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Pancreatic Neoplasms: HELP
Articles by Jens M. Werner
Based on 124 articles published since 2009
(Why 124 articles?)
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Between 2009 and 2019, Jens Werner wrote the following 124 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4 · 5
1 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.

2 Editorial Prognosis of resected pancreatic cancer: is the refined resection margin status dispensable? 2012

Hartwig, Werner / Werner, Jens / Büchler, Markus W. · ·Langenbecks Arch Surg · Pubmed #22820875.

ABSTRACT: -- No abstract --

3 Editorial R0 in pancreatic cancer surgery: surgery, pathology, biology, or definition matters? 2010

Büchler, Markus W / Werner, Jens / Weitz, Jürgen. · ·Ann Surg · Pubmed #20485128.

ABSTRACT: -- No abstract --

4 Review Surgery of Cystic Tumors of the Pancreas - Why, When, and How? 2018

D'Haese, Jan G / Werner, Jens. ·Department of General, Visceral, and Transplantation Surgery, Ludwig Maximilians-University, Munich, Germany. ·Visc Med · Pubmed #30182025.

ABSTRACT: The management of cystic pancreatic neoplasms has increasingly gained clinical attention due to their frequent incidental detection by cross-sectional imaging and their potential for progression to pancreatic cancer. Surgical resection is warranted for all mucinous cystic neoplasms, solid pseudopapillary neoplasms, and main-duct intraductal papillary mucinous neoplasms since these lesions harbor a major risk for malignant transformation. For branch-duct IPMN (BD-IPMN), the risk for malignancy is considerably lower so that some lesions may be safely followed while others require surgical resection. The clinical challenge lies in making the correct preoperative diagnosis and estimation of the risk of malignancy in BD-IPMN. Therefore, the existing evidence and current guidelines on the management of cystic lesions of the pancreas are summarized and controversially discussed from a surgical point of view.

5 Review Surgical resection strategies for locally advanced pancreatic cancer. 2015

Gluth, Alexander / Werner, Jens / Hartwig, Werner. ·Department of General, Visceral, Transplantation, Vascular, and Thoracic Surgery, LMU University Hospital, Marchioninistraße 15, 81377, Munich, Germany. · Department of General, Visceral, Transplantation, Vascular, and Thoracic Surgery, LMU University Hospital, Marchioninistraße 15, 81377, Munich, Germany. werner.hartwig@med.uni-muenchen.de. ·Langenbecks Arch Surg · Pubmed #26115737.

ABSTRACT: BACKGROUND: Despite all improvements in tumor diagnostics and treatment, pancreatic cancer is still the fourth leading cause of cancer-related death in the Western world. It is mostly diagnosed at a locally advanced or metastasized stage because of the lack of early symptoms. A radical margin-free surgical resection offers the only potential cure for locoregional disease. Over the last decades, several surgical strategies and techniques have evolved to optimize oncologic radical resections and thus to improve long-term outcome of patients. PURPOSE: The purpose of this review was to describe the various surgical strategies and techniques for locally advanced pancreatic cancer and to evaluate their influence on long-term outcome. CONCLUSIONS: Locally advanced pancreatic cancer should not generally be deemed unresectable. Various surgical techniques offer a good chance of margin-free tumor resection, even if surrounding organs or vessels are involved. Because of potentially higher peri- and postoperative morbidity rates, patients should be selected properly and are best treated in specialized high-volume centers.

6 Review Quality assessment of the guidelines on cystic neoplasms of the pancreas. 2015

Falconi, Massimo / Crippa, Stefano / Chari, Suresh / Conlon, Kevin / Kim, Sun-Whe / Levy, Philippe / Tanaka, Masao / Werner, Jens / Wolfgang, Christopher L / Pezzilli, Raffaele / Castillo, Carlos Fernandez-Del. ·Division of Pancreatic Surgery, Università Politecnica delle Marche, Ospedali Riuniti, Ancona, Italy. · Pancreas Interest Group, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA. · Department of Surgery, Trinity College, Dublin, Ireland. · Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea. · Pôle des Maladies de l'Appareil Digestif, Service de Gastroentérologie-Pancréatologie, Hospital Beaujon, APHP, Clichy Cedex, Faculté Denis Diderot, DHU Unity, France. · Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan. · Department of Surgery, Ludwig-Maximilian University of Munich, Munich, Germany. · Department of Surgery and The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD, USA. · Pancreas Unit, Department of Digestive System, Sant'Orsola-Malpighi Hospital, Via Massarenti 9, 40138 Bologna, Italy. Electronic address: raffaele.pezzilli@aosp.bo.it. · Pancreas and Biliary Program, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. ·Pancreatology · Pubmed #26100659.

ABSTRACT: BACKGROUND: Though cystic pancreatic neoplasms (CPNs) are being increasingly detected, their evaluation and management are still debated and have lead to publication of multiple guidelines for diagnostic work-up, indications for resection, and non-operative management with follow-up strategies of CPNs. AIMS: To analyze available guidelines in order to evaluate their overall quality and clinical applicability, indications for surgical resection and its extent, modalities and timing of follow-up when non-operative management is indicated. METHODS: After a systematic search of the English literature, we selected eight guidelines for assessment according to the Appraisal of Guidelines, Research and Evaluation in Europe (AGREE) II instrument. RESULTS: One guideline received the lower AGREE score regarding the "scope and purpose", "rigor of development" and "clarity and presentation" domains, whereas one received the best score for "stakeholder involvement" domain. No differences were found among different guidelines regarding the "applicability". The overall quality assessment score showed that only two guidelines were significantly lower than the others. According to the practical utilization recommendation score, four guidelines were considered as having full applicability in clinical practice. CONCLUSION: Existing guidelines provide adequate guidance, at least with the present knowledge, for the management of cystic pancreatic lesions; however, not any one was satisfactory to all aspects related to the management of CPN. An update of the existing guidelines should be considered if and when more evidence-based data are available.

