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Fritz-Line Vélayoudom-Céphise, Pierre Duvillard, Lydia Foucan, Julien Hadoux, Cecile N Chougnet, Sophie Leboulleux, David Malka, Joël Guigay, Diane Goere, Thierry Debaere, Caroline Caramella, Martin Schlumberger, David Planchard, Dominique Elias, Michel Ducreux, Jean-Yves Scoazec, and Eric Baudin

The new WHO classification of gastroenteropancreatic (GEP) neuroendocrine tumors (NET) implies that G3 neoplasms with mitotic index >20 and/or Ki67 index >20% are neuroendocrine carcinomas (NEC), described as poorly differentiated, small or large cell types, by analogy with lung NEC. To characterize the subgroup of non-small-cell-type GEP and thoracic NET with mitotic index >20 and/or Ki67 >20% according to their pathological features, response to cisplatin and overall survival (OS). We reviewed pathological and clinical presentation of G3 non-small-cell-type NET referred to our institution for 5 years. Data from 166 patients with metastatic thoracic and GEP-NET were collected. Twenty-eight patients (17%) fulfill the inclusion criteria. Tumors were classified as well-differentiated NET (G3-WDNET) in 42.8% of cases and poorly differentiated, large-cell NEC (G3-LCNEC) in 57.2% of cases. Plasma chromogranin A or neuron-specific enolase were elevated in 42 and 25% respectively of G3-WDNET and 31 and 50% of G3-LCNEC. Somatostatin receptor scintigraphy was positive in 88 and 50% of G3-WDNET or G3-LCNEC respectively. Complete or partial response to cisplatin was observed in 31% of cases, all classified as G3-LCNEC. The median OS was 41 months for G3-WDNET but 17 months for G3-LCNEC (P=0.34). Short survival was observed in 25% of G3-WDNET but 62.5% of G3-LCNEC patients (P=0.049). G3 ENETS GEP and thoracic neuroendocrine neoplasms (NEN) could constitute a heterogeneous subgroup of NEN as regards diagnosis, prognosis, and treatment. If confirmed, future classifications may consider splitting them into two groups according to their morphological differentiation.

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Halfdan Sorbye, Grace Kong, and Simona Grozinsky-Glasberg

Peptide receptor radionuclide therapy (PRRT) is an established treatment for grade 1 and 2 gastroenteropancreatic neuroendocrine tumors with an increased uptake on somatostatin receptor imaging (SRI). Patients with metastatic high-grade (WHO G3) gastroenteropancreatic neuroendocrine neoplasms (NET G3 and NEC) represent a heterogeneous subgroup with poor prognosis and standard platinum-etoposide chemotherapy have limited therapeutic benefit. However, there is promising emerging evidence supporting the effectiveness of PRRT in SRI-positive G3 disease. A review search for studies reporting on PRRT in gastroenteropancreatic neuroendocrine neoplasms G3 was performed: four studies with more than ten cases were found. PRRT was mainly given as second- or third-line treatment in patients with progressive disease. Most patients had a pancreatic primary, 50% had well-differentiated tumors, and most had a Ki-67 <55%. Three studies showed similar results with promising response rates (31–41%) and disease control rates (69–78%). Progression-free survival (11–16 months) and survival (22–46 months) were best concerning patients with a Ki-67 <55%. Progression-free survival was 19 months in NET G3, 11 months for lowNEC (Ki-67 ≤55%) and 4 months for highNEC (Ki-67 >55%). PRRT should be considered for patients with increased uptake on SRI, both in gastroenteropancreatic NET G3 cases and as well as in NEC cases with a Ki-67 21–55%. PRRT for NEC with a Ki-67 >55% is less defined, but could be considered in highly selected cases after response to initial chemotherapy where all residual disease have high uptake on SRI. Dual tracer using 18F-FDG PET/CT and SRI provides important information for patient selection for PRRT in this heterogeneous complex high-grade disease.

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M Heetfeld, C N Chougnet, I H Olsen, A Rinke, I Borbath, G Crespo, J Barriuso, M Pavel, D O'Toole, T Walter, and other Knowledge Network members

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.

