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Pancreatic Neoplasms: HELP
Articles by Wilko Weichert
Based on 28 articles published since 2010
(Why 28 articles?)
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Between 2010 and 2020, Wilko Weichert wrote the following 28 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Article Image-Based Molecular Phenotyping of Pancreatic Ductal Adenocarcinoma. 2020

Kaissis, Georgios A / Ziegelmayer, Sebastian / Lohöfer, Fabian K / Harder, Felix N / Jungmann, Friederike / Sasse, Daniel / Muckenhuber, Alexander / Yen, Hsi-Yu / Steiger, Katja / Siveke, Jens / Friess, Helmut / Schmid, Roland / Weichert, Wilko / Makowski, Marcus R / Braren, Rickmer F. ·Technical University of Munich, School of Medicine, Department of Diagnostic and Interventional Radiology, 81675 Munich, Germany. · Imperial College of Science, Technology and Medicine, Faculty of Engineering, Department of Computing, SW7 2AZ London, UK. · Technical University of Munich, School of Medicine, Institute for Pathology, 81675 Munich, Germany. · Institute of Developmental Cancer Therapeutics, West German Cancer Center, University Hospital Essen, 45147 Essen, Germany. · Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, parter site Essen, Germany) and German Cancer Research Center, DKFZ, 69120 Heidelberg, Germany. · Technical University of Munich, School of Medicine, Surgical Clinic and Policlinic, 81675 Munich, Germany. · Technical University of Munich, School of Medicine, Department of Internal Medicine II, 81675 Munich, Germany. ·J Clin Med · Pubmed #32155990.

ABSTRACT: To bridge the translational gap between recent discoveries of distinct molecular phenotypes of pancreatic cancer and tangible improvements in patient outcome, there is an urgent need to develop strategies and tools informing and improving the clinical decision process. Radiomics and machine learning approaches can offer non-invasive whole tumor analytics for clinical imaging data-based classification. The retrospective study assessed baseline computed tomography (CT) from 207 patients with proven pancreatic ductal adenocarcinoma (PDAC). Following expert level manual annotation, Pyradiomics was used for the extraction of 1474 radiomic features. The molecular tumor subtype was defined by immunohistochemical staining for KRT81 and HNF1a as quasi-mesenchymal (QM) vs. non-quasi-mesenchymal (non-QM). A Random Forest machine learning algorithm was developed to predict the molecular subtype from the radiomic features. The algorithm was then applied to an independent cohort of histopathologically unclassifiable tumors with distinct clinical outcomes. The classification algorithm achieved a sensitivity, specificity and ROC-AUC (area under the receiver operating characteristic curve) of 0.84 ± 0.05, 0.92 ± 0.01 and 0.93 ± 0.01, respectively. The median overall survival for predicted QM and non-QM tumors was 16.1 and 20.9 months, respectively, log-rank-test

2 Article SUMO pathway inhibition targets an aggressive pancreatic cancer subtype. 2020

Biederstädt, Alexander / Hassan, Zonera / Schneeweis, Christian / Schick, Markus / Schneider, Lara / Muckenhuber, Alexander / Hong, Yingfen / Siegers, Gerrit / Nilsson, Lisa / Wirth, Matthias / Dantes, Zahra / Steiger, Katja / Schunck, Kathrin / Langston, Steve / Lenhof, H-P / Coluccio, Andrea / Orben, Felix / Slawska, Jolanta / Scherger, Anna / Saur, Dieter / Müller, Stefan / Rad, Roland / Weichert, Wilko / Nilsson, Jonas / Reichert, Maximilian / Schneider, Günter / Keller, Ulrich. ·Medical Clinic and Policlinic III, Klinikum rechts der Isar, Technical University Munich, München, Germany. · Medical Clinic and Polyclinic II, Klinikum rechts der Isar, Technical University Munich, München, Germany. · Department of Hematology, Oncology and Tumor Immunology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Berlin, Germany. · Center for Bioinformatics, Saarland Informatics Campus, Saarland University, Saarbrücken, Germany. · Saarbrücken Graduate School of Computer Science, Saarland Informatics Campus, Saarland University, Saarbrücken, Germany. · Institute of Pathology, Technical University Munich, München, Germany. · Department of Surgery, Sahlgrenska Cancer Center, Gothenburg University, Gothenburg, Sweden. · German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany. · Goethe University, Medical School, Institute of Biochemistry II, Frankfurt, Germany. · Oncology Drug Discovery Unit, Takeda Pharmaceuticals International Co, Cambridge, Massachusetts, USA. · Institute for Translational Cancer Research and Experimental Cancer Therapy, Technical University Munich, München, Germany. · Institute of Molecular Oncology and Functional Genomics, Technical University Munich, München, Germany. · Medical Clinic and Polyclinic II, Klinikum rechts der Isar, Technical University Munich, München, Germany guenter.schneider@tum.de ulrich.keller@charite.de. · Department of Hematology, Oncology and Tumor Immunology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Berlin, Germany guenter.schneider@tum.de ulrich.keller@charite.de. ·Gut · Pubmed #32001555.

ABSTRACT: OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) still carries a dismal prognosis with an overall 5-year survival rate of 9%. Conventional combination chemotherapies are a clear advance in the treatment of PDAC; however, subtypes of the disease exist, which exhibit extensive resistance to such therapies. Genomic MYC amplifications represent a distinct subset of PDAC with an aggressive tumour biology. It is clear that hyperactivation of MYC generates dependencies that can be exploited therapeutically. The aim of the study was to find and to target MYC-associated dependencies. DESIGN: We analysed human PDAC gene expression datasets. Results were corroborated by the analysis of the small ubiquitin-like modifier (SUMO) pathway in a large PDAC cohort using immunohistochemistry. A SUMO inhibitor was used and characterised using human and murine two-dimensional, organoid and in vivo models of PDAC. RESULTS: We observed that MYC is connected to the SUMOylation machinery in PDAC. Components of the SUMO pathway characterise a PDAC subtype with a dismal prognosis and we provide evidence that hyperactivation of MYC is connected to an increased sensitivity to pharmacological SUMO inhibition. CONCLUSION: SUMO inhibitor-based therapies should be further developed for an aggressive PDAC subtype.

3 Article A machine learning algorithm predicts molecular subtypes in pancreatic ductal adenocarcinoma with differential response to gemcitabine-based versus FOLFIRINOX chemotherapy. 2019

Kaissis, Georgios / Ziegelmayer, Sebastian / Lohöfer, Fabian / Steiger, Katja / Algül, Hana / Muckenhuber, Alexander / Yen, Hsi-Yu / Rummeny, Ernst / Friess, Helmut / Schmid, Roland / Weichert, Wilko / Siveke, Jens T / Braren, Rickmer. ·Department of Diagnostic and Interventional Radiology, School of Medicine, Technical University of Munich, Munich, Germany. · Department of Pathology, School of Medicine, Technical University of Munich, Munich, Germany. · Department of Internal Medicine II, School of Medicine, Technical University of Munich, Munich, Germany. · Department of Surgery, School of Medicine, Technical University of Munich, Munich, Germany. · Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany. · German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. ·PLoS One · Pubmed #31577805.

