Association of tea and coffee consumption and biliary tract cancer risk: The Biliary Tract Cancers Pooling Project.

BACKGROUND AND AIMS: Tea and coffee are widely consumed beverages worldwide. We evaluated their association with biliary tract cancer (BTC) incidence. APPROACH AND RESULTS: We pooled data from 15 studies in the Biliary Tract Cancers Pooling Project to evaluate associations between tea and coffee consumption and biliary tract cancer development. We categorized participants as nondrinkers (0 cup/day), moderate drinkers (>0 and <3 cups/day), and heavy drinkers (≥3 cups/day). We estimated multivariable HRs and 95% CIs using Cox models. During 29,911,744 person-years of follow-up, 851 gallbladder, 588 intrahepatic bile duct, 753 extrahepatic bile duct, and 458 ampulla of Vater cancer cases were diagnosed. Individuals who drank tea showed a statistically significantly lower incidence rate of gallbladder cancer (GBC) relative to tea nondrinkers (HR=0.77; 95% CI, 0.64-0.91), and intrahepatic bile duct cancer (IHBDC) had an inverse association (HR=0.81; 95% CI, 0.66-1.00). However, no associations were observed for extrahepatic bile duct cancer (EHBDC) or ampulla of Vater cancer (AVC). In contrast, coffee consumption was positively associated with GBC, with a higher incidence rate for individuals consuming more coffee (HR<3 cups/day =1.29; 95% CI, 1.01-1.66; HR≥3 cups/day =1.49; 95% CI, 1.11-1.99, Ptrend=0.01) relative to coffee nondrinkers. However, there was no association between coffee consumption and GBC when restricted to coffee drinkers. There was little evidence of associations between coffee consumption and other biliary tract cancers. CONCLUSIONS: Tea consumption was associated with a lower incidence of GBC and possibly IHBDC. Further research is warranted to replicate the observed positive association between coffee and GBC.

Associations between cigarette smoking and biliary tract cancer by anatomic subsite and sex: a prospective cohort study in Japan.

PURPOSE: Biliary tract cancer (BTC) has not been considered a tobacco-related cancer, largely because of inconclusive results from epidemiological studies. We herein evaluate the association between cigarette smoking and risk of death from BTC by anatomic subsite and sex using data from a large, prospective cohort study in Japan. METHODS: The present study included 97,030 Japanese individuals who were enrolled in 1988-1990 and followed until 31 December 2009. Cox proportional hazards regression models were used to estimate relative risks (RRs) and 95% confidence intervals (CIs) for the association of BTC with cigarette smoking, including smoking status, number of cigarettes smoked per day, and pack-years of smoking. RESULTS: During a mean follow-up of 16.2 years, we documented 484 deaths (187 from gallbladder cancers and 297 from cancers of other and unspecified biliary tract parts). After adjustment for sex, age, body mass index, alcohol consumption, and history of gallstones, current smokers had a higher risk of death due to BTC (RR = 1.35, 95% CI = 1.01-1.79) than never smokers. In the analyses by anatomic subsite, current smoking was associated with an increased risk of death from gallbladder cancer (RR = 1.89 95% CI = 1.19-3.02), whereas no evidence of an association was noted for cancers of other and unspecified biliary tract parts (RR = 1.10, 95% CI = 0.77-1.58). Moreover, mortality risk increased with an increasing number of cigarettes smoked per day and pack-years of smoking, particularly for gallbladder cancer in men. CONCLUSION: Cigarette smoking is associated with an increased risk of death from BTC, particularly gallbladder cancer, in Japanese men.

Risk of carcinogenesis in the biliary epithelium of children with congenital biliary dilatation through epigenetic and genetic regulation.

