Search Results (646)

Background/Objectives: The TOPAZ-1 phase III trial reported a survival benefit of using durvalumab, an anti-programmed death ligand 1 (anti-PD-L1) antibody, in combination with gemcitabine and cisplatin (GCD) treatment in patients with advanced biliary tract cancer. This retrospective study investigated the efficacy and safety of GCD treatment for advanced biliary tract cancer in real-world conditions. Methods: The study subjects were 52 patients with biliary tract cancer who received GCD therapy between January 2023 and May 2024. The observation parameters included the modified Glasgow Prognostic Score (mGPS), neutrophil–lymphocyte ratio (NLR), platelet–lymphocyte ratio (PLR), tumor markers (CEA, CA19-9), overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events. Results: The cohort included 36 men and 16 women, with a median age of 73.0 years. There were 36 cases of cholangiocarcinoma (distal: 10, perihilar: 19, intrahepatic: 7), 13 cases of gallbladder cancer, and 3 cases of ampullary carcinoma. The stages were locally advanced in 30 cases and metastatic in 22 cases. Biliary drainage was performed in 30 cases. There were 38 cases receiving first-line therapy and 14 cases receiving second-line or later treatments. The median values at the start of GCD therapy were ALB 3.7 g/dL, CRP 0.39 mg/dL, NLR 2.4, PLR 162.5, CEA 4.8 ng/mL, and CA19-9 255.9 U/mL. The mGPS distribution was 0:23 cases, 1:18 cases, and 2:11 cases. The treatment outcomes were ORR 25.0% (CR 2 cases, PR 11 cases), DCR 78.8% (SD 28 cases, PD 10 cases, NE 1 case), median PFS 8.6 months, and median OS 13.9 months. The PLR was suggested to be useful for predicting PFS. A decrease in CEA at six weeks after the start of treatment was a significant predictor of PFS and OS. Gallbladder cancer had a significantly poorer prognosis compared to other cancers. The immune-related adverse events included hypothyroidism in two cases, cholangitis in one case, and colitis in one case. Conclusions: The ORR, DCR, and PFS were comparable to those in the TOPAZ-1 trial. Although limited by its retrospective design and small sample size, this study suggests that GCD therapy is an effective treatment regimen for unresectable biliary tract cancer in real-world clinical practice. Full article

Background/Objectives: Cystic fibrosis (CF) is a rare autosomal recessive genetic disease that has a progressive and multisystemic course. The spectrum and frequency of mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) vary both in European countries and in other geographical regions. The aim of our retrospective study was to present the genetic variants identified in a group of 48 CF patients from the Moldova region (Romania), as well as to establish genotype–phenotype correlations. Methods: Genetic testing was initially performed for 38 CFTR mutations, and in heterozygous patients or those in whom no mutation was detected, CFTR gene sequencing (NGS) was performed. Results: The compound heterozygous genotype was identified in 26 (54.16%) of the patients (with one of the alleles being F508del), while 22 (45.83%) patients had the homozygous F508del genotype. The F508del variant was the most frequent (69.79%), followed by G542X (6.25%, 6/96). Several new variants were also identified that had not been reported in other studies from Romania (R1158X, K598*, R347H, c.2589_2599del, R496H, and CFTRdele2). Phenotypic manifestations in patients with CFTR class I, II, III and VII variants (homozygous and compound heterozygous) were more severe compared to those in patients with CFTR class IV, V and VI mutations, with the data obtained being consistent with those in the literature. Respiratory tract involvement was present in 77.08% of the patients, being more frequent in patients with the compound heterozygous genotype compared to the homozygous F508del genotype. Most patients had exocrine pancreatic insufficiency (EPI) (85.41%). Gastrointestinal manifestations included hepatocytolysis (66.66%) and biliary cirrhosis (0.41%). Meconium ileus was detected in 18.75% of patients, all with a compound heterozygous genotype. Conclusions: We compared the results obtained with data from the literature and correlated the detected CFTR variant (genotype) with the phenotypic manifestations, highlighting certain particularities present in some patients. Genetic testing allows for early diagnosis and adapted management, including personalized treatment for each patient. Identification of novel unclassified CFTR variants still remains a challenge for clinicians. NGS-based screening of heterozygous healthy carriers is important for both genetic counseling and prenatal diagnosis. Full article

