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Introduction: The aim of this study was to investigate the role of circulating regulatory T cells (Tregs) as a novel marker associated with liver metastases and treatment response to transarterial embolization (TAE) in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs)., Methods: Circulating Tregs, defined as the CD4+CD25+CD127low/- population, were examined by flow cytometry in peripheral blood mononuclear cells from patients with GEP-NETs. Clinicopathological parameters, radiologic response, and hepatic progression-free survival (hPFS) data were collected., Results: The association between circulating Tregs and clinicopathological parameters was analyzed in 139 GEP-NET patients. Higher Treg levels were significantly associated with more progressive clinical features, including a higher WHO grade, more advanced TNM stage, and the presence of liver metastases. A Treg level ≥8.015% distinguished between patients with and without liver metastases. Among a cohort of 51 GEP-NET patients who were subjected to TAE for reducing liver metastasis burden, patients with higher Treg levels depicted unfavorable responses and significantly reduced hPFS after TAE treatment. We also revealed that patients with Treghigh (≥8.975%) displayed significantly shorter median hPFS than patients with Treglow (<8.975%). Additionally, after adjusting for other confounding clinical parameters, the association between Tregs and treatment response as well as hPFS remained significant, suggesting that Tregs may have a strong and independent prognostic impact in GEP-NETs., Conclusion: Our data suggest that circulating Tregs are a novel immunological marker associated with liver metastases and treatment response to TAE in patients with GEP-NETs., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background: Neuroendocrine neoplasms (NENs) represent clinically and genetically heterogeneous malignancies, thus a comprehensive understanding of underlying molecular characteristics, prognostic signatures, and potential therapeutic targets is urgently needed., Methods: Next-generation sequencing (NGS) and immunohistochemistry were applied to acquire genomic and immune profiles of NENs from 47 patients., Results: Difference was distinguished based on differentiation grade and primary localization. Poorly differentiated neuroendocrine carcinomas (NECs) and well-differentiated neuroendocrine tumors (NETs) harbored distinct molecular features; we observed that tumor mutational burden (TMB) and tumor neoantigen burden (TNB) were significantly higher in NECs versus NETs. Notably, we identified a 7-gene panel (MLH3, NACA, NOTCH1, NPAP1, RANBP17, TSC2, and ZFHX4) as a novel prognostic signature in NENs; patients who carried mutations in any of the 7 genes exhibited significantly poorer survival. Furthermore, loss of heterozygosity (LOH) and germline homogeneity in human leukocyte antigen (HLA) are common in NENs, accounting for 39% and 36%, respectively. Notably, HLA LOH was an important prognostic biomarker for a subgroup of NEN patients. Finally, we analyzed clinically actionable targets in NENs, revealing that TMB high (TMB-H) or gene mutations in TP53, KRAS, and HRAS were the most frequently observed therapeutic indicators, which granted eligibility to immune checkpoint blockade (ICB) and targeted therapy., Conclusion: Our study revealed heterogeneity of NENs, and identified novel prognostic signatures and potential therapeutic targets, which directing improvements of clinical management for NEN patients in the foreseeable future., (© The Author(s) 2023. Published by Oxford University Press.)

Objective: To evaluate the efficacy and outcome of transarterial embolization (TAE) plus octreotide long-acting repeatable (LAR) on patients with low-to-intermediate neuroendocrine tumor liver metastases (NETLM)., Methods: One hundred and sixteen patients with G1/G2 NETLM treated with TAE plus octreotide LAR at the First Affiliated Hospital, Sun Yat-sen University between January 12, 2016 and September 24, 2020 were reviewed. Radiological response was evaluated according to response evaluation criterion in solid tumor version 1.1. Overall progression-free survival (PFS) was assessed. Intrahepatic and extrahepatic PFS were evaluated in the whole cohort and in patients with the extrahepatic disease (EHD), respectively. Factors affecting treatment response and overall PFS were analyzed using the logistic regression model and Cox proportional hazard model. Adverse events were recorded and evaluated according to Common Terminology Criteria for Adverse Events 5.0., Results: The median overall PFS of the whole cohort was 13.6 months. For the patients with EHD, the median intrahepatic PFS and extrahepatic PFS were 13.6 and 26.1 months, respectively. The median overall PFS of patients with hepatic tumor burden (HTB) <10%, 10%-25%, 25%-50%, and >50% were 25.2, 13.6, 11.2, and 12.3 months, respectively. Ki67 >10%, HTB >50%, and bone metastasis were independently associated with overall PFS. The objective response rate was 78.4%. In patients with HTB 25%-50% and >50%, responders (complete response or partial response) had significant prolonged PFS compared with nonresponders (stable disease or progression disease). Ki67 >10%, bone metastasis, and clear tumor margin were independently associated with response to TAE. The most frequent adverse events that occurred after TAE were postembolization syndrome, and no treatment-associated death occurred during the perioperative period., Conclusion: Transarterial embolization plus octreotide LAR can significantly prolong the PFS of neuroendocrine tumor liver metastases, especially with high HTB over 50%. Selected patients with HTB >25% (ki67 ≤10%, absence of bone metastasis, clear tumor margin) could derive prognostic advantage from the combined treatment., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Expanded myeloid-derived suppressor cells (MDSCs) correlate with disseminated metastases and poor prognosis in various human cancers. However, the role of MDSCs in gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) is still unknown. We investigated the distribution of MDSCs and their clinical significance in patients with GEP-NENs., Methods: Peripheral blood mononuclear cells (PBMCs) and paraffin-embedded tumor tissues were acquired from patients with GEP-NENs. Multicolor flow cytometry was performed to determine the frequency of MDSCs in peripheral blood, and immunohistochemistry was performed to determine the distribution of MDSCs in primary NEN tissues., Results: Compared to healthy donors, patients with GEP-NENs had significantly higher levels of circulating monocytic (M)-MDSCs. Frequency of M-MDSCs in both peripheral blood and primary NEN tissues was significantly higher in GEP-NEN patients with metastases compared to patients without metastases. Tumor-infiltrating M-MDSCs can serve as a valuable prognostic marker of metastasis in patients with GEP-NENs, as indicated by the area under the curve (AUC) = 0.71; 95% confidence interval (CI) = 0.56-0.87, p < 0.01., Conclusions: High M-MDSC levels were associated with significantly increased metastases in patients with GEP-NENs. M-MDSCs appear to be a promising prognostic immunologic biomarker and therapeutic target in GEP-NEN management.

