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Purpose: This paper outlines the consensus of the Italian Association for Neuroendocrine Tumors(Itanet), the Italian Association of Nuclear Medicine (AIMN), the Italian Society of Endocrinology (SIE), and the Italian Association of Medical Oncology (AIOM) on treating neuroendocrine neoplasms (NENs)with radioligand therapy (RLT)., Methods: A list of 10 questions regarding using RLT ingastroenteropancreatic neuroendocrine tumors (GEP-NETs) was addressed after a careful review of theavailable literature. compiling information from the MEDLINE database, augmented with expert opinionsand recommendations, aligns with the latest scientific research and the author's extensive knowledge.The recommendations are evaluated using the GRADE system, showcasing the level of evidence andthe strength of the recommendations., Results and Conclusions: Specifically, this paper focuses on thesubcategories of well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs) thatexpress somatostatin receptors and are considered suitable for RLT, according to internationalguidelines., Competing Interests: Declarations. Conflict of interest: MA received honoraria as consultants from AAA, Novartis and Recordati outside the submitted work, CMG received honoraria as consultants from Novartis and ITM outside the submitted work, MC received honoraria as consultants from AAA, Novartis, Advanz, Harpoon Therapeutics, Merck, Harbour Biomedical outside the submitted work, AF received honoraria as support for research project and scientific organization from Novartis and Ipsen, NF received honoraria as consultants and speakers from Novartis and ITM outside the submitted work, FS received honoraria as consultants and speakers from AAA, outside the submitted work, MM received honoraria as consultants and speakers from AAA, outside the submitted work. The other authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this manuscript., (© 2024. The Author(s).)

Background: The role of prophylactic primary tumor resection (PTR) in patients with small intestinal neuroendocrine tumors (SI-NETs) and unresectable liver metastases is a matter of debate., Objective: We aimed to evaluate outcomes in patients with SI-NETs who underwent PTR, according to the presence of metastasis and symptoms from primary., Material and Methods: Data from patients who underwent PTR for SI-NETs from a single referral center (2007-2023) were prospectively collected. Patients were divided into three groups: non-metastatic (M0) and metastatic with primary tumor-related symptoms (MS) or metastatic asymptomatic (MA). Kaplan-Meier curves for overall survival (OS) and event-free survival (EFS) were generated and compared by group. Univariate and multivariable Cox regression analyses were performed to assess the significance of risk factors., Results: Of 147 patients, 53 were M0, 23 were MS, and 71 were MA. Median follow-up was 26 months. The 5- and 10-year OS estimates were 100% and 100% in M0 patients, 82 and 21% in MS patients, and 89 and 80% in MA patients, respectively (p < 0.001). Median EFS was 91 months overall and 43,126 months and not reached for the MS, MA, and M0 groups, respectively (p < 0.001). In multivariable analysis, MS (hazard ratio [HR] 3.92, 95% confidence interval [CI] 1.71-9.52), functioning tumors (HR 1.98, 95% CI 1.03-3.81), and G2 grade (HR 3.20, 95% CI 1.64-6.85) were associated with a shorter EFS., Conclusions: In this large retrospective series, the MS group had a significantly worse OS and EFS compared with M0 and MA. This finding suggests that prophylactic PTR might benefit SI-NET patients with unresectable liver metastases, as symptom development could impair long-term prognosis after surgery., Competing Interests: DISCLOSURE: Maria Danieli, Uberto Fumagalli Romario, Davide Radice, Simonetta Pozzi, Francesca Spada, Luigi Funicelli, Nicola Fazio, and Emilio Bertani have no conflicts of interest to declare that may be relevant to the contents of this study., (© 2024. Society of Surgical Oncology.)