PURPOSES: Congenital biliary dilatation (CBD), defined as pancreaticobiliary maljunction (PBM) with biliary dilatation, is a high risk factor for biliary tract cancer (BTC). KRAS and p53 mutations reportedly affect this process, but the mechanisms are unclear, as is the likelihood of BTC later in life in children with CBD. We investigated potential carcinogenetic pathways in children with CBD compared with adults. METHODS: The subjects of this study were nine children with CBD and 13 adults with PBM (10 dilated, 3 non-dilated) without BTC who underwent extrahepatic bile duct resections, as well as four control patients who underwent pancreaticoduodenectomy for non-biliary cancer. We evaluated expressions of Ki-67, KRAS, p53, histone deacetylase (HDAC) and activation-induced cytidine deaminase (AID) in the biliary tract epithelium immunohistochemically. RESULTS: The Ki-67 labeling index (LI) and expressions of KRAS, p53, HDAC, and AID in the gallbladder epithelium were significantly higher or tended to be higher in both the children with CBD and the adults with PBM than in the controls. CONCLUSIONS: BTC may develop later in children with CBD and in adults with PBM, via HDAC and AID expression and through epigenetic and genetic regulation.

Immunotherapy for Biliary Tract Cancer in the Era of Precision Medicine: Current Knowledge and Future Perspectives.

Biliary tract cancers (BTC) represent a heterogeneous and aggressive group of tumors with dismal prognosis. For a long time, BTC has been considered an orphan disease with very limited therapeutic options. In recent years a better understanding of the complex molecular landscape of biology is rapidly changing the therapeutic armamentarium. However, while 40-50% of patients there are molecular drivers susceptible to target therapy, for the remaining population new therapeutic options represent an unsatisfied clinical need. The role of immunotherapy in the continuum of treatment of patients with BTC is still debated. Despite initial signs of antitumor-activity, single-agent immune checkpoint inhibitors (ICIs) demonstrated limited efficacy in an unselected population. Therefore, identifying the best partner to combine ICIs and predictive biomarkers represents a key challenge to optimize the efficacy of immunotherapy. This review provides a critical analysis of completed trials, with an eye on future perspectives and possible biomarkers of response.

Approach to Resectable Biliary Cancers.

OPINION STATEMENT: Biliary malignancies, although rare, can be some of the most challenging to manage surgically. Intrahepatic cholangiocarcinomas are resectable if there is no evidence of metastatic disease. These tumors are managed with anatomic resection and portal lymphadenectomy when centrally located or multiple in a single lobe. Non-anatomic resection can be performed for solitary peripheral tumors with minimally invasive techniques. It is not our practice to routinely employ neoadjuvant chemotherapy prior to resection of these tumors. Hepatic arterial infusion chemotherapy is utilized at our institution in highly selected patients in the context of an ongoing clinical trial for unresectable tumors. Hilar cholangiocarcinomas, when resectable (i.e., ipsilateral arterial involvement or lack of vascular involvement), are managed with right or left (extended) hepatectomy, caudate resection, and portal lymphadenectomy. Distal cholangiocarcinomas are managed with pancreaticoduodenectomy. Neoadjuvant chemotherapy is not routinely used in our treatment algorithm of extrahepatic cholangiocarcinomas. Nodal involvement and positive margin (R1) resection necessitates adjuvant chemotherapy. Finally, gallbladder carcinoma is managed with radical cholecystectomy, anatomic segment IVb/V resection, and portal lymphadenectomy. Adjuvant chemotherapy is employed routinely amongst patients with T2 or higher tumors and those with positive lymph nodes.

Seropositivity for Helicobacter pylori and hepatobiliary cancers in the PLCO study.

Helicobacter has been suggested to play a possible role in hepatitis, gallstones, and hepatobiliary tumours. We assessed whether seropositivity to 15 H. pylori proteins was associated with subsequent incidence of 74 biliary tract and 105 liver cancer cases vs. 357 matched controls in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). Odds ratios and 95% confidence intervals were computed by conditional logistic regression after adjustment for known hepatobiliary cancer risk factors. H. pylori seropositivity was not associated with either biliary tract (1.76, 0.90-3.46) or liver cancer (0.87, 0.46-1.65). CagA seropositivity was associated with both endpoints, although the latter association was not statistically significant (biliary tract: 2.16, 1.03-4.50; liver cancer: 1.96, 0.98-3.93) and neither association was statistically significant after correcting for multiple comparisons. Together, these results suggest possible associations between H. pylori and hepatobiliary cancer and suggest the value of future studies investigating the association.Trial registration number: NCT00339495.

