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Highlighting concerns about the acceptance of oncologic therapies with no proven benefit, this article compares the interpretation of the clinical trial results of several studies conducted to identify a better therapy for patients with biliary tract cancer.

Treatment options for patients with biliary tract cancer are limited, and the prognosis is poor. CTX-009, a novel bispecific antibody targeting both DLL4 and VEGF-A, has demonstrated antitumor activity in patients with advanced cancers as both a monotherapy and in combination with chemotherapy. In a phase II study of patients with advanced biliary tract cancer who had received one or two prior therapies, CTX-009 with paclitaxel demonstrated a 37.5% overall response rate (ORR). Described here is the design of and rationale for COMPANION-002, a randomized phase II/III study, which will evaluate the safety and efficacy of CTX-009 in combination with paclitaxel versus paclitaxel alone as second-line treatment for patients with advanced biliary tract cancer. The primary end point is ORR, and crossover is allowed.Clinical Trial Registration: NCT05506943 (ClinicalTrials.gov).

Biliary tract cancers are a rare diagnosis with a rising incidence. Up to 20% of patients have peritoneal metastases, resulting in symptoms of ascites, abdominal pain and potential bowel obstruction. A standard of care systemic treatment comprises gemcitabine, cisplatin and durvalumab (gem/cis/durva). However, the clinical benefit among patients with peritoneal metastases remains unknown. Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) delivers chemotherapy directly to the peritoneal space, which could potentially improve efficacy with minimal systemic toxicity. We describe the design of a Phase I study investigating PIPAC with nab-paclitaxel plus systemic gem/cis/durva among biliary tract cancer patients with peritoneal metastases who have not received prior systemic treatment. The primary end point is safety of PIPAC with nab-paclitaxel in combination with systemic gem/cis/durva. Clinical Trial Registration:NCT05285358 (ClinicalTrials.gov) Article highlights Biliary tract cancers Biliary tract cancers include cholangiocarcinoma (intra-hepatic and extra-hepatic) and gallbladder cancer. Up to 20% of patients will have peritoneal metastases, which can cause ascites, abdominal pain and potential bowel obstruction. Systemic treatment landscape Standard of care first-line systemic treatment comprises gemcitabine, cisplatin and anti-PD-1/L1 immunotherapy (e.g. durvalumab). The addition of nab-paclitaxel to the combination of gemcitabine plus cisplatin showed promising results in a Phase II single-arm study, but a Phase III randomized study showed no significant improvement in efficacy with the triplet combination compared with gemcitabine plus cisplatin alone, potentially due to increased toxicity. The benefit of systemic treatment among patients with peritoneal metastases has not been thoroughly investigated. Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) PIPAC delivers chemotherapy in an aerosolized form directly to the intraperitoneal space, allowing for lower doses of chemotherapy to be used; this may increase peritoneal tumor uptake and reduce systemic uptake, potentially reducing toxicities. Multiple studies in Europe and one study in the United States have demonstrated the feasibility and safety of PIPAC with multiple chemotherapies (including nab-paclitaxel) among patients with a variety of cancer diagnoses and peritoneal metastases. Phase I study of PIPAC in patients with advanced biliary tract cancer NCT05285358 is a Phase I single-arm study investigating PIPAC with nab-paclitaxel in combination with systemic gemcitabine, cisplatin and durvalumab in patients with advanced biliary tract cancer and peritoneal metastases who have not previously received systemic therapy. The primary objective is safety of PIPAC with nab-paclitaxel in combination with systemic chemotherapy (gemcitabine plus cisplatin) and immunotherapy (durvalumab). [ABSTRACT FROM AUTHOR]

Aim: To evaluate real-world treatment patterns, survival and healthcare-resource utilization in US patients with advanced biliary tract cancers (BTC) receiving systemic therapy. Patients & methods: This study used claims data from the Healthcare Integrated Research Database (HIRD®) linked to clinical data from the Cancer Care Quality Program (January 1, 2015–September 30, 2020). Results: Of 413 patients, 84.5% received gemcitabine-based first-line (1L) treatment, 46% received second-line treatment, and 16.5% received third-line (3L) treatment. All-cause mortality was 53% and approximately 70% of patients had ≥1 inpatient visit. The total mean per-patient-per-month all-cause costs were $19,589 for 1L and $33,534 for 3L treatment. Conclusion: Results showed poor survival, significant resource use and high costs as treatment line progresses for patients with advanced BTC. Plain Language Summary Our research explored which treatments US patients with advanced biliary tract cancers (BTC) received and how long they lived for. We analyzed information from a US database, called the Healthcare Integrated Research Database (HIRD®), which holds information related to healthcare insurance claims. Out of 413 patients in the database, 84.5% were initially given a combination treatment involving a chemotherapy called gemcitabine. We also found that 46% of patients received a type of second treatment (also known as second-line therapy), and 16.5% received a third treatment (third-line therapy). During treatment, around 70% of patients needed to stay in hospital at least once. The cost of healthcare was more expensive for patients receiving later lines of therapy, with the average monthly cost per patient for first-line treatment being $19,589 and third-line treatment being $33,534. Furthermore, just over half of the 413 patients died from any causes, showing the poor outlook these patients face. This information is important for understanding the real-world management of patients with BTC, so that their care can be improved in the future. Article highlights This study evaluated real-world treatment patterns, survival, healthcare-resource utilization (HCRU) and costs in patients with advanced biliary tract cancers (BTC) receiving systemic therapy in the US before the recent approval of immuno-oncology (IO)-based regimens. The study was an observational, retrospective cohort study among adults with advanced BTC, identified through medical and pharmacy claims from the Healthcare Integrated Research Database (HIRD®), linked to clinical data from the Cancer Care Quality Program (CCQP). Among 413 patients included in the study, 84.5% of patients received gemcitabine-based first-line (1L) therapy, 46% of patients received a second-line therapy and 16.5% received a third-line (3L) therapy. All-cause mortality was 53% with a median survival of 11.5 months. Approximately 70% of patients had ≥1 inpatient visit and hospitalization was the key driver for HCRU. The total mean per-patient-per-month, all-cause cost increased with progression of line of treatment from 1L treatment ($19,589) to 3L treatment ($33,534). The results highlight poor patient outcomes coupled with high HCRU and costs before the recent approval of IO-based regimens, indicating the need for novel treatment options. [ABSTRACT FROM AUTHOR]

What is this summary about? Researchers wanted to study whether the research drug zanidatamab could help people with a type of cancer called biliary tract cancer. In some people, biliary tract cancer cells make extra copies of a gene called HER2 (also called ERBB2). This is known as being HER2-amplified. Zanidatamab is an antibody designed to destroy cancer cells that have higher-than-normal HER2 protein or gene levels. Zanidatamab is currently under research and is not yet approved for any diseases. Participants in this phase 2b clinical study had tumors that were HER2-amplified and at the advanced or metastatic stage. Participants also had cancer which had become worse after previous chemotherapy or had side effects that were too bad to continue chemotherapy. They also had to meet other requirements to be enrolled. Researchers measured the amount of HER2 protein in the tumor samples of the participants who were enrolled. There were 80 participants with tumors that were both HER2 amplified and had higher-than-normal HER2 protein amounts (considered to be 'HER2-positive'). There were 7 participants with tumors that were HER2-amplified, but had little-to-no levels of the HER2 protein (considered to be 'HER2-low'). All participants in the study were treated with zanidatamab and no other cancer treatments once every 2 weeks. What are the key takeaways? In the HER2-positive group, 33 of 80 (41%) participants had their tumors shrink by 30% or more of their original size. In half of these participants, their tumors did not grow for 13 months or longer. No participant in the HER2-low group had their tumors shrink by 30% or more. In total, 63 of 87 participants (72%) had at least one side effect believed to be related to zanidatamab treatment. Most side effects were mild or moderate in severity. No participant died from complications related to zanidatamab. Diarrhea was one of the more common side effects and was experienced by 32 of 87 participants (37%). Side effects related to receiving zanidatamab through the vein, such as chills, fever, or high blood pressure, were experienced by 29 of 87 participants (33%). What are the conclusions reported by the researchers? The results of this study support the potential for zanidatamab as a new therapy for people with HER2-positive biliary tract cancer after they had already received chemotherapy. More research is occurring to support these results. Clinical Trial Registration:NCT04466891 (HERIZON-BTC-01 study) Tweetable Abstract The HERIZON-BTC-01 study revealed zanidatamab as a potentially effective treatment for HER2-positive biliary tract cancer after standard chemotherapy fails. Read more in the lay summary by @hardingjjmd, @DrShubhamPant, and coauthors. #BiliaryTractCancer #HER2 #zanidatamab Infographic [ABSTRACT FROM AUTHOR]