Background: Up to 50% of patients with advanced small-intestinal neuroendocrine tumors (SI-NETs) and carcinoid syndrome (CS) develop carcinoid heart disease (CHD). However, the true frequency and prognostic markers for CHD in CS are lacking. We described the real-world management of patients in two NET referral centers in this clinical context and relationships between clinical features, including CHD and overall survival (OS)., Patients and Methods: This is a retrospective analysis of patients with stage IV SI-NET and CS, treated at the European Institute of Oncology in Milan and Uppsala University in Sweden between 2015 and 2021. CHD was defined as at least one moderate right-sided heart valve defect. Median OS and cumulative incidence of CHD were estimated from the diagnosis of metastatic disease, and the association between clinical parameters with both OS and occurrence of CHD was evaluated., Results: We included 165 patients, with 97% having low-intermediate-grade SI-NETs and 86% having synchronous liver metastases. Ninety-eight patients (59%) became refractory to full label dose of somatostatin analogues and 25% developed a CHD. At CHD diagnosis, baseline urine 5-hydroxyindoleacetic acid (24-h u5-HIAA) value and plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) value were known in 76% of patients. Moderate-to-severe tricuspid insufficiency was the most common alteration of CHD. Prognosis was significantly impaired by CHD (multivariable hazard ratio for OS = 2.85, P < 0.001). The median OS from the CHD diagnosis was 4.5 years [95% confidence interval (CI) 2.1-7.2 years], and the 5-year survival rate was 34% (95% CI 13% to 57%)., Conclusions: In our study population of SI-NET patients with CS, more than half had a refractory carcinoid syndrome (RCS) and one-quarter developed a CHD, with a negative impact on OS. Therefore, it is recommended to screen and monitor patients with CS for CHD, ideally with a combination of u5-HIAA, NT-proBNP values, and echocardiography at CS baseline, preferably in NET referral centers., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Radio-guided surgery (RGS) holds promise for improving surgical outcomes in neuroendocrine tumors (NETs). Previous studies showed low specificity (SP) using γ-probes to detect radiation emitted by radio-labeled somatostatin analogs., Objective: We aimed to assess the sensitivity (SE) and SP of the intraoperative RGS approach using a β-probe with a per-lesion analysis, while assessing safety and feasibility as secondary objectives., Methods: This prospective, single-arm, single-center, phase II trial (NCT05448157) enrolled 20 patients diagnosed with small intestine NETs (SI-NETs) with positive lesions detected at 68 Ga-DOTA-TOC positron emission tomography/computed tomography (PET/CT). Patients received an intravenous injection of 1.1 MBq/Kg of 68Ga-DOTA-TOC 10 min prior to surgery. In vivo measurements were conducted using a β-probe. Receiver operating characteristic (ROC) analysis was performed, with the tumor-to-background ratio (TBR) as the independent variable and pathology result (cancer vs. non-cancer) as the dependent variable. The area under the curve (AUC), optimal TBR, and absorbed dose for the surgery staff were reported., Results: The intraoperative RGS approach was feasible in all cases without adverse effects. Of 134 specimens, the AUC was 0.928, with a TBR cut-off of 1.35 yielding 89.3% SE and 86.4% SP. The median absorbed dose for the surgery staff was 30 µSv (range 12-41 µSv)., Conclusion: This study reports optimal accuracy in detecting lesions of SI-NETs using the intraoperative RGS approach with a novel β-probe. The method was found to be safe, feasible, and easily reproducible in daily clinical practice, with minimal radiation exposure for the staff. RGS might potentially improve radical resection rates in SI-NETs., Clinical Trials Registration: 68 Ga-DOTATOC Radio-Guided Surgery with β-Probe in GEP-NET (RGS GEP-NET) [NCT0544815; https://classic., Clinicaltrials: gov/ct2/show/NCT05448157 ]., (© 2024. Society of Surgical Oncology.)

