Nab-paclitaxel plus capecitabine as first-line treatment for advanced biliary tract cancers:An open-label,non-randomized,phase II clinical trial

BACKGROUND Biliary tract cancers(BTCs)are a heterogeneous group of tumors with high malignancy,poor prognosis,and limited treatment options.AIM To explore the efficacy and safety of nab-paclitaxel plus capecitabine as first-line treatment for advanced and metastatic BTCs.METHODS This open-label,non-randomized,double-center,phase II clinical trial recruited systemic therapy-naive patients with unresectable or metastatic BTCs between April 2019 and June 2022 at Beijing Cancer Hospital and the First Hospital of China Medical University.Eligible patients were administered nab-paclitaxel(150 mg/m2,day 1)and capecitabine(2000 mg/m2,twice daily,days 1-7)in 14-day cycles until experiencing intolerable toxicity or disease progression.The primary outcome was the objective response rate(ORR).The secondary outcomes included the disease control rate(DCR),overall survival(OS),progression-free survival(PFS),and safety.RESULTS A total of 44 patients successfully completed the trial,with a median age of 64.00 years(interquartile range,35.00-76.00),and 26(59.09%)were females.Tumor response assessment was impeded for one patient due to premature demise from tumor hemorrhage.Among the remaining 43 patients undergoing at least one imaging assessment,the ORR was 23.26%[95%confidence interval(CI):11.80%-38.60%],and the DCR was 69.77%(95%CI:53.90%-82.80%).The median OS was 14.1 months(95%CI:8.3-19.9),and the median PFS was 4.4 months(95%CI:2.5-6.3).A total of 41 patients(93.18%)experienced at least one adverse event(AE),with 10 patients(22.73%)encountering grade≥3 AEs,and the most frequent AEs of any grade were alopecia(79.50%),leukopenia(54.55%),neutropenia(52.27%),and liver dysfunction(40.91%),and no treatment-related deaths were documented.CONCLUSION Nab-paclitaxel plus capecitabine may be an effective and safe first-line treatment strategy for patients with advanced or metastatic BTCs.

Clinical and socioeconomic determinants of survival in biliary tract adenocarcinomas

BACKGROUND Despite advances in detection and treatments,biliary tract cancers continue to have poor survival outcomes.Currently,there is limited data investigating the significance of socioeconomic status,race/ethnicity,and environmental factors in biliary tract cancer survival.Data from the Surveillance,Epidemiology,and End Results database for biliary and gallbladder adenocarcinomas were extracted from 1975 to 2016.Socioe-conomic data included smoking,poverty level,education,adjusted household income,and percentage of foreign-born persons and urban population.Survival was calculated with Cox proportional hazards models for death in the 5-year period following diagnosis.RESULTS Our study included 15883 gallbladder,11466 intrahepatic biliary,12869 extrahepatic biliary and 7268 ampulla of Vater adenocarcinoma cases.When analyzing county-specific demographics,patients from counties with higher incomes were associated with higher survival rates[hazard ratio(HR)=0.97,P<0.05].Similarly,counties with a higher percentage of patients with a college level education and counties with a higher urban population had higher 5-year survival rates(HR=0.96,P=0.002 and HR=0.97,P=0.004,respectively).CONCLUSION Worse survival outcomes were observed in lower income counties while higher income and education level were associated with higher 5-year overall survival among gallbladder and biliary malignancies.

Association between gut microbiota and hepatocellular carcinoma and biliary tract cancer:A mendelian randomization study

