Currently, the incidence of digestive system tumors has been increasing annually, thus becoming a prevalent cause of cancer‑related mortalities. Although significant strides have been made in targeting the molecular mechanisms that underpin the development of these tumors, their treatment and prognosis still pose substantial challenges. This is primarily due to the ambiguity of early diagnostic indicators and the fact that most digestive system tumors are detected at an advanced stage. However, epigenetic modifications are capable of altering the expression of oncogenes and regulating biological processes in cancer. In recent years, the study of methylation in relation to tumor pathogenesis has become a focus of prominent research. Among the various types of methylation, 5‑methylcytosine (m5C) methylation plays a crucial role in the development of digestive system tumors and is anticipated to serve as a novel therapeutic target. However, to date, a comprehensive and systematic review concerning the role of m5C methylation in digestive system tumors is lacking. Consequently, the present study reviewed the role of m5C methylation in digestive system tumors such as esophageal cancer, gastric cancer and hepatocellular carcinoma, with the aim of providing a valuable reference for future research endeavors.

The bile duct transports bile fluid from the liver to the gallbladder and small intestine. It contains bioactive peptides, including galanin (GAL) and its receptors (GAL1-3-R). Spexin (SPX), a member of the GAL peptide family, activates GAL2-R and GAL3-R. Its expression in perihilar bile ducts or in perihilar cholangiocarcinoma (pCCA), the most common biliary cancer, is largely unknown. This study investigated SPX expression in healthy, cholestatic, and malignant bile duct tissues. Immunohistochemistry was used to evaluate SPX in healthy (n = 4), peritumoral (PIT) (n = 23) and pCCA (n = 34) tissues. Score values of SPX expression were calculated and statistically analyzed. In healthy and PIT tissues with or without cholestasis, SPX expression was predominantly observed in cholangiocytes and nerve fibers. In pCCA, tumor cells also expressed SPX. SPX levels were similar across healthy, peritumoral, and cholangiocytes/tumor cells. In a small pCCA patient cohort (n = 19), SPX expression did not correlate with tumor grade or patient survival (p = 0.0838). The substantial expression of SPX in cholangiocytes and nerve fibers in the bile duct indicates that SPX contributes via galaninergic signaling to gall bladder function. The presence of SPX in submucosal nerve fibers suggests a neuromodulatory role, possibly involving bile duct motility. SPX expression did not correlate with survival in pCCA, whereas previous findings on GAL suggest a prognostic value. This highlights the need for joint studies of SPX and GAL in larger cohorts.

Cholangiocarcinoma (CCA) is a rare but devastating liver cancer which is commonly diagnosed at a late stage and often resistant to chemotherapy. Bcl-2 family members, which control apoptotic cell death, are known to be involved in the chemoresistance of some cancer types. This study investigated the role of Bcl-2 family members in the chemoresistance of cholangiocarcinoma organoids (CCAOs) in both undifferentiated and matured branching phenotypes (BRCCAOs). Patient-derived CCAOs and BRCCAOs were cultured to assess chemoresistance to an FDA-approved anticancer drug panel by testing cell viability using ATP quantification and apoptotic cell death by cleaved caspase 3 staining. More specifically, sensitivity to the first-line drug gemcitabine was tested in combination with Bcl-2 family inhibitors or activators. We found that in gemcitabine-resistant CCAOs, inhibition of Bcl-xl could overcome gemcitabine resistance and induce apoptotic cell death. Although inhibition of Mcl-1 or activation of Bax induced spontaneous cell death, this could not overcome gemcitabine resistance. The BRCCAOs, which mimic tumor architecture better than CCAOs, show broader chemoresistance to anticancer drugs. Of note, in the resistant BRCCAOs, Bcl-xl inhibition could restore gemcitabine sensitivity. In conclusion, this study shows that targeting Bcl-xl can overcome chemoresistance to gemcitabine in CCA organoids. CCAOs and BRCCAOs provide good preclinical models for testing new drug combinations and assessing personalized therapeutic approaches.

Cholangiocarcinoma (CC) remains one of the most challenging biliary tract malignancies, with limited therapeutic options and poor survival rates. We report the discovery and mechanistic investigation of usnic acid (UA) enantiomers as novel anti-CC agents. We identified the lichen Cladonia foliacea as a potential source of anticancer agents and developed a sustainable protocol to isolate (S)-UA as the most abundant metabolite. Our comprehensive comparative study of both enantiomers revealed time-dependent enantio-preference in their anti-cancer activity. While (S)-UA demonstrated twice the potency at 24 h, (R)-UA exhibited nearly ten-fold greater activity at 48 h and 72 h, particularly at lower concentrations (2.9 and 29 mM). Overall, both enantiomers inhibited EGI-1 cell proliferation in the micromolar range in a dose- and time-dependent manner. In silico studies and kinase profiling identified MNK2 as a primary target, with subsequent validation confirming direct binding and inhibition. Mechanistic studies demonstrated that UA enantiomers modulate the MAPK pathway, leading to decreased phosphorylation of eIF4E and suppression of cancer-promoting proteins. The successful translation of activity from 2D cell cultures to patient-derived 3D organoid models further validates their therapeutic potential. Our findings establish usnic acid as a promising natural product scaffold for CC treatment and provide detailed insights into its mechanism of action through MNK2 targeting and MAPK pathway modulation, with important considerations for enantiomer-specific temporal efficacy.

Numerous studies have reported the association between preoperative albumin-bilirubin (ALBI) grade and survival outcomes in patients with cholangiocarcinoma (CCA). However, the results are inconsistent. Therefore, we conducted a meta-analysis to comprehensively evaluate the relationship between ALBI grade and prognosis of CCA patients.

We retrieved the databases (Pubmed,Embase and Web of science) to search articles about the association of ALBI grade with prognostic value in CCA patients. Hazard ratios (HR) and 95% confidence intervals (CI) were used to summarize survival outcomes. STATA 12.0 was used to implement the data analyses.

11 studies from 10 articles comprising 2841 patients were included in the meta-analysis. The pooled results showed that high ALBI grade was significantly associated with poor overall survival (OS) (HR: 1.75, 95% CI: 1.32-2.31) and relapse-free survival(RFS)(HR:1.95;95%CI:1.37-2.13). Subgroup analysis further showed that high ALBI grade had better predictive value for Asian population(HR:1.92;95%CI:1.46-2.51). Sensitivity analysis indicated that the results of the meta-analysis were stable.