Neuroendocrine neoplasms (NENs) are rare tumors with diverse clinical behaviors. Large databases like the Surveillance, Epidemiology, and End Results (SEER) program and national NEN registries have provided significant epidemiological knowledge, but they have limitations given the recent advancements in NEN diagnostics and treatments. For instance, newer imaging techniques and therapies have revolutionized NEN management, rendering older data less representative. Additionally, crucial parameters, like the Ki67 index, are missing from many databases. Acknowledging these gaps, the Italian Association for Neuroendocrine Tumors (Itanet) initiated a national multicenter prospective database in 2019, aiming to gather data on newly-diagnosed gastroenteropancreatic neuroendocrine (GEP) NENs. This observational study, coordinated by Itanet, includes patients from 37 Italian centers. The database, which is rigorously maintained and updated, focuses on diverse parameters including age, diagnostic techniques, tumor stage, treatments, and survival metrics. As of October 2023, data from 1,600 patients have been recorded, with an anticipation of reaching 3600 by the end of 2025. This study aims at understanding the epidemiology, clinical attributes, and treatment strategies for GEP-NENs in Italy, and to introduce the Itanet database project. Once comprehensive follow-up data will be acquired, the goal will be to discern predictors of treatment outcomes and disease prognosis. The Itanet database will offer an unparalleled, updated perspective on GEP-NENs, addressing the limitations of older databases and aiding in optimizing patient care. STUDY REGISTRATION: This protocol was registered in clinicaltriasl.gov (NCT04282083)., (© 2024. The Author(s).)

Precision medicine describes a target-related approach to tailoring diagnosis and treatment of the individual patient. While this personalized approach is revoluzionizing many areas of oncology, it is quite late in the field of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs), in which there are few molecular alterations to be therapeutically targeted. We critically reviewed the current evidence about precision medicine in GEP NENs, focusing on potential clinically relevant actionable targets for GEP NENs, such as the mTOR pathway, MGMT, hypoxia markers, RET, DLL-3, and some general agnostic targets. We analysed the main investigational approaches with solid and liquid biopsies. Furthermore, we reviewed a model of precision medicine more specific for NENs that is the theragnostic use of radionuclides. Overall, currently no true predictive factors for therapy have been validated so far in GEP NENs, and the personalized approach is based more on clinical thinking within a NEN-dedicated multidisciplinary team. However, there is a robust background to suppose that precision medicine, with the theragnostic model will yield new insights in this context soon., Competing Interests: Declaration of Competing Interest A.L.S. have no conflict of interests to declare. N.F. has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AAA, Ipsen, Sanofi, Merck and has participated on a data safety Monitoring Board or Advisory Board of AAA, HutchMed, Merck, Novartis and MSD., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

We conducted a retrospective/prospective worldwide study on patients with neuroendocrine neoplasms (NENs) and a molecularly proven SARS-CoV-2 positivity. Preliminary results regarding 85 patients of the INTENSIVE study have been published in 2021. Now we are reporting the 2-year analysis.Here, we are reporting data from consecutive patients enrolled between 1 June 2020, and 31 May 2022. Among the 118 contacted centers, 25 were active to enroll and 19 actively recruiting at the time of data cut-off for a total of 280 patients enrolled. SARS-CoV-2 positivity occurred in 47.5% of patients in 2020, 35.1% in 2021, and 17.4% in 2022. The median age for COVID-19 diagnosis was 60 years. Well-differentiated tumors, non-functioning, metastatic stage, and gastroenteropancreatic (GEP) primary sites represented most of the NENs. COVID-19-related pneumonia occurred in 22.8% of the total, with 61.3% of them requiring hospitalization; 11 patients (3.9%) needed sub-intensive or intensive care unit therapies and 14 patients died (5%), in 11 cases (3.9%) directly related to COVID-19. Diabetes mellitus and age at COVID-19 diagnosis > 70 years were significantly associated with COVID-19 mortality, whereas thoracic primary site with COVID-19 morbidity. A significant decrease in both hospitalization and pneumonia occurred in 2022 vs 2020. In our largest series of NEN patients with COVID-19, the NEN population is similar to the general population of patients with NEN regardless of COVID-19. However, older age, non-GEP primary sites and diabetes mellitus should be carefully considered for increased COVID-19 morbidity and mortality. Relevant information could be derived by integrating our results with NENs patients included in other cancer patients with COVID-19 registries.