BACKGROUND An increasing number of studies have begun to discuss the relationship between gut microbiota and diseases,yet there is currently a lack of corresponding articles describing the association between gut microbiota and hepatocellular carcinoma(HCC)and biliary tract cancer(BTC).This study aims to explore the relationship between them using Mendelian randomization(MR)analysis method.AIM To assess the relationship between gut microbiota and HCC and BTC.METHODS We obtained Genome-wide association study(GWAS)data for the gut microbiome from the intestinal microbiota genomic library(MiBioGen,https://mibiogen.gcc.rug.nl/).Additionally,we accessed data pertaining to HCC and BTC from the IEU open GWAS platform(https://gwas.mrcieu.ac.uk/).Our analysis employed fundamental instrumental variable analysis methods,including inverse-variance weighted,MR and Egger.To ensure the dependability of the results,we subjected the results to tests for multiple biases and heterogeneity.RESULTS During our investigation,we discovered 11 gut microbiota linked to an increased risk to BTC and HCC.The former included the genus Eubacterium hallii group(P=0.017),Candidatus Soleaferrea(P=0.034),Flavonifractor(P=0.021),Lachnospiraceae FCS020(P=0.034),the order Victivallales(P=0.018),and the class Lentisphaeria(P=0.0.18).The latter included the genus Desulfovibrio(P=0.042),Oscillibacter(P=0.023),the family Coriobacteriaceae(P=0.048),the order Coriobacteriales(P=0.048),and the class Coriobacteriia(P=0.048).Furthermore,in BTC,we observed 2 protective gut microbiota namely the genus Dorea(P=0.041)and Lachnospiraceae ND3007 group(P=0.045).All results showed no evidence of multiplicity or heterogeneity.CONCLUSION This study explores a causal link between gut microbiota and HCC and BTC.These insights may enhance the mechanistic knowledge of microbiota-related HCC and BTC pathways,potentially informing therapeutic strategies.

Impact of open hepatectomy on postoperative bile leakage in patients with biliary tract cancer

BACKGROUND Bile leakage is a common and serious complication of open hepatectomy for the treatment of biliary tract cancer.AIM To evaluate the incidence,risk factors,and management of bile leakage after open hepatectomy in patients with biliary tract cancer.METHODS We retrospectively analyzed 120 patients who underwent open hepatectomy for biliary tract cancer from February 2018 to February 2023.Bile leak was defined as bile drainage from the surgical site or drain or the presence of a biloma on imaging.The incidence,severity,timing,location,and treatment of the bile leaks were recorded.The risk factors for bile leakage were analyzed using univariate and multivariate logistic regression analyses.RESULTS The incidence of bile leak was 16.7%(20/120),and most cases were grade A(75%,15/20)according to the International Study Group of Liver Surgery classification.The median time of onset was 5 d(range,1-14 d),and the median duration was 7 d(range,2-28 d).The most common location of bile leakage was the cut surface of the liver(70%,14/20),followed by the anastomosis site(25%,5/20)and the cystic duct stump(5%,1/20).Most bile leaks were treated conservatively with drainage,antibiotics,and nutritional support(85%,17/20),whereas some required endoscopic retrograde cholangiopancreatography with stenting(10%,2/20)or percutaneous transhepatic cholangiography with drainage(5%,1/20).Risk factors for bile leakage include male sex,hepatocellular carcinoma,major hepatectomy,blood loss,and blood transfusion.CONCLUSION Bile leakage is a frequent complication of open hepatectomy for biliary tract cancer.However,most cases are mild and can be conservatively managed.Male sex,hepatocellular carcinoma,major hepatectomy,blood loss,and blood transfusion were associated with an increased risk of bile leak.

Current status of the biliary tract malformation

The choledochal cyst(CC)can be better termed as biliary tract malformation because of the close association of embryology and etiology in the causation of CC.Contrary to Babbitt's postulation of reflux,damage and dilatation,reflux was not demonstrable as the causative factor in all varieties of CC.High pressure in the biliary system,otherwise termed ductal hypertension,is put forth as an alternative to explain the evolution of CC.The forme fruste type,which does not find a place in the standard classification,typifies the ductal hypertension hypothesis.Hence a closer,in-depth review would be able to highlight this apt terminology of biliary tract malformation.

