon. There is a lack of data with
regard tothe benefit of extended pulmonary metastasectomy. The purpose
of this study is to describe our surgical en bloc approach and to assess the
outcome and survival.
Methods: We retrospectively analyzed all patients, who underwent pulmonary resection for metastatic disease from extrathoracic carcinoma
with en bloc hemivertebrectomy or total vertebrectomy between January
2003 and December 2012. Survival was estimated by the Kaplan-Meier
method. Log-rank analyses were used to compare groups.
Results: Location of the primary cancer in 12 patients (age 51.8 ± 18.9
years, 8 males) were testicular (n = 3), renal (n = 3) and other (n = 6),
respectively. Median time interval between therapy of the primary cancer
and metastasectomy was 31.6 ± 1.9 months. Seven patients (58%) had
induction therapy before surgery. Indications for metastasectomy were
curative intend in nine and palliative intend (neurologic impairment, instable spine) in three patients, respectively. Resections were complete in
9 patients (75%). Morbidity and mortality were 33% and 0%. Median, 1and 5-year survivals were 48.0 ± 14.0 months (CI 95% 20.6-75.4), 83%
and 35%, respectively. Surgeries with palliative intend (p = 0.003) and
age ≥ 65 years (p = 0.003) were associated with inferior survival.
Conclusions: Pulmonary metastasectomy with en bloc hemivertebrectomy
or total vertebrectomy can be performed safely. These extended resections
in curative intend offer promising long-term survival in highly selected patients. Patients aged ≥ 65 years should be selected very carefully for surgery.
ID 415
Are chemotherapy and radiotherapy risk factors for postoperative delirium in elderly cancer patients undergoing
elective surgery? Observational study in two tertiary
university hospitals.
B. Neuner1, M. Schmidt1, E. Weiss-Gerlach1,
V. von Dossow-Hanfstingl2, K. Hartmann1, C. Spies1
Charité – Universitatsmedizin Berlin, Klinik für Anästhesiologie mit
Schwerpunkt operative Intensivmedizin, Berlin, Deutschland
2
LMU München, Dept. of Anesthesiology, München
1
Introduction: Many elderly cancer patients undergo surgery. Age and
impaired physical status are risk factors for post-operative delirium
(POD), a cognitive disorder with disorientation, hallucinations and disturbance of vigilance.
Objectives: To evaluate the independent association of pre-operative
chemotherapy and radiotherapy on POD in ≥ 65 year old cancer patients.
Methods: Between 02- 2011 and 09-2012 and after ethical committee approval and written informed consent the study was conducted in 2 tertiary
university hospitals in Germany. Patients were categorized according to
the American Society of Anesthesiologists physical status classification
system (ASA PS) score. Post-operatively patients were screened for POD
using the Nursing Delirium Screening Scale (Nu-DESC) respectively the
Confusion Assessment Method for the ICU (CAM-ICU) within 7 days
post-operative. Multivariate analysis was by logistic regression analysis.
Results: Overall 658 patients (mean age 71.8 years, 68.4% males) with
prostate cancers (38.8%), ovarian cancers (13.7%), other cancers of the
genito-urinary tract (16.0%), upper gastroinstestinal tract (21.1%) and
colorectal cancers (10.5%) were included. Preoperatively 77 patients
(11.7%) had received chemotherapy and 27 (4.1%) radiotherapy. Within the first 7 days after operation 61 patients (9.3%) developed POD. In
Abstracts
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multivariate analysis adjusted for age, gender, ASA PS score and tumor
site, study participants after preoperative chemotherapy were at decreased
risk for POD, Odds Ratio = 0.23 (95%-confidence interval (0.07–0.73)),
p = 0.012 while study participants after radiotherapy showed a tendency
for increased POD: OR = 3.1 (95%-CI (0.9–10.3)), p = 0.07.
Conclusion: Pre-operative chemotherapy in cancer patients is associated
with post-operative delirium.
Tumor and Cell Biology
cells, this effect was almost completely abrogated by Nrf2. Accordingly, p38- and Smad3-phosphorylation was diminished whereas p42/
p44-phosphorylation was enhanced under these conditions. Moreover,
Nrf2 induces a migratory phenotype in HPDE cells though inhibiting
TGF-b1 associated EMT-characteristics. Interestingly, krasG12V expression is dispensable for these effects in HPDE cells.
Our data show that Nrf2 is induced under inflammatory conditions and
counteracts the anti-proliferative function of TGF-b1 already in non-malignant pancreatic ductal epithelial cells. This could be a mechanism by
which the anti-tumorigenic function of TGF-b1 is suppressed, also underscoring the pro-tumorigenic role of Nrf2 that can manifest already in
early stages of pancreatic ductal adenocarcinoma development.
ID 081
Interlude of cGMP and cGMP/protein kinase G type I in
pancreatic adenocarcinoma cells
S. Karakhanova, J. Werner, A. Bazhin
cAMP and cGMP signaling is important both for normal and cancer cells.
This signaling is controlled by adenylyl and guanylyl cyclases (GC) and
cyclic nucleotide phosphodiesterases (PDE). One of the direct targets
for cGMP is protein kinase G (PKG). The main aim of this work was
to investigate cGMP and PKG signaling in pancreatic adenocarcinoma
(PDAC) cells. PKG activity, cGMP and calcium level were measured
with the CycLex Cyclic GMP dependent protein kinase (cGK) Assay Kit,
with the DetectX® Cyclic GMP Colorimetric EIA Kit, and with the Fluo-4
NW Calcium Assay Kit, correspondingly. Proteome ProfilerTM Array was
done using Human Phospho-Kinase Array and Human Phospho-MAPK
Array Kits. Here, we show for the first time that functional PKGI is expressed in PDAC cells. We demonstrate that the specific PKGI inhibitorDT3 induces cytotoxicity through necrosis and reduces proliferation and
migration of PDAC cells. Besides, ERK1/2 and p38 can be considered
as potential targets for PKGI in PDAC cells. Furthermore, we show that
PDE and NO-GC regulate the cGMP level in PDAC cells affecting proliferation of the cells. cGMP and PKG signaling may be a target for developing new therapeutical approaches for PDAC.
ID 127
The anti-oxidative transcription factor Nuclear factor E2
related factor-2 (Nrf2) counteracts the effect of TGF-b1 on
proliferation in pancreatic ductal epithelial cells – a protumorigenic function of Nrf2?
M. Kruppa1, S. Arfmann-Knübel2, R. Simon3, G. Sauter3,
J.R. Izbicki4, H. Schäfer2, S. Sebens1
UKSH Campus Kiel, Institut für Experimentelle Medizin, AG Inflammatorische Karzinogenese, Kiel, Deutschland
2
UKSH Campus Kiel, Klinik für Innere Medizin I, Labor für Molekulare
Gastroenterologie & Hepatologie, Kiel, Deutschland
3
Universitätsklinikum Hamburg-Eppendorf, Institut für Pathologie, Hamburg, Deutschland
4
Universitätsklinikum Hamburg-Eppendorf, Klinik und Poliklinik für Allgemein-, Viszeral- und Thoraxchirurgie, Hamburg, Deutschland
1
Nuclear factor E2 related factor-2 (Nrf2) is an oxidative stress inducible
transcription factor mediating cytoprotective responses. Thereby, Nrf2
protects e.g. epithelial cells exposed to inflammation from oxidative cell
damage and mutagenesis supporting an anti-tumorigenic effect of Nrf2.
However, Nrf2 is deregulated in many tumors and confers therapy resistance, thus pointing to a pro-tumorigenic role. A similar duality in tumorigenesis is known for the Transforming Growth Factor-beta 1 (TGF-b1).
Based on the observation that activated Nrf2 (phospho-Nrf2) is present
in pancreatic ductal epithelium during chronic pancreatitis (CP) and in
precursor lesions of PDAC (IPMNs), this study aimed at elucidating the
combined effects of Nrf2 and TGF-b1 on proliferation of HPDE pancreatic ductal epithelial cells as well as the underlying signalling pathways.
While TGF-b1 treatment markedly reduced the proliferation of HPDE
Abstracts
ID 128
Regulatory T-cells and CD4+T-effector cells both mediate
epithelial-mesenchymal transition in pancreatic ductal
epithelial cells
E. Grage-Griebenow1, L. Goebel1, A. Gorys1, O. Helm1,
R. Mennrich1, S. Freitag-Wolf2, I. Vogel3, T. Becker4, M. Ebsen5,
C. Röcken6, D. Kabelitz7, H. Schäfer8, S. Sebens1
Institute für Experimentelle Medizin, UKSH Campus Kiel, AG Inflammatorische Karzinogenese, Kiel, Deutschland
2
UKSH Campus Kiel, Institut für Medizinische Informatik und Statistik, Kiel,
Deutschland
3
Städtisches Krankenhaus, Chirurgische Klinik, Kiel, Deutschland
4
UKSH Campus Kiel, Klinik für Allgemeine Chirurgie und Thoraxchirurgie,
Kiel, Deutschland
5
Städtisches Krankenhaus, Institut für Pathologie, Kiel, Deutschland
6
UKSH Campus Kiel, Institut für Pathologie, Kiel, Deutschland
7
UKSH Campus Kiel, Institut für Immunologie, Kiel, Deutschland
8
UKSH Campus Kiel, Klinik für Innere Medizin I, Labor für Molekulare
Gastroenterologie & Hepatologie, Kiel, Deutschland
1
Progression of pancreatic ductal adenocarcinoma (PDAC) is characterized by an accumulation of CD4+ T-cells in the tumoral stroma. Regulatory T-cells (Tregs) and effector T-cells (Teffs) are the most prominent
CD4+ T-cell subsets being abundant already in chronic pancreatitis (CP).
Recent reports indicate that epithelial-mesenchymal transition (EMT)
might be induced in the ductal epithelium already during chronic inflammation promoting PDAC development.
This study aimed to investigate the impact of CD4+ T-cells on EMT induction in human pancreatic ductal epithelial (HPDE) cells in vitro and to
correlate these data with findings from immunohistochemical analysis of
pancreatic tissues from CP and PDAC patients.
[CD4+CD25+CD127-CD49d-FoxP3+]Tregs and [CD4+CD25-CD127+
CD49d+FoxP3-]effector T-cells (Teffs) isolated from leukocyte concentrates of healthy donors by magnetic bead separation were directly co-cultured for 72 hours with HPDE cells. Compared to HPDE cells cultured
alone, not only Treg co-cultured but also Teff co-cultured HPDE cells
exhibited a markedly upregulated expression of the mesenchymal marker
proteins vimentin and L1CAM, whereas no alteration in the expression of
the epithelial marker e-cadherin was noted. In line with this finding, the
expression level of both mesenchymal marker proteins in the pancreatic
ductal epithelium was greater in PDAC than in CP tissues correlating with
elevated numbers of CD4+ T-cells.
In summary, these data point to a common role of Tregs and CD4+ Teffs
in EMT induction in pancreatic ductal epithelial cells already in CP. This
supports the view that EMT commences early during inflammation paving the way for PDAC development.
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ID 166
Expression of human aryl hydrocarbon receptor and
ARNT is upregulated after chemotherapy in recurrent
glioblastoma multiforme
M. Timmer, R. Tjiong, G. Röhn, R. Goldbrunner
The aryl hydrocarbon receptor (AhR) is a transcription factor, which has
been attributed a role in human cancerogenesis and TGF-b signaling. The
endogenous tumor-promoting ligand of the human AhR kynurenine was
discovered recently. It is constitutively generated by tumor cells via tryptophan-2, 3-dioxygenase (TDO), a neuron-derived tryptophan-degrading
enzyme.
We used real-time RT-PCR to quantify the expression of AhR, TDO, the
AhR nuclear translocator (ARNT), and the repressor of AhR (AHRR).
We examined a set of 70 human glioma samples representing the differences between the three degrees of malignancy (WHO grade II-IV),
primary and recurrent gliomas, pure and mixed astrocytic tumors, and
with and without radio- and/or chemotherapy. We also studied whether
the expression profile changes as the same tumor progresses in 20 individual patients.
Both, the expression of AhR and ARNT were significantly increased after
chemotherapy (CTx). The AhR was upregulated from 0.69 before CTx
to 3.49 after CTx in secondary GBM and from 0.76 to 1.51 in primary
GBM respectively (p = 0.003). The mRNA expression of ARNT was increased from 1.37 before CTx to 2.7 after CTx in secondary- and from
0.86 to 1.68 in primary GBM (p = 0.009). In contrast, TDO expression
was downregulated during temozolomide CTx in GBM from 0.77 to 0.35
(p = 0.03). Moreover, ARNT was significantly upregulated in grade II and
grade III astrocytomas compared to peritumoral tissue (p < 0.0001).
These results provide evidence for an important pathophysiological role
of the AhR with profound implications for cancer and immune biology
and could have broad implications for potential targeted therapies.
ID 189
Isolation of circulating tumor cells in vivo by the
CellCollector™ technology
S. Herold1, R. Hoda2, L. Gasiorowski3, P. Nowaczyk4, K. Haubold1,
W. Dyszkiewicz5, D. Murawa4, G. Theil2, B. Długaszewska1,
K. Lücke1
GILUPI GmbH, Potsdam, Deutschland
Martin Luther University, Halle, Deutschland
3
Medical University Poznan, Department of Thoracic Surgery, Poznan,
Polen
4
Wielkopolska Cancer Centre, Poznan, Polen
5
Medical University Poznan, Poznan, Polen
1
2
Background: Circulating tumor cells (CTCs) are discussed as a prognostic biomarker. Whereas current methods isolate CTCs in vitro; the
novel CellCollector™ is an in vivo technology. The aim was to assess the
CellCollector™ system with non-small cell lung cancer (NSCLC), breast
cancer (BC), colorectal cancer (CRC) and prostate cancer (PC) patients,
and to compare it to the CellSearch® method.
Methods: The device was inserted in a cubital vein via a standard cannula
for thirty minutes. CTCs were captured by an antibody directed against
the epithelial cell adhesion molecule (EpCAM) on the CellCollector™
surface. To confirm the CTCs’ binding, immunohistochemical staining
against EpCAM/Cytokeratins and CD45 was performed. More than 450
applications of the CellCollector™ in cancer patients and over 50 controls
were performed. Samples of 126 cancer patients and 15 control subjects
were also tested in the CellSearch® system.
Results: The device was well tolerated in more than 500 applications
without side effects. A direct comparison of the CellCollector™ and CellSearch® resulted in detection rates of 74.5% and 18.2%, respectively.