High ALBI grade predicted adverse survival outcomes in CCA patients. ALBI grade may be an efficient and convenient prognostic indicator in CCA patients for Asian population.

Extrachromosomal circular DNAs (eccDNAs) have gained attention as key players in cancer heterogeneity, potentially associated with elevated oncogene copy numbers in many cancers. While the presence of eccDNA in both normal and cancer cells is confirmed, its influence on gene-level alterations in cancer cells remains largely unexplored. This study delves into the genomic profiles of eccDNA in cholangiocarcinoma (CCA), an aggressive biliary tract cancer with extensive heterogeneity and diverse molecular alterations, using a modified long-read CircleSeq method. We reveal distinct eccDNA characteristics in CCA compared to non-tumor cells, focusing on genic components and chromosomal origins. Analysing read depth differences in oncogene-containing eccDNA; we identified potential eccDNA candidates that may be relevant for CCA biology. Subsequent bioinformatics analysis was performed using the established CReSIL tool, revealing distinct patterns of these oncogenes, particularly genes in the RAS/BRAF pathway, suggesting a potential functional role. These findings highlight the remarkable heterogeneity and diverse origins of eccDNA in CCA. This study establishes the first profiling of eccDNA in cholangiocarcinoma and paves the way for further investigation of its potential contribution to oncogene amplification and disease progression.

Despite the growing interest in liver transplantation for cholangiocarcinomas (CCA), conclusive evidence is lacking. We sought to evaluate the outcomes of liver transplantation for intrahepatic cholangiocarcinoma in Brazil.

Retrospective database analysis of patients undergoing liver transplantation for hepatocellular carcinoma (HCC) within Milan criteria in São Paulo, Brazil. Anatomopathological examination of the explanted liver with the presence of intrahepatic cholangiocarcinoma (iCCA) or combined hepatocellular-cholangiocarcinoma (cHCC-CCA) comprised the study group (50 patients). They were compared to a 1:3 HCC-matched cohort.

Study group had lower survival rates than HCC controls (survival at 1, 3, and 5 years, 70.0 %, 57.5 %, and 57.5 % versus 78.7 %, 71.4 %, and 66.6 %, p = 0.019). 5-year survival rates of the control group, cHCC-CCA, and iCCA group were 66.6 %, 59.6 %, and 50.0 % (p = 0.017). There was no statistically significant difference in survival for study group patients with tumors up to 3 cm compared to their controls (p = 0.086).

Patients with CCA had worse outcomes after liver transplantation than those with HCC. Interesting results were found in the more individualized analyses, but because of the limited number of patients, caution should be taken when analyzing them.

Surgery is the only curative therapeutic option for resectable extrahepatic cholangiocarcinoma, but recurrence is common, and prognosis is poor. There is an unmet clinical need for improved decision-making regarding adjuvant chemotherapy (ACT). Herein, we evaluated the usefulness of monitoring longitudinal circulating tumor DNA (ctDNA) for molecular residual disease (MRD) in patients from the STAMP trial, which compared the efficacy of adjuvant capecitabine (CAP) vs. gemcitabine plus cisplatin (GemCis).

Between July 2017 and November 2020, 101 patients were randomized 1:1 to receive GemCis (n = 50) or CAP (n = 51). Efficacy outcomes were analyzed with an extended follow-up of 19 months from the previous report. From a biomarker cohort of 89 patients, longitudinal plasma samples (n = 254) were prospectively collected post-surgery before ACT, and on-ACT at 12 and 24 weeks from cycle 1 day 1 (C1D1). ctDNA was evaluated using a personalized, tumor-informed, 16-plex PCR next-generation sequencing assay and was correlated with clinical outcomes.

In the extended follow-up analysis, median disease-free survival (DFS) and overall survival did not significantly differ between the CAP and GemCis groups. Significantly inferior DFS was associated with ctDNA positivity before ACT (hazard ratio [HR] 1.8; p = 0.029), on-ACT at 12 weeks from C1D1 (HR 7.72; p <0.001), on-ACT at 24 weeks from C1D1 (HR 5.24; p <0.001), and anytime post-surgery (HR 3.81; p <0.001). Analysis of pre-treatment to on-treatment ctDNA dynamics revealed that serially ctDNA-negative patients exhibited a significantly longer DFS compared to those with sustained ctDNA positivity (HR 6.7; p <0.001) or those who turned ctDNA positive (HR 5.8; p <0.001).

In patients with resected extrahepatic cholangiocarcinoma, ctDNA status and dynamics predicted recurrence during adjuvant therapy, and may help optimize clinical decision-making.

The findings from this study highlight the critical role of ctDNA as a prognostic biomarker and monitoring tool for patients with resected extrahepatic cholangiocarcinoma. By demonstrating the superiority of ctDNA to predict disease recurrence compared to conventional biomarkers such as cancer antigen 19-9 and carcinoembryonic antigen, this study underscores its potential in guiding decision-making during adjuvant chemotherapy. These results may be crucial to refine post-surgical treatment strategies and improve patient outcomes. The practical application of ctDNA monitoring could lead to more personalized treatment approaches, enabling timely interventions based on molecular residual disease status.

NCT03079427.

The aim of the study is to investigate the ability of preoperative CT (Computed Tomography)-based radiomics signature to predict microvascular invasion (MVI) of intrahepatic mass-forming cholangiocarcinoma (IMCC) and develop radiomics-based prediction models.

Preoperative clinical data, basic CT features, and radiomics features of 121 IMCC patients (44 with MVI and 77 without MVI) were retrospectively reviewed. The loading and display of CT images, delineation of the volume of interest, and feature extraction were performed using 3D Slicer. Radiomics features were selected by the LASSO logistic regression model. Multivariate logistic regression analysis was used to establish the radiomics model, radiologic model, and combined model in the training set (n = 85) to predict the MVI of IMCC, and then verified in the validation set (n = 36).

Among the 3948 radiomics features extracted from multiphase dynamic enhanced CT imaging, 16 most stable features were selected. The AUC of the radiomics model for predicting MVI in the training set and validation set were 0.935 and 0.749, respectively. The AUC of the radiologic model for predicting MVI in the training set and validation set were 0.827 and 0.796, respectively. When radiomics and radiologic models are combined, the predictive performance of the combined model (constructed with shape, intratumoral vessels, portal venous phase tumor-liver CT ratio, and radscore) is optimal, with an AUC of 0.958 in the training set and 0.829 in the test set for predicting MVI.

CT radiomics signature is a powerful predictor for predicting MVI. The preoperative combined model (constructed with shape, intratumoral vessels, portal venous phase tumor-liver CT ratio, and radscore) performed well in predicting the MVI.

