scholarly journals Unmet Needs in High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms (WHO G3)

2018 ◽  
Vol 108 (1) ◽  
pp. 54-62 ◽  
Author(s):  
Halfdan Sorbye ◽  
Eric Baudin ◽  
Ivan Borbath ◽  
Martyn Caplin ◽  
Jie Chen ◽  
...  
Keyword(s):  
Patient Group ◽  
Unmet Needs ◽  
Proliferation Rate ◽  
Pancreatic Tumors ◽  
Neuroendocrine Neoplasms ◽  
Low Grade ◽  
High Grade ◽  
Primary Tumor Site ◽  
Net G3 ◽  
Well Differentiated

Gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) are classified based on morphology and graded based on their proliferation rate as either well-differentiated low-grade (G1 to G2) neuroendocrine tumors (NET) or poorly differentiated high-grade (G3) neuroendocrine carcinomas (NEC). Recently, a new subgroup of well-differentiated high-grade pancreatic tumors (NET G3) has been defined. The GEP NEN G3 group consisting of both NEC and NET G3 has recently been shown to be a quite heterogeneous patient group concerning prognosis and treatment benefit, depending on factors such as the primary tumor site, differentiation, proliferation rate, and molecular alterations. In this review we discuss the existing data on diagnostics, treatment, and biomarkers in this patient group, the unmet needs, and the future perspectives.

hPG80 (Progastrin), a novel blood-based biomarker for detection of neuroendocrine neoplasms.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15038-e15038
Author(s):  
Aman Chauhan ◽  
Alexandre Prieur ◽  
Jill Kolesar ◽  
Susanne M. Arnold ◽  
Léa Payen ◽  
...  
Keyword(s):  
Prospective Trial ◽  
Large Cell ◽  
Cancer Center ◽  
Neuroendocrine Neoplasms ◽  
Blood Collection ◽  
Study Cohort ◽  
Gastrointestinal Hormone ◽  
Low Grade ◽  
High Grade ◽  
Well Differentiated

e15038 Background: Neuroendocrine neoplasms (NENs) are heterogeneous tumors which originate from various organs and are of variable aggressiveness based on grade and morphology. Current biomarkers for NENs lack sensitivity and specificity, especially for high-grade NENs (small and large cell neuroendocrine carcinomas). hPG80, progastrin, is a novel bio-marker which is easily measured in plasma using an ELISA test. Physiologically, hPG80, an 80 amino acid protein, is the precursor of the gastrointestinal hormone gastrin. It is synthetized by gastric antrum G cells, and then processed into gastrin by multiple enzymatic processes. In pathological conditions, the GAST gene, which encodes hPG80, was shown to be over-expressed in human solid tumors from various primary sites. hPG80 is unprocessed and released from the tumor cells and becomes detectable in the blood. This study is the first to explore hPG80 in NENs. Methods: hPG80 was quantified in the plasma from 31 NEN patients using DxPG80 technology (ECS-Progastrin, Switzerland). Additional 69 samples are currently undergoing analysis. Progastrin concentrations in 18-70 YO (n = 557) and 18-25 YO (n = 137) healthy blood donors were compared to 31 stage IV NENs patients. The study was IRB approved. Results: Current data are for 31 patients. Data on total 100 patients will be presented at ASCO 2020. Mean age of study cohort at the time of blood collection was 60.9 years. 21 patients had grade 1 and 2 well differentiated NET. 10 patients had high grade NEN (Small cell, large cell and poorly differentiated NEC). High grade sub cohort also included two well differentiated grade 3 NET patients. Mean hPG80 in NENs was 14.17 pM as compared to 2.04 pM and 0.99 pM in 18-70 and 18-25 YO control groups (p < 0.0001), respectively. Subgroup analysis of NENs revealed mean hPG80 of 24.61 pM in high-grade NENs (n = 10) vs 10.88 pM in G1/2 NETs (n = 21). Conclusions: This first-ever study of plasma hPG80 in NENs suggests hPG80 may be a diagnostic blood-based biomarker in both low and high-grade NENs and further study is warranted. A prospective trial is ongoing in high-grade NEN to evaluate its role in monitoring of disease (NCT03958045) and further studies in low-grade NETs are underway. This research was supported by Cancer Center Support Grant (CCSG) from the National Cancer Institute (P30 CA177558) and ECS Progastrin.

