Cholangiocarcinoma Research Articles

Long-Term Survivor of Intrahepatic Cholangiocarcinoma for over 18 Years: Case Study with Longitudinal Histo-molecular and Tumor Immune Microenvironment Characterization and Systematic Review of the Literature

BackgroundIntrahepatic cholangiocarcinoma is a biliary neoplasm usually showing a dismal prognosis. In early stages, surgical resection is the best treatment option, significantly increasing the overall survival. This approach is also recommended in the case of relapsing disease. In this study, we report the case of a patient affected by intrahepatic cholangiocarcinoma with multiple relapses and still alive for over 18 years. We also provide a systematic review regarding long-survivor (> 60 months) of intrahepatic cholangiocarcinoma.Case PresentationA 41-year-old woman with no pathological history was diagnosed with localized intrahepatic cholangiocarcinoma and surgically treated with left hepatectomy. After the first intervention, the patients underwent three further surgical resections because of locoregional recurrences. Histologically, there were some significant similarities among all neoplasms, including the tubule-glandular architecture, but also morphological heterogeneity. The tumor immune microenvironment remained stable across the different lesions. The molecular analysis with next-generation sequencing demonstrated that all neoplasms shared the same genomic profile, including NBN and NOTCH3 mutations and chromosomes 1 and 3 alterations.ConclusionsThis case study highlights the essential role of a stringent follow-up after resection of intrahepatic cholangiocarcinoma for detecting early relapsing tumors. Moreover, it shows the importance of the molecular characterization of multiple tumors for understanding their real nature. The accurate study of long-surviving patients highlights the features that are critical for outcome improvement.

Development and Validation of a Predictive Risk Score for Blood Transfusion in Patients Undergoing Curative-Intent Surgery for Intrahepatic Cholangiocarcinoma.

Among patients undergoing liver resection for intrahepatic cholangiocarcinoma (ICC), perioperative bleeding requiring blood transfusion is a common complication, yet preoperative identification of patients at risk for transfusion remains challenging. The objective of this study was to develop a preoperative risk score for blood transfusion requirement during surgery for ICC. Patients undergoing curative-intent liver surgery for ICC (1990-2020) were identified from a multi-institutional database. A predictive model was developed and validated. An easy-to-use risk calculator was made available online. Among 1420 patients, 300 (21.1%) received an intraoperative transfusion. Independent predictors of transfusion included severe preoperative anemia (OR = 1.65, 95% CI 1.10-2.47), T2 category or higher (OR = 2.00, 95% CI 1.36-3.02), positive lymph nodes (OR = 1.75, 95% CI 1.32-2.32) and major resection (OR = 2.56, 95%CI 1.85-3.58). Receipt of blood transfusion significantly correlated with worse outcomes. The model showed good discriminative ability in both training (AUC = 0.68, 95% CI 0.66-0.72) and bootstrapping validation (C-index = 0.67, 95% CI 0.65-0.70) cohorts. An online risk calculator of blood transfusion requirement was developed (https://catalano-giovanni.shinyapps.io/TransfusionRisk). Intraoperative blood transfusion was significantly associated with poor postoperative outcomes among patients undergoing surgery for ICC. The identification of patients at high risk of transfusion could improve perioperative patient care and blood resources allocation.

Burden of gastrointestinal cancers among working-age population over past thirty years in China.

Although gastrointestinal (GI) cancers have been becoming a great public health concern in China, there is currently a lack of comprehensive literature on the overall burden and changing trends of GI cancers in the working-age population. To assess the burden of GI cancers and to examine the overall, age- and gender-specific trends among the working-age population in China from 1990 to 2019. Data were extracted from the Global Burden of Disease Study 2019. The burden of GI cancers was indicated by incidence, mortality, disability-adjusted life-years (DALYs), age-standardized incidence rate (ASIR), age-standardized mortality rate, and age-standardized DALYs rate. Trends in the burden of GI cancers from 1990 to 2019 were examined using annual percent change and average annual percent change with Joinpoint regression models. For overall GI cancers, a declining trend was observed in the ASIR, age-standardized mortality rate, and age-standardized DALYs rate, with reductions of 0.74%, 2.23%, and 2.22%, respectively, from 1999 to 2019 in the Chinese working-age population. However, an increasing trend was observed in the ASIR for overall GI cancers from 2016-2019. The number of either incident cases, mortality cases, and DALYs was higher for colon/rectum cancer and liver cancer in younger participants but lower for esophageal, gallbladder, biliary tract, pancreatic, and stomach cancer among older subjects. Moreover, sex disparity in the GI cancers burden was also examined over 30 years. The total burden of GI cancers remained heavy among the working-age population in China, although declining trends were observed from 1999 to 2019. Disparities in the GI cancers burden existed between sexes, age groups, and cancer types. Population-based precision prevention strategies are needed to tackle GI cancers among working-age individuals, considering the age, sex, and cancer type disparities in China.

