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Pancreatic Neoplasms: HELP
Articles by Peter Schirmacher
Based on 19 articles published since 2010
(Why 19 articles?)
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Between 2010 and 2020, P. Schirmacher wrote the following 19 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review [Frozen section diagnostics in visceral surgery. Liver, bile ducts and pancreas]. 2012

Mogler, C / Flechtenmacher, C / Schirmacher, P / Bergmann, F. ·Pathologisches Institut, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 220/21, 69120, Heidelberg, Deutschland. ·Pathologe · Pubmed #22892660.

ABSTRACT: Intraoperative examination of specimens from the liver, bile ducts, gallbladder and pancreas are widely used in routine fresh frozen section diagnostics. The main clinical requests focus on diagnosis of masses of unknown dignity as well as evaluation of surgical margins in oncological resections. In addition, assessment of organ quality for transplantation is also often required.

2 Clinical Trial Polymorphonuclear neutrophils promote dyshesion of tumor cells and elastase-mediated degradation of E-cadherin in pancreatic tumors. 2012

Gaida, Matthias M / Steffen, Thomas Große / Günther, Frank / Tschaharganeh, Darjus F / Felix, Klaus / Bergmann, Frank / Schirmacher, Peter / Hänsch, Gertrud M. ·Institute of Pathology, University of Heidelberg, Heidelberg, Germany. ·Eur J Immunol · Pubmed #23001948.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) presenting with a micropapillary growth pattern is frequently associated with a prominent neutrophil infiltration into the tumor. The relevance of neutrophil infiltrates for tumor progression, however, is still debated. To gain insight into the role of polymorphonuclear neutrophils (PMNs) in PDAC, we assessed their effect on pancreatic tumor cells grown in vitro as monolayers. Time-lapse video microscopy showed a PMN-induced dyshesion of the tumor cells, and subsequent experiments revealed that this dyshesion was due to PMN elastase-mediated degradation of E-cadherin, an adhesion molecule that mediates the intercellular contact of the tumor cells. E-cadherin degradation by elastase or--(for comparison) down-modulation by specific siRNA, significantly increased the migratory capacity of the pancreatic tumor cells, leading to the hypothesis that PMNs could contribute to the invasive tumor growth. To address this issue, biopsies of patients with PDAC (n = 112) were analyzed. We found that E-cadherin expression correlated negatively with PMN infiltration, compatible with the notion that E-cadherin is cleaved by PMN-derived elastase, which in turn could result in the dispersal of the tumor cells, enhanced migratory capacity and thus invasive tumor growth.

3 Article Next generation sequencing of the cellular and liquid fraction of pancreatic cyst fluid supports discrimination of IPMN from pseudocysts and reveals cases with multiple mutated driver clones: First findings from the prospective ZYSTEUS biomarker study. 2019

Volckmar, Anna-Lena / Endris, Volker / Gaida, Matthias M / Leichsenring, Jonas / Stögbauer, Fabian / Allgäuer, Michael / von Winterfeld, Moritz / Penzel, Roland / Kirchner, Martina / Brandt, Regine / Neumann, Olaf / Sültmann, Holger / Schirmacher, Peter / Rudi, Jochen / Schmitz, Daniel / Stenzinger, Albrecht. ·Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany. · Division of Cancer Genome Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany. · Department of Gastroenterology, Oncology and Diabetology, Theresienkrankenhaus und St. Hedwigsklinik, Academic Teaching Hospital, Mannheim, Germany. · German Cancer Consortium (DKTK), Partner Site Heidelberg, and German Cancer Research Center (DKFZ), Heidelberg, Germany. ·Genes Chromosomes Cancer · Pubmed #30230086.

ABSTRACT: Approximately half of all pancreatic cysts are neoplastic, mainly comprising intraductal papillary mucinous neoplasms (IPMN), which can progress to invasive carcinoma. Current Fukuoka guidelines have limited sensitivity and specificity in predicting progression of asymptomatic pancreatic cysts. We present first results of the prospective ZYSTEUS biomarker study investigating (i) whether detection of driver mutations in IPMN by liquid biopsy is technically feasible, (ii) which compartment of IPMN is most suitable for analysis, and (iii) implications for clinical diagnostics. Twenty-two patients with clinical inclusion criteria were enrolled in ZYSTEUS. Fifteen cases underwent endoscopic ultrasound (EUS)-guided fine-needle aspiration and cytological diagnostics. Cellular and liquid fraction of the cysts of each case were separated and subjected to deep targeted next generation sequencing (NGS). Clinical parameters, imaging findings (EUS and MRI), and follow-up data were collected continuously. All IPMN cases (n = 12) showed at least one mutation in either KRAS (n = 11) or GNAS (n = 4). Three cases showed both KRAS and GNAS mutations. Six cases harbored multiple KRAS/GNAS mutations. In the three cases with pseudocysts, no KRAS or GNAS mutations were detected. DNA yields were higher and showed higher mutation diversity in the cellular fraction. In conclusion, mutation detection in pancreatic cyst fluid is technically feasible with more robust results in the cellular than in the liquid fraction. Current results suggest that, together with imaging, targeted sequencing supports discrimination of IPMN from pseudocysts. The prospective design of ZYSTEUS will provide insight into diagnostic value of NGS in preoperative risk stratification. Our data provide evidence for an oligoclonal nature of IPMN.

