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Background: Neuroendocrine tumors (NETs) are a group of heterogenous tumors originating from neuroendocrine system. Approximately, 40 percent will go through liver metastases, and liver-directed therapy was proved to improve the survival outcome. Parenchyma-sparing hepatectomy is advocated for the resection of NETs liver metastases while the possible relatively low negative margin rate is concerned. Indocyanine green (ICG) fluorescence imaging provides a real-time navigation on determination of surgical margins in colorectal cancer liver metastases. However, there was no previous study that reported the applications of ICG fluorescence imaging in NETs liver metastases. The present study aimed to evaluate the feasibility and security of using ICG fluorescence imaging to determine surgical margins of NETs liver metastases during operation., Methods: A retrospective two-arm cohort study was performed on 25 consecutive patients with NETs liver metastases who underwent laparoscopic parenchyma-sparing hepatectomy (LPSH). Patients were divided into two groups according to whether or not the ICG fluorescence imaging was used. Data on sociodemographic characteristics, laboratory parameters, pathology results, and surgical outcomes were collected., Results: A total of 145 tumors pathologically diagnosed with NETs liver metastases were resected from 25 patients. The pathological results indicated negative margins in all tumors (102/102) in LPSH with ICG fluorescence imaging group. The negative margin rate was significantly higher in LPSH using the ICG fluorescence imaging (100% v.s 88.4%, p = 0.002). Surgical outcomes, including operation time, estimated blood loss, intraoperative transfusion rate, and postoperative morbidity, were comparable between LPSH with and without ICG fluorescence imaging groups., Conclusion: ICG fluorescence imaging showed the potential to identify tumor boundaries and determine surgical margins. This technique may serve as a valuable intraoperative navigation in patients with NETs liver metastases., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The incidence of nonfunctional pancreatic neuroendocrine neoplasms (NF-pNENs) has been increasing annually. This study is aimed at investigating the clinicopathological characteristics and high-risk factors of NF-pNENs and the influence of surgical treatment on the prognosis of NF-pNEN patients with liver metastases., Methods: pNEN patients in this study were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. This study analyzed patients diagnosed with NF-pNENs from 2000 to 2017 who met the inclusion criteria. A retrospective analysis of the clinicopathological characteristics of NF-pNEN patients was conducted. Kaplan-Meier method was used to calculate the survival time. A multivariate Cox regression model was used to analyze the survival outcomes and risk factors., Results: From 2000 to 2017, the SEER database registered 10576 patients with pNENs and 1774 patients with liver metastases. Cox analysis revealed that age, sex, primary site, grade, tumor stage, surgery, tumor size, and liver metastasis were risk factors of prognosis, with grade being the most influential index. Patients with NF-pNENs with liver metastasis and no metastasis had different primary site, grade, and tumor size. In general, a higher grade was associated with a larger tumor and a greater risk of liver metastasis. Meanwhile, patients with liver metastasis showed that those with tumors originated from the tail of the pancreas had better prognoses than those with tumors originated from other parts. Surgical treatment can improve the prognosis of patients with liver metastases, despite the tumor grade., Conclusions: The incidence of pNENs has been increasing annually, and the liver has been the most common site of metastasis. Liver metastasis in patients with NF-pNENs, related to tumor size and grade, affected their long-term survival. Surgery significantly improved the prognosis of patients with liver metastases secondary to NF-pNENs with different grades., Competing Interests: The authors declare no competing interests., (Copyright © 2022 Abuduhaibaier Sadula et al.)

