Pick Topic
Review Topic
List Experts
Examine Expert
Save Expert
  Site Guide ··   
Pancreatic Neoplasms: HELP
Articles by Wouter W. DE Herder
Based on 48 articles published since 2010
(Why 48 articles?)
||||

Between 2010 and 2020, W. de Herder wrote the following 48 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Guideline NANETS treatment guidelines: well-differentiated neuroendocrine tumors of the stomach and pancreas. 2010

Kulke, Matthew H / Anthony, Lowell B / Bushnell, David L / de Herder, Wouter W / Goldsmith, Stanley J / Klimstra, David S / Marx, Stephen J / Pasieka, Janice L / Pommier, Rodney F / Yao, James C / Jensen, Robert T / Anonymous4960666. ·Department of Medical Oncology, Dana-Farber Cancer Institute, Boston MA 02115, USA. Matthew_kulke@dfci.harvard.edu ·Pancreas · Pubmed #20664472.

ABSTRACT: Well-differentiated neuroendocrine tumors (NETs) of the stomach and pancreas represent 2 major subtypes of gastrointestinal NETs. Historically, there has been little consensus on the classification and management of patients with these tumor subtypes. We provide an overview of well-differentiated NETs of the stomach and pancreas and describe consensus guidelines for the treatment of patients with these malignancies.

2 Editorial Unmet Needs in the Field of Neuroendocrine Neoplasms of the Gastrointestinal Tract, Pancreas, and Respiratory System: Reports by the ENETS Group. 2019

de Herder, Wouter W / Capdevila, Jaume. ·Department of Internal Medicine, Erasmus MC, ENETS Center of Excellence, Erasmus MC Cancer Center, Rotterdam, The Netherlands, w.w.deherder@erasmusmc.nl. · Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Barcelona, Spain. ·Neuroendocrinology · Pubmed #30517944.

ABSTRACT: -- No abstract --

3 Editorial Gastroenteropancreatic neuroendocrine tumors (GEP-NETs). 2012

de Herder, Wouter W. · ·Best Pract Res Clin Gastroenterol · Pubmed #23582912.

ABSTRACT: -- No abstract --

4 Review Role of biomarker tests for diagnosis of neuroendocrine tumours. 2018

Hofland, Johannes / Zandee, Wouter T / de Herder, Wouter W. ·ENETS Center of Excellence, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, Netherlands. j.hofland@erasmusmc.nl. · ENETS Center of Excellence, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, Netherlands. ·Nat Rev Endocrinol · Pubmed #30158549.

ABSTRACT: Neuroendocrine tumours (NETs) are neoplasms that arise from neuroendocrine cells. Neuroendocrine cells and their tumours can secrete a wide range of amines and polypeptide hormones into the systemic circulation. This feature has triggered widespread investigation into circulating biomarkers for the diagnosis of NETs as well as for the prediction of the biological behaviour of tumour cells. Classic examples of circulating biomarkers for gastroenteropancreatic NETs include chromogranin A, neuron-specific enolase and pancreatic polypeptide as well as hormones that elicit clinical syndromes, such as serotonin and its metabolites, insulin, glucagon and gastrin. Biomarker metrics of general markers for diagnosing all gastroenteropancreatic NET subtypes are limited, but specific hormonal measurements can be of diagnostic value in select cases. In the past decade, methods for detecting circulating transcripts and tumour cells have been developed to improve the diagnosis of patients with NETs. Concurrently, modern scanning techniques and superior radiotracers for functional imaging have markedly expanded the options for clinicians dealing with NETs. Here, we review the latest research on biomarkers in the NET field to provide clinicians with a comprehensive overview of relevant diagnostic biomarkers that can be implemented in dedicated situations.

5 Review Clinical benefit of systemic treatment in patients with advanced pancreatic and gastrointestinal neuroendocrine tumours according to ESMO-MCBS and ASCO framework. 2017

de Hosson, L D / van Veenendaal, L M / Schuller, Y / Zandee, W T / de Herder, W W / Tesselaar, M E T / Klümpen, H J / Walenkamp, A M E. ·Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen. · Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam. · Department of Medical Oncology, Academic Medical Center, Amsterdam. · Department of Endocrinology, Erasmus Medical Center, Rotterdam, The Netherlands. ·Ann Oncol · Pubmed #29045525.

ABSTRACT: Background: Assessment of clinical benefit of systemic treatments of rare diseases including gastroenteropancreatic neuroendocrine tumours (GEP-NET) is challenging. Recently several tools have been developed to grade the clinical benefit of cancer drugs. The European Society for Medical Oncology (ESMO) has developed the ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS). The American Society of Clinical Oncology (ASCO) has developed and revised the ASCO framework consisting of the Net Health Benefit (NHB) score juxtaposed against the costs of the treatment. In this review, we graded systemic treatments for GEP-NET patients with both frameworks. Methods: The electronic databases (PubMed and EMBASE) were searched for papers reporting comparative trials, conducted in adult GEP-NET patients in the English language. Papers were assessed according to the ESMO-MCBS and the NHB part of the ASCO revised Framework (NHB-ASCO-F) by four independent assessors, and discrepancies were discussed. Results: The search yielded 32 trials of which 6 were eligible for grading with the ESMO-MCBS resulting in scores of 2 or 3. Eight trials were eligible for grading with the NHB-ASCO-F, resulting in scores between 37.6 and 57.4. Trials that were not primary assessable by the tools were analysed separately. Consensus between assessors was reached in 68% of trials with the ESMO-MCBS and in 23% of trials with the NHB-ASCO-F. Conclusion: The currently used systemic treatments for GEP-NET patients had low scores according to the NHB-ASCO-F and none could be graded as meaningful clinical beneficial according to the ESMO-MCBS. Despite the low incidence, the heterogeneous patient population and relatively long natural course of NET, future studies on new treatment modalities should aim for high clinical benefit outcomes.

6 Review GEPNETs update: Radionuclide therapy in neuroendocrine tumors. 2015

van der Zwan, Wouter A / Bodei, Lisa / Mueller-Brand, Jan / de Herder, Wouter W / Kvols, Larry K / Kwekkeboom, Dik J. ·Department of Nuclear MedicineErasmus MC, University Medical Center, s-Gravendijkwal 230, 3015CE Rotterdam, The NetherlandsDepartment of Nuclear MedicineEuropean Institute of Oncology, Milan, ItalyDepartment of Nuclear MedicineUniversity Hospital Basel, Basel, SwitzerlandDepartment of GI OncologyH. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA w.vanderzwan@erasmusmc.nl. · Department of Nuclear MedicineErasmus MC, University Medical Center, s-Gravendijkwal 230, 3015CE Rotterdam, The NetherlandsDepartment of Nuclear MedicineEuropean Institute of Oncology, Milan, ItalyDepartment of Nuclear MedicineUniversity Hospital Basel, Basel, SwitzerlandDepartment of GI OncologyH. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA. ·Eur J Endocrinol · Pubmed #25117465.

