Hypomethylation of LINE-1 and Alu in well-differentiated neuroendocrine tumors (pancreatic endocrine tumors and carcinoid tumors)

Purpose Standard, intravenous chemotherapy regimens for neuroendocrine tumors have been associated with limited response rates and significant toxicity. We evaluated the efficacy of an oral regimen of temozolomide and thalidomide in patients with metastatic carcinoid, pheochromocytoma, or pancreatic neuroendocrine tumors. Patients and Methods Twenty-nine patients were treated with a combination of temozolomide, administered at a dose of 150 mg/m2 for 7 days, every other week, and thalidomide at doses of 50 to 400 mg daily. Patients were followed for evidence of toxicity, biochemical response, radiologic response, and survival. Results Treatment with temozolomide and thalidomide was associated with an objective biochemical (chromogranin A) response rate of 40%, and a radiologic response rate of 25% (45% among pancreatic endocrine tumors, 33% among pheochromocytomas, and 7% among carcinoid tumors). The median duration of response was 13.5 months, 1-year survival was 79%, and 2-year survival was 61%. The median administered dose of temozolomide was 150 mg/m2, and the median administered dose of thalidomide was 100 mg daily. Grade 3-4 toxicities were uncommon, with the exception of grade 3-4 lymphopenia, which developed in 69% of the patient population. Opportunistic infections occurred in three patients (10%) during the time of lymphopenia, and included single cases of Pneumocystis carinii pneumonia, disseminated varicella zoster virus, and herpes simplex virus. Conclusion Orally administered temozolomide and thalidomide seems to be an active regimen for the treatment of neuroendocrine tumors. In this 29-patient study, this regimen appeared more active in pancreatic endocrine tumors than in carcinoid tumors.

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Molecular Pathology of Well-Differentiated Pulmonary and Thymic Neuroendocrine Tumors: What Do Pathologists Need to Know?

Endocrine Pathology ◽

10.1007/s12022-021-09668-z ◽

2021 ◽

Vol 32 (1) ◽

pp. 154-168 ◽

Cited By ~ 1

Author(s):

Marco Volante ◽

Ozgur Mete ◽

Giuseppe Pelosi ◽

Anja C. Roden ◽

Ernst Jan M. Speel ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Young Patients ◽

Carcinoid Tumors ◽

Neuroendocrine Neoplasms ◽

Grey Zone ◽

Cell Hyperplasia ◽

Ki 67 ◽

Familial Form ◽

Well Differentiated ◽

Neuroendocrine Carcinomas

AbstractThoracic (pulmonary and thymic) neuroendocrine tumors are well-differentiated epithelial neuroendocrine neoplasms that are classified into typical and atypical carcinoid tumors based on mitotic index cut offs and presence or absence of necrosis. This classification scheme is of great prognostic value but designed for surgical specimens, only. Deep molecular characterization of thoracic neuroendocrine tumors highlighted their difference with neuroendocrine carcinomas. Neuroendocrine tumors of the lung are characterized by a low mutational burden, and a high prevalence of mutations in chromatin remodeling and histone modification-related genes, whereas mutations in genes frequently altered in neuroendocrine carcinomas are rare. Molecular profiling divided thymic neuroendocrine tumors into three clusters with distinct clinical outcomes and characterized by a different average of copy number instability. Moreover, integrated histopathological, molecular and clinical evidence supports the existence of a grey zone category between neuroendocrine tumors (carcinoid tumors) and neuroendocrine carcinomas. Indeed, cases with well differentiated morphology but mitotic/Ki-67 indexes close to neuroendocrine carcinomas have been increasingly recognized. These are characterized by specific molecular profiles and have an aggressive clinical behavior. Finally, thoracic neuroendocrine tumors may arise in the background of genetic susceptibility, being MEN1 syndrome the well-defined familial form. However, pathologists should be aware of rarer germline variants that are associated with the concurrence of neuroendocrine tumors of the lung or their precursors (such as DIPNECH) with other neoplasms, including but not limited to breast carcinomas. Therefore, genetic counseling for all young patients with thoracic neuroendocrine neoplasia and/or any patient with pathological evidence of neuroendocrine cell hyperplasia-to-neoplasia progression sequence or multifocal disease should be considered.

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Oxaliplatin and 5-fluorouracil (FOLFOX) in advanced well differentiated digestive neuroendocrine tumors: a multicenter national retrospective study from the French Group of Endocrine Tumors (GTE)

Neuroendocrinology ◽

10.1159/000518650 ◽

2021 ◽

Author(s):

Paul Girot ◽

Eric Baudin ◽

Hélène Senellart ◽

Nadia Bouarioua ◽

Olivia Hentic ◽

...

