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Background: Controversy surrounds the indications for endoscopic treatment (ET) versus surgery in addressing gastrointestinal neuroendocrine neoplasms (GI-NENs). This paper aims to compare the long-term survival prognosis between ET and surgery for patients with GI-NENs., Methods: A retrospective analysis of GI-NEN patients diagnosed between 2000 and 2020 was conducted using the SEER database. Overall survival (OS) and cancer-specific survival (CSS) were estimated using the Kaplan-Meier method. Prognostic factors were assessed through univariate and multivariate Cox regression analyses. Propensity score matching (PSM) was employed to adjust for clinical variables., Results: This study encompassed 12,016 patients with GI-NENs, with 3732 patients (31.1%) undergoing ET and 8284 patients (68.9%) opting for surgery. The rectum was the most frequent location for ET, while the small bowel was the predominant site for surgery. Both the ET and surgical groups exhibited similar overall survival risk and cancer-specific survival risk before and after matching. No significant differences in the 1-year, 3-year, 5-year, and 10-year OS and CSS rates were observed between the ET and surgery groups after PSM. Nevertheless, subgroup analysis revealed a significantly better CSS in the ET group than the surgery group, particularly in stage I and tumors sized <10mm ( P <0.01). In the colon subgroup, the OS and CSS of the ET group were superior to those of the surgery group ( P <0.05)., Conclusion: Endoscopic treatment and surgery demonstrate comparable long-term survival prognoses for treating GI-NENs. ET emerges as a viable option for patients averse to surgical interventions., Competing Interests: The authors declare no conflicts of interest, (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Well-calibrated models for personalized prognostication of patients with gastrointestinal neuroendocrine neoplasms (GINENs) are limited. This study aimed to develop and validate a machine-learning model to predict the survival of patients with GINENs., Methods: Oblique random survival forest (ORSF) model, Cox proportional hazard risk model, Cox model with least absolute shrinkage and selection operator penalization, CoxBoost, Survival Gradient Boosting Machine, Extreme Gradient Boosting survival regression, DeepHit, DeepSurv, DNNSurv, logistic-hazard model, and PC-hazard model were compared. We further tuned hyperparameters and selected variables for the best-performing ORSF. Then, the final ORSF model was validated., Results: A total of 43,444 patients with GINENs were included. The median (interquartile range) survival time was 53 (19-102) months. The ORSF model performed best, in which age, histology, M stage, tumor size, primary tumor site, sex, tumor number, surgery, lymph nodes removed, N stage, race, and grade were ranked as important variables. However, chemotherapy and radiotherapy were not necessary for the ORSF model. The ORSF model had an overall C index of 0.86 (95% confidence interval, 0.85-0.87). The area under the receiver operation curves at 1, 3, 5, and 10 years were 0.91, 0.89, 0.87, and 0.80, respectively. The decision curve analysis showed superior clinical usefulness of the ORSF model than the American Joint Committee on Cancer Stage. A nomogram and an online tool were given., Conclusion: The machine learning ORSF model could precisely predict the survival of patients with GINENs, with the ability to identify patients at high risk for death and probably guide clinical practice., (© 2024 S. Karger AG, Basel.)

Purpose: Approved systemic therapies for advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have shown limited capacity to reduce tumor burden and no antitumor activity after progression to targeted agents (TAs). We investigated the efficacy and safety of lenvatinib in patients with previously treated advanced GEP-NETs., Patients and Methods: This was a multicenter, single-arm, open-label, phase II trial with two parallel cohorts (ClinicalTrials.gov identifier: NCT02678780) involving 21 institutions in 4 European countries. Eligible patients had histologically confirmed advanced grade 1-2 pancreatic (panNET) or GI (GI-NET) NETs with documented tumor progression after treatment with a TA (panNET) or somatostatin analogs (GI-NET). Patients were treated with lenvatinib 24 mg once daily until disease progression or treatment intolerance. The primary end point was overall response rate by central radiology review. Secondary end points included progression-free survival, overall survival, duration of response, and safety., Results: Between September 2015 and March 2017, a total of 111 patients were enrolled, with 55 (panNET) and 56 (GI-NET) patients in each cohort. The median follow-up was 23 months. The overall response rate was 29.9% (95% CI, 21.6 to 39.6): 44.2% (panNET) and 16.4% (GI-NET). The median (range) duration of response was 19.9 (8.4-30.8) and 33.9 (10.6-38.3) months in the panNET and GI-NET groups, respectively. The median progression-free survival was 15.7 months (95% CI, 14.1 to 19.5). The most common adverse events were fatigue, hypertension, and diarrhea; 93.7% of patients required dose reductions or interruptions., Conclusion: We report the highest centrally confirmed response reported to date with a multikinase inhibitor in advanced GEP-NETs, with a particularly strong response in the panNET cohort. This study provides novel evidence for the efficacy of lenvatinib in patients with disease progression following treatment with other TAs, suggesting the potential value of lenvatinib in the treatment of advanced GEP-NETs., Competing Interests: Jaume CapdevilaConsulting or Advisory Role: Bayer, Eisai, Sanofi, Exelixis, Novartis, Ipsen, Pfizer, Merck Serono, Advanced Accelerator Applications, LillySpeakers' Bureau: Bayer, Eisai, Sanofi, Novartis, Ipsen, Pfizer, Merck Serono, LillyResearch Funding: Eisai, AstraZeneca, Advanced Accelerator Applications, Novartis, Ipsen, Bayer, PfizerTravel, Accommodations, Expenses: Pfizer, Ipsen, Eisai Nicola FazioHonoraria: Novartis, Ipsen, Merck, Sanofi, Advanced Accelerator ApplicationsConsulting or Advisory Role: Novartis/Ipsen, Advanced Accelerator Applications, Pfizer, Ipsen, Merck Serono, MSD OncologyResearch Funding: Novartis, Merck Serono, Ipsen, MSDOther Relationship: Springer, Il Pensiero Scientifico Editore Carlos Lopez LopezHonoraria: Roche, Merck, Sanofi, Novartis, Pfizer, Eisai, Ipsen, Bayer, AstraZeneca, Servier, Bristol Myers Squibb, MSD Oncology, Advanced Accelerator ApplicationsConsulting or Advisory Role: Amgen, Roche, Sanofi, Merck, Servier, Pfizer, Ipsen, Bayer, Eisai, AstraZenecaResearch Funding: Amgen, Roche, Merck, Merck Sharp & Dohme, AstraZeneca Spain, Sanofi, Bayer, Ipsen, Eisai, Bristol Myers Squibb, Boehringer IngelheimTravel, Accommodations, Expenses: Roche, Pfizer, Merck, Servier, Amgen, Ipsen Alex TeuleHonoraria: Ipsen, Novartis, AAA HealthCare, PfizerConsulting or Advisory Role: AAA HealthCare Juan ValleHonoraria: IpsenConsulting or Advisory Role: Ipsen, Novartis, AstraZeneca, Merck, Agios, Pfizer, PCI Biotech, Incyte, Keocyt, QED Therapeutics, Pieris Pharmaceuticals, Genoscience Pharma, Mundipharma EDO GmbH, Wren Laboratories, Nucana, Servier, Debiopharm Group, Imaging Equipment Limited, Hutchison MediPharma, Zymeworks, Aptitude Health, Sirtex Medical, BaxterSpeakers' Bureau: Novartis, Ipsen, Nucana, Imaging Equipment Limited, Mylan, IncyteTravel, Accommodations, Expenses: Nucana, Pfizer, Lilly Nicholas ReedHonoraria: Novartis, Ipsen, Eisai, Roche, LillyConsulting or Advisory Role: Novartis, Ipsen, EisaiSpeakers' Bureau: RocheResearch Funding: Novartis, Ipsen, Exelixis, Lilly Enrique GrandeHonoraria: Pfizer, Bristol Myers Squibb, Ipsen, Roche, Eisai, Eusa Pharma, MSD, Genzyme, Advanced Accelerator Applications, Novartis, Pierre Fabre, Lexicon, Celgene, Janssen-Cilag, Astellas Pharma, AstraZeneca, Lilly, EUSA PharmaConsulting or Advisory Role: MSD, Pfizer, Ipsen, Roche, Bristol Myers SquibbResearch Funding: Roche, Pfizer, AstraZeneca, Ipsen, Molecular Templates, Lexicon, Astellas PharmaTravel, Accommodations, Expenses: Bristol Myers Squibb, Roche/Genentech, Pfizer, Janssen-Cilag, Ipsen Rocio Garcia-CarboneroHonoraria: Ipsen, Roche, Sanofi, Servier, Novartis, Pfizer, Merck, PharmaMar, Advanced Accelerator Applications, Bristol Myers Squibb, AstraZeneca, Lilly, Boehringer Ingelheim, Gilead Sciences, Sysmex, Pierre Fabre, Midatech Pharma, Advanz Pharma, HMP, Bayer, MSDConsulting or Advisory Role: Ipsen, Novartis, Pfizer, HMP, Advanced Accelerator Applications, Bayer, PharmaMar, Merck, MSD, Pierre FabreResearch Funding: Pfizer, Bristol Myers Squibb, MSDTravel, Accommodations, Expenses: Roche, Merck Paula J FonsecaOther Relationship: Ipsen Jorge HernandoSpeakers' Bureau: Eisai, Ipsen, Roche, Acraf, Advanced Accelerator ApplicationsTravel, Accommodations, Expenses: Ipsen, Novartis, Advanced Accelerator Applications, Roche, AstraZeneca, Eisai Francesca SpadaConsulting or Advisory Role: Ipsen, Novartis, Advanced Accelerator ApplicationsSpeakers' Bureau: Ipsen, Novartis, Advanced Accelerator ApplicationsTravel, Accommodations, Expenses: Ipsen, Novartis, Advanced Accelerator Applications Vicente AlonsoConsulting or Advisory Role: Amgen, Sanofi/Regeneron, Ipsen, Servier, Merck SeronoTravel, Accommodations, Expenses: Merck Serono, Roche, Novartis, Amgen, Sanofi/Regeneron, Ipsen, Servier Alfredo BerrutiConsulting or Advisory Role: Janssen-Cilag, Astellas Pharma, AmgenSpeakers' Bureau: Janssen-Cilag, Astellas PharmaResearch Funding: Astellas Pharma, Janssen-CilagTravel, Accommodations, Expenses: Janssen-Cilag, Sanofi, Sanofi Adelaida La CastaTravel, Accommodations, Expenses: Amgen, Roche, MSD Oncology Sevilla IsabelConsulting or Advisory Role: Ipsen, Pfizer, AmgenSpeakers' Bureau: Ipsen, PharmaMar, Sanofi, AAA HealthCareTravel, Accommodations, Expenses: Ipsen Patrizia KumpResearch Funding: Bristol Myers SquibbTravel, Accommodations, Expenses: Ipsen Pablo GajateConsulting or Advisory Role: Ipsen, Roche, EisaiSpeakers' Bureau: IPSEN, Pfizer, Novartis, EisaiTravel, Accommodations, Expenses: Ipsen, Pfizer Ignacio MatosSpeakers' Bureau: MSDResearch Funding: ESMO Angela LamarcaConsulting or Advisory Role: EISAI, Nutricia, Ipsen, QED Therapeutics, RocheSpeakers' Bureau: Merck, Ipsen, Pfizer, Novartis, Incyte, Advanced Accelerator ApplicationsResearch Funding: Ipsen, RocheTravel, Accommodations, Expenses: Abbott Nutrition, Ipsen, Pfizer, Celgene, Novartis, Advanced Accelerator Applications, Sirtex Medical, Bayer, Delcath Systems, Mylan, NanoString Technologies Toni IbrahimConsulting or Advisory Role: EISAI, Novartis, SanofiTravel, Accommodations, Expenses: Ipsen, Pharmamar, NovartisNo other potential conflicts of interest were reported.