Specifity rates were 91% and 93%, respectively. Regardless of the disease
128
stage, in nearly all compared samples the number of CTCs detected with
the CellCollectorTM was higher or equal to CellSearch®.
Conclusions: With a detection rate of over 75% this new device overcomes present limitations in CTC-enrichment. Future implementation
into clinical practice may improve early detection, prognosis and therapy
monitoring of cancer patients. Captured CTCs are ready for molecular
characterization and will help to establish personalized treatment regiments.
ID 201
microRNA-449 depletion promotes chronic obstructive
pulmonary disorders independently of tobacco smoke
exposure
M. Lizé, A. Klimke, C. Herr, M. Schuldt, R. Bals, M. Kessel,
M. Dobbelstein
Institut für Molekulare Onkologie, AG Dobbelstein, Göttingen, Deutschland
MicroRNA-449 expression is associated with apoptosis (p53 regulation)
and ciliated differentiation (notch regulation). It is specifically expressed
in the airway epithelia. A knockdown of miR-449 was shown to inhibit
ciliogenesis in a frog model.
To rigorously assess the function of miR-449 in vivo, we engineered a
mouse strain with global deletion of the miR-449 locus. Against all expectations, the genetic ablation of miR-449 did not cause an obvious ciliary phenotype, and this is not due to a compensatory up-regulation of
its homologues miR-34abc. The bronchial epithelium is slightly affected
with a decrease in Clara cells and an increase in Goblet cells.
To evaluate the role of miR-449 in the regeneration of airway epithelia, we exposed the mice to long-term cigarette smoke. Lung function
analysis revealed typical chronic obstructive pulmonary disorder (COPD)
symptoms in the smoke-exposed mice regardless of their miR-449 status.
Surprisingly, the non-exposed miR-449 knockout animals (KO) acquired
COPD symptoms with age. A Muc5ac up-regulation was observed in all
COPD cohorts, characteristic of Goblet cell hyperplasia and enhanced
mucus production. This was accompanied by the induction of genes
responsible for regeneration and proliferation: the replication marker
Mcm3, the CDK inhibitor p27 and Sox2, a marker for stem cells. Additionnally, the miR-449 depleted control mice have more macrophages in
the lungs, indicative of inflammation.
To conclude, miR-449 is not required for ciliogenesis in the mouse but its
loss promotes COPD probably through Goblet cell hyperplasia, enhanced
inflammation and hyperproliferation.
ID 215
miR-199b-3p: A novel potential growth inhibitor in PDAC
H. Zöllner, A. Maghnouj, S. Hahn
Bochum, Deutschland
Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related deaths worldwide, due to a late detection and lack of specific
therapeutic targets and ineffective therapies. Novel strategies for both
the diagnosis and treatment of this disease are urgently needed. MicroRNAs (miRNAs) are small (~21–25 nucleotides), endogenous, noncoding
RNAs that are involved in varoius biological processes through suppression of target gene expression. Rapidly accumulating evidence indicates
that the expression of miRNAs is deregulated in cancer. This provides potential applications for cancer therapy as well as for early tumor detection.
Characterization of the ‘pancreatic miRNome’ in normal and in PDAC tissue demonstrated that miR-199b was a downregulated miRNA in this cancer type but not in normal tissue. To elucidate its potential biological role
in PDAC, miR-199b-3p was overexpressed via a doxycycline-inducible
lentiviral vector system in several PDAC cell lines. This induced growth
inhibition in all cell lines, attributable to a cell cycle arrest at the G1 phase.
In addition, miR-199b-3p effect on tumor growth was examined by an in
Abstracts
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Index
vivo nude mouse xenograft model using PDAC cell lines. Mice bearing
cells inducibly overexpressing miR-199b-3p developed tumors more slowly compared to control cells after induction with doxycycline.
Combining global gene expression analyses of miR-199b-3p xenograft
derived from transgenic PDAC line PancTuI with in silico miRNA target
expression, we identified potential miRNA-199b-3p targets. However,
the functional characterization of these genes and their role in carcinogenesis as well as the underlying mechanism of the G1 cell cycle arrest
have yet to be explored.
ID 229
Coherence of polarization phenotype of tumor associated
macrophages, cytokine levels and progression free
survival in ovarian cancer
M. Jansen1, S. Reinartz1, R. Müller2, S. Müller-Brüsselbach2,
T. Schumann2, F. Finkernagel2, A. Wortmann2, W. Meissner2,
M. Krause2, U. Wagner1
Uniklinikum Gießen und Marburg GmbH, Klinik für Gynäkologie, gynäkologische Endokrinologie und Onkologie, Marburg, Deutschland
2
Universität Marburg, Institut für Molekularbiologie und Tumorforschung,
1
Background: Tumor associated macrophages (TAMs) are present in the
ascites fluid of advanced serous ovarian cancer. The anti-inflammatory
M2-polarization on TAMs has been thought to be important for development, progression and metastasizing of ovarian carcinoma. We hypothesized that a certain kind of phenotype of TAMs is associated with a worse
outcome in primary advanced ovarian cancer.
Methods: We analyzed the polarization phenotype of ascites derived TAMs
and the cytokine milieu of ascites of 30 women. Ascites fluid was obtained
during initial debulking surgery for primary ovarian cancer. Preparation of
TAMs, FACS analysis for surface expression markers and gene profiling
were described earlier. Cytokine analysis was performed with commercially available ELISAs. The experimental and clinical data (e.g. progression
free survival (PFS)) of 20 patients were available for this analysis.
Results: Seventeen out of these featured a mixed- polarization phenotype
of the M1/M2 classification. The M2- surface marker CD 163 showed
an inverse association with PFS (p < 0,01). CD 163 expression was positively correlated with the concentration of the cytokines IL-6 and IL-10
(p < 0,01) is ascites fluid; both cytokines are active to induce CD 163 expression. Consequently, PFS was likewise found to be inverse associated
with the concentration of these cytokines (p < 0,01).
Conclusion: The presence of TAMs with high CD 163 expression was
demonstrated, which correlated positively with IL-6 and IL-10 levels in
ascites but inversely with PFS. This results warrant further investigations
of TAMs in ovarian cancer.
ID 240
CA125 (MUC16) gene silencing suppresses tumour
growth through activation of PI3K/Akt signaling pathways
of ovarian and breast cancer cells
S. Kage, S. Reinartz, U. Wagner
Universitätsklinikum Giessen und Marburg GmbH, Klinik für Gynäkologie,
Gynäkologische Endokrinologie und Onkologie, Marburg, Deutschland
Background: The tumour associated antigen CA125 (MUC16) is commonly expressed in ovarian cancer and can also be detected in other tumour of epithelial origin. The aim of the present study was to investigate
the impact of MUC16 gene silencing on the growth properties of ovarian
and breast cancer cells.
Methods: Four ovarian and one breast cancer cell lines with differential
MUC16 expression were transfected with MUC16 shRNA. Successful silencing of MUC16 was detected by quantitative real-time PCR. We analysed the cellular effects linked to oncogenesis, such as proliferation, cell
cycle and apoptosis after transient or stable MUC16 knockdown. Signaling
pathways influenced by MUC16 were then examined by Western Blot.
Abstracts
Results: The growth of all tested MUC16+ tumour cells was significantly
suppressed by induction of caspase-dependent apoptosis after transient
transfection with MUC16 shRNA, irrespective of the initial MUC16 expression level and cancer origin. Growth inhibition could be confirmed
in stable MUC16 knockdown clones, albeit caspase-dependent death
pathways seemed no longer be activated. Furthermore Akt activation was
suppressed in all stable MUC16 knockdown clones, which correlated
with translocation of AIF to the nucleus and downregulation of the anti-apoptotic Bcl-2.
Conclusion: Our results provide evidence for a central role of MUC16 in
cancer cell survival pathways regulated through the PI3K/Akt signaling
pathway.
ID 341
Chronic inflammation-mediated tumor cell proliferation
and chemoresistance is driving tumor progression in
pancreatic cancer
T. Grimmig1, R. Mönch1, K. Höland1, C.- T. Germer2,
A.M. Waaga-Gasser1, M. Gasser2
2
1
Background: Recent data demonstrate chronic inflammation associated
with Toll-like receptor (TLR) signalling mediates carcinogenesis and tumor progression. The aim of this study was to determine the role of specifically TLR7 and TLR8 expression and signalling in cell proliferation
and chemoresistance for pancreatic cancer.
Methods: Gene and protein expression of TLR7, TLR8, NF-kB and
COX-2 in pancreatic cancer (UICC stages II and III), chronic pancreatitis and normal pancreatic tissue as well as in the human pancreatic cancer cell line PANC1 was examined. For further in vitro studies TLR7 or
TLR8 overexpressing PANC1 cell lines were generated. Effects of TLR
overexpression and stimulation on cell proliferation and chemoresistance
to 5-FU were analysed by MTS and AlamarBlue assays.
Results: Increased TLR expression was found in late stage tumors compared to earlier stages and chronic pancreatitis. No or occasionally low expression was detected in normal pancreatic tissue. Stimulation of TLR7 or
TLR8 overexpressing PANC1 cells with R848 resulted in elevated expression levels of NF-kB and COX-2. Additionally, increased cell proliferation
and reduced chemosensitivity were demonstrated under TLR stimulation.
Conclusion: Our data demonstrate for the first time a stage-dependent
increase in TLR7 and TLR8 expression in pancreatic cancer and chronic
pancreatitis. Additionally, our findings in TLR7 or TLR8 overexpressing
PANC1 cells suggest chronic inflammation-mediated TLR7/8 signalling
leading to cancer cell proliferation and chemoresistance. These findings
emphasize the particular role of TLR7 and TLR8 in pancreatic cancer and
their relevance as potential targets for cancer therapy.
ID 348
The functional integrity of c-Myc-specific tumor
metabolism is determined by a novel interaction of HIF-1α
and Annexin A1
N. Rohwer1, F. Bindel2, C. Grimm3, H. Lehrach3, M. de Graauw4,
B. Wiedenmann1, S. Kempa2, T. Cramer1,5
Charité – Universitätsmedizin Berlin, Campus Virchow-Klinikum, Medizinische Klinik m.S. Hepatologie und Gastroenterologie, Berlin, Deutschland
2
Max-Delbrück-Centrum für Molekulare Medizin, Berlin Institute for Medical
Systems Biology, Berlin, Deutschland
3
Max-Planck-Institut für Molekulare Genetik, Berlin, Deutschland
4
Universiteit Leiden, Amsterdam, Niederlande
5
Molekulares Krebsforschungszentrum, Berlin, Deutschland
1
Solid tumors are characterized by robust therapy resistance. Hence, the
identification of pathways regulating resistance is a central prerequisite
to improve cancer therapy. Our earlier work characterized the hypox-
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ia-inducible factor HIF-1α as a pivotal mediator of therapy resistance.
We established a stable, shRNA-mediated inhibition of HIF-1α and noted
that gastric cancer cells were able to compensate the loss of HIF-1α. To
further characterize the underlying mechanisms, we performed transcriptome analyses. We found a group of ~30 genes that were upregulated in
HIF-1α-deficient cells and hypothesized that these genes confer survival upon loss of HIF-1α. We further elucidated the role of Annexin A1
(ANXA1), one of the identified genes. Strikingly, simultaneous knockdown of HIF-1α and ANXA1 resulted in a complete growth arrest. Given the importance of HIF-1α for tumor metabolism we characterized the
central carbon metabolism. Interestingly, this revealed a robust impairment of both canonical and reductive glutamine metabolism in HIF-1α/
ANXA-deficient cells, reasoning for reduced TCA cycle activity. This
notion led us to characterize the expression of the oncogene c-myc. Strikingly, c-myc expression was completely lost upon combined inhibition
of HIF-1α and ANXA1. Retroviral transfection of c-myc into HIF-1α/
ANXA1-deficient cells was able to rescue proliferation supporting the
involvement of c-myc in the observed growth defect. Taken together,
ANXA1 is able to compensate the loss of HIF-1α in cancer cells, a hitherto unrecognized role for ANXA1. Furthermore, this work has identified
an interaction between HIF-1α and ANXA1 in the regulation of c-myc
with potential importance for cancer pathogenesis and therapy.
ID 360
Functional Connection between C/EBPβ and Cyclin D1 in
Tumorigenesis
J. Schiller, A. Leutz
Max-Delbrück-Center for Molecular Medicine, Berlin, Deutschland
Overexpression of cyclin D1 is a very frequent event in human tumorigenesis. Cyclin D1 is mainly known as a Cdk-dependent regulator of
pRb, catalyzing entry into the cell cycle. Several studies suggest, however, that nuclear gene and chromatin regulatory functions of cyclin D1 are
more important in tumor formation than its function in controlling pRb.
A previous gene profiling meta-analysis of more than 500 tumor samples
revealed consistent co-expression of the transcription factor C/EBPβ with
cyclin D1 target genes. C/EBPβ regulates cell differentiation and proliferation and has been shown to be an important factor in cyclin D1-overexpressing malignancies such as multiple myeloma and breast cancer.
We set out to unravel the molecular connection between cyclin D1 and
C/EBPβ and show that cyclin D1 binds to C/EBPβ via two binding sites.
Binding is tightly regulated by structural C/EBPβ alterations that depend
on post-translational modifications. The type of interaction has severe impact on cyclin D1 biology: N-terminal C/EBPβ interaction causes cytoplasmic retention and proteasomal degradation of cyclin D1, while C-terminal C/EBPβ binding promotes nuclear localization of cyclin D1.The
interaction between both transcription factors also results in altered binding of partner proteins, including Cdk4 and the arginine methyltransferase PRMT5, suggesting modified outcome in gene regulation.
Our data suggest a model where C/EBPβ regulates nuclear cyclin D1
function by controlling its sub-cellular localization and stability. When C/
EBPβ functions are deregulated, nuclear cyclin D1 may accumulate and
support tumorigenesis. This model also entails a pharmacological potential of altering enzymes that modify the C/EBPβ structure.