Associations between reproductive factors and biliary tract cancers in women from the Biliary Tract Cancers Pooling Project.

BACKGROUND & AIMS: Gallbladder cancer (GBC) is known to have a female predominance while other biliary tract cancers (BTCs) have a male predominance. However, the role of female reproductive factors in BTC etiology remains unclear. METHODS: We pooled data from 19 studies of >1.5 million women participating in the Biliary Tract Cancers Pooling Project to examine the associations of parity, age at menarche, reproductive years, and age at menopause with BTC. Associations for age at menarche and reproductive years with BTC were analyzed separately for Asian and non-Asian women. Hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards models, stratified by study. RESULTS: During 21,681,798 person-years of follow-up, 875 cases of GBC, 379 of intrahepatic bile duct cancer (IHBDC), 450 of extrahepatic bile duct cancer (EHBDC), and 261 of ampulla of Vater cancer (AVC) occurred. High parity was associated with risk of GBC (HR ≥5 vs. 0 births 1.72; 95% CI 1.25-2.38). Age at menarche (HR per year increase 1.15; 95% CI 1.06-1.24) was associated with GBC risk in Asian women while reproductive years were associated with GBC risk (HR per 5 years 1.13; 95% CI 1.04-1.22) in non-Asian women. Later age at menarche was associated with IHBDC (HR 1.19; 95% CI 1.09-1.31) and EHBDC (HR 1.11; 95% CI 1.01-1.22) in Asian women only. CONCLUSION: We observed an increased risk of GBC with increasing parity. Among Asian women, older age at menarche was associated with increased risk for GBC, IHBDC, and EHBDC, while increasing reproductive years was associated with GBC in non-Asian women. These results suggest that sex hormones have distinct effects on cancers across the biliary tract that vary by geography. LAY SUMMARY: Our findings show that the risk of gallbladder cancer is increased among women who have given birth (especially women with 5 or more children). In women from Asian countries, later age at menarche increases the risk of gallbladder cancer, intrahepatic bile duct cancer and extrahepatic bile duct cancer. We did not see this same association in women from Western countries. Age at menopause was not associated with the risk of any biliary tract cancers.

New Treatment Options for Advanced Biliary Tract Cancer.

OPINION STATEMENT: The standard of care first-line therapy for patients with advanced biliary tract cancers eligible for treatment continues to be the combination of gemcitabine and cisplatin. Based on the promising results of a phase II study, an ongoing multi-institutional phase III study is assessing the benefit of adding nab-paclitaxel to the chemotherapy doublet, and appropriate patients should be considered for enrollment at participating centers. We would recommend early comprehensive genomic profiling of patients' tumors to identify potentially targetable aberrations with available therapies. Results with therapeutic implications include tumors with microsatellite instability/deficient mismatch repair, alterations in FGFR, IDH1/2, and HER-2, and potentially other molecular vulnerabilities. Patients in whom a targetable genomic abnormality is found should be matched with appropriate agent. If a targetable fusion or mutation is not detected, patients eligible for second-line therapy should be considered for either clinical trial enrollment or a second-line cytotoxic chemotherapy regimen such as modified FOLFOX. Strategies incorporating immunotherapy into the treatment of patients with microsatellite stable advanced biliary tract cancers have yielded largely disappointing results thus far, and routine use of checkpoint inhibitors outside of a clinical trial is not recommended.

British Society of Gastroenterology and UK-PSC guidelines for the diagnosis and management of primary sclerosing cholangitis.

These guidelines on the management of primary sclerosing cholangitis (PSC) were commissioned by the British Society of Gastroenterology liver section. The guideline writing committee included medical representatives from hepatology and gastroenterology groups as well as patient representatives from PSC Support. The guidelines aim to support general physicians, gastroenterologists and surgeons in managing adults with PSC or those presenting with similar cholangiopathies which may mimic PSC, such as IgG4 sclerosing cholangitis. It also acts as a reference for patients with PSC to help them understand their own management. Quality of evidence is presented using the AGREE II format. Guidance is meant to be used as a reference rather than for rigid protocol-based care as we understand that management of patients often requires individual patient-centred considerations.