Despite advances in surgery, chemotherapy, and radiation treatments for pancreatic ductal adenocarcinoma (PDAC), 5-year survival rates remain at nearly 11%. Cholangiocarcinoma, while not as severe, also possesses similar survival rates. Fewer than 20% of patients are surgical candidates at time of diagnosis; therefore, it is imperative that alternative therapies are effective for non-surgical patients. There are several thermal ablative techniques, including radiofrequency ablation (RFA), high-intensity focused ultrasound (HIFU), microwave ablation (MWA), alcohol ablation, stereotactic body radiotherapy (SBRT), cryoablation, irreversible electroporation (IRE), biliary intraluminal brachytherapy, and biliary photodynamic therapy (PDT). Emerging literature in animal models and human patients has demonstrated that endoscopic ultrasound (EUS)-guided RFA (EUS-RFA) prevents tumor progression through coagulative necrosis, protein denaturation, and activation of anticancer immunity in local and distant tumor tissue (abscopal effect). RFA treatment has been shown to not only reduce tumor-associated immunosuppressive cells but also increase functional T cells in distant tumor cells not treated with RFA. The remarkable ability to reduce tumor progression and promote tumor microenvironment (TME) remodeling makes RFA a very promising non-surgical therapy technique that has the potential to reduce mortality in this patient population. EUS-RFA offers superior precision and safety compared to other ablation techniques for pancreatic and biliary cancers, due to real-time imaging capabilities and minimally invasive nature. Future research should focus on optimizing RFA protocols, exploring combination therapies with chemotherapy or immunotherapy, and expanding its use in patients with metastatic disease. This review article will explore the current data and underlying pathophysiology of EUS-RFA while also highlighting the role of ablative therapies as a whole in immune activation response. Full article

Background and Aims: Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease frequently associated with fatigue and mild cognitive impairment. Brain-derived neurotrophic factor (BDNF) plays key roles in neuroplasticity, immune regulation, and metabolism. This study aimed to evaluate plasma BDNF levels in early-stage PBC and examine their clinical and biochemical associations. Methods: In this observational study, plasma BDNF, IL-6, and IL-18 concentrations were measured by ELISA in 45 patients with early-stage PBC and 31 age- and sex-matched healthy controls (mean age 60.5 years; 96% women). All participants underwent liver elastography using point shear wave elastography (ElastPQ), Doppler ultrasound, laboratory testing, and assessment of cognitive function (PHES) and fatigue severity (MFIS). Non-invasive fibrosis scores (APRI, FIB-4) were calculated. Results: Median plasma BDNF concentrations were significantly higher in PBC patients than in controls [median: 21.04 ng/mL (IQR: 10.68–38.07) vs. 5.80 ng/mL (IQR: 4.58–7.54); p < 0.0001]. In PBC patients, higher BDNF levels correlated inversely with liver stiffness measured by ElastPQ (R = −0.39, p = 0.0258), spleen dimensions, splenic vein flow volume (R = −0.49, p = 0.0018), suggesting an association with milder liver fibrosis and early hemodynamic alterations. A trend toward association between BDNF and IL-6 levels was observed in multivariate analysis. No significant associations were found between BDNF concentrations and markers of hepatocellular injury, cognitive performance, or fatigue severity. Conclusions: Plasma BDNF concentrations are elevated in early-stage PBC and inversely correlate with liver fibrosis severity. No significant associations were found with hepatocellular injury, cognitive function, or fatigue. These findings suggest that BDNF may play a protective role against hepatic fibrogenesis, or alternatively, that BDNF concentrations may decline with advancing liver disease. Further studies are needed to clarify its significance in PBC. Full article