Purpose: Well-differentiated stage IV neuroendocrine neoplasms (NEN) have an extremely heterogeneous, unpredictable clinical behavior. Survival prognostic markers, such as the recently proposed NEP-Score, would be very useful for better defining therapeutic strategies. We aim to verify NEP-Score applicability in an independent cohort of stage IV well-differentiated (WD) gastroentero-pancreatic (GEP) NEN, and identify a derivate prognostic marker taking into account clinical and pathological characteristics at diagnosis., Methods: Age, site of primary tumor, primary tumor surgery, symptoms, Ki67, timing of metastases of 27 patients (10 females; mean age at diagnosis 60.2 ± 2.9 years) with stage IV WD GEP NEN were evaluated to calculate the NEP-Score at the end of follow-up (NEP-T). We calculated the NEP-Score at diagnosis (NEP-D), which does not consider the appearance of new metastases during follow-up. Patients were subdivided according to whether they were alive or not at the end of follow-up (EOF) and an NEP-Score threshold was investigated to predict survival., Results: Mean NEP-T and mean NEP-D were significantly lower in 15 live patients as compared to 12 deceased patients (p < 0.01) at EOF. We identified an NEP-D = 116 as the cutoff that significantly predicts survival. No gender differences were identified., Conclusions: In our series, we confirmed NEP-Score applicability. In addition, we propose NEP-D as a simple, quick and cheap prognostic score that can help clinicians in decision making. NEP-D threshold can predict NEN aggressiveness and may be used to define the best personalized therapeutic strategy.

Background: Attributable to the high likelihood of developing distant metastatic disease, resection of poorly differentiated gastroenteropancreatic neuroendocrine neoplasms is generally contraindicated. Some patients with no distant metastatic disease will nonetheless undergo surgical resection and their outcomes are not known. We aimed to determine whether surgery confers survival advantage over systemic therapy alone for patients with non-metastatic poorly differentiated gastroenteropancreatic neuroendocrine neoplasms., Methods: We performed a retrospective cohort study (2000-2012) of adults in the California Cancer Registry who had poorly differentiated gastroenteropancreatic neuroendocrine neoplasms (World Health Organization Grade 3) and no clinical evidence of distant metastasis (M0). Patients who underwent surgery were compared with those managed non-operatively. The adjusted Cox proportional hazards model was used to assess the risk of death., Results: Among 2,245 patients (45% female, 21% pancreatic, 79% gastrointestinal), 1,549 (69%) were treated with surgery, and 696 (31%) received either systemic therapy or palliative measures alone. Median survival was 31 months after surgery versus 9 months after non-operative therapy (log-rank test, P < .001). Rates of 5-year overall survival were 39% after surgery versus 10% in the non-operative group. Adjusting for age, sex, comorbidities, receipt of chemotherapy, and tumor size and location, patients treated with surgery had a 58% lower likelihood of death compared with non-operative therapy (hazard ratio: 0.42, 95% confidence interval: 0.36-0.50, P < .001). Restricting our results to those patients who were found to have no distant metastasis intraoperatively (ie, pathologically M0), 5-year survival after surgery reached 44%., Conclusion: While poorly differentiated gastroenteropancreatic neuroendocrine neoplasms carries a poor prognosis, for patients with no evidence of metastatic disease, resection appears to confer significant improvement in long-term survival. Although caution and an individualized approach in treating poorly differentiated gastroenteropancreatic neuroendocrine neoplasms is advised, future guidelines might reflect this survival advantage., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to characterize the tumor microenvironment of patients with gastroenteropancreatic neuroendocrine tumors relative to progression-free survival (PFS)., Methods: Immune profiling for CD3, CD8, programmed death-1/programmed death-ligand 1, and indoleamine 2,3-dioxygenase expression in 2 cohorts of gastroenteropancreatic neuroendocrine tumors: patients with short PFS (<4 years, n = 12) versus long PFS (≥4 years, n = 14) after surgery. Immune infiltrates in the tumor and interface were quantified. Programmed death-ligand 1 expression was determined within the tumor, stroma, and interface., Results: Patients with shorter PFS had larger tumors (P = 0.02), mostly in the pancreas (P = 0.04). We observed a higher mean expression of CD3+, CD8+, programmed death-1+ cells, and indoleamine 2,3-dioxygenase at the interface compared with the tumor: log 10 mean differences 0.56 (95% confidence interval [CI], 0.43-0.68; P < 0.0001), 0.45 (95% CI, 0.32-0.59; P = 0.0002), 0.50 (95% CI, 0.40-0.61; P < 0.0001), and 0.24 (95% CI, 0.03-0.46; P = 0.046), respectively. Patients with longer PFS had higher intratumoral CD3+ T cells, log 10 mean difference 0.38 (95% CI, 0.19-0.57; P = 0.004). Programmed death-ligand 1 expression tended to be higher among patients with shortened PFS (odds ratio, 2.00; 95% CI, 0.68-5.91)., Conclusions: Higher intratumoral CD3+ T-cell infiltrate was associated with longer PFS after resection., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Patients with sporadic neuroendocrine neoplasms may exhibit a higher risk of a second primary tumor than the general population., Aim: This study aimed to analyze the occurrence of second primary malignancies., Methods: A retrospective cohort of 2757 patients with sporadic lung and gastro-entero-pancreatic neuroendocrine neoplasms, managed at eight Italian tertiary referral Centers, was included., Results: Between 2000 and 2019, a second primary malignancy was observed in 271 (9.8%) neuroendocrine neoplasms patients with 32 developing a third tumor. There were 135 (49.8%) females and the median age was 64 years. The most frequent locations of the second tumors were breast (18.8%), prostate (12.5%), colon (9.6%), blood tumors (8.5%), and lung (7.7%). The second primary tumor was synchronous in 19.2% of cases, metachronous in 43.2%, and previous in 37.6%. As concerned the neuroendocrine neoplasms, the 5- and 10-year survival rates were 87.8% and 74.4%, respectively. PFS for patients with a second primary malignancy was shorter than for patients without a second primary malignancy. Death was mainly related to neuroendocrine neoplasms., Conclusion: In NEN patients the prevalence of second primary malignancies was not negligible, suggesting a possible neoplastic susceptibility. Overall survival was not affected by the occurrence of a second primary malignancy., Competing Interests: Declaration of Competing Interest The Authors have no conflicts of interest to declare., (Copyright © 2020 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Opinion Statement: The clinical scenario of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) is continuously changing due to significant improvements in the definition of their molecular landscapes and the introduction of innovative therapeutic approaches. Many efforts are currently employed in the integration of the genetics/epigenetics and clinical information. This is leading to an improvement of tumor classification, prognostic stratification and ameliorating the management of patients based on a personalized approach.