ABSTRACT: Peptide receptor radionuclide therapy (PRRT) is a promising new treatment modality for inoperable or metastasized gastroenteropancreatic neuroendocrine tumors (GEPNETs) patients. Most studies report objective response rates in 15-35% of patients. Also, outcome in terms of progression free survival (PFS) and overall survival compares very favorably with that for somatostatin analogs, chemotherapy, or new, 'targeted' therapies. They also compare favorably to PFS data for liver-directed therapies. Two decades after the introduction of PRRT, there is a growing need for randomized controlled trials comparing PRRT to 'standard' treatment, that is treatment with agents that have proven benefit when tested in randomized trials. Combining PRRT with liver-directed therapies or with targeted therapies could improve treatment results. The question to be answered, however, is whether a combination of therapies performed within a limited time-span from one another results in a better PFS than a strategy in which other therapies are reserved until after (renewed) tumor progression. Randomized clinical trials comparing PRRT with other treatment modalities should be undertaken to determine the best treatment options and treatment sequelae for patients with GEPNETs.

7 Review GEP-NETS update: functional localisation and scintigraphy in neuroendocrine tumours of the gastrointestinal tract and pancreas (GEP-NETs). 2014

de Herder, Wouter W. ·Section of Endocrinology, Department of Internal Medicine, Erasmus MC, 's Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands. ·Eur J Endocrinol · Pubmed #24723670.

ABSTRACT: For patients with neuroendocrine tumours (NETs) of the gastrointestinal tract and pancreas (GEP) (GEP-NETs), excellent care should ideally be provided by a multidisciplinary team of skilled health care professionals. In these patients, a combination of nuclear medicine imaging and conventional radiological imaging techniques is usually mandatory for primary tumour visualisation, tumour staging and evaluation of treatment. In specific cases, as in patients with occult insulinomas, sampling procedures can provide a clue as to where to localise the insulin-hypersecreting pancreatic NETs. Recent developments in these fields have led to an increase in the detection rate of primary GEP-NETs and their metastatic deposits. Radiopharmaceuticals targeted at specific tumour cell properties and processes can be used to provide sensitive and specific whole-body imaging. Functional imaging also allows for patient selection for receptor-based therapies and prediction of the efficacy of such therapies. Positron emission tomography/computed tomography (CT) and single-photon emission CT/CT are used to map functional images with anatomical localisations. As a result, tumour imaging and tumour follow-up strategies can be optimised for every individual GEP-NET patient. In some cases, functional imaging might give indications with regard to future tumour behaviour and prognosis.

8 Review Incidence of gastroenteropancreatic neuroendocrine tumours: a systematic review of the literature. 2014

Fraenkel, M / Kim, M / Faggiano, A / de Herder, W W / Valk, G D / Anonymous2710778. ·Endocrinology, Soroka University Medical Center and the Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheeba, Israel Mount Sinai Medical Center, New York, New York, USA Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy Endocrinology, National Cancer Institute, Fondazione G. Pascale, Naples, Italy Erasmus MC, Rotterdam, The Netherlands Department of Internal Medicine, Division of Gastroenterology, University Medical Center Utrecht, Utrecht, The Netherlands. ·Endocr Relat Cancer · Pubmed #24322304.

ABSTRACT: Based on the current medical literature, the worldwide incidence of neuroendocrine tumours (NETs) seems to have increased; however, a systematic literature overview is lacking. This study aimed to collect all available data on the incidence of gastroenteropancreatic (GEP)-NETs and characteristics of population to establish their epidemiology. A sensitive MEDLINE search was carried out. The papers were selected via a cascade process that restricted the initial pool of 7991 articles to 33, using predefined inclusion and exclusion criteria. Original articles evaluating the incidence of sporadic GEP-NETs in regional, institutional and national registries were considered. The majority of data originated from the US National Cancer Institute Surveillance, Epidemiology and End Results database and from national cancer registries in Western Europe. Generally, because of the retrospective nature of existing databases the outcomes of studies might be biased, which hinders the drawing of firm conclusions. The age-adjusted incidence of GEP-NETs has increased steadily over the past four decades (1973-2007), increasing 3.65-fold in the USA and 3.8- to 4.8-fold in the UK. Incidence has changed variably from one anatomical site to another. The greatest increase in incidence occurred for gastric and rectal NETs, while the smallest increase occurred for small intestine NETs. There were gender and racial differences, which differed site by site and, in some cases, changed over time. The incidence rates (IRs) of GEP-NETs have increased significantly in the last 40 years. Data are only available from North America, Western Europe and Japan. A site-by-site analysis revealed that the IRs of some NETs increased more than those of others.

9 Review New therapeutic options for metastatic malignant insulinomas. 2011

de Herder, Wouter W / van Schaik, Ellen / Kwekkeboom, Dik / Feelders, Richard A. ·Department of Internal Medicine, Sector of Endocrinology, Erasmus MC, Rotterdam, the Netherlands. w.w.deherder@erasmusmc.nl ·Clin Endocrinol (Oxf) · Pubmed #21649688.

ABSTRACT: Insulinomas are the most common, functioning, pancreatic neuroendocrine tumours. The great majority (>90%) of insulinomas are nonmetastatic at presentation and can be surgically cured. The <10% patients with distant (liver-bone) metastases have a median survival of < 2 years. Everolimus and sunitinib have been recently introduced as targeted therapies for metastatic pancreatic neuroendocrine tumours. An additional advantage of everolimus in the treatment of patients with metastatic insulinomas is its capability to increase blood glucose levels. Peptide receptor radiotherapy using radiolabelled somatostatin analogues has also been shown to be successful in controlling tumour growth of metastatic pancreatic neuroendocrine tumours. In patients with metastatic insulinomas, this therapeutic modality was also effective in controlling hypoglycaemia, even in the presence of tumour regrowth. With the introduction of these new therapeutic modalities, the therapeutic arsenal for the 'tailor-made' approach of patients with metastatic insulinomas is further expanded.

10 Review Somatostatin receptor-targeted radionuclide therapy in patients with gastroenteropancreatic neuroendocrine tumors. 2011

Kwekkeboom, Dik J / de Herder, Wouter W / Krenning, Eric P. ·Department of Nuclear Medicine, Erasmus Medical Center, 's Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands. d.j.kwekkeboom@erasmusmc.nl ·Endocrinol Metab Clin North Am · Pubmed #21349418.

