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Pancreatic Neoplasms: HELP
Articles by Anja Rinke
Based on 16 articles published since 2010
(Why 16 articles?)
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Between 2010 and 2020, A. Rinke wrote the following 16 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review [Pancreatic neuroendocrine tumors : Current treatment concepts]. 2019

Rinke, A / Gress, T M. ·Klinik für Gastroenterologie, Endokrinologie, Stoffwechsel und klinische Infektiologie, UKGM - Universitätsklinikum Gießen und Marburg GmbH, Standort Marburg, Baldingerstraße, 35043, Marburg, Deutschland. sprenger@med.uni-marburg.de. · Klinik für Gastroenterologie, Endokrinologie, Stoffwechsel und klinische Infektiologie, UKGM - Universitätsklinikum Gießen und Marburg GmbH, Standort Marburg, Baldingerstraße, 35043, Marburg, Deutschland. gress@med.uni-marburg.de. ·Internist (Berl) · Pubmed #30623195.

ABSTRACT: The number of cases diagnosed as pancreatic neuroendocrine neoplasia (pNEN) is steadily increasing. The 2017 World Health Organization classification defines a new subgroup of morphologically well differentiated tumors with an elevated proliferation rate (Ki-67 over 20%) as neuroendocrine tumor (NET) G3. Due to the heterogeneity of pNEN regarding etiology (sporadic versus hereditary), symptoms (hormone syndrome versus non-functional tumor), and prognosis (ranging from benign behavior to highly malignant), multidisciplinary management by experienced physicians is required. This is especially true as the number of therapeutic options has increased, while we still lack comparative trials. This overview aims to summarize the multidisciplinary therapeutic options, their selection criteria and the recommendations of the new German S2k guideline.

2 Review Unmet Needs in Functional and Nonfunctional Pancreatic Neuroendocrine Neoplasms. 2019

Jensen, Robert T / Bodei, Lisa / Capdevila, Jaume / Couvelard, Anne / Falconi, Massimo / Glasberg, Simona / Kloppel, Günter / Lamberts, Steven / Peeters, Marc / Rindi, Guido / Rinke, Anja / Rothmund, Mathias / Sundin, Anders / Welin, Staffan / Fazio, Nicola / Anonymous1371017 / Anonymous1381017. ·Cell Biology Section, NIDDK, National Institutes of Health, Bethesda, Maryland, USArobertj@bdg10.niddk.nih.gov. · Memorial Sloan Kettering Cancer Center, New York, New York, USA. · Department of Medical Oncology, Vall d'Hebron University Hospital, Vall Hebron Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona, Spain. · Service de Pathologie, Hôpital Bichat, Paris, France. · Chirurgia del Pancreas, Università Vita e Salute, San Raffaele Hospital IRCCS, Milan, Italy. · Neuroendocrine Unit, Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. · Institute of Pathology, Technische Universität München, Munich, Germany. · Department of Internal Medicine, Division of Endocrinology, Erasmus Medical Center, Rotterdam, The Netherlands. · Department of Oncology, Antwerp University Hospital, Edegem, Belgium. · Institute of Anatomic Pathology, Policlinico A. Gemelli, Università Cattolica del Sacro Cuore, Rome, Italy. · Department of Gastroenterology, UKGM Marburg and Philipps University, Marburg, Germany. · Department of Surgery, Philipps University, Marburg, Germany. · Department of Radiology, Institute of Surgical Sciences, Uppsala University, Uppsala, Sweden. · Endocrine Oncology Unit, Department of Medical Sciences, University Hospital, Uppsala, Sweden. · Gastrointestinal and Neuroendocrine Oncology Unit, European Institute of Oncology (IEO), Milan, Italy. ·Neuroendocrinology · Pubmed #30282083.

ABSTRACT: Recently, the European Neuroendocrine Tumor Society (ENETS) held working sessions composed of members of the advisory board and other neuroendocrine neoplasm (NEN) experts to attempt to identify unmet needs in NENs in different locations or with advanced/poorly differentiated NENs. This report briefly summarizes the main proposed areas of unmet needs in patients with functional and nonfunctional pancreatic NENs.

3 Review The Role of Cytotoxic Chemotherapy in Advanced Pancreatic Neuroendocrine Tumors. 2017

Krug, Sebastian / Gress, Thomas M / Michl, Patrick / Rinke, Anja. ·Department of Internal Medicine I, Martin-Luther University Halle/Wittenberg, Halle, Germany. ·Digestion · Pubmed #28728148.

