Biliary tract carcinoma (BTC) is an aggressive cancer with a poor prognosis, and chemotherapy's effectiveness is limited, especially after first-line therapy failure. Circulating tumor cells (CTCs) offer a promising platform for in vitro drug-sensitivity testing to optimize subsequent-line chemotherapy, but the clinical efficacy and prognostic value remain underexplored. In this study, we retrospectively analyzed 85 advanced BTC patients, with 25 receiving CTC-based drug-sensitivity-guided chemotherapy (CSBT), 15 receiving FOLFOX based chemotherapy, and 45 receiving empirical therapy. CTCs were enriched and tested for drug sensitivity using a glucose uptake assay. Therapeutic efficacy, including patient response, progression-free survival (PFS), overall survival (OS), and toxicity profiles, was evaluated. The results indicated that the objective response rate (ORR) was 16% in CSBT, 6.7% in FOLFOX, and 4.4% in the empirical group. The disease control rate (DCR) was significantly higher in CSBT group (56%) compared to the FOLFOX (20%) and empirical therapy (22.2%; p < 0.05) groups. Median PFS (mPFS) was significantly prolonged in the CSBT group (5.4 months) versus the FOLFOX (1.9 months) and empirical therapy (2.7 months; p < 0.05) groups. Median OS (mOS) was extended in the CSBT group (12 months) compared with the FOLFOX (5.1 months) and EBT group (7.8 months), with a significant improvement during the first year of treatment (p < 0.05). Toxicity profiles were similar across all groups. This study demonstrates, for the first time, that CTC-based drug sensitivity testing offers a potential strategy to guide subsequent anti-cancer therapy for advanced BTC, providing a safe and effective approach to improving patient prognosis.

Introduction:Biliary tract malignancies (BTM) represent a significant global health challenge, ranking as the third leading cause of cancer-associated mortality. Despite their clinical impact, prognosis remains poor, necessitating the discovery of robust molecular markers to guide risk stratification and precision oncology. Objectives:1.to study the distribution of molecular markers among cases and control for predictive value,sensitivity and specificity.2.to study the role of molecular markers in outcome of BTM. Material and Methods:Retrospective observational study done in radiologically suspected 70 patients in department of surgery between 2013 to 2015.Specimen sent for IHC &amp; HPE and the result of molecular markers are compared among cases and control..Conclusion and Result:In our study,Muc-1 expression is more specific whereas cyclin D1 expression is more sensitive indicator in differentiating between benign and malignant biliary tract carcinomas, Expression of Muc1 and Muc 4 significantly(p&lt;0.05) correlates with high grade of malignancy whereas Muc2 and Cyclin D1 is associated with low grade malignancy but statistically insignificant.(p&gt;0.05) .Among these molecular markers expression of Muc-2 significantly affect outcome and its expression is associated with better outcome in patients with Biliary tract malignancy

The anti-PD-L1 antibody has been applied for use in first-line advanced biliary duct cancer patients. However, clinical evidence of toripalimab in combination with biweekly 5-fluorouracil (5-FU) is limited and predictive biomarkers of treatment benefits remain unclear. This prospective study enrolled patients with unresectable or metastatic BTC who received toripalimab in combination with gemcitabine and biweekly 5-FU. The primary endpoints were progression-free survival (PFS) and objective response rate (ORR). Secondary endpoints included overall survival (OS) and safety. Exploratory analyses evaluated associations between programmed cell death-ligand 1 (PD-L1) expression or tumor mutational burden (TMB) and clinical outcomes. A total of 30 patients were enrolled, with a median follow-up duration of 16.0 months. The ORR was 13.0%. The median PFS and OS were 5.3 months (95% CI: 3.59-7.01) and 11.7 months (95% CI: 6.07-17.33), respectively. Subgroup analyses revealed no significant association between PD-L1 status or TMB level and improved PFS. All patients experienced adverse events (AEs), while grade 3-4 AEs occurred in eight patients (26.7%), most commonly anemia (20.0%), leukocytopenia (13.3%), and nausea (6.6%). No grade 5 AEs were observed, and the safety profile was considered manageable. Toripalimab in combination with gemcitabine and 5-fluorouracil showed promising efficacy and was well-tolerated as a first-line therapy in advanced biliary duct cancer patients. Although PD-L1 expression and TMB did not predict treatment benefit, larger studies are needed to validate potential biomarkers and further optimize immunochemotherapy strategies for BTC.