ABSTRACT: Treatment with radiolabeled somatostatin analogs is a promising tool in the management of patients with inoperable or metastasized neuroendocrine tumors. Symptomatic improvement may occur with all (111)Indium-, (90)Yttrium-, or (177)Lutetium-labeled somatostatin analogs used for peptide receptor radionuclide therapy. If kidney protective agents are used, the side-effects are few and mild, and the median duration of the therapy response is 30 and 40 months, respectively. Overall survival is several years from diagnosis. These data compare favorably with the limited number of alternative treatments. If more widespread use of PRRT can be guaranteed, such therapy may become the therapy of first choice.

11 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.

12 Clinical Trial A Phase II Study of BEZ235 in Patients with Everolimus-resistant, Advanced Pancreatic Neuroendocrine Tumours. 2016

Fazio, Nicola / Buzzoni, Roberto / Baudin, Eric / Antonuzzo, Lorenzo / Hubner, Richard A / Lahner, Harald / DE Herder, Wouter W / Raderer, Markus / Teulé, Alexandre / Capdevila, Jaume / Libutti, Steven K / Kulke, Matthew H / Shah, Manisha / Dey, Debarshi / Turri, Sabine / Aimone, Paola / Massacesi, Cristian / Verslype, Chris. ·European Institute of Oncology, Milan, Italy nicola.fazio@ieo.it. · IRCCS National Tumor Institute, Milan, Italy. · Institut Gustave Roussy, Villejuif, France. · Careggi University Hospital, Florence, Italy. · The Christie NHS Foundation Trust, Manchester, U.K. · University of Duisburg-Essen, Essen, Germany. · Erasmus MC, Rotterdam, the Netherlands. · University Hospital of Vienna, Vienna, Austria. · Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona, Spain. · Montefiore Medical Center and Albert Einstein College of Medicine, New York, NY, U.S.A. · Dana-Farber Cancer Institute, Boston, MA, U.S.A. · The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH, U.S.A. · Novartis Healthcare Private Limited, Hyderabad, India. · Novartis Pharma AG, Basel, Switzerland. · Novartis Oncology, Paris, France. · University Hospitals Leuven, Leuven, Belgium. ·Anticancer Res · Pubmed #26851029.

ABSTRACT: BACKGROUND: This was a two-stage, phase II trial of the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor BEZ235 in patients with everolimus-resistant pancreatic neuroendocrine tumours (pNETs) (NCT01658436). PATIENTS AND METHODS: In stage 1, 11 patients received 400 mg BEZ235 orally twice daily (bid). Due to tolerability concerns, a further 20 patients received BEZ235 300 mg bid. Stage 2 would be triggered by a 16-week progression-free survival (PFS) rate of ≥60% in stage 1. RESULTS: As of 30 June, 2014, 29/31 patients had discontinued treatment. Treatment-related grade 3/4 adverse events were reported in eight (72.7%) patients at 400 mg and eight (40.0%) patients at 300 mg, including hyperglycaemia, diarrhoea, nausea, and vomiting. The estimated 16-week PFS rate was 51.6% (90% confidence interval=35.7-67.3%). CONCLUSION: BEZ235 was poorly tolerated by patients with everolimus-resistant pNETs at 400 and 300 mg bid doses. Although evidence of disease stability was observed, the study did not proceed to stage 2.

13 Article Prognostic factors and survival in MEN1 patients with gastrinomas: Results from the DutchMEN study group (DMSG). 2019

van Beek, Dirk-Jan / Nell, Sjoerd / Pieterman, Carolina R C / de Herder, Wouter W / van de Ven, Annenienke C / Dekkers, Olaf M / van der Horst-Schrivers, Anouk N / Drent, Madeleine L / Bisschop, Peter H / Havekes, Bas / Borel Rinkes, Inne H M / Vriens, Menno R / Valk, Gerlof D. ·Department of Endocrine Surgical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands. · Department of Endocrine Oncology, University Medical Center Utrecht, Utrecht, The Netherlands. · Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. · Department of Endocrinology, Radboud University Medical Center, Nijmegen, The Netherlands. · Departments of Endocrinology and Metabolism and Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. · Department of Endocrinology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. · Department of Internal Medicine, Section of Endocrinology, Amsterdam UMC location, VU University Medical Center, Amsterdam, The Netherlands. · Department of Endocrinology and Metabolism, Amsterdam UMC location Academic Medical Center, Amsterdam, The Netherlands. · Department of Internal Medicine, Division of Endocrinology, Maastricht University Medical Center, Maastricht, The Netherlands. ·J Surg Oncol · Pubmed #31401809.

ABSTRACT: BACKGROUND AND OBJECTIVES: Gastrinomas are the most prevalent functioning neuroendocrine tumors (NET) in multiple endocrine neoplasia type 1 (MEN1). Guidelines suggest medical therapy in most patients, but surgery may be considered in a subgroup. Currently, factors to guide management are necessary. This population-based cohort study assessed prognostic factors of survival in patients with MEN1-related gastrinomas. METHODS: Patients with MEN1 having gastrinomas were identified in the Dutch MEN1 database from 1990 to 2014 based on fasting serum gastrin (FSG) levels and/or pathology. Predictors of overall survival were assessed using Cox regression. RESULTS: Sixty-three patients with gastrinoma (16% of the MEN1 population) were identified. Five- and 10-year overall survival rates were 83% and 65%, respectively. Prognostic factors associated with overall survival were initial FSG levels ≥20x upper limit of normal (ULN) (hazard ratio [HR], 6.2 [95% confidence interval, 1.7-23.0]), pancreatic NET ≥2 cm (HR 4.5; [1.5-13.1]), synchronous liver metastases (HR 8.9; [2.1-36.7]), gastroduodenoscopy suspicious for gastric NETs (HR 12.7; [1.4-115.6]), and multiple concurrent NETs (HR 5.9; [1.2-27.7]). CONCLUSION: Life expectancy of patients with MEN1 gastrinoma is reduced. FSG levels and pancreatic NETs ≥2 cm are prognostic factors. FSG levels might guide surveillance intensity, step-up to additional diagnostics, or provide arguments in selecting patients who might benefit from surgery.

