Advances in immunotherapy for biliary tract cancers

Biliary tract cancers(BTC),a heterogeneous disease with poor prognosis,including gallbladder cancer(GBC),intrahepatic cholangiocarcinoma(ICC),and extrahepatic cholangiocarcinoma(ECC).Although surgery is currently the primary regimen to treat BTC,most BTC patients are diagnosed at an advanced stage and miss the opportunity of surgical eradication.As a result,non-surgical therapy serves as the main intervention for advanced BTC.In recent years,immunotherapy has emerged as one of the most promising therapies in a number of solid cancers,and it includes immune checkpoint inhibitors(ICIs)monotherapy or combined therapy,tumor vaccines,oncolytic virus immunotherapy,adoptive cell therapy(ACT),and cytokine therapy.However,these therapies have been practiced in limited clinical settings in patients with BTC.In this review,we focus on the discussion of latest advances of immunotherapy in BTC and update the progress of multiple current clinical trials with different immunotherapies.

Isoliquiritigenin induces HMOX1 and GPX4-mediated ferroptosis in gallbladder cancer cells

Background:Gallbladder cancer(GBC)is the most common malignant tumor of biliary tract.Isoliquiritigenin(ISL)is a natural compound with chalcone structure extracted from the roots of licorice and other plants.Relevant studies have shown that ISL has a strong anti-tumor ability in various types of tumors.However,the research of ISL against GBC has not been reported,which needs to be further investigated.Methods:The effects of ISL against GBC cells in vitro and in vivo were characterized by cytotoxicity test,RNA-sequencing,quantitative real-time polymerase chain reaction,reactive oxygen species(ROS)detection,lipid peroxidation detection,ferrous ion detection,glutathione disulphide/glutathione(GSSG/GSH)detection,lentivirus transfection,nude mice tumorigenesis experiment and immunohistochemistry.Results:ISL significantly inhibited the proliferation of GBC cells in vitro.The results of transcriptome sequencing and bioinformatics analysis showed that ferroptosis was the main pathway of ISL inhibiting the proliferation of GBC,and HMOX1 and GPX4 were the key molecules of ISL-induced ferroptosis.Knockdown of HMOX1 or overexpression of GPX4 can reduce the sensitivity of GBC cells to ISL-induced ferroptosis and significantly restore the viability of GBC cells.Moreover,ISL significantly reversed the iron content,ROS level,lipid peroxidation level and GSSG/GSH ratio of GBC cells.Finally,ISL significantly inhibited the growth of GBC in vivo and regulated the ferroptosis of GBC by mediating HMOX1 and GPX4.Conclusion:ISL induced ferroptosis in GBC mainly by activating p62-Keap1-Nrf2-HMOX1 signaling pathway and downregulating GPX4 in vitro and in vivo.This evidence may provide a new direction for the treatment of GBC.

大豆异黄酮genistein的长期暴露通过下调MCM复合物抑制胆囊癌增殖的研究

大豆异黄酮是天然的酪氨酸激酶抑制剂,与多种肿瘤发病率和死亡率的降低密切相关.同时,酪氨酸激酶如ERBB2的激活是胆囊炎转化为胆囊癌的重要机制,因此,研究长期接触大豆异黄酮与胆囊癌的发生和发展之间的关系十分重要.这项85对的病例对照研究发现,高血浆大豆异黄酮genistein水平与较低的胆囊癌风险相关(≥326.0与≤19.3 ng/mL对比,OR=0.15,95%可信区间0.04~0.59;趋势检验P=0.016),并且genistein暴露水平与胆囊癌组织中Ki67表达负相关(85例).与这些结果一致,体外和体内的长期genistein暴露模型中,胆囊癌细胞的增殖受到抑制.长期暴露于genistein降低了ERBB2的酪氨酸激酶活性,并影响了PTK6-AKT-GSK3β轴的功能,导致胆囊癌细胞中MCM复合物的表达下调.总之,长期接触与大豆制品摄入相关的genistein可能在预防甚至抑制胆囊癌的增殖方面起到一定的作用.

Hepatopancreatoduodenectomy for advanced biliary malignancies

Background:Hepatopancreatoduodenectomy(HPD)has been considered the only curative treatment for metastatic cholangiocarcinoma and some locally advanced gallbladder cancers(GBCs).However,HPD has not yet been included in treatment guidelines as a standard surgical procedure in consideration of its morbidity and mortality rates.The aim of this study was to evaluate the safety and effectiveness of HPD in treating biliary malignancies.Methods:The medical records of 57 patients with advanced biliary cancer undergoing HPD from January 2009 to December 2019 were retrospectively retrieved.A case-control analysis was conducted at our department.Patients with advanced GBC who underwent HPD(HPD-GBC group)were compared with a control group(None-HPD-GBC group).Baseline characteristics,preoperative treatments,tumor pathologic features,operative results,and prognosis were assessed.Results:Thirteen patients with cholangiocarcinoma and 44 patients with GBC underwent HPD at our department.Significant postoperative complications(grade III or greater)and postoperative pancreatic fistula were observed in 24(42.1%)and 15(26.3%)patients,respectively.One postoperative death occurred in the present study.Overall survival(OS)was longer in patients with advanced cholangiocarcinoma than in those with GBC(median survival time[MST],31 months vs.11 months;P<0.001).In the subgroup analysis of patients with advanced GBC,multivariate analysis demonstrated that T4 stage tumors(P=0.012),N2 tumors(P=0.001),and positive margin status(P=0.004)were independently associated with poorer OS.Patients with either one or more prognostic factors exhibited a shorter MST than patients without those prognostic factors(P<0.001).Conclusion:HPD could be performed with a relatively low mortality rate and an acceptable morbidity rate in an experienced highvolume center.For patients with advanced GBC without an N2 or T4 tumor,HPD can be a preferable treatment option.