Abstract Background and Aims Cholangiocarcinoma (CCA) is a rare and aggressive malignancy originating from the bile ducts, characterized by a poor prognosis and limited treatment options. Potentially curative interventions include surgical resection with negative margins (R0) and liver transplantation. However, despite these treatments, the likelihood of post-surgical recurrence remains high, with 50–70% of patients experiencing disease recurrence within five years. This highlights the urgent need for reliable prognostic biomarkers to guide clinical decision-making and personalize postoperative care. Numerous prognostic biomarkers identified in tumor tissue for CCA have been proposed, but many studies suffer from limitations such as single-center designs, small patient cohorts, and semi-quantitative techniques such as immunohistochemistry. These methods often rely on observer interpretation and antibody specificity, which can compromise objectivity and reproducibility. To overcome these limitations, we aimed to identify and validate robust quantitative prognostic biomarkers for CCA by analyzing tumor mRNA expression, integrating them using machine learning (ML), and developing a web-based tool to predict tumor recurrence and overall survival (OS). Method A systematic literature review was conducted to identify candidate prognostic tissue biomarkers for CCA, which were further validated using Cox proportional hazards (PH) OS analyses in five independent transcriptomic cohorts. An international multicenter cohort of 221 patients undergoing tumor resection was assembled, and tumor mRNA expression was analyzed using high-throughput TaqMan OpenArray RT-qPCR. Associations between clinical and molecular features and recurrence-free survival (RFS) and OS were assessed using Cox PH analyses. Six ML survival models were trained and evaluated using nested cross-validation, followed by feature reduction. Shapley Additive exPlanations (SHAP) values were applied to assess feature importance and enhance model interpretability. Results Among 496 candidate CCA prognostic biomarkers identified from the literature, 52 showed prognostic value in Cox PH analyses across transcriptomic cohorts. In the multicenter validation cohort, integrative Cox PH analyses incorporating clinical variables and gene expression identified 11 genes significantly associated with RFS and 25 with OS. The 11 RFS-associated genes, combined with five clinical variables, were used to train six ML survival models, among which the random survival forest (RSF) model demonstrated the highest predictive accuracy. Following training of RSF models across all combinations of four genes and five clinical variables, and subsequent feature importance–based selection, a final model incorporating three genes (FSCN1, LDHA, and SLC2A1) and four clinical variables (CCA subtype, resection margin status, biological sex, and age at surgery) achieved a testing time-dependent AUC of 0.82. This model significantly stratified patients into high- and low recurrence-risk groups, with a median RFS (mRFS) of 8 months and 70 months, respectively. In addition, an OS prediction model using the same feature set achieved a testing AUC of 0.775 and significantly stratified patients according to 5-year OS risk, with a median OS (mOS) of 23 months in the high-risk group and 77 months in the low-risk group. Conclusion We identified and validated a robust panel of prognostic tissue biomarkers in patients with resected CCA. Integration of these biomarkers with clinical variables into ML-based prognostic models enabled accurate prediction of RFS and OS. The resulting web-based tool allows clinicians to input RT-qPCR results for the validated biomarkers and obtain precise, individualized prognostic predictions for postoperative recurrence and survival.

BACKGROUND AND AIMS:Cholangiocarcinoma (CCA) is an aggressive cancer with rising incidence and mortality worldwide. Chronic liver disease (CLD) is a well-recognized risk factor, but its influence on tumor presentation and clinical outcomes remains unclear. We aimed to compare the clinical course of CCA in patients with and without CLD. METHODS:We retrospectively analyzed 3,743 patients diagnosed with CCA between 2010 and 2024 across international centers. CLD was defined by documented primary sclerosing cholangitis, cirrhosis, viral hepatitis, or other chronic liver disorders; remaining patients were classified as non-CLD. Demographic, clinical, biochemical, treatment, and survival features were compared. RESULTS:Among the CCA cohort, 993 patients had CLD. Compared with non-CLD patients (n=2,750), those with CLD were more frequently male (67% vs. 53%) and younger (median age 63 vs. 66 years). CLD-CCA patients more often presented with intrahepatic tumors (64% vs. 42%), better performance status (ECOG 0: 53% vs. 35%), lower CA19.9 levels (56 vs. 135 U/mL), and earlier-stage disease (localized: 57% vs. 43%; metastatic: 23% vs. 31%). In propensity score-matched analyses, patients with prior CLD were diagnosed at earlier CCA stages than non-CLD controls. Consequently, curative-intent tumor surgery was performed more frequently in CLD patients (60% vs. 48%), resulting into longer median overall survival (mOS 12.2 vs. 11.1 months; HR 0.88, 95%CI 0.80-0.98) and higher 5-year survival (OR 1.70, 95%CI 1.37-2.11), particularly in intrahepatic CCA (mOS: 14.2 vs. 11.1 months; HR 0.77, 95%CI 0.68-0.87; 5-year survival OR 2.19, 95%CI 1.60-3.01). Treatment responses across modalities were comparable between groups. CONCLUSION:Pre-existing CLD is associated with earlier-stage CCA diagnosis and improved survival, supporting the implementation of structured surveillance strategies in high-risk CLD populations. IMPACT AND IMPLICATIONS:This international multicenter study show that pre-existing CLD is associated with earlier-stage CCA diagnosis, likely due to closer clinical surveillance, greater eligibility for curative-intent surgery, and improved survival. Treatment responses were similar regardless of CLD status. These findings support established surveillance in high-risk groups and highlight the need to optimize strategies for selected moderate-to-high risk CLD populations, alongside prospective evaluation of their clinical utility, cost-effectiveness, and potential refinement through more accurate non-invasive biomarkers.

