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Pancreatic Neoplasms: HELP
Articles by Philippe Ruszniewski
Based on 83 articles published since 2009
(Why 83 articles?)
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Between 2009 and 2019, P. Ruszniewski wrote the following 83 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4
1 Guideline ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: pre- and perioperative therapy in patients with neuroendocrine tumors. 2009

Akerström, Göran / Falconi, Massimo / Kianmanesh, Reza / Ruszniewski, Philippe / Plöckinger, Ursula / Anonymous1010637 / Anonymous1020637. ·Department of Surgery, Uppsala University Hospital, SE-751 85 Uppsala, Sweden. goran.akerstrom@kirurgi.uu.se ·Neuroendocrinology · Pubmed #19713712.

ABSTRACT: -- No abstract --

2 Editorial New treatments of pancreatic neuroendocrine tumors: why using them? How to use them? 2012

Raymond, Eric / Ruszniewski, Philippe. · ·Target Oncol · Pubmed #22669625.

ABSTRACT: -- No abstract --

3 Review Gastroenteropancreatic Well-Differentiated Grade 3 Neuroendocrine Tumors: Review and Position Statement. 2016

Coriat, Romain / Walter, Thomas / Terris, Benoît / Couvelard, Anne / Ruszniewski, Philippe. ·Department of Gastroenterology, Cochin Teaching Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France romain.coriat@cch.aphp.fr. · Hospices Civils de Lyon, Hôpital Edouard Herriot, Service d'Oncologie Digestive, Lyon Cedex 03, France Université Claude Bernard Lyon 1, Université de Lyon, , Lyon, France. · Department of Pathology, Cochin Teaching Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France. · Department of Pathology, Bichat Hospital, Assistance Publique-Hôpitaux de Paris, Départements Hospitalo Universitaires, Paris, France Department of Gastroenterology and Pancreatology, Beaujon Hospital, Assistance Publique-Hôpitaux de Paris, Départements Hospitalo Universitaires, Clichy, France. · Université Paris Diderot, Sorbonne Paris Cité, Paris, France Department of Gastroenterology and Pancreatology, Beaujon Hospital, Assistance Publique-Hôpitaux de Paris, Départements Hospitalo Universitaires, Clichy, France. ·Oncologist · Pubmed #27401895.

ABSTRACT: : In 2010, the World Health Organization (WHO) classification of neuroendocrine neoplasms was reviewed and validated the crucial role of the proliferative rate. According to the WHO classification 2010, gastroenteropancreatic neuroendocrine neoplasms are classified as well-differentiated neuroendocrine tumors (NETs) of grade 1 or 2 in up to 84%, or poorly differentiated neuroendocrine carcinomas in 6%-8%. Neuroendocrine carcinomas are of grade G. Recently, a proportion of neuroendocrine tumors presenting a number of mitoses or a Ki-67 index higher than 20% and a well-differentiated morphology have been identified, calling for a new category, well-differentiated grade 3 NET (NET G-3). Studies that have reported the characteristics of neuroendocrine neoplasms have identified more well-differentiated NET G-3 than neuroendocrine carcinomas. The main localizations of NET G-3 are the pancreas, stomach, and colon. Treatment for NET G-3 is not standardized and is balanced between G-1/2 neuroendocrine tumor and neuroendocrine carcinoma treatments. In nonmetastatic neuroendocrine tumors, the European and American guidelines recommended a surgical resection for localized neuroendocrine neoplasm, irrespective of the tumor grading. In NET G-3, chemotherapy is the benchmark if the main treatment goal is reduction of the tumor mass, particularly if it would allow a secondary surgery. In the present work, we review the epidemiology and make recommendations for the management of NET G-3. IMPLICATIONS FOR PRACTICE: Neuroendocrine tumors presenting a number of mitoses or a Ki-67 index higher than 20% and a well-differentiated morphology have been identified and named well-differentiated grade 3 neuroendocrine tumors (NET G-3). The main localizations of NET G-3 are the pancreas, stomach, and colon. The prognosis is worse than that for NET G-2. In nonmetastatic NET G-3, surgery appeared to be the first option. The chemotherapy regimen in pancreatic NET G-3 should be in line with that implemented in NET G-1/2 when the Ki-67 index is below 55% and should be in line with that implemented for neuroendocrine carcinoma when Ki-67 is above 55%.

4 Review Sunitinib in pancreatic neuroendocrine tumors. 2012

Raymond, Eric / Hammel, Pascal / Dreyer, Chantal / Maatescu, Christian / Hentic, Olivia / Ruszniewski, Philippe / Faivre, Sandrine. ·Department of Medical Oncology (INSERM U728-Paris 7 Diderot University), Beaujon University Hospital, 100 boulevard du Général Leclerc, 92110, Clichy, France. eric.raymond@bjn.aphp.fr ·Target Oncol · Pubmed #22661319.

ABSTRACT: Sunitinib is an oral multitarget tyrosine kinase inhibitor with potent antiangiogenic properties. Preclinical data have demonstrated that pancreatic neuroendocrine tumors depend on vascular endothelial growth factor receptors and platelet growth factor receptors-signaling pathways for tumor angiogenesis. Sunitinib has recently been approved for the treatment of patients with advanced, progressive pancreatic neuroendocrine tumors. Sunitinib has demonstrated clinically meaningful improvements in progression-free survival in a double-blinded randomized trial against placebo, setting progression-free survival as a valid endpoint for the evaluation of novel agents in patients with pancreatic neuroendocrine tumors. Although patients who progressed in this phase III trial were allowed to cross-over, a trend toward improvement in overall survival was also observed. In this trial, side effects reported with sunitinib were those previously reported in other tumor types, including hand-foot syndrome, diarrhea, and hypertension. This trial also investigated patient-reported outcome and showed that treatment with sunitinib did not affect quality of life of patient. Interestingly, this trial showed that sunitinib could be combined with somatostatin analogues without affecting the safety profile of either sunitinib or somatostatin analogues. Since the overall survival of patients with well-differentiated neuroendocrine tumors remains sufficiently long, it is worth considering using alternate sequences of targeted therapy (such as everolimus) and chemotherapy to optimize the care of patients with advanced diseases. The optimal sequence for using chemotherapy, everolimus, and sunitinib will remain to be established in clinical trials.

5 Review An overview of hereditary pancreatitis. 2012

Rebours, Vinciane / Lévy, Philippe / Ruszniewski, Philippe. ·Pôle des Maladies de l'Appareil Digestif, Service de Gastroentérologie - Pancréatologie, Hôpital Beaujon, AP-HP, Université Denis Diderot-Paris VII, Clichy, France. vinciane.rebours@bjn.aphp.fr ·Dig Liver Dis · Pubmed #21907651.

ABSTRACT: Hereditary pancreatitis is a rare cause of chronic pancreatitis. The prevalence was evaluated to 0.3/100000 in Western Countries. Genetic disorders are due to mutations of the PRSS1 gene on the long arm of the chromosome 7, encoding for the cationic trypsinogen. The inheritance pattern is autosomal dominant with an incomplete penetrance (80%). Since 1996, more than 30 mutations were found. The three more common mutations are R122H, N29I and A16V. First symptoms begin since childhood, mainly before 10 years old. Main symptoms are pancreatic pain and acute pancreatitis (>70%). CP morphological changes as pancreatic calcifications are diagnosed at a median age of 22-25 years. Exocrine and endocrine pancreatic insufficiency occurred in 34% and 26% at a median age of 29 and 38 years. No clinical differences exist according to the mutation type. No excess of mortality in hereditary pancreatitis population compared to general population was found, despite a real risk of cancer. The cumulative risks of pancreatic cancer at 50, 60 and, 75 years are 10%, 18.7% and, 53.5%, respectively. The relative risk of cancer increases in smokers and is evaluated to 8.55. Hereditary pancreatitis diagnosis permits to propose an adapted management in expert centres.

6 Review Imaging IPMN: take home messages and news. 2011

Vullierme, M P / d'Assignies, G / Ruszniewski, P / Vilgrain, V. ·Radiology department, Beaujon hospital, 100, boulevard General-Leclerc, 92110 Clichy, France. marie-pierre.vullierme@bjn.aphp.fr ·Clin Res Hepatol Gastroenterol · Pubmed #21616741.

ABSTRACT: IPMN is a frequent disease involving pancreatic duct. This disease could be malignant (parenchymal invasive adenocarcinoma), particularly if the main pancreatic duct is involved (this involvement is considered present if > 6 mm), if this enlargement reaches 10 mm or more, and if the pathological phenotype is biliopancreatic or intestinal (malignancy is less frequent if gastric one). Invasiveness is suspected if hypodense parenchymal lesion is present, particularly near a cystical lesion or MPD, a mural nodule of the wall, or if MPD wall has got a contrast uptake. Mural nodules inside cystic branch duct are associated with in situ grade 3 malignancies. MPD IPMN must be resected to prevent malignancy. The follow-up of isolated branch duct cysts relies upon MDCT and MRI, every two years if lesion is less than 1cm. Every one year if bigger, particularly if more than to 3 cm.