HPG80 (Progastrin), a novel blood-based biomarker for detection of neuroendocrine neoplasms.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 628-628
Author(s):  
Aman Chauhan ◽  
Alexandre Prieur ◽  
Jill Kolesar ◽  
Susanne Arnold ◽  
Thierry Cousin ◽  
...  
Keyword(s):  
Prospective Trial ◽  
Large Cell ◽  
Cancer Center ◽  
Neuroendocrine Neoplasms ◽  
Blood Collection ◽  
Study Cohort ◽  
Gastrointestinal Hormone ◽  
Low Grade ◽  
High Grade ◽  
Well Differentiated

628 Background: Neuroendocrine neoplasms (NENs) are heterogeneous tumors which originate from various organs and are of variable aggressiveness based on grade and morphology. Current biomarkers for NENs lack sensitivity and specificity, especially for high-grade NENs (small and large cell neuroendocrine carcinomas). hPG80, progastrin, is a novel bio-marker which is easily measured in plasma using an ELISA test. Physiologically, hPG80, an 80 amino acid protein, is the precursor of the gastrointestinal hormone gastrin. It is synthetized by gastric antrum G cells, and then processed into gastrin by multiple enzymatic processes. In pathological conditions, the GAST gene, which encodes hPG80, was shown to be over-expressed in human solid tumors from various primary sites. hPG80 is unprocessed and released from the tumor cells and becomes detectable in the blood. This study is the first to explore hPG80 in NENs. Methods: hPG80 was quantified in the plasma from 31 NEN patients using DxPG80 technology (ECS-Progastrin, Switzerland). Progastrin concentrations in 18-70 YO (n = 557) and 18-25 YO (n = 137) healthy blood donors were compared to 31 stage IV NENs patients. The study was IRB approved. Results: Mean age of study cohort at the time of blood collection was 60.9 years. 21 patients had grade 1 and 2 well differentiated NET. 10 patients had high grade NEN (Small cell, large cell and poorly differentiated NEC). High grade sub cohort also included two well differentiated grade 3 NET patients. Mean hPG80 in NENs was 14.17 pM as compared to 2.04 pM and 0.99 pM in 18-70 and 18-25 YO control groups (p < 0.0001), respectively. Subgroup analysis of NENs revealed mean hPG80 of 24.61 pM in high-grade NENs (n = 10) vs 10.88 pM in G1/2 NETs (n = 21). Conclusions: This first-ever study of plasma hPG80 in NENs suggests hPG80 may be a diagnostic and/prognostic blood-based biomarker in both low and high-grade NENs and further study is warranted. A prospective trial is ongoing in high-grade NEN to evaluate its role in monitoring of disease (NCT03958045) and further studies in low-grade NETs are underway. This research was supported by Cancer Center Support Grant (CCSG) from the National Cancer Institute (P30 CA177558) and ECS Progastrin.

scholarly journals Impact of Pathological Stratification on the Clinical Outcomes of Advanced Well-Differentiated/Dedifferentiated Liposarcoma Treated with Trabectedin

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1453
Author(s):  
Chiara Fabbroni ◽  
Giovanni Fucà ◽  
Francesca Ligorio ◽  
Elena Fumagalli ◽  
Marta Barisella ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Proportional Hazards ◽  
Case Series ◽  
Progression Free Survival ◽  
Cox Proportional Hazards ◽  
Low Grade ◽  
High Grade ◽  
Retrospective Case ◽  
Well Differentiated ◽  
The Impact