ABSTRACT: BACKGROUND: Pancreatic neuroendocrine tumors (PNETs) are rare neoplasms accounting for less than 5% of all pancreatic malignancies. These tumors are characterized by clinical and prognostical heterogeneity and are predominantly diagnosed in a metastatic stage. Cytotoxic chemotherapy, along with alkylating agents and antimetabolites as well as molecular targeted agents (everolimus, sunitinib), is used in the treatment of advanced PNETs. After the approval of lanreotide for unresectable PNETs, an additional therapeutic option has become available; however, the best sequence of therapies and patient stratification to different treatments remains challenging. Furthermore, no randomized phase-3 trials or head-to-head comparisons are available to support treatment decisions. SUMMARY: The publication of 3 large single-center retrospective studies on streptozocin-(STZ)-based chemotherapy in advanced PNETs in 2015 confirmed the effectiveness of this treatment as described in previously reported trials. All studies investigated markers for progression-free and overall survival and strongly supported the value of the Ki-67 index as a robust prognostic marker. Interestingly, chemotherapy consistently displayed antitumor efficacy in different therapeutic lines. Moreover, a recent study of dacarbazine (DTIC) in a cohort of patients predominantly with PNETs demonstrated that a once monthly infusional DTIC schedule was well tolerated and yielded similar response rates (RR) as STZ-based schedules. Given the overall good tolerability of a monthly infusion and RR similar to STZ schedules, DTIC thus represents a feasible alternative or additional treatment option for PNETs. In this article, we review the current standard and summarize the most recent advances in the field of cytotoxic chemotherapy for PNET patients. Key Messages: (1) Despite the lack of phase3 trials, cytotoxic chemotherapy offers efficacy for patients with advanced PNETs; (2) the best therapeutic option and sequence remain open since comparable randomized studies are lacking; (3) careful patient selection and treatment stratification may increase overall outcome; and (4) currently, no biomarkers for clinical routine exist to predict response to chemotherapy.

4 Review Combination of cross-sectional and molecular imaging studies in the localization of gastroenteropancreatic neuroendocrine tumors. 2014

Toumpanakis, Christos / Kim, Michelle K / Rinke, Anja / Bergestuen, Deidi S / Thirlwell, Christina / Khan, Mohid S / Salazar, Ramon / Oberg, Kjell. ·Neuroendocrine Tumour Unit, Royal Free Hospital, London, UK. ·Neuroendocrinology · Pubmed #24458014.

ABSTRACT: Molecular imaging modalities exploit aspects of neuroendocrine tumors (NET) pathophysiology for both diagnostic imaging and therapeutic purposes. The characteristic metabolic pathways of NET determine which tracers are useful for their visualization. In this review, we summarize the diagnostic value of all available molecular imaging studies, present data about their use in daily practice in NET centers globally, and finally make recommendations about the appropriate use of those modalities in specific clinical scenarios. Somatostatin receptor scintigraphy (SRS) continues to have a central role in the diagnostic workup of patients with NET, as it is also widely available. However, and despite the lack of prospective randomized studies, many NET experts predict that Gallium-68 ((68)Ga)-DOTA positron emission tomography (PET) techniques may replace SRS in the future, not only because of their technical advantages, but also because they are superior in patients with small-volume disease, in patients with skeletal metastases, and in those with occult primary tumors. Carbon-11 ((11)C)-5-hydroxy-L-tryptophan (5-HTP) PET and (18)F-dihydroxyphenylalanine ((18)F-DOPA) PET are new molecular imaging techniques of limited availability, and based on retrospective data, their sensitivities seem to be inferior to that of (68)Ga-DOTA PET. Glucagon-like-peptide-1 (GLP-1) receptor imaging seems promising for localization of the primary in benign insulinomas, but is currently available only in a few centers. Fluorine-18 ((18)F)-fluorodeoxyglucose ((18)F-FDG) PET was initially thought to be of limited value in NET, due to their usually slow-growing nature. However, according to subsequent data, (18)F-FDG PET is particularly helpful for visualizing the more aggressive NET, such as poorly differentiated neuroendocrine carcinomas, and well-differentiated tumors with Ki67 values >10%. According to limited data, (18)F-FDG-avid tumor lesions, even in slow-growing NET, may indicate a more aggressive disease course. When a secondary malignancy has already been established or is strongly suspected, combining molecular imaging techniques (e.g. (18)F-FDG PET and (68)Ga-DOTA PET) takes advantage of the diverse avidities of different tumor types to differentiate lesions of different origins. All the above-mentioned molecular imaging studies should always be reviewed and interpreted in a multidisciplinary (tumor board) meeting in combination with the conventional cross-sectional imaging, as the latter remains the imaging of choice for the evaluation of treatment response and disease follow-up.

5 Clinical Trial Evaluating lanreotide as maintenance therapy after first-line treatment in patients with non-resectable duodeno-pancreatic neuroendocrine tumours. 2017