7 Review [Cystic tumors of the pancreas: diagnosis and therapy]. 2015

D'Haese, Jan G / Hartwig, Werner / Angele, Martin / Werner, Jens. ·Klinik für Allgemeine, Viszeral-, Transplantations-, Gefäß- und Thoraxchirurgie am Klinikum, Universität München, Standort Großhadern Marchioninistr. 15, D-81377, München, Deutschland, Jens.Werner@med.uni-muenchen.de. ·MMW Fortschr Med · Pubmed #26015016.

ABSTRACT: -- No abstract --

8 Review A systematic review of localization, surgical treatment options, and outcome of insulinoma. 2014

Mehrabi, Arianeb / Fischer, Lars / Hafezi, Mohammadreza / Dirlewanger, Antje / Grenacher, Lars / Diener, Markus K / Fonouni, Hamidreza / Golriz, Mohammd / Garoussi, Camelia / Fard, Nassim / Rahbari, Nuh N / Werner, Jens / Büchler, Markus W. ·From the Departments of *General, Visceral, and Transplantation Surgery, †Radiology, and ‡Anesthesiology, University of Heidelberg, Heidelberg, Germany. ·Pancreas · Pubmed #24921202.

ABSTRACT: OBJECTIVE: Insulinoma with an incidence of 0.4% is a rare pancreatic tumor. Preserving surgery is the treatment of choice. Exact localization is necessary to plan the appropriate approach. This article gives an overview on localization and surgical strategies for treatment of insulinoma. METHODS: In this systematic review, 114 articles with 6222 cases of insulinoma were reviewed with emphasis on localization techniques and surgical treatment. RESULTS: Insulinoma happens mostly in the fifth decade of life, with a higher incidence in men. They occur mostly sporadic (94%), benign (87%), and single (90%). Insulinomas are mostly smaller than 20 mm (84%). The tumors are distributed almost equally in the pancreas. CONCLUSIONS: Computed tomography is routinely used as first choice preoperatively. Intraoperative inspection, palpation, and sonography were applied with high success rate. Intraoperative sonography is considered as the most reliable technique. Enucleation is the most administered type of surgery (56%). Different types of resection include distal pancreatectomy (32%), Whipple procedure (3%), and subtotal pancreatectomy (<3%). Despite the development of laparoscopy, open approach is the favorite method (90%). The most common surgical complication is fistula. The mortality rate of open approach was higher (4 vs 0%). Despite high cure rate, recurrence of insulinoma occurs in 7% after surgery.

9 Review Two immune faces of pancreatic adenocarcinoma: possible implication for immunotherapy. 2014

Bazhin, Alexandr V / Shevchenko, Ivan / Umansky, Viktor / Werner, Jens / Karakhanova, Svetlana. ·Department of General Surgery, University of Heidelberg, Im Neuenheimer Feld 156, 69120, Heidelberg, Germany, alexandr.bazhin@med.uni-heidelberg.de. ·Cancer Immunol Immunother · Pubmed #24129765.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human neoplasms, having extremely poor prognosis with a 5-year survival rate of <1 % and a median survival of 6 months. In contrast to other malignancies, pancreatic cancer is highly resistant to chemotherapy and targeted therapy. Therefore, new treatment options are urgently needed to improve the survival of patients with PDAC. Based on our data showing that patients with higher CD8+ T cell tumour infiltration exhibited prolonged overall and disease-free survival compared to patients with lower or without CD8+ T cell tumour infiltration, we suggested that immunotherapy could be a promising treatment option for PDAC. However, clinical data from the chemoradioimmunotherapy with interferon-α (IFN) trial did not point to an improved efficiency of chemoradiation combined with IFN as compared to chemoradiotherapy alone, suggesting an important role of the immune suppression induced by PDAC and/or unspecific immune stimulation. In support of this hypothesis, we found that the PDAC patients and experimental mice had an increased number of regulatory T cells and myeloid-derived suppressor cells. These results allowed us to conclude that PDAC provokes not only an anti-tumour immune response, but also strong immune suppression. Thus, we supposed that new immunotherapeutical strategies should involve not only stimulation of the immune system of PDAC patients, but also exert control over the tumour immune suppressive milieu.

10 Review Improvement of surgical results for pancreatic cancer. 2013

Hartwig, Werner / Werner, Jens / Jäger, Dirk / Debus, Jürgen / Büchler, Markus W. ·Department of General, Visceral, and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany. · National Cancer Center, University of Heidelberg, Heidelberg, Germany. · Department of Radiation Oncology, University of Heidelberg, Heidelberg, Germany. · Department of General, Visceral, and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany. Electronic address: markus.buechler@med.uni-heidelberg.de. ·Lancet Oncol · Pubmed #24079875.

ABSTRACT: Surgery is the only potential hope of cure for patients with pancreatic cancer. Advantageous tumour characteristics and complete tumour resection are the factors most relevant for a positive prognosis, so detection of premalignant or early invasive lesions, combined with safe and oncologically adequate surgery, is an important goal. The experience and volume of both the individual surgeon and hospital are of paramount importance to achieve low morbidity and adequate management of complications. Most pancreatic cancers are locally advanced or metastatic when diagnosed and need multimodal therapy. With increasing evidence on surgical and perioperative aspects of pancreatic cancer therapy, short-term and long-term outcomes of resectable and borderline resectable pancreatic cancer are improving.