Extracellular vesicles (EVs) are nanoscale structures involved in intercellular communication and play a key role in cancer pathology. Intrahepatic cholangiocarcinoma (ICC) is a highly invasive malignancy marked by abnormal sialylated glycosylation. Analyzing proteins and glycans in EVs provides insights into ICC molecular subtyping and mechanisms. Optimizing EV isolation methods for ICC-derived EVs enables comprehensive proteomic and glycomic analysis.

We systematically evaluated five EV isolation methods-Ultracentrifugation (UC), exoEasy, Total Exosome Isolation (TEI), EVtrap, and ÄKTA-by analyzing the biophysical properties, proteomic profiles, and glycomic structures of EVs. Subsequently, we applied TMT-based quantitative proteome and light/heavy methylamine labeling for the quantification of sialylated N-glycan linkage isomers to investigate alterations in proteins and N-glycans within EVs secreted by HuCCT1 and HCCC-9810 cells with overexpressing ST6 β‑galactoside α2,6‑sialyltransferase 1 (ST6GAL1).

By evaluating the biophysical properties, proteome, and N-glycome of EVs extracted using five different methods, UC was identified as the optimal approach for this study, as it offered a balance between operational complexity, cost-effectiveness, and the preservation of EVs activity. In this study, a total of 1,928 high-confidence proteins and over 84 high-confidence glycans were quantified. EVs secreted by HuCCT1 and HCCC-9810 cells overexpressing ST6GAL1 exhibited consistent upregulation of 16 proteins, consistent downregulation of 10 proteins, as well as consistent upregulation of 3 glycans and consistent downregulation of 3 glycans.

Quantitative proteomic and glycomic analysis of ICC-derived EVs revealed that ST6GAL1 overexpression led to significant alterations in proteins involved in cancer cell adhesion and glycosylation pathways, along with specific changes in N-glycan structures. Notably, these modifications extended beyond α2,6-sialylation, suggesting that interactions between glycosyltransferases and glycans may drive these alterations.

Background/Objectives: Primary sclerosing cholangitis (PSC) is a rare, incurable liver disease characterized by chronic biliary inflammation and fibrosis. PSC is a significant risk factor for biliary tract cancer (BTC). This study aims to evaluate STAT3 expression in BTC and its prognostic significance as well as explore the potential of organoids derived from PSC and liver tumor patients as an in vitro model for testing novel therapeutic strategies in both PSC and BTC. Methods: Fresh tissue samples obtained from 10 PSC patients through targeted endoscopic retrograde cholangiography (ERC) and biopsy samples from liver tumor patients were used to establish organoid cultures. Organoids were treated with different agents and the therapeutic effect was measured by CellTiterGlo. Treatment with the JAK inhibitor baricitinib was followed by the measurement of cytokine concentrations in the supernatant. Archived formalin-fixed paraffin-embedded (FFPE) samples from 55 surgically resected BTC tumors were analyzed for STAT3 expression using immunohistochemistry. Results: We successfully established organoid cultures from all ERC samples. STAT3 protein expression was detected in 56% of tumor samples and 69% of the immune microenvironment. STAT3 positivity in the immune cell compartment was associated with longer disease-free survival, although the multivariate analysis could not confirm its value as an independent prognostic factor. Chemotherapy testing on liver tumor organoids showed various degrees of decreases in viability after treatment with gemcitabine, cisplatin, and cabozantinib. Baricitinib treatment significantly reduced IL-6 and MCP-1 secretion in cholangiocarcinoma Conclusions: The patient-derived organoid model of PSC and liver tumors is a valuable tool for testing novel and established therapeutic strategies, including JAK inhibitors and chemotherapy regimens. STAT3 expression in the immune microenvironment of BTC may serve as a prognostic marker. Further studies are needed to explore the integration of co-cultured organoid systems with stromal and immune components to improve physiological relevance.

Stenting malignant hilar biliary obstruction (MHBO) is challenging due to its complex structure, and it is less effective than blockages in the distal bile duct area. Plastic stents (PSs) and metal stents (MSs) are commonly used for stenting MHBO. This study aims to compare the outcomes of PSs and MSs in MHBO patients.

We conducted a search of medical databases up to March 2024. Using a fixed-effect model, we analyzed the risk ratios (RRs) of the outcomes between the PS and MS groups. We calculated the RR for clinical and technical success, reinterventions, and adverse events, as well as the hazard ratio (HR) for survival and stent patency.

This analysis includes five randomized controlled trials (RCTs) that met the inclusion criteria, comprising a total of 322 patients (156 in the PS group and 166 in the MS group). Significant differences (P < .05) in favor of the MS group were found in the reinterventions (RR 1.80, 95% CI 1.07-3.04), and stent patency (HR 0.54, 95% CI 0.32-0.90). There were no significant differences (P > 0.05) between the PS and MS groups regarding technical success (RR 1.01, 95% CI 0.94-1.09), clinical success (RR 0.86, 95% CI 0.69-1.07), overall survival (HR 0.71, 95% CI 0.47-1.05), stent migration (RR 0.69, 95% CI 0.08-6.02), stent occlusion (RR1.32, 95% CI 0.97-1.81), and adverse events (RR 0.80, 95% CI 0.53-1.20).

Both PS and MS are effective for managing MHBO, while MS offers greater efficacy in increased stent patency and lower reintervention rates. Key message What is already known on this topic Metal stents (MSs) and plastic stents (PSs) are used for palliative treatment of malignant hilar biliary obstruction (MHBO). MSs significantly reduced the need for reinterventions compared to PSs in patients with MHBO. What this study adds There were no significant differences between MSs and PSs in terms of technical success, clinical success, overall survival, stent migration, stent occlusion, or adverse events. How this study might affect research, practice, or policy The study's findings may prompt researchers to design more targeted studies to further investigate these specific outcomes in MHBO patients. The results encourage endoscopists to consider patient-specific factors, such as life expectancy and preference for minimizing recurrent procedures, when choosing between MSs and PSs for MHBO.

