96. Jahrestagung der Deutschen Gesellschaft für Pathologie e. V ...

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provided information on survival times and utilities. Costs were assessed from the Swiss health care system perspective. Results. Remaining life-time costs ranged from EUR 3’983 (no cetuximab) to EUR 38’662 (no testing). Gains of 0.491 QALYs compared to the reference strategy were achieved by KRAS/BRAF testing. Compared to KRAS/BRAF, the KRAS testing strategy yielded an additional gain of 0.002 QALYs. Testing with KRAS/BRAF was the most cost-effective approach (incremental cost-effectiveness ratio; EUR 62’653/QALY) compared to the reference strategy. In Switzerland, KRAS and BRAF testing could lead to annual savings of EUR 591’170 and a loss of 1.89 QALYs compared with KRAS alone (1,003 new mCRC patients annually). Compared with no cetuximab, the usage of KRAS and BRAF testing would require an annual net investment of about EUR 30.9 million to acquire a gain of 493 QALYs. Conclusions. While new predictive test are introduced in pathology, the health economic implications of these tests remain mainly unknown. This study has shown that testing for KRAS and BRAF mutations in mCRC patients prior to cetuximab treatment would be favourable in a Swiss health care context. This model could also be used for comparable decision problems arising with other predictive tests, which are of highest relevance for oncologists, pathologists, and health policy makers. References 1 . Blank PR, Moch H et al (2011) . Clin Cancer Res FR-P-079 HER-2/neu expression in locally advanced rectal cancer (cUICC II/ III) and its correlation with long-term prognosis L .-C . Conradi1 , H . Stycen1 , T . Sprenger1 , J . Gaedcke1 , K . Homayounfar1 , H .A . Wolff1 , H . Becker1 , B .M . Ghadimi1 , J . Rüschoff2 , P . Middel1 , T . Beissbarth1 , T . Liersch1 1 2 University Medical Center Göttingen, Göttingen, Pathologie Nordhessen, Kassel Aims. With the implementation of multimodal treatment strategies including neoadjuvant radiochemotherapy (RCT), the prognosis of locally advanced rectal cancer has been improved over the last two decades. Most actual clinical trials aim to further develop therapy by intensification of agents administered. We examined Her2/neu in rectal cancer patients to evaluate its expression as a potential drug target as well as its capacity as predictive and prognostic biomarker. Methods. Two-hundred-sixty-four patients (192 male, 72 female; median age 64 years) with locally advanced rectal cancer (cUICC-II/III) were included in this study. Preoperative RCT (50.4 Gy and concomitant either 5-FU or 5-FU and oxaliplatin) was administered in 217 patients followed by surgical resection with total mesorectal excision (TME). Another 75 patients received postoperative RCT. All patients were treated within phase-II/III trials of the German Rectal Cancer Study Group or analogous to these standardized protocols. Her2-/neu expression from pretreatment biopsies and corresponding resection specimens were assessed by immunohistochemical staining and SISH-analysis Results. A positive Her-2/neu expression was found in 12.4% of all pretreatment tumor biopsy samples and in 29.3% of the resection specimens. The correlation of the pre-treatment Her-2/neu status did not show a significant correlation with the grade of tumor regression. However, patients with a higher Her-2/neu protein expression as measured in the resection specimen showed a significant survival benefit (p=0.045) and a prolonged disease free survival (p=0.05) compared with patients having low intratumoral Her-2/neu expression during the follow-up (median 41 months). The 5-year survival rate was 96.5% (Her-2/neu positive) versus 79.9% (Her-2/neu negative). Conclusions. Her-2/neu might be a promising drug target in a significant proportion of rectal cancer patients and should be further assessed within prospective clinical trials. Furthermore the Her-2/neu status seems to be a valuable prognostic marker within the multimodal treatment of advanced rectal cancer. FR-P-080 Functional characterization of necroptosis in colorectal cancer M . Metzig1 , D . Fuchs2 , S . Macher-Goeppinger 1 , P . Schirmacher3 , W . Roth1 1Institute of Pathology, University of Heidelberg; German Cancer Research Center (DKFZ), Heidelberg, Heidelberg, 2German Cancer Research Center (DKFZ), Heidelberg, 3Institute of Pathology, University of Heidelberg, Heidelberg Aims. Necroptosis is a recently discovered, RIP1-dependent form of programmed necrosis. Recent evidence indicates that this type of cell death plays an important role in both physiologic and pathologic cellular processes. While different stimuli, e.g. members of the tumor necrosis factor (TNF) family, have been identified as inducers of necroptosis, only little is known about the underlying signaling cascades and effector molecules of necroptosis. The aim of our project is to further