Background: This study aimed to develop a nomogram that predicts the overall survival (OS) of rectal neuroendocrine tumours (NETs)., Methods: We retrospectively analysed 310 patients with rectal neuroendocrine tumours in 5 hospitals in southern China. All of the patients were assigned to the training set. A multivariable analysis using Cox proportional hazards regression was performed using the training set, and a nomogram was constructed. It was validated on a dataset obtained from the Surveillance, Epidemiology, and End Result (SEER) database of America (n = 547)., Results: In the training set, the nomogram exhibited improved discrimination power compared with the WHO grade guidelines (Herrell's C-index, 0.872 vs 0.794; p < 0.001) and was also better than the seventh AJCC TNM classification (Herrell's C-index, 0.872 vs 0.817; p < 0.001). In the SEER validation dataset, the discrimination was also excellent (C-index, 0.648 vs 0.583, p < 0.001 and 0.648 vs 0.603, p = 0.016, respectively, compared with G grade and TNM classification). Calibration of the nomogram predicted individual survival corresponding closely with the actual survival., Conclusions: We developed a nomogram predicting 1- and 3-year OS of patients with rectal neuroendocrine tumours. Validation revealed excellent discrimination and calibration, suggesting good clinical utility.

Introduction: The pathological grading of pancreatic neuroendocrine neoplasms (pNENs) is an independent predictor of survival and indicator for treatment. Deep learning (DL) with a convolutional neural network (CNN) may improve the preoperative prediction of pNEN grading., Methods: Ninety-three pNEN patients with preoperative contrast-enhanced computed tomography (CECT) from Hospital I were retrospectively enrolled. A CNN-based DL algorithm was applied to the CECT images to obtain 3 models (arterial, venous, and arterial/venous models), the performances of which were evaluated via an eightfold cross-validation technique. The CECT images of the optimal phase were used for comparing the DL and traditional machine learning (TML) models in predicting the pathological grading of pNENs. The performance of radiologists by using qualitative and quantitative computed tomography findings was also evaluated. The best DL model from the eightfold cross-validation was evaluated on an independent testing set of 19 patients from Hospital II who were scanned on a different scanner. The Kaplan-Meier (KM) analysis was employed for survival analysis., Results: The area under the curve (AUC; 0.81) of arterial phase in validation set was significantly higher than those of venous (AUC 0.57, p = 0.03) and arterial/venous phase (AUC 0.70, p = 0.03) in predicting the pathological grading of pNENs. Compared with the TML models, the DL model gave a higher (although insignificantly) AUC. The highest OR was achieved for the p ratio <0.9, the AUC and accuracy for diagnosing G3 pNENs were 0.80 and 79.1% respectively. The DL algorithm achieved an AUC of 0.82 and an accuracy of 88.1% for the independent testing set. The KM analysis showed a statistical significant difference between the predicted G1/2 and G3 groups in the progression-free survival (p = 0.001) and overall survival (p < 0.001)., Conclusion: The CNN-based DL method showed a relatively robust performance in predicting pathological grading of pNENs from CECT images., (© 2019 S. Karger AG, Basel.)

Purpose: To assess whether parameters on preprocedural CT can be utilized to predict the response of NETLM to transcatheter arterial bland embolization (TAE)., Methods: We retrospectively reviewed 135 target lesions from 48 NETLM patients who underwent TAE and with complete preprocedural multiphasic CT. Parameters on preprocedural CT including the longest diameter, mean attenuation value in nonenhanced, arterial, and portal-venous phases were collected from each target lesion. Radiological responses were assessed according to RECIST 1.1. The parameters of responder lesions and nonresponder lesions were compared. Arterial enhancement index (AEI) and portal-venous enhancement index (PEI) were calculated. The predictive function of AEI and PEI on tumor response was analyzed by receiver operating characteristic (ROC) curve., Results: A total of 72.6% target lesions had a partial response. For patients, the objective response rate was 72.9%. Mean attenuation values of responder lesions were significantly higher than nonresponder lesions in both arterial and portal-venous phases (105.36 ± 37.24 vs. 76.01 ± 19.19, p < 0.001; 96.61 ± 24.04 vs. 82.12 ± 21.37, p = 0.002). ROC curve showed that both AEI and PEI were effective in predicting tumor response (area under the curve [AUC] 0.757, p < 0.001; AUC 0.655, p = 0.005)., Conclusion: AEI and PEI, parameters from evaluation of CT pretreatment attenuation of NETLMs, could predict response to TAE treatment., (© 2019 S. Karger AG, Basel.)