Objective: The aim of the study was to assess the impact of systemic markers of inflammation on the outcomes in patients with neuroendocrine tumors (NETs) treated with everolimus or placebo (as measured by baseline neutrophil-to-lymphocyte ratio [NLR] and lymphocyte-to-monocyte ratio [LMR])., Methods: Patient data (gastrointestinal, pancreatic, and lung NETs) from 2 large phase 3 studies, RADIANT-3 (n = 410) and RADIANT-4 (n = 302), were pooled and analyzed. The primary end point was centrally assessed progression-free survival (PFS) as estimated by the Kaplan-Meier method., Results: In the pooled population, elevated LMR (median PFS, 11.1 months; 95% confidence interval, 9.3-13.7; hazard ratio, 0.69; P < 0.001) and reduced NLR (median PFS, 10.8 months; 95% confidence interval, 9.2-11.7; hazard ratio, 0.75; P = 0.0060) correlated with longer PFS among all patients. These markers were also found to be prognostic in the everolimus- and placebo-treated subgroups., Conclusions: Data from this study suggest that LMR and NLR are robust prognostic markers for NETs and could potentially be used to identify patients who may receive or are receiving the most benefit from targeted therapies. As both are derived from a complete blood count, they can be routinely used in clinical practice, providing valuable information to clinicians and patients alike., Competing Interests: D.L.C. reports personal fees and nonfinancial support from Novartis and Ipsen and grants from Merck KGaA, outside the submitted work. J.C.Y. reports personal fees from Novartis, Ipsen, Mallinckrodt, Tarveda, Crinetics, Hutchison Medi, Chiasma, Exelixis, and Nektar, outside the submitted work. F.H. was an employee of Novartis (during the time of this research). A.R. is an employee of Novartis. J.S. reports personal fees from Ipsen, Lexicon, and Novartis, outside the submitted work. M.P. reports honoraria for presentations/advisory boards from Ipsen, Pfizer, Lexicon, and Novartis and research support from former institutions—Charité, Ipsen, and Novartis. S.S. reports others from Novartis during the conduct of the study and personal fees from Novartis and Ipsen, outside the submitted work. The other authors declare no conflict of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: The objective of this study was to evaluate racial differences in cancer treatment and survival in gastroenteropancreatic neuroendocrine tumor (GEP-NET) patients., Methods: Using the Surveillance, Epidemiology, and End Results Registry, we identified patients with GEP-NETs of the stomach, small intestine (SI), colon, rectum, appendix, and pancreas diagnosed between 1973 and 2014. Demographic, cancer, and treatment information were collected and compared using χ2 tests. Multivariable logistic and Cox regression were used to determine disparities in receiving treatment and overall survival., Results: We identified 19,031 GEP-NET patients: 2839 were non-Hispanic Blacks, 12,832 non-Hispanic Whites, 2098 Hispanics, and 1262 Asians. African Americans and Hispanics with SI and pancreatic NETs were less likely to be treated with surgery (odds ratio, 0.6; 95% confidence interval [CI], 0.46-0.69; odds ratio, 0.71; 95% CI, 0.51-0.99, respectively). African American race was not an independent predictor of survival; there was a strong trend in stomach, SI, and pancreas NETs (hazard ratio [HR], 1.31; 95% CI, 1-1.7; HR, 1.2; 95% CI, 0.99-1.45; HR, 1.22; 95% CI, 1-1.48, respectively)., Conclusions: Our study provides evidence of racial disparities in treatment and survival across GEP-NET primary sites and racial groups. Further studies should be performed to improve our understanding of the reason for these disparities., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The value of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for patients with peritoneally metastasized goblet-cell carcinoids (GCCs) and mixed adenoneuroendocrine carcinomas (MANECs) is currently unclear. We compared outcomes of CRS-HIPEC to surgery alone for peritoneally metastasized GCCs and MANECs., Patients and Methods: Two cohorts were obtained from the Netherlands Cancer Registry (n = 569): patients with peritoneally metastasized GCCs and MANECs treated with CRS-HIPEC in Dutch and Belgian centers (n = 45), and patients treated with surgery alone. Primary outcome was overall survival (OS). Secondary outcomes were morbidity and hospital mortality. After propensity score matching, OS was compared in univariate and multivariate analyses. A systematic literature review was conducted following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines from database inception to June 25, 2018., Results: After matching for sex, tumor stage, lymph node stage, and liver metastases, CRS-HIPEC was associated with improved median OS in the combined GCC and MANEC group and the separate GCC subgroup in univariate (GCC + MANEC: 39 vs. 12 months, P < .001; GCC: 39 vs. 12 months, P = .017) and multivariate analysis (GCC + MANEC: hazard ratio 4.27, 95% confidence interval 1.88-9.66, P = .001; GCC: hazard ratio 2.77, 95% confidence interval 1.06-7.26, P = .038). Acceptable grade III-IV morbidity (17.5%) and mortality (0) were seen after CRS-HIPEC. The literature review supported these findings., Conclusion: CRS-HIPEC is associated with substantial survival benefit in patients with peritoneally metastasized GCCs and MANECs compared to surgery alone and is a safe treatment option. These data support centralized care of GCC and MANEC patients with peritoneal spread in expert centers offering CRS-HIPEC., (Copyright © 2020. Published by Elsevier Inc.)

Objective: To study the clinical characteristics and classification of gastric neuroendocrine neoplasm(NEN) and prognostic factors of mixed adenoneuroendocrine carcinoma (MANEC) and gastric neuroendocrine carcinoma(NEC). Methods: A total of 148 gastric NENs were divided into type Ⅰ, type Ⅱ and type Ⅲ based on the classification of European Neuroendocrine Tumor Society (ENETS). Kaplan-Meier test and Cox regression model were used in univariate and multivariate survival analysis in 108 cases with pathological G3 gastric NEN. Results: In this study, the percentages of type Ⅰ, type Ⅱ and type Ⅲ were 25.0%(37), 3.4%(5) and 71.6%(106) respectively. Among type Ⅰ patients, 28(75.7%) lesions were located in gastric fundus or body, 29(78.4%) had bumps. Lymph node involvement was found in 4 (10.8%) patients. Twenty-six (70.3%) patients received endoscopic treatment and 11 (29.7%) with surgery. All 5 type Ⅱ patients presented lesions in gastric fundus or body, including 4 with ulcers, who were all treated by endoscope. Three type Ⅱ patients had gastrinoma, and 2 combined with multiple endocrine neoplasmⅠ. In type Ⅲ patients, 56(52.8%) showed ulcerative lesions. The majority of patients (102, 96.2%) had a single lesion, 94(88.7%) with lymph node or other organ metastasis. In this study, no deaths were reported in gastric NEN with a pathological grade of G1 or G2. The mortality rate was 38.9%(42/108) in patients with G3 NEN. Survival analysis suggested that age, metastasis of tumor were associated with poor prognosis ( P =0.041, 0.025). Conclusions: Patients with gastric NEN have heterogenous clinical presentations according to gender, age, endoscopic features, infiltration and metastasis, and pathological grade. Aging and metastasis are negative prognostic factors of G3 gastric NEN.

Background: Neuroendocrine neoplasia (NEN) are rare and heterogenous tumours. Few data exist on the impact of surgical therapy., Materials and Methods: This is a retrospective analysis of prospectively collected data of gastroenteropancreatic NEN in the German NET-Registry (1999-2012). It focuses on patients without distant metastases (limited disease, LD, stage I-IIIB)., Results: Data of 2239 patients with NEN were recorded. Median age was 59 years, the gender ratio was 1:1.3 (f:m). A total of 986 patients (44%) had LD, and the 5-year survival rate (5 years) was 77% for all and 90% for patients with LD. A total of 1635 patients (73%) received a surgical therapy (1st to 6th line); the 5 and 10 ysr were 83/65% after and 59/35% without surgery for all patients (p < .001). The resection margins in the LD patients were 76%, 16%, and 3% for R0, R1 and R2, respectively. The 10 ysr was 84%, 59% and 42% for R0, R1 and R2 resections, respectively (p = .021 R0/R1, p < .001 R0/R2). The R0 resection rate was 75% for G1/G2 NET and 67% for G3 NEC., Conclusion: The rate of complete tumour resection (R0) in LD is independent of tumour grading, and R0 resection is the key determinant of long-term survival, as demonstrated by the 10 ysr. of 84%. All NEN patients with limited disease should be considered for operation, if possible, as the best 10-year survival is shown after an R0 resection.

Objective: The aim of this study was to determine outcomes of primary tumor resection in metastatic neuroendocrine tumors across all primary tumor sites., Background: Primary tumor resection (PTR) may offer a survival benefit in metastatic gastrointestinal neuroendocrine tumors (GI-NETs); however, few studies have examined the effect of primary site and grade on resection and survival., Methods: This is a retrospective study of patients with metastatic GI-NETs at presentation between 2005 and 2011 using the California Cancer Registry (CCR) dataset merged with California Office of Statewide Health Planning and Development (OSHPD) inpatient longitudinal database. Primary outcome was overall survival (OS). Univariate and multivariate (MV) analyses were performed using the Pearson Chi-squared tests and Cox proportional hazard, respectively. OS was estimated using the Kaplan-Meier method and log-rank test., Results: A total of 854 patients with GI-NET metastases on presentation underwent 392 PTRs. Liver metastases occurred in 430 patients; 240 received liver treatment(s). PTR improved OS in patients with untreated metastases (median survival 10 vs 38 months, P < 0.001). On MV analysis adjusted for demographics, tumor stage, grade, chemotherapy use, Charlson comorbidity index, primary tumor location, or treatment of liver metastases, PTR with/without liver treatment improved OS in comparison to no treatment [hazard ratio (HR) 0.50, P < 0.001 and 0.39, P < 0.001, respectively]. PTR offered a survival benefit across all grades (low-grade, HR 0.38, P = 0.002 and high-grade, HR 0.62, P = 0.025) CONCLUSION:: PTR in GI-NET is associated with a better survival, with or without liver treatment, irrespective of grade. This study supports the resection of the primary tumor in patients with metastatic GI-NETs, independent of liver treatment.

The ACS established an online risk calculator to help surgeons make patient-specific estimates of postoperative morbidity and mortality. Our objective was to assess the accuracy of the ACS-NSQIP calculator for estimating risk after curative intent resection for primary GI neuroendocrine tumors (GI-NETs). Adult patients with GI-NET who underwent complete resection from 2000 to 2017 were identified using a multi-institutional database, including data from eight academic medical centers. The ability of the NSQIP calculator to accurately predict a particular outcome was assessed using receiver operating characteristic curves and the area under the curve (AUC). Seven hundred three patients were identified who met inclusion criteria. The most commonly performed procedures were resection of the small intestine with anastomosis (N = 193, 26%) and partial colectomy with anastomosis (N = 136, 18%). The majority of patients were younger than 65 years (N = 482, 37%) and ASA Class III (N = 337, 48%). The most common comorbidities were diabetes (N = 128, 18%) and hypertension (N = 395, 56%). Complications among these patients based on ACS NSQIP definitions included any complication (N = 132, 19%), serious complication (N = 118, 17%), pneumonia (N = 7, 1.0%), cardiac complication (N = 1, 0.01%), SSI (N = 80, 11.4%), UTI (N = 17, 2.4%), venous thromboembolism (N = 18, 2.5%), renal failure (N = 16, 2.3%), return to the operating room (N = 27, 3.8%), discharge to nursing/rehabilitation (N = 22, 3.1%), and 30-day mortality (N = 9, 1.3%). The calculator provided reasonable estimates of risk for pneumonia (AUC = 0.721), cardiac complication (AUC = 0.773), UTI (AUC = 0.716), and discharge to nursing/rehabilitation (AUC = 0.779) and performed poorly (AUC < 0.7) for all other complications Fig. 1). The ACS-NSQIP risk calculator estimates a similar proportion of risk to actual events in patients with GI-NET but has low specificity for identifying the correct patients for many types of complications. The risk calculator may require modification for some patient populations.