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ID 386
Novel apoptosis inducers in the acute lymphatic leukemia
cell line JM
N. van den Höfel1, E. Carosati2, G.M. Randazzo2, A. Abo Houf1,
R. Mannhold3, G. Cruciani2, S. Funke1, S. Heikaus1,
H.E. Gabbert1, C. Mahotka1
Universitätsklinikum Düsseldorf, Insitut für Pathologie, Düsseldorf,
Deutschland
2
University of Perugia, Chemometrics and Cheminformatics, Perugia,
Italien
3
Universitätsklinikum Düsseldorf, Düsseldorf, Deutschland
1
Aims: Dysregulation of apoptosis is an early hallmark of cancer. The
balance between pro- and anti-apoptotic factors is important for drug responses. The IAPs are – as caspase inhibitors – key factors of the core
apoptosis machinery and aberrantly expressed in various tumors. Inhibiting IAPs renders tumor cells potentially responsive for apoptosis inducing signals. Here we report the discovery of novel apoptosis inducers,
based on a fast and efficient ligand based virtual screening approach.
Methods: Multistep ligand based virtual screening, proliferation and
apoptosis assays, flow cytometry, Western Blotting.
Results: (1) A ligand based virtual screening approach delivered 31 hit
candidates. (2) All compounds were tested for solubility with different
solvents in vitro and under cell culture conditions: 7/31 compounds aggregate and show crystal-like structures at approximately 10–100 µM.
(3) Time-dependent dose-response-curves reveal 10–40% cell death for
3 compounds, designated LBPS-1, -3, and -5 in a proliferation assay. (4)
Enhancement of compounds by death receptor ligand TRAIL does not
increase dose-effect relation. (5) Determination of cell death by Nicoletti
staining reveals that a predominant part of cell death is due to apoptosis. (6) Analysis of intracellular caspase activity shows an activation of
caspase-3 to be correlated with peak levels of apoptosis. (7) Degradation
of the cIAP-1 target might hint at the putative molecular mode of action.
(8) Tumor type independency of the action of the novel compounds is
shown in different tumor cell lines.
Conclusion: Virtual screening is a powerful tool to detect new chemotypes of apoptosis promoting agents for the treatment of cancer.
Abstracts
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Index
Tyrosine Kinase Inhibitors
ID 040
Sorafenib in locally advanced or metastatic patients
with radioactive iodine-refractory differentiated thyroid
cancer: The phase 3 DECISION trial.
M.S. Brose1, C. Nutting2, B. Jarzab3, R. Elisei4, S. Siena5,
L. Bastholt6, C. de la Fourchardiere7, F. Pacini8, R. Paschke9,
Y.K. Shong10, S.I. Sherman11, J.W.A. Smit12, J. Chung13,
C. Kappeler14, I. Molnar13, M. Schlumberger15
The University of Pennsylvania, Abramson Cancer Center, Philadelphia,
Vereinigte Staaten Von Amerika
2
Royal Marsden Hospital, London, Großbritannien
3
Maria Sklodowska-Curie Memorial Cancer Centre and Institute of
Oncology, Gliwice, Polen
4
University of Pisa, Department of Clinical and Experimental Medicine,
Pisa, Italien
5
Ospedale Niguarda Ca’ Granda, Milan, Italien
6
Odense Universtiy Hospital, Odense, Dänemark
7
Hospices Civils-Centre Anticancereux, Lyon, Frankreich
8
University of Siena, Unit of Endocrinology, Siena, Italien
9
Leipzig University, Department for Endocrinology and Nephrology,
Leipzig, Deutschland
10
University of Ulsan College of Medicine, Asan Medicine Center, Seoul,
Korea, Republik
11
The University of Texas, MD Anderson Cancer Center, Houston, Vereinigte Staaten Von Amerika
12
Radboud University Nijmegen Medical Center, Department of Internal
Medicine, Nijmegen, Niederlande
13
Bayer Healthcare Pharmaceuticals, Montville, Vereinigte Staaten Von
Amerika
14
15
1
Background: Sorafenib, an orally active inhibitor of VEGFR1-3 and Raf
kinases, has shown promising clinical activity in single-arm phase 2 studies in radioactive iodine (RAI)-refractory differentiated thyroid cancer
(DTC). The double-blind, randomized, multi-center phase 3 DECISION
trial examined sorafenib efficacy and safety vs placebo in patients with
progressive RAI-refractory DTC (NCT 00895674).
Methods: Patients with locally advanced/metastatic RAI-refractory
DTC who progressed in the preceding 14 months were randomized 1:1
to sorafenib 400 mg bid po or placebo. Placebo patients were allowed
to receive sorafenib open-label upon progression. The primary endpoint
was progression free survival (PFS) assessed every 8 wks by independent
radiologic review using modified RECIST 1.0 and analyzed by stratified
log-rank statistics at α = 0.01 (one-sided). Secondary endpoints included overall survival (OS), response rate (RR; complete + partial response
[PR]), and safety.
Results: A total of 417 patients were randomized (207 to sorafenib and
210 to placebo); median age 63 yr, 52% female. Tumor histology by independent assessment was 57% papillary, 25% follicular and 10% poorly
differentiated. 96% of patients had metastatic disease; the most common
metastatic lesions were lung (86%), lymph node (51%) and bone (27%).
The primary endpoint was met: median PFS 10.8 months (sorafenib) vs
5.8 months (placebo); HR 0.587, 95% CI 0.454–0.758, p.
Conclusions:Sorafenib significantly improved PFS compared with placebo in patients with progressive RAI-refractory DTC. Tolerability was
consistent with the known sorafenib safety profile.
Abstracts
ID 107
Specific inhbitor of ERK 1/2 AEZS-131: Anticancer
activity in models of human cancers with and without
overactivation of ERK1/2
J. Engel1, A. Hönig2, S. Meyer2, J. Dietl2, B. Kwok1, O. Ortmann1,
J. Hahne2
Medizinische Universität Regensburg, Klinik für Frauenheilkunde und
Geburtshilfe, Regensburg, Deutschland
2
Universitätsfrauenklinik Würzburg, Würzburg, Deutschland
1
Introduction: The RAS/RAF/MEK/ERK pathway is activated in more
than 30% of human cancers. The current study investigates specific ERK
inhibitor AEZS-131 in models of endometrial, ovarian and breast cancer
with and without mutations in the MAPK-pathway.
Methods: ERK-inhibition was determined by analyzing phosphorylation status of downstream target of ERK1/2 RSK-1. Mode of cell death
induced by AEZS-131 was explored by FACS-analysis. Cytoxicity was
evaluated by MTT-assay in 3 endometrial, 6 breast and 5 ovarian cancer
cell lines. Potential synergy with the host´s tumour immune response was
evaluated by NK-cell lysis assay.
Results: In MDA-MB-435s cells RSK-1 phosphorylation was reduced
by 50% subsequent to treatment with AEZS-131. Treatment with AEZS131 dose-dependently induced necrotic cell death in the majority of the
cell lines. Accordingly, in those cells cytotoxicity induced by AEZS-131
could not be inhibited by a pan-caspase inhibitor.
AEZS-131 effectively inhibited cell growth with IC50 in the low mM
range in 3 ovarian, 5 breast and 3 endometrial cancer cell lines, of which
2 mammary and 2 endometrial harboured mutations in the ERK-pathway. The compound was ineffective in 1 breast and 2 ovarian cancer lines
without mutations in the ERK-pathway. Treatment with AEZS-131 dose
dependently increased cell lysis by natural killer cells, suggesting potential synergistic effects with the host anti-tumour response.
Discussion: We could demonstrate good anti-tumour activity of ERK1/2
inhibitor AEZS-131 in a panel of breast, ovarian and endometrial cancers
in -vitro. Cytotoxicity was pronounced in cancers harbouring a mutation
in the MAPK-pathway, but did also occur in cancer cell lines negative for
such mutations.
ID 202
Circulating tumor cell composition and molecular
markers in metastasized renal cell carcinoma (mRCC)
T. Gauler, I. Nel, K. Bublitz, L. Lazaridis, M. Schuler,
A.-C. Hoffmann
Deutschland
Background: Circulating tumor cell (CTC) numbers have been studied
as a timely and minimally invasive tool for monitoring the therapy response in advanced cancers. We recently described a detection method
based on multiparameter immunofluorescence microscopy (MPIM) that
amongst others includes epithelial markers such as CK or EpCAM, mesenchymal and stem cell-like markers. Here, we have studied different
subtypes of CTC in patients with metastatic renal cell cancer (mRCC) and
their association with the response and progression-free survival (PFS) to
antiangiogenic therapies. Furthermore we evaluated the correlation of angiogenesis related molecular markers with these individual CTC profiles.
Methods: Peripheral blood was drawn from 16 consecutive mRCC patients receiving antiangiogenic therapies. Individual CTC profiles were
analyzed by MIPIM. The expression of angiogenesis-related genes was
studied by quantitative RT-PCR analysis in EpCAM-enriched and depleted CTC fractions. Results were correlated to treatment outcomes.
Results: Multiple CTC subtypes with epithelial, mesenchymal, stem celllike or mixed-cell characteristics were detected. The presence and quantity of N-cadherin-positive or CD133-positive CTC was associated with
inferior PFS following antiangiogenic therapy. High mRNA expression of
HIF1A, VEGFA, KDR1 and FGFR were associated with response to first-
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line antiangiogenic therapy. There was an inverse correlation between
high expression of HIF1A, VEGFA, KDR1 and FGFR and the presence of
N-cadherin-positive and CD133-positive CTC.
Conclusions: Patients with mRCC exhibit distinct CTC profiles, which
associate with the outcome of antiangiogenic therapies. Prospective evaluation of phenotypic and genetic CTC profiling as prognostic and predictive marker is warranted.
ID 422
BARIS: A phase I trial to evaluate the safety and
tolerability of combined BIBF 1120 and RAD001 in solid
tumors and to determine the maximum tolerated dose
(MTD) of the combination
M. Scheffler1, M. Gardizi1, M. Bos1, L. Nogova1, I. Papachristou2,
T. Persigehl3, F. Dietlein3, T. Zander3, J. Wolf1
2
Universität, Zentrum für Klinische Studien, Köln, Deutschland
3
1
Background: Simultaneious inhibition of several signalling pathways
involved in angiogenesis as well as in tumor cell growth regulation by
kinase inhibitor combination therapy may increase therapeutic efficacy.
Here we evaluate the combination of the mTOR-inhibitor RAD001 (everolimus) and the triple kinase (FGFR, VEGFR, PDGFR) inhibitor BIBF
1120 (nintedanib). In addition we use DCE-MRI for early identification
of patients with benefit from BIBF 1120.
Methods: This is a phase I trial with 3 dosage arms in a classical
„3+3»-design. Eligible are all patients with relapsed or refractory advanced/metastatic solid tumors for whom no further standard therapies
are available. All patients will start with a 2-week run-in phase of BIBF
1120. DCE-MRI scans will be performed at baseline staging, on day 3
and day 14. On day 14, there will be 12 hours-pharmacokinetic (PK)
assessment. Combination therapy starts on day 15. After two weeks of
combination therapy, on day 29, a DCE-MRI scan and 12-hours PK will
be performed. Restaging will be performed on day 57.
Results:12 patients have been enrolled so far. In one patient with FGFR-amplified lung cancer, there was a partial response after six weeks of
therapy. No DLTs were detected within the first dosage step. Tolerability of the combination was good, as there were no toxicities of CTC-AE
grade 3 or greater. In arm B, there has been one DLT (elevation of transaminases), which turned out to be reversibel.
Discussion: So far, the combination of BIBF 1120 and RAD001 seems
tob e very good tolerated, demonstrating activity in a patient with NSCLC
and FGFR1-amplification. Enrollment into the second dosage stage has
already started.
The trial is registered under NCT01349296 (clinicaltrials.gov).
Pflegerische Beiträge
ID 132
Demenz – die etwas andere Herausforderung für
professionell Pflegende in der Onkologie
Pflegenden zunehmend mit Patientinnen und Patienten sowie Angehörigen konfrontiert, die an den verschiedensten Formen von Demenz leiden. Bisher gibt es in Deutschland keine Untersuchungen zu den hieraus
resultierenden Belastungen der professionell Pflegenden und zu deren
Fortbildungsbedarfen in diesem sehr speziellen Arbeitsbereich. Folglich
existieren auch keine Angebote, die das Pflegepersonal für diese besonderen Aufgaben weiterqualifizieren.
Methode: Mittels qualitativer Interviews wird onkologisches Pflegepersonal nach seinen Belastungen in der pflegerischen Arbeit mit dementiell
Erkrankten befragt. Ergänzende, offen gestellte Fragen des Interviews
dienen dazu, die Bewältigungsstrategien herauszufinden, mit denen die
Pflegenden versuchen, die Situation zu entlasten. Abschließende Fragen
richten sich auf die speziellen Fortbildungsbedarfe der Pflegenden, so
dass mit dieser Erhebung eine erste explorative Studie zur spezifischen
Belastungs- und Bedarfssituation im onkologischen Pflegeberich vorliegt.
Ergebnis: Bisher wurden 100 Fragebögen versandt. Aufgrund der sehr
guten Netzwerkarbeit ist eine Rücklaufquote von 60% sehr wahrscheinlich, so dass bei zügiger Auswertung Ergebnisse bis Ende des Jahres 2013
vorliegen werden, die ihrerseits erste Veröffentlichungen im Februar
2014 ermöglichen.
ID 165
Haustierbesuch auf der Palliativstation der
Universitätsklinik Frankfurt am Main
J. Kunze, C. Gog
Universitätklinik Frankfurt am Main, Palliativstation – UCT, Frankfurt am
Main, Deutschland
Haustiere haben einen hohen Stellenwert in der Familie. Durch die Kommunikation zwischen Mensch und Tier entsteht eine tiefe Bindung zueinander. Kommt es zum Fortschreiten einer Erkrankung mit Aufenthalt auf
einer Palliativstation, führt dies bei Mensch und Tier zu einem schmerzhaften Verlust und Abbruch der Beziehung.
Wir entwickelten deshalb ein Konzept zur Realisierung eines Haustierbesuches auf der Palliativstation an der viele Bereiche der Universitätsklinik
Frankfurt am Main (Leitung der Krankenhaushygiene, Ärztliche Leitung
der Palliativstation, Betriebsärztliche Leitung, Tierpsychologin, Fachpersonal der Palliativstation) beteiligt waren.
Vorbereitungen: Alle notwendigen Impfungen des Haustieres müssen
vom Tierarzt durchgeführt werden. Der Klinikbesuch sollte in Begleitung der jetzigen Bezugsperson des Hundes erfolgen. Das Einverständnis
des Personals nach Durchführung eines Tierallergentests ist einzuholen.