This study aims to compare the effectiveness and safety of anti-programmed cell death protein 1 (PD-1) immunotherapy and tyrosine kinase inhibitors (TKIs) combined with intra-arterial therapy (IAT) or systemic chemotherapy, and anti-PD-1 immunotherapy combined with IAT or systemic chemotherapy in patients with advanced biliary tract carcinoma (BTC). Patients with BTC who received IAT combined with anti-PD-1 immunotherapy and/or TKIs or the combination of systemic chemotherapy with anti-PD-1 immunotherapy and/or TKIs were divided into 4 groups according to inclusion and exclusion criteria: the combination of IAT with TKIs and anti-PD-1 immunotherapy group (ITP group), the systemic chemotherapy combined with TKIs and anti-PD-1 immunotherapy group (CTP group), the combination of IAT with anti-PD-1 immunotherapy group (IP group) and the systemic chemotherapy combined with anti-PD-1 immunotherapy group (CP group). The baseline characteristics, progression-free survival (PFS), treatment efficacy and adverse reactions were compared between ITP and CTP groups and between IP and CP groups, and risk factors related to PFS were analyzed. The median PFS in ITP group was 3.975 months, and the 6-month-PFS was 31.6%; the median PFS in CTP group was 3.285 months, and the 6-month-PFS was 11.1%. There was a statistical difference between ITP group and CTP group. The median PFS in the IP and CP groups were 4.534 months and 2.267 months, respectively, which were also statistically significant. The objective response rate and disease control rate (DCR) of ITP and CTP groups were not statistically significant. There was no significant difference in objective response rate and DCR between IP group and CP group. The lymph node metastasis was an independent risk factor for PFS. Compared with the CTP group, the ITP group had a higher incidence of post-treatment fever and difficulty urination, and the IP group had a higher incidence of 3 degree AST elevation and difficulty urination than the CP group. IAT combined with anti-PD-1 immunotherapy and TKIs or IAT combined with anti-PD-1 immunotherapy for advanced BTC were relatively effective and safe. The lymph node metastasis was an independent risk factor affecting the prognosis of advanced BTC.

This study investigated the correlation between future liver remnant (FLR) hypertrophy and iodine content in the FLR following portal vein embolization, as measured by dual-energy computed tomography (DECT) with direct injection of the contrast agent into the portal vein. In this prospective study conducted at a single center, 39 patients with biliary tract carcinoma underwent right portal vein embolization prior to extended hepatectomy. After portal vein embolization, DECT was performed after injecting iodinated contrast medium into the portal vein, allowing the quantification of iodine concentration and iodine content in the FLR. Liver volumes were assessed before and after portal vein embolization to calculate the degree of hypertrophy and kinetic growth rate of the FLR. Correlations between iodine content and hypertrophy indices, such as degree of hypertrophy and kinetic growth rate, were analyzed. Post-portal vein embolization volumetric CT for FLR hypertrophy evaluation was performed at a median of 25days (21-30days). Early-phase iodine content of the left hepatic lobe on DECT was significantly correlated with both the degree of hypertrophy (DH; r = 0.380, p = 0.038) and the kinetic growth rate (KGR; r = 0.401, p = 0.028), as determined using Pearson's correlation analysis. Likewise, late-phase iodine content of the left hepatic lobe was significantly correlated with DH (r = 0.403, p = 0.011) and KGR (r = 0.337, p = 0.036). Higher iodine content in the FLR was associated with greater FLR hypertrophy after portal vein embolization. However, because the correlation observed in this study was modest, the predictive ability of this parameter could not be established. Nevertheless, DECT-based iodine quantification may provide complementary information on FLR function and warrants further investigation as a potential biomarker in future studies.

BackgroundMalignancies of the biliary tract system, commonly termed biliary tract carcinoma (BTC), and primarily include cholangiocarcinoma (CC). BTC is most often diagnosed at an advanced stage, when surgical resection is no longer feasible, and systemic therapy is therefore frequently used. Immunotherapy, antiangiogenic targeted treatments, precision medicine, and chemotherapy have all improved the management of BTC in recent years. While arterial infusion chemotherapy has demonstrated notable efficacy in hepatocellular carcinoma, its role and outcomes in CC remain less defined, with limited and sometimes inconsistent study results, necessitating further investigation. However, these strategies continue to fall short of meeting full clinical needs, and limitations remain prominent.MethodsThis randomized, open-label, multicenter phase II trial will enroll 60 participants with advanced BTC. The inclusion criteria comprised: age >18 years, advanced BTC diagnosis, no prior systemic therapy, at least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, Eastern Cooperative Oncology Group (ECOG) performance status 0-1.Participants are randomized 1:1 to Cohort 1 [one cycle of hepatic arterial infusion gemcitabine + oxaliplatin (GEMOX) followed by one cycle of intravenous GEMOX] or Cohort 2 (two cycles of intravenous GEMOX). Both cohorts receive intravenous adebrelimab (1,200 mg, day 1) and oral anlotinib (12 mg daily, 2 weeks on/1 week off) per 21-day cycle. After combination chemotherapy, patients with clinical benefit continue adebrelimab plus anlotinib. We will conduct safety visits on the first day of each cycle. The primary endpoint is the 6-month progression-free survival (PFS) rate. Secondary endpoints include PFS, objective response rate, overall survival, and safety.DiscussionThis trial aims to demonstrate the efficacy and safety of adebrelimab combined with anlotinib and GEMOX in advanced BTC, with an expectation that arterial infusion chemotherapy may improve 6-month PFS. We expect that arterial infusion chemotherapy may have better 6-month PFS rate.Trial RegistrationThis clinical trial has been registered on the Chinese Clinical Trial Registry. Clinical trial information: ChiCTR2500102333.