Background: Neuroendocrine neoplasm is a rare solid tumor. Metastatic pattern of the gastrointestinal neuroendocrine neoplasm (GI-NEN) has not been fully explored., Methods: Data were obtained from the Surveillance, Epidemiology, and End Results (SEER) database (SEER-9 registry) from 1973 to 2015. Incidence was estimated by Joinpoint regression analyses. Data with additional treatment fields of GI-NEN were extracted from the SEER-18 registry from 1 January 2010 to 31 December 2015. A total of 14 685 GI-NEN patients were included in this study. Statistical analyses were performed with SPSS 25.0, the Intercooled Stata SE 15.0, and GraphPad Prism 7., Results: Incidence of GI-NENs increased from 0.51 per 100 000 patients in 1973 to 6.20 per 100 000 patients in 2015. Of them, 2003 patients were stage IV GI-NEN at the time of diagnosis, including 1459 (72.84%) patients with liver metastasis, 144 (7.19%) lung metastasis, 115 (5.74%) bone metastasis, and 27 (1.35%) brain metastasis. Esophageal NEN had the highest risk of metastasis (52.68%). The median survival for patients with liver, lung, bone, and brain metastasis was 38, 6, 9, and 2 months, respectively. The presence of lung or liver metastasis indicated higher risk of concurrent existence of bone and brain metastasis than those without., Conclusion: Bone and brain metastasis should be screened in the GI-NEN patients if they had lung or liver metastasis. Findings of the current study could help clinicians to identify distant metastasis of GI-NENs as early as possible, and by which, to improve survival rate of GI-NENs., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Introduction : 177 Lutetium-[DOTA°,Tyr 3 ]octreotate ( 177 Lu-DOTATATE) is a type of peptide receptor radionuclide therapy that garnered FDA approval in January 2018 for the treatment of somatostatin receptor-positive gastroenteropancreatic (GEP) neuroendocrine tumor (NET) patients. The therapy approval was based on findings from the randomized international phase III NETTER-1 trial as well as outcome data from a large European registry. The mechanism of the drug stems directly from its structure: a somatostatin analog (octreotate) selectively binding to somatostatin receptor expressing cells and being internalized, along with a chelated beta-emitting isotope 177 Lu. Areas Covered : Herein we describe the pharmacology, clinical efficacy and adverse event data from prospective and retrospective studies with 177 Lu-DOTATATE. We discuss the role of 177 Lu-DOTATATE within the current treatment landscape for GEP NET patients. Expert Opinion : 177 Lu-DOTATATE represents a unique addition to the treatment armamentarium for GEP NETs because of its potential to elicit tumor cytoreduction, which is rare among other existing treatment options, and prolonged disease control. Where 177 Lu-DOTATATE fits into the treatment sequence for GEP NET patients remains an area of active investigation.

Background: Primary gallbladder neuroendocrine tumors (NETs) are rare, poorly understood cancers infrequently encountered at even the largest of tertiary referral centers. We therefore sought to identify a large cohort of patients with gallbladder NETs using a national database, with the aim of defining treatment modalities employed and survival associated with these uncommon malignancies., Methods: Patients with primary gallbladder NETs were identified in the National Cancer Database, and clinicopathologic characteristics were recorded. A univariate log-rank survival analysis was completed for patients who underwent resection. Parameters found to be significant were entered into a multivariate accelerated failure time analysis. For context, survival comparisons were included for patients who underwent resections for NETs at any gastrointestinal site and for gallbladder adenocarcinoma., Results: Overall, 754 patients with gallbladder NETs were identified. Patients were predominantly female (n = 518, 69%), White (n = 503, 67%), presented with stage IV disease (n = 295, 39%) and had high-grade lesions (n = 312, 41%). The majority underwent resection (n = 480, 64%), primarily simple cholecystectomy (n = 431, 90%), whereas a minority received multimodal therapy (n = 145, 21%). Among patients who underwent resection, older age (p = 0.001), large cell histology (p = 0.012), and positive margins (p = 0.030) were independently associated with worse overall survival. Patients with gallbladder NETs had improved survival relative to those with gallbladder adenocarcinoma (p = 0.001), but significantly worse survival than patients with NETs from other gastrointestinal sites (p < 0.001)., Conclusions: Primary gallbladder NETs are aggressive lesions that carry a worse prognosis than NETs of other gastrointestinal sites. Older age, positive margins, and large cell histology are associated with abbreviated survival after resection.

Objective: The chemopreventive effect of aspirin (ASA) has been observed in the setting of colorectal cancer and other solid neoplasms. Recently, ASA has demonstrated a promising anti-proliferative effect on GEP-NENs in vitro . However, the direct anti-neoplastic impact of ASA on GEP-NEN clinical outcome is yet to be clarified. Materials and methods: All the GEP-NEN patients followed up in three European Centers from January 2005 to September 2016 were retrospectively enrolled. Patients taking ASA in doses of 75-100 mg daily for cardiovascular prevention for at least six months were evaluated. The possible association between ASA and disease grading, staging, primary site, OS and PFS were evaluated. Results: Two hundred fifty one patients were included (117 males, median age 63 years). Of these, 64 patients were prescribed with ASA. No clear impact on OS or PFS was observed in GEP-NEN patients taking ASA compared to those not taking it. ASA intake was related with the patients' older age. At Cox multivariate analysis, stage IV and Ki-67 resulted independent predictors for OS and PFS. In the setting of intestinal NENs, a suggestive, but not statistically significant, protective role of ASA on PFS was observed [HR 0.41 (95% CI: 0.13-1.29)]. Conclusions: Despite ASA showed promising anti-proliferative effects in vitro and a chemopreventive action in NENs has been reported, a clear impact of ASA on survival in NENs has not emerged from the present study. However, in the subgroup of patients with small-intestine NENs, ASA showed a trend toward a protective role.

Objectives: Patients with neuroendocrine tumors (NETs) are at increased risk of mortality from competing causes in light of the improvement in overall survival over recent decades. The purpose of this study was to explore the competing causes of deaths and the risk factors associated with competing mortality., Materials and Methods: The Surveillance, Epidemiology, and End Results database was used to identify patients diagnosed with NETs between 1973 and 2015. Risk of competing mortality was estimated by the standardized mortality ratios (SMRs) and by using the Fine and Gray multivariate regression model., Results: Of the 29,981 NET patients, 42.5% of the deaths that occurred during follow-up were attributed to competing causes (83.9% from noncancer causes and 16.1% from second primary neoplasms). Overall SMR of competing mortality was 2.50 (95% confidence interval [CI]: 2.43-2.56). The SMR of noncancer causes was 2.65 (95% CI: 2.58-2.73), with the highest risk present within the first year of diagnosis. The SMR of second primary neoplasms was 1.91 (95% CI: 1.79-2.04), with the highest risk observed after 10-year postdiagnosis. A drastic rise in competing mortality was observed in the last decade between 2005 and 2015. Advanced age, black race, small intestinal and gastric NETs, and surgery were significantly associated with competing mortality. Female, pancreatic and recto-anal NETs, distant and regional spread, chemotherapy and radiotherapy were significantly associated with lower competing mortality., Conclusions: Competing mortality plays an increasingly significant role over the years and may hamper efforts made to improve survival outcomes in NET patients.

Neuroendocrine tumors (NET) are rare tumors for which somatostatin analogs (SSA) are used not only for symptom control due to a functioning tumor, but also for the disease control of unresectable NET. The efficacy of SSA for midgut NET has been verified by previous studies, but insufficient evidence exists for SSA treatment of NET in the foregut and hindgut (F/H-NET). The aim of this retrospective study was to evaluate the efficacy of SSA for unresectable F/H-NET. Patients with unresectable F/H-NET treated with SSA between February 2011 and August 2017 at our hospital were retrospectively reviewed. Parameters of efficacy were progression-free survival (PFS), overall survival, objective response rate (ORR), and adverse events. Twelve cases with unresectable F/H-NET were extracted from our database. With a median follow-up time of 25.9 months, the median PFS was 13.6 months. Two- and 3-year survival rates were 87.5 and 62.5%, respectively. The ORR was 8.3%, and the disease control rate was 75%. Serious adverse events were not observed. Subgroup analysis, including G1/G2, and hepatic tumor load, which is the volume of NET liver metastases, did not reveal a difference in PFS. The efficacy and safety of SSA for F/H-NET seemed similar to that found in the PROMID study, highlighting its relevance for the treatment of this disease.

Aim: Purpose of this study was to evaluate the association of the spatial heterogeneity (asphericity, ASP) in intra-therapeutic SPECT/ CT imaging of somatostatin receptor (SSR) positive metastatic gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) for morphological treatment response to peptide receptor radionuclide therapy (PRRT). Secondly, we correlated ASP derived form a pre-therapeutic OctreoScan (ASP[In]) and an intra-therapeutic [177Lu]-SPECT/CT (ASP[Lu])., Materials and Methods: Data from first therapy cycle [177Lu-DOTA0-Tyr3]octreotate ([177Lu]-DOTATATE)-PRRT was retrospectively analyzed in 33 patients (m = 20; w = 13; median age, 72 [46-88] years). The evaluation of response to PRRT was performed according to RECIST 1.1 in responding lesions [RL (SD, PR, CR), n = 104] and non-responding lesions [NRL (PD), n = 27]. The association of SSR tumor heterogeneity with morphological response was evaluated by Kruskal-Wallis test and receiver operating characteristic curve (ROC). The optimal threshold for separation (RL vs. NRL) was calculated using the Youden-index. Relationship between pre- and intra-therapeutic ASP was determined with Spearman's rank correlation coefficient (ρ) and Bland-Altman plots., Results: A total of 131 lesions (liver: n = 59, lymph nodes: n = 48, bone: n = 19, pancreas: n = 5) were analyzed. Lesions with higher ASP values showed a significantly poorer response to PRRT (PD, median: 11.3, IQR: 8.5-15.5; SD, median: 3.4, IQR: 2.1-4.5; PR, median 1.7, IQR: 0.9-2.8; CR, median: 0.5, IQR: 0.0-1.3); Kruskal-Wallis, p<0.001). ROC analyses revealed a significant separation between RL and NRL for ASP after 4 months (AUC 0.85, p<0.001) and after 12 months (AUC 0.94, p<0.001). The optimal threshold for ASP was >5.45% (sensitivity 96% and specificity 82%). The correlation coefficient of pre- and intra-therapeutic ASP revealed ρ = 0.72 (p <0.01). The mean absolute difference between ASP[In] and ASP[Lu] was -0.04 (95% Limits of Agreement, -6.1-6.0)., Conclusion: Pre- and intra-therapeutic ASP shows a strong correlation and might be an useful tool for therapy monitoring., Competing Interests: The authors have declared that no competing interests exist.

