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Pancreatic Neoplasms: HELP
Articles by Volker Fendrich
Based on 51 articles published since 2010
(Why 51 articles?)
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Between 2010 and 2020, V. Fendrich wrote the following 51 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Review Familial Pancreatic Cancer. 2018

Benzel, Julia / Fendrich, Volker. · ·Oncol Res Treat · Pubmed #30269130.

ABSTRACT: Familial pancreatic cancer accounts for 10% of all patients with pancreatic cancer. Because the 5-year survival rate of pancreatic cancer is only 7%, screening programs for high-risk individuals are essential and might be advantageous. Pancreatic ductal adenocarcinoma mostly shows symptoms at an advanced state and treatment is not efficient enough to cure most patients. People with hereditary tumor syndromes or their affected relatives can also be included in such screening programs. Besides the collection of data to investigate the background of the disease, these screening programs aim to diagnose and treat precursor lesions so that more dangerous, invasive lesions are prevented. These precursor lesions can be pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasm, and mucinous cystic neoplasm. This review summarizes the latest knowledge of pancreatic screening programs, shows the procedure of pancreatic cancer screening, and gives an overview of current guidelines.

2 Review Chemoprevention and Treatment of Pancreatic Cancer: Update and Review of the Literature. 2018

Benzel, Julia / Fendrich, Volker. ·Department of Visceral-, Thoracic- and Vascular Surgery, Philipps-University Marburg, Marburg, Germany. · Hopp Children's Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany. · Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Clinic for Endocrine Surgery, Schön Klinik Hamburg Eilbek, Hamburg, Germany. ·Digestion · Pubmed #29587290.

ABSTRACT: BACKGROUND: Pancreatic ductal adenocarcinoma is one of the most lethal types of cancer with a 5-year survival rate of around 7%. Due to the relatively poor prognosis, the potential need of an effective chemoprevention is highly needed. SUMMARY: Different risk factors like smoking or hereditary tumour syndromes should be known for early detection of pancreatic intraepithelial neoplasia. Chemopreventive dietary agents include curcumin, capsaicin and flavonoid, whereas potential chemopreventive drugs compromise aspirin, metformin or statins. This review aims to give an overview on potential risk factors for the development of pancreatic cancer. Furthermore, we try to summarise known chemopreventive agents to support the fight against this lethal disease. Key Messages: On the one hand, there are natural agents that exhibit preventive properties and can lead to the prohibition of pancreatic cancer. On the other hand, there are drugs and agents that are currently used in other contexts and are thus already approved and studied in terms of their mechanisms of effects and the related secondary effects.

3 Review [Early endocrine neoplasia of the pancreas]. 2018

Fendrich, V / Bartsch, D K. ·Klinik für Endokrine Chirurgie, Schön Klinik Hamburg Eilbek, Hamburg, Deutschland. vfendrich@schoen-kliniken.de. · Klinik für Visceral‑, Thorax- und Gefäßchirurgie, Standort Marburg, Universitätsklinikum Gießen und Marburg GmbH, Marburg, Deutschland. ·Chirurg · Pubmed #29098308.

ABSTRACT: Pancreatic endocrine neoplasias (pNENs) are uncommon but fascinating tumors with a rising incidence. In accordance to its location, size and grading, the decision to operate the patient should always be made in an interdisciplinary approach. This article provides a comprehensive review of the current literature addressing the current challenges in pNEN surgery and shows that patients with completely resected small pNENs generally have an excellent prognosis, but also that surveillance may be a powerful tool.

4 Review Systematic review of active surveillance versus surgical management of asymptomatic small non-functioning pancreatic neuroendocrine neoplasms. 2017

Partelli, S / Cirocchi, R / Crippa, S / Cardinali, L / Fendrich, V / Bartsch, D K / Falconi, M. ·Pancreatic Surgery Unit, Pancreas Translational and Clinical Research Centre, San Raffaele Scientific Institute, 'Vita-Salute' University, Milan, Italy. · Department of Digestive and Liver Surgery Unit, St Maria Hospital, Terni, Italy. · Department of Surgery, Polytechnic University of Marche Region, Ancona, Italy. · Department of Visceral, Thoracic and Vascular Surgery, Philipps-University Marburg, Marburg, Germany. ·Br J Surg · Pubmed #27706803.

ABSTRACT: BACKGROUND: The incidence of asymptomatic, sporadic, small non-functioning pancreatic neuroendocrine neoplasms (NF-PNENs) has increased in recent decades. Conservative treatment has been advocated for these tumours. The aim of this study was systematically to evaluate the literature on active surveillance and to compare this with surgical management for asymptomatic sporadic small NF-PNENs. METHODS: PubMed, Embase and the Cochrane Library were searched systematically for studies that compared the active surveillance of asymptomatic, sporadic, small NF-PNENs with surgical management. PRISMA guidelines for systematic reviews were followed. RESULTS: After screening 3915 records, five retrospective studies with a total of 540 patients were included. Of these, 327 patients (60·6 per cent) underwent active surveillance and 213 (39·4 per cent) had surgery. There was wide variation in the tumour diameter threshold considered as inclusion criterion (2 cm to any size). The median length of follow-up ranged from 28 to 45 months. Measurable tumour growth was observed in 0-51·0 per cent of patients. Overall, 46 patients (14·1 per cent) underwent pancreatic resection after initial conservative treatment. In most patients the reason was an increase in tumour size (19 of 46). There were no disease-related deaths in the active surveillance group in any of the studies. CONCLUSION: This systematic review suggests that active surveillance of patients affected by sporadic, small, asymptomatic NF-PNENs may be a good alternative to surgical treatment.

5 Review The role of pancreatic and duodenal homeobox 1 as a therapeutic target in pancreatic cancer. 2014

Fendrich, Volker / Lauth, Matthias. ·Philipps-University Marburg, Department of Surgery , Baldingerstrasse, D-35043 Marburg , Germany +49 64215869141 ; +49 64215863851 ; fendrich@med.uni-marburg.de. ·Expert Opin Ther Targets · Pubmed #25078025.

