Search Results (224)

Gallbladder cancer (GBC) is the most common biliary tract malignancy and is among the most lethal gastrointestinal cancers. Since its inclusion in cancer staging manuals, the GBC Tumour–Node–Metastasis (TNM) classification has undergone repeated revisions intended to improve anatomical precision and prognostic discrimination. This narrative review traces the evolution of GBC staging across AJCC editions and the 2025 UICC TNM update and critically examines whether these refinements have translated into clinically meaningful risk stratification. In the 2025 UICC TNM 9 grouping, Stage IA corresponds to T1aN0M0 and Stage IB to T1bN0M0, while T2aN0M0 and T2bN0M0 remain Stage IIA and IIB, respectively. Structured literature searches were performed to identify historical staging documents, population-based analyses, validation studies, and prognostic reports relevant to stage migration, survival discrimination, and emerging staging modifiers. Successive changes, including T-category refinement and the transition from nodal location to nodal burden, have improved anatomical resolution. However, available validation studies suggest that gains in overall prognostic performance remain modest, with reported concordance indices often remaining near 0.66. Contemporary evidence increasingly shows that tumour location, adequacy of lymphadenectomy, number of positive lymph nodes, lymph node ratio, log odds of positive lymph nodes, obstructive jaundice, residual disease status, and selected molecular alterations may capture inter-patient heterogeneity beyond anatomy alone. Future staging refinement should therefore preserve TNM as a common anatomical language while developing validated parallel modifiers that support more individualized prognostication and treatment selection. Full article

Background: This study evaluated the association between cumulative chemotherapy exposure and overall survival (OS) in patients with advanced biliary tract cancer (BTC) and explored baseline factors associated with prolonged treatment continuation. Methods: Patients with advanced BTC receiving systemic chemotherapy were stratified by cumulative chemotherapy exposure (<8 vs. ≥8 cycles) and analyzed retrospectively. Logistic regression analysis identified baseline factors associated with receiving ≥8 chemotherapy cycles. OS was evaluated using Kaplan–Meier and landmark-adjusted time-dependent Cox proportional hazards analyses. Results: Among 86 patients analyzed, those receiving ≥8 chemotherapy cycles demonstrated more favorable inflammatory and nutritional profiles and lower metastatic burden. Median OS was longer in patients who received ≥8 chemotherapy cycles (n = 40) than in those who received <8 cycles (n = 46) (19.3 vs. 6.5 months, respectively; log-rank p < 0.001). Multivariable logistic regression identified metastatic disease as an independent factor associated with a lower likelihood of receiving ≥8 cycles (OR 0.34, 95% CI 0.12–0.97, p = 0.044). In landmark-adjusted multivariable analysis (n = 66), receiving ≥8 chemotherapy cycles remained independently associated with longer OS (HR 0.46, 95% CI 0.22–0.96, p = 0.039). Restricted cubic spline analysis demonstrated progressive hazard reduction with increasing chemotherapy exposure, although the magnitude of reduction attenuated beyond approximately 8 cycles. Conclusion: Greater cumulative chemotherapy exposure was associated with prolonged OS in advanced BTC, with attenuation of the survival benefit beyond approximately 8 cycles. Sustained treatment exposure may partly reflect preserved physiological reserve and ability to maintain systemic therapy in real-world clinical practice. Full article

Immune checkpoint inhibitor (ICI)-based combinations have become central systemic treatment options for advanced hepatocellular carcinoma (HCC) and are now being integrated into selected intermediate-stage settings. As tumor responses have improved, some patients who were not initially candidates for curative-intent treatment may later become candidates for resection, ablation, or liver transplantation. However, radiographic response alone does not define curative-intent candidacy, and no shared framework currently guides how post-immunotherapy response should be translated into a treatment decision. Terminology also differs regionally: Asian literature frames a resection-anchored paradigm, whereas Western practice uses transplant-anchored downstaging. This narrative review proposes a multidisciplinary framework for immunotherapy-based conversion to curative-intent treatment in HCC. We first clarify the lexicon of conversion, downstaging, bridging, neoadjuvant therapy, post-ICI transplantation, and drug-free or treatment-free status. We then summarize conversion-relevant evidence across key clinical decision settings, including transarterial chemoembolization (TACE)-unsuitable intermediate-stage disease, portal vein tumor thrombus or macrovascular invasion, borderline-resectable or locally advanced disease, and transplant downstaging or bridging. The central framework defines curative-intent transition through the intersection of three domains: technical suitability, oncologic suitability, and physiologic or liver-reserve suitability. Biomarkers, imaging response, tumor-marker kinetics, liver function, and treatment-related toxicity are discussed as inputs into candidacy rather than as response measures alone. Finally, we propose a multidisciplinary workflow and highlight lessons from pancreatic cancer, biliary tract cancer, and colorectal liver metastases. As an expert-opinion-based framework, this approach should structure multidisciplinary discussion rather than serve as validated selection criteria; harmonized terminology, prospective conversion registries, and conversion-specific endpoints are needed for prospective validation. Full article