11 Review Advanced-stage pancreatic cancer: therapy options. 2013

Werner, Jens / Combs, Stephanie E / Springfeld, Christoph / Hartwig, Werner / Hackert, Thilo / Büchler, Markus W. ·Department of General, Visceral, and Transplantation Surgery, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany. ·Nat Rev Clin Oncol · Pubmed #23629472.

ABSTRACT: Pancreatic ductal adenocarcinoma is one of the most aggressive cancers, and surgical resection is a requirement for a potential cure. However, the majority of patients are diagnosed with advanced-stage disease, either metastatic (50%) or locally advanced cancer (30%). Although palliative chemotherapy is the standard of care for patients with metastatic disease, management of locally advanced adenocarcinoma is controversial. Several treatment options, including extended surgical resections, neoadjuvant therapy with subsequent resections, as well as palliative radiotherapy and/or chemotherapy, should be considered. However, there is little evidence available to support treatment options for locally advanced disease. As valid predictive biomarkers for stratification of therapy are not available today, future trials need to define the role of the different treatment options. This Review summarizes the current evidence and discusses available treatment options for both locally advanced and metastatic pancreatic adenocarcinoma.

12 Review The role of the tumor endothelium in leukocyte recruitment in pancreatic cancer. 2012

Schmidt, Jan / Mocevicius, Paulius / Werner, Jens / Ryschich, Eduard. ·Department of Surgery, University of Heidelberg, Germany. ·Surgery · Pubmed #22770953.

ABSTRACT: BACKGROUND: Although pancreatic cancer tissue frequently induces an immune reaction, immunocompetent cells are not able to eliminate the tumor. One potential cause for this ineffective immune response is that a number of active, tumor-cytotoxic T cells are not able to invade into the tumor. METHODS: A potential barrier for invading leukocytes can be the tumor endothelium, which controls recruitment of leukocytes from circulating blood into the tissue. Although attenuated expression of adhesion molecules on the tumor endothelium has been proposed as a mechanism which suppresses intratumoral leukocyte infiltration, the relevance of adhesion molecules for leukocyte recruitment in tumor tissue is poorly understood. RESULTS: The leukocyte extravasation in normal pancreas during acute pancreatitis follows the "classic" leukocyte recruitment cascade and is controlled by the overexpression of endothelial adhesion molecules, such as selectins, intracellular adhesion molecule-1, and platelet endothelial cell adhesion molecule-1. In contrast to acute inflammation in normal pancreas, leukocyte recruitment in pancreatic cancer is a slow process, which does not show a strong dependence on intracellular adhesion molecule-1. In addition, pancreatic cancer has a high degree of heterogeneity of both immunogenic properties and the distribution of tumor-infiltrating leukocytes, such as CD8(+), CD4(+), or regulatory T cells. CONCLUSION: Additional studies may clarify whether T cell recruitment and their activity in pancreatic cancer can be enhanced by modulation of endothelial adhesion molecules.

13 Review Intraductal papillary mucinous neoplasms of the pancreas--a surgical disease. 2012

Werner, Jens / Fritz, Stefan / Büchler, Markus W. ·Department of General and Visceral Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany. ·Nat Rev Gastroenterol Hepatol · Pubmed #22392299.

ABSTRACT: Cystic pancreatic neoplasms are increasingly recognized, with intraductal papillary mucinous neoplasms of the pancreas (IPMNs) being the most frequently observed type. IPMNs are characterized by mucin production and epithelial growth within the pancreatic ducts, and are generally differentiated according to location: main pancreatic duct, its major side branches, or both (mixed type). IPMNs vary from benign to malignant and are considered precursor lesions of pancreatic adenocarcinoma. However, the exact time to neoplastic transformation and whether all IPMNs progress to malignant tumors is unclear. Surgical resection is warranted for all main-duct and mixed-type IPMNs (they harbor a high risk of malignancy of ~70%). By contrast, branch-duct IPMNs progress to cancer in only ~30% of cases. Thus, according to current guidelines (Sendai criteria), asymptomatic side-branch IPMNs <3 cm in size without suspicious radiological features (such as size progression) can be treated conservatively. Lately, even this approach has become controversial, owing to a number of Sendai-negative IPMNs showing malignant transformation. Although most IPMNs should be resected by standard oncological procedures (including lymphadenectomy), small Sendai-negative IPMNs can be treated with limited resections. This Review summarizes current knowledge of the treatment of IPMNs, with a particular focus on surgical approaches to this disease.

14 Review Postoperative pancreatic fistula. 2011

Hackert, Thilo / Werner, Jens / Büchler, Markus W. ·Department of Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany. ·Surgeon · Pubmed #21672661.

ABSTRACT: Postoperative pancreatic fistula is an important complication after pancreatic resection. The frequency of its incidence varies between 3% after pancreatic head resections and up to 30% following distal pancreatectomy. In recent years, the international definition of pancreatic fistula has been standardised according to the approach of the International Study Group on Pancreatic Fistula (ISGPF). Consequently, results from different studies have become comparable and the historically reported fistula rates can be evaluated more critically. The present review summarises the currently available data on incidence, risk factors, fistula-associated complications and management of postoperative pancreatic fistula.