ABSTRACT: INTRODUCTION: Pancreatic cancer is one of the most lethal cancer types known with no successful clinical therapy available and a 5-year survival rate of < 5%. Demographic calculations predict pancreatic cancer to be the second-leading cause of cancer-related deaths by 2030. Hence, the identification of novel drug targets and the subsequent development of novel therapeutic strategies are of utmost importance. AREAS COVERED: In this review, the authors describe the role of the transcription factor pancreatic and duodenal homeobox 1 (Pdx1) in pancreatic organ development and pancreatic cancer. Published data suggest that Pdx1 possesses oncogenic traits fostering cell proliferation, inhibition of apoptosis and increased cell invasion. Resulting from these findings, the authors discuss the potential use of Pdx1 as an anticancer drug target. EXPERT OPINION: In summary, Pdx1 should be considered as an interesting potential molecular target in future therapeutic approaches. Although no specific therapies exploiting Pdx1 are available at the moment and more preclinical data has to be accumulated, several putative applications in the areas of cancer diagnostics and therapy are conceivable.

6 Review Familial pancreatic cancer--status quo. 2014

Fendrich, Volker / Langer, Peter / Bartsch, Detlef K. ·National Case Collection of Familial Pancreatic Cancer of the Deutsche Krebshilfe (FaPaCa), Department of Surgery, Philipps-University Marburg, Baldingerstrasse, 35043, Marburg, Germany, fendrich@med.uni-marburg.de. ·Int J Colorectal Dis · Pubmed #23948969.

ABSTRACT: INTRODUCTION: Familial pancreatic cancer (FPC) is defined by families with at least two first-degree relatives with confirmed pancreatic ductal adenocarcinoma (PDAC) that do not fulfill the criteria of other inherited tumor syndromes with an increased risk for the development of PDAC, such as hereditary pancreatitis or hereditary breast and ovarian cancer. FPC is mostly autosomal dominant inherited and presents with a heterogeneous phenotype. Although the major gene defect has not yet been identified, some important germline mutations in the BRCA2-, PALB2-, and ATM-genes are causative in some FPC families. FPC SCREENING: It is suggested by experts to include high-risk individuals in a screening program with a multidisciplinary approach under research protocol conditions. However, neither biomarkers nor reliable imaging modalities for the detection of high-grade precursor lesions are yet available. Most screening programs are currently based on endoscopic ultrasound and magnetic resonance imaging, and first data demonstrated that precursor lesions (pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasm) of PDAC can be identified. Timing and extent of surgery are still a matter of debate. SCOPE OF THE REVIEW: The present review focuses on the clinical phenotype of FPC, its histopathological characteristics, known underlying genetic changes, genetic counseling, and screening.

7 Review Novel molecular targets for the treatment of gastroenteropancreatic endocrine tumors: answers and unsolved problems. 2012

Capurso, Gabriele / Fendrich, Volker / Rinzivillo, Maria / Panzuto, Francesco / Bartsch, Detlef K / Delle Fave, Gianfranco. ·Digestive and Liver Disease Unit, S. Andrea Hospital, Faculty of Medicine and Psychology, Sapienza University of Rome at S. Andrea Hospital, Via di Grottarossa 1035, 00189 Rome, Italy. gianfranco.dellefave@uniroma1.it. ·Int J Mol Sci · Pubmed #23344019.

ABSTRACT: As more knowledge on molecular alterations favoring carcinogenesis and spreading of gastroenteropancreatic endocrine tumors has become available, a number of targeted agents interfering with key growth and angiogenic pathways have been explored in preclinical and clinical studies. The mTOR inhibitor Everolimus, and the multi-target antiangiogenetic agent Sunitinib, have been shown to be effective and thus have been approved by the FDA for treatment of pancreatic endocrine tumors. However, there is little data on the primary resistance to targeted agents on these tumors. The goals of the present review are to elucidate the possible advantage of combined treatments in overcoming induced resistances, and to identify biomarkers able to predict clinical efficacy. Moreover, the role of interesting targets for which a strong biological rationale exists, and specific inhibitors are available, such as the Src Family Kinases and the Hedgehog Pathway, are discussed. There is now need for more preclinical studies on cell lines and animal models to provide a stronger preclinical background in this field, as well as clinical trials specifically comparing one targeted therapy with another or combining different targeted agents.

8 Review Chemoprevention of pancreatic cancer-one step closer. 2012

Fendrich, Volker. ·Department of Surgery, Philipps University Marburg, Baldingerstrasse, 35043 Marburg, Germany. fendrich@med.uni-marburg.de ·Langenbecks Arch Surg · Pubmed #22350613.

ABSTRACT: BACKGROUND: Since for pancreatic cancer the mortality rate approaches the incidence rate with only 1-4% of all patients surviving 5 years, it would be would be of great value to provide chemopreventive treatment for high-risk individuals. DISCUSSION: The preclinical study of pancreatic intraepithelial neoplasia (PanINs) has recently been made possible by the generation of genetically modified animal models, which recapitulate human PanINs and invasive pancreatic cancer on a genetic and histomorphologic level. Very recently, several groups have reported first evidence of chemoprevention of pancreatic cancer.

9 Review Surgical treatment of gastrointestinal neuroendocrine tumors. 2011

Fendrich, Volker / Bartsch, Detlef K. ·Department of Surgery, Philipps University Marburg, Baldingerstrasse, Marburg, Germany. fendrich@med.uni-marburg.de ·Langenbecks Arch Surg · Pubmed #21279821.

ABSTRACT: INTRODUCTION: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are uncommon but clinically challenging and fascinating tumors. GEP-NETs present as either functional or as nonfunctional tumors. Functional tumors are commonly associated with a specific hormonal syndrome directly related to a hormone secreted by the tumor, like gastrinomas with a Zollinger-Ellison syndrome or carcinoid syndrome in patients with neuroendocrine tumors (NET) of the ileum. Nonfunctional tumors do not secrete a hormone resulting in a clinical syndrome. METHODS: The natural course of GEP-NETs is highly variable. Small, benign neoplasms such as 90% of all insulinomas or gastric endocrine tumors type 1 are readily curable by surgical resection; however, most other GEP-NETs have a much less favorable prognosis. Patients with completely resected tumors generally have a good prognosis, and an aggressive surgical approach in patients with advanced disease may also prolong survival. CONCLUSIONS: This review focuses on the current standards of surgical treatment of gastric endocrine tumors, NETs of the pancreas (PNET) and NETs of the ileum. Although the evidence level is low in many instances due to the lack of randomized controlled trials, important treatment recommendations can be given.