Abstract Introduction: Gallbladder carcinoma (GBC) is a rare but aggressive tumor. Operability is crucial for survival, yet late-stage diagnosis is common due to its asymptomatic nature. This study evaluates the clinical features and surgical outcomes of GBC treatment. Patients and Methods: A retrospective study was conducted on GBC patients who underwent surgery at Viet Duc University Hospital (2015–2022). Inoperable cases and those with incomplete records were excluded. Clinical characteristics, surgical details, and outcomes were analyzed. Results: Among 41 patients, most were diagnosed at advanced stages, with T3 being the most common stage (51.2%). Open surgery (51.2%) was slightly more frequent than laparoscopic procedures. Cholecystectomy alone was performed in 31.7%, while others required hepatectomy or lymphadenectomy. The average hospital stay was 8 ± 3.5 days, with complications occurring in 3 cases and one postoperative death. Mid-term survival was poor, with 31.7% surviving less than six months and 29.3% living for 1–3 years. Conclusions: GBC is often diagnosed late, limiting surgical success and survival. Despite surgical resection, prognosis remains poor, highlighting the need for earlier detection and improved treatment strategies. Abbreviations: GBC: Gallbladder carcinoma, CT: Computed tomography, MRI: Magnetic resonance imaging, CA 19-9: Carbohydrate antigen 19-9, CEA: Carcinoembryonic antigen Keywords: Gallbladder cancer, surgical treatment, mid-term survival References Baria K, De Toni EN, Yu B, Jiang Z, Kabadi SM, Malvezzi M. Worldwide Incidence and Mortality of Biliary Tract Cancer. Gastro Hep Adv. 2022;1(4):618-626. doi:10.1016/j.gastha.2022.04.007 Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin. 2017;67(1):7-30. doi:10.3322/caac.21387 Goetze TO. Gallbladder carcinoma: Prognostic factors and therapeutic options. World J Gastroenterol. 2015;21(43):12211-12217. doi:10.3748/wjg.v21.i43.12211 Nguyen TP, Luu HN, Nguyen MVT, et al. Attributable Causes of Cancer in Vietnam. JCO Glob Oncol. 2020;6:JGO.19.00239. doi:10.1200/JGO.19.00239 Hundal R, Shaffer EA. Gallbladder cancer: epidemiology and outcome. Clin Epidemiol. 2014;6:99-109. doi:10.2147/CLEP.S37357 Strom BL, Maislin G, West SL, et al. Serum CEA and CA 19-9: potential future diagnostic or screening tests for gallbladder cancer? Int J Cancer. 1990;45(5):821-824. doi:10.1002/ijc.2910450505 Agarwal AK, Kalayarasan R, Javed A, Gupta N, Nag HH. The role of staging laparoscopy in primary gall bladder cancer--an analysis of 409 patients: a prospective study to evaluate the role of staging laparoscopy in the management of gallbladder cancer. Ann Surg. 2013;258(2):318-323. doi:10.1097/SLA.0b013e318271497e Zhou D, Wang J, Quan Z, Yang Y, Ma F. Improvement in the diagnosis and treatment of T2 gallbladder carcinoma is pivotal to improvement in the overall prognosis for this disease. Biosci Trends. 2019;13(1):1-9. doi:10.5582/bst.2019.01039 Maplanka C. Gallbladder cancer, treatment failure and relapses: the peritoneum in gallbladder cancer. J Gastrointest Cancer. 2014;45(3):245-255. doi:10.1007/s12029-014-9597-8 Morgan MA. Bile duct dilatation | Radiology Reference Article | Radiopaedia.org. Radiopaedia. doi:10.53347/rID-34179 Gaillard F. Lymph node enlargement | Radiology Reference Article | Radiopaedia.org. Radiopaedia. doi:10.53347/rID-2752 Truong PH, Clinical, Paraclinical, Pathological and Surgical Outcomes for Gallbladder Cancer, Sub-specialist Thesis, Hanoi Medical University, 2008 Do MH, Treatment Outcome for Gallbladder Cancer at Viet Duc University Hospital, Master thesis, Hanoi Medical University, 2021 Rathanaswamy S, Misra S, Kumar V, et al. Incidentally Detected Gallbladder Cancer- The Controversies and Algorithmic Approach to Management. Indian J Surg. 2012;74(3):248-254. doi:10.1007/s12262-012-0592-7 Sachan A, Saluja SS, Nekarakanti PK, et al. Raised CA19–9 and CEA have prognostic relevance in gallbladder carcinoma. BMC Cancer. 2020;20(1):826. doi:10.1186/s12885-020-07334-x Park YJ, Hwang S, Kim KH, et al. Prognosis of patients with pT1b/T2 gallbladder carcinoma who have undergone laparoscopic cholecystectomy as an initial operation. Korean J Hepato-Biliary-Pancreat Surg. 2013;17(3):113-117. doi:10.14701/kjhbps.2013.17.3.113 Watson H, Dasari B, Wyatt J, et al. Does a second resection provide a survival benefit in patients diagnosed with incidental T1b/T2 gallbladder cancer following cholecystectomy? HPB. 2017;19(2):104-107. doi:10.1016/j.hpb.2016.11.006 Alrawashdeh W, Kamarajah SK, Gujjuri RR, et al. Systematic review and meta-analysis of survival outcomes in T2a and T2b gallbladder cancers. HPB. 2022;24(6):789-796. doi:10.1016/j.hpb.2021.12.019 Balakrishnan A, Barmpounakis P, Demiris N, et al. Surgical outcomes of gallbladder cancer: the OMEGA retrospective, multicentre, international cohort study. eClinicalMedicine. 2023;59. doi:10.1016/j.eclinm.2023.101951 Feng X, Cao JS, Chen MY, et al. Laparoscopic surgery for early gallbladder carcinoma: A systematic review and meta-analysis. World J Clin Cases. 2020;8(6):1074-1086. doi:10.12998/wjcc.v8.i6.1074 Vogel A, Bridgewater J, Edeline J, et al. Biliary tract cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023;34(2):127-140. doi:10.1016/j.annonc.2022.10.506 Zhao X, Li XY, Ji W. Laparoscopic versus open treatment of gallbladder cancer: A systematic review and meta-analysis. J Minimal Access Surg. 2018;14(3):185-191. doi:10.4103/jmas.JMAS_223_16 Lee BJH, Yap QV, Low JK, Chan YH, Shelat VG. Cholecystectomy for asymptomatic gallstones: Markov decision tree analysis. World J Clin Cases. 2022;10(29):10399-10412. doi:10.12998/wjcc.v10.i29.10399 Mathur AV. Need for Prophylactic Cholecystectomy in Silent Gall Stones in North India. Indian J Surg Oncol. 2015;6(3):251-255. doi:10.1007/s13193-015-0418-8 Prabhu RS, Hwang J. Adjuvant therapy in biliary tract and gall bladder carcinomas: a review. J Gastrointest Oncol. 2017;8(2):302-313. doi:10.21037/jgo.2017.01.17. Download file PDF

