Search Results (1,055)

Cholangiocarcinoma (CCA) is a highly malignant tumor originating from the epithelium of the bile ducts. It has an insidious onset, is difficult to diagnose in its early stages, has a low rate of curative resection, and carries an extremely poor prognosis. Among these, intrahepatic cholangiocarcinoma (iCCA), as the most representative subtype, is a classic “immunologically cold tumor.” The response rate to single-agent immunotherapy is only 5–10%, and the mechanisms of immune resistance are complex and not yet fully elucidated. The tumor microenvironment, serving as the core site of immune resistance, forms a highly immunosuppressive network composed of cancer-associated fibroblasts, hypoxia, metabolic reprogramming, and epigenetic abnormalities; a population of immunosuppressive cells centered on tumor-associated macrophages further amplifies tolerance signals; and the gut–biliary microbiome exerts systemic immune regulation via the gut–liver axis. Based on mutant mouse models generated via tail vein injection and in-depth studies of mutations in key signaling pathways, our understanding of the mechanisms underlying iCCA’s immune resistance is deepening at both the molecular and systems levels. This article reviews the local and systemic regulatory mechanisms of immune resistance in primary iCCA, summarizes the research value of experimental and preclinical models, and reviews novel strategies such as tumor microenvironment remodeling, activation of immune cell networks, microbiome interventions, and multidimensional combination therapies. It analyzes current research bottlenecks and clinical challenges and outlines the future direction of precision immunotherapy, aiming to provide a theoretical basis and new insights for overcoming iCCA immunotherapy resistance and advancing clinical translation. Full article

The carcinogenic liver fluke Opisthorchis viverrini underlies one of the world’s heaviest burdens of bile duct cancer, yet for decades it was treated as a single, genetically uniform parasite whose transmission was shaped mainly by environment and human behavior. However, advances in molecular biology have fundamentally reshaped this conceptual model. Evidence accumulated over the past three decades demonstrates that O. viverrini comprises geographically structured populations linked to hydrological connectivity, host distribution, and long-term evolutionary processes across interconnected river systems of mainland Southeast Asia, particularly within the Lower Mekong Basin. This review synthesizes research on the systematics and population structure of O. viverrini and its Bithynia snail hosts, tracing the transition from early allozyme studies to contemporary DNA-based and genomic approaches. Collectively, mitochondrial, nuclear, microsatellite, and intron markers reveal strong spatial structuring among parasite populations, while genetic patterns observed in snail hosts show partial geographic concordance with parasite population structure, suggesting that both may be influenced by shared hydrological organization, ecological isolation, and host connectivity across endemic aquatic systems. Population structure is strongly scale-dependent, with local panmixia often occurring within connected aquatic systems but pronounced differentiation emerging across broader geographic regions. Together, these findings indicate that transmission dynamics are shaped not only by environmental and behavioral factors, but also by evolutionary and landscape-level processes influencing host and parasite connectivity. Finally, we emphasize the increasing significance of population genomics and landscape genetics in understanding how transmission systems persist, disperse, reconnect, and respond to environmental change across endemic landscapes. Full article

Neutrophil extracellular traps (NETs) are web-like structures composed of decondensed DNA, histones, and proteins released by activated neutrophils. Originally identified as an innate defense mechanism against pathogens, NETs have since been implicated in cancer progression and immune evasion. Within the tumor microenvironment (TME), NETs suppress anti-tumor immunity through multiple mechanisms, including the physical exclusion of CD8⁺ cytotoxic T lymphocytes from the tumor interior and upregulation of exhaustion markers via checkpoint ligands. This review synthesizes current preclinical and clinical evidence on the interplay between NETs and CD8⁺ T cells across multiple malignancies, including non-small cell lung cancer, pancreatic ductal adenocarcinoma, cholangiocarcinoma, colorectal cancer, bladder cancer, hepatocellular carcinoma, skin cancer, and penile cancer. Cancer-specific mechanisms of NET-mediated immune suppression are discussed, including IL-8, IL-17, CXCL6, and TGF-β-driven NETosis pathways. Clinical data consistently demonstrate that elevated NET levels correlate with reduced CD8⁺ T cell infiltration, T cell dysfunction, and worse patient outcomes. Emerging therapeutic strategies targeting this axis are reviewed, including DNase I-mediated NET degradation, Peptidyl arginine deiminase 4 (PAD4) inhibition, CXCR2 blockade, and combination approaches with immune checkpoint inhibitors. These interventions have shown promise in restoring CD8⁺ T cell cytotoxicity and overcoming immunotherapy resistance in preclinical models. Collectively, the evidence supports the NET-CD8⁺ T cell axis as a promising prognostic and therapeutic target warranting further clinical investigation. Full article

