Research On Biomarkers Of Hepatobiliary Malignancies And Clinical Practice Of Immune, Targeted And Local Treatmen

Background:The function of exosome includes cell-to-cell communication,neovascularization,metastasis of cancer cell and drug resistance,which plays an important part in the occurrence and progression of hepatocellular carcinoma(HCC).Since there are few mechanism studies in this field,our goal is to identify exosome-related genes in HCC,establish a reliable prognostic model for liver cancer patients and explore its underlying mechanisms.Methods:The exoRbase database and The Cancer Genome Atlas(TCGA)database were used to analyze differentially expressed genes(DEGs).Cox regression and least absolute shrinkage and selection operator(LASSO)analysis were applied to determine DEGs closely related to overall survival(OS).Then the exosome-related prognostic model was constructed in TCGA and validated in the database of International Cancer Genome Consortium(ICGC).Nomogram was performed to predict the survival.CIBERSORT was used to estimate the score of different type of immune cells.DEGs related to immunotherapy were used to predict the effect of immunotherapy.Results:Forty-eight exosome-related DEGs were obtained and five genes(XPO1,IFI30,FBXO16,CALM1,MORC3)among them were selected to construct a predictive model.Then we divided the HCC patients into low-risk and high-risk groups by the best cut-off value according to the X-tile software.The HCC patients in the high-risk group had significantly poorer prognosis than those in the low-risk group.(P=0.009,HR=2.65)Meanwhile,high-risk group exhibited higher proportion of tumor-infiltrating regulatory T cells(Tregs)and macrophages M2 compared with low-risk group.Moreover,the features related to exosome could positively regulate immune response.Further analysis showed higher risk score was associated with higher expression of immune checkpoint genes including PD-L1,PD-L2,TIGIT,and IDO1.Conclusions:Our research showed a novel signature based on exosome-related genes was potential for biomarkers for the prognosis of HCC,providing an immunological perspective for the development of precision treatment.Background:A combination of tyrosine kinase inhibitors(TKIs)and anti-PD-1 antibodies with local regional therapy has elicited yield substantial clinical benefits in patients who have hepatocellular carcinoma(HCC)with extrahepatic metastases.Using this treatment strategy to convert HCC patients with extrahepatic metastases from unresectable to resectable has not yet been reported.Methods:Consecutive hepatocellular carcinoma patients with extrahepatic metastases who received first-line therapy with a combination of TKIs and anti-PD-1 antibodies and at least one local regional therapy were analyzed.Lenvatinib was administered at a dosage of 12 mg(for patients with a body weight≥60 kg)or 8 mg(for patients with a body weight<60 kg)orally once a day.The PD-1 dose included a fixed dosage of 200 mg(240 mg for toripalimab)every 3 weeks or a fixed dosage of 3 mg/kg body weight every 3 weeks.The clinical objective response was measured by the mRECIST criteria and safety assessment and grading were recorded in the electronic medical records or collected by the investigators using the Common Terminology Criteria for Adverse Events(version 4.0)as a reference.Results:From May 2019 to March 2021,a total of nine patients with localized disease who received first-line systemic therapy were enrolled.At baseline,all of them had oligometastatic disease,namely,Barcelona Clinic Liver Cancer stage C(or Chinese Liver Cancer stage ⅢB).The most common treatment administered was lenvatinib plus anti-PD-1 antibody and transarterial chemoembolization,and the median time span from systemic therapy to surgery was 3.2(IQR,2.8-6.2)months.Three patients achieved a pathological complete response.Six patients underwent laparoscopic surgery,and the other 3 patients underwent open surgery.After a median follow-up of 10.2(IQR,8.6-20.0)months,7 patients survived without disease recurrence,and 2 experienced tumor recurrence.All patients had any-grade AEs,and 55.6%of the patients experienced grade 3 AEs.Fatigue was the most common AE,followed by elevated aminotransferase levels and hypertension.Conclusion:Stereotactic therapy is a feasible conversion therapy for HCC patients with extrahepatic metastases to become resectable.This is the first study to analyze therapeutic outcomes of patients receiving these therapies for HCC with extrahepatic metastases,and the exact role of stereotactic therapy and subsequent liver resection in this patient population requires further confirmation in prospective randomized controlled trials.Background:Programmed