Ursodeoxycholic acid (UDCA) is widely used to treat cholestatic liver diseases such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), yet its molecular mechanisms remain unclear. This study investigated the impact of long-term UDCA therapy on circulating levels of the microRNAs miR-34a and miR-506, which are implicated in PBC pathogenesis, and explored associated changes in inflammatory markers and signaling pathways. Serum samples from patients with PBC and PSC were collected before and after UDCA treatment and analyzed for miRNA expression as well as levels of TREM-2 and sCD163. In vitro studies using human cholangiocytes and lipopolysaccharide (LPS) stimulation assessed changes in the expression of miR-34a, TREM-2, and ADAM17. The results showed that the baseline levels of miR-34a and miR-506 were significantly elevated in PBC patients compared to controls and were significantly reduced after UDCA therapy in PBC but not in PSC. UDCA also decreased serum levels of TREM-2 and sCD163. In vitro, it suppressed the LPS-induced expression of miR-34a and ADAM17 while enhancing TREM-2 expression. Single-cell RNA sequencing of liver tissue and immunofluorescence staining confirmed TREM-2 expression in cholangiocytes. These findings suggest that UDCA modulates key inflammatory pathways and miRNAs in PBC, providing mechanistic insights into its therapeutic effect Full article

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is one of the fastest-growing hepatic disorders worldwide. During its natural course, MASLD tends to progress from isolated steatosis of the liver to Metabolic Dysfunction-Associated Alcoholic Steatohepatitis (MASH), advanced fibrosis, and finally cirrhosis, with the risk of developing hepatocellular carcinoma (HCC). Although frequently related to overweight or obesity and other components of the metabolic syndrome (MS), MASLD can also be present in individuals without such risk factors. The mechanisms leading to MASLD are incompletely elucidated and may involve many proinflammatory and pro-fibrotic pathways, disrupted biliary acid homeostasis, and gut microbiota dysbiosis. Aldosterone and its interaction with the mineralocorticoid receptor (MR) are thought to participate in the pathogenesis of MASLD through the modulation of inflammation and fibrosis. Remarkably, blockade of the MR in experimental models was shown to improve MASH and fibrosis through mechanisms that need further characterization. So far, however, few clinical studies have explored the effect of MR blockade in the management of MASH and associated fibrosis. This review is intended to summarize the recent animal and human data concerning the interaction between MR pathways and MASLD. Full article

Introduction: Liver transplantation remains the definitive treatment for end-stage liver disease but faces critical challenges including organ shortages and preservation difficulties, particularly with extended criteria donor (ECD) grafts. Hypothermic machine perfusion (HMP) represents a promising alternative to traditional static cold storage (SCS). Methods: This retrospective study analyzed outcomes from 62 liver transplant recipients between 2016 and 2025, comparing 8 grafts preserved by HMP using the Liver Assist^® system and 54 grafts preserved by SCS. Parameters assessed included postoperative complications, hemodynamic stability, ischemia times, and survival outcomes. Results: HMP significantly reduced surgical (0% vs. 75.9%, p = 0.01) and biliary complications (0% vs. 34.4%, p = 0.004), improved hemodynamic stability post-reperfusion (∆MAP%: 1 vs. 21, p = 0.006), and achieved superior one-year survival rates (100% vs. 84.4%). Despite longer ischemia periods, grafts treated with HMP exhibited fewer adverse effects from ischemia-reperfusion injury. Discussion: These findings highlight the substantial benefits of HMP, particularly in improving graft quality from marginal donors and reducing postoperative morbidity. Further adoption of this technology could significantly impact liver transplantation outcomes by expanding the viable donor pool. Conclusions: The study underscores the effectiveness of hypothermic machine perfusion (HMP) as a superior preservation method compared to traditional static cold storage (SCS), HMP appears to be associated with improved short-term outcomes in liver transplantation. By substantially reducing postoperative complications and enhancing graft viability, HMP emerges as a pivotal strategy for maximizing the use of marginal donor organs. Further research and broader clinical implementation are recommended to validate these promising results and to fully harness the potential of HMP in liver transplantation. Full article

