Liver transplantation as an alternative for the treatment of intrahepatic cholangiocarcinoma: Past, present, and future directions

Intrahepatic cholangiocarcinoma(iCCA)is a rare biliary tract cancer with high mortality rate.Complete resection of the iCCA lesion is the first choice of treatment,with good prognosis after margin-negative resection.Unfortunately,only 12%-40% of patients are eligible for resection at presentation due to cirrhosis,portal hypertension,or large tumor size.Liver transplantation(LT)offers margin-negative iCCA extirpation for patients with unresectable tumors.Initially,iCCA was a contraindication for LT until size-based selection criteria were introduced to identify patients with satisfied post-LT outcomes.Recent studies have shown that tumor biology-based selection can yield high post-LT survival in patients with locally advanced iCCA.Another selection criterion is the tumor response to neoadjuvant therapy.Patients with response to neoadjuvant therapy have better outcomes after LT compared with those without tumor response to neoadjuvant therapy.Another index that helps predict the treatment outcome is the biomarker.Improved survival outcomes have also opened the door for living donor LT for iCCA.Patients undergoing LT for iCCA now have statistically similar survival rates as patients undergoing resection.The combination of surgery and locoregional and systemic therapies improves the prognosis of iCCA patients.

Liver transplantation as an alternative for the treatment of perihilar cholangiocarcinoma: A critical review

Background:Perihilar cholangiocarcinoma(phCCC)is a dismal malignancy.There is no consensus regard-ing the best treatment for patients with unresectable phCCC.The present review aimed to gather the current pieces of evidence for liver transplantation and liver resection as a treatment for phCCC and to build better guidance for clinical practice.Data sources:The search was conducted in PubMed,Embase,Cochrane,and LILACS.The related references were searched manually.Inclusion criteria were:reports in English or Portuguese literature that a)patients with confirmed diagnosis of phCCC;b)patients treated with a curative intent;c)patients with the outcomes of liver resection and liver transplantation.Case reports,reviews,letters,editorials,conference abstracts and papers with full-text unavailability were excluded from the analysis.Results:Most of the current literature is based on observational retrospective studies with low grades of evidence.Liver resection has better long-term outcomes than systemic chemotherapy or palliation ther-apy and liver transplantation is a good alternative for selected patients with unresectable phCCC.All candidates for resection or transplantation should be medically fit and free of intrahepatic or extrahep-atic diseases.As a general rule,patients presenting with a tumor having a longitudinal size>3 cm or extending below the cystic duct,lymph node disease,confirmed extrahepatic dissemination;intraoper-atively diagnosed metastatic disease;a history of other malignancies within the last five years,and did not complete chemoradiation regimen and were medically unfit should not be considered for transplan-tation.Some of these criteria should be individually assessed.Liver transplantation or resection should only be considered in highly experienced hepatobiliary centers,and any decision-making must be based on a multidisciplinary evaluation.Conclusions:phCCC is a complex condition with high morbidity.Surgical therapies,including hepatec-tomy and liver transplantation,are the best option for better long-term disease-free survival.

Establishment of a cholangiocarcinoma risk evaluation model based on mucin expression levels

BACKGROUND Cholangiocarcinoma(CCA)is a highly malignant cancer,characterized by frequent mucin overexpression.MUC1 has been identified as a critical oncogene in the progression of CCA.However,the comprehensive understanding of how the mucin family influences CCA progression and prognosis is still incomplete.AIM To investigate the functions of mucins on the progression of CCA and to establish a risk evaluation formula for stratifying CCA patients.METHODS Single-cell RNA sequencing data from 14 CCA samples were employed for elucidating the roles of mucins,complemented by bioinformatic analyses.Subse-quent validations were conducted through spatial transcriptomics and immuno-histochemistry.The construction of a risk evaluation model utilized the least absolute shrinkage and selection operator regression algorithm,which was further confirmed by independent cohorts and diverse data types.RESULTS CCA tumor cells with elevated levels of MUC1 and MUC4 showed activated nucleotide metabolic pathways and increased invasiveness.MUC5AC-high cells were found to promote CCA progression through WNT signaling.MUC5B-high cells exhibited robust cellular oxidation activities,leading to resistance against antitumoral treatments.MUC13-high cells were observed to secret chemokines,recruiting and transforming macrophages into the M2-polarized state,thereby suppressing antitumor immunity.MUC16-high cells were found to promote tumor progression through interleukin-1/nuclear factor kappa-light-chain-enhancer of activated B cells signaling upon interaction with neutrophils.Utilizing the expression levels of these mucins,a risk factor evaluation formula for CCA was developed and validated across multiple cohorts.CCA samples with higher risk factors exhibited stronger metastatic potential,chemotherapy resistance,and poorer prognosis.CONCLUSION Our study elucidates the functional mechanisms through which mucins contribute to CCA development,and provides tools for risk stratification in CCA.

Causal roles of gut microbiota in cholangiocarcinoma etiology suggested by genetic study

BACKGROUND Cholangiocarcinoma(CCA)is a highly malignant biliary tract cancer with poor prognosis.Previous studies have implicated the gut microbiota in CCA,but evidence for causal mechanisms is lacking.AIM To investigate the causal relationship between gut microbiota and CCA risk.METHODS We performed a two-sample mendelian randomization study to evaluate potential causal associations between gut microbiota and CCA risk using genome-wide association study summary statistics for 196 gut microbial taxa and CCA.Genetic variants were used as instrumental variables.Multiple sensitivity analyses assessed result robustness.RESULTS Fifteen gut microbial taxa showed significant causal associations with CCA risk.Higher genetically predicted abundance of genus Eubacteriumnodatum group,genus Ruminococcustorques group,genus Coprococcus,genus Dorea,and phylum Actinobacteria were associated with reduced risk of gallbladder cancer and extrahepatic CCA.Increased intrahepatic CCA risk was associated with higher abundance of family Veillonellaceae,genus Alistipes,order Enterobacteriales,and phylum Firmicutes.Protective effects against CCA were suggested for genus Collinsella,genus Eisenbergiella,genus Anaerostipes,genus Paraprevotella,genus Parasutterella,and phylum Verrucomicrobia.Sensitivity analyses indicated these findings were reliable without pleiotropy.CONCLUSION This pioneering study provides novel evidence that specific gut microbiota may play causal roles in CCA risk.Further experimental validation of these candidate microbes is warranted to consolidate causality and mechanisms.

National guidelines for the diagnosis and treatment of hilar cholangiocarcinoma

A consensus meeting of national experts from all major national hepatobiliary centres in the country was held on May 26,2023,at the Pakistan Kidney and Liver Institute&Research Centre(PKLI&RC)after initial consultations with the experts.The Pakistan Society for the Study of Liver Diseases(PSSLD)and PKLI&RC jointly organised this meeting.This effort was based on a comprehensive literature review to establish national practice guidelines for hilar cholangiocarcinoma(hCCA).The consensus was that hCCA is a complex disease and requires a multidisciplinary team approach to best manage these patients.This coordinated effort can minimise delays and give patients a chance for curative treatment and effective palliation.The diagnostic and staging workup includes high-quality computed tomography,magnetic resonance imaging,and magnetic resonance cholangiopancreato-graphy.Brush cytology or biopsy utilizing endoscopic retrograde cholangiopancreatography is a mainstay for diagnosis.However,histopathologic confirmation is not always required before resection.Endoscopic ultrasound with fine needle aspiration of regional lymph nodes and positron emission tomography scan are valuable adjuncts for staging.The only curative treatment is the surgical resection of the biliary tree based on the Bismuth-Corlette classification.Selected patients with unresectable hCCA can be considered for liver transplantation.Adjuvant chemotherapy should be offered to patients with a high risk of recurrence.The use of preoperative biliary drainage and the need for portal vein embolisation should be based on local multidisciplinary discussions.Patients with acute cholangitis can be drained with endoscopic or percutaneous biliary drainage.Palliative chemotherapy with cisplatin and gemcitabine has shown improved survival in patients with irresectable and recurrent hCCA.

Removal of intrahepatic bile duct stone could reduce the risk of cholangiocarcinoma

Hepatolithiasis(HL)poses a significant risk for cholangiocarcinoma(CCA)development,with reported incidences ranging from 5%-13%.Risk factors include older age,smoking,hepatitis B infection,and prolonged HL duration.Chronic inflammation and mechanical stress on the biliary epithelium contribute to CCA pathogenesis.Hepatectomy reduces CCA risk by removing stones and atrophic liver segments.However,residual stones and incomplete removal increase CCA risk.Kim et al identified carbohydrate antigen 19-9,carcinoembryonic antigen,and stone laterality as CCA risk factors,reaffirming the importance of complete stone removal.Nonetheless,challenges remain in preventing CCA recurrence post-surgery.Longer-term studies are needed to elucidate CCA risk factors further.

Removal of intrahepatic bile duct stone could reduce the risk of cholangiocarcinoma: A single-center retrospective study in South Korea

BACKGROUND Intrahepatic duct(IHD)stones are among the most important risk factors for cholangiocarcinoma(CCC).Approximately 10%of patients with IHD stones develop CCC;however,there are limited studies regarding the effect of IHD stone removal on CCC development.AIM To investigate the association between IHD stone removal and CCC development.METHODS We retrospectively analyzed 397 patients with IHD stones at a tertiary referral center between January 2011 and December 2020.RESULTS CCC occurred in 36 of the 397 enrolled patients.In univariate analysis,chronic hepatitis B infection(11.1%vs 3.0%,P=0.03),carbohydrate antigen 19-9(CA19-9,176.00 vs 11.96 II/mL,P=0.010),stone located in left or both lobes(86.1%vs 70.1%,P=0.042),focal atrophy(52.8%vs 26.9%,P=0.001),duct stricture(47.2%vs 24.9%,P=0.004),and removal status of IHD stone(33.3%vs 63.2%,P<0.001)were significantly different between IHD stone patients with and without CCC.In the multivariate analysis,CA19-9>upper normal limit,carcinoembryonic antigen>upper normal limit,stones located in the left or both lobes,focal atrophy,and complete removal of IHD stones without recurrence were independent factors influencing CCC development.However,the type of removal method was not associated with CCC risk.CONCLUSION Complete removal of IHD stones without recurrence could reduce CCC risk.

Ex vivo liver resection and auto-transplantation and special systemic therapy in perihilar cholangiocarcinoma treatment

This editorial contains comments on the article“Systematic sequential therapy for ex vivo liver resection and autotransplantation:A case report and review of li-terature”in the recent issue of World Journal of Gastrointestinal Surgery.It points out the actuality and importance of the article and focuses primarily on the role and place of ex vivo liver resection and autotransplantation(ELRAT)and systemic therapy,underlying molecular mechanisms for targeted therapy in perihilar cho-langiocarcinoma(pCCA)management.pCCA is a tough malignancy with a high proportion of advanced disease at the time of diagnosis.The only curative option is radical surgery.Surgical excision and reconstruction become extremely com-plicated and not always could be performed even in localized disease.On the other hand,ELRAT takes its place among surgical options for carefully selected pCCA patients.In advanced disease,systemic therapy becomes a viable option to prolong survival.This editorial describes current possibilities in chemotherapy and reveals underlying mechanisms and projections in targeted therapy with ki-nase inhibitors and immunotherapy in both palliative and adjuvant settings.Fi-broblast grow factor and fibroblast grow factor receptor,human epidermal grow-th factor receptor 2,isocitrate dehydrogenase,and protein kinase cAMP activated catalytic subunit alpha(PRKACA)and beta(PRKACB)pathways have been ac-tively investigated in CCA in last years.Several agents were introduced and approved by the Food and Drug Administration.They all demonstrated mean-ingful activity in CCA patients with no global change in outcomes.That is why every successfully treated patient counts,especially those with advanced disease.In conclusion,pCCA is still hard to treat due to late diagnosis and extremely complicated surgical options.ELRAT also brings some hope,but it could be performed in very carefully selected patients.Advanced disease requires systemic anticancer treatment,which is supposed to be individualized according to the genetic and molecular features of cancer cells.Targeted therapy in combination with chemo-immunotherapy could be effective in susceptible patients.

Current interventional options for palliative care for patients with advanced-stage cholangiocarcinoma

Primary biliary tract tumors are malignancies that originate in the liver,bile ducts,or gallbladder.These tumors often present with jaundice of unknown etiology,leading to delayed diagnosis and advanced disease.Currently,several palliative treatment options are available for primary biliary tract tumors.They include percutaneous transhepatic biliary drainage(PTBD),biliary stenting,and surgical interventions such as biliary diversion.Systemic therapy is also commonly used for the palliative treatment of primary biliary tract tumors.It involves the administration of chemotherapy drugs,such as gemcitabine and cisplatin,which have shown promising results in improving overall survival in patients with advanced biliary tract tumors.PTBD is another palliative treatment option for patients with unresectable or inoperable malignant biliary obstruction.Biliary stenting can also be used as a palliative treatment option to alleviate symptoms in patients with unresectable or inoperable malignant biliary obstruction.Surgical interventions,such as biliary diversion,have traditionally been used as palliative options for primary biliary tract tumors.However,biliary diversion only provides temporary relief and does not remove the tumor.Primary biliary tract tumors often present in advanced stages,making palliative treatment the primary option for improving the quality of life of patients.

Phospholipase A2 enzymes PLA2G2A and PLA2G12B as potential diagnostic and prognostic biomarkers in cholangiocarcinoma

BACKGROUND Phospholipase A2(PLA2)enzymes are pivotal in various biological processes,such as lipid mediator production,membrane remodeling,bioenergetics,and maintaining the body surface barrier.Notably,these enzymes play a significant role in the development of diverse tumors.AIM To systematically and comprehensively explore the expression of the PLA2 family genes and their potential implications in cholangiocarcinoma(CCA).METHODS We conducted an analysis of five CCA datasets from The Cancer Genome Atlas and the Gene Expression Omnibus.The study identified differentially expressed genes between tumor tissues and adjacent normal tissues,with a focus on PLA2G2A and PLA2G12B.Gene Set Enrichment Analysis was utilized to pinpoint associated pathways.Moreover,relevant hub genes and microRNAs for PLA2G2A and PLA2G12B were predicted,and their correlation with the prognosis of CCA was evaluated.RESULTS PLA2G2A and PLA2G12B were discerned as differentially expressed in CCA,manifesting significant variations in expression levels in urine and serum between CCA patients and healthy individuals.Elevated expression of PLA2G2A was correlated with poorer overall survival in CCA patients.Additionally,the study delineated pathways and miRNAs associated with these genes.CONCLUSION Our findings suggest that PLA2G2A and PLA2G12B may serve as novel potential diagnostic and prognostic markers for CCA.The increased levels of these genes in biological fluids could be employed as non-invasive markers for CCA,and their expression levels are indicative of prognosis,underscoring their potential utility in clinical settings.

Outcomes of liver resection in hepatitis C virus-related intrahepatic cholangiocarcinoma:A systematic review and meta-analysis

BACKGROUND Cholangiocarcinoma is the second most common primary liver malignancy.Its incidence and mortality rates have been increasing in recent years.Hepatitis C virus(HCV)infection is a risk factor for development of cirrhosis and cholan-giocarcinoma.Currently,surgical resection remains the only curative treatment option for cholangiocarcinoma.We aim to study the impact of HCV infection on outcomes of liver resection(LR)in intrahepatic cholangiocarcinoma(ICC).AIM To study the outcomes of curative resection of ICC in patients with HCV(i.e.,HCV+)compared to patients without HCV(i.e.,HCV-).METHODS We conducted a systematic review and meta-analysis of randomized controlled trials(RCTs)and observational studies to assess the outcomes of LR in ICC in HCV+patients compared to HCV-patients in tertiary care hospitals.PubMed,EMBASE,The Cochrane Library and Scopus were systematically searched from inception till August 2023.Included studies were RCTs and non-RCTs on patients≥18 years old with a diagnosis of ICC who underwent LR,and compared outcomes between patients with HCV+vs HCV-.The primary outcomes were overall survival(OS)and recurrence-free survival.Secondary outcomes include perioperative mortality,operation duration,blood loss,intrahepatic and extrahepatic recurrence.RESULTS Seven articles,published between 2004 and 2021,fulfilled the selection criteria.All of the studies were retrospective studies.Age,incidence of male patients,albumin,bilirubin,platelets,tumor size,incidence of multiple tumors,vascular invasion,bile duct invasion,lymph node metastases,and stage 4 disease were comparable between HCV+and HCV-group.Alanine transaminase[MD 22.20,95%confidence interval(CI):13.75,30.65,P<0.00001]and aspartate transaminase levels(MD 27.27,95%CI:20.20,34.34,P<0.00001)were significantly higher in HCV+group compared to HCV-group.Incidence of cirrhosis was significantly higher in HCV+group[odds ratio(OR)5.78,95%CI:1.38,24.14,P=0.02]compared to HCV-group.Incidence of poorly differentiated disease was significantly higher in HCV+group(OR 2.55,95%CI:1.34,4.82,P=0.004)compared to HCV-group.Incidence of simultaneous hepatocellular carcinoma lesions was significantly higher in HCV+group(OR 8.31,95%CI:2.36,29.26,P=0.001)compared to HCV-group.OS was significantly worse in the HCV+group(hazard ratio 2.05,95%CI:1.46,2.88,P<0.0001)compared to HCV-group.CONCLUSION This meta-analysis demonstrated significantly worse OS in HCV+patients with ICC who underwent curative resection compared to HCV-patients.

A model of five genes of tumor microenvironment predicts prognosis in Cholangiocarcinoma

Background:Cholangiocarcinoma(CCA)is highly malignant and has a poor prognosis has a high malignant degree and poor prognosis.The purpose of this study is to develop a new prognostic model based on genes related to the tumor microenvironment(TME).Methods:Derived from the discerned differentially expressed genes within The Cancer Genome Atlas(TCGA)dataset,this investigation employed the methodology of weighted gene co-expression network analysis(WGCNA)to ascertain gene co-expressed modules intricately linked to the Tumor Microenvironment(TME)among Cholangiocarcinoma(CCA)patients.The genes associated with prognosis,as identified through Cox regression analysis,were employed in the formulation of a predictive model.This model underwent validation,leading to the development of a risk score formula and nomogram.Concurrently,we validated the model’s reliability using data from CCA patients in the Gene Expression Omnibus(GEO)database(accession:GSE107943).Results:6139 DEGs were divided into 10 co-expressed gene modules using WGCNA.Among these,two modules(blue module with 832 genes and brown module with 1379 genes)showed high correlation with the TME.Five prognostic genes(BNIP3,COL4A3,SPRED3,CEBPB,PLOD2)were identified through Cox regression analysis,and a prognostic model and risk score formula were developed based on these genes.Risk score formula:Risk score=BNIP3×1.70520-COL4A3×2.39815+SPRED3×1.17936+CEBPB×0.40456+PLOD2×0.24785.Kaplan-Meier survival analysis revealed that the survival probabilities of the low-risk group were significantly higher than those of the high-risk group.Furthermore,the related evaluation indexes suggested that the model exhibited strong predictive ability.Conclusion:The prognostic model,based on five TME-related genes(BNIP3,COL4A3,SPRED3,CEBPB,PLOD2),could accurately assess the prognosis of CCA patients to aid in guiding clinical decisions.

Compliance with enhanced recovery after surgery predicts long-term outcome after hepatectomy for cholangiocarcinoma

BACKGROUND Enhanced recovery after surgery(ERAS)program has been proved to improve postoperative outcome for many surgical procedures,including liver resection.There was limited evidence regarding the feasibility and benefit of ERAS in patients who underwent liver resection for cholangiocarcinoma.AIM To evaluate the feasibility of ERAS in patients who underwent liver resection for cholangiocarcinoma and its association with patient outcomes.METHODS We retrospectively analyzed 116 cholangiocarcinoma patients who underwent hepatectomy at Srinagarind Hospital,Khon Kaen University between January 2015 and December 2016.The primary outcome was the compliance with ERAS.To determine the association between ERAS compliance and patient outcomes.the patients were categorized into those adhering more than and equal to 50%(ERAS≥50),and below 50%(ERAS<50)of all components.Details on type of surgical procedure,preoperative and postoperative care,tumor location,postoperative laboratory results,and survival time were evaluated.The compliance with ERAS was measured by the percentage of ERAS items achieved.The Kaplan-Meier curve was used for survival analysis.RESULTS The median percentage of ERAS goals achieved was 40%(±12%).Fourteen patients(12.1%)were categorized into the ERAS≥50 group,and 102 patients were in the ERAS<50 group.Postoperative hospital stay was significantly shorter in the ERAS≥50 group[8.9 d,95%confidence interval(CI):7.3-10.4 d]than in the ERAS<50 group(13.7 d,95%CI:12.2-15.2 d)(P=0.0217).No hepatobiliary-related complications or in-hospital mortality occurred in the ERAS≥50 group.Overall survival was significantly higher in the ERAS≥50 group.The median survival of the patients in the ERAS<50 group was 1257 d(95%CI:853.2-1660.8 d),whereas that of the patients in the ERAS≥50 group was not reached.CONCLUSION Overall ERAS compliance for patients who underwent liver resection for cholangiocarcinoma is poor.Greater ERAS compliance could predict in-hospital,short-term,and long-term outcomes of the patients.

Liver transplantation in the management of cholangiocarcinoma:Evolution and contemporary advances

Cholangiocarcinoma(CCA)is an aggressive malignancy arising from the biliary epithelium.It may occur at any location along the biliary tree with the perihilar area being the most common.Prognosis is poor with 5-year overall survival at less than 10%,typically due to unresectable disease at presentation.Radical surgical resection with clear margins offers a chance of cure in patients with resectable tumours,but is frequently not possible due to locally advanced disease.On the other hand,orthotopic liver transplantation(LT)allows for a radical and potentially curative resection for these patients,but has been historically controversial due to the limited supply of donor grafts and previously poor outcomes.In patients with perihilar CCA,within specific criteria and following the implementation of a protocol combining neoadjuvant chemoradiation and LT,excellent results have been achieved in the last decades,resulting in its increasing acceptance as an indication for LT and the standard of care in several centres with significant experience.However,in intrahepatic CCA,the role of LT remains controversial and owing to dismal previous results it is not an accepted indication.Nevertheless,more recent studies have demonstrated favourable results with LT in early intrahepatic CCA,indicating that,under defined criteria,its role may increase in the future.This review highlights the history and contemporary advances of LT in CCA,with particular focus on the improving outcomes of LT in intrahepatic and perihilar CCA and future perspectives.

Role of routine lymph node dissection alongside resection ofintrahepatic cholangiocarcinoma: Systematic review and metaanalysis

BACKGROUND The global incidence of intrahepatic cholangiocarcinoma(ICCA)is soaring.Due to often delayed presentation,only a narrow spectrum of the disease is usually surgically resectable.To more accurately stage the disease,reduce recurrence,and improve overall survival,surgical teams are increasingly performing intraoperative lymph node dissection(LND)as well.This procedure has its associated morbidity,while there is no consensus or formal guidelines on its role in this setting.Hence,there is a need to better delineate the evidence for performing LND alongside surgical resection of the ICCA.AIM To perform a systematic review and meta-analysis on the role of LND in improving prognostication and survival post-resection of ICCA.METHODS We performed a systematic literature search using Pubmed,Medline,Embase,and the Cochrane Library,for all studies involving LND,ICCA,and surgical resection using several keywords,Medical Subject Headings(MeSH)tags,and appropriate synonyms.All clinical studies comparing curative intent resection of ICCA with LND vs resection without LND were included,while single-arm case series,studies with insufficient data,and duplicates were excluded.We included all English-language studies from the different academic databases up till early December 2022.The primary outcome measures were set for overall survival(OS)and disease-free survival(DFS).RESULTS This systematic review and meta-analysis included 15 studies that fulfilled the selection criteria comprising 11413 patients with surgically-resectable ICCA,of whom 6424(56.3%)underwent hepatectomy with LND while the remainder underwent hepatectomy only.In patients who underwent LND,on average,27.7%of the resected lymph nodes were positive for metastatic disease.Overall,the results showed that performing LND did not significantly improve OS or DFS.However,the effect of LND on OS showed a degree of variability by geographical region,in Eastern and Western countries.As LND is increasingly being performed,further time-based analysis was undertaken to identify time-dependent changes in the role of LND.An increasing adoption of LND was not associated with improved OS.Furthermore,no roles were identified for neoadjuvant/adjuvant chemotherapy or increasing lymph node retrieval in improving OS either.CONCLUSION LND might aid in staging,prognosticating,and deciding further management of resected ICCA,but does not improve OS and DFS and is unsuitable for high-risk patients unlikely to benefit from further treatments.

Development of a model based on the age-adjusted Charlson comorbidity index to predict survival for resected perihilar cholangiocarcinoma

BACKGROUND Perihilar cholangiocarcinoma(pCCA)has a poor prognosis and urgently needs a better predictive method.The predictive value of the age-adjusted Charlson comorbidity index(ACCI)for the long-term prognosis of patients with multiple malignancies was recently reported.However,pCCA is one of the most surgically difficult gastrointestinal tumors with the poorest prognosis,and the value of the ACCI for the prognosis of pCCA patients after curative resection is unclear.AIM To evaluate the prognostic value of the ACCI and to design an online clinical model for pCCA patients.METHODS Consecutive pCCA patients after curative resection between 2010 and 2019 were enrolled from a multicenter database.The patients were randomly assigned 3:1 to training and validation cohorts.In the training and validation cohorts,all patients were divided into low-,moderate-,and high-ACCI groups.Kaplan-Meier curves were used to determine the impact of the ACCI on overall survival(OS)for pCCA patients,and multivariate Cox regression analysis was used to determine the independent risk factors affecting OS.An online clinical model based on the ACCI was developed and validated.The concordance index(C-index),calibration curve,and receiver operating characteristic(ROC)curve were used to evaluate the predictive performance and fit of this model.RESULTS A total of 325 patients were included.There were 244 patients in the training cohort and 81 patients in the validation cohort.In the training cohort,116,91 and 37 patients were classified into the low-,moderate-and high-ACCI groups.The Kaplan-Meier curves showed that patients in the moderate-and high-ACCI groups had worse survival rates than those in the low-ACCI group.Multivariable analysis revealed that moderate and high ACCI scores were independently associated with OS in pCCA patients after curative resection.In addition,an online clinical model was developed that had ideal C-indexes of 0.725 and 0.675 for predicting OS in the training and validation cohorts.The calibration curve and ROC curve indicated that the model had a good fit and prediction performance.CONCLUSION A high ACCI score may predict poor long-term survival in pCCA patients after curative resection.High-risk patients screened by the ACCI-based model should be given more clinical attention in terms of the management of comorbidities and postoperative follow-up.

Liver transplantation for combined hepatocellular carcinoma and cholangiocarcinoma:A multicenter study

BACKGROUND Patients with combined hepatocellular carcinoma and cholangiocarcinoma(cHCC-CC)are not traditionally considered eligible for liver transplantation(LT)AIM To compare outcomes between living donor LT(LDLT)patients with hepatocellular carcinoma(HCC)and LT patients with cHCC-CC and to identify risk factors for tumor recurrence and death after LT in cHCC-CC patients.METHODS Data for pathologically diagnosed cHCC-CC patients(n=111)who underwent LT from 2000 to 2018 were collected for a nine-center retrospective review.Patients(n=141)who received LDLT for HCC at Samsung Medical Center from January 2013 to March 2017 were selected as the control group.Seventy patients in two groups,respectively,were selected by 1:1 matching.RESULTS Cumulative disease-free survival(DFS)and overall survival(OS)in the cHCC-CC group were significantly worse than in the HCC group both before and after matching.Extrahepatic recurrence incidence in the cHCC-CC group was higher than that in the HCC group(75.5%vs 33.3%,P<0.001).Multivariate analysis demonstrated that the cHCC-CC group had significantly higher rates of tumor recurrence and death compared to the HCC group.In cHCC-CC subgroup analysis,frequency of locoregional therapies>3,tumor size>3 cm,and lymph node metastasis were predisposing factors for tumor recurrence in multivariate analysis.Only a maximum tumor size>3 cm was a predisposing factor for death.CONCLUSION The poor prognosis of patients diagnosed with cHCC-CC after LT can be predicted based on the explanted liver.Frequent regular surveillance for cHCC-CC patients should be required for early detection of tumor recurrence.

γ-aminobutyric acid B2 receptor:A potential therapeutic target for cholangiocarcinoma in patients with diabetes mellitus