Gemcitabine plus cisplatin (GemCis) has been served as an important first-line chemotherapy backbone for unresectable locally advanced or metastatic biliary tract cancer (BTC). However, cisplatin is unsuitable for all patients. Gemcitabine plus carboplatin (GemCarbo) is frequently used as an alternative, but direct comparative data remain limited. We retrospectively review patients with unresectable locally advanced or metastatic BTC who received first-line GemCis or GemCarbo at Songklanagarind Hospital between 2011 and 2025. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and selected laboratory-based safety outcomes. Propensity score matching was applied to reduce baseline treatment selection bias. Among 154 eligible patients, 95 received GemCis and 59 received GemCarbo. In the overall cohort, median OS was 8.44 months with GemCarbo and 9.82 months with GemCis (HR, 1.18; 95% CI, 0.82–1.70; p = 0.382). After propensity score matching, median OS was 8.44 months with GemCarbo and 11.63 months with GemCis (HR, 1.26; 95% CI, 0.84–1.90; p = 0.271). Median PFS was 4.27 and 5.75 months (HR, 0.91; 95% CI, 0.62–1.33; p = 0.617). ORR and DCR were comparable among evaluable patients. Increased serum creatinine was more frequent with GemCis, whereas hematologic toxicities were comparable. GemCarbo showed no statistically significant difference in OS or PFS compared with GemCis, suggesting that it may be considered as an alternative when cisplatin is unsuitable. However, prospective validation is warranted. Full article

Background/Objectives: Hardikar syndrome (HDKR) is an X-linked dominant disorder caused by pathogenic variants in the Mediator complex subunit 12 (MED12) gene, predominantly affecting females. It is characterized by multisystem congenital anomalies involving the foregut, biliary tract, craniofacial structures, eyes, skeleton, and genitourinary system, with generally preserved neurodevelopment. Only 34 cases have been reported to date, and most exhibit multiple congenital anomalies. We describe a female infant who presented with progressive cholestatic liver disease and complex hepatobiliary malformations, including an absent gallbladder and paucity of bile ducts, with unremarkable prenatal imaging. The clinical course was notable for hepatosplenomegaly, markedly elevated total bile acids, portal hypertension with esophageal varices, and eventual liver failure. Methods: Whole-exome sequencing (WES) was performed to investigate the underlying genetic etiology, followed by parental segregation analysis using Sanger sequencing to confirm and characterize the identified variant. Results: WES identified a novel de novo intronic heterozygous variant in MED12 (c.3868-5C>G). Unlike most previously reported cases, the predominant and early manifestation in our case was severe hepatobiliary disease with limited additional anomalies, suggesting possible phenotypic variability within the MED12-related Hardikar syndrome spectrum. The identified MED12 variant is classified as a variant of uncertain significance (VUS). Conclusions: This case underscores the diagnostic utility of WES in infants with unexplained cholestasis, highlights the importance of considering noncoding variants, and illustrates the value of reporting well-characterized patients carrying novel VUS, thereby contributing to the growing body of clinical and molecular evidence on MED12-related Hardikar syndrome. Full article