Biliary tract cancer (BTC) is a rare and aggressive malignancy with increasing incidence. Most BTC cases are diagnosed with metastatic disease which carries a 5‐year survival rate of <5%. Physical activity, diet, and obesity might be associated with BTC risk, but studies have been limited particularly in African descendants. We addressed this knowledge gap by evaluating associations of BTC risk with obesity, physical activity, and dietary intakes in 723,326 adult participants in four cohort studies conducted in China, the United Kingdom, and the United States. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) in each cohort; results were combined using meta‐analysis. All cohorts had ≥11 median follow‐up years with 839 incident BTC cases combined. BTC risk was positively associated with body mass index (BMI) and waist‐to‐hip ratio (WHR) whereas physical activity, fruit intake, and fish intake were inversely associated. HR and (95% CI) comparing BMI >35.0 to 18.5–24.9: 1.71 (1.26, 2.31), p‐trend <.0001; comparing BMI‐adjusted WHR top to bottom quartile: 1.20 (0.94, 1.53), p‐trend =.05; comparing ≥15–0 metabolic equivalent task‐hours/week 0.76 (0.61, 0.94), p‐trend =.009; comparing highest to lowest intake tertile for fruit and fish 0.79 (0.66, 0.95), p‐trend =.01; 0.82 (0.68, 0.98), p‐trend =.04, respectively. Associations were, in general, similar across ancestry groups. Our study provides strong evidence for important roles of obesity, diet, and physical activity in BTC etiology and stresses the need for lifestyle modification to combat the rising incidence of this fatal malignancy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to identify the risk factors associated with ampullary duodenal carcinoma (a-DC) and develop a clinical model to dynamically and accurately predict the risk of lymph node metastasis (LNM) in a-DC patients. Methods: Data from 4077 patients (2004–2020) were extracted from the Surveillance, Epidemiology, and End Results database to form a training cohort, while 173 cases (2010–2020) from Zhejiang Provincial People's Hospital in China were used as an external validation cohort. A reliable LASSO-logistic method was employed to identify independent risk factors for a-DC LNM, and a nomogram was developed based on these factors to assess the risk of a-DC LNM. The nomogram was evaluated using the Akaike information criterion, misclassification error, area under the curve, and likelihood ratio test. Finally, the nomogram's accuracy and generalizability were externally validated.. Results: After screening using LASSO and logistic regression four variables were identified as independent risk factors for a-DC LNM: sex (P < 0.001), tumor size (P < 0.001), grade (P < 0.001), and tumor extension (P < 0.001). The area under the curve of the nomogram was 74.8% in the training group and 88.9% in the external validation group. The calibration curves demonstrated that the LNM predictions made by the nomogram were in satisfactory agreement with the actual observed LNM. Additionally, the decision curve analysis curves indicated effective clinical utility of the nomogram. Conclusions: A nomogram based on the LASSO-logistic analysis was constructed to predict a-DC LNM, demonstrating good performance and clinical application value. [ABSTRACT FROM AUTHOR]

Background: A recent phase 2A clinical study of Atractylodes lancea (Thunb.) DC. (AL) in patients with advanced-stage intrahepatic cholangiocarcinoma (iCCA) demonstrated significant reduction of the risk of tumor progression and mortality with a dose ranging from 1,000 to 2,000 mg. The present study aimed to determine the potential dosage regimen of AL for further phase 2B clinical study. Methods: Plasma-concentration time profiles of total AL bioactivity and clinical efficacy in patients with advanced-stage iCCA were obtained from Phase 2 A study. The population pharmacokinetic (pop-PK) model was developed. The pop-PK model and Monte-Carlo (MC) simulation, in conjunction with maximum concentration of AL (Cmax) as a cut-off criterion, was performed and validated with clinical data. The optimal model was used to simulate further dosage regimens and clinical efficacy of AL. Results: The pop-PK properties of total AL bioactivity were best described by a compartmental model with zero-order absorption (without delay) and linear clearance. None of the investigated covariates improved model accuracy.The developed pop-PK with MC simulations following once-daily dosing of 1,000 mg and 2,000 mg adequately predicted the clinical efficacy (tumor progression and mortality). The once-daily dose of 2,500 mg is recommended for further phase 2B clinical study due to its relatively high efficacy on tumor progression inhibition (73%) and mortality rate reduction (71%) without excessive number of the administered capsules (23 capsules) and low risk of toxicities (<5%). Conclusions: The applied pop-PK model with MC simulation, along with the appropriate cut-off pharmacokinetic parameters, can be used as a potential tool for supporting dosage prediction and selection for clinical studies, and thus reducing the rate of drug development failures. Trial registration: www.thaiclinicaltrials.org, WHO ICTRP search, TCTR20210129007, Registed 29 January 2021. [ABSTRACT FROM AUTHOR]

Background/Objectives: Biliary tract cancer (BTC) is a rare but aggressive malignancy that requires surgical treatment. However, postoperative recurrence rates are high, and reliable predictors of recurrence are limited. This study aimed to investigate the effectiveness of cell-free DNA (cfDNA) and circulating tumor cells (CTCs) in predicting early recurrence after curative surgery and complete adjuvant therapy in patients with BTC. Methods: Twenty-four patients who underwent R0 and R1 resections and completed adjuvant therapy for BTC between September 2019 and March 2022 were followed up until March 2024. Patients were categorized into early recurrence (ER) and non-ER groups, using one year as the cutoff for recurrence. Results: The combination score derived from ultrashort fragments of cfDNA, vimentin-positive CTCs, and carbohydrate antigen (CA) 19-9 levels showed a statistically significant difference between the ER and non-ER groups (p-value < 0.001). The receiver operating characteristic curve from the combination score and CA 19-9 levels yielded areas under the curve of 0.891 and 0.750, respectively. Conclusions: Although further research is required, these findings suggest that cfDNA and CTCs may increase the accuracy of predicting postoperative recurrence in patients with BTC. [ABSTRACT FROM AUTHOR]

The document is a poster listing for the Asia Pacific Journal of Clinical Oncology, detailing various research topics presented at a conference. The topics cover a wide range of areas, including basic and translational research, clinical research, epidemiology, health services, supportive care, and trials in progress. The research presented focuses on diverse aspects of cancer care, such as biomarkers, stem cells, treatment approaches, quality of life, and survivorship care. The poster session includes a variety of studies aimed at improving cancer care, addressing disparities, and enhancing patient outcomes. [Extracted from the article]

Background Biliary tract cancer (BTC) is a highly malignant tumor, with limited therapy regimens and short response duration. In this study, we aim to assess the efficacy and safety of the combination of camrelizumab, apatinib, and capecitabine as the first- or second-line treatment in patients with advanced BTC. Methods In this phase 2, nonrandomized, prospective study, eligible patients received camrelizumab (200 mg, d1, Q3W), apatinib (250 mg, qd, d1-d21, Q3W), and capecitabine (1000 mg/m², bid, d1-d14, Q3W) until trial discontinued. The primary endpoint was the objective response rate (ORR). The secondary endpoints were disease control rate, progression-free survival (PFS), overall survival (OS), and safety. Results From July 2019 to April 2023, we enrolled a total of 28 patients, of whom 14 patients were in the first-line treatment setting and 14 patients were in the second-line setting. At the data cutoff (April 30, 2023), the median follow-up duration was 18.03 months. Eight of 28 patients reached objective response (ORR: 28.57%), with an ORR of 50% and 7.1% for first-line and second-line treatment patients (P  = .033). The median PFS was 6.30 months and the median OS was 12.80 months. Grade 3 or 4 adverse events (AEs) occurred in 9 (32.14%) patients, including elevated transaminase, thrombocytopenia, etc. No serious treatment-related AEs or treatment-related deaths occurred. Conclusions In this trial, the combination of camrelizumab, apatinib, and capecitabine showed promising antitumor activity and manageable toxicity in patients with advanced BTC, especially in the first-line setting. Clinical Trial Registration NCT04720131. [ABSTRACT FROM AUTHOR]

Due to the widespread use of cancer genetic testing in gastrointestinal cancer, the BRCA1/2 genetic mutation has been identified in biliary tract cancer as well as pancreatic cancer. Niraparib is a poly(ADP-ribose) polymerase (PARP) inhibitor, and PARP inhibitors exert their cytotoxicity against cancer cells in the context of homologous recombination deficiency, such as BRCA mutations, via the mechanism of synthetic lethality. The aim of this phase II NIR-B trial is to evaluate the efficacy and safety of niraparib for patients with unresectable advanced or recurrent biliary tract cancer, pancreatic cancer or other gastrointestinal cancers with germline or somatic BRCA1/2 mutations revealed by genetic testing. The primary end point is an investigator-assessed objective response rate in each cohort. Clinical Trial Registration:jRCT2011200023 (ClinicalTrials.gov) Plain Language Summary A clinical study to confirm the efficacy and safety of niraparib for people with advanced biliary tract, pancreatic and other abdominal cancers with the BRCA genetic mutation: the NIR-B trial. BRCA gene is involved in repairing DNA injury and plays an important role in cancer growth. Cells with a mutation in the BRCA gene cannot repair DNA using a method called homologous recombination repair. Niraparib is part of a class of drugs called 'PARP inhibitors' that inhibit enzymes called 'PARP' involved in repairing DNA injury, and has shown efficacy against cancers with BRCA gene mutations. BRCA gene mutations are infrequent but have been found in a variety of cancers. The NIR-B trial is a clinical trial to evaluate the efficacy and safety of niraparib for people with advanced biliary tract, pancreatic and other abdominal cancers with BRCA gene mutations. Executive summary Background Recent comprehensive genomic profiling testing has revealed therapeutic target molecules. It has been proven that the BRCA1/2 genetic mutation has been identified in biliary tract and pancreatic cancer. Niraparib is classified as a poly(ADP-ribose) polymerase (PARP) inhibitor, and PARP inhibitors exert cytotoxicity against cancer cells in the context of homologous recombination deficiency, such as BRCA mutations, by the mechanism of synthetic lethality. Niraparib has been shown to be selective for PARP1/2 as well as more cytotoxic than other PARP inhibitors owing to its PARP-trapping activity. NIR-B trial This NIR-B trial is a multicenter, open-label, single-arm, three-cohort and basket-type phase II study, with the aim to evaluate the efficacy and safety of niraparib for patients with unresectable advanced or recurrent biliary tract cancer, pancreatic cancer and other gastrointestinal cancers with germline or somatic BRCA1/2 mutations observed on genetic testing. Eligible patients will be enrolled at six trial sites in Japan. Patients with a body weight ≥77 kg and platelet count ≥150,000/mm3 will be administered 300 mg of niraparib orally once daily, while patients with a body weight <77 kg or platelet count <150,000/mm3 will be administered 200 mg of niraparib orally once daily. The primary end point is an investigator-assessed objective response rate (ORR) in each cohort with a threshold ORR of 10% and an expected ORR of 35%. The key secondary end points are progression-free survival, overall survival, disease control rate, duration of response and safety. Pretreatment tumor tissue and serial circulating tumor DNA will be collected and analyzed to investigate the resistance mechanisms and to provide a clinically meaningful biomarker that can be used to identify and implement treatment changes. The trial was initiated in January 2021, and enrollment is ongoing. [ABSTRACT FROM AUTHOR]