The prevalence of intrahepatic cholangiocarcinoma (ICC) is increasing globally. Despite advancements in comprehending this intricate malignancy and formulating novel therapeutic approaches over the past few decades, the prognosis for ICC remains poor. Owing to the high degree of malignancy and insidious onset of ICC, numerous cases are detected at intermediate or advanced stages of the disease, hence eliminating the chance for surgical intervention. Moreover, because of the highly invasive characteristics of ICC, recurrence and metastasis postresection are prevalent, leading to a 5-year survival rate of only 20%-35% following surgery. In the past decade, different methods of treatment have been investigated, including transarterial chemoembolization, transarterial radioembolization, radiotherapy, systemic therapy, and combination therapies. For certain patients with advanced ICC, conversion treatment may be utilized to facilitate surgical resection and manage disease progression. This review summarizes the definition of downstaging conversion treatment and presents the clinical experience and evidence concerning conversion treatment for advanced ICC.

Cholangiocarcinoma (CCA) is a highly aggressive malignancy, and early diagnosis remains challenging. Metabolic biomarkers are increasingly recognized as promising tools for the early detection of cancer. However, a comprehensive exploration of metabolic alterations in CCA, especially from a global metabolic perspective, has yet to be fully realized. To identify reliable metabolic markers for the early diagnosis of CCA and to explore its potential pathogenesis through an in-depth analysis of global metabolism.

Serum samples from 30 CCA patients and 31 healthy individuals were analyzed using an unbiased UPLC-Q-TOF-MS based metabolomics approach. Principal component analysis (PCA) and orthogonal projections to latent structures discriminant analysis (OPLS-DA) were applied to identify potential biomarkers. High-resolution MS/MS and available standards were used to further confirm the identified metabolites. A systematic metabolic pathway analysis was conducted to interpret the biological roles of these biomarkers and explore their relevance to CCA progression.

A total of 25 marker metabolites were identified, including lysophosphatidylcholines (LysoPCs), phosphatidylcholines (PCs), organic acids, sphinganine, and ketoleucine. These metabolites effectively distinguished CCA patients from healthy controls, with an AUC of 0.995 for increased biomarkers and 0.992 for decreased biomarkers in positive mode. In negative mode, the AUC for increased and decreased biomarkers was 0.899 and 0.976, respectively. The metabolic pathway analysis revealed critical biological functions linked to these biomarkers, offering insights into the molecular mechanisms underlying CCA initiation and progression.

This study identifies novel metabolic biomarkers for the early diagnosis of CCA and provides a deeper understanding of the metabolic alterations associated with the disease. These findings could contribute to the development of diagnostic strategies and therapeutic interventions for CCA.

Cholangiocarcinoma (CCA) is a significant health concern in Thailand, as the age-standardized rates (ASR) and other trends fluctuate across different regions. However, comprehensive national estimates are lacking. This study examined the Thai ASR of CCA trends from 2012 to 2021 and projected the incidence rates to 2026.

This retrospective cohort analysis examined 6379 CCA cases from population-based cancer registries (PBCRs) in the northern, central, northeastern, and southern regions for the time period January 1, 2012, to December 31, 2021. The Joinpoint, age-period-cohort, and Nordpred models were used to assess CCA incidence trends and predictions.

CCA incidence trends in Thailand showed a decrease, with an average annual percentage change (AAPC) of -7.20% (95% CI: -11.04 to -3.19) for males, and -5.81% (95% CI: -10.81 to -0.54) for females. The projected incidence rate per 100,000 person-years for 2026 varied slightly according to the model: Joinpoint (males: 6.1, females: 3.4), age-period-cohort (males: 6.0, females: 3.3), and Nordpred (males: 5.5, females: 3.4). Regional analyses revealed decreasing trends in the northern and northeastern regions, with 2026 projections indicating further declines exceeding the 10-year trends. Owing to the small sample size, trends in the central and southern regions could not be determined.

Thailand's CCA rate has generally decreased but varies geographically; the northern and northeastern regions remain at high risk. To minimize CCA nationally, initiatives should be maintained, new risk factors explored, diagnostics improved, and regional variances addressed.

The Graduate School of Khon Kaen University.

Claudins are key components of tight junctions, essential for maintaining cellular adhesion, regulating intercellular molecule transport, and preserving cell polarity. Altered claudin expression can lead to tight junction dysfunction, potentially disrupting signaling pathways and contributing to the development of epithelial cancers. This study aims to explore the understudied role of CLDN18.2 in intrahepatic cholangiocarcinoma and its relationship with clinical outcomes. We analyzed tissue samples from 182 patients who underwent curative surgery for intrahepatic cholangiocarcinoma. Our research examined the relationship between CLDN18.2 expression and various clinical factors, including patient characteristics, pathological findings, and survival metrics such as overall survival (OS), disease-free survival (DFS), metastasis-free survival (MeFS), and local recurrence-free survival (LRFS). Overexpression of CLDN18.2 showed significant associations with R1 resection (p = 0.032) and advanced T stage (p = 0.043). Univariate analysis revealed that high CLDN18.2 expression was correlated with poorer OS (p = 0.0002), DFS (p < 0.0001), LRFS (p < 0.0001), and MeFS (p < 0.0001). Multivariate analysis further confirmed that high CLDN18.2 expression was independently associated with worse OS (p = 0.015), DFS (p < 0.001), LRFS (p < 0.001), and MeFS (p < 0.001). Overexpression of CLDN18.2 was associated with unfavorable clinical prognosis and adverse pathological features in intrahepatic cholangiocarcinoma. These findings suggest that CLDN18.2 could serve as a potential prognostic biomarker for intrahepatic cholangiocarcinoma.

CCA is a highly desmoplastic malignant cancer and is the second most common primary liver malignancy after hepatocellular carcinoma (HCC), accounting for approximately 15% of all primary liver tumors. CCA has a poor prognosis, with an average five-year survival rate of 9%, which is lower than that of pancreatic cancer. Although considerable efforts have been invested into the genomics, epigenetics, and risk factors, very little is known about what might have been the key causes for the high malignancy level of CCA. In this review, we analyze the incidence and mortality of CCA in different regions based on data from 1994 to 2022 obtained from the International Agency for Research on Cancer (IARC), discuss the current status of treatment of the disease, and focus on what might be the main factors contributing to the high malignancy level of CCA: alkalosis caused by the Fenton reaction, hypoxia, and the TIME. The review includes studies published from 1979 to 2024, aiming to provide an updated synthesis of basic early classical theoretical knowledge and current knowledge about CCA. By revealing the epidemiological characteristics of CCA, the potential mechanisms of high malignancy, and the current challenges of treatment, this review aims to provide new directions for future cancer research, promote the development of personalized treatment strategies, and facilitate a deeper understanding and the more effective management of CCA worldwide.