Paradigm shift of chemotherapy and systemic treatment for biliary tract cancer

Biliary tract cancers(BTC)are frequently identified at late stages and have a poor prognosis due to limited systemic treatment regimens.For more than a decade,the combination of gemcitabine and cis-platin has served as the first-line standard treatment.There are few choices for second-line chemo-therapy.Targeted treatment with fibroblast growth factor receptor 2 inhibitors,neurotrophic tyrosine receptor kinase inhibitors,and isocitrate dehydrogenase 1 inhibitors has had important results.Immune checkpoint inhibitors(ICI)such as pembrolizumab are only used in first-line treatment for microsatellite instability high patients.The TOPAZ-1 trial's outcome is encouraging,and there are several trials underway that might soon put targeted treatment and ICI combos into first-line options.Newer targets and agents for existing goals are being studied,which may represent a paradigm shift in BTC management.Due to a scarcity of targetable mutations and the higher toxicity profile of the current medications,the new category of drugs may occupy a significant role in BTC therapies.

Endoscopic retrograde cholangiopancreatography in pancreatic and biliary tract disease in Korean children

AIM:To assess the indications,findings,therapeutic procedures,safety,and complications of endoscopic retrograde cholangiopancreatography(ERCP) performed in Korean children.METHODS:The demographic characteristics,indications for ERCP,findings,therapeutic procedures,and complications of 122 pediatric patients who underwent 245 ERCPs in the Asan Medical Center between June 1994 and March 2008 were investigated.RESULTS:The mean age of the 122 patients was 8.0 ± 4.2 years.Indications were biliary pathology in 78(64.0%),pancreatic pathology in 43(35.2%),and chronic abdominal pain in one.Biliary indications included choledochal cysts in 40,choledocholithiasis in 24,suspected sclerosing cholangitis in 8,trauma in 2,and other conditions in 4.Pancreatic indications includedacute pancreatitis in 7,acute recurrent pancreatitis in 11,chronic pancreatitis in 20,trauma in 3,and pancreatic mass in 2.Of the 245 ERCPs,success rate was 98.4% and 190(77.6%) were for therapeutic purposes,including endoscopic nasal drainage(51.8%),biliary sphincterotomy(38.0%),pancreatic sphincterotomy(23.3%),stent insertion(15.1%),stone extraction(18.8%),and balloon dilatation(11.0%).Complications were postERCP pancreatitis in 16(6.5%),ileus in 23(9.4%),hemorrhage in 2(0.8%),perforation in 2(0.8%),sepsis in 1(0.4%),and impacted basket in 1(0.4%).There were no procedure-related deaths,and most complications improved under supportive care.CONCLUSION:This study showed that there is a high incidence of choledochal cyst and diagnostic and therapeutic ERCP for the management of various biliary and pancreatic diseases was safe and effective in Korean children.

Iatrogenic bile duct injuries from biliary tract surgery

BACKGROUND:Cholecystectomy is the most commonly performed procedure in general surgery.However,bile duct injury is a rare but still one of the most common complications.These injuries sometimes present variably after primary surgery.Timely detection and appropriate management decrease the morbidity and mortality of the operation. METHODS:Five cases of iatrogenic bile duct injury(IBDI) were managed at the Department of Surgery,First Affiliated Hospital,Xi’an Jiaotong University.All the cases who underwent both open and laparoscopic cholecystectomy had persistent injury to the biliary tract and were treated accordingly. RESULTS:Recovery of the patients was uneventful.All patients were followed-up at the surgical outpatient department for six months to three years.So far the patients have shown good recovery. CONCLUSIONS:In cases of IBDI it is necessary to perform the operation under the supervision of an experienced surgeon who is specialized in the repair of bile duct injuries,and it is also necessary to detect and treat the injury as soon as possible to obtain a satisfactory outcome.

Reoperation for benign biliary tract diseases in 149 cases: causes and prevention