clarify the mechanism of programmed necrosis and to analyze its biological significance in colorectal carcinoma. Methods. Cytotoxicity and apoptosis assay, FACS analysis, immunohistochemistry, RNA isolation, quantitative real-time PCR, cloning of expression vectors, co-immunoprecipitations. Results. We screened multiple cytotoxic stimuli for the induction of necroptosis in various colorectal carcinoma cell lines. We found a differential increase in sensitivity to cell death induced by specific drugs when co-treated with a pancaspase-inhibitor. Since a RIP1-specific inhibitor (necrostatin 1) diminished this effect we concluded that cells were dying due to necroptosis. Drug-induced necroptosis was further dependent on TNF receptor 1 (TNFR1) signaling. Overexpression of RIP3 has been shown to reconstitute the ability to undergo necroptosis in response to different stimuli in so far insensitive colon carcinoma cell lines. To assess the biological significance of RIP3 in colon cancer we analyzed protein and mRNA expression levels in human colorectal carcinoma samples. RIP3 expression was significantly reduced in colon carcinoma specimens compared to normal tissue. Conclusions. Chemotherapeutic drugs induce necroptosis in colon carcinoma cells in a TNFR1 and RIP3 dependent manner. RIP3 expression is reduced in colon carcinoma suggesting a physiologic function of necroptosis in tissue homeostasis. The possibility to re-sensitize carcinoma cells to necroptosis-inducing stimuli points towards novel therapeutic options in cancer therapy. FR-P-081 High HSP70 and HSP27 expression levels are independent adverse prognostic factors in primary resected colon cancer K . Bauer1 , U . Nitsche2 , J . Slotta-Huspenina1 , E . Drecoll1 , C . Hann von Weyhern1,3 , R . Rosenberg2 , H . Höfler1,4 , R . Langer1 1 2 Technische Universität München, Institute of Pathology, München, Technische Universität München, Klinikum rechts der Isar, München, 3Städtisches Klinikum München, Klinikum Harlaching, München, 4Institute of Pathology, Helmholtz-Zentrum München, Oberschleissheim Aims. The expression of Heat Shock Proteins (HSPs) is increased in various cancers and has been shown to correlate with biological tumor behaviour. We aimed to assess the impact of HSP70, HSP60 and HSP27 expression patterns with pathological features of colon carcinomas and patients survival in a large collection of colon cancer. Methods. HSP expression was determined by immunohistochemistry on a tissue microarray containing cancer tissue of 355 patients with primary resected colon carcinomas. Expression patterns were correlated with pathologic features (UICC pTNM category, tumor grading) and survival. Expression of HSP27, HSP60 and HSP70 was assessed in cancer tissue ranging from negative to high. Results. Expression of HSP27, HSP60 and HSP70 can be detected in colon carcinomas. High HSP70 expression was associated with worse overall survival (p
Abstracts tioned above. For patients without lymph node or distant metastases (UICC stages I/II) and with complete tumor excision, HSP70 expression was the only independent prognostic factor for survival (p=0.001) and superior to UICC pT category. In left sided UICC stage I/II carcinomas, high HSP27 expression also had adverse prognostic impact and was an independent prognostic factor (p=0.016) besides HSP70 (p=0.002). There was no correlation between HSP27, HSP60 and HSP70 expression among each other and with UICC pT category, presence of lymph node, distant metastases or tumor grading. Conclusions. High HSP70 and HSP27 expression is associated with worse clinical outcome. Determination of tumoral HSP70 and HSP27 may be used as additional biomarker for risk stratification in colon cancer patients especially in UICC stage I/II patients. FR-P-082 p.G13D mutations in the KRAS oncogene are associated with sensitivity of colorectal carcinoma cells to anti-EGFR antibody treatment I . Messner1 , S .E . Baldus1 , H .E . Gabbert1 , K .-L . Schäfer1 1Heinrich-Heine-University Düsseldorf, Inst . of Pathology, Düsseldorf Aims. Targeted therapies with the anti-EGFR antibodies panitumumab (Pmab) or cetuximab (Cmab) have shown significant benefit for patients suffering from metastatic colorectal carcinoma (mCRC). According to the approval by the American Food and Drug Administration and the European Medicines Agency, application of these antibodies is restricted to tumors without mutation in the KRAS oncogene. However, a recent metaanalysis of 579 CRC patients treated with cmab indicated that patients with p.G13D-mutated tumors (exchange of glycine at codon 13 to aspartic acid) showed a longer overall survival compared to patients with tumors mutated in KRAS codon 12. In order to study the functional impact of the subtype of KRAS mutation on the efficiency of EGFR-targeted therapies in CRC, we have determined the KRAS mutation status of colorectal carcinoma cell lines and correlated these data to