Site-specific N-glycan alterations on haptoglobin as potential biomarkers for distinguishing intrahepatic cholangiocarcinoma from hepatocellular carcinoma

Intrahepatic cholangiocellular carcinoma (ICC) is a challenging malignancy marked by subtle early symptoms and a high mortality rate, making effective diagnostic markers crucial for early detection and improved patient outcomes. Currently, the conventional diagnosis of ICC is not easily distinguishable from Hepatocellular Carcinoma (HCC) and lacks highly specific and sensitive diagnostic markers. Protein glycosylation, pivotal in biological processes, shows promise for cancer biomarkers due to its association with disease progression. This study aims to develop a novel biomarker discovery framework for ICC utilizing site-specific quantitative N-glycoproteomics to overcome the limitations of existing diagnostic approaches. Employing a tandem mass tag (TMT)-based quantitative analysis, we profiled serum glycoproteins from ICC, HCC, and control cohorts at site-specific glycosylation level. The identified markers underwent further validation in an independent cohort using label-free quantitative methods. Ultimately, we identified five site-specific N-glycans on haptoglobin (HP) as potential biomarkers (AUC > 0.9) for distinguishing ICC from HCC. This finding represents a considerable advance over traditional biomarkers, highlighting the significance of protein glycosylation alterations in ICC pathogenesis. This research, therefore, sets a new precedent for biomarker discovery in ICC, with potential applications in other cancers characterized by glycosylation abnormalities.

Diffusion-Weighted Magnetic Resonance Imaging for the Diagnosis of Lymph Node Metastasis in Patients with Biliary Tract Cancer.

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.

The HALP score as a prognostic factor in metastatic biliary cancer.

Biliary tract cancers are serious diseases and new biomarkers may be useful for the optimal management and prediction of these cases. This study aimed to evaluate the prognostic significance of the hemoglobin, albumin, lymphocyte, and platelet (HALP) score, a novel composite marker, in patients with metastatic biliary tract cancer. Patients with biliary tract cancers were analyzed retrospectively. Laboratory values, patient and disease characteristics, and survival rates were evaluated. The diagnostic impact of the HALP score was assessed with regression analyses. The study included 106 individuals with metastatic biliary tract cancer. Based on the median HALP score, ≥ 2.22 was considered a high score and < 2.22 was considered low. The overall average survival time was found to be 11.4months. Patients with low HALP scores had median overall survival of 9.5months, while those with high HALP scores had median overall survival of 15.9months. In multivariate analysis, Eastern Cooperative Oncology Group performance status, CA19-9 level, and HALP score remained significant predictors of overall survival. The HALP score appears to be a useful prognostic marker in patients with metastatic biliary tract cancer.

A Phase II Placebo-Controlled Study of the Effect and Safety of Nanvuranlat in Patients with Advanced Biliary Tract Cancers Previously Treated by Systemic Chemotherapy.

To evaluate the efficacy and safety of nanvuranlat [an L-type amino acid transporter 1 inhibitor] monotherapy as a later-line treatment in advanced, metastatic, and refractory biliary tract cancers. A multicenter, randomized, double-blind, placebo-controlled phase II study was conducted across fourteen leading Japanese cancer centers and hospitals. Nanvuranlat 25 mg/m2/day or placebo was given intravenously in cycles of 5 consecutive days, followed by 9 days off. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival and disease control rate. Subgroup analysis was performed in patients with high L-type amino acid transporter 1 expression and biliary tract cancer subtypes. A total of 211 patients were screened, of which 105 eligible patients were randomized. Among these, 70 received nanvuranlat and 35 received placebo. Nanvuranlat demonstrated an improvement in PFS when compared with placebo (HR, 0.56; 95% confidence interval, 0.34-0.90; P = 0.02). Grade 3 or higher adverse events were reported in 30.0% and 22.9% of those in the nanvuranlat and placebo groups, respectively. The overall survival was not statistically different between nanvuranlat- and placebo-treated patients. An exploratory analysis indicated that nanvuranlat is warranted to evaluate its long-term clinical benefit in patients with intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer. Compared with placebo, nanvuranlat improved PFS in patients with advanced and refractory biliary tract cancer with an acceptable safety profile. Further studies of this promising compound are warranted in the population of patients who are exhausted from treatment options.