Haustiere, die nicht an der Leine geführt werden, müssen durch andere
geeignete Vorkehrungen gesichert werden. Hunde und Katzen sind zuvor
zu bürsten und die Pfoten des Tieres müssen vor dem Betreten des Personalaufzuges gesäubert und getrocknet werden.
Durchführung: Haustierbesuch ist nur im Einzelzimmer gestattet. Es erfolgt die Abholung am Personalaufzug durch zuständige Pflegekraft. Die
Besuchsdauer beschränkt sich auf max. 2 Stunden. Danach Händedesinfektion aller beteiligten Personen.
Nachbereitungen: Das Patientenbett komplett frisch beziehen und Desinfektion aller Oberflächen. Zimmer lüften und Bodenreinigung durch
Reinigungskraft initiieren.
Es konnten in der Zwischenzeit bereits mehrere Haustierbesuche erfolgreich auf der Palliativstation umgesetzt werden.
T. Dreischer
Carus Akademie am Universitätsklinikum Carl Gustav Carus Dresden,
Department CPD, Dresden, Deutschland
Fragestellung: Welche Situationen erleben in der Onkologie tätige Pflegende im Umgang mit dementiell Erkrankten als besonders belastend
und wie bewältigen sie diese Situationen? Davon ausgehend soll geklärt
werden, welche Fortbildungsbedarfe die professionell Pflegenden äußern.
Situationsbeschreibung: Der Anteil dementiell Erkrankter nimmt in
Deutschland aufgrund der demographischen Entwicklung bekanntermaßen stetig zu. Daher werden auch die in der Onkologie professionell
132
Abstracts
Inhalt
Index
ID 196
ID 448
Pflegekonzept in der Integrativen Onkologie
S. Kuhlmann , O. Langels , P. Voiß , A. Paul , G.J. Dobos ,
S. Kümmel1
1
2
1,2
2
2
Kliniken Essen-Mitte, Klinik für Senologie / Brustzentrum, Essen,
Deutschland
2
Kliniken Essen-Mitte, Klinik für Naturheilkunde und Integrative Medizin,
Essen, Deutschland
1
Hintergrund: Die Integrative Onkologie kombiniert konventionelle
Schulmedizin mit evidenzbasierten, komplementärmedizinischen Verfahren. Diese umfassen Medizinsysteme (z.B. traditionell chinesische Medizin), Mind-Body-Therapien (z.B. Ernährung, Bewegung, Entspannung),
manipulative körperbezogene Praktiken wie Massage sowie den Einsatz
von Vitaminen / Mineralien, medizinischen Tees und klinisch bewährten
Hausmitteln. Das Ziel der Integrativen Onkologie ist, Nebenwirkungen
primärer Tumortherapien zu reduzieren und die gesundheitsbezogene Lebensqualität der Patienten zu steigern.
Dieses Konzept wird seit 2010 an den Kliniken Essen-Mitte, gemeinschaftlich durch das Brustzentrum und die Klinik für Naturheilkunde und
Integrative Medizin, praktiziert.
Diskussion: Unser Pflegekonzept in der Integrativen Onkologie umfasst
u.a. regelmäßige, gemeinsame ärztliche und pflegerische Visiten, den
Einsatz von medizinischen Auflagen, Akupunktur, Schröpfen, verschiedene Massageformen, Aromatherapie, Fußbäder, Information zu weiteren pflegerischen Anwendungen, Anleitung zu Selbsthilfestrategien aus
der Mind-Body-Medizin. Eine Schlüsselfunktion kommt der Breast Care
Nurse zu, die die Patientin bereits ab Diagnosemitteilung unterstützend
mit Aufklärung, Information, Koordination, seelischer Unterstützung im
gesamten Behandlungsablauf begleitet. Sie ist von Anfang an wichtige
Ansprechpartnerin für die Patientin und fungiert als Bindeglied zwischen
den einzelnen Disziplinen.
Fazit: Eine evidenz-basierte, integrativ onkologische Versorgung bietet
die Möglichkeit für ein effektives Nebenwirkungsmanagement und eine
ganzheitliche Versorgung des onkologischen Patienten.
Abstracts
«Ohne Pflege geht’s nicht»: Etablierung der
Radioonkologischen Pflegeberatungsambulanz
H. John1,2
MHH, Radioonkologie, Hannover, Deutschland
Med. Hochschule, Radioonkologie- Pflegeberatungsambulanz, Hannover,
Deutschland
1
2
Einleitung: Onkologische Erkrankungen gehen mit physischen u. psychischen Belastungen einher. Moderne Behandlungsmöglichkeiten erfordern Umdenken. Es braucht Behandlungskonzepte, welche Selbstpflege und salutogenetisches Verstehen fördern.
Frage: Hat eine pflegerische Beratung mit dem Ansatz der Stärkung von
Selbstpflegekompetenz Einfluss auf Angst und andere Nebenwirkungen
bei ambulanter Radiatio?
Methodik: Bedarfsermittlung, Hospitationen, Bildung Projektgruppe,
Pflegeempfehlungen wurden nach wissenschaftlichen Kriterien erstellt.
Individuelle Copingstrategien werden im obligatorischen pflegerischen
Beratungsgespräch entwickelt. Datensammlung und Evaluation folgen.
Fallbesprechungen finden statt. Florenze e.V. unterstützt das Projekt.
Ergebnis Die Wirksamkeit ist bisher subjektiv zu bewerten. Erfahrungen
zeigen, dass patientenorientierte Aufklärung dem Gefühl von Kontrollverlust entgegen wirkt.
Fazit: Die Pflegeberatung ist eine Ergänzung und Qualitätssteigerung in
der Patientenversorgung mit hoher Akzeptanz .Die Regelversorgung wird
angestrebt.
133
Inhalt
Index
Author Index
A
Aaspõllu, A., 195
Abbas, M., 60
Abendroth, A., 92, 218
Abo Houf, A., 386
Abo-Madyan, Y., 248
Abou-Dakn, M., 328
Aboumadian, A. Y., 251
Abraham, J., 32
Abramczyk, M., 92
Abu Jawad, J., 97, 389
Ackermann, M., 238
Adamietz, I., 370, 397, 430
Adenis, A., 6
Adhami, B., 124
Adwan, H., 138, 141, 143, 145
Adzersen, K. -H., 179
Agaimy, A., 56
Ahmadzadehfar, H., 49
Ahrens, M., 38
Aigner, K., 441
Akram, I., 145
Aksnes, A. -K., 36
Aktas, B., 68, 94, 136, 456
Al Ghazal, A., 281
Al-Batran, S. -E., 160, 174, 194
Albers, P., 311, 371
Albert, U. -S., 105
Albrecht, S., 450, 451
Aldabbas, O., 251
Almgren, P., 99, 101, 228
Almstedt, K., 270
Alten, N., 116
Altmann, A., 441
Aminossadati, B., 432
Amit, M., 51
Andergassen, U., 449
Anders, M. P., 198, 210
Andratschke, N., 429
Andrzejewski, D., 168
Angerer-Shpilenya, M., 334
Ansmann, L., 83, 226
Arenz, D., 90
Arfmann-Knübel, S., 127
Arndt, S., 458
Arndt, V., 45
Arnold, D., 429
Arnold, G., 389
Asen, M., 362
Astor, D., 249
Atanackovic, D., 119
Ataseven, B., 395
Attard, G., 195
Atzpodien, J., 447
Augustin, D., 456
Aumann, J., 173
Aumann, K., 356, 366
Aumann, N., 366
Azizian, A., 263, 296
Fax +49 761 4 52 07 14
[email protected]
www.karger.com
www.karger.com/ort
B
Baaijens, M., 161
Baasner, A., 277, 453
Baba, H., 38
Baba, H. A., 199
Baccelli, I., 67, 68
Bach, F., 457
Bache, M., 17, 260
Bachinger, A., 116
Bachmann, C., 16
Backes, C., 406
Badalamenti, G., 10, 11
Bahlo, J., 500
Bahra, M., 443
Baklayan, A., 207
Bals, R., 201
Baltin, C. T. H., 364
Bamberg, M., 261
Bani, M. R., 150
Bankfalvi, A., 94
Banys, M., 327, 368
Banzer, W., 361, 420
Baras, N., 258
Barnes, B., 140
Barone, C., 6
Barsoum, M., 461
Bartels, S., 35
Bartmann, C., 167
Bartsch, H., 185, 187
Bastholt, L., 40
Battista, M., 50
Battmann, A., 174
Batzler, U., 317
Bauer, A., 406
Bauer, P., 412
Bauer, S., 12, 13, 85, 218
Bauerfeind, I., 269
Bauerschlag, D., 120
Baum, M., 395
Baum, S., 243
Baumann, F., 221, 253, 364, 396
Baumann, F. T., 353, 374
Baumann, K., 432
Baumann, K., 231, 244, 416
Baumann, K. H., 329
Baumann, K., 153, 454
Baumann, W., 83
Baumgart, S., 163
Baur, F., 125
Bausewein, C., 266
Bayer, C. M., 270, 294
Bayer, C., 280
Bazhin, A., 79, 80, 81
Bechstein, W. O., 300
Beck, E., 168, 172
Beck, H., 171
Becker, A., 452
Becker, C., 95
Becker, D., 302
Becker, M., 58
Becker, N., 121, 131, 179
Becker, S., 262, 327
Becker, T., 128
Beckert, S., 3
Beckmann, K., 352
Beckmann, M., 337
Beckmann, M. W., 150, 270, 294, 352,
385, 449
Bedke, J., 311
Begus-Nahrmann, Y., 37
Behrens, D., 173, 208
Behringer, D. M., 457
Behringer, D., 414
Beissbarth, T., 321
Bekeredjian-Ding, I., 75
Belau, A., 222, 231, 416
Belka, C., 395
Bellen, G., 114
Belova, I., 380, 418
Belting, M., 99, 101, 228
Benndorf, D., 421
Benz-Jansen, C., 454
Benz-Weißer, A., 428
Beraldi, A., 205, 207
Berdel, W., 457
Bergatt-Kuhl, B., 458
Bergelt, C., 223
Berger, A., 18, 63, 169, 241
Berger, M., 135, 289
Berger, M. R., 138, 141, 143, 145
Berger, S., 135
Bergmann, A., 99, 101, 228
Bergmann, C., 97
Berking, C., 447
Bernardi, A., 361
Berndt, U., 314
Bernhardt, C., 93
Bernschein, A., 460, 461, 462
Bersi, H., 220
Bertsch, T., 113
Bertz, H., 34
Bertz, J., 140
Besseler, M., 41
Bettinger, D., 342
Betz, B., 31
Betzler, C., 333
Beulertz, J., 221, 253
Bey, I., 458
Beyer, I., 224
Bichev, D., 74
Biegner, T., 100
Bielfeld, C., 321
Bielow, C., 322
Biersack, H. -J., 49
Biesenbaum, D., 326
Bindel, F., 348
Birkner, B., 382
Birninger, N., 308
Bitzer, E. M., 61, 65
Bitzer, J., 236
Inhalt
Index
Bitzer, M., 412
Blackstein, M. E., 10, 11
Blassl, C., 182, 190
Blay, J. -Y., 10, 11, 12, 13
Blettner, M., 110
Bloch, W., 221, 253, 291, 353, 364, 374,
396
Blohmer, J. U., 395
Blumenstengel, K., 191
Bläker, H., 88
Blümcke, B., 277, 453
Bob, R., 436
Bobersky, S., 139
Boda-Heggemann, J., 87
Boehnke, K., 299
Boellaard, R., 439
Boersch, I., 168
Bogdahn, U., 310
Bojunga, J., 232
Bokemeyer, C., 62, 302, 304
Bollschweiler, E., 364
Bolt, T. A., 160
Bonacker, J., 400
Bongartz, R., 276, 373, 383
Bonin, M., 185, 187
Boos, J., 42, 71
Bootz, F., 272, 295
Boral, A., 233
Bos, M., 22, 112, 376, 381, 404, 414, 422,
431, 439
Bosserhoff, A. -K., 310
Bouché, O., 6
Boyiadzis, M., 461
Braicu, E. I., 234, 347
Brandi, L., 419
Brandt, H., 95
Braun, S., 328
Brechtel, A., 4, 175
Brehm, B., 385
Brehmer, S., 248
Breitbart, E. W., 198, 210
Breitenbuecher, F., 97
Breitenbücher, F., 85
Bremer, M., 395
Brennan, B., 350
Brenner, H., 44, 45, 88, 282, 283, 382
Breuer, F., 124
Brock, M., 264
Brockhoff, G., 16
Bronsert, P., 356, 366
Brose, M. S., 40
Brucker, S., 261
Bruland, O., 36
Brunel-Geuder, L., 150
Brunner, G., 447
Bruns, C., 333
Bruns, C. J., 217
Brückner, K., 314
Brüggemann, K., 271
Brümmendorf, T. H., 376, 381
Bublitz, K., 202
Bucan, V., 193
Buchholz, M., 391, 394
Buchholz, S., 114, 305
Budach, W., 62
Buderath, P., 94
Buettner, R., 22
Author Index
Buettner, S., 325
Bulsara, M., 395
Burfeind, P., 200, 206
Burghaus, S., 352
Burke, T., 14
Burwinkel, B., 67
Busch, C. -J., 119, 301
Busch, C., 403
Busch, R., 219, 500
Buttmann, N., 180
Bölükbas, S., 340, 402, 410, 427
Böttcher, S., 219, 500
Bühler, H., 370, 397, 430
Bürkle, B., 384
Büther, F., 372, 377
Büttner, R., 112, 376, 381, 404, 414, 431,
439
C
Cacsire Castillo-Tong, D., 234
Camaj, P., 217
Camara, O., 449
Canon, J. -L., 126
Canzler, U., 231, 244, 250, 329, 416, 432
Cao, H., 224
Cardoso Martins, A. S., 297
Carosati, E., 379, 386
Casali, P. G., 10, 11, 12, 13
Celik, E., 108
Celik, I., 384
Chang, J., 12
Chang-Claude, J., 45, 88
Chawla, R., 358
Chekerov, R., 234, 328, 347
Chen, S., 73
Chen, Y. -R., 52
Choudhury, K., 198
Christgen, M., 455
Christiansen, H., 365, 390
Chromik, A., 391, 394
Chung, J., 40
Cibula, D., 416
Cihon, F., 6, 7, 8
Clauditz, T. S., 119
Clausen, S., 248
Claussen, C. D., 54
Clemens, M., 222, 456
Clement, P., 98
Codo, P., 406
Coleman, R. E., 57, 64
Concin, N., 234
Conradi, L. C., 296
Constantinidou, M., 442
Cornely, O. A., 69, 72, 75, 90
Cortes-Incio, D., 85
Coy, J. F., 100
Craft, A., 350
Cramer, C., 164
Cramer, T., 319, 322, 348
Croner, R., 95, 129
Cross, A., 64
Cruciani, G., 379, 386
D
Daheim, M., 73
Dahlmann, M., 268
Dahm, S., 140, 258, 405