4 Article Overcoming chemoresistance in pancreatic cancer cells: role of the bitter taste receptor T2R10. 2018

Stern, Louisa / Giese, Nathalia / Hackert, Thilo / Strobel, Oliver / Schirmacher, Peter / Felix, Klaus / Gaida, Matthias M. ·Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany. · Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany. ·J Cancer · Pubmed #29556329.

ABSTRACT: Bitter taste receptors (T2Rs) are G-protein coupled transmembrane proteins initially identified in the gustatory system as sensors for the taste of bitter. Recent evidence on expression of these receptors outside gustatory tissues suggested alternative functions, and there is growing interest of their potential role in cancer biology. In this study, we report for the first time, expression and functionality of the bitter receptor family member T2R10 in both human pancreatic ductal adenocarcinoma (PDAC) tissue and PDAC derived cell lines. Caffeine, a known ligand for T2R10, rendered the tumor cells more susceptible to two standard chemotherapeutics, Gemcitabine and 5-Fluoruracil. Knocking down T2R10 in the cell line BxPC-3 reduced the caffeine-induced effect. As possible underlying mechanism, we found that caffeine via triggering T2R10 inhibited Akt phosphorylation and subsequently downregulated expression of ABCG2, the so-called multi-drug resistance protein that participates in rendering cells resistant to a variety of chemotherapeutics. In conclusion, T2R10 is expressed in pancreatic cancer and it downmodulates the chemoresistance of the tumor cells.

5 Article Changes in the microarchitecture of the pancreatic cancer stroma are linked to neutrophil-dependent reprogramming of stellate cells and reflected by diffusion-weighted magnetic resonance imaging. 2018

Mayer, Philipp / Dinkic, Christine / Jesenofsky, Ralf / Klauss, Miriam / Schirmacher, Peter / Dapunt, Ulrike / Hackert, Thilo / Uhle, Florian / Hänsch, G Maria / Gaida, Matthias M. ·Clinic for Diagnostic and Interventional Radiology, University Hospital Heidelberg, Heidelberg, Germany. · Clinic for Gynecology and Obstetrics, University Hospital Heidelberg, Heidelberg, Germany. · Clinic for Internal Medicine II, University Hospital Mannheim, Medical Faculty Heidelberg, Mannheim, Germany. · Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany. · Clinic for Orthopedics and Trauma Surgery, University Hospital Heidelberg, Heidelberg, Germany. · Department of General, Visceral, and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany. · Clinic for Anesthesiology, University Hospital Heidelberg, Heidelberg, Germany. · Institute of Immunology, University Heidelberg, Heidelberg, Germany. ·Theranostics · Pubmed #29290790.

ABSTRACT: In pancreatic cancer (PDAC) intratumor infiltration of polymorphonuclear neutrophils (PMN) is associated with histologically apparent alterations of the tumor growth pattern. The aim of this study was to examine possible associations between PMN infiltration, tumor microarchitecture, and water diffusivity in diffusion-weighted magnetic resonance imaging (DW-MRI), and to further asses the underlying mechanisms.

6 Article Genome-wide genetic and epigenetic analyses of pancreatic acinar cell carcinomas reveal aberrations in genome stability. 2017

Jäkel, Cornelia / Bergmann, Frank / Toth, Reka / Assenov, Yassen / van der Duin, Daniel / Strobel, Oliver / Hank, Thomas / Klöppel, Günter / Dorrell, Craig / Grompe, Markus / Moss, Joshua / Dor, Yuval / Schirmacher, Peter / Plass, Christoph / Popanda, Odilia / Schmezer, Peter. ·Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. · Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany. · Department of General and Visceral Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany. · Institute of Pathology, Technical University Munich, Trogerstr. 18, 81675, Munich, Germany. · Department of Pediatrics, Papé Family Pediatric Research Institute, Oregon Stem Cell Center, Oregon Health and Science University, Portland, OR, 97239, USA. · Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, 9112102, Jerusalem, Israel. · Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. p.schmezer@dkfz.de. ·Nat Commun · Pubmed #29109526.