Purpose: Grade 3 neuroendocrine tumor (NET G3) is a novel pathologic category within gastro-entero-pancreatic (GEP) neuroendocrine neoplasms (NENs) but its clinical behavior and therapeutic management still remain challenging. Prognostic and predictive factors aiding NET G3 management are needed., Patients and Methods: We performed a retrospective analysis from 2015 to 2020 of all patients with > 20% Ki-67, well-differentiated NETs evaluated within our NEN-dedicated multidisciplinary team. We divided the sample according the timing of NET G3 diagnosis, the radiotracers distribution and Ki-67. We analyzed the correlation between these NET G3 features and clinical outcomes., Results: Among 3238 multidisciplinary discussion reports, we selected 55 patients, 48 from GEP and 7 from an occult GEP origin. In 45 patients, NET G3 diagnosis occurred at the beginning of clinical history (upfront-NET G3), whereas in 10, during the NET G1-G2 clinical history (late-NET G3). Patients with ≤ 30% (34/55) vs. > 30% Ki-67 (21/55) had a better overall survival (OS) (p = 0.042); patients with a homogeneous vs. inhomogeneous/negative 68 Gallium( 68 Ga)-DOTA-Peptide Positron Emission Tomography (PET)/computed tomography (CT) showed a trend to a better OS, and a significant better progression-free survival (PFS) (p = 0.033). A better OS was observed for negative/inhomogeneous vs. homogeneous 18-fluorodeoxyglucose ( 18 FDG)-PET/CT (p = 0.027). A trend to a better OS was reported in late- vs. upfront-NET G3, while the latter showed a significantly better response rate (RR) (p = 0.048)., Conclusion: Our findings suggested that Ki-67 cutoff, functional imaging and the timing to NET G3 diagnosis may help clinicians in more accurate selection of NET G3 management. Prospective studies are needed., (© 2021. Italian Society of Endocrinology (SIE).)

Updates in classification of gastro-entero-pancreatic neuroendocrine neoplasms better reflect the biological characteristics of these tumours. In the present study, we analysed the characteristics of neuroendocrine tumours that could aid in a more precise stratification of risk groups. In addition, we have highlighted the importance of grade (re)assessment based on investigation of secondary tumour lesions. Two hundred and sixty-four cases of neuroendocrine tumours of gastro-entero-pancreatic origin from three centres were included in the study. Tumour morphology, mitotic count and Ki67 labelling index were evaluated in specimens of primary tumours, lymph node metastases and distant metastases. These variables were correlated with overall survival (OS) and relapse-free survival (RFS). Tumour stage, number of affected lymph nodes, presence of tumour deposits and synchronous/metachronous metastases were tested as possible prognostic features. Mitotic count, Ki-67 labelling index, primary tumour site, tumour stage, presence of tumour deposits and two or more affected lymph nodes were significant predictors of OS and RFS. At the same time, mitotic count and Ki-67 labelling index can be addressed as continuous variables determining prognosis. We observed a very high correlation between the measures of proliferative activity in primary and secondary tumour foci. The presence of isolated tumour deposits was identified as an important determinant of both RFS and OS for pancreatic (hazard ratio [HR] = 7.61, 95% confidence interval [CI] = 3.96-14.6, P < 0.0001 for RFS; HR = 3.28, 95% CI = 1.56-6.87, P = 0.0017 for OS) and ileal/jejunal neuroendocrine tumours (HR = 1.98, 95% CI = 1.25-3.13, P = 0.0036 for RFS and HR 2.59, 95% CI = 1.27-5.26, P = 0.009 for OS). The present study identifies the presence of mesenterial tumour deposits as an important prognostic factor for gastro-entero-pancreatic neuroendocrine tumours, provides evidence that proliferative parameters need to be treated as continuous variables and further supports the importance of grade determination in all available tumour foci., (© 2021 British Society for Neuroendocrinology.)