Background: Preeclampsia, a condition of high blood pressure during pregnancy, is linked to microangiopathy in various organs and may contribute to cancer development. This study aimed to evaluate cancer risk in women with newly diagnosed preeclampsia. Methods: We conducted a nationwide, population-based retrospective study using data from the Korean National Health Insurance claims database (2008–2020). Women diagnosed with preeclampsia between 2009 and 2013 were compared to a control group who underwent appendectomy but did not have preeclampsia. Participants with a prior cancer diagnosis were excluded. Cancer occurrence was assessed using the International Classification of Diseases, 10th revision codes. Results: Data from 42,380 preeclampsia patients and 105,327 controls were analyzed. Cancer incidence rates were 333.1 per 100,000 person-years in the preeclampsia group and 377.0 in controls. Preeclampsia was associated with significantly higher risks of gallbladder and biliary tract cancers (HR 5.49, 95% CI 1.23–24.50), breast cancer (HR 1.17, 95% CI 1.02–1.34), and thyroid cancer (HR 1.21, 95% CI 1.10–1.34). However, it was linked to lower risks of ovarian cancer (HR 0.44, 95% CI 0.27–0.74) and leukemia (HR 0.36, 95% CI 0.16–0.81). All hazard ratios were adjusted for age, which differed substantially between the two groups; unadjusted incidence rates and age-adjusted hazard ratios therefore differed in direction for some sites. Conclusions: Preeclampsia was associated with an increased risk of certain cancers, including breast and thyroid cancers, and with a decreased risk of ovarian cancer and leukemia. Because the control group was older than the preeclampsia group, crude incidence rates and age-adjusted hazard ratios differed in direction; the age-adjusted estimates should therefore be regarded as the primary findings. Several site-specific associations, particularly those based on small event counts (e.g., gallbladder and biliary tract cancer), should be interpreted as exploratory and warrant replication. Full article

Biliary tract cancers (BTCs) comprise a heterogeneous group of malignancies arising from the biliary tree, including cholangiocarcinomas and gallbladder carcinomas. Although their incidence is rising globally in Western countries, these cancers are rare and most often diagnosed at advanced stages. Their molecular heterogeneity and frequent resistance to therapy further contribute to their dismal prognosis. In recent years, molecular profiling studies have led to a better understanding of BTC biology and have opened new therapeutic opportunities, particularly for patients with advanced or metastatic disease. Alterations in DNA damage repair (DDR) genes have been identified in a substantial proportion of BTC cases, with some cohorts observing frequencies approaching ~70%. These genetic alterations play a critical role in tumorigenesis and disease progression and may contribute to treatment resistance. In this article, we discuss the current knowledge on: (1) the main DDR signaling pathways; (2) the prevalence of DDR gene alterations across BTC subtypes; (3) the potential of DDR gene alterations as prognostic and/or predictive biomarkers of treatment response; and (4) the latest advances in DDR-based targeted therapies and ongoing clinical trials in BTC. 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

Background: The biliary and pancreatic tract is increasingly recognized as a microbial ecosystem rather than a sterile environment. Dysbiosis contributes to inflammation, bile acid alterations, and carcinogenesis, with distinct microbiota profiles linked to progression from benign to malignant conditions. Clinical factors, including gut–liver axis disruption and biliary stenting, may further exacerbate microbial imbalance. Objective: The objective of this study is to synthesize current evidence and identify knowledge gaps on the role of biliary microbiota in pancreaticobiliary carcinogenesis and its implications for diagnosis, prognosis, and therapy. Methods: This scoping review was conducted following PRISMA-ScR guidelines. A systematic search of PubMed, Web of Science, and Scopus was performed for studies published between January 2015 and December 2025, guided by the PICo framework. Results: Included studies primarily characterized changes in microbiota composition to identify microbial biomarkers associated with pancreaticobiliary diseases. Predictive bioinformatics analyses suggest that dysbiosis may promote carcinogenesis through metabolic and inflammatory pathways. Machine learning approaches identified microbiota-based signatures with potential diagnostic value for precancerous lesions, although discrimination remains limited. Biliary dysbiosis was also associated with outcomes related to biliary stenting, chemoprophylaxis, postoperative complications, and responses to chemotherapy or surgery. Conclusions: Integration of microbiota profiling with predictive bioinformatics and machine learning may improve understanding of pancreaticobiliary carcinogenesis. Identifying microbial and functional biomarkers could enable personalized diagnostic and therapeutic strategies, ultimately improving patient outcomes. Full article

The undesired prognosis of biliary tract cancer is mainly attributed to the difficulty in detecting cancer lesions, including intraepithelial neoplasia, and other hurdles in procuring sufficient pathological samples by forceps biopsy and brushing, or even their combination. However, the transpapillary approach under endoscopic retrograde cholangiopancreatography (ERCP) is the mainstream approach for the work-up and treatment of biliary tract diseases, especially biliary tract cancers, because the ERCP-guided approach efficiently enables simultaneous biliary drainage for the treatment of cholangitis/jaundice and specimen acquisition for the diagnosis of biliary tract lesions. To improve diagnostic accuracy, several studies have been conducted on the feasibility and efficacy of genomic analysis of endoscopic specimens, namely, brushing samples, forceps biopsy samples, and aspiration samples such as bile with sensitivities ranging from 47 to 100%, with specificities ranging from 69 to 100%. Clinical use of genomic analysis remains heterogeneous due to the panel and next-generation sequencing system. For the efficient and precise treatment of patients with biliary tract cancer, future diagnosis and treatment should be based on molecular and genetic analyses. In this article, we review and summarize the comprehensive gene panel analyses of transpapillary brushing/biopsy/aspiration specimens for biliary tract cancer using next-generation sequencing, promoting effective clinical practice and providing a basis for future studies. Full article