Simple Summary: Treatment options for intrahepatic cholangiocarcinoma (iCCA), a highly malignant tumor with poor prognosis, are limited. Recent developments in immunotherapy and immune checkpoint inhibitors (ICIs) have offered new hope for treating iCCA. However, several issues remain, including the identification of reliable biomarkers of response to ICIs and immune-based combinations. Tumor immune microenvironment (TIME) of these hepatobiliary tumors has been evaluated and is under assessment in order to boost the efficacy of ICIs and to convert these immunologically "cold" tumors to "hot" tumors. Herein, we examine the role of iCCA TIME, highlighting its mechanisms, current applications and challenges, and future research directions. Treatment options for intrahepatic cholangiocarcinoma (iCCA), a highly malignant tumor with poor prognosis, are limited. Recent developments in immunotherapy and immune checkpoint inhibitors (ICIs) have offered new hope for treating iCCA. However, several issues remain, including the identification of reliable biomarkers of response to ICIs and immune-based combinations. Tumor immune microenvironment (TIME) of these hepatobiliary tumors has been evaluated and is under assessment in this setting in order to boost the efficacy of ICIs and to convert these immunologically "cold" tumors to "hot" tumors. Herein, the review TIME of ICCA and its critical function in immunotherapy. Moreover, this paper also discusses potential avenues for future research, including novel targets for immunotherapy and emerging treatment plans aimed to increase the effectiveness of immunotherapy and survival rates for iCCA patients. [ABSTRACT FROM AUTHOR]

Background and Aim Methods Results Conclusions The global burden of gallbladder and biliary tract cancer (GBTC) has been on the rise, making it a major public health concern. We aim to comprehensively analyze sex disparities in the temporal trends of GBTC incidence, mortality, and disability‐adjusted life years (DALYs) regionally and globally from 2010 to 2019.Age‐standardized rates of GBTC incidence, death, and DALYs were analyzed utilizing the Global Burden of Disease study 2019.From 2010 to 2019, the estimated annual percent change (APC) of the age‐standardized incidence rates (ASIRs) and age‐standardized disability‐adjusted life years (ASDALYs) due to GBTC globally decreased in both sexes (males, APC: −0.80%; APC: −1.00%) and (females, APC: −0.89%; APC: −0.96%). At the same time, age‐standardized death rates (ASDRs) decreased only in males (APC: −0.82%) and remained stable in females. By regions, ASIRs and ASDR increased in both sexes only in Southeast Asia (SEA) but decreased in the other regions. All regions had decreased ASDALYs except for an increase in ASDALYs for females only in the SEA region (APC: 0.41%), and males have a stable trend.Our study reveals substantial geographic variance in the burden of GBTC, specifically in the SEA region. Therefore, localized interventional methodologies must be undertaken to effectively address this global burden from GBTC. [ABSTRACT FROM AUTHOR]

Background: The clinical significance of the lymph node ratio (LNR), the number of metastatic lymph nodes per dissected lymph node, has not been sufficiently clarified in ampullary cancer. Methods: Among patients diagnosed histopathologically with ampullary cancer between 1980 and 2018, the study included 106 who underwent pathological radical resection by pancreaticoduodenectomy. The relationships between the LNR and metastatic lymph node sites and prognosis were examined. Results: Multivariate analysis revealed that sex and lymph node metastasis were independent prognostic factors. In the 46 patients (43%) with metastatic lymph nodes, the LNR in the recurrence group was significantly higher than that in the non-recurrence group (0.15 ± 0.11 vs. 0.089 ± 0.071, p = 0.025). The receiver operating characteristic curve demonstrated that the LNR cut-off value, 0.07 (area under the curve = 0.70, sensitivity 81%, specificity 56%), was a significant indicator for recurrence (22% vs. 61%, p = 0.016) and prognosis (5-year survival: 48% vs. 83%, p = 0.028). Among the metastatic lymph node sites in the 46 positive cases, lymph node metastases developed from the peripancreatic head region (80%, 37/46) to the superior mesenteric artery (33%, 15/46) and para-aortic (11%, 5/46) regions. Conclusion: Lymph node metastasis is an independent prognostic factor, and the LNR is a significant indicator for recurrence and prognosis in patients with ampullary cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Survival for patients with biliary tract cancer (BTC) is poor, especially in the advanced stage, where curative treatments are not available. While chemotherapy and immunotherapy are used in standard practice, antibody–drug conjugates (ADCs) have emerged as a novel therapy option. ADCs potentially enhance cancer cell death and reduce side effects. The anti-HER2 ADC Trastuzumab Deruxtecan (T-Dxd) has shown survival benefit for patients whose tumours are HER2-positive, including a subgroup of BTCs. In April 2024, the regulatory authority FDA approved T-Dxd for adults with unresectable or metastatic HER2-positive solid tumours, including BTCs, lacking other treatment options. Ongoing trials are exploring other potentially actionable BTC molecular alterations. This review will discuss the current evidence and ongoing research in this subject area. Background: Biliary tract cancers (BTCs) are aggressive in nature, often presenting asymptomatically until they are diagnosed at an advanced stage. Surgical resection or liver transplantation are potential curative options. However, a large proportion of patients present with incurable locally advanced or metastatic disease and most of these patients are only eligible for palliative chemotherapy or best supportive care. More recently, targeted therapies have proven beneficial in a molecularly selected subgroup of patients with cholangiocarcinoma who have progressed on previous lines of systemic treatment. However, only a minority of patients with BTCs whose tumours harbour specific molecular alterations can access these therapies. Methods: In relation to ADCs, studies regarding use of antibody–drug conjugates in cancer, particularly in BTCs, were searched in Embase (1974 to 2024) and Ovid MEDLINE(R) (1946 to 2024) to obtain relevant articles. Examples of current clinical trials utilising ADC treatment in BTCs were extracted from the ClinicalTrials.gov trial registry. Conclusions: Overall, this review has highlighted that ADCs have shown encouraging outcomes in cancer therapy, and this should lead to further research including in BTCs, where treatment options are often limited. The promising results observed with ADCs in various cancers underscore their potential as a transformative approach in oncology, warranting continued exploration and development and the need for education on the management of their specific toxicities. By addressing current challenges and optimising ADC design and application, future studies could potentially improve treatment outcomes for patients with BTCs and beyond, potentially in both early and advanced stage settings. [ABSTRACT FROM AUTHOR]

Background: Population-based studies that examine the associations between hyperthyroidism and cancer risk have yielded inconsistent results. It remains unclear whether the risks of different cancers increase in patients with Graves' disease (GD) who received antithyroid drugs (ATDs) as initial treatment. We aimed to determine whether cancer risk increases in patients with GD, compared with controls. Methods: This nationwide retrospective cohort study utilized data from the National Health Information Database of South Korea. We included 29,502 patients aged >20 years with GD, who received ATDs as initial treatment, and 57,173 age- and sex-matched controls. The primary outcome was the incidence of various types of cancers. Hazard ratios (HRs) with confidence intervals (CIs) for cancer risk were estimated using Cox proportional hazards models. We also analyzed HR by follow-up period since the diagnosis of GD, accounting for surveillance effect. Results: The risk of biliary tract and pancreatic cancers (HR: 1.41, CI: 1.24–1.60), thyroid cancer (HR: 15.51, CI: 12.29–19.57), prostate cancer (HR: 1.48, CI: 1.28–1.71), and ovarian cancer (HR: 1.31, CI: 1.13–1.52) was elevated in the GD group than in the control group even after the first year of follow-up was excluded. The increased risk of these cancers persisted after a follow-up period of more than 5 years. The risk of thyroid cancer in patients with GD was higher during the initial follow-up period (1 to <2 years) (HR: 19.35, CI: 7.66–48.87) compared with that in the follow-up period exceeding 2 years. The cancer risk estimates remained significant after excluding patients with GD who underwent subsequent radioactive iodine therapy. Conclusion: In this large-scale population-based study, GD was associated with increased risks of biliary tract and pancreatic, prostate, ovarian, and thyroid cancers. The increased risk of thyroid cancer, particularly during the initial follow-up period, may be a surveillance effect. [ABSTRACT FROM AUTHOR]