Daigeler, A., 5
Dall, P., 176
Dammer, U., 294
Dan Costa, S., 273
Dandekar, G., 125, 152, 220, 235
Daniel, P. T., 169
Danker, H., 109
Dathe, G., 172
Daum, S., 74
Davies, C., 299
De Dosso, S., 457
de Graauw, M., 348
De Gregorio, N., 244, 250, 329, 337, 416
de Hoog, S., 72
de la Fourchardiere, C., 40
de Zwart, P., 62
Dechene, A., 92
Decker, T., 449
deFigueiredo, M., 34
Degel, F., 446
Degen, C., 20
Demetri, G. D., 10, 11, 12, 13
Demidova, O., 322
Denecke, T., 443
Dengler, J., 188
Derks, C., 85, 136
Dexel, S., 413
Diab, F., 170
Dieckmann, K. -P., 311
Diefenbach, K., 6
Dierks, S., 200
Dietel, M., 88, 209, 265
Dieterich, M., 400
Dietl, J., 107, 167
Dietlein, F., 422
Dietlein, M., 439
Dietrich, D., 272, 274
Dietz, A., 109, 362
Dikomey, E., 301
Diller, M., 305
Dirksen, U., 336, 350, 445
Dirnhofer, S., 408
Distel, L., 21, 115, 306
Dittrich, C., 369
Dobbelstein, M., 201
Dobos, G. J., 196
Dold, S., 344
Doll, M., 287, 424, 426
Dollinger, G., 192
Dommach, M., 457
Domschke, C., 67
Donders, G., 114
Donel, E., 122
Dormann, A., 330
Dountsop, P., 212
Drecoll, E., 279
Dreger, P., 500
Dreher, L., 162, 184
Dreischer, T., 132
Drendel, V., 356
Drescher, C., 224
Dressel, R., 206
Drewes, C., 269
Drozdz, S., 367
Du Bois, A., 222, 231, 244, 250, 329, 416,
432
Dubrowinskaja, N., 60
135
Inhalt
Index
Duma, M. N., 280
Dunst, J., 429
Dyszkiewicz, W., 189
Döhner, H., 500
Dönges, T., 410
Dörken, B., 443
Dörr, M., 134
Długaszewska, B., 189
E
Eberhardt, W. E. 85, 102, 209, 389, 404
Eberle, A., 44, 282
Eberle, J., 18, 63, 241
Eberlein, M., 402, 410, 427
Ebert, M. P., 457
Ebert, A., 328
Ebsen, M., 128
Eckel, R., 147, 293
Eckert, A. W., 260, 292, 393
Eckert, D., 444
Eckert, F., 62
Efferth, T., 52
Eggeling, S., 387
Egger, M., 160
Eggert, J., 176
Ehmann, M., 87
Eich, H. T., 278, 372, 377
Eichhorn, T., 52
Eichhorst, B. F., 90, 219, 500
Eichstaedt, M., 414
Eidt, S., 254
Eigentopf, A., 131
Eisele, A. -C., 98
Eisele, G., 98, 213
Eisenacher, M., 38, 199
Elisei, R., 40
Ellmann, A., 21
Ellwart, J., 333
Elter, T., 396, 439
Eltrop, S., 303
Emons, G., 103, 104, 222, 231
Emrich, K., 44, 282
Engbers, A., 271
Engel, C., 237
Engel, J., 84, 107, 134, 147, 155, 293
Engel-Riedel, W., 102, 116, 431, 439
Engström, G., 99, 101, 228
Erbes, T., 78
Erdmann-Reusch, B., 318
Erlbeck, M., 205
Ernst, I., 372, 377
Ernstmann, N., 83, 226
Erz, P., 314
Eschenburg, H., 35, 48
Eucker, J., 442
Ewald, C., 24, 25
Ewald-Riegler, N., 250
Exner, A. -K., 96
Ezziddin, S., 49
F
Fackler-Schwalbe, I., 438
Fahlbusch, M., 371
Fakhrian, K., 370
Falcone, A., 6, 7, 8, 9
Falini, B., 436
Fang, F., 36, 47
136
Farace, F., 195
Farahati, J., 417
Fasching, P. A., 150, 270, 294, 352, 385,
449, 450, 451
Faschingbauer, F., 294
Fasola, G., 126
Fecher, D., 152, 235
Fehm, T., 68, 182, 183, 185, 187, 190,
195, 222, 231, 244, 250, 262, 270, 327,
329, 332, 337, 366, 416, 419, 425, 449,
450, 451
Feisel-Schwickeradi, G., 176, 222
Feiten, S., 130
Fend, F., 366
Feng, Q., 224
Fersis, N., 270
Feustel, T., 172
Feyen, O., 100
Feyer, P., 395
Fichtner, I., 208
Fietkau, R., 21, 56, 115, 306
Fink, A., 219, 500
Finkelmeier, F., 232, 342
Finkernagel, F., 229
Fischer, D., 153, 454
Fischer, I., 41
Fischer, J., 332
Fischer, J., 442
Fischer, K., 219, 500
Fisseler-Eckhoff, A., 402
Fleckenstein, J., 87, 395
Fleckenstein, K., 171
Fleisch, M., 425
Flier, A., 391, 394
Flieser-Hartl, M., 31
Floca, R., 151
Forner, D., 250
Forstbauer, H., 455
Fotopoulou, C., 250, 347
Frangenberg, A., 460
Frank, O., 188, 191
Frechen, S., 414
Frei, K., 324
Freitag, D., 24, 25, 433
Freitag, L., 85
Freitag-Wolf, S., 128
Frese, M., 304
Freytag, M., 119
Fridrich, C., 378
Friederich, H. -C., 4
Friedl, T. W., 449, 450, 451
Friedrich, S., 121, 179
Friese, K., 266, 395
Friesenhahn, V., 130
Frisse, S., 353
Fritzsche, K., 34
Fröhner, M., 106
Fuchs, A., 252
Fuchs, I., 430
Fuhr, U., 404, 414
Funke, B., 459, 461, 462
Funke, S., 386
Fürst, S. T., 244, 329
G
Gabbert, H. E., 246, 379, 386
Gabrysiak, T., 191
Gaedcke, J., 263, 296, 321
Gajda, M., 163
Galle, P., 216
Galle, P. R., 255
Gallmeier, E., 297
Gamba, S., 217
Garcia Vargas, J. E., 39, 47, 64
Gardizi, M., 22, 376, 381, 404, 414, 422,
431, 439, 460
Gasiorowski, L., 189
Gasser, M., 335, 338, 341
Gastinger, I., 409, 411
Gauler, T., 85, 97, 202, 204, 389
Geater, S. L., 242
Gebauer, F., 181
Gebauer, G., 337, 368
Gebauer, K., 60
Gebhard, S., 50
Geffers, R., 355, 358
Gehrmann, M., 50, 280
Geinitz, H., 280
Geisler, K., 150
Geissler, E. K., 375
Geist, T., 414
Gelderblom, H., 10, 11, 13
Georgii, J., 385
Gerber, B., 337, 400, 416
Gerhardt, A., 249
Gerigk, U., 376, 381
Gerken, G., 92, 199
Gerken, M., 298
Gerland, L., 353
Germer, C. -T., 335, 338, 341
Gerstenhauer, M., 307
Gerstner, A., 295
Ghadimi, M., 263, 296, 321
Giedl, J., 405
Gieseler, F., 308
Giger-Pabst, U., 388, 392
Gil, Z., 51
Gillissen, B., 169
Giordano, F. A., 248
Girgert, R., 104
Girst, S., 192
Gittler, A., 243, 428
Glanemann, M., 344
Glatzle, J., 3
Glockzin, G., 298
Gloede, T. D., 83
Glossmann, J. P., 461
Glossmann, J. -P., 459, 462
Gluz, O., 455, 456
Glüer, C., 403
Go, W., 126
Goebel, L., 128
Goepfert, K., 216
Goertz, O., 5
Goettig, T., 440
Goetze, T., 256
Gog, C., 165
Goker, E., 457
Goldbrunner, R., 162, 164, 166, 184
Goldmann-Posch, U., 269
Goldwasser, M., 233
Gondos, A., 44, 282
Gorys, A., 128
Gottschlik, Y., 314
Author Index
Inhalt
Index
Grade, M., 263, 296, 321
Graf, C., 58
Graf, L., 314
Graf, M., 151
Graf von der Schulenburg, J. -M., 209
Grage-Griebenow, E., 128
Gramatzki, D., 324
Gramatzki, M., 324
Gratzke, A. -L., 193
Grehl, S., 389
Greiner, W., 120
Greinert, R., 198, 210
Greubel, C., 192
Greve, B., 278, 372, 377
Griebel, L. -F., 329
Grimm, C., 348
Grimm, D., 303
Grimm, M., 100
Grimmig, T., 335, 338, 341
Grischke, E., 16
Grob, P., 114
Grobe, T., 61, 65
Grohs, R., 172
Grohé, C., 102
Gropp-Meier, M., 231, 416
Gros, S., 333
Grosu, A. L., 111
Grothey, A., 6, 7, 8, 9
Groß, M. -L., 131
Groß, S. E., 83
Grube, S., 24, 25, 433
Gruber, I., 327
Gröne, J., 349
Gründker, C., 103, 104
Gschwend, J., 122
Guckenberger, M., 429
Guo, Y., 297
Gutekunst, K., 361
Göhl, J., 56, 129
Göhler, T., 176
Gölz, T., 34
Göpfert, K., 255
Görgen, P., 462
Götte, M., 42, 71, 271, 275, 278
Göttel, R., 89
Göttlich, C., 235
Götz, C., 279
Günther, B., 365
Güttler, A., 17
Gütz, S., 102
H
Haase, M., 103
Haberland, B., 266
Haberland, J., 140, 258
Habermann, A., 244, 329
Habermann, J. K., 227
Hack, C. C., 171, 270
Hadaschik, B., 4
Haderlein, M., 21, 115
Haeberle, L., 294
Haertl, C., 217
Haetscher, N., 300
Haeusler, N., 168
Hagen-Aukamp, C., 223
Hagenbeck, C., 450, 451
Hager, B., 106
Author Index
Hahlbohm, U., 197
Hahn, M., 262
Hahn, S., 215, 394
Hahn, S. A., 93, 139
Hahne, A., 82
Hahne, J., 107
Hahnen, E., 277, 452, 453
Hailemariam-Jahn, T., 285
Hallek, M., 219, 346, 396, 458, 459, 461,
462, 500
Halloul, Z., 398
Hamann, C., 282
Hamm, R., 52
Hamprecht, A., 72
Hanenberg, H., 419
Hanker, L. C., 231, 244, 250, 329, 337,
416, 432
Hann von Weyhern, C., 62
Hantschmann, P., 244, 329
Happold, C., 320
Harati, K., 5
Harbeck, N., 266, 267, 269, 353, 455, 456
Hardt, M., 363
Harnicek, D., 297
Harter, P., 231, 244, 329, 337, 416, 432
Hartkopf, A. D., 67, 68, 262, 327
Hartmann, A., 352
Hartmann, E., 325
Hartmann, J., 62
Hartmann, K., 415
Hartmann, M., 175
Hartmann, M., 311
Hartmann, S., 400
Hartmund, L., 200
Hasdemir, D. B., 309
Hasenburg, A., 244, 250, 303, 416
Haslerud, T., 49
Hassan, H., 278
Hassenkamp, P., 212
Hatwig, R., 460
Hau, P., 310
Haubold, K., 189
Hauch, S., 94
Hauke, J., 277, 452, 453
Haun, M., 175
Haus, U., 136
Hautzel, H., 371
Haverkamp, U., 372, 377
Hedblad, B., 99, 101, 228, 299
Hedderich, M., 153
Heiden, E., 363
Heidenreich, A., 284, 286, 311, 313, 334,
354, 357, 423
Heikaus, S., 379, 386
Heil, J., 67
Heilmann, V., 176
Heimann, S., 69
Hein, A., 270, 294, 352
Heinecke, A., 447
Heinemann, V., 217, 266
Heinig, K., 124
Heinrich, A., 153
Heinrich, B., 216
Heinrich, G., 449
Heinrich, M., 234
Heinz, W., 69
Heinzelmann, J., 163
Heinzmann, F., 355
Heisig, S., 239
Heiss, C., 244, 329
Heizmann, C. W., 268
Helle, S. I., 39
Hellmich, M., 383, 461
Hellriegel, M., 244, 250, 329
Hellwig, B., 50
Helm, O., 128
Henderson, D., 299
Hengstler, J., 50
Henke, M., 111
Henkel, T., 112
Hennenlotter, J., 100
Hense, J., 85, 136
Hentschel, M., 417
Hepp, P. G., 449
Herkommer, K., 122
Hermanek, P., 56, 345
Hermann, R., 390
Hermann, S., 121
Hero, B., 90
Herold, N., 276
Herold, S., 189
Herr, C., 201
Herr, D., 323
Herrmann, P., 268
Herschbach, P., 124
Hertrampf, K., 133
Herwig, U., 416
Herz, S., 156, 157
Herzog, W., 175
Heuckmann, J., 316
Heudorfer, F., 310
Heukamp, L., 22, 112, 404, 414, 431,
439, 461
Heukamp, L. C., 346, 376, 381
Heusinger, K., 352
Heußner, P., 205, 207
Heydenreich, M., 159
Heymanns, J., 130
Hiddemann, W., 205, 207
Hildebrandt, B., 88
Hildebrandt, G., 429
Hillemanns, P., 231, 244, 250, 329
Hilpert, F., 244, 250, 329, 337, 416
Hils, R., 337
Hindenburg, H. -J., 146
Hinke, A., 176
Hirsch, T., 5
Hirschfeld, M., 76, 77, 78
Hjorth, L., 350
Hoberg, C., 370
Hoda, R., 189
Hoffarth, S., 97
Hoffmann, A., 38
Hoffmann, A. -C., 199, 202, 204, 212
Hoffmann, G., 50
Hoffmann, O., 136
Hoffmann, T. K., 119
Hoffmann, W., 343
Hoffmeister, M., 45, 88, 382
Hofheinz, R., 457
Hofheinz, R., 160, 429
Hofmann, D., 456
Hofmann, D., 455
Hofmann, H., 100
137
Inhalt
Index
Hofstädter, F., 307
Hoheisel, J., 406
Hohenberger, P., 10, 11, 13, 325
Hohenberger, W., 56, 95, 129
Hohenfellner, M., 405
Hohmeyer, A., 355
Holleczek, B., 44, 282, 283
Holländer, M., 124
Holm, P., 279
Holtick, U., 346
Holzer, K., 300
Honisch, E., 332, 419
Hoppe, P., 115
Horger, M., 54, 62
Horn, O., 156
Horsch, L. D., 379
Hoster, E., 205, 207
Hoyer, J., 150
Hozaeel, W., 194
Hrgovic, I., 285, 287, 424, 426
Huber, J., 4, 106, 175, 405
Humblet, Y., 6
Hurtz, H. -J., 124
Häberle, L., 352
Hänse, N., 194
Häring, J., 230
Höland, K., 341
Hölscher, A., 178, 364
Hölzel, D., 84, 147, 293
Hönig, A., 107
Höwner, A., 199
Hübner, J., 270
Hülsdünker, T., 396
Hülsewig, C., 275
Hünerlitürkoglu, A. -N., 381
Hüttner, N. B. M., 270
I
Iborra, S., 329
Ibrahim, S. A., 278
Ignatiadis, M., 369
Ignatov, A., 273
Ignatov, T., 273
Ihorst, G., 34
Ihrig, A., 4
Ilieva, Y., 289
Ilm, K., 331
Ilmberger, C., 186
Ingold-Heppner, B., 88
Inwald, E. C., 307
Issels, R., 297
Izbicki, J. R., 127, 181
J
Jabar, S., 336
Jacke, C. O., 105
Jackisch, C., 222, 291
Jackson, E. K., 86
Jaehde, U., 171
Jagota, A., 328
Jahn, P., 32
Jallal, N., 246
Janni, W., 68, 110, 190, 270, 369, 449,
450, 451
Jansen, L., 44, 45, 88, 282, 283
Jansen, M., 229
Janssen, E., 359
138
Jarzab, B., 40
Jauch, K. -W., 186, 333
Jeffers, M., 11
Jehn, U., 204
Jilg, C., 356
Jirakova Trnkova, Z., 6
Jo, P., 263, 296
Joensuu, H., 10, 11
Johannessen, D. C., 39
John, H., 365, 448
Joka, M., 186
Jokic, M., 73
Jonat, W., 403
Jones, T., 174
Joseph, D., 395
Jud, S. M., 150, 294, 385
Judson, I., 350
Jueckstock, J., 329
Juhasz-Böss, I., 243, 323, 421
Jung, J., 83
Jung, M.
