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Pancreatic Neoplasms: HELP
Articles by Dr. H Friess
Based on 138 articles published since 2008
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Between 2008 and 2019, H. Friess wrote the following 138 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4 · 5 · 6
1 Guideline Consensus statement on mandatory measurements in pancreatic cancer trials (COMM-PACT) for systemic treatment of unresectable disease. 2018

Ter Veer, Emil / van Rijssen, L Bengt / Besselink, Marc G / Mali, Rosa M A / Berlin, Jordan D / Boeck, Stefan / Bonnetain, Franck / Chau, Ian / Conroy, Thierry / Van Cutsem, Eric / Deplanque, Gael / Friess, Helmut / Glimelius, Bengt / Goldstein, David / Herrmann, Richard / Labianca, Roberto / Van Laethem, Jean-Luc / Macarulla, Teresa / van der Meer, Jonathan H M / Neoptolemos, John P / Okusaka, Takuji / O'Reilly, Eileen M / Pelzer, Uwe / Philip, Philip A / van der Poel, Marcel J / Reni, Michele / Scheithauer, Werner / Siveke, Jens T / Verslype, Chris / Busch, Olivier R / Wilmink, Johanna W / van Oijen, Martijn G H / van Laarhoven, Hanneke W M. ·Department of Medical Oncology, Cancer Center Amsterdam, Academic Medical Center, Amsterdam, Netherlands. · Department of Surgery, Cancer Center Amsterdam, Academic Medical Center, Amsterdam, Netherlands. · Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, USA. · Department of Internal Medicine III, Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Munich, Germany. · Methodology and Quality of Life in Oncology Unit, University Hospital of Besançon, Besançon, France. · Royal Marsden NHS Foundation Trust, London and Surrey, UK. · Department of Medical Oncology, Institut de Cancérologie de Lorraine and Lorraine University, Vandoeuvre-lès-Nancy, France. · Department of Gastroenterology and Digestive Oncology, University Hospitals Gasthuisberg Leuven and KU Leuven, Leuven, Belgium. · Department of Oncology, Hôpital Riviera-Chablais, Vevey, Switzerland. · Department of Surgery, Technical University of Munich, Klinikum rechts der Isar, Munich, Germany. · Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden. · Nelune Cancer Centre, Prince of Wales Hospital, Prince of Wales Clinical School University of New South Wales, Randwick, NSW, Australia. · Department of Medical Oncology, University Hospital Basel, Basel, Switzerland. · Cancer Center, ASST Papa Giovanni XXIII, Bergamo, Italy. · Department of Gastroenterology, Gastrointestinal Cancer Unit, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium. · Vall d'Hebron University Hospital (HUVH), Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. · Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK. · Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan. · Gastrointestinal Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY, USA. · Department of Hematology, Oncology and Tumor Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany; Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany; Berlin Institute of Health, Berlin, Germany. · Department of Oncology, Karmanos Cancer Center, Wayne State University, Detroit, MI, USA. · Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Department of Internal Medicine I, Medical University Vienna, Vienna, Austria. · Division of Solid Tumor Translational Oncology, West German Cancer Cancer, University Hospital Essen, Essen, Germany; German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany. · Department of Digestive Oncology, University Hospitals Leuven, Leuven, Belgium. · Department of Medical Oncology, Cancer Center Amsterdam, Academic Medical Center, Amsterdam, Netherlands. Electronic address: h.vanlaarhoven@amc.uva.nl. ·Lancet Oncol · Pubmed #29508762.

ABSTRACT: Variations in the reporting of potentially confounding variables in studies investigating systemic treatments for unresectable pancreatic cancer pose challenges in drawing accurate comparisons between findings. In this Review, we establish the first international consensus on mandatory baseline and prognostic characteristics in future trials for the treatment of unresectable pancreatic cancer. We did a systematic literature search to find phase 3 trials investigating first-line systemic treatment for locally advanced or metastatic pancreatic cancer to identify baseline characteristics and prognostic variables. We created a structured overview showing the reporting frequencies of baseline characteristics and the prognostic relevance of identified variables. We used a modified Delphi panel of two rounds involving an international panel of 23 leading medical oncologists in the field of pancreatic cancer to develop a consensus on the various variables identified. In total, 39 randomised controlled trials that had data on 15 863 patients were included, of which 32 baseline characteristics and 26 prognostic characteristics were identified. After two consensus rounds, 23 baseline characteristics and 12 prognostic characteristics were designated as mandatory for future pancreatic cancer trials. The COnsensus statement on Mandatory Measurements in unresectable PAncreatic Cancer Trials (COMM-PACT) identifies a mandatory set of baseline and prognostic characteristics to allow adequate comparison of outcomes between pancreatic cancer studies.

2 Guideline Definition of a standard lymphadenectomy in surgery for pancreatic ductal adenocarcinoma: a consensus statement by the International Study Group on Pancreatic Surgery (ISGPS). 2014

Tol, Johanna A M G / Gouma, Dirk J / Bassi, Claudio / Dervenis, Christos / Montorsi, Marco / Adham, Mustapha / Andrén-Sandberg, Ake / Asbun, Horacio J / Bockhorn, Maximilian / Büchler, Markus W / Conlon, Kevin C / Fernández-Cruz, Laureano / Fingerhut, Abe / Friess, Helmut / Hartwig, Werner / Izbicki, Jakob R / Lillemoe, Keith D / Milicevic, Miroslav N / Neoptolemos, John P / Shrikhande, Shailesh V / Vollmer, Charles M / Yeo, Charles J / Charnley, Richard M / Anonymous3050801. ·Department of Surgery, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands. · Department of Surgery, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands. Electronic address: D.J.Gouma@amc.nl. · Department of Surgery and Oncology, Pancreas Institute, University of Verona, Verona, Italy. · Department of First Surgery, Agia Olga Hospital, Athens, Greece. · Department of General Surgery, Instituto Clinico Humanitas IRCCS, University of Milan, Milan, Italy. · Department of HPB Surgery, Hopital Edouard Herriot, Lyon, France. · Department of Surgery, Karolinska Institutet at Karolinska University Hospital, Huddinge, Stockholm, Sweden. · Department of General Surgery, Mayo Clinic, Jacksonville, FL. · Department of General-, Visceral- and Thoracic-Surgery, University Hospital Hamburg-Eppendorf, Hamburg, Germany. · Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany. · Professorial Surgical Unit, University of Dublin, Trinity College, Dublin, Ireland. · Department of Surgery, Clinic Hospital of Barcelona, University of Barcelona, Barcelona, Spain. · First Department of Digestive Surgery, Hippokrateon Hospital, University of Athens, Athens, Greece; Section for Surgical Research, Department of Surgery, Medical University of Graz, Graz, Austria. · Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. · Department of Surgery, Massachusetts General Hospital and the Harvard Medical School, Boston, MA. · First Surgical Clinic, Clinical Center of Serbia, University of Belgrade, Belgrade, Serbia. · Department of Molecular and Clinical Cancer Medicine, Liverpool Cancer Research-UK Centre, University of Liverpool, Liverpool, UK. · Department of Gastrointestinal and HPB Surgical Oncology, Tata Memorial Hospital, Mumbai, India. · Department of Surgery, Penn Medicine, The University of Pennsylvania, Philadelphia, PA. · Department of Surgery, Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, PA. · Department of HPB & Transplant Surgery, Freeman Hospital, Newcastle upon Tyne, UK. ·Surgery · Pubmed #25061003.