Background: Surufatinib showed superior efficacy in extrapancreatic neuroendocrine tumours (NETs) in the phase 3 SANET-ep study. In SANET-p, we aimed to assess the efficacy and safety of surufatinib in patients with advanced pancreatic NETs., Methods: SANET-p was a multicentre, randomised, double-blind, placebo-controlled, phase 3 study, done in 21 hospitals across China. Eligible patients were adults (aged 18 years or older) with progressive, advanced, well differentiated pancreatic NETs, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and progression on up to two kinds of previous systemic regimens for advanced disease. Patients were randomly assigned (2:1) via an interactive web response system to receive 300 mg of surufatinib or placebo, taken orally once per day in consecutive 4-week treatment cycles until disease progression, intolerable toxicity, withdrawal of consent, poor compliance, use of other antitumour medication, pregnancy, loss to follow-up, or if the investigator deemed discontinuation in the patient's best interest. Randomisation was done centrally using stratified block randomisation (block size three), stratified by pathological grade, previous systemic antitumour treatment, and ECOG performance status score. Patients, investigators, research staff, and the sponsor study team were masked to treatment allocation. Crossover to surufatinib was permitted for patients in the placebo group with disease progression. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population, which included all patients in randomisation. A pre-planned interim analysis was done at 70% of the predicted progression-free survival events. This study is registered at ClinicalTrials.gov, NCT02589821., Findings: Between Feb 18, 2016, and Nov 11, 2019, of 264 patients who were screened, 172 (65%) patients were randomly assigned to receive surufatinib (n=113) or placebo (n=59). The median follow-up was 19·3 months (95% CI 9·3-19·4) in the surufatinib group and 11·1 months (5·7-35·9) in the placebo group. The median investigator-assessed progression-free survival was 10·9 months (7·5-13·8) for surufatinib versus 3·7 months (2·8-5·6) for placebo (hazard ratio 0·49, 95% CI 0·32-0·76; p=0·0011). The trial met the early stopping criteria at the interim analysis and was terminated on recommendation from the independent data monitoring committee. The most common grade 3 or worse treatment-related adverse events were hypertension (43 [38%] of 113 with surufatinib vs four [7%] of 59 with placebo), proteinuria (11 [10%] vs one [2%]), and hypertriglyceridaemia (eight [7%] vs none). Treatment-related serious adverse events were reported in 25 (22%) patients in the surufatinib group and four (7%) patients in the placebo group. There were three on-treatment deaths in the surufatinib group, including two deaths due to adverse events (gastrointestinal haemorrhage [possibly treatment-related] and cerebral haemorrhage [unlikely to be treatment-related]), and one death attributed to disease progression. One on-treatment death in the placebo group was attributed to disease progression., Interpretation: Surufatinib significantly improves progression-free survival and has an acceptable safety profile in patients with progressive, advanced pancreatic NETs, and could be a potential treatment option in this patient population., Funding: Hutchison MediPharma., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Therapeutic options for advanced neuroendocrine tumours (NETs) are limited. We investigated the efficacy and safety of surufatinib (HMPL-012, sulfatinib) in patients with extrapancreatic NETs., Methods: SANET-ep was a randomised, double-blind, placebo-controlled, phase 3 trial undertaken at 24 hospitals across China. Patients (aged 18 years or older) with unresectable or metastatic, well differentiated, extrapancreatic NETs, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and progression on no more than two types of previous systemic regimens were enrolled. Patients were centrally randomly assigned (2:1) using stratified block randomisation (block size 3) via an interactive web response system to receive oral surufatinib at 300 mg per day or matching placebo. Randomisation was stratified by tumour origin, pathological grade, and previous treatment. Patients, investigators, research staff and the sponsor study team were masked to treatment allocation. Crossover to the surufatinib group was allowed for patients in the placebo group at disease progression. The primary endpoint was investigator-assessed progression-free survival, which was analysed in the intention-to-treat population. A preplanned interim analysis was done at 70% of predicted progression-free survival events. This study was registered with ClinicalTrials.gov, NCT02588170. Follow-up is ongoing., Findings: Between Dec 9, 2015, and March 31, 2019, 198 patients were randomly assigned to surufatinib (n=129) or placebo (n=69). Median follow-up was 13·8 months (95% CI 11·1-16·7) in the surufatinib group and 