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Pancreatic Neoplasms: HELP
Articles by Jens T. Siveke
Based on 50 articles published since 2008
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Between 2008 and 2019, J. Siveke wrote the following 50 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
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 [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 --

3 Editorial The increasing diversity of KRAS signaling in pancreatic cancer. 2014

Siveke, Jens T. ·II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. Electronic address: jens.siveke@lrz.tum.de. ·Gastroenterology · Pubmed #25167989.

ABSTRACT: -- No abstract --

4 Editorial KRAS above and beyond - EGFR in pancreatic cancer. 2012

Siveke, Jens T / Crawford, Howard C. · ·Oncotarget · Pubmed #23174662.

ABSTRACT: -- No abstract --

5 Review Epigenetic treatment of pancreatic cancer: is there a therapeutic perspective on the horizon? 2017

Hessmann, Elisabeth / Johnsen, Steven A / Siveke, Jens T / Ellenrieder, Volker. ·Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Goettingen, Goettingen, Germany. · Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, Goettingen, Germany. · Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. · West German Cancer Center, University Hospital Essen, Essen, Germany. ·Gut · Pubmed #27811314.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) constitutes one of the most aggressive malignancies with a 5-year survival rate of <7%. Due to growing incidence, late diagnosis and insufficient treatment options, PDAC is predicted to soon become one of the leading causes of cancer-related death. Although intensified cytostatic combinations, particularly gemcitabine plus nab-paclitaxel and the folinic acid, fluorouracil, irinotecan, oxaliplatin (FOLFIRINOX) protocol, provide some improvement in efficacy and survival compared with gemcitabine alone, a breakthrough in the treatment of metastatic pancreatic cancer remains out of sight. Nevertheless, recent translational research activities propose that either modulation of the immune response or pharmacological targeting of epigenetic modifications alone, or in combination with chemotherapy, might open highly powerful therapeutic avenues in GI cancer entities, including pancreatic cancer. Deregulation of key epigenetic factors and chromatin-modifying proteins, particularly those responsible for the addition, removal or recognition of post-translational histone modifications, are frequently found in human pancreatic cancer and hence constitute particularly exciting treatment opportunities. This review summarises both current clinical trial activities and discovery programmes initiated throughout the biopharma landscape, and critically discusses the chances, hurdles and limitations of epigenetic-based therapy in future PDAC treatment.

6 Review MYC in pancreatic cancer: novel mechanistic insights and their translation into therapeutic strategies. 2016

Hessmann, E / Schneider, G / Ellenrieder, V / Siveke, J T. ·Clinic for Gastroenterology and Gastrointestinal Oncology, University Medical Center Goettingen, Goettingen, Germany. · Department of Internal Medicine II, Medizinische Klinik, Klinikum rechts der Isar, Technische Universität, Munich, Germany. · German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. ·Oncogene · Pubmed #26119937.

ABSTRACT: Owing to its aggressiveness, late detection and marginal therapeutic accessibility, pancreatic ductal adenocarcinoma (PDAC) remains a most challenging malignant disease. Despite scientific progress in the understanding of the mechanisms that underly PDAC initiation and progression, the successful translation of experimental findings into effective new therapeutic strategies remains a largely unmet need. The oncogene MYC is activated in many PDAC cases and is a master regulator of vital cellular processes. Excellent recent studies have shed new light on the tremendous functions of MYC in cancer and identified inhibition of MYC as a likewise beneficial and demanding effort. This review will focus on mechanisms that contribute to deregulation of MYC expression in pancreatic carcinogenesis and progression and will summarize novel biological findings from recent in vivo models. Finally, we provide a perspective, how regulation of MYC in PDAC may contribute to the development of new therapeutic approaches.

7 Review Patients with Advanced Pancreatic Cancer and Hyperbilirubinaemia: Review and German Expert Opinion on Treatment with nab-Paclitaxel plus Gemcitabine. 2015

Vogel, Arndt / Kullmann, Frank / Kunzmann, Volker / Al-Batran, Salah-Eddin / Oettle, Helmut / Plentz, Ruben / Siveke, Jens / Springfeld, Christoph / Riess, Hanno. ·Klinik fx00FC;r Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Germany. ·Oncol Res Treat · Pubmed #26599274.

ABSTRACT: In patients with advanced unresectable pancreatic cancer, the prognosis is generally poor. Within recent years, new treatment options such as the FOLFIRINOX regimen (5-fluorouracil, leucovorin, irinotecan and oxaliplatin) or the combination of nanoparticle albumin-bound (nab)-paclitaxel plus gemcitabine have shown a clinically relevant survival benefit over the standard gemcitabine in patients with good performance status. Unfortunately, patients with hyperbilirubinaemia, who constitute a substantial proportion of the pancreatic cancer patients, have been excluded from most clinical studies. Consequently, our knowledge on the appropriate medical treatment of this patient group is limited. In a meeting of German medical oncology experts, the available clinical evidence and own clinical experience regarding the management of patients with advanced pancreatic cancer and hyperbilirubinaemia was discussed. The present publication summarises the discussion outcomes with regard to appropriate management of these patients, including consensus-based recommendations for nab-paclitaxel/gemcitabine treatment, according to the best available evidence. In summary, knowledge of the underlying aetiology of hyperbilirubinaemia and the metabolisation routes of the cytotoxic drugs is crucial before initiating chemotherapy. As effective treatment options should also be made available to patients with comorbid conditions, including hyperbilirubinaemia, the experts provide advice for an initial dose reduction of chemotherapy with nab-paclitaxel/gemcitabine based on the total bilirubin level in patients with biliary obstruction or extensive liver metastasis.

8 Review Translational research in pancreatic ductal adenocarcinoma: current evidence and future concepts. 2014

Kruger, Stephan / Haas, Michael / Ormanns, Steffen / Bächmann, Sibylle / Siveke, Jens T / Kirchner, Thomas / Heinemann, Volker / Boeck, Stefan. ·Stephan Kruger, Michael Haas, Sibylle Bächmann, Volker Heinemann, Stefan Boeck, Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, D-81377 Munich, Germany. ·World J Gastroenterol · Pubmed #25152580.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) is one of the major causes for cancer death worldwide. Treatment of metastatic disease remains challenging as only certain patients benefit from advances made with the intensified chemotherapy regimen folinic acid, irinotecan and oxaliplatin, the epidermal growth factor receptor inhibitor erlotinib or the recently FDA-approved nab-paclitaxel. Up to date, no established approach for prediction of treatment response or specific treatment allocation exists. Translational research was able to identify a number of potential biomarkers that might help to improve the dismal prognosis of PDA by facilitating upfront treatment allocation. This topic highlight is focused on current evidence on potential biomarkers for tumor biology, prognosis and prediction of treatment efficacy.

