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Combination chemotherapy with gemcitabine and a platinum-based agent is regarded as a standard treatment for patients with advanced biliary-tract cancer. Results of phase 2 trials of single-agent erlotinib in biliary-tract cancer and of gemcitabine plus erlotinib in pancreatic cancer have shown modest benefits. Therefore, we aimed to investigate the efficacy of gemcitabine and oxaliplatin plus erlotinib versus chemotherapy alone for advanced biliary-tract cancer. In this open label, randomised, phase 3 trial, we randomly assigned patients (in a 1:1 ratio) with metastatic biliary-tract cancer (cholangiocarcinoma, gallbladder cancer, or ampulla of Vater cancer) to receive either first-line treatment with chemotherapy alone (gemcitabine 1000 mg/m2 on day 1 and oxaliplatin 100 mg/m2 on day 2) or chemotherapy plus erlotinib (100 mg daily). Treatment was repeated every 2 weeks until disease progression or unacceptable toxic effects. Randomisation was done centrally (stratified by participating centre and presence of measurable lesion). The primary endpoint was progression-free survival. Analyses were by intention-to-treat. This study is registered with ClinicalTrials.gov, number NCT01149122. 133 patients were randomly assigned to the chemotherapy alone group and 135 to the chemotherapy plus erlotinib group. The groups were balanced except for a higher proportion of patients with cholangiocarcinoma in the group given erlotinib than in the chemotherapy alone group (96 [71%] patients vs 84 [63%]). Median progression-free survival was 4·2 months (95% CI 2·7–5·7) in the chemotherapy alone group and 5·8 months (95% CI 4·6–7·0) in the chemotherapy plus erlotinib group (hazard ratio [HR] 0·80, 95% CI 0·61–1·03; p=0·087). Significantly more patients had an objective response in the chemotherapy plus erlotinib group than in the chemotherapy alone group (40 patients vs 21 patients; p=0·005), but median overall survival was the same in both groups (9·5 months [95% CI 7·5–11·5] in the chemotherapy alone group and 9·5 months [7·6–11·4] in the chemotherapy plus erlotinib group; HR 0·93, 0·69–1·25; p=0·611). All-cause deaths within 30 days of random assignment occurred in one (1%) of the patients in the chemotherapy alone group and in four (3%) of those in the chemotherapy plus erlotinib group. The most common grade 3–4 adverse event was febrile neutropenia (eight [6%] patients in the chemotherapy alone group and six [4%] in the chemotherapy plus erlotinib group). No patient died of treatment-related causes during the study. Subgroup analyses by primary site of disease showed that for patients with cholangiocarcinoma, the addition of erlotinib to chemotherapy significantly prolonged median progression-free survival (5·9 months [95% CI 4·7–7·1] for chemotherapy plus erlotinib vs 3·0 months [1·1–4·9] for chemotherapy alone; HR 0·73, 95% CI 0·53–1·00; p=0·049). Although no significant difference in progression-free survival was noted between groups, the addition of erlotinib to gemcitabine and oxaliplatin showed antitumour activity and might be a treatment option for patients with cholangiocarcinoma. None.

Background Biliary tract cancers (BTCs) are a series of heterogeneous malignancies that are broadly grouped based on the anatomical site where they arise into subtypes including intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma (ECC), gallbladder cancer (GBC), and ampulla of Vater cancer (AVC). Methods and Results The present study provides an overview of the epidemiology of the various BTCs based on data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database from 2000 to 2018. Distinct differences in both incidence and mortality rates were observed for these BTCs as a function of age, sex, ethnicity, and calendar year. In 2018, BTCs emerged as the fifth most prevalent form of alimentary tract cancer in the USA. While the incidence and mortality of ICC appear to be increasing, the incidence rates of GBC, ECC, and AVC have remained stable, as have the corresponding mortality rates. The most common and deadliest BTCs in 2018 were ICC and GBC among males and females, respectively. The ethnic groups exhibiting the highest incidence rates of these different BTCs were American Indians and Alaska Natives for GBC, and Asian and Pacific Islanders for ICC, ECC, and AVC. The incidence of all of these forms of BTC rose with age. There were some variations in BTCs in terms of staging, locoregional surgical treatments, adjuvant therapies, and prognostic outcomes from 2000 to 2018. Conclusions The epidemiological characteristics, staging, locoregional surgical treatments, adjuvant therapies, and prognostic outcomes were distinct for each of these BTCs.