BACKGROUND: Failure to diagnose and treat benign bi- liary tract disease relatively common surgical disease may cause serious consequences. Since the introduction of B- mode ultrasonography, CT, or MRI early and accurate diagnosis of the disease has been possible. In clinical prac- tice, however, these methods have not been adequately used. Inappropriate surgical procedures can also lead to bile duct injury or stenosis after injury, residual cholecystitis, stenosis after cholangiojejunostomy, or stenosis of the Od- di' s sphincter. But improvement of the diagnosis and treat- ment of benign biliary tract disease remains a great chal- lenge to clinicians. METHODS: A total of 149 patients with benign biliary tract disease who had received reoperation from June 1988 to June 2001 were analyzed retrospectively. Among them 95 patients (63.76%) received operation twice and 38 (25.5%) underwent 3 operations. Sixteen patients (10.74%) needed 4 or more operations. The procedures for the first opera- tion included cholecystectomy (71 patients, 47.65%), cho- lecystectomy with exploration of the common bile duct (42, 28.19%), cholangiojejunostomy (21, 14.1%), and la- paroscopic cholecystectomy (15, 10.06%). RESULTS: The causes for reoperation included residual and recurrent bile duct stones in 53 patients (35.57%), bile duct injury or stenosis after injury in 41 (27.52%), residual cho- lecystitis with or without stones in 28 (18.8%), stenosis af- ter cholangiojejunostomy in 17 (11.41%), stenosis of the Oddi's sphincter in 5 (5.35%), and others in 5 (5.35%). Four patients (2.68%) died after operation. CONCLUSIONS: To prevent reoperation for benign biliary tract diseases, the following measures should be taken to in- crease preoperative diagnostic rate, to understand condi- tions of the biliary tract by using imaging techniques and cholangiography, to examine comprehensively and careful- ly with choledochoscopy, cholangiography and B-mode ul-trasonography intraoperatively, to choose appropriate ope- rative procedures to decrease the rate of residual stones, and to decide the time for the first repair according to inju- ry type of the bile duct. Roux-en-Y hepaticojejunostomy with cholangioplasty is the best operation for the recon- struction of the biliary tract.

T-tube vs no T-tube for biliary tract reconstruction in adult orthotopic liver transplantation:An updated systematic review and metaanalysis

BACKGROUND Whether to use a T-tube for biliary anastomosis during orthotopic liver transplantation(OLT)remains a debatable question.Some surgeons chose to use a T-tube because they believed that it reduces the incidence of biliary strictures.Advances in surgical techniques during the last decades have significantly decreased the overall incidence of postoperative biliary complications.Whether using a T-tube during OLT is still associated with the reduced incidence of biliary strictures needs to be re-evaluated.AIM To provide an updated systematic review and meta-analysis on using a T-tube during adult OLT.METHODS In the electronic databases MEDLINE,PubMed,Scopus,ClinicalTrials.gov,the Cochrane Library,the Cochrane Hepato-Biliary Group Controlled Trails Register,and the Cochrane Central Register of Controlled Trials,we identified 17 studies(eight randomized controlled trials and nine comparative studies)from January 1995 to October 2020.The data of the studies before and after 2010 were separately extracted.We chose the overall biliary complications,bile leaks or fistulas,biliary strictures(anastomotic or non-anastomotic),and cholangitis as outcomes.Odds ratios(ORs)with 95%confidence intervals(CIs)were calculated to describe the results of the outcomes.Furthermore,the test for overall effect(Z)was used to test the difference between OR and 1,where P≤0.05 indicated a significant difference between OR value and 1.RESULTS A total of 1053 subjects before 2010 and 1346 subjects after 2010 were included in this meta-analysis.The pooled results showed that using a T-tube reduced the incidence of postoperative biliary strictures in studies before 2010(P=0.012,OR=0.62,95%CI:0.42-0.90),while the same benefit was not seen in studies after 2010(P=0.60,OR=0.76,95%CI:0.27-2.12).No significant difference in the incidence of overall biliary complications(P=0.37,OR=1.41,95%CI:0.66-2.98),bile leaks(P=0.89,OR=1.04,95%CI:0.63-1.70),and cholangitis(P=0.27,OR=2.00,95%CI:0.59-6.84)was observed between using and not using a T-tube before 2010.However,using a T-tube appeared to increase the incidence of overall biliary complications(P=0.049,OR=1.49,95%CI:1.00-2.22),bile leaks(P=0.048,OR=1.91,95%CI:1.01-3.64),and cholangitis(P=0.02,OR=7.21,95%CI:1.37-38.00)after 2010.A random-effects model was used in biliary strictures(after 2010),overall biliary complications(before 2010),and cholangitis(before 2010)due to their heterogeneity(I2=62.3%,85.4%,and 53.6%,respectively).In the sensitivity analysis(only RCTs included),bile leak(P=0.66)lost the significance after 2010 and a random-effects model was used in overall biliary complications(before 2010),cholangitis(before 2010),bile leaks(after 2010),and biliary strictures(after 2010)because of their heterogeneity(I2=92.2%,65.6%,50.9%,and 80.3%,respectively).CONCLUSION In conclusion,the evidence gathered in our updated meta-analysis showed that the studies published in the last decade did not provide enough evidence to support the routine use of T-tube in adults during OLT.