14 Article Effects of Ketoconazole on ACTH-Producing and Non-ACTH-Producing Neuroendocrine Tumor Cells. 2019

Herrera-Martínez, Aura D / Feelders, Richard A / de Herder, Wouter W / Castaño, Justo P / Gálvez Moreno, María Ángeles / Dogan, Fadime / van Dungen, Rosanna / van Koetsveld, Peter / Hofland, Leo J. ·Department of Internal Medicine, Division of Endocrinology, Erasmus MC, Wytemaweg 80, 3015, CN, Rotterdam, The Netherlands. · Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Córdoba, Spain. · Department of Internal Medicine, Division of Endocrinology, Erasmus MC, Wytemaweg 80, 3015, CN, Rotterdam, The Netherlands. l.hofland@erasmusmc.nl. ·Horm Cancer · Pubmed #31102172.

ABSTRACT: Prolonged remission of hypercortisolism with steroidogenesis inhibitors has been described in patients with ectopic adrenocorticotropic hormone (ACTH) syndrome. The anti-proliferative and pro-apoptotic effect of ketoconazole in human cancer cells was previously suggested. The aim of this study was to explore the effects of ketoconazole on ACTH-producing and non-ACTH-producing neuroendocrine tumor (NET) cell lines. The effects of ketoconazole alone, and in combination with somatostatin analogs, were evaluated in two human cell lines: DMS-79 (ectopic ACTH-producing small cell lung carcinoma) and BON-1 (human pancreatic NET). Total DNA measurement, apoptosis, cell cycle, chromogranin A (CgA)/proopiomelanocortin (POMC) expression by qRT-PCR, serotonin, CgA, and ACTH secretion assays were performed. In both cell lines, ketoconazole significantly suppressed cell growth and colony formation in a dose and time-dependent manner. The effect in DMS-79 was primarily cytotoxic, while it was more apoptotic in BON-1 cells. Ketoconazole also induced increase in G0/G1 phase in both cell lines and arrest in phase G2/M of BON-1 cells. Ketoconazole did not affect the secretion of serotonin, CgA, ACTH, or the mRNA expression of CgA and POMC. Decreased serotonin secretion was observed after the combination treatment with pasireotide. These results suggest a direct effect of ketoconazole on cell proliferation, apoptosis, and cell cycle in both ACTH- and non-ACTH-producing NET cells.

15 Article Symptomatic and Radiological Response to 177Lu-DOTATATE for the Treatment of Functioning Pancreatic Neuroendocrine Tumors. 2019

Zandee, Wouter T / Brabander, Tessa / Blažević, Anela / Kam, Boen L R / Teunissen, Jaap J M / Feelders, Richard A / Hofland, Johannes / de Herder, Wouter W. ·Department of Internal Medicine, Sector of Endocrinology, Erasmus Medical Center and Erasmus MC Cancer Institute, Rotterdam, Netherlands. · Department of Radiology & Nuclear Medicine, Erasmus Medical Center and Erasmus MC Cancer Institute, Rotterdam, Netherlands. ·J Clin Endocrinol Metab · Pubmed #30566620.

ABSTRACT: PURPOSE: Peptide receptor radionuclide therapy (PRRT) with the radiolabeled somatostatin analogue [Lutetium-177-DOTA0-Tyr3]octreotate (177Lu-DOTATATE) is widely applied for inoperable metastatic small intestinal and nonfunctioning pancreatic neuroendocrine tumors (pNETs). The aim of this study is to describe the safety and efficacy of the treatment of functioning pNETs. METHODS: Patients were treated with up to four cycles of 177Lu-DOTATATE with an intended dose of 7.4 Gbq per cycle. Radiological (Response Evaluation Criteria in Solid Tumors 1.1), symptomatic, and biochemical response were analyzed retrospectively for all patients with a functioning pNET (insulinoma, gastrinoma, VIPoma, and glucagonoma) treated with 177Lu-DOTATATE. Quality of life (QOL) was assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core Module questionnaire. RESULTS: Thirty-four patients with a metastatic functioning pNET (European Neuroendocrine Tumor Society grade 1 or 2) were included: 14 insulinomas, 5 VIPomas, 7 gastrinomas, and 8 glucagonomas. Subacute hematological toxicity, grade 3 or 4 occurred in 4 patients (12%) and a hormonal crisis in 3 patients (9%). PRRT resulted in partial or complete response in 59% of patients and the disease control rate was 78% in patients with baseline progression. 71% of patients with uncontrolled symptoms had a reduction of symptoms and a more than 80% decrease of circulating hormone levels was measured during follow-up. After PRRT, median progression-free survival was 18.1 months (interquartile range: 3.3 to 35.7) with a concurrent increase in QOL. CONCLUSION: Treatment with 177Lu-DOTATATE is a safe and effective therapy resulting in radiological, symptomatic and biochemical response in a high percentage of patients with metastatic functioning pNETs. Hormonal crises occur relatively frequent and preventive therapy should be considered before and/or during PRRT.

16 Article Salvage peptide receptor radionuclide therapy with [ 2019

van der Zwan, W A / Brabander, T / Kam, B L R / Teunissen, J J M / Feelders, R A / Hofland, J / Krenning, E P / de Herder, W W. ·Department of Radiology & Nuclear Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands. w.vanderzwan@erasmusmc.nl. · Department of Radiology & Nuclear Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands. · Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands. · Cyclotron Rotterdam BV, Erasmus Medical Centre, Rotterdam, The Netherlands. ·Eur J Nucl Med Mol Imaging · Pubmed #30267116.

ABSTRACT: PURPOSE: Therapy with [ METHODS: Patients with progressive bronchial NET or GEP-NET were selected for re-(re)treatment if they had benefited from initial peptide receptor radionuclide therapy (I-PRRT) with a minimal progression-free survival (PFS) of 18 months. Patients received an additional cumulative dose of 14.8 GBq of [ RESULTS: The safety and efficacy analyses included 181 patients and 168 patients, respectively, with bronchial NET or GEP-NET. Overall median follow-up was 88.6 months (95% CI 79.0-98.2). Median cumulative doses were 44.7 GBq (range 26.3-46.4 GBq) during R-PRRT (168 patients) and 59.7 GBq (range 55.2-≤60.5 GBq) during RR-PRRT (13 patients). Objective response and stable disease, as best response, were observed in 26 patients (15.5%) and 100 patients (59.5%) following R-PRRT, and in 5 patients (38.5%) and 7 patients (53.8%) following RR-PRRT, respectively. Median PFS was 14.6 months (95% CI 12.4-16.9) following R-PRRT and 14.2 months (95% CI 9.8-18.5) following RR-PRRT. Combined overall survival (OS) after I-PRRT plus R-PRRT and RR-PRRT was 80.8 months (95% CI 66.0-95.6). Grade III/IV bone marrow toxicity occurred in 6.6% and 7.7% of patients after R-PRRT and RR-PRRT, respectively. Salvage therapy resulted in a significantly longer OS in patients with bronchial NET, GEP-NET and midgut NET than in a nonrandomized control group. The total incidence of acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) was 2.2%. No PRRT-related grade III/IV nephrotoxicity was observed. CONCLUSION: A cumulative dose of up to 60.5 GBq salvage PRRT with [

17 Article Hotspot DAXX, PTCH2 and CYFIP2 mutations in pancreatic neuroendocrine neoplasms. 2019

Vandamme, T / Beyens, M / Boons, G / Schepers, A / Kamp, K / Biermann, K / Pauwels, P / De Herder, W W / Hofland, L J / Peeters, M / Van Camp, G / Op de Beeck, K. ·Center of Oncological Research (CORE), University of Antwerp, Antwerp, Belgium. · Section of Endocrinology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. · Center of Medical Genetics, University of Antwerp, Antwerp, Belgium. · Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands. · Department of Pathology, University of Antwerp, Antwerp, Belgium. ·Endocr Relat Cancer · Pubmed #30021865.