Symptoms of gastroenteropancreatic located neuroendocrine neoplasms (GEP-NENs) are often related to food intake and manifest as abdominal pain or diarrhoea which can influence patients nutritional status. Malnutrition is common in cancer patients and influences quality of life, treatment options and survival but is also present in up to 40% of patients with GEP-NENs. As part of malnutrition there are often deficiencies in fat-soluble vitamins, mainly vitamin D. Little knowledge exists on trace elements. Several factors influence the development of malnutrition such as size and localisation of the primary tumour as well as metastases, side effects from treatment but also hormone production of the tumour itself. One of the main influencing factors leading to malnutrition is diarrhoea which leads to dehydration and electrolyte disturbances. Treatment of diarrhoea should be guided by its cause. Screening for malnutrition should be part of routine care in every GEP-NEN patient. Multidisciplinary treatment including dietician support is necessary for all malnourished patients with GEP-NENs., Competing Interests: Conflict-of-interest statement: No conflict of interest.

Aim: The aim of this study is to investigate the clinicopathological characteristics, as well as explore the prognostic accuracy of the proposed new classification in gastrointestinal NENs (GI-NENs) patients., Methods: Patients diagnosed with GI-NENs were retrospectively indentified from existing databases of the pathological institute at our institution from January 2009 to November 2015., Results: We identified 414 patients with GI-NENs, 250 cases were diagnosed as neuroendocrine tumor G1 (NET G1), 25 as neuroendocrine tumor G2 (NET G2), 53 as neuroendocrine tumor G3 (NET G3), 55 as neuroendocrine carcinoma G3 (NEC G3), and 31 as mixed adenoneuroendocrine carcinoma (MANEC); the overall survival (OS) rate at three years were 94.9%, 91.7%, 74.3%, 62.7% and 38.1%, respectively. The difference in progression-free survival (PFS) duration among the patients with NET G1, NET G2, NET G3, NEC G3, and MANEC was statistically significant (P < 0.001). However, the PFS of NEC G3 and MANEC was low and similar (P = 0.090). In multivariate analysis of patients with GI-NENs, surgical margin, comorbidity, proposed new classification and tumor location were useful predictors of OS (P < 0.05)., Conclusion: Our findings suggest that the proposed new classification can accurately reflect the clinical outcome, together with surgical margin, comorbidity, and tumor location may be meaningful prognostic factors for the OS of GI-NENs., (© 2017 John Wiley & Sons Australia, Ltd.)

Neuroendocrine neoplasms (NENs) are heterogeneous tumors originating from neuroendocrine cells. Their malignant potential varies from indolence to high-grade malignancy (carcinomas). We studied the survival of all NENs in Norway according to malignant potential and different primary sites. We identified all NEN cases diagnosed in 1993 to 2015 and reported to the national population-based Cancer Registry of Norway. We included 62 morphological types. According to morphological characteristics and known disease behavior, we stratified the tumors into two different groups: low/intermediate aggressiveness and high aggressiveness. A total of 17,128 NENs were analyzed. Median age was 67 years and 47.6% were females. The most common primary sites were in the lungs and the gastroenteropancreatic (GEP) system. The 5-year relative survival in patients with low/intermediate aggressive NENs was 64.8% (95% CI, 63.3-66.2) and high aggressive NENs 8.4% (95% CI, 7.8-9.1). Females had higher survival rates than males (p <0.001). The relative 5-year survival rate in patients younger than 50 years was 89.1% (95% CI, 87.4-90.7) vs 41.0% (95% CI, 34.9-46.9) in patients ≥80 years. In multivariable analysis gender, age at diagnosis, time of diagnosis, stage and primary sites were all predictors of outcome both in patients with low/intermediate tumors and high aggressive tumors. Survival improved significantly over time, regardless of sex, age and tumor stage., (© 2017 UICC.)

Background & Aims: Survival times vary among patients with neuroendocrine tumors (NETs) - even among those with the same site, stage, and grade of primary tumor. This makes it difficult to select treatment for patients with unresectable NETs because some patients can survive decades without treatment. 68 Gallium-DOTATATE positron emission tomography with computed tomography ( 68 Ga-DOTATATE PET/CT) is a sensitive imaging technique for detection of NETs. We investigated the prognostic accuracy of 68 Ga-DOTATATE PET/CT-based analysis of tumor volume in patients with NETs., Methods: We performed a prospective study of 184 patients with NETs (128 [69.6%] with metastases and 11 patients [6.0%] with locally advanced disease) at the National Institutes of Health Clinical Center (Bethesda, MD) from 2013 through 2017. All patients underwent 68 Ga-DOTATATE PET/CT image analysis and total 68 Ga-DOTATATE-Avid tumor volume ( 68 Ga-DOTATATE TV) was determined. We also measured fasting serum chromogranin A, neuron-specific enolase, gastrin, glucagon, vasoactive intestinal peptide, pancreatic polypeptide, and 24-hour urinary 5-hydroxyindoleacetic acid levels in all patients. Disease progression was defined as a new lesion or a growth of a known lesion during the interval between baseline 68 Ga-DOTATATE PET/CT scan and follow-up imaging (14.0 ± 6.1 months; range, 1-35 months). The primary outcomes were progression-free survival (PFS) and disease-specific mortality during a median follow-up time of 18 months (range, 4-35 months)., Results: We found an inverse correlation between quartiles of 68 Ga-DOTATATE TV and PFS (P = .001) and disease-specific survival (P = .002). A 68 Ga-DOTATATE TV of 7.0 mL or more was associated with higher odds of disease progression (hazard ratio, 3.0; P = .04). A 68 Ga-DOTATATE TV of 35.8 mL or more was associated with increased risk of disease-specific death (hazard ratio, 10.6) in multivariable analysis (P = .01), as well as in subgroup analysis of patients with pancreatic NETs., Conclusions: In a prospective study, we demonstrated the prognostic utility of 68 Ga-DOTATATE TV in a large cohort of patients with NETs, in terms of PFS and disease-specific mortality., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Mesenteric fibrosis (MF) surrounding a lymph node metastasis is a known phenomenon in midgut neuroendocrine tumors (NETs) with characteristic radiological appearance. Its etiology is poorly understood as it affects some but not all midgut NET patients with lymphatic involvement. This study assessed a potential relationship of MF with carcinoid syndrome, urinary 5-hydroxyindoleacetic acid (5-HIAA), and carcinoid heart disease (CHD)., Methods: A cohort of 81 patients with pathologically proven NETs with the primary site in the midgut and mesenteric lymphatic metastases on imaging were retrospectively included. Imaging characteristics of lymphatic and hepatic metastases at diagnosis (size, number, burden, and morphologic features, including presence of MF), Ki67 grading, 5-HIAA, functionality, and development of CHD were analyzed., Results: Overall, 54% of patients had MF. The presence of MF was more frequently associated with mesenteric vessel encasement (100 vs. 46% without MF; p < 0.001), presence of hepatic metastases (91 vs. 62%; p = 0.002), larger hepatic tumor burden (15 vs. 5%; p = 0.001), and functionality (86 vs. 43%; p < 0.001). Multivariate analysis revealed 5-HIAA ≥395 µmol/day (p = 0.020), age (p = 0.013), and largest lymphatic metastasis ≥24 mm (p = 0.009) as independent predictors of MF, while functionality (p = 0.098) and CHD (p = 0.070) showed a tendency towards significance. MF was associated with decreased time to development of CHD in functional midgut NETs (p = 0.043)., Conclusions: We found a significant association of MF with metastatic patterns and with criteria of functionality. The association of MF with elevated 5-HIAA, and consecutively with carcinoid syndrome and potential development of CHD, suggests a linked pathophysiological mechanism, which might be similar to that of endocardial fibrosis., (© 2017 S. Karger AG, Basel.)