Re-expression of RASSF1A by 5-Aza-CdR Induced Demethylation of the Promoter Region in Human Biliary Tract Carcinoma Cells

Hypermethylation of the promoter region is an important mean for the transcriptional repression of a number of cancer-associated genes, and over-expression and/or increased activity of DNA methyltransferase are considered to be the main cause of promoter hypermethylation. In order to further explore the epigenetic mechanism of tumor suppressor gene RASSF1A inactivation, 5-aza-2’-deoxycytidine (5-Aza-CdR), a DNA methyltransferase inhibitor, was used to treat the human biliary tract carcinoma cell line QBC-939 at the concentration of 5 μmol/L for 24 h in this study. Af- ter the chemical intervention with 5-Aza-CdR, the methylation status in the promoter region of RASSF1A gene was detected by methylation specific PCR (MS-PCR), and the expression alteration of RASSF1A mRNA and protein were observed by RT-PCR and Western Blot respectively. Following the treatment with 5-Aza-CdR, methylaiton status in the promoter region of RASSF1A gene was re- versed from methylation to unmethylation. A 280 bp DNA band which represented RASS1FA expres- sion at transcriptional level and a 40 kDa (1kDa=0.9921 ku) protein band which represented RASSF1A expression at protein level were detected by RT-PCR and Western Blot respectively in the experimental group cells and there were no corresponding bands in the control group cells. The ex- perimental results suggest that 5-Aza-CdR can induce demethylation in the promoter region of RASSF1A. It can also reverse epigenetic transcriptional silencing caused by DNA methylation and induce the re-expression of RASSF1A in QBC-939. This study also suggest that the mechanism of RASSF1A inactivation is very closely related to the methylation of the promoter region, which may provide a new epigenetic understanding for tumor related gene inactivation and the pathogenesis of biliary tract carcinoma.

Current and emerging immunotherapeutic approaches for biliary tract cancers

Background:Biliary tract cancers(BTCs)comprise a heterogeneous group of aggressive malignancies with unfavorable prognoses.The benefit of chemotherapy seems to have reached a bottleneck and,therefore,new effective therapeutic strategies for advanced BTCs are needed.Molecularly targeted therapies in selected patients are rapidly changing the situation.However,the low frequency of specific driver alterations in BTCs limits their wide application.Recently,immunotherapeutic approaches are also under active investigation in BTCs,but the role of immunotherapy in BTCs remains controversial.Data sources:Pub Med,Web of Science,and meeting resources were searched for relevant articles published from January 2017 to May 2022.The search aimed to identify current and emerging immunotherapeutic approaches for BTCs.Information on clinical trials was obtained from https://clinicaltrials.gov/and http://www.chictr.org.cn/.Results:Immunotherapy in BTC patients is currently under investigation,and most of the investigations focused on the application of immune checkpoint inhibitors(ICIs).However,only a subgroup of BTCs with microsatellite-instability high(MSI-H)/DNA mismatch repair-deficient(d MMR)or tumor mutational burden-high(TMB-H)benefit from monotherapy of ICIs,and limited activity was observed in the second or subsequent settings.Nevertheless,promising results come from studies of ICIs in combination with other therapeutic approaches,including chemotherapy,in advanced BTCs,with a moderate toxicity profile.Recent studies demonstrated that compared to GEMCIS alone,durvalumab plus GEMCIS significantly improved patient survival(TOPAZ-1 trial)and that ICIs-combined chemoimmunotherapy is poised to become a new frontline therapy option,regardless of TMB and MMR/MSI status.Adoptive cell therapy and peptide-or dendritic-based cancer vaccines are other immunotherapeutic options that are being studied in BTCs.Numerous biomarkers have been investigated to define their predictive role in response to ICIs,but no predictive biomarker has been validated,except MSI-H/dMMR.Conclusions:The role of immunotherapy in BTCs is currently under investigation and the results of ongoing studies are eagerly anticipated.Several studies have demonstrated the safety and efflcacy of ICIs in combination with chemotherapy in treatment-naive patients,such as the phaseⅢTOPAZ-1 trial,which will change the standard care of first-line chemotherapy for advanced BTCs.However,further research is needed to understand the best combination with immunotherapy and to discover more predictive biomarkers to guide clinical practice.

