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  • Author: Simona Grozinsky-Glasberg x
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Simona Grozinsky-Glasberg, Ilan Shimon, Márta Korbonits and Ashley B Grossman

Neuroendocrine tumours (NETs) represent a heterogeneous family of neoplasms, which may develop from different endocrine glands (such as the pituitary, the parathyroid or the neuroendocrine adrenal glands), endocrine islets (within the thyroid or pancreas) as well as from endocrine cells dispersed between exocrine cells throughout the digestive and respiratory tracts. The development of somatostatin analogues (SSA) as important diagnostic and treatment tools has revolutionised the clinical management of patients with NETs. However, although symptomatic relief and stabilisation of tumour growth for various periods of time are observed in many patients treated with SSA, tumour regression is rare. Possible mechanisms when this does occur include antagonism of local growth factor release and effects, probably including activation of tyrosine and serine–threonine phosphatases, and indirect effects via anti-angiogenesis. The development of new SSA, new drug combination therapies and chimaeric molecules should further improve the clinical management of these patients, as should a more complete understanding of their mode of action.

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Krystallenia I Alexandraki, Gregory A Kaltsas, Simona Grozinsky-Glasberg, Eleftherios Chatzellis and Ashley B Grossman

Gastrointestinal neuroendocrine neoplasms (GI-NENs) are increasingly being recognised, while appendiceal NENs (aNENs) currently constitute the third most common GI-NEN. Appendiceal NENs are generally considered to follow an indolent course with the majority being localised at diagnosis. Thus, the initial surgical approach is not that of a planned oncological resection. Due to the localised nature of the disease in the majority of cases, subsequent biochemical and radiological assessment are not routinely recommended. Histopathological criteria (size, mesoappendiceal invasion, Ki-67 proliferation index, neuro- and angio-invasion) are mainly used to identify those patients who are also candidates for a right hemicolectomy. Goblet cell carcinoids are a distinct entity and should be treated as adenocarcinomas. Despite the absence of any substantial prospective data regarding optimal management and follow-up, recent consensus statements and guidelines have been published. The purpose of this review is to overview the published studies on the diagnosis and management of appendiceal NENs and to suggest a possible management protocol.

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Shani Avniel-Polak, Gil Leibowitz, Victoria Doviner, David J Gross and Simona Grozinsky-Glasberg

Patients with neuroendocrine neoplasms (NENs) often require systemic treatment, which is frequently limited by the emergence of drug resistance. mTOR inhibitors (mTORi), such as RAD001 (everolimus), have been shown to inhibit neoplasm progression. mTORi stimulates autophagy, a degradation pathway that might promote the survival of neoplasm cells that are exposed to anti-cancer therapy. Chloroquine (CQ), a well-known anti-malarial and anti-rheumatic drug, suppresses autophagy. Based on our previous results, we hypothesized that CQ may enhance the anti-tumorigenic effects of mTORi by inhibiting autophagy and we aimed to examine the anti-tumorigenic effect of CQ, alone or in combination with RAD001. We established a NEN subcutaneous xenograft mouse model and evaluated the effect of the drugs on tumor growth, mTOR pathway, autophagy and apoptosis. CQ alone and in combination with RAD001 significantly decreased neoplasm volume. Histopathological analysis revealed that the combination of CQ and RAD001 markedly inhibited mTOR activity and neoplasm cell growth, along with accumulation of autophagosomes and increased apoptosis. In conclusion, CQ enhances the anti-tumorigenic effect of RAD001 in vivo by inhibiting autophagy. Clinical trials addressing the effects of CQ therapy on neoplasm progression in patients with NENs, mainly in those treated with mTORi, are warranted.

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Esben Andreas Carlsen, Nicola Fazio, Dan Granberg, Simona Grozinsky-Glasberg, Hojjat Ahmadzadehfar, Chiara Maria Grana, Wouter T Zandee, Jaroslaw Cwikla, Martin A Walter, Peter Sandor Oturai, Anja Rinke, Andrew Weaver, Andrea Frilling, Sara Gritti, Anne Kirstine Arveschoug, Amichay Meirovitz, Ulrich Knigge and Halfdan Sorbye

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.