9 Review Approach to cystic lesions of the pancreas. 2014

Schmid, Roland M / Siveke, Jens T. ·II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Ismaningerstr. 22, 81675, München, Deutschland, roland.schmid@lrz.tum.de. ·Wien Med Wochenschr · Pubmed #24254128.

ABSTRACT: Cystic lesions of the pancreas are detected more frequently due to the improvement of imaging technologies. Their prevalence increases with age. In 95 % of cases, the spectrum of cystic neoplasia includes intraductal papillary mucinous neoplasia (IPMN), mucinous cystic neoplasia (MCN), serous cystic neoplasia, and solid pseudopapillary neoplasia (SPN). Diagnostic procedures aim to distinguish between neoplastic cystic and non-neoplastic cystic lesions as well as serous and mucinous lesions because of their different malignant potential. In most cases,cystic lesions are detected incidentally by computed tomography and magnetic resonance imaging (MRI) performed for other reasons. In our opinion, MRI/magnetic resonance cholangiopancreatography (MRCP) and endoscopic ultrasound (EUS) are complementary diagnostic procedures. In doubtful cases, cyst fluid analysis might be performed. The most frequent lesions are IPMNs. MRI/MRCP allows the detection of the number of cystic lesions, the relation to the main pancreatic duct, and the size of the lesion. EUS is superior to evaluate mural nodules. The relation to the main pancreatic duct can more easily appreciated with secretin MRI, MCN, SPN as well as main-duct type IPMN and BD-IPMN with "high-risk stigmata" for malignancy should be resected. Asymptomatic BD-IPMN without mural nodules, no main duct involvement, and a size less than 30 mm can be followed with a watchful waiting strategy.

10 Review The role of insulin and IGF system in pancreatic cancer. 2013

Trajkovic-Arsic, Marija / Kalideris, Evdokia / Siveke, Jens T. ·II Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Ismaningerstr 22, 81675 Munich, Germany. trajkovicmarija1@gmail.com ·J Mol Endocrinol · Pubmed #23493758.

ABSTRACT: The importance of the IGF system in carcinogenesis has been established for many solid cancers. It is well known that individuals with higher circulating levels of the IGF1 ligand present an increased risk of cancer. However, therapies with monoclonal antibodies targeting the IGF1 receptor (IGF1R) have been largely unsuccessful. One of the potential reasons for this failure is the existence of the highly homologous insulin receptor (IR), which appears to be at least equally efficient as the IGF1R in the transition of mitogenic signals to the nucleus and promotion of cell growth. Furthermore, IGF1 and insulin receptors can form hybrid receptors sensitive to stimulation of all three ligands of the system: insulin, IGF1, and IGF2. Although the connection between insulin, diabetes, and cancer has been established for years now, clear evidence that demonstrate the redundancy of insulin and insulin receptors and insulin-like growth factors and their receptors in cancer is missing. In this review, we focus on the contribution of insulin and IGFs to carcinogenesis in the insulin-producing organ, the pancreas. We give a short summary on the complexity of insulin and the IGF system in the pancreas and their potential roles in pancreatic cancer, especially pancreatic ductal adenocarcinoma. Finally, we discuss drug-targeting options of this system and the rationale of simultaneous targeting of both the insulin and the IGF systems.

11 Review Genetically engineered mouse models of pancreatic cancer: unravelling tumour biology and progressing translational oncology. 2012

Mazur, Pawel K / Siveke, Jens T. ·II. Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Ismaningerstr. 22, München 81675, Germany. ·Gut · Pubmed #21873467.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) remains a devastating disease despite tremendous scientific efforts. Numerous trials have failed to improve the outcome on this deadliest of all major cancers. Potential causes include a still insufficient understanding of key features of this cancer and imperfect preclinical models for identification of active agents and mechanisms of therapeutic responses and resistance. Modern genetically engineered mouse models of PDAC faithfully recapitulate the genetic and biological evolution of human PDAC, thereby providing a potentially powerful tool for addressing tumour biological issues as well as strategies for early detection and assessment of responses to therapeutic interventions. Here, the authors will discuss opportunities and challenges in the application of genetically engineered mouse models for translational approaches in pancreatic cancer and provide a non-exhaustive list of examples with already existing or future clinical relevance.

12 Clinical Trial Efficacy of gemcitabine plus erlotinib in rash-positive patients with metastatic pancreatic cancer selected according to eligibility for FOLFIRINOX: A prospective phase II study of the 'Arbeitsgemeinschaft Internistische Onkologie'. 2018

Haas, M / Siveke, J T / Schenk, M / Lerch, M M / Caca, K / Freiberg-Richter, J / Fischer von Weikersthal, L / Kullmann, F / Reinacher-Schick, A / Fuchs, M / Kanzler, S / Kunzmann, V / Ettrich, T J / Kruger, S / Westphalen, C B / Held, S / Heinemann, V / Boeck, S. ·Department of Medicine III, University Hospital, LMU Munich, Munich, Germany. Electronic address: michael.haas@med.lmu.de. · 2nd Medical Department, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany; Division of Solid Tumor Translational Oncology (DKTK, Partner Site Essen), West German Cancer Center, University Hospital Essen, Essen, Germany. · Department of Haematology and Oncology, Hospital Barmherzige Brüder, Regensburg, Germany. · Department of Medicine A, Universitätsmedizin Greifswald, Ernst-Moritz-Arndt University, Greifswald, Germany. · Department of Internal Medicine I, Klinikum Ludwigsburg, Ludwigsburg, Germany. · Practice for Haematology and Oncology, Dresden, Germany. · Department of Oncology, Gesundheitszentrum St. Marien, Amberg, Germany. · Department of Medicine I, Klinikum Weiden, Weiden, Germany. · Department of Haematology and Oncology, St. Josef-Hospital, Ruhr University, Bochum, Germany. · Department of Gastroenterology, Hepatology and Gastrointestinal Oncology, Klinikum Bogenhausen, Munich, Germany. · Department of Internal Medicine II, Leopoldina Krankenhaus Schweinfurt, Schweinfurt, Germany. · Department of Medical Oncology, University Hospital of Wuerzburg, Wuerzburg, Germany. · Department of Internal Medicine I, University of Ulm, Ulm, Germany. · Department of Medicine III, University Hospital, LMU Munich, Munich, Germany. · ClinAssess GmbH, Leverkusen, Germany. ·Eur J Cancer · Pubmed #29549862.