Lepage, Côme / Dahan, Laetitia / Bouarioua, Nadia / Toumpanakis, Christos / Legoux, Jean-Louis / Le Malicot, Karine / Guimbaud, Rosine / Smith, Denis / Tougeron, David / Lievre, Astrid / Cadiot, Guillaume / Di Fiore, Frédéric / Bouhier-Leporrier, Karine / Hentic, Olivia / Faroux, Roger / Pavel, Marianne / Borbath, Ivan / Valle, Juan W / Rinke, Anja / Scoazec, Jean-Yves / Ducreux, Michel / Walter, Thomas. ·Department of Digestive Oncology, Burgundy Franche-Conté University, University hospital Dijon, Dijon, France; Burgundy Franche-Conté University, EPICAD, INSERM LNC UMR1231, Dijon, France; French Federation of Digestive Oncology (FFCD), INSERM LNC UMR1231 EPICAD, Dijon, France. Electronic address: come.lepage@u-bourgogne.fr. · Department of Digestive Oncology, Aix-Marseille University - Assistance Publique Hôpitaux de Marseille, Marseille, France. · Department of Gastroenterology and Digestive Oncology, Saint Etienne, France. · Royal Free Hospital, Neuroendocrine Tumour Unit, Londres, Grande-Bretagne, UK. · Regional Hospital of Orleans, Orleans, France. · French Federation of Digestive Oncology (FFCD), INSERM LNC UMR1231 EPICAD, Dijon, France. · Hôpital Rangueil, Toulouse, France. · Hôpital Haut Lévêque, Service d'hépato-gastroentérologie, Pessac, France. · Hôpital de la Milétrie, Poitiers, France. · CHU de Rennes-Hôpital Pontchaillou, Rennes, France. · Hôpital Robert Debré, Reims, France. · CHU Charles Nicolle, Rouen, France. · CHU Côte de Nacre, Caen, France. · Hôpital Beaujon, Clichy, France. · CH Les Oudairies, La Roche sur Yon, France. · Charite Campus Virchow Kinikum, Berlin, Germany. · Cliniques universitaires Saint-Luc, Bruxelles, Belgium. · University of Manchester, Division of Cancer Sciences/The Christie NHS Foundation Trust, Manchester, UK. · University Hospital Marburg, Marburg, Germany. · Pathology Department, Gustave Roussy, Villejuif, France. · Gastrointestinal Oncology Department, Gustave Roussy Institute, Villejuif, France; Faculté de Médecine, Paris Sud University Le Kremlin Bicêtre, France. · Edouard Herriot Hospital, Department of Gastroenterology, Hospices Civils de Lyon, Lyon, France. ·Dig Liver Dis · Pubmed #28292641.

ABSTRACT: INTRODUCTION: Patients with metastatic or locally advanced, non-resectable, grade 1 or 2 well-differentiated duodeno-pancreatic (WDDP) NETs are treated following European guidelines. Patients (Pts) with aggressive disease, i.e. progressive and/or symptomatic metastases and/or with significant hepatic invasion (>30-50%), and/or bone metastases, anti-tumour therapy should receive systemic combination of chemotherapy once disease control is obtained. AIM(S): The aim is to stop chemotherapy until progression. REMINET is an academic randomized, double-blind, placebo-controlled, phase II/III study designed to evaluate lanreotide (LAN) as maintenance treatment after L1 chemotherapy in G1-G2 WDDP NET. MATERIALS AND METHODS: Main eligibility criteria: adults pts with a metastatic (synchronous or metachronous) or locally advanced, non-resectable, grade 1 or 2 WDDP NETs and documented control disease after L1 therapy at least 4 weeks prior to randomization. RESULTS: 222 patients will be randomly assigned in a 1:1 ratio to receive 120mg LAN or placebo, every 28 days, until disease progression or unacceptable toxicity. The aim of the phase II part is to demonstrate a 6-months PFS >45% in LAN arm. Secondary endpoints are PFS according to central review, overall survival, safety and quality of life. A bio-bank of frozen blood will be constituted. CONCLUSION: The study is currently open in France, Germany, Belgium, United Kingdom and Ireland. A total of 25 patients are randomized (NCT02288377).

6 Article [Gastroenteropancreatic neuroendocrine tumors]. 2019

Breitling, Lutz Philipp / Rinke, Anja / Gress, Thomas Mathias. · ·Dtsch Med Wochenschr · Pubmed #31634929.

ABSTRACT: Neuroendocrine neoplasms (NEN) are increasingly diagnosed tumors with great clinical and prognostic heterogeneity. One of the peculiarities of NEN is the presence of a clinical hormone syndrome in about 30 % of cases. Somatostatin receptor imaging plays an important role in the diagnosis of spreading and in the planning of therapy. NEN patients should be co-supervised by specialized centers and if possible treated as part of studies. In the case of NEN with no or only circumscribed metastases, complete resection in curative intention is generally the highest therapeutic goal. Small neuroendocrine tumors (NET) G1 of the stomach, duodenum and rectum can be curatively endoscopically resected. In the case of a metastatic, non-curative disease, an antiproliferative therapy with the aim of growth control takes place. In patients with functionally active tumors, an antisecretory or symptomatic therapy is used to control the hormone syndrome. The treatment of metastatic NET is often multimodal and must be established by an experienced interdisciplinary team. The prognosis of NEN is mainly determined by the stage at the time of diagnosis, tumor differentiation, grading and localization of the primary tumor.