10 Review [Diagnosis and surgical management of neureondocrine pancreatic tumours]. 2010

Fendrich, V / Bartsch, D K. ·Universitätsklinikum Giessen und Marburg, Klinik für Visceral-, Thorax- und Gefässchirurgie, Marburg, Deutschland. fendrich@med.uni-marburg.de ·Zentralbl Chir · Pubmed #20549584.

ABSTRACT: The only chance of cure for patients with pancreatic endocrine tumours (PETs) is complete surgical removal not only of the primary tumour, but also of local or distant metastases. This is true for gastrinomas, vipomas, glucagonomas, somatostatinomas and non-functional pancreatic endocrine tumours. An aggressive surgical approach leads to cure in patients with benign tumours, and may achieve long-term survival in patients with malignant NPTs.

11 Article Chemoprevention with Somatuline© Delays the Progression of Pancreatic Neuroendocrine Neoplasms in a Mouse Model of Multiple Endocrine Neoplasia Type 1 (MEN1). 2019

Lopez, Caroline L / Joos, Barbara / Bartsch, Detlef K / Manoharan, Jerena / Albers, Max / Slater, Emily P / Bollmann, Carmen / Roth, Sylvia / Bayer, Aninja / Fendrich, Volker. ·Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, 35041, Marburg, Germany. · Department of Endocrine Surgery, Schön Klinik Hamburg Eilbek, Dehnhaide 120, 22081, Hamburg, Germany. fendrich@schoen-kliniken.de. ·World J Surg · Pubmed #30600364.

ABSTRACT: OBJECTIVE: Long-acting synthetic somatostatin analogues (SSA) are an essential part of the treatment of neuroendocrine neoplasms. We evaluated the chemopreventive effects of a long-acting somatostatin analogue on the development of pancreatic neuroendocrine neoplasms (pNENs) in a genetically engineered MEN1 knockout mouse model. MATERIALS AND METHODS: Heterozygote MEN1 knockout mice were injected every 28 days subcutaneously with the somatostatin analogue lanreotide (Somatuline Autogel©; Ipsen Pharma) or a placebo starting at day 35 after birth. Mice were euthanized after 6, 9, 12, 15 and 18 months, and the size and number of pNENs were measured due histological analysis and compared to the placebo group. RESULTS: The median tumor size of pNENs was statistically significantly smaller after 9 (control group vs. SSA group; 706.476 µm CONCLUSION: Long-acting somatostatin analogues may be an effective chemopreventive approach to delay the progression of MEN1-associated pNENs. After our preclinical results, we would recommend to evaluate the effects of long-acting SSA in a prospective clinical trial.

12 Article Chemoprevention with Enalapril and Aspirin in Men1(+/T) Knockout Mouse Model. 2018

Manoharan, Jerena / Fendrich, Volker / Di Fazio, Pietro / Bollmann, Carmen / Roth, Silvia / Joos, Barbara / Mintziras, Ioannis / Albers, Max B / Ramaswamy, Annette / Bertolino, Philippe / Zhang, Chang X / Slater, Emily P / Bartsch, Detlef K / Lopez-Lopez, Caroline L. ·Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Marburg, Germanyjerena_manoharan@outlook.com. · Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Marburg, Germany. · Department of Pathology, Philipps University Marburg, Marburg, Germany. · Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR5286, Université Lyon 1, Lyon, France. ·Neuroendocrinology · Pubmed #30025403.

ABSTRACT: Pancreatic neuroendocrine neoplasias (pNEN) are the most common cause of death in adult patients with multiple endocrine neoplasia type 1 (MEN1). So far, only few chemopreventive strategies (e.g., with somatostatin analogues) have been evaluated for MEN1 associated pNENs. In this experimental study on 75 Men1(+/T) knockout mice, the effect of aspirin (n = 25) and an inhibitor of angiotensin-I converting enzyme (enalapril, n = 25) compared to controls (n = 25) were evaluated as single chemopreventive strategies for pNENs after 6, 9, 12, 15, and 18 months. After each study period, mice were sacrificed and the resected pancreata were evaluated by histopathological analysis, immunostaining, and real-time PCR. PNEN size and number was measured. Aspirin and enalapril lead to a pNEN size reduction of 80% (167,518 vs. 838,876 µm2, p < 0.001) and 79% (174,758 vs. 838,876 µm2, p < 0.001) compared to controls. Furthermore, aspirin and enalapril treatment resulted in a significant reduction of the number of pNENs by 33%, (p = 0.04) and 41% (p = 0.002) respectively. The apoptosis marker caspase 3 revealed a higher positive expression in pNEN of treated Men1(+/T) mice. Immunostaining of VEGF in pNEN detected a downregulation of its expression in treated Men1(+/T) mice compared to the control group. REL A transcript was significantly downregulated in 18-months treated enalapril Men1(+/T) mice, but not in aspirin-treated Men1(+/T) mice. There was no significant difference in the Ki-67 index. Using a transgenic mouse model that imitates human MEN1, this study provides first evidence that aspirin and enalapril are effective chemopreventive agents that aid in the progression of pNENs.

13 Article Expression of neuropeptide Y and its receptors Y1 and Y2 in pancreatic intraepithelial neoplasia and invasive pancreatic cancer in a transgenic mouse model and human samples of pancreatic cancer. 2018

Waldmann, Jens / Fendrich, Volker / Reichert, Martin / Hecker, Andreas / Bartsch, Detlef K / Padberg, Winfried / Holler, Julia P N. ·Department of Surgery, University Hospital Giessen and Marburg, Campus Giessen and Marburg, Giessen and Marburg, Germany. · Department of Surgery, University Hospital Giessen and Marburg, Campus Giessen and Marburg, Giessen and Marburg, Germany. Electronic address: julia.p.holler@chiru.med.uni-giessen.de. ·J Surg Res · Pubmed #29433879.