Biliary tract reconstruction using jejunal tube:an experimental study in dogs

BACKGROUND:To physiologically reconstruct the biliary tract,Crema et al suggested the application of the Monti principle to the biliary tract,already used in humans for the urinary tract.With this technique,a jejunal segment is transversely retubularized.This study aimed to evaluate the efficacy of jejunal tube interposition between the common bile duct and duodenum in dogs.METHODS:Thirteen dogs underwent a laparoscopic common bile duct ligature,followed by a biliodigestive connection by jejunal tube interposition after one week.The levels of glutamic-pyruvic and glutamic-oxalacetic transaminases,total bilirubins,alkaline phosphatase and gamma-glutamyltransferase were assessed before surgery and thereafter weekly until euthanasia,which was performed 6 weeks after biliodigestive connection.RESULTS:Data on 9 dogs were analyzed statistically.The dogs presented with obstructive jaundice after common bile duct ligature,as confirmed by biochemical examination.They showed a statistically significant reduction in cholestasis after biliodigestive connection by jejunal tube interposition and were healthy until the end of the experiment.CONCLUSION:A statistically significant reduction was seen in total bilirubin and canalicular enzymes(alkaline phosphatase and gamma-glutamyltransferase)in the 9 dogs 6 weeks after biliodigestive connetion by jejunal tube interposition.

Multi-institutional retrospective analysis of FOLFIRI in patients with advanced biliary tract cancers

BACKGROUND Gemcitabine plus platinum is the standard of care first-line treatment for advanced biliary tract cancers(BTC).There is no established second-line therapy,and retrospective reviews report median progression-free survival(PFS)less than 3 mo on second-line therapy.5-Fluorouracil plus irinotecan(FOLFIRI)is a commonly used regimen in patients with BTC who have progressed on gemcitabine plus platinum,though there is a paucity of data regarding its efficacy in this population.AIM To assess the efficacy of FOLFIRI in patients with biliary tract cancers.METHODS We retrospectively identified patients with advanced BTC who were treated with FOLFIRI at MD Anderson,University of Michigan and Mayo Clinic in Jacksonville.Data were collected on patient demographics,BTC subtype,response per RECIST v1.1,progression and survival.RESULTS Ninety-eight patients were included of which 74(75%)had metastatic and 24(25%)had locally advanced disease at the time of treatment with FOLFIRI.The median age was 60(range,22-86)years.The number of patients with extrahepatic cholangiocarcinoma,gall bladder cancer and intrahepatic cholangiocarcinoma were 10,17 and 71,respectively.FOLFIRI was used as 1st,2nd,3rd or 4th–Nth lines in 8,50,36 and 4 patients,respectively.Median duration on FOLFIRI in the entire cohort was 2.2(range,0.5-8.4)mo.The median PFS and overall survival were 2.4(95%confidence interval(CI):1.7-3.1)and 6.6(95%CI:4.7-8.4)mo,respectively.Median PFS for patients treated with FOLFIRI in 1st,2nd,3rd or 4th–Nth lines were 3.1,2.5,2.3 and 1.5 mo,respectively.Eighteen patients received concurrent bevacizumab(n=13)or EGFR-targeted therapy(n=5)with FOLFIRI,with a median PFS of 2.7 mo(95%CI:1.7-5.1).CONCLUSION In this largest multi-institution retrospective review of 98 patients with BTC treated with FOLFIRI,efficacy appears to be modest with outcomes similar to other cytotoxic chemotherapy regimens.