Background: In neuroendocrine tumor (NET), complete surgery could better the prognosis. Radioguided surgery (RGS) with β - -radioisotopes is a novel approach focused on developing a new probe that, detecting electrons and operating with low background, provides a clearer delineation of the lesions with low radiation exposition for surgeons. As a first step to validate this procedure, ex vivo specimens of tumors expressing somatostatin receptors, as small intestine neuroendocrine tumor (SI-NET), were tested. Materials and Methods: SI-NET presents a high uptake of a beta-emitting radiotracer, 90 Y-DOTATOC. Five SI-NET patients were enrolled after performing a 68 Ga-DOTATOC positron emission tomography/computed tomography (CT) and a CT enterography; 24 h before surgery, they received 5 mCi of 90 Y-DOTATOC. Results: Surgery was performed as routine. Tumors and surrounding tissue were sectioned in different samples and examined ex vivo with the beta-detecting probe. All the tumor samples showed high counts of radioactivity that was up to a factor of 18 times higher than the corresponding cutoff value, with a sensitivity of 96% and a specificity of 100%. Conclusions: These first ex vivo RGS tests showed that this probe can discriminate very effectively between tumor and healthy tissues by the administration of low activities of 90 Y-DOTATOC, allowing more precise surgery.

The recent World Health Organization classification for gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) classified poorly differentiated GEP-NENs into small cell and large cell categories. The present study aimed to assess the differences in outcomes between patients with both histological categories. The Surveillance, Epidemiology and End Results (SEER) database (1975-2016) was accessed and patients with small cell and large cell GEP-neuroendocrine carcinomas (NECs) were extracted. Differences in survival outcomes were explored through Kaplan-Meier survival estimates and multivariable Cox regression models. In total, 2204 patients with GEP-NEC were identified in the survival cohort, including 1698 patients with small cell NEC (77%) and 506 patients with large cell NEC (23%). Using Kaplan-Meier analysis/log-rank testing, large cell GEP-NEC was associated with better overall survival compared to small cell NEC (P < 0.01). Using multivariable Cox regression analysis, large cell GEP-NEC was associated with better overall survival (large cell GEP-NEC versus small cell GEP-NEC, hazard ratio = 0.77; 95% confidence interval = 0.68-0.86) and cancer-specific survival (large cell GEP-NEC versus small cell GEP-NEC, hazard ratio = 0.79; 95% 95% confidence interval = 0.69-0.91). Patients with small cell GEP-NEC have worse survival outcomes compared to those with large cell GEP-NEC. Further efforts are needed to identify biological differences and treatment sensitivities between both histological categories., (© 2021 British Society for Neuroendocrinology.)

Background: In gastroenteropancreatic (GEP) high-grade neuroendocrine neoplasms (H-NENs), Ki-67 threshold of 55% defines three prognosis subclasses: neuroendocrine tumor (NET) G3, neuroendocrine carcinoma (NEC) <55%, and NEC ≥55%. We investigated whether the molecular profiling of H-NENs differs among these subcategories and evaluated potential therapeutic targets, including PD-L1., Methods: In GEP-NEN patients, we evaluated: (i) 55% threshold for Ki-67 labeling index for further stratifying NEC and (ii) immunoreactivity and gene mutations by immunohistochemistry and targeted next-generation sequencing (T-NGS)., Results: Fifteen NETs G3 and 39 NECs were identified. Ki-67 labeling index was <55% in 9 NECs and ≥55% in 30 NECs. Gene mutations by NGS (TP53, 32.9%; KRAS, 5.5%; BRAF, 4.1%) were detected in 46.6% NENs, significantly enriched in NEC ≥55% (76.7%) compared to NEC <55% (55.6%) or NET (20.0%). PD-L1 staining in tumor-infiltrating lymphocytes was observed in NEC ≥55% (36.7%; p = 0.03). Median OS was 4.3 years in NET G3, 1.8 years in NEC <55%, and 0.7 years in NEC ≥55% (p <0.0001); it was 2.3 years with NGS wild-type, 0.7 years with ≥1 mutation (p <0.0001), 0.8 years in PD-L1-positive patients, and 1.7 years in PD-L1-negative subjects (p = 0.0004). In multivariate analysis, only the proposed subclassification approach yielded statistically significant differences between groups (NEC <55% vs. NET G3, HR 14.1, 95% CI 2.2-89.8, p = 0.005; NEC ≥55% vs. NET G3, HR 25.8, 95% CI 3.9-169, p = 0.0007)., Conclusions: These findings identify NEC ≥55% as a biologically and prognostically distinct subtype and pave the way for more personalized treatment., (© 2019 S. Karger AG, Basel.)

