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.

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.

[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.

Increased Prevalence of Alpha-1-Antitrypsin Deficiency in Patients with Biliary Tract Cancer and Its Associated Clinicopathological Features.

Alpha-1 antitrypsin deficiency (A1ATD) is underdiagnosed and associated with liver diseases. Here, we genotyped 130 patients with biliary tract cancer (BTC) scheduled for liver resection and found A1ATD in 10.8% of the patients. A1ATD was found in all BTC subtypes, and patients had similar clinical features as non-A1ATD BTC, not permitting their identification using clinical routine liver tests. In intrahepatic cholangiocarcinoma (iCCA), the abundance of A1AT protein was increased in the tumor and appeared to be influenced by the genomic alterations. On the one hand, BTC with A1ATD had lower perineural invasion at histopathology and displayed a longer survival, suggesting that a deficiency in this protein is associated with a less aggressive phenotype. On the other hand, iCCA with high A1AT expression had more advanced tumor staging and enriched pathways for complement system and extracellular matrix interactions, indicating that A1AT protein might contribute to a more aggressive phenotype. With increased awareness, screening, and basic studies, A1ATD could represent one more layer of stratification for future targeted therapies in BTC.

Inflammatory bowel disease increases the risk of hepatobiliary pancreatic cancer: A two-sample Mendelian randomization analysis of European and East Asian populations.

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.

Early Decision Making in a Randomized Phase II Trial of Atezolizumab in Biliary Tract Cancer Using a Tumor Growth Inhibition-Survival Modeling Framework.

We assess the longitudinal tumor growth inhibition (TGI) metrics and overall survival (OS) predictions applied to patients with advanced biliary tract cancer (BTC) enrolled in IMbrave151 a multicenter randomized phase II, double-blind, placebo-controlled trial evaluating the efficacy and safety of atezolizumab with or without bevacizumab in combination with cisplatin plus gemcitabine. Tumor growth rate (KG) was estimated for patients in IMbrave151. A pre-existing TGI-OS model for patients with hepatocellular carcinoma in IMbrave150 was modified to include available IMbrave151 study covariates and KG estimates and used to simulate IMbrave151 study outcomes. At the interim progression-free survival (PFS) analysis (98 patients, 27 weeks follow-up), clear separation in tumor dynamic profiles with a faster shrinkage rate and slower KG (0.0103 vs. 0.0117 week-1 ; tumor doubling time 67 vs. 59 weeks; KG geometric mean ratio of 0.84) favoring the bevacizumab containing arm was observed. At the first interim analysis for PFS, the simulated OS hazard ratio (HR) 95% prediction interval (PI) of 0.74 (95% PI: 0.58-0.94) offered an early prediction of treatment benefit later confirmed at the final analysis, observed HR of 0.76 based on 159 treated patients and 34 weeks of follow-up. This is the first prospective application of a TGI-OS modeling framework supporting gating of a phase III trial. The findings demonstrate the utility for longitudinal TGI and KG geometric mean ratio as relevant end points in oncology studies to support go/no-go decision making and facilitate interpretation of the IMbrave151 results to support future development efforts for novel therapeutics for patients with advanced BTC.

Devimistat in Combination with Gemcitabine and Cisplatin in Biliary Tract Cancer: Preclinical Evaluation and Phase Ib Multicenter Clinical Trial (BilT-04).

PURPOSE: Devimistat (CPI-613) is a novel inhibitor of tumoral mitochondrial metabolism. We investigated the effect of devimistat in vitro and in a phase Ib clinical trial in patients with advanced biliary tract cancer (BTC). PATIENTS AND METHODS: Cell viability assays of devimistat ± gemcitabine and cisplatin (GC) were performed and the effect of devimistat on mitochondrial respiration via oxygen consumption rate (OCR) was evaluated. A phase Ib/II trial was initiated in patients with untreated advanced BTC. In phase Ib, devimistat was infused over 2 hours in combination with GC on days 1 and 8 every 21 days with a primary objective to determine the recommended phase II dose (RP2D). Secondary objectives included safety, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS: In vitro, devimistat with GC had a synergistic effect on two cell lines. Devimistat significantly decreased OCR at higher doses and in arms with divided dosing. In the phase Ib trial, 20 patients received a median of nine cycles (range, 3-19). One DLT was observed, and the RP2D of devimistat was determined to be 2,000 mg/m2 in combination with GC. Most common grade 3 toxicities included neutropenia (n = 11, 55%), anemia (n = 4, 20%), and infection (n = 3, 15%). There were no grade 4 toxicities. After a median follow-up of 15.6 months, ORR was 45% and median PFS was 10 months (95% confidence interval, 7.1-14.9). Median OS is not yet estimable. CONCLUSIONS: Devimistat in combination with GC is well tolerated and has an acceptable safety profile in patients with untreated advanced BTC.