ABSTRACT: INTRODUCTION: In metastatic pancreatic ductal adenocarcinoma (mPDAC) treatment, erlotinib is known to be more effective in patients developing skin rash. Treatment with the FOLFIRINOX regimen is only performed in fit patients following defined inclusion criteria. The present study investigates the efficacy of gemcitabine plus erlotinib (gem/erlotinib) in rash-positive patients fit for FOLFIRINOX. PATIENTS AND METHODS: For this prospective phase II study, 150 patients were recruited in 20 centres. All patients received gem/erlotinib for 4 weeks (run-in phase); the subsequent treatment was determined by the development of skin rash: patients with rash grades 1-4 continued with gem/erlotinib, rash-negative patients were switched to FOLFIRINOX. Primary study end-point was to achieve a 1-year survival rate in rash-positive patients ≥40%. RESULTS: Ninety patients were deemed positive for skin rash by the end of the run-in phase, showing a 1-year survival rate of 40.0% (95% confidence interval [CI] 29.8-50.9). Median overall survival (OS) was 10.1 months, progression-free survival (PFS) was 3.8 months and overall response rate (ORR) was 23.3%. Patients switched to FOLFIRINOX (n = 27) had a 1-year survival rate of 48.1% (95% CI 28.7-68.1), a median OS of 10.9 months, a median PFS of 6.6 months and an ORR of 33.3%. Rash-negative patients had a lower quality of life at baseline but seemed to experience an improved control of pain during FOLFIRINOX. CONCLUSIONS: First-line treatment with gem/erlotinib was effective in fit, rash-positive mPDAC patients achieving a 1-year survival rate comparable to previous reports for FOLFIRINOX. The study was registered at clinicaltrials.gov (NCT0172948) and Eudra-CT (2011-005471-17).

13 Clinical Trial Gemcitabine combined with the monoclonal antibody nimotuzumab is an active first-line regimen in KRAS wildtype patients with locally advanced or metastatic pancreatic cancer: a multicenter, randomized phase IIb study. 2017

Schultheis, B / Reuter, D / Ebert, M P / Siveke, J / Kerkhoff, A / Berdel, W E / Hofheinz, R / Behringer, D M / Schmidt, W E / Goker, E / De Dosso, S / Kneba, M / Yalcin, S / Overkamp, F / Schlegel, F / Dommach, M / Rohrberg, R / Steinmetz, T / Bulitta, M / Strumberg, D. ·Department of Hematology/Oncology, University Bochum, Marien Hospital Herne, Herne. · Oncoscience AG, Wedel. · Klinikum Rechts der Isar TU München, München. · University Hospital Münster, Münster. · Department of Hematology and Medical Oncology, University Medical Center Mannheim, Mannheim. · Augusta-Kranken-Anstalt, Bochum. · St. Josef Hospital, Med. Klinik I, Bochum, Germany. · Ege University Medical School, Izmir, Turkey. · Oncology Institute of Southern Switzerland, Bellinzona, Switzerland. · Department of Medicine, University Medical Center Schleswig-Holstein, Kiel, Germany. · Hacettepe University Hospital, Ankara, Turkey. · Medical Practice for Oncology and Hematology, Recklinghausen. · St. Antonius Hospital, Eschweiler. · Sana-Kliniken, Medizinisches Versorgungszentrum Onkologie, Düsseldorf. · Gemeinschaftspraxis und Tagesklinik fuer Haematologie, Onkologie und Gastroenterologie, Halle. · Group Practice Hematology/Oncology Cologne, Cologne. · CRM Biometrics GmbH, Rheinbach, Germany. ·Ann Oncol · Pubmed #28961832.

ABSTRACT: Background: This randomized study was designed to investigate the superiority of gemcitabine (gem) plus nimotuzumab (nimo), an anti-epidermal growth factor receptor monoclonal antibody, compared with gem plus placebo as first-line therapy in patients with advanced pancreatic cancer. Patients and methods: Patients with previously untreated, unresectable, locally advanced or metastatic pancreatic cancer were randomly assigned to receive gem: 1000 mg/m2, 30-min i.v. once weekly (d1, 8, 15; q29) and nimo: fixed dose of 400 mg once weekly as a 30-min infusion, or gem plus placebo, until progression or unacceptable toxicity. The primary end point was overall survival (OS), secondary end points included time to progression, overall response rate, safety and quality of life. Results: A total of 192 patients were randomized, with 186 of them being assessable for efficacy and safety (average age 63.6 years). One-year OS/progression-free survival (PFS) was 34%/22% for gem plus nimo compared with 19%/10% for gem plus placebo (HR = 0.69; P = 0.03/HR = 0.68; P = 0.02). Median OS/PFS was 8.6/5.1 months for gem plus nimo versus 6.0/3.4 mo in the gem plus placebo group (HR = 0.69; P = 0.0341/HR = 0.68; P = 0.0163), with very few grade 3/4 toxicities. KRAS wildtype patients experienced a significantly better OS than those with KRAS mutations (11.6 versus 5.6 months, P = 0.03). Conclusion: This randomized study showed that nimo in combination with gem is safe and well tolerated. The 1-year OS and PFS rates for the entire population were significantly improved. Especially, those patients with KRAS wildtype seem to benefit. The study was registered as protocol ID OSAG101-PCS07, NCT00561990 and EudraCT 2007-000338-38.

14 Clinical Trial Quality-adjusted survival with combination nal-IRI+5-FU/LV vs 5-FU/LV alone in metastatic pancreatic cancer patients previously treated with gemcitabine-based therapy: a Q-TWiST analysis. 2017