Several gemcitabine-based regimens are effective as first-line treatments for advanced biliary tract carcinoma (BTC), while fluorouracil, folinic acid, and oxaliplatin (FOLFOX) is commonly used as second-line therapy in Western countries. This study aimed to investigate the efficacy and safety of FOLFOX in Japanese patients. We retrospectively reviewed cases of BTC patients who were refractory to or intolerant of at least one gemcitabine-based regimen and subsequently received FOLFOX. Data on clinical characteristics, adverse events, treatment responses, and patient outcomes were collected. Because the FOLFOX regimen have not been approved in Japan, we have followed the appropriate procedures for the off-label use of FOLFOX in accordance with each institution's regulations and relevant laws and regulations. A total of 50 patients were included. Grade 3 or higher adverse events occurred in 30 patients (60%), 21 patients (42%) requiring dose reduction, and 24 patients (48%) requiring treatment delays. No treatment-related deaths occurred. The objective response rate (ORR) was 6%, with a disease control rate of 56%. The median progression-free survival (PFS) and overall survival (OS) were 3.4months and 6.8months, respectively. Among 14 patients who received FOLFOX as second-line treatment after gemcitabine and cisplatin, the ORR, median PFS, and median OS were 14%, 4.6months, and 7.5months, respectively. This study suggested the efficacy and safety of FOLFOX as a second-line or later treatment option also for Japanese patients with advanced BTC.