Objective: To identify a reliable early indicator of deriving progression-free survival (PFS) benefit in patients with advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs) treated with octreotide long-acting repeatable (LAR)., Methods: We investigated the images of 50 patients with well-differentiated advanced GEP-NETs treated with LAR octreotide and underwent baseline and follow-up thoracic, abdominal, and pelvic computed tomography. Receiver-operating characteristic (ROC) analysis and the Kaplan-Meier method were used to identify the optimal threshold to distinguish between those with and without significant improvement of PFS., Results: The optimal threshold for determining a response to octreotide LAR was -10% ΔSLD, with a sensitivity and specificity of 85.7% and 80%, respectively. At this threshold, 19 patients were responders and 31 were non-responders; the median PFS was 20.2 and 7.6 months in responders and non-responders (hazard ratio, 2.66; 95% confidence interval, 1.32-5.36)., Conclusion: A 10% shrinkage in tumor size is an optimal early predictor of response to octreotide LAR in advanced GEP-NETs., Key Points: • Octreotide LAR can significantly prolong PFS among patients with well-differentiated advanced GEP-NETs. • No optimal tumor size-based response criteria are reported in GEP-NETs with octreotide. • Ten percent tumor shrinkage is a reliable indicator of the response to octreotide for advanced GEP-NETs.

Objective: We propose a computer-aided method to assess response to drug treatment, using CT imaging-based volumetric and density measures in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and diffuse liver metastases., Methods: Twenty-five patients with GEP-NETs with diffuse liver metastases were enrolled. Pre- and posttreatment CT examinations were retrospectively analyzed. Total tumor volume (volume) and mean volumetric tumor density (density) were calculated based on tumor segmentation on CT images. The maximum axial diameter (tumor size) for each target tumor was measured on pre- and posttreatment CT images according to Response Evaluation Criteria In Solid Tumors (RECIST). Progression-free survival (PFS) for each patient was measured and recorded., Results: Correlation analysis showed inverse correlation between change of volume and density (Δ( V + D )), change of volume (Δ V ), and change of tumor size (Δ S ) with PFS ( r = -0.653, P =0.001; r = -0.617, P =0.003; r = -0.548, P =0.01, respectively). There was no linear correlation between Δ D and PFS ( r = -0.226, P =0.325)., Conclusion: The changes of volume and density derived from CT images of all lesions showed a good correlation with PFS and may help assess treatment response.

Aim: This study was conducted to analyze the risk factors associated with lymph node metastasis in rectal neuroendocrine neoplasms (NENs)., Materials & Methods: A total of 419 patients with rectal NENs were enrolled. A univariate analysis of risk factors of lymph node metastasis was conducted using a χ 2 test, and a multivariate analysis was conducted using a logistic regression analysis., Results: Univariate and multivariate regression analysis revealed that tumor size, G grade and the depth of tumor invasion were independent risk factors for lymph node metastasis (p < 0.05)., Conclusion: Rectal NENs patients with a larger tumor size, deeper tumor invasion or a higher G grade had a higher risk of regional lymph node metastasis.

Background: How to evaluate the prognostic significance of lymphatic metastasis in patients with small bowel (jejunoileal) neuroendocrine tumors (SBNETs) is still not conclusive., Methods: Data for patients with SBNETs, but without distant metastasis, were retrieved from the Surveillance, Epidemiology, and End Results database. Recursive partitioning analysis (RPA) was used for classification development by combining examined lymph nodes (ELNs) and lymph node ratio (LNR)., Results: Overall, 1925 patient records were retrieved. Patients with N0 and N1 disease (based on the definition of the European Neuroendocrine Tumor Society [ENETS] staging classification) did not have different OS (p = 0.7867), nor did patients with N0, N1 (< 12 positive nodes), and N2 (≥ 12 positive nodes) disease based on the definition of American Joint Committee on Cancer (AJCC) 8th edition staging classification (p = 0.5276). However, Cox regression analysis indicated that both ELNs (hazard ratio [HR] 0.968, 95% confidence interval [CI] 0.949-0.987; p = 0.0013) and LNR (HR 2.288, 95% CI 1.122-3.682; p = 0.0006) were prognostic factors. Using RPA, we combined ELNs and LNR, and patients were reclassified into three groups (group 1: ELNs ≥ 12, any LNR; group 2: ELNs < 12, LNR < 0.35; group 3: ELNs < 12, LNR ≥ 0.35). Survival analysis and multivariate Cox regression showed that groups 1, 2, and 3 had progressively worse survival. Furthermore, we found that ELNs ≥ 12 could remarkably improve patient survival (p < 0.001)., Conclusions: The current definition of lymphatic metastasis could not help predict patient survival. Our newly proposed classification of lymphatic metastasis is better than the ENETS and AJCC 8th edition staging classifications in evaluating the prognostic significance of lymphatic metastasis in SBNETs. Systematic resection of lymph nodes (≥ 12) could help improve patient survival.