Background. We previously showed that grading can prognosticate the outcome of retroperitoneal liposarcoma (LPS). In the present study, we aimed to explore the impact of pathological stratification using grading on the clinical outcomes of patients with advanced well-differentiated LPS (WDLPS) and dedifferentiated LPS (DDLPS) treated with trabectedin. Patients: We included patients with advanced WDLPS and DDLPS treated with trabectedin at the Fondazione IRCCS Istituto Nazionale dei Tumori between April 2003 and November 2019. Tumors were categorized in WDLPS, low-grade DDLPS, and high-grade DDLPS according to the 2020 WHO classification. Patients were divided in two cohorts: Low-grade (WDLPS/low-grade DDLPS) and high-grade (high-grade DDLPS). Results: A total of 49 patients were included: 17 (35%) in the low-grade cohort and 32 (65%) in the high-grade cohort. Response rate was 47% in the low-grade cohort versus 9.4% in the high-grade cohort (logistic regression p = 0.006). Median progression-free survival (PFS) was 13.7 months in the low-grade cohort and 3.2 months in the high-grade cohort. Grading was confirmed as an independent predictor of PFS in the Cox proportional-hazards regression multivariable model (adjusted hazard ratio low-grade vs. high-grade: 0.45, 95% confidence interval: 0.22–0.94; adjusted p = 0.035). Conclusions: In this retrospective case series, sensitivity to trabectedin was higher in WDLPS/low-grade DDLPS than in high-grade DDLPS. If confirmed in larger series, grading could represent an effective tool to personalize the treatment with trabectedin in patients with advanced LPS.

scholarly journals INSM1 Is a Highly Specific Marker of Neuroendocrine Differentiation in Primary Neoplasms of the Gastrointestinal Tract, Appendix, and Pancreas

2020 ◽  
Vol 153 (6) ◽  
pp. 811-820 ◽  
Author(s):  
Kelsey E McHugh ◽  
Sanjay Mukhopadhyay ◽  
Erika E Doxtader ◽  
Christopher Lanigan ◽  
Daniela S Allende
Keyword(s):  
Goblet Cell ◽  
Neuroendocrine Differentiation ◽  
Neuroendocrine Neoplasms ◽  
Specific Marker ◽  
Low Grade ◽  
Ki 67 ◽  
Neuroendocrine Markers ◽  
Primary Neoplasms ◽  
Poorly Differentiated ◽  
Well Differentiated

Abstract Objectives INSM1 has been described as a sensitive and specific neuroendocrine marker. This study aims to compare INSM1 with traditional neuroendocrine markers in gastrointestinal neuroendocrine neoplasms. Methods Retrospective review (2008-2018) was used to retrieve paraffin-embedded tissue from 110 gastrointestinal neuroendocrine neoplasms and controls that was subsequently stained with INSM1, synaptophysin, chromogranin, CD56, and Ki-67. Results INSM1 was positive in 16 of 17 (94.1%) gastric, 17 of 18 (94.4%) pancreatic, 13 of 18 (72.2%) small bowel, 17 of 21 (81.0%) colonic, and 26 of 36 (72.2%) appendiceal tumors. INSM1 was positive in 58 of 70 (82.9%) well-differentiated neuroendocrine tumors, 17 of 20 (85.0%) poorly differentiated neuroendocrine carcinomas, 8 of 11 (72.7%) low-grade goblet cell adenocarcinomas (grade 1), and 6 of 9 (66.7%) high-grade goblet cell adenocarcinomas (grade 2/3). INSM1 sensitivity for neuroendocrine neoplasms (80.9%) was less than that of synaptophysin (99.1%), chromogranin (88%), and CD56 (95.3%); specificity was higher (95.7% vs 86.0%, 87.3%, and 86.0%, respectively). Conclusions INSM1 is a useful marker of neuroendocrine differentiation in gastrointestinal neuroendocrine and mixed neuroendocrine neoplasms. Compared with traditional neuroendocrine markers, INSM1 is less sensitive but more specific.

scholarly journals Chloroquine induces apoptosis in pancreatic neuroendocrine neoplasms via endoplasmic reticulum stress

2020 ◽  
Vol 27 (7) ◽  
pp. 431-439
Author(s):  
Kenzo Nakano ◽  
Toshihiko Masui ◽  
Akitada Yogo ◽  
Yuichiro Uchida ◽  
Asahi Sato ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Cell Lines ◽  
Apoptotic Cell ◽  
Tumour Size ◽  
Neuroendocrine Neoplasms ◽  
Low Grade ◽  
Pancreatic Neuroendocrine Neoplasms ◽  
Dismal Prognosis ◽  
Well Differentiated

