Percutaneous transhepatic cholangiography:An effective option for endo-biliary radiofrequency ablation before stent insertion in unresectable biliary cancer?

Biliary cancer is a highly aggressive disease that is typically diagnosed at advanced stages when surgical removal is no longer an option.In these cases,palliative care and mechanical widening of the blocked biliary system are preferred.The insertion of a stent is often necessary to prevent the recurrence of blockages caused by cancer progression.Prior to stent placement,endo-biliary radiofrequency ablation(EB-RFA)appears to result in longer-lasting stent effectiveness without increasing the risk of severe complications.However,its impact on overall survival is not yet clear.Additionally,while endoscopic retrograde cholangiopancreatography is the most common method for performing EB-RFA,percutaneous transhepatic cholangiodrainage seems to be a safe and potentially more efficient alternative,particularly for long,angulated,or significantly narrowed bile ducts.

Overexpression of β3/γ2 chains of laminin-5 and MMP7 in biliary cancer

AIM： To clarify the clinicopathological significance of laminin-5 y2 （LNγ2） and 133 （LNI33） chains and MMP7 expression in biliary tract cancer. METHODS： We analyzed the association between immunohistochemically detected LNγ2, LNβ3, and MMP7 expression in biliary tract cancer and clinicopathological characteristics. Activity of MMP7 was analyzed by casein zymography. An in vitro invasion assay after treatment with MMP7-specific siRNA was performed. RESULTS： LNγ2 expression was predominantly observed in carcinoma cells at the invasive front. LNγ2 expression was seen in 57% of patients with biliary tract cancer, and was associated with depth of invasion, histologic type, and advanced stage. The expression pattern of LNβ3 was classified Into two types： invasive front dominant type （38%） and diffuse type （28%）.The invasive front dominant type was associated with histologic type and advanced stage. MMP7 positivity was correlated with LNγ2 or LNβ3 expression but not with clinicopathological characteristics. Active MMP7 detected by casein zymography was correlated with depth of invasion and advanced stage. Downregulation of MMP7 expression by siRNA resulted in a significant decrease in biliary tract cancer cell invasion in vitro.CONCLUSION： Our results suggest that LNγ2 and LNβ3, in conjunction with MMP7, play a key role in the progression of biliary tract cancer.

Epidemiology of biliary tract cancer in China:A narrative review

Biliary tract cancer(BTC)is a group of rare malignancies that affect the gallbladder and bile ducts.Although rare,BTC is becoming a significant public health burden in China,particularly among males and older individuals.The increasing trends in BTC incidence and mortality in China are influenced by various demographic,environmental,and lifestyle factors.In this review,we examine available epidemiological data on the incidence,mortality,prognosis,and trends of different BTC subtypes in China.We also discuss the challenges and opportunities for improving the prevention,diagnosis,and management of BTC in China,and identify areas for further research and intervention.The article aims to provide a better understanding of the epidemiological features of BTC in China and to inform public health strategies and clinical practice.

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/m^(2),day 1)and capecitabine(2000 mg/m^(2),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.

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.

Transmembrane serine protease 4 expression in the prognosis of radical resection for biliary tract cancer

BACKGROUND Recent advancements in biliary tract cancer(BTC)treatment have expanded beyond surgery to include adjuvant therapy,yet the prognosis remains poor.Identifying prognostic biomarkers could enhance the assessment of patients who have undergone radical resection for BTC.AIM To determine transmembrane serine protease 4(TMPRSS4)utility as a prognostic biomarker of radical resection for BTC.METHODS Medical records of patients who underwent radical resection for BTC,excluding intrahepatic cholangiocarcinoma,were retrospectively reviewed.The associations between TMPRSS4 expression and clinicopathological factors,overall survival,and recurrence-free survival were analyzed.RESULTS Among the 85 patients undergoing radical resection for BTC,46(54%)were TMPRSS4-positive.The TMPRSS4-positive group exhibited significantly higher preoperative carbohydrate antigen 19-9(CA19-9)values and greater lymphatic invasion than the TMPRSS4-negative group(P=0.019 and 0.039,respectively).Postoperative overall survival and recurrence-free survival were significantly worse in the TMPRSS4-positive group(median survival time:25.3 months vs not reached,P<0.001;median survival time:28.7 months vs not reached,P=0.043,respectively).Multivariate overall survival analysis indicated TMPRSS4 positivity,pT3/T4,and resection status R1 were independently associated with poor prognosis(P=0.032,0.035 and 0.030,respectively).TMPRSS4 positivity correlated with preoperative CA19-9 values≥37 U/mL and pathological tumor size≥30 mm(P=0.016 and 0.038,respectively).CONCLUSION TMPRSS4 is a potential prognostic biomarker of radical resection for BTC.