Immunotherapy has emerged as a transformative approach in gastrointestinal (GI) cancers, addressing historically poor survival rates in advanced-stage disease. Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis demonstrate remarkable efficacy in colorectal cancer with deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H), exemplified by trials like NICHE-2 achieving exceptional pathological response rates. However, significant limitations persist, including resistance in some dMMR/MSI-H tumors, minimal efficacy in proficient mismatch repair (pMMR) tumors, and low overall response rates across most GI malignancies due to tumor heterogeneity and immune evasion mechanisms. Predictive biomarkers such as tumor mutational burden (TMB) and PD-L1 expression are crucial for optimizing patient selection, while hypermutated pMMR tumors with POLE mutations represent emerging therapeutic opportunities. In pancreatic adenocarcinoma, where survival remains dismal, combination strategies with chemotherapy and novel approaches like cancer vaccines show promise but lack transformative breakthroughs. Esophagogastric cancers benefit from ICIs combined with chemotherapy, particularly in MSI-H and HER2-positive tumors, while hepatocellular carcinoma has achieved significant progress with combinations like atezolizumab–bevacizumab and durvalumab–tremelimumab surpassing traditional therapies. Biliary tract cancers show modest improvements with durvalumab–chemotherapy combinations. Despite these advances, immunotherapy faces substantial challenges including immune-related adverse events, acquired resistance through cancer immunoediting, and the need for biomarker-driven approaches to overcome tumor microenvironment barriers. This review discusses key clinical trials, therapeutic progress, and emerging modalities including CAR T-cell therapies and combination strategies, emphasizing the critical need to address resistance mechanisms and refine precision medicine approaches to fully realize immunotherapy’s potential in GI malignancies. Full article

Liver fibrosis is a frequent pathological outcome of long-term liver diseases, arising from sustained damage to the liver. Two main types of liver damage can trigger fibrotic progression: hepatocellular injury, often caused by viral infections, alcohol, or metabolic disorders, and cholestatic injury, associated with impaired bile flow due to autoimmune or congenital conditions. Despite diverse etiologies, liver fibrosis exhibits conserved biological processes, including hepatocyte death, chronic inflammation, disruption of epithelial or endothelial barriers, and excessive deposition of extracellular matrix (ECM) components. These coordinated events reflect the complex interplay among parenchymal damage, immune activation, and fibrogenic signaling pathways. If unresolved, fibrosis may progress to cirrhosis, liver failure, or hepatocellular carcinoma. In the pursuit of non-invasive biomarkers for early detection and monitoring of fibrosis, extracellular vesicles (EVs) have garnered significant attention. Among the diverse cargoes within EVs, microRNAs (miRNAs) have emerged as particularly promising due to their stability, disease-specific expression patterns, and involvement in fibrogenic signaling. This review explores the role of EV-associated miRNAs in liver fibrosis, highlighting key candidates implicated in hepatocellular and cholestatic injury and their clinical potential as diagnostic and prognostic biomarkers, with special focus on MAFLD/MASH, primary sclerosing cholangitis, primary biliary cholangitis, and biliary atresia as representatives. Full article

Hepatobiliary diseases, which include disorders of the liver, gallbladder, and bile ducts, remain a major global health concern. A significant proportion of deaths worldwide are attributed to hepatic diseases, accounting for 4% of the total global mortality in 2023. Among benign hepatobiliary diseases, metabolic dysfunction-associated steatotic liver disease is the most prevalent liver pathology, with a concerning rise in incidence, while it is recognized as the leading cause of liver transplantation in the United States. However, there is a notable rise over time in cases of autoimmune hepatobiliary disorders, including autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis. Meanwhile, hepatocellular carcinoma still remains the most frequently diagnosed hepatobiliary malignancy, constituting the third leading cause of malignancy-related mortality globally. Meanwhile, cholangiocarcinoma and gallbladder cancer are the second and third most common hepatobiliary malignancies, respectively, both exhibiting highly aggressive malignant behavior. Despite the notable advances in biomarkers and the development of therapeutic tools, early diagnosis and monitoring are considered pivotal for the management of the aforementioned pathologies. The development of new non-invasive biomarkers that can effectively identify, monitor these pathologies, and guide their management is considered a necessity. Extracellular vesicles (EVs) constitute nanoparticles with several embedded cargoes, with a significant role in intercellular communication, which are considered promising biomarkers in several diseases, including viral, metabolic, autoimmune, and malignant diseases. In this review, we will shed light on the role of EVs as novel frontiers in hepatobiliary diseases. Full article