Background: The neuronal intermediate filament alpha-internexin (α-internexin) is a cytoskeleton protein which is involved in the tumor initiation and progression. In this study, we examined the expression and prognosis value of α-internexin in gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs)., Methods: α-internexin was detected with immunohistochemical staining in 286 tumor specimens from patients with GEP-NENs. Methylation status of α-internexin was evaluated by bisulfite genomic sequencing. We assessed the prognostic value of α-internexin and its correlation with relevant clinicalpathological characteristics., Results: The reduced/loss of expression rate of α-internexin in GEP-NEN was 73.4% (210/286), while the positive expression rate was 26.6% (76/286). The difference of α-internexin deficiency was not statistically significant between gastrointestinal NENs (GI-NENs) and pancreatic NENs (pNENs). However, we found significant difference of reduced/loss of α-internexin expression among different sites of GI-NENs (χ 2  = 43.470, P < 0.001). The reduced/loss of expression of α-internexin was significantly associated with poorly differentiation (P < 0.001) and advanced tumor stage (P < 0.001). Univariate analyses showed that reduced/loss of expression of α-internexin predicted worse overall survival (OS) in GEP-NEN patients (P < 0.001), especially in subtype of GI-NENs (P < 0.001). However, in multivariable regression analysis, α-internexin expression was not an independent prognostic factor. The hypermethylation of α-internexin gene was significantly correlated with protein deficiency in GI-NENs, but not in pNENs. Hypermethylation of several CpG sites was significantly associated with poorly differentiated and advanced stage (P values range from 0.018 to 0.044). However, the methylation status of α-internexin was not associated with patient OS., Conclusions: The expression of α-internexin was highly heterougeneous in different sites of GEP-NENs. The reduced/loss of expression of α-internexin was closely related to tumors with aggressiveness and patient's adverse prognosis. The hypermethylation of the regulatory region examined may be an important epigenetic regulation mechanism of α-internexin deficiency in subtype of GI-NENs.

Introduction: Elevated serum procalcitonin (PCT) was reported in patients with certain type of neuroendocrine neoplasms (NENs)., Objective: The aim of this study was to assess the role of elevated serum PCT in NENs from digestive system., Patients and Methods: Serum PCT and serum CgA level were measured in 155 patients with NENs from digestive system., Results: Elevated serum PCT was found in 63 patients (40.6%). Grade 3 disease was a significant factor associated with elevated serum PCT (OR, 9.24; 95%CI, 3.04-28.08; P<0.001). Serum PCT level was significantly decreased after treatment both in patients with stable disease (P=0.003) and patients with partial remission (P=0.001). In these patients, serum PCT level significantly increased again at the time of progression disease (P=0.001). Elevated serum PCT was a significant factor of worse survival (HR, 2.86; 95%CI, 1.36-6.03; P=0.006). Compared with patients with normal serum PCT and CgA level, patients with either PCT or CgA elevated and patients with both PCT and CgA elevated had progressively worse survival. Additionally, PCT expression in tumor cells was found in 24.0% of patients but did not correlate with other clinicopathological factors, including serum PCT., Conclusions: Serum PCT is elevated in part of patients with NENs of digestive system, especially in patients with grade 3 disease. Serum PCT level can help evaluate treatment response and its elevation indicates poor prognosis. Combination of serum PCT and CgA can improve outcome prediction., (Copyright © 2017 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Background: The current study aimed to establish a novel nomogram to predict the overall survival of individual Chinese patients with gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). Furthermore, this study sought to externally validate this nomogram using the Surveillance, Epidemiology, and End Results (SEER) database., Methods: The records of 1183 patients with GEP-NENs treated at five high-capacity institutions in China between 2005 and 2015 were retrospectively analysed. In addition, 10 236 GEP-NEN cases from the SEER database were included as an external validation set., Results: A multivariate analysis using Cox proportional hazards (PHs) regression was performed, and a nomogram was constructed. Discrimination, calibration, and external validation were performed using the SEER data set. The multivariate Cox model indicated that age, tumour size, differentiation, lymph node metastases, and distant metastases were independent covariates associated with survival. With respect to the training set, the nomogram exhibited better discrimination power than TNM classification (Harrell's concordance index (C-index): 0.837 vs 0.784, P=0.006). Discrimination was also excellent and superior to that of TNM classification for the SEER-based validation set (C-index: 0.808 vs 0.717, P<0.001). The calibrated nomogram predicted a survival rate that closely corresponded to the actual survival rate., Conclusions: We developed a nomogram that predicted the 3- and 5-year overall survival rates of patients with GEP-NENs. Validation revealed excellent discrimination and calibration for this nomogram, suggesting that it exhibits satisfactory clinical utility that might improve individualised predictions of survival risks and lead to the creation of additional clinical therapies.

Objective: To study the rate of elevated common biomarkers of digestive tumors, including carcinoembryonic antigen (CEA), alpha fetoprotein (AFP), carbohydrate antigen 125 (CA125) and carbohydrate antigen 19-9 (CA19-9), in gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN) and their prognostic values in GEP-NEN., Methods: Clinicopathological data of patients with GEP-NEN treated in The First Affiliated Hospital, Sun Yat-sen University from January 2011 to December 2016 were retrospectively studied. The inclusion criteria were as follows: patients with complete clinicopathological data including AFP, CEA, CA125 and CA19-9 level before treatment; patients without previous or other concomitant cancer; patients diagnosed as sporadic but not familial NEN. Serum AFP level >30 μg/L, CEA level >7.5 μg/L, CA125 level >52.5 μg/L and CA19-9 level >52.5 kU/L were defined as elevation respectively. Kaplan-Meier analysis and Log-rank test were applied to investigate the prognostic role of these biomarkers., Results: A total of 170 patients with GEP-NEN were enrolled, and 105 (61.8%) patients were male with median age of 52.5 years. Thirty-six (21.2%), 77 (45.3%) and 57 (33.5%) cases were gastric, intestinal and pancreatic NEN respectively. Elevated AFP, CEA, CA125 and CA19-9 were found in 3(1.8%), 19(11.2%), 22(12.9%) and 21(12.4%) patients. Elevated CEA was related with G3 disease (OR=4.78, 95%CI:1.28-17.85, P=0.020) and elevated CA125 was related with distant metastasis (OR=51.60, 95%CI:5.76-462.44, P=0.000) while elevated CA19-9 was related with both G3 disease (OR=3.81; 95%CI:1.21-11.99, P=0.022) and distant metastasis(OR=4.87; 95%CI:1.41-16.75, P=0.012). The median follow-up was 22.5 months. Forty-six patients (27.1%) died during the follow-up. Patients with elevated CEA, CA125 or CA19-9 had worse overall survival compared with their counterparts with the median survivals of 14 months (95%CI:5.4 to 22.6 months, χ 2 =15.582, P=0.000), 6 months (95%CI:3.2 to 8.8 months, χ 2 =37.627, P=0.001) and 10 months (95%CI:0 to 20.6 months, χ 2 =50.187, P=0.000) respectively. Furthermore, patients with more than two elevated biomarkers (median survival 6 months, 95%CI:4.37-7.63 months) had worse survival than patients with only one elevated biomarker (median survival 26 months, 95%CI:15.68-36.32 months, χ 2 =9.295, P=0.002)., Conclusions: Elevation of AFP, CEA, CA125 or CA19-9 is not common in GEP-NEN. Patients with elevation of these biomarkers have poor survival.