7 Article Peptide receptor radionuclide therapy in gastroenteropancreatic NEN G3: a multicenter cohort study. 2019

Carlsen, Esben Andreas / Fazio, Nicola / Granberg, Dan / Grozinsky-Glasberg, Simona / Ahmadzadehfar, Hojjat / Grana, Chiara Maria / Zandee, Wouter T / Cwikla, Jaroslaw / Walter, Martin A / Oturai, Peter Sandor / Rinke, Anja / Weaver, Andrew / Frilling, Andrea / Gritti, Sara / Arveschoug, Anne Kirstine / Meirovitz, Amichay / Knigge, Ulrich / Sorbye, Halfdan. ·Department of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet, Copenhagen, Denmark. · Department of Biomedical Sciences, Cluster for Molecular Imaging, University of Copenhagen, Copenhagen, Denmark. · Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, IEO, European Institute of Oncology IRCCS, Milan, Italy. · Department of Medical Sciences, Uppsala University, Uppsala, Sweden. · Neuroendocrine Tumor Unit, Department of Endocrinology & Metabolism, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. · Department of Nuclear Medicine, University Hospital Bonn, Bonn, Germany. · Division of Nuclear Medicine, IEO, European Institute of Oncology IRCCS, Milan, Italy. · Erasmus Medical Center, Rotterdam, The Netherlands. · Medical School, University of Warmia and Mazury, Olsztyn, Poland. · Department of Nuclear Medicine, University Hospital of Geneva, Geneva, Switzerland. · Department of Gastroenterology, University Hospital Gießen and Marburg, Marburg, Germany. · Department of Oncology, Churchill Hospital, Oxford, UK. · Department of Surgery and Cancer, Imperial College London, London, UK. · Department of Nuclear Medicine and PET, Aarhus University Hospital, Aarhus, Denmark. · Department of Oncology and Radiation Therapy Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. · Departments of Surgical Gastroenterology and Clinical Endocrinology, Rigshospitalet, Copenhagen, Denmark. · Department of Oncology, Haukeland University Hospital, Bergen, Norway. · Department of Clinical Science, University of Bergen, Bergen, Norway. ·Endocr Relat Cancer · Pubmed #30540557.

ABSTRACT: Peptide receptor radionuclide therapy (PRRT) is an established treatment of metastatic neuroendocrine tumors grade 1-2 (G1-G2). However, its possible benefit in high-grade gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN G3) is largely unknown. We therefore aimed to assess the benefits and side effects of PRRT in patients with GEP NEN G3. We performed a retrospective cohort study at 12 centers to assess the efficacy and toxicity of PRRT in patients with GEP NEN G3. Outcomes were response rate, disease control rate, progression-free survival (PFS), overall survival (OS) and toxicity. We included 149 patients (primary tumor: pancreatic n = 89, gastrointestinal n = 34, unknown n = 26). PRRT was first-line (n = 30), second-line (n = 62) or later-line treatment (n = 57). Of 114 patients evaluated, 1% had complete response, 41% partial response, 38% stable disease and 20% progressive disease. Of 104 patients with documented progressive disease before PRRT, disease control rate was 69%. The total cohort had median PFS of 14 months and OS of 29 months. Ki-67 21-54% (n = 125) vs Ki-67 ≥55% (n = 23): PFS 16 vs 6 months (P < 0.001) and OS 31 vs 9 months (P < 0.001). Well (n = 60) vs poorly differentiated NEN (n = 62): PFS 19 vs 8 months (P < 0.001) and OS 44 vs 19 months (P < 0.001). Grade 3-4 hematological or renal toxicity occurred in 17% of patients. This large multicenter cohort of patients with GEP NEN G3 treated with PRRT demonstrates promising response rates, disease control rates, PFS and OS as well as toxicity in patients with mainly progressive disease. Based on these results, PRRT may be considered for patients with GEP NEN G3.

8 Article Therapeutic targeting of tumor-associated macrophages in pancreatic neuroendocrine tumors. 2018

Krug, Sebastian / Abbassi, Rami / Griesmann, Heidi / Sipos, Bence / Wiese, Dominik / Rexin, Peter / Blank, Annika / Perren, Aurel / Haybaeck, Johannes / Hüttelmaier, Stefan / Rinke, Anja / Gress, Thomas M / Michl, Patrick. ·Department of Internal Medicine I, Martin Luther University Halle-Wittenberg, Halle, Saale, Germany. · Department of Gastroenterology and Endocrinology, Philipps-University, Marburg, Germany. · Institute of Pathology and Neuropathology, University Hospital of Tübingen, Tübingen, Germany. · Department of Visceral, Thoracic and Vascular Surgery, Philipps-University, Marburg, Germany. · Institute of Pathology, Philipps-University, Marburg, Germany. · Institute of Pathology, University of Bern, Bern, Switzerland. · Department of Pathology, Otto-von-Guericke-University, Magdeburg, Germany. · Institute of Molecular Medicine, Martin Luther University Halle-Wittenberg, Halle, Saale, Germany. ·Int J Cancer · Pubmed #29696624.