7 Review Mixed endocrine somatostatinoma of the ampulla of vater associated with a neurofibromatosis type 1: a case report and review of the literature. 2010

Deschamps, Lydia / Dokmak, Safi / Guedj, Nathalie / Ruszniewski, Philippe / Sauvanet, Alain / Couvelard, Anne. ·Department of Pathology, CHU Pierre Zobda-Quitman, Fort-de-France, France. ·JOP · Pubmed #20065557.

ABSTRACT: CONTEXT: Mixed endocrine tumors are double neoplasms with both glandular and endocrine components; these tumors are rare, especially those arising in the ampulla of Vater. Ampullary somatostatinomas are classically associated with neurofibromatosis type 1. We herein describe the first reported case of a mixed endocrine somatostatinoma of the ampulla of Vater associated with neurofibromatosis type 1; we also present a review of the literature of the 7 mixed endocrine tumors of the ampulla which have been reported so far. CASE REPORT: A 49-year-old woman presented with atypical abdominal pain. Endoscopic examination revealed a tumor involving the ampulla of Vater and a CT scan identified stenoses of both the distal common bile duct and the main pancreatic duct. A pancreaticoduodenectomy was performed and pathological examination revealed two tumor components, exocrine (high grade adenoma with infiltrative adenocarcinoma) and endocrine (expressing somatostatin hormone) with lymph node metastases originating from both types. The patient was treated with adjuvant chemotherapy and has had no recurrence for 3 years. DISCUSSION: In ampullary somatostatinomas, psammoma bodies are pathognomonic and chromogranin A is rarely expressed: these features should alert the pathologist to an association with neurofibromatosis type 1. The management of patients with mixed tumors is challenging. The treatment of choice is surgery, and adjuvant chemotherapy should be adapted to the most aggressive component, i.e. the exocrine one. CONCLUSION: Because of their rarity, the diagnosis of ampullary mixed endocrine tumors is difficult. Our case points out the characteristic features of these neoplasms and their possible association with neurofibromatosis type 1.

8 Clinical Trial Clinical and Biomarker Evaluations of Sunitinib in Patients with Grade 3 Digestive Neuroendocrine Neoplasms. 2018

Pellat, Anna / Dreyer, Chantal / Couffignal, Camille / Walter, Thomas / Lombard-Bohas, Catherine / Niccoli, Patricia / Seitz, Jean François / Hentic, Olivia / André, Thierry / Coriat, Romain / Faivre, Sandrine / Zappa, Magaly / Ruszniewski, Philippe / Pote, Nicolas / Couvelard, Anne / Raymond, Eric. ·Medical Oncology, Hôpital Saint Antoine, AP-HP, Paris, France. · Biostatistics, Hôpital Bichat, AP-HP, Paris, France. · Gastroenterology, Hôpital Edouard Herriot, Lyon, France. · Medical Oncology, Hôpital Edouard Herriot, Lyon, France. · Medical Oncology, Hôpital La Timone, Marseille, France. · Gastroenterology and Digestive Oncology, Hôpital La Timone, Marseille, France. · Gastroenterology, Hôpital Beaujon, AP-HP, Clichy, France. · Gastroenterology and Digestive Oncology, Hôpital Cochin, AP-HP, Sorbonne Paris Cité, Paris, France. · Medical Oncology, Hôpital Beaujon, AP-HP, Paris, France. · Radiology, Hôpital Beaujon, AP-HP, Clichy, France. · Department of Pathology Beaujon-Bichat, AP-HP, DHU UNITY, Clichy, France. · Medical Oncology, Hôpital Saint Joseph, AP-HP, Paris, France. ·Neuroendocrinology · Pubmed #29518779.

ABSTRACT: BACKGROUND/AIMS: Angiogenesis is extensively developed in well-differentiated pancreatic neuroendocrine tumours (PanNET) where sunitinib was shown to prolong progression-free survival, leading to nationwide approval. However, clinical experience in patients with grade 3 gastroenteropancreatic neuroendocrine neoplasms (GEPNEN-G3) remains limited. This prospective phase II trial evaluated potential predictive biomarkers of sunitinib activity in patients with advanced GEPNEN-G3. METHODS: Sunitinib was given at a dose of 37.5 mg/day as a continuous daily dosing until progression or unacceptable toxicity. Evaluation of activity was based on RECIST1.1. Safety was evaluated according to NCI-CTCAE v4. Pharmacokinetics of sunitinib and its main active metabolite SU12662 were evaluated. All tumour samples were reviewed histologically for tumour differentiation. PDGFRβ, carbonic anhydrase 9, Ki-67, VEGFR2, and p-AKT were quantified using immunohistochemistry and their expression correlated with response by RECIST1.1. RESULTS: Thirty-one patients were included and 26 had available histological tissue. Six and 20 patients presented well-differentiated tumours (NET-G3) and neuroendocrine carcinoma (NEC), respectively. Eighteen patients responded to sunitinib (4 experienced partial responses and 14 tumour stabilization). A high p-AKT expression correlated with lower response to sunitinib (OR 0.94, 95% CI 0.89-0.99, p = 0.04). Safety and PK exposure to sunitinib and SU12662 in these patients were consistent with that reported in PanNET. CONCLUSION: Sunitinib showed evidence of activity in patients with GEPNEN-G3 with expected toxicity profile. In the NET-G3 and NEC groups, 4/6 and 11/20 patients were responders, respectively. High p-AKT expression predicted a lower response to sunitinib. Our study allowed the identification of a potential biomarker of resistance/sensitivity to sunitinib in aggressive GEPNEN-G3.

9 Clinical Trial A randomized, open-label, phase 2 study of everolimus in combination with pasireotide LAR or everolimus alone in advanced, well-differentiated, progressive pancreatic neuroendocrine tumors: COOPERATE-2 trial. 2017

Kulke, M H / Ruszniewski, P / Van Cutsem, E / Lombard-Bohas, C / Valle, J W / De Herder, W W / Pavel, M / Degtyarev, E / Brase, J C / Bubuteishvili-Pacaud, L / Voi, M / Salazar, R / Borbath, I / Fazio, N / Smith, D / Capdevila, J / Riechelmann, R P / Yao, J C. ·Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA. · Department of Gastroenterology and Pancreatology University of Paris VII and Beaujon Hospital, Paris, France. · Department of Digestive Oncology, University Hospitals Gasthuisberg/Leuven and KU Leuven, Leuven, Belgium. · Department of Medical Oncology, Edouard Herriot Hospital, Lyon, France. · Department of Medical Oncology, University of Manchester/The Christie Hospital, Manchester, UK. · Department of Endocrine Oncology, Erasmus University Medical Center, Rotterdam, The Netherlands. · Department of Hepatology and Gastroenterology, Charité University of Medicine, Berlin, Germany. · Department of Oncology, Novartis AG, Basel, Switzerland. · Department of Oncology, Novartis Pharmaceuticals Corporation, East Hanover, USA. · Department of Medical Oncology, Catalan Institute of Oncology, IDIBELL, Hospital of Barcelona, Barcelona, Spain. · Department of Gastroenterology Saint-Luc University Hospital, Brussels, Belgium. · Department of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, Milan, Italy. · Department of Oncology, St. Andrew Hospital, Bordeaux, France. · Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Spain. · Department of Oncology, Cancer Institute of the State of São Paulo, São Paulo, Brazil. · Department of Gastrointestinal and Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, USA. ·Ann Oncol · Pubmed #28327907.

ABSTRACT: Background: Several studies have demonstrated the antitumor activity of first-generation somatostatin analogs (SSAs), primarily targeting somatostatin receptor (sstr) subtypes 2 and 5, in neuroendocrine tumors (NET). Pasireotide, a second-generation SSA, targets multiple sstr subtypes. We compared the efficacy and safety of pasireotide plus everolimus to everolimus alone in patients with advanced, well-differentiated, progressive pancreatic NET. Patients and methods: Patients were randomized 1 : 1 to receive a combination of everolimus (10 mg/day, orally) and pasireotide long-acting release (60 mg/28 days, intramuscularly) or everolimus alone (10 mg/day, orally); stratified by prior SSA use, and baseline serum chromogranin A and neuron-specific enolase. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, objective response rate, disease control rate, and safety. Biomarker response was evaluated in an exploratory analysis. Results: Of 160 patients enrolled, 79 were randomized to the combination arm and 81 to the everolimus arm. Baseline demographics and disease characteristics were similar between the treatment arms. No significant difference was observed in PFS: 16.8 months in combination arm versus 16.6 months in everolimus arm (hazard ratio, 0.99; 95% confidence interval, 0.64-1.54). Partial responses were observed in 20.3% versus 6.2% of patients in combination arm versus everolimus arm; however, overall disease control rate was similar (77.2% versus 82.7%, respectively). No significant improvement was observed in median overall survival. Adverse events were consistent with the known safety profile of both the drugs; grade 3 or 4 fasting hyperglycemia was seen in 37% versus 11% of patients, respectively. Conclusions: The addition of pasireotide to everolimus was not associated with the improvement in PFS compared with everolimus alone in this study. Further studies to delineate mechanisms by which SSAs slow tumor growth in NET are warranted.