Peptide receptor radionuclide therapy (PRRT) is an established treatment of metastatic neuroendocrine tumors grade 1-2 (G1-G2). However, its possible benefit in high-grade gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN G3) is largely unknown. We therefore aimed to assess the benefits and side effects of PRRT in patients with GEP NEN G3. We performed a retrospective cohort study at 12 centers to assess the efficacy and toxicity of PRRT in patients with GEP NEN G3. Outcomes were response rate, disease control rate, progression-free survival (PFS), overall survival (OS) and toxicity. We included 149 patients (primary tumor: pancreatic n = 89, gastrointestinal n = 34, unknown n = 26). PRRT was first-line (n = 30), second-line (n = 62) or later-line treatment (n = 57). Of 114 patients evaluated, 1% had complete response, 41% partial response, 38% stable disease and 20% progressive disease. Of 104 patients with documented progressive disease before PRRT, disease control rate was 69%. The total cohort had median PFS of 14 months and OS of 29 months. Ki-67 21-54% (n = 125) vs Ki-67 ≥55% (n = 23): PFS 16 vs 6 months (P < 0.001) and OS 31 vs 9 months (P < 0.001). Well (n = 60) vs poorly differentiated NEN (n = 62): PFS 19 vs 8 months (P < 0.001) and OS 44 vs 19 months (P < 0.001). Grade 3-4 hematological or renal toxicity occurred in 17% of patients. This large multicenter cohort of patients with GEP NEN G3 treated with PRRT demonstrates promising response rates, disease control rates, PFS and OS as well as toxicity in patients with mainly progressive disease. Based on these results, PRRT may be considered for patients with GEP NEN G3.

In recent years, there have been important scientific advances in the biologic characterization of neuroendocrine neoplasms and in their treatment. This review will describe these scientific advances, the evolving systemic treatment approaches, and important topics to be addressed in future research.

Gastroenteropancreatic neuroendocrine neoplasms grade 3, all of them with >20% Ki-67, can be heterogeneous on the basis of their morphological features, comprising well and poorly differentiated neoplasms; the former are named tumors and the latter carcinomas. Several papers about gastroenteropancreatic neuroendocrine neoplasms grade 3 heterogeneity have been reporting over the last years by clinicians and pathologists, indicating that the differential diagnosis between named tumors grade 3 and named carcinomas grade 3 may be relevant in defining a different approach in terms of characterization of disease, staging, and treatment. To well define the sub-type of gastroenteropancreatic neuroendocrine neoplasms grade 3 pathologist's expertise in recognizing tumor morphology, immunohistochemical, and molecular techniques were reported remarkable. Although current evidence about grade 3 gastroenteropancreatic neuroendocrine neoplasms heterogeneity is still far from producing validated specific therapies for specific subcategories, the hypotheses generated from the several retrospective analyses published so far on this topic represent solid bases for designing prospective therapeutic clinical trials in homogenous clinical settings.

Gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs) are currently classified as grade (G) 1, G2 and G3, in accordance with the 2010 WHO classification. G1 and G2 are named neuroendocrine tumors (NETs) whereas G3 neuroendocrine carcinomas (NECs). While advanced G1 and G2 are usually treated with several different therapies, including somatostatin analogs, chemotherapy, interferon, molecular targeted agents, peptide receptor radionuclide therapy (PRRT) and liver-directed treatments, advanced G3 NECs are usually treated with a platinum-etoposide chemotherapy, trusting their clinical homogeneity is similar to that of small cell lung cancer. However, over the last years a number of reports suggested that 2010 WHO G3 GEP NECs are more heterogeneous than expected. Therefore, we critically reviewed the literature about this topic and reported pathological and clinical considerations on 2010 WHO G3 GEP NEC category proposing new sub-categories. Over the last five years, six studies specifically investigating large series of G3 GEP NECs have been published, including around 800 patients. Tumor morphology and Ki-67 Labeling Index (that will be mentioned as Ki-67 in this manuscript) combination has been reported as a tool to define two or even three subgroups of this category with different prognosis and potentially different therapeutic approach. Prospective trials are warranted to investigate if several types of therapy other than the platinum/etoposide chemotherapy can be effective in well differentiated GEP NEN with 21-55% Ki-67 and alkylating-based chemotherapy in poorly differentiated GEP NEN with 21-55% Ki-67., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Introduction: Patients with small intestine neuroendocrine tumors present with liver metastases in 50-75% of cases at diagnosis. The aim of the present study was to assess prognostic factors in patients with liver metastases from intestinal neuroendocrine tumor after primary tumor surgical removal with or without liver surgery or radiofrequency ablation. The primary endpoint was disease-specific survival., Methods: Data regarding seventy-eight consecutive patients with liver metastases who undergone primary tumor surgical removal between 1996 and 2011 were extracted from the institutional tumor registry and retrospectively analyzed., Results: Liver tumor burden was <25% in 43 (55.1%) 25-50% in 30 (38.5%) and >50% in 5 (6.4%) patients. For the whole cohort of patients disease-specific survival at 3, 5 and 8 years was 93.2%, 83.6% and 77.3%, respectively. Fifteen patients who underwent radical liver surgery were all alive with a median survival of 106 months (range 18-152 months). In multivariate analysis the Ki-67 index in a continuous fashion significantly correlate with prognosis (p = 0.021). Liver tumor burden (p = 0.036) and extrahepatic involvement (p = 0.03), were the most powerful prognosticators for patients who underwent only debulking surgery., Conclusion: The Ki-67 index, the liver tumor burden and the presence of extrahepatic metastases should be carefully considered in the selection criteria for liver debulking in asymptomatic patients., (Copyright © 2015 IJS Publishing Group Limited. Published by Elsevier Ltd. All rights reserved.)

Background: Preclinical and clinical studies suggest synergistic activity between somatostatin analogues and mammalian target of rapamycin inhibitors. The activity and safety of everolimus was assessed in combination with octreotide long-acting repeatable (LAR) in patients with neuroendocrine tumors (NETs) of gastroenteropancreatic and lung origin., Methods: This was a phase 2, multicenter trial using a Simon's 2-stage minimax design. Treatment-naive patients with advanced well-differentiated NETs of gastroenteropancreatic tract and lung origin received everolimus 10 mg daily, in combination with octreotide LAR 30 mg every 28 days. The primary endpoint was objective response rate (ORR)., Results: A total of 50 patients (median age, 60.5 years) were enrolled. Primary tumor sites were: pancreas (14 patients), lung (11 patients), ileum (9 patients), jejunum and duodenum (2 patients), and unknown (14 patients). Thirteen patients (26%) had carcinoid syndrome. Treatment-related adverse events (AEs) were mostly grade 1 or 2; the only grade 4 AE was mucositis in 1 patient, whereas grade 3 AEs included skin rash in 1 case (2%), stomatitis in 4 cases (8%), and diarrhea in 11 cases (22%). The ORR was 18%; 2% of patients had a complete response (CR), 16% a partial response (PR) and 74% achieved stable disease (SD). All CRs and all PRs as well as 92% of SDs had a duration ≥ 6 months. The clinical benefit (CR+PR+SD) was 92%. At a median follow-up of 277 days, median time to progression and overall survival were not reached., Conclusions: The everolimus-octreotide LAR combination was active and well tolerated in these previously treated patients with advanced NETs, suggesting a possible role as first-line treatment in patients with NET., (© 2014 American Cancer Society.)