Tratamiento quirúrgico del colangiocarcinoma extrahepático / Surgical Treatment of Extrahepatic Cholangiocarcinoma

Introducción: El colangiocarcinoma constituye la neoplasia de la vía biliar más frecuente, la cual es responsable de una alta morbimortalidad. Objetivo: Determinar la morbilidad y la mortalidad por colangiocarcinoma extrahepático en el Servicio de Cirugía del Hospital Universitario Manuel Ascunce Domenech. Métodos: Se realizó un estudio descriptivo, prospectivo y observacional de pacientes que ingresaron en el Servicio de Cirugía General con diagnóstico de colangiocarcinoma extrahepático entre septiembre de 2018 y enero del 2022. El universo estuvo conformado por 21 pacientes que cumplieron con los criterios de inclusión. Se utilizaron métodos estadísticos descriptivos y cálculos con valores porcentuales. Resultados: La mayor incidencia de los pacientes fueron del sexo masculino y blancos, con el 71,4 por ciento y el 85,7 por ciento respectivamente. Predominó el adenocarcinoma como variedad histológica con un 85,7 por ciento, así como el colangiocarcinoma proximal y la variante esclerosante de su clasificación. El 71,4 por ciento de los pacientes egresaron vivos y con una cirugía con finalidad curativa. Conclusiones: La mayoría de los pacientes fueron masculinos, de color blanco y de procedencia rural. Los hallazgos más frecuentes fueron la localización proximal y la variante esclerosante. A más de la mitad de los pacientes se les realizó procedimiento de Hess y Whipple con finalidad curativa. La fuga biliar, el adenocarcinoma como tipo histológico y el estado al egreso vivo prevaleció en todos los pacientes(AU)

Introduction: Cholangiocarcinoma is the most frequent biliary tract neoplasm responsible for high morbidity and mortality. Objective: To determine morbidity and mortality due to extrahepatic cholangiocarcinoma in the surgery service of Hospital Universitario Manuel Ascunce Domenech. Methods: A descriptive, prospective and observational study was carried out with patients admitted to the general surgery service with a diagnosis of extrahepatic cholangiocarcinoma between September 2018 and January 2022. The study universe consisted of 21 patients who met the inclusion criteria. Descriptive statistical methods and calculations with percentage values were used. Results: The highest incidence of patients were male and white-skinned, accounting for 71.4 percent and 85.7 percent, respectively. Adenocarcinoma predominated as histological variety, representing 85.7 percent, together with proximal cholangiocarcinoma and the sclerosing variant of its classification. 71.4 percent of the patients were discharged alive and after curative surgery. Conclusions: Most of the patients were male, white-skinned and from rural origin. The most frequent findings were a proximal location and the sclerosing variant. Over half the patients underwent Hess and Whipple procedure with curative purpose. Biliary leakage, adenocarcinoma as histologic type, and the condition of alive at discharge prevailed in all patients(AU)

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.

Light-to-Moderate Alcohol Consumption Increases the Risk of Biliary Tract Cancer in Prediabetes and Diabetes, but Not in Normoglycemic Status: A Nationwide Cohort Study.

PURPOSE: To determine whether the dose-response association between alcohol consumption and the risk of biliary tract cancer (BTC), including cholangiocarcinoma (CCA) and gallbladder cancer (GBC), differs according to glycemic status. PATIENTS AND METHODS: This nationwide cohort study included 9,520,629 individuals age ≥ 20 years without a history of cancer who underwent national health screening under the Korean National Health Insurance Service in 2009. The participants were followed up until December 2018 for BTC development. Cox proportional hazard regression analysis was performed to estimate risk. RESULTS: During the 78.3 million person-years of follow-up, 21,079 patients were newly diagnosed with BTC. In individuals with prediabetes and diabetes, light-to-moderate alcohol consumption increased the risk of CCA (adjusted hazard ratio [aHR], 1.20; 95% CI, 1.13 to 1.28 and aHR, 1.58; 95% CI, 1.47 to 1.69) and GBC (aHR, 1.18; 95% CI, 1.07 to 1.31 and aHR, 1.45; 95% CI, 1.28 to 1.64). In normoglycemic individuals, light-to-moderate alcohol consumption was not associated with CCA or GBC risk. When heavy alcohol consumption was combined with diabetes, CCA and GBC risk increased synergistically (aHR, 2.04; 95% CI, 1.83 to 2.26; and aHR, 1.65; 95% CI, 1.33 to 2.04, respectively; all P < .001). Prediabetes and heavy alcohol consumption had a synergistic interactive effect on CCA and GBC risks (all P < .001). Comparable results were obtained for intrahepatic and extrahepatic CCA analyses. CONCLUSION: Even light-to-moderate alcohol consumption was associated with an increased risk of BTC in individuals with prediabetes and diabetes, but not in normoglycemic individuals. Complete avoidance of alcohol consumption may help reduce the risk of BTC in patients with prediabetes and diabetes, suggesting the need for individualized prevention strategies for BTC.