the in vitro sensitivity of these cells to cmab and Pmab. Methods. Using a set of 15 colorectal cancer cell lines, the KRAS mutation status was evaluated by Sanger sequencing. Mutations in the potential predictive biomarkers BRAF and PIK3CA as well as protein expression of EGFR and PTEN were also determined. In vitro sensitivity of tumor cells to anti-EGFR antibodies was measured by standard MTT assays. Results. Seven of 15 cell lines showed a KRAS mutation including four cell lines exhibiting the p.G13D mutation. If these cell lines were treated using panitumumab or cetuximab, a significant growth inhibition was observed, while cell lines showing a KRAS mutation at codon 12 or 61 were not sensitive to anti-EGFR treatment. Only three of eight cell lines showing KRAS wild type status were sensitive to Pmab and cmab. Noteworthy, all of the five resistant KRAS wild type cell lines were either characterized by BRAF mutation or by absence of EGFR or PTEN protein expression, respectively. No correlation between PIK3CA mutation status and sensitivity to anti-EGFR treatment could be demonstrated. Conclusions. Our in vitro data from colon carcinoma cell lines indicate that tumor cells showing the KRAS p.G13D mutation may respond to EGFR-targeted therapy. Therefore, subtype analysis of KRAS mutation should be included in prospective clinical trials analyzing the responsiveness of CRC to cmab or Pmab. In KRAS wild type tumor cells, additional aberrations like BRAF mutation and loss of EGFR or PTEN expression may lead to resistance to EGFR-targeted therapy and should be considered as additional negative predictive biomarkers. 110 | Der Pathologe · Supplement 1 · 2012 FR-P-083 UBCH10 overexpression in human colorectal cancers S . Piscuoglio1 , P . Pallante2 , L . Tornillo3 , A . Fusco2 , L . Terracciano 3 1 2 University of Basel, Department of Biomedicine, basel, Switzerland, University of Naples, Istituto di Endocrinologia ed Oncologia Sperimentale “G . Salvatore” (IEOS-CNR) c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare, naples, Italy, 3University of Basel, Institute of Pathology, Basel, Switzerland Aims. Colorectal cancer is the result of the accumulation of different genetic modifications including critical genes involved in the control of cell proliferation. In a large number of carcinomas with worst prognosis, lesions are not diagnosed until the disease is at an advanced stage. To diagnose cancer at an early stage and to establish more effective therapies featuring of key molecules in carcinogenesis is a critical step. UBCH10 (also known as E2C or UBE2C) is a cell cycle-related protein involved in mitosis completion. UbcH10 participates in proper metaphase to anaphase transition, and abrogation of UbcH10 results in the premature separation of sister chromatids. Thus, UbcH10 is essential for cell cycle progression, and his expression is cell-cycle dependent and related to proliferation. The aim of this study is to investigate the association of UbcH10 gene expression with clinicopathological features and tumor progression of colorectal cancer. Methods. We investigated the expression of the UBCH10 genes in a tissue microarray platform consisting of normal and neoplastic colorectal cancers (CRC) tissues by immunohistochemistry. UBCH10 was detectable in 889 patients. Immunoreactivity was scored semi-quantitatively by evaluating the number of positive tumor cells over the total number of tumor cells. Scores were assigned using 5% intervals and ranged from 0% to 100%. Median protein expression levels were used as cut-off scores to define protein marker positivity and the findings were associated with clinical-pathological parameters. Results. Our results demonstrated that UBCH10 is overexpressed in CRCs tissues compared to normal colon (p
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Inhalt Der Pathologe · Supplement
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Inhalt Der Pathologe · Supplement
Page 6 and 7:
Editorial Liebe Kolleginnen und Kol
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Kolorektales Karzinom 2 VO-005 Tran
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Keynote Lecture VO-014 Genetic dete
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(AMACR, FASN, GOLM1, GSP-pi, ERG) t
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to assess the correct rate of R1 re
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DNA damage, and cytotoxic drugs. Au
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HCV-positive formalin-fixed and par
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well as MET activation were examine
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or BRAF mutation, c-MYC and SIRT1 e
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AG Pneumopathologie III DO-032 Remo
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immature granulopoiesis showed a st