Pelzer, Uwe / Blanc, Jean-Frédéric / Melisi, Davide / Cubillo, Antonio / Von Hoff, Daniel D / Wang-Gillam, Andrea / Chen, Li-Tzong / Siveke, Jens T / Wan, Yin / Solem, Caitlyn T / Botteman, Marc F / Yang, Yoojung / de Jong, Floris A / Hubner, Richard A. ·Department of Hematology/Oncology/Tumorimmunology, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. · Service d'Hépato-Gastroentérologie et Oncologie Digestive, Hôpital Haut-Lévêque, CHU de Bordeaux, Inserm UMR 1053, Université de Bordeaux, Bordeaux, France. · Digestive Molecular Clinical Oncology Unit, University of Verona, Piazzale L.A. Scuro, 10, 37134 Verona, Italy. · Servicio de Oncologia Médica, Centro Integral Oncológico Clara Campal (CIOCC), Hospital Universitario Madrid Sanchinarro, Calle Oña, 10, 28050 Madrid, Spain. · Virginia G. Piper Cancer Center at HonorHealth/TGen, 10460N 92nd St #206, Scottsdale, AZ 85258, USA. · Division of Oncology, Washington University in St Louis, 660 South Euclid Avenue, St Louis, MO 63110, USA. · National Institute of Cancer Research, National Health Research Institutes, 2F, No. 367, Sheng-Li Road, Tainan 70456, Taiwan. · Division of Solid Tumor Translational Oncology, DKTK Partner Site Essen, West German Cancer Center, University Hospital Essen, Hufelandstrasse 55, 45147 Essen, Germany. · German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. · Pharmerit International, 4350 East-West Hwy #430, Bethesda, MD 20814, USA. · Shire, Plc, 650 East Kendal St, Cambridge, MA 02142, USA. · Department of Global Medical Affairs Oncology, Shire GmbH, Zählerweg 10, 6300 Zug, Switzerland. · Department of Medical Oncology, Christie Hospital NHS Foundation Trust, 550 Wilmslow Rd, Manchester M20 4BX, UK. ·Br J Cancer · Pubmed #28350787.

ABSTRACT: BACKGROUND: In the NAPOLI-1 Phase 3 trial, nal-IRI+5-fluorouracil and leucovorin (5-FU/LV) significantly improved median overall survival (6.1 vs 4.2 months, P=0.012) and progression-free survival (3.1 vs 1.5 months, P=0.0001) vs 5-FU/LV alone in metastatic pancreatic adenocarcinoma patients previously treated with gemcitabine-based therapy. This analysis evaluated between treatment differences in quality-adjusted time without symptoms of disease progression or toxicity (Q-TWiST). METHODS: Overall survival was partitioned into time with grade ⩾3 toxicity (TOX), disease progression (REL), and time without disease progression symptoms or grade ⩾3 toxicity (TWiST). Mean Q-TWiST was calculated by weighting time spent by a utility of 1.0 for TWiST and 0.5 for TOX and REL. In threshold analyses, utility for TOX and REL were varied from 0.0 to 1.0. RESULTS: Patients in nal-IRI+5-FU/LV (n=117) vs 5-FU/LV (n=119) had significantly more mean time in TWiST (3.4 vs 2.4 months) and TOX (1.0 vs 0.3 months) but similar REL (2.5 vs 2.7 months). In the base case, nal-IRI+5-FU/LV patients had 1.3 months (95% CI, 0.4-2.1; 5.1 vs 3.9) greater Q-TWiST (threshold analyses range: 0.9-1.6 months). CONCLUSIONS: Within NAPOLI-1, nal-IRI+5-FU/LV resulted in statistically significant and clinically meaningful gains in quality-adjusted survival vs 5-FU/LV alone.

15 Clinical Trial Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. 2016

Wang-Gillam, Andrea / Li, Chung-Pin / Bodoky, György / Dean, Andrew / Shan, Yan-Shen / Jameson, Gayle / Macarulla, Teresa / Lee, Kyung-Hun / Cunningham, David / Blanc, Jean F / Hubner, Richard A / Chiu, Chang-Fang / Schwartsmann, Gilberto / Siveke, Jens T / Braiteh, Fadi / Moyo, Victor / Belanger, Bruce / Dhindsa, Navreet / Bayever, Eliel / Von Hoff, Daniel D / Chen, Li-Tzong / Anonymous3111266. ·Washington University School of Medicine, St Louis, MO, USA. · Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital and National Yang-Ming University School of Medicine, Taipei, Taiwan. · St László Teaching Hospital, Budapest, Hungary. · St John of God Hospital, Subiaco, WA, Australia. · National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan. · TGen, Phoenix, and HonorHealth, Scottsdale, AZ, USA. · Vall d'Hebron University Hospital (HUVH) and Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. · Seoul National University Hospital, Seoul, South Korea. · The Royal Marsden Hospital, London, UK. · Hôpital Saint-André, Bordeaux, France. · The Christie NHS Foundation Trust, Manchester, UK. · China Medical University Hospital, Taichung, Taiwan. · Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil. · Klinikum rechts der Isar der T U München, Munich, Germany. · Comprehensive Cancer Centers of Nevada, Las Vegas, NV, USA. · Merrimack Pharmaceuticals, Cambridge, MA, USA. · National Institute of Cancer Research, National Health Research Institutes, Tainan, and Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan. Electronic address: leochen@nhri.org.tw. ·Lancet · Pubmed #26615328.

ABSTRACT: BACKGROUND: Nanoliposomal irinotecan showed activity in a phase 2 study in patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapies. We assessed the effect of nanoliposomal irinotecan alone or combined with fluorouracil and folinic acid in a phase 3 trial in this population. METHODS: We did a global, phase 3, randomised, open-label trial at 76 sites in 14 countries. Eligible patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapy were randomly assigned (1:1) using an interactive web response system at a central location to receive either nanoliposomal irinotecan monotherapy (120 mg/m(2) every 3 weeks, equivalent to 100 mg/m(2) of irinotecan base) or fluorouracil and folinic acid. A third arm consisting of nanoliposomal irinotecan (80 mg/m(2), equivalent to 70 mg/m(2) of irinotecan base) with fluorouracil and folinic acid every 2 weeks was added later (1:1:1), in a protocol amendment. Randomisation was stratified by baseline albumin, Karnofsky performance status, and ethnic origin. Treatment was continued until disease progression or intolerable toxic effects. The primary endpoint was overall survival, assessed in the intention-to-treat population. The primary analysis was planned after 305 events. Safety was assessed in all patients who had received study drug. This trial is registered at ClinicalTrials.gov, number NCT01494506. FINDINGS: Between Jan 11, 2012, and Sept 11, 2013, 417 patients were randomly assigned either nanoliposomal irinotecan plus fluorouracil and folinic acid (n=117), nanoliposomal irinotecan monotherapy (n=151), or fluorouracil and folinic acid (n=149). After 313 events, median overall survival in patients assigned nanoliposomal irinotecan plus fluorouracil and folinic acid was 6.1 months (95% CI 4.8-8.9) vs 4.2 months (3.3-5.3) with fluorouracil and folinic acid (hazard ratio 0.67, 95% CI 0.49-0.92; p=0.012). Median overall survival did not differ between patients assigned nanoliposomal irinotecan monotherapy and those allocated fluorouracil and folinic acid (4.9 months [4.2-5.6] vs 4.2 months [3.6-4.9]; 0.99, 0.77-1.28; p=0.94). The grade 3 or 4 adverse events that occurred most frequently in the 117 patients assigned nanoliposomal irinotecan plus fluorouracil and folinic acid were neutropenia (32 [27%]), diarrhoea (15 [13%]), vomiting (13 [11%]), and fatigue (16 [14%]). INTERPRETATION: Nanoliposomal irinotecan in combination with fluorouracil and folinic acid extends survival with a manageable safety profile in patients with metastatic pancreatic ductal adenocarcinoma who previously received gemcitabine-based therapy. This agent represents a new treatment option for this population. FUNDING: Merrimack Pharmaceuticals.