15 Clinical Trial Influence of interferon-alpha combined with chemo (radio) therapy on immunological parameters in pancreatic adenocarcinoma. 2014

Karakhanova, Svetlana / Mosl, Beate / Harig, Sabine / von Ahn, Katharina / Fritz, Jasmin / Schmidt, Jan / Jäger, Dirk / Werner, Jens / Bazhin, Alexandr V. ·Department of General Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany. Svetlana.karakhanova@med.uni-heidelberg.de. · Department of General Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany. beate.mosl@med.uni-heidelberg.de. · Department of General Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany. Dirk.Jaeger@med.uni-heidelberg.de. · Department of General Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany. katharinavonahn@hotmail.com. · Department of General Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany. jasminfritz@web.de. · Department of General Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany. Jan.Schmidt@hirslanden.ch. · National Centre for Tumor Disease, University Hospital Heidelberg, 69120 Heidelberg, Germany. Dirk.Jaeger@med.uni-heidelberg.de. · Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University, 81377 Munich, Germany. jens.werner@med.uni-heidelberg.de. · Department of General Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany. Alexandr.bazhin@med.uni-heidelberg.de. ·Int J Mol Sci · Pubmed #24608924.

ABSTRACT: Prognosis of patients with carcinoma of the exocrine pancreas is particularly poor. A combination of chemotherapy with immunotherapy could be an option for treatment of pancreatic cancer. The aim of this study was to perform an immunomonitoring of 17 patients with pancreatic cancer from the CapRI-2 study, and tumor-bearing mice treated with combination of chemo (radio) therapies with interferon-2α. Low doses of interferon-2α led to a decrease in total leukocyte and an increase in monocyte counts. Furthermore, we observed a positive effect of interferon-2α therapy on the dendritic cells and NK (natural killer) cell activation immediately after the first injection. In addition, we recorded an increased amount of interferon-γ and IL-10 in the serum following the interferon-2α therapy. These data clearly demonstrate that pancreatic carcinoma patients also show an immunomodulatory response to interferon-2α therapy. Analysis of immunosuppressive cells in the Panc02 orthotopic mouse model of pancreatic cancer revealed an accumulation of the myeloid-derived suppressor cells in spleens and tumors of the mice treated with interferon-2α and 5-fluorouracil. The direct effect of the drugs on myeloid-derived suppressor cells was also registered in vitro. These data expose the importance of immunosuppressive mechanisms induced by combined chemo-immunotherapy.

16 Clinical Trial Phase I study evaluating the treatment of patients with locally advanced pancreatic cancer with carbon ion radiotherapy: the PHOENIX-01 trial. 2013

Combs, Stephanie E / Habermehl, Daniel / Kieser, Meinhard / Dreher, Constantin / Werner, Jens / Haselmann, Renate / Jäkel, Oliver / Jäger, Dirk / Büchler, Markus W / Debus, Jürgen. ·Department of Radiation Oncology, University Hospital of Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany. Stephanie.combs@med.uni-heidelberg.de. ·BMC Cancer · Pubmed #24034562.

ABSTRACT: BACKGROUND: Treatment options for patients with locally advanced pancreatic cancer include surgery, chemotherapy as well as radiotherapy. In many cases, surgical resection is not possible, and therefore treatment alternatives have to be performed. Chemoradiation has been established as a convincing treatment alternative for locally advanced pancreatic cancer. Carbon ions offer physical and biological characteristics. Due to their inverted dose profile and the high local dose deposition within the Bragg peak precise dose application and sparing of normal tissue is possible. Moreover, in comparison to photons, carbon ions offer an increased relative biological effectiveness (RBE), which can be calculated between 1.16 and 2.46 depending on the pancreatic cancer cell line as well as the endpoint analyzed. Japanese Data on the evaluation of carbon ion radiation therapy showed promising results for patients with pancreatic cancer. METHODS AND DESIGN: The present PHOENIX-01 trial evaluates carbon ion radiotherapy using the active rasterscanning technique in patients with advanced pancreatic cancer in combination with weekly gemcitabine and adjuvant gemcitabine. Primary endpoint is toxicity, secondary endpoints are overall survival, progression-free survival and response. DISCUSSION: The physical and biological properties of the carbon ion beam promise to improve the therapeutic ratio in patients with pancreatic cancer: Due to the inverted dose profile dose deposition in the entry channel of the beam leads to sparing of normal tissue; the Bragg peak can be directed into the defined target volume, and the sharp dose fall-off thereafter again spares normal tissue behind the target volume. The higher RBE of carbon ions, which has been shown also for pancreatic cancer cell lines in the preclinical setting, is likely to contribute to an increase in local control, and perhaps in OS. Early data from Japanese centers have shown promising results. In conclusion, this is the first trial to evaluate actively delivered carbon ion beams in patients with locally advanced pancreatic cancer within a dose-escalation strategy. TRIAL REGISTRATION: NCT01795274.

17 Clinical Trial Clinical phase I/II trial to investigate neoadjuvant intensity-modulated short term radiation therapy (5 × 5 Gy) and intraoperative radiation therapy (15 Gy) in patients with primarily resectable pancreatic cancer - NEOPANC. 2012

Roeder, Falk / Timke, Carmen / Saleh-Ebrahimi, Ladan / Schneider, Lutz / Hackert, Thilo / Hartwig, Werner / Kopp-Schneider, Annette / Hensley, Frank W / Buechler, Markus W / Debus, Juergen / Huber, Peter E / Werner, Jens. ·Clinical Cooperation Unit Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany. F.Roeder@dkfz.de. ·BMC Cancer · Pubmed #22443802.