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Tobias Krauss, Alfonso Massimiliano Ferrara, Thera P Links, Ulrich Wellner, Irina Bancos, Andrey Kvachenyuk, Karina Villar Gómez de las Heras, Marina Y Yukina, Roman Petrov, Garrett Bullivant, Laura von Duecker, Swati Jadhav, Ursula Ploeckinger, Staffan Welin, Camilla Schalin-Jäntti, Oliver Gimm, Marija Pfeifer, Joanne Ngeow, Kornelia Hasse-Lazar, Gabriela Sansó, Xiaoping Qi, M Umit Ugurlu, Rene E Diaz, Nelson Wohllk, Mariola Peczkowska, Jens Aberle, Delmar M Lourenço Jr, Maria A A Pereira, Maria C B V Fragoso, Ana O Hoff, Madson Q Almeida, Alice H D Violante, Ana R P Quidute, Zhewei Zhang, Mònica Recasens, Luis Robles Díaz, Tada Kunavisarut, Taweesak Wannachalee, Sirinart Sirinvaravong, Eric Jonasch, Simona Grozinsky-Glasberg, Merav Fraenkel, Dmitry Beltsevich, Viacheslav I Egorov, Dirk Bausch, Matthias Schott, Nikolaus Tiling, Gianmaria Pennelli, Stefan Zschiedrich, Roland Därr, Juri Ruf, Timm Denecke, Karl-Heinrich Link, Stefania Zovato, Ernst von Dobschuetz, Svetlana Yaremchuk, Holger Amthauer, Özer Makay, Attila Patocs, Martin K Walz, Tobias B Huber, Jochen Seufert, Per Hellman, Raymond H Kim, Ekaterina Kuchinskaya, Francesca Schiavi, Angelica Malinoc, Nicole Reisch, Barbara Jarzab, Marta Barontini, Andrzej Januszewicz, Nalini Shah, William F Young Jr, Giuseppe Opocher, Charis Eng, Hartmut P H Neumann and Birke Bausch

Pancreatic neuroendocrine tumors (PanNETs) are rare in von Hippel–Lindau disease (VHL) but cause serious morbidity and mortality. Management guidelines for VHL-PanNETs continue to be based on limited evidence, and survival data to guide surgical management are lacking. We established the European-American-Asian-VHL-PanNET-Registry to assess data for risks for metastases, survival and long-term outcomes to provide best management recommendations. Of 2330 VHL patients, 273 had a total of 484 PanNETs. Median age at diagnosis of PanNET was 35 years (range 10–75). Fifty-five (20%) patients had metastatic PanNETs. Metastatic PanNETs were significantly larger (median size 5 vs 2 cm; P < 0.001) and tumor volume doubling time (TVDT) was faster (22 vs 126 months; P = 0.001). All metastatic tumors were ≥2.8 cm. Codons 161 and 167 were hotspots for VHL germline mutations with enhanced risk for metastatic PanNETs. Multivariate prediction modeling disclosed maximum tumor diameter and TVDT as significant predictors for metastatic disease (positive and negative predictive values of 51% and 100% for diameter cut-off ≥2.8 cm, 44% and 91% for TVDT cut-off of ≤24 months). In 117 of 273 patients, PanNETs >1.5 cm in diameter were operated. Ten-year survival was significantly longer in operated vs non-operated patients, in particular for PanNETs <2.8 cm vs ≥2.8 cm (94% vs 85% by 10 years; P = 0.020; 80% vs 50% at 10 years; P = 0.030). This study demonstrates that patients with PanNET approaching the cut-off diameter of 2.8 cm should be operated. Mutations in exon 3, especially of codons 161/167 are at enhanced risk for metastatic PanNETs. Survival is significantly longer in operated non-metastatic VHL-PanNETs.