274
Junginger, T., 345
Junker, K., 163
Junker, S., 412
Jäger, B., 449, 450, 451
Jäger, E., 26, 27, 361
Jäger, M., 76, 77, 78
Jäger, M., 194
Jückstock, J. K., 244, 449
Jürgens, H., 336, 350, 445
K
Kaatz, R., 227
Kabelitz, D., 128
Kadhim, K., 138, 141
Kage, S., 240
Kahraman, D., 439
Kaiser, F., 30, 31
Kaiser, G., 92
Kajüter, H., 44
Kalder, M., 105
Kalff, R., 24, 25, 433
Kambartel, K., 381
Kaminski, B., 376, 414
Kaminsky, B., 431
Kampmann, E., 297
Kanaar, R., 297
Kang, T. -W., 355, 358
Kang, Y. -K., 10, 11, 12, 13
Kannen, V., 338
Kappeler, C., 10, 13, 40
Kappler, M., 260
Kapteina, S., 383
Karakhanova, S., 79, 80, 81
Karl, A., 311
Karthaus, M., 6, 7, 126
Kasimir-Bauer, S., 94
Kaskel, P., 14
Kasper, B., 325
Kasper, S., 85, 92, 97, 136
Kasprowicz, N., 195
Kasprowicz, N. S., 332
Katalinic, A., 53, 133, 282, 317
Katay, I., 414
Kates, R., 456
Kates, R. E., 455
Kaufmann, M., 395
Kaufmann, R., 285, 287, 288, 424, 426
Kaulfuß, S., 200, 206
Keck, B., 106, 405
Keil, E., 328
Keilholz, U., 299
Keller, A., 406
Keller, A., 249
Keller, K., 344
Keller, T., 94
Kemmner, W., 331
Kempa, S., 319, 322, 348
Kemper, B., 271
Kerkhoff, A., 457
Kerschgens, C., 223
Kessel, M., 201
Kesting, M., 279
Kesting, S., 42, 71
Keszte, J., 109, 362
Kettelhake, A., 319, 322
Ketterer, M., 121
Keyver-Paik, M. -D., 250
Khalaf, F., 49
Kiani, A., 444
Kiechle, M., 437
Kiesel, L., 271, 275, 278
Kilger, U., 99
Killing, F., 259
Kim, M., 338
Kimmig, R., 94, 136, 416
Kimminger, A., 84
Kind, M., 326
Kippenberger, S., 424, 426
Kirkovits, T., 269
Kirn, V., 373
Kitz, J., 296
Klaschik, K., 277
Klassen, O., 148
Klaus, B., 250
Klawonn, F., 358
Kleboth, K., 130
Klein, F., 443
Klein, P., 120
Kleinert, R., 178
Klempert, I., 265
Kliesch, S., 311
Klimke, A., 201
Klinkhammer-Schalke, M., 214, 307
Kloor, M., 88
Klose, T., 211
Kluba, T., 62
Klug, S. J., 405
Klunker, D., 194
Kneba, M., 457, 500
Knecht, R., 119, 301
Kneissl, P., 403
Knuth, A., 119
Knösel, T., 297
Ko, Y. D., 113, 171, 381
Kobe, C., 439
Kobelt, D., 173
Koch, J., 369
Koch, M. C., 294
Koch, T., 176
Koch, U., 223
Kochanneck, A., 370
Kocher, M., 108, 257
Koerner, R., 359
Author Index
Inhalt
Index
Kogosov, M., 60
Kohl, M., 136
Koliamitra, C., 221
Kolk, A., 279
Koller, M., 214, 307
Kollmar, O., 312, 344, 428
Kollmeier, J., 102
Konerding, M. A., 238
Kong, A., 369
Konstantinov, S., 289
Korfel, A., 406
Kosian, P., 347
Koslowsky, T., 254
Kosse, J., 231, 244, 329, 337, 416
Kossow, J., 136
Kostenko, A., 461
Kotrba, J., 260
Kotzsch, M., 17
Kovacheva, M., 135
Kowalski, C., 226
Kowalski, F., 252
Krabisch, P., 416, 432, 456
Krakau, M., 330
Krause, M., 229
Krauth, K. A., 118
Krawczyk, N., 327
Kraywinkel, K., 106, 140, 180, 258, 317,
405
Krege, S., 311
Kreienberg, R., 110
Kreipe, H. H., 455
Kreis, M. E., 345, 349
Kreppel, M., 51
Kretzschmar, L., 328
Kreuzeder, J., 291
Kreuzer, K. -A., 219, 461, 500
Krex, D., 98
Kriegs, M., 301
Kristiansen, G., 272, 274
Krombholz, A. S., 24
Kron, F., 461
Kron, M., 122, 462
Kronenberg, C., 328
Kronenberger, B., 232, 342
Kruppa, M., 127
Kruseova, J., 350
Krämer, S., 373, 378, 383
Krüger, S., 376, 381
Kuczyk, M. A., 60, 311
Kudelin, N., 340, 427
Kuhlmann, J. D., 94
Kuhlmann, S., 196
Kuhn, E., 225
Kuhn, N. -F., 18
Kuhn, P., 225
Kunze, J., 165
Kunze, S., 108
Kunzmann, V., 113
Kurbacher, C. M., 124, 156, 157, 413
Kurbacher, J. A., 156, 157, 413
Kurschat, P., 346
Kuru, T., 4
Kurzeder, C., 231, 432
Kusche, D., 245
Kuss, I., 10, 11, 12, 13
Kvasnicka, H. -M., 408
Kwok, B., 107
Author Index
Kähnert, H., 96
Kämpfe, D., 259
Kästner, P., 37
Köberle, V., 232, 342
Köhler, A., 390
König, F., 39
König, K., 112, 431
König, K., 100
König, V., 118
Königsrainer, A., 3, 62
Königsrainer, I., 3
Köppler, H., 130
Kümmel, S., 196, 455
L
Laban, S., 119, 301
Ladenstein, R., 350
Laffers, W., 295
Lahmann, P. H., 343
Lamb, T., 174
Lammertsma, A., 439
Landenberger, M., 32
Lang, S., 86, 97
Lang, S. A., 298, 375
Lange, M., 299
Lange, N., 378
Langels, O., 196
Langenberg, R., 368
Langenbuch, T., 59
Langer, M., 90
Langhammer, S., 149
Langheinrich, M., 129
Lardinois, D., 408
Laschke, M., 344
Lathan, B., 191
Latta, S., 353
Lattrich, C., 230, 305
Laubender, R., 217
Lauber, K., 297
Laurent, D., 6
Lautner, M. H. W., 292
Lazaridis, L., 202
Le Cesne, A., 10, 11
Le Coutre, P., 188
Leahy, M. G., 10, 11
Lebrecht, A., 50
LeDeley, M. C., 350
Ledwon, P., 168
Lee, B. H., 136
Lee, L. D., 349
Leenders, F., 316
Lehnerdt, C., 136
Lehnerdt, G., 212
Lehnhardt, M., 5
Lehrach, H., 299, 348
Leibbrand, B., 96
Leidinger, P., 406
Leisse, A., 272
Leitzke, S., 461
Lemos, C., 363
Lennert, J., 41
Lenz, H. J., 6, 7, 8, 9
Lenzen, G., 176
Lepique, J., 156, 157, 413
Leplow, B., 314
Leukel, P., 310
Leutz, A., 360
Lewis, J. D., 255
Lewis, I., 350
Li, Z., 224
Lieber, A., 224
Liebl, A., 95
Liebrich, C., 416
Liedtke, B., 456
Liefold, M., 172
Liekweg, A., 171
Lindberg, P., 214
Linde, I., 294, 385
Lindhofer, H., 194
Lindner, L., 297
Link, K., 113
Linnig, M., 216, 255
Lintermans, A., 114
Linthorst, M., 161
Lippert, H., 409, 411
Litiere, S., 369
Lizé, M., 201
Lloyd, A. J., 57
Lohr, F., 87
Longerich, T., 355, 358
Lorence, R., 242
Lorenz, C., 65
Lorenz, W., 214
Lorenz-Salehi, F., 456
Losem, C., 188
Losensky, W., 306
Lotze, C., 318
Lotze, M., 461
Ludwig, C., 116
Lueck, H. -J., 222
Luley, K., 160
Lux, M. P., 150
Luyten, A., 244, 329
Löhberg, C. R., 150
Löppenberg, B., 264
Lück, A., 124
Lück, H. -J., 231, 337
Lücke, K., 189
Lüftner, D., 291
Lütkens, T., 119
M
Maass, N., 120, 270
Maderer, A., 255
Madhavan, D., 67
Maghnouj, A., 93, 215
Magnet, F., 116
Mahner, S., 222, 231, 234, 244, 250, 303,
329, 416, 432
Mahnke, E., 430
Mahotka, C., 379, 386
Mai, S., 87
Maier, W., 44
Maisel, T., 444
Majchrzak, B., 93
Maki, R. G., 10, 11
Makowiec, F., 356
Malek, N., 358, 412
Malgorzata, K., 351
Malkomes, P., 300
Mallmann, P., 244, 329, 373, 374, 378,
383
Malter, M., 344
Malter, W., 373, 374, 378, 383
139
Inhalt
Index
Mandapathil, M., 86
Manjer, J., 99, 101, 228
Mannhold, R., 379, 386
Mansmann, U., 155
Marcinkowski, P., 268
Marec Berard, P., 350
Markiefka, B., 373, 383
Markowetz, J., 97
Markus, P., 92
Marmé, F., 67, 68, 416
Martin, K., 408
Martin, R., 295
Martinez, M., 174
Marx, C., 192
Mascia, M., 365
Massey, D., 242
Mastrobuoni, G., 319, 322
Mattner, U. -M., 124
Mattonet, C., 376, 414, 439
Matzdorff, A., 252
Maurer, C., 345, 500
Mavroudis, D., 369
Mavrova, R., 243, 323
Mayer, B., 186
Mayer, F., 160
Mayer, J., 500
Mayer, K., 49
Mayer, S., 303
Meese, E., 406
Meier, K., 315
Meier, W., 231, 244, 250, 329, 337, 416,
432
Meier-Stiegen, F., 190
Meiler, J., 85, 92
Meincke, M., 188, 191
Meindl, A., 277, 452
Meintker, L., 69
Meisner, C., 182
Meissner, M., 285, 287, 288, 424, 426
Meissner, W., 229
Meister, E. F., 109
Melander, O., 99, 101, 228
Melcher, C., 419, 450, 451
Menge, F., 325
Menger, M., 312, 344
Menger, M. D., 428
Mennrich, R., 128
Merger, M., 416
Merkel, S., 56, 129, 345
Merkelbach-Bruse, S., 112, 376, 381
Merseburger, A. S., 60
Merten, F., 434
Messina, C., 369
Metelmann, H. -R., 28
Metzler-Nolte, N., 139
Meyenburg-Altwarg, I., 365
Meyer, A., 362
Meyer, A., 390
Meyer, B. C., 309
Meyer, F., 398, 409, 411
Meyer, H., 38
Meyer, H. E., 199
Meyer, J., 206
Meyer, K., 310
Meyer, M., 460
Meyer, M., 461
Meyer, S., 107
140
Michael, P., 18
Michelis, S., 434
Mierau, A., 396
Milanovic, D., 111
Milde-Langosch, K., 167
Mineur, L., 6
Modest, D. P., 217
Modl, S., 273
Modugno, C., 67
Moehler, M., 216
Mohr, C., 389
Mohrmann, S., 332
Mok, T., 242
Molnar, I., 40
Morgen, R. -L., 387
Moritz, B., 113
Motsch, E., 131
Moustakis, C., 372, 377
Muche, T., 252
Mueck, A., 183
Muhs, H. -J., 100
Multhoff, G., 192, 280
Mundhenke, C., 366
Mundt, A., 411
Munz, A., 100
Murawa, D., 189
Mustea, A., 244, 329
Muth, M., 291
Mysliwietz, J., 333
Möckel, S., 310
Mögele, M., 114
Möhler, M., 255
Möller, D., 20
Möller, P., 281
Mönch, R., 335, 338, 341
Möslein, G., 399, 401
Müller, A., 417
Müller, B., 328
Müller, C., 359
Müller, F. H. H., 417
Müller, L., 113
Müller, M. C., 188
Müller, P., 408
Müller, R., 229
Müller, S., 3
Müller, V., 68, 450, 451
Müller-Brüsselbach, S., 229
Müller-Mattheis, V., 371
Münscher, A., 119
Münstedt, K., 250
N
Nadtotschi, T., 100
Nagel, W., 157
Nassir, M., 347
Nees, J., 67
Neidhardt, G., 452
Nel, I., 199, 202, 204, 212
Nelson, P., 333
Nennecke, A., 44
Nestoriuc, Y., 239
Netter, P., 214
Neubauer, H., 182, 183, 185, 187, 190,
425
Neugebauer, J. K., 449
Neuhaus, P., 443
Neumaier, B., 439
Neumann, M., 425
Neumann, M., 83
Neumann, V., 78
Neuner, B., 415, 446
Neureiter, D., 351
Neuser, P., 244, 329
Neusser, S., 61, 65
Neven, P., 114
Neves, R. P., 425
Neyns, B., 98
Nguemgo-Kouam, P., 370, 397
Niederacher, D., 332, 419, 425
Nietzer, S., 125, 152, 220, 235
Nietzschmann, A. -T., 247
Nieß, H., 333
Nikkhah, G., 98
Nils, H., 160
Nilsson, P., 99, 101, 228
Nilsson, S., 36, 57, 64
Nimmrich, I., 102