16 Clinical Trial pERK, pAKT and p53 as tissue biomarkers in erlotinib-treated patients with advanced pancreatic cancer: a translational subgroup analysis from AIO-PK0104. 2014

Ormanns, Steffen / Siveke, Jens T / Heinemann, Volker / Haas, Michael / Sipos, Bence / Schlitter, Anna Melissa / Esposito, Irene / Jung, Andreas / Laubender, Rüdiger P / Kruger, Stephan / Vehling-Kaiser, Ursula / Winkelmann, Cornelia / Fischer von Weikersthal, Ludwig / Clemens, Michael R / Gauler, Thomas C / Märten, Angela / Geissler, Michael / Greten, Tim F / Kirchner, Thomas / Boeck, Stefan. ·Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, München, Germany. stefan.boeck@med.uni-muenchen.de. ·BMC Cancer · Pubmed #25164437.

ABSTRACT: BACKGROUND: The role of pERK, pAKT and p53 as biomarkers in patients with advanced pancreatic cancer has not yet been defined. METHODS: Within the phase III study AIO-PK0104 281 patients with advanced pancreatic cancer received an erlotinib-based 1st-line regimen. Archival tissue from 153 patients was available for central immunohistochemistry staining for pERK, pAKT and p53. Within a subgroup analysis, biomarker data were correlated with efficacy endpoints and skin rash using a Cox regression model. RESULTS: Fifty-five out of 153 patients were classified as pERKlow and 98 patients as pERKhigh; median overall survival (OS) was 6.2 months and 5.7 months, respectively (HR 1.29, p = 0.16). When analysing pERK as continuous variable, the pERK score was significantly associated with OS (HR 1.06, 95% CI 1.0-1.12, p = 0.05). Twenty-one of 35 patients were pAKTlow and 14/35 pAKThigh with a corresponding median OS of 6.4 months and 6.8 months, respectively (HR 1.03, p = 0.93). Four out of 50 patients had a complete loss of p53 expression, 20 patients a regular expression and 26 patients had tumors with p53 overexpression. The p53 status had no impact on OS (p = 0.91); however, a significant improvement in progression-free survival (PFS) (6.0 vs 1.8 months, HR 0.24, p = 0.02) and a higher rate of skin rash (84% vs 25%, p = 0.02) was observed for patients with a regular p53 expression compared to patients with a complete loss of p53. CONCLUSION: pERK expression may have an impact on OS in erlotinib-treated patients with advanced pancreatic cancer; p53 should be further investigated for its potential role as a predictive marker for PFS and skin rash. TRIAL REGISTRATION: NCT00440167 (registration date: February 22, 2007).

17 Article Extended RAS analysis and correlation with overall survival in advanced pancreatic cancer. 2017

Haas, Michael / Ormanns, Steffen / Baechmann, Sibylle / Remold, Anna / Kruger, Stephan / Westphalen, Christoph B / Siveke, Jens T / Wenzel, Patrick / Schlitter, Anna Melissa / Esposito, Irene / Quietzsch, Detlef / Clemens, Michael R / Kettner, Erika / Laubender, Ruediger P / Jung, Andreas / Kirchner, Thomas / Boeck, Stefan / Heinemann, Volker. ·Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Marchioninistr. 15, Munich 81377, Germany. · Institute of Pathology, Ludwig-Maximilians-University of Munich, Germany and German Cancer Consortium (DKTK), Partner Site Munich, Thalkirchner Str. 36, Munich 80377, Germany. · 2nd Medical Department, Klinikum Rechts der Isar, Technical University of Munich, Ismaninger Str. 22, Munich 81675, Germany. · German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. · Division of Solid Tumour Translational Oncology, German Cancer Consortium (DKTK), Partner Site Essen, University Hospital Essen, Hufelandstr. 55, Essen 45147, Germany. · Institute of Pathology, Technical University of Munich, Trogerstr. 18, Munich 81675, Germany. · Institute of Pathology, Heinrich Heine University of Duesseldorf, Moorenstr. 5, Duesseldorf 40225, Germany. · Department of Internal Medicine II, Klinikum Chemnitz gGmbH, Flemmingstr. 2, Chemnitz 09116, Germany. · Department of Hematology and Oncology, Mutterhaus der Boromaeerinnen, Feldstr. 16, Trier 54290, Germany. · Department of Hematology and Oncology, Klinikum Magdeburg, Birkenallee 34, Magdeburg 39130, Germany. · Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-University of Munich, Marchioninistr. 15, Munich 81377, Germany. ·Br J Cancer · Pubmed #28449008.

ABSTRACT: BACKGROUND: Mutations in the KRAS gene can be detected in about 70-90% of pancreatic cancer (PC) cases. Whether these mutations have a prognostic or predictive value remains elusive. Furthermore, the clinical relevance of the extended RAS (KRAS+NRAS) mutational status is unclear in PC. METHODS: We prospectively defined a PC patient population who received erlotinib-free chemotherapy regimens. A statistically significant difference between KRAS wild-type and KRAS mutated tumours in at least 160 patients in this population would support the assumption of a rather prognostic role of KRAS. RESULTS: One hundred and seventy-eight tumour samples were collected from prospective clinical studies and successfully analysed for the extended RAS status: 37 tumours were KRAS wild-type (21%), whereas 141 (79%) carried a KRAS mutation; 132 of these mutations were found in KRAS exon 2 (74%), whereas only 9 mutations (5%) were detected in KRAS exon 3. Within KRAS exon 4 and NRAS exons 2-4, no mutations were apparent. There was no significant difference in overall survival for KRAS wild-type vs mutant patients (9.9 vs 8.3 months, P=0.70). CONCLUSIONS: Together with the results of the AIO-PK-0104-trial, the present analysis supports the notion that KRAS mutation status is rather predictive than prognostic in advanced PC.