3D Modeling: Insights into the Metabolic Reprogramming of Cholangiocarcinoma Cells.

Developing accurate in vitro models that replicate the in vivo tumor environment is essential for advancing cancer research and therapeutic development. Traditional 2D cell cultures often fail to capture the complex structural and functional heterogeneity of tumors, limiting the translational relevance of findings. In contrast, 3D culture systems, such as spheroids, provide a more physiologically relevant context by replicating key aspects of the tumor microenvironment. This study aimed to compare the metabolism of three intrahepatic cholangiocarcinoma cell lines in 2D and 3D cultures to identify metabolic shifts associated with spheroid formation. Cells were cultured in 2D on adhesion plates and in 3D using ultra-low attachment plates. Metabolic exchange rates were measured using NMR, and intracellular metabolites were analyzed using LC-MS. Significant metabolic differences were observed between 2D and 3D cultures, with notable changes in central carbon and glutathione metabolism in 3D spheroids. The results suggest that 3D cultures, which more closely mimic the in vivo environment, may offer a more accurate platform for cancer research and drug testing.

Safety of pressurized intraperitoneal aerosolized chemotherapy in biliary cancer patients with peritoneal metastases.

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).

Measurable imaging-based changes in enhancement of intrahepatic cholangiocarcinoma after radiotherapy reflect physical mechanisms of response.

Although escalated doses of radiation therapy (RT) for intrahepatic cholangiocarcinoma (iCCA) are associated with durable local control (LC) and prolonged survival, uncertainties persist regarding personalized RT based on biological factors. Compounding this knowledge gap, the assessment of RT response using traditional size-based criteria via computed tomography (CT) imaging correlates poorly with outcomes. We hypothesized that quantitative measures of enhancement would more accurately predict clinical outcomes than size-based assessment alone and developed a model to optimize RT. Pre-RT and post-RT CT scans of 154 patients with iCCA were analyzed retrospectively for measurements of tumor dimensions (for RECIST) and viable tumor volume using quantitative European Association for Study of Liver (qEASL) measurements. Binary classification and survival analyses were performed to evaluate the ability of qEASL to predict treatment outcomes, and mathematical modeling was performed to identify the mechanistic determinants of treatment outcomes and to predict optimal RT protocols. Multivariable analysis accounting for traditional prognostic covariates revealed that percentage change in viable volume following RT was significantly associated with OS, outperforming stratification by RECIST. Binary classification identified ≥33% decrease in viable volume to optimally correspond to response to RT. The model-derived, patient-specific tumor enhancement growth rate emerged as the dominant mechanistic determinant of treatment outcome and yielded high accuracy of patient stratification (80.5%), strongly correlating with the qEASL-based classifier. Following RT for iCCA, changes in viable volume outperformed radiographic size-based assessment using RECIST for OS prediction. CT-derived tumor-specific mathematical parameters may help optimize RT for resistant tumors.

Spatial resolved transcriptomics reveals distinct cross-talk between cancer cells and tumor-associated macrophages in intrahepatic cholangiocarcinoma

BackgroundMultiple studies have shown that tumor-associated macrophages (TAMs) promote cancer initiation and progression. However, the reprogramming of macrophages in the tumor microenvironment (TME) and the cross-talk between TAMs and malignant subclones in intrahepatic cholangiocarcinoma (iCCA) has not been fully characterized, especially in a spatially resolved manner. Deciphering the spatial architecture of variable tissue cellular components in iCCA could contribute to the positional context of gene expression containing information pathological changes and cellular variability.MethodsHere, we applied spatial transcriptomics (ST) and digital spatial profiler (DSP) technologies with tumor sections from patients with iCCA.ResultsThe results reveal that spatial inter- and intra-tumor heterogeneities feature iCCA malignancy, and tumor subclones are mainly driven by physical proximity. Tumor cells with TME components shaped the intra-sectional heterogenetic spatial architecture. Macrophages are the most infiltrated TME component in iCCA. The protein trefoil factor 3 (TFF3) secreted by the malignant subclone can induce macrophages to reprogram to a tumor-promoting state, which in turn contributes to an immune-suppressive environment and boosts tumor progression.ConclusionsIn conclusion, our description of the iCCA ecosystem in a spatially resolved manner provides novel insights into the spatial features and the immune suppressive landscapes of TME for iCCA.