ABSTRACT: Pancreatic acinar cell carcinoma (ACC) is an aggressive exocrine tumor with largely unknown biology. Here, to identify potential targets for personalized treatment, we perform integrative genome-wide and epigenome-wide analyses. The results show frequently aberrant DNA methylation, abundant chromosomal amplifications and deletions, and mutational signatures suggesting defective DNA repair. In contrast to pancreatic ductal adenocarcinoma, no recurrent point mutations are detected. The tumor suppressors ID3, ARID1A, APC, and CDKN2A are frequently impaired also on the protein level and thus potentially affect ACC tumorigenesis. Consequently, this work identifies promising therapeutic targets in ACC for drugs recently approved for precision cancer therapy.

7 Article Pancreatic Cancer Surgery: The New R-status Counts. 2017

Strobel, Oliver / Hank, Thomas / Hinz, Ulf / Bergmann, Frank / Schneider, Lutz / Springfeld, Christoph / Jäger, Dirk / Schirmacher, Peter / Hackert, Thilo / Büchler, Markus W. ·*Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany †Institute of Pathology Heidelberg, Heidelberg, Germany ‡National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany. ·Ann Surg · Pubmed #27918310.

ABSTRACT: OBJECTIVE: To assess the relevance of resection margin status for survival outcome after resection and adjuvant therapy for pancreatic cancer. BACKGROUND: The definitions for R0 and R1 margin status after resection for pancreatic cancer are controversial. The strict definition of R0 requiring a 1 mm tumor-free margin is not commonly accepted. Reported R0/R1 rates and associated survival are highly heterogeneous. METHODS: A standardized protocol with rigorous assessment of circumferential margins and the R0 definition with a 1 mm free margin were introduced into clinical routine in 2005. From a prospective database, patients undergoing pancreatoduodenectomy for pancreatic adenocarcinoma between January 1, 2006 and December 12, 2012 were identified. The rates of R0 (≥1 mm margin), R1 (<1 mm clearance), and R1 (direct margin involvement) status and associated survival were assessed by uni- and multivariable analyses. RESULTS: Of 561 patients included, 112 patients (20.0%) had R0 and 449 patients (80.0%) had R1 resections, including 123 (21.9%) R1 (≤1 mm) and 326 (58.1%) R1 (direct) resections. A total of 438 (85.9%) received adjuvant therapy. With R0, R1 (<1 mm), and R1 (direct) status the median survival times and 5-year survival rates were 41.6, 27.5, and 23.4 months; and 37.7%, 30.1%, and 20.3%, respectively (P < 0.0001). By multivariable analysis, margin status was confirmed to be independently associated with survival. CONCLUSIONS: In the context of adjuvant therapy, the resection margin status remains an important independent determinant of postresection survival. R0/R1 resection rates and associated survival vary significantly with the definitions used. An international consensus is urgently needed to achieve comparability with respect to studies and protocols on patients with adjuvant therapy.

8 Article Expression of the bitter receptor T2R38 in pancreatic cancer: localization in lipid droplets and activation by a bacteria-derived quorum-sensing molecule. 2016

Gaida, Matthias M / Mayer, Christine / Dapunt, Ulrike / Stegmaier, Sabine / Schirmacher, Peter / Wabnitz, Guido H / Hänsch, G Maria. ·Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany. · Department for Gynecology and Obstetrics, University Hospital Heidelberg, Heidelberg, Germany. · Department for Orthopedics, University Hospital Heidelberg, Heidelberg, Germany. · Institute of Immunology, University Heidelberg, Heidelberg, Germany. ·Oncotarget · Pubmed #26862855.

ABSTRACT: T2R38 belongs to the family of bitter receptors and was initially detected in cells of the oral cavity. We now describe expression of T2R38 in tumor cells in patients with pancreatic cancer and in tumor-derived cell lines. T2R38 is localized predominantly intracellular in association with lipid droplets, particularly with the lipid droplet membrane. The receptor can be activated by the bona fide ligand for T2R38, phenylthiourea (PTU), and by N-acetyl-dodecanoyl homoserine (AHL-12), a quorum sensing molecule of Pseudomonas aeruginosa, the latter is the only known natural ligand for T2R38. In response to PTU or AHL-12, key transcription factors are activated including phosphorylation of the MAP kinases p38 and ERK1/2, and upregulation of NFATc1. Moreover, we found increased expression of the multi-drug resistance protein 1 (also known as ABCB1), a transmembrane transporter molecule, participating in shuttling of a plethora of drugs, such as chemotherapeutics or antibiotics. In conclusion, our data indicate a new, additional function of the taste receptor T2R38 beyond sensing "bitter". Moreover, because T2R38 can be stimulated by a bacteria-derived signaling molecule the receptor could link microbiota and cancer.