Background: Biliary tract cancers (BTCs), encompassing cholangiocarcinoma and gallbladder carcinoma, are aggressive malignancies with poor prognosis and increasing incidence in selected regions worldwide. Advances in imaging, biomarker profiling, immunotherapy, and targeted therapies have improved treatment options but have also increased the economic pressure on health systems. Understanding the economic evidence on BTC is therefore important for resource allocation and health technology assessment. Methods: We systematically searched PubMed/MEDLINE, Embase, Scopus, and Web of Science for peer-reviewed economic studies of BTC published from January 2010 to March 2025. Eligible studies included cost-effectiveness, cost–utility, cost–benefit, cost-of-illness, and resource-use analyses. The review followed PRISMA reporting principles. Reporting completeness was assessed using CHEERS 2022, and methodological credibility was appraised using the Drummond framework. Results: Twenty studies were included: 13 cost-effectiveness or cost–utility analyses and seven cost-of-illness or resource-use studies. Conventional chemotherapy strategies, including gemcitabine plus cisplatin in some settings and other cytotoxic combinations in selected jurisdictions, generally produced more favorable economic results than newer systemic therapies, although findings varied by country, threshold, comparator, and price assumptions. First-line immunotherapy combinations and biomarker-directed targeted therapies frequently produced ICERs above jurisdiction-specific willingness-to-pay thresholds at current prices, often requiring substantial price reductions to approach cost-effectiveness. Real-world studies showed high resource use and costs, particularly with hospitalizations and later treatment lines. Evidence on screening and prevention was limited, with one study suggesting that ultrasound surveillance may be cost-effective in a liver fluke-endemic region of Thailand. Discussion: The available economic evidence suggests that affordability and jurisdiction-specific value assessment are central to BTC policy decisions. Current prices for several immunotherapy and targeted agents limit cost-effectiveness in published models, while evidence on prevention, early detection, and care-pathway interventions remains sparse and context-specific. Full article

Opisthorchis viverrini (OV) is a liver fluke endemic to the Lower Mekong Basin. Infections often begin in childhood and are causally linked to cholangiocarcinoma, an often-fatal bile duct cancer. Anthelmintic treatment is the primary control strategy, but infection can recur. Therefore, additional strategies are needed. This study assessed the impact of “The Magic Glasses Opisthorchiasis” (MGO), a cartoon-based intervention, on schoolchildren’s OV-related knowledge, attitudes and practices (KAP). A cluster (school)-randomised controlled trial was conducted in Cambodia, Laos and Thailand. Clusters were randomised into either school health education only or with MGO. OV KAP was measured using a standardised questionnaire. FGDs and interviews were also conducted in intervention schools with schoolchildren, parents, and teachers. Cambodia intervention knowledge and attitude scores improved by 19.2 (p < 0.001) and 25.3 (p < 0.001) percentage points, respectively, relative to the control. Laos intervention knowledge and attitude scores improved by 19.0 (p < 0.001) and 14.2 (p < 0.001) percentage points. However, Thailand’s intervention knowledge and attitude scores declined by 23.3 (p < 0.001) and 15.8 percentage points (p < 0.001). There were no improvements in behaviour scores in any country, but parents and schoolchildren in Cambodia and Laos reported improved fish preparation practices, suggesting positive spillover effects from MGO. The findings support MGO as an effective tool for school-based health education. Full article