ABSTRACT: PURPOSE: Development of a supervised machine-learning model capable of predicting clinically relevant molecular subtypes of pancreatic ductal adenocarcinoma (PDAC) from diffusion-weighted-imaging-derived radiomic features. METHODS: The retrospective observational study assessed 55 surgical PDAC patients. Molecular subtypes were defined by immunohistochemical staining of KRT81. Tumors were manually segmented and 1606 radiomic features were extracted with PyRadiomics. A gradient-boosted-tree algorithm was trained on 70% of the patients (N = 28) and tested on 30% (N = 17) to predict KRT81+ vs. KRT81- tumor subtypes. A gradient-boosted survival regression model was fit to the disease-free and overall survival data. Chemotherapy response and survival were assessed stratified by subtype and radiomic signature. Radiomic feature importance was ranked. RESULTS: The mean±STDEV sensitivity, specificity and ROC-AUC were 0.90±0.07, 0.92±0.11, and 0.93±0.07, respectively. The mean±STDEV concordance indices between the disease-free and overall survival predicted by the model based on the radiomic parameters and actual patient survival were 0.76±0.05 and 0.71±0.06, respectively. Patients with a KRT81+ subtype experienced significantly diminished median overall survival compared to KRT81- patients (7.0 vs. 22.6 months, HR 4.03, log-rank-test P = <0.001) and a significantly improved response to gemcitabine-based chemotherapy over FOLFIRINOX (10.14 vs. 3.8 months median overall survival, HR 2.33, P = 0.037) compared to KRT81- patients, who responded significantly better to FOLFIRINOX over gemcitabine-based treatment (30.8 vs. 13.4 months median overall survival, HR 2.41, P = 0.027). Entropy was ranked as the most important radiomic feature. CONCLUSIONS: The machine-learning based analysis of radiomic features enables the prediction of subtypes of PDAC, which are highly relevant for disease-free and overall patient survival and response to chemotherapy.

4 Article Still a hopeless case for personalized oncology? Pancreatic cancer revisited. 2019

Weichert, Wilko / Sprick, Martin R / Siveke, Jens T. ·Member of the German Cancer Consortium (DKTK), Institute of Pathology, Technical University Munich, 81675 Munich, Germany. ·Oncoscience · Pubmed #30800713.

ABSTRACT: -- No abstract --

5 Article Borderline-resectable pancreatic adenocarcinoma: Contour irregularity of the venous confluence in pre-operative computed tomography predicts histopathological infiltration. 2019

Kaissis, Georgios A / Lohöfer, Fabian K / Ziegelmayer, Sebastian / Danner, Julia / Jäger, Carsten / Schirren, Rebekka / Ankerst, Donna / Ceyhan, Güralp O / Friess, Helmut / Rummeny, Ernst J / Weichert, Wilko / Braren, Rickmer F. ·Institute for diagnostic and interventional Radiology, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany. · Department of Surgery, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany. · Department of Mathematics, Technische Universität München, Garching, Germany. · Department of General Pathology and Pathological Anatomy, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany. ·PLoS One · Pubmed #30601813.

ABSTRACT: PURPOSE: The purpose of the current study was to compare CT-signs of portal venous confluence infiltration for actual histopathological infiltration of the vein or the tumor/vein interface (TVI) in borderline resectable pancreatic ductal adenocarcinoma (PDAC). METHODS AND MATERIALS: 101 patients with therapy-naïve, primarily resected PDAC of the pancreatic head without arterial involvement were evaluated. The portal venous confluence was assessed for contour irregularity (defined as infiltration) and degree of contact. The sensitivity and specificity of contour irregularity versus tumor to vein contact >180° as well as the combination of the signs for tumor cell infiltration of the vessel wall or TVI was calculated. Overall survival (OS) was compared between groups. RESULTS: Sensitivity and specificity of contour irregularity for identification of tumor infiltration of the portal venous confluence or the TVI was higher compared to tumor to vessel contact >180° for tumor cell infiltration (96%/79% vs. 91%/38% respectively, p<0.001). The combination of the signs increased specificity to 92% (sensitivity 88%). Patients with contour irregularity/ tumor to vein contact >180°/ both signs had significantly worse overall survival (16.2 vs. 26.5 months/ 17.9 vs. 37.4 months/ 18.5 vs. 26.5 months respectively, all p<0.05). CONCLUSION: Portal venous confluence contour irregularity is a strong predictor of actual tumor cell infiltration of the vessel wall or the TVI and should be noted as such in radiological reports.

6 Article Levels of the Autophagy-Related 5 Protein Affect Progression and Metastasis of Pancreatic Tumors in Mice. 2019

Görgülü, Kivanc / Diakopoulos, Kalliope N / Ai, Jiaoyu / Schoeps, Benjamin / Kabacaoglu, Derya / Karpathaki, Angeliki-Faidra / Ciecielski, Katrin J / Kaya-Aksoy, Ezgi / Ruess, Dietrich A / Berninger, Alexandra / Kowalska, Marlena / Stevanovic, Marija / Wörmann, Sonja M / Wartmann, Thomas / Zhao, Yue / Halangk, Walter / Voronina, Svetlana / Tepikin, Alexey / Schlitter, Anna Melissa / Steiger, Katja / Artati, Anna / Adamski, Jerzy / Aichler, Michaela / Walch, Axel / Jastroch, Martin / Hartleben, Götz / Mantzoros, Christos S / Weichert, Wilko / Schmid, Roland M / Herzig, Stephan / Krüger, Achim / Sainz, Bruno / Lesina, Marina / Algül, Hana. ·Klinik und Poliklinik für Innere Medizin II, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. · Institute of Molecular Immunology and Experimental Oncology, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. · Klinik für Chirurgie Bereich Experimentelle Operative Medizin, Universitätsklinikum Magdeburg, Magdeburg, Germany. · Institute of Translational Medicine, University of Liverpool, Liverpool, UK. · Institute of Pathology, Technische Universität München, Munich, Germany and German Cancer Consortium, Munich, Germany. · Institute of Pathology, Technische Universität München, Munich, Germany and German Cancer Consortium, Munich, Germany; Comparative Experimental Pathology, Institute of Pathology, Technische Universität München, Munich, Germany. · Institute of Experimental Genetics, Genome Analysis Centre, Helmholtz Zentrum München, Neuherberg, Germany. · Institute of Experimental Genetics, Genome Analysis Centre, Helmholtz Zentrum München, Neuherberg, Germany; Institute for Diabetes and Cancer, German Center for Diabetes Research, Neuherberg, Germany; Lehrstuhl für Experimentelle Genetik, Technische Universität München, Freising-Weihenstephan, Germany. · Research Unit Analytical Pathology, Helmholtz Zentrum München, Neuherberg, Germany. · Helmholtz Diabetes Center and German Diabetes Center, Helmholtz Zentrum München, Neuherberg, Germany. · Institute for Diabetes and Cancer, German Center for Diabetes Research, Neuherberg, Germany. · Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Centre, Harvard Medical School, Boston, Massachusetts. · Department of Biochemistry, School of Medicine, Autónoma University of Madrid, Madrid, Spain. · Klinik und Poliklinik für Innere Medizin II, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. Electronic address: marina.lesina@tum.de. · Klinik und Poliklinik für Innere Medizin II, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. Electronic address: hana.alguel@mri.tum.de. ·Gastroenterology · Pubmed #30296435.

ABSTRACT: BACKGROUND AND AIMS: Cells in pancreatic ductal adenocarcinoma (PDAC) undergo autophagy, but its effects vary with tumor stage and genetic factors. We investigated the consequences of varying levels of the autophagy related 5 (Atg5) protein on pancreatic tumor formation and progression. METHODS: We generated mice that express oncogenic Kras in primary pancreatic cancer cells and have homozygous disruption of Atg5 (A5;Kras) or heterozygous disruption of Atg5 (A5 RESULTS: A5 CONCLUSIONS: In mice that express oncogenic Kras in pancreatic cells, heterozygous disruption of Atg5 and reduced protein levels promotes tumor development, whereas homozygous disruption of Atg5 blocks tumorigenesis. Therapeutic strategies to alter autophagy in PDAC should consider the effects of ATG5 levels to avoid the expansion of resistant and highly aggressive cells.