Survival and cardiovascular disease mortality among primary liver cancer patients: A population-based study

BackgroundThe prognosis of primary liver cancer (PLC) was influenced by death due to non-cancer causes, particularly death related to cardiovascular disease (CVD). This study aimed to analyze mortality of non-cancer causes and identify the independent risk factors associated with CVD-related deaths in PLC patients. MethodsIn total, 112140 patients were enrolled from the Surveillance, Epidemiology, and End Results (SEER) database (2000–2019). Independent risk factors for death from CVD in patients with PLC were identified by Cox proportional hazards model. ResultsThe median follow-up time of all PLC patients was 76 months (interquartile range (IQR): 36–129). The median overall survival (OS) was 12 months (IQR: 3–40). Patients with intrahepatic cholangiocarcinoma (ICC) had shorter OS than patients with hepatocellular carcinoma (HCC) (8 vs. 14 months; P < 0.001). A total of 87299 deaths were observed, among which 61477 (70.42 % of all deaths) were from PLC, and 12727 (14.58 % of all deaths) were from other cancers. Of all non-cancer deaths (9276, 10.63 %), 2860(30.86 %) were results of CVD. PLC patients had higher risks on CVD-related deaths, compared with general population (standard mortality ratio, SMR, 2.20; 95 % confidence interval, CI, 2.12–2.28). Typically, the highest SMRs appeared in the first year following cancer diagnosis. The multivariable analysis revealed the characteristics listed as followed to be independently risk factors of CVD: age, male (hazard ratio, HR: 1.248, 95%CI: 1.147–1.359), black race (HR: 1.334, 95%CI: 1.195–1.490), year 2016–2019 of diagnosis (HR 0.758, 95%CI: 0.671–0.856), ICC (HR: 1.202, 95%CI: 1.086–1.330), without surgery (HR: 2.479, 95%CI: 2.266–2.711) and without chemotherapy (HR: 2.211, 95%CI: 2.033–2.403). ConclusionIt is essential to take cardiovascular health into consideration at the time of diagnosis for PLC patients as the risk of CVD mortality is significantly higher than that of general population.

Using machine learning methods to investigate the impact of age on the causes of death in patients with early intrahepatic cholangiocarcinoma who underwent surgery.

The impact of age on the causes of death (CODs) in patients with early-stage intrahepatic cholangiocarcinoma (ICC) who had undergone surgery was analyzed in this study. A total of 1555 patients (885 in the older group and 670 in the younger group) were included in this study. Before and after applying inverse probability of treatment weighting (IPTW), the different CODs in the 2 groups were further investigated. Additionally, 7 different machine learning models were used as predictive tools to identify key variables, aiming to evaluate the therapeutic outcome in early ICC patients undergoing surgery. Before (5.92 vs. 4.08years, P < 0.001) and after (6.00 vs. 4.08years, P < 0.001) IPTW, the younger group consistently showed longer overall survival (OS) compared with the older group. Before IPTW, there were no significant differences in cholangiocarcinoma-related deaths (CRDs, P = 0.7) and secondary malignant neoplasms (SMNs, P = 0.78) between the 2 groups. However, the younger group had a lower cumulative incidence of cardiovascular disease (CVD, P = 0.006) and other causes (P < 0.001) compared with the older group. After IPTW, there were no differences between the 2 groups in CRDs (P = 0.2), SMNs (P = 0.7), and CVD (P = 0.1). However, the younger group had a lower cumulative incidence of other CODs compared with the older group (P < 0.001). The random forest (RF) model showed the highest C-index of 0.703. Time-dependent variable importance bar plots showed that age was the most important factor affecting the 2-, 4-, and 6-year survival, followed by stage and size. Our study confirmed that younger patients have longer OS compared with older patients. Further analysis of the CODs indicated that older patients are more likely to die from CVDs. The RF model demonstrated the best predictive performance and identified age as the most important factor affecting OS in early ICC patients undergoing surgery.