Keyword(s):

Retrospective Study ◽

Neuroendocrine Tumors ◽

Endocrine Tumors ◽

French Group ◽

Well Differentiated

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Prediction of Progression-Free Survival in Patients With Advanced, Well-Differentiated, Neuroendocrine Tumors Being Treated With a Somatostatin Analog: The GETNE-TRASGU Study

Journal of Clinical Oncology ◽

10.1200/jco.19.00980 ◽

2019 ◽

Vol 37 (28) ◽

pp. 2571-2580 ◽

Cited By ~ 8

Author(s):

Alberto Carmona-Bayonas ◽

Paula Jiménez-Fonseca ◽

Ángela Lamarca ◽

Jorge Barriuso ◽

Ángel Castaño ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Failure Time ◽

Somatostatin Analogs ◽

Progression Free Survival ◽

Accelerated Failure Time Model ◽

Endocrine Tumors ◽

First Line ◽

Ki 67 ◽

Free Survival ◽

Well Differentiated

PURPOSE Somatostatin analogs (SSAs) are recommended for the first-line treatment of most patients with well-differentiated, gastroenteropancreatic (GEP) neuroendocrine tumors; however, benefit from treatment is heterogeneous. The aim of the current study was to develop and validate a progression-free survival (PFS) prediction model in SSA-treated patients. PATIENTS AND METHODS We extracted data from the Spanish Group of Neuroendocrine and Endocrine Tumors Registry (R-GETNE). Patient eligibility criteria included GEP primary, Ki-67 of 20% or less, and first-line SSA monotherapy for advanced disease. An accelerated failure time model was developed to predict PFS, which was represented as a nomogram and an online calculator. The nomogram was externally validated in an independent series of consecutive eligible patients (The Christie NHS Foundation Trust, Manchester, United Kingdom). RESULTS We recruited 535 patients (R-GETNE, n = 438; Manchester, n = 97). Median PFS and overall survival in the derivation cohort were 28.7 (95% CI, 23.8 to 31.1) and 85.9 months (95% CI, 71.5 to 96.7 months), respectively. Nine covariates significantly associated with PFS were primary tumor location, Ki-67 percentage, neutrophil-to-lymphocyte ratio, alkaline phosphatase, extent of liver involvement, presence of bone and peritoneal metastases, documented progression status, and the presence of symptoms when initiating SSA. The GETNE-TRASGU (Treated With Analog of Somatostatin in Gastroenteropancreatic and Unknown Primary NETs) model demonstrated suitable calibration, as well as fair discrimination ability with a C-index value of 0.714 (95% CI, 0.680 to 0.747) and 0.732 (95% CI, 0.658 to 0.806) in the derivation and validation series, respectively. CONCLUSION The GETNE-TRASGU evidence-based prognostic tool stratifies patients with GEP neuroendocrine tumors receiving SSA treatment according to their estimated PFS. This nomogram may be useful when stratifying patients with neuroendocrine tumors in future trials. Furthermore, it could be a valuable tool for making treatment decisions in daily clinical practice.

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New WHO classification for pancreatic endocrine tumors: Is time to leave the previous one?

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e14647 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e14647-e14647

Author(s):

Claudio Ricci ◽

Davide Campana ◽

Marina Macchini ◽

Silvia Vecchiarelli ◽

Giovanni Taffurelli ◽

...

Keyword(s):

Sensitivity Analysis ◽

Multivariate Analysis ◽

Who Classification ◽

Palliative Surgery ◽

Tnm Stage ◽

Endocrine Tumors ◽

Pancreatic Endocrine Tumors ◽

Poorly Differentiated ◽

Well Differentiated ◽

Atypical Resection

e14647 Background: In 2010 WHO released a new classification (NWHO) system for endocrine pancreatic tumours (NETs). The aims of this study was to compare the NWHO and previous one (OWHO) in patients affected by NETs. Methods: From January 1980 to December 2010, 89 consecutives patients underwent surgical intervention for PNETs Data regarding sex, age, presence of symptoms, hormonal status, presence of MEN1, surgical procedure, R status, TNM stage, older and new WHO classification and disease specific survival (DSS) were prospectively collected. Multivariate analysis, including OWHO and NWHO, was carried out to evaluate the independent factors related to DSS. A sensitivity analysis was performed to include patients in which NWHO was impossible to be calculated. Results: Mean age of patients was 54.7 ± 14.2 years. There were 46 (51.7%) female and 43 (48.3%) male. Symptoms were present in 68 (76.4%) patients. Fifty-two (58.4%) patients had non-functioning NETs. Left pancreatectomy was performed in 48 (53.9%) cases, atypical resection in 22 (24.7%), pancreaticoduodenectomy in 12 (13.5%), total pancreatectomy in 2 (2.2%) and palliative surgery in 5 (5.6%). R0/1 resection was carried out in 79(88.7%) cases. According TNM stage there were: I, 27 (30.3%); II 29 (32.6%); III, 22 (24.7%); IV, 11 (12.4%). According OWHO 46 (51.7%) patients had a well differentiated tumours (WDT), 32 (36%) well differentiated carcinoma (WDCa), 11(12.4%) poorly differentiated carcinoma (PDCa). The NWHO was available only in 49 (55.1 %) patients: 20 (22.5%) NET G1, 25 (28.1%) NET G2, 4 (4.5%) neuroendocrine carcinomas (NEC) G3. At multivariate analysis OWHO and R2 status were the only independent factors related to DSS (RR=6.7, p<0.001 and RR 2.0, p=0.018 respectively). OWHO stratifies DSS better than NWHO: RR 0.12 (C.I. 95% 0.01-0.99; p=0.049) and RR 0.16 (C.I 95% 0.16-0.05; p=0.002) comparing WDT vs WDCa and WDCa vs PDCa, respectively. The sensitivity analysis confirmed in two model the superiority of OWHO while in others two we did not find any difference. Conclusions: In our experience OWHO still remains the best prognostic factor to predict DSS in patients with NETs .