ABSTRACT: Pancreatic neuroendocrine tumors (PNETs) represent a heterogeneous group of neuroendocrine neoplasms with varying biological behavior and response to treatment. Although targeted therapies have been shown to improve the survival for patients at advanced stage, resistance to current therapies frequently occurs during the course of therapy. Previous reports indicate that the infiltration of tumor-associated macrophages (TAMs) in PNETs might correlate with tumor progression and metastasis formation. We aimed to evaluate the prognostic and functional impact of TAMs in human PNETs in vitro and in vivo and to investigate the effect of therapeutic targeting TAMs in a genetic PNET mouse model. TAM expression pattern was assessed immunohistochemically in human PNET tissue sections and a tissue-micro-array of PNET tumors with different functionality, stage, and grading. The effect of liposomal clodronate on TAM cell viability was analyzed in myeloid cell lines and isolated murine bone macrophages (mBMM). In vivo, RIP1Tag2 mice developing insulinomas were treated with liposomal clodronate or PBS-Liposomes. Tumor progression, angiogenesis and immune cell infiltration were assessed by immunohistochemistry. In human, insulinomas TAM density was correlated with invasiveness and malignant behavior. Moreover, TAM infiltration in liver metastases was significantly increased compared to primary tumors. In vitro, Liposomal clodronate selectively inhibited the viability of myeloid cells and murine bone macrophages, leaving PNET tumor cell lines largely unaffected. In vivo, repeated application of liposomal clodronate to RIP1Tag2 mice significantly diminished the malignant transformation of insulinomas, which was accompanied by a reduced infiltration of F4/80-positive TAM cells and simultaneously by a decreased microvessel density, suggesting a pronounced effect of clodronate-induced myeloid depletion on tumor angiogenesis. Concomitant treatment with the antiangiogenic TKI sunitinib, however, did not show any synergistic effects with liposomal clodronate. TAMs are crucial for malignant transformation in human PNET and correlate with metastatic behavior. Pharmacological targeting of TAMs via liposomal clodronate disrupts tumor progression in the RIP1Tag2 neuroendocrine tumor model and was associated with reduced tumor angiogenesis. Based on these results, using liposomal clodronate to target proangiogenic myeloid cells could be employed as novel therapeutic avenue in highly angiogenic tumors such as PNET.

9 Article Functional Imaging in the Follow-Up of Enteropancreatic Neuroendocrine Tumors: Clinical Usefulness and Indications. 2017

Merola, Elettra / Pavel, Marianne E / Panzuto, Francesco / Capurso, Gabriele / Cicchese, Noemi / Rinke, Anja / Gress, Thomas M / Iannicelli, Elsa / Prosperi, Daniela / Pizzichini, Patrizia / Prasad, Vikas / Kump, Patrizia / Lipp, Rainer / Partelli, Stefano / Falconi, Massimo / Wiedenmann, Bertram / Delle Fave, Gianfranco. ·Digestive and Liver Diseases Unit, Sant'Andrea Hospital, 00189 Rome, Italy. · Department of Hepatology and Gastroenterology, Charité Universitätsmedizin, 13353 Berlin, Germany. · Department of Gastroenterology, University Hospital, 35043 Marburg, Germany. · Department of Radiology, Sant'Andrea Hospital, 00189 Rome, Italy. · Division of Nuclear Medicine, Sant'Andrea Hospital, 00189 Rome, Italy. · Department of Nuclear Medicine, Campus Virchow-Klinikum, Charité Universitätsmedizin, 13353 Berlin, Germany. · Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University, 8036 Graz Austria. · Division of Nuclear Medicine, Department of Radiology, Medical University, 8036 Graz Austria. · Pancreatic Surgery Unit, Vita-Salute University, San Raffaele Hospital Istituto di Ricovero e Cura a Carattere Scientifico, 20132 Milan, Italy. ·J Clin Endocrinol Metab · Pubmed #28324047.

ABSTRACT: Context: Functional imaging tests (FITs) detecting somatostatin receptor expression [i.e., somatostatin receptor scintigraphy, 68Ga-DOTA positron emission tomography/computed tomography (CT)] have a pivotal role in the diagnosis of neuroendocrine tumors (NETs), although their indication during follow-up still needs to be clarified. Objective: Investigate the role of FITs after diagnosis of metastatic enteropancreatic NETs, identifying patients who might benefit from these exams. Design: Multicenter retrospective analysis of metastatic enteropancreatic NETs. Setting: Analysis of imaging tests performed between January 1995 and December 2015 in Rome, Berlin, Milan, Marburg, or Graz. Subjects: One hundred forty-three patients with metastatic pancreatic NETs and small intestine NETs, at least 2-year follow-up, and positive FITs. Interventions: Patients had received CT every 6 months (unless clinical conditions and tumor behavior required shorter intervals) and FIT every 12 months. Main Outcome Measures: Clinical usefulness of FITs, defined as changes in patient management (indication to biopsy, medical therapy, surgery, or further imaging tests) due only to FITs. Results: FITs affected management in 73.4% of patients, mostly when G2 vs G1 [odds ratio (OR), 2.40; 95% confidence interval (CI), 1.09 to 5.27; P = 0.03]. Changes were observed in a 12-month time frame especially with pancreatic NETs vs small intestine NETs (OR, 2.89; 95% CI, 1.09 - 7.67; P = 0.03) or metastases since diagnosis vs developed during follow-up (OR, 4.00; 95% CI, 1.43 to 11.17; P < 0.01). Conclusions: FITs used in addition to CT in the follow-up of stage IV enteropancreatic NETs improve patient management (especially for G2 tumors). Follow-up program should be tailored according to tumor features.