ABSTRACT: BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is among the most dismal of human malignancies. Neuropeptides have shown to be implicated in angiogenesis, tumor growth, and formation of distant metastases in various solid tumors. In the present study, we used a genetically engineered mouse model of pancreatic cancer to evaluate the impact of neuropeptide Y (NPY) and its receptors 1 (Y1) and 2 (Y2) in preneoplastic lesions and pancreatic cancer as a potential target with antiproliferative properties. In addition, human PDAC tissue was analyzed. MATERIALS AND METHODS: By interbreeding conditional LsL-Trp53 RESULTS: NPY and Y1 expressions were detected in human and murine pancreatic samples, but expression levels were similar in neoplastic and non-neoplastic tissue. Y2 revealed a significant increase of expression in the transgenic mouse model in PanIN lesions and pancreatic cancer compared to control. This holds also true for human samples of pancreatic cancer. Immunohistochemistry of Y2 in murine and human samples of PanINs and pancreatic carcinoma revealed an increased expression in PanIN lesions and pancreatic cancer. CONCLUSIONS: Y2 is strongly overexpressed in pancreatic cancer and may modulate angiogenesis.

14 Article Genetic and pharmacologic abrogation of Snail1 inhibits acinar-to-ductal metaplasia in precursor lesions of pancreatic ductal adenocarcinoma and pancreatic injury. 2018

Fendrich, Volker / Jendryschek, Frederike / Beeck, Saskia / Albers, Max / Lauth, Matthias / Esni, Farzad / Heeger, Kristin / Dengler, Janina / Slater, Emily P / Holler, Julia P N / Baier, Aninja / Bartsch, Detlef K / Waldmann, Jens. ·Department of Surgery, University of Marburg, Marburg, Germany. v.fendrich@web.de. · Department of Surgery, University of Marburg, Marburg, Germany. · IMT, Marburg, Germany. · Department of Surgery, John G. Rangos Research Center, University of Pittsburgh, Pittsburgh, PA, USA. · Department of Internal Medicine, Division of Gastroenterology University Hospital Giessen and Marburg, Campus Marburg, Marburg, Germany. · Department of Surgery, University Hospital Giessen and Marburg, Campus Giessen, Giessen, Germany. ·Oncogene · Pubmed #29367759.

ABSTRACT: Pancreatic cancer (PDAC) is one of the most dismal of human malignancies. Inhibiting or delaying the progression of precursor lesions of PDAC, pancreatic intraepthial neoplasia (PanINs), to invasive cancer, would be a major step. In the present study, we used a transgenic murine model of pancreatic cancer to evaluate the impact of a conditional knockout of the transcription factor Snail1, a major factor in epithelial-to-mesenchymal transition, on acinar-to-ductal formation and on PanIN progression. By interbreeding conditional LsL-Snail

15 Article Is Routine Screening of Young Asymptomatic MEN1 Patients Necessary? 2017

Manoharan, Jerena / Raue, Friedhelm / Lopez, Caroline L / Albers, Max B / Bollmann, Carmen / Fendrich, Volker / Slater, Emily P / Bartsch, Detlef K. ·Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, 35041, Marburg, Germany. jerena.manoharan@uk-gm.de. · Practice and Molecular Laboratory, Brueckenstrasse 21, 69120, Heidelberg, Germany. · Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, 35041, Marburg, Germany. ·World J Surg · Pubmed #28321559.

ABSTRACT: BACKGROUND: Recent clinical practice guidelines recommend that routine screening of MEN1 mutation carriers should start at the age of 5 years. The occurrence of clinically relevant MEN1 organ manifestations in children (≤18 years) was evaluated. METHODS: Two prospective collected databases of MEN1 patients (n = 166) who underwent annual screening were retrospectively analyzed for organ manifestations in MEN1 patients ≤18 years. The follow-up was based on the most recent screening examination until December 2015. RESULTS: Twenty [11 females, 9 males, (12%)] of 166 MEN1 patients were diagnosed with at least one organ manifestation at age ≤18 years. The most frequent manifestation was mild asymptomatic pHPT (n = 9, 45%, age range 8-18 years). Eight (40%) young patients had pNENs (three non-functioning pNENs, five insulinomas, age range 9-18 years). All five insulinomas were diagnosed based on hypoglycemic symptoms. The other organ manifestations were asymptomatic pituitary adenomas in six patients (30%, age range 15-18 years) and a bronchial carcinoid in one 15-year-old patient. Only six (30%) patients ≤18 years had clinically relevant organ manifestations. CONCLUSION: Symptomatic or severe manifestations in MEN1 patients rarely occur below the age of 16 years. With regard to psychological burden and cost-effectiveness, routine screening of asymptomatic MEN1 patients should be postponed at least until the age of 16 years.

16 Article Refinement of screening for familial pancreatic cancer. 2016

Bartsch, D K / Slater, E P / Carrato, A / Ibrahim, I S / Guillen-Ponce, C / Vasen, H F A / Matthäi, E / Earl, J / Jendryschek, F S / Figiel, J / Steinkamp, M / Ramaswamy, A / Vázquez-Sequeiros, E / Muñoz-Beltran, M / Montans, J / Mocci, E / Bonsing, B A / Wasser, M / Klöppel, G / Langer, P / Fendrich, V / Gress, T M. ·Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Marburg, Germany. · Department of Medical Oncology, Ramon y Cajal University Hospital, IRYCIS, Madrid, Spain. · Department of Gastroenterology & Hepatology, Leiden University Medical Center, Leiden, The Netherlands. · Department of Radiology, Philipps University Marburg, Marburg, Germany. · Department of Gastroenterology and Endocrinology, Philipps University Marburg, Marburg, Germany. · Department of Pathology, Philipps University Marburg, Marburg, Germany. · Department of Gastroenterology, Ramon y Cajal University Hospital, IRYCIS, Madrid, Spain. · Department of Radiology, Ramon y Cajal University Hospital, IRYCIS, Madrid, Spain. · Department of Pathology, Ramon y Cajal University Hospital, IRYCIS, Madrid, Spain. · Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands. · Department of Radiology, Leiden University Medical Centre, Leiden, The Netherlands. · Department of Pathology, Consultation Centre for Pancreatic Tumors, Technical University Munich, Munich, Germany. · Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Marburg, Germany Department of General Surgery, Klinikum Hanau GmbH, Hanau, Germany. ·Gut · Pubmed #27222532.