ABSTRACT: BACKGROUND: The lymph node (Ln) status of patients with resectable pancreatic ductal adenocarcinoma is an important predictor of survival. The survival benefit of extended lymphadenectomy during pancreatectomy is, however, disputed, and there is no true definition of the optimal extent of the lymphadenectomy. The aim of this study was to formulate a definition for standard lymphadenectomy during pancreatectomy. METHODS: During a consensus meeting of the International Study Group on Pancreatic Surgery, pancreatic surgeons formulated a consensus statement based on available literature and their experience. RESULTS: The nomenclature of the Japanese Pancreas Society was accepted by all participants. Extended lymphadenectomy during pancreatoduodenectomy with resection of Ln's along the left side of the superior mesenteric artery (SMA) and around the celiac trunk, splenic artery, or left gastric artery showed no survival benefit compared with a standard lymphadenectomy. No level I evidence was available on prognostic impact of positive para-aortic Ln's. Consensus was reached on selectively removing suspected Ln's outside the resection area for frozen section. No consensus was reached on continuing or terminating resection in cases where these nodes were positive. CONCLUSION: Extended lymphadenectomy cannot be recommended. Standard lymphadenectomy for pancreatoduodenectomy should strive to resect Ln stations no. 5, 6, 8a, 12b1, 12b2, 12c, 13a, 13b, 14a, 14b, 17a, and 17b. For cancers of the body and tail of the pancreas, removal of stations 10, 11, and 18 is standard. Furthermore, lymphadenectomy is important for adequate nodal staging. Both pancreatic resection in relatively fit patients or nonresectional palliative treatment were accepted as acceptable treatment in cases of positive Ln's outside the resection plane. This consensus statement could serve as a guide for surgeons and researchers in future directives and new clinical studies.

3 Guideline Extended pancreatectomy in pancreatic ductal adenocarcinoma: definition and consensus of the International Study Group for Pancreatic Surgery (ISGPS). 2014

Hartwig, Werner / Vollmer, Charles M / Fingerhut, Abe / Yeo, Charles J / Neoptolemos, John P / Adham, Mustapha / Andrén-Sandberg, Ake / Asbun, Horacio J / Bassi, Claudio / Bockhorn, Max / Charnley, Richard / Conlon, Kevin C / Dervenis, Christos / Fernandez-Cruz, Laureano / Friess, Helmut / Gouma, Dirk J / Imrie, Clem W / Lillemoe, Keith D / Milićević, Miroslav N / Montorsi, Marco / Shrikhande, Shailesh V / Vashist, Yogesh K / Izbicki, Jakob R / Büchler, Markus W / Anonymous1520795. ·Department of Surgery, Klinikum Großhadern, University of Munich, Munich, Germany. · Department of Gastrointestinal Surgery, Penn Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA. · Department of Digestive Surgery, Centre Hospitalier Intercommunal, Poissy, France. · Department of Surgery, Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, PA. · Department of Molecular and Clinical Cancer Medicine, Liverpool Cancer Research-UK Centre, University of Liverpool, Liverpool, UK. · Department of HPB Surgery, Hopital Edouard Herriot, Lyon, France. · Department of Surgery, Karolinska Institutet at Karolinska University Hospital, Huddinge, Stockholm, Sweden. · Department of General Surgery, Mayo Clinic, Jacksonville, FL. · Department of Surgery and Oncology, Pancreas Institute, University of Verona, Verona, Italy. · Department of General-, Visceral- and Thoracic-Surgery, University Hospital Hamburg-Eppendorf, Hamburg, Germany. · Department of HPB & Transplant Surgery, Freeman Hospital, Newcastle upon Tyne, UK. · Professorial Surgical Unit, University of Dublin, Trinity College, Dublin, Ireland. · Department of First Surgery, Agia Olga Hospital, Athens, Greece. · Department of Surgery, Clinic Hospital of Barcelona, University of Barcelona, Barcelona, Spain. · Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. · Department of Surgery, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands. · Academic Unit of Surgery, University of Glasgow, Glasgow, UK. · Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA. · First Surgical Clinic, Clinical Center of Serbia, University of Belgrade, Belgrade, Serbia. · Department of General Surgery, Instituto Clinico Humanitas IRCCS, University of Milan, Milan, Italy. · Department of Gastrointestinal and HPB Surgical Oncology, Tata Memorial Hospital, Mumbai, India. · Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany. Electronic address: markus.buechler@med.uni-heidelberg.de. ·Surgery · Pubmed #24856668.

ABSTRACT: BACKGROUND: Complete macroscopic tumor resection is one of the most relevant predictors of long-term survival in pancreatic ductal adenocarcinoma. Because locally advanced pancreatic tumors can involve adjacent organs, "extended" pancreatectomy that includes the resection of additional organs may be needed to achieve this goal. Our aim was to develop a common consistent terminology to be used in centers reporting results of pancreatic resections for cancer. METHODS: An international panel of pancreatic surgeons working in well-known, high-volume centers reviewed the literature on extended pancreatectomies and worked together to establish a consensus on the definition and the role of extended pancreatectomy in pancreatic cancer. RESULTS: Macroscopic (R1) and microscopic (R0) complete tumor resection can be achieved in patients with locally advanced disease by extended pancreatectomy. Operative time, blood loss, need for blood transfusions, duration of stay in the intensive care unit, and hospital morbidity, and possibly also perioperative mortality are increased with extended resections. Long-term survival is similar compared with standard resections but appears to be better compared with bypass surgery or nonsurgical palliative chemotherapy or chemoradiotherapy. It was not possible to identify any clear prognostic criteria based on the specific additional organ resected. CONCLUSION: Despite increased perioperative morbidity, extended pancreatectomy is warranted in locally advanced disease to achieve long-term survival in pancreatic ductal adenocarcinoma if macroscopic clearance can be achieved. Definitions of extended pancreatectomies for locally advanced disease (and not distant metastatic disease) are established that are crucial for comparison of results of future trials across different practices and countries, in particular for those using neoadjuvant therapy.

4 Guideline Borderline resectable pancreatic cancer: a consensus statement by the International Study Group of Pancreatic Surgery (ISGPS). 2014

Bockhorn, Maximilian / Uzunoglu, Faik G / Adham, Mustapha / Imrie, Clem / Milicevic, Miroslav / Sandberg, Aken A / Asbun, Horacio J / Bassi, Claudio / Büchler, Markus / Charnley, Richard M / Conlon, Kevin / Cruz, Laureano Fernandez / Dervenis, Christos / Fingerhutt, Abe / Friess, Helmut / Gouma, Dirk J / Hartwig, Werner / Lillemoe, Keith D / Montorsi, Marco / Neoptolemos, John P / Shrikhande, Shailesh V / Takaori, Kyoichi / Traverso, William / Vashist, Yogesh K / Vollmer, Charles / Yeo, Charles J / Izbicki, Jakob R / Anonymous1510795. ·Department of General, Visceral and Thoracic Surgery, University Hospital Hamburg-Eppendorf, Hamburg, Germany. · Department of HPB Surgery, Hôpital Edouard Herriot, Lyon, France. · Academic Unit of Surgery, University of Glasgow, Glasgow, UK. · First Surgical Clinic, Clinical Center of Serbia, University of Belgrade, Belgrade, Serbia. · Department of Surgery, Karolinska Institutet at Karolinska University Hospital, Huddinge, Stockholm, Sweden. · Department of General Surgery, Mayo Clinic, Jacksonville, FL. · Department of Surgery and Oncology, Pancreas Institute, University of Verona, Verona, Italy. · Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany. · Department of HPB & Transplant Surgery, Freeman Hospital, Newcastle upon Tyne, UK. · Professorial Surgical Unit, University of Dublin, Trinity College, Dublin, Ireland. · Department of Surgery, Clinic Hospital of Barcelona, University of Barcelona, Barcelona, Spain. · First Department of Surgery, Agia Olga Hospital, Athens, Greece. · Department of Digestive Surgery, Centre Hospitalier Intercommunal, Poissy, France. · Department of Surgery, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. · Department of Surgery, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands. · Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA. · Department of General Surgery, Instituto Clinico Humanitas IRCCS, University of Milan, Milan, Italy. · Department of Molecular and Clinical Cancer Medicine, Liverpool Cancer Research-UK Centre, University of Liverpool, Liverpool, UK. · Department of Gastrointestinal and HPB Surgical Oncology, Tata Memorial Centre, Mumbai, India. · Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan. · St. Luke's Clinic - Center For Pancreatic and Liver Diseases, Boise, ID. · Department of Gastrointestinal Surgery, Penn Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA. · Department of Surgery, Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, PA. · Department of General, Visceral and Thoracic Surgery, University Hospital Hamburg-Eppendorf, Hamburg, Germany. Electronic address: izbicki@uke.de. ·Surgery · Pubmed #24856119.