18 Article Imaging and targeted therapy of pancreatic ductal adenocarcinoma using the theranostic sodium iodide symporter (NIS) gene. 2017

Schmohl, Kathrin A / Gupta, Aayush / Grünwald, Geoffrey K / Trajkovic-Arsic, Marija / Klutz, Kathrin / Braren, Rickmer / Schwaiger, Markus / Nelson, Peter J / Ogris, Manfred / Wagner, Ernst / Siveke, Jens T / Spitzweg, Christine. ·Department of Internal Medicine II and IV, University Hospital of Munich, LMU Munich, Munich, Germany. · Department of Internal Medicine II, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany. · Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany. · German Cancer Consortium (DKTK), Partner Site Essen and German Cancer Research Center (DKFZ), Heidelberg, Germany. · Department of Radiology, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany. · Department of Nuclear Medicine, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany. · Clinical Biochemistry Group, Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Munich, Germany. · Department of Pharmaceutical Chemistry, Laboratory of MacroMolecular Cancer Therapeutics (MMCT), University of Vienna, Vienna, Austria. · Pharmaceutical Biotechnology, Department of Pharmacy, Center for System-Based Drug Research and Center for Nanoscience, LMU Munich, Munich, Germany. ·Oncotarget · Pubmed #28380420.

ABSTRACT: The theranostic sodium iodide symporter (NIS) gene allows detailed molecular imaging of transgene expression and application of therapeutic radionuclides. As a crucial step towards clinical application, we investigated tumor specificity and transfection efficiency of epidermal growth factor receptor (EGFR)-targeted polyplexes as systemic NIS gene delivery vehicles in an advanced genetically engineered mouse model of pancreatic ductal adenocarcinoma (PDAC) that closely reflects human disease. PDAC was induced in mice by pancreas-specific activation of constitutively active KrasG12D and deletion of Trp53. We used tumor-targeted polyplexes (LPEI-PEG-GE11/NIS) based on linear polyethylenimine, shielded by polyethylene glycol and coupled with the EGFR-specific peptide ligand GE11, to target a NIS-expressing plasmid to high EGFR-expressing PDAC. In vitro iodide uptake studies in cell explants from murine EGFR-positive and EGFR-ablated PDAC lesions demonstrated high transfection efficiency and EGFR-specificity of LPEI-PEG-GE11/NIS. In vivo 123I gamma camera imaging and three-dimensional high-resolution 124I PET showed significant tumor-specific accumulation of radioiodide after systemic LPEI-PEG-GE11/NIS injection. Administration of 131I in LPEI-PEG-GE11/NIS-treated mice resulted in significantly reduced tumor growth compared to controls as determined by magnetic resonance imaging, though survival was not significantly prolonged. This study opens the exciting prospect of NIS-mediated radionuclide imaging and therapy of PDAC after systemic non-viral NIS gene delivery.

19 Article Histone deacetylase class-I inhibition promotes epithelial gene expression in pancreatic cancer cells in a BRD4- and MYC-dependent manner. 2017

Mishra, Vivek Kumar / Wegwitz, Florian / Kosinsky, Robyn Laura / Sen, Madhobi / Baumgartner, Roland / Wulff, Tanja / Siveke, Jens T / Schildhaus, Hans-Ulrich / Najafova, Zeynab / Kari, Vijayalakshmi / Kohlhof, Hella / Hessmann, Elisabeth / Johnsen, Steven A. ·Department of General, Visceral and Pediatric Surgery, Göttingen Center for Molecular Biosciences, University Medical Center Göttingen, Justus-von-Liebig-Weg 11, 37077 Göttingen, Germany. · 4SC AG, Am Klopferspitz 19a, 82152 Planegg-Martinsried, Germany. · German Consortium for Translational Cancer Research (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. · Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany. · Department of Pathology, University Medical Center Göttingen, Robert-Koch-Strasse 40, 37075 Göttingen, Germany. · Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Robert-Koch-Strasse 40, 37075 Göttingen, Germany. ·Nucleic Acids Res · Pubmed #28369619.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with a particularly dismal prognosis. Histone deacetylases (HDAC) are epigenetic modulators whose activity is frequently deregulated in various cancers including PDAC. In particular, class-I HDACs (HDAC 1, 2, 3 and 8) have been shown to play an important role in PDAC. In this study, we investigated the effects of the class I-specific HDAC inhibitor (HDACi) 4SC-202 in multiple PDAC cell lines in promoting tumor cell differentiation. We show that 4SC-202 negatively affects TGFβ signaling and inhibits TGFβ-induced epithelial-to-mesenchymal transition (EMT). Moreover, 4SC-202 markedly induced p21 (CDKN1A) expression and significantly attenuated cell proliferation. Mechanistically, genome-wide studies revealed that 4SC-202-induced genes were enriched for Bromodomain-containing Protein-4 (BRD4) and MYC occupancy. BRD4, a well-characterized acetyllysine reader, has been shown to play a major role in regulating transcription of selected subsets of genes. Importantly, BRD4 and MYC are essential for the expression of a subgroup of genes induced by class-I HDACi. Taken together, our study uncovers a previously unknown role of BRD4 and MYC in eliciting the HDACi-mediated induction of a subset of genes and provides molecular insight into the mechanisms of HDACi action in PDAC.

20 Article Context-Dependent Epigenetic Regulation of Nuclear Factor of Activated T Cells 1 in Pancreatic Plasticity. 2017

Chen, Nai-Ming / Neesse, Albrecht / Dyck, Moritz Lino / Steuber, Benjamin / Koenig, Alexander O / Lubeseder-Martellato, Clara / Winter, Thore / Forster, Teresa / Bohnenberger, Hanibal / Kitz, Julia / Reuter-Jessen, Kirsten / Griesmann, Heidi / Gaedcke, Jochen / Grade, Marian / Zhang, Jin-San / Tsai, Wan-Chi / Siveke, Jens / Schildhaus, Hans-Ulrich / Ströbel, Philipp / Johnsen, Steven A / Ellenrieder, Volker / Hessmann, Elisabeth. ·Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Germany. · Signaling and Transcription Laboratory, Department of Gastroenterology, Philipp's University, Marburg, Germany. · II. Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technische Universität, Munich, Germany. · Institute of Pathology, University Medical Center Göttingen, Germany. · Department of Internal Medicine I, University Medical Center Halle, Germany. · Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Germany. · Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, Minnesota; School of Pharmaceutical Sciences and Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, PR China. · Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan. · German Cancer Consortium and German Cancer Research Center, Heidelberg, Germany; Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany. · Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Germany. Electronic address: elisabeth.hessmann@med.uni-goettingen.de. ·Gastroenterology · Pubmed #28188746.