ABSTRACT: OBJECTIVE: Surveillance programmes are recommended for individuals at risk (IAR) of familial pancreatic cancer (FPC) to detect early pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC). However, the age to begin screening and the optimal screening protocol remain to be determined. METHODS: IAR from non-CDKN2A FPC families underwent annual screening by MRI with endoscopic ultrasonography (EUS) in board-approved prospective screening programmes at three tertiary referral centres. The diagnostic yield according to age and different screening protocols was analysed. RESULTS: 253 IAR with a median age of 48 (25-81) years underwent screening with a median of 3 (1-11) screening visits during a median follow-up of 28 (1-152) months. 134 (53%) IAR revealed pancreatic lesions on imaging, mostly cystic (94%), on baseline or follow-up screening. Lesions were significantly more often identified in IAR above the age of 45 years (p<0.0001). In 21 IAR who underwent surgery, no significant lesions (PDAC, pancreatic intraepithelial neoplasia (PanIN) 3 lesions, high-grade intraductal papillary mucinous neoplasia (IPMN)) were detected before the age of 50 years. Potentially relevant lesions (multifocal PanIN2 lesions, low/moderate-grade branch-duct IPMNs) occurred also significantly more often after the age of 50 years (13 vs 2, p<0.0004). The diagnostic yield of potentially relevant lesions was not different between screening protocols using annual MRI with EUS (n=98) or annual MRI with EUS every 3rd year (n=198) and between IAR screened at intervals of 12 months (n=180) or IAR that decided to be screened at ≥24 months intervals (n=30). CONCLUSIONS: It appears safe to start screening for PDAC in IAR of non-CDKN2a FPC families at the age of 50 years. MRI-based screening supplemented by EUS at baseline and every 3rd year or when changes in MRI occur appears to be efficient.

17 Article Robotic-Assisted Approach Improves Vessel Preservation in Spleen-Preserving Distal Pancreatectomy. 2016

Eckhardt, Sabine / Schicker, Christoph / Maurer, Elisabeth / Fendrich, Volker / Bartsch, Detlef K. ·Department of Visceral, Thoracic and Vascular Surgery, University Hospital of Marburg, Marburg, Germany. ·Dig Surg · Pubmed #27160088.

ABSTRACT: BACKGROUND: Vessel-preserving spleen preservation (SP) during distal pancreatectomy (DP) is supposed to be beneficial for patients with benign and borderline tumors. This study evaluated the first experiences with robotic-assisted laparoscopic DP (RA-LDP) and its rate of vessel preservation and SP compared to conventional laparoscopic DP (C-LDP). METHODS: Patients scheduled for spleen-preserving DP for benign or borderline tumors by either C-LDP or RA-LDP were retrieved from a prospective database and retrospectively analyzed regarding vessel-preservation and SP, conversion rate, blood loss, operating time, complications, perioperative blood transfusion, postoperative hospital stay (PHS) and mortality. RESULTS: Twenty-nine patients underwent C-LDP and 12 patients underwent RA-LDP between September 2009 and May 2015. SP rates were 79% (23 of 29) in the C-LDP and 92% (11 of 12) in the RA-LDP group (p = 0.32). Splenic vessels could be preserved in 17% (5 of 29) of the C-LDP and 50% (6 of 12) of the RA-LDP group (p = 0.052). Operating time, intraoperative blood loss, the number of perioperative red blood cell transfusions, overall morbidity and the rate of postoperative pancreatic fistulas were not different between the groups. PHS was shorter in the RA-LDP group (10.5 vs. 13 days; p = 0.02). CONCLUSION: RA-LDP for benign or borderline tumors of the pancreas is a safe procedure and tended to be associated with a better vessel-preservation rate, thereby making it a good alternative to C-LDP.

18 Article Benefit of Surveillance for Pancreatic Cancer in High-Risk Individuals: Outcome of Long-Term Prospective Follow-Up Studies From Three European Expert Centers. 2016

Vasen, Hans / Ibrahim, Isaura / Ponce, Carmen Guillen / Slater, Emily P / Matthäi, Elvira / Carrato, Alfredo / Earl, Julie / Robbers, Kristin / van Mil, Anneke M / Potjer, Thomas / Bonsing, Bert A / de Vos Tot Nederveen Cappel, Wouter H / Bergman, Wilma / Wasser, Martin / Morreau, Hans / Klöppel, Günter / Schicker, Christoph / Steinkamp, Martin / Figiel, Jens / Esposito, Irene / Mocci, Evelina / Vazquez-Sequeiros, Enrique / Sanjuanbenito, Alfonso / Muñoz-Beltran, Maria / Montans, José / Langer, Peter / Fendrich, Volker / Bartsch, Detlef K. ·Hans Vasen, Isaura Ibrahim, Kristin Robbers, Anneke M. van Mil, Thomas Potjer, Bert A. Bonsing, Wilma Bergman, Martin Wasser, and Hans Morreau, Leiden University Medical Center, Leiden · Wouter H. de Vos tot Nederveen Cappel, Isala Clinics, Zwolle, the Netherlands · Carmen Guillen Ponce, Alfredo Carrato, Julie Earl, Evelina Mocci, Enrique Vazquez-Sequeiros, Alfonso Sanjuanbenito, Maria Muñoz-Beltran, and José Montans, Ramón y Cajal University Hospital, Ramón y Cajal Health Research Institute, Madrid, Spain · Emily P. Slater, Elvira Matthäi, Volker Fendrich, and Detlef K. Bartsch, University Hospital Marburg · Christoph Schicker, Martin Steinkamp, and Jens Figiel, Philipps University Marburg, Marburg · Günter Klöppel, Consultation Centre for Pancreatic and Endocrine Tumors, Technical University Munich · Peter Langer, Klinikum Hanau, Hanau, Germany · and Irene Esposito, Innsbruck University Hospital, Innsbruck, Austria. ·J Clin Oncol · Pubmed #27114589.