Purpose: To determine the efficacy and safety of sunitinib in Chinese patients with unresectable or metastatic pancreatic neuroendocrine tumors (pNETs) and the clinical significance of steady-state sunitinib serum concentrations., Methods: We conducted a multicenter retrospective study including six centers from across China. A total of 60 patients with unresectable or metastatic pNETs who were treated with sunitinib were evaluated retrospectively., Results: The median overall survival (OS) was 47.5 months and the median time to progression (TTP) was 15.3 months. The objective response rate was 5.0%, and the stable disease (SD) rate was 81.7%. About 35.2% of patients required a dosage decrease from 37.5 to 25 mg/day due to adverse events, which in most cases were alleviated or disappeared with the dosage reduction. In 14 patients who experienced sunitinib-related hypertension, 2 achieved a partial response (PR) and 11 had SD. The median OS and TTP of these 14 patients experienced hypertension were both not reached. The median Css of sunitinib was similar between patients treated with sunitinib 37.5 and 25 mg/day (P = 0.955), but higher in patients who had PR than in those who achieved SD or progressive disease, although no statistically significant difference was found (P = 0.173)., Conclusions: Sunitinib had similar treatment efficacy to western patients with pNET in China. A 25 mg/day dosage was better tolerated than 37.5 mg/day in Chinese patients, and there were no significant differences in sunitinib Css between the two dosage groups. Patients with higher sunitinib Css seem to have better efficacy. Sunitinib-related hypertension may be a predictor of a better treatment effect.

Background: The clinicopathological characteristics of small intestinal neuroendocrine neoplasms (SI-NENs) and the prognostic validity of WHO grading classification for SI-NENs are still unknown in Asian patients., Methods: 277 patients and 8315 patients with SI-NENs were retrieved respectively from eleven Chinese hospitals and Surveillance, Epidemiology, and End Results (SEER) cancer registry. Overall survival was used as the major study outcome. Survival analysis using Kaplan-Meier analysis with log-rank test and cox regression analysis were applied., Results: Clinicopathological characteristics of SI-NENs were quite different among different races. Duodenum was the predominant tumor site in Chinese patients and Asian/Pacific Islander patients but not in white patients from SEER database. Patients with duodenal NENs tended to have more localized disease than patients with jejunal/ileal NENs which were confirmed by patients from SEER database. Grade 3 or poorly differentiated/undifferentiated tumor were more common and tumor size was significantly larger in ampullary NENs compared with that in non-ampullary duodenal NENs. As for the prognostic validity of WHO grading classification, survival between patients with grade 1 and grade 2 disease was not significantly different. Ki-67 index of 5% might be a better threshold between grade 1 and grade 2 than Ki-67 index of 2% in SI-NENs., Conclusions: Our study revealed that the clinicopathological characteristics of SI-NENs among different races were quite different. This might because duodenal NENs was much more common in Chinese patients and Asian/Pacific Islander patients. Duodenal NENs and jejunal/ileal NENs, ampullary and non-ampullary duodenal NENs shared different characteristics. Ki-67 index of 5% might be a better threshold between grade 1 and grade 2 in SI-NENs.

Background: Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a heterogeneous group of rare tumors. Many issues in terms of epidemiologic features, pathogenesis, and treatment of GEP-NENs are still under discussion. Our study aimed to analyze the clinicopathologic characteristics and prognosis of Chinese patients with GEP-NENs., Methods: Complete clinicopathologic data and survival information of 1183 patients with GEP-NENs treated between 2005 and 2015 were collected from five medical centers in Guangdong Province, China. Patient survival was estimated using the Kaplan-Meier method and analyzed using the log-rank test; prognostic factors were analyzed using the Cox proportional hazards model., Results: The most common tumor location was the rectum (37.4%), followed by the pancreas (28.1%), stomach (20.7%), small intestine (7.2%), appendix (3.4%), and colon (3.3%). After initial definitive diagnosis, 1016 (85.9%) patients underwent surgery. The 1-, 3-, and 5-year overall survival (OS) rates for the entire cohort were 87.9%, 78.5%, and 72.8%, respectively. The 3-year OS rates of patients with G1, G2, and G3 tumors were 93.1%, 82.7%, and 43.1%, respectively (P < 0.001). The 3-year OS rates of patients with stage I, II, III, and IV tumors were 96.0%, 87.3%, 64.0%, and 46.8%, respectively (P < 0.001). Patients with distant metastasis who underwent palliative surgery had a longer survival than those who did not (P = 0.003). Similar survival benefits of palliative surgery were observed in patients with neuroendocrine tumor (P = 0.031) or neuroendocrine carcinoma (P = 0.046). In multivariate analysis, age, grade, N category, M category, and surgery were found to be independent prognostic factors., Conclusions: Patients with GEP-NENs who are women, younger than 50 years old, have smaller tumor size, have lower tumor grade, have lower T/N/M category, and who undergo surgery can have potentially longer survival time. Our data showed that surgery can improve the prognosis of GEP-NEN patients with distant metastasis. However, randomized controlled trials need to be conducted to establish the optimal criteria for selecting patients to undergo surgery.