Role of [18F]FAPI-04 in staging and therapeutic management of intrahepatic cholangiocarcinoma: prospective comparison with [18F]FDG PET/CT

BackgroundFluorine-18 fluorodeoxyglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) has some limitations in diagnosis of Intrahepatic cholangiocarcinoma (ICC).Materials and methodsPatients with histologically confirmed ICC who underwent both [18F]FDG and 18F-labeled fibroblast-activation protein inhibitors ([18F]FAPI)-04 PET/CT were prospectively analyzed. The maximum standard uptake value (SUVmax), tumor-to-background ratio (TBR), metabolic tumor volume (MTV), total lesion glycolysis (TLG), [18F]FAPI–avid tumor volume (FTV), total lesion fibroblast activation protein expression (TLF) were compared between the two modalities by paired Wilcoxon signed-rank test and Mann–Whitney U test, and McNemar’s test was used to assess the diagnostic accuracy between the two techniques.ResultsIn total, 23 patients with 389 lesions were included. Compared to [18F]FDG, [18F]F-FAPI-04 PET/CT demonstrated a higher detection rate for intrahepatic lesions (86.3% vs. 78.2% P = 0.040), lymph node metastases (85.2% vs. 68.2%, P = 0.007), peritoneal metastases (100% vs. 93.8%), and bone metastases (100% vs. 70.5%, P < 0.001). [18F]FAPI-04 PET showed higher SUVmax, TBR and greater tumor burden values than [18F]FDG PET in non-cholangitis intrahepatic lesions (SUVmax: 8.7 vs. 6.4, P < 0.001; TBR: 8.0 vs. 3.5, P < 0.001; FTV vs. MTV: 41.3 vs. 12.4, P < 0.001; TLF vs. TLG: 223.5 vs. 57.0, P < 0.001), lymph node metastases (SUVmax: 6.5 vs. 5.5, P = 0.042; TBR: 5.4 vs. 3.9, P < 0.001; FTV vs. MTV: 2.0 vs. 1.5, P = 0.026; TLF vs. TLG: 9.0 vs. 7.8 P = 0.024), and bone metastases (SUVmax: 9.7 vs. 5.25, P < 0.001; TBR: 10.8 vs. 3.0, P < 0.001; TLF vs. TLG: 9.8 vs. 4.2, P < 0.001). However, [18F]FDG showed higher radiotracer uptake (SUVmax: 14.7 vs. 8.4, P < 0.001; TBR: 7.4 vs. 2.8, P < 0.001) than [18F]FAPI-04 PET/CT for 6 patients with obstructive cholangitis. [18F]FAPI-04 PET/CT yielded a change in planned therapy in 6 of 23 (26.1%) patients compared with [18F]FDG.Conclusions[18F]FAPI-04 PET/CT had higher detection rate and radiotracer uptake than [18F]FDG PET/CT in intrahepatic lesions, lymph node metastases, and distant metastases, especially in bone. Therefore, [18F]FAPI-04 PET/CT may be a promising technique for diagnosis and staging of ICC.Trial registrationClinical Trials, NCT05485792. Registered 1 August 2022, retrospectively registered, https//clinicaltrials.gov/study/NCT05485792?cond=NCT05485792&rank=1.

Artificial Intelligence-Powered Spatial Analysis of Tumor-Infiltrating Lymphocytes as a Potential Biomarker for Immune Checkpoint Inhibitors in Patients with Biliary Tract Cancer.