Background: In the phase 3 RADIANT-4 trial, everolimus increased progression-free survival compared with placebo in patients with advanced, progressive, non-functional, well-differentiated gastrointestinal or lung neuroendocrine tumours (NETs). We now report the health-related quality of life (HRQOL) secondary endpoint., Methods: RADIANT-4 is a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial done in 97 centres in 25 countries worldwide. Adults (aged ≥18 years) were eligible for the study if they had pathologically confirmed, advanced (unresectable or metastatic), non-functional, well-differentiated (grade 1 or 2) NETs of lung or gastrointestinal origin. Patients were randomly allocated (2:1) using block randomisation (block size of three) by an interactive voice response system to receive oral everolimus (10 mg per day) or placebo, both with best supportive care, with stratification by tumour origin, WHO performance status, and previous somatostatin analogue treatment. HRQOL was assessed with the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire at baseline (visit 2, day 1), every 8 weeks (± 1 week) during the study for the first 12 months after randomisation, and every 12 weeks thereafter until study drug discontinuation. The primary endpoint, reported previously, was progression-free survival assessed by central review; HRQOL was a prespecified secondary endpoint. The prespecified secondary outcome measure was time to definitive deterioration (≥7 points) in FACT-G total score. Analyses were done on the full analysis set, consisting of all randomised patients, by intention to treat. Only data obtained while receiving the randomly allocated treatment were included in this analysis. Enrolment for RADIANT-4 was completed on Aug 23, 2013, but the trial is ongoing pending final analysis of the key secondary endpoint of overall survival. This trial is registered with ClinicalTrials.gov, number NCT01524783., Findings: Between April 3, 2012, and Aug 23, 2013, 302 patients were enrolled; 205 were randomly allocated everolimus and 97 were assigned placebo. At baseline, 193 (94%) of 205 patients assigned everolimus and 95 (98%) of 97 allocated placebo had completed either fully or partly the FACT-G questionnaire; at week 48, 70 (83%) of 84 patients assigned everolimus and 22 (85%) of 26 allocated placebo completed FACT-G. Median time to definitive deterioration in FACT-G total score was 11·27 months (95% CI 9·27-19·35) with everolimus and 9·23 months (5·52-not estimable) with placebo (adjusted hazard ratio 0·81, 95% CI 0·55-1·21; log-rank p=0·31)., Interpretation: HRQOL was maintained for patients with advanced, non-functional, gastrointestinal or lung NETs, with no relevant differences noted between the everolimus and placebo groups. In view of the previous RADIANT-4 findings of longer progression-free survival with everolimus, our findings suggest that everolimus delays disease progression while preserving overall HRQOL, even with the usual toxic effects related to active targeted drug treatment for cancer., Funding: Novartis Pharmaceuticals., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: To investigate the clinical characteristics, pathological classification and prognostic factors of gastrointestinal neuroendocrine neoplasms (GI-NENs)., Methods: Clinicopathological data of 119 GI-NENs patients at Shanghai Renji Hospital from November 2007 to December 2016 were analyzed retrospectively. According to the classification and grading criteria of the WHO Neuroendocrine Tumor 2010 edition, patients were classified pathologically to realize the malignant degree of tumors. The overall survival rate was calculated by Kaplan-Meier curve, the prognostic risk factors were analyzed by Cox regression model, and the factors including the platelet/lymphocyte ratio (PLR) and neutrophil/lymphocyte ratio (NLR) were included in the analysis in addition to the routine clinicopathological factors., Results: Of 119 patients with GI-NENs, there were 83 cases (69.7%) of male and 36 cases (30.3%) of female. The age of patients ranged from 24 to 86 (median 61) years. Tumor locations included the stomach(n=70, 58.8%), duodenum(n=10, 8.4%), small intestine(n=2, 1.7%), appendix(n=3, 2.5%), colon(n=12, 10.1%), and rectum(n=22, 18.5%). The tumor diameter was 0.6 to 20 cm, the mean diameter was 5.4 cm, and the median diameter was 4 cm. There were 25 cases of G1 neuroendocrine tumor (NET), 7 cases of G2 NET and 87 cases of G3 neuroendocrine carcinoma (NEC). Among the 119 patients, 113 cases (95%) had complete follow-up, and the median follow-up was 75 (1 to 112) months. The 5-years overall survival rate was 58.4%. The survival rate of G1 NET, G2 NET and G3 NEC were 100%, 71.4%, 44.4%, and the difference was statistically significant (P=0.000). Univariate analysis showed that age ≥61 years (P=0.000), tumor located in the stomach, duodenum and colon (P=0.041), tumor size ≥4 cm (P=0.002), pathology classification of G3 NEC (P=0.000), late TNM staging (P=0.000) and blood PLR ≥133 (P=0.017) were associated with lower 5-year survival rate, but blood NLR level was not(P=0.263). Multivariate analysis showed that the patient age (HR=3.036, 95%CI: 1.548 to 5.956, P=0.001), the pathology classification(HR = 1.852, 95%CI:1.099 to 3.122, P=0.021), lymph node metastasis (HR=2.635, 95%CI:1.198 to 5.797, P=0.016) and distant metastasis (HR=2.685, 95%CI:1.383 to 5.214, P=0.004) were independent risk factors affecting the prognosis of patients, but the blood PLR level was not (HR=1.735, 95%CI: 0.947 to 3.176, P=0.074)., Conclusions: The malignant degree of GI-NEN is quite high, and the prognosis of patients is relatively poor. The age, pathological type and TNM staging are closely related to the prognosis of patients. Preoperative blood PLR may play a role in the prediction of prognosis, but preoperative blood NLR is not related with the prognosis of patients.

A meta-analysis has systematically investigated the antineoplastic efficacy and safety of somatostatin analogs (SSAs) in advanced gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs). Randomized controlled trials (RCTs) reporting the hazard ratio (HR) for disease progression (DP) were evaluated. Response rate and risk ratio (RR) for adverse events were also analyzed. A total of 289 patients (143 receiving SSAs vs. 146 placebo) were evaluated from two RCTs. A significant benefit from SSAs in terms of disease control was observed (HR 0.41, 95% CI: 0.29 to 0.58, P < 0.01; I20%), response rate being 58.0% vs. 32.2%, respectively.The occurrence of adverse events significantly differed from the placebo arm only in terms of biliary stones (RR 3.79, 95% CI: 1.28 to 11.17, P = 0.02; I20%). In conclusion, SSAs showed an antiproliferative effect in advanced GEP-NETs, with a good safety profile.

Background: Neuroendocrine tumours (NETs) are heterogeneous, with varying presentations and treatment options. To our knowledge, there are no randomized and few long-term studies of patient outcomes. The role of surgical and medical therapy for local, regional and metastatic disease continues to be evaluated in the literature., Methods: We conducted a population-based search of the provincial cancer registry to identify patients with gastrointestinal NETs from the stomach, small intestine, colon and rectum diagnosed between 1990 and 2005 and assessed their outcomes., Results: We examined clinicopathological information on the outcomes of 530 patients with gastrointestinal NETs. The overall incidence of NETs increased from 11 per million to 19 per million during the study period. Advancing stage and patient age were associated with poor overall or disease-specific outcomes. Surgery, both curative and palliative, was associated with decreased risk of overall (hazard ratio [HR] 0.5, p < 0.001) and disease-specific (HR 0.5, p < 0.001) death. The biggest benefit was observed in patients with distant disease, in whom 5-year disease-specific survival for R0 resections was nearly double that for patients with macroscopic residual disease (92% v. 48%, p = 0.009). Older age was associated with poor 5-year overall and disease-specific survival ( p < 0.001)., Conclusion: There has been a significant increase in incidence of gastrointestinal NETs, and advancing patient age, but not sex, is linked to poor outcomes in terms of overall and disease-specific survival. Surgery, both curative and palliative, was associated with decreased risk of overall and disease-specific death. Compared with patients with residual macroscopic disease, patients with distant disease were nearly twice as likely to survive 5 years if they had R0 resections. The use of radioisotope therapy and long-acting octreotide therapy was also associated with improved outcomes overall.

Background and Objective: Neuroendocrine liver metastasis tumors (NELM) are a heterogeneous group of neoplasms with varied histologic features and a wide range of clinical behaviors. We aimed to identify the fraction of patients cured after liver surgery for NELM., Methods: Cure fraction models were used to analyze 376 patients who underwent hepatectomy with curative intent for NELM., Results: The median and 5-year disease-free survival (DFS) were 4.5 years and 46%, respectively. The probability of being cured from NELM by liver surgery was 44%; the time to cure was 5.1 years. In a multivariable cure model, type of neuroendocrine tumor (NET), grade of tumor differentiation, and rate of liver involvement resulted as independent predictors of cure. The cure fraction for patients with well differentiated NELM from gastrointestinal NET or a functional pancreatic NET, and with <50% of liver-involvement was 95%. Patients who had moderately/poorly differentiated NELM from a non-functional pancreatic NET, and with <50% of liver-involvement was 43%. In the presence of all the three unfavorable prognostic factors (nonfunctional PNET, liver involvement >50%, moderately/poorly differentiation), the cure fraction was 8%., Conclusions: Statistical cure after surgery for NELM is possible, and allow for a more accurate prediction of long-term outcome among patients with NELM undergoing liver resection., (© 2017 Wiley Periodicals, Inc.)

Purpose: Current staging criteria for gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs), while useful, have limitations. In this study, we used a population-based registry to evaluate the prognostic utility of the current staging systems and assess whether evidence-based modifications can improve survival predictions., Methods: We identified patients with confirmed GEP-NENs from the Surveillance, Epidemiology and End Results registry. We assigned tumour-node-metastasis status according to American Joint Committee on Cancer and European Neuroendocrine Tumor Society criteria. We derived a revised staging classification using Kaplan-Meier methods and Cox regression to assess disease-specific survival and compared the accuracy of potential models based on the Akaike Information Criterion (AIC) and Harrell's C-index. The revised classification was validated in an independent set., Results: We identified 10,268 patients with GEP-NENs. We found that multiple stages, as determined by current criteria, misclassified patients' prognosis. In particular, stage IIIB (T1-4N1) had overlapping survival with stage IIIA (T4N0). A revised system which reclassifies N1 disease into different stages based on T status (T1-2N1, T3N1 and T4N1) had an improved AIC (difference = 38) and C-index (0.86) compared to current staging. These revisions improved predictions in patients with both low and high-grade tumours from all primary sites. Results also were confirmed across all primary sites in the validation set., Conclusion: Current staging guidelines misclassify the prognosis of N1 patients. Our results suggest that a revised system could lead to better prognostication for GEP-NEN patients. Further validation followed by implementation of these revisions may improve treatment selection and design of clinical trials., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Gastrointestinal neuroendocrine tumors have frequent loss of DPC4/SMAD4 expression, a known tumor suppressor. The impact of SMAD4 loss on gastrointestinal neuroendocrine tumors aggressiveness or cancer-related patient outcomes is not defined. We examined the expression of SMAD4 in resected gastrointestinal neuroendocrine tumors and its impact on oncologic outcomes., Methods: Patients who underwent complete curative operative resection of gastrointestinal neuroendocrine tumors were identified retrospectively (n = 38). Immunohistochemical staining for SMAD4 expression was scored by a blinded pathologist and correlated with clinicopathologic features and oncologic outcomes., Results: Twenty-nine percent of the gastrointestinal neuroendocrine tumors were SMAD4-negative and 71% SMAD4-positive. Median overall survival was 155 months (95% confidence interval, 102-208 months). Loss of SMAD4 was associated with both decreased median disease-free survival (28 months; 95% confidence interval, 16-40) months compared with 223 months (95% confidence interval, 3-443 months) for SMAD4-positive patients (P = .03) and decreased median disease-specific survival (SMAD4: 137 [95% confidence interval, 81-194] months versus SMAD4-positive: 204 [95% confidence interval, 143-264] months; P = .04). This translated into a decrease in median overall survival (SMAD4-negative: 125 (95% confidence interval, 51-214) months versus SMAD4-positive: 185 (95% confidence interval, 138-232) months; P = .02)., Conclusion: Consistent with the known biology of the DPC4/SMAD4 gene, an absence of its protein expression in primary gastrointestinal neuroendocrine tumors was negatively associated with outcomes after curative operative resection., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Aims: Neuroendocrine gastroenteropancreatic tumors are infrequently found neoplasms. Our objective was to analyze the survival rates for all sites that they occur in by studying different variables., Materials and Methods: A retrospective study was carried out using records for a 7-year period from January 1, 2008 to December 31, 2014 on neuroendocrine gastroenteropancreatic tumors patients diagnosed at the Pontevedra-Salnés Hospital Complex. The variables used were as follows: age at diagnosis, tumor size, presence or absence of metastases at diagnosis, cell proliferation index, Ki-67 of each tumor, treatments received, postdiagnosis survival time, existence or not of tumor progression, and time from diagnosis to progression and from diagnosis to mortality. In relation to treatments, the information recorded was whether the treatment was endoscopic, surgical, or pharmacological., Results: Ninety-three neuroendocrine tumors made up a ratio of 4.42 cases per 100,000 inhabitants per annum. The median patient follow-up time was 44 months. The overall 5-year survival rate for patients who were followed up for a minimum of 60 months (49 patients) was 65.3%. The progression-free survival was 75.6% for 41 patients who were followed up for a minimum of 60 months. The survival rate for patients receiving endoscopic treatment was 100%, as there was no patient mortality recorded for those treated by endoscopic resection during the follow-up period., Conclusion: Pancreatic neuroendocrine tumors may be managed conservatively in elderly patients by either monitoring them with imaging studies or treating them with somatostatin analogs. In the case of digestive tract tumors (stomach, duodenum, and rectum) that meet the criteria for endoscopic resection, this is a reliable and safe technique in the long term.