Background Early-Onset Gastrointestinal Cancers concerns tumors in people under 50. Accumulating evidence suggests a significant increase in the burden of colorectal cancer in young adults. We investigated the global burden and spatiotemporal trends of the 6 major gastrointestinal (GI) cancers, including colon and rectum cancer (CRC), esophageal cancer (EC), gallbladder and biliary tract cancer (GBTC), liver cancer (LC), pancreatic cancer (PC), and stomach cancer (SC). in young adults, based on cancer-specific incidence and mortality. Methods All data for 6 early-onset (EO) GI cancers were obtained from the Global Burden of Disease study. Age-standardized incidence rate (ASIR), age-standardized death rate (ASDR), and corresponding estimated annual percentage change (EAPC) were calculated to assess temporal trends from 1990 to 2019. Results The global number of cases and deaths from all EO-GI cancers has risen since 1990, reaching 539,750 and 309,200, respectively in 2019. ASIR and ASDR decreased for most EO-GI cancers (total, esophageal, gallbladder and biliary tract (GBTC), liver, and stomach cancers), while EO-pancreatic cancer showed an upward trend. EO colorectal cancer had increased incidence and stable mortality. However, these trends varied by sex, age, region, and economic status. Men had a higher burden of EO GI cancers (except GBTC), and older populations were more affected. Asia, particularly East Asia, had a significant burden, while the Americas showed the largest increase. Areas with Middle and High-middle sociodemographic indices had a relatively high burden of EO-GI cancers. Conclusions The absolute burden of EO-GI cancers is rising worldwide, but the standardized burden has decreased, This indicates that we have made considerable progress in treatment and early detection.

The Life Span Study (LSS) of atomic bomb survivors has consistently demonstrated significant excess radiation-related risks of liver cancer since the first cancer incidence report. Here, we present updated information on radiation risks of liver, biliary tract and pancreatic cancers based on 11 additional years of follow-up since the last report, from 1958 to 2009. The current analyses used improved individual radiation doses and accounted for the effects of alcohol consumption, smoking and body mass index. The study participants included 105,444 LSS participants with known individual radiation dose and no known history of cancer at the start of follow-up. Cases were the first primary incident cancers of the liver (including intrahepatic bile duct), biliary tract (gallbladder and other and unspecified parts of biliary tract) or pancreas identified through linkage with population-based cancer registries in Hiroshima and Nagasaki. Poisson regression methods were used to estimate excess relative risks (ERRs) and excess absolute risks (EARs) associated with DS02R1 doses for liver (liver and biliary tract cancers) or pancreas (pancreatic cancer). We identified 2,016 incident liver cancer cases during the follow-up period. Radiation dose was significantly associated with liver cancer risk (ERR per Gy: 0.53, 95% CI: 0.23 to 0.89; EAR per 10,000 person-year Gy: 5.32, 95% CI: 2.49 to 8.51). There was no evidence for curvature in the radiation dose response (P=0.344). ERRs by age-at-exposure categories were significantly increased among those who were exposed at 0–9, 10–19 and 20–29 years, but not significantly increased after age 30 years, although there was no statistical evidence of heterogeneity in these ERRs (P = 0.378). The radiation ERRs were not affected by adjustment for smoking, alcohol consumption or body mass index. As in previously reported studies, radiation dose was not associated with risk of biliary tract cancer (ERR per Gy: –0.02, 95% CI: –0.25 to 0.30). Radiation dose was associated with a nonsignificant increase in pancreatic cancer risk (ERR per Gy: 0.38, 95% CI: <0 to 0.83). The increased risk was statistically significant among women (ERR per Gy: 0.70, 95% CI: 0.12 to 1.45), but not among men.