Review of practice informing data and current state of NCCN consensus guidelines in hepatobiliary cancers

The most important recent updates to the US National Comprehensive Cancer Network(NCCN)guidelines include the addition of new immunotherapy agents to the armamentarium for both hepatocellular carcinoma(HCC)and biliary tract cancers(1).The publication and subsequent the US Food and Drug Administration(FDA)approval of the Single Tremelimumab Regular Interval Durvalumab(STRIDE)regimen established in the phase III HIMALAYA trial(2)adds an important option for first-line systemic treatment of advanced HCC and was included in the NCCN guidelines with the 4.

Inhibition of histone deacetylase for the treatment of biliary tract cancer:A new effective pharmacological approach

AIM： To investigate in vitro and in vivo therapeutic effects of histone deacetylase inhibitors NVP-LAQ824 and NVP-LBH589 on biliary tract cancer. METHODS： Cell growth inhibition by NVP-LAQ824 and NVP-LBH589 was studied in vitro in 7 human biliary tract cancer cell lines by MTT assay. In addition, the antitumoral effect of NVP-LBH589 was studied in a chimeric mouse model. Anti-tumoral drug mechanism was assessed by immunoblotting for acH4 and p21^WAFl/CIP-1, PARP assay, cell cycle analysis, TUNEL assay, and immunhistochemistry for MIB-1. RESULTS： In vitro treatment with both compounds significantly suppressed the growth of all cancer cell lines [mean IC50 （3 d） 0.11 and 0.05 μmol/L, respectively], and was associated with hyperacetylation of nucleosomal histone H4, increased expression of p21^WAF-1/CIP-1, induction of apoptosis （PARP cleavage）, and cell cycle arrest at G2/M checkpoint. After 28 d, NVP- LBH589 significantly reduced tumor mass by 66% （bile duct cancer） and 87% （gallbladder cancer） in vivo in comparison to placebo, and potentiated the efficacy of gemcitabine. Further analysis of the tumor specimens revealed increased apoptosis by TUNEL assay and reduced cell proliferation （MIB-1）. CONCLUSION： Our findings suggest that NVP-LBH589 and NVP-LAQ824 are active against human biliary tract cancer in vitro. In addition, NVP-LBH589 demonstrated significant in vivo activity and potentiated the efficacy of gemcitabine. Therefore, further clinical evaluation of this new drug for the treatment of biliary tract cancer is recommended.

Effect of histone deacetylase inhibitor on proliferation of biliary tract cancer cell lines

AIM: To explore the effect of histone deacetylase inhibitor, trichostatin A (TSA) on the growth of biliary tract cancer cell lines (gallbladder carcinoma cell line and cholangiocarcinoma cell line) in vivo and in vitro, and to investigate the perspective of histone deacetylase inhibitor in its clinical application. METHODS: The survival rates of gallbladder carcinoma cell line (Mz-ChA-l cell line) and cholangiocarcinoma cell lines (QBC939, KMBC and OZ cell lines) treated with various doses of TSA were detected by methylthiazoy tetrazolium (MTT) assay. A nude mouse model of transplanted gallbladder carcinoma (Mz-ChA-l cell line) was successfully established, and changes in the growth of transplanted tumor after treated with TSA were measured. RESULTS: TSA could inhibit the proliferation of gallbladder carcinoma cell line (Mz-ChA-l cell line) and cholangiocarcinoma cell lines (QBC939, KMBC and OZ cell lines) in a dose-dependent manner. After the nude mouse model of transplanted gallbladder carcinoma (Mz- ChA-l cell line) was successfully established, the growth of cancer was inhibited in the model after treated with TSA. CONCLUSION: TSA can inhibit the growth of cholangiocarcinoma and gallbladder carcinoma cell lines in vitro and in vivo.

Efficacy and safety of gemcitabine-based chemotherapies in biliary tract cancer:A meta-analysis

AIM: To investigate the efficacy and safety of gemcitabine (Gem)-based combination chemotherapies for the treatment of advanced biliary tract cancer.