Pancreatic ductal adenocarcinoma (PDAC) and biliary tract cancers (BTCs) remain highly lethal gastrointestinal malignancies because of late presentation, marked molecular heterogeneity, and limited durable benefit from conventional systemic therapy. This narrative review summarizes recent advances in both diseases, focusing on practice-informing clinical trials, biomarker-driven treatment strategies, and translational insights into tumor biology and resistance. In PDAC, progress includes refinement of perioperative management, broader germline and somatic testing, recognition of DNA damage repair-deficient subsets, and development of KRAS-directed therapies and rational combination strategies. In BTCs, especially intrahepatic cholangiocarcinoma, comprehensive molecular profiling has expanded precision oncology through actionable alterations such as FGFR2 rearrangements, IDH1 mutations, HER2 amplification/overexpression, BRAF V600E, NTRK fusions, and MSI-high/dMMR status. Immunotherapy has a clearer role in selected BTC populations, whereas in PDAC benefit remains largely restricted to rare biomarker-defined subsets. Across both diseases, circulating tumor DNA is emerging as a promising tool for prognostication, minimal residual disease assessment, response monitoring, and early resistance detection. Contemporary care increasingly depends on early molecular profiling, individualized treatment sequencing, and integration of targeted therapies, biomarker-guided immunotherapy, and clinical trials. Full article

Lymphoplasmacytic gastritis (LPG) is one of the most prevalent chronic diseases affecting cheetahs (Acinonyx jubatus) under human care, yet its underlying cause remains unresolved. Gastric inflammation occurs in the majority of adult captive cheetahs but is uncommon in free-ranging populations, suggesting that management-related factors contribute to disease pathogenesis. This review proposes that LPG represents a bile acid-driven gastroenteropathy arising from disruption of the natural feeding ecology of the cheetah. In free-ranging systems, cheetahs consume large episodic meals separated by prolonged fasting intervals and ingest whole-prey containing substantial connective tissue and collagen. In captivity, feeding patterns are typically characterized by smaller, more frequent meals and diets dominated by lean skeletal muscle with reduced structural complexity. I hypothesize that this mismatch alters gastric emptying kinetics, disrupts coordinated pancreatic and biliary secretion, and destabilizes fat digestion. Inefficient lipolysis may impair micelle formation and promote bile acid mislocalization within the gastrointestinal tract, increasing mucosal exposure to hydrophobic bile acids capable of inducing chemical epithelial injury. Within this framework, lymphoplasmacytic gastritis is interpreted as a secondary inflammatory reaction to chronic bile acid-mediated mucosal stress rather than a primary immune-mediated disorder. The model also provides a mechanistic explanation for the frequent coexistence of gastritis with fat and protein maldigestion in captive cheetahs. Differential responses to antimicrobial therapy, glucocorticoids, sulfasalazine, pancreatic enzyme supplementation, and bile acid-modifying agents are broadly consistent with this proposed mechanism. Recognition of LPG as a physiologically driven gastroenteropathy has important implications for management, emphasizing restoration of feast–fast feeding patterns, inclusion of collagen-rich carcass components, and targeted modulation of bile acid composition and signaling. Full article