Cholangiocarcinoma (CCA) is a highly lethal hepatobiliary malignancy, with prognosis is influenced by anatomical subtypes and etiological factors. This study successfully established three CCA cell lines: KKU-097, KKU-466, and KKU-610, from the primary tumors of patients in liver fluke-endemic areas. These cells represent the perihilar CCA (pCCA) and intrahepatic CCA (iCCA) subtypes. Comprehensive analyses, including histopathology, molecular profiling, biomarkers, cancer phenotype characterization, and drug sensitivity testing with standard chemotherapeutics, were conducted. Whole-exome sequencing was performed to explore genetic alterations. All three cell lines exhibited adherent growth with an epithelial morphology and positive expression of the bile duct epithelial markers CK-7 and CK-19. Cytogenetic analysis revealed highly complex hypertriploid karyotypes with multiple chromosomal aberrations. Among the cell lines, KKU-610 demonstrated higher growth and invasion rates, whereas KKU-466 and KKU-097 cells exhibited less aggressive phenotypes. Drug sensitivity testing demonstrated relative resistance to gemcitabine as a monotherapy and in combination with cisplatin in all three cells. Genomic profiling identified targetable mutations, highlighting these new cell lines as valuable models for investigating the pathogenesis of CCA and evaluating therapeutic strategies.

Choledocholithiasis has been reported to be associated with the occurrence of cholangiocarcinoma (CCA); however, the association has not yet been sufficiently demonstrated. This study aimed to evaluate the association between choledocholithiasis (common bile duct stones) and CCA.

This nationwide retrospective cohort study used the Health Insurance Review and Assessment database of individuals diagnosed with choledocholithiasis between 2008 and 2009 in South Korea. Individuals were stratified by age, and CCA was categorized into extrahepatic CCA (ECA) and intrahepatic CCA (ICA). The standardized incidence ratio (SIR) was calculated to compare CCA incidence between patients with choledocholithiasis and the general population.

The study enrolled 20,808 patients with choledocholithiasis (52.35% men and 47.65% women; male-to-female ratio: 1.09:1). Over a 10-year follow-up period, CCA occurred in 548 (2.64%) patients, comprising 238 (1.14%) ECA cases and 310 (1.48%) ICA cases. The SIR was 25.23 (95% confidence interval [CI]: 21.98-28.85) for ECA and 24.64 (95% CI: 21.87-27.73) for ICA. Statistical significance persisted even after excluding cases within the first 2 years from the index date, with an SIR of 18.63 (95% CI: 16.23-21.28) for ICA and 12.73 (95% CI: 10.50-15.30) for ECA. The SIRs peaked in patients diagnosed with choledocholithiasis at the age of 70-79 years (SIR 16.61, 95% CI: 11.83-22.69) for ECA and 60-69 years (SIR 29.27, 95% CI: 23.53-36.03) for ICA.

Our study demonstrated a significant association between choledocholithiasis and cholangiocarcinoma, particularly those in their 70s for ECA and 60s for ICA. However, causation cannot be established due to the retrospective design.

Resection outcomes for perihilar cholangiocarcinoma differ between Western and Eastern centres, but reasons behind these disparities remain unclear. This study aimed to compare current outcomes between a Western and an Eastern expert centre to identify prognostic factors.

Patients who underwent hepatobiliary resection for perihilar cholangiocarcinoma between 2010 and 2022 at Karolinska University Hospital (Stockholm, Sweden) and Cancer Institute Hospital (Tokyo, Japan) were retrospectively included. Primary outcome was overall survival. Secondary outcomes were disease-free survival, postoperative complications and 90-day mortality rate.

Two hundred and forty-nine patients were included (Cancer Institute Hospital n = 159, Karolinska n = 90). Median overall survival was 20.4 months at Karolinska and 52.0 months at Cancer Institute Hospital (P < 0.001). Median disease-free survival was 11.9 months at Karolinska and 32.4 months at Cancer Institute Hospital (P < 0.001). Advanced tumours, ASA class ≥III, poor differentiation and radial margin positivity were more common in the Western cohort. Treatment centre, T-status, N1-status, resection side, R1-status, age and carbohydrate antigen 19-9 were prognostic for overall survival. The Eastern cohort had a lower rate of postoperative complications (24.5%) and a lower mortality rate (2.5%) compared with the Western cohort (51.1% and 10.0%).

Advanced tumour stage and radial margin positivity contributed to poor long-term survival in the Western cohort. A higher burden of co-morbidity and a higher rate of extended resections with smaller remnant liver volume influenced the Western postoperative mortality rate.

Cholestasis, characterized by impaired bile flow, is associated with an increased risk of cholangiocarcinoma (CCA), a malignancy originating from the biliary epithelium and hepatocytes. Hepatic nuclear receptors (NRs) are pivotal in regulating bile acid and metabolic homeostasis, and their dysregulation is implicated in cholestatic liver diseases and the progression of liver cancer. This review elucidates the role of various hepatic NRs in the pathogenesis of cholestasis-to-CCA progression. It explores their impact on bile acid metabolism as well as their interactions with other signaling pathways implicated in CCA development. Additionally, it introduces available murine models of cholestasis/primary sclerosing cholangitis leading to CCA and discusses the clinical potential of targeting hepatic NRs as a promising approach for the prevention and treatment of cholestatic liver diseases and CCA. Understanding the complex interplay between hepatic NRs and cholestasis-to-CCA pathology holds promise for the development of novel preventive and therapeutic strategies for this devastating disease.

Cholangiocarcinomas are a highly heterogeneous group of malignancies that, despite recent progress in the understanding of their molecular pathogenesis and clinical management, continue to pose a major challenge to public health. The traditional view posits that cholangiocarcinomas derive from the neoplastic transformation of cholangiocytes lining the biliary tree. However, increasing genetic and experimental evidence has recently pointed to a more complex, and nuanced, scenario for the potential cell of origin of cholangiocarcinomas. Hepatocytes as well as hepatic stem/progenitor cells are being considered as additional potential sources, depending on microenvironmental contexts, including liver injury. The hypothesis of potentially diverse cells of origin for cholangiocarcinoma, albeit controversial, is certainly not surprising given the plasticity of the cells populating the liver as well as the existence of liver cancer subtypes with mixed histologic and molecular features. This review carefully examines the current pathologic, genomic, and experimental evidence supporting the existence of multiple cells of origin of liver and biliary tract cancers, with particular focus on cholangiocarcinoma and combined hepatocellular-cholangiocarcinoma.