ABSTRACT: BACKGROUND: This position statement was developed to expedite a consensus on definition and treatment for borderline resectable pancreatic ductal adenocarcinoma (BRPC) that would have worldwide acceptability. METHODS: An international panel of pancreatic surgeons from well-established, high-volume centers collaborated on a literature review and development of consensus on issues related to borderline resectable pancreatic cancer. RESULTS: The International Study Group of Pancreatic Surgery (ISGPS) supports the National Comprehensive Cancer Network criteria for the definition of BRPC. Current evidence supports operative exploration and resection in the case of involvement of the mesentericoportal venous axis; in addition, a new classification of extrahepatic mesentericoportal venous resections is proposed by the ISGPS. Suspicion of arterial involvement should lead to exploration to confirm the imaging-based findings. Formal arterial resections are not recommended; however, in exceptional circumstances, individual therapeutic approaches may be evaluated under experimental protocols. The ISGPS endorses the recommendations for specimen examination and the definition of an R1 resection (tumor within 1 mm from the margin) used by the British Royal College of Pathologists. Standard preoperative diagnostics for BRPC may include: (1) serum levels of CA19-9, because CA19-9 levels predict survival in large retrospective series; and also (2) the modified Glasgow Prognostic Score and the neutrophil/lymphocyte ratio because of the prognostic relevance of the systemic inflammatory response. Various regimens of neoadjuvant therapy are recommended only in the setting of prospective trials at high-volume centers. CONCLUSION: Current evidence justifies portomesenteric venous resection in patients with BRPC. Basic definitions were identified, that are currently lacking but that are needed to obtain further evidence and improvement for this important patient subgroup. A consensus for each topic is given.

5 Guideline [S3-guideline exocrine pancreatic cancer]. 2013

Seufferlein, T / Porzner, M / Becker, T / Budach, V / Ceyhan, G / Esposito, I / Fietkau, R / Follmann, M / Friess, H / Galle, P / Geissler, M / Glanemann, M / Gress, T / Heinemann, V / Hohenberger, W / Hopt, U / Izbicki, J / Klar, E / Kleeff, J / Kopp, I / Kullmann, F / Langer, T / Langrehr, J / Lerch, M / Löhr, M / Lüttges, J / Lutz, M / Mayerle, J / Michl, P / Möller, P / Molls, M / Münter, M / Nothacker, M / Oettle, H / Post, S / Reinacher-Schick, A / Röcken, C / Roeb, E / Saeger, H / Schmid, R / Schmiegel, W / Schoenberg, M / Siveke, J / Stuschke, M / Tannapfel, A / Uhl, W / Unverzagt, S / van Oorschot, B / Vashist, Y / Werner, J / Yekebas, E / Anonymous230779 / Anonymous240779 / Anonymous250779. ·Klinik für Innere Medizin I, Universitätsklinikum Ulm. · Klinik für Allgemeine Chirurgie, Viszeral-, Thorax-, Transplantations- und Kinderchirurgie, Universitätsklinikum Kiel. · Klinik für Radioonkologie und Strahlentherapie, Charité Universitätsmedizin Berlin. · Chirurgische Klinik und Poliklinik, Klinikum rechts der Isar, TU München. · Institut für Allgemeine Pathologie, Klinikum rechts der Isar, TU München. · Strahlenklinik, Universitätsklinikum Erlangen. · Leitlinienprogramm Onkologie, Deutsche Krebsgesellschaft e. V., Berlin. · I. Medizinische Klinik und Poliklinik, Universitätsmedizin Mainz. · Klinik für Allgemeine Innere Medizin, Onkologie/Hämatologie, Gastroenterologie und Infektiologie, Klinikum Esslingen. · Klinik für Allgemeine Chirurgie, Viszeral-, Gefäß- und Kinderchirurgie, Universitätsklinikum des Saarlandes Homburg/Saar. · Klinik für Gastroenterologie, Endokrinologie und Stoffwechsel, Universitätsklinikum Gießen und Marburg. · Medizinischen Klinik und Poliklinik III, Klinikum der Universität München LMU. · Chirurgische Klinik, Universitätsklinikum Erlangen. · Klinik für Allgemein- und Viszeralchirurgie, Universitätsklinikum Freiburg. · Klinik für Allgemein-, Viszeral- und Thoraxchirurgie, Universitätsklinikum Hamburg-Eppendorf. · Klinik für Allgemeine Chirurgie, Thorax-, Gefäß- und Transplantationschirurgie, Universitätsmedizin Rostock. · AWMF-Institut für Medizinisches Wissensmanagement, Marburg. · Medizinische Klinik I, Klinikum Weiden. · Klinik für Allgemein-, Gefäß- und Viszeralchirurgie, Martin-Luther-Krankenhaus Berlin. · Klinik und Poliklinik für Innere Medizin A, Universitätsmedizin Greifswald. · Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm. · Institut für Pathologie, Marienkrankenhaus Hamburg. · Medizinische Klinik - Schwerpunkt Gastroenterologie, Endokrinologie, Infektiologie, Caritasklinikum Saarbrücken. · Institut für Pathologie, Universitätsklinikum Ulm. · Klinik und Poliklinik für Strahlentherapie und Radiologische Onkologie, Klinikum rechts der Isar, TU München. · Klinik für Strahlentherapie und Radioonkologie, Klinikum Stuttgart. · AWMF-Institut für Medizinisches Wissensmanagement, Berlin. · Medizinische Klinik mit Schwerpunkt Hämatologie und Onkologie, Charité Universitätsmedizin Berlin. · Chirurgische Klinik, Universitätsmedizin Mannheim. · Abt. für Hämatologie und Onkologie, St. Josef-Hospital, Klinikum der Ruhr-Universität Bochum. · Institut für Pathologie, Universitätsklinikum Kiel. · Medizinische Klinik II, SP Gastroenterologie, Universitätsklinikum Gießen und Marburg. · Klinik für Viszeral-, Thorax- und Gefäßchirurgie, Universitätsklinikum Dresden. · II. Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, TU München. · Medizinische Klinik, Klinikum der Ruhr-Universität Bochum. · Klinik für Chirurgie, Rotkreuzklinikum München. · Klinik für Strahlentherapie, Universitätsklinikum Essen. · Institut für Pathologie, Ruhr-Universität Bochum. · Chirurgische Klinik, St. Josef-Hospital, Klinikum der Ruhr-Universität Bochum. · Institut für Medizinische Epidemiologie, Biometrie und Informatik, Martin-Luther-Universität Halle-Wittenberg. · Klinik und Poliklinik für Strahlentherapie, Universitätsklinikum Würzburg. · Klinik für Allgemeine, Viszerale und Transplantationschirurgie, Universitätsklinikum Heidelberg. · Klinik für Allgemein-, Thorax- und Viszeralchirurgie, Klinikum Darmstadt. ·Z Gastroenterol · Pubmed #24338757.