Gastroenteropancreatic neuroendocrine neoplam (GEP-NEN) is a rare group of tumors with its incidence rising significantly in recent decades. Because of the late presentation of the disease and limitations in conventional biomarkers, about 50% of GEP-NEN patients manifests advanced disease when diagnosed. Therefore, it is vital to identify circulating biomarkers which can not only be used for early diagnosis but also accurately evaluating the biological behavior of GEP-NEN. This review summarizes the advances of circulating biomarkers in diagnosing and evaluating efficacy of treatment in GEP-NEN. Well-known circulating biomarkers include chromogranin A (CgA), pancreastatin (PST), chromogranin B (CgB), neuron-specific enolase (NSE) and pancreatic peptide(PP). Novel biomarkers including circulating tumor cell(CTC), microRNA and NETest are promising biomarkers with potential clinical benefit, but further researches are needed before their clinical applications.

Background: The aim of this study was to assess and compare the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) and the Choi criteria in evaluating the early response of advanced gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) treated with sunitinib., Methods: Eighteen patients with pathologically proven advanced GEP-NENs treated with sunitinib were enrolled in the study. Pre- and post-treatment CT scans (plain, biphasic enhanced CT scan) were performed on all patients. Changes in the target tumor size and density from pre-treatment to 1.4-3.1 months after treatment were measured and recorded for each patient. Tumor responses were identified using RECIST 1.1 and Choi criteria. The time to tumor progression (TTP) for each patient was measured and compared between groups using the Kaplan-Meier method., Results: Among the 18 patients, 4 (22%) exhibited a partial response (PR), 9 (50%) exhibited stable disease (SD), and 5 (28%) experienced progressive disease (PD), using RECIST 1.1. However, based on the Choi criteria, 8 (44%) patients exhibited a PR, 4 (22%) exhibited SD, and 6 (33%) experienced PD. According to RECIST 1.1, the median TTP of PR, SD and PD group were 16.6, 10.8 and 2.3 months, respectively. The TTP of the PR group was significantly longer than that of the PD group (P = 0.007) but insignificant when compared to the SD group (P = 0.131). According to Choi criteria, the median TTP of PR, SD and PD group were not reached, 10.8 and 2.3 months, respectively. The TTP of the PR group was significantly longer than that of the SD (P = 0.026) and PD groups (P < 0.001)., Conclusion: The Choi criteria appear to be more sensitive and more precise than RECIST 1.1 in assessing the early response of advanced GEP-NENs treated with sunitinib.

Purpose The European Neuroendocrine Tumor Society (ENETS) and the American Joint Committee on Cancer (AJCC) staging classifications are two widely used systems in managing pancreatic neuroendocrine tumors. However, there is no universally accepted system. Methods An analysis was performed to evaluate the application of the ENETS and AJCC staging classifications using the SEER registry (N = 2,529 patients) and a multicentric series (N = 1,143 patients). A modified system was proposed based on analysis of the two existing classifications. The modified system was then validated. Results The proportion of patients with AJCC stage III disease was extremely low for both the SEER series (2.2%) and the multicentric series (2.1%). For the ENETS staging system, patients with stage I disease had a similar prognosis to patients with stage IIA disease, and patients with stage IIIB disease had a lower hazard ratio for death than did patients with stage IIIA disease. We modified the ENETS staging classification by maintaining the ENETS T, N, and M definitions and adopting the AJCC staging definitions. The proportion of patients with stage III disease using the modified ENETS (mENETS) system was higher than that of the AJCC system in both the SEER series (8.9% v 2.2%) and the multicentric series (11.6% v 2.1%). In addition, the hazard ratio of death for patients with stage III disease was higher than that for patients with stage IIB disease. Moreover, statistical significance and proportional distribution were observed in the mENETS staging classification. Conclusion An mENETS staging classification is more suitable for pancreatic neuroendocrine tumors than either the AJCC or ENETS systems and can be adopted in clinical practice.