Abstract Background Biliary tract cancers (BTCs), including gallbladder cancer (GBC) and cholangiocarcinoma (CCA), are rare but aggressive malignancies with distinct molecular landscapes and poor prognoses. Genomic profiling has revealed significant molecular alterations, but the genomic landscape of BTC in the Indian population remains underexplored. This study aims to comprehensively characterize the mutation landscape of BTC in the Indian population. Methods A total of 154 BTC cases, including 69 CCA and 85 GBC, were retrospectively analyzed using data collected from various targeted sequencing panels. Somatic mutations, copy number variations (CNVs), and gene fusions in key oncogenic and tumor suppressor genes were identified from these panel reports. Downstream analyses were performed to derive key biological insights, including pathway enrichment and mutual exclusivity and co-occurrence analyses of genomic alterations. Results TP53 was the most frequently mutated gene (53%), followed by KRAS (18%), ARID1A (9%), IDH1 (7%), and PIK3CA (7%). Recurrent amplifications were observed in MYC (12%) and ERBB2 (9%). Pathway enrichment analysis revealed significant dysregulation in the PI3K-AKT-mTOR, Notch, and Wnt/β-catenin signaling pathways. Notably, IDH1 mutations were primarily observed in CCA, while STK11 mutations were exclusive to GBC, highlighting distinct molecular characteristics between the two subtypes. PD-L1-negative tumors exhibited distinct genomic alterations, notably SMAD4 mutations, which were associated with reduced PD-L1 expression. This loss of SMAD4, involved in TGF-β signaling, could impair immune response regulation and facilitate immune evasion. Conclusions This study provides a comprehensive molecular profiling of BTCs in the Indian population, revealing key genomic alterations, subtype-specific differences, and associations with immune features. The findings underscore the importance of molecular profiling in guiding personalized treatment strategies.

Background Both inflammatory bowel disease (IBD) and hepato‐pancreato‐biliary cancers (HPBC) have been established to cause a huge socioeconomic burden. Epidemiological studies have revealed a close association between IBD and HPBC. Methods Herein, we utilized inverse‐variance weighting to conduct a two‐sample Mendelian randomization analysis. We sought to investigate the link between various subtypes of IBD and HPBC. To ensure the accuracy and consistency of our findings, we conducted heterogeneity tests, gene pleiotropy tests, and sensitivity analyses. Results Compared to the general population, IBD patients in Europe exhibited a 1.22‐fold increased incidence of pancreatic cancer (PC) with a 95% confidence interval (CI) of 1.0022–1.4888 (p = 0.0475). We also found a 1.14‐fold increased incidence of PC in Crohn's disease (CD) patients with (95% CI: 1.0017–1.3073, p = 0.0472). In the East Asian population, the incidence of hepatocellular carcinoma (HCC) was 1.28‐fold higher (95% CI = 1.0709–1.5244, p = 0.0065) in IBD patients than in the general population. Additionally, ulcerative colitis (UC) patients displayed 1.12‐fold (95% CI: 1.1466–1.3334, p < 0.0001) and 1.31‐fold (95% CI: 1.0983–1.5641, p = 0.0027) increased incidences of HCC and cholangiocarcinoma (CCA), respectively. Finally, the incidence of PC was 1.19‐fold higher in CD patients than in the general population (95% CI = 1.0741–1.3132, p = 0.0008). Conclusion Our study validated that IBD is a risk factor for HPBC. This causal relationship exhibited significant heterogeneity in different European and East Asian populations.

BackgroundGallstones may result in inflammation, altered bile flow, and changes in metabolic hormone levels, thereby increasing cancer risk. However, previous studies for gallstones and cancers of the liver, biliary tract and pancreas in the U.S. were relatively limited.MethodsWe followed 115,036 women from the Nurses’ Health Study (1982–2012) and 49,729 men from the Health Professionals Follow-up Study (1986–2012). History of gallstones, including with or without performed cholecystectomy, was reported at baseline and updated through biennial questionnaires. The Cox proportional hazard regression model was used to calculate multivariable hazard ratios (HRs) and 95% confidence intervals (95% CIs).ResultsDuring up to 30-year follow-up, we identified 204 incidents of liver cancer, 225 biliary tract cancer and 1147 pancreatic cancer cases. Compared to those without gallstones diagnosis, the multivariable HRs for individuals with gallstones (untreated or with cholecystectomy) were 1.60 for liver cancer (95% CI: 1.14–2.26), 4.79 for biliary tract cancer (95% CI: 3.02–7.58), and 1.13 for pancreatic cancer (95% CI: 0.96–1.32). The multivariable HRs for individuals with cholecystectomy were 1.33 for liver cancer (95% CI: 0.90–1.95) and 1.15 for pancreatic cancer (95% CI: 0.98–1.36).ConclusionsGallstones were associated with a higher risk of cancers of the liver, biliary tract and possibly pancreas.