Background and Aims: The best adjuvant chemotherapy for resected biliary tract cancer (BTC) is under debate, with capecitabine supported by weak evidence. Aim of this network meta‐analysis is to estimate the efficacy of different phase II/III regimens, comparing monotherapies (gemcitabine or fluoropyrimidines) head‐to‐head, against observation and combination regimens. Methods: A comprehensive literature search was conducted on PubMed and EMBASE for phase II/III randomized clinical trials (RCTs) available as of December 2023, reporting hazard ratios (HRs) of overall survival (OS) and event‐free survival (EFS). A frequentist framework employing a random‐effects model was applied; treatment rankings were outlined according to P‐score, based on direct and indirect evidence. Exploratory subgroup analyses for OS were also performed (primary site, resected margin status and nodal involvement). Results: Six RCTs (1979 total patients) were identified. Fluoropyrimidine monotherapy showed significantly better OS (HR.84 [.72–.97]) and EFS (HR.79 [.69–.91]) than observation, as any monotherapy did (HR.84 [.74–.96]; HR.79 [.70–.89]). In the head‐to‐head comparison for OS, only S1 confirmed to be superior to observation alone (HR.69 [.49–.98]) while fluoropyrimidines achieved the best P score (.81), similarly to any monotherapy (0.92). Combinations failed to prove superior to monotherapies with respect both to OS and EFS. Subgroup analyses were inconclusive due to results' inconsistency and limited sample size. Conclusions: Our work confirmed that adjuvant chemotherapy grants OS and EFS benefit for resected BTC patients. Fluoropyrimidines appeared the most effective option, confirming capecitabine as the preferred choice for the Western population. Key points: The administration of chemotherapy after surgery in primary liver cancers arising from biliary cells is needed to reduce the risk of disease relapse. Different chemotherapy regimens are available. From our study, we confirmed that capecitabine is the most effective option compared to doublet regimens in terms of disease‐free patients' survival and overall survival. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to investigate the efficacy, long-term prognosis and safety of combining chemotherapy with regorafenib and immune checkpoint inhibitors as first-line treatment for patients with advanced biliary tract carcinoma (BTC). Methods: In this single arm phase II trial, twenty-nine patients with advanced BTC were included, all of whom received gemcitabine-based chemotherapy combined with regorafenib and immune checkpoint inhibitors as the first-line treatment. And the study analyzed anti-tumor efficacy, long-term prognosis, and adverse reactions. Results: Among the patients, 0 patient achieved complete response, 18 patients (62.1%) achieved partial response, 8 patients (27.6%) had stable disease, and 3 patients (10.3%) experienced progressive disease. The corresponding objective response rate (ORR) was 18/29 (62.1%), and the disease control rate (DCR) was 26/29 (89.7%). The median overall survival (OS) was 16.9 months (95% confidence interval [CI]: 12.0 -21.8) and the median progress free survival (PFS) was 10.2 months (95% CI: 7.8-12.6). The 1-year OS and PFS were 65% (95% CI: 0.479-0.864) and 41% (95% CI: 0.234-0.656), respectively. The incidence of adverse reactions was 27/29 (93.1%), and the incidence of grade III/IV adverse reactions was 5/29 (17.2%). Conclusion: The combination of chemotherapy, regorafenib, and immune checkpoint inhibitors as a first-line treatment for patients with advanced BTC may has good anti-tumor efficacy without causing serious adverse reactions, and can significantly improve the long-term prognosis. [ABSTRACT FROM AUTHOR]

Background: Poor survival outcomes in periampullary cancer highlight the need for improvement in biomarkers and the development of novel therapies. Redox proteins, including the thioredoxin system, play vital roles in cellular antioxidant systems. Methods: In this retrospective study, thioredoxin (Trx), thioredoxin-interacting protein (TxNIP), and thioredoxin reductase (TrxR) protein expression was assessed in 85 patients with pancreatic ductal adenocarcinoma (PDAC) and 145 patients with distal bile duct or ampullary carcinoma using conventional immunohistochemistry. Results: In patients with PDAC, high cytoplasmic TrxR expression was significantly associated with lymph node metastasis (p = 0.033). High cytoplasmic and nuclear Trx expression was significantly associated with better overall survival (p = 0.018 and p = 0.006, respectively), and nuclear Trx expression remained significant in multivariate Cox regression analysis (p < 0.0001). In distal bile duct and ampullary carcinomas, high nuclear TrxR expression was associated with vascular (p = 0.001) and perineural (p = 0.021) invasion, and low cytoplasmic TxNIP expression was associated with perineural invasion (p = 0.025). High cytoplasmic TxNIP expression was significantly associated with better overall survival (p = 0.0002), which remained significant in multivariate Cox regression analysis (p = 0.013). Conclusions: These findings demonstrate the prognostic importance of Trx system protein expression in periampullary cancers. [ABSTRACT FROM AUTHOR]

Purpose: Recently introduced hybrid 2-[18 F]-fluoro-2-deoxy-D-glucose (18 F-FDG) Positron Emission Tomography (PET) combined with Magnetic Resonance Imaging (MRI) may aid in proper diagnosis and staging of perihilar cholangiocarcinoma (pCCA). The aim of this study is to assess the effect of 18 F-FDG PET/MRI on diagnosis and clinical decision making in the pre-operative work up of pCCA. Methods: In this single-centre pilot study patients with presumed resectable pCCA underwent state-of-the-art 18 F-FDG hybrid PET/MRI using digital silicone photomultiplier detectors integrated within a 3-Tesla bore. Data were collected on several baseline and imaging characteristics. The primary outcome measure was the added diagnostic information and the effect on clinical decision making. Secondary aim was to correlate quantitative PET signal intensity to patient- and tumour characteristics. High and low SUVmax subgroups related to the mean value were made. Significance of lesion- and patient characteristics with the high and low SUVmax subgroups, as well as TLR and TBR, was evaluated with Fisher's exact test or Mann-Whitney-U test. Results: In total 14 patients were included (mean age 62.4 years, 64% male). Final diagnosis was pCCA in 10 patients (71.4%), follicular lymphoma in one patient (7.1%) and benign disease in the remaining three patients. FDG-PET/MRI added valuable diagnostic information in six (43%) patients and affected clinical decision making in two of these patients (14%) by increasing confidence for malignancy which lead to the decision for surgery on short term. High SUVmax values were seen in half of cases with pCCA and half of cases with non-cancerous lesions. In addition, high SUVmax values were directly associated with primary sclerosing cholangitis when present (p = 0.03). Conclusion: Simultaneous 18 F-FDG-PET/MRI added diagnostic information in six of fourteen patients and influenced clinical decision making in two patients (14%) with presumed resectable pCCA. [ABSTRACT FROM AUTHOR]

Background: As a second-line therapy, oxaliplatin/fluorouracil/leucovorin (FOLFOX) remains the standard of care for patients with biliary tract cancer (BTC); however, its efficacy is suboptimal. The aim of this study was to evaluate whether, compared with chemotherapy alone, the immune checkpoint inhibitor (ICI) combination regimen improved the overall survival (OS) in patients with advanced BTC. Methods: Patients diagnosed with advanced BTC who received chemotherapy or ICI combination therapy as second-line (L2) treatment between January 1, 2018, and April 1, 2022, were retrospectively identified. Results: A total of 98 patients with BTCs were reviewed and recruited: the chemotherapy group (cohort A, n = 40), the chemotherapy plus ICIs group (cohort B, n = 27), and the tyrosine kinase inhibitor (TKIs) plus ICIs group (cohort C, n = 31). The median progression-free survival (PFS) and median OS were 2.6 months (95% confidence interval [CI]: 1.7-4.2) and 7.8 months (95% CI: 5.9-12.0) for cohort A, 4.3 months (95% CI: 2.9-8.4) and 10.9 months (95% CI: 7.67-NA) for cohort B, 5.1 months (95% CI: 4.0-8.3) and 10.1 months (95% CI: 8.23-NA) for cohort C, respectively. The confirmed overall response rates were 7.5% (3/40, cohort A), 22.2% (6/27, cohort B), and 19.4% (6/31, cohort C), whereas the disease control rates were 47.5% (19/40, cohort A), 77.8% (21/27, cohort B), and 77.4% (24/31, cohort C). Grade 3 or higher treatment-related adverse reaction were reported in 20.0% (cohort A), 37.0% (cohort B), and 41.9% (cohort C) of the patients. Conclusions: The ICI combination strategy beyond first-line (L1) systemic chemotherapy plays a positive role in advanced BTCs. Both TKIs plus ICIs and chemotherapy plus ICIs could be considered candidates for trials and applied as competitive L2 treatment regimens for advanced BTCs in clinical practice. [ABSTRACT FROM AUTHOR]

Objective: Despite several observational studies attempting to investigate the potential association between type 1 diabetes mellitus (T1DM) and the risk of digestive cancers, the results remain controversial. The purpose of this study is to examine whether there is a causal relationship between T1DM and the risk of digestive cancers. Methods: We conducted a Mendelian randomisation (MR) study to systematically investigate the effect of T1DM on six most prevalent types of digestive cancers (oesophageal cancer, stomach cancer, hepatocellular carcinoma, biliary tract cancer, pancreatic cancer, and colorectal cancer). A total of 1,588,872 individuals were enrolled in this analysis, with 372,756 being the highest number for oesophageal cancer and 3,835 being the lowest for pancreatic cancer. Multiple MR methods were performed to evaluate the causal association of T1DM with the risk of six site-specific cancers using genome-wide association study summary data. Sensitivity analyses were also conducted to assess the robustness of the observed associations. Results: We selected 35 single nucleotide polymorphisms associated with T1DM as instrumental variables. Our findings indicate no significant effect of T1DM on the overall risk of oesophageal cancer (OR= 0.99992, 95% CI: 0.99979-1.00006, P= 0.2866), stomach cancer (OR=0.9298,95% CI: 0.92065-1.09466, P= 0.9298), hepatocellular carcinoma (OR= 0.99994,95% CI: 0.99987-1.00001, P= 0.1125), biliary tract cancer (OR=0.97348,95% CI: 0.8079-1.1729, P= 0.7775)), or pancreatic cancer (OR =1.01258, 95% CI: 0.96243-1.06533, P= 0.6294). However, we observed a causal association between T1DM and colorectal cancer (OR=1.000, 95% CI: 1.00045-1.0012, P<0.001), indicating that T1DM increases the risk of colorectal cancer. We also performed sensitivity analyses, which showed no heterogeneity or horizontal pleiotropy. For the reverse MR from T1DM to six digestive cancers, no significant causal relationships were identified. Conclusions: In this MR study with a large number of digestive cancer cases, we found no evidence to support the causal role of T1DM in the risk of oesophageal cancer, stomach cancer, hepatocellular carcinoma, biliary tract cancer, or pancreatic cancer. However, we found a causal positive association between T1DM and colorectal cancer. Further large-scale prospective studies are necessary to replicate our findings. [ABSTRACT FROM AUTHOR]