Background: Insomnia and stress-related sleep disorders are increasingly recognized as systemic conditions linked to the microbiota–gut–brain axis (MGBA). With growing clinical interest in natural products that modulate the gut environment, this systematic review evaluates the efficacy and mechanisms of non-pharmacological interventions, specifically probiotics, prebiotics, dietary indices, and botanicals, in alleviating insomnia, restoring circadian rhythms, and modulating neurochemical markers. Methods: In strict accordance with PRISMA 2020 guidelines, we searched PubMed, ScienceDirect, Scopus, and The Cochrane Library for English language studies published from inception to March 31, 2026. Eligibility was restricted to studies with rigorously controlled designs, specifically randomized controlled trials (RCTs) and controlled in vivo animal studies. Interventions had to target the gut microbiota, with primary outcomes measuring sleep quality (subjective or objective) or sleep-related neurochemical markers. We excluded uncontrolled, single-arm, or observational designs; in vitro studies; non-original research; and studies involving subjects with severe medical or psychiatric comorbidities (e.g., cancer, ADHD, severe psychiatric disorders) to prevent confounding variables, though mild-to-moderate anxiety and depression were permitted. Risk of bias was assessed using the Cochrane RoB 2.0 and SYRCLE tools. Due to significant methodological heterogeneity, a narrative synthesis stratified by intervention and population was conducted. This review was not registered in PROSPERO. Results: A total of 56 studies (33 humans, 23 animals) met the inclusion criteria. Taxonomic nomenclature was updated to reflect 2020 reclassifications (e.g., Lactiplantibacillus plantarum). In human trials, interventions significantly improved subjective sleep metrics (PSQI, ISI). Recent additions demonstrated the efficacy of the Dietary Index for Gut Microbiota (DI-GM) and the improvement in N3 sleep latency by yeast mannan. Furthermore, whole-food patterns (e.g., the MIND diet) and Traditional Chinese Medicine (TCM) decoctions successfully enriched beneficial taxa, such as Bacteroides coprophilus, and increased short-chain fatty acid (SCFA) production. Animal models demonstrated that “psychobiotic” strains (Bifidobacterium breve, Lacticaseibacillus paracasei), prebiotics (GOS/PDX), and TCM formulas effectively restored GABA/5-HT profiles, lowered morning cortisol, and facilitated REM rebound in PCPA-induced models, while also consolidating non-rapid eye movement (NREM) sleep and downregulating clock genes (Per1/Per2). Conclusions: Psychobiotics, prebiotics, and botanicals represent a highly viable non-pharmacological strategy for treating insomnia. However, current evidence is constrained by a heavy reliance on subjective human questionnaires, short follow-up durations limiting insight into long-term stability, and a substantial translational gap between mechanistic rodent models and human clinical outcomes. Full article

Cholangiocarcinoma (CCA) is an aggressive and molecularly heterogeneous malignancy characterized by a profoundly immunosuppressive tumor microenvironment (TME) and historically limited therapeutic options. Recent advances have redefined the treatment paradigm, with phase III trials establishing chemoimmunotherapy as a standard of care and multi-omic profiling elucidating the interplay between tumor genomics, stromal architecture, and immune regulation. Despite these gains, durable clinical benefit remains confined to a minority of patients, reflecting convergent mechanisms of primary and acquired resistance—including immune exclusion, myeloid-dominant suppression, and genotype-driven “cold” tumor states. In this review, we synthesize emerging insights into the immune landscape of CCA, integrating data from single-cell, spatial, and translational studies to define the cellular and molecular circuits governing immune evasion. Beyond canonical biomarkers such as mismatch repair and microsatellite status, we highlight how spatial organization of immunity—in particular, tertiary lymphoid structures, dynamic myeloid and stromal interactions, and pathway-level features—shape immunotherapy responsiveness. We also examine how tumor-intrinsic alterations, including IDH1 mutation, FGFR2 fusions, KRAS activation, and MTAP loss, define distinct immunologic phenotypes with direct implications for immunotherapeutic response and biomarker-driven patient selection. We evaluate the expanding clinical trial landscape of immunotherapy in CCA and more broadly in BTC, including adoptive cell therapies and cancer vaccines. Together, these advances position CCA as a paradigm of how tumor genotype and microenvironment co-evolve to define immunotherapy sensitivity and resistance. Full article

Cholangiocarcinoma (CCA) in Northeast Thailand is characterized by late diagnosis and poor prognosis, creating a critical need for effective early-detection biomarkers. This study utilized a multi-omics approach to identify novel diagnostic targets and improve CCA screening. Initial serum proteomic and transcriptomic analyses revealed significant upregulation of the luteinizing hormone/choriogonadotropin receptor (LHCGR) in CCA patients, correlating with advanced disease stages. Interaction network analysis subsequently identified its circulating ligand, beta-human chorionic gonadotropin (β-hCG), as a highly translatable clinical target. The protein expression of β-hCG was assessed via immunohistochemistry (IHC) in 100 tissue samples, and serum levels of β-hCG, alongside routine markers (CA19-9, AFP, and CEA), were quantified in a cohort of 405 individuals, including 153 CCA patients. IHC confirmed significantly higher β-hCG expression in tumor tissues compared to adjacent areas (p < 0.0001). Serum β-hCG levels were significantly elevated in CCA patients and correlated with tumor volume and reduced overall survival. Diagnostically, a combined multiparameter panel (β-hCG, carbohydrate antigen 19-9, carcinoembryonic antigen, and alpha-fetoprotein) yielded excellent accuracy in distinguishing CCA from healthy controls (AUC: 0.962) and hepatocellular carcinoma cases (AUC: 0.890). However, discriminatory efficiency was notably lower when differentiating CCA from benign biliary diseases (AUC: 0.680) and liver metastases (AUC: 0.705). In conclusion, activation of the LHCGR signaling axis is a novel pathophysiological feature in CCA. When integrated into a multi-marker blood panel, circulating β-hCG serves as a valuable complementary risk-stratification and prognostic tool, though further optimization is required to overcome limited specificity in the presence of confounding liver pathologies before routine clinical implementation. Full article