Nishida, T., 10, 11
Nissen, S. -O., 315
Nitz, U., 455, 456
Nitzsche, A., 83
Nix, O., 151
Nißler, V., 95
Noack, C., 170
Noble-Pyott, C., 197
Nogová, L., 112, 376, 381, 404, 414, 422,
431, 439
Noldus, J., 264
Nordlohne, M. W., 309
Normolle, D., 461
Noureddine, R., 92
Novopashenny, I., 442
Novotny, V., 405
Nowaczyk, P., 189
Nuding, B., 455
Nutting, C., 40
Nymbach, N., 156
Nürnberg, D., 434
O
O‘Brien, D., 242
O‘Bryan Tear, C. G., 39, 47, 64
O‘Byrne, K. J., 242
O‘Sullivan, J. M., 39
Ober, A., 449
Oberlin, O., 350
Oberländer, M., 227
Oberthür, R., 206
Ochsenbein, A., 98
Ocker, M., 351
Odom, D., 12
Oellerich, T., 300
Ohlinger, K., 315
Okhrimenko, A., 268
Olbrich, C., 328
Oliner, K., 126
Orho-Melander, M., 99, 101, 228
Ortmann, O., 107, 114, 123, 230, 273,
305, 307
Osburg, S., 83
Osterland, M., 268
Ostermann, H., 120
Ostheimer, C., 17
Otremba, B., 124
Author Index
Inhalt
Index
Ottmann, O. G., 188
Otto, R., 409
Otto, U., 223
Overkamp, F., 457
O’Shannessy, D. J., 347
P
Pabst, A. M., 238
Pabst, F., 109
Pabst, U., 260, 384
Pacini, F., 40
Padur, W., 259
Paelecke-Habermann, Y., 247
Pahernik, S., 405
Pahle, J., 173
Palisaar, J., 264
Palmer, M. R., 136
Panse, J., 376, 381, 431
Pantel, K., 67, 68, 449
Paolucci, V., 256
Papachristou, I., 404, 422, 439
Papendorf, F., 365
Park-Simon, T. -W., 222, 395
Parker, C., 36, 39, 57, 64
Parker, C., 47
Paschke, R., 40
Patel, S., 51
Paul, A., 38, 92
Paul, A., 196
Pauligk, C., 160
Paulsen, M., 52
Pawar, V., 8, 9
Pedro Neves, R., 190
Peifer, M., 112
Peipp, M., 324
Pelzer, U., 443
Pereszlenyi, A., 387
Perrakis, A., 95
Perrech, M., 162, 184
Persigehl, T., 422, 439
Persson, J., 224
Pervaiz, A., 143
Pesic, M., 358
Pester, L., 90
Pestka, A., 449
Petat-Dutter, K., 185, 187
Peter, S., 75
Peters, I., 60
Petersen, C., 244, 301, 429
Peterson, L., 75
Petsch, S., 41, 405
Pfaff, H., 83, 226
Pfirrmann, R. W., 394
Pfister, D., 284, 286, 313, 354, 357, 423
Pfisterer, J., 244, 250, 329, 416
Pföhler, C., 359
Pförtner, R., 389
Picard, M., 98
Piccart, M., 369
Pierga, J. -Y., 369
Pietzke, M., 322
Pigorsch, S., 395
Piiper, A., 232, 342
Pinter, A., 285, 424, 426
Piper, C., 284, 284, 286, 313, 354, 357,
423
Pisarenko, I., 397
Author Index
Piso, P., 298
Plötner, U., 14
Plötz, M., 169
Pogorzelski, M., 97
Polednik, M., 251
Pollmanns, A., 456
Porres, D., 284, 286, 313, 354, 357, 423
Possinger, K., 120, 442
Potenberg, J., 28, 328, 416
Poths, S., 185, 187
Pottek, T., 311
Potthoff, K., 148
Potzner, M., 102
Prange, S., 304
Prasauskas, V., 114
Premsrirut, P. K., 358
Preuss, K. -D., 359
Priesch-Grzeszkowiak, B., 397
Primo, S., 217
Pritzkuleit, R., 44, 133
Prokop, A., 253
Proschek, D., 58
Ptok, H., 345, 409, 411
Puhl, G., 443
Pujade-Lauraine, E., 337
Putzker, M., 211
Pöttgen, C., 389
Q
Quast, A., 63
Quast, D., 399
Quast, S. -A., 18, 169, 241
Quidde, J., 429
Quint, K., 351
R
Raabe, E., 294
Rack, B., 68, 195, 369
Rack, B. K., 449, 450, 451
Radicke, M., 385
Radosa, J., 323
Rafiyan, M. -R., 194
Rahimi-Nedjat, R., 236
Rahnenführer, J., 50
Raida, M., 223
Rambow, A. -C., 403
Rammensee, H. -G., 412
Randazzo, G. M., 379, 386
Randerath, W., 431
Randerath, W. J., 376, 381
Ranft, A., 336, 350, 445
Rapp, F., 433
Rasper, M., 336
Rath, H. M., 223
Rau, J., 222, 231, 432
Rauh, C., 270, 385
Rave-Fränk, M., 206
Redekopf, J., 375
Regenbrecht, C., 208, 299, 363
Regierer, A., 442
Reich, W., 292, 393
Reichardt, P., 10, 11, 12, 13
Reichelt, R., 124, 413
Reif, S., 6
Reifenberger, G., 320
Reimer, T., 400, 456
Reimers, K., 193
Reinartz, S., 229, 240
Reinbold, R., 278
Reinecke, P., 246
Reinert, S., 100
Reinhardt, C., 73
Reis, A., 150
Reis, H., 85, 136
Reiser, M., 376
Reiter, W. W., 432
Renner, S. P., 352
Retz, M., 311
Reuss, A., 337, 416
Reuss-Borst, M., 46
Reuter, D., 457
Reuß, A., 250
Rexrodt, P., 29
Reymond, M., 384, 388, 392
Rezai, N., 455
Rhiem, K., 276, 277, 407, 437
Riabinska, A., 73
Richly, H., 85, 136, 218
Richter, B., 222, 231, 244, 250, 329, 416
Richter, G., 197
Richter, R., 234
Richters, L., 437
Ridwelski, K., 409
Rieckmann, T., 301
Rieger, L., 29
Rieger, M., 300
Riemenschneider, M. J., 310
Riess, H., 88, 443
Riess, O., 185, 187
Riethdorf, S., 67, 68
Riethmüller, C., 271
Rieß, O., 412
Rivera, F., 126
Rivera Markelova, M., 173
Rodt, T., 309
Rody, A., 153, 270, 454
Roedel, C., 429
Roesler, B., 321
Roessler, M., 113
Roghmann, F., 264
Rohde, H., 75
Rohr, I., 234
Rohrberg, R., 457
Rohwer, N., 348
Roller, J., 344
Rommens, P. -M., 58
Roos, F., 285
Rosenbaum, D., 42, 71
Rosenthal, H., 309
Rot, S., 260
Roth, P., 406
Roth, W., 88
Rothe, S., 328
Rotmann, A. -R., 177
Rottmann, M., 147
Ruberg, K., 171
Rudolph, I., 319, 322
Rupertus, K., 312
Ruppert, M., 26, 27
Ruppert, R., 345
Rustemeyer, R., 285
Rustler, V., 253
Rutkowski, P., 10, 11, 13
Röcken, C., 128, 366
141
Inhalt
Index
Rödel, C., 395
Röhn, G., 162, 164, 166, 184
Rüffer, J. U., 41
Rüssel, J., 326
Rützel, J. D., 250
S
Sabet, A., 49
Sage, E. K., 280
Sagheb, K., 236
Salamon, J., 181
Salamone, S., 113
Salem, M., 456
Salem Gassar, E., 275
Salendo, J., 263, 296, 435
Salmen, J. C., 449
Salomo, D., 444
Salzmann, D., 41
Saric, T., 162
Sartor, A. O., 57
Sartor, O., 36, 64
Sasazuki, T., 331
Sauer, A., 188, 191
Sauter, G., 119, 127
Sauvigny, D., 255
Savic, S., 408
Schaal, K., 76
Schaffrin-Nabe, D., 66
Schafhausen, P., 75
Schaller, G., 430
Scharf, J. -G., 206
Scharf, J. -P., 328, 337
Scharhag-Rosenberger, F., 148
Schechtmann, G., 320
Scheer, M., 51
Scheffler, M., 376, 381, 404, 414, 422,
431, 439, 461
Scheid, C., 461
Scheller, K., 393
Schellerer, V., 56, 95, 129
Schellong, G., 276
Schellongowski, P., 330
Schem, C., 403
Schenk, A., 221
Scherer, R., 60
Scherwitz, P., 254
Scheulen, M. E., 136, 218
Schildhaus, H. -U., 376, 381, 404
Schiller, J., 360
Schilling, D., 280
Schilling, G., 302, 304
Schilling, J., 14, 146
Schiltz, D., 269
Schindler, C., 176
Schinköthe, T., 267, 269
Schirmacher, P., 88, 209, 355, 358
Schirra, J., 186
Schirren, J., 340, 402, 410, 427
Schittenhelm, J., 16
Schlaak, J. F., 38, 199
Schlaak, M., 346, 408
Schlag, P. M., 268
Schlechter, C., 20
Schlegel, F., 457
Schlegel, U., 98
Schlegel, W., 151
Schlesinger-Raab, A., 134, 293
142
Schlichting, A., 48
Schlitt, H. J., 298, 375
Schlumberger, M., 40
Schlösser, H., 346
Schlößer, H. A., 254
Schmalenberg, H., 160
Schmalfeldt, B., 222, 231, 244, 250, 329,
416
Schmdit, H., 32
Schmeling, C., 389
Schmelz, H. U., 311
Schmid, K., 136
Schmid, K. W., 85, 92, 97, 404
Schmid, S., 356, 366
Schmid, T. E., 192, 280
Schmidt, W. E., 457
Schmidt, E., 103
Schmidt, K., 361, 375, 420
Schmidt, M., 50
Schmidt, M., 415, 446
Schmidt, M., 148
Schmidt-Rhode, P., 124
Schmidt-Wolf, I., 458, 461, 462
Schmiedek, P., 248
Schmiegel, W., 93
Schmitt, S., 100
Schmitz, S., 381
Schmoll, H. -J., 326
Schmutzler, R., 276, 277, 407, 437, 452,
453
Schneck, H., 182, 183, 190
Schneeweiss, A., 67, 68, 148, 449
Schneeweiss, R., 163
Schneider, A., 379
Schneider, C., 399, 401
Schneider, E. M., 441
Schneider, F., 248
Schneider, M. O., 294
Schneider, R., 399, 401
Schneider-Kappus, W., 188
Schnell, R., 414
Schnittner, U., 460
Schnurbein, G., 452
Schochter, F., 449, 450, 451
Schoffski, P., 10, 11
Schollmayer, F., 221
Scholz, M., 195
Schott, S., 67, 68, 403
Schrader, A. J., 36, 281, 311
Schrader, M., 281, 311
Schrader, T., 168
Schrauder, M. G., 150, 352
Schroeder, C., 412
Schroeder, M., 170
Schroeder, T., 69, 300
Schröck, A., 272
Schröder, C., 167
Schröder, W., 250
Schubert, D., 53
Schubert, S., 75
Schubert-Fritschle, G., 84, 134, 147, 293
Schuette, W., 209
Schuldt, M., 201
Schuler, M., 85, 92, 97, 136, 202, 204,
218, 233, 242, 404
Schulmann, K., 93
Schulte, K., 330
Schultheis, B., 457
Schultheiß, M., 342
Schultz, S., 182, 185, 187
Schulz, H., 381
Schulz, S., 425
Schulz, V., 124
Schulz-Wendtland, R., 150, 294, 385
Schulze, H. -J., 447
Schumacher, D., 299, 363
Schumacher, U., 167, 181
Schumann, C., 102
Schumann, T., 229
Schwarting, A., 58
Schwartzberg, L., 126
Schwarz, B., 217
Schwedas, M., 367
Schween, U., 413
Schweitzer, C., 156
Schweitzer, N., 309
Schwentner, L., 110
Schwickert, A., 271
Schwinger, U., 188
Schäfer, H., 127, 128
Schäfer, R., 208, 299
Schäfer, U., 170
Schäffeler, N., 43
Schöler, S., 94
Schöning, E. -M., 315
Schüler, S., 230, 305
Schütz, F., 68, 291
Scobioala, S., 372, 377
Sebens, S., 127, 128
Sedelmayr, M., 280
Seeger, H., 182, 183
Seel, J., 192
Seeliger, H., 349
Seemann, H., 206
Seggewiß, J., 271
Sehouli, J., 222, 231, 234, 244, 328, 329,
337, 347, 416, 432
Seidel, C., 60
Seidenader, J., 4
Seifert, H., 75
Seitz, S., 123
Seitz-Rosenhagen, M., 248
Seiz, L., 273
Selbach, J., 176
Sell, C., 343
Semrau, R., 108, 257, 373, 383
Sequist, L. V., 242
Serke, M., 22, 102, 203, 376, 381, 431
Serth, J., 60
Serve, H., 300
Shak, S., 455
Shan, M., 39
Shaw, A. T., 233
Shedden Mora, M., 239
Sherman, S. I., 40
Shimabukuro-Vornhagen, A., 254, 346
Shinde, R., 14