7 Article Regulation of Epithelial Plasticity Determines Metastatic Organotropism in Pancreatic Cancer. 2018

Reichert, Maximilian / Bakir, Basil / Moreira, Leticia / Pitarresi, Jason R / Feldmann, Karin / Simon, Lauren / Suzuki, Kensuke / Maddipati, Ravikanth / Rhim, Andrew D / Schlitter, Anna M / Kriegsmann, Mark / Weichert, Wilko / Wirth, Matthias / Schuck, Kathleen / Schneider, Günter / Saur, Dieter / Reynolds, Albert B / Klein-Szanto, Andres J / Pehlivanoglu, Burcin / Memis, Bahar / Adsay, N Volkan / Rustgi, Anil K. ·Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, 900 Biomedical Research Building II/III, 415 Curie Boulevard, Philadelphia, PA 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, 900 Biomedical Research Building II/III, 415 Curie Boulevard, Philadelphia, PA 19104, USA; Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University Munich, Medizinische Klinik, Ismaninger Str. 22, Munich 81675, Germany. Electronic address: maximilian.reichert@tum.de. · Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, 900 Biomedical Research Building II/III, 415 Curie Boulevard, Philadelphia, PA 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, 900 Biomedical Research Building II/III, 415 Curie Boulevard, Philadelphia, PA 19104, USA. · Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, 900 Biomedical Research Building II/III, 415 Curie Boulevard, Philadelphia, PA 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, 900 Biomedical Research Building II/III, 415 Curie Boulevard, Philadelphia, PA 19104, USA; Department of Gastroenterology, Hospital Clínic, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd), IDIBAPS, University of Barcelona, Catalonia, Spain. · Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University Munich, Medizinische Klinik, Ismaninger Str. 22, Munich 81675, Germany. · Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, 900 Biomedical Research Building II/III, 415 Curie Boulevard, Philadelphia, PA 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, 900 Biomedical Research Building II/III, 415 Curie Boulevard, Philadelphia, PA 19104, USA; Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan. · Division of Gastroenterology, Hepatology and Nutrition, MD Anderson Cancer Center, Houston, TX, USA. · Institute of General Pathology and Pathological Anatomy, Technical University of Munich, Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany. · Institute of Pathology, Heidelberg University, Heidelberg, Germany. · Institute of Pathology, Heinrich-Heine University and University Hospital Düsseldorf, Düsseldorf 40225, Germany. · Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA. · Histopathology Facility, Fox Chase Cancer Center, Philadelphia, PA, USA. · Department of Pathology and Laboratory Medicine, Emory University Hospital, Atlanta, GA, USA. · Department of Pathology, Koc University Hospital, Istanbul, Turkey. · Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, 900 Biomedical Research Building II/III, 415 Curie Boulevard, Philadelphia, PA 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, 900 Biomedical Research Building II/III, 415 Curie Boulevard, Philadelphia, PA 19104, USA. Electronic address: anil2@pennmedicine.upenn.edu. ·Dev Cell · Pubmed #29920275.

ABSTRACT: The regulation of metastatic organotropism in pancreatic ductal a denocarcinoma (PDAC) remains poorly understood. We demonstrate, using multiple mouse models, that liver and lung metastatic organotropism is dependent upon p120catenin (p120ctn)-mediated epithelial identity. Mono-allelic p120ctn loss accelerates Kras

8 Article None 2018

Heining, Christoph / Horak, Peter / Uhrig, Sebastian / Codo, Paula L / Klink, Barbara / Hutter, Barbara / Fröhlich, Martina / Bonekamp, David / Richter, Daniela / Steiger, Katja / Penzel, Roland / Endris, Volker / Ehrenberg, Karl Roland / Frank, Stephanie / Kleinheinz, Kortine / Toprak, Umut H / Schlesner, Matthias / Mandal, Ranadip / Schulz, Lothar / Lambertz, Helmut / Fetscher, Sebastian / Bitzer, Michael / Malek, Nisar P / Horger, Marius / Giese, Nathalia A / Strobel, Oliver / Hackert, Thilo / Springfeld, Christoph / Feuerbach, Lars / Bergmann, Frank / Schröck, Evelin / von Kalle, Christof / Weichert, Wilko / Scholl, Claudia / Ball, Claudia R / Stenzinger, Albrecht / Brors, Benedikt / Fröhling, Stefan / Glimm, Hanno. ·Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden, Dresden, Germany. · University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany. · German Cancer Research Center (DKFZ), Heidelberg, Germany. · German Cancer Consortium (DKTK), Dresden, Germany. · Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and DKFZ, Heidelberg, Germany. · Section for Personalized Oncology, Heidelberg University Hospital, Heidelberg, Germany. · DKTK, Heidelberg, Germany. · Division of Applied Bioinformatics, DKFZ and NCT Heidelberg, Heidelberg, Germany. · Faculty of Biosciences, Heidelberg University, Heidelberg, Germany. · Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg, Germany. · Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany. · National Center for Tumor Diseases (NCT) Dresden, Dresden, Germany. · Division of Radiology, DKFZ, Heidelberg, Germany. · Institute of Pathology, Technical University Munich, Munich, Germany. · DKTK, Munich, Germany. · Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany. · Department of Medical Oncology, NCT, Heidelberg, Germany. · Division of Theoretical Bioinformatics, DKFZ, Heidelberg, Germany. · Department for Bioinformatics and Functional Genomics, Institute for Pharmacy and Molecular Biotechnology and BioQuant, Heidelberg University, Heidelberg, Germany. · Bioinformatics and Omics Data Analytics, DKFZ, Heidelberg, Germany. · Division of Applied Functional Genomics, DKFZ, Heidelberg, Germany. · Department of Oncology, Klinikum Garmisch-Partenkirchen, Garmisch-Partenkirchen, Germany. · Department of Oncology, Sana Kliniken Lübeck, Lübeck, Germany. · Department of Gastroenterology, Hepatology and Infectious Diseases, Tübingen University Hospital, Tübingen, Germany. · DKTK, Tübingen, Germany. · Department of Radiology, Tübingen University Hospital, Tübingen, Germany. · Department of Surgery, Heidelberg University Hospital, Heidelberg, Germany. · DKFZ-Heidelberg Center for Personalized Oncology (HIPO), Heidelberg, Germany. · Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and DKFZ, Heidelberg, Germany. hanno.glimm@nct-dresden.de stefan.froehling@nct-heidelberg.de. · Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden, Dresden, Germany. hanno.glimm@nct-dresden.de stefan.froehling@nct-heidelberg.de. ·Cancer Discov · Pubmed #29802158.

ABSTRACT: We used whole-genome and transcriptome sequencing to identify clinically actionable genomic alterations in young adults with pancreatic ductal adenocarcinoma (PDAC). Molecular characterization of 17 patients with PDAC enrolled in a precision oncology program revealed gene fusions amenable to pharmacologic inhibition by small-molecule tyrosine kinase inhibitors in all patients with

9 Article Pancreatic neuroendocrine carcinomas reveal a closer relationship to ductal adenocarcinomas than to neuroendocrine tumors G3. 2018

Konukiewitz, Björn / Jesinghaus, Moritz / Steiger, Katja / Schlitter, Anna Melissa / Kasajima, Atsuko / Sipos, Bence / Zamboni, Giuseppe / Weichert, Wilko / Pfarr, Nicole / Klöppel, Günter. ·Institute of Pathology, Technical University of Munich, 81675 Munich, Germany. Electronic address: b.konukiewitz@tum.de. · Institute of Pathology, Technical University of Munich, 81675 Munich, Germany. Electronic address: moritz.jesinghaus@tum.de. · Institute of Pathology, Technical University of Munich, 81675 Munich, Germany. Electronic address: katja.steiger@tum.de. · Institute of Pathology, Technical University of Munich, 81675 Munich, Germany. Electronic address: melissa.schlitter@web.de. · Institute of Pathology, Technical University of Munich, 81675 Munich, Germany. Electronic address: atsuko.kasajima@tum.de. · Institute of Pathology, University Hospital of Tuebingen, 72076 Tuebingen, Germany. Electronic address: Bence.Sipos@med.uni-tuebingen.de. · Institute of Pathology, Sacro Cuore Don Calabria Hospital, 37024 Negrar, Verona, Italy. Electronic address: giuseppe.zamboni@sacrocuore.it. · Institute of Pathology, Technical University of Munich, 81675 Munich, Germany. Electronic address: wilko.weichert@tum.de. · Institute of Pathology, Technical University of Munich, 81675 Munich, Germany. Electronic address: nicole.pfarr@tum.de. · Institute of Pathology, Technical University of Munich, 81675 Munich, Germany. Electronic address: guenter.kloeppel@alumni.uni-kiel.de. ·Hum Pathol · Pubmed #29596894.