Gallbladder cancer (GBC) is an aggressive tumor that, together with the cholangiocarcinomas, constitutes the spectrum of biliary tract cancer (BTC). These tumors are characterized by a frequently late diagnosis, marked genomic heterogeneity, variable response to cytotoxic therapies, and poor overall survival in advanced stages. Nevertheless, the characterization of the tumor microenvironment (TME) and the identification of actionable molecular targets have driven the development of biological therapies. This review summarizes current and emerging evidence on monoclonal antibodies, bispecific antibodies, and antibody–drug conjugates (ADCs) in the management of GBC. The analysis addresses the early exploration of autoantibodies as potential diagnostic biomarkers, mechanistic hypotheses of immune evasion, and the clinical translation of targeted agents in the metastatic setting. Additionally, we critically discuss the extrapolation of data from global BTC trials to the specific GBC setting, the integration of population genetics into epidemiological studies such as the EULAT Eradicate GBC initiative, and the preliminary status of immunotherapy in perioperative scenarios. Full article

Fibroblast growth factor receptor 2 (FGFR2) inhibitors such as pemigatinib are targeted therapies for cholangiocarcinoma with FGFR2 alterations. While generally well tolerated, they are associated with unique adverse events. Calciphylaxis, a potentially fatal vascular calcification disorder, is a rare complication. We present a 43-year-old woman with metastatic intrahepatic cholangiocarcinoma harboring an FGFR2 fusion who developed calciphylaxis after seven months of pemigatinib therapy. Despite drug discontinuation, antibiotics, and multidisciplinary supportive care, she deteriorated rapidly and died from sepsis and advanced disease. Histopathological analysis confirmed dermal and vascular calcifications consistent with calciphylaxis. This case highlights the importance of early recognition of cutaneous lesions in patients on FGFR inhibitors. Prompt cessation of therapy, management of metabolic derangements, and consideration of sodium thiosulfate may be lifesaving. Full article

IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory disorder characterised by elevated serum levels of IgG4 and multiorgan damage. Its diagnosis is challenging and requires a careful integration of clinical, radiological, serological and histological data. Pancreatic and biliary involvement is one of the most common manifestations of IgG4-RD, presenting as type 1 autoimmune pancreatitis (AIP) and IgG4-related sclerosing cholangitis (IgG4-SC), two entities that often occur synchronously and may mimic malignancy in the form of pancreatic ductal adenocarcinoma (PDAC) and cholangiocarcinoma, respectively. The main objective of this article is to illustrate the key imaging features of AIP and IgG4-SC on computed tomography (CT) and magnetic resonance imaging (MRI), providing a comprehensive review of their current diagnostic criteria and discussing their differential diagnosis with other benign and malignant conditions. Full article

Background: Gemcitabine, cisplatin and durvalumab or pembrolizumab are standard first-line treatments for advanced or metastatic biliary tract cancer (BTC). Older patients with BTC may be frail or have contraindications to cisplatin. At our institution, oxaliplatin has been used as an alternative to cisplatin. Methods: In this evaluation, we report the safety and efficacy of gemcitabine with oxaliplatin and durvalumab as a first-line treatment of BTC. The primary objective was overall survival (OS). Secondary objectives included time to progression (TTP), disease control rate (DCR), and the incidence of treatment-related toxicities. Results: Twenty-nine patients were included. The majority were Caucasian (97%) and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1 (97%). Median age was 72 years old. Sixty-six percent had intrahepatic cholangiocarcinoma. Baseline renal insufficiency and/or hearing impairment were the most common reasons for cisplatin contraindication. Median follow-up was 20.6 months. Treatment cycles were every 28 days with durvalumab (1500 mg) given on day 1 and gemcitabine (range 600 mg/m²–1000 mg/m²) plus oxaliplatin (median dose 70 mg/m²) given on days 1 and 15. Median OS was 15.7 months (95% CI: 6.9-NA), median TTP was 6.7 months (95% CI 3.88-NA), and DCR was 76%. Median time on treatment was 3.15 months. Twelve patients (41%) required a dose adjustment, with myelosuppression as the most common toxicity. Conclusions: Oxaliplatin, in combination with durvalumab and gemcitabine, is a suitable platinum substitute for advanced BTC patients when cisplatin is contraindicated. Our analysis showed similar efficacy and no new safety concerns. Given the small sample size, our analysis is hypothesis-generating and calls for a larger prospective analysis. Full article