Cholangiocarcinoma (CCA) is an aggressive and heterogeneous malignancy of the biliary tree that carries a poor prognosis. Multiple features at the genetic, epigenetic, and microenvironmental levels have been identified to better characterize CCA carcinogenesis. Genetic alterations, such as mutations in IDH1/2, BAP1, ARID1A, and FGFR2, play significant roles in CCA pathogenesis, with variations across different subtypes, races/ethnicities, and causes. Epigenetic dysregulation, characterized by DNA methylation and histone modifications, further contributes to the complexity of CCA, influencing gene expression and tumor behavior. Furthermore, CCA cells exchange autocrine and paracrine signals with other cancer cells and the infiltrating cell types that populate the microenvironment, including cancer-associated fibroblasts and tumor-associated macrophages, further contributing to an immunosuppressive niche that supports tumorigenesis. This review explores the multifaceted genetic, epigenetic, and microenvironmental drivers of CCA. Understanding these diverse mechanisms is essential for characterizing the complex pathways of CCA carcinogenesis and developing targeted therapies to improve patient outcomes.

Cholangiocarcinoma (CCA) is a rare but highly malignant carcinoma of bile duct epithelial cells with a poor prognosis. The major risk factors of CCA carcinogenesis and progression are cholestatic liver diseases. The key feature of primary sclerosing cholangitis and primary biliary cholangitis is chronic cholestasis. It indicates a slowdown of hepatocyte secretion of biliary lipids and metabolites into bile as well as a slowdown of enterohepatic circulation (bile acid recirculation) of bile acids with dysbiosis of the gut microbiome. This leads to enterohepatic recirculation and an increase of toxic secondary bile acids. Alterations of serum and liver bile acid compositions via the disturbed enterohepatic circulation of bile acids and the disturbance of the gut microbiome then activate a series of hepatic and cancer cell signaling pathways that promote CCA carcinogenesis and progression. This review focuses on the mechanistic roles of bile acids and the gut microbiome in the pathogenesis and progression of CCA. It also evaluates the therapeutic potential of targeting the gut microbiome and bile acid-mediated signaling pathways for the therapy and prophylaxis of CCA.

Cholangiocarcinomas (CCAs) are a heterogeneous group of malignant tumors that originate from the biliary tract. They are usually diagnosed in advanced stages, leading to a poor prognosis for affected patients. As CCA often arises as a sporadic cancer in individuals lacking specific risk factors or with heterogeneous backgrounds, and there are no defined high-risk groups, the implementation of effective surveillance programs for CCA is problematic. The identification and validation of new biomarkers useful for risk stratification, diagnosis, prognosis, and prediction of treatment response remains an unmet need for patients with CCA, even though numerous studies have been conducted lately to try to discover and validate CCA biomarkers. In this review, we overview the available information about the different types of biomarkers that have been investigated in recent years using minimally invasive biospecimens (blood, serum/plasma, bile, and urine) and their potential usefulness in diagnosis, prognosis, and risk stratification. It is widely accepted that early detection of CCA will impact patients' outcomes, by improving survival rates, quality of life, and the possibility of less invasive and/or curative treatments; however, challenges to its translation and clinical application for patients with CCA need to be resolved.

Cancer disparities are well-established across measures of cancer incidence and mortality. Cholangiocarcinoma, a common hepatic malignancy, is no exception to these inequities. Globally and within the United States, Asian, Hispanic, and Indigenous peoples of the Americas, Alaskan Natives, and Pacific Islander populations experience higher incidence rates of cholangiocarcinoma. These same groups and non-Hispanic Black individuals simultaneously experience lower disease-specific survival, highlighting the role of social factors in cholangiocarcinoma outcome inequities. Higher age-standardized death rates from cholangiocarcinoma are associated with a lower social determinant index (SDI) in Andean Latin America, Southern Latin America, and Central sub-Saharan Africa. SDI, which evaluates education, fertility, and income, can be used to model the social determinants of health (SDOH). The SDOH also affect cholangiocarcinoma survival in the United States as factors such as migratory status, insurance status, and geographic location can cause treatment delays and worsened outcomes. Despite these inequities, limited research exists on the topic of disparities in cholangiocarcinoma when compared with other malignancies, and clinical trial under-representation remains a significant concern. Representing diverse populations in cholangiocarcinoma clinical trials is exceedingly important as populations with the highest incidence are simultaneously under-represented in clinical trials. Diversity in clinical trial enrollment and research regarding cholangiocarcinoma is needed to create robust databases and biobanks that can be used to develop targeted treatments and guidelines. In addition, risk factors, including parasitic infections, infectious diseases, and environmental exposures, are associated with cholangiocarcinoma but vary by global region, highlighting the need to study unique risk factors for cholangiocarcinoma across diverse populations. Without research that represents the populations that suffer most from this cancer, incidence and mortality inequities will continue to have a disproportionate burden.

Cholangiocarcinoma (CCA) is a malignant tumor that originates from the bile duct epithelium and with a poor outcome due to lack of effective early diagnostic methods. Surgical resection is the preferred method for cure, but treatment options are limited for advanced diseases, such as distant metastatic or locally progressive tumors. Therefore, it is urgent to explore other new treatment methods. As modern living standards rise, the acceptance of high-fat, high-protein, and high-carbohydrate diets is growing among the public, and the resulting metabolic abnormalities are intimately linked to the initiation and spread of tumors. Metabolic reprogramming is a key mechanism in the process of tumor development and progression and is closely related to cancer cell proliferation, metastasis and drug resistance. Fatty acid (FA) metabolism, an integral component of cancer cell metabolism, can provide an energy source for cancer cells and participate in cell signaling, the regulation of the immune response and the maintenance of homeostasis of the internal environment, which are closely linked to the development and progression of CCA. Therefore, a better understanding of FA metabolism may provide promising strategies for early diagnosis, prognostic assessment and targeted therapy for CCA patients. In this paper, we review the effects of FA metabolism on CCA development and progression, summarize related mechanisms and the existing clinical applications of targeted lipid metabolism in CCA, and explore new targets for CCA metabolic therapy.

We conducted this observational study to investigate patterns of fibroblast growth factor receptor 2 (FGFR2) fusions or rearrangements, and how they relate to other characteristics of patients with unresectable advanced cholangiocarcinoma.

Patients aged 20 years or older with intrahepatic cholangiocarcinoma (ICC) or perihilar cholangiocarcinoma (PHC) had tumor samples assessed for FGFR2 fusions or rearrangements by a break-apart fluorescence in situ hybridization probe kit analyzed at a central laboratory; multivariate analyses using a logistic regression model were conducted to investigate the relationship between FGFR2 fusions or rearrangements and patients' baseline characteristics; two cut-off values (p-values of 0.15 and 0.05) were used.