Background: Patients with advanced midgut neuroendocrine tumors who have had disease progression during first-line somatostatin analogue therapy have limited therapeutic options. This randomized, controlled trial evaluated the efficacy and safety of lutetium-177 ( 177 Lu)-Dotatate in patients with advanced, progressive, somatostatin-receptor-positive midgut neuroendocrine tumors., Methods: We randomly assigned 229 patients who had well-differentiated, metastatic midgut neuroendocrine tumors to receive either 177 Lu-Dotatate (116 patients) at a dose of 7.4 GBq every 8 weeks (four intravenous infusions, plus best supportive care including octreotide long-acting repeatable [LAR] administered intramuscularly at a dose of 30 mg) ( 177 Lu-Dotatate group) or octreotide LAR alone (113 patients) administered intramuscularly at a dose of 60 mg every 4 weeks (control group). The primary end point was progression-free survival. Secondary end points included the objective response rate, overall survival, safety, and the side-effect profile. The final analysis of overall survival will be conducted in the future as specified in the protocol; a prespecified interim analysis of overall survival was conducted and is reported here., Results: At the data-cutoff date for the primary analysis, the estimated rate of progression-free survival at month 20 was 65.2% (95% confidence interval [CI], 50.0 to 76.8) in the 177 Lu-Dotatate group and 10.8% (95% CI, 3.5 to 23.0) in the control group. The response rate was 18% in the 177 Lu-Dotatate group versus 3% in the control group (P<0.001). In the planned interim analysis of overall survival, 14 deaths occurred in the 177 Lu-Dotatate group and 26 in the control group (P=0.004). Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 1%, 2%, and 9%, respectively, of patients in the 177 Lu-Dotatate group as compared with no patients in the control group, with no evidence of renal toxic effects during the observed time frame., Conclusions: Treatment with 177 Lu-Dotatate resulted in markedly longer progression-free survival and a significantly higher response rate than high-dose octreotide LAR among patients with advanced midgut neuroendocrine tumors. Preliminary evidence of an overall survival benefit was seen in an interim analysis; confirmation will be required in the planned final analysis. Clinically significant myelosuppression occurred in less than 10% of patients in the 177 Lu-Dotatate group. (Funded by Advanced Accelerator Applications; NETTER-1 ClinicalTrials.gov number, NCT01578239 ; EudraCT number 2011-005049-11 .).

Background: According to the latest WHO classification, neuroendocrine neoplasm (NEN) G3 of the gastrointestinal tract is defined by a proliferation index Ki67 above 20%. Gastrointestinal neuroendocrine carcinoma (NEC) is a rare and highly aggressive malignancy and despite responsiveness to chemotherapy, overall survival is poor. In the last 3-4 years, the heterogeneity of the NEN G3 group has become evident., Summary: In addition to the proliferative activity, the tumour differentiation seems to play a major role, further dividing the NEN G3 group into neuroendocrine tumour (NET) G3 and NEC. NET G3 often arise in the pancreas, and their median proliferation rate is lower and prognosis is better as compared to NEC. However, NET G3 show a limited response to platinum-based chemotherapy. Lack of specific data for NET G3 hampers clear therapeutic recommendations. Cisplatin combined with etoposide is the established standard regimen for advanced gastrointestinal NEC. Substituting carboplatin for cisplatin or irinotecan for etoposide is considered alternative first-line regimen. There is no standard second-line treatment; options are discussed within this review., Key Points: (1) In NEN G3, the distinction between NET G3 and NEC G3 is clinically and prognostically meaningful. (2) Platinum-based chemotherapy remains the recommended first-line treatment in metastasized NEC patients. (3) There is no established standard for NET G3; treatments established for NET G2 such as temozolomide-based chemotherapy or peptide receptor radiotherapy may be considered. (4) Specific trials for NET G3 are necessary. (5) New therapies for NEC are urgently needed. Checkpoint inhibitors should be evaluated., (© 2017 S. Karger AG, Basel.)

Background/aims: Currently, there is no definite consensus about the prognostic factors of neuroendocrine tumors (NETs). We evaluate epidemiology, survival and especially prognostic factors in NETs., Materials and Methods: Patients who had a NET and were diagnosed between 2000 and 2014 at a tertiary care center were included. Demographic data, tumor characteristics and survival rates were evaluated, retrospectively., Results: Two-hundred and thirty-three patients (123 male, 110 female; median age, 55 years [16-92 years]) took part in the study. Primary NET sites were the lung (n=56), stomach (n=50), pancreas (n=39), colorectal (n=21), small intestine (n=19), and appendix (n=19). According to the NET classification by the WHO in 2010, 60% (n=140) of patients were grade-1, 15% (n=35) were grade-2, and 25% (n=58) were grade-3. According to TNM staging, 88 patients (37.8%) were stage I, 30 patients (12.8%) were stage II, 22 patients (9.5%) were stage III, and 93 patients (39.9%) were stage IV. Univariate analysis revealed significant associations between gender, age, grade, lymph node metastasis, distant metastasis, stage, and the number of organs impacted by metastases and overall survival. However, with multivariate analysis only age greater than 55 years, advancing grade, and inoperable tumors were significantly associated with shortened survival. Five-year survival was 81% in grade-1, 34% in grade-2, and 9% in grade-3 NETs., Conclusion: This study is the most comprehensive study in Turkey that has evaluated NETs using a multidisciplinary approach. Also, we suggest that age, operability and especially grade rather than stage are the most important prognostic factors in NETs.

Objective: To determine if urinary 5-hydroxyindoleacetic acid (5-HIAA) excretion is of prognostic value for overall survival (OS) in patients with a gastrointestinal neuroendocrine tumour (NET) and to compare the prognostic value with patient characteristics, ENETS/WHO grading, ENETS TNM staging and biomarkers., Design and Methods: Data was collected from patients with a gastrointestinal NET or a NET with gastrointestinal metastases and available 5-HIAA excretion in 24-h urine samples. Laboratory results were stratified for urinary 5-HIAA and chromogranin A (CgA): <2× upper limit of normal (ULN), 2-10× ULN, or >10× ULN. For neuron-specific enolase (NSE), this was the reference range or >1× ULN. OS was compared using Kaplan-Meier and log-rank tests, and hazard ratios were calculated using Cox regression for univariate and multivariate analyses., Results: A total of 371 patients were included, 46.6% female with a mean age of 59.9 years. OS was shortest in patients with urinary 5-HIAA excretion >10× ULN vs reference range (median 83 months vs 141 months, P = 0.002). In univariate analysis, urinary 5-HIAA excretion >10× ULN was a negative predictor (HR 1.62, 95% CI: 1.09-2.39). However, in multivariate analysis, only age (HR 1.04, 95% CI: 1.01-1.08), grade 3 disease (HR 5.09, 95% CI: 2.20-11.79), NSE >1× ULN (HR 2.36, 95% CI: 1.34-4.14) and CgA >10× ULN (HR 3.61, 95% CI: 1.56-8.34) remained as the predictors., Conclusion: Urinary 5-HIAA excretion >10× ULN is a negative predictor for OS. However, when added to other biomarkers and grading, it is no longer a predictor for OS. Therefore, it should only be determined to assess carcinoid syndrome and not for prognostic value., (© 2016 European Society of Endocrinology.)