ABSTRACT: Mutations in DAXX/ATRX, MEN1 and genes involved in the phosphoinositide-3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway have been implicated in pancreatic neuroendocrine neoplasms (pNENs). However, mainly mutations present in the majority of tumor cells have been identified, while proliferation-driving mutations could be present only in small fractions of the tumor. This study aims to identify high- and low-abundance mutations in pNENs using ultra-deep targeted resequencing. Formalin-fixed paraffin-embedded matched tumor-normal tissue of 38 well-differentiated pNENs was sequenced using a HaloPlex targeted resequencing panel. Novel amplicon-based algorithms were used to identify both single nucleotide variants (SNVs) and insertion-deletions (indels) present in >10% of reads (high abundance) and in <10% of reads (low abundance). Found variants were validated by Sanger sequencing. Sequencing resulted in 416,711,794 reads with an average target base coverage of 2663 ± 1476. Across all samples, 32 high-abundance somatic, 3 germline and 30 low-abundance mutations were withheld after filtering and validation. Overall, 92% of high-abundance and 84% of low-abundance mutations were predicted to be protein damaging. Frequently, mutated genes were MEN1, DAXX, ATRX, TSC2, PI3K/Akt/mTOR and MAPK-ERK pathway-related genes. Additionally, recurrent alterations on the same genomic position, so-called hotspot mutations, were found in DAXX, PTCH2 and CYFIP2. This first ultra-deep sequencing study highlighted genetic intra-tumor heterogeneity in pNEN, by the presence of low-abundance mutations. The importance of the ATRX/DAXX pathway was confirmed by the first-ever pNEN-specific protein-damaging hotspot mutation in DAXX. In this study, both novel genes, including the pro-apoptotic CYFIP2 gene and hedgehog signaling PTCH2, and novel pathways, such as the MAPK-ERK pathway, were implicated in pNEN.

18 Article Competitive Testing of the WHO 2010 versus the WHO 2017 Grading of Pancreatic Neuroendocrine Neoplasms: Data from a Large International Cohort Study. 2018

Rindi, Guido / Klersy, Catherine / Albarello, Luca / Baudin, Eric / Bianchi, Antonio / Buchler, Markus W / Caplin, Martyn / Couvelard, Anne / Cros, Jérôme / de Herder, Wouter W / Delle Fave, Gianfranco / Doglioni, Claudio / Federspiel, Birgitte / Fischer, Lars / Fusai, Giuseppe / Gavazzi, Francesca / Hansen, Carsten P / Inzani, Frediano / Jann, Henning / Komminoth, Paul / Knigge, Ulrich P / Landoni, Luca / La Rosa, Stefano / Lawlor, Rita T / Luong, Tu V / Marinoni, Ilaria / Panzuto, F / Pape, Ulrich-Frank / Partelli, Stefano / Perren, Aurel / Rinzivillo, Maria / Rubini, Corrado / Ruszniewski, Philippe / Scarpa, Aldo / Schmitt, Anja / Schinzari, Giovanni / Scoazec, Jean-Yves / Sessa, Fausto / Solcia, Enrico / Spaggiari, Paola / Toumpanakis, Christos / Vanoli, Alessandro / Wiedenmann, Bertram / Zamboni, Giuseppe / Zandee, Wouter T / Zerbi, Alessandro / Falconi, Massimo. ·Institute of Pathology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma-Università Cattolica del Sacro Cuore, Roma ENETS Center of Excellence, Rome, Italyguido.rindi@unicatt.it. · Service of Biometry and Clinical Epidemiology, Research Department, and IRCCS Fondazione Policlinico San Matteo, Pavia, Italy. · Pathology Unit, San Raffaele Scientific Institute, Milan, Italy. · Department of Oncology, Cancer Campus, Villejuif, France. · Department of Endocrinology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma-Università Cattolica del Sacro Cuore, Roma ENETS Center of Excellence, Rome, Italy. · Department of Surgery, University Hospital Heidelberg, Neu Heidelberg, Germany. · Neuroendocrine Tumour Unit, Centre for Gastroenterology, London, United Kingdom. · Department of Pathology, Hopital Beaujon, Paris ENETS Center of Excellence, Clichy, France. · Section Endocrinology, Department of Internal Medicine, Erasmus University Medical Center and and Erasmus MC Cancer Institute Rotterdam, Rotterdam ENETS Center of Excellence, Rotterdam, The Netherlands. · Digestive and Liver Disease Unit, Sant'Andrea University Hospital, Roma ENETS Center of Excellence, Rome, Italy. · Department of Pathology, Rigshospitalet, Copenhagen University Hospital, Copenhagen ENETS Center of Excellence, Copenhagen, Denmark. · Department of Surgery, University College, Royal Free Hospital, London ENETS Center of Excellence, London, United Kingdom. · Pancreatic Surgery, Humanitas Clinical and Research Center, Humanitas Milan ENETS Center of Excellence, Milan, Italy. · Department of Surgery, Rigshospitalet, Copenhagen University Hospital, Copenhagen ENETS Center of Excellence, Copenhagen, Denmark. · Institute of Pathology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma-Università Cattolica del Sacro Cuore, Roma ENETS Center of Excellence, Rome, Italy. · Department of Hepatology and Gastroenterology, Charité, Campus Virchow Klinikum and Charite Mitte, University Medicine Berlin, Berlin ENETS Center of Excellence, Berlin, Germany. · Institute of Pathology, Stadtspital Triemli, Zurich, Switzerland. · Department of Surgery and Oncology, General and Pancreatic Surgery, The Pancreas Institute, Verona ENETS Center of Excellence, Verona, Italy. · Department of Pathology, Ospedale di Circolo, Università dell'Insubria, Varese, Italy. · Section of Pathology and ARC-Net Research Centre, Department of Diagnostics and Public Health, University and Hospital Trust of Verona, Verona ENETS Center of Excellence, Verona, Italy. · Department of Pathology, University College, Royal Free Hospital, London ENETS Center of Excellence, London, United Kingdom. · Institute of Pathology, University of Bern, Bern, Switzerland. · Pancreatic Surgery Unit, San Raffaele Scientific Institute, Milan, Italy. · Department of Pathology, Marche Polytechnic University, Ancona, Italy. · Department of Gastroenterology and Pancreatology, Hopital Beaujon, Paris ENETS Center of Excellence, Clichy, France. · Department of Medical Oncology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma-Università Cattolica del Sacro Cuore, Roma ENETS Center of Excellence, Rome, Italy. · Department of Medical Biology and Pathology, Cancer Campus, Villejuif, France. · Department of Molecular Medicine, University of Pavia, Pavia, Italy. · Pathology Department, Humanitas Clinical and Research Center, Humanitas Milan ENETS Center of Excellence, Milan, Italy. · Department of Pathology, Sacro Cuore-Don Calabria Hospital, Negrar, Italy. ·Neuroendocrinology · Pubmed #30300897.