10 Article Stage IV Gastro-Entero-Pancreatic Neuroendocrine Neoplasms: A Risk Score to Predict Clinical Outcome. 2017

Panzuto, Francesco / Merola, Elettra / Pavel, Marianne Ellen / Rinke, Anja / Kump, Patrizia / Partelli, Stefano / Rinzivillo, Maria / Rodriguez-Laval, Victor / Pape, Ulrich Frank / Lipp, Rainer / Gress, Thomas / Wiedenmann, Bertram / Falconi, Massimo / Delle Fave, Gianfranco. ·Department of Digestive and Liver Disease, Sapienza University of Rome - Sant'Andrea Hospital, Rome, Italy. · Department of Hepatology and Gastroenterology, Charité Campus Mitte and Virchow Clinic, Charité University Medicine, Berlin, Germany. · Department of Gastroenterology, Philipps-University of Marburg, Germany. · Clinical Division of Gastroenterology, Medical University Graz, Austria. · Division of Pancreatic Surgery, Vita-Salute University, San Raffaele Scientific Institute, Milan, Italy. · Department of Radiology Charité University, Campus Virchow Klinikum, Berlin, Germany. · Clinical Division of Oncology, Medical University Graz, Austria. · Department of Digestive and Liver Disease, Sapienza University of Rome - Sant'Andrea Hospital, Rome, Italy gianfranco.dellefave@uniroma1.it. ·Oncologist · Pubmed #28232598.

ABSTRACT: BACKGROUND: Several risk factors predict clinical outcome in gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs); however, the impact of their combination has not been investigated so far. PATIENTS AND METHODS: A retrospective analysis of stage IV GEP-NENs was performed. Multivariate analysis for progression of disease (PD) was performed by Cox proportional hazards method to obtain a risk score. Area under the curve obtained by receiver operating characteristic analysis was used to assess the score performance. Progression-free survival analysis was performed by Kaplan-Meier method. RESULTS: Two hundred eighty-three stage IV GEP-NENs were evaluated, including 93 grade 1 neuroendocrine tumors (32.9%), 153 grade 2 neuroendocrine tumors (54%), and 37 grade 3 neuroendocrine carcinomas (13.1%). Independent risk factors for PD were Ki67, proportion of metastatic liver involvement, and presence of extra-abdominal metastases. The risk score was calculated as follows: (0.025 × Ki67) + [(0 if no liver metastases or liver involvement <25%) OR (0.405 if liver involvement 25%-50%) OR (0.462 if liver involvement >50%)] + [(0 if no extra-abdominal metastases) OR (0.528 if extra-abdominal metastases present)]. The risk score accuracy to predict PD was superior compared with the G grading system (area under the curve: 0.705 and 0.622, respectively). Three subgroups of patients with low, intermediate, and high risk of PD according to risk score were identified, median progression-free survival being 26 months, 19 months, and 12 months, respectively. CONCLUSION: In stage IV GEP-NENs, a risk score able to predict PD was obtained by combining Ki67, proportion of metastatic liver involvement, and presence of extra-abdominal metastases. The score may help to discriminate patients with different progression risk level to plan tailored therapeutic approaches and follow-up programs.

11 Article Relevance of dihydropyrimidine-dehydrogenase and thymidylate-synthase in patients with pancreatic neuroendocrine neoplasms treated with 5-FU-based chemotherapy. 2017

Krug, S / Boch, M / Nimphius, W / Gress, T M / Michl, P / Rinke, A. ·Department of Internal Medicine I, Martin Luther University, Halle (Saale), Germany; Department of Gastroenterology and Endocrinology, Philipps-University, Marburg, Germany. · Institute of Pathology, Philipps-University, Marburg, Germany. · Department of Gastroenterology and Endocrinology, Philipps-University, Marburg, Germany. · Department of Internal Medicine I, Martin Luther University, Halle (Saale), Germany. Electronic address: patrick.michl@uk-halle.de. ·Pancreatology · Pubmed #28027897.

ABSTRACT: BACKGROUND: Chemotherapy with 5-FU and Streptozotocin (STZ) is recommended as first-line treatment in patients with metastatic pancreatic neuroendocrine neoplasms (PNEN). However, data about biomarkers involved in the 5-FU metabolism to predict response are still limited. OBJECTIVES: Evaluation of clinicopathological features and potential predictive and prognostic markers of patients with PNEN treated with 5-FU based regimens. PATIENTS AND METHODS: We retrospectively analyzed 41 patients with PNEN who were treated at the University Hospital Marburg between 2000 and 2013. Dihydropyrimidine-Dehydrogenase (DPD) and Thymidylate-Synthase (TS) expression was correlated with treatment response in 19 patients who had available tumour tissue and response data. The median overall survival (OS) and progression free survival (PFS) were calculated using Kaplan-Meier and Cox regression methods, respectively. RESULTS: The median PFS in patients receiving 5-FU/STZ was 17 months with a median OS of 50 months. Objective response rate (ORR) and disease control rate (DCR) were 32% and 73%, respectively. Biochemical response (p = 0.005) and high DPD expression (p = 0.018) were predictive markers of response to 5-FU-based chemotherapy. Univariate analysis identified Ki-67 > 10%, no biochemical response, positive 5-HIAA levels and TS deficiency as independent risk factors for shorter PFS. Moreover, performance status (PS) ≥1 was an independent risk factors for impaired OS. CONCLUSIONS: DPD expression and biochemical response represent promising predictive biomarkers for response to 5-FU based chemotherapy. Moreover, Ki-67, PS and TS are independent prognostic markers of OS and PFS in patients with PNEN.