ABSTRACT: Pancreatic neuroendocrine carcinoma is a rare aggressive tumor commonly harboring TP53 and RB1 alterations and lacking neuroendocrine-related genetic changes such as mutations in MEN1 and ATRX/DAXX. Little is known about its genetic profile with regard to that of pancreatic ductal adenocarcinoma. We therefore conducted a detailed genetic study in 12 pancreatic neuroendocrine carcinomas of large cell (n = 9) and small cell type (n = 3) using massive parallel sequencing applying a 409-gene panel on an Ion Torrent system. The genetic data were compared with known data of pancreatic ductal adenocarcinoma and correlated with exocrine lineage marker expression. A similar analysis was performed in 11 pancreatic neuroendocrine tumors G3. Neuroendocrine carcinomas harbored 63 somatic mutations in 45 different genes, affecting most commonly TP53 (8/12 cases), KRAS (5/12 cases), and RB1 (loss of expression with or without deletion in 4/12 cases). Five carcinomas had both TP53 and KRAS mutations. Neuroendocrine tumors G3 only shared singular mutations in 5 different genes with neuroendocrine carcinomas, including TP53, CDKN2A, ARID1A, LRP1B, and APC, affecting 5 different cases. Most KRAS-positive neuroendocrine carcinomas also expressed MUC1 (4/5) and carcinoembryonic antigen (3/5) as markers of ductal differentiation. Our data indicate that almost half of the pancreatic neuroendocrine carcinomas are genetically and phenotypically related to pancreatic ductal adenocarcinoma, and might therefore respond to chemotherapies targeting the latter carcinomas.

10 Article MTOR inhibitor-based combination therapies for pancreatic cancer. 2018

Hassan, Zonera / Schneeweis, Christian / Wirth, Matthias / Veltkamp, Christian / Dantes, Zahra / Feuerecker, Benedikt / Ceyhan, Güralp O / Knauer, Shirley K / Weichert, Wilko / Schmid, Roland M / Stauber, Roland / Arlt, Alexander / Krämer, Oliver H / Rad, Roland / Reichert, Maximilian / Saur, Dieter / Schneider, Günter. ·Medical Clinic and Polyclinic II, Klinikum rechts der Isar, Technical University Munich, 81675 München, Germany. · Institute of Pathology, Heinrich-Heine University and University Hospital Düsseldorf, 40225 Düsseldorf, Germany. · Department of Nuclear Medicine, Klinikum rechts der Isar, Technical University Munich, 81675 München, Germany. · German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany. · Department of Surgery, Klinikum rechts der Isar, Technical University of Munich, 81675 München, Germany. · Molecular Biology, Centre for Medical Biotechnology (ZMB), University Duisburg-Essen, 45141 Essen, Germany. · Institute of Pathology, Technische Universität München, 81675 München, Germany. · Molecular and Cellular Oncology/ENT, University Medical Center Mainz, Langenbeckstrasse 1, Mainz 55131, Germany. · Laboratory of Molecular Gastroenterology and Hepatology, 1st Department of Internal Medicine, University Hospital Schleswig-Holstein, Kiel, Germany. · Department of Toxicology, University of Mainz Medical Center, Mainz 55131, Germany. · Division of Gastroenterology and Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. ·Br J Cancer · Pubmed #29384525.

ABSTRACT: BACKGROUND: Although the mechanistic target of rapamycin (MTOR) kinase, included in the mTORC1 and mTORC2 signalling hubs, has been demonstrated to be active in a significant fraction of patients with pancreatic ductal adenocarcinoma (PDAC), the value of the kinase as a therapeutic target needs further clarification. METHODS: We used Mtor floxed mice to analyse the function of the kinase in context of the pancreas at the genetic level. Using a dual-recombinase system, which is based on the flippase-FRT (Flp-FRT) and Cre-loxP recombination technologies, we generated a novel cellular model, allowing the genetic analysis of MTOR functions in tumour maintenance. Cross-species validation and pharmacological intervention studies were used to recapitulate genetic data in human models, including primary human 3D PDAC cultures. RESULTS: Genetic deletion of the Mtor gene in the pancreas results in exocrine and endocrine insufficiency. In established murine PDAC cells, MTOR is linked to metabolic pathways and maintains the glucose uptake and growth. Importantly, blocking MTOR genetically as well as pharmacologically results in adaptive rewiring of oncogenic signalling with activation of canonical extracellular signal-regulated kinase and phosphoinositide 3-kinase-AKT pathways. We provide evidence that interfering with such adaptive signalling in murine and human PDAC models is important in a subgroup. CONCLUSIONS: Our data suggest developing dual MTORC1/TORC2 inhibitor-based therapies for subtype-specific intervention.

11 Article Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes. 2018

Mueller, Sebastian / Engleitner, Thomas / Maresch, Roman / Zukowska, Magdalena / Lange, Sebastian / Kaltenbacher, Thorsten / Konukiewitz, Björn / Öllinger, Rupert / Zwiebel, Maximilian / Strong, Alex / Yen, Hsi-Yu / Banerjee, Ruby / Louzada, Sandra / Fu, Beiyuan / Seidler, Barbara / Götzfried, Juliana / Schuck, Kathleen / Hassan, Zonera / Arbeiter, Andreas / Schönhuber, Nina / Klein, Sabine / Veltkamp, Christian / Friedrich, Mathias / Rad, Lena / Barenboim, Maxim / Ziegenhain, Christoph / Hess, Julia / Dovey, Oliver M / Eser, Stefan / Parekh, Swati / Constantino-Casas, Fernando / de la Rosa, Jorge / Sierra, Marta I / Fraga, Mario / Mayerle, Julia / Klöppel, Günter / Cadiñanos, Juan / Liu, Pentao / Vassiliou, George / Weichert, Wilko / Steiger, Katja / Enard, Wolfgang / Schmid, Roland M / Yang, Fengtang / Unger, Kristian / Schneider, Günter / Varela, Ignacio / Bradley, Allan / Saur, Dieter / Rad, Roland. ·Center for Translational Cancer Research (TranslaTUM), Technische Universität München, 81675 Munich, Germany. · Department of Medicine II, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany. · German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. · Institute of Pathology, Technische Universität München, 81675 Munich, Germany. · The Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge CB10 1SA, UK. · Comparative Experimental Pathology, Technische Universität München, 81675 Munich, Germany. · Anthropology & Human Genomics, Department of Biology II, Ludwig-Maximilians Universität, 82152 Martinsried, Germany. · Helmholtz Zentrum München, Research Unit Radiation Cytogenetics, 85764 Neuherberg, Germany. · Department of Veterinary Medicine, University of Cambridge, Cambridge CB3 0ES, UK. · Instituto de Medicina Oncológica y Molecular de Asturias (IMOMA), 33193 Oviedo, Spain. · Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, 33006 Oviedo, Spain. · Institute of Oncology of Asturias (IUOPA), HUCA, Universidad de Oviedo, 33011 Oviedo, Spain. · Nanomaterials and Nanotechnology Research Center (CINN-CSIC), Universidad de Oviedo, 33940 El Entrego, Spain. · Medizinische Klinik und Poliklinik II, Klinikum der LMU München-Grosshadern, 81377 Munich, Germany. · Instituto de Biomedicina y Biotecnología de Cantabria (UC-CSIC), 39012 Santander, Spain. ·Nature · Pubmed #29364867.