Background Gallbladder and biliary tract cancer (GBTC) poses a growing public health challenge in China, with considerable disparities across age and sex. Understanding long-term epidemiological patterns is essential for informing cancer control strategies and future projections. Methods Data from the Global Burden of Disease Study 2021 were used to assess GBTC burden in China from 1990 to 2021. Indicators analyzed included incidence, prevalence, mortality, disability-adjusted life years (DALYs), years lived with disability (YLDs), and years of life lost (YLLs). Joinpoint regression, age-period-cohort (APC) analysis, decomposition analysis, and Bayesian APC (BAPC) models were employed to explore temporal trends and project future burden through 2030. Results In 2021, China reported 51,720 new GBTC cases, with an age-standardized incidence rate (ASIR) of 2.49 per 100,000. Males exhibited higher burden than females across all indicators. Incidence, prevalence, mortality, and DALYs were highest in older age groups. From 1990 to 2021, China experienced increasing trends in incidence and prevalence, while age-standardized mortality rates (ASMR) declined. Compared to global trends, China's ASIR rose while global rates declined. DALYs decreased in both contexts but more steeply globally. Joinpoint regression revealed sex-specific shifts, with males showing consistent increases in incidence and females experiencing periods of both decline and rise. APC analysis highlighted increasing incidence among post-1950 birth cohorts and decreasing mortality in recent cohorts. Decomposition analysis indicated that rising incidence was driven by epidemiological changes and population growth, while mortality reduction was linked to medical improvements. BAPC models projected a continued rise in incidence, particularly among males. Conclusions The burden of GBTC in China is rising, especially among men and older adults. While mortality has improved, incidence continues to grow, highlighting the need for targeted prevention, early detection, and gender-specific public health policies.

Background Gallbladder and biliary tract cancer (GBTC) is a significant health burden in China, exacerbated by the rising prevalence of high body mass index (BMI). Understanding the trends and factors contributing to mortality and disability associated with GBTC is crucial for targeted public health interventions. Methods We utilized data from the Global Burden of Disease (GBD) Study to assess the burden of GBTC attributable to high BMI in China from 1990 to 2021. Age-standardized rates of deaths, disability-adjusted life years (DALYs), years lived with disability (YLDs), and years of life lost (YLLs) were analyzed. Joinpoint regression and decomposition analyses were conducted to evaluate trends and identify contributing factors, including aging, population growth, and epidemiological changes. Gender-specific differences were also assessed. Results In 2021, GBTC deaths attributable to high BMI in China reached 4,053, with males experiencing a higher overall burden than females, particularly in older age groups. While females showed a higher mortality and overall burden in the 60 to 79 age range, this trend reversed in older age brackets, with males experiencing steeper increases in mortality and disability-related indicators beyond age 80. The age-standardized DALYs rate mirrored this pattern, with higher rates in males in advanced age groups. From 1990 to 2021, China saw a steady increase in GBTC burden attributable to high BMI, contrasting with a global decline. Joinpoint analysis indicated marked rises in mortality and DALYs rates after 2005, especially in males. Decomposition analysis identified population growth and aging as major drivers of increased deaths, while epidemiological changes primarily contributed to rising DALYs, with a stronger impact observed in males. Conclusions The burden of GBTC attributable to high BMI in China has increased substantially over the last three decades, driven by population growth, aging, and epidemiological shifts. The trends highlight a growing gender disparity, with males experiencing a greater rise in mortality and disability. Public health strategies targeting obesity and metabolic risk factors are critical to mitigating the increasing GBTC burden.

Biliary tract cancers (BTCs), including bile duct cancer (BDC), gallbladder cancer (GC), and ampullary cancer (AC), are characterized by poor prognosis and increasing incidence. Identifying risk factors is essential for early detection, yet few studies have evaluated multiple risk factors for BTCs comprehensively within a large cohort. This study investigated risk factors for BTC subtypes using a large regional database from Shizuoka Prefecture, Japan. A cohort of 2,571,418 individuals was analyzed based on insurance claims from April 2012 to September 2021. Participants without medical checkups or with an observation period of less than one year were excluded, leaving 625,513 eligible participants. BTC incidence was assessed using multivariate Cox proportional hazards regression, incorporating health checkup data and comorbidities. Over a median follow-up of 6.2 years, 1433 cases of BDC, 838 cases of GC, and 205 cases of AC were identified. Shared risk factors across BTC subtypes included older age, male sex, elevated liver function, and cardiometabolic conditions such as hypertension and diabetes. Subtype-specific risk factors were also observed: hepatitis virus infection for BDC, bile duct stones for BDC and GC, gallbladder stones for GC, and rheumatic disease for AC. These findings emphasize both common and unique risk factors for BTC subtypes.