9 Article Acinar cell carcinomas of the pancreas: a molecular analysis in a series of 57 cases. 2014

Bergmann, Frank / Aulmann, Sebastian / Sipos, Bence / Kloor, Matthias / von Heydebreck, Anja / Schweipert, Johannes / Harjung, Andreas / Mayer, Philipp / Hartwig, Werner / Moldenhauer, Gerhard / Capper, David / Dyckhoff, Gerhard / Freier, Kolja / Herpel, Esther / Schleider, Anja / Schirmacher, Peter / Mechtersheimer, Gunhild / Klöppel, Günter / Bläker, Hendrik. ·Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 224, D-69120, Heidelberg, Germany, frank.bergmann@med.uni-heidelberg.de. ·Virchows Arch · Pubmed #25298229.

ABSTRACT: Pancreatic acinar cell carcinomas (PACs) are rare but are distinct aggressive neoplasms that phenotypically differ from pancreatic ductal adenocarcinomas (PDACs) and pancreatic neuroendocrine neoplasms (PNENs). Despite recent work on the genetic changes of PACs, their molecular pathogenesis is still poorly understood. In this study, we focus on a comparative genomic hybridization analysis. Based on frequent chromosomal imbalances, the involvement of DCC and c-MYC in the pathogenesis of PACs is further investigated. Moreover, we examine markers harboring potential therapeutic relevance (K-RAS, BRAF, EGFR, MGMT, HSP90, L1CAM, Her2). PACs revealed a microsatellite stable, chromosomal unstable genotype, defined by recurrent chromosomal losses of 1p, 3p, 4q, 5q, 6q, 8p, 9p, 11q, 13q, 16q, and 18, as well as gains of 1q, 7, 8q, 12, 17q, and 20q. Subsets of PAC displayed reduction/loss of DCC (79 %) and c-MYC-amplification (17 %). Significant EGFR expression occurred in 42 %, HSP90 expression in 98 %, L1CAM expression in 72 %, and loss of MGMT in 26 %. Two cases carried a K-RAS mutation. Mutations of EGFR or BRAF were not detected. All cases were Her2/neu-negative. PACs display characteristic chromosomal imbalances which are distinctly different from those in pancreatic ductal adenocarcinomas and pancreatic neuroendocrine neoplasms. Our findings suggest that DCC and c-MYC alterations may play an important role in the pathogenesis of PACs. Furthermore, EGFR, MGMT, HSP90, and L1CAM may be useful as therapeutic markers and predictors of response to therapy in a subset of PACs.

10 Article Early epigenetic downregulation of WNK2 kinase during pancreatic ductal adenocarcinoma development. 2014

Dutruel, C / Bergmann, F / Rooman, I / Zucknick, M / Weichenhan, D / Geiselhart, L / Kaffenberger, T / Rachakonda, P S / Bauer, A / Giese, N / Hong, C / Xie, H / Costello, J F / Hoheisel, J / Kumar, R / Rehli, M / Schirmacher, P / Werner, J / Plass, C / Popanda, O / Schmezer, P. ·Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany. · Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Australia. · Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Functional Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany. · Brain Tumor Research Center, Department of Neurosurgery, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA. · Department of Hematology and Oncology, University Hospital Regensburg, Regensburg, Germany. ·Oncogene · Pubmed #23912455.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is usually incurable. Contrary to genetic mechanisms involved in PDAC pathogenesis, epigenetic alterations are ill defined. Here, we determine the contribution of epigenetically silenced genes to the development of PDAC. We analyzed enriched, highly methylated DNAs from PDACs, chronic pancreatitis (CP) and normal tissues using CpG island microarrays and identified WNK2 as a prominent candidate tumor suppressor gene being downregulated early in PDAC development. WNK2 was further investigated in tissue microarrays, methylation analysis of early pancreatic intraepithelial neoplasia (PanIN), mouse models for PDAC and pancreatitis, re-expression studies after demethylation, and cell growth assays using WNK2 overexpression. Demethylation assays confirmed the link between methylation and expression. WNK2 hypermethylation was higher in tumor than in surrounding inflamed tissues and was observed in PanIN lesions as well as in a PDAC mouse model. WNK2 mRNA and protein expressions were lower in PDAC and CP compared with normal tissues both in patients and mouse models. Overexpression of WNK2 led to reduced cell growth, and WNK2 expression in tissues correlated negatively with pERK1/2 expression, a downstream target of WNK2 responsible for cell proliferation. Downregulation of WNK2 by promoter hypermethylation occurs early in PDAC pathogenesis and may support tumor cell growth via the ERK-MAPK pathway.