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Factors Related to Long-Term Survival in Patients Affected by Well-Differentiated Endocrine Tumors of the Pancreas

ISRN Surgery ◽

10.5402/2012/389385 ◽

2012 ◽

Vol 2012 ◽

pp. 1-5 ◽

Cited By ~ 5

Author(s):

Riccardo Casadei ◽

Claudio Ricci ◽

Paola Tomassetti ◽

Davide Campana ◽

Francesco Minni

Keyword(s):

Multivariate Analysis ◽

Who Classification ◽

Cox Regression ◽

Univariate Analysis ◽

Endocrine Tumors ◽

Term Survival ◽

Long Term Survival ◽

Pancreatic Endocrine Tumors ◽

Well Differentiated

Aim. To identify factors related to survival in patients affected by well-differentiated PETs (benign, uncertain behavior, and carcinoma) who underwent R0 pancreatic resection. Methods. Retrospective study of 74 consecutive patients followed up from January 1980 to December 2011. Prognostic factors were sex, age, type of tumor, presence of symptoms, type of surgical procedure, size of tumor, lymph nodes status, WHO classification, and TNM stage. Overall survival was evaluated using the Kaplan-Meier method. Cox regression analyses were used to identify the factors associated with prognosis in univariate and multivariate analysis. Results. The mean follow-up of all the patients was months. The 5–10-year long-term survival was 90.9% and 79.1%, respectively. At univariate analysis, patient age <55 years was significantly related to a better long-term survival compared to patients age ≥55 years ( months versus months; ). Multivariate analysis showed that female gender (), patients without comorbidities (), and patients affected by well-differentiated benign pancreatic endocrine tumors ( and in relation to tumors with uncertain behavior and carcinomas, resp.) were factors significantly related to a better long-term survival. Conclusions. Patients factors were strongly related to a better long-term survival in patients observed. WHO classification is a very useful prognostic tool for well-differentiated PETs.

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Safety and Efficacy of the S-1/Temozolomide Regimen in Patients with Metastatic Neuroendocrine Tumors

Neuroendocrinology ◽

10.1159/000480402 ◽

2017 ◽

Vol 106 (4) ◽

pp. 318-323 ◽

Cited By ~ 4

Author(s):

Jiuda Zhao ◽

Hong Zhao ◽

Yihebali Chi

Keyword(s):

Neuroendocrine Tumors ◽

Locally Advanced ◽

Progression Free Survival ◽

Somatostatin Analogues ◽

Response To Treatment ◽

Endocrine Tumors ◽

Free Survival ◽

Safety And Efficacy ◽

Highly Active ◽

Pancreatic Endocrine Tumors

Purpose: Both capecitabine alone and capecitabine in combination with temozolomide have activities against neuroendocrine tumors (NETs). However, the role of S-1 in NETs is still unknown. We performed a study to evaluate the safety and efficacy of the S-1/temozolomide (STEM) regimen in patients with locally advanced or metastatic NETs. Methods: A retrospective review was conducted in 20 patients with locally advanced or metastatic NETs treated with the STEM regimen. Of the patients, 15 (75.00%) had failed 1 or more lines of treatment with somatostatin analogues, sunitinib, everolimus, anlotinib, or other chemotherapy regimens. The patients received S-1 at 40 mg/m2 orally twice daily on days 1-14 and temozolomide 200 mg orally once daily on days 10-14 of a 21-day cycle. The patients were followed up for evidence of object response, toxicity, and progression-free survival. Results: Response to treatment was assessed using RECIST 1.1. Eight patients (40.00%) achieved a partial response (PR), and another 8 (40.00%) had stable disease (SD). The clinical benefit rate (PR and SD) was 80.00%. The median progression-free survival was not achieved. Only 1 patient (5.00%) had grade 3 adverse events. Among the patients with NETs of different origins, 4 (40.00%) and 5 (50.00%) with pancreatic NETs attained PR and SD, respectively. Four (40.00%) and 3 patients (30.00%) with nonpancreatic NETs attained PR and SD, respectively. Conclusions: The STEM regimen is exceptionally highly active and well tolerated in patients with locally advanced or metastatic NETs. Even in patients who showed disease progression with previous therapies, it is still highly active. In this 20-patient study, the regimen appeared to be similarly active in pancreatic endocrine tumors and nonpancreatic NETs.

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