CD98 is a promising prognostic biomarker in biliary tract cancer

ABSTRACT： CD98 has been described to play a crucial role in tumor progression and survival. However, the role of CD98 in biliary tract cancer remains unclear. We found that 36.7% of all patients with biliary tract cancer had a high CD98 expression. Statistical analysis using Spearman＇s rank correlation showed that CD98 was significantly correlated with L-type amino acid transporter 1 （LAT1, r=0.562, P〈0.001）, Ki-67 （r=0.230, P=0.006） and CD34 （r=0.290, P=0.005）. Multivariate analysis confirmed that a high CD98 expression was an independent prognostic factor for predicting poor outcome. CD98 is closely associated with tumor growth, biological aggressiveness, and survival of patients. With these data we proposed that CD98 expression is necessary for the development and pathogenesis of biliary tract cancer.

Complex liver retransplantation to treat graft loss due to long-term biliary tract complication after liver transplantation: A case report

BACKGROUND Loss of graft function after liver transplantation(LT) inevitably requires liver retransplant. Retransplantation of the liver(Re LT) remains controversial because of inferior outcomes compared with the primary orthotopic LT(OLT).Meanwhile, if accompanied by vascular complications such as arterial and portal vein(PV) stenosis or thrombosis, it will increase difficulties of surgery. We hereby introduce our center’s experience in Re LT through a complicated case of ReLT.CASE SUMMARY We report a patient who suffered from hepatitis B-associated cirrhosis and underwent LT in December 2012. Early postoperative recovery was uneventful.Four months after LT, the patient’s bilirubin increased significantly and he was diagnosed with an ischemic-type biliary lesion caused by hepatic artery occlusion. The patient underwent percutaneous transhepatic cholangial drainage and repeatedly replaced intrahepatic biliary drainage tube regularly for 5 years.The patient developed progressive deterioration of liver function and underwent liver re-transplant in January 2019. The operation was performed in a classic OLT manner without venous bypass. Both the hepatic artery and PV were occluded and could not be used for anastomosis. The donor PV was anastomosed with the recipient’s left renal vein. The donor hepatic artery was connected to the recipient’s abdominal aorta. The bile duct reconstruction was performed in an end-to-end manner. The postoperative process was very uneventful and the patient was discharged 1 mo after retransplantation.CONCLUSION With the development of surgical techniques, portal thrombosis and arterial occlusion are no longer contraindications for ReLT.

Biliary tract cancer stem cells-translational options and challenges

Management of biliary tract cancer remains challenging. Tumors show high recurrence rates and therapeutic resistance, leading to dismal prognosis and short survival. The cancer stem cell model states that a tumor is a heterogeneous conglomerate of cells, in which a certain subpopulation of cells-the cancer stem cells-possesses stem cell properties. Cancer stem cells have high clinical relevance due to their potential contributions to development, progression and aggressiveness as well as recurrence and metastasis of malignant tumors. Consequently, reliable identification of as well as pharmacological intervention with cancer stem cells is an intensively investigated and promising research field. The involvement of cancer stem cells in biliary tract cancer is likely as a number of studies demonstrated their existence and the obvious clinical relevance of several established cancer stem cell markers in biliary tract cancer models and tissues. In the present article, we review and discuss the currently available literature addressing the role of putative cancer stem cells in biliary tract cancer as well as the connection between known contributors of biliary tract tumorigenesis such as oncogenic signaling pathways, micro-RNAs and the tumor microenvironment with cancer stem cells.