ABSTRACT: PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis. Hereditary factors play a role in the development of PDAC in 3% to 5% of all patients. Surveillance of high-risk groups, may facilitate detection of PDAC at an early stage. The aim of this study was to assess whether surveillance aids detection of early-stage PDAC or precursor lesions (PRLs) and improves the prognosis. PATIENTS AND METHODS: Screening outcomes were collected from three European centers that conduct prospective screening in high-risk groups including families with clustering of PDAC (familial pancreatic cancer [FPC]) or families with a gene defect that predisposes to PDAC. The surveillance program consisted of annual magnetic resonance imaging, magnetic resonance cholangiopancreatography, and/or endoscopic ultrasound. RESULTS: Four hundred eleven asymptomatic individuals participated in the surveillance programs, including 178 CDKN2A mutation carriers, 214 individuals with FPC, and 19 BRCA1/2 or PALB2 mutation carriers. PDAC was detected in 13 (7.3%) of 178 CDKN2A mutation carriers. The resection rate was 75%, and the 5-year survival rate was 24%. Two CDKN2A mutation carriers (1%) underwent surgical resection for low-risk PRL. Two individuals (0.9%) in the FPC cohort had a pancreatic tumor, including one advanced PDAC and one early grade 2 neuroendocrine tumor. Thirteen individuals with FPC (6.1%) underwent surgical resection for a suspected PRL, but only four (1.9%) had high-risk lesions (ie, high-grade intraductal papillary mucinous neoplasms or grade 3 pancreatic intraepithelial neoplasms). One BRCA2 mutation carrier was found to have PDAC, and another BRCA2 mutation carrier and a PALB2 mutation carrier underwent surgery and were found to have low-risk PRL. No serious complications occurred as consequence of the program. CONCLUSION: Surveillance of CDNK2A mutation carriers is relatively successful, detecting most PDACs at a resectable stage. The benefit of surveillance in families with FPC is less evident.

19 Article Identification of tissue-specific cell death using methylation patterns of circulating DNA. 2016

Lehmann-Werman, Roni / Neiman, Daniel / Zemmour, Hai / Moss, Joshua / Magenheim, Judith / Vaknin-Dembinsky, Adi / Rubertsson, Sten / Nellgård, Bengt / Blennow, Kaj / Zetterberg, Henrik / Spalding, Kirsty / Haller, Michael J / Wasserfall, Clive H / Schatz, Desmond A / Greenbaum, Carla J / Dorrell, Craig / Grompe, Markus / Zick, Aviad / Hubert, Ayala / Maoz, Myriam / Fendrich, Volker / Bartsch, Detlef K / Golan, Talia / Ben Sasson, Shmuel A / Zamir, Gideon / Razin, Aharon / Cedar, Howard / Shapiro, A M James / Glaser, Benjamin / Shemer, Ruth / Dor, Yuval. ·Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel; · Department of Neurology, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel; · Department of Surgical Sciences/Anesthesiology and Intensive Care, Uppsala University Hospital, SE-751 85 Uppsala, Sweden; · Sahlgrenska University Hospital, S-431 80 Molndal, Sweden; · Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, S-431 80 Molndal, Sweden; · Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, S-431 80 Molndal, Sweden; Institute of Neurology, University College London, London WC1N 3BG, United Kingdom; · Department of Cell and Molecular Biology, Karolinska Institute, Stockholm 171-77, Sweden; · Division of Endocrinology, University of Florida College of Medicine, Gainesville, FL 32610; · Benaroya Research Institute, Seattle, WA 98101; · Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland OR 97239; · Department of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel; · Department of Surgery, Marburg University, 35037 Marburg, Germany; · Department of Oncology, Chaim Sheba Medical Center, Tel Hashomer, Israel; · Department of Experimental Surgery, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel; · Department of Surgery and the Clinical Islet Transplant Program, University of Alberta, Edmonton, AB T6G 2R3, Canada; · Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel beng@cc.huji.ac.il shemer.ru@mail.huji.ac.il yuvald@ekmd.huji.ac.il. · Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel; beng@cc.huji.ac.il shemer.ru@mail.huji.ac.il yuvald@ekmd.huji.ac.il. ·Proc Natl Acad Sci U S A · Pubmed #26976580.

ABSTRACT: Minimally invasive detection of cell death could prove an invaluable resource in many physiologic and pathologic situations. Cell-free circulating DNA (cfDNA) released from dying cells is emerging as a diagnostic tool for monitoring cancer dynamics and graft failure. However, existing methods rely on differences in DNA sequences in source tissues, so that cell death cannot be identified in tissues with a normal genome. We developed a method of detecting tissue-specific cell death in humans based on tissue-specific methylation patterns in cfDNA. We interrogated tissue-specific methylome databases to identify cell type-specific DNA methylation signatures and developed a method to detect these signatures in mixed DNA samples. We isolated cfDNA from plasma or serum of donors, treated the cfDNA with bisulfite, PCR-amplified the cfDNA, and sequenced it to quantify cfDNA carrying the methylation markers of the cell type of interest. Pancreatic β-cell DNA was identified in the circulation of patients with recently diagnosed type-1 diabetes and islet-graft recipients; oligodendrocyte DNA was identified in patients with relapsing multiple sclerosis; neuronal/glial DNA was identified in patients after traumatic brain injury or cardiac arrest; and exocrine pancreas DNA was identified in patients with pancreatic cancer or pancreatitis. This proof-of-concept study demonstrates that the tissue origins of cfDNA and thus the rate of death of specific cell types can be determined in humans. The approach can be adapted to identify cfDNA derived from any cell type in the body, offering a minimally invasive window for diagnosing and monitoring a broad spectrum of human pathologies as well as providing a better understanding of normal tissue dynamics.

20 Article Minimally Invasive Versus Open Pancreatic Surgery in Patients with Multiple Endocrine Neoplasia Type 1. 2016

Lopez, Caroline L / Albers, Max B / Bollmann, Carmen / Manoharan, Jerena / Waldmann, Jens / Fendrich, Volker / Bartsch, Detlef K. ·Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, 35041, Baldingerstrasse, Marburg, Germany. lopez@med.uni-marburg.de. · Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, 35041, Baldingerstrasse, Marburg, Germany. ·World J Surg · Pubmed #26956903.