Menopausal hormone therapy and biliary tract cancer: a population-based matched cohort study in Sweden.

BACKGROUND: This study tested the hypothesis that contemporary menopausal hormonal therapy (MHT) increases the risk of biliary tract cancer. The risk of cancer of the biliary tract (gallbladder and extra-hepatic bile ducts) may be increased following estrogen exposure. MATERIAL AND METHODS: This was a nationwide population-based matched cohort study in Sweden. Data from the Swedish Prescribed Drug Register identified all women exposed to systemic MHT in 2005-2012. Group-level matching (1:3 ratio) was used to select women unexposed to MHT from the same study base, matched for history of delivery, thrombotic events, hysterectomy, age, smoking- and alcohol related diseases, obesity, and diabetes. Conditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Comparing 290,186 women exposed to MHT with 870,165 unexposed, MHT did not increase the OR of biliary tract cancer. The OR of gallbladder cancer was rather decreased in MHT users (OR 0.58, 95% CI 0.43-0.79), but this association became attenuated and statistically non-significant after adjusting for gallstone disease (OR 0.84, 95% CI 0.60-1.15). The OR of extra-hepatic bile duct cancers was 0.83 (95% CI 0.61-1.15). There were no clear differences when the analyses were stratified for estrogen or estrogen/progestogen combinations. MHT increased the risk of gallstone disease (OR 6.95, 95% CI 6.64-7.28). CONCLUSIONS: Contemporary MHT does not seem to increase the risk of biliary tract cancer. The decreased risk of gallbladder cancer may be explained by the increased use of surgery for symptomatic gallstones in MHT users.

Transitional care for patients with surgical pediatric hepatobiliary disease: Choledochal cysts and biliary atresia.

Choledochal cysts (CDCs) and biliary atresia (BA) are rare pediatric hepatobiliary anomalies that require surgical intervention due to increased risk of malignancy and liver failure, respectively. The underlying disease and operative procedures place patients at risk for long-term complications, which may continue to affect them into adulthood. Lack of a transitional care model in the health-care system potentiates the challenges they will face following aging out of their pediatric providers' care. We sought to elucidate the long-term complications and challenges patients with CDCs and BA face, review the current literature regarding transitioning care, and propose guidelines aiding adult providers in continued care and surveillance of these patients. A literature review was performed to assess short-term and long-term complications after surgery and the current standards for transitioning care in patients with a history of CDCs and BA. While transitional programs exist for patients with other gastrointestinal diseases, there are few that focus on CDCs or BA. Generally, authors encourage medical record transmission from pediatric to adult providers, ensuring accuracy of information and compliance with treatment plans. Patients with CDCs are at risk for developing biliary malignancies, cholangitis, and anastomotic strictures after resection. Patients with BA develop progressive liver failure, necessitating transplantation. There are no consensus guidelines regarding timing of follow up for these patients. Based on the best available evidence, we propose a schema for long-term surveillance.

Meta-analysis of risk of developing malignancy in congenital choledochal malformation.

BACKGROUND: Choledochal malformations comprise various congenital cystic dilatations of the extrahepatic and/or intrahepatic biliary tree. Choledochal malformation is generally considered a premalignant condition, but reliable data on the risk of malignancy and optimal surgical treatment are lacking. The objective of this systematic review was to assess the prevalence of malignancy in patients with choledochal malformation and to differentiate between subtypes. In addition, the risk of malignancy following cystic drainage versus complete cyst excision was assessed. METHODS: A systematic review of PubMed and Embase databases was performed in accordance with the PRISMA statement. A meta-analysis of the risk of malignancy following cystic drainage versus complete cyst excision was undertaken in line with MOOSE guidelines. Prevalence of malignancy was defined as the rate of biliary cancer before resection, and malignant transformation as new-onset biliary cancer after surgery. RESULTS: Eighteen observational studies were included, reporting a total of 2904 patients with a median age of 36 years. Of these, 312 in total developed a malignancy (10·7 per cent); the prevalence of malignancy was 7·3 per cent and the rate of malignant transformation was 3·4 per cent. Patients with types I and IV choledochal malformation had an increased risk of malignancy (P = 0·016). Patients who underwent cystic drainage had an increased risk of developing biliary malignancy compared with those who had complete cyst excision, with an odds ratio of 3·97 (95 per cent c.i. 2·40 to 6·55). CONCLUSION: The risk of developing malignancy among patients with choledochal malformation was almost 11 per cent. The malignancy risk following cystic drainage surgery was four times higher than that after complete cyst excision. Complete surgical resection is recommended in patients with choledochal malformation.