ABSTRACT: BACKGROUND & AIMS: The ability of exocrine pancreatic cells to change the cellular phenotype is required for tissue regeneration upon injury, but also contributes to their malignant transformation and tumor progression. We investigated context-dependent signaling and transcription mechanisms that determine pancreatic cell fate decisions toward regeneration and malignancy. In particular, we studied the function and regulation of the inflammatory transcription factor nuclear factor of activated T cells 1 (NFATC1) in pancreatic cell plasticity and tissue adaptation. METHODS: We analyzed cell plasticity during pancreatic regeneration and transformation in mice with pancreas-specific expression of a constitutively active form of NFATC1, or depletion of enhancer of zeste 2 homologue 2 (EZH2), in the context of wild-type or constitutively activate Kras, respectively. Acute and chronic pancreatitis were induced by intraperitoneal injection of caerulein. EZH2-dependent regulation of NFATC1 expression was studied in mouse in human pancreatic tissue and cells by immunohistochemistry, immunoblotting, and quantitative reverse transcription polymerase chain reaction. We used genetic and pharmacologic approaches of EZH2 and NFATC1 inhibition to study the consequences of pathway disruption on pancreatic morphology and function. Epigenetic modifications on the NFATC1 gene were investigated by chromatin immunoprecipitation assays. RESULTS: NFATC1 was rapidly and transiently induced in early adaptation to acinar cell injury in human samples and in mice, where it promoted acinar cell transdifferentiation and blocked proliferation of metaplastic pancreatic cells. However, in late stages of regeneration, Nfatc1 was epigenetically silenced by EZH2-dependent histone methylation, to enable acinar cell redifferentiation and prevent organ atrophy and exocrine insufficiency. In contrast, oncogenic activation of KRAS signaling in pancreatic ductal adenocarcinoma cells reversed the EZH2-dependent effects on the NFATC1 gene and was required for EZH2-mediated transcriptional activation of NFATC1. CONCLUSIONS: In studies of human and mouse pancreatic cells and tissue, we identified context-specific epigenetic regulation of NFATc1 activity as an important mechanism of pancreatic cell plasticity. Inhibitors of EZH2 might therefore interfere with oncogenic activity of NFATC1 and be used in treatment of pancreatic ductal adenocarcinoma.

21 Article Oncogenic KRas-induced Increase in Fluid-phase Endocytosis is Dependent on N-WASP and is Required for the Formation of Pancreatic Preneoplastic Lesions. 2017

Lubeseder-Martellato, Clara / Alexandrow, Katharina / Hidalgo-Sastre, Ana / Heid, Irina / Boos, Sophie Luise / Briel, Thomas / Schmid, Roland M / Siveke, Jens T. ·Clinic and Polyclinic for Internal Medicine II, Klinikum Rechts der Isar, Technical University of Munich, Germany. Electronic address: clara.lubeseder-martellato@tum.de. · Clinic and Polyclinic for Internal Medicine II, Klinikum Rechts der Isar, Technical University of Munich, Germany. · Institute of Radiology, Klinikum Rechts der Isar, Technical University of Munich, Germany. · Clinic and Polyclinic for Internal Medicine II, Klinikum Rechts der Isar, Technical University of Munich, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center, DKFZ, Heidelberg, Germany. · Clinic and Polyclinic for Internal Medicine II, Klinikum Rechts der Isar, Technical University of Munich, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center, DKFZ, Heidelberg, Germany; Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK), Partner Site Essen, West German Cancer Center, University Hospital Essen, Germany. Electronic address: j.siveke@dkfz.de. ·EBioMedicine · Pubmed #28057438.

ABSTRACT: Fluid-phase endocytosis is a homeostatic process with an unknown role in tumor initiation. The driver mutation in pancreatic ductal adenocarcinoma (PDAC) is constitutively active KRas

22 Article Co-clinical Assessment of Tumor Cellularity in Pancreatic Cancer. 2017

Heid, Irina / Steiger, Katja / Trajkovic-Arsic, Marija / Settles, Marcus / Eßwein, Manuela R / Erkan, Mert / Kleeff, Jörg / Jäger, Carsten / Friess, Helmut / Haller, Bernhard / Steingötter, Andreas / Schmid, Roland M / Schwaiger, Markus / Rummeny, Ernst J / Esposito, Irene / Siveke, Jens T / Braren, Rickmer F. ·Institute of Radiology, Klinikum rechts der Isar, Technische Universität München, Germany. · Institute of Pathology, Klinikum rechts der Isar, Technische Universität München, Germany. · 2nd Medical Department, Klinikum rechts der Isar, Technische Universität München, Germany. · German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. · Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK), partner site Essen, University Hospital Essen, Essen, Germany. · Department of Surgery, Koc University School of Medicine, Istanbul, Turkey. · Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Germany. · Institute of Medical Statistics and Epidemiology, Klinikum rechts der Isar, Technische Universität München, Germany. · Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland. · Department of Nuclear Medicine, Klinikum rechts der Isar, Technische Universität München, Germany. · Institute of Pathology, Universitätsklinikum Düsseldorf, Düsseldorf, Germany. rbraren@tum.de j.siveke@dkfz-heidelberg.de Irene.Esposito@med.uni-duesseldorf.de. · 2nd Medical Department, Klinikum rechts der Isar, Technische Universität München, Germany. rbraren@tum.de j.siveke@dkfz-heidelberg.de Irene.Esposito@med.uni-duesseldorf.de. · Institute of Radiology, Klinikum rechts der Isar, Technische Universität München, Germany. rbraren@tum.de j.siveke@dkfz-heidelberg.de Irene.Esposito@med.uni-duesseldorf.de. ·Clin Cancer Res · Pubmed #27663591.

ABSTRACT:

23 Article Hes1 Controls Exocrine Cell Plasticity and Restricts Development of Pancreatic Ductal Adenocarcinoma in a Mouse Model. 2016

Hidalgo-Sastre, Ana / Brodylo, Roxanne L / Lubeseder-Martellato, Clara / Sipos, Bence / Steiger, Katja / Lee, Marcel / von Figura, Guido / Grünwald, Barbara / Zhong, Suyang / Trajkovic-Arsic, Marija / Neff, Florian / Schmid, Roland M / Siveke, Jens T. ·II Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. · Department of Pathology, University Hospital Tübingen, Tübingen, Germany. · Comparative Experimental Pathology Unit, Institute for General Pathology and Pathological Anatomy, Technical University of Munich, Munich, Germany. · Institute of Molecular Immunology and Experimental Oncology, Technical University of Munich, Munich, Germany. · German Cancer Consortium and German Cancer Research Center, Heidelberg, Germany; Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany. · II Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany; German Cancer Consortium and German Cancer Research Center, Heidelberg, Germany. · II Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany; German Cancer Consortium and German Cancer Research Center, Heidelberg, Germany; Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany. Electronic address: j.siveke@dkfz.de. ·Am J Pathol · Pubmed #27639167.