[This corrects the article DOI: 10.3389/fimmu.2025.1611365.].

[This corrects the article DOI: 10.1016/j.lanepe.2024.101170.].

In recent years, treatment options for patients with advanced biliary tract cancer (BTC) have increased significantly due to the positive results from phase 2/3 clinical trials of immune checkpoint inhibitors, combined with chemotherapy, and molecularly targeted agents. These advances have led to the need for molecular testing to identify actionable alterations and patients amenable to targeted therapies. However, these improvements have brought with them many questions and challenges, including the identification of resistance mechanisms and therapeutic sequences. In this Series paper we aim to provide an overview of the current systemic treatment options for patients with BTC, highlighting disparities in access to innovative treatments and molecular testing across European countries, which lead to inequalities in the possibilities of treating patients with advanced BTC. We also discuss how ongoing European collaborative projects, such as the COST Action Precision-BTC-Network CA22125, supported by COST (European Cooperation in Science and Technology), linked to the European Network for the Study of Cholangiocarcinoma (ENSCCA), can help overcome these disparities and improve the current scenario.

Objetivo Evaluar la seguridad y eficacia de la quimioembolización transarterial con microesferas radiopacas cargadas con doxorrubicina (rDEB-TACE) en pacientes con carcinoma hepatocelular (CHC). Materiales y métodos Este estudio observacional retrospectivo de un solo centro incluyó a todos los pacientes mayores de 18 años diagnosticados con CHC y tratados con rDEB-TACE entre 2017 y 2020 en nuestra institución. La eficacia de rDEB-TACE se evaluó mediante la respuesta al tratamiento a los 1, 3 y 6 meses, el tiempo hasta la progresión (TTP) y la supervivencia global (OS). La seguridad se evaluó según la ocurrencia de eventos adversos (EA). La distribución de rDEB se clasificó en distribución general: tipo 1 (intratumoral), tipo 2 (intratumoral-arteria nutricia) y tipo 3 (arteria nutricia); y por distribución intratumoral (0-50% y 50-100%). Resultados Se incluyeron 21 pacientes con 36 lesiones tratadas con rDEB-TACE. El tiempo medio de seguimiento fue de 17 meses (RQI: 6,0-45,5). La respuesta objetiva local y global a los 1, 3 y 6 meses fue del 86%, 85%, 84%, y 91%, 78% y 84%, respectivamente. La mediana de TTP fue de 27,0 meses (IC 95%: 8,9-28,1) y la mediana de OS fue de 54,9 meses (IC 95%: 16,3-no estimable). No se reportaron eventos adversos mayores. El tipo de distribución de partículas más común fue el tipo 2 (69,4%). La concordancia entre la distribución de partículas en el cone beam TC intraprocedimiento y el TC de seguimiento fue alta (kappa=0,80). La mayoría de las lesiones tratadas mostraron una distribución intratumoral de partículas del 50-100%, con una mayor tasa de respuesta objetiva local (95,5% vs. 71,4%) y global (100% vs. 71,4%) en este grupo en comparación con el grupo de 0-50%. Conclusión La rDEB-TACE es un tratamiento seguro y eficaz para el CHC. La distribución de rDEB puede evaluarse con precisión y predecir la respuesta radiológica temprana.