ABSTRACT: BACKGROUND: The current standard treatment, at least in Europe, for patients with primarily resectable tumors, consists of surgery followed by adjuvant chemotherapy. But even in this prognostic favourable group, long term survival is disappointing because of high local and distant failure rates. Postoperative chemoradiation has shown improved local control and overalls survival compared to surgery alone but the value of additional radiation has been questioned in case of adjuvant chemotherapy. However, there remains a strong rationale for the addition of radiation therapy considering the high rates of microscopically incomplete resections after surgery. As postoperative administration of radiation therapy has some general disadvantages, neoadjuvant and intraoperative approaches theoretically offer benefits in terms of dose escalation, reduction of toxicity and patients comfort especially if hypofractionated regimens with highly conformal techniques like intensity-modulated radiation therapy are considered. METHODS/DESIGN: The NEOPANC trial is a prospective, one armed, single center phase I/II study investigating a combination of neoadjuvant short course intensity-modulated radiation therapy (5 × 5 Gy) in combination with surgery and intraoperative radiation therapy (15 Gy), followed by adjuvant chemotherapy according to the german treatment guidelines, in patients with primarily resectable pancreatic cancer. The aim of accrual is 46 patients. DISCUSSION: The primary objectives of the NEOPANC trial are to evaluate the general feasibility of this approach and the local recurrence rate after one year. Secondary endpoints are progression-free survival, overall survival, acute and late toxicity, postoperative morbidity and mortality and quality of life. TRIAL REGISTRATION: NCT01372735.

18 Clinical Trial Randomized controlled phase I/II study to investigate immune stimulatory effects by low dose radiotherapy in primarily operable pancreatic cancer. 2011

Timke, Carmen / Winnenthal, Hubertus Schmitz / Klug, Felix / Roeder, Falk F F / Bonertz, Andreas / Reissfelder, Christoph / Rochet, Nathalie / Koch, Moritz / Tjaden, Christine / Buechler, Markus W / Debus, Juergen / Werner, Jens / Beckhove, Philipp / Weitz, Jürgen / Huber, Peter E. ·Department of Radiation Oncology, German Cancer Research Center and University Hospital Center, Heidelberg, Germany. ·BMC Cancer · Pubmed #21489291.

ABSTRACT: BACKGROUND: The efficiencies of T cell based immunotherapies are affected by insufficient migration and activation of tumor specific effector T cells in the tumor. Accumulating evidence exists on the ability of ionizing radiation to modify the tumor microenvironment and generate inflammation. The aim of this phase I/II clinical trial is to evaluate whether low dose single fraction radiotherapy can improve T cell associated antitumor immune response in patients with pancreatic cancer. METHODS/DESIGN: This trial has been designed as an investigator initiated; prospective randomised, 4-armed, controlled Phase I/II trial. Patients who are candidates for resection of pancreatic cancer will be randomized into 4 arms. A total of 40 patients will be enrolled. The patients receive 0 Gy, 0.5 Gy, 2 Gy or 5 Gy radiation precisely targeted to their pancreatic carcinoma. Radiation will be delivered by external beam radiotherapy using a 6 MV Linac with IMRT technique 48 h prior to the surgical resection. The primary objective is the determination of an active local external beam radiation dose, leading to tumor infiltrating T cells as a surrogate parameter for antitumor activity. Secondary objectives include local tumor control and recurrence patterns, survival, radiogenic treatment toxicity and postoperative morbidity and mortality, as well as quality of life. Further, frequencies of tumor reactive T cells in blood and bone marrow as well as whole blood cell transcriptomics and plasma-proteomics will be correlated with clinical outcome. An interim analysis will be performed after the enrollment of 20 patients for safety reasons. The evaluation of the primary endpoint will start four weeks after the last patient's enrollment. DISCUSSION: This trial will answer the question whether a low dose radiotherapy localized to the pancreatic tumor only can increase the number of tumor infiltrating T cells and thus potentially enhance the antitumor immune response. The study will also investigate the prognostic and predictive value of radiation-induced T cell activity along with transcriptomic and proteomic data with respect to clinical outcome.

19 Article Indications for resection and perioperative outcomes of surgery for pancreatic neuroendocrine neoplasms in Germany: an analysis of the prospective DGAV StuDoQ|Pancreas registry. 2019

Mintziras, Ioannis / Keck, Tobias / Werner, Jens / Fichtner-Feigl, Stefan / Wittel, Uwe / Senninger, Norbert / Vowinkel, Thorsten / Köninger, Jörg / Anthuber, Matthias / Geißler, Bernd / Bartsch, Detlef Klaus / Anonymous2391606. ·Department of Visceral-, Thoracic- and Vascular Surgery, Philipps-University Marburg, Baldingerstrasse, 35043, Marburg, Germany. ioannis.mintziras@uk-gm.de. · Clinic for Surgery, University Clinic Schleswig-Holstein, UKSH Campus Lübeck, Lübeck, Germany. · Department of General, Visceral, Vascular and Transplant Surgery, Klinikum Der Universität München, Munich, Germany. · Department of General and Visceral Surgery, University Clinic Freiburg, Freiburg, Germany. · Department of General and Visceral Surgery, University Clinic Münster, Münster, Germany. · Department of General and Visceral Surgery, Klinikum Oldenburg, Oldenburg, Germany. · Department of General-, Visceral- and Vascular Surgery, St. Josefskrankenhaus, Freiburg, Germany. · Department of General, Visceral, Thoracic and Transplant Surgery, Katharinenhospital, Stuttgart, Germany. · Department of General, Visceral and Transplant Surgery, Klinikum Augsburg, Augsburg, Germany. · Department of Visceral-, Thoracic- and Vascular Surgery, Philipps-University Marburg, Baldingerstrasse, 35043, Marburg, Germany. ·Surg Today · Pubmed #31240463.