Cancer Stem cells and their cellular origins in primary liver and biliary tract cancers.

UNLABELLED: Liver and biliary tract cancers are highly aggressive, are heterogeneous in their phenotypic traits, and result in clinical outcomes that are difficult to manage. Cancers have subpopulations of cells termed "cancer stem cells" (CSCs) that share common intrinsic signaling pathways for self-renewal and differentiation with normal stem cells. These CSCs likely have the potential to evolve over time and to give rise to new genetically and functionally diverse subclones by accumulating genetic mutations. Extrinsic signaling from the tumor microenvironment, including the CSC niche, has been implicated in tumor initiation/progression and heterogeneity through dynamic crosstalk. CSCs have become recognized as pivotal sources of tumor initiation/progression, relapse/metastasis, and chemoresistance. CONCLUSION: The origins of CSCs are hypothesized to derive from the transformation of normal stem/progenitors and/or from the reprogramming of adult cells that converts them to stem/progenitor traits; however, the precise mechanisms have not yet been fully elucidated. (Hepatology 2016;64:645-651).

Immunotherapeutic Approaches to Biliary Cancer.

OPINION STATEMENT: Biliary tract cancers (BTCs) are rare aggressive neoplasms with a poor prognosis and a median survival of less than 1 year in the locally advanced or metastatic setting. Among the few patients who undergo curative resection the recurrence rates are high. About 90% of patients are detected at advanced stages, and systemic chemotherapy is the mainstay of their treatment. The treatment options for these patients are limited and multiple modalities of therapy from targeted therapy to immunotherapy and combination therapies (immunotherapy, targeted therapy, and chemotherapy) have been tested in this disease. Targeted therapies have failed to show a survival benefit. The deregulation of the immune system plays a significant role in the pathogenesis of BTCs. Therefore, immunotherapy, especially, immune checkpoint inhibitors hold great promise for this group of cancers. Numerous trials of immunotherapy in BTC are currently ongoing. In this review, we will discuss the available data and evidence for immunotherapy in BTC.

Exogenous estrogen and the risk of biliary tract cancer - a population-based study in a cohort of Swedish men treated for prostate cancer.

BACKGROUND: To assess the role of exogenous estrogen in the etiology of biliary tract cancer, a nationwide population-based cohort study in Sweden was performed. METHODS: The study included all men in Sweden with prostate cancer diagnosed in 1961-2008. Due to treatment standards, patients diagnosed in 1961-1980 were considered more exposed to estrogen, while those diagnosed in 1981-2008 were regarded less exposed. Standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) were calculated to estimate the risk of biliary tract cancer in cohort members compared to the corresponding Swedish male population. RESULTS: After 849 307 person-years of follow-up in 203 131 prostate cancer patients, there were 41 incident gallbladder cancers and 36 cancers of the extra-hepatic bile ducts. In overall, there were no apparent differences in the risk of gallbladder cancer or bile duct cancer between patients diagnosed in 1961-1980 and patients diagnosed in 1981-2008. However, in patients diagnosed in 1961-1980, there was a statistically non-significant increased risk of gallbladder cancer (SIR 1.34; 95% CI 0.71-2.29) and extra-hepatic bile duct cancer (SIR 1.20; 95% CI 0.55-2.28) > 5 years of follow-up after the prostate cancer diagnosis. No such association was found for patients diagnosed in 1981-2008. Sensitivity analyses excluding prostate cancer patients exposed to potential confounding factors did not change the SIRs. CONCLUSIONS: Long exposure to high doses of exogenous estrogen might increase the risk of biliary tract cancer. However, any potential excess risk of bile duct cancer resulted by prolonged exposure to high doses of exogenous estrogen seems to be small.