Cholangiocarcinoma (CCA) is a cancer that originates within the bile ducts. Traditionally considered to be a rare neoplasm, increased awareness of CCA alongside advancements in diagnosis and the rising prevalence of certain risk factors have contributed to a global increase in incidence and mortality. CCAs are highly heterogeneous from the clinical, histomorphological and molecular perspectives but commonly share a poor prognosis. These tumours usually develop and progress silently; by the time they are detected, it is often too late for curative surgical intervention. In such cases, current therapeutic approaches offer modest survival improvements and are generally considered palliative. Although well-known risk factors predispose individuals to developing CCA, the majority of cases are considered sporadic, occurring without any identifiable underlying condition. Over the past decade, substantial collaborative efforts have been made to improve our understanding of the aetiopathogenesis of these tumours, aiming to identify novel biomarkers and therapeutic targets to develop more effective treatments. The ultimate goal is to improve patient outcomes and overall well-being. However, there are significant gaps in our understanding of the molecular mechanisms that drive cholangiocarcinogenesis. In this international Consensus Statement, which is endorsed by the European Network for the Study of Cholangiocarcinoma, we provide a critical overview of the latest advancements in the field of CCA. We highlight the key aspects of CCA aetiopathogenesis and clinical management and provide insights into promising new treatments. Finally, we provide a set of consensus recommendations and future research priorities for CCA based on a Delphi panel questionnaire involving international experts. In this Consensus Statement, an international panel of experts present an overview of the latest developments in the field of cholangiocarcinoma. A set of consensus recommendations and research priorities is provided.

The 2026 BCLC update incorporates recent therapeutic advances in HCC into its recommendations, while preserving simplicity. Each disease stage remains directly linked to its evidence-based first-line treatment option. The BCLC algorithm provides guidance for evaluating patient prognosis and proposes a therapeutic strategy according to the current scientific evidence. Tumour boards require structured methodologies to address clinical complexity. Beyond published evidence, decision-making should incorporate biological, psychosocial, and contextual factors that may affect morbidity, feasibility, and patient vulnerability. Such a multidimensional approach ensures treatments remain evidence-based and patient-centred. The updated clinical decision-making chapter embeds the CUSE (Complexity, Uncertainty, Subjectivity, Emotion) framework. CUSE turns unavoidable doubt into a shared, iterative process to: (i) define the therapeutic goal (survival, tumour control, quality of life, etc.); (ii) grade each option, noting evidence strength and gaps; (iii) align choices with comorbidities, feasibility, oncologic risk, and patient values and goals; and (iv) select a plan with regular check-ins as new information or needs arise.

The eradication of the Hepatitis C Virus (HCV) reduce the risk of liver cancer (LC), but lifestyle changes after cure may counterbalance its benefit. Our study investigates lifestyle changes that occur in HCV patients with Sustained Virological Response (SVR) after direct-acting antiviral (DAA) treatment. In this prospective, single-center study, HCV patients with advanced liver disease (F3/F4) treated and cured with DAA were invited to fill a lifestyle habits questionnaire in and perform abdominal ultrasound (US), blood extraction and anthropometric measurements within the 1st month after SVR and every 6 months thereafter until 48 months of follow-up, LC development, death, or loss to follow-up. This prospective cohort included 182 patients with SVR after DAA in this first analysis through the 4 years of follow-up. At the time of SVR, 65.9

Background & Aims:Early-onset gastrointestinal cancers represent a growing global health concern. Among these, early-onset biliary tract cancer (EO-BTC) remains relatively understudied. In this systematic review, we synthesize current evidence for EO-BTC. Methods:A comprehensive systematic literature search was performed across multiple databases. Original studies investigating epidemiology, risk factors, clinical presentation, pathological and/or molecular features, treatment, and prognosis of EO-BTC were included and synthesized. Meta-analyses were performed using the Mantel-Haenszel and generic inverse variance methods with random-effects models. Results:In total, 32 studies were included. EO-BTC incidence varied by anatomical subtype, with a notable increase in early-onset intrahepatic cholangiocarcinoma. Disparities in ethnicity and socioeconomic status were apparent between younger and older patients. Clinically, the disease was often diagnosed at a more advanced stage in younger patients (for stage IV, odds ratio [OR], 1.31; 95% CI, 1.19-1.43; p <0.001; I 2 , 62%) and was associated with a higher prevalence of intrahepatic cholangiocarcinoma (OR, 1.41; 95% CI, 1.23-1.61; p <0.001; I 2 , 49%). FGFR2 fusions were significantly more common in early-onset cases (OR, 2.81; 95% CI, 2.31-3.64; p <0.001; I 2 , 0%). Younger patients had fewer comorbidities and more frequently received curative-intent local and systemic therapies (surgery: OR, 1.38; 95% CI, 1.22-1.57; p <0.001; I 2 , 85%). Prognostic data were heterogeneous; however, pooled analysis suggested a trend to improved OS in patients with early-onset disease (unadjusted hazard ratio [HR], 0.84; 95% CI, 0.75-0.93; p = 0.001; I 2 , 81%); adjusted HR, 0.78; 95% CI, 0.66-0.94; p = 0.007; I 2 , 91%). Conclusions:EO-BTC represents a clinically and molecularly distinct subset within biliary tract cancers, with emerging epidemiological patterns, a higher prevalence of actionable molecular alterations, and differences in treatment allocation. Further prospective and age-stratified studies are needed to guide age-adapted detection and therapeutic strategies. PROSPERO ID:CRD420251039039. Impact and implications:This systematic review highlights that EO-BTC exhibits different epidemiological and molecular patterns compared with later-onset disease, including a higher prevalence of intrahepatic subtypes and greater frequency of targetable alterations, such as FGFR2 fusions. These findings underscore the importance of incorporating routine molecular profiling and the integration of stratified management pathways into clinical practice. From a public health perspective, the rising incidence of EO-BTC, especially among individuals without traditional risk factors, highlights the urgent need for increased awareness and the development of risk-adapted early detection strategies. Interestingly, younger patients were more likely to undergo surgical resection, even those with advanced-stage disease. This trend might reflect a greater clinical willingness to pursue aggressive approaches in this population, likely influenced by better performance status and fewer comorbidities. However, it also reinforces the need for careful patient selection to avoid unnecessary surgical morbidity when the anticipated oncological benefit is limited. Overall, these findings emphasize the need for prospective, age-stratified studies to better define prognostic models and guide personalized therapeutic approaches for this distinct patient population.