Biliary tract carcinoma (BTC) is a highly aggressive malignancy,and the majority of patients present with advanced stage at first diagnosis which resulting in poor prognosis. Traditional chemotherapy and monotherapy have shown limited efficacy in treating BTC. However,with the continuous emergence of clinical research findings and updates to relevant guidelines,there have been some breakthroughs in systemic therapies for BTC. This paper analyzes domestic and international literature on neoadjuvant therapy and conversion therapy for BTC,aiming to provide a reference for clinical research. Overall,research on neoadjuvant therapy and conversion therapy remains in the preliminary exploration phase. Current evidence suggests that combination strategies involving immunotherapy and chemotherapy,with or without targeted therapy,have demonstrated promising clinical efficacy,offering new hope for neoadjuvant therapy and conversion therapy in BTC. Furthermore,the evolution of precision targeted therapies offers better opportunities for personalized treatment,and the combination of local interventions and systemic therapies demonstrates promising therapeutic potential. However,the optimal strategies and timing for surgery of neoadjuvant therapy and conversion therapy have not yet been standardized. Moreover,most studies lack precise designs to address the heterogeneity of BTC,new therapies have not yet reached the ideal stage of personalized treatment,further research is warranted to address these challenges.

PurposeTo assess the incidence, clinical characteristics, and post-progression management strategy of resistance to immunotherapy–chemotherapy combination in unresectable biliary tract carcinoma (uBTC).ExperimentalDesignPatients with uBTC from multiple centers who received immunotherapy–chemotherapy combination were retrospectively included. Baseline characteristics, treatments, pattern of progression, and posttreatment managements were recorded. The primary endpoint was post-progression survival (PPS).ResultsOut of 194 patients, 130 (67.0%) developed resistance, including 78 (40.2%) with acquired resistance (AR) and 52 (26.8%) with primary resistance (PR). Normal CA19-9 level and combining target therapy were more common in patients with AR. Patients with both AR and PR commonly experience deterioration in general condition and systemic progression. Patients with AR and PR showed no difference in patterns of progression or current post-progression management strategies. A total of 103 (79.2%) patients receiving post-resistance antitumor treatments showed improved prognosis than those receiving best supportive care, while patients with AR received additional survival benefit than those with PR. Changing immunotherapy regimen after resistance brings significant survival benefit in patients with AR (mPPS: 15.1 vs. 9.50 months, HR = 0.41), but not those with PR. Adding/switching target therapy regimens (HR = 0.39) and local regional therapies (LRT) (HR = 0.36) after resistance brings potential benefit in patients with PR.ConclusionsChanging immunotherapy regimen is a promising strategy for overcoming AR to first-line immunotherapy–chemotherapy combination in uBTC, while adjusting targeted therapy and adding LRT may help overcome PR.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00262-025-04181-2.

Cholangiocarcinoma is an aggressive malignancy of the epithelial tissue of the biliary tract, which has been classified as either intrahepatic or extrahepatic. A 62-year-old woman with recurring heartburn for a year was diagnosed with dyspepsia syndrome. MRI examination of the abdomen showed multiple hepatic masses compressing the common bile duct. A multiphase abdominal CT scan examination and histological picture of liver mass biopsy showed hepatocellular carcinoma, with a differential diagnosis of cholangiocarcinoma. Quantitative CEA was high, and Ca 19-9 examinations were normal. The final diagnosisof intrahepatic cholangiocarcinoma was given to patients with a plan of cisplatin-gemcitabine chemotherapy. However, the BPJS restrictions prevented gemcitabine from being used for BTC cases, so patients were instead given 5-fluorouracil and leucovorin (FUFA) for 6 cycles, but by the third cycle, there was progression with the onset of metastatic lung nodules, and the patient eventually passed away. The progression of the disease in this case was attributed to delayed diagnosis, suboptimal management, and the unavailability of first-line systemictherapy regimens. The most significant impediments to the management of this case were the absence of molecular profiling, a crucial component in the selection of targeted therapy, and BPJS’s restriction on the utilization of firstline chemotherapy agents, specifically gemcitabine. The standard of care in the management of advanced biliary tract cancer-cholangiocarcinoma cases involves performing next-generation sequencing (NGS) for molecular profiling and administering first-line therapy consisting of a combination of systemic chemotherapy (cisplatin-gemcitabine) with targeted therapy (durvalumab).