Simple Summary: This study assessed the preoperative diagnostic efficacy of the apparent diffusion coefficient on diffusion-weighted magnetic resonance imaging for identifying lymph node metastasis in biliary tract cancer, comparing it with the diagnostic efficacy of short-axis and long-axis diameters of lymph nodes measured by computed tomography. The results demonstrated that the minimum ADC value provided the highest diagnostic accuracy. Objective: The diagnostic efficacy of the apparent diffusion coefficient (ADC) in diffusion-weighted magnetic resonance imaging (DW-MRI) for lymph node metastasis in biliary tract cancer was investigated in the present study. Methods: In total, 112 surgically resected lymph nodes from 35 biliary tract cancer patients were examined in this study. The mean and minimum ADC values of the lymph nodes as well as the long-axis and short-axis diameters of the lymph nodes were assessed by computed tomography (CT). The relationship between these parameters and the presence of histological lymph node metastasis was evaluated. Results: Histological lymph node metastasis was detected in 31 (27.7%) out of 112 lymph nodes. Metastatic lymph nodes had a significantly larger short-axis diameter compared with non-metastatic lymph nodes (p = 0.002), but the long-axis diameter was not significantly different between metastatic and non-metastatic lymph nodes. The mean and minimum ADC values for metastatic lymph nodes were significantly reduced compared with those for non-metastatic lymph nodes (p < 0.001 for both). However, the minimum ADC value showed the highest accuracy for the diagnosis of histological lymph node metastasis, with an area under the curve of 0.877, sensitivity of 87.1%, specificity of 82.7%, and accuracy of 83.9%. Conclusions: The minimum ADC value in DW-MRI is highly effective for the diagnosis of lymph node metastasis in biliary tract cancer. Accurate preoperative diagnosis of lymph node metastasis in biliary tract cancer should enable the establishment of more appropriate treatment strategies. [ABSTRACT FROM AUTHOR]

The article focuses on the advancements and challenges of immune checkpoint blockade (ICB) therapy in cancer treatment. Topics include the historical context and development of ICB, mechanisms of action and resistance, and the exploration of biomarkers and combination therapies to enhance efficacy and overcome treatment limitations.

Background: Immune checkpoint blockade (ICB)-based immunotherapy has inspired new hope for advanced biliary tract cancer (BTC) treatment; however, there are no prior studies that primarily focus on different anatomical types of unresectable BTCs reacting differently to ICB. Methods: We retrospectively collected data on advanced BTC patients who received anti-programmed cell death protein 1 (anti-PD1) therapy from two affiliated hospitals of Sun Yat-Sen university. The effects of anti-PD1 were compared for different anatomical sites. The GSE32225 and GSE132305 datasets were used to further analyze differences in the immune microenvironments between intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC). Results: A total of 198 advanced BTC patients were enrolled in this study, comprising 142 patients with ICC and 56 with other cancer types ("Others" group), including ECC and gallbladder cancer. In the anti-PD1 treated patients, the ICC group (n = 90) achieved longer median progression-free survival (mPFS) (9.5 vs. 6.2 months, p = 0.02) and median overall survival (mOS) (15.1 vs. 10.7 months, p = 0.02) than the Others group (n = 26). However, chemotherapy did not show different effects between the two groups (mOS: 10.6 vs. 12.1 months, p = 0.20; mPFS: 4.9 vs. 5.7 months, p = 0.83). For the first-line anti-PD1 therapy, the ICC group (n = 70) achieved higher mOS (16.0 vs. 11.8 months, p = 0.04) than the Others group (n = 19). Moreover, most chemokines, chemokine receptors, major histocompatibility complex molecules, immunostimulators, and immunoinhibitors were stronger in ICC than ECC; furthermore, CD8+ T cells and M1 macrophages were higher in ICC than ECC for most algorithms. The immune differential genes were mainly enriched in antigen processing and presentation as well as the cytokine receptors. Conclusions: This study shows that the efficacy of anti-PD1 therapy was higher in ICC than in other types of BTCs. Differences in the immune-related molecules and cells between ICC and ECC indicate that ICC could benefit more from immunotherapy. [ABSTRACT FROM AUTHOR]

Background and aims: Sarcopenia has been associated with poor prognosis in patients with malignant tumors. However, its impact on the outcomes of patients with biliary tract cancer (BTC) undergoing surgical resection remains unclear and warrants further review. This study aims to summarize the available evidence on this issue. Methods: A systematic search was conducted in PubMed, Embase, Web of Science, and the Cochrane Library for eligible studies up to March 10, 2024. We extracted data on overall survival (OS), recurrence free survival (RFS), and postoperative major complications from the included studies as the outcomes of interest. Following data synthesis and analysis, we assessed the heterogeneity and performed subgroup analyses. Additionally, the potential for publication bias was evaluated. Results: A total of 26 studies involving 4292 BTC patients were ultimately retrieved. The findings indicated that sarcopenia was significantly associated with reduced OS in BTC patients after surgery (adjusted HR: 2.03, 95% CI: 1.65–2.48, P < 0.001, I2 = 57.4%). Moreover, sarcopenia may also be linked to poorer RFS (adjusted HR: 2.15, 95% CI: 1.79–2.59, P < 0.001, I2 = 0%) and increased postoperative major complications (OR: 1.22, 95% CI 1.02–1.47, P = 0.033, I2 = 29.2%) as well. Notably, no significant publication bias was detected through funnel plots and Egger's tests. Conclusion: Sarcopenia is associated with poorer OS in BTC patients following surgery. Additionally, it may serve as a prognostic indicator for poorer RFS and increased postoperative major complications. Further studies are warrant to standardize existing definitions and validate these findings. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To evaluate the economic impact of pembrolizumab combined with gemcitabine and cisplatin versus placebo combined with gemcitabine and cisplatin for the first-line treatment of patients with advanced biliary tract cancer in China. METHODS: From the perspective of China’ s health system, the willingness-to-pay (WTP) threshold was set at 3 times of China’ s gross domestic product ( GDP) per capita in 2022, that is 257 094. 00 RMB/ quality-adjusted life year (QALY), Markov model and partitioned survival model were constructed to conduct cost-effectiveness analysis, univariate sensitivity analysis and probabilistic sensitivity analysis were used to analyze the effects of parameters on the model’s robustness, and to analyze the economic outcome of pembrolizumab under the patient assistance program scenario. RESULTS: The results of Markov model analysis showed that the incremental cost-effectiveness ratio (ICER) was 2 758 043. 34 RMB/QALY for the pembrolizumab group versus the placebo group, and 730 319. 70 RMB/QALY under the patient assistance program scenario, which were both higher than the set WTP threshold; in the absence of patient assistance program, the cost-effectiveness price of pembrolizumab was 1 452. 45 RMB/100 mg, and the partitioned survival model results had validated the Markov model results. CONCLUSIONS: Under the WTP threshold of 3 times of 2022 China’s per capita GDP, pembrolizumab combined with chemotherapy for the first-line treatment of advanced biliary tract cancer does not have cost-effectiveness advantage, and lowering the price of pembrolizumab can increase the probability of its cost-effectiveness advantage. [ABSTRACT FROM AUTHOR]

Background/Aims: Advanced pancreatic and biliary tract cancers can invade the duodenum and cause duodenal hemorrhagic stenosis. This study aimed to evaluate the efficacy of covered self-expandable metal stents in the treatment of cancer-related duodenal hemorrhage with stenosis. Methods: Between January 2014 and December 2016, metal stents were placed in 51 patients with duodenal stenosis. Among these patients, a self-expandable covered metal stent was endoscopically placed in 10 patients with hemorrhagic duodenal stenosis caused by pancreatobiliary cancer progression. We retrospectively analyzed the therapeutic efficacy of the stents by evaluating the technical and clinical success rates based on successful stent placement, degree of oral intake, hemostasis, stent patency, and overall survival. Results: The technical and clinical success rates were 100%. All 10 patients achieved a gastric outlet obstruction scoring system score of three within two weeks after the procedure and had no recurrence of melena. The median stent patency duration and overall survival after stent placement were 52 days (range, 20-220 days) and 66.5 days (range, 31-220 days), respectively. Conclusions: Endoscopic placement of a covered metal stent for hemorrhagic duodenal stenosis associated with pancreatic or biliary tract cancer resulted in duodenal hemostasis, recanalization, and improved quality of life. [ABSTRACT FROM AUTHOR]