ABSTRACT: Perturbation of pancreatic acinar cell state can lead to acinar-to-ductal metaplasia (ADM), a precursor lesion to the development of pancreatic ductal adenocarcinoma (PDAC). In the pancreas, Notch signaling is active both during development and in adult cellular differentiation processes. Hes1, a key downstream target of the Notch signaling pathway, is expressed in the centroacinar compartment of the adult pancreas as well as in both preneoplastic and malignant lesions. In this study, we used a murine genetic in vivo approach to ablate Hes1 in pancreatic progenitor cells (Ptf1a

24 Article Pancreatic Premalignant Lesions Secrete Tissue Inhibitor of Metalloproteinases-1, Which Activates Hepatic Stellate Cells Via CD63 Signaling to Create a Premetastatic Niche in the Liver. 2016

Grünwald, Barbara / Harant, Veronika / Schaten, Susanne / Frühschütz, Monika / Spallek, Ria / Höchst, Bastian / Stutzer, Katharina / Berchtold, Sonja / Erkan, Mert / Prokopchuk, Olga / Martignoni, Marc / Esposito, Irene / Heikenwalder, Mathias / Gupta, Aayush / Siveke, Jens / Saftig, Paul / Knolle, Percy / Wohlleber, Dirk / Krüger, Achim. ·Institut für Molekulare Immunologie und Experimentelle Onkologie, Technische Universität München, München, Germany. · Chirurgische Klinik Technische Universität München, München, Germany. · Institut für Pathologie, Klinikum rechts der Isar, Technische Universität München, München, Germany. · Institut für Virologie, Technische Universität München, München, Germany. · II. Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, München, Germany. · Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Kiel, Germany. · Institut für Molekulare Immunologie und Experimentelle Onkologie, Technische Universität München, München, Germany. Electronic address: achim.krueger@tum.de. ·Gastroenterology · Pubmed #27506299.

ABSTRACT: BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) metastasizes to liver at early stages, making this disease highly lethal. Tissue inhibitor of metalloproteinases-1 (TIMP1) creates a metastasis-susceptible environment in the liver. We investigated the role of TIMP1 and its receptor CD63 in metastasis of early-stage pancreatic tumors using mice and human cell lines and tissue samples. METHODS: We obtained liver and plasma samples from patients in Germany with chronic pancreatitis, pancreatic intra-epithelial neoplasia, or PDAC, as well as hepatic stellate cells (HSCs). We performed studies with Ptf1a RESULTS: Chronic pancreatitis, pancreatic intra-epithelial neoplasia, and PDAC tissues from patients expressed higher levels of TIMP1 protein than normal pancreas. The premalignant pancreatic lesions that developed in KPC and CPK mice expressed TIMP1 and secreted it into the circulation. In vitro and in vivo, TIMP1 activated human or mouse HSCs, which required interaction between TIMP1 and CD63 and signaling via phosphatidylinositol 3-kinase, but not TIMP1 protease inhibitor activity. This signaling pathway induced expression of endogenous TIMP1. TIMP1 knockdown in HSCs reduced their activation. Cultured TIMP1-activated human and mouse HSCs began to express stromal-derived factor-1, which induced neutrophil migration, a marker of the premetastatic niche. Mice with pancreatic intra-epithelial neoplasia-derived systemic increases in TIMP1 developed more liver metastases after injections of pancreatic cancer cells than mice without increased levels of TIMP1. This increase in formation of liver metastases from injected pancreatic cancer cells was not observed in TIMP1 or CD63 knockout mice. CONCLUSIONS: Expression of TIMP1 is increased in chronic pancreatitis, pancreatic intra-epithelial neoplasia, and PDAC tissues from patients. TIMP1 signaling via CD63 leads to activation of HSCs, which create an environment in the liver that increases its susceptibility to pancreatic tumor cells. Strategies to block TIMP1 signaling via CD63 might be developed to prevent PDAC metastasis to the liver.

25 Article Membranous CD24 drives the epithelial phenotype of pancreatic cancer. 2016

Lubeseder-Martellato, Clara / Hidalgo-Sastre, Ana / Hartmann, Carolin / Alexandrow, Katharina / Kamyabi-Moghaddam, Zahra / Sipos, Bence / Wirth, Matthias / Neff, Florian / Reichert, Maximilian / Heid, Irina / Schneider, Günter / Braren, Rickmer / Schmid, Roland M / Siveke, Jens T. ·II. Medizinische Klinik und Poliklinik, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany. · Current address: Klinik für Anaesthesiologie, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany. · Institute of Pathology, University Tübingen, Tübingen, Germany. · German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. · Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. · Institute of Radiology, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany. · Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany. ·Oncotarget · Pubmed #27203385.

ABSTRACT: Surface CD24 has previously been described, together with CD44 and ESA, for the characterization of putative cancer stem cells in pancreatic ductal adenocarcinoma (PDAC), the most fatal of all solid tumors. CD24 has a variety of biological functions including the regulation of invasiveness and cell proliferation, depending on the tumor entity and subcellular localization. Genetically engineered mouse models (GEMM) expressing oncogenic KrasG12D recapitulate the human disease and develop PDAC. In this study we investigate the function of CD24 using GEMM of endogenous PDAC and a model of cerulein-induced acute pancreatitis. We found that (i) CD24 expression was upregulated in murine and human PDAC and during acute pancreatitis (ii) CD24 was expressed exclusively in differentiated PDAC, whereas CD24 absence was associated with undifferentiated tumors and (iii) membranous CD24 expression determines tumor subpopulations with an epithelial phenotype in grafted models. In addition, we show that CD24 protein is stabilized in response to WNT activation and that overexpression of CD24 in pancreatic cancer cells upregulated β-catenin expression augmenting an epithelial, non-metastatic signature. Our results support a positive feedback model according to which (i) WNT activation and subsequent β-catenin dephosphorylation stabilize CD24 protein expression, and (ii) sustained CD24 expression upregulates β-catenin expression. Eventually, membranous CD24 augments the epithelial phenotype of pancreatic tumors. Thus we link the WNT/β-catenin pathway with the regulation of CD24 in the context of PDAC differentiation.

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