ABSTRACT: BACKGROUND: The World Health Organization (WHO) and the American Joint Cancer Committee (AJCC) modified the grading of pancreatic neuroendocrine neoplasms from a three-tier (WHO-AJCC 2010) to a four-tier system by introducing the novel category of NET G3 (WHO-AJCC 2017). OBJECTIVES: This study aims at validating the WHO-AJCC 2017 and identifying the most effective grading system. METHOD: A total of 2,102 patients were enrolled; entry criteria were: (i) patient underwent surgery; (ii) at least 2 years of follow-up; (iii) observation time up to 2015. Data from 34 variables were collected; grading was assessed and compared for efficacy by statistical means including Kaplan-Meier method, Cox regression analysis, Harrell's C statistics, and Royston's explained variation in univariable and multivariable analyses. RESULTS: In descriptive analysis, the two grading systems demonstrated statistically significant differences for the major category sex but not for age groups. In Cox regression analysis, both grading systems showed statistically significant differences between grades for OS and EFS; however, no statistically significant difference was observed between the two G3 classes of WHO-AJCC 2017. In multivariable analysis for the two models fitted to compare efficacy, the two grading systems performed equally well with substantially similar optimal discrimination and well-explained variation for both OS and EFS. The WHO-AJCC 2017 grading system retained statistically significant difference between the two G3 classes for OS but not for EFS. CONCLUSIONS: The WHO-AJCC 2017 grading system is at least equally performing as the WHO-AJCC 2010 but allows the successful identification of the most aggressive PanNET subgroup. Grading is confirmed as probably the most powerful tool for predicting patient survival.

19 Article Identifying Prognostic Factors for Well-Differentiated Metastatic Pancreatic Neuroendocrine Tumours: A Retrospective International Multicentre Cohort Study. 2018

Jiménez-Fonseca, Paula / Krug, Sebastian / Tamagno, Gianluca / Fierro Maya, Felipe / Monléon Getino, Antonio / Rodriguez Casado, Clara Isabel / Costa, Frederico / de Herder, Wouter W / Jann, Henning. ·Hospital Universitario Central de Asturias, Oviedo, Spain. · Martin Luther Universität, Halle (Saale), Germany. · Mater Misericordiae University Hospital, Dublin, Ireland. · Instituto Nacional de Cancerologia, Bogota, Colombia. · Universitat de Barcelona, Barcelona, Spain. · Hospital Sirio-Libanes, Sao Paulo, Brazil. · Erasmus Medical Center, Rotterdam, The Netherlands. · Charité, Universitätsmedizin Berlin, Berlin, Germanyhenning.jann@charite.de. ·Neuroendocrinology · Pubmed #30025389.

ABSTRACT: Pancreatic neuroendocrine tumours (pNETs) represent rare neoplasms of all NETs often presenting without functional activity. Many sporadic non-functioning pNET patients are already metastatic at the time of diagnosis, and the therapeutic approach to such patients is mostly palliative. In this international, multicentre, retrospective cohort study, we assessed the prognostic value of a set of anthropometric, clinical, biochemical, radiological and pathological parameters at baseline and the impact of the therapeutic strategies on the survival of patients with sporadic grade 1/2, stage IV, non-functioning pNETs. Three hundred and twelve consecutive patients diagnosed between 1993 and 2010 were included. The median overall survival (OS) was 6.6 years and survival at 5 and 10 years was 62 and 34% respectively. On univariate analysis, Eastern Cooperative Oncology Group (ECOG) status ≥2, grade 2, bilobar hepatic metastases, synchronous metastases, and high chromogranin A, alkaline-phosphatase and lactic-dehydrogenase were associated with a significant reduction of OS. Palliative/curative surgery and loco-regional hepatic interventions were significant factors improving OS. On multivariate analysis, ECOG status ≥2, synchronous metastases, Ki-67 ≥10%, and high alkaline-phosphatase correlated significantly with an increased risk of death. Both palliative/curative surgery and loco-regional hepatic interventions had a positive impact on OS. Although most parameters did not prove to be independent OS predictors at multivariate analysis, they showed a tendency towards that. Future prospective studies including larger patient populations may give greater clarity. We believe the integration of these parameters has the potential to provide a reliable prognostic score for the stratification of patients with sporadic well-differentiated metastatic non-functioning pNETs.

20 Article DNA methylation profiling in MEN1-related pancreatic neuroendocrine tumors reveals a potential epigenetic target for treatment. 2018

Conemans, E B / Lodewijk, L / Moelans, C B / Offerhaus, G J A / Pieterman, C R C / Morsink, F H / Dekkers, O M / de Herder, W W / Hermus, A R / van der Horst-Schrivers, A N / Drent, M L / Bisschop, P H / Havekes, B / Brosens, L A A / Dreijerink, K M A / Borel Rinkes, I H M / Timmers, H Th M / Valk, G D / Vriens, M R. ·Departments of Surgery, University Medical Center Utrecht, Utrecht, The Netherlands. · Departments of Internal Medicine, University Medical Center Utrecht, Utrecht, The Netherlands. · Departments of Section Endocrinology, Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands. · Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands. · Departments of Endocrinology and Metabolism and Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. · Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. · Department of Endocrinology, Radboud University Medical Center, Nijmegen, The Netherlands. · Department of Endocrinology, University Medical Center Groningen, Groningen, The Netherlands. · Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, The Netherlands. · Division of Endocrinology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands. · Regenerative Medicine Center and Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands. · German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center (DKFZ) and Department of Urology, Medical Center-University of Freiburg, Freiburg, Germany. ·Eur J Endocrinol · Pubmed #29903750.