Recently, anti-programmed cell death-1/anti-programmed cell death ligand-1 (anti-PD1/L1) immunotherapy has been demonstrated for its efficacy when combined with cytotoxic chemotherapy in randomized phase 3 trials for advanced biliary tract cancer (BTC). However, no biomarker predictive of benefit has been established for anti-PD1/L1 in BTC. Here, we evaluated tumor-infiltrating lymphocytes (TIL) using artificial intelligence-powered immune phenotype (AI-IP) analysis in advanced BTC treated with anti-PD1. Pretreatment hematoxylin and eosin (H&E)-stained whole-slide images from 339 patients with advanced BTC who received anti-PD1 as second-line treatment or beyond, were employed for AI-IP analysis and correlative analysis between AI-IP and efficacy outcomes with anti-PD1. Next, data and images of the BTC cohort from The Cancer Genome Atlas (TCGA) were additionally analyzed to evaluate the transcriptomic and mutational characteristics of various AI-IP in BTC. Overall, AI-IP were classified as inflamed [high intratumoral TIL (iTIL)] in 40 patients (11.8%), immune-excluded (low iTIL and high stromal TIL) in 167 patients (49.3%), and immune-desert (low TIL overall) in 132 patients (38.9%). The inflamed IP group showed a substantially higher overall response rate compared with the noninflamed IP groups (27.5% vs. 7.7%, P < 0.001). Median overall survival and progression-free survival were significantly longer in the inflamed IP group than in the noninflamed IP group (OS, 12.6 vs. 5.1 months; P = 0.002; PFS, 4.5 vs. 1.9 months; P < 0.001). In the TCGA cohort analysis, the inflamed IP showed increased cytolytic activity scores and IFNγ signature compared with the noninflamed IP. AI-IP based on spatial TIL analysis was effective in predicting the efficacy outcomes in patients with BTC treated with anti-PD1 therapy. Further validation is necessary in the context of anti-PD1/L1 plus gemcitabine-cisplatin.

The causal relationship between drinking water and gastrointestinal cancers: a two‐sample mendelian randomization analysis

AbstractCancers of the digestive tract are a series of diseases that seriously affects the health and life quality of the population worldwide, and the etiology is closely related to various daily habits. Drinking water is a daily human activity, but the intrinsic connection between water intake and gastrointestinal (GI) cancers is still unclear. We used the two‐sample mendelian randomization (TSMR) method to explore the potential causal relationship between water consumption and GI cancers. We obtained the integrated GWAS data of water intake (ukb‐b‐14 898), as well as the GWAS results of oral cavity cancer (ieu‐b‐4961), esophageal cancer (ebi‐a‐GCST90018841), gastric cancer (ebi‐a‐GCST90018849), liver cancer (ieu‐b‐4953), hepatic bile duct cancer (ebi‐a‐GCST90018803), pancreatic cancer (ebi‐a‐GCST90018893) and colorectal cancer (ebi‐a‐GCST90018588) through the online database “IEU OPEN GWAS PROJECT”. Using inverse variance weighting (IVW) method, weighted median method, MR Egger regression method, simple model method, and weighted model method to jointly study the causal relationship between water intake and GI cancers. Mendelian randomization analysis showed a negative correlation between water consumption and esophageal cancer (weighted media, OR = 0.215, p = .021; MR Egger, OR = 0.033, p = .040; weighted mode, OR = 0.162, p = .045), a positively association with pancreatic cancer (IVW, OR = 2.663, p = .033). There is a potential positive correlation between water intake and gastric cancer as well as colorectal cancer, but not statistically significant. The associations between water intake and oral cavity cancer, liver cancer and hepatic bile duct cancer remain uncertain. Therefore, Increased amount of drinking water may help to prevent the incidence of esophageal cancer, but might promote the development of pancreatic cancer.

Anatomic Versus Non-anatomic Liver Resection for Intrahepatic Cholangiocarcinoma: A Systematic Review and Patient-Level Meta-Analysis.

The current standard treatment for intrahepatic cholangiocarcinoma (ICC) involves complete liver resection with negative surgical margins and lymphadenectomy, followed by adjuvant chemotherapy. Debate is ongoing regarding the necessity of systematic anatomic resection (AR). This study aimed to summarize existing literature to determine whether AR leads to better oncologic outcomes than non-AR for patients with resectable ICC. A systematic literature review (PubMed, Embase, and Google Scholar) was performed until December 2023. Only studies comparing the oncologic outcomes of AR and non-AR for ICC using propensityscorematching or inverse probability of treatmentweighting were considered. A meta-analysis of aggregated data for perioperative variables and a reconstructed patient-level meta-analysis for survival data were performed. Five articles were gathered (n = 930 patients after matching: 465 AR/465 non-AR patients). The overall survival (OS) rates were higher in the AR group than in the non-AR group at 1, 3, and 5 years (71.5%, 46.1% and 34.3% vs. 63.6%, 32.9%, and 24.8%, respectively; hazard ratio [HR] 0.74; 95% CI 0.63-0.87; P < 0.001). The same results were observed for the disease-free survival (DFS) rates (58.3%, 33.4%, and 24.5% for AR vs. 45.6%, 23.1%, and 17.4% for non-AR; HR 0.74; 95% CI 0.63-0.86; P < 0.001). The results were confirmed in the two-stage meta-analysis for OS (HR 0.73; P < 0.001) and DFS (HR 0.73; P < 0.001). No differences were observed between the two approaches in terms of operative time, intraoperative blood loss, overall and major morbidity, and hospital length of stay. By pooling the available evidence, the current study demonstrated that AR for ICC patients is associated with better OS and DFS without any negative impact on postoperative outcomes.