Background: Effective systemic therapies for patients with advanced, progressive neuroendocrine tumours of the lung or gastrointestinal tract are scarce. We aimed to assess the efficacy and safety of everolimus compared with placebo in this patient population., Methods: In the randomised, double-blind, placebo-controlled, phase 3 RADIANT-4 trial, adult patients (aged ≥18 years) with advanced, progressive, well-differentiated, non-functional neuroendocrine tumours of lung or gastrointestinal origin were enrolled from 97 centres in 25 countries worldwide. Eligible patients were randomly assigned in a 2:1 ratio by an interactive voice response system to receive everolimus 10 mg per day orally or identical placebo, both with supportive care. Patients were stratified by tumour origin, performance status, and previous somatostatin analogue treatment. Patients, investigators, and the study sponsor were masked to treatment assignment. The primary endpoint was progression-free survival assessed by central radiology review, analysed by intention to treat. Overall survival was a key secondary endpoint. This trial is registered with ClinicalTrials.gov, number NCT01524783., Findings: Between April 3, 2012, and Aug 23, 2013, a total of 302 patients were enrolled, of whom 205 were allocated to everolimus 10 mg per day and 97 to placebo. Median progression-free survival was 11·0 months (95% CI 9·2-13·3) in the everolimus group and 3·9 months (3·6-7·4) in the placebo group. Everolimus was associated with a 52% reduction in the estimated risk of progression or death (hazard ratio [HR] 0·48 [95% CI 0·35-0·67], p<0·00001). Although not statistically significant, the results of the first pre-planned interim overall survival analysis indicated that everolimus might be associated with a reduction in the risk of death (HR 0·64 [95% CI 0·40-1·05], one-sided p=0·037, whereas the boundary for statistical significance was 0·0002). Grade 3 or 4 drug-related adverse events were infrequent and included stomatitis (in 18 [9%] of 202 patients in the everolimus group vs 0 of 98 in the placebo group), diarrhoea (15 [7%] vs 2 [2%]), infections (14 [7%] vs 0), anaemia (8 [4%] vs 1 [1%]), fatigue (7 [3%] vs 1 [1%]), and hyperglycaemia (7 [3%] vs 0)., Interpretation: Treatment with everolimus was associated with significant improvement in progression-free survival in patients with progressive lung or gastrointestinal neuroendocrine tumours. The safety findings were consistent with the known side-effect profile of everolimus. Everolimus is the first targeted agent to show robust anti-tumour activity with acceptable tolerability across a broad range of neuroendocrine tumours, including those arising from the pancreas, lung, and gastrointestinal tract., Funding: Novartis Pharmaceuticals Corporation., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Introduction: We hypothesized that an elevated preoperative alkaline phosphatase (AP) predicted worse outcomes for patients undergoing transarterial chemoembolization (TACE) for neuroendocrine tumor (NET) liver metastases., Methods: We reviewed all patients who underwent TACE for metastatic NET between 2009 and 2013. Survival was evaluated using preprocedure variables., Results: One hundred and nine patients underwent 210 TACE procedures. The average age was 57.7 years (range 20-78). Primary sites included pancreas (N = 20), other gastrointestinal (N = 52), lung (N = 9), and unknown (N = 28). The tumor was grade 1 in 68 (62 %), grade 2 in 21 (19 %), and grade 3 in 3 (3 %). Extrahepatic disease was present in 54 (50 %) and greater than 50 % hepatic tumor burden by imaging in 63 (58 %). Elevated bilirubin occurred in 8 (7 %), elevated AP in 22 (20 %), elevated ALT in 21 (19 %), and elevated AST in 41 (38 %). Univariate predictors included tumor grade (43 vs 27 vs 21 months, p = 0.015), hepatic tumor burden (59 vs 37 months, p = 0.009), and elevated AP (59 vs 23 months, p < 0.001). On multivariate analysis, only elevated AP (p = 0.001) predicted worse survival., Conclusions: Elevated AP prior to TACE for metastatic NET portends a worse survival outcome, even more so than tumor grade or extent of hepatic disease.

Somatostatin analogues (SSA) have demonstrated antiproliferative activity in addition to efficacy for carcinoid symptom control in functional neuroendocrine tumors (NET). A post hoc analysis of the placebo arm of the RAD001 In Advanced Neuroendocrine Tumors-2 (RADIANT-2) study was conducted to assess the efficacy of octreotide long-acting repeatable (LAR) on progression-free survival (PFS) and overall survival (OS) estimated using the Kaplan-Meier method. Out of 213 patients randomized to placebo plus octreotide LAR in RADIANT-2, 196 patients with foregut, midgut, or hindgut NET were considered for present analysis. Of these, 41 patients were SSA-treatment naïve and 155 had received SSA therapy before study entry. For SSA-naïve patients, median PFS by adjudicated central review was 13.6 (95% CI 8.2-22.7) months. For SSA-naïve patients with midgut NET (n=24), median PFS was 22.2 (95% CI 8.3-29.5) months. For patients who had received SSA previously, the median PFS was 11.1 (95% CI 8.4-14.3) months. Among the SSA-pretreated patients who had midgut NET (n=119), the median PFS was 12.0 (95% CI 8.4-19.3) months. Median OS was 35.8 (95% CI 32.5-48.9) months for patients in the placebo plus octreotide LAR arm; 50.6 (36.4 - not reached) months for SSA-naïve patients and 33.5 (95% CI 27.5-44.7) months for those who had received prior SSA. This post hoc analysis of the placebo arm of the large phase 3 RADIANT-2 study provides data on PFS and OS among patients with progressive NET treated with octreotide therapy., (© 2015 The authors.)

Aim: This study aimed to evaluated prognostic factors of patients with GEP-NETs after primary tumor resection comparing pancreatic and gastro-enteric locations., Methods: Patients undergone surgery for primary GEP-NETs between 01/2000 and 03/2012 were considered. All specimens were reclassified according to the WHO 2010 scheme., Results: A total of 83 patients were considered: 37 pancreatic NETs (pNET) and 46 gastroenteric NETs (GE-NET). The two groups were similar in terms of age, sex and tumors size. A higher rate of patients with pNETs had Ki67 score ≥3 (64.8% vs. 39%, p = 0.027) while the rates of Mitotic Index ≥2x10HPF (62% pNET vs. 50% GE-NET, p = 0.374) and diagnosis of neuroendocrine carcinoma NEC (16.2% pNET vs. 17.3% GE-NET, p = 0.100) were similar. The rates of distant metastases (GE-NETs 30.4% vs. p-NETs 29.7%, p = 0.944) and liver metastases (19.5% GE-NET vs. 27% pNET, p = 0.421) were comparable. Radical resection was achieved in a similar proportion in both groups [33 patients (89.1%) pNET vs. 36 (78.2%) GE-NET, p = 0.393]. After a median follow-up of 47.1 months overall 3, 5 and 10-years survival rates of whole patients were 88.1%, 81.2% and 76.7%. There was not difference on 5-years overall survival between pNET (81.4%) and GE-NET (81%, p = 0.901). At multivariate analysis age ≥70 [OR 4.177 (CI 95% 1.26-13.8), p = 0.019] and NEC [OR 5.932 (CI 95% 1.81-19.40), p < 0.001] were negative prognostic factors of survival., Conclusion: Overall survival of GEP-NET after resection of primary tumors seems to be correlated to patient's age and WHO 2010 staging system but not to primary tumor site., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objective: To assess the prognostic value in Chinese patients of two new systems, the World Health Organization (WHO)-2010 and the American Joint Committee on Cancer and the Union for International Cancer Control (AJCC/UICC) systems, for the classification of gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN)., Methods: One hundred and three patients with GEP-NEN treated at the First Affiliated Hospital of Nanjing Medical University from January 2003 to December 2011 were included in the study. All patients were diagnosed pathologically and had complete follow-up data. Univariate and multivariate analyses of their clinicopathological characteristics were performed., Results: The 5-year survival rates were 95%, 74%, 24% and 15% based on the AJCC/UICC stages I to IV, and 92%, 62% and 29% according to WHO-2010 grades 1 to 3, respectively, in patients with GEP-NEN. A higher mortality was observed in patients with AJCC/UICC stage III and IV tumors compared with those at stage I-II, and patients with stage II compared with those with stage I, whereas there was no difference in survival between stage IV and III patients. Based on the WHO-2010 grading classification, patients with grade 3 tumors had the lowest survival rate than those with grade 1 and 2 tumors, followed by patients with grade 2 tumors., Conclusion: The WHO-2010 and AJCC/UICC staging systems can effectively evaluate the prognosis of patients with GEP-NEN, although the latter might not accurately discriminate the prognosis of patients with local metastasis from those having distant metastasis., (© 2015 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.)

Aim of the Study: Gastro-intestinal neuroendocrine tumours (GI-NETs) are chemotherapy-resistant tumours. Bevacizumab, an inhibitor of vascular endothelial growth factor (VEGF), has shown promising results in several phase II trials of gastro-entero-pancreatic-NETs. We assessed bevacizumab combined with capecitabine, specifically in GI-NET patients., Patients and Methods: BEvacizumab in The Treament of neuroEndocrine tumoRs (BETTER) was a multicentre, open-label, non-randomised, two-group phase II trial. Here we present the group of patients with progressive, metastatic, well-differentiated GI-NETs. Patients Eastern Cooperative Oncology Group-performance status (ECOG-PS)⩽2, Ki-67 proliferation rate <15% and no prior systemic chemotherapy were treated with bevacizumab (7.5 mg/kg/q3w) and capecitabine (1000 mg/m2 twice daily, orally d1-14, resumed on d22) for 6-24 months. The primary end-point was progression-free survival (PFS); secondary end-points included overall survival (OS), response rate, safety and quality of life., Results: Of the 49 patients included, 53% were men, median age was 60 years (41-82), primary tumour site was ileal in 82% patients and Ki-67 was <15% in 48 patients and not available for one patient. After a maximum of 24 month follow-up per patient, the median PFS by investigator assessment was 23.4 months [95% confidence interval (CI): 13.2; not reached] and the overall disease control rate was 88% (18% partial response, 70% stable disease). The 2-year survival rate was 85%. Median OS was not reached. The most frequent grade 3-4 adverse events were hypertension (31%), diarrhoea (14%) and hand-foot syndrome (10%)., Conclusion: The combination of bevacizumab and capecitabine showed clinical activity and a manageable safety profile in the treatment of GI-NETs that warrant confirmation in a randomised phase III trial., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: We previously reported that midgut neuroendocrine tumors (NETs) often develop alternative lymphatic drainage owing to lymphatic obstructions from extensive mesenteric lymphadenopathy, making intraoperative lymphatic mapping mandatory. We hypothesize that this innovative approach needs a longer term validation., Methods: We updated our results by reviewing 303 patients who underwent cytoreduction from November 2006 to October 2011. Of these patients, 112 had lymphatic mappings and 98 were for midgut NET primaries. Among them, 77 mappings were for the initial cytoreduction and 35 were for reexploration and further cytoreduction. The operative findings, pathology reports, and long-term surgical outcomes were reviewed., Results: Lymphatic mapping changed traditional resection margins in 92% of patients. Of the 35 patients who underwent reexploration without initial mapping, 19 (54%) showed a recurrence at or near the anastomotic sites. In contrast, none of the 112 mapped patients had shown signs of recurrence in a 1- to 5-year follow-up. Additionally, 20 of 45 ileocecal valves (44.4%) were spared in patients whose tumors were at the terminal ileum that, traditionally, would call for a right hemicolectomy., Conclusion: With a longer follow-up, lymphatic mapping has proven to be a safe and effective way to prevent local recurrences and preserve the ileocecal valve for selected patients., (Copyright © 2014 Elsevier Inc. All rights reserved.)