ABSTRACT: -- No abstract --

6 Guideline European experts consensus statement on cystic tumours of the pancreas. 2013

Del Chiaro, Marco / Verbeke, Caroline / Salvia, Roberto / Klöppel, Gunter / Werner, Jens / McKay, Colin / Friess, Helmut / Manfredi, Riccardo / Van Cutsem, Eric / Löhr, Matthias / Segersvärd, Ralf / Anonymous3140750. ·Division of Surgery, CLINTEC, Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden. Electronic address: marco.del-chiaro@karolinska.se. ·Dig Liver Dis · Pubmed #23415799.

ABSTRACT: Cystic lesions of the pancreas are increasingly recognized. While some lesions show benign behaviour (serous cystic neoplasm), others have an unequivocal malignant potential (mucinous cystic neoplasm, branch- and main duct intraductal papillary mucinous neoplasm and solid pseudo-papillary neoplasm). European expert pancreatologists provide updated recommendations: diagnostic computerized tomography and/or magnetic resonance imaging are indicated in all patients with cystic lesion of the pancreas. Endoscopic ultrasound with cyst fluid analysis may be used but there is no evidence to suggest this as a routine diagnostic method. The role of pancreatoscopy remains to be established. Resection should be considered in all symptomatic lesions, in mucinous cystic neoplasm, main duct intraductal papillary mucinous neoplasm and solid pseudo-papillary neoplasm as well as in branch duct intraductal papillary mucinous neoplasm with mural nodules, dilated main pancreatic duct >6mm and possibly if rapidly increasing in size. An oncological partial resection should be performed in main duct intraductal papillary mucinous neoplasm and in lesions with a suspicion of malignancy, otherwise organ preserving procedures may be considered. Frozen section of the transection margin in intraductal papillary mucinous neoplasm is suggested. Follow up after resection is recommended for intraductal papillary mucinous neoplasm, solid pseudo-papillary neoplasm and invasive cancer.

7 Editorial Epigenomic therapies: the potential of targeting SIRT6 for the treatment of pancreatic cancer. 2017

Demir, Ihsan Ekin / Ceyhan, Güralp O / Friess, Helmut. ·a Department of Surgery, Klinikum rechts der Isar , Technische Universität München , Munich , Germany. ·Expert Opin Ther Targets · Pubmed #27885875.

ABSTRACT: -- No abstract --

8 Review Insulin/IGF-driven cancer cell-stroma crosstalk as a novel therapeutic target in pancreatic cancer. 2018

Mutgan, Ayse Ceren / Besikcioglu, H Erdinc / Wang, Shenghan / Friess, Helmut / Ceyhan, Güralp O / Demir, Ihsan Ekin. ·Department of Surgery, Klinikum rechts der Isar, Technical University Munich, München, Germany. · Department of Histology and Embryology, Gazi University Institute of Health Sciences, Ankara, Turkey. · Department of Surgery, Klinikum rechts der Isar, Technical University Munich, München, Germany. ekin.demir@tum.de. ·Mol Cancer · Pubmed #29475434.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is unrivalled the deadliest gastrointestinal cancer in the western world. There is substantial evidence implying that insulin and insulin-like growth factor (IGF) signaling axis prompt PDAC into an advanced stage by enhancing tumor growth, metastasis and by driving therapy resistance. Numerous efforts have been made to block Insulin/IGF signaling pathway in cancer therapy. However, therapies that target the IGF1 receptor (IGF-1R) and IGF subtypes (IGF-1 and IGF-2) have been repeatedly unsuccessful. This failure may not only be due to the complexity and homology that is shared by Insulin and IGF receptors, but also due to the complex stroma-cancer interactions in the pancreas. Shedding light on the interactions between the endocrine/exocrine pancreas and the stroma in PDAC is likely to steer us toward the development of novel treatments. In this review, we highlight the stroma-derived IGF signaling and IGF-binding proteins as potential novel therapeutic targets in PDAC.

9 Review A look at the progress of treating pancreatic cancer over the past 20 years. 2018

Goess, Ruediger / Friess, Helmut. ·a Department of Surgery, School of Medicine , Technical University of Munich , Munich , Germany. ·Expert Rev Anticancer Ther · Pubmed #29334794.

ABSTRACT: INTRODUCTION: Pancreatic cancer is known to be the deadliest of all common cancers. Despite all efforts in pancreatic cancer treatment, the five-year survival rates at diagnosis over the past 20 years have only increased from 5% to 8%. Assuming that pancreatic cancer is going to become the second most frequent cause of cancer related death in the next 20 years, we are all encouraged to treat patients in clinical trials to gain improvements in this devastating disease. Areas covered: This review will provide a summary of pancreatic cancer treatment over the last 20 years, starting with the pivotal study in 1997 which showed the superiority of gemcitabine over 5-FU in advanced pancreatic cancer and is marked as the beginning of a new era in pancreatic cancer treatment. This review will also focus on improvements in different areas of treatment, including pancreatic surgery, adjuvant treatment, neoadjuvant therapy and palliative therapy. Expert commentary: The treatment of pancreatic cancer has changed substantially in the last 20 years compared to almost no improvements in the decades before. This provides hope that more effective treatment options will become available in the near future. Particularly, new concepts such as neoadjuvant therapy in resectable and borderline-resectable tumors may potentially shift treatment strategies.

10 Review [Resection of main duct and mixed type IPMN ≥5 mm]. 2017

Ceyhan, G O / Scheufele, F / Friess, H. ·Klinik und Poliklinik für Chirurgie, Klinikum rechts der Isar, Technischen Universität München, Ismaninger Str. 22, 81675, München, Deutschland. · Klinik und Poliklinik für Chirurgie, Klinikum rechts der Isar, Technischen Universität München, Ismaninger Str. 22, 81675, München, Deutschland. helmut.friess@tum.de. ·Chirurg · Pubmed #28842734.

ABSTRACT: The incidence of cystic pancreatic lesions is steadily increasing due to the technical advances in imaging. Within the group of cystic pancreatic lesions intraductal papillary mucinous neoplasms (IPMNs) depict an important entity. Due to a possible progression to malignancy the clinical strategy has to be well chosen. For primary diagnostic work-up imaging by magnetic resonance imaging (MRI) with MR cholangiopancreatography (MRCP) and computed tomography (CT) scanning is recommended. Additional information can be gained by endosonography and a biopsy of the cystic lesion, allowing analysis of biomarkers, such as GNAS and KRAS mutation as wells as NLR. These can help to differentiate between IPMN and other cystic lesions although the clinical importance for the diagnosis of main duct (MD) and mixed IPMN is limited. The current guidelines (Fukuoka and EU guidelines) recommend resection of MD and mixed IPMN following oncological standards. For the definition of MD-IPMN, a duct dilatation between 5-10 mm is needed when following the current guidelines; however, current publications claim an even lower cut-off of ≥5 mm due to the risk of malignant progression. Intraoperative frozen sections are recommended to evaluate the margins status and extended resection is recommended for residual high-grade dysplasia. Surveillance of potentially at risk patients is recommended at regular intervals of 6-12 months while patients with malignant IPMN should be followed according to pancreatic cancer protocols. A screening for extrapancreatic malignancy is not indicated.