ABSTRACT: The poor correlation of mutational landscapes with phenotypes limits our understanding of the pathogenesis and metastasis of pancreatic ductal adenocarcinoma (PDAC). Here we show that oncogenic dosage-variation has a critical role in PDAC biology and phenotypic diversification. We find an increase in gene dosage of mutant KRAS in human PDAC precursors, which drives both early tumorigenesis and metastasis and thus rationalizes early PDAC dissemination. To overcome the limitations posed to gene dosage studies by the stromal richness of PDAC, we have developed large cell culture resources of metastatic mouse PDAC. Integration of cell culture genomes, transcriptomes and tumour phenotypes with functional studies and human data reveals additional widespread effects of oncogenic dosage variation on cell morphology and plasticity, histopathology and clinical outcome, with the highest Kras

12 Article Pancreatic Ductal Adenocarcinoma Subtyping Using the Biomarkers Hepatocyte Nuclear Factor-1A and Cytokeratin-81 Correlates with Outcome and Treatment Response. 2018

Muckenhuber, Alexander / Berger, Anne Katrin / Schlitter, Anna Melissa / Steiger, Katja / Konukiewitz, Björn / Trumpp, Andreas / Eils, Roland / Werner, Jens / Friess, Helmut / Esposito, Irene / Klöppel, Günter / Ceyhan, Güralp O / Jesinghaus, Moritz / Denkert, Carsten / Bahra, Marcus / Stenzinger, Albrecht / Sprick, Martin R / Jäger, Dirk / Springfeld, Christoph / Weichert, Wilko. ·Institute of Pathology, Technical University Munich and German Cancer Consortium (DKTK; partner site Munich), Munich, Germany. · Department of Medical Oncology, Heidelberg University Hospital and National Center for Tumor Diseases, Heidelberg, Germany. · Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany. · Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM GmbH, Heidelberg, Germany. · German Cancer Consortium (DKTK), Heidelberg, Germany. · Division of Theoretical Bioinformatics and Heidelberg Center for Personalised Oncology (DKFZ-HIPO), German Cancer Research Center (DKFZ), Heidelberg, Germany. · Department for Bioinformatics and Functional Genomics, Institute for Pharmacy and Molecular Biotechnology (IPMB) and BioQuant, Heidelberg University, Heidelberg, Germany. · Department of Surgery, University Hospital of the Ludwig-Maximilian University, Munich, Germany. · Department of Surgery, University Hospital of the Technical University Munich, Munich, Germany. · Institute of Pathology, University Hospital Düsseldorf, Düsseldorf, Germany. · Institute of Pathology, Charité University Medicine Berlin and German Cancer Consortium (DKTK; partner site Berlin), Berlin, Germany. · Department of Surgery, Charité University Medicine Berlin, Berlin, Germany. · Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany. · Institute of Pathology, Technical University Munich and German Cancer Consortium (DKTK; partner site Munich), Munich, Germany. wilko.weichert@tum.de. ·Clin Cancer Res · Pubmed #29101303.

ABSTRACT:

13 Article R0 Versus R1 Resection Matters after Pancreaticoduodenectomy, and Less after Distal or Total Pancreatectomy for Pancreatic Cancer. 2018

Demir, Ihsan Ekin / Jäger, Carsten / Schlitter, A Melissa / Konukiewitz, Björn / Stecher, Lynne / Schorn, Stephan / Tieftrunk, Elke / Scheufele, Florian / Calavrezos, Lenika / Schirren, Rebekka / Esposito, Irene / Weichert, Wilko / Friess, Helmut / Ceyhan, Güralp O. ·Department of Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. · Institute for Pathology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. · Institute for Medical Statistics and Epidemiology, Technical University of Munich, Munich, Germany. · Institute of Pathology, Heinrich Heine University, Düsseldorf, Germany. ·Ann Surg · Pubmed #28692477.

ABSTRACT: OBJECTIVE: The aim of this study was to decipher the true importance of R0 versus R1 resection for survival in pancreatic ductal adenocarcinoma (PDAC). SUMMARY OF BACKGROUND DATA: PDAC is characterized by poor survival, even after curative resection. In many studies, R0 versus R1 does not result in different prognosis and does not affect the postoperative management. METHODS: Pubmed, Embase, and Cochrane databases were screened for prognostic studies on the association between resection status and survival. Hazard ratios (HRs) were pooled in a meta-analysis. Furthermore, our prospective database was retrospectively screened for curative PDAC resections according to inclusion criteria (n = 254 patients) between July 2007 and October 2014. RESULTS: In the meta-analysis, R1 was associated with a decreased overall survival [HR 1.45 (95% confidence interval, 95% CI 1.37-1.52)] and disease-free survival [HR 1.44 (1.30-1.59)] in PDAC when compared with R0. Importantly, this effect held true only for pancreatic head resection both in the meta-analysis [R0 ≥0 mm: HR 1.21 (1.05-1.39) vs R0 ≥1 mm: HR 1.66 (1.46-1.89)] and in our cohort (R0 ≥0 mm: 31.8 vs 14.5 months, P < 0.001; R0 ≥1 mm, 41.2 vs 16.8 months; P < 0.001). Moreover, R1 resections were associated with advanced tumor disease, that is, larger tumor size, lymph node metastases, and extended resections. Multivariable Cox proportional hazard model suggested G3, pN1, tumor size, and R1 (0 mm/1 mm) as independent predictors of overall survival. CONCLUSION: Resection margin is not a valid prognostic marker in publications before 2010 due to heterogeneity of cohorts and lack of standardized histopathological examination. Within standardized pathology protocols, R-status' prognostic validity may be primarily confined to pancreatic head cancers.

14 Article pT but not pN stage of the 8th TNM classification significantly improves prognostication in pancreatic ductal adenocarcinoma. 2017

Schlitter, Anna Melissa / Jesinghaus, Moritz / Jäger, Carsten / Konukiewitz, Björn / Muckenhuber, Alexander / Demir, Ihsan Ekin / Bahra, Marcus / Denkert, Carsten / Friess, Helmut / Kloeppel, Günter / Ceyhan, Güralp O / Weichert, Wilko. ·Institute of Pathology, Technical University Munich, Munich, Germany. Electronic address: melissa.schlitter@tum.de. · Institute of Pathology, Technical University Munich, Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich, Germany. · Department of Surgery, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany. · Institute of Pathology, Technical University Munich, Munich, Germany. · Department of Surgery, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich, Germany. · Department of Surgery, Charité University Hospital, Berlin, Germany. · Institute of Pathology, Charité University Hospital, Berlin, Germany; German Cancer Consortium (DKTK), Partner Site Berlin, Germany. ·Eur J Cancer · Pubmed #28802189.

ABSTRACT: The UICC TNM (tumour-node-metastasis) staging system for pancreatic ductal adenocarcinoma (PDAC) has been a matter of debate over decades because survival prediction based on T stages was weak and unreliable. To improve staging, the recently published 8th TNM edition (2016) introduced a conceptually completely changed strictly size-based T staging system and a refined N stage for PDAC. To investigate the clinical value of the novel TNM classification, we compared the prognostic impact of pT and pN stage between the 7th and 8th edition in two well-characterised independent German PDAC cohorts from different decades, including a total number of 523 patients. Former UICC T staging (7th edition 2009) resulted in a clustering of pT3 cases (72% and 85% of cases per cohort, respectively) and failed to show significant prognostic differences between the four stages in one of the investigated cohorts (p = 0.074). Application of the novel size-based T stage system resulted in a more equal distribution of cases between the four T categories with a predominance of pT2 tumours (65% and 60% of cases). The novel pT staging algorithm showed greatly improved discriminative power with highly significant overall differences between the four pT stages in both investigated cohorts in univariate and multivariate analyses (p < 0.001, each). In contrast, no prognostic differences were observed between the recently introduced pN1 and pN2 categories in both cohorts (p = 0.970 and p = 0.061). pT stage of resected PDAC patients according to the novel UICC staging protocol (8th edition) significantly improves patient stratification, whereas introduction of an extended N stage protocol does not demonstrate high clinical relevance in our cohorts.

15 Article Perspective of αvβ6-Integrin Imaging for Clinical Management of Pancreatic Carcinoma and Its Precursor Lesions. 2017

Steiger, Katja / Schlitter, Anna-Melissa / Weichert, Wilko / Esposito, Irene / Wester, Hans-Jürgen / Notni, Johannes. ·1 Institute of Pathology, Technische Universität München, Munich, Germany. · 2 German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany. · 3 Institute of Pathology, Universitätsklinikum Düsseldorf, Heinrich-Heine University, Düsseldorf, Germany. · 4 Chair of Pharmaceutical Radiochemistry, Technische Universität München, Garching, Germany. ·Mol Imaging · Pubmed #28627323.