Objectives: To analyze the factors associated with recurrent choledocholithiasis following endoscopic retrograde cholangiopancreatography (ERCP) with biliary sphincterotomy (BS). Methods: A retrospective, observational, and analytical cohort study was conducted. Patients who underwent ERCP with BS for benign biliary pathology and were followed for a minimum of two years were included. Demographic and clinical data were collected, including the indication for the procedure, endoscopic findings, performance and timing of cholecystectomy (before or after ERCP), and the need for repeat procedures. Episodes of choledocholithiasis were defined as those occurring at least six months after the initial ERCP. Follow-up continued until patient death, loss of follow-up, or the conclusion of the study. Results: A total of 576 patients were included, with a mean age of 71 years and an average follow-up duration of 131 months. Sixty-nine cases of recurrent choledocholithiasis were documented (11.96%). Multivariate analysis identified the following predictive factors for recurrence: age over 50 years, bile duct dilation upon initial evaluation, history of biliary surgery, cytology sampling, placement of biliary stents, repeated ERCP, biliary diversion procedures, and cholecystectomy prior to the index ERCP. Conclusions: Biliary duct dilation, advanced age, and any previous manipulation of the biliary tree are associated with an increased risk of recurrent choledocholithiasis. Cholecystectomy performed after the initial ERCP was not associated with a reduced recurrence risk. Full article

Background: Baicalin (BG) has been used in the treatment of many diseases. However, the effect of hepatic insufficiency on its pharmacokinetics has not been reported, and there is a lack of clinical guidance for the use of BG in patients with hepatic impairment. Methods: Carbon tetrachloride (CCl₄)-induced rat models were used to simulate hepatic failure patients to assess the effect of hepatic impairment on the pharmacokinetics and distribution of BG. In vitro metabolism and transporter studies were employed to elucidate the potential mechanisms. Results: After intragastric administration of 10 mg/kg of BG, the peak plasma concentration and exposure (AUC_0–t) of BG decreased by 64.6% and 52.6%, respectively, in CCl₄-induced rats. After intravenous administration, the AUC_0–t decreased by 73.6%, and unlike in the control group, the second absorption peak of BG was not obvious in the concentration–time curve of CCl₄-induced rats. The cumulative excretion of BG in the feces increased, but that in the bile decreased. In vivo data indicated that the absorption and enterohepatic circulation of BG were affected. In vitro studies found that the hydrolysis of BG to the aglycone baicalein decreased significantly in the intestinal tissues and contents of the CCl₄-induced rats. And BG was identified as a substrate for multiple efflux and uptake transporters, such as breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins (MRPs), organic anion transporting polypeptides (OATP1B1, 1B3, 2B1), and organic anion transporters (OATs). The bile acids accumulated by liver injury inhibited the uptake of BG by OATPs, especially that by OATP2B1. Conclusions: Hepatic impairment reduced BG hydrolysis by intestinal microflora and inhibited its transporter-mediated biliary excretion, which synergistically led to the attenuation of the enterohepatic circulation of BG, which altered its pharmacokinetics. Full article