Racial and Sex Differences in Genomic Profiling of Intrahepatic Cholangiocarcinoma.

Racial and sex disparities in the incidence and outcomes of patients with intrahepatic cholangiocarcinoma (iCCA) exist, yet potentialgenomic variations of iCCA based on race and sex that might be contributing to disparate outcomeshave not been well studied. Data from the American Association for Cancer ResearchProject GENIE registry (version 15.0) were analyzed to assess genetic variations in iCCA. Adult patients (age >18 years) with histologically confirmed iCCA who underwent next-generation sequencing were included in the analytic cohort. Racial and sex variations in genomic profiling of iCCA were examined. The study enrolled 1068 patients from 19 centers (White, 71.9%; Black, 5.1%; Asian, 8.4%, other, 14.6%). The male-to-female ratio was 1:1. The majority of the patients had primary tumors (73.7%), whereas 23.0% had metastatic disease sequenced. While IDH1 mutations occurred more frequently in White versus Black patients (20.8% vs. 5.6%; p = 0.021), FGFR2 mutations tended to be more common among Black versus White populations (27.8% vs. 16.1%; p = 0.08). Males were more likely to have TP53 mutations than females (24.3% vs. 18.2%, p = 0.016), whereas females more frequently had IDH1 (23.3% vs 16.0 %), FGFR2 (21.0% vs. 11.3%), and BAP1 (23.4% vs. 14.5%) mutations than males (all p < 0.05). Marked variations in the prevalence of other common genomic alterations in iCCA were noted across different races and sexes. Distinct genomic variations exist in iCCA across race and sex. Differences in mutational profiles of iCCA patients highlight the importance of including a diverse patient population in iCCA clinical trials as well as the importance ofrecognizing different genetic drivers that may be targetable to treatdistinct patient cohorts.

PARP-1 selectively impairs KRAS-driven phenotypic and molecular features in intrahepatic cholangiocarcinoma

ObjectiveIntrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver cancer with limited therapeutic options. KRAS mutations are among the most abundant genetic alterations in iCCA associated with poor clinical...

Primary Liver Cancer Risk and Mortality in Patients With Alcohol-Related Cirrhosis in England and Denmark: Observational Cohort Studies.

Patients with alcohol-related cirrhosis (ALD cirrhosis) have an increased risk of primary liver cancer (hepatocellular carcinoma [HCC] or intrahepatic cholangiocarcinoma [iCCA]). England recommends surveillance for HCC in these patients, while Denmark does not. We performed an observational cohort study using the English Clinical Practice Research Datalink and the nationwide Danish healthcare registries to identify 17,110 English (2000-2016) and 22,122 Danish (1994-2022) patients with diagnosis codes of ALD cirrhosis. We computed and compared incidence rates and cumulative incidence of primary liver cancer, annual ultrasound scan rates, and mortality following diagnosis of primary liver cancer. The overall risk of primary liver cancer was similar in England and Denmark: 5-year risk was 2.24% (95% confidence interval 2.00-2.49) in England (iCCA 0.07%, HCC 2.16%) and 2.36% (2.15-2.57) in Denmark (iCCA 0.05%, HCC 2.30%). The annual rate of ultrasound scans per person was 0.65 (0.63-0.67) in England and 0.44 (0.42-0.46) in Denmark. The 1-year mortality after a diagnosis of primary liver cancer was 59.2% (54.4-64.0) in England and 60.9% (57.4-64.4) in Denmark. The 3-year risks of HCC in those on vs off surveillance in England were 2.3% (1.0-4.6) vs 1.5% (1.0-2.2). The risk of primary liver cancer was the same in English and Danish patients with ALD cirrhosis, and HCCs constituted 97% of primary liver cancers. Mortality with primary liver cancer was equally high in both countries. Notably, in England, where guidance recommends biannual HCC surveillance with ultrasound, patients with ALD cirrhosis were undergoing fewer than 1 ultrasound scan per year.