ABSTRACT: OBJECTIVE: Epigenetic changes contribute to pancreatic neuroendocrine tumor (PanNET) development. Hypermethylation of promoter DNA as a cause of tumor suppressor gene silencing is a well-established oncogenic mechanism that is potentially reversible and therefore an interesting therapeutic target. Multiple endocrine neoplasia type 1 (MEN1) is the most frequent cause of inherited PanNETs. The aim of this study was to determine promoter methylation profiles in MEN1-related PanNETs. DESIGN AND METHODS: Methylation-specific multiplex ligation-dependent probe amplification was used to assess promoter methylation of 56 tumor suppressor genes in MEN1-related ( RESULTS: We found promoter methylation of a large number of potential tumor suppressor genes. CMI (median CMI: 912 vs 876, CONCLUSION: Promoter hypermethylation is a frequent event in MEN1-related and sporadic PanNETs. Targeting DNA methylation could be of therapeutic value in MEN1 patients with advanced PanNETs.

21 Article None 2018

Iacovazzo, Donato / Flanagan, Sarah E / Walker, Emily / Quezado, Rosana / de Sousa Barros, Fernando Antonio / Caswell, Richard / Johnson, Matthew B / Wakeling, Matthew / Brändle, Michael / Guo, Min / Dang, Mary N / Gabrovska, Plamena / Niederle, Bruno / Christ, Emanuel / Jenni, Stefan / Sipos, Bence / Nieser, Maike / Frilling, Andrea / Dhatariya, Ketan / Chanson, Philippe / de Herder, Wouter W / Konukiewitz, Björn / Klöppel, Günter / Stein, Roland / Korbonits, Márta / Ellard, Sian. ·Centre for Endocrinology, Barts and The London School of Medicine, Queen Mary University of London, EC1M 6BQ London, United Kingdom. · Institute of Biomedical and Clinical Science, University of Exeter Medical School, EX2 5DW Exeter, United Kingdom. · Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232. · Serviço de Endocrinologia e Diabetes, Hospital Universitário Walter Cantídio, Universidade Federal do Ceará, 60430-372 Fortaleza, Brazil. · Division of Endocrinology and Diabetes, Department of Internal Medicine, Kantonsspital St. Gallen, CH-9007 St. Gallen, Switzerland. · Section of Endocrine Surgery, Division of General Surgery, Department of Surgery, University of Vienna, A-1090 Vienna, Austria. · Division of Diabetes, Endocrinology and Metabolism, University Hospital of Basel, CH-4031 Basel, Switzerland. · Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital of Bern, Inselspital, CH-3010 Bern, Switzerland. · Department of Pathology, University of Tübingen, 72076 Tübingen, Germany. · Department of Surgery and Cancer, Imperial College London, W12 0HS London, United Kingdom. · Elsie Bertram Diabetes Centre, Norfolk and Norwich University Hospitals NHS Foundation Trust, NR4 7UY Norwich, United Kingdom. · Service d'Endocrinologie et des Maladies de la Reproduction, Assistance Publique-Hôpitaux de Paris, Hôpital de Bicêtre, F-94275 Le Kremlin-Bicêtre, France. · INSERM 1185, Faculté de Médicine Paris Sud, Université Paris-Saclay, F-94276 Le Kremlin-Bicêtre, France. · Department of Internal Medicine, Sector of Endocrinology, ENETS Centre of Excellence for Neuroendocrine Tumors, Erasmus MC, 3015 Rotterdam, The Netherlands. · Department of Pathology, Consultation Center for Pancreatic and Endocrine Tumors, Technical University of Munich, 81675 Munich, Germany. · Centre for Endocrinology, Barts and The London School of Medicine, Queen Mary University of London, EC1M 6BQ London, United Kingdom; m.korbonits@qmul.ac.uk. ·Proc Natl Acad Sci U S A · Pubmed #29339498.

ABSTRACT: The β-cell-enriched MAFA transcription factor plays a central role in regulating glucose-stimulated insulin secretion while also demonstrating oncogenic transformation potential in vitro. No disease-causing

22 Article Expression of p27 2018

Conemans, E B / Raicu-Ionita, G M / Pieterman, C R C / Dreijerink, K M A / Dekkers, O M / Hermus, A R / de Herder, W W / Drent, M L / van der Horst-Schrivers, A N A / Havekes, B / Bisschop, P H / Offerhaus, G J / Borel Rinkes, I H M / Valk, G D / Timmers, H Th M / Vriens, M R. ·Department of Surgery, University Medical Center Utrecht, PO box 85500, 3508 GA, Utrecht, The Netherlands. · Department of Internal Medicine, University Medical Center Utrecht, Utrecht, The Netherlands. · Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands. · Department of Endocrinology and Metabolism and Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. · Department of Endocrinology, Radboud University Medical Center, Nijmegen, The Netherlands. · Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. · Department of Internal Medicine, Section Endocrinology, VU University Medical Center, Amsterdam, The Netherlands. · Department of Endocrinology, University Medical Center Groningen, Groningen, The Netherlands. · Department of Internal Medicine, Division of Endocrinology, Maastricht University Medical Center, Maastricht, The Netherlands. · Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, The Netherlands. · Section Stem Cells, Regenerative Medicine Center and Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands. · Department of Surgery, University Medical Center Utrecht, PO box 85500, 3508 GA, Utrecht, The Netherlands. mvriens@umcutrecht.nl. ·J Endocrinol Invest · Pubmed #29134609.

ABSTRACT: PURPOSE: Pancreatic neuroendocrine tumors are a major manifestation of multiple endocrine neoplasia type 1 (MEN1). This tumor syndrome is caused by germline mutations in MEN1, encoding menin. Insight into pathogenesis of these tumors might lead to new biomarkers and therapeutic targets for these patients. Several lines of evidence point towards a role for p27 METHODS: In this study, we characterized protein expression of p27 RESULTS: Expression of p27 CONCLUSIONS: These findings indicate that loss of p18

23 Article Persistent Hematologic Dysfunction after Peptide Receptor Radionuclide Therapy with 2018

Bergsma, Hendrik / van Lom, Kirsten / Raaijmakers, Marc H G P / Konijnenberg, M / Kam, B L Boen L R / Teunissen, Jaap J M / de Herder, Wouter W / Krenning, Eric P / Kwekkeboom, Dik J. ·Department of Radiology and Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands bergsmahb@gmail.com. · Department of Hematology, Erasmus Medical Center, Rotterdam, The Netherlands; and. · Department of Radiology and Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. · Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. ·J Nucl Med · Pubmed #28775205.