Inhibitor of differentiation proteins do not influence prognosis of biliary tract cancer

AIM:To investigate the expression and clinical relevance of inhibitor of differentiation(ID)proteins in biliary tract cancer.METHODS:ID protein expression was analyzed in129 samples from patients with advanced biliary tract cancer(BTC)(45 extrahepatic,50 intrahepatic,and 34 gallbladder cancers),compared to normal controls and correlated with clinical an pathological parameters.RESULTS:ID1-3 proteins are frequently overexpressed in all BTC subtypes analyzed.No correlation between increased ID protein expression and tumor grading,tumor subtype or treatment response was detected.Survival was influenced primary tumor localization(extrahepatic vs intrahepatic and gall bladder cancer,OS 1.5 years vs 0.9 years vs 0.7 years,P=0.002),by stage at diagnosis(OS 2.7 years in stageⅠv s 0.6 years in stageⅣ,P<0.001),resection status and response to systemic chemotherapy.In a multivariate model,ID protein expression did not correlate with clinical prognosis.Nevertheless,there was a trend of shorter OS in patients with loss of cytoplasmic ID4 protein expression(P=0.076).CONCLUSION:ID protein expression is frequently deregulated in BTC but does not influence clinical prognosis.Their usefulness as prognostic biomarkers in BTC is very limited.

Effect of antisense DNMT3b gene eukaryotic expression plasmid on expression of the DNMT3b gene in human biliary tract carcinoma cells

BACKGROUND: Hypermethylation of the promoter region is one of the major mechanisms of tumor suppressor gene inactivation. DNA methyltransferase 3b (DNMT3b), an enzyme that participates in the establishment of de novo methylation patterns, is highly expressed in many tumor cells and tissues, and it is closely associated with hypermethylation of the promoter of tumor suppressor genes. The aim of this study was to explore the effect of transfection with antisense DNMT3b gene eukaryotic expression plasmid on the expression of the DNMT3b gene in human biliary tract carcinoma cell. METHODS: The constructed antisense DNMT3b gene eukaryotic expression plasmid was transfected into the human biliary tract carcinoma cell line QBC-939 with lipofectamine transfection reagent, and positive cell clones were formed using G418 selection after transfection. The constructed recombinant plasmid was transfected into QBC-939 cells successfully and was confirmed by amplification of the exogenous neo^R gene with the polymerase chain reaction method. The expression of DNMT3b gene mRNA and protein was detected by semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and flow cytometry respectively. RESULTS: Following transfection, the mRNA level of the DNMT3b gene decreased from 0.956±0.053 to 0.209±0.023, and the protein level of the DNMT3b gene also decreased from (75.38±3.22)% to (29.87±3.46)%. Very significant differences were observed both at the transcription and posttranscription levels in the expression of the DNMT3b gene between the non-tranfection group and the antisense DN- MT3b gene eukaryotic expression plasmid transfection group (P<0.01). CONCLUSIONS: Transfection with the antisense DNMT3b gene eukaryotic expression plasmid can significantly reduce the expression level of the DNMT3b gene in the human biliary tract carcinoma cell line QBC-939. This study may provide a valid method to investigate the function of the DNMT3b gene and its role in biliary tract carcinoma.

Effect of Antisense MBD1 Gene Eukaryotic Expression Plasmid on Expression of MBD1 Gene in Human Biliary Tract Carcinoma Cells

Hypermethylation of the promoter region is one of the major mechanism of tumor suppressor gene inactivation. In order to provide a research tool for the study on the function of MBD1 gene in DNA methylation and tumorigenesis, antisense MBD1 gene eukaryotic expression plasmid was constructed and transfected into human biliary tract carcinoma cell line QBC-939 to observe its effect on the expression of MBD1 mRNA and protein by using RT-PCR and FCM respectively. Following the transfection, the mRNA level of MBD1 gene decreased from 0. 912±0.022 to 0. 215±0. 017, and the protein level of MBD1 gene also decreased from （80.19±5.05） %to （35.11±4.05） %. There were very significant differences in the expression both at the transcription and post-transcription levels of MBD1 gene between non-tranfection group and the antisense MBD1 gene eukaryotic expression plasmid transfection group （P〈0.01）. It was suggested that transfection with the antisense MBD1 gene eukaryotic expression plasmid can significantly reduce the expression level of MBD1 gene in QBC-939, and this study may provide a valid tool for the investigation of the function of MBD1 gene and its role in biliary tract carcinoma.