10 Clinical Trial Sunitinib in pancreatic neuroendocrine tumors: updated progression-free survival and final overall survival from a phase III randomized study. 2017

Faivre, S / Niccoli, P / Castellano, D / Valle, J W / Hammel, P / Raoul, J-L / Vinik, A / Van Cutsem, E / Bang, Y-J / Lee, S-H / Borbath, I / Lombard-Bohas, C / Metrakos, P / Smith, D / Chen, J-S / Ruszniewski, P / Seitz, J-F / Patyna, S / Lu, D R / Ishak, K J / Raymond, E. ·Medical Oncology and Gastroenterology Department, Service Inter-Hospitalier de Cancérologie, Hôpital Beaujon and Paris Diderot University, Clichy. · Cancer Care, Institut Paoli-Calmettes, and RENATEN Network, Marseille, France. · Department of Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain. · Medical Oncology Department, The University of Manchester/The Christie NHS Foundation Trust, Manchester, UK. · Translational Medicine - Digestive Cancers, Institut Paoli-Calmettes and RENATEN Network, Marseille, France. · Eastern Virginia Medical School Streilitz Diabetes Research Center and Neuroendocrine Unit, Norfolk, USA. · Digestive Oncology Unit, University Hospitals Leuven and KU Leuven, Leuven, Belgium. · Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea. · Hepato-Gastroenterology Unit, Cliniques Universitaires Saint-Luc, Brussels, Belgium. · Medical Oncology Department, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France. · McGill University Hospital Centre, Montreal, Canada. · Oncology Department, University Hospital, Bordeaux, France. · Linkou Chang Gung Memorial Hospital and Chang Gung University, Tao-Yuan, Taiwan. · Centre Hospitalier Universitaire Timone, Assistance Publique-Hôpitaux de Marseille, Aix-Marseille Université, and RENATEN Network, Marseille, France. · Pfizer Oncology, La Jolla, USA. · Department of Evidera, St-Laurent, Canada. ·Ann Oncol · Pubmed #27836885.

ABSTRACT: Background: In a phase III trial in patients with advanced, well-differentiated, progressive pancreatic neuroendocrine tumors, sunitinib 37.5 mg/day improved investigator-assessed progression-free survival (PFS) versus placebo (11.4 versus 5.5 months; HR, 0.42; P < 0.001). Here, we present PFS using retrospective blinded independent central review (BICR) and final median overall survival (OS), including an assessment highlighting the impact of patient crossover from placebo to sunitinib. Patients and methods: In this randomized, double-blind, placebo-controlled study, cross-sectional imaging from patients was evaluated retrospectively by blinded third-party radiologists using a two-reader, two-time-point lock, followed by a sequential locked-read, batch-mode paradigm. OS was summarized using the Kaplan-Meier method and Cox proportional hazards model. Crossover-adjusted OS effect was derived using rank-preserving structural failure time (RPSFT) analyses. Results: Of 171 randomized patients (sunitinib, n = 86; placebo, n = 85), 160 (94%) had complete scan sets/time points. By BICR, median (95% confidence interval [CI]) PFS was 12.6 (11.1-20.6) months for sunitinib and 5.8 (3.8-7.2) months for placebo (HR, 0.32; 95% CI 0.18-0.55; P = 0.000015). Five years after study closure, median (95% CI) OS was 38.6 (25.6-56.4) months for sunitinib and 29.1 (16.4-36.8) months for placebo (HR, 0.73; 95% CI 0.50-1.06; P = 0.094), with 69% of placebo patients having crossed over to sunitinib. RPSFT analysis confirmed an OS benefit for sunitinib. Conclusions: BICR confirmed the doubling of PFS with sunitinib compared with placebo. Although the observed median OS improved by nearly 10 months, the effect estimate did not reach statistical significance, potentially due to crossover from placebo to sunitinib. Trial registration number: NCT00428597.

11 Clinical Trial Anti-tumour effects of lanreotide for pancreatic and intestinal neuroendocrine tumours: the CLARINET open-label extension study. 2016

Caplin, Martyn E / Pavel, Marianne / Ćwikła, Jarosław B / Phan, Alexandria T / Raderer, Markus / Sedláčková, Eva / Cadiot, Guillaume / Wolin, Edward M / Capdevila, Jaume / Wall, Lucy / Rindi, Guido / Langley, Alison / Martinez, Séverine / Gomez-Panzani, Edda / Ruszniewski, Philippe / Anonymous721030. ·Royal Free HospitalLondon, UKCharité University Medicine BerlinBerlin, GermanyUniversity of Warmia and MazuryOlsztyn, PolandUniversity of Texas MD Anderson Cancer CenterHouston, Texas, USAUniversity HospitalVienna, AustriaDepartment of Oncology of the First Faculty of Medicine and General Teaching HospitalPrague, Czech RepublicRobert-Debré HospitalReims, FranceMarkey Cancer CenterUniversity of Kentucky, Lexington, Kentucky, USAVall d'Hebron University HospitalBarcelona, SpainWestern General HospitalEdinburgh, UKUniversità Cattolica del Sacro CuoreRome, ItalyIpsenLes Ulis, FranceIpsenBasking Ridge, New Jersey, USABeaujon HospitalClichy, FranceParis Diderot UniversityParis, France m.caplin@ucl.ac.uk. · Royal Free HospitalLondon, UKCharité University Medicine BerlinBerlin, GermanyUniversity of Warmia and MazuryOlsztyn, PolandUniversity of Texas MD Anderson Cancer CenterHouston, Texas, USAUniversity HospitalVienna, AustriaDepartment of Oncology of the First Faculty of Medicine and General Teaching HospitalPrague, Czech RepublicRobert-Debré HospitalReims, FranceMarkey Cancer CenterUniversity of Kentucky, Lexington, Kentucky, USAVall d'Hebron University HospitalBarcelona, SpainWestern General HospitalEdinburgh, UKUniversità Cattolica del Sacro CuoreRome, ItalyIpsenLes Ulis, FranceIpsenBasking Ridge, New Jersey, USABeaujon HospitalClichy, FranceParis Diderot UniversityParis, France. · Royal Free HospitalLondon, UKCharité University Medicine BerlinBerlin, GermanyUniversity of Warmia and MazuryOlsztyn, PolandUniversity of Texas MD Anderson Cancer CenterHouston, Texas, USAUniversity HospitalVienna, AustriaDepartment of Oncology of the First Faculty of Medicine and General Teaching HospitalPrague, Czech RepublicRobert-Debré HospitalReims, FranceMarkey Cancer CenterUniversity of Kentucky, Lexington, Kentucky, USAVall d'Hebron University HospitalBarcelona, SpainWestern General HospitalEdinburgh, UKUniversità Cattolica del Sacro CuoreRome, ItalyIpsenLes Ulis, FranceIpsenBasking Ridge, New Jersey, USABeaujon HospitalClichy, FranceParis Diderot UniversityParis, France Royal Free HospitalLondon, UKCharité University Medicine BerlinBerlin, GermanyUniversity of Warmia and MazuryOlsztyn, PolandUniversity of Texas MD Anderson Cancer CenterHouston, Texas, USAUniversity HospitalVienna, AustriaDepartment of Oncology of the First Faculty of Medicine and General Teaching HospitalPrague, Czech RepublicRobert-Debré HospitalReims, FranceMarkey Cancer CenterUniversity of Kentucky, Lexington, Kentucky, USAVall d'Hebron University HospitalBarcelona, SpainWestern General HospitalEdinburgh, UKUniversità Cattolica del Sacro CuoreRome, ItalyIpsenLes Ulis, FranceIpsenBasking Ridge, New Jersey, USABeaujon HospitalClichy, FranceParis Diderot UniversityParis, France. ·Endocr Relat Cancer · Pubmed #26743120.

ABSTRACT: In the CLARINET study, lanreotide Autogel (depot in USA) significantly prolonged progression-free survival (PFS) in patients with metastatic pancreatic/intestinal neuroendocrine tumours (NETs). We report long-term safety and additional efficacy data from the open-label extension (OLE). Patients with metastatic grade 1/2 (Ki-67 ≤ 10%) non-functioning NET and documented baseline tumour-progression status received lanreotide Autogel 120 mg (n = 101) or placebo (n = 103) for 96 weeks or until death/progressive disease (PD) in CLARINET study. Patients with stable disease (SD) at core study end (lanreotide/placebo) or PD (placebo only) continued or switched to lanreotide in the OLE. In total, 88 patients (previously: lanreotide, n = 41; placebo, n = 47) participated: 38% had pancreatic, 39% midgut and 23% other/unknown primary tumours. Patients continuing lanreotide reported fewer adverse events (AEs) (all and treatment-related) during OLE than core study. Placebo-to-lanreotide switch patients reported similar AE rates in OLE and core studies, except more diarrhoea was considered treatment-related in OLE (overall diarrhoea unchanged). Median lanreotide PFS (core study randomisation to PD in core/OLE; n=101) was 32.8 months (95% CI: 30.9, 68.0). A sensitivity analysis, addressing potential selection bias by assuming that patients with SD on lanreotide in the core study and not entering the OLE (n=13) had PD 24 weeks after last core assessment, found median PFS remaining consistent: 30.8 months (95% CI: 30.0, 31.3). Median time to further PD after placebo-to-lanreotide switch (n=32) was 14.0 months (10.1; not reached). This OLE study suggests long-term treatment with lanreotide Autogel 120 mg maintained favourable safety/tolerability. CLARINET OLE data also provide new evidence of lanreotide anti-tumour benefits in indolent and progressive pancreatic/intestinal NETs.

12 Clinical Trial Lanreotide in metastatic enteropancreatic neuroendocrine tumors. 2014

Caplin, Martyn E / Pavel, Marianne / Ćwikła, Jarosław B / Phan, Alexandria T / Raderer, Markus / Sedláčková, Eva / Cadiot, Guillaume / Wolin, Edward M / Capdevila, Jaume / Wall, Lucy / Rindi, Guido / Langley, Alison / Martinez, Séverine / Blumberg, Joëlle / Ruszniewski, Philippe / Anonymous1220800. ·From Royal Free Hospital, London (M.E.C.) · Charité University Medicine Berlin, Berlin (M.P.) · University of Warmia and Mazury, Olsztyn, Poland (J.B.Ć.) · University of Texas M.D. Anderson Cancer Center, Houston (A.T.P.) · University Hospital, Vienna (M.R.) · Department of Oncology of the First Faculty of Medicine and General Teaching Hospital, Prague, Czech Republic (E.S.) · Robert-Debré Hospital, Reims (G.C.), Ipsen, Les Ulis, (A.L., S.M., J.B.), Beaujon Hospital, Clichy (P.R.), and Paris Diderot University, Paris (P.R.) - all in France · Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles (E.M.W.) · Vall d'Hebron University Hospital, Barcelona (J.C.) · Western General Hospital, Edinburgh (L.W.) · and Università Cattolica del Sacro Cuore, Rome (G.R.). ·N Engl J Med · Pubmed #25014687.

ABSTRACT: BACKGROUND: Somatostatin analogues are commonly used to treat symptoms associated with hormone hypersecretion in neuroendocrine tumors; however, data on their antitumor effects are limited. METHODS: We conducted a randomized, double-blind, placebo-controlled, multinational study of the somatostatin analogue lanreotide in patients with advanced, well-differentiated or moderately differentiated, nonfunctioning, somatostatin receptor-positive neuroendocrine tumors of grade 1 or 2 (a tumor proliferation index [on staining for the Ki-67 antigen] of <10%) and documented disease-progression status. The tumors originated in the pancreas, midgut, or hindgut or were of unknown origin. Patients were randomly assigned to receive an extended-release aqueous-gel formulation of lanreotide (Autogel [known in the United States as Depot], Ipsen) at a dose of 120 mg (101 patients) or placebo (103 patients) once every 28 days for 96 weeks. The primary end point was progression-free survival, defined as the time to disease progression (according to the Response Evaluation Criteria in Solid Tumors, version 1.0) or death. Secondary end points included overall survival, quality of life (assessed with the European Organization for Research and Treatment of Cancer questionnaires QLQ-C30 and QLQ-GI.NET21), and safety. RESULTS: Most patients (96%) had no tumor progression in the 3 to 6 months before randomization, and 33% had hepatic tumor volumes greater than 25%. Lanreotide, as compared with placebo, was associated with significantly prolonged progression-free survival (median not reached vs. median of 18.0 months, P<0.001 by the stratified log-rank test; hazard ratio for progression or death, 0.47; 95% confidence interval [CI], 0.30 to 0.73). The estimated rates of progression-free survival at 24 months were 65.1% (95% CI, 54.0 to 74.1) in the lanreotide group and 33.0% (95% CI, 23.0 to 43.3) in the placebo group. The therapeutic effect in predefined subgroups was generally consistent with that in the overall population, with the exception of small subgroups in which confidence intervals were wide. There were no significant between-group differences in quality of life or overall survival. The most common treatment-related adverse event was diarrhea (in 26% of the patients in the lanreotide group and 9% of those in the placebo group). CONCLUSIONS: Lanreotide was associated with significantly prolonged progression-free survival among patients with metastatic enteropancreatic neuroendocrine tumors of grade 1 or 2 (Ki-67 <10%). (Funded by Ipsen; CLARINET ClinicalTrials.gov number, NCT00353496; EudraCT 2005-004904-35.).

13 Clinical Trial Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. 2011

Raymond, Eric / Dahan, Laetitia / Raoul, Jean-Luc / Bang, Yung-Jue / Borbath, Ivan / Lombard-Bohas, Catherine / Valle, Juan / Metrakos, Peter / Smith, Denis / Vinik, Aaron / Chen, Jen-Shi / Hörsch, Dieter / Hammel, Pascal / Wiedenmann, Bertram / Van Cutsem, Eric / Patyna, Shem / Lu, Dongrui Ray / Blanckmeister, Carolyn / Chao, Richard / Ruszniewski, Philippe. ·Service Inter-Hospitalier de Cancérologie et Service de Gastroenteropancréatologie, Hôpital Beaujon, Clichy, France. eric.raymond@bjn.aphp.fr ·N Engl J Med · Pubmed #21306237.

ABSTRACT: BACKGROUND: The multitargeted tyrosine kinase inhibitor sunitinib has shown activity against pancreatic neuroendocrine tumors in preclinical models and phase 1 and 2 trials. METHODS: We conducted a multinational, randomized, double-blind, placebo-controlled phase 3 trial of sunitinib in patients with advanced, well-differentiated pancreatic neuroendocrine tumors. All patients had Response Evaluation Criteria in Solid Tumors-defined disease progression documented within 12 months before baseline. A total of 171 patients were randomly assigned (in a 1:1 ratio) to receive best supportive care with either sunitinib at a dose of 37.5 mg per day or placebo. The primary end point was progression-free survival; secondary end points included the objective response rate, overall survival, and safety. RESULTS: The study was discontinued early, after the independent data and safety monitoring committee observed more serious adverse events and deaths in the placebo group as well as a difference in progression-free survival favoring sunitinib. Median progression-free survival was 11.4 months in the sunitinib group as compared with 5.5 months in the placebo group (hazard ratio for progression or death, 0.42; 95% confidence interval [CI], 0.26 to 0.66; P<0.001). A Cox proportional-hazards analysis of progression-free survival according to baseline characteristics favored sunitinib in all subgroups studied. The objective response rate was 9.3% in the sunitinib group versus 0% in the placebo group. At the data cutoff point, 9 deaths were reported in the sunitinib group (10%) versus 21 deaths in the placebo group (25%) (hazard ratio for death, 0.41; 95% CI, 0.19 to 0.89; P=0.02). The most frequent adverse events in the sunitinib group were diarrhea, nausea, vomiting, asthenia, and fatigue. CONCLUSIONS: Continuous daily administration of sunitinib at a dose of 37.5 mg improved progression-free survival, overall survival, and the objective response rate as compared with placebo among patients with advanced pancreatic neuroendocrine tumors. (Funded by Pfizer; ClinicalTrials.gov number, NCT00428597.).

14 Clinical Trial Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. 2010

Yao, James C / Lombard-Bohas, Catherine / Baudin, Eric / Kvols, Larry K / Rougier, Philippe / Ruszniewski, Philippe / Hoosen, Sakina / St Peter, Jessica / Haas, Tomas / Lebwohl, David / Van Cutsem, Eric / Kulke, Matthew H / Hobday, Timothy J / O'Dorisio, Thomas M / Shah, Manisha H / Cadiot, Guillaume / Luppi, Gabriele / Posey, James A / Wiedenmann, Bertram. ·Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 426, Houston, TX 77030, USA. jyao@mdanderson.org ·J Clin Oncol · Pubmed #19933912.

ABSTRACT: PURPOSE No established treatment exists for pancreatic neuroendocrine tumor (NET) progression after failure of chemotherapy. Everolimus (RAD001), an oral inhibitor of mammalian target of rapamycin, in combination with octreotide has demonstrated encouraging antitumor activity in patients with NETs. PATIENTS AND METHODS This open-label, phase II study assessed the clinical activity of everolimus in patients with metastatic pancreatic NETs who experienced progression on or after chemotherapy. Patients were stratified by prior octreotide therapy (stratum 1: everolimus 10 mg/d, n = 115; stratum 2: everolimus 10 mg/d plus octreotide long-acting release [LAR], n = 45). Tumor assessments (using Response Evaluation Criteria in Solid Tumors) were performed every 3 months. Chromogranin A (CgA) and neuron-specific enolase (NSE) were assessed monthly if elevated at baseline. Trough concentrations of everolimus and octreotide were assessed. Results By central radiology review, in stratum 1, there were 11 partial responses (9.6%), 78 patients (67.8%) with stable disease (SD), and 16 patients (13.9%) with progressive disease; median progression-free survival (PFS) was 9.7 months. In stratum 2, there were two partial responses (4.4%), 36 patients (80%) with SD, and no patients with progressive disease; median PFS was 16.7 months. Patients with an early CgA or NSE response had a longer PFS compared with patients without an early response. Coadministration of octreotide LAR and everolimus did not impact exposure to either drug. Most adverse events were mild to moderate and were consistent with those previously seen with everolimus. CONCLUSION Daily everolimus, with or without concomitant octreotide LAR, demonstrates antitumor activity as measured by objective response rate and PFS and is well tolerated in patients with advanced pancreatic NETs after failure of prior systemic chemotherapy.

15 Article Tumor growth rate as a metric of progression, response, and prognosis in pancreatic and intestinal neuroendocrine tumors. 2019

Dromain, Clarisse / Pavel, Marianne E / Ruszniewski, Philippe / Langley, Alison / Massien, Christine / Baudin, Eric / Caplin, Martyn E / Anonymous2211132. ·Department of Diagnostic and Interventional Radiology, CHUV University Hospital, Lausanne, Switzerland. Clarisse.Dromain@chuv.ch. · Department of Medicine 1, Division of Endocrinology and Diabetology, Friedrich-Alexander Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany. · Division of Gastroenterology and Pancreatology, Beaujon Hospital, Clichy, France. · Faculty of Medicine, Paris Diderot University, Paris, France. · Ipsen, Boulogne-Billancourt, France. · APHP, Hypertension unit, Georges Pompidou European Hospital, F-75015, Paris, France. · Endocrine Tumour and Nuclear Medicine Unit, Gustave-Roussy Cancer Campus, Villejuif, France. · Neuroendocrine Tumour Unit, Department of Gastroenterology, Royal Free Hospital, London, UK. ·BMC Cancer · Pubmed #30642293.

ABSTRACT: BACKGROUND: Lanreotide depot/autogel antitumor activity in intestinal/pancreatic neuroendocrine tumors (NETs) was demonstrated in the phase-3 CLARINET study (NCT00353496), based on significantly prolonged progression-free survival (PFS) versus placebo. METHODS: During CLARINET, patients with metastatic intestinal/pancreatic NETs received lanreotide depot/autogel 120 mg or placebo every 4 weeks for 96 weeks. Imaging data (response evaluation criteria in solid tumors [RECIST] v1.0, centrally reviewed) were re-evaluated in this post hoc analysis of tumor growth rate (TGR) in NETs. TGR (%/month) was calculated from two imaging scans during relevant periods: pre-treatment (TGR RESULTS: TGR CONCLUSIONS: TGR provides valuable information on tumor activity and prognosis in patients with metastatic intestinal/pancreatic NETs, and identifies early lanreotide depot/autogel antitumor activity. TRIAL REGISTRATION: Retrospective registration, 18 July 2006; EudraCT: 2005-004904-35; ClinicalTrials.gov: NCT00353496 .

16 Article Contrast harmonic EUS for the prediction of pancreatic neuroendocrine tumor aggressiveness (with videos). 2018

Palazzo, Maxime / Napoléon, Bertrand / Gincul, Rodica / Pioche, Mathieu / Pujol, Bertrand / Lefort, Christine / Fumex, Fabien / Hautefeuille, Vincent / Fabre, Monique / Cros, Jérome / Felce, Michèle / Couvelard, Anne / Sauvanet, Alain / Lévy, Philippe / Ruszniewski, Philippe / Palazzo, Laurent. ·Beaujon Hospital, Department of Digestive Endoscopy, Assistance Publique Hôpitaux de Paris, Clichy, France. · Department of Gastroenterology, Jean Mermoz Private Hospital, Lyon, France. · Department of Gastroenterology, Edouard Herriot Hospital, Lyon, France. · Department of Gastroenterology, Amiens-Picardie University Hospital, Amiens, France. · Department of Pathology, Gustave Roussy Institute, Villejuif, France. · Department of Pathology, Beaujon Hospital, Clichy, France. · Department of Pathology, Bichat Hospital, Paris, France. · Department of Hepatobiliary and Pancreatic Surgery, Beaujon Hospital, Clichy, France. · Department of Gastroenterology and Pancreatology, Beaujon Hospital, Clichy, France. · Department of Endoscopy, Trocadéro Clinic, Paris, France. ·Gastrointest Endosc · Pubmed #29325706.

ABSTRACT: BACKGROUND AND AIMS: Contrast harmonic EUS (CH-EUS) has the ability to depict tumor microvasculature. Decreased microvascular density has been identified as a factor associated with tumor aggressiveness. We aimed to study the accuracy of CH-EUS for the prediction of pancreatic neuroendocrine tumor (PNET) aggressiveness. METHODS: Between June 2009 and March 2015, all consecutive patients with histology-proven PNETs and CH-EUS examination were included. Nine endosonographers blindly analyzed all videos. CH-EUS tumor aggressiveness was defined as a heterogeneous enhancement at the early arterial phase. The final diagnosis of tumor aggressiveness was defined as follows: G3 tumors, morphologic and/or histologic findings of metastatic disease in G1/G2 tumors. Diagnostic values were calculated. Intratumoral microvascular density and fibrosis were assessed on pathologic specimens. RESULTS: Eighty-one tumors were included, of which 26 were aggressive (32.1%). In CH-EUS 35 tumors (43.2%) had a heterogeneous enhancement. The overall accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of CH-EUS for the diagnosis of tumor aggressiveness were 86%, 96%, 82%, 71%, and 98%, respectively. The interobserver agreement among the 9 endosonographers was good (k = .66). The intraobserver agreement was excellent for the junior (κ = .83) and senior (κ = .82) endosonographers. Heterogeneous tumors at CH-EUS corresponded to fewer vascular and more fibrotic tumors (P < .01). CONCLUSIONS: CH-EUS is accurate in the prediction of PNET aggressiveness and could be a decision-making element in their management.

17 Article Prognosis of sporadic resected small (≤2 cm) nonfunctional pancreatic neuroendocrine tumors - a multi-institutional study. 2018

Sallinen, Ville J / Le Large, Tessa Y S / Tieftrunk, Elke / Galeev, Shamil / Kovalenko, Zahar / Haugvik, Sven-Petter / Antila, Anne / Franklin, Oskar / Martinez-Moneo, Emma / Robinson, Stuart M / Panzuto, Francesco / Regenet, Nicolas / Muffatti, Francesca / Partelli, Stefano / Wiese, Dominik / Ruszniewski, Philippe / Dousset, Bertrand / Edwin, Bjørn / Bartsch, Detlef K / Sauvanet, Alain / Falconi, Massimo / Ceyhan, Güralp O / Gaujoux, Sebastien / Anonymous571208. ·Department of Abdominal Surgery, Helsinki University Hospital, University of Helsinki, Helsinki, Finland; Department of Transplantation and Liver Surgery, Helsinki University Hospital, University of Helsinki, Helsinki, Finland. Electronic address: ville.salinen@helsinki.fi. · Department of Surgery, VU University Medical Center, Amsterdam, The Netherlands. · Department of Surgery, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany. · General Surgery Department, Saint Luke's Clinical Hospital, Saint Petersburg, Russia. · Federal Medical and Rehabilitation Center, Department of Surgical Oncology, Moscow, Russia. · The Intervention Center, Oslo University Hospital, Oslo, Norway; Department of Surgery, Drammen Hospital, Vestre Viken Hospital Trust, Drammen, Norway. · Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Tampere, Finland. · Department of Surgical and Perioperative Sciences, Umea University, Umea, Sweden. · Gastroenterology Department, Hospital Universitario Cruces, Barakaldo, Bizkaia, Spain. · Department of HPB Surgery, Freeman Hospital, Newcastle Upon Tyne, UK. · Digestive and Liver Disease Unit, Sant'Andrea Hospital - Sapienza University of Rome, Italy. · Department of Digestive and Endocrine Surgery, Institut des Maladies Digestives (IMAD), Nantes 44093, France. · Chirurgia Del Pancreas, Chirurgia Del Pancreas, Pancreas Translational & Clinical Research Center, Università Vita e Salute, Ospedale San Raffaele IRCC, Milano, Italy. · Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Marburg, Germany. · Department of Gastroenterology, Pôle des Maladies de L'Appareil Digestif (PMAD), DHU Unity, Clichy 92110, France; Université Paris Diderot, Paris, France. · Department of Digestive, Pancreatic and Endocrine Surgery, Cochin Hospital, APHP, Paris, France; Faculté de Médecine Paris Descartes, Université Paris Descartes, Sorbonne Paris Cité, Paris, France. · The Intervention Center, Oslo University Hospital, Oslo, Norway; Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway. · Université Paris Diderot, Paris, France; AP-HP, Hôpital Beaujon, Department of Hepato-Pancreato-Biliary Surgery, Pôle des Maladies de L'Appareil Digestif (PMAD), DHU Unity, University Paris VII, AP-HP, Hôpital Beaujon, Clichy 92110, France. ·HPB (Oxford) · Pubmed #28988702.

ABSTRACT: BACKGROUND: Malignant potential of small (≤20 mm) nonfunctional pancreatic neuroendocrine tumors (sNF-PNET) is difficult to predict and management remain controversial. The aim of this study was to assess the prognosis of sporadic nonmetastatic sNF-PNETs. METHODS: Patients were identified from databases of 16 centers. Outcomes and risk factors for recurrence were identified by uni- and multivariate analyses. RESULTS: sNF-PNET was resected in 210 patients, and 66% (n = 138) were asymptomatic. Median age was 60 years, median tumor size was 15 mm, parenchyma-sparing surgery was performed in 42%. Postoperative mortality was 0.5% (n = 1), severe morbidity rate was 14.3% (n = 30), and 14 of 132 patients (10.6%) with harvested lymph nodes had metastatic lymph nodes. Tumor size, presence of biliary or pancreatic duct dilatation, and WHO grade 2-3 were independently associated with recurrence. Patients with tumors sized ≤10 mm were disease free at last follow-up. The 1-, 3- and 5-year disease-free survival rates for patients with tumors sized 11-20 mm on preoperative imaging were 95.1%, 91.0%, and 87.3%, respectively. CONCLUSIONS: In sNF-PNETs, the presence of biliary or pancreatic duct dilatation or WHO grade 2-3 advocate for surgical treatment. In the remaining patients, a wait-and-see policy might be considered.

18 Article Chemotherapy for Well-Differentiated Pancreatic Neuroendocrine Tumours with a Ki-67 Index ≥10%: Is There a More Effective Antitumour Regimen? A Retrospective Multicentre Study of the French Group of Endocrine Tumours (GTE). 2018

Roquin, Guillaume / Baudin, Eric / Lombard-Bohas, Catherine / Cadiot, Guillaume / Dominguez, Sophie / Guimbaud, Rosine / Niccoli, Patricia / Legoux, Jean-Louis / Mitry, Emmanuel / Rohmer, Vincent / Ruszniewski, Philippe / Walter, Thomas / Ducreux, Michel / Couvelard, Anne / Scoazec, Jean-Yves / Ramond-Roquin, Aline / Caroli-Bosc, François-Xavier / Hentic, Olivia. ·Department of Hepatogastroenterology and Digestive Oncology, CHU Angers, Angers University, LUNAM University, Angers, France. ·Neuroendocrinology · Pubmed #28152531.

ABSTRACT: BACKGROUND: The best chemotherapy regimen for well- differentiated pancreatic neuroendocrine tumours (pNETs) with a Ki-67 index ≥10% is still debated. We evaluated the antitumour efficacy of various first-line chemotherapy regimens (streptozocin based, platinum based, or dacarbazine/temozolomide based) in this situation. METHODS: In this retrospective multicentre study of the French Group of Endocrine Tumours (GTE), we recruited consecutive patients with advanced well-differentiated pNETs and a Ki-67 index ≥10% receiving chemotherapy between 2000 and 2012. The primary endpoint was progression-free survival (PFS) according to RECIST. RESULTS: Seventy-four patients (42 men, median age 55.5 years) were enrolled from 10 centres. Fifty-one patients (69%) had grade 2 NET and 61 (82%) were stage IV. Median overall survival was 36.3 months. Forty-four patients (59%) received streptozocin-based, 18 (24%) platinum-based, and 12 (16%) dacarbazine/temozolomide-based chemotherapy regimens. These 3 groups were similar regarding age, functioning tumours, grade, the number of metastatic sites, and surgery for primary tumours, but not regarding surgery for metastases and time since diagnosis. Grade 3 NET (HR 2.15, 95% CI: 1.18-3.92, p = 0.012) and age above 55 years (HR 1.84, 95% CI: 1.06-3.18, p = 0.030) were associated with shorter median PFS in the multivariate analyses. Compared to streptozocin-based chemotherapy, no difference was found in terms of PFS for the platinum-based or for the dacarbazine/temozolomide-based chemotherapy regimen: median PFS was 7.2, 7.5, and 7.2 months, respectively (p = 0.51). CONCLUSIONS: Patients with intermediate or highly proliferative well-differentiated pNETs may benefit from 1 of the 3 chemotherapy regimens. Increased age and grade 3 were associated with shorter median PFS. Randomised studies searching for response predictors and the best efficacy-tolerance ratio are required to personalise the strategy.

19 Article Management of gastric neuro-endocrine tumours in a large French national cohort (GTE). 2017

Manfredi, Sylvain / Walter, Thomas / Baudin, Eric / Coriat, Romain / Ruszniewski, Philippe / Lecomte, Thierry / Laurenty, Anne-Pascale / Goichot, Bernard / Rohmer, Vincent / Roquin, Guillaume / Cojocarasu, Oana-Zvetlana / Lombard-Bohas, Catherine / Lepage, Côme / Morcet, Jeff / Cadiot, Guillaume. ·CHU Dijon, hepato-gastroenterology unit, University of Bourgogne Franche-Comté, INSERM, LNC UMR1231, F-21000, Dijon, France. sylvain.manfredi@chu-dijon.fr. · Département d'Oncologie Médicale, Hospices Civils de Lyon, Hôpital Edouard Herriot, 69437, Lyon, cedex 03, France. · Gustave Roussy, Département d'Oncologie Endocrinienne, 94805, Villejuif cedex, France. · Department of Gastroenterology and Digestive Oncology, Cochin Teaching Hospital, Paris Descartes University, Paris, France. · Beaujon Hospital and Paris Diderot University, Clichy, France. · CHRU de Tours, service d'Hépato-Gastroenterologie, CNRS, UMR 7292, GICC & Université Francois-Rabelais, Tours, France. · Department of Medical Oncology, Institut Claudius Regaud, Toulouse, France. · Department of Internal Medicine, Endocrinology and Nutrition, Hôpitaux Universitaires de Strasbourg, Faculté de Médecine, Université de Strasbourg, Strasbourg, France. · Service d'endocrinologie et maladies métaboliques, CHU d'Angers, 4 rue Larrey, 49100, Angers, France. · Service d'Hépato-Gastro-Entérologie, CHU Angers, Angers, France. · CH Le Mans, Le Mans, France. · CHU Dijon, hepato-gastroenterology unit, University of Bourgogne Franche-Comté, INSERM, LNC UMR1231, F-21000, Dijon, France. · CIC, Université de Rennes 1, Rennes, France. · Department of Hepato-Gastroenterology and Digestive Oncology, Robert-Debré University Hospital, Reims, France. ·Endocrine · Pubmed #28664309.

ABSTRACT: INTRODUCTION: Gastric neuro-endocrine tumours are rare. European guidelines for the management of neuro-endocrine tumours have been published in 2012. The aim of our survey was to study the management of gastric neuro-endocrine tumours registered in the national cohort. A prospective national cohort registers the Neuro-endocrine tumours in France since January 2003 (GTE network). We reviewed all the individual medical reports of gastric neuro-endocrine tumours in order to collect data on treatment. RESULTS: One hundred and ninety seven gastric neuro-endocrine tumours diagnosed between 1964 and 2013 in 20 centres were registered. For 181 cases data were considered complete for our survey. Eighty four tumours were type 1 (46.4%); five types 2 (2.8%); 52 types 3 (28.7%) and 40 types 4 (22.1%). Types 1 and 2 were first endoscopically managed in 93 and 60% of cases, respectively, whereas surgery was first done in 45 and 42%, respectively, of types 3 and 4. Systemic treatment, chemotherapy and/or somatostatin analogue, was first administered exclusively for types 3 and 4. Near 3% of types 1 and 40% of types 2 received at a time somatostatin analogue treatment. Five-year survival rates were 98.3, 100, 63.2 and 31.8% for types 1, 2, 3 and 4, respectively. CONCLUSION: The great majority of gastric neuro-endocrine tumours registered in this national cohort are treated in accordance with the current guidelines. The survival rates we reported must be interpreted with caution, because this cohort registered preferentially selected patients eligible for treatment. The registration of all the gastric neuro-endocrine tumours, in particular type 1 considered as benign and type 4 not eligible for specific anti-cancer treatment must be encouraged.

20 Article Epidemiology of pancreatic cancer in France: descriptive study from the French national hospital database. 2017

Maire, Frédérique / Cibot, Jean-Olivier / Compagne, Catherine / Hentic, Olivia / Hammel, Pascal / Muller, Nelly / Ponsot, Philippe / Levy, Philippe / Ruszniewski, Philippe. ·aGastroenterology-Pancreatology unit, Beaujon Hospital, Clichy, Paris-Diderot University bCustomizer, Paris cSigma-tau, Issy les, Moulineaux, France. ·Eur J Gastroenterol Hepatol · Pubmed #28471829.

ABSTRACT: INTRODUCTION: Although indirect evidence suggests that the incidence of pancreatic adenocarcinoma has increased in the last decade, few data are available in European countries. The aim of the present study was to update the epidemiology of pancreatic cancer in France in 2014 from the French national hospital database (Programme de Médicalisation des Systèmes d'Information). PATIENTS AND METHODS: All patients hospitalized for pancreatic cancer in France in 2014 in public or private institutions were included. Patient and stays (length, type of support, institutions) characteristics were studied. The results were compared with those observed in 2010. RESULTS: A total of 13 346 (52% men, median age 71 years) new patients were treated for pancreatic cancer in 2014, accounting for a 12.5% increase compared with 2010. Overall, 22% of patients were operated on. Liver metastases were present in 60% of cases. The disease accounted for 146 680 hospital stays (+24.8% compared with 2010), 76% of which were related to chemotherapy (+32%). The average annual number and length of stay were 7 and 2.6 days, respectively. In 2014, 11 052 deaths were reported (+15.8%). CONCLUSION: Approximately 13 350 new cases of pancreatic cancer were observed in France in 2014. The increase in incidence was associated with a marked increase in hospital stays for chemotherapy.

21 Article Antisecretory Effects of Chimeric Somatostatin/Dopamine Receptor Ligands on Gastroenteropancreatic Neuroendocrine Tumors. 2017

Couvelard, Anne / Pélaprat, Didier / Dokmak, Safi / Sauvanet, Alain / Voisin, Thierry / Couvineau, Alain / Ruszniewski, Philippe. ·From the *Faculté de Médecine Xavier Bichat, INSERM U1149, Centre de Recherche sur l'Inflammation (CRI), DHU Unity, Université Paris Diderot; †Université Paris Diderot; ‡Département de Pathologie Beaujon-Bichat, Hôpital Bichat, DHU UNITY, AP-HP, Paris; and §Département de Chirurgie Pancréatico-Biliaire and ∥Département de Gastroentérologie-Pancréatologie, Hôpital Beaujon, DHU UNITY, AP-HP, Clichy, France. ·Pancreas · Pubmed #28375946.

ABSTRACT: OBJECTIVES: The recent finding that gastroenteropancreatic neuroendocrine tumors expressed the dopaminergic D2 receptor in addition to somatostatin (sst) receptors suggested that multiple targeting approaches might decrease hormone hypersecretion more effectively than sst agonists alone. METHODS: To test this hypothesis, (i) we measured the expression of sst receptor type 2 (sst2 receptor) and D2 receptor in 11 gastroenteropancreatic neuroendocrine tumors and (ii) we compared the ability of lanreotide, cabergoline, their combination, and sst/D2 chimeric ligands to decrease chromogranin A (CgA), gastrin, or serotonin release in primary cultures derived from these tumors. RESULTS: Moderate to high positivity was observed for sst2 receptor and D2 receptor, the latter being more expressed in pancreatic tumors. Lanreotide decreased CgA secretion in all cultures, but only 3 tumors responded to cabergoline. No additivity was observed in lanreotide. BIM 23A781 decreased CgA release to the same extent as lanreotide, whereas the other chimeric ligands were less efficient. However, BIM 23A781 was 50 times less potent than lanreotide. Similar patterns were found for gastrin or serotonin. CONCLUSION: No improvement was brought by the sst/D2 combination or chimeric ligands. Factors that underlie these tissue-specific differences remain to be elucidated.

22 Article Neuroendocrine liver metastases: Vascular patterns on triple-phase MDCT are indicative of primary tumour location. 2017

Ronot, Maxime / Cuccioli, Francesco / Dioguardi Burgio, Marco / Vullierme, Marie-Pierre / Hentic, Olivia / Ruszniewski, Philippe / d'Assignies, Gaspard / Vilgrain, Valérie. ·Department of Radiology, University Hospitals Paris Nord Val de Seine, Beaujon, Clichy, Hauts-de-Seine, France; University Paris Diderot, Sorbonne Paris Cité, Paris, France; INSERM U1149, centre de recherche biomédicale Bichat-Beaujon, CRB3, Paris, France. Electronic address: maxime.ronot@aphp.fr. · Department of Radiology, University Hospitals Paris Nord Val de Seine, Beaujon, Clichy, Hauts-de-Seine, France. · Department of Pancreatology, University Hospitals Paris Nord Val de Seine, Beaujon, Clichy, Hauts-de-Seine, France. · University Paris Diderot, Sorbonne Paris Cité, Paris, France; Department of Pancreatology, University Hospitals Paris Nord Val de Seine, Beaujon, Clichy, Hauts-de-Seine, France. · Department of Radiology, University Hospitals Paris Nord Val de Seine, Beaujon, Clichy, Hauts-de-Seine, France; University Paris Diderot, Sorbonne Paris Cité, Paris, France; INSERM U1149, centre de recherche biomédicale Bichat-Beaujon, CRB3, Paris, France. ·Eur J Radiol · Pubmed #28267533.

ABSTRACT: PURPOSE: To re-evaluate and compare CT features of neuroendocrine liver metastases (NLM) from pancreatic (p) and enteric (e) gastroenteropancreatic (GEP) tumours. MATERIAL AND METHODS: From 2006-2013, all patients with proven GEP-neuroendocrine tumours (NETs) with at least one NLM, no previous treatment were included. On unenhanced, arterial and portal phases, NLMs were characterized as hypo-, iso- or hyperattenuating in consensus by 2 radiologists blinded to clinical data. Enhancement patterns (EP) corresponded to the combination of arterial/portal CT attenuation. RESULTS: 78 patients (43 men, 55%, mean 56±13 yo) and 559NLMs were analyzed. pNLMs were more frequently hypoattenuating on unenhanced CT than eNLMs (72% vs. 57%, p<0.001). 70% of the lesions were hypervascular with no significant difference between pNLMs and eNLMs (p=0.32). eNLMs were more frequently hypoattenuating on portal phase than pNLMs (88% vs. 56%, p<0.001). eNLMs were more frequently hyper/hypo than pNLMs (56% vs. 28%, p<0.001). pNLMs were more frequently hyper/iso than eNLMs (33% vs. 8%, p<0.001). Other NLMs showed various patterns, including hypo/hypo in 12%. CONCLUSION: Most NLMs of GEP tumours are hypervascular but the enhancement pattern on multiphasic CT depends on the primary tumour. These differences are helpful when the primary tumour has not been diagnosed.

23 Article MGMT expression predicts response to temozolomide in pancreatic neuroendocrine tumors. 2016

Cros, J / Hentic, O / Rebours, V / Zappa, M / Gille, N / Theou-Anton, N / Vernerey, D / Maire, F / Lévy, P / Bedossa, P / Paradis, V / Hammel, P / Ruszniewski, P / Couvelard, A. ·Department of PathologyAP-HP, DHU UNITY, Beaujon University Hospital, Clichy, France U1149 - University Paris DiderotParis, France. · Department of Gastroenterology and PancreatologyAP-HP, DHU UNITY, Beaujon University Hospital, Clichy, France. · U1149 - University Paris DiderotParis, France Department of Gastroenterology and PancreatologyAP-HP, DHU UNITY, Beaujon University Hospital, Clichy, France. · Department of RadiologyAP-HP, DHU UNITY, Beaujon Hospital, Clichy, France. · Department of PathologyAP-HP, DHU UNITY, Beaujon University Hospital, Clichy, France. · Department of Somatic GeneticAP-HP, DHU UNITY, Bichat University Hospital, Paris, France. · Methodology and Quality of Life in Oncology Unit (EA 3181)University Hospital of Besançon, Besançon, France. · U1149 - University Paris DiderotParis, France Department of Digestive OncologyAP-HP, DHU UNITY, Beaujon University Hospital, Clichy, France. · U1149 - University Paris DiderotParis, France Department of PathologyAP-HP, DHU UNITY, Bichat University Hospital, Paris, France anne.couvelard@bch.aphp.fr. ·Endocr Relat Cancer · Pubmed #27353036.

ABSTRACT: Temozolomide (TEM) showed encouraging results in well-differentiated pancreatic neuroendocrine tumors (WDPNETs). Low O(6)-methylguanine-DNA methyltransferase (MGMT) expression and MGMT promoter methylation within tumors correlate with a better outcome under TEM-based chemotherapy in glioblastoma. We aimed to assess whether MGMT expression and MGMT promoter methylation could help predict the efficacy of TEM-based chemotherapy in patients with WDPNET. Consecutive patients with progressive WDPNET and/or liver involvement over 50% who received TEM between 2006 and 2012 were retrospectively studied. Tumor response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 guidelines. Nuclear expression of MGMT was assessed by immunochemistry (H-score, 0-300) and MGMT promoter methylation by pyrosequencing. Forty-three patients (21 men, 58years (27-84)) with grade 1 WDPNET (n=6) or 2 (n=36) were analyzed. Objective response, stable disease, and progression rates were seen in 17 patients (39.5%), 18 patients (41.9%), and 8 patients (18.6%), respectively. Low MGMT expression (≤50) was associated with radiological objective response (P=0.04) and better progression-free survival (PFS) (HR=0.35 (0.15-0.81), P=0.01). Disease control rate at 18months of treatment remained satisfying with an MGMT score up to 100 (74%) but dropped with a higher expression. High MGMT promoter methylation was associated with a low MGMT expression and longer PFS (HR=0.37 (0.29-1.08), P=0.05). Low MGMT score (≤50) appears to predict an objective tumor response, whereas an intermediate MGMT score (50-100) seems to be associated with prolonged stable disease.

24 Article Unraveling the intrafamilial correlations and heritability of tumor types in MEN1: a Groupe d'étude des Tumeurs Endocrines study. 2015

Thevenon, J / Bourredjem, A / Faivre, L / Cardot-Bauters, C / Calender, A / Le Bras, M / Giraud, S / Niccoli, P / Odou, M F / Borson-Chazot, F / Barlier, A / Lombard-Bohas, C / Clauser, E / Tabarin, A / Pasmant, E / Chabre, O / Castermans, E / Ruszniewski, P / Bertherat, J / Delemer, B / Christin-Maitre, S / Beckers, A / Guilhem, I / Rohmer, V / Goichot, B / Caron, P / Baudin, E / Chanson, P / Groussin, L / Du Boullay, H / Weryha, G / Lecomte, P / Schillo, F / Bihan, H / Archambeaud, F / Kerlan, V / Bourcigaux, N / Kuhn, J M / Vergès, B / Rodier, M / Renard, M / Sadoul, J L / Binquet, C / Goudet, P. ·CHU de DijonCentre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, University of Burgundy, EA4271 GAD, Dijon, FranceINSERMCIC1432, Dijon, FranceCentre Hospitalier Universitaire de DijonCentre d'Investigation Clinique, éssais cliniques/épidémiologie clinique, Dijon FranceCentre Hospitalier Régional et Universitaire de LilleService de Médecine interne et Endocrinologie, Clinique Marc Linquette, Lille, FranceHospices Civils de LyonHôpital E. Herriot, Génétique moléculaire et clinique, Lyon, FranceCentre Hospitalier Universitaire de NantesClinique d'Endocrinologie, Nantes, FranceAPHMservice d'Oncologie Médicale, Institut Paoli-Calmettes, Université Aix-Marseille, Marseille, FranceCHRU de LilleService d'Hormonologie, Métabolisme-Nutrition, Oncologie, Pôle de Biologie Pathologie Génétique, Université de Lille2, Lille, FranceHospices Civils de Lyon et Université LYON1Groupement hospitalier Est, Fédération d'Endocrinologie, Lyon, FranceAP-HMHôpital la Conception, Laboratoire de Biologie Moléculaire, Marseille, FranceAix-Marseille UniversityCRN2M UMR 7286-CNRS, Marseille, FranceHospices Civils de LyonHôpital E. Herriot, Service d'Oncologie, Lyon, FranceUniversité Paris-DescartesFaculté de Médecine Paris-Descartes-Paris-V, UMR-S970, Paris, FranceAPHPHôpital Cochin, Laboratoire d'Oncogénétique, Paris, FranceCentre Hospitalier Universitaire et Université de Bordeaux 2Service d'Endocrinologie,Hôpital du Haut Levêque, Pessac,FranceAPHPHôpital Cochin, Service de Biochimie et de Génétique Moléculaire,Paris, FranceCentre Hospitalier Universitaire de GrenobleService d'Endocrinologie, Diabète et Maladies métaboliques, Hôpital Michalon, Grenoble,FranceCentre Hospitalier Universitaire de LiègeDomaine Universitaire du Sart-Tilman, University of Liège, Laboratoire de génétique moléculaire, Liège, BelgiumAPHPHôpital Beaujon et Université Paris 7 Denis Diderot, Service de Gastroentérologie-pancréa ·Eur J Endocrinol · Pubmed #26392472.

ABSTRACT: BACKGROUND: MEN1, which is secondary to the mutation of the MEN1 gene, is a rare autosomal-dominant disease that predisposes mutation carriers to endocrine tumors. Most studies demonstrated the absence of direct genotype-phenotype correlations. The existence of a higher risk of death in the Groupe d'étude des Tumeurs Endocrines-cohort associated with a mutation in the JunD interacting domain suggests heterogeneity across families in disease expressivity. This study aims to assess the existence of modifying genetic factors by estimating the intrafamilial correlations and heritability of the six main tumor types in MEN1. METHODS: The study included 797 patients from 265 kindred and studied seven phenotypic criteria: parathyroid and pancreatic neuroendocrine tumors (NETs) and pituitary, adrenal, bronchial, and thymic (thNET) tumors and the presence of metastasis. Intrafamilial correlations and heritability estimates were calculated from family tree data using specific validated statistical analysis software. RESULTS: Intrafamilial correlations were significant and decreased along parental degrees distance for pituitary, adrenal and thNETs. The heritability of these three tumor types was consistently strong and significant with 64% (s.e.m.=0.13; P<0.001) for pituitary tumor, 65% (s.e.m.=0.21; P<0.001) for adrenal tumors, and 97% (s.e.m.=0.41; P=0.006) for thNETs. CONCLUSION: The present study shows the existence of modifying genetic factors for thymus, adrenal, and pituitary MEN1 tumor types. The identification of at-risk subgroups of individuals within cohorts is the first step toward personalization of care. Next generation sequencing on this subset of tumors will help identify the molecular basis of MEN1 variable genetic expressivity.

25 Article Can pancreatic neuroendocrine tumour biopsy accurately determine pathological characteristics? 2015

Rebours, Vinciane / Cordova, Jacqueline / Couvelard, Anne / Fabre, Monique / Palazzo, Laurent / Vullierme, Marie Pierre / Hentic, Olivia / Sauvanet, Alain / Aubert, Alain / Bedossa, Pierre / Ruszniewski, Philippe. ·Pancreatology Department, Beaujon Hospital, AP-HP, Clichy, Paris-Diderot University, France; Inserm U773-CRB3, Paris-Diderot University, Paris, France. Electronic address: vinciane.rebours@bjn.aphp.fr. · Pancreatology Department, Beaujon Hospital, AP-HP, Clichy, Paris-Diderot University, France. · Inserm U773-CRB3, Paris-Diderot University, Paris, France; Pathology Department, Bichat Hospital, AP-HP, Paris-Diderot University, France. · Pathology Department, Institut Gustave Roussy, Villejuif, France. · Endoscopy and Gastroenterology Department, Clinique du Trocadéro, Paris, France. · Radiology Department, Beaujon Hospital, AP-HP, Clichy, Paris-Diderot University, France. · Pancreatic Surgery Department, Beaujon Hospital, AP-HP, Clichy, Paris-Diderot University, France. · Pathology Department, Beaujon Hospital, AP-HP, Clichy, Paris-Diderot University, France. · Pancreatology Department, Beaujon Hospital, AP-HP, Clichy, Paris-Diderot University, France; Inserm U773-CRB3, Paris-Diderot University, Paris, France. ·Dig Liver Dis · Pubmed #26169284.

ABSTRACT: BACKGROUND: Assessment of the pathological characteristics of pancreatic neuroendocrine tumours is crucial for appropriate management. We compared preoperative pathological data with surgical specimens for accuracy. METHODS: Surgical patients with pancreatic neuroendocrine tumours who underwent preoperative endoscopic ultrasound-guided fine needle aspiration of the primary tumour or biopsy of liver metastasis were retrospectively included. Tumour differentiation and the Ki67 proliferation index on biopsies were compared with pancreatic specimens. RESULTS: Fifty-seven patients were included. A preoperative biopsy of the primary tumour or of a liver metastasis was obtained in 48 and 9 patients respectively. Tumour differentiation was high in 98%, and poor in 2% on biopsy and high in 100% of surgical specimens. Ki67 index values were 0 (0-19) and 2 (0-15) on biopsy and surgical specimens (p=0.01). Correlation between preoperative and surgical findings was stronger for liver (r=0.62, p=0.001) than for pancreas (r=0.23, p=0.11). Correlation for pancreas varied according to the tumour pattern: solid (r=0.24, p=0.16), mixed (r=0.91, p=0.0036) or cystic (r=0.04, p=0.89). Tumour grade was different between pancreatic biopsies and surgical specimens, for grade 1 (63% vs 37%) and grade 2 (28% vs 72%), p=0.0007. CONCLUSIONS: Tumour grade assessment is accurate in biopsies of liver metastases of pancreatic neuroendocrine tumours, while pancreatic fine-needle aspiration biopsies are less accurate.

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