ABSTRACT: Peptide receptor radionuclide therapy (PRRT) may induce long-term toxicity to the bone marrow (BM). The aim of this study was to analyze persistent hematologic dysfunction (PHD) after PRRT with

24 Article Management of MEN1 Related Nonfunctioning Pancreatic NETs: A Shifting Paradigm: Results From the DutchMEN1 Study Group. 2018

Nell, Sjoerd / Verkooijen, Helena M / Pieterman, Carolina R C / de Herder, Wouter W / Hermus, Ad R / Dekkers, Olaf M / van der Horst-Schrivers, Anouk N / Drent, Madeleine L / Bisschop, Peter H / Havekes, Bas / Borel Rinkes, Inne H M / Vriens, Menno R / Valk, Gerlof D. ·Department of Endocrine Surgical Oncology and Endocrine Oncology, University Medical Center Utrecht, Utrecht, The Netherlands. · Imaging Division, University Medical Center Utrecht, Utrecht, The Netherlands. · Department of Endocrine Oncology, University Medical Center Utrecht, Utrecht, The Netherlands. · Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. · Department of Endocrinology, Radboud University Medical Center, Nijmegen, The Netherlands. · Departments of Endocrinology and Metabolism and Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. · Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. · Department of Internal Medicine, Section of Endocrinology, VU University Medical Center, Amsterdam, The Netherlands. · Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, The Netherlands. · Department of Internal Medicine, Division of Endocrinology, Maastricht University Medical Center, Maastricht, The Netherlands. · Department of Endocrine Surgical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands. ·Ann Surg · Pubmed #28257328.

ABSTRACT: OBJECTIVE: To assess if surgery for Multiple Endocrine Neoplasia type 1 (MEN1) related nonfunctioning pancreatic neuroendocrine tumors (NF-pNETs) is effective for improving overall survival and preventing liver metastasis. BACKGROUND: MEN1 leads to multiple early-onset NF-pNETs. The evidence base for guiding the difficult decision who and when to operate is meager. METHODS: MEN1 patients diagnosed with NF-pNETs between 1990 and 2014 were selected from the DutchMEN1 Study Group database, including > 90% of the Dutch MEN1 population. The effect of surgery was estimated using time-dependent Cox analysis with propensity score restriction and adjustment. RESULTS: Of the 152 patients, 53 underwent surgery and 99 were managed by watchful waiting. In the surgery group, tumors were larger and faster-growing, patients were younger, more often male, and were more often treated in centers that operated more frequently. Surgery for NF-pNETs was not associated with a significantly lower risk of liver metastases or death, [adjusted hazard ratio (HR) = 0.73 (0.25-2.11)]. Adjusted HR's after stratification by tumor size were: NF-pNETs <2 cm = 2.04 (0.31-13.59) and NF-pNETs 2-3 cm = 1.38 (0.09-20.31). Five out of the 6 patients with NF-pNETs >3 cm managed by watchful waiting developed liver metastases or died compared with 6 out of the 16 patients who underwent surgery. CONCLUSIONS: MEN1 patients with NF-pNETs <2 cm can be managed by watchful waiting, hereby avoiding major surgery without loss of oncological safety. The beneficial effect of a surgery in NF-pNETs 2 to 3 cm requires further research. In patients with NF-pNETs >3 cm, watchful waiting seems not advisable.

25 Article Long-Term Natural Course of Small Nonfunctional Pancreatic Neuroendocrine Tumors in MEN1-Results From the Dutch MEN1 Study Group. 2017

Pieterman, Carolina R C / de Laat, Joanne M / Twisk, Jos W R / van Leeuwaarde, Rachel S / de Herder, Wouter W / Dreijerink, Koen M A / Hermus, Ad R M M / Dekkers, Olaf M / van der Horst-Schrivers, Anouk N A / Drent, Madeleine L / Bisschop, Peter H / Havekes, Bastiaan / Borel Rinkes, Inne H M / Vriens, Menno R / Valk, Gerlof D. ·Department of Endocrine Oncology, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands. · Department of Clinical Epidemiology and Biostatistics, VU University Medical Center, 1007 MB Amsterdam, The Netherlands. · Department of Health Sciences, VU University, 1007 MB Amsterdam, The Netherlands. · Department of Internal Medicine, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands. · Department of Endocrinology, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands. · Departments of Endocrinology and Metabolism and Clinical Epidemiology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands. · Department of Endocrinology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, The Netherlands. · Department of Internal Medicine, Section of Endocrinology, VU University Medical Center, 1007 MB Amsterdam, The Netherlands. · Department of Endocrinology and Metabolism, Academic Medical Center, 1100 DD Amsterdam, The Netherlands. · Department of Internal Medicine, Division of Endocrinology, Maastricht University Medical Center, 6202 AZ Maastricht, The Netherlands. · Department of Endocrine Surgical Oncology, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands. ·J Clin Endocrinol Metab · Pubmed #28938468.

ABSTRACT: Background: Pancreatic neuroendocrine tumors (pNETs) are highly prevalent in patients with multiple endocrine neoplasia type 1 (MEN1), and metastatic disease is an important cause of MEN1-related mortality. Especially small nonfunctional (NF) pNETs pose a challenge to the treating physician and more information is needed regarding their natural course. We assessed long-term natural history of small NF-pNETs and its modifiers in the Dutch MEN1 population. Patients and Methods: Retrospective longitudinal observational cohort study of patients with small (<2 cm) NF-pNETs from the Dutch national MEN1 database, which includes >90% of the Dutch MEN1 population. Modifiers of long-term natural course were analyzed using linear mixed-models analysis. Results: Growth rate of the 115 included small NF-pNETs from 99 patients was slow (0.4 mm/y; 95% confidence interval, 0.15 to 0.59). Seventy percent of the tumors was stable and a subgroup of 30% of the tumors was growing (1.6 mm/y; 95% confidence interval, 1.1 to 2.0). No differences in clinical characteristics were identified between growing and stable tumors. Within the subgroup of growing tumors, germline missense mutations were significantly associated with accelerated growth compared with nonsense and frameshift mutations. Conclusion: The majority of small NF-pNETs are stable at long-term follow-up, irrespective of the underlying MEN1 genotype. A subgroup of tumors is slowly growing but cannot be identified on clinical grounds. In this subgroup, tumors with missense mutations exhibited faster growth. Additional events appear necessary for pNETs to progress. Future studies should be aimed at identifying these molecular driving events, which could be used as potential biomarkers.

Next