Intrahepatic cholangiocarcinoma (ICC) is a malignant tumor with a poor prognosis, marked by a postoperative recurrence rate of 50-60% and a 5-year survival rate of 8-30%. Abnormal tumor metabolism, particularly, amino acid metabolism, plays a key role in malignant progression. However, the molecular mechanisms linking amino acid metabolism to ICC progression remain unclear.

Bioinformatics was used to identity the key amino acid metabolism related gene in ICC, qRT-PCR, western blotting and immunohistochemical (IHC) were used to detect the expression of ANXA1 in normal tissues or ICC tissues and cells at mRNA and protein levels. The effects of ANXA1 on the proliferation ability of ICC in vitro and in vivo were investigated using CCK8, cloning formation experiment, EdU, IHC, nude mice subcutaneous tumorigenesis model. Immunoprecipitation, mass spectrometry analysis, protein ubiquitin level detection test, immunofluorescence co-localization, and redox stress metabolite detection test were used to explore the metabolism-related regulatory mechanism of ANXA1.

we employed bioinformatics analysis to classify ICC into metabolic subgroups with distinct prognoses and identified the associated biomarker Annexin A1(ANXA1), whose high expression is correlated with poor prognosis and promotes ICC development. Mass spectrometry analysis revealed that ANXA1 interacts with the key enzyme in glutamine metabolism, glutamic-oxaloacetic transaminase 1(GOT1). Through in vitro and in vivo experiments, overexpressed ANXA1 stabilizes GOT1 by recruiting the deubiquitinase USP5. This stabilization enhances glutamine uptake, as well as the production of aspartate and glutamate, which in turn reduces oxidative stress, thereby promoting tumor cell growth. Moreover, knockdown of ANXA1 combined with glutamine uptake inhibition significantly suppressed ICC cell proliferation and Inhibited subcutaneous tumor formation and growth.

These results suggest that the ANXA1/USP5/GOT1 axis promotes glutamine metabolism and ICC proliferation and growth. Inhibiting ANXA1 alongside glutamine uptake inhibition offers a promising strategy for treating ICC.

Mass-forming intrahepatic cholangiocarcinoma (MF-ICC) is the second most common primary liver cancer and liver resection offers the best chance of possible cure. This study aimed to assess treatment outcomes and prognostic factors for long-term survival in patients who underwent curative-intent liver resection.

A retrospective analysis was conducted on prospectively collected data from patients with MF-ICC managed at the Royal North Shore/North Shore Private Hospital from January 1998 to October 2023. Baseline, peri-operative and long-term outcomes have been analysed, including an overall survival (OS) and disease-free survival (DFS) analysis.

During the 25-year study period, 47 patients underwent curative-intent liver resection for primary MF-ICC at a median age of 70 years. The median OS was 36 months, with a 5-year OS of 33%. Multiple liver tumours (HR = 2.84; 95% CI = 1.24-6.48; P = 0.013) and a positive resection margin (HR = 2.46; 95% CI = 1.10-5.52; P = 0.029) were identified as independent predictors of poor long-term OS. Recurrence occurred in 62% of patients after a median DFS of 16 months, with poor tumour differentiation (HR = 3.93; 95% CI = 1.62-9.54; P = 0.002) and elevated tumour markers (HR = 3.47; 95% CI = 1.53-7.87; P = 0.003) as independent predictors of poor DFS.

Liver resection can offer a significant chance for prolonged survival in a highly selected population of patients with MF-ICC. However, the surgical challenges inherent in treating this rare disease are evident, emphasizing the need for a multimodal approach and continued exploration of additional therapies to enhance personalized treatment strategies.

The aim of the study is to investigate the ability of preoperative CT (Computed Tomography)-based radiomics signature to predict microvascular invasion (MVI) of intrahepatic mass-forming cholangiocarcinoma (IMCC) and develop radiomics-based prediction models.

Preoperative clinical data, basic CT features, and radiomics features of 121 IMCC patients (44 with MVI and 77 without MVI) were retrospectively reviewed. The loading and display of CT images, delineation of the volume of interest, and feature extraction were performed using 3D Slicer. Radiomics features were selected by the LASSO logistic regression model. Multivariate logistic regression analysis was used to establish the radiomics model, radiologic model, and combined model in the training set (n = 85) to predict the MVI of IMCC, and then verified in the validation set (n = 36).

Among the 3948 radiomics features extracted from multiphase dynamic enhanced CT imaging, 16 most stable features were selected. The AUC of the radiomics model for predicting MVI in the training set and validation set were 0.935 and 0.749, respectively. The AUC of the radiologic model for predicting MVI in the training set and validation set were 0.827 and 0.796, respectively. When radiomics and radiologic models are combined, the predictive performance of the combined model (constructed with shape, intratumoral vessels, portal venous phase tumor-liver CT ratio, and radscore) is optimal, with an AUC of 0.958 in the training set and 0.829 in the test set for predicting MVI.

CT radiomics signature is a powerful predictor for predicting MVI. The preoperative combined model (constructed with shape, intratumoral vessels, portal venous phase tumor-liver CT ratio, and radscore) performed well in predicting the MVI.

Intrahepatic cholangiocarcinoma (iCCA) is the second most common liver malignancy with poor prognosis and limited treatment options.

To identify the most effective drug for transarterial chemoembolization (TACE) in cholangiocarcinoma and evaluate the efficacy and safety of combining it with gemcitabine and cisplatin (GemCis) for unresectable iCCA.

Cholangiocarcinoma cell lines (RBE, HuCC-T1) were treated with 10 chemotherapeutic drugs, and cytotoxicity was assessed by cell counting kit-8 assays. Tumor-bearing nude mice were treated with idarubicin or GemCis, and tumor growth was monitored. Clinical data from 85 iCCA patients were analyzed to evaluate the efficacy and safety of idarubicin-TACE combined with GemCis.

Idarubicin demonstrated the highest cytotoxicity, significantly outperforming GemCis, the standard first-line therapies. In tumor-bearing mouse models, idarubicin and GemCis treatments significantly slowed tumor growth, with idarubicin showing particularly pronounced effects on days 12 and 15 (P < 0.05). In retrospective analysis, the median overall survival (OS) and progression-free survival (PFS) in the combination therapy group were significantly longer than those in the GemCis alone group (median OS, 16.23 months vs 10.07 months, P = 0.042; median PFS, 7.73 months vs 6.30 months, P = 0.023). Additionally, major grade 3/4 adverse events (AEs) in the combination therapy group were abdominal pain (26.3% vs 6.5%, P = 0.049) and elevated transaminases (42.1% vs 12.9%, P = 0.038). Most AEs were mild to moderate and manageable.

Idarubicin demonstrated higher cytotoxicity than GemCis, significantly inhibiting tumor growth in tumor-bearing mouse models. Preliminary clinical results suggest that local idarubicin-TACE combined with GemCis may offer improved survival outcomes for iCCA patients with a manageable safety profile.

This study was aimed at examining the causes of death (CODs) in patients with advanced intrahepatic cholangiocarcinoma (ICC) undergoing chemotherapy (CT). In addition, machine learning models were incorporated to predