Prognostic value of lymph nodes count on survival of patients with distal cholangiocarcinomas

AIM To evaluate the prognostic value of the number of retrieved lymph nodes(LNs) and other prognostic factors for patients with distal cholangiocarcinomas, and to determine the optimal retrieved LNs cut-off number.METHODS The Surveillance, Epidemiology and End Results database was used to screen for patients with distal cholangiocarcinoma. Patients with different numbers of retrieved LNs were divided into three groups by the X-tile program. X-tile from Yale University is a useful tool for outcome-based cut-point optimization. The Kaplan-Meier method and Cox regression analysis were utilized for survival analysis.RESULTS A total of 449 patients with distal cholangiocarcinoma met the inclusion criteria. The Kaplan-Meier survival analysis for all patients and for N1 patients revealed no significant differences among patients with different retrieved LN counts in terms of overall and cancerspecific survival. In patients with node-negative distal cholangiocarcinoma, patients with four to nine retrieved LNs had a significantly better overall(P = 0.026) and cancer-specific survival(P = 0.039) than others. In the subsequent multivariate analysis, the number of retrieved LNs was evaluated to be independently associated with survival. Additionally, patients with four to nine retrieved LNs had a significantly lower overall mortality risk [hazard ratio(HR) = 0.39; 95% confidence interval(CI): 0.20-0.74] and cancer causespecific mortality risk(HR = 0.32; 95%CI: 0.15-0.66) than other patients. Additionally, stratified survival analyses showed persistently better overall and cancerspecific survival when retrieving four to nine LNs in patients with any T stage of tumor, a tumor between 20 and 50 mm in diameter, or a poorly differentiated or undifferentiated tumor, and in patients who were ≤ 70-years-old. CONCLUSION The number of retrieved LNs was an important independent prognostic factor for patients with nodenegative distal cholangiocarcinoma. Additionally, patients with four to nine retrieved LNs had better overall and cancer-specific survival rates than others, but the reason and mechanism were unclear. This conclusion should be validated in future studies.

Comparison of concomitant and subsequent cholangiocarcinomas associated with hepatolithiasis:Clinical implications

AIM:To compare the outcomes of concomitant cholangiocarcinoma(C-CCA)and subsequent cholangiocar-cinoma(S-CCA)associated with hepatolithiasis. METHODS:From December 1987 to December 2007, 276 patients underwent hepatic resection for hepa-tolithiasis in Changhua Christian Hospital.Sixty-five patients were excluded due to incomplete medical records and the remaining 211 patients constituted our study population base.Ten patients were diag-nosed with C-CCA based on the preoperative biopsy or postoperative pathology.During the follow-up period, 12 patients developed S-CCA.The diagnosis of S-CCA was made by image-guided biopsy or by pathology if surgical intervention was carried out.Patient charts were reviewed to collect clinical information.Parameters such as CCA incidence,interval from operation to CCA diagnosis,interval from CCA diagnosis to disease-related death,follow-up time,and mortality rate were calculated for both the C-CCA and S-CCA groups.The outcomes of the C-CCA and S-CCA groups were math-ematically compared and analysed. RESULTS:Our study demonstrates the clinical implications and the survival outcomes of C-CCA and S-CCA. Among the patients with unilateral hepatolithiasis,the incidence rates of C-CCA and S-CCA were fairly similar (4.8%vs 4.5%,respectively,P=0.906).However,for the patients with bilateral hepatolithiasis,the incidence rate of S-CCA(12.2%)was higher than that of C-CCA (4.7%),although the sample size was limited and the difference between two groups was not statistically sig-nificant(P=0.211).The average follow-up time was 56 mo for the C-CCA group and 71 mo for the S-CCA group.Regard to the average time intervals from operation to CCA diagnosis,S-CCA was diagnosed after 67 mo from the initial hepatectomy.The average time intervals from the diagnoses of CCA to disease-related death was 41 mo for the C-CCA group and 4 mo for the S-CCA group,this difference approached statistical sig-nificance(P=0.075).Regarding the rates of overall and disease-related mortality,the C-CCA group had signifi-cantly lower overall mortality(70%vs 100%,P=0.041) and disease-related mortality(60%vs 100%,P=0.015) than the S-CCA group.For the survival outcomes of two groups,the Kaplan-Meier curves corresponding to each group also demonstrated better survival outcomes for the C-CCA group(log rank P=0.005).In the C-CCA group,three patients were still alive at the time of data analysis,all of them had free surgical margins and did not have pathologically proven lymph node metastasis at the time of the initial hepatectomy.In the S-CCA group,only one patient had chance to undergo a second hepatectomy,and all 12 S-CCA patients had died at the time of data analysis. CONCLUSION:C-CCA has better outcomes than S-CCA.The first hepatectomy is crucial because most patients with recurrent CCA or S-CCA are not eligible for repeated surgical intervention.

Fas counterattack in cholangiocarcinoma:a mechanism for immune evasion in human hilar cholangiocarcinomas

AIM: To investigate FasL expression in hilar cholangiocarcinoma tissues and cultured cholangiocarcinoma cells, and to assess its ability to induce apoptosis. METHODS: We studied the expression of FasL by human hilar cholangiocaroinomas tissues by immunohistochemistry, and the QBC939 cholangiocarcinoma cell line by RT-PCR, immunohistochemistry, and Western Blot. TUNEL and flow cytometry were used to detect apoptotic cells. RESULTS: Prevalent expression of FasL was detected in 39 resected hilar cholangiocarcinoma tissues. TUNEL staining disclosed a high level of cell death among lymphocytes infiltrating FasL positive areas of tumor. FasL mRNA and protein expressions in cholangiocarcinoma cells could induce Jurkat cells. CONCLUSION: Hilar cholangiocarcinomas may elude immunological surveillance by inducing, via Fas/FasL system, the apoptosis of activated lymphocytes.

Molecular Detection of FGFR2 Rearrangements in Resected Intrahepatic Cholangiocarcinomas:FISH Could Be An Ideal Method in Patients with Histological Small Duct Subtype

Background and Aims:Intrahepatic cholangiocarcinoma(ICC)is a subtype of primary liver cancer for which effective therapeutic agents are lacking.Fibroblast growth factor receptor 2(FGFR2)has become a promising therapeutic target in ICC;however,its incidence and optimum testing method have not been fully assessed.This study investigated the rearrangement of FGFR2 in intrahepatic cholangiocarcinoma using multiple molecular detection methods.Methods:The samples and clinical data of 167 patients who underwent surgical resection of intrahepatic cholangiocarcinoma in Zhongshan hospital,Fudan university were collected.The presence of FGFR2 gene rearrangement was confirmed using fluorescence in situ hybridization(FISH)and targeted next-generation sequencing(NGS).FGFR2 protein expression was determined using immunohistochemistry(IHC).The concordance between the methods was statistically compared.PD-L1 expression was also assessed in this cohort.The clinicopathological characteristics and genomic profile related to FGFR2 rearrangements were also analyzed to assist candidatescreening for targeted therapies.Results:FGFR2 rearrangement was detected in 21 of the 167 ICC cases(12.5%)using FISH.NGS analysis revealed that FGFR2 rearrangement was present in 16 of the 20 FISH-positive cases,which was consistent with the FISH results(kappa value=0.696,p<0.01).IHC showed that 80 of the 167 cases(48%)were positive for FGFR2 expression,which was discordant with both FISH and NGS results.By comparison,FGFR2-positivity tended to correlate with unique clinicopathological subgroups,featuring early clinical stage,histologically small duct subtype,and reduced mucus production(P<0.05),with improved overall survival(p<0.05).FGFR2-positivity was not associated with PD-L1 expression in ICCs.In genome research,we identified eight partner genes fused with FGFR2,among which FGFR2-BICC1 was the most common fusion type.BAP1,CDKN2A,and CDKN2B were the most common concomitant genetic alterations of FGFR2,whereas KRAS and IDH1 mutations were mutually exclusive to FGFR2 rearrangements.Conclusions:FISH achieved satisfactory concordance with NGS,has potential value for FGFR2 screening for targeted therapies.FGFR2 detection should be prioritized for unique clinical subgroups in ICC,which features a histological small duct subtype,early clinical stage,and reduced mucus production.

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.

Hepatolithiasis:Epidemiology,presentation,classification and management of a complex disease

The term hepatolithiasis describes the presence of biliary stones within the intrahepatic bile ducts,above the hilar confluence of the hepatic ducts.The disease is more prevalent in Asia,mainly owing to socioeconomic and dietary factors,as well as the prevalence of biliary parasites.In the last century,owing to migration,its global incidence has increased.The main pathophysiological mechanisms involve cholangitis,bile infection and biliary strictures,creating a self-sustaining cycle that perpetuates the disease,frequently characterised by recurrent episodes of bacterial infection referred to as syndrome of“recurrent pyogenic cholangitis”.Furthermore,long-standing hepatolithiasis is a known risk factor for development of intrahepatic cholangiocarcinoma.Various classifications have aimed at providing useful insight of clinically relevant aspects and guidance for treatment.The management of symptomatic patients and those with complications can be complex,and relies upon a multidisciplinary team of hepatologists,endoscopists,interventional radiologists and hepatobiliary surgeons,with the main goal being to offer relief from the clinical presentations and prevent the development of more serious complications.This comprehensive review provides insight on various aspects of hepatolithiasis,with a focus on epidemiology,new evidence on pathophysiology,most important clinical aspects,different classification systems and contemporary management.

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.

New trends in diagnosis and management of gallbladder carcinoma

Gallbladder(GB)carcinoma,although relatively rare,is the most common biliary tree cholangiocarcinoma with aggressiveness and poor prognosis.It is closely associated with cholelithiasis and long-standing large(>3 cm)gallstones in up to 90%of cases.The other main predisposing factors for GB carcinoma include molecular factors such as mutated genes,GB wall calcification(porcelain)or mainly mucosal microcalcifications,and GB polyps≥1 cm in size.Diagnosis is made by ultrasound,computed tomography(CT),and,more precisely,magnetic resonance imaging(MRI).Preoperative staging is of great importance in decisionmaking regarding therapeutic management.Preoperative staging is based on MRI findings,the leading technique for liver metastasis imaging,enhanced three-phase CT angiography,or magnetic resonance angiography for major vessel assessment.It is also necessary to use positron emission tomography(PET)-CT or ^(18)F-FDG PET-MRI to more accurately detect metastases and any other occult deposits with active metabolic uptake.Staging laparoscopy may detect dissemination not otherwise found in 20%-28.6%of cases.Multimodality treatment is needed,including surgical resection,targeted therapy by biological agents according to molecular testing gene mapping,chemotherapy,radiation therapy,and immunotherapy.It is of great importance to understand the updated guidelines and current treatment options.The extent of surgical intervention depends on the disease stage,ranging from simple cholecystectomy(T1a)to extended resections and including extended cholecystectomy(T1b),with wide lymph node resection in every case or IV-V segmentectomy(T2),hepatic trisegmentectomy or major hepatectomy accompanied by hepaticojejunostomy Roux-Y,and adjacent organ resection if necessary(T3).Laparoscopic or robotic surgery shows fewer postoperative complications and equivalent oncological outcomes when compared to open surgery,but much attention must be paid to avoiding injuries.In addition to surgery,novel targeted treatment along with immunotherapy and recent improvements in radiotherapy and chemotherapy(neoadjuvant-adjuvant capecitabine,cisplatin,gemcitabine)have yielded promising results even in inoperable cases calling for palliation(T4).Thus,individualized treatment must be applied.

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.

Glucagon-like peptide 1 receptor agonist:A potential game changer for cholangiocarcinoma

Glucagon-like peptide-1 receptor(GLP-1R)agonist,a subgroup of incretin-based anti-diabetic therapies,is an emerging medication with benefits in reducing blood glucose and weight and increasing cardiovascular protection.Contrarily,concerns have been raised about GLP-1R agonists increasing the risk of particular cancers.Recently,several epidemiological studies reported contradictory findings of incretin-based therapy on the risk modification for cholangiocarcinoma(CCA).The first cohort study demonstrated that incretin-based therapy was associated with an increased risk of CCA.Later studies,however,showed a null effect of incretinbased therapy on CCA risk for dipeptidyl peptidase-4 inhibitor nor GLP-1R agonist.Mechanistically,glucagon-like peptide 1 receptor is multifunctional,including promoting cell growth.High GLP-1R expressions were associated with progressive phenotypes of CCA cells in vitro.Unexpectedly,the GLP-1R agonist showed anti-tumor effects on CCA cells in vitro and in vivo with unclear mechanisms.Our recent report also showed that GLP-1R agonists suppressed the expression of GLP-1R in CCA cells in vitro and in vivo,leading to the inhibition of CCA tumor growth.This editorial reviews recent evidence,discusses the potential effects of GLP-1R agonists in CCA patients,and proposes underlying mechanisms that would benefit from further basic and clinical investigation.

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.

Current considerations on intraductal papillary neoplasms of the bile duct and pancreatic duct

Pancreatobiliary intraductal papillary neoplasms(IPNs)represent precursors of pancreatic cancer or bile duct cholangiocarcinoma that can be detected and treated.Despite advances in diagnostic methods,identifying these premalignant lesions is still challenging for treatment providers.Modern imaging,biomarkers and molecular tests for genomic alterations can be used for diagnosis and follow-up.Surgical intervention in combination with new chemotherapeutic agents is considered the optimal treatment for malignant cases.The balance between the risk of malignancy and any risk of resection guides management policy;therefore,treatment should be individualized based on a meticulous preoperative assessment of high-risk stigmata.IPN of the bile duct is more aggressive;thus,early diagnosis and surgery are crucial.The conservative management of low-risk pancreatic branch-duct lesions is safe and effective.

Establishing prognostic models for intrahepatic cholangiocarcinoma based on immune cells

BACKGROUND Intrahepatic cholangiocarcinoma(ICC)is a malignant liver tumor that is challenging to treat and manage and current prognostic models for the disease are inefficient or ineffective.Tumor-associated immune cells are critical for tumor development and progression.The main goal of this study was to establish models based on tumor-associated immune cells for predicting the overall survival of patients undergoing surgery for ICC.AIM To establish 1-year and 3-year prognostic models for ICC after surgical resection.METHODS Immunohistochemical staining was performed for CD4,CD8,CD20,pan-cytokeratin(CK),and CD68 in tumors and paired adjacent tissues from 141 patients with ICC who underwent curative surgery.Selection of variables was based on regression diagnostic procedures and goodness-of-fit tests(PH assumption).Clinical parameters and pathological diagnoses,combined with the distribution of immune cells in tumors and paired adjacent tissues,were utilized to establish 1-and 3-year prognostic models.RESULTS This is an important application of immune cells in the tumor microenvironment.CD4,CD8,CD20,and CK were included in the establishment of our prognostic model by stepwise selection,whereas CD68 was not significantly associated with the prognosis of ICC.By integrating clinical data associated with ICC,distinct prognostic models were derived for 1-and 3-year survival outcomes using variable selection.The 1-year prediction model yielded a C-index of 0.7695%confidence interval(95%CI):0.65-0.87 and the 3-year prediction model produced a C-index of 0.69(95%CI:0.65-0.73).Internal validation yielded a C-index of 0.761(95%CI:0.669-0.853)for the 1-year model and 0.693(95%CI:0.642-0.744)for the 3-year model.CONCLUSION We developed Cox regression models for 1-year and 3-year survival predictions of patients with ICC who underwent resection,which has positive implications for establishing a more comprehensive prognostic model for ICC based on tumor immune microenvironment and immune cell changes in the future.

Conversion therapy in advanced perihilar cholangiocarcinoma based on patient-derived organoids:A case report

BACKGROUND Patient-derived organoids(PDOs)have been demonstrated to predict the response to drugs in multiple cancer types.However,it remains unclear about its application in cholangiocarcinoma.CASE SUMMARY A 59-year-old woman was admitted to the hospital due to upper abdominal pain for over 8 months.According to relevant examinations,she was diagnosed as perihilar cholangiocarcinoma(pCCA)with intrahepatic metastasis and perihilar lymphatic metastasis.After multidisciplinary team discussion,percutaneous transhepatic cholangiodrainage was performed to relieve biliary obstruction,and puncture biopsy was conducted to confirm the pathological diagnosis.Transarterial chemoembolization with nab-paclitaxel was used in combination with toripalimab and lenvatinib,but the levels of tumor markers including alpha fetal protein,carcinoembryonic antigen,carbohydrate antigen 15-3 and cancer antigen 125 were still raised.The PDO for drug screening showed sensitive to gemcitabine and cisplatin.Accordingly,the chemotherapy regimen was adjusted to gemcitabine and cisplatin in combination with toripalimab and lenvatinib.After 4 cycles of treatment,the tumor was assessed resectable,and radical surgical resection was performed successfully.One year after surgery,the patient was still alive,and no recurrence or occurred.CONCLUSION PDOs for drug sensitivity contribute to screening effective chemotherapy drugs for advanced pCCA,promoting conversion therapy and improving the prognosis.

Elevated ETV4 expression in cholangiocarcinoma is linked to poor prognosis and may guide targeted therapies

Cholangiocarcinoma(CCA),a highly aggressive bile duct cancer,is associated with late-stage diagnosis and limited treatment options,leading to poor patient outcomes.Early detection and personalized treatment strategies are crucial.The study by Wang et al highlights the prognostic potential of the PEA3 subfamily genes(ETV1,ETV4,and ETV5)in CCA,identifying ETV4 as a particularly promising biomarker.Their bioinformatic analysis revealed that elevated ETV4 expression correlates with poorer survival,positioning it as a strong indicator of disease progression.These findings suggest that ETV4 could enhance prognostic precision and guide personalized therapies,although further validation through large-scale clinical trials is essential.Challenges in clinical application include the need for comprehensive experimental validation and addressing the tumor heterogeneity in CCA.Future research should focus on validating these biomarkers in diverse cohorts and developing targeted therapies,especially in regions where CCA is endemic.

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.