80MO Durvalumab (D) plus tremelimumab (T) in advanced biliary tract carcinoma (BTC) patients (Pts) after failure of platinum-based chemotherapy (CTx): Final results of the IMMUNOBIL GERCOR D18-1 PRODIGE-57 phase II trial

96P Dynamic circulating tumor DNA guided adjuvant therapy for biliary tract carcinoma: A prospective study (NCT06171321)

The efficacy and safety of conventional first-line chemotherapeutic regimens for the treatment of advanced biliary tract carcinomas (ABTCs) have been unsatisfactory. We aimed to explore alternative chemotherapeutic regimens capable of providing improved efficacy and fewer side-effects. Multicentre, randomised, phase II clinical trial. Patients with unresectable advanced-stage tumors, or those who have developed recurrence or metastasis following initial radical surgery, between January 2021 and November 2022 were included. The participants were randomised to either a gemcitabine-cisplatin group (GC) or an albumin-paclitaxel-cisplatin group (NC). Progression-free survival (PFS) was the primary outcome, whereas overall survival (OS), and objective response rate (ORR) were the secondary outcomes. The trial enrolled 75 patients and had a median follow-up period of 11 months. The median PFS (mPFS) was 7.8 m (95% confidence interval [CI]: 5.4-14.0 m) in the NC group, and 7.0 m (95%CI: 3.9-10.1 m) in the GC group (p = 0.0034, hazard ratio [HR] = 0.5136, 95%CI: 0.3136-0.8411). Median OS for the NC group was 12.4 m (95%CI: 7.3-22.3 m) and for the GC group was 12.1 m (95%CI: 6.7-20.7 m), with no significant differences (p = 0.4592, HR = 0.811, 95%CI: 0.463-1.442). PFS rates at 6 and 8 months were 52.6% vs. 73.0% and 13.2% vs. 35.1% for the NC and the GC group, respectively (p < 0.05). As the secondary endpoint, ORR rates, there was no significant difference between the two groups. GC group had 13 (34.2%) patients achieved ORR, while NC group had 14 (37.8%). Regarding safety, In the context of thrombocytopenia, the incidence was significantly lower in the NC group compared to the GC group (27% vs 50%, P = 0.041). Conversely, with regard to sensory neuropathy, the NC group demonstrated a higher incidence (62.1% vs 36.8%, P = 0.028). In this phase II non-inferiority trial, NC demonstrated comparable efficacy to GC in advanced BTC, with a trend toward improved PFS and a potentially favorable hematological toxicity profile. Further studies are warranted to confirm these findings in the context of a modern immunotherapy-based standard. Clinical Trials.gov identifiers: NCT04692051. Registered October 31, 2018. https://www.chictr.org.cn/showproj.html?proj=38440 .

Characterization and clinical outcomes of rare biliary adenosquamous carcinoma.

Chronic constipation and irritable bowel syndrome (IBS) manifest as prevalent gastrointestinal disorders, while digestive tract cancers (DTCs) present formidable challenges to global well-being. However, extant observational studies proffer uncertain insights into potential causal relationships of constipation and IBS with susceptibility to DTCs. We executed Mendelian randomization (MR) analysis to establish causal connections between these conditions and seven distinct categories of DTCs, including colorectal carcinoma (CRC), hepatocellular cancer (HCC), esophageal malignancy (ESCA), pancreatic adenocarcinoma (PAAD), biliary tract carcinoma (BTCs), gastric carcinoma (GC), and small intestine neoplasm (SIC). Leveraging instrumental variables (IVs) obtained from GWAS data of the FinnGen database, we employed a range of analytical methodologies, including inverse-variance weighting multiplicative random effects (IVW_MRE), inverse-variance weighting fixed effects (IVW_FE), maximum likelihood (ML), weighted median (WM), MR‒Egger regression, and the MR-PRESSO test. We observed a substantial linkage between genetically predicted constipation and increased vulnerability to PAAD (OR = 2.29, 95% CI: 1.422-3.69, P = 0.001) via the IVW method. Following the removal of outlier SNPs through MR-PRESSO, genetically predicted IBS was affiliated with an increased risk of CRC (OR = 1.17, 95% CI: 1-1.37, P = 0.05). Nonetheless, decisive causal correlations of constipation or IBS with other DTCs remain elusive. In summary, genetically predicted constipation was associated with an augmented PAAD risk, and IBS was associated with an increased CRC susceptibility within European cohorts, in agreement with some observational studies. Nevertheless, the causal associations of constipation and IBS with other DTCs remain inconclusive.