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ned, if well-defined mantle zones,
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phomas). Most prominent gains or am
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DO-062 Tumor-associated macrophages
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DO-080 DOG1: an immunohistochemical
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AG Oralpathologie DO-087 Detection
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DO-094 Do activated fibroblasts inf
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DO-101 Histopathological analysis o
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DO-108 Identification of potential
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Conclusions. In conclusion, 454 par
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subgroup of patients with B-Raf mut
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DO-002b Impact of terminologies in
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Methods. We performed MCPyV-FISH of
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FR-013 HPV-genotype distribution in
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Methods. Three different techniques
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(i.e. investment in equipment and e
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FR-032 COLD-PCR: a powerful tool in
Page 60 and 61: dissection (MBLND) technique to imp
Page 62 and 63: SO-005 Prevalence of mutations in s
Page 64 and 65: SO-011 Methylation profiling and in
Page 66 and 67: more effective than SAHA alone and
Page 68 and 69: SO-022 Specialized pathology review
Page 70 and 71: SO-027 Ki-67 in mitotic score group
Page 72 and 73: nificantly associated with advanced
Page 74 and 75: liver did not correlate with the mu
Page 76 and 77: AG Paidopathologie II SO-046 Overex
Page 78 and 79: Results. Histomorphology of the ova
Page 80 and 81: p42 and p27 have not yet been inves
Page 82 and 83: SO-068 Recent advances in understan
Page 84 and 85: SO-075 A novel, dual role of CCN3 i
Page 86 and 87: Pancreatic Adenocarcinoma SG-137 Se
Page 88 and 89: sease and 30 colon cancer serum sam
Page 90 and 91: Conclusions. Although CRC is charac
Page 92 and 93: differentiated and TNM stage III or
Page 94 and 95: pressed moderate levels of the prot
Page 96 and 97: FR-P-037 MALDI imaging reveals COX7
Page 98 and 99: in the context of therapy response
Page 100 and 101: on primary cells of wild-type and c
Page 102 and 103: chemotherapy was recommended and co
Page 104 and 105: aims are twofold: 1) to verify the
Page 106 and 107: Results. Her2/neu status in TMAs an
Page 108 and 109: prognostic impact was found in rect
Page 112 and 113: Methods. Biopsy specimens from 430
Page 114 and 115: the OS rate was 53% for patients wi
Page 116 and 117: FR-P-098 Immunohistological stainin
Page 118 and 119: FR-P-104 Histopathological evaluati
Page 120 and 121: within the earliest morphologic det
Page 122 and 123: Conclusions. In primary imaging a g
Page 124 and 125: fibrotic neointma development as we
Page 126 and 127: FR-P-129 Alpha-1-antitrypsin-PiZ-an
Page 128 and 129: FR-P-136 The expression of central
Page 130 and 131: cosa and in the periarterial tissue
Page 132 and 133: FR-P-149 Combination of Castleman d
Page 134 and 135: or without different concentrations
Page 136 and 137: Results. In 18 cases (79%) the caus
Page 138 and 139: FR-P-168 Autopsy findings in a 2-ye
Page 140 and 141: FR-P-174 MPGN-like glomerulonephrit
Page 142 and 143: Poster: Gynäkopathologie und Mamma
Page 144 and 145: SA-P-011 Genetic aberrations of pre
Page 146 and 147: Mechanismen, die eine Progression d
Page 148 and 149: internet server. A network of inter
Page 150 and 151: Methods. HE-gefärbte Schnittpräpa
Page 152 and 153: Conclusions. The newly released 450
Page 154 and 155: and desmoplastic reaction are diffe
Page 156 and 157: one patient revealed more than 9 mi
Page 158 and 159: situation, the V600E mutation in th
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SA-P-064 Evolution of molecular pat
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nic markers such as myf4 and MyoD1
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Conclusions. To our knowledge, this
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SA-P-085 Expression of the eukaryot
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Results. The papillary RCC type II
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SA-P-098 Male infertility: assessme
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SA-P-104 Process oriented scientifi
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Conclusions. The IBDW offers a uniq
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L Lasitschka F. DO-046 Lehmann A. F
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96. Jahrestagung der Deutschen Gesellschaft für Pathologie e. V ...

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