ABSTRACT: PURPOSE: Pancreatic neuroendocrine neoplasms (pNENs) are rare, and their surgical management is complex. This study evaluated the current practice of pNEN surgery across Germany, including its adherence with guidelines and its perioperative outcomes. METHODS: Patients who underwent surgery for pNENs (April 2013-June 2017) were retrieved from the prospective StuDoQ|Pancreas registry of the German Society of General and Visceral Surgery and retrospectively analyzed. RESULTS: A total of 287 patients (53.7% male) with a mean age of 59.2 ± 14.2 years old underwent pancreatic resection for pNENs. Tumors were localized in the pancreatic head (40.4%), body (23%), or tail (36.6%). A total of 239 (83.3%) patients underwent formal resection with lymphadenectomy, 40 (14%) parenchyma-sparing resection, and 8 (2.8%) only exploration. Fifty (17.4%) patients underwent a minimally invasive approach. Among the 245 patients with complete pathological information, 42 (17.1%) had distant metastases, 78 (31.8%) had stage I tumors, 74 (30.2%) stage II, and 51 (20.8%) stage III. A total of 112 (45.7%) patients had G1 tumors, 101 (41.2%) G2, and 24 (9.8%) G3. Nodal involvement on imaging was an independent predictor of lymph node metastasis according to the multivariable analysis (odds ratio: 0.057; 95% confidence interval: 0.016-0.209; p < 0.01). R0 resection was reported in 240 (83.6%) patients. The 30- and 90-day mortality rates were 2.8% and 4.2%, respectively. CONCLUSION: In Germany the rate of potential curative resection for pNEN is high. However, formal pancreatic resection seems to be overrepresented, while minimally invasive resection is underrepresented.

20 Article Implementation of Current ENETS Guidelines for Surgery of Small (≤2 cm) Pancreatic Neuroendocrine Neoplasms in the German Surgical Community: An Analysis of the Prospective DGAV StuDoQ|Pancreas Registry. 2019

Mintziras, Ioannis / Keck, Tobias / Werner, Jens / Fichtner-Feigl, Stefan / Wittel, Uwe / Senninger, Norbert / Vowinkel, Thorsten / Köninger, Jörg / Anthuber, Matthias / Geißler, Bernd / Bartsch, Detlef Klaus / Anonymous2561082. ·Department of Visceral-, Thoracic- and Vascular Surgery, Philipps-University Marburg, Baldingerstrasse, 35043, Marburg, Germany. ioannis.mintziras@uk-gm.de. · Clinic for Surgery, University Clinic Schleswig-Holstein, UKSH Campus Lübeck, Lübeck, Germany. · Department of General, Visceral, Vascular and Transplant Surgery, Klinikum der Universität München, Munich, Germany. · Department of General and Visceral Surgery, University Clinic Freiburg, Freiburg, Germany. · Department of General and Visceral Surgery, University Clinic Münster, Münster, Germany. · Department of General and Visceral Surgery, Katharinenhospital, Stuttgart, Germany. · Department of General, Visceral and Transplant Surgery, Klinikum Augsburg, Augsburg, Germany. · Department of Visceral-, Thoracic- and Vascular Surgery, Philipps-University Marburg, Baldingerstrasse, 35043, Marburg, Germany. ·World J Surg · Pubmed #30097704.

ABSTRACT: BACKGROUND: ENETS guidelines recommend parenchyma-sparing procedures without formal lymphadenectomy, ideally with a minimally invasive laparoscopic approach for sporadic small pNENs (≤2 cm). Non-functioning (NF) small pNENs can also be observed. The aim of the study was to evaluate how these recommendations are implemented in the German surgical community. METHODS: Data from the prospective StuDoQ|Pancreas registry of the German Society of General and Visceral Surgery were analyzed regarding patient's demographics, tumor characteristics, surgical procedures, histology and perioperative outcomes. RESULTS: Eighty-four (29.2%) of 287 patients had sporadic pNENs ≤2 cm. Forty-three (51.2%) patients were male, and the mean age at diagnosis was 58.8 ± 15.6 years. Twenty-five (29.8%) pNENs were located in the pancreatic head. The diagnosis pNEN was preoperatively established in 53 (65%) of 84 patients. Sixty-two (73.8%) patients had formal pancreatic resections, including partial pancreaticoduodenectomy or total pancreatectomy (21.4%). Only 22 (26.2%) patients underwent parenchyma-sparing resections and 23 (27.4%) patients had minimally invasive procedures. A lymphadenectomy was performed in 63 (75.4%) patients, and lymph node metastases were diagnosed in 6 (7.2%) patients. Eighty-two (97.7%) patients had an R0 resection. Sixty (72%) tumors were classified G1, 24 (28%) tumors G2. Twenty-seven (32.2%) of 84 patients had postoperative relevant Clavien-Dindo grade ≥3 complications. Thirty- and 90-day mortalities were 2.4% and 3.6%. CONCLUSIONS: ENETS guidelines for surgery of small pNENs are yet not well accepted in the German surgical community, since the rate of formal resections with standard lymphadenectomy is high and the minimally invasive approach is underused. The attitude to operate small NF tumors seems to be rather aggressive.

21 Article Surgical treatment of pNET - Experience of a "high-volume" center. 2018

Bösch, Florian / Hofmann, Katharina / Coenen, Michaela / Pratschke, Sebastian / Thomas, Michael / Knösel, Thomas / Bruns, Christiane J / Guba, Markus / Werner, Jens / Angele, Martin K. ·Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany. · Department of Medical Informatics, Biometry and Epidemiology, IBE, Chair for Public Health and Health Services Research, Research Unit for Biopsychosocial Health, Ludwig-Maximilians-Universität (LMU) München, Munich, Germany. · Institute of Pathology, Ludwig-Maximilians-Universität (LMU) München, Munich, Germany. · Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany; Department of General, Visceral, and Cancer Surgery, University of Cologne, Cologne, Germany. · Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany. Electronic address: martin.angele@med.uni-muenchen.de. ·Surg Oncol · Pubmed #30217295.