11 Review The impact of neoadjuvant therapy on the histopathological features of pancreatic ductal adenocarcinoma - A systematic review and meta-analysis. 2017

Schorn, Stephan / Demir, Ihsan Ekin / Reyes, Carmen Mota / Saricaoglu, Cemil / Samm, Nicole / Schirren, Rebekka / Tieftrunk, Elke / Hartmann, Daniel / Friess, Helmut / Ceyhan, Güralp Onur. ·Department of Surgery, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. · Department of Surgery, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. Electronic address: gueralp.ceyhan@tum.de. ·Cancer Treat Rev · Pubmed #28342938.

ABSTRACT: BACKGROUND: Due to increased rates of curative tumor resections exceeding 60% after FOLFIRINOX-treatment, neoadjuvant therapy/NTx is increasingly recognized as an effective therapy option for downstaging borderline or locally advanced pancreatic ductal adenocarcinoma/PDAC. Yet, the effects of NTx on the common histopathological features of PDAC have not been systematically analysed. Therefore, the aim of the current study was to assess the impact of NTx on relevant histopathological features of PDAC. PATIENTS AND METHODS: Biomedical databases were systematically screened for predefined searching terms related to NTx and PDAC. The Preferred-Reporting-Items-for-Systematic-review-and-Meta-Analysis/PRISMA-guidelines were used to perform a systematic review and meta-analysis. Articles meeting the predefined criteria were analysed on relevance, and a meta-analysis was performed. RESULTS: A total of 9031 studies could be identified that analysed the effect of NTx on PDAC. Only 35 studies presented comparative data on the histological features of neoadjuvantly treated vs. upfront resected PDAC patients. In meta-analyses, the beneficial effect of NTx was reflected by reduced tumor size (T1/2: RR 2.87, 95%-CI: 1.52-5.42, P=0.001, T3/4: RR 0.78, 95%-CI: 0.69-0.89, P=0.0002), lower N-Stage (N0: RR 2.14, 95%-CI: 1.85-2.46, P<0.00001, N1: RR 0.59, 95%-CI: 0.53-0.65, P<0.00001), higher R0-rates (R0: RR 1.13, 95%-CI: 1.08-1.18, P<0.00001, R1: RR 0.66, 95%-CI: 0.58-0.76, P<0.00001), less perineural invasion (Pn1: RR 0.78, 95%-CI: 0.73-0.83, P<0.00001), less lymphatic vessel invasion (RR: 0.50, 95%-CI: 0.36-0.70, P<0.0001) and fewer G3-tumors (RR 0.82, 95%-CI: 0.71-0.94, P=0.005). CONCLUSIONS: NTx in PDAC seems to exert its beneficial effect in borderline or locally advanced PDAC over genuine tumor downstaging. Thus, although at least 40% of all NTx treated patients remain unresectable even with modern NTx regimes, neoadjuvantly treated PDAC showed not only increasing resectability rates especially after FOLFIRINOX, but even reach a lower tumor stage than primarily resected PDAC.

12 Review The influence of neural invasion on survival and tumor recurrence in pancreatic ductal adenocarcinoma - A systematic review and meta-analysis. 2017

Schorn, Stephan / Demir, Ihsan Ekin / Haller, Bernhard / Scheufele, Florian / Reyes, Carmen Mota / Tieftrunk, Elke / Sargut, Mine / Goess, Ruediger / Friess, Helmut / Ceyhan, Güralp Onur. ·Department of Surgery, Klinikum Rechts der Isar, Technical University of Munich, Germany. · Institute of Medical Statistics and Epidemiology, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. · Department of Surgery, Klinikum Rechts der Isar, Technical University of Munich, Germany. Electronic address: gueralp.ceyhan@tum.de. ·Surg Oncol · Pubmed #28317579.

ABSTRACT: OBJECTIVES: To assess the impact of neural invasion/NI on overall survival/OS and tumor recurrence in pancreatic ductal adenocarcinoma/PDAC. SUMMARY BACKGROUND DATA: NI is a histopathological hallmark of PDAC. Although some studies suggested an important role for NI on OS, disease-free/DFS and progression-free survival/PFS in PDAC, there is still no consensus on the actual role of NI on survival and local recurrence in PDAC. METHODS: Pubmed, Cochrane library, Ovid and Google Scholar were screened for the terms "pancreatic ductal adenocarcinoma", "pancreatic cancer", "survival", "tumor recurrence" and "perineural invasion". The Preferred-Reporting-Items-for-Systematic-review-and-Meta-Analysis/PRISMA-guidelines were used for systematic review and meta-analysis. Articles meeting predefined criteria were critically analysed on relevance, and meta-analyses were performed by pooling univariate and multivariate hazard ratios/HR. RESULTS: A total number of 25 studies on the influence of NI on tumor recurrence, and 121 studies analysing the influence of NI on survival were identified by systematic review. The HR of the univariate (HR 1.88; 95%-CI 1.71-2.07; p < 0.00001) and multivariate meta-analysis (HR 1.68; 95%-CI 1.47-1.92; p < 0.00001) showed a major impact of NI on OS. Likewise, NI was associated with decreased DFS (HR 2.53; 95%-CI: 1.67-3.83; p = 0.0001) and PFS (HR 2.41; 95%-CI: 1.73-3.37: p < 0.00001) multivariate meta-analysis. CONCLUSIONS: Although the power of this study is limited by missing pathological procedures to assess the true incidence of NI, NI appears to be an independent prognostic factor for OS, DFS and PFS in PDAC. Therefore, NI should be increasingly considered in patient stratification and in the development of novel therapeutic algorithms.

13 Review Preoperative biliary stenting versus operation first in jaundiced patients due to malignant lesions in the pancreatic head: A meta-analysis of current literature. 2017

Scheufele, Florian / Schorn, Stephan / Demir, Ihsan Ekin / Sargut, Mine / Tieftrunk, Elke / Calavrezos, Lenika / Jäger, Carsten / Friess, Helmut / Ceyhan, Güralp Onur. ·Department of Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. · Department of Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. Electronic address: gueralp.ceyhan@tum.de. ·Surgery · Pubmed #28043693.

ABSTRACT: BACKGROUND: Obstructive jaundice is a common presenting symptom among patients with pancreatic cancer. While benefits of preoperative biliary drainage have been suggested by previous studies, recent evidence has shown no significant improvements of preoperative biliary drainage on the postoperative outcome but rather an increase of complications. There is no clear consensus on whether to treat malignant obstructive jaundice with preoperative biliary drainage prior to operative intervention or to proceed directly to resection. Thus, our aim was to elucidate the impact of preoperative biliary drainage of obstructive jaundice due to malignant pancreatic head tumors on postoperative morbidity and mortality. METHODS: We conducted a meta-analysis in accordance with the PRISMA guidelines and carried out a systematic search of medical databases. The results were analyzed according to predefined criteria. We pooled the incidence of overall complications, wound infection, pancreatic fistula, intra-abdominal abscess, and death within the perioperative time period. RESULTS: We initially identified 1,816 studies, and 25 of these (22 retrospective studies, 3 randomized controlled trials) were finally included in the analysis with a total number of 6,214 patients. Analysis revealed an increased incidence of overall complications (odds ratio: 1.40; 95% confidence interval: 1.14-1.72; P = .002) and wound infections (odds ratio: 1.94; 95% confidence interval: 1.48-2.53; P < .00001) in patients receiving preoperative biliary drainage compared to operative intervention first. Mortality, incidence of pancreatic fistula, or intra-abdominal abscess formation were not affected by preoperative biliary drainage. CONCLUSION: Preoperative biliary drainage does not have a beneficial effect on postoperative outcome. The increase of postoperative overall complications and wound infections urges for precise indications for preoperative biliary drainage and against routine preoperative biliary decompression.