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Giovanni Vitale, Alessandra Dicitore, Concetta Sciammarella, Sergio Di Molfetta, Manila Rubino, Antongiulio Faggiano, and Annamaria Colao

Somatostatin analogs have an important role in the medical therapy of neuroendocrine tumors (NETs). Octreotide and lanreotide, both somatostatin analogs binding with high affinity for the somatostatin receptor (SSTR)2, can control symptoms in functional NETs. In addition, these compounds, because of their antiproliferative effects, can stabilize growth of well-differentiated NETs. Pasireotide is a novel multireceptor-targeted somatostatin analog with high affinity for SSTR1, 2, 3, and 5. This review provides an overview of the state of the art of pasireotide in the treatment of NETs, with the aim of addressing clinical relevance and future perspectives for this molecule in the management of NETs.

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Maria Chiara Zatelli, Erika Maria Grossrubatscher, Elia Guadagno, Concetta Sciammarella, Antongiulio Faggiano, and Annamaria Colao

The prognosis of neuroendocrine neoplasms (NENs) is widely variable and has been shown to associate with several tissue- and blood-based biomarkers in different settings. The identification of prognostic factors predicting NEN outcome is of paramount importance to select the best clinical management for these patients. Prognostic markers have been intensively investigated, also taking advantage of the most modern techniques, in the perspective of personalized medicine and appropriate resource utilization. This review summarizes the available data on the possible role of circulating tumor cells and microRNAs as prognostic markers in NENs.

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Annemiek Walenkamp, Guillermo Crespo, Felipe Fierro Maya, Reidar Fossmark, Peter Igaz, Anja Rinke, Gianluca Tamagno, Giovanni Vitale, Kjell Öberg, and Tim Meyer

In the past few years, there have been advances in the treatment of neuroendocrine tumours (NETs) and improvements in our understanding of NET biology. However, the benefits to patients have been relatively modest and much remains yet to be done. The ‘Hallmarks of Cancer’, as defined by Hanahan and Weinberg, provide a conceptual framework for understanding the aberrations that underlie tumourigenesis and to help identify potential targets for therapy. In this study, our objective is to review the major molecular characteristics of NETs, based on the recently modified ‘Hallmarks of Cancer’, and highlight areas that require further research.

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C Bouvier

Nurse developments in the management of neuroendocrine tumours have changed significantly over the past three years. At the Royal Free Hospital we set up the nurse specialist role due to the expansion of patients being referred to the specialist unit, and the obvious need for a nursing input into their care. The nurse specialist can make a significant contribution within the context of a multidisciplinary team especially in the production of guidelines and policies to ensure and maintain high standards of practice, education for the patient, and the provision of expertise and security that the patient requires when diagnosed with a rare disease.

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Charlotte Veyrat-Durebex, Nathalie Bouzamondo, Morgane Le Mao, Juan Manuel Chao de la Barca, Céline Bris, Xavier Dieu, Gilles Simard, Cédric Gadras, Lydie Tessier, Delphine Drui, Françoise Borson-Chazot, Anne Barlier, Pascal Reynier, and Delphine Prunier-Mirebeau

Thirty percent of medullary thyroid carcinomas (MTCs) are related to dominant germline pathogenic variants in the RET proto-oncogene. According to their aggressiveness, these pathogenic variants are classified in three risk levels: ‘moderate’, ‘high’ and ‘highest’. The present study compares the metabolomics profiles of five pathogenic variants, whether already classified or not. We have generated six stable murine fibroblast cell lines (NIH3T3) expressing the WT allele or variants of the human RET gene, with different levels of pathogenicity, including the M918V variant that is yet to be accurately classified. We carried out a targeted metabolomics study of the cell extracts with a QTRAP mass spectrometer, using the Biocrates Absolute IDQ p180 kit, which allows the quantification of 188 endogenous molecules. The data were then subjected to multivariate statistical analysis. One hundred seventy three metabolites were accurately measured. The metabolic profiles of the cells expressing the RET variants were found to be correlated with their oncogenic risk. In addition, the statistical model we constructed for predicting the oncogenic risk attributed a moderate risk to the M918V variant. Our results indicate that metabolomics may be useful for characterizing the pathogenicity of the RET gene variants and their levels of aggressiveness.