ABSTRACT: ß

16 Article Succession of transiently active tumor-initiating cell clones in human pancreatic cancer xenografts. 2017

Ball, Claudia R / Oppel, Felix / Ehrenberg, Karl Roland / Dubash, Taronish D / Dieter, Sebastian M / Hoffmann, Christopher M / Abel, Ulrich / Herbst, Friederike / Koch, Moritz / Werner, Jens / Bergmann, Frank / Ishaque, Naveed / Schmidt, Manfred / von Kalle, Christof / Scholl, Claudia / Fröhling, Stefan / Brors, Benedikt / Weichert, Wilko / Weitz, Jürgen / Glimm, Hanno. ·Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany. · Department of Medical Oncology, National Center for Tumor Diseases (NCT), Heidelberg, Germany. · German Cancer Consortium (DKTK), University of Heidelberg, Heidelberg, Germany. · Department of General Surgery, University of Heidelberg, Heidelberg, Germany. · Department of Visceral, Thoracic and Vascular Surgery, University Hospital Dresden, Dresden, Germany. · Department of Surgery, University of Munich, Munich, Germany. · Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany. · Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Heidelberg Center for Personalized Oncology, DKFZ-HIPO, DKFZ, Heidelberg, Germany. · Heidelberg University Hospital, Heidelberg, Germany. · Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany hanno.glimm@nct-heidelberg.de. ·EMBO Mol Med · Pubmed #28526679.

ABSTRACT: Although tumor-initiating cell (TIC) self-renewal has been postulated to be essential in progression and metastasis formation of human pancreatic adenocarcinoma (PDAC), clonal dynamics of TICs within PDAC tumors are yet unknown. Here, we show that long-term progression of PDAC in serial xenotransplantation is driven by a succession of transiently active TICs producing tumor cells in temporally restricted bursts. Clonal tracking of individual, genetically marked TICs revealed that individual tumors are generated by distinct sets of TICs with very little overlap between subsequent xenograft generations. An unexpected functional and phenotypic plasticity of pancreatic TICs

17 Article High prevalence of incidental and symptomatic venous thromboembolic events in patients with advanced pancreatic cancer under palliative chemotherapy: A retrospective cohort study. 2017

Berger, Anne Katrin / Singh, Hans Martin / Werft, Wiebke / Muckenhuber, Alexander / Sprick, Martin R / Trumpp, Andreas / Weichert, Wilko / Jäger, Dirk / Springfeld, Christoph. ·National Center for Tumor Diseases (NCT), Department of Medical Oncology, University Hospital Heidelberg, Heidelberg, Germany. Electronic address: anne.berger@med.uni-heidelberg.de. · National Center for Tumor Diseases (NCT), Department of Medical Oncology, University Hospital Heidelberg, Heidelberg, Germany. · Hochschule Mannheim, University of Applied Sciences, Mannheim, Germany. · Institute of Pathology, Technische Universität München (TUM), München, Germany. · Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), Heidelberg, Germany; Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany. ·Pancreatology · Pubmed #28462862.

ABSTRACT: OBJECTIVES: Pancreatic cancer patients are at high risk for venous thromboembolic events (VTEs), and chemotherapy is a known additional risk factor. In this context, there is a controversial discussion whether prophylactic anticoagulation should be offered to all outpatients receiving chemotherapy. METHODS: In this retrospective study, we analyzed incidental and symptomatic VTEs in 150 pancreatic cancer patients receiving either gemcitabine-based chemotherapy or chemotherapy according to the FOLFIRINOX protocol. RESULTS: VTEs were identified in 25% of patients, but were not associated with an adverse survival. There was no significant difference in VTE incidence between patients treated with gemcitabine-based chemotherapy or the more intensive FOLFIRINOX protocol. A commonly used risk score to predict VTEs in cancer patients did not predict the occurrence of VTEs in our patients. The occurrence of VTEs was not associated with one of the recently described pancreatic cancer subtypes. CONCLUSION: One quarter of pancreatic cancer patients treated with palliative chemotherapy develops symptomatic or incidental VTEs that cannot be predicted by type of chemotherapy, subtype of pancreatic cancer or a commonly used risk score. Further studies are necessary to identify patients at risk, and to better define which patients at risk should be treated with prophylactic anticoagulation.

18 Article Somatostatin receptor expression related to TP53 and RB1 alterations in pancreatic and extrapancreatic neuroendocrine neoplasms with a Ki67-index above 20. 2017

Konukiewitz, Björn / Schlitter, Anna Melissa / Jesinghaus, Moritz / Pfister, Dominik / Steiger, Katja / Segler, Angela / Agaimy, Abbas / Sipos, Bence / Zamboni, Giuseppe / Weichert, Wilko / Esposito, Irene / Pfarr, Nicole / Klöppel, Günter. ·Institute of Pathology, Technical University of Munich, Munich, Germany. · Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Institute of Pathology, Friedrich-Alexander University Erlangen-Nuremberg, University Hospital, Erlangen, Germany. · Institute of Pathology, University Hospital of Tuebingen, Tuebingen, Germany. · Institute of Pathology, Sacro Cuore Hospital of Negrar, Verona, Italy. · Institute of Pathology, Heinrich-Heine-University, Düsseldorf, Germany. ·Mod Pathol · Pubmed #28059098.

ABSTRACT: Somatostatin receptor 2A expression is a feature of well-differentiated neuroendocrine neoplasms and is important for their diagnosis and therapy. Little is known about somatostatin receptor 2A expression in poorly differentiated neuroendocrine neoplasms in relation to TP53 and RB1 status and how these features may contribute to the separation of well from poorly differentiated neuroendocrine neoplasms with a proliferation index above 20%. This study investigates the expression of somatostatin receptors, p53 and Rb1, and TP53 alterations in pancreatic and extrapancreatic well and poorly differentiated neuroendocrine neoplasms (Ki67-index >20%). Thirty-seven poorly differentiated neuroendocrine neoplasms of pancreatic (n=12) and extrapancreatic origin (n=25) as well as 10 well-differentiated neuroendocrine neoplasms of the pancreas (n=9) and rectum (n=1) with a Ki67-index >20% were immunostained for synaptophysin, chromogranin A, Ki67, CD56, p53, Rb1, ATRX, DAXX, progesterone receptor, somatostatin receptor 2A, somatostatin receptor 5, and cytokeratin 20, and sequenced for TP53, exons 5-9. Somatostatin receptor 2A was positive in 6/37 of poorly differentiated and in 8/10 of well-differentiated neuroendocrine neoplasms. One well-differentiated and two poorly differentiated neuroendocrine neoplasms expressed somatostatin receptor 5. Abnormal nuclear p53 and Rb1 staining was found in 29/37 and 22/37 poorly differentiated neuroendocrine neoplasms, respectively, whereas all well-differentiated neuroendocrine neoplasms showed normal p53 and Rb1 expression. TP53 gene alterations were restricted to poorly differentiated neuroendocrine neoplasms (24/34) and correlated well with p53 expression. All cases were progesterone receptor negative. Somatostatin receptor 2A expression is not limited to well-differentiated neuroendocrine neoplasms but also occurs in 16% of poorly differentiated neuroendocrine neoplasms from various sites. Most poorly differentiated neuroendocrine neoplasms are characterized by TP53 alterations and Rb1 loss, usually in the absence of somatostatin receptor 2A expression. In the pancreas, these criteria contribute to separate well-differentiated neuroendocrine neoplasms with a Ki67-index above 20% from poorly differentiated neuroendocrine neoplasms.