Of the 453 patients observed, 25 (5.5%) had FGFR2 fusions or rearrangements, corresponding with 7.4% (23/306) of patients with ICC and 1.4% (2/144) of patients with PHC. Of 426 evaluable patients, FGFR2 fusions or rearrangements were associated with hepatitis C antibodies (odds ratio [OR] 6.901; p < 0.05); patients who had PHC versus ICC (OR 0.273; p < 0.05) or were men (OR 0.431; p < 0.15) were less likely to have FGFR2 fusions or rearrangements. Of 252 evaluable patients with ICC, FGFR2 fusions or rearrangements were associated with hepatitis C antibodies (OR 9.500; p < 0.05); patients who were men (OR 0.419; p < 0.05) or were aged ≥65 years (OR 0.406; p < 0.15) were less likely to have FGFR2 fusions or rearrangements.

This large observational study helps to characterize factors associated with FGFR2 fusions or rearrangements. Further study is warranted to explore differences in prevalence among different geographic populations and patients with PHC.

Primary cilia have been considered tumor-suppressing organelles in cholangiocarcinoma (CCA), though the mechanisms behind their protective role are not fully understood. This study investigates how the loss of primary cilia affects DNA damage response (DDR) and DNA repair processes in CCA. Human cholangiocyte cell lines were used to examine the colocalization of DNA repair proteins at the cilia and assess the impact of experimental deciliation on DNA repair pathways. Deciliation was induced using shRNA knockdown or CRISPR knockout of IFT20, IFT88, or KIF3A, followed by exposure to the genotoxic agents cisplatin, methyl methanesulfonate (MMS), or irradiation. Cell survival, cell cycle progression, and apoptosis rates were evaluated, and DNA damage was assessed using comet assays and γH2AX quantification. An in vivo liver-specific IFT88 knockout model was generated using Cre/Lox recombination. Results showed that RAD51 localized at the cilia base, while ATR, PARP1, CHK1 and CHK2 were found within the cilia. Deciliated cells displayed dysregulation in critical DNA repair. These cells also showed reduced survival and increased S-phase arrest after genotoxic challenges as compared to ciliated cells. Enhanced DNA damage was observed via increased γH2AX signals and comet assay results. An increase in γH2AX expression was also observed in our in vivo model, indicating elevated DNA damage. Additionally, key DDR proteins, such as ATM, p53, and p21, were downregulated in deciliated cells after irradiation. This study underscores the crucial role of primary cilia in regulating DNA repair and suggests that targeting cilia-related mechanisms could present a novel therapeutic approach for CCA. New and Noteworthy: Our findings reveal a novel connection between primary cilia and DNA repair in cholangiocytes. We showed that DDR and DNA repair proteins localize to cilia, and that deciliation leads to impaired cell survival and S-phase arrest under genotoxic stress. Deciliated cells exhibit heightened DNA damage, evidenced by increased γH2AX signals and comet assay results, a phenotype mirrored in in vivo IFT88 knockout mice. Furthermore, key DDR regulators, including ATM, p53, and p21, are downregulated in deciliated cells following irradiation, highlighting a crucial role for primary cilia in maintaining genome stability.

This study aimed to investigate the relationship between gut microbiota composition, fecal metabolites, and postoperative prognosis in patients with extrahepatic cholangiocarcinoma (eCCA). A total of 53 patients with resectable eCCA and 21 healthy volunteers as a control group were included. 16S rRNA gene sequencing and metabolomic analyses revealed significant differences in the gut microbial community structure and altered fecal metabolites profiles between eCCA patients and healthy controls. Univariate and multivariate Cox regression analyses indicated that factors such as preoperative total bilirubin, indirect bilirubin, and specific metabolites were closely associated with overall survival in patients with eCCA post-surgery. The constructed nomogram model further demonstrated the predictive value of these factors, achieving a C-index of 0.718, with calibration curves confirming its strong predictive performance. In conclusion, gut microbiota composition and fecal metabolites play a crucial role in the surgical prognosis of eCCA patients, providing new insights for clinical prognostic assessment.

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.

To assess the efficacy and safety of PD-1 and PD-L1 immune checkpoint inhibitors (ICIs) in managing advanced intrahepatic cholangiocarcinoma (ICC).

A retrospective analysis of treatment data for patients with advanced ICC who received ICIs at the Second Affiliated Hospital of Chongqing Medical University from the inception of the inpatient medical record database until 30 April 2024. The analysis concentrated on the safety and efficacy of the treatment. The primary endpoint was progression-free survival (PFS), while the secondary endpoints included overall survival (OS) and safety. The Kaplan-Meier method was employed to plot survival curves, and differences between groups were assessed using log-rank tests.

96 patients diagnosed with ICC were included, comprising 60 males (62.50%) and 36 females (37.50%). 85 patients exhibited disease progression, 22 patients succumbed, and 38 patients were lost to follow-up finally. Those who initiated immunotherapy promptly following first-line antitumor treatment exhibited a notably prolonged PFS compared to those experiencing tumor progression (5.63 months (95%CI: 3.12~8.14) vs 2.50 months (95%CI: 1.83~3.17), P=0.002). However, no significant disparity in the PFS with immunotherapy in different lines therapy(P=0.406) and the OS was observed between the two groups(P=0.360). 18 patients (18.75%) experienced treatment-emergent adverse events (AEs), with 3 patients encountering AEs of grade ≥3. All patients returned to normal after symptomatic treatment.

In patients with advanced ICC, the timely initiation of ICIs as adjuvant therapy following first-line antitumor treatment can result in favorable efficacy and a good safety profile.