death-1(PD-1)or Programmed death ligand-1(PD-L1)combined with tyrosine kinase inhibitors(TKIs)and locoregional therapy has proven effective against solid tumors.Using this treatment strategy to convert biliary tract cancer(BTC)patients from unresectable to resectable has not yet been reported.Methods:Consecutive biliary tract cancer patients who received the therapy with a combination of PD-1 or PD-L1 with TKIs or locoregional therapy were analyzed.Lenvatinib was administered at a dosage of 12 mg(for patients with a body weight≥ 60 kg)or 8 mg(for patients with a body weight<60 kg)orally once a day.The PD-1 dose included a fixed dosage of 200 mg(240 mg for toripalimab)every 3 weeks or a fixed dosage of 3 mg/kg body weight every 3 weeks.The clinical objective response was measured by the RECIST 1.1 criteria and safety assessment and grading were recorded in the electronic medical records or collected by the investigators using the Common Terminology Criteria for Adverse Events(version 4.0)as a reference.Results:Eighty-four patients with advanced biliary tract cancer who received conversion therapy were enrolled,and finally thirteen patients downstaged the tumor and eleven patients underwent conventional surgery.The most common treatment administered was lenvatinib plus PD-1 and transarterial chemoembolization,and the median time span from systemic therapy to surgery was 8.3(IQR,6.2-9.8)months.One patient achieved a pathological complete response.Six patients underwent laparoscopic surgery,and the other 5 patients underwent open surgery.All patients had some AE,and 45.5%of the patients experienced grade 3 AEs.Fatigue was the most common AE,followed by elevated aminotransferase levels and hypertension.The median follow-up time from initially therapy was 18.4(IQR,13.2-22.1)months,one patients died due to the progression of disease and one patient occurred a tumor recurrence and metastasis,and the other nine out of eleven patients were all get disease-free survival till now.Conclusion:Conversion therapy is feasible for BTC patients,and with careful preparation and evaluation,the subsequent surgical resection is effective and safe.All cases who underwent surgery in our study are positive for PD-L1,and the relationship between PD-L1 and treatment response requires further confirmation in prospective randomized controlled trials.Background:Anti-PD-1 antibodies plus lenvatinib therapeutic regimens have demonstrated a relatively high antitumor response in hepatocellular carcinoma;however,the efficacy and safety of anti-PD-1 antibodies plus lenvatinib in patients with advanced gallbladder cancer has not been reported.Methods:Advanced gallbladder cancer patients who received anti-PD-1 antibodies plus lenvatinib were retrospectively screened.Overall survival(OS),progression-free survival(PFS),objective response rate(ORR),disease control rate(DCR),clinical benefit rate(CBR),PD-L1 expression and safety were evaluated.Lenvatinib was administered at a dosage of 12 mg(for patients with a body weight≥60 kg)or 8 mg(for patients with a body weight<60 kg)orally once a day.The PD-1 dose included a fixed dosage of 200 mg(240 mg for toripalimab)every 3 weeks or a fixed dosage of 3 mg/kg body weight every 3 weeks.The clinical objective response was measured by the RECIST 1.1 criteria and safety assessment and grading were recorded in the electronic medical records or collected by the investigators using the Common Terminology Criteria for Adverse Events(version 4.0)as a reference.The study also recorded the influence of the expression of PD-L1 on PFS and OS.Results:A total of 31 patients were included in this study.Overall,the ORR was 32.3%,the DCR was 83.9%,and the CBR was 41.9%.Among 31 patients,3 patients received conventional surgery,and 1 patient achieved a pathological complete response.After a median follow-up of 8 months and 23 deaths,the median PFS was 5.0 months(95%CI:4.1-8.0 months),and the median OS was 11.3 months(95%CI:7.5-20.9 months).Adverse events(AEs)were reported in all 31 patients,and 58.1%of the patients experienced grade 3 AEs.The most commonly observed grade 3 AEs included fatigue(5/31,16.1%),decreased appetite(5/31,16.1%),hypertension(4/31,12.9%)and bilirubin elevation(4/31,12.9%).Subgroup analysis revealed that PD-L1 positive tumor cells maybe associate with a longer PFS.Conclusion:Anti-PD-1 antibodies plus lenvatinib represent an effective and tolerable therapy for patients with advanced gallbladder cancer,and the positive expression of PD-L1 related a longer PFS.This is the first study to analyze the therapeutic outcomes of patients receiving these therapies,and the exact role requires further confirmation in prospective randomized controlled trials.