Part 1:clinical Observation Of Immune Checkpoint Inhibitors In The Treatment Of Advanced Pancreatic Cancer And Biliary Tract Cancer Part 2:the Expression Of Notch Signaling Pathway Related Proteins In SCLC

Background:In recent years,immune checkpoint inhibitors have been used with great success in the treatment of various cancers.However,when used in monotherapy,immune checkpoint inhibitors have poor effect on pancreatic cancer and biliary tract cancer(BTCs)and the related clinical data were insufficient.This study assessed the efficacy and safety of the use of immune checkpoint inhibitors for the treatment of advanced pancreatic cancer and BTCs.Patients and methods:Patients with advanced pancreatic cancer and BTCs treated with PD-1/PD-L1 inhibitors from 2015 to 2018 were retrospectively enrolled,and those treated with conventional chemotherapy during the same period were also enrolled.The present study was divided into three parts:the first part included 43 patients with advanced pancreatic cancer who were treated with immunotherapy(including monotherapy and combined therapy);In the second part 58 patients with advanced pancreatic cancer were included(22 in immune combined chemotherapy group and 36 in the chemotherapy group)for comparative analysis;The third part included 77 cases of patients with advanced BTCs(38 cases in the immune combined chemotherapy group,20 cases in the immune monotherapy group,and 19 cases in the chemotherapy group)for comparative analysis.All patients received at least 2 cycles of conventional chemotherapy or PD-1/PD-L1 inhibitor monotherapy or combination therapy(the combination regimen includes chemotherapy,targeted drugs and CTLA-4 inhibitors).Results:For advanced pancreatic cancer patients who treated with immunotherapy,the objective response rate(ORR)was 10.5%,the disease control rate(DCR)was 50%,the median progression-free survival(mPFS)was 2.3 months,and the median overall survival(mOS)was 5.1 months.The mOS was longer for patients receiving combined therapy than for those receiving PD-1/PD-L1 inhibitor monotherapy(5.4 vs 2.0 months,P=0.020).PD-1 inhibitor combined with chemotherapy presented significantly longer OS and PFS than chemotherapy group(mOS 18.1 vs 6.1 months,P=0.021;mPFS 3.2 vs 2.0 months,P=0.041).Patients receiving immunotherapy as a first-line treatment had prolonged survival compared with those receiving it as a second-line or multiple-line treatment,but the difference was not statistically significant(mOS:7.0 vs 5.1 vs 2.8 months,P=0.161).There was a reduction in the serum level of C A19-9 associated with the response to treatment.Adverse events were tolerable and were mainly grade 1 and 2.The immune-related adverse events that occurred were hypothyroidism,diarrhea,and rash.The survival and the efficacy of immune combined chemotherapy were significantly improved in patients with BTCs and the adverse events were tolerable.The mOS and mPFS were 14.9 months and 5.1 months respectively in immune combined chemotherapy group,which were significantly longer than those of immune monotherapy group(mOS 4.1 months,P=0.001;mPFS 2.2 months,P=0.014)and chemotherapy group(mOS 6.0 months,P=0.011;mPFS 2.4 months,P=0.003).The ORR and DCR were 34.2%and 89.5%respectively in immune combined chemotherapy group,both significantly higher than the other groups(P<0.05).Conclusion:Immune checkpoint inhibitors showed a certain efficacy in the treatment of advanced pancreatic cancer and BTCs and could confer long-term survival benefits.Combined therapy was more effective and may serve as an alternative option.Further studies should be performed.Background:Small cell lung cancer(SCLC)is an aggressive neuroendocrine tumor with limited therapeutic developments in the past forty years.There has been increasing interest in the components of the Notch signaling pathway,particularly Delta-like ligand 3(DLL3),as promising therapeutic targets.Methods:Using immunohistochemistry(OHC),we assessed the expression patterns of DLL3 and its associated proteins DLL1,DLL4,ASCL1 and Notchl in 145 patients with SCLC.We investigated the prevalence of these proteins and their association with the clinical characteristics of patients.Results:A total of 134(92.4%)patients had positive DLL3 expression.Notchl expression was significantly lower than that of DLL3,DLL1,DLL4 and ASCL1(P<0.05).High DLL3 expression was closely related to poor curative effects and survival of patients with advanced stage disease who underwent first-line treatment,but the differences were significant only for median progression-free survival(mPFS)(5.2 months vs 12.0 months,P=0.043,HR=0.39).In patients who underwent surgery,having a vascular tumor embolus and not receiving adjuvant chemotherapy were both negative prognostic factors for overall survival(OS)and disease-free survival(DFS)(P<0.05).High DLL3 expression was significantly associated with high Ki-67 expression.The differences between DLL3 and Notch1 expression in limited stage(LS)and extensive stage(ES)disease were statistically significant.Conclusions:DLL3 is highly expressed in most Chinese SCLC patients.DLL3,DLL1,DLL4,and ASCL1 were all involved in promoting tomorigenesis,and Notch signaling was inhibited.High DLL3 expression showed a trend toward poor curative effects and survival of SCLC patients and warrants further study.