Treatment of biliary tract carcinoma over the last 30 years.

Surgical resection could offer the only chance of a long-term cure for biliary tract carcinoma. However, only a small percentage of these patients can undergo surgery based on the progression of the disease. Most patients with biliary tract carcinoma receive palliative chemotherapy. Until 2010, patients with unresectable biliary tract carcinoma received fluorouracil (5-FU), gemcitabine (GEM), and cisplatin (CDDP)-based chemotherapies. The ABC-02 study established GEM with CDDP as the first-line therapy for patients with unresectable biliary tract carcinoma, and phase III studies indicated that several combinations of anti-cancer drugs such as GEM with S-1 benefited patients. In contrast, clinical studies on targeted therapy dosages for biliary tract carcinoma in the 2010s failed to corroborate the advantages of administering cancer treatment with or without other anticancer drugs. Due to the easy access to cancer panels, precision medicines (such as ivosidenib for IDH1 mutations, pemigatinib for FGFR2 fusions, and entrectinib and larotrectinib for NTRK fusions) were recently found to be effective in the treatment of patients with these genetic alterations. Moreover, many clinical studies on immune checkpoint inhibitors for advanced biliary tract carcinoma are currently underway and could provide more effective treatment options in the near future.

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.

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.

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.

Associations between hepatitis B virus exposure and the risk of extrahepatic digestive system cancers: A hospital-based, case-control study (SIGES).

OBJECTIVES: This case-control study was aimed to investigate associations between HBV infection and extrahepatic digestive system cancers. METHODS: The patients of gastric, small intestinal, colonic, rectal, anal, biliary tract, and pancreatic cancers were retrospectively collected between 2016.5 and 2017.12. Simultaneously, the healthy controls were collected from the health check-up registry, and cancer-free status was confirmed based on medical records. Propensity score matching was performed to reduce bias. Multinomial logit model and conditional logistic regression model were used to assess the risk of individual cancer according to HBV serological markers and classifications. RESULTS: Totally, 4748 patients involving seven cancers, and 57,499 controls were included. After matching, HBsAg was associated with increased risk of gastric cancer (aOR = 1.39, 95% CI: 1.05-1.85), and anti-HBs served as a protective factor for gastric (aOR = 0.72, 95% CI: 0.61-0.85), colonic (aOR = 0.73, 95% CI: 0.60-0.89), rectal (aOR = 0.73, 95% CI: 0.63-0.85), and pancreatic (aOR = 0.58, 95% CI: 0.42-0.82) cancers. Compared to subgroups with non-infection and vaccination status, inactive HBsAg carriers and active HBV infection subgroup were correlated with gastric carcinogenesis (aOR = 1.41, 95% CI: 1.03-1.93). However, no clear association was found between HBV infection and other cancers. CONCLUSIONS: HBV infection was potentially associated with an increased risk of gastric cancer. The development mechanism of HBV-associated gastric cancer needs to investigate further.

Experience With Anti-PD-1 Antibody, Camrelizumab, Monotherapy for Biliary Tract Cancer Patients and Literature Review.

BACKGROUND: Novel immunotherapy is one of the options for advanced biliary tract cancer (BTC) patients who are traditionally intolerant to chemotherapy. However, clinical evidence for single immunotherapy with pembrolizumab or nivolumab is limited. The present study assessed the safety and efficiency of the anti-PD-1 antibody, camrelizumab, as monotherapy in patients with unresectable or recurrent BTC. METHODS: A retrospective evaluation was conducted among 4 patients with BTC, including 2 with intrahepatic cholangiocellular carcinoma (ICC), one with extrahepatic bile duct cancer, and one with gallbladder cancer. The patients with unresectable or recurrent BTC were refractory or intolerant to gemcitabine plus cisplatin treatment regimens and received at least one intravenous dose (3 mg/kg) of camrelizumab monotherapy every 3 weeks. Gene sequencing analysis was also performed for biomarker screening. Patient reaction was evaluated according to modified response evaluation criteria in solid tumor (RECIST) version 1.1, progression-free survival (PFS), and toxicity. RESULTS: In this cohort, 1 patient with recurrent ICC had a positive response to treatment, with a substantial tumor size reduction in liver and lung metastases verified using a radiological test after receiving 3 cycles of camrelizumab. The PFS was 4.9 months. The remaining 3 patients showed no response to treatment and experienced disease progression. RNA sequence analysis didn't found high expression on genes that related to PD-L1, microsatellite instability, tumor mutation burden, and DNA mismatch repair in these patients. Grade 3 treatment-related adverse event was observed in 1 patient. CONCLUSIONS: Anti-PD-1 antibody camrelizumab had a manageable safety profile in patients with advanced BTC. This initial assessment of camrelizumab monotherapy provides effective evidence for patients with refractory BTC in biomarker-unselected patients.

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.

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.