Shirasawa, S., 331
Shong, Y. K., 40
Sicking, I., 50
Siebenlist, K., 87
Siebenwirth, C., 192
Sieber, S., 125
Siena, S., 6, 7, 8, 9, 40
Author Index
Inhalt
Index
Simeonova, A., 87
Simon, M., 98
Simon, R., 127
Singer, S., 109, 110, 362
Sinistra, J., 312
Sinn, M., 443
Sipos, B., 412
Sitek, B., 38, 199
Siveke, J., 457
Sklenar, S., 387
Sklenarova, H., 175
Skottky, S., 85
Slottky, S., 136
Smit, J. W. A., 40
Smith, J., 268
Sobrero, A., 6, 7, 8, 9
Socinski, M., 461
Sohn, C., 67, 68, 403
Solaß, W., 384, 388, 392
Solbach, C., 50
Solomayer, E. F., 68, 243, 262, 323, 395,
421
Somers, E., 347
Song, H., 224
Sonnenschein, U., 113
Soppa, B., 21
Sorgius, D., 194
Sorkin, M., 148
Sos, M., 404, 439
Sotiriou, C., 369
Sotlar, K., 185, 187
Spaeth-Schwalbe, E., 438
Spagnoli, G., 408
Spang, R., 310
Speiser, D. E., 408
Sperk, E., 249, 395
Sperling, J., 344, 428
Spies, C., 415, 446
Spillmann, D., 275
Spitzner, M., 321
Sponholz, S., 427
Sprossmann-Günther, G., 28
Stachs, A., 400
Stadler, R., 346, 408
Staebler, A., 16
Staebler, A., 327
Stamatis, G., 85
Stamm, K., 112
Starbatty, B., 459
Staudacher, K., 57, 64
Staudinger, M., 324
Stausberg, J., 155
Steckelberg, E., 46
Steering, C., 261
Stefek, A., 456
Stegelmann, F., 188
Stegmaier, C., 252
Steguweit, H., 346
Steil, V., 87
Stein, A., 8, 9, 429
Stein, H., 436
Stein, U., 268, 331, 363
Steinau, H. -U., 5
Steindorf, K., 148
Steinert, R., 409
Steinestel, J., 281
Steinestel, K., 281
Author Index
Steinger, B., 214
Steinle, A., 213
Steinmetz, T., 457
Steinmetz, K., 174
Steinsiek, L., 303
Stenzl, A., 100
Stern, S., 188
Sternfeld, T., 29, 30, 31
Steuber, T., 57
Stevens, J., 379
Stickeler, E., 76, 77, 78, 356, 366
Stiegler, H., 14
Stieler, F., 87
Stieler, J., 443
Stilgenbauer, S., 219, 500
Stippel, D., 178
Stippel, D. L., 254
Stock, C., 271, 275, 382
Stoecklein, N. H., 332
Stoelben, E., 116, 257, 431, 439
Stoetzer, O., 113
Stojceva, N., 320
Stolzenbach, F., 163
Strasburg, J., 387
Strassburg, J., 345
Straub, M., 279
Strauss, A., 47
Strauss, H. -G., 329
Strauß, H. -G., 244, 250
Streichert, T., 167
Strik, H., 351
Stroeder, J., 323
Strohbach, F., 89
Struck, J., 99, 101, 228
Strumberg, D., 384, 388, 392, 457
Ströbel, P., 296
Strölin, P., 64
Stubert, J., 400
Stupp, R., 98
Sturm, M., 412
Stuschke, M., 389
Stäbler, A., 366
Stöckle, M., 163
Stürzl, M., 95
Suleiman, A., 414
Suter, L., 447
Suttmann, I., 113
Svedman, C., 455
Swoboda, S., 38
Syha, R., 54
Sänger, J., 100
Sörgel, F., 414
Sütterlin, M., 231, 249, 395
Tebbe, S., 191
Temming, S., 257
Tempfer, C., 384
Teriete, P., 100
Terstappen, L., 195
Terszowski, G., 408
Tesch, H., 120, 176, 191, 291
Tessen, H. -W., 35, 48, 89
Teufel, M., 43
Tewes, M., 85, 136
Thangarajah, F., 383
Theil, G., 189
Thelen, L., 73
Theobald, M., 58
Theuer, M., 172
Theurich, S., 346, 408
Thiel, C., 420
Thiel, E., 406
Thiel, F., 244, 329, 352
Thielecke, C., 14
Thies, B., 295
Thill, M., 337, 416
Thissen, A., 284, 286, 313
Thissen, A. K., 354, 357
Thomalla, J., 130
Thomas, C., 237
Thomas, M., 102, 175, 209, 233
Thomas, R., 73, 112, 316, 404
Thomssen, C., 314
Thuß-Patience, P., 74
Timmer, M., 162, 164, 166, 184
Ting, S., 85, 97, 136
Tischendorf, L., 154
Tiwari, S., 403
Tjiong, R., 166
Tobias, J., 395
Tonn, J., 98
Torsten, U., 328
Towers, R., 403
Treeck, O., 230, 305
Treese, C., 74
Trefzer, U., 18
Trepel, M., 302
Treppner, S., 458
Tretter, W., 84
Tribius, S., 301
Trillsch, F., 234, 250, 303
Trippler, M., 38
Tritschler, I., 213
Trojan, J., 232
Trumpp, A., 67, 68
Tummes, D., 414
Töpelt, K., 414, 431, 439
T
Tabatabai, G., 98
Tabernero, J., 6
Takacz, S., 243
Tanner, B., 244, 329
Tanovi_, A., 297
Tao, S., 88
Taran, F. -A., 262
Tari, S., 205
Tasar, A., 171
Taubert, H., 260
Tauchert, F. K., 26, 27
Taylor, K. J., 236
U
Udelnow, A., 398
Uder, M., 385
Uhl, W., 391, 394
Ulbach, K., 266
Uleer, C., 456
Uleer, C., 337
Ullrich, A., 223
Ulrich, A., 88
Ulrich, C., 148
Ulrich, U., 328
Ulrike, S., 343
Upleger, F., 124
143
Inhalt
Index
V
v. Lilienfeld-Toal, M., 75
Vaidya, J., 395
Valesky, E., 285, 287, 288, 424, 426
van Cutsem, E., 6, 7, 8, 9
van den Berg, H., 350
van den Höfel, N., 386
van der Zee, J., 161
van Erps, T., 423
Van Ewijk, R., 110
van Geel, A., 161
van Gool, R., 57
Van Gorp, T., 234
van Rensburg, R., 224
van Rhoon, G., 161
van Roye, C., 130
Vanezi, M., 49
Vehling-Kaiser, U., 29, 30, 31, 188
Vehreschild, J., 69, 72
Vehreschild, M. J. G., 69, 72, 75, 90
Velasco, J., 299
Ventola, A., 195
Vestergaard, A., 440
Vettorazzi, E., 250
Vijaya Kumar, A., 275
Vilardo, L., 278
Vizler, C., 195
Vogel, A., 309, 429
Vogel, H. -J., 109
Vogel, I., 128
Vogel, U., 182, 366
Vogel, W., 75
Vogelzang, N. J., 39, 47, 64
Vogt, L., 361, 420
Vogt, P. M., 193
Vogt, T., 359
Voigt, W., 225
Voiß, P., 196
Volgelzang, N., 57
Volkmer, B., 198, 210
Vollmann, A., 310
von Bergwelt-Baildon, M., 69, 254, 346,
408
von Bodman, C., 264
von Dehn-Rotfelser, K., 186
von Dossow-Hanfstingl, V., 415
von Hardenberg, S., 200
von Kries, A., 137
von Levetzow, C., 461
von Mehren, M., 10, 11
von Pawel, J., 102
Von Schumann, R., 456
von Tresckow, J., 90
von Wilucki, J., 294
von Winterfeld, M., 74, 88
Vordermark, D., 17, 247
Vossebein, I., 97
W
Waaga-Gasser, A. M., 335, 338, 341
Wachter, D., 352
Wacker, F., 309
Wagner, A., 7, 9
Wagner, C., 375
Wagner, D., 172
Wagner, F., 385
Wagner, S., 150
144
Wagner, U., 105, 229, 240
Wagner, W., 311
Wahba, R., 178
Wahlers, K., 72
Waidmann, O., 232, 342
Waldmann, A., 53, 133, 153, 454
Waldschmidt, D., 178, 461
Walles, H., 125, 152, 220, 235
Wallwiener, D., 16, 43, 185, 187, 261,
262, 270, 327
Wallwiener, M., 67, 68, 261, 262
Walter, B., 405
Walter, C., 37, 236, 237, 238
Walter, J., 24, 25, 433
Walter, M., 185, 187
Walther, W., 173
Wang, Y., 217, 333
Wappenschmidt, B., 277, 437, 452, 453
Wassermann, K., 407
Weber, F., 38, 199
Weber, K., 56, 129
Weber-Lassalle, N., 452
Wedel, B., 454
Weghake, E., 271
Wehler, T., 58
Weide, R., 130
Weigang-Köhler, K., 113
Weigel, A., 442
Weiling, M., 306
Weise, S., 247
Weiss, S., 306
Weiss-Gerlach, E., 415
Weiß, C., 102
Weißbach, L., 311
Weißenborn, C., 273
Wellenberg, N., 38
Weller, M., 98, 213, 320, 324, 406
Weller, P., 212
Welt, A., 85, 136
Welte, Y., 208
Welzel, G., 248, 249, 251
Wendling, J., 136
Wendt, T. G., 367
Wendtner, C., 219, 500
Wenkel, E., 150, 385
Wennhold, K., 346
Wenz, F., 87, 248, 249, 251, 395, 429
Wenz, H. -J., 133
Werner, D., 160, 174
Werner, J., 79, 80, 81
Werner, J. A., 86
Werner, M., 356, 366
Wesselmann, J. S., 219
Wessling, G., 156, 157
Westermann, A., 219
Westermann, S., 295
Wetzel, C., 123
Whiteside, T., 86
Wichmann, H., 260
Wick, A., 98
Wick, W., 98
Wickert, M., 43
Wicklein, D., 167, 181
Wickmann, U., 163
Wiedemann, M., 84
Wiedenmann, B., 348
Wiek, C., 419
Wienands, J., 321
Wiench, B., 52
Wierecky, J., 124
Wiesweg, M., 85, 92, 136, 218, 404
Wilhelm, J., 172
Wilhelm, M., 113
Wilhems, D., 292
Wilke, J., 176
Wilkens, J., 192
Willinek, W., 49
Willmann, L., 4
Wilmer, A., 171
Wiltfang, J., 133
Wimberger, P., 94, 231, 244, 250, 329,
337, 432
Wincheringer, B., 172
Wind, S., 242
Winkel, A., 117, 245
Winkler, E., 175
Winkler, S., 115
Winter, C., 42, 71
Winter, E., 311
Winters, S., 461
Wirsing, U., 91
Wirth, M., 106, 405
Wirtz, M., 83, 226
Wirtz, P., 374
Wirtz, R., 50
Wischnewsky, M., 442
Wiskemann, J., 148
Wisplinghoff, H., 69
Wittenberg, T., 385
Wittmann, L., 216
Woelber, L., 303
Wohlschläger, J., 85
Wolf, J., 460
Wolf, J., 233
Wolf, J., 22, 112, 376, 381, 404, 414, 422,
431, 439, 458, 459, 461, 462
Wolf, U., 140
Wolff, H., 263, 321
Wolff, H. A., 296
Wolff, K. D., 279
Wolff, S., 409
Wollbrück, D., 362
Wollschlaeger, K., 250
Wolpert, F., 213
Wolter, K., 358
Wolters, R., 442
Worm, K., 85, 136
Wortmann, A., 229
Wu, Y. -L., 12, 242
Wuestefeld, T., 358
Wullich, B., 405
Wurster, I., 182
Wöckel, A., 110
Wöge, M., 434
Wölber, L., 244, 329
Wölke, G., 155
Wömpner, C., 404, 414
Wünsch, A., 34
Würstlein, R., 226, 266, 267, 269, 455
X
Xu, J. -M., 10, 11
Author Index
Inhalt
Index
Y
Yalcin, S., 457
Yamamoto, N., 242
Yang, J. C., 242
Yang, N. -S., 52
Yaspo, M. -L., 299
Ychou, M., 6, 7, 8, 9
Yeganeh, B., 368
Yip, G. W., 275
Yoshino, T., 6, 7, 8, 9
Yu, H., 126
Yumul, R., 224
Z
Zamarchi, R., 195
Zander, T., 422, 431, 439, 461
Author Index
Zaun, S., 120, 209
Zeilinger, R., 234
Zeman, F., 307
Zenclussen, A., 273
Zender, L., 355, 358
Zengerling, F., 311
Zermann, D. -H., 159
Zeuzem, S., 232
Zey, A., 219
Zhao, L., 333
Zhao, Y., 217, 333
Zheng, C., 77
Ziebart, T., 238
Zieker, D., 3
Zielberg, D., 441
Ziemann, C., 344, 428
Zieren, J., 384, 388, 392
Zimmer, P., 221, 364, 396
Zipfel, S., 43
Zippelius, A., 408
Zirrgiebel, U., 209
Zlobinskaya, O., 192
Zmarsly, I., 5
Zorr, A., 231
Zou, J., 64
Zwink, N., 382
Zöhrer, F., 385
Zöller, J., 51
Zöllner, H., 215
145

abstracts - 31. Deutscher Krebskongress 2014

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