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Cristina Romei, Raffaele Ciampi, Pinuccia Faviana, Laura Agate, Eleonora Molinaro, Valeria Bottici, Fulvio Basolo, Paolo Miccoli, Furio Pacini, Aldo Pinchera, and Rossella Elisei

A low sodium iodide symporter (NIS) expression has been shown in papillary thyroid carcinomas (PTCs) harboring the BRAFV600E mutation. In the present study, we analyzed the mRNA expression of thyroid differentiation genes, glucose transporter (GLUT)-1 and GLUT-3, in 78 PTCs according to the presence of BRAFV600E or RET/PTC rearrangements. We found BRAFV600E and RET/PTC rearrangements in 35.8 and 19.4% of PTCs respectively. The mRNA expression of NIS and thyroperoxidase (TPO) genes were significantly lower (P<0.0001 and P=0.004 respectively) in BRAFV600E-positive PTC with respect to non-mutated samples. In support of this result, immunohistochemistry showed that the percentage of NIS-positive cells was significantly lower (P=0.005) in BRAFV600E-mutated PTC (mean 53.5%) than in negative cases (mean 72.6%). In contrast, no difference either in NIS or in any other thyroid differentiation genes' mRNA expression was found in PTC with or without RET/PTC rearrangements. When GLUT-1 and GLUT-3 mRNA expression was considered, no correlation was found either in BRAFV600E- nor in RET/PTC-mutated cases. In conclusion, this study confirmed the presence of a genetic alteration of BRAF and/or RET oncogenes in 64% of PTC cases and revealed a significant correlation of BRAFV600E mutation with a lower expression of both NIS and TPO. This latter finding could indicate that an early dedifferentiation process is present at the molecular level in BRAFV600E-mutated PTC, thus suggesting that the previously demonstrated poor prognostic significance of BRAFV600E mutation could be related to the dedifferentiation process more than to a more advanced stage at diagnosis.

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Esther Korpershoek, Bart-Jeroen Petri, Francien H van Nederveen, Winand N M Dinjens, Albert A Verhofstad, Wouter W de Herder, Sonja Schmid, Aurel Perren, Paul Komminoth, and Ronald R de Krijger

Pheochromocytomas (PCCs) are rare tumors that arise from chromaffin tissue in the adrenal medulla, but can also occur in the abdomen outside the adrenals and are then called sympathetic paragangliomas (sPGLs). According to the literature, between 15 and 25% of apparently sporadic adrenal PCC and sPGL are caused by germline mutations in RET, von Hippel–Lindau disease (VHL), succinate dehydrogenase subunit B (SDHB), or subunit D SDHD. However, few studies have addressed the mutationfrequency of these candidate genes in selected subgroups of PCC andsPGL, such as bilateral adrenal PCC or extra-adrenal sPGL, and none have looked at somatic mutations by analyzing tumor tissue. Therefore, we have investigated the occurrence of germline and somatic mutations in RET, VHL, SDHB, and SDHD in comparatively large series of bilateral adrenal PCC (n = 33 patients) and sPGL (n = 26 patients), with the aim of determining the mutation frequency of each of these genes and to establish a genetic testing algorithm. Twenty-one RET, two VHL germline, and one SDHD mutations were found in the patients with bilateral adrenal PCC. In sPGL, one novel SDHB germline and one novel SDHB somatic mutation were observed. In addition, two SDHD germline mutations were found. We conclude that germline RET mutations are predominantly found in bilateral PCC, and that somatic and germline SDHB and SDHD mutations usually occur in sPGL, which has practical consequences for genetic testing algorithms. We suggest that sequential mutation analysis should be directed first at RET, followed by VHL and SDHD for patients with bilateral adrenal PCC at diagnosis, and at SDHB and SDHD for patients with sPGL.