Objectives: Although systemic chemotherapy (SC) is the mainstay for treating unresectable intrahepatic cholangiocarcinoma (ICC), its efficacy is limited and it causes severe systemic side effects. This study focuses on evaluating the effectiveness and safety of hepatic arterial infusion chemotherapy (HAIC) in combination with lenvatinib plus programmed death-1 (PD-1) inhibitors (HLP), compared to SC in combination with lenvatinib plus PD-1 inhibitors (SCLP) for unresectable ICC. Methods: We analyzed patients initially diagnosed with unresectable ICC at our center between March 2021 and December 2023, classifying them into HLP and SCLP groups according to treatment regimen. This study assessed and compared overall survival (OS), progression-free survival (PFS), tumor response, and safety outcomes across the two treatment groups. Results: This study enrolled 53 subjects in total; 25 were treated with HLP and 28 with SCLP. The two groups showed well-matched baseline characteristics. The HLP group reported an extended median OS (12.8 vs. 11.0 months, p = 0.310) and a prolonged median PFS (8.8 vs. 6.4 months, p = 0.043), compared to the SCLP group. The HLP group had a better objective response rate (ORR) (52% vs. 25%, p = 0.043) and disease control rate (DCR) (96% vs. 78.6%, p = 0.104). Based on OS (p = 0.019) and PFS (p = 0.032) results, those without extrahepatic metastasis seemed to benefit more significantly from the HLP regimen than from the SCLP regimen. The HLP group experienced fewer grade 3-4 adverse events (AEs) than the SCLP group. Conclusions: The HLP regimen for unresectable ICC is an effective and safe strategy and is potentially better suited for patients without extrahepatic metastases.

Despite complete resection, the recurrence rate of biliary tract cancer (BTC) remains high, leading to poor prognosis. Postoperative adjuvant chemotherapy (ACT) following radical resection may substantially reduce the recurrence risk by eradicating micrometastatic lesions. However, the benefits of postoperative ACT and the optimal ACT strategy are still unclear for BTC. The objectives of this study are to evaluate the prognostic value of ACT and compare the effectiveness of different ACTs among BTC patients after curative resection.

A comprehensive literature search was conducted across PubMed, Cochrane Library, Web of Science, and EMBASE databases to identify randomized controlled trials (RCTs) comparing the benefits of ACT versus no intervention or other ACTs in BTC patients after curative resection. A random-effects network meta-analysis was performed to compare overall survival (OS) and relapse-free survival (RFS). The quality of evidence was rated using the Grading of Recommendations Assessment, Development, and Evaluation framework.

Eight RCTs comprising 1803 patients were included in the meta-analysis. ACT was associated with significant improvements in 5-year all-cause mortality [four RCTs, hazard rate (HR) 0.93; 95% confidence interval (CI), 0.87-1.00, marginally significant; low-certainty evidence], RFS (five RCTs, HR 0.87; 95% CI, 0.78-0.98; moderate-certainty evidence), and OS (7 studies, HR 0.85; 95% CI, 0.75-0.96; low-certainty evidence) compared with observation. ACT had significantly better survival benefits on patients with negative margins (R0), lymph node-positive (N+), and tumor node metastasis classification (TNM) stage I/II ( P < 0.05). Further network meta-analysis demonstrated that fluorouracil-based ACT was significantly inferior to gemcitabine-based ACT (HR 1.20; 95% CI, 1.10-1.25) in improving RFS. However, both were superior to observation ( P < 0.05). No statistical difference in OS was observed between gemcitabine-based and fluorouracil-based chemotherapy (HR 1.00; 95% CI, 0.86-1.20). In subgroup analysis, fluorouracil-based ACT but not gemcitabine-based ACT achieved significantly better OS benefits on patients with N+ (HR 0.67; 95% CI, 0.52-0.86) and R0 (HR 0.69; 95% CI, 0.54-0.88).

Compared with observation, ACT should be routinely recommended to improve survival outcomes in BTC patients after curative resection, especially for those with R0, N+, and TNM stage I/II. Gemcitabine-based ACT performed better than other chemotherapies in improving RFS. This network meta-analysis provides precise information for determining the best adjuvant treatment for resected BTC. Further thorough and high-quality RCTs are needed.

Gastric cancer (GC) is a significant worldwide health concern and is a leading cause of cancer-related mortality. Immunotherapy has arisen as a promising strategy to stimulate the patient's immune system in combating cancer cells. Nevertheless, the effectiveness of immunotherapy in individuals with gastric cancer (GC) is not yet optimal. Thus, it is crucial to discover biomarkers capable appof predicting the advantages of immunotherapy for tailored treatment. The tumor microenvironment (TME) and its constituents, including cancer-associated fibroblasts (CAFs), exert a substantial influence on immune responses and treatment outcomes. In this investigation, we utilized single-cell RNA sequencing to profile CAFs in GC and established a scoring method, referred to as the CAF score (CAFS), for the prediction of patient prognosis and response to immunotherapy. Through our analysis, we successfully identified distinct subgroups within CAFs based on CAF score (CAFS), namely CAFS-high and CAFS-low subgroups. Notably, we noted that individuals within the CAFS-high subgroup experienced a lessF favorable prognosis and displayed diminished responsiveness to immunotherapy in contrast to the CAFS low subgroup. Furthermore, we analyzed the mutation and immune characteristics of these subgroups, identifying differentially mutated genes and immune cell compositions. We established that CAFS could forecast treatment advantages in patients with gastric cancer, both for chemotherapy and immunotherapy. Its efficacy was additionally confirmed in contrast to other biomarkers, including Tumor Immune Dysfunction and Exclusion (TIDE) and Immunophenotypic Score (IPS). These findings emphasize the clinical relevance and potential utility of CAFS in guiding personalized treatment strategies for gastric cancer.

This study aimed to assess the significance of elevated carbohydrate antigen (CA) 19-9 in postoperative surveillance of extrahepatic bile duct cancer and to identify short-term recurrence predictors.

This retrospective study included patients with elevated CA 19-9 post-curative surgery. Patients were categorized into positive and negative CT groups based on the detection of recurrence at CA 19-9 elevation. Short-term recurrence was defined as recurrence within 6 months in the negative CT group. We identified the factors associated with short-term recurrence and devised a predictive nomogram.

Among the 190 patients, 91 (47.9 %) exhibited tumor recurrence with CA 19-9 elevation (CT-positive group), whereas 99 (52.1 %) showed no recurrence (CT-negative group). In the CT-negative group (n = 99), 22 (22.2 %) experienced short-term tumor recurrence within 6 months. Preoperative CA 19-9 (odds ratio [OR]: 1.5, p = 0.016), postoperative CA 19-9 (OR: 1.9, p = 0.047), adjuvant treatment (OR: 3.5, p = 0.032), and the absence of inflammation (OR: 3.5, p = 0.045) were predictors of short-term recurrence. The area under the curve of the nomogram was 0.80 (95 % CI: 0.69-0.90).

Despite elevated CA 19-9 levels, approximately 50 % of patients exhibited no recurrence during postoperative surveillance for extrahepatic bile duct cancer. Factors influencing short-term recurrence encompass pre- and postoperative CA 19-9, adjuvant treatment, and inflammatory status.