BackgroundThe prognosis is still dismal, although several tyrosine kinase inhibitors (TKIs) with/without immune checkpoint inhibitors (ICIs) have shown promising results in the treatment of biliary tract carcinoma (BTC). However, the combination of hepatic artery infusion chemotherapy (HAIC) with ICIs and TKIs may have potential in patients with BTC, according to the success of such a regimen for hepatocellular carcinoma. Hence, this study aimed to evaluate the preliminary efficacy and safety profile of combination therapy with HAIC plus ICI and lenvatinib in BTC patients.MethodsThis retrospective study included all BTC patients histologically diagnosed with combination therapy, which included HAIC with Gemox (Gemox-HAIC), programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) inhibitor, and lenvatinib from July 2021 to October 2023. The outcomes were the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety profile.ResultsThe median follow-up period was 7.0 months (range: 1.0–28.0 months). The ORR and DCR were 72.7% and 90.9%, respectively, with 0.0% CR, 72.7% PR, 18.2% SD, and 9.1% PD. The median PFS was 6.1 (4.3–8.0 (95% CI) months, and the 12-month accumulating PFS rate was 26.0%. The median OS was 10.3 (8.1–12.5 (95% CI) months, and the 12-month accumulating OS rate was 43.2%. The major adverse events included leukopenia (22.7%), thrombocytopenia (22.7%), vomiting (9.1%), etc. All AEs were grade 1–2 except for grade 3–4 leukopenia and 3–4 thrombocytopenia in one patient.ConclusionThe combination therapy of Gemox-HAIC with ICIs and lenvatinib shows promising efficacy and tolerable safety profiles in BTC patients.

4081 Background: Anti-VEGF in combination with anti-PD1/PD-L1 represents a synergistic therapeutic strategy that has demonstrated efficacy, prolonging survival in cancers like HCC, RCC, and NSCLC. This combination induces modifications in the tumor microenvironment, leading to a reduction in immunosuppressive cells, improved dendritic cell maturation, antigen presentation, downregulation of immune checkpoint molecules, and enhanced T-cell activity. Combining CTLA-4 inhibitors with anti PD-1/PD-L1 enhances T-cell mediated anti-tumor responses by leveraging distinct yet complementary mechanisms. Targeting VEGF, PD-L1, and CTLA-4 pathways simultaneously in HCC and BTC provides a novel approach that hasn’t been tested in clinical trials. Our group previously reported in vivo activity in murine BTC models and preliminary clinical results supporting this triplet combination in BTC. The aim of this study is to determine if VEGF inhibition with anti-CTLA-4 and anti-PD-LI therapy augments antitumor immunity and clinical responses in HCC and BTC patients. Methods: This was a Phase II trial conducted to evaluate efficacy of durvalumab, bevacizumab and tremelimumab in advanced HCC BCLC stage C or BTC. Participants received bevacizumab at 7.5mg/kg and durvalumab 1150mg every 3 weeks by IV infusion on Day 1 of Cycle 1 (durvalumab) and Day 1 of Cycle 2 (bevacizumab). Tremelimumab at a dose of 300mg was administered by IV infusion only once on Day 1 of Cycle 1. The combination of durvalumab and bevacizumab continued in 3-week cycles until disease progression or unacceptable toxicity. Primary endpoint was 6-month progression-free survival (PFS) and secondary endpoints were safety, overall survival (OS) and best overall response (BOR). Correlative studies assessing immune response were performed. Results: Between March 2021 and August 2024, 27 patients were enrolled (HCC: 6pts, BTC: 21pts). The median age was 66y (39-80) and 62% were male. 37% of the patients enrolled received prior ICI. As of November 4 th , 2024, with a median follow-up of 8mos, mPFS was 3.5mos and mOS 9.5mos in all 27 efficacy-evaluable pts. The estimated 6 months PFS rate was 37%. The BOR was partial response in 4 pts (18%) followed by stable disease in 9pts (40%). The most common grade 3-4 TRAEs were lymphopenia (6pts, 22%), anemia (9pts, 33%), diarrhea/colitis (7pts, 25.9%), elevated lipase (4pts, 14.8%). Treatment discontinuation related to AEs occurred in 7pts (26%). One treatment-related death occurred secondary to an upper gastrointestinal bleed. Conclusions: The combination of durvalumab, bevacizumab and tremelimumab did not meet its primary endpoint but demonstrated a clinically meaningful overall survival benefit. No new safety signals were seen. Clinical trial information: NCT03937830 .