11 Article Intensity modulated radiotherapy as neoadjuvant chemoradiation for the treatment of patients with locally advanced pancreatic cancer. Outcome analysis and comparison with a 3D-treated patient cohort. 2013

Combs, S E / Habermehl, D / Kessel, K / Bergmann, F / Werner, J / Brecht, I / Schirmacher, P / Jäger, D / Büchler, M W / Debus, J. ·Department of Radiation Oncology, University Hospital of Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany. Stephanie.Combs@med.uni-heidelberg.de ·Strahlenther Onkol · Pubmed #23896630.

ABSTRACT: BACKGROUND: To evaluate outcome after intensity modulated radiotherapy (IMRT) compared to 3D conformal radiotherapy (3D-RT) as neoadjuvant treatment in patients with locally advanced pancreatic cancer (LAPC). MATERIALS AND METHODS: In total, 57 patients with LAPC were treated with IMRT and chemotherapy. A median total dose of 45 Gy to the PTV_baseplan and 54 Gy to the PTV_boost in single doses of 1.8 Gy for the PTV_baseplan and median single doses of 2.2 Gy in the PTV_boost were applied. Outcomes were evaluated and compared to a large cohort of patients treated with 3D-RT. RESULTS: Overall treatment was well tolerated in all patients and IMRT could be completed without interruptions. Median overall survival was 11 months (range 5-37.5 months). Actuarial overall survival at 12 and 24 months was 36 % and 8 %, respectively. A significant impact on overall survival could only be observed for a decrease in CA 19-9 during treatment, patients with less pre-treatment CA 19-9 than the median, as well as weight loss during treatment. Local progression-free survival was 79 % after 6 months, 39 % after 12 months, and 13 % after 24 months. No factors significantly influencing local progression-free survival could be identified. There was no difference in overall and progression-free survival between 3D-RT and IMRT. Secondary resectability was similar in both groups (26 % vs. 28 %). Toxicity was comparable and consisted mainly of hematological toxicity due to chemotherapy. CONCLUSION: IMRT leads to a comparable outcome compared to 3D-RT in patients with LAPC. In the future, the improved dose distribution, as well as advances in image-guided radiotherapy (IGRT) techniques, may improve the use of IMRT in local dose escalation strategies to potentially improve outcome.

12 Article Chemoradiation in patients with isolated recurrent pancreatic cancer - therapeutical efficacy and probability of re-resection. 2013

Habermehl, Daniel / Brecht, Ingo C / Bergmann, Frank / Welzel, Thomas / Rieken, Stefan / Werner, Jens / Schirmacher, Peter / Büchler, Markus W / Debus, Jürgen / Combs, Stephanie E. ·Department of Radiation Oncology, University Hospital of Heidelberg, Im Neuenheimer Feld 400, Heidelberg, 69120, Germany. daniel.habermehl@med.uni-heidelberg.de ·Radiat Oncol · Pubmed #23369246.

ABSTRACT: BACKGROUND: In the present retrospective analysis we analysed the therapeutic outcome of a set of patients, who were treated with chemoradiation (CRT) for recurrent pancreatic cancer (RPC) in a single institution. PATIENTS AND METHODS: Forty-one patients had a history of primary resection for pancreatic cancer. In case of an unresectable recurrency patients were treated with CRT at our institution between 2002 and 2010 with a median dose of 48.4 Gy (range 39.6-54 Gy). Concurrent chemotherapy regimes included Gemcitabine (GEM) in 37/41 patients (90%) and Fluorouracil (FU) or Capecitabine (CAP) in 4/41 patients (10%). Patients were re-evaluated after CRT with computed tomography and/or explorative laparotomy. During re-resection or laparotomy 15 patients received an additional intraoperative radiotherapy (IORT) with a median dose of 15 Gy (range 12-15 Gy). Median age was 65 years (range 39-76 years) and there were 26 male and 15 female patients. RESULTS: The median overall survival (mOS), local control (LC) and progression-free survival (PFS) were 16.1, 13.8 and 6.9 months respectively for all patients after the first day of CRT. Re-resection was possible in five patients (12%) and a complete remission (CR) as defined by tumor-free biopsy was seen in 6 patients (15%). When re-resection could be achieved after CRT mOS was improved to 28.3 months (n = 5 patients, 95%-CI 10.2 - 46.3 months). Patients receiving IORT had a significantly improved mOS compared to no IORT (p = 0.034). Fifteen patients (37%) experienced a local tumour progression and main site of distant metastasis was the liver (11 patients, 27%).Overall treatment-related toxicity was mild, grade III hematologic toxicity was observed in 11 patients (27%). CONCLUSION: In summary we observed a good therapeutic response with mild to moderate toxicity levels for CRT in RPC. Overall survival and PFS were clearly improved in case of induction of a complete remission (tumor-free biopsies) or after achieving a re-resection, thus providing a curative intended therapy even in case of disease recurrence.

