| Objective:Neuroendocrine carcinomas(NECs)of the digestive tract are rare solid tumor and show high agressive and malignancy behavior,early rapid metastasis and poor clinical prognosis.Compared with the significant progress in other solid cancer,such as targeted therapies and immunotherapies,treatment of NECs has lagged behind during the past three decades,and the regimen of platinum-based chemotherapy being unchanged as the first-line standard treatment.Sensitivity to initial standard treatment regimen is usually transient and followed by a refractory platinum or recurrence and metastasis disease,which offen leading to death.In recent years,a deeper exploring on the biological mechanisms of tumors,the loss of Notch signaling pathway has been considered as an important event of pulmonary neuroendocrine tumorigenesis,disease progression and chemotherapy resistance.Notch1 is the most widely studied receptor in Notch signaling pathway,and Ascl1 is a key factor in cellular neuroendocrine transcription.which are differentially expressed in both normal lung tissues and pulmonary neuroendocrine tumor tissues.it is a potential biomarker and therapeutic target for small cell lung cancer.However,there is uncertainty regarding the mechanistic roles of Notch1,Ascl1 biomarkers in digestive tract NECs patients.Purposes:The aim was to analyse the tumor expression of Notch1,Ascl1 in digestive tract NECs and each biomarker’s potential association with clinicopathological factors,the efficacy of platinum-based treatment and prognosis.Methods:A total of 65 patients with NECs diagnosed by pathology from January 2018 to December 2020 were selected by consulting electronic medical records,and complete case data,sufficient tissue wax samples and follow-up of first-line progression-free survival(PFS),overallsurvival(OS)and other survival data were included in the study.40 patients with advanced stage at initial diagnosis,and 25 patients were treated by operation.Immunohistochemical analysis was used to detect the expression of Notch1 and Ascl1 in digestive tract NECs and adjacent normal tissues.According to the detection results,the patients were divided into high expression group and low expression group.The paired chi-square test was used for comparison of the difference among postoperative cancer tissues and adjacent normal tissues groups in terms of the expression of Notch1 and Ascl1.Spearman’s rank correlation test was utilized to assess the correlation among the expression of Notch1 and Ascl1.The associations between Notch1,Ascl1 expression and clinical characteristics were analyzed using chi-square test or Fisher exact test.The calculations for first-line PFS and OS were estimated using the Kaplan-Meier method,and differences in survival distributions were evaluated using the log-rank test.the function diagram of survival curve was drawn.COX proportional hazard regression model was used for multivariate analysis to predict the prognostic risk factors of digestive tract NECs.P values less than 0.05 were considered statistically significant.Results:1.The results of immunohistochemistry showed that Notch1 and Ascl1 were expressed in both NECs carcinoma and adjacent normal tissues.Nocth1 protein was localized in cytoplasm or cell membrane.In 65 cases of cancer tissue specimens,47.7%(n = 31)of cancer tissues had high expression of Notch1,of which 15.4%(10/65)were high expression in postoperative cancer tissues.Compared with the high expression group of paracancerous normal tissues(n =25),the expression of Notch1 in postoperative cancer tissues was significantly down-regulated(the positive rates were 40% and 76% respectively,P=0.012).Ascl1 protein is localized in the nucleus.High expression of Ascl1 was found in 41.5% of 65 cases of cancer tissue,of which20% of postoperative tissue samples were high expression(13/65).Compared with the high expression group of normal tissue adjacent to cancer(n=5),the expression of Ascl1 in postoperative cancer tissue was significantly up-regulated(the positive rate was 20% and 52% respectively,P=0.021).2.Clinicopathological analysis showed that the expression of Notch1 and Ascl1 was not significantly correlated with sex,age,primary location of tumor,Cg A expression,Sy N expression,CD56 expression and Ki-67 increment index(P>0.05).3.The results of Notch1 and survival data analysis show that the ORR,m PFS and m OS were 26.5%,6.3 months and 10.5 months in the Notch1 low expression group.In the Notch1 high expression group,ORR was 51.6%,m PFS was 9.6 months,and m OS was 12.2 months.Compared with the low expression group of Notch1,the high expression group had higher ORR(P=0.037)and longer m PFs and m OS(P=0.008 and P=0.005).4.The results of Ascl1 and survival data analysis show that the ORR,m PFS and m OS of ASCL1 low expression group were 39.5%,7.9 months and 11.5 months respectively.The ORR,m PFS and m OS of ASCL1 high expression group were 37.1%,7.3 months and 9.6 months respectively.Compared with the high expression group of ASCL1,the increase of ORR and m PFS in the low expression group was not significant(P=0.842 and P=0.630),but the m OS in the low expression group was significantly prolonged(P=0.031).5.The COX risk proportional regression model presented that patients with Notch1 low expression(HR: 2.669 95%CI: 1.281-5.561 P=0.009)and ASCL1 high expression(HR: 2.119 95%CI: 1.039-4.324 P= 0.039)were independent factors affecting the prognosis of NECs.Conclusion:1.The expression of Notch1 was low in digestive tract NECs carcinoma,while Ascl1 was high in digestive tract NECs carcinoma.2.No significant differences were observed between Notch1,ASCL1 high and low expression groups in variables including sex,age,primary location of tumor,Cg A expression,Sy N expression,CD56 expression and Ki-67 increment index(P >0.05).3.Notch1 can be used as a biomarker for predicting the efficacy of platinum-based therapy in the first line of advanced digestive tract NECs.4.Low expression of Notch1 and high expression of Ascl1 can be considered as independent risk factors for poor prognosis of advanced gastrointestinal NECs. |
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