ABSTRACT: BACKGROUND: Neuroendocrine tumors of the pancreas (pNETs) are a rare disease. Grading according to the Ki67-index is the most validated risk factor. Nevertheless, controversies exist concerning other prognostic factors. The aim of this study was to evaluate published risk factors. METHODS: Patients with pancreatic NETs who underwent surgery at our department from 2000 to 2014 were analyzed. The patient and tumor characteristics were evaluated. Kaplan-Meier analyses, univariate calculations as well as multivariate analyses were performed. RESULTS: In total, 98 patients underwent surgery due to a pNET. The final study population consisted of 88 patients. Univariate analysis demonstrated that overall survival is influenced by tumor grading, local resection margin and presence of distant metastases. However, in the multivariate analysis, only grading and the resection margin had prognostic significance. The size of the primary tumor directly correlated with the probability of metastases. Multivisceral operations had no influence on morbidity or mortality. CONCLUSIONS: Resection of pNETs is the only curative treatment and is safe. Since the incidence of pNETs is low, treatment should be performed at a high-volume center.

22 Article Cholinergic Signaling via Muscarinic Receptors Directly and Indirectly Suppresses Pancreatic Tumorigenesis and Cancer Stemness. 2018

Renz, Bernhard W / Tanaka, Takayuki / Sunagawa, Masaki / Takahashi, Ryota / Jiang, Zhengyu / Macchini, Marina / Dantes, Zahra / Valenti, Giovanni / White, Ruth A / Middelhoff, Moritz A / Ilmer, Matthias / Oberstein, Paul E / Angele, Martin K / Deng, Huan / Hayakawa, Yoku / Westphalen, C Benedikt / Werner, Jens / Remotti, Helen / Reichert, Maximilian / Tailor, Yagnesh H / Nagar, Karan / Friedman, Richard A / Iuga, Alina C / Olive, Kenneth P / Wang, Timothy C. ·Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich; and German Cancer Research Center (DKFZ), Heidelberg, Germany. · Division of Digestive and Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York. · Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Sakamoto, Nagasaki, Japan. · Department of Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. · Division of Oncology, Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York. · Perlmutter Cancer Center, New York University Langone Medical Center, New York, New York. · Department of Pathology, and Molecular Medicine and Genetics Center, The Fourth Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China. · Department of Gastroenterology, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan. · Department of Internal Medicine III, Hospital of the University of Munich, Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich; and German Cancer Research Center (DKFZ), Heidelberg, Germany. · Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York. · Biomedical Informatics Shared Resource of the Herbert Irving Comprehensive Cancer Center and Department of Biomedical Informatics, Columbia University Medical Center, New York, New York. · Department of Pathology and Cell Biology and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York. · Division of Digestive and Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York. tcw21@columbia.edu. ·Cancer Discov · Pubmed #30185628.

ABSTRACT: In many solid tumors, parasympathetic input is provided by the vagus nerve, which has been shown to modulate tumor growth. However, whether cholinergic signaling directly regulates progression of pancreatic ductal adenocarcinoma (PDAC) has not been defined. Here, we found that subdiaphragmatic vagotomy in LSL-

23 Article Immune Cell and Stromal Signature Associated With Progression-Free Survival of Patients With Resected Pancreatic Ductal Adenocarcinoma. 2018

Mahajan, Ujjwal Mukund / Langhoff, Eno / Goni, Elisabetta / Costello, Eithne / Greenhalf, William / Halloran, Christopher / Ormanns, Steffen / Kruger, Stephan / Boeck, Stefan / Ribback, Silvia / Beyer, Georg / Dombroswki, Frank / Weiss, Frank-Ulrich / Neoptolemos, John P / Werner, Jens / D'Haese, Jan G / Bazhin, Alexandr / Peterhansl, Julian / Pichlmeier, Svenja / Büchler, Markus W / Kleeff, Jörg / Ganeh, Paula / Sendler, Matthias / Palmer, Daniel H / Kohlmann, Thomas / Rad, Roland / Regel, Ivonne / Lerch, Markus M / Mayerle, Julia. ·Department of Medicine II, University Hospital, LMU Munich, Germany; Department of Medicine A, University Medicine Greifswald, Greifswald, Germany. · Department of Medicine A, University Medicine Greifswald, Greifswald, Germany. · Department of Medicine II, University Hospital, LMU Munich, Germany. · Institute of Translational Medicine, University of Liverpool, Liverpool, UK. · Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany. · Department of Medicine III, University Hospital, LMU Munich, Germany. · Department of Pathology, University Medicine Greifswald, Greifswald, Germany. · Institute of Translational Medicine, University of Liverpool, Liverpool, UK; Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany. · Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany. · Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany. · Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther University Halle-Wittenberg, Halle, Germany. · Institute of Translational Medicine, University of Liverpool, Liverpool, UK; Clatterbridge Cancer Centre NHS Foundation Trust, Wirral, UK. · Department of Community Medicine, University Medicine Greifswald, Greifswald, Germany. · Center for Translational Cancer Research (TranslaTUM), Technische Universität München, Munich, Germany. · Department of Medicine II, University Hospital, LMU Munich, Germany; Department of Medicine A, University Medicine Greifswald, Greifswald, Germany. Electronic address: julia.mayerle@med.uni-muenchen.de. ·Gastroenterology · Pubmed #30092175.