ABSTRACT: OBJECTIVE: The role of minimally invasive pancreatic surgery for pancreatic neuroendocrine neoplasms (pNENs) in patients with multiple endocrine neoplasia type 1 (MEN1) is not well defined. The aim of this study was to compare the outcome of minimally invasive versus open pancreatic resections in patients with MEN1. MATERIALS AND METHODS: Prospectively collected data of MEN1 patients who underwent a primary distal pancreatic resection and/or enucleation for non-functioning pNENs or insulinoma were retrospectively analyzed regarding the outcome of minimally invasive or open pancreatic resections. RESULTS: Thirty-three patients underwent primary pancreatic resection for either organic hyperinsulinism (n = 9, 27 %) or non-functioning pNENs >1 cm in size (n = 24, 73 %) between 1987 and 2015. 21 (64 %) patients underwent an open surgical (group 1) and 12 patients (36 %) a minimally invasive approach, either laparoscopic (n = 8) or robotic assisted (n = 4) (group 2). Both groups were comparable regarding age, gender, number, and size of pancreatic tumors. In both groups, the hyperinsulinism of all patients (9/9,100 %) could be cured and all NF-pNENs >1 cm could be resected. Group 2 had a significant shorter operative time (200 vs. 260 min; p = 0.036), less intraoperative blood loss (120 vs. 280 ml; p < 0.001), and a shorter hospital stay (11 vs. 15.5 days; p = 0.034). The rate of patients with postoperative complications, especially postoperative pancreatic fistulas, was not different between groups (62 % group 1 vs. 67 % group 2, p = 0.74). CONCLUSION: Minimally invasive distal pancreatic resections and enucleations are feasible and safe in MEN1 patients with insulinoma or non-functioning pNENs.

21 Article C-Reactive Protein as a New Prognostic Factor for Survival in Patients With Pancreatic Neuroendocrine Neoplasia. 2016

Wiese, Dominik / Kampe, Katharina / Waldmann, Jens / Heverhagen, Anna E / Bartsch, Detlef K / Fendrich, Volker. ·Department of Visceral, Thoracic, and Vascular Surgery, University Hospital Marburg, 35033 Marburg, Germany. ·J Clin Endocrinol Metab · Pubmed #26678655.

ABSTRACT: CONTEXT: Patients with pancreatic neuroendocrine neoplasia (pNEN) show great variability in prognosis and treatment response. Additional prognostic markers might help in individual therapeutic decision making. OBJECTIVE: The objective of the study was to investigate the association between preoperative plasma levels of C-reactive protein (CRP) and overall survival (OS) in pNEN. DESIGN: This was a single-center, retrospective analysis of long-term prospective patient-database. SETTING: The study was conducted at a tertiary referral center. PATIENTS: All 149 patients with sporadic pNENs were eligible for retrospective analysis. MAIN OUTCOME MEASURE: Cumulative overall survival, compared between patients with elevated and normal CRP levels, was measured. RESULTS: Median OS for patients with elevated CRP levels was 1093 days (SE 1261, 95% confidence interval [CI] 0-3565), compared with 6859 days (SE 1252, 95% CI 4405-9313) for patients with normal CRP levels. Log rank test showed a significant correlation between CRP and OS (P < .001). In univariate Cox regression, patients with elevated CRP levels had a significantly higher hazard ratio for death (3.27; 95%-CI 1.74-6.16; P < .001). This finding persisted after multivariable adjustment. Furthermore, OS was associated with the presence of liver metastases (hazard ratio 3.17; 95% CI 1.88-5.35; P < .001), incomplete resection (R1/R2 status; hazard ratio 3.99; 95% CI 2.16-7.35; P < .001) and Ki-67 percentage (hazard ratio 5.05; 95% CI 2.17-11.76; P < .001). CONCLUSION: CRP is an independent prognostic marker in patients with pNEN. Pretreatment CRP measurements should be considered for incorporation into prospective studies of outcome in patients with pNENs and clinical trials of systemic therapies for these tumors.

22 Article Modulation of PKM alternative splicing by PTBP1 promotes gemcitabine resistance in pancreatic cancer cells. 2016

Calabretta, S / Bielli, P / Passacantilli, I / Pilozzi, E / Fendrich, V / Capurso, G / Fave, G Delle / Sette, C. ·Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy. · Department of Science Medical/Chirurgic and Translational Medicine, University of Rome La Sapienza, Rome, Italy. · Laboratory of Neuroembryology, Fondazione Santa Lucia, Rome, Italy. · Department of Clinic and Molecular Medicine, University of Rome La Sapienza, Rome, Italy. · Department of Surgery, Philipps-University Marburg, Marburg, Germany. ·Oncogene · Pubmed #26234680.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and incurable disease. Poor prognosis is due to multiple reasons, including acquisition of resistance to gemcitabine, the first-line chemotherapeutic approach. Thus, there is a strong need for novel therapies, targeting more directly the molecular aberrations of this disease. We found that chronic exposure of PDAC cells to gemcitabine selected a subpopulation of cells that are drug-resistant (DR-PDAC cells). Importantly, alternative splicing (AS) of the pyruvate kinase gene (PKM) was differentially modulated in DR-PDAC cells, resulting in promotion of the cancer-related PKM2 isoform, whose high expression also correlated with shorter recurrence-free survival in PDAC patients. Switching PKM splicing by antisense oligonucleotides to favor the alternative PKM1 variant rescued sensitivity of DR-PDAC cells to gemcitabine and cisplatin, suggesting that PKM2 expression is required to withstand drug-induced genotoxic stress. Mechanistically, upregulation of the polypyrimidine-tract binding protein (PTBP1), a key modulator of PKM splicing, correlated with PKM2 expression in DR-PDAC cell lines. PTBP1 was recruited more efficiently to PKM pre-mRNA in DR- than in parental PDAC cells. Accordingly, knockdown of PTBP1 in DR-PDAC cells reduced its recruitment to the PKM pre-mRNA, promoted splicing of the PKM1 variant and abolished drug resistance. Thus, chronic exposure to gemcitabine leads to upregulation of PTBP1 and modulation of PKM AS in PDAC cells, conferring resistance to the drug. These findings point to PKM2 and PTBP1 as new potential therapeutic targets to improve response of PDAC to chemotherapy.

23 Article Long-Term Outcomes of Surgical Management of Pancreatic Neuroendocrine Tumors with Synchronous Liver Metastases. 2015

Partelli, Stefano / Inama, Marco / Rinke, Anja / Begum, Nehara / Valente, Roberto / Fendrich, Volker / Tamburrino, Domenico / Keck, Tobias / Caplin, Martyn E / Bartsch, Detlef / Thirlwell, Christina / Fusai, Giuseppe / Falconi, Massimo. ·Pancreatic Surgery Unit, University Hospital of Ancona, Ancona, Italy. ·Neuroendocrinology · Pubmed #26043944.