14 Review Definition and classification of chyle leak after pancreatic operation: A consensus statement by the International Study Group on Pancreatic Surgery. 2017

Besselink, Marc G / van Rijssen, L Bengt / Bassi, Claudio / Dervenis, Christos / Montorsi, Marco / Adham, Mustapha / Asbun, Horacio J / Bockhorn, Maximillian / Strobel, Oliver / Büchler, Markus W / Busch, Olivier R / Charnley, Richard M / Conlon, Kevin C / Fernández-Cruz, Laureano / Fingerhut, Abe / Friess, Helmut / Izbicki, Jakob R / Lillemoe, Keith D / Neoptolemos, John P / Sarr, Michael G / Shrikhande, Shailesh V / Sitarz, Robert / Vollmer, Charles M / Yeo, Charles J / Hartwig, Werner / Wolfgang, Christopher L / Gouma, Dirk J / Anonymous2270883. ·Department of Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Electronic address: m.g.besselink@amc.nl. · Department of Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. · Department of Surgery and Oncology, Pancreas Institute, University of Verona, Verona, Italy. · Department of First Surgery, Agia Olga Hospital, Athens, Greece. · Department of Surgery, Humanitas Research Hospital and University, Milan, Italy. · Department of HPB Surgery, Hopital Edouard Herriot, HCL, UCBL1, Lyon, France. · Department of Surgery, Mayo Clinic, Jacksonville, FL. · Department of General-, Visceral-, and Thoracic-Surgery, University Hospital Hamburg-Eppendorf, Hamburg, Germany. · Department of General, Visceral, and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany. · Department of HPB & Transplant Surgery, Freeman Hospital, Newcastle upon Tyne, UK. · Professorial Surgical Unit, University of Dublin, Trinity College, Dublin, Ireland. · Department of Surgery, Clinic Hospital of Barcelona, University of Barcelona, Barcelona, Spain. · First Department of Digestive Surgery, Hippokrateon Hospital, University of Athens, Athens, Greece; Section for Surgical Research, Department of Surgery, Medical University of Graz, Graz, Austria. · Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. · Department of Surgery, Massachusetts General Hospital and the Harvard Medical School, Boston, MA. · Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK. · Division of Subspecialty General Surgery, Mayo Clinic, Rochester, MN. · Department of GI and HPB Surgical Oncology, Tata Memorial Hospital, Mumbai, India. · Department of Surgical Oncology, Medical University in Lublin, Poland. · Department of Surgery, Penn Medicine, The University of Pennsylvania, Philadelphia, PA. · Department of Surgery, Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, PA. · Division of Pancreatic Surgery, Department of General, Visceral, and Transplantation Surgery, Ludwig Maximilians University, University of Munich, Germany. · Department of Surgery, Johns Hopkins Medicine, Baltimore, MD. ·Surgery · Pubmed #27692778.

ABSTRACT: BACKGROUND: Recent literature suggests that chyle leak may complicate up to 10% of pancreatic resections. Treatment depends on its severity, which may include chylous ascites. No international consensus definition or grading system of chyle leak currently is available. METHODS: The International Study Group on Pancreatic Surgery, an international panel of pancreatic surgeons working in well-known, high-volume centers, reviewed the literature and worked together to establish a consensus on the definition and classification of chyle leak after pancreatic operation. RESULTS: Chyle leak was defined as output of milky-colored fluid from a drain, drain site, or wound on or after postoperative day 3, with a triglyceride content ≥110 mg/dL (≥1.2 mmol/L). Three different grades of severity were defined according to the management needed: grade A, no specific intervention other than oral dietary restrictions; grade B, prolongation of hospital stay, nasoenteral nutrition with dietary restriction, total parenteral nutrition, octreotide, maintenance of surgical drains, or placement of new percutaneous drains; and grade C, need for other more invasive in-hospital treatment, intensive care unit admission, or mortality. CONCLUSION: This classification and grading system for chyle leak after pancreatic resection allows for comparison of outcomes between series. As with the other the International Study Group on Pancreatic Surgery consensus statements, this classification should facilitate communication and evaluation of different approaches to the prevention and treatment of this complication.

15 Review Neural plasticity in pancreatitis and pancreatic cancer. 2015

Demir, Ihsan Ekin / Friess, Helmut / Ceyhan, Güralp O. ·Department of Surgery, Klinikum Rechts der Isar, Technische Universität München, Ismaninger Strasse 22, D-81675 Munich, Germany. ·Nat Rev Gastroenterol Hepatol · Pubmed #26460352.

ABSTRACT: Pancreatic nerves undergo prominent alterations during the evolution and progression of human chronic pancreatitis and pancreatic cancer. Intrapancreatic nerves increase in size (neural hypertrophy) and number (increased neural density). The proportion of autonomic and sensory fibres (neural remodelling) is switched, and are infiltrated by perineural inflammatory cells (pancreatic neuritis) or invaded by pancreatic cancer cells (neural invasion). These neuropathic alterations also correlate with neuropathic pain. Instead of being mere histopathological manifestations of disease progression, pancreatic neural plasticity synergizes with the enhanced excitability of sensory neurons, with Schwann cell recruitment toward cancer and with central nervous system alterations. These alterations maintain a bidirectional interaction between nerves and non-neural pancreatic cells, as demonstrated by tissue and neural damage inducing neuropathic pain, and activated neurons releasing mediators that modulate inflammation and cancer growth. Owing to the prognostic effects of pain and neural invasion in pancreatic cancer, dissecting the mechanism of pancreatic neuroplasticity holds major translational relevance. However, current in vivo models of pancreatic cancer and chronic pancreatitis contain many discrepancies from human disease that overshadow their translational value. The present Review discusses novel possibilities for mechanistically uncovering the role of the nervous system in pancreatic disease progression.

16 Review Pancreatic disease in 2014: Pancreatic fibrosis and standard diagnostics. 2015

Ceyhan, Güralp O / Friess, Helmut. ·Department of Surgery, Klinikum Rechts der Isar, Technische Universität München, 81675 Munich, Germany. ·Nat Rev Gastroenterol Hepatol · Pubmed #25560846.

ABSTRACT: -- No abstract --

17 Review The role of inflammation in pancreatic cancer. 2014

Hausmann, Simone / Kong, Bo / Michalski, Christoph / Erkan, Mert / Friess, Helmut. ·Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Ismaningerstrasse 22, 81675, Munich, Germany. ·Adv Exp Med Biol · Pubmed #24818722.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with an extremely poor prognosis. Inflammatory processes have emerged as key mediators of pancreatic cancer development and progression. In genetically engineered mouse models, induction of pancreatitis accelerates PDAC development, and patients with chronic pancreatitis are known to have a higher risk of developing pancreatic cancer. In recent years, much effort has been given to identify the underlying mechanisms that contribute to inflammation-induced tumorigenesis. Many inflammatory pathways have been identified and inhibitors have been developed in order to prevent cancer development and progression. In this chapter, we discuss the role of inflammatory pathways in the initiation and progression of pancreatic cancer as well as the role of inhibitors used in treatment and prevention of pancreatic cancer.