Although pancreatic neuroendocrine neoplasms (PanNENs) are generally indolent, patients with distant metastasis have a dismal prognosis. Recently, the autophagy inhibitor chloroquine (CQ) has been shown to suppress the tumour growth of PanNENs, but the detailed mechanisms have not been elucidated. Furthermore, these results were obtained from poorly differentiated cell lines rather than well-differentiated cell lines, which is the most prevalent type in this tumour. To explore the mechanism and efficacy of CQ on PanNENs, we applied CQ to cell lines and evaluated the resulting apoptosis and endoplasmic reticulum (ER) stress. CQ treatment induced ER stress, and an unfolded protein response was activated through the PERK-eIF2α-ATF4 pathway, resulting in the expression of the pro-apoptotic protein C/EBP homologous protein (CHOP), which reflects ER-stress-mediated apoptotic cell death. Furthermore, hydroxychloroquine (HCQ) was effective in Men1 heterozygous-deficient (Men1+/ΔN3-8) mice, a mouse PanNEN model that is considered to correspond to human low-grade PanNEN. HCQ administration decreased tumour size in Men1+/ΔN3-8 mice. In the HCQ group, histological analyses revealed that proliferative activity was unchanged, but apoptosis was accelerated, accompanied by CHOP expression. These results suggest that autophagy inhibition by CQ/HCQ could be used for the treatment of PanNEN, including the well-differentiated type.

Everolimus in combination with octreotide LAR as the first-line treatment for advanced neuroendocrine tumors: A phase II trial of the I.T.M.O. (Italian Trials in Medical Oncology) group.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 4136-4136 ◽  
Author(s):  
Emilio Bajetta ◽  
Laura Catena ◽  
Nicola Fazio ◽  
Sara Pusceddu ◽  
Pamela Biondani ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Phase Ii ◽  
Medical Oncology ◽  
Objective Response ◽  
Complete Response ◽  
Multicenter Trial ◽  
Pancreatic Tumors ◽  
Primary Tumor Site ◽  
Octreotide Lar ◽  
Well Differentiated

4136^ Background: Everolimus has shown antitumor activity in patients (pts) with advanced pancreatic neuroendocrine tumors (NETs). We aimed to assess efficacy and safety of everolimus in combination with octreotide long-acting repeatable (LAR) in patients with well differentiated NETs of gastroenteropancreatic and of lung origin. Methods: We performed a phase II, multicenter trial using a Simon two-stage minmax design. Pts with advanced well differentiated, previously untreated NETs of the gastroenteropancreatic tract and of the lung received octreotide LAR 30 mg every 28 days in conjunction with everolimus 10 mg per day continuously. The primary endpoint was objective response rate (ORR). Results: A total of 50 pts (58% males) were enrolled. The median age was 60.5 years (range 25-76). Primary tumor site was pancreas in 14 (28%), unknown in 14 (28%), lung in 11 (22%), ileum in 9 (18%) and jejunum and duodenum in 2 (4%) of pts. 13 (26%) pts had carcinoid syndrome. The ORR, calculated on the ITT population, was 20.0% (95% CI 8.9-31.1): 2 patients (4%) had a complete response (CR), 8 (16%) a partial response (PR). Thirty-six patients (72%) achieved stable disease (SD). All CR and all PR as well as 91.7% of SD had a duration ≥ 6 months. Clinical benefit (CR+PR+SD) was 92%. At a median follow-up of 277 days, the median time to progression (TTP) was 16.3 months (95% CI 10.7-20.1). Overall survival could not be assessed. Treatment-related adverse events (AEs) were mostly of grade 1 or 2; the only grade 4 AE was mucositis in 1 patient, while grade 3 AEs included skin rash in 1 case, stomatitis in 4 cases (8%) and diarrhea in 11 cases (22%). Conclusions: Everolimus in combination with octreotide LAR has shown to be active and well tolerated in advanced NETs and, in this study, not only in primary pancreatic tumors. Compared to other clinical trials with everolimus in NETs, the observed ORR in this study was higher. Aknowledgements: The Authors thank the Italian Trials in Medical Oncology (I.T.M.O.) group and Novartis Pharma for the support provided. Clinical trial information: 2008-007153-13.

