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. 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. 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. 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.

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). 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. 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 (χ2 = 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. 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.

¹⁷⁷Lu-Dotatate is increasingly used in patients with advanced neuroendocrine tumour (NET). However, few prognostic markers are available to stratify progression-free survival (PFS) of patients who received ¹⁷⁷Lu-Dotatate. Clinicopathological data including baseline circulating biomarkers of patients with advanced NET who received ¹⁷⁷Lu-Dotatate were routinely collected and were retrospectively analysed. Continuous variables were normalized by dividing them by their upper normal limits. The whole data set was randomly divided into a training set and a validation set. Univariate and multivariate logistic regression analyses were used to identify independent markers and to develop a scoring model to predict treatment failure at 1 year. In total, 195 patients were included. Elevated baseline chromogranin A (CgA), normal creatinine and previous chemotherapy were three risk factors independently associated with 1-year treatment failure. By combining these risk factors, a scoring model was developed which could accurately predict 1-year treatment failure both in the training set (area under curve, AUC, 0.813; 95% CI, 0.731–0.895; P< 0.001) and in the validation set (AUC, 0.816; 95% CI, 0.644–0.968; P< 0.001). After selecting a score of 29.7 as the cut-off value of the scoring model, patients could be stratified into two groups namely low-risk and high-risk with significantly different 1-year treatment failure rate, PFS and overall survival (OS; P< 0.001) both in the training set and validation set. In conclusion, baseline CgA, creatinine level and previous chemotherapy were independently associated with 1-year treatment failure of patients with advanced NET who received ¹⁷⁷Lu-Dotatate and the scoring model and prognostic stratification based on these markers could accurately predict 1-year treatment failure, PFS and OS.