18 Review The role of stroma in pancreatic cancer: diagnostic and therapeutic implications. 2012

Erkan, Mert / Hausmann, Simone / Michalski, Christoph W / Fingerle, Alexander A / Dobritz, Martin / Kleeff, Jörg / Friess, Helmut. ·Department of General Surgery, Klinikum rechts der Isar, Technische Universität München, Ismaningerstrasse 12, 81675 Munich, Germany. m.mert.erkan@googlemail.com ·Nat Rev Gastroenterol Hepatol · Pubmed #22710569.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is one of the five most lethal malignancies worldwide and survival has not improved substantially in the past 30 years. Desmoplasia (abundant fibrotic stroma) is a typical feature of PDAC in humans, and stromal activation commonly starts around precancerous lesions. It is becoming clear that this stromal tissue is not a bystander in disease progression. Cancer-stroma interactions effect tumorigenesis, angiogenesis, therapy resistance and possibly the metastatic spread of tumour cells. Therefore, targeting the tumour stroma, in combination with chemotherapy, is a promising new option for the treatment of PDAC. In this Review, we focus on four issues. First, how can stromal activity be used to detect early steps of pancreatic carcinogenesis? Second, what is the effect of perpetual pancreatic stellate cell activity on angiogenesis and tissue perfusion? Third, what are the (experimental) antifibrotic therapy options in PDAC? Fourth, what lessons can be learned from Langton's Ant (a simple mathematical model) regarding the unpredictability of genetically engineered mouse models?

19 Review The impact of the activated stroma on pancreatic ductal adenocarcinoma biology and therapy resistance. 2012

Erkan, Mert / Reiser-Erkan, Carolin / Michalski, Christoph W / Kong, Bo / Esposito, Irene / Friess, Helmut / Kleeff, Jorg. ·Department of General Surgery, Klinikum rechts der Isar, Technische Universität München, Germany. m.mert.erkan@googlemail.com ·Curr Mol Med · Pubmed #22272725.

ABSTRACT: Around 95% of patients diagnosed with pancreatic cancer will die of their disease within 5 years, three quarters within a year. The major hurdle in improving prognosis is the lack of a therapeutic time window. Early cancerous lesions are far beneath our threshold of detection. Therefore, at the time of diagnosis even early (T1) tumors can be metastatic and resistant to conventional treatments. Several therapies targeting epithelial tumor cells-all showing impressive results in vitro and in animal experiments-have failed to show relevant effects in clinical trials. This discrepancy between experimental data and clinical reality results mostly from the inefficiency of our current experimental setups in recreating the tumor microenvironment. Forming more than 80% of the tumor mass, the fibrotic stroma of pancreatic ductal adenocarcinoma is not a passive scaffold for the malignant cells but an active player in carcinogenesis. This component is mostly missing in the xeno-/allograft- mouse models. Although tumors are bigger if stellate cells are co-implanted, due to the disproportionate cancer/stromal cell ratio and -possibly- too rapid tumor growth, the stromal reaction is much smaller than in human pancreatic cancer. One the other hand, desmoplasia is present only in some of the genetically engineered mouse models. Clinically, stromal activity of the pancreatic ductal adenocarcinoma has as great an impact on patient prognosis as the lymph node status of the tumor. The exact molecular mechanisms behind this observation remain obscure. However, one possible fundamental biologic explanation could be that selective pressure applied by the stroma leads to the evolution of cancer cells. Consequently, somatic evolution of invasive cancer could be viewed as a sequence of phenotypical adaptations to this barrier, highlighting the importance of the fibrotic tumor microenvironment in the behavior of pancreatic cancer. In this review, the interaction of the epithelial tumor cells with the stroma in humans and in various animal models is scrutinized, and novel therapeutic options for uncoupling cancer-stroma interactions are discussed.

20 Review Palliative resections versus palliative bypass procedures in pancreatic cancer--a systematic review. 2012

Gillen, Sonja / Schuster, Tibor / Friess, Helmut / Kleeff, Jörg. ·Department of Surgery, Technische Universität München, Munich, Germany. ·Am J Surg · Pubmed #21872208.

ABSTRACT: BACKGROUND: Although resection is the only treatment option that offers a chance for prolonged survival in pancreatic cancer, R2 resections are controversial and not a generally accepted approach. METHODS: A systematic review and meta-analysis of studies of patients with pancreatic cancer was performed to analyze R2 resections in comparison with palliative surgical bypass procedures. Trials were identified by searching MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from 1966 to February 2011. RESULTS: Four cohort studies were identified comparing 138 patients with R2 resections with 261 patients undergoing surgical bypass procedures. Morbidity and mortality were increased in the R2 resection group, with pooled risk ratios of 1.75 (95% confidence interval [CI], 1.35-2.26; P < .0001) and 2.98 (95% CI, 1.31-6.75; P = .009), respectively. R2 resections were associated with longer operating times (mean difference, 164 minutes; 95% CI, 127-201 minutes; P < .00001) and hospital stays (mean difference, 5 days; 95% CI, 1-9 days; P = .02). Pooled median survival times were 8.2 months for R2 resection and 6.7 months for palliative bypass procedures. CONCLUSIONS: Planned palliative R2 resections are not justified in patients with pancreatic cancer.

21 Review From tissue turnover to the cell of origin for pancreatic cancer. 2011

Kong, Bo / Michalski, Christoph W / Erkan, Mert / Friess, Helmut / Kleeff, Jörg. ·Department of Surgery, Technische Universität München, Ismaningerstrasse 22, 81675 Munich, Germany. ·Nat Rev Gastroenterol Hepatol · Pubmed #21750515.

ABSTRACT: The identity of the cell of origin for pancreatic ductal adenocarcinoma (PDAC) has long been debated. PDAC has a ductal morphology, but there is no formal proof that it originates from the ductal compartment. Targeting Kras expression to adult acinar or endocrine lineages induces the formation of tumors reminiscent of human PDAC, but only in the presence of concomitant inflammation. Apart from cells of the Pdx1-positive lineage in the adult pancreas, which can be transformed (albeit with low frequency), the cells susceptible to acquiring or retaining oncogenic mutations remain elusive. Hypothetically, a subset of cells that renew the adult organ physiologically or regenerate it upon severe tissue damage would be more susceptible to oncogenic transformation than mature, differentiated cells. Such a compartment could consist of putative pancreatic stem cells, progenitor cells, facultative stem cells or transdifferentiated bone marrow cells. An integrated approach combining techniques from stem cell and cancer biology will be necessary to define and map these cells.

22 Review Insulin-like growth factor signaling as a therapeutic target in pancreatic cancer. 2011

Rieder, Simon / Michalski, Christoph W / Friess, Helmut / Kleeff, Jörg. ·Department of Surgery, Technische Universität München, Ismaninger Strasse 22, Munich, Germany. ·Anticancer Agents Med Chem · Pubmed #21492074.