Targeted medical therapy of biliary tract cancer:Recent advances and future perspectives

The limited efficacy of cytotoxic therapy for advanced biliary tract and gallbladder cancers emphasizes the need for novel and more effective medical treatment options. A better understanding of the specific biological features of these neoplasms led to the development of new targeted therapies, which take the abundant expression of several growth factors and cognate tyrosine kinase receptors into account. This review will briefly summarize the status and future perspectives of antiangiogenic and growth factor receptor-based pharmacological approaches for the treatment of biliary tract and gallbladder cancers. In view of multiple novel targeted approaches, the rationale for innovative therapies, such as combinations of growth factor (receptor)-targeting agents with cytotoxic drugs or with other novel anticancer drugs will be highlighted.

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.

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.

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.

Adjuvant treatment in biliary tract cancer: To treat or not to treat?

Biliary tract cancer is a rare malignant tumor. There is limited knowledge about biology and natural history of this disease and considerable uncertainty remains regarding its optimal diagnostic and therapeutic man- agement. The role of adjuvant therapy is object of debate and controversy. Although resection is identified as the most effective and the only potentially curative treatment, there is no consensus on the impact of ad- juvant chemotherapy and/or radiotherapy on the high incidence of disease recurrence and on survival. This is mainly due to the rarity of this disease and the consequent difficulty in performing randomized trials. The only two prospectively controlled trials concluded that adjuvant chemotherapy did not improve survival. Most of the retrospective trials, which had limited sample size and included heterogeneous patients population and non-standardized therapies, suggested a marginal benefit of chemoradiotherapy in reducing locoregional recurrence and an uncertain impact on survival. Welldesigned multi-institutional randomized trials are necessary to clarify the role of adjuvant therapy. Two ongoing phase Ⅲ trials may provide relevant information.

Guidelines for hepatobiliary cancers:treatment strategies in the East and West

Hepatocellular carcinoma(HCC)is the most common type of primary liver cancer originating from hepatocytes,whereas intrahepatic cholangiocarcinoma(ICC)occurs in parts of the bile ducts within the liver and is the second most common primary malignant liver tumor.Extrahepatic cholangiocarcinoma develops in the bile ducts outside the liver and includes hilar and distal bile duct cancers.

Treatment outcomes of chemotherapy between unresectable and recurrent biliary tract cancer

AIM: To evaluate the differences in the treatment outcomes between the unresectable and recurrent biliary tract cancer patients who received chemotherapy.

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.

Combining of chemotherapy with targeted therapy for advanced biliary tract cancer:A systematic review and meta-analysis

BACKGROUND Targeted therapy(TT)has resulted in controversial efficacy as first-line treatment for biliary tract cancer(BTC).More efficacy comparisons are required to clarify the overall effects of chemotherapy(CT)combined with TT and CT alone on advanced BTC.AIM To conduct a meta-analysis of the available evidence on the efficacy of CT combined with TT for advanced BTC.METHODS The PubMed,EMBASE,ClinicalTrials,Scopus and Cochrane Library databases were systematically searched for relevant studies published from inception to August 2022.Only randomized clinical trials(RCTs)including comparisons between the combination of gemcitabine-based CT with TT and CT alone as firstline treatment for advanced BTC were eligible(PROSPERO-CRD42022313001).The odds ratios(ORs)for the objective response rate(ORR)and hazard ratios(HRs)for both progression-free survival(PFS)and overall survival(OS)were calculated and analyzed.Subgroup analyses based on different targeted agents,CT regimens and tumor locations were prespecified.RESULTS Nine RCTs with a total of 1361 individuals were included and analyzed.The overall analysis showed a significant improvement in ORR in patients treated with CT+TT compared to those treated with CT alone(OR=1.43,95%CI:1.11-1.86,P=0.007)but no difference in PFS or OS.Similar trends were observed in the subgroup treated with agents targeting epidermal growth factor receptor(OR=1.67,95%CI:1.17-2.37,P=0.004)but not in the subgroups treated with agents targeting vascular endothelial growth factor receptor or mesenchymal-epithelial transition factor.Notably,patients who received a CT regimen of gemcitabine+oxaliplatin in the CT+TT arm had both a higher ORR(OR=1.75,95%CI:1.20-2.56,P=0.004)and longer PFS(HR=0.83,95%CI:0.70-0.99,P=0.03)than those in the CT-only arm.Moreover,patients with cholangiocarcinoma treated with CT+TT had significantly increased ORR and PFS(ORR,OR=2.06,95%CI:1.27-3.35,PFS,HR=0.79,95%CI:0.66-0.94).CONCLUSION CT+TT is a potential first-line treatment for advanced BTC that leads to improved tumor control and survival outcomes,and highlighting the importance of CT regimens and tumor types in the application of TT.