Gallbladder cancer (GBC) starts in the epithelial tissue (lining of the bile duct and gallbladder). It is a type of aggressive cancer called adenocarcinoma that can spread to other tissues. Among all cases of biliary tract cancer, 50% is from GBC. It is a deadly cancer with a survival rate of 17.6% between 2007 and 2013. GBC is rarely found in the Western world, but it is commonly found in South Asia. In Southeast Asian countries, GBC plays a significant role in cancer-related morbidity and mortality. GBC incidence exhibits marked regional variability, a rare condition in the western population but having a higher frequency in India, especially the Indo-Gangetic belt and some northeast districts excluding Nagaland. This might be attributed to the differences in environmental factors and genetic predisposition modulating carcinogenesis. In GBC, only 10% of cases are identified in the early stages. The low rate of early detection is due to the lack of screening techniques and the aggressive characteristics of the tumor. Various risk factors are associated with GBC, for example, chronic cholecystitis with or without gallstones, obesity, exposure to heavy metals such as lead and arsenic, bacterial infection, congenital biliary cysts, and abnormal pancreaticobiliary duct junction. The risk factors can cause chronic gallbladder mucosa irritation, leading to dysplasia and neoplasia. GBC can form metaplasia to dysplasia in a time span of 5-15 years, then to carcinoma in situ, and finally to invasive cancer. Dysbiosis is responsible for various diseases, including cancer. Multiple triggers can cause dysbiosis, for example, environmental changes, inflammation, infection, medications, dietary changes, or genetic predisposition. Various researches show that Helicobacter pylori, human papillomavirus, Hepatitis B virus, and Hepatitis C virus microbial species can cause cancer. They are the major species responsible for 90% of infection-associated cancers. Various studies demonstrate that the strains of Salmonella and Helicobacter colonize are linked to developing GBC. While the mechanisms linking gut microbiota to GBC are not fully understood, several studies have suggested a potential association. According to a study, certain gut microbiomes, such as Fusobacterium nucleatum, found glut in GBC tissues, compared to adjacent normal tissues. By evaluating gut microbiome dysbiosis, we can see the potential link between gut microbiome dysbiosis and GBC; it may provide valuable insights into the development and progression of GBC. It could lead to the identification of new diagnostic markers and the development of novel therapeutic strategies. In GBC, the evaluation of gut microbiome dysbiosis (involving evaluating the composition, diversity, and functional capacity of the gut microbiome in patients) has emerged as a promising method for understanding the molecular mechanisms and identifying biomarkers for early prevention and detection of GBC and also investigating the possibility of any link between the gut microbiome and host immune response. In conclusion, evaluating gut microbiome dysbiosis in GBC is a promising direction for identifying potential early detection and prevention biomarkers. Additional investigation is therefore needed to determine the role of gut microbiome dysbiosis in the development and progression of GBC and to identify reliable biomarkers for clinical use. [ABSTRACT FROM AUTHOR]

Introduction: Most patients with advanced gallbladder cancer are treated with multiagent chemotherapy. Immune checkpoint inhibitors offer the possibility of a durable response with less toxicity. This prospective, multicenter, open‐label study was designed to evaluate the anticancer activity of nivolumab plus ipilimumab in patients with advanced gallbladder cancer. Methods: Nineteen patients with advanced gallbladder cancer refractory to ≥1 previous therapy received nivolumab 240 mg intravenously every 2 weeks and ipilimumab 1 mg/kg intravenously every 6 weeks until disease progression or unacceptable toxicity. The primary end point was confirmed radiographic overall response rate (ORR) (complete response [CR] + partial response [PR] confirmed on subsequent scan); secondary end points included unconfirmed overall response, clinical benefit rate (confirmed and unconfirmed responses + stable disease >6 months), progression‐free survival, overall survival, and toxicity. Results: The confirmed ORR was 16% (CR, n = 1 [5%]; PR, n = 2 [11%]); all were microsatellite stable, and the confirmed CR had undetectable programmed death‐ligand 1 by immunohistochemistry. The unconfirmed ORR and clinical benefit rates were both 32%. The median duration of response was 14.8 months (range, 4–35.1+ months). The 6‐month progression‐free survival was 26% (95% CI, 12–55). The median overall survival was 7.0 months (95% CI, 3.9–19.1). The most common toxicities were fatigue (32%), anemia (26%), and anorexia (26%). Aspartate aminotransferase elevation was the most common grade 3/4 toxicity (11%). There was 1 possibly related death (sepsis with attendant hepatic failure). Conclusions: Ipilimumab plus nivolumab was well tolerated and showed modest efficacy with durable responses in previously treated patients with advanced gallbladder cancer. Clinical Trial Registration: NCT02834013 (ClincialTrials.gov). Plain Language Summary: This prospective study assessed the efficacy and safety of nivolumab plus ipilimumab in 19 patients with advanced gallbladder cancer refractory to previous therapy. The combination demonstrated modest efficacy with a 16% confirmed overall response rate, durable responses, and manageable toxicities, suggesting potential benefits for this challenging patient population. Ipilimumab plus nivolumab demonstrated modest efficacy with durable responses and manageable toxicity in previously treated patients with advanced gallbladder cancer. [ABSTRACT FROM AUTHOR]

Oxysterols have been implicated in biliary tract cancer (BTC), and Niemann-Pick C1–like 1 (NPC1L1) has been associated with oxysterol uptake in biliary and intestinal cells. Thus, our study aims to investigate the potential causal link between genetically proxied NPC1L1 inhibitors and the risk of BTC. In this study, we employed two genetic instruments as proxies for NPC1L1 inhibitors, which included LDL cholesterol-associated genetic variants located within or in close proximity to the NPC1L1 gene, as well as expression quantitative trait loci (eQTLs) of the NPC1L1 gene. Effect estimates were calculated using the Inverse-variance-weighted MR (IVW-MR) and summary-data-based MR (SMR) methods. In MR analysis using the IVW method, both proxy instruments from the UK Biobank and the GLGC demonstrated a positive association between NPC1L1-mediated LDL cholesterol and BTC risk, with odds ratios (OR) of 10.30 (95% CI = 1.51–70.09; P = 0.017) and 5.61 (95% CI = 1.43–21.91; P = 0.013), respectively. Moreover, SMR analysis revealed a significant association between elevated NPC1L1 expression and increased BTC risk (OR = 1.19, 95% CI = 1.04–1.37; P = 0.014). This MR study suggests a causal link between NPC1L1 inhibition and reduced BTC risk. NPC1L1 inhibitors, like ezetimibe, show potential for chemoprevention in precancerous BTC patients, requiring further clinical investigation. [ABSTRACT FROM AUTHOR]

Background: Gastrointestinal tumors represent a significant component of the cancer burden in Asia. This study aims to evaluate the burden of gastrointestinal tumors in Asia from 1990 to 2021 using data from the Global Burden of Disease Study 2021 (GBD 2021). Methods: The absolute incidence, mortality, and disability adjusted life years (DALYs) number and rate of six gastrointestinal tumors(colon and rectum cancer (CRC), stomach cancer (SC), pancreatic cancer (PC), esophageal cancer (EC), liver cancer (LC) and gallbladder and biliary tract cancer (GBTC)) in 48 Asian countries were extracted from GBD 2021. Differences were analyzed based on gender, age, year, location and socio-demographic index (SDI). Results: In 2021, SC accounted for the highest disease burden in Asia (DALYs=16.41million [95% UI: 13.70, 19.62]). From 1990 to 2021, the age-standardized incidence rates of EC, LC, and SC in Asia declined, while the incidence rates of CRC and PC increased significantly, with CRC showing the largest rise (AAPC=1.08 [95% CI: 1.02 to 1.12]). Gastrointestinal tumors DALY rates peaked at age 70 and above, with males generally exhibiting higher rates than females. Furthermore, East Asia bears a higher burden compared to other Asian subregions. A higher SDI correlates with increased DALY rates for PC, but no linear relationship was observed for other gastrointestinal tumors. Conclusion: The burden of gastrointestinal tumors in Asia remains high and may continue to increase. Therefore, effective prevention and treatment measures are essential to address the challenge posed by gastrointestinal tumors. [ABSTRACT FROM AUTHOR]

Background: Pancreatic and biliary tract cancers are digestive system tumors with dismal prognosis and limited treatment options. The effectiveness of conventional surgical interventions, radiation therapy, and systemic therapy is restricted in these cases. Furthermore, clinical trials have shown that immunotherapy using immune checkpoint inhibitors has only demonstrated modest clinical results when applied to patients with pancreatobiliary tumors. This highlights the importance of implementing combination immunotherapy approaches or exploring alternative therapeutic strategies to improve treatment outcomes. Materials and Methods: We reviewed the relevant literature on chimeric antigen receptor (CAR)-T cell therapy for pancreatobiliary cancers from PubMed/Medline and ClinicalTrials.gov and retrieved the relevant data accordingly. Attention was additionally given to the examination of grey literature with the aim of obtaining additional details regarding ongoing clinical trials. We mainly focused on abstracts and presentations and e-posters and slides of recent important annual meetings (namely ESMO Immuno-Oncology Congress, ESMO Congress, ASCO Virtual Scientific Program, ASCO Gastrointestinal Cancers Symposium). Results: CAR-T cell therapy has emerged as a promising and evolving treatment approach for pancreatic and biliary tract cancer. This form of adoptive cell therapy utilizes genetic engineering to modify the expression of specific antibodies on the surface of T cells enabling them to target specific cancer-associated antigens and to induce potent anti-tumor activity. The aim of this review is to provide an updated summary of the available evidence from clinical trials that have explored the application of CAR-T cell therapy in treating pancreatobiliary cancers. Conclusions: While the utilization of CAR-T cell therapy in pancreatobiliary cancers is still in its initial phases with only a limited amount of clinical data available, the field is advancing rapidly, incorporating novel technologies to mitigate potential toxicities and enhance antigen-directed tumor eradication. [ABSTRACT FROM AUTHOR]