12 Article Low dose DTIC is effective and safe in pretreated patients with well differentiated neuroendocrine tumors. 2016

Mueller, Daniela / Krug, Sebastian / Majumder, Moushumee / Rinke, Anja / Gress, Thomas Matthias. ·Department of Gastroenterology, University Hospital Marburg, Baldinger Strasse, D35043, Marburg, Germany. · Department of Gastroenterology, University of Halle, Ernst-Grube-Straße 40, D 06120, Halle, Germany. · Department of Gastroenterology, University Hospital Marburg, Baldinger Strasse, D35043, Marburg, Germany. sprengea@uni-marburg.de. ·BMC Cancer · Pubmed #27538897.

ABSTRACT: BACKGROUND: Streptozocin (STZ) based chemotherapy is recommended for patients with metastatic pancreatic neuroendocrine tumors (pNET). Temozolomide as mono- or combination therapy has been suggested to be a promising alternative. However, the treatment is costly and not approved for the treatment of pNETs. Dacarbazine (DTIC) shares the active metabolite with temozolomide and is broadly available at a low cost. The aim of this study was a retrospective evaluation of the efficacy and tolerability of a lower dose DTIC-regimen in patients with progressive advanced NETs. METHODS: We retrospectively analyzed 75 patients with NETs predominantly of pancreatic origin treated at our center between 1998 and 2013. 650 mg/m(2) of DTIC were administered intravenously over 60 min every 4 weeks. Morphological response was assessed according to RECIST1.1 criteria. The median progression free survival (PFS) was calculated using Kaplan-Meier and Cox regression methods, respectively. Univariate analyses of possible prognostic markers were performed. RESULTS: The objective response rate (ORR) was 27 % for the entire cohort and 32 % in 50 pNET patients, respectively. Stable disease (SD) was documented in 29 patients (39 %). Median PFS (mPFS) in patients receiving DTIC was 7 months (3.9-10; 95 % confidence interval). Radiological and biochemical response were the only significant prognostic markers for longer PFS in univariate analysis. Treatment was well tolerated. Nausea was the most common side effect (31 %), only one case (1.3 %) of grade 3 toxicity (vomiting) occurred. CONCLUSION: Low dose DTIC chemotherapy is an effective and well-tolerated treatment option in patients with progressive well differentiated neuroendocrine neoplasms, especially of pancreatic origin.

13 Article Sunitinib Efficacy in Patients with Advanced pNET in Clinical Practice. 2016

Lahner, H / Rinke, A / Unger, N / Poeppel, T D / Kühl, H / Lehmann, N / Führer, D. ·Department of Endocrinology and Metabolism, Division of Laboratory Research, University of Duisburg-Essen, Essen, Germany. · Department of Gastroenterology and Endocrinology, Philipps University Marburg, Marburg Germany. · Department of Nuclear Medicine, University of Duisburg-Essen, Essen, Germany. · Institute of Diagnostic and Interventional Radiology and Neuroradiology, University of Duisburg-Essen, Essen, Germany. · Institute of Medical Informatics, Biometry, and Epidemiology, University of Duisburg-Essen, Essen, Germany. ·Horm Metab Res · Pubmed #27101094.

ABSTRACT: Sunitinib treatment leads to improvement in progression-free survival in patients with advanced pancreatic neuroendocrine tumours (pNETs). However, limited data exist regarding the effectiveness, safety and tolerability in clinical practice. We present the results of the first detailed pNET cohort analysis since sunitinib was approved. Patients with advanced, differentiated pNET treated with sunitinib were retrospectively analysed. All patients had progressive disease before start of sunitinib treatment. Twenty-one patients, with a median age of 64 years (range 28-78), were included in this study. Nineteen patients could be analysed for treatment effectiveness. Twelve (57%) patients exhibited either a partial response (1 patient) or stable disease (11 patients) according to the RECIST criteria. The median progression-free survival was 7.0 months (95% CI 3.0-12.0); the probability of being event-free at 6 months was 52.6% (95% CI 28.4-72.1). Potential influencing factors as Ki-67 index, age or duration of disease did not show significant correlations with the response to sunitinib therapy. Considering the differences in patients' characteristics, sunitinib in daily practice showed effectiveness parameters similar to the phase III trial.