e16181 Background: Adjuvant cytotoxic chemotherapies can improve recurrence-free survival (RFS) for a range of gastrointestinal malignancies. By previous systematic review of phase III randomized controlled trials (RCTs) for colorectal cancer, observed RFS improvements were driven by early divergences that occurred during active chemotherapy; late recurrence dynamics were not influenced by adjuvant therapy use. The broader applicability of this finding is not known. Methods: PubMed, Cochrane Library (CENTRAL), Embase, Scopus, and Web of Science were queried from database inception to May 16, 2024 for phase III RCTs including pancreatic, gastroesophageal, hepatocellular, and biliary tract malignancies. Trials where significant differences in RFS were observed between experimental (adjuvant chemotherapy) and control (resection alone) arms were included. Summary data were extracted from Kaplan-Meier curves using DigitizeIT, and absolute differences in RFS were compared at matched intervals (i.e., RFS event rate) using Wilcoxon matched-pairs signed rank tests. Results: A total of 3233 manuscripts were eligible for screening. After screening, 14 RCTs were selected, inclusive of periampullary (n = 4), gastroesophageal (n = 5), hepatocellular (HCC) (n = 4), and biliary tract (n = 1) carcinomas – representing 5104 patients. Across pooled RCTs, the highest rates of recurrence were observed in the first year following resection. Median RFS event rate was significantly higher with resection alone (0-0.5 years: resection alone 44.9 [IQR 14.2-84.1] vs. adjuvant chemotherapy 26.4 [IQR 7.7-41.9], p &lt; 0.001; 0.5-1 years: resection alone 33.2 [22.7-42.1] vs. adjuvant chemotherapy 25.0 [13.8-44.5]; p = 0.007). No difference was observed during later intervals from postoperative randomization (1-2 years: p = 0.952; 2-3 years: p = 0.191; 3-4 years: p = 0.999; 4-5 years: p = 0.110). For the subset of trials where ≤6 months of adjuvant chemotherapy was used (n = 6), improvements in RFS event rates were observed only while therapy was being administered (0-0.5 years: p = 0.031). Conclusions: Across multiple gastrointestinal malignancies, improvements in RFS associated with active adjuvant chemotherapy regimens are driven by early changes in recurrence dynamics. These data may provide in vivo understanding of residual tumor cell populations after curative-intent resection and how chemotherapy can be best used to prevent recurrence. RFS event rates in the overall cohort (n=5104). Interval (years) Surgery alone (median [IQR]) Adjuvant therapy (median [IQR]) p-value 0-0.5 44.9 [14.2-84.1] 26.4 [7.7-41.9] &lt;0.001 0.5-1 33.2 [22.7-42.1] 25.0 [13.8-44.5] 0.007 1-2 14.6 [11.7-19.1] 16.9 [10.6-21.0] 0.952 2-3 7.1 [4.1-9.6] 6.4 [4.5-7.9] 0.191 3-4 3.9 [2.5-5.0] 3.7 [1.0-5.1] 0.999 4-5 0.2 [0.0-2.2] 2.3 [0.1-3.8] 0.110

Abstract BackgroundThis open‐label, single‐arm, phase 1b dose escalation and expansion study (ClinicalTrials.gov identifier NCT04178460) explored the safety, tolerability, and antitumor activity of tebotelimab, a programmed cell death protein 1 × lymphocyte‐activation gene 3 bispecific monoclonal antibody, in combination with niraparib, a poly(adenosine diphosphate ribose) polymerase inhibitor, in patients with gastric cancer, triple‐negative breast cancer (TNBC), biliary tract carcinoma (BTC), and endometrial carcinoma.MethodsIn the escalation phase, patients with locally advanced or metastatic gastric cancer who failed ≥2 prior systemic treatments received tebotelimab (120, 300, or 600 mg) intravenously once every 2 weeks (Q2W). In the expansion phase, patients with previously treated gastric cancer, TNBC, BTC, or endometrial carcinoma received tebotelimab at the recommended phase 2 dose (RP2D). All patients received niraparib orally once daily with an individualized starting dose.ResultsFrom June 11, 2020, to January 29, 2022, 60 patients were enrolled. All received ≥1 dose of the study drug. The RP2D for tebotelimab was determined to be 600 mg Q2W, without dose‐limiting toxicities observed. Grade ≥3 and serious treatment‐emergent adverse events (TEAEs) occurred in 39 patients (65.0%) and 25 patients (41.7%), respectively, with no treatment‐related death. Immune‐related TEAEs occurred in 28 patients (46.7%). In those who had target lesions at baseline and received the RP2D, the investigator‐assessed, confirmed overall response rate per Response Evaluation Criteria in Solid Tumors, version 1.1, was 5.3% (one of 19), 20.0% (two of 10), 8.3% (one of 12), and 0% (zero of three) for gastric cancer, TNBC, BTC, and endometrial carcinoma, respectively.ConclusionsTebotelimab plus niraparib preliminarily demonstrated a tolerated and manageable safety profile and limited antitumor activity in patients with previously treated solid tumors.