19 Article Patient-derived xenografts of gastrointestinal cancers are susceptible to rapid and delayed B-lymphoproliferation. 2017

Dieter, Sebastian M / Giessler, Klara M / Kriegsmann, Mark / Dubash, Taronish D / Möhrmann, Lino / Schulz, Erik R / Siegl, Christine / Weber, Sarah / Strakerjahn, Hendrik / Oberlack, Ava / Heger, Ulrike / Gao, Jianpeng / Hartinger, Eva-Maria / Oppel, Felix / Hoffmann, Christopher M / Ha, Nati / Brors, Benedikt / Lasitschka, Felix / Ulrich, Alexis / Strobel, Oliver / Schmidt, Manfred / von Kalle, Christof / Schneider, Martin / Weichert, Wilko / Ehrenberg, K Roland / Glimm, Hanno / Ball, Claudia R. ·Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany. · German Cancer Consortium (DKTK), Heidelberg, Germany. · Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany. · Department of Surgery, Heidelberg University Hospital, Heidelberg, Germany. · Department of Applied Bioinformatics, NCT Heidelberg and DKFZ, Heidelberg, Germany. · Heidelberg Center for Personalized Oncology, DKFZ-HIPO, DKFZ, Heidelberg, Germany. · Institute of Pathology, Technische Universität München (TUM), Munich, Germany. · DKTK, Munich, Germany. · Department of Medical Oncology, NCT Heidelberg, Heidelberg, Germany. · Department of Internal Medicine VI, Heidelberg University Hospital, Heidelberg, Germany. ·Int J Cancer · Pubmed #27935045.

ABSTRACT: Patient-derived cancer xenografts (PDX) are widely used to identify and evaluate novel therapeutic targets, and to test therapeutic approaches in preclinical mouse avatar trials. Despite their widespread use, potential caveats of PDX models remain considerably underappreciated. Here, we demonstrate that EBV-associated B-lymphoproliferations frequently develop following xenotransplantation of human colorectal and pancreatic carcinomas in highly immunodeficient NOD.Cg-Prkdc

20 Article A new classification method for MALDI imaging mass spectrometry data acquired on formalin-fixed paraffin-embedded tissue samples. 2017

Boskamp, Tobias / Lachmund, Delf / Oetjen, Janina / Cordero Hernandez, Yovany / Trede, Dennis / Maass, Peter / Casadonte, Rita / Kriegsmann, Jörg / Warth, Arne / Dienemann, Hendrik / Weichert, Wilko / Kriegsmann, Mark. ·Center for Industrial Mathematics, University of Bremen, Bremen, Germany; SCiLS GmbH, Bremen, Germany. Electronic address: tboskamp@uni-bremen.de. · Center for Industrial Mathematics, University of Bremen, Bremen, Germany. · MALDI Imaging Lab, University of Bremen, Bremen, Germany. · SCiLS GmbH, Bremen, Germany. · Center for Industrial Mathematics, University of Bremen, Bremen, Germany; MALDI Imaging Lab, University of Bremen, Bremen, Germany; SCiLS GmbH, Bremen, Germany. · Proteopath GmbH, Trier, Germany. · Proteopath GmbH, Trier, Germany; Center for Histology, Cytology and Molecular Diagnostic, Trier, Germany. · Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany. · Thoraxklinik Heidelberg, University of Heidelberg, Heidelberg, Germany. · Institute of Pathology, Technical University of Munich, Munich, Germany. ·Biochim Biophys Acta Proteins Proteom · Pubmed #27836618.

ABSTRACT: Matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) shows a high potential for applications in histopathological diagnosis, and in particular for supporting tumor typing and subtyping. The development of such applications requires the extraction of spectral fingerprints that are relevant for the given tissue and the identification of biomarkers associated with these spectral patterns. We propose a novel data analysis method based on the extraction of characteristic spectral patterns (CSPs) that allow automated generation of classification models for spectral data. Formalin-fixed paraffin embedded (FFPE) tissue samples from N=445 patients assembled on 12 tissue microarrays were analyzed. The method was applied to discriminate primary lung and pancreatic cancer, as well as adenocarcinoma and squamous cell carcinoma of the lung. A classification accuracy of 100% and 82.8%, resp., could be achieved on core level, assessed by cross-validation. The method outperformed the more conventional classification method based on the extraction of individual m/z values in the first application, while achieving a comparable accuracy in the second. LC-MS/MS peptide identification demonstrated that the spectral features present in selected CSPs correspond to peptides relevant for the respective classification. This article is part of a Special Issue entitled: MALDI Imaging, edited by Dr. Corinna Henkel and Prof. Peter Hoffmann.

21 Article CYP3A5 mediates basal and acquired therapy resistance in different subtypes of pancreatic ductal adenocarcinoma. 2016

Noll, Elisa M / Eisen, Christian / Stenzinger, Albrecht / Espinet, Elisa / Muckenhuber, Alexander / Klein, Corinna / Vogel, Vanessa / Klaus, Bernd / Nadler, Wiebke / Rösli, Christoph / Lutz, Christian / Kulke, Michael / Engelhardt, Jan / Zickgraf, Franziska M / Espinosa, Octavio / Schlesner, Matthias / Jiang, Xiaoqi / Kopp-Schneider, Annette / Neuhaus, Peter / Bahra, Marcus / Sinn, Bruno V / Eils, Roland / Giese, Nathalia A / Hackert, Thilo / Strobel, Oliver / Werner, Jens / Büchler, Markus W / Weichert, Wilko / Trumpp, Andreas / Sprick, Martin R. ·Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), Heidelberg, Germany. · Divison of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Department of Pathology, University of Heidelberg, Heidelberg, Germany. · National Center for Tumor Diseases (NCT), Heidelberg, Germany. · Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany. · Heidelberg Pharma GmbH, Ladenburg, Germany. · Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany. · Department of General, Visceral and Transplantation Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany. · Institute of Pathology, Charité-Universitätsmedizin Berlin, Berlin, Germany. · Institute of Pharmacy and Molecular Biotechnology, Bioquant, University of Heidelberg, Heidelberg, Germany. · Heidelberg Center for Personalized Oncology (DKFZ-HIPO), German Cancer Research Center, Heidelberg, Germany. · Department of General and Visceral Surgery, University Hospital Heidelberg, Heidelberg, Germany. · German Cancer Consortium (DKTK), Heidelberg, Germany. ·Nat Med · Pubmed #26855150.

ABSTRACT: Although subtypes of pancreatic ductal adenocarcinoma (PDAC) have been described, this malignancy is clinically still treated as a single disease. Here we present patient-derived models representing the full spectrum of previously identified quasi-mesenchymal (QM-PDA), classical and exocrine-like PDAC subtypes, and identify two markers--HNF1A and KRT81--that enable stratification of tumors into different subtypes by using immunohistochemistry. Individuals with tumors of these subtypes showed substantial differences in overall survival, and their tumors differed in drug sensitivity, with the exocrine-like subtype being resistant to tyrosine kinase inhibitors and paclitaxel. Cytochrome P450 3A5 (CYP3A5) metabolizes these compounds in tumors of the exocrine-like subtype, and pharmacological or short hairpin RNA (shRNA)-mediated CYP3A5 inhibition sensitizes tumor cells to these drugs. Whereas hepatocyte nuclear factor 4, alpha (HNF4A) controls basal expression of CYP3A5, drug-induced CYP3A5 upregulation is mediated by the nuclear receptor NR1I2. CYP3A5 also contributes to acquired drug resistance in QM-PDA and classical PDAC, and it is highly expressed in several additional malignancies. These findings designate CYP3A5 as a predictor of therapy response and as a tumor cell-autonomous detoxification mechanism that must be overcome to prevent drug resistance.

22 Article Profiling of cMET and HER Family Receptor Expression in Pancreatic Ductal Adenocarcinomas and Corresponding Lymph Node Metastasis to Assess Relevant Pathways for Targeted Therapies: Looking at the Soil Before Planting the Seed. 2016

Muckenhuber, Alexander / Babitzki, Galina / Thomas, Marlene / Hölzlwimmer, Gabriele / Zajac, Magdalena / Jesinghaus, Moritz / Bergmann, Frank / Werner, Jens / Stenzinger, Albrecht / Weichert, Wilko. ·From the *Institute of Pathology, University Hospital Heidelberg, Ruprecht-Karls Universität, Heidelberg; †Roche Pharma Research and Early Development, Roche Innovation Center, Penzberg, Germany; ‡AstraZeneca, Personalized Healthcare and Biomarkers, Innovative Medicines and Early Development, Cambridge, United Kingdom; §Department of Surgery, University Hospital Grosshadern, Ludwig-Maximilians-Universität, München, Germany; ∥National Center for Tumor Diseases, Heidelberg; and ¶German Cancer Consortium (DKTK), Dresden, Germany. ·Pancreas · Pubmed #26825865.