ABSTRACT: BACKGROUND & AIMS: Changes to the microenvironment of pancreatic ductal adenocarcinomas (PDACs) have been associated with poor outcomes of patients. We studied the associations between composition of the pancreatic stroma (fibrogenic, inert, dormant, or fibrolytic stroma) and infiltration by inflammatory cells and times of progression-free survival (PFS) of patients with PDACs after resection. METHODS: We obtained 1824 tissue microarray specimens from 385 patients included in the European Study Group for Pancreatic Cancer trial 1 and 3 and performed immunohistochemistry to detect alpha smooth muscle actin, type 1 collagen, CD3, CD4, CD8, CD68, CD206, and neutrophils. Tumors that expressed high and low levels of these markers were compared with patient outcomes using Kaplan-Meier curves and multivariable recursive partitioning for discrete-time survival tree analysis. Prognostic index was delineated by a multivariable Cox proportional hazards model of immune cell and stromal markers and PFS. Findings were validated using 279 tissue microarray specimens from 93 patients in a separate cohort. RESULTS: Levels of CD3, CD4, CD8, CD68, and CD206 were independently associated with tumor recurrence. Recursive partitioning for discrete-time survival tree analysis identified a high level of CD3 as the strongest independent predictor for longer PFS. Tumors with levels of CD3 and high levels of CD206 associated with a median PFS time of 16.6 months and a median prognostic index of -0.32 (95% confidence interval [CI] -0.35 to -0.31), whereas tumors with low level of CD3 cell and low level of CD8 and high level of CD68 associated with a median PFS time of 7.9 months and a prognostic index of 0.32 (95% CI 0.050-0.32); we called these patterns histologic signatures. Stroma composition, when unassociated with inflammatory cell markers, did not associate significantly with PFS. In the validation cohort, the histologic signature resulted in an error matrix accuracy of predicted response of 0.75 (95% CI 0.64-0.83; accuracy P < .001). CONCLUSIONS: In an analysis of PDAC tissue microarray specimens, we identified and validated a histologic signature, based on leukocyte and stromal factors, that associates with PFS times of patients with resected PDACs. Immune cells might affect the composition of the pancreatic stroma to affect progression of PDAC. These findings provide new insights into the immune response to PDAC.

24 Article Therapies Targeting the Tumor Stroma and the VEGF/VEGFR Axis in Pancreatic Ductal Adenocarcinoma: a Systematic Review and Meta-Analysis. 2018

Lu, Zipeng / Weniger, Maximilian / Jiang, Kuirong / Boeck, Stefan / Zhang, Kai / Bazhin, Alexander / Miao, Yi / Werner, Jens / D'Haese, Jan G. ·Pancreas Center & Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China. · Department of General, Visceral, and Transplantation Surgery, Ludwig Maximilians-University, Marchioninistraße 15, 81377, Munich, Germany. · Department of Internal Medicine III and Comprehensive Cancer Center, Ludwig Maximilians-University, Marchioninistr. 15, 81377, Munich, Germany. · Pancreas Center & Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China. miaoyi@njmu.edu.cn. ·Target Oncol · Pubmed #30062609.

ABSTRACT: Abundant tumor stroma is a hallmark of pancreatic ductal adenocarcinoma (PDAC), and is suggested to play a role in the resistance of this deadly disease to systemic treatment. Despite promising results from preclinical studies, clinical trials with therapies targeting the tumor stroma and the vascular endothelial growth factor (VEGF) and its receptor VEGFR yielded conflicting results. With this systematic review and meta-analysis, we aim to summarize the existing evidence in this important field with a special focus on anti-VEGF/VEGFR therapy. A total of 24 clinical studies were included in the qualitative synthesis, and six randomized controlled trials (RCTs) investigating anti-VEGF/VEGFR agents were further included in the quantitative synthesis. The qualitative synthesis revealed a treatment advantage of combined therapy with nab-paclitaxel, while the meta-analysis on anti-VEGF/VEGFR drugs demonstrated marginal improvement of objective response rates and progression-free survival, but not overall survival. Stroma targeting is a promising and rapidly-developing treatment strategy in PDAC. However, novel drugs balancing stroma depletion and modulation are needed.

25 Article Antimicrobial Peptide Human Neutrophil Peptide 1 as a Potential Link Between Chronic Inflammation and Ductal Adenocarcinoma of the Pancreas. 2018

Pausch, Thomas / Adolph, Sarah / Felix, Klaus / Bauer, Andrea S / Bergmann, Frank / Werner, Jens / Hartwig, Werner. · ·Pancreas · Pubmed #29683978.

ABSTRACT: OBJECTIVES: Defensins are antimicrobial peptides playing a role in innate immunity, in epithelial cell regeneration, and in carcinogenesis of inflammation-triggered malignancies. We analyzed this role in pancreatic ductal adenocarcinoma (PDAC) in the context of its association with chronic pancreatitis (CP). METHODS: Human tissue of healthy pancreas, CP, and PDAC was screened for defensins by immunohistochemistry. Defensin α 1 (human neutrophil peptide 1 [HNP-1]) expression was validated using mass spectrometry and microarray analysis. Human neutrophil peptide 1 expression and influences of proinflammatory cytokines (tumor necrosis factor α, interleukin 1β, and interferon γ) were studied in human pancreatic cancer cells (Colo 357, T3M4, PANC-1) and normal human pancreatic duct epithelial cells (HPDE). RESULTS: Accumulation of HNP-1 in malignant pancreatic ductal epithelia was seen. Spectrometry showed increased expression of HNP-1 in CP and even more in PDAC. At RNA level, no significant regulation was found. In cancer cells, HNP-1 expression was significantly higher than in HPDE. Proinflammatory cytokines significantly led to increased HNP-1 levels in culture supernatants and decreased levels in lysates of cancer cells. In HPDE cytokines significantly decreased HNP-1 levels. CONCLUSIONS: Inflammatory regulation of HNP-1 in PDAC tissue and cells indicates that HNP-1 may be a link between chronic inflammation and malignant transformation in the pancreas.

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