ABSTRACT: BACKGROUND: The value of surgical resection in the management of pancreatic neuroendocrine tumors (PNET) with liver metastases (LM) is still debated. The aim of this study was to evaluate the outcomes of surgery of PNET with LM. METHODS: Patients with PNET with synchronous LM between 2000 and 2011 from 4 high-volume institutions were included. The patients were divided into 3 groups: curative resection, palliative resection, and no resection. RESULTS: Overall, 166 patients were included. Eighteen patients (11%) underwent curative resection, 73 patients (43%) underwent palliative resection, and 75 patients (46%) underwent conservative treatment. The median overall survival (OS) from the time of diagnosis was 73 months. Patients who underwent curative resection had a significantly better median OS from the initial diagnosis compared with those who underwent palliative resection and those who were conservatively treated (97 vs. 89 vs. 36 months, p = 0.0001). The median OS from the time of diagnosis in those patients who underwent radical or palliative resection was 97 months, with a 5-year survival rate of 76%. On multivariate analysis, factors associated with OS from the time of diagnosis were the presence of bilobar metastases, tumor grading, and curative resection in a first model. On a second model, curative or palliative surgery was an independent predictor of OS. Among 91 patients who underwent surgery, the presence of pancreatic neuroendocrine carcinoma G3 was the only factor independently associated with a poorer survival after surgery (median OS: 35 vs. 97 months, p < 0.0001). CONCLUSIONS: Patients with LM from PNET benefit from surgical resection, although surgery should be reserved to well- or moderately differentiated forms.

24 Article Inhibition of heat shock protein 90 with AUY922 represses tumor growth in a transgenic mouse model of islet cell neoplasms. 2014

Fendrich, Volker / Wichmann, Sven / Wiese, Dominik / Waldmann, Jens / Lauth, Matthias / Rexin, Peter / L-Lopez, Carolin / Schlitt, Hans J / Bartsch, Detlef K / Lang, Sven A. ·Department of Surgery, Philipps University Marburg, Marburg, Germany. ·Neuroendocrinology · Pubmed #25301256.

ABSTRACT: BACKGROUND: This study was designed to evaluate the role of heat shock protein 90 (HSP90) in tumor progression of murine islet cell tumors. Blockade of HSP90 has recently been proposed as a therapeutic target, but effects in models of islet cell tumors with AUY922, a newly developed HSP90 inhibitor, have not been examined. MATERIAL AND METHODS: The carcinoid cell line BON-1 and the HSP90 inhibitor AUY922 were used to determine effects on signaling and growth in vitro. In vivo transgenic RIP1-Tag2 mice, which develop islet cell neoplasms, were treated with vehicle or AUY922 (25 mg/kg/twice per week) from week 5 until death. The resected pancreata were evaluated macroscopically and microscopically by immunohistochemistry. Quantitative real-time PCR was performed for HSP90 targets with RNA from islets isolated from treated and untreated RIP1-Tag2 mice. RESULTS: HSP90 blockade impaired constitutive and growth factor-induced signaling in vitro. Moreover, HSP90 inhibition attenuated in vitro cell growth in a dose-dependent manner. In vivo, AUY922 significantly reduced tumor volume by 92% compared to untreated controls (p = 0.000), and median survival in the used transgenic mouse model was prolonged (110 vs. 119 days; p = 0.75). Quantitative real-time PCR for downstream target genes of HSP90 demonstrated significant downregulation in the islet cell tumors of RIP1-Tag2 mice treated with AUY922, confirming our ability to achieve effective pharmacologic levels of AUY922 within the desired tissue site in vivo. CONCLUSION: This is the first study to show that the HSP90 antagonist AUY922 may provide a new option for therapy of islet cell neoplasms.

25 Article CUX1: a modulator of tumour aggressiveness in pancreatic neuroendocrine neoplasms. 2014

Krug, Sebastian / Kühnemuth, Benjamin / Griesmann, Heidi / Neesse, Albrecht / Mühlberg, Leonie / Boch, Michael / Kortenhaus, Juliane / Fendrich, Volker / Wiese, Dominik / Sipos, Bence / Friemel, Juliane / Gress, Thomas M / Michl, Patrick. ·Departments of GastroenterologyEndocrinology and MetabolismSurgeryPhilipps-University Marburg, Baldingerstraße, 35043 Marburg, GermanyDepartment of PathologyEberhard-Karls-University Tübingen, Tübingen, GermanyDepartment of PathologyUniversity Hospital Zurich, Zurich, Switzerland. · Departments of GastroenterologyEndocrinology and MetabolismSurgeryPhilipps-University Marburg, Baldingerstraße, 35043 Marburg, GermanyDepartment of PathologyEberhard-Karls-University Tübingen, Tübingen, GermanyDepartment of PathologyUniversity Hospital Zurich, Zurich, Switzerland michlp@med.uni-marburg.de. ·Endocr Relat Cancer · Pubmed #25248790.

ABSTRACT: Pancreatic neuroendocrine neoplasms (PNENs) constitute a rare tumour entity, and prognosis and treatment options depend on tumour-mediating hallmarks such as angiogenesis, proliferation rate and resistance to apoptosis. The molecular pathways that determine the malignant phenotype are still insufficiently understood and this has limited the use of effective combination therapies in the past. In this study, we aimed to characterise the effect of the oncogenic transcription factor Cut homeobox 1 (CUX1) on proliferation, resistance to apoptosis and angiogenesis in murine and human PNENs. The expression and function of CUX1 were analysed using knockdown and overexpression strategies in Ins-1 and Bon-1 cells, xenograft models and a genetically engineered mouse model of insulinoma (RIP1Tag2). Regulation of angiogenesis was assessed using RNA profiling and functional tube-formation assays in HMEC-1 cells. Finally, CUX1 expression was assessed in a tissue microarray of 59 human insulinomas and correlated with clinicopathological data. CUX1 expression was upregulated during tumour progression in a time- and stage-dependent manner in the RIP1Tag2 model, and associated with pro-invasive and metastatic features of human insulinomas. Endogenous and recombinant CUX1 expression increased tumour cell proliferation, tumour growth, resistance to apoptosis, and angiogenesis in vitro and in vivo. Mechanistically, the pro-angiogenic effect of CUX1 was mediated via upregulation of effectors such as HIF1α and MMP9. CUX1 mediates an invasive pro-angiogenic phenotype and is associated with malignant behaviour in human insulinomas.

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