13 Article Epithelial-to-mesenchymal transition in pancreatic ductal adenocarcinoma and pancreatic tumor cell lines: the role of neutrophils and neutrophil-derived elastase. 2012

Grosse-Steffen, Thomas / Giese, Thomas / Giese, Nathalia / Longerich, Thomas / Schirmacher, Peter / Hänsch, G Maria / Gaida, Matthias M. ·Institut für Immunologie, Universität Heidelberg, Germany. t.grosse-steffen@web.de ·Clin Dev Immunol · Pubmed #23227088.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is frequently associated with fibrosis and a prominent inflammatory infiltrate in the desmoplastic stroma. Moreover, in PDAC, an epithelial-to-mesenchymal transition (EMT) is observed. To explore a possible connection between the infiltrating cells, particularly the polymorphonuclear neutrophils (PMN) and the tumor cell transition, biopsies of patients with PDAC (n = 115) were analysed with regard to PMN infiltration and nuclear expression of β-catenin and of ZEB1, well-established indicators of EMT. In biopsies with a dense PMN infiltrate, a nuclear accumulation of β-catenin and of ZEB1 was observed. To address the question whether PMN could induce EMT, they were isolated from healthy donors and were cocultivated with pancreatic tumor cells grown as monolayers. Rapid dyshesion of the tumor cells was seen, most likely due to an elastase-mediated degradation of E-cadherin. In parallel, the transcription factor TWIST was upregulated, β-catenin translocated into the nucleus, ZEB1 appeared in the nucleus, and keratins were downregulated. EMT was also induced when the tumor cells were grown under conditions preventing attachment to the culture plates. Here, also in the absence of elastase, E-cadherin was downmodulated. PMN as well as prevention of adhesion induced EMT also in liver cancer cell line. In conclusion, PMN via elastase induce EMT in vitro, most likely due to the loss of cell-to-cell contact. Because in pancreatic cancers the transition to a mesenchymal phenotype coincides with the PMN infiltrate, a contribution of the inflammatory response to the induction of EMT and-by implication-to tumor progression is possible.

14 Article Neoadjuvant chemoradiation with Gemcitabine for locally advanced pancreatic cancer. 2012

Habermehl, Daniel / Kessel, Kerstin / Welzel, Thomas / Hof, Holger / Abdollahi, Amir / Bergmann, Frank / Rieken, Stefan / Weitz, Jürgen / Werner, Jens / Schirmacher, Peter / Büchler, Markus W / Debus, Jürgen / Combs, Stephanie E. ·Department of Radiation Oncology, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany. daniel.habermehl@med.uni-heidelberg.de ·Radiat Oncol · Pubmed #22385572.

ABSTRACT: INTRODUCTION: To evaluate efficacy and secondary resectability in patients with locally advanced pancreatic cancer (LAPC) treated with neoadjuvant chemoradiotherapy (CRT). PATIENTS AND METHODS: A total of 215 patients with locally advanced pancreatic cancer were treated with chemoradiation at a single institution. Radiotherapy was delivered with a median dose of 52.2 Gy in single fractions of 1.8 Gy. Chemotherapy was applied concomitantly as gemcitabine (GEM) at a dose of 300 mg/m2 weekly, followed by adjuvant cycles of full-dose GEM (1000 mg/m2). After neoadjuvant CRT restaging was done to evaluate secondary resectability. Overall and disease-free survival were calculated and prognostic factors were estimated. RESULTS: After CRT a total of 26% of all patients with primary unresectable LAPC were chosen to undergo secondary resection. Tumour free resection margins could be achieved in 39.2% (R0-resection), R1-resections were seen in 41.2%, residual macroscopic tumour in 11.8% (R2) and in 7.8% resection were classified as Rx. Patients with complete resection after CRT showed a significantly increased median overall survival (OS) with 22.1 compared to 11.9 months in non-resected patients. Median OS and disease-free survival (DFS) of all patients were 12.3 and 8.1 months respectively. In most cases the first site of disease progression was systemic with hepatic (52%) and peritoneal (36%) metastases. DISCUSSION: A high percentage of patients with locally advanced pancreatic cancer can undergo secondary resection after gemcitabine-based chemoradiation and has a relative long-term prognosis after complete resection.