In patients at risk of hepatocellular carcinoma (HCC), new focal liver lesions identified at ultrasound screening require further characterization by CT or MRI. If these techniques cannot conclusively characterize a lesion, a biopsy or an alternative imaging modality such as contrast-enhanced ultrasound (CEUS) is considered. We aimed to determine the diagnostic yield of CEUS in a sequential noninvasive diagnostic strategy for solitary nodules ≤ 20 mm detected in cirrhotic patients during US surveillance characterized as inconclusive on MRI. Post hoc analysis of a single-center prospective cohort of high-risk patients (Child A or B) with no prior history of HCC and new liver nodules (≤ 20 mm) detected on screening US who underwent CEUS after inconclusive MRI (LI-RADS-2, LI-RADS-3, LI-RADS-4, or LI-RADS-M) between January 2006 and February 2017. We compared the characterization of nodules by LI-RADS v.2018 alone vs characterization after considering subsequent CEUS-LR v.2017 against the final diagnosis by biopsy or follow-up. Of the 75 nodules included, CEUS upgraded 45 (63.4

Background:This study assessed the pharmacokinetic interactions between dolutegravir (DTG)-based antiretroviral therapy (ART) and immunosuppressants in solid organ transplantation (SOT) recipients with HIV and ART safety. Methods:A phase IV, single-center, open-label, single-arm clinical trial (DTG-SOT, NCT03360682) including adult SOT recipients with HIV conducted between 2017 and 2019. People with HIV with plasma viral load <50 copies/mL during ≥12 months and receiving stable raltegravir-based ART during ≥6 months were switched to tenofovir disoproxil fumarate/emtricitabine or lamivudine/abacavir + DTG and followed up for 48 weeks. Immunosuppressant pharmacokinetic parameters were compared before and 2 weeks after ART switch (primary outcome). Efficacy and safety were analyzed at 48 weeks by intention-to-treat analysis. Results:Nineteen consecutive participants (median, 57 years; interquartile range, 51-60), mostly liver recipients (63.2%), received DTG/lamivudine/abacavir (63.2%) and DTG + emtricitabine/tenofovir disoproxil fumarate (36.8%). Pharmacokinetic parameters changed, albeit not significantly, before and after ART, for mycophenolic acid (maximum [Cmax] +63%, trough [Cmin] +53%, area under the curve [AUC] +16%; n = 7) and cyclosporine A (Cmax -64%, Cmin +14%, AUC -47%; n = 2), with smaller changes for tacrolimus (Cmax +14%, Cmin -29%, AUC -9%; n = 7). No participants experienced acute rejection or virological failure and CD4+ cell counts and percentages remained unchanged during follow-up. Three (15.8%) discontinued treatment because of adverse events. Estimated glomerular filtration rate decreased (P = 0.0015) and creatinine increased (P = 0.0001) slightly. Conclusions:DTG-based ART lacked clinically significant drug-drug interactions with tacrolimus and mycophenolic acid. Switching to DTG-based ART was effective in people with HIV SOT recipients. More studies are needed to evaluate DTG safety in this setting.