Background/Objectives: Cholangiocarcinoma (CCA) is a highly heterogeneous malignancy of the biliary tract with limited diagnostic tools for early detection. Current serum markers, such as CA19-9, lack specificity and sensitivity, particularly in early-stage disease, which hinders the effectiveness of curative interventions. This narrative review evaluates the limitations of existing diagnostic approaches and explores the potential of combining liquid biopsy (LB) technologies with CRISPR/Cas-based systems for precise, minimally invasive biomarker detection. Methods: A narrative review was conducted, synthesizing literature from 2018 to 2025 across PubMed, MDPI, Web of Science, Google Scholar, and Embase using MeSH terms such as “cholangiocarcinoma,” “liquid biopsy,” “miRNA,” and “CRISPR/Cas.” Results: Circulating microRNAs (e.g., miR-21, miR-16, miR-877) exhibit high diagnostic accuracy. The RACE (Rolling Circle Amplification-assisted CRISPR/Cas9 Cleavage) platform shows promise for detecting extracellular vesicle (EV)-derived miRNAs with high sensitivity and single-nucleotide specificity. When paired with liquid biopsy, CRISPR-based assays enable real-time, cost-effective, and multiplexed detection of tumor-specific biomarkers. Conclusions: The introduction of LB combined with CRISPR/Cas systems could potentially revolutionize the early and accurate diagnosis of CCA, thereby advancing the overall treatment strategy. However, this method is still under development and requires further testing before it can be incorporated into routine diagnostics. Full article

Sjogren’s disease (SjD) is a systemic autoimmune disease primarily affecting the exocrine glands. Systemic manifestations, including hepatic involvement, are increasingly recognized. This study aimed to delineate the clinical features and associated factors of autoimmune hepatic involvement in SjD. A retrospective analysis was conducted on patients diagnosed with SjD at Seoul St. Mary’s Hospital over the past 10 years. Autoimmune hepatic involvement was defined by fulfilling diagnostic criteria for autoimmune hepatitis (AIH) or primary biliary cholangitis (PBC). Clinical, serological, and demographic data were obtained from medical records. Among 1119 patients with SjD, 51 (4.6%) had autoimmune hepatic involvement. AIH (64.7%) was the most common type, followed by PBC (27.5%) and overlapping disease (7.8%). Compared to those without hepatic involvement, affected patients were older at diagnosis (p = 0.003) and showed higher frequencies of thrombocytopenia, splenomegaly, anti-centromere antibody (ACA), and elevated antinuclear antibody titers as measured by indirect immunofluorescence (IFI-HEp-2) (all p < 0.001). Multivariable analysis identified splenomegaly, elevated IFI-HEp-2 titer, and ACA positivity as independent factors associated with hepatic involvement. Most patients responded well to immunosuppressive therapy, with only a small proportion (15.7%) progressing to liver fibrosis. Autoimmune hepatic involvement is relatively uncommon but clinically meaningful in patients with SjD. Full article

Intrahepatic cholangiocarcinoma (iCCA) is a malignancy with limited treatment options in advanced stages. Recently, targeted therapies against fibroblast growth factor receptor 2 (FGFR2) fusions have emerged as a promising approach for selected patients. Tasurgratinib, a selective FGFR1–3 inhibitor, was approved in Japan in 2024 for second-line treatment of FGFR2 fusion-positive biliary tract cancer. We report the case of a 55-year-old female with advanced iCCA harboring an FGFR2-BICC1 fusion, who experienced a rapid clinical response to tasurgratinib following disease progression on gemcitabine, cisplatin, and durvalumab (GCD). Following the failure of GCD therapy, treatment with oral tasurgratinib was initiated at 140 mg/day and subsequently reduced to 105 mg/day due to Grade 2 diarrhea. Within weeks, imaging and tumor markers indicated a partial response, accompanied by a reduction in ascites, and improved performance status. The response sustained for several months without evidence of disease progression. Notably, no substantial clinical hyperphosphatemia or anorexia was observed during treatment. This is the first report to describe the real-world clinical efficacy of tasurgratinib in an iCCA patient with FGFR2-BICC1 fusion. Our findings suggest that tasurgratinib can provide a rapid and durable response with manageable toxicity in molecularly selected patients who have progressed on standard therapies. Full article