Double common bile duct with choledochal cyst and cholelithiasis: report of a case.

Double common bile duct (DCBD) is a rare congenital anomaly of the biliary system, often associated with biliary lithiasis, choledochal cyst, pancreaticobiliary maljunction (PBM), and upper gastrointestinal tract malignancies. We report a case of type I DCBD with choledochal cyst and cholelithiasis in a 52-year-old Chinese man. We also reviewed 24 cases of DCBD reported in the Chinese literature between 1965 and 2012. Most (58.3%) of these cases were classified as type I DCBD, with accompanying choledocholithiasis in 79.2%, cholecystolithiasis in 37.5%, choledochal cyst in 33.3%, and PBM in 8.3%. There was no case of concomitant cancer. The type and coexistence of PBM with DCBD are clinically important because of its close implications with concomitant pathology. Most Chinese people with DCBD have type I. Moreover, the high incidences of choledochal cyst and biliary lithiasis and the extremely low incidences of PBM and biliary cancer are the major clinical characteristics of DCBD in China.

[Microbiome and Biliary Tract Cancer].

Biliary tract cancers encompass a group of malignancies that affect the bile ducts and gallbladder and are associated with a poor prognosis, often due to late diagnosis and limited treatment options. The incidence of biliary tract cancer has been increasing gradually, underscoring the need for a better understanding of its pathogenesis and potential risk factors. Research suggests that biliary tract cancer may develop through a combination of genetic and epigenetic alterations, as well as environmental factors. The role of microbial exposure and the human microbiome in the pathogenesis of biliary tract cancer is an emerging area of interest. Traditionally, the biliary tree was considered sterile under normal conditions, but recent studies have identified associations between specific microbiological patterns and inflammatory biliary diseases and cancer. The human microbiome plays a crucial role in maintaining host homeostasis and interacting with the host's immune system. Dysbiosis, or an imbalance in the microbiome composition, has been implicated in the development of various diseases, including cancer. Hence, dysbiosis in the biliary tract might trigger the pathogenesis of biliary tract cancer. Advances in next-generation sequencing technology have provided researchers with a more comprehensive view of the microbiota and their potential roles in health and disease, providing more evidence of the relationship between the microbiota and biliary tract cancer. This review summarizes the latest evidence of the microbiome that would be associated with biliary tract cancer.

Durvalumab Plus Gemcitabine and Cisplatin in Patients with Advanced Biliary Tract Cancer: An Exploratory Analysis of Real-World Data.

BACKGROUND: The combination of gemcitabine and cisplatin (gem/cis) with the anti-PD-L1-antibody durvalumab was recently approved as first line therapy for biliary tract cancer (BTC) based on the results of the TOPAZ-1 trial. OBJECTIVE: We aim to analyse the feasibility and efficacy of the triple combination therapy in patients with BTC in a real-world setting and in correspondence with the genetic alterations of the cancer. METHODS: In this single-centre retrospective analysis, all patients with BTC and treated with durvalumab plus gem/cis from April 2022 to September 2023 were included. Survival and treatment response were investigated, within the context of the inclusion and exclusion criteria of TOPAZ-1 and in correspondence with genetic alterations of the cancer. RESULTS: In total, 35 patients, of which 51% met the inclusion criteria of the TOPAZ-1 trial, were analysed. Patients treated within TOPAZ-1 criteria did not have a significantly different median overall survival and progression free survival than the rest of the patients (10.3 versus 9.7 months and 5.3 versus 5 months, respectively). The disease control rate of patients within the TOPAZ-1 criteria was 61.1%, in comparison to 58.8% in the rest of patients. A total of 51 grade 3 and 4 adverse events were observed without significant differences in the subgroups. No specific correlating patterns of genetic alterations with survival and response were observed. CONCLUSIONS: The treatment of advanced patients with BTC with durvalumab and gem/cis, even beyond the inclusion criteria of the TOPAZ-1 trial, shows promising safety.