15 Article Expression and therapeutic relevance of heat-shock protein 90 in pancreatic endocrine tumors. 2012

Mayer, Philipp / Harjung, Andreas / Breinig, Marco / Fischer, Lars / Ehemann, Volker / Malz, Mona / Scherübl, Hans / Britsch, Sarah / Werner, Jens / Kern, Michael A / Bläker, Hendrik / Schirmacher, Peter / Bergmann, Frank. ·Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 220, D-69120 Heidelberg, Germany. ·Endocr Relat Cancer · Pubmed #22194440.

ABSTRACT: Pancreatic endocrine tumors (PET) represent a heterogenous group of neoplasms. Although surgical resection is considered a safe and effective treatment for many PET, therapeutic options for inoperable and progressive PET are limited. The expression of heat-shock protein (HSP) 90 was investigated in 120 clinically and pathomorphologically well-characterized PET from 84 patients using immunohistochemistry. In addition, in 19 snap-frozen PET and in three healthy pancreatic tissues, we performed immunoblot analyses, and in 15 snap-frozen PET and in three healthy pancreatic tissues, we investigated the expression of HSP90 isoforms by means of semiquantitative RT-PCR. Functional tests were conducted using the human pancreas carcinoid cell line BON and the mouse insulinoma cell line β-TC-3. HSP90 was expressed in 95% of the PET patients. The transcript levels of the HSP90 isoforms HSP90α, HSP90β, glucose-related protein 94, and TNF receptor-associated protein 1 were significantly increased in PET compared with non-neoplastic pancreatic tissues. The treatment of the cell lines BON and β-TC-3 with the HSP90 inhibitors 17-allylamino-17-demethoxygeldanamycin and 17-dimethylaminoethylamino-17-demethoxy-geldanamycin resulted in significant, dose-dependent reduction of cell viability, cell cycle arrest, and increased apoptosis. Furthermore, HSP90 inhibition induced the degradation and inactivation of several oncogenetic HSP90 client proteins in a time- and dose-dependent manner. HSP90 inhibitors increased the therapeutic effects of doxorubicin and 5-fluorucacil in BON and β-TC-3 cells. HSP90 is expressed in the vast majority of PET and its inhibition reveals significant treatment effects in vitro. Thus, HSP90 qualifies as a promising new target.

16 Article MHC class II expression in pancreatic tumors: a link to intratumoral inflammation. 2012

Gaida, Matthias M / Welsch, Thilo / Herpel, Esther / Tschaharganeh, Darjus F / Fischer, Lars / Schirmacher, Peter / Hänsch, G Maria / Bergmann, Frank. ·Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 220, Heidelberg, Germany. ·Virchows Arch · Pubmed #22120497.

ABSTRACT: Major histocompatibility complex class II antigens (MHC class II) are constitutively expressed by professional antigen presenting cells and present antigenic peptides to specific CD4+ T lymphocytes. MHC class II expression, however, can also be induced on epithelial cells and in a variety of solid tumors. We tested MHC class II expression on tissue samples derived from patients with pancreatic ductal adenocarcinoma (PDAC) and pancreatic endocrine tumors (PET). Immunohistochemistry revealed MHC class II expression in 86 of 112 (76.8%) PDAC samples and in 30 of 43 (70.0%) PET samples. In PDAC and PET, MHC class II expression correlated significantly with severity and activity of intratumoral inflammation, as well as with the infiltration of CD4+ T lymphocytes. High MHC class II expression significantly correlated with a better histological grade of differentiation in PDAC. In vitro MHC class II expression could be induced on PDAC tumor cell lines by interferon-γ. These cells were then able to present the staphylococci enterotoxin B superantigen to T lymphocytes, which resulted in T cell proliferation. Our findings suggest that MHC class II expression on pancreatic tumor cells is induced by the intratumoral inflammatory reaction in pancreatic tumors.

17 Article Discovered on gastrointestinal stromal tumor 1 (DOG1) is expressed in pancreatic centroacinar cells and in solid-pseudopapillary neoplasms--novel evidence for a histogenetic relationship. 2011

Bergmann, Frank / Andrulis, Mindaugas / Hartwig, Werner / Penzel, Roland / Gaida, Matthias M / Herpel, Esther / Schirmacher, Peter / Mechtersheimer, Gunhild. ·Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 220, D-69120 Heidelberg, Germany. frank.bergmann@med.uni-heidelberg.de ·Hum Pathol · Pubmed #21295818.