Objective: To investigate the clinicopathological characteristics and their relationship with prognosis of colorectal neuroendocrine neoplasms (NEN)., Methods: Medical records of 329 patients with colorectal NEN between June 2001 and July 2016 from 6 large scale centers in China were reviewed to investigate the clinicopathological characteristics and their relationship with prognosis of colorectal NEN., Results: (1) Colonic NEN: A total of 41 patients with colonic NEN were enrolled from The First Affiliated Hospital of Sun Yat-sen University(n=11), Sun Yat-sen University Cancer Center (n=15), Guangdong General Hospital (n=10), Sun Yet-san Memorial Hospital of Sun Yat-sen University (n=3) and Fudan University Shanghai Cancer Center (n=2). 41 cases, including 20 males and 21 females with a mean age of (58.7±4.7) years. Twenty-three colonic NEN originated in hindgut (23/41, 56.1%), and 20 patients were stage IIII( (20/41, 48.8%). Nine cases (22.0%) were neuroendocrine tumor(NET), 25(61.0%) were neuroendocrine carcinoma (NEC) and 7(17.1%) were mixed adenoendocrine carcinoma (MANEC). Six cases (14.6%) were G1 grade, 3(7.3%) were G2 grade and 32(78.1%) were G3 grade. Ulcerative or cauliflower-like tumors were the most common appearance under endoscopy (both 9/41, 22.0%). Thirty-three patients (80.5%) underwent surgery. During follow-up, 19 cases died and the 3-year survival rate was 46.1%. Multivariate analysis revealed that stage IIII( was an independent risk factor of poor prognosis (HR=3.871, 95%CI:1.342 to 11.167, P=0.012) in colonic NEN patients. (2) Rectal NEN: A total of 288 patients with rectal NEN were enrolled from The First Affiliated Hospital of Sun Yat-sen University(n=130), Nanfang Hospital of Southern Medical University (n=115) and Fudan University Shanghai Cancer Center (n=43). Two hundred and eighty-eight cases, including 181 males and 107 females with a mean age of (47.7±1.5) years. One hundred and ninety-seven patients were stage I((197/288, 68.4%). Of 288 rectal NEN cases, 267(92.7%) were NET, 20(7.0%) were NEC and 1(0.3%) was MANEC; 214(74.3%) were G1 grade, 53(18.4%) were G2 grade and 21(7.3%) were G3 grade. Submucosal tumor was the most common appearance under endoscopy(164/288, 56.9%). Most of the rectal NET G1/G2 tumors were submucosal(146/214, 68.2%;18/53,34.0% respectively) while most of G3 tumors were cauliflower-like (14/21,66.7%). A total of 175 patients (60.8%) underwent endoscopic therapy, while 96 patients(33.3%) underwent surgery. During follow-up, 12 cases died and 3-year survival rate was 94.0%. Multivariate analysis revealed that poor differentiation as NEC or MANEC(HR=8.919, 95% CI:1.911 to 41.637, P=0.005) and stage III( to IIII((HR=10.304, 95%CI:1.772 to 59.916, P=0.009) were independent risk factors of poor prognosis in rectal NEN patients., Conclusions: The clinicopathological manifestations of rectal NEN and colonic NEN are quite different. Rectal NEN are more common with better differentiation and has better prognosis than colonic NEN.

Pancreatic neuroendocrine neoplasms (p-NENs) are slowly growing tumors with frequent liver metastasis. There is a variety of approaches to treat non-functional p-NENs with synchronous liver metastasis (LM) which complicates the determination of optimal treatment. Based on updated literature review, we discussed the treatment strategy determinants for p-NEN with LM. According to the resectability of primary tumor, the WHO 2010 grade classification and the radiological type of liver metastasis, the CSNET group reached agreements on a number of issues, including the following. Prior to treatment, biopsy is required to confirm pathology. Liver biopsy is important for more accurate grading of tumor and percutaneous core needle biopsy is more available than EUS-FNA. In patients with unresectable primary, surgical resection for liver-metastatic lesions should be avoided. Curative surgery is recommended for G1/G2 p-NET with type I LM and R1 resection also seems to improve overall survival rate. Cytoreductive surgery is recommended for G1/G2 p-NET with type II LM in select patients, and should meet stated requirements. Surgical resection for G1/G2 p-NET with type III LM and p-NEC with LM should be avoided, and insufficient evidence exists to guide the surgical treatment of G3 p-NET with LM. Liver transplantation may be an option in highly select patients. In addition, the optimal time for surgical approach is still required for more evidence.

Objectives: We aimed to evaluate the multi-slice computed tomography (MSCT) features of pancreatic neuroendocrine neoplasms (P-NENs) and analyse the correlation between the MSCT features and pathological classification of P-NENs., Methods: Forty-one patients, preoperatively investigated by MSCT and subsequently operated on with a histological diagnosis of P-NENs, were included. Various MSCT features of the primary tumour, lymph node, and distant metastasis were analysed. The relationship between MSCT features and pathologic classification of P-NENs was analysed with univariate and multivariate models., Results: Contrast-enhanced images showed significant differences among the three grades of tumours in the absolute enhancement (P = 0.013) and relative enhancement (P = 0.025) at the arterial phase. Univariate analysis revealed statistically significant differences among the tumours of different grades (based on World Health Organization [WHO] 2010 classification) in tumour size (P = 0.001), tumour contour (P < 0.001), cystic necrosis (P = 0.001), tumour boundary (P = 0.003), dilatation of the main pancreatic duct (P = 0.001), peripancreatic tissue or vascular invasion (P < 0.001), lymphadenopathy (P = 0.011), and distant metastasis (P = 0.012). Multivariate analysis suggested that only peripancreatic tissue or vascular invasion (HR 3.934, 95 % CI, 0.426-7.442, P = 0.028) was significantly associated with WHO 2010 pathological classification., Conclusions: MSCT is helpful in evaluating the pathological classification of P-NENs., Key Points: • P-NENs are potentially malignant, and classification of P-NENs carries important prognostic value. • MSCT plays an important role in the diagnosis and staging of P-NENs. • Correlations between classification of P-NENs and imaging findings have not been systematically evaluated. • MSCT could predict P-NENs classification and may be a useful prognostication tool.