Efficacy and Toxicity Analysis of Capecitabine and Temozolomide in Neuroendocrine Neoplasms

2021 ◽  
pp. 1-8
Author(s):  
Taymeyah Al-Toubah ◽  
Eleonora Pelle ◽  
Tiffany Valone ◽  
Mintallah Haider ◽  
Jonathan R. Strosberg
Keyword(s):  
Opportunistic Infections ◽  
Progression Free Survival ◽  
Pancreatic Tumors ◽  
Prolonged Treatment ◽  
Cancer Center ◽  
Neuroendocrine Neoplasms ◽  
Significant Activity ◽  
Large Patient ◽  
Toxicity Analysis ◽  
Well Differentiated

Background: The capecitabine/temozolomide (CAPTEM) regimen has significant activity in advanced neuroendocrine tumors (NETs). Questions exist regarding activity in pancreatic versus nonpancreatic NETs, risk of opportunistic infections, long-term myelotoxicity, and safety of prolonged treatment duration. Analysis of large patient cohorts is needed for the evaluation of rare toxicities and assessment of risk factors. Methods: We conducted a retrospective study of all patients with advanced NETs seen at Moffitt Cancer Center between January 2008 and June 2019 who received treatment with CAPTEM. Results: A total of 462 patients were eligible. The objective radiographic response rate was 46%, and the disease control rate was 81%. Median progression-free survival (PFS) was 18 months (95% CI, 14.0–21.9 months) and median overall survival was 51 months (95% CI, 42.8–59.2 months): 62 months in well-differentiated NETs versus 14 months in poorly differentiated neuroendocrine carcinomas (P<.0001). Patients with primary pancreatic tumors had the highest partial response rates and longest median PFS. Incidences of grade 4 thrombocytopenia and neutropenia were 7% and 3%, respectively, and substantially higher in women than men (P=.02 and P=.004, respectively). Only 1 case (0.2%) of suspected Pneumocystis pneumonia (PCP) was observed in a patient receiving corticosteroids. Three patients developed myelodysplastic disease, all of whom had received prior peptide receptor radiotherapy (PRRT). There were no acute treatment-related deaths; 1 patient died 2 months after a thrombocytopenic bleed. Conclusions: The CAPTEM regimen is exceptionally safe. Efficacy is particularly robust in well-differentiated pancreatic NETs. Severe myelotoxicity is rare; the risk of grade 4 cytopenias is significantly increased in women, and therefore sex-based dosing should be considered. There were no cases of myelodysplastic syndromes, except among patients who had received PRRT, a known risk factor. The risk of PCP is negligible.

scholarly journals Increased incidence trend of low-grade and high-grade neuroendocrine neoplasms

Endocrine ◽  
2017 ◽  
Vol 58 (2) ◽  
pp. 368-379 ◽  
Author(s):  
Emanuele Leoncini ◽  
Paolo Boffetta ◽  
Michail Shafir ◽  
Katina Aleksovska ◽  
Stefania Boccia ◽  
...  
Keyword(s):  
Neuroendocrine Neoplasms ◽  
Low Grade ◽  
High Grade ◽  
Incidence Trend

scholarly journals Molecular profiling of appendiceal serrated lesions, polyps and mucinous neoplasms: a single-centre experience

2021 ◽  
Author(s):  
Giada Munari ◽  
Gianluca Businello ◽  
Paola Mattiolo ◽  
Gianmaria Pennelli ◽  
Marta Sbaraglia ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Rare Event ◽  
Neuroendocrine Neoplasms ◽  
Low Grade ◽  
Tubular Adenoma ◽  
High Grade ◽  
Mismatch Repair Deficiency ◽  
Repair Deficiency ◽  
Mucinous Neoplasms ◽  
Serrated Lesions