Background: GBC is an aggressive biliary tract malignancy with limited survival. Although actionable genomic alterations (AGAs) are increasingly recognized in GBC, their prognostic association in real-world practice remains incompletely defined because genomic status is often confounded by stage at presentation and treatment selection. We evaluated the association between documented AGA status and overall survival (OS) using a tiered matching strategy to account for major clinical confounders. Methods: Using the TriNetX Global Collaborative Network, we identified adults with GBC and stratified them into patients with at least one documented AGA in KRAS, TP53, ERBB2, IDH1, FGFR1, PIK3CA, or ARID1A, and a comparison cohort with no documented AGA (representing a real-world population of untested and wild-type patients). Two 1:1 propensity score-matched models were constructed: Model 1 matched for age, sex, and race/ethnicity; Model 2 additionally matched for metastatic disease, surgical resection, and chemotherapy history. Outcomes were evaluated using risk analysis and Kaplan–Meier survival methods. Results: A marked disparity in genomic documentation was observed before matching, with unknown race recorded in 51.0% of the comparison cohort versus 3.7% of the documented AGA cohort. In the demographic-matched analysis (Model 1), the documented AGA cohort had higher mortality (52.8% vs. 42.5%, p < 0.001) and shorter median OS (684 vs. 948 days; HR 1.23, p = 0.006). In the primary stage- and treatment-matched analysis (Model 2), mortality remained higher in the documented AGA cohort (56.2% vs. 43.0%), corresponding to an absolute risk difference of 13.2% (p < 0.001). Median OS was numerically shorter in the documented AGA cohort (750 vs. 784 days), although the proportional hazards assumption was violated, supporting interpretation based primarily on absolute risk measures. In exploratory subgroup analyses, KRAS alterations were associated with worse survival, whereas the TP53 subgroup was limited by small sample size. Conclusions: In this real-world matched analysis, the presence of documented AGAs in GBC were associated with higher mortality even after matching for major demographic, stage-related, and treatment-related variables. These findings support the prognostic relevance of genomic status in GBC and underscore the need to address disparities in access to genomic documentation and testing. Full article

The biliary tract, long considered a sterile environment, is now recognized to harbor a resident microbiota with important implications for health and disease. This review aims to summarize current knowledge on the composition and function of the biliary microbiota in physiological conditions, and its alterations in pathological states such as infection and lithiasis, with a particular focus on antimicrobial resistance. In healthy individuals, the biliary microbiota appears to be shaped by bile acids and gut–bile axis interactions, playing a role in local immune modulation. In disease, microbial dysbiosis contributes to conditions such as acute cholecystitis, cholangitis, and gallstone formation, with distinct microbial signatures linked to specific stone types. Common biliary pathogens, including E. coli, Enterococcus spp., Pseudomonas spp., and K. pneumoniae, often exhibit concerning resistance patterns, impacting therapeutic strategies. Emerging evidence highlights the interplay between intestinal and biliary microbiota, suggesting potential diagnostic and prognostic applications. Understanding these dynamics opens new avenues for microbiota-informed antibiotic stewardship, targeted microbiota modulation, and precision medicine approaches. Further research, particularly culture-independent and longitudinal studies, is crucial to fully elucidate the clinical significance of the biliary microbiota and to integrate microbiota profiling into patient management strategies. Full article

Background/Objectives: Distal cholangiocarcinoma is a rare biliary tract cancer typically treated with pancreaticoduodenectomy. Comparative evidence specifically addressing minimally invasive versus open pancreaticoduodenectomy for this disease remains scarce. Methods: We conducted an updated systematic review and pairwise meta-analysis of comparative studies limited to distal cholangiocarcinoma. Binary outcomes were summarized as odds ratios, continuous outcomes as mean differences, and overall survival as hazard ratios. The primary survival analysis included only directly reported hazard ratios from prespecified matched or weighted cohorts; hazard ratios reconstructed from Kaplan–Meier curves were examined only in sensitivity analyses. Results: Six retrospective comparative studies involving 1623 patients met the inclusion criteria. Minimally invasive surgery was associated with lower blood loss (mean difference, −104.93 mL; 95% CI, −145.30 to −64.57; I² = 16.3%). No clear differences were found in clinically relevant postoperative pancreatic fistula (odds ratio, 1.03; 95% CI, 0.85 to 1.25), major morbidity (odds ratio, 0.96; 95% CI, 0.64 to 1.43), or R0 resection (odds ratio, 1.22; 95% CI, 0.96 to 1.56). In the primary overall survival analysis based on directly reported hazard ratios, the pooled hazard ratio was 0.93 (95% CI, 0.57 to 1.52; I² = 1.3%). In the sensitivity analysis incorporating eligible reconstructed hazard ratios, the pooled hazard ratio was 0.88 (95% CI, 0.73 to 1.05). In an exploratory recurrence-related survival family analysis based on directly reported estimates, the pooled hazard ratio was 0.95 (95% CI, 0.83 to 1.07; I² = 0.0%). Conclusions: Minimally invasive pancreaticoduodenectomy may reduce blood loss without clear evidence of worse major postoperative or oncologic outcomes in distal cholangiocarcinoma. However, the available evidence is entirely observational and should be interpreted with caution. Full article