ABSTRACT: Solid-pseudopapillary neoplasms of the pancreas are tumors of low malignant potential whose histogenesis has been discussed controversially. In the series of 15 solid-pseudopapillary neoplasms presented here, we demonstrate that discovered on gastrointestinal stromal tumor 1 is expressed significantly by these tumors (diffuse expression in 8 cases, focal expression in 4 cases, and scarce expression in 3 cases). Similar to the high expression of CD117, this finding parallels the immunohistochemical findings in gastrointestinal stromal tumors. Using double immunohistochemistry and immunofluorescence, we furthermore show that centroacinar cells express discovered on gastrointestinal stromal tumors 1. Thus, our findings suggest that, similarly to CD10 or vimentin, the expression of discovered on gastrointestinal stromal tumors 1 may serve as a novel marker for centroacinar cells and for solid-pseudopapillary neoplasms, which is suggestive of a centroacinar origin of these neoplasms.

18 Article Expression of A disintegrin and metalloprotease 10 in pancreatic carcinoma. 2010

Gaida, Matthias M / Haag, Natascha / Günther, Frank / Tschaharganeh, Darjus F / Schirmacher, Peter / Friess, Helmut / Giese, Nathalia A / Schmidt, Jan / Wente, Moritz N. ·Institute of Pathology, University of Heidelberg, Heidelberg, Germany. ·Int J Mol Med · Pubmed #20596609.

ABSTRACT: The protease ADAM10 influences progression and metastasis of cancer cells and is overexpressed in various malignancies. Therefore, the aim of our study was to evaluate the expression and potential function of ADAM10 in the pathophysiology of pancreatic cancer (PDAC). ADAM10 expression in normal pancreatic (NP), chronic pancreatitis (CP), PDAC tissues, as well as PDAC cell lines was determined. To evaluate whether rhADAM10 or ADAM10 silencing influences cancer cell viability, MTT assay was used. Matrigel invasion and wound healing assays were performed to observe influence on invasion and migration. ADAM10 mRNA was expressed in all samples of NP, CP and PDAC tissue and cell lines. Western blotting and immunohistochemistry revealed stronger ADAM10 expression in PDAC than in NP. ADAM10 silencing or rhADAM10 had no effect on cell viability. ADAM10 silencing markedly reduced invasiveness and migration of cancer cells. These findings establish ADAM10 as a contributing factor in PDAC invasion and metastasis.

19 Article Expression of L1CAM, COX-2, EGFR, c-KIT and Her2/neu in anaplastic pancreatic cancer: putative therapeutic targets? 2010

Bergmann, Frank / Moldenhauer, Gerhard / Herpel, Esther / Gaida, Matthias M / Strobel, Oliver / Werner, Jens / Esposito, Irene / Müerköster, Susanne Sebens / Schirmacher, Peter / Kern, Michael A. ·Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 220, D-69120 Heidelberg, Germany. frank.bergmann@med.uni-heidelberg.de ·Histopathology · Pubmed #20459551.

ABSTRACT: AIMS: Undifferentiated (anaplastic) pancreatic cancer and undifferentiated pancreatic carcinoma with osteoclast-like giant cells (giant cell tumour) are rare variants of pancreatic ductal adenocarcinoma. Representing biologically highly aggressive neoplasms, they are frequently diagnosed at an advanced stage. The response to established chemo- or radiochemotherapeutic treatment regimens is poor, and undifferentiated pancreatic cancer generally has a dismal prognosis. As additional therapeutic options have not yet been investigated in undifferentiated pancreatic cancer, the aim was to analyse the expression of putative therapeutic targets that have shown promising results in various other neoplasms. METHODS AND RESULTS: Fifteen cases of undifferentiated pancreatic cancer (seven containing osteoclast-like giant cells) were investigated clinicopathologically and immunohistochemically for putative therapeutic targets. Whereas L1CAM, cyclooxygenase (COX)-2 and epidermal growth factor receptor (EGFR) were found to be significantly expressed in 80%, 93% and 87% of the investigated tumours, respectively, there was no substantial expression of c-kit (CD117) and there was no detectable expression of Her2/neu. CONCLUSIONS: The expression of L1CAM, COX-2 and EGFR in the majority of undifferentiated pancreatic carcinomas suggests that they might represent targets for adjuvant therapy in anaplastic pancreatic cancer. On the other hand, c-kit and Her2/neu seem to have no relevance for the therapy of these tumours.