Despite several therapeutic advancements, the proportion of patients with advanced biliary tract cancers (BTC) surviving 5 years from diagnosis remains dismal. The increasing recognition of targetable genetic alterations in BTCs has ushered in a new era in the treatment of these patients. Newer therapeutic agents targeting mutations such as isocitrate dehydrogenase (IDH), fibroblastic growth factor receptor (FGFR), human epidermal growth factor receptor (HER), and so on have established a new standard of care for treatment upon progression on frontline therapy in patients with disease harboring these mutations. The current review aims to concisely summarize progress with various targeted therapy options for BTC. We also briefly discuss future directions in clinical and translational research for the adoption of a personalized approach for the treatment of unresectable or advanced BTC. Several new agents continue to emerge as feasible treatment options for patients with advanced BTC harboring targetable mutations. There is a growing need to identify mechanisms to conquer primary and acquired resistance to these agents. The identification of potential biomarkers that predict response to targeted therapy may be helpful in adopting a more tailored approach. All patients receiving treatment for advanced BTC should undergo tissue genomic profiling at diagnosis. [ABSTRACT FROM AUTHOR]

Cholangiocarcinoma (CCA), an aggressive biliary tract cancer, carries a grim prognosis with a 5‐year survival rate of 5%–15%. Standard chemotherapy regimens for CCA, gemcitabine plus cisplatin (GemCis) or its recently approved combination with durvalumab demonstrate dismal clinical activity, yielding a median survival of 12–14 months. Increased serotonin accumulation and secretion have been implicated in the oncogenic activity of CCA. This study investigated the therapeutic efficacy of telotristat ethyl (TE), a tryptophan hydroxylase inhibitor blocking serotonin biosynthesis, in combination with standard chemotherapies in preclinical CCA models. Nab‐paclitaxel (NPT) significantly enhanced animal survival (60%), surpassing the marginal effects of TE (11%) or GemCis (9%) in peritoneal dissemination xenografts. Combining TE with GemCis (26%) or NPT (68%) further increased survival rates. In intrahepatic (iCCA), distal (dCCA) and perihilar (pCCA) subcutaneous xenografts, TE exhibited substantial tumour growth inhibition (41%–53%) compared to NPT (56%–69%) or GemCis (37%–58%). The combination of TE with chemotherapy demonstrated enhanced tumour growth inhibition in all three cell‐derived xenografts (67%–90%). PDX studies revealed TE's marked inhibition of tumour growth (40%–73%) compared to GemCis (80%–86%) or NPT (57%–76%). Again, combining TE with chemotherapy exhibited an additive effect. Tumour cell proliferation reduction aligned with tumour growth inhibition in all CDX and PDX tumours. Furthermore, TE treatment consistently decreased serotonin levels in all tumours under all therapeutic conditions. This investigation decisively demonstrated the antitumor efficacy of TE across a spectrum of CCA preclinical models, suggesting that combination therapies involving TE, particularly for patients exhibiting serotonin overexpression, hold the promise of improving clinical CCA therapy. [ABSTRACT FROM AUTHOR]

The incidence of biliary tract cancer is increasing in developed countries and is generating renewed interest in the scientific community due to the evidence of a high percentage (approximately 40%) of potentially targetable molecular alterations. However, to date, patient selection and the development of therapeutic approaches remain challenging due to the need for accurate diagnosis, adequate sampling, a specialized team for molecular analysis, centralization of patients in high-volume centers capable of supporting the high cost of these methods, and the feasibility of clinical studies on diseases with aggressive onset and poor prognosis. In this article, we would like to provide a detailed overview of the necessary tools for diagnostic framing and the various therapeutic scenarios being investigated concerning the most frequently detected molecular alterations. [ABSTRACT FROM AUTHOR]

Although numerous observational studies have reported on the association between alcohol consumption and cancer, insufficient studies have estimated the causality. Our study evaluated the causal relationship between various types of cancer according to the frequency of drinking and the amount of alcohol consumed. The research data were obtained from the publicly available MR-Base platform. The frequency and amount of drinking were selected as the exposure, and 16 cancer types were selected as the outcome. Two-sample summary data Mendelian randomization (2SMR) was conducted to examine the causality between alcohol consumption and cancer type. Additionally, for cancers suspected of pleiotropy, outliers were removed and re-analyzed through radial MR. The MR results using the inverse variance weighted (IVW) method were different before and after removing outliers. The biggest differences were found for esophageal cancer and biliary tract cancer. For esophageal cancer, after removing outliers (rs13102973, rs540606, rs650558), the OR (95% CI) was 3.44 (1.19–9.89), which was statistically significant (p = 0.02172). Even in biliary tract cancer, after removing outliers (rs13231886, rs58905411), the OR (95% CI) was 3.86 (0.89–16.859), which was of borderline statistical significance (p = 0.07223). The strongest association was found for esophageal cancer. For other cancers, the evidence was not sufficient to draw conclusions. More research is needed to understand the causality between drinking and cancer. [ABSTRACT FROM AUTHOR]

Abstract Background A recent phase 2A clinical study of Atractylodes lancea (Thunb.) DC. (AL) in patients with advanced-stage intrahepatic cholangiocarcinoma (iCCA) demonstrated significant reduction of the risk of tumor progression and mortality with a dose ranging from 1,000 to 2,000 mg. The present study aimed to determine the potential dosage regimen of AL for further phase 2B clinical study. Methods Plasma-concentration time profiles of total AL bioactivity and clinical efficacy in patients with advanced-stage iCCA were obtained from Phase 2 A study. The population pharmacokinetic (pop-PK) model was developed. The pop-PK model and Monte-Carlo (MC) simulation, in conjunction with maximum concentration of AL (Cmax) as a cut-off criterion, was performed and validated with clinical data. The optimal model was used to simulate further dosage regimens and clinical efficacy of AL. Results The pop-PK properties of total AL bioactivity were best described by a compartmental model with zero-order absorption (without delay) and linear clearance. None of the investigated covariates improved model accuracy.The developed pop-PK with MC simulations following once-daily dosing of 1,000 mg and 2,000 mg adequately predicted the clinical efficacy (tumor progression and mortality). The once-daily dose of 2,500 mg is recommended for further phase 2B clinical study due to its relatively high efficacy on tumor progression inhibition (73%) and mortality rate reduction (71%) without excessive number of the administered capsules (23 capsules) and low risk of toxicities (

Abstract Background and aims Sarcopenia has been associated with poor prognosis in patients with malignant tumors. However, its impact on the outcomes of patients with biliary tract cancer (BTC) undergoing surgical resection remains unclear and warrants further review. This study aims to summarize the available evidence on this issue. Methods A systematic search was conducted in PubMed, Embase, Web of Science, and the Cochrane Library for eligible studies up to March 10, 2024. We extracted data on overall survival (OS), recurrence free survival (RFS), and postoperative major complications from the included studies as the outcomes of interest. Following data synthesis and analysis, we assessed the heterogeneity and performed subgroup analyses. Additionally, the potential for publication bias was evaluated. Results A total of 26 studies involving 4292 BTC patients were ultimately retrieved. The findings indicated that sarcopenia was significantly associated with reduced OS in BTC patients after surgery (adjusted HR: 2.03, 95% CI: 1.65–2.48, P

Introduction: This study assesses the effectiveness of durvalumab with platinum and gemcitabine for biliary tract cancers (BTC). It aims to confirm the TOPAZ-1 trial results in a real-world context and explore the link between BTC molecular profiles and patient outcomes. Methods: A retrospective analysis was conducted on 102 BTC patients treated with durvalumab, platinum, and gemcitabine at five cancer centers in Austria and one in Germany from 2022 to 2024. Molecular profiling used targeted DNA and RNA assays. Clinical endpoints, including progression-free survival (PFS) and overall survival (OS), were assessed using log-rank tests and Cox regression, with correlations to second-line molecular-targeted therapies. Results: Among 102 patients, 60.8% had intrahepatic cholangiocarcinoma. The treatment achieved a disease control rate of 71.57% and an overall response rate of 35.11%. Median PFS was 6.51 months, and OS was 13.61 months. Patients under 65 had significantly better OS. Alterations in chromatin remodeling or homologous recombination repair genes were not predictive of survival benefit (HR: 0.45; p = 0.851 and HR: 1.63; p = 0.26, respectively). Patients with molecular-informed second-line therapy showed a trend toward survival benefit (HR: 0.23; p = 0.052). Conclusion: This study confirms the phase 3 trial results of durvalumab with platinum and gemcitabine, providing a substantial real-world dataset with detailed molecular characterization. No specific patient subgroup showed a markedly better response to durvalumab based on conventional NGS panels. Further research is needed to explore the link between immunotherapy responses and molecular subgroups. [ABSTRACT FROM AUTHOR]

Background: Lenvatinib, programmed cell death 1 (PD-1) antibodies, and gemcitabine and oxaliplatin (GEMOX) chemotherapy have shown significant antitumor activity as first-line therapy against biliary tract cancer. This study evaluated their efficacy and safety as non-first-line therapy in advanced gallbladder cancer (GBC). Methods: Patients with advanced GBC who received lenvatinib combined with anti-PD-1 antibodies and GEMOX chemotherapy as a non-first-line therapy were retrospectively analyzed. The primary endpoints were overall survival (OS) and progression-free survival (PFS), and the secondary endpoints were objective response rate (ORR) and safety. Results: A total of 36 patients with advanced GBC were included in this study. The median follow-up time was 11.53 (95% confidence interval (CI): 2.2–20.9) months, and the ORR was 36.1%. The median OS and PFS were 15.1 (95% CI: 3.2–26.9) and 6.1 (95% CI: 4.9–7.2) months, respectively. The disease control rate (DCR) and clinical benefit rate (CBR) were 75% and 61.1%, respectively. Subgroup analysis demonstrated that patients with programmed cell death-ligand 1 (PD-L1) expression had significantly longer PFS and OS than those without PD-L1 expression. Additionally, patients with a neutrophil–lymphocyte ratio (NLR) < 5.57 had a longer OS than those with an NLR ≥ 5.57. All patients experienced adverse events (AEs), with 61.1% experiencing grade 3 or 4 AEs, including myelosuppression (13.9%) and fatigue (13.3%), alanine transaminase or aspartate transaminase levels (8.3%), and diarrhea (8.3%). No grade 5 AEs were reported. Conclusion: Anti-PD-1 antibodies combined with lenvatinib and GEMOX chemotherapy are effective and well-tolerated as a non-first-line therapy in advanced GBC. PD-L1 expression and baseline NLR may potentially predict treatment efficacy. [ABSTRACT FROM AUTHOR]