14 Article Characteristics and treatment of patients with G3 gastroenteropancreatic neuroendocrine neoplasms. 2015

Heetfeld, M / Chougnet, C N / Olsen, I H / Rinke, A / Borbath, I / Crespo, G / Barriuso, J / Pavel, M / O'Toole, D / Walter, T / Anonymous4100834. ·Department of Hepatology and GastroenterologyCharité University Hospital Berlin, Berlin, GermanyDepartment of Nuclear MedicineHopital Saint Louis, Paris, FranceDepartment of Surgical GastroenterologyEuropean NET Center of Excellence, Rigshospitalet, DenmarkDepartment of Internal MedicineDivision of Gastroenterology and Endocrinology, Philipps University, Marburg, GermanyDepartment of GastroenterologyCliniques Universitaires Saint-Luc, Bruxelles, BelgiumDepartment of Medical OncologyHospital Universitario de Burgos, Burgos, SpainDepartment of Medical OncologyHospital Univeristario La Paz, Madrid, SpainDepartment of Clinical Medicine and GastroenterologySt James's and St Vincent's Hospitals and TCD, Dublin, IrelandDepartment of Hepatology and GastroenterologyEdouard Herriot Hospital, University of Lyon, 69437 Lyon Cedex 03, France. · Department of Hepatology and GastroenterologyCharité University Hospital Berlin, Berlin, GermanyDepartment of Nuclear MedicineHopital Saint Louis, Paris, FranceDepartment of Surgical GastroenterologyEuropean NET Center of Excellence, Rigshospitalet, DenmarkDepartment of Internal MedicineDivision of Gastroenterology and Endocrinology, Philipps University, Marburg, GermanyDepartment of GastroenterologyCliniques Universitaires Saint-Luc, Bruxelles, BelgiumDepartment of Medical OncologyHospital Universitario de Burgos, Burgos, SpainDepartment of Medical OncologyHospital Univeristario La Paz, Madrid, SpainDepartment of Clinical Medicine and GastroenterologySt James's and St Vincent's Hospitals and TCD, Dublin, IrelandDepartment of Hepatology and GastroenterologyEdouard Herriot Hospital, University of Lyon, 69437 Lyon Cedex 03, France thomas.walter@chu-lyon.fr. ·Endocr Relat Cancer · Pubmed #26113608.

ABSTRACT: Data on gastroenteropancreatic neuroendocrine neoplasms (NEN) G3 (well-differentiated neuroendocrine tumors (NET G3) and neuroendocrine carcinoma (NEC)) are limited. We retrospectively study patients with NET G3 and NEC from eight European centers. Data examined included clinical and pathological characteristics at diagnosis, therapies and outcomes. Two hundred and four patients were analyzed (37 NET G3 and 167 NEC). Median age was 64 (21-89) years. Tumor origin included pancreas (32%) and colon-rectum (27%). The primary tumor was resected in 82 (40%) patients. Metastatic disease was evident at diagnosis in 88% (liver metastases: 67%). Median Ki-67 index was 70% (30% in NET G3 and 80% in NEC; P<0.001). Median overall survival (OS) for all patients was 23 (95% CI: 18-28) months and significantly higher in NET G3 (99 vs 17 months in NEC; HR=8.3; P<0.001). Platinum-etoposide first line chemotherapy was administered in 113 (68%) NEC and 12 (32%) NET G3 patients. Disease control rate and progression free survival (PFS) were significantly higher in NEC compared to NET G3 (P<0.05), whereas OS was significantly longer in NET G3 (P=0.003). Second- and third-line therapies (mainly FOLFIRI and FOLFOX) were given in 79 and 39 of NEC patients; median PFS and OS were 3.0 and 7.6 months respectively after second-line and 2.5 and 6.2 months after third-line chemotherapy. In conclusion, NET G3 and NEC are characterized by significant differences in Ki-67 index and outcomes. While platinum-based chemotherapy is effective in NEC, it seems to have limited value in NET G3.

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

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

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

16 Article Management of a metastasized high grade insulinoma (G3) with refractory hypoglycemia: case report and review of the literature. 2014

Scharf, Michael / Mueller, Daniela / Koenig, Ute / Pfestroff, Andreas / Nimphius, Wilhelm / Figiel, Jens / Rinke, Anja / Koenig, Alexander / Gress, Thomas. ·Department of Gastroenterology and Endocrinology, Philipps-University, Marburg, Germany. · Department of Nuclear Medicine, Philipps-University, Marburg, Germany. · Department of Pathology, Philipps-University, Marburg, Germany. · Department of Radiology, Philipps-University, Marburg, Germany. · Department of Gastroenterology and Endocrinology, Philipps-University, Marburg, Germany. Electronic address: gress@med.uni-marburg.de. ·Pancreatology · Pubmed #25459566.

ABSTRACT: Insulinomas represent the most common functional neuroendocrine tumor of the pancreas. They are usually solitary, benign, well differentiated (G1/G2) and curable by surgery. We describe the case of a 45 year old male Caucasian with a unique malignant, metastasized pancreatic insulinoma (Ki 67 of 70%, G3). To control excessive insulin production emanating in refractory hypoglycemia and growth of the highly proliferating tumor a multimodal therapeutic approach including the consecutive use of tumor debulking surgery, chemotherapy, TACE, SIRT, PRRT as well as a drug therapy with diazoxide, somatostatin analogs and everolimus was employed. Chemotherapy with carboplatin/etoposide plus everolimus provided the longest normoglycemic period. After progress chemotherapy with dacarbazine had the most positive effect, while debulking approaches such as surgery and liver directed therapies, as well as PRRT were less efficient with only transient success.