Endobiliary photodynamic therapy (PDT) in cholangiocarcinoma (CCA) is used mainly for local palliation of malignant biliary obstruction, particularly in extrahepatic and perihilar disease. This Review synthesizes the clinical evidence on endobiliary PDT while using drainage, infection control, stent strategy, light delivery, and systemic-therapy context as an interpretive framework rather than as practice recommendations. This narrative review was informed by targeted searching of PubMed/MEDLINE, Embase, and Web of Science from database inception through to 31 December 2025, supplemented by reference-list screening. We prioritized prospective studies, comparative cohorts, systematic reviews, and relevant guidance documents. Across the literature, the clearest support for PDT concerns selected local biliary palliation, including decompression, stent patency or delayed dysfunction, and symptom relief. Survival signals remain inconsistent: early positive studies contrast with the negative PHOTOSTENT-02 randomized trial and are highly confounded by drainage adequacy, infection control, retreatment strategy, and systemic-therapy access. We therefore interpret PDT as a context-dependent local biliary strategy rather than an established survival-prolonging treatment, and we highlight the clinical variables that make published outcome signals more or less interpretable. Full article

In this review, we explore the evolving role of endoscopic ultrasound (EUS) in diagnosing and managing pancretobiliary malignancies. For solid pancreatic lesions, techniques like fine-needle biopsy (FNB), contrast-enhanced EUS (CE-EUS), and macroscopic on-site evaluation (MOSE) improve sample quality and diagnostic accuracy. In cystic pancreatic lesions, fine-needle aspiration (FNA), molecular testing, and confocal laser endomicroscopy (nCLE) aid in distinguishing benign from malignant cysts. For cholangiocarcinoma, EUS guided sampling is more accurate than CT in assessing distal lesions and lymph node metastases, while combining EUS with magnetic resonance cholangiography (MRC) enhances diagnostic sensitivity. In gallbladder cancer, EUS surpasses CT and MRI in detecting lymphadenopathy and staging tumors. EUS-FNB (Fine needle biopsy) improves biopsy accuracy, especially for unresectable cases. These advancements highlight EUS as a critical tool for early cancer detection, staging, and tissue acquisition. Beyond diagnosis, EUS plays a pivotal therapeutic role in managing complications such as malignant biliary obstruction and gastric outlet obstruction, offering minimally invasive alternatives like EUS-guided biliary drainage and gastroenterostomy with high clinical success and improved patient outcomes. Full article

Intrahepatic cholangiocarcinoma (ICC) is an aggressive liver malignancy with a rising global incidence and limited therapeutic options. Vascular invasion (VI) is a hallmark of advanced disease, correlating with early recurrence and dismal prognosis, yet its tumor microenvironment (TME) drivers remain elusive. We analyzed single-cell RNA sequencing (scRNA-seq) data from 25 ICC samples to systematically characterize the cellular composition and molecular features related to VI. By integrating bulk RNA-seq data, spatial transcriptomics, and multiplex immunofluorescence, we identified a distinct subset of tumor-like cancer-associated fibroblasts (CAFs), termed tCAFs, enriched in VI-positive tumors. Functional enrichment analyses revealed that tCAFs were prominently associated with hypoxia and angiogenesis pathways, findings corroborated by the significant upregulation of tCAF markers (MME and NT5E) in ICC-derived CAFs under hypoxic conditions in vitro. Cell–cell communication analysis and spatial mapping uncovered that tCAFs might promote VI primarily through VEGF signaling interactions with endothelial cells. Integrative bioinformatics and RT-qPCR validation identified three key functional genes in tCAFs: SLC2A1, PTGS2, and PLOD2. In endothelial sprouting assays, pharmacological inhibition of SLC2A1 exerted a pronounced suppressive effect. Consistently, sprouting assays using ICC-derived CAFs with SLC2A1 knockdown confirmed that its downregulation significantly reduced endothelial sprouting capacity. Importantly, administration of the SLC2A1 inhibitor BAY-876 effectively suppressed tumor progression and intrahepatic metastasis in the orthotopic ICC mouse model. Our findings define a VI-associated cellular ecosystem and molecular landscape in ICC, unveiling a novel hypoxia–tCAFs–endothelial cells axis. Furthermore, we identify SLC2A1 as a clinically relevant therapeutic target, offering new insights into tumor VI. Full article