Purpose: The clinical effectiveness of triple chemotherapy consisting of gemcitabine, cisplatin plus either S-1 (GCS), durvalumab (DGC), or pembrolizumab (PGC) as first-line treatment for advanced biliary tract cancer (BTC) has been reported. However, their comparative cost-effectiveness is unclear. We conducted a model-based cost-effectiveness analysis from the perspective of Japanese healthcare payer. Methods: A 10-year partitioned survival model was constructed by comparing the time-dependent hazards of the KHBO1401-MITSUBA, TOPAZ-1, and KEYNOTE-966 trials. The cost and utility came from previously published reports. Quality-adjusted life years (QALY) were used to measure the effects on health. Costs for direct medical care were taken into account. There was a one-way analysis and a probability sensitivity analysis. A willingness-to-pay threshold of 7.5 million yen (57,034 USD) per QALY was defined. Results: The incremental costs per QALY for GCS, DGC, and PGC in the base case study were 3,779,374 JPY (28,740 USD), 86,058,056 JPY (65,4434 USD), and 28,982,059 JPY (220,396 USD), respectively. No parameter had an influence beyond the threshold in a one-way sensitivity analysis. A probabilistic sensitivity analysis revealed that the probability of GCS, DGC, and PGC being cost-effective at the threshold was 85.6%, 0%, and 0%, respectively. Conclusion: Given the current circumstances, it is probable that triple therapy utilizing GCS will emerge as a plausible and efficient primary chemotherapy strategy for patients with advanced BTC in the Japanese healthcare system, as opposed to DGC and PGC. [ABSTRACT FROM AUTHOR]

Abstract Background Despite the recent advances in cancer treatment, the therapeutic options for patients with biliary tract cancer are still very limited and the prognosis very poor. More than 50% of newly diagnosed patients with biliary tract cancer are not amenable to curative surgical treatment and thus treated with palliative systemic treatment. Malignant bile duct obstructions in patients with perihilar and/or ductal cholangiocarcinoma (CCA) represents one of the most important challenges in the management of these patients, owning to the risk represented by developing life-threatening cholangitis which, in turn, limits the use of systemic treatment. For this reason, endoscopic stenting and/or bile duct decompression is the mainstay of treatment of these patients. Data on efficacy and safety of adding radiofrequency ablation (RFA) to biliary stenting is not conclusive. The aim of this multicenter, randomized trial is to evaluate the effect of intraductal RFA prior to bile duct stenting in patients with unresectable perihilar or ductal CCA undergoing palliative systemic therapy. Methods/Design ACTICCA-2 is a multicenter, randomized, controlled, open-label, investigator-initiated trial. 120 patients with perihilar or ductal CCA with indication for biliary stenting and systemic therapy will be randomized 1:1 to receive either RFA plus bile duct stenting (interventional arm) or bile duct stenting alone (control arm). Patients will be stratified by trial site and tumor location (perihilar vs. ductal). Both arms receive palliative systemic treatment according to the local standard of care determined by a multidisciplinary tumorboard. The primary endpoint is time to first biliary event, which is determined by an increase of bilirubin to > 5 mg/dl and/or the occurrence of cholangitis leading to premature stent replacement and/or disruption of chemotherapy. Secondary endpoints include overall survival, safety according to NCI CTCAE v5, quality of life assessed by questionnaires (EORTC QLQ-C30 and QLQ-BIL21), clinical event rate at 6 months after RFA and total days of over-night stays in hospital. Follow-up for the primary endpoint will be 6 months, while survival assessment will be continued until end of study (maximum follow-up 30 month). All patients who are randomized and who underwent endoscopic stenting will be used for the primary endpoint analysis which will be conducted using a cause-specific Cox proportional hazards model with a frailty for trial site and fixed effects for the treatment group, tumor location, and stent material. Discussion ACTICCA-2 is a multicenter, randomized, controlled trial to assess efficacy and safety of adding biliary RFA to bile duct stenting in patients with CCA receiving palliative systemic treatment. Trial registration The study is registered with ClinicalTrials.gov (NCT06175845) and approved by the local ethics committee in Hamburg, Germany (2024-101232-BO-ff). This manuscript reflects protocol version 1 as of January 9th, 2024. Graphical Abstract

Luohang Ni,&ast; Jianing Xu,&ast; Quanpeng Li, Xianxiu Ge, Fei Wang, Xueting Deng, Lin Miao Medical Center for Digestive Diseases, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xueting Deng; Lin Miao, Email xtdeng@njmu.edu.cn; linmiao@njmu.edu.cnAbstract: Biliary tract cancer (BTC) represents a challenging malignancy characterized by aggressive behavior, high relapse rates, and poor prognosis. In recent years, immunotherapy has revolutionized the treatment landscape for various cancers, but its efficacy in BTC remains limited. This article provides a comprehensive overview of the advances in preclinical and clinical studies of immunotherapy for BTC. We explore the potential of immune checkpoint inhibitors in reshaping the management of BTC. Despite disappointing results thus far, ongoing clinical trials are investigating the combination of immunotherapy with other treatment modalities. Furthermore, research on the tumor microenvironment has unveiled novel targets for immunotherapeutic interventions. By understanding the current state of immunotherapy in BTC and highlighting future directions, this article aims to fuel further exploration and ultimately improve patient outcomes in this challenging disease.Keywords: biliary tract cancer, cancer immunotherapy, tumor microenvironment, immune checkpoint inhibitors, clinical trials

Abstract Background Accumulating evidence suggests that the gut microbiota and metabolites can modulate tumor responses to immunotherapy; however, limited data has been reported on biliary tract cancer (BTC). This study used metagenomics and metabolomics to identify characteristics of the gut microbiome and metabolites in immunotherapy-treated BTC and their potential as prognostic and predictive biomarkers. Methods This prospective cohort study enrolled 88 patients with BTC who received PD-1/PD-L1 inhibitors from November 2018 to May 2022. The microbiota and metabolites significantly enriched in different immunotherapy response groups were identified through metagenomics and LC-MS/MS. Associations between microbiota and metabolites, microbiota and clinical factors, and metabolites and clinical factors were explored. Results Significantly different bacteria and their metabolites were both identified in the durable clinical benefit (DCB) and non-durable clinical benefit (NDB) groups. Of these, 20 bacteria and two metabolites were significantly associated with survival. Alistipes were positively correlated with survival, while Bacilli, Lactobacillales, and Pyrrolidine were negatively correlated with survival. Predictive models based on six bacteria, four metabolites, and the combination of three bacteria and two metabolites could all discriminated between patients in the DCB and NDB groups with high accuracy. Beta diversity between two groups was significantly different, and the composition varied with differences in the use of immunotherapy. Conclusions Patients with BTC receiving immunotherapy have specific alterations in the interactions between microbiota and metabolites. These findings suggest that gut microbiota and metabolites are potential prognostic and predictive biomarkers for clinical outcomes of anti-PD-1/PD-L1-treated BTC.

Abstract Background Patients diagnosed with pancreatic, biliary tract, and liver cancer often suffer from a progressive loss of muscle mass. Given the considerable functional impairments in these patients, high musculoskeletal weight loads may not be well tolerated by all individuals. The use of blood-flow restricted resistance training (BFR-T) which only requires low training loads may allow for a faster recovery of muscle due to avoidance of high levels of mechanical muscle stress associated with high-load resistance exercise. This study aims to investigate whether BFR-T can prevent or slow down the loss of skeletal muscle mass and enhance the functional capacity and mental health of patients with pancreatic, biliary tract, and liver cancer. Methods The PREV-Ex exercise trial is a multicenter two-armed randomized controlled trial. Patients will be randomized to an exercise program consisting of home-based low-load BFR-T during a combined pre- and postoperative period for a total of 6–10 weeks (prehabilitation and rehabilitation), or to a control group. Protein supplementation will be given to both groups to ensure adequate protein intake. The primary outcomes, skeletal muscle thickness and muscle cross-sectional area, will be assessed by ultrasound. Secondary outcomes include the following: (i) muscle catabolism-related and inflammatory bio-markers (molecular characteristics will be assessed from a vastus lateralis biopsy and blood samples will be obtained from a sub-sample of patients); (ii) patient-reported outcome measures (self-reported fatigue, health-related quality of life, and nutritional status will be assessed through validated questionnaires); (iii) physical fitness/performance/activity (validated tests will be used to evaluate physical function, cardiorespiratory fitness and maximal isometric muscle strength. Physical activity and sedentary behavior (assessed using an activity monitor); (iv) clinical outcomes: hospitalization rates and blood status will be recorded from the patients’ medical records; (v) explorative outcomes of patients’ experience of the exercise program which will be evaluated using focus group/individual interviews. Discussion It is worthwhile to investigate new strategies that have the potential to counteract the deterioration of skeletal muscle mass, muscle function, strength, and physical function, all of which have debilitating consequences for patients with pancreatic, biliary tract, and liver cancer. The expected findings could improve prognosis, help patients stay independent for longer, and possibly reduce treatment-related costs. Trial registration ClinicalTrials.gov NCT05044065. Registered on September 14, 2021.