Abstract Purpose Non-neuroendocrine neoplasms of the appendix are a phenotypically heterogeneous group of lesions; a comprehensive molecular characterization of these tumors is still lacking. Methods A total of 52 samples taken from 49 patients was evaluated: 18 sessile serrated lesions (SSL; 3 with dysplasia), 2 high-grade tubular adenomas, 1 tubulo-villous adenoma,1 hyperplastic polyp, 18 low-grade appendiceal mucinous neoplasms (LAMN), 3 high-grade appendiceal mucinous neoplasms (HAMN) and 9 mucinous adenocarcinomas. Hotspot mutational profiling of the RNF43, SMAD4, KRAS, NRAS, BRAF and PIK3CA genes was performed. Expression of p53, MLH1, PMS2, MSH2, and MSH6 was evaluated by immunohistochemistry. Results KRAS was the most frequently mutated gene (53.9% of cases), followed by RNF43 (15.4%), and BRAF (13.5%). In particular: KRAS was mutated in 44.4% of adenocarcinomas, 66.7% of HAMNs, 61.1% of LAMNs, 53.3% of SSL without dysplasia and in 66.7% of SSL with dysplasia; RNF43 was mutated in 33.3% of adenocarcinomas, 66.7% of HAMNs, 11.1% of LAMNs and in 6.7% of SSL without dysplasia; BRAF was mutated in 11.1% of adenocarcinomas, 26.7% of SSL without dysplasia and in 5.6% of LAMNs. Only a case of high-grade tubular adenoma showed mismatch repair deficiency, while immunohistochemical expression of p53 was altered in 21.1% of cases. Conclusions The histological phenotypic similarities between appendicular mucinous lesions and serrated colon lesions do not reflect a similar genetic landscape. Mismatch repair deficiency is a rare event during appendiceal mucinous carcinogenesis.

scholarly journals The molecular characteristics of high-grade gastroenteropancreatic neuroendocrine neoplasms

2021 ◽  
Author(s):  
Andreas Venizelos ◽  
Hege Elvebakken ◽  
Aurel Perren ◽  
Oleksii Nikolaienko ◽  
Wei Deng ◽  
...  
Keyword(s):  
Copy Number ◽  
Primary Tumour ◽  
Treatment Strategies ◽  
Morphological Differentiation ◽  
Molecular Characteristics ◽  
Neuroendocrine Neoplasms ◽  
High Grade ◽  
Braf Mutations ◽  
Molecular Features ◽  
Net G3

High-grade (HG) gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) are rare but have a very poor prognosis and represent a severely understudied class of tumours. Molecular data for HG GEP-NEN are limited and treatment strategies for the carcinoma subgroup (HG GEP-NEC) are extrapolated from small-cell lung cancer (SCLC). After pathological re-evaluation, we analysed DNA from tumours and matched blood samples from 181 HG GEP-NEN patients; 152 neuroendocrine carcinomas (NEC) and 29 neuroendocrine tumours (NET G3). Based on sequencing of 360 cancer related genes, we assessed mutations and copy number alterations (CNA). For NEC, frequently mutated genes were TP53 (64%), APC (28%), KRAS (22%) and BRAF (20%). RB1 was only mutated in 14%, but CNAs affecting RB1 were seen in 34%. Other frequent copy number losses were ARID1A (35%), ESR1 (25%) and ATM (31%). Frequent amplifications/gains were found in MYC (51%) and KDM5A (45%). While these molecular features had limited similarities with SCLC, we found potentially targetable alterations in 66% of the NEC samples. Mutations and CNA varied according to primary tumour site with BRAF mutations mainly seen in colon (49%), and FBXW7 mutations mainly seen in rectal cancers (25%). 8/152 (5.3%) NEC were microsatellite instable (MSI). NET G3 had frequent mutations in MEN1 (21%), ATRX (17%), DAXX, SETD2 and TP53 (each 14%). We show molecular differences in HG GEP-NEN, related to morphological differentiation and site of origin. Limited similarities to SCLC and a high fraction of targetable alterations indicates a high potential for better personalized treatments.

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