16·6 months (9·2-not calculable) in the placebo group. Investigator-assessed median progression-free survival was 9·2 months (95% CI 7·4-11·1) in the surufatinib group versus 3·8 months (3·7-5·7) in the placebo group (hazard ratio 0·33; 95% CI 0·22-0·50; p<0·0001). As the trial met the predefined criteria for early discontinuation of the study at the interim analysis, the study was terminated early, as recommended by the independent data monitoring committee. The most common treatment-related adverse events of grade 3 or worse were hypertension (47 [36%] of 129 patients in the surufatinib group vs nine [13%] of 68 patients in the placebo group) and proteinuria (25 [19%] vs zero). Treatment-related serious adverse events were reported in 32 (25%) of 129 patients in the surufatinib group and nine (13%) of 68 patients in the placebo group. Treatment-related deaths occurred in three patients in the surufatinib group (disseminated intravascular coagulation and hepatic encephalopathy, liver injury, and death with unknown reason) and one patient in the placebo group (cachexia and respiratory failure)., Interpretation: Progression-free survival was significantly longer in patients given surufatinib compared with patients given placebo, and surufatinib has a favourable benefit-to-risk profile in patients with progressive, advanced, well differentiated extrapancreatic NETs. Our results suggest that surufatinib might be a new treatment option for this population., Funding: Hutchison MediPharma., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Neuroendocrine tumor(NET) is a kind of highly heterogeneous and ubiquitous tumor, frequently localized in the gastrointestinal tract and pancreas. Surgery combined with regional ablation, endocrine therapy,chemotherapy and targeted therapy presents a favorable prognosis when treated with G1 or G2 gastroenteropancreatic neuroendocrine tumor(GEP-NET). However, there are only limited therapeutic strategies for metastatic unresectable tumors and poorly differentiated NEC,which are closely related to the special tumor microenvironment of neuroendocrine tumors.Targeting tumor microenvironment therapy is an important method in current systematic therapy, but till now the knowledge of neuroendocrine tumor microenvironment and its related treatment are limited. This article will specifically introduce the characteristics of tumor microenvironment in GEP-NET from the following aspects: the formation of enrichment vascular supply in TME,the role of tumor stroma,immune cells and cancer associacted fibroblast, and immune checkpoint and future trend of immunotherapy.

Liver metastasis is the one of the main prognostic factors of pancreatic neuroendocrine neoplasm (PNEN). With the development of multidisciplinary collaboration among surgical oncology, medical oncology, and intervention treatment, the treatment of PNEN with liver metastasis gradually tends to become diversification. Surgery is still the only way for curing the patients with pancreatic neuroendocrine tumor with liver metastasis when the histological types are G1 and G2. Medical oncology and intervention treatment could be selected for those having PNEN with diffuse liver metastasis or those cannot tolerate surgery. Liver transplantation only suits for a small number of selected patients. The present article explored the relationship between histological classifications and the treatment options of PNEN with liver metastasis, and discussed the specific treatments from perspectives of surgical treatment, medical treatment and intervention treatment.

Background: Pancreatic neuroendocrine tumors (pNETs) are a type of tumors with the characteristics of easy metastasis and recurrence. Till date, the risk factors affecting the prognosis are still in the debate. In this study, several risk factors will be discussed combined with our cases and experience., Methods: Thirty-three patients diagnosed as pNETs were enrolled and the clinical features, blood tests, pathological features, surgical treatment, and follow-up data of these patients were collected and analyzed., Results: In this study, operation time of G3 cases was longer than G1/G2 cases (P = 0.017). The elevated level of tumor markers such as AFP, CEA, Ca125, and Ca19-9 may predict easier metastasis, earlier recurrence, and poor prognosis (P = 0.007). The presence of cancer embolus and nerve invasion increases along with the TNM stage (P = 0.037 and P = 0.040), and the incidence of positive surgical margin increased (P = 0.007). When the presence of nerve invasion occurs, the chance of cancer embolus and lymph node metastasis also increases (P = 0.016 and P = 0.026)., Conclusions: pNETs were tumors with the features of easy recurrence and metastasis and many risk factors could affect its prognosis such as the elevated levels of tumor markers and the presence of nerve invasion, except some recognized risk factors. If one or more of these factors existed, postoperative treatments may be needed to improve prognosis.