ABSTRACT: OBJECTIVES: Comprehensive assessment of cMET and HER family receptor tyrosine kinases expression, changes of expression during metastatic progression, amplification status of the MET gene, and correlations with patient characteristics in pancreatic ductal adenocarcinoma (PDAC) was conducted. METHODS: We investigated 56 PDACs and corresponding lymph node metastases for HER1 to HER4 and cMET expression by immunohistochemistry, as well as cMET gene copy numbers by chromogenic in situ hybridization. RESULTS: Of all receptor tyrosine kinases evaluated, cMET expression was highest with 46.5% of tumors showing moderate or strong expression and a weak correlation with gene copy number status (P = 0.04; Spearman ρ = 0.28). cMET expression was increased in metastases. In contrast, expression levels of HER family receptors were generally low both in primaries and metastases. A weak yet significant correlation of HER1 and cMET expression levels was observed (P < 0.001; Spearman ρ = 0.44) and HER1 was often present in poorly differentiated tumors (G3, P = 0.049). CONCLUSIONS: Our data suggest that cMET might constitute an interesting molecule for combining targeted and chemotherapeutic approaches in PDAC, because expression is frequent and increased during metastatic progression. In PDAC, cMET protein expression might be a more useful stratification biomarker than cMET gene amplification, which does not seem to be its primary regulator.

23 Article Ataxia-telangiectasia-mutated protein kinase levels stratify patients with pancreatic adenocarcinoma into prognostic subgroups with loss being a strong indicator of poor survival. 2015

Kamphues, Carsten / Bova, Roberta / Bahra, Marcus / Klauschen, Frederick / Muckenhuber, Alexander / Sinn, Bruno V / Warth, Arne / Goeppert, Benjamin / Endris, Volker / Neuhaus, Peter / Weichert, Wilko / Stenzinger, Albrecht. ·From the *Department of General, Visceral and Transplantation Surgery, and †Institute of Pathology, Charité University Hospital, Berlin; ‡Institute of Pathology, University Hospital Heidelberg; and §National Center for Tumor Diseases, Heidelberg, Germany. ·Pancreas · Pubmed #25423555.

ABSTRACT: OBJECTIVES: Recently, aberrations in the gene encoding for ataxia-telangiectasia-mutated (ATM) protein kinase have been reported for pancreatic ductal adenocarcinomas (PDAC). These findings argue that ATM deficiency may play a role during carcinogenesis. Therefore, in this study, we investigated the clinical relevance of ATM expression and ATM activation in PDAC. METHODS: Both ATM expression and nuclear phosphoSer1981-ATM levels were assessed by immunohistochemistry in a cohort of 133 PDAC and correlated with clinicopathological parameters. RESULTS: We found stratification in prognostic subgroups. Complete loss of Ser1981-ATM was indicative of the worst prognosis (median survival, 10.8 vs 14.3 months [low expression] vs 31.1 months [high expression], P < 0.001). Similarly, analysis of ATM expression demonstrated absent expression levels of ATM to be associated with dismal prognosis (median survival, 9.6 months), whereas expression of ATM in general was associated with increased survival (17.7 months, P = 0.001). CONCLUSIONS: Our analysis shows that both ATM expression and activated ATM are prognostic markers in PDAC with respect to standard clinicopathological parameters. These results suggest that ATM should be further explored as prognostic as well as predictive factor with respect to conventional chemotherapies and for putative synthetic lethal approaches.

24 Article KRAS mutations in codon 12 or 13 are associated with worse prognosis in pancreatic ductal adenocarcinoma. 2014

Sinn, Bruno V / Striefler, Jana K / Rudl, Marc A / Lehmann, Annika / Bahra, Marcus / Denkert, Carsten / Sinn, Marianne / Stieler, Jens / Klauschen, Frederick / Budczies, Jan / Weichert, Wilko / Stenzinger, Albrecht / Kamphues, Carsten / Dietel, Manfred / Riess, Hanno. ·From the Departments of *Pathology, †Hematology, Oncology and Tumor Immunology, and ‡General, Visceral, and Transplantation Surgery, Charité - Universitätsmedizin Berlin, Berlin; and §Department of Pathology, University Hospital Heidelberg, Heidelberg, Germany. ·Pancreas · Pubmed #24681874.

ABSTRACT: OBJECTIVE: Mutations in the KRAS and P53 genes belong to the most frequently observed genetic alterations in pancreatic ductal adenocarcinoma. The aim of this study was to examine the frequency and prognostic impact of KRAS mutations. In addition, we attempted to define molecular subgroups with distinct biologic behavior by combination of KRAS sequencing data with p53 protein expression data. METHODS: KRAS mutational analyses were performed in a study group of 153 patients by Sanger sequencing. Immunohistochemistry for p53 was performed on tissue microarrays. RESULTS: KRAS mutations in codon 12 or 13 were found in 68% of cases. Nuclear staining for p53 was detectable in 110 (68%) of 162 evaluable cases. We found no correlation between KRAS mutational status and p53 expression. KRAS mutational status but not p53 immunohistochemistry was an independent prognostic factor in the study group (P = 0.02). In a stratified analysis according to KRAS mutational status, p53 expression failed to define prognostic groups beyond the impact of KRAS mutational status. CONCLUSIONS: Our results support the crucial role of KRAS mutational status in pancreatic cancer biology. KRAS mutational status may serve as a prognostic marker. However, its predictive role for targeted therapies remains to be evaluated.

25 Article High SIRT1 expression is a negative prognosticator in pancreatic ductal adenocarcinoma. 2013

Stenzinger, Albrecht / Endris, Volker / Klauschen, Frederick / Sinn, Bruno / Lorenz, Katja / Warth, Arne / Goeppert, Benjamin / Ehemann, Volker / Muckenhuber, Alexander / Kamphues, Carsten / Bahra, Marcus / Neuhaus, Peter / Weichert, Wilko. ·Institute of Pathology, and National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany. albrecht.stenzinger@med.uni-heidelberg.de. ·BMC Cancer · Pubmed #24088390.

ABSTRACT: BACKGROUND: Several lines of evidence indicate that Sirt1, a class III histone deacetylase (HDAC) is implicated in the initiation and progression of malignancies and thus gained attraction as druggable target. Since data on the role of Sirt1 in pancreatic ductal adenocarcinoma (PDAC) are sparse, we investigated the expression profile and prognostic significance of Sirt1 in vivo as well as cellular effects of Sirt1 inhibition in vitro. METHODS: Sirt1 expression was analyzed by immunohistochemistry in a large cohort of PDACs and correlated with clinicopathological and survival data. Furthermore, we investigated the impact of overexpression and small molecule inhibition on Sirt1 in pancreatic cancer cell culture models including combinatorial treatment with chemotherapy and EGFR-inhibition. Cellular events were measured quantitatively in real time and corroborated by conventional readouts including FACS analysis and MTT assays. RESULTS: We detected nuclear Sirt1 expression in 36 (27.9%) of 129 PDACs. SIRT1 expression was significantly higher in poorly differentiated carcinomas. Strong SIRT1 expression was a significant predictor of poor survival both in univariate (p = 0.002) and multivariate (HR 1.65, p = 0.045) analysis. Accordingly, overexpression of Sirt1 led to increased cell viability, while small molecule inhibition led to a growth arrest in pancreatic cancer cells and impaired cell survival. This effect was even more pronounced in combinatorial regimens with gefitinib, but not in combination with gemcitabine. CONCLUSIONS: Sirt1 is an independent prognosticator in PDACs and plays an important role in pancreatic cancer cell growth, which can be levered out by small molecule inhibition. Our data warrant further studies on SIRT1 as a novel chemotherapeutic target in PDAC.

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