BACKGROUND The association between diabetes mellitus(DM)and the increased risk and progression of cholangiocarcinoma(CCA)has been reported with unclear underlying mechanisms.Previous studies showed thatγ-aminobutyric acid(GABA)B2 receptor(GABBR2)was upregulated in CCA cells cultured in high glucose(HG)conditions.Roles of GABA receptors in CCA progression have also been studied,but their association with DM and hyperglycemia in CCA remains unclarified.AIM To investigate the effects of hyperglycemia on GABBR2 expression and the potential use of GABBR2 as a CCA therapeutic target.METHODS CCA cells,KKU-055 and KKU-213A,were cultured in Dulbecco Modified Eagle’s Medium supplemented with 5.6 mmol/L(normal glucose,NG)or 25 mmol/L(HG)glucose and assigned as NG and HG cells,respectively.GABBR2 expression in NG and HG cells was investigated using real-time quantitative polymerase chain reaction and western blot.Expression and localization of GABBR2 in CCA cells were determined using immunocytofluorescence.GABBR2 expression in tumor tissues from CCA patients with and without DM was studied using immunohistochemistry,and the correlations of GABBR2 with the clinicopathological characteristics of patients were analyzed using univariate analysis.Effects of baclofen,a GABA-B receptor agonist,on CCA cell proliferation and clonogenicity were tested using the MTT and clonogenic assays.Phospho-kinases arrays were used to screen the affected signaling pathways after baclofen treatment,and the candidate signaling molecules were validated using the public transcriptomic data and western blot.RESULTS GABBR2 expression in CCA cells was induced by HG in a dose-and time-dependent manner.CCA tissues from patients with DM and hyperglycemia also showed a significantly higher GABBR2 expression compared with tumor tissues from those with euglycemia(P<0.01).High GABBR2 expression was significantly associated with a poorer non-papillary histological subtype but with smaller sizes of CCA tumors(P<0.05).HG cells of both tested CCA cell lines were more sensitive to baclofen treatment.Baclofen significantly suppressed the proliferation and clonogenicity of CCA cells in both NG and HG conditions(P<0.05).Phospho-kinase arrays suggested glycogen synthase kinase 3(GSK3),β-catenin,and the signal transducer and activator of transcription 3(STAT3)as candidate signaling molecules under the regulation of GABBR2,which were verified in NG and HG cells of the individual CCA cell lines.Cyclin D1 and c-Myc,the common downstream targets of GSK3/β-catenin and STAT3 involving cell proliferation,were accordingly downregulated after baclofen treatment.CONCLUSION GABBR2 is upregulated by HG and holds a promising role as a therapeutic target for CCA regardless of the glucose condition.

mRNA vaccine development for cholangiocarcinoma:a precise pipeline

Cholangiocarcinoma(CHOL)is one of the most aggressive tumors worldwide and cannot be effectively treated by conventional and novel treatments,including immune checkpoint blockade therapy.The mRNA vaccine-based immunotherapeutic strategy has attracted much attention for various diseases,however,its application in CHOL is limited due to the thoughtlessness in the integration of vaccine design and patient selection.A recent study established an integrated path for identifying potent CHOL antigens for mRNA vaccine development and a precise stratification for identifying CHOL patients who can benefit from the mRNA vaccines.In spite of a promising prospect,further investigations should identify immunogenic antigens and onco-immunological characteristics of CHOL to guide the clinical application of CHOL mRNA vaccines in the future.

Pathogen detection in patients with perihilar cholangiocarcinoma:Implications for targeted perioperative antibiotic therapy

Background:Cholestasis should be relieved by biliary drainage prior to major liver resection.This condition is often associated with bacterial colonization of the otherwise sterile biliary system.Cholangitis reduces the regenerative capacity of the remaining liver.Therefore,targeted antibiotic therapy is a key feature in perioperative treatment in patients with perihilar cholangiocarcinoma(pCCC).Methods:Between December 1999 and December 2017,251 pCCC patients were treated in our center.In total,115 patients underwent a microbiological analysis.In addition to the characterization of the specific microorganisms and antibiotic resistance,we analyzed subgroups according to preoperative intervention.Results:Enterococci(87/254,34%)and Enterobacteria(65/254,26%)were the most frequently detected genera.In 43%(50/115)of patients,Enterococcus faecalis was found in the bile duct sample.Enterococcus faecium(29/115)and Escherichia coli(29/115)were detected in 25%of patients.In patients with percutaneous transhepatic biliary drainage(3/8,38%)or stents(24/79,30%),Enterococcus faecium was diagnosed most frequently(P<0.05).Enterococcus faecium and Klebsiella oxytoca were significantly more frequently noted in the time period after 2012(P<0.05).With regard to fungal colonization,the focus was on various Candida strains,but these strains generally lacked resistance.Conclusions:pCCC patients exhibit specific bacterial colonization features depending on the type of preoperative biliary intervention.Specifically,targeted antibiosis should be applied in this patient cohort to minimize the risk of biliary complications after major liver resection.In our cohort,the combination of meropenem and vancomycin represents an effective perioperative medical approach.