ABSTRACT: Insulin-like growth factor-1 (IGF-1) leads via its receptor IGF-1R to the activation of the PI3K/Akt pathway, providing antiapoptotic signals to pre-malignant and malignant cells. In pancreatic cancer, IGF-1 and its receptor are constitutively overexpressed. Mammalian target of rapamycin (mTOR) is the main mediator of mitogenic stimuli transduced by PI3K/Akt. Interestingly, inhibition of mTOR activates PI3K/Akt by up-regulating IGF-1R signaling. Several targeted agents have been developed to inhibit the activity of IGF-1 or to block IGF-1R. These pharmaceuticals may offer additional ways of stimulating apoptosis in neoplastic cells. Yet, there are difficulties in targeting this pathway: The ideal anti-cancer drug target is expressed only in cancer cells; however, IGF-1 and its receptor IGF-1R are ubiquitously expressed throughout the body. Moreover, when using antibodies against IGF-1R, the structurally similar insulin receptor might also be blocked, leading to hyperglycemia as a severe side effect. There are currently several phase I/II trials investigating IGF-1 and its receptor as a drug target in various kinds of cancer. Specifically, therapeutic effects on pancreatic cancer by combining a humanized monoclonal antibody against IGF-1R with other chemotherapeutics are being investigated. To improve the clinical outcome of mTOR inhibitors such as everolimus, it has been suggested to use combination therapies of mTOR inhibitors and IGF-1/IGF-1R inhibitors. In theory, this would counterbalance the feedback effects of mTOR inhibition on IGF-1 signaling. In conclusion, IGF-1 and its receptor are promising new drug targets in cancer therapy. Combination therapies of IGF-1/IGF-1R inhibitors and mTOR inhibitors could improve the clinical outcome.

23 Review [Unresectable pancreatic cancer--palliative interventional and surgical treatment]. 2010

Hüser, N / Assfalg, V / Michalski, C W / Gillen, S / Kleeff, J / Friess, H. ·Klinikum rechts der Isar der Technischen Universität München, Chirurgische Klinik und Poliklinik, München, Deutschland. ·Zentralbl Chir · Pubmed #21154206.

ABSTRACT: In most cases pancreatic cancer appears in a non-curatively resectable stage at time the diagnosis is made. Thus, palliative treatment concepts come to the fore in these patients. Patients without metastases, but presenting with marginally resectable or locally non-resectable tumours should not be treated in a palliative therapeutic scheme. These patients should be enrolled in neoadjuvant radiochemotherapy trials. After finishing treatment and restaging, a potentially curative resection can be achieved in approximately one-third of these patients. Within the scope of the best possible palliative care, excision of metastases together with resection of the primary cancer represents a therapeutic option to be contemplated in selected cases. For distinct locally unresectable or metastasised advanced pancreatic cancer, treatment of bile duct or duodenal obstruction is an essential part of the comprehensive palliative therapy. However, both endoscopic / percutaneous stenting procedures and surgical bypass makeshifts constitute safe and highly effective therapeutic alternatives in this context. In the case of operative drainage of the biliary tract the prophylactic creation of a gastro-intestinal bypass (double bypass) is recommended. The decision on a surgical versus an endoscopic procedure for palliation depends considerably on the tumour stage and the estimated prognosis and has to be determined interdisciplinary and individually in each case.

24 Review Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages. 2010

Gillen, Sonja / Schuster, Tibor / Meyer Zum Büschenfelde, Christian / Friess, Helmut / Kleeff, Jörg. ·Department of Surgery, Technische Universität München, Munich, Germany. ·PLoS Med · Pubmed #20422030.

ABSTRACT: BACKGROUND: Pancreatic cancer has an extremely poor prognosis and prolonged survival is achieved only by resection with macroscopic tumor clearance. There is a strong rationale for a neoadjuvant approach, since a relevant percentage of pancreatic cancer patients present with non-metastatic but locally advanced disease and microscopic incomplete resections are common. The objective of the present analysis was to systematically review studies concerning the effects of neoadjuvant therapy on tumor response, toxicity, resection, and survival percentages in pancreatic cancer. METHODS AND FINDINGS: Trials were identified by searching MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials from 1966 to December 2009 as well as through reference lists of articles and proceedings of major meetings. Retrospective and prospective studies analyzing neoadjuvant radiochemotherapy, radiotherapy, or chemotherapy of pancreatic cancer patients, followed by re-staging, and surgical exploration/resection were included. Two reviewers independently extracted data and assessed study quality. Pooled relative risks and 95% confidence intervals were calculated using random-effects models. Primary outcome measures were proportions of tumor response categories and percentages of exploration and resection. A total of 111 studies (n = 4,394) including 56 phase I-II trials were analyzed. A median of 31 (interquartile range [IQR] 19-46) patients per study were included. Studies were subdivided into surveys considering initially resectable tumors (group 1) and initially non-resectable (borderline resectable/unresectable) tumors (group 2). Neoadjuvant chemotherapy was given in 96.4% of the studies with the main agents gemcitabine, 5-FU (and oral analogues), mitomycin C, and platinum compounds. Neoadjuvant radiotherapy was applied in 93.7% of the studies with doses ranging from 24 to 63 Gy. Averaged complete/partial response probabilities were 3.6% (95% CI 2%-5.5%)/30.6% (95% CI 20.7%-41.4%) and 4.8% (95% CI 3.5%-6.4%)/30.2% (95% CI 24.5%-36.3%) for groups 1 and 2, respectively; whereas progressive disease fraction was estimated to 20.9% (95% CI 16.9%-25.3%) and 20.8% (95% CI 14.5%-27.8%). In group 1, resectability was estimated to 73.6% (95% CI 65.9%-80.6%) compared to 33.2% (95% CI 25.8%-41.1%) in group 2. Higher resection-associated morbidity and mortality rates were observed in group 2 versus group 1 (26.7%, 95% CI 20.7%-33.3% versus 39.1%, 95% CI 29.5%-49.1%; and 3.9%, 95% CI 2.2%-6% versus 7.1%, 95% CI 5.1%-9.5%). Combination chemotherapies resulted in higher estimated response and resection probabilities for patients with initially non-resectable tumors ("non-resectable tumor patients") compared to monotherapy. Estimated median survival following resection was 23.3 (range 12-54) mo for group 1 and 20.5 (range 9-62) mo for group 2 patients. CONCLUSIONS: In patients with initially resectable tumors ("resectable tumor patients"), resection frequencies and survival after neoadjuvant therapy are similar to those of patients with primarily resected tumors and adjuvant therapy. Approximately one-third of initially staged non-resectable tumor patients would be expected to have resectable tumors following neoadjuvant therapy, with comparable survival as initially resectable tumor patients. Thus, patients with locally non-resectable tumors should be included in neoadjuvant protocols and subsequently re-evaluated for resection.

25 Review Molecular mechanism of pancreatic cancer--understanding proliferation, invasion, and metastasis. 2010

Mihaljevic, André L / Michalski, Christoph W / Friess, Helmut / Kleeff, Jörg. ·Chirurgische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Ismaningerstrasse 22, 81675, Munich, Germany. ·Langenbecks Arch Surg · Pubmed #20237938.

ABSTRACT: INTRODUCTION: The purpose of this review is to highlight the molecular mechanisms leading to the development and progression of pancreatic ductal adenocarcinoma (PDAC) with particular emphasis on tumor cell proliferation, local invasion, and metastasis. Recent advances in the field of PDAC biology have shed light on the molecular events that trigger PDAC initiation and maintenance. RESULTS: It is now clear that apart from the genetic alterations within the tumor cells, interactions of the tumor with its environment are necessary for proliferation and invasion. Interestingly, a number of developmental signaling pathways are reactivated in PDAC. Progress has also been made in the understanding of the molecular events that govern the process of metastasis. CONCLUSION: Although our understanding of the mechanisms underlying PDAC pathobiology are more advanced than ever, little progress has been made in the clinical treatment of PDAC, and successful bench-to-bedside transfer of knowledge to boost new treatment options is still unsatisfying.

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