Objective: The objective of our study was to compare the CT features of gastroenteric neuroendocrine neoplasms (GE-NENs) with the pathologic classification and to analyze the correlation between the CT features and classification of GE-NENs., Materials and Methods: Fifty-six cases of pathologically and immunohisto-chemically proven GE-NENs, including 25 cases of neuroendocrine tumors (NETs) (i.e., G1 and G2 tumors) and 31 cases of neuroendocrine carcinomas (NECs) (i.e., G3 tumors and mixed adenoneuroendocrine carcinomas) were studied. We analyzed various CT features of the primary tumor, nodal status, and metastasis and compared these features with pathologic grading., Results: The CT features that favor NEC over NET include larger tumor size (> 4.0 cm), transmural invasion, circumscribed tumor with both intra- and extraluminal involvement, circumferential growth, areas of cystic change or necrosis, ulceration, mesenteric fat infiltration, and lymphadenopathy, with p values of 0.044, 0.002, 0.024, 0.008, 0.002, 0.007, 0.002, and < 0.001, respectively. The CT features that do not distinguish between the two types of GE-NENs include tumor boundary, growth pattern, degree of enhancement, adjacent organ invasion, distant organ metastasis, and peritoneal seeding, with p values of 0.277, 0.153, 0.672, 1.000, 0.159, and 0.877, respectively., Conclusion: CT can be useful in the classification of GE-NENs.

Background: The aim of this study was to assess and compare the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) and the Choi criteria in evaluating the early response of advanced gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) treated with sunitinib.Methods: Eighteen patients with pathologically proven advanced GEP-NENs treated with sunitinib were enrolled in the study. Pre- and post-treatment CT scans (plain, biphasic enhanced CT scan) were performed on all patients. Changes in the target tumor size and density from pre-treatment to 1.4-3.1 months after treatment were measured and recorded for each patient. Tumor responses were identified using RECIST 1.1 and Choi criteria. The time to tumor progression (TTP) for each patient was measured and compared between groups using the Kaplan-Meier method.Results: Among the 18 patients, 4 (22%) exhibited a partial response (PR), 9 (50%) exhibited stable disease (SD), and 5 (28%) experienced progressive disease (PD), using RECIST 1.1. However, based on the Choi criteria, 8 (44%) patients exhibited a PR, 4 (22%) exhibited SD, and 6 (33%) experienced PD. According to RECIST 1.1, the median TTP of PR, SD and PD group were 16.6, 10.8 and 2.3 months, respectively. The TTP of the PR group was significantly longer than that of the PD group (P = 0.007) but insignificant when compared to the SD group (P = 0.131). According to Choi criteria, the median TTP of PR, SD and PD group were not reached, 10.8 and 2.3 months, respectively. The TTP of the PR group was significantly longer than that of the SD (P = 0.026) and PD groups (P < 0.001).Conclusion: The Choi criteria appear to be more sensitive and more precise than RECIST 1.1 in assessing the early response of advanced GEP-NENs treated with sunitinib. [ABSTRACT FROM AUTHOR]

Background and Aims: Diagram, diagnosis, and treatment with endoscopic submucosal dissection (ESD) for upper gastrointestinal submucosal tumors (SMTs) remain controversial, although endoscopic ultrasonography (EUS) and ESD have been established in diagnosis and treatment of SMTs in decades, respectively. In this study, we have investigated prospectively the profile of upper gastrointestinal SMTs, assessed the effect and feasibility of ESD in upper gastrointestinal SMTs treatment, as well as value of EUS in pre-ESD diagnosis and post-ESD follow-up for gastrointestinal SMTs.Methods: The upper gastrointestinal SMTs patients detected with endoscopy were further checked by EUS, then received series ESD treatment, and fulfilled 3- and 12-month follow-up EUS detection between July 2011 and March 2015. The parameters of SMTs with EUS examination (size, original layer) and treatment with ESD (en bloc resection rate, procedure time, procedure-related complications) were investigated and analyzed.Results: A total number of 224 patients with upper gastrointestinal SMTs were enrolled, and 108 (48.2 %) were men. The mean age was 50.4 ± 12.0 years (range 19-77 years). In total, 92 (41.1 %), 14 (6.3 %), 61 (27.2 %), 22 (9.8 %), 25 (11.2 %), and 10 (4.5 %) SMTs were located in esophagus, cardiac, fundus, body and antrum of stomach, duodenum, respectively. Two hundred and eight (92.9 %) patients were successfully treated with an en bloc ESD, while other 16 patients (7.1 %) suffered ESD failure (5.3 %, 12 case) or severe complications (1.8 %, 4 cases). The mean procedure time of ESD was 47.4 ± 27.3 min (range 10-180 min). The mean size of the SMTs measured with ESD samples was 13.6 ± 9.5 mm (range 4-113 mm). In total, 87 (38.8 %), 23 (10.3 %), and 114 (50.9 %) tumors originated from muscularis mucosa, submucosa, and muscularis propria, respectively. The majority of SMTs were leiomyoma (109, 48.7 %) and gastrointestinal stromal tumors (GIST) (77, 34.4 %), while other SMTs were confirmed as ectopic pancreas (21, 9.4 %), adenoid tumor (8, 3.6 %), lipoma (5, 2.2 %), neuroendocrine tumor (3, 1.3 %), and granulosa cell tumor (1, 0.4 %). The accuracy rate of EUS in pathological diagnosis or original layer was 82.6 % (185/224) or 74.6 % (167/224). Residual tumors were detected with EUS in 3 patients (1.3 %) in 3-month follow-up and no recurrence during 12-month follow-up period.Conclusions: The predominant SMTs in upper gastrointestinal tract were leiomyoma in esophageal tumors which originated from muscularis mucosae and GIST in stomach which originated from muscularis propria detected satisfactorily with EUS. This study showed that ESD was a safe and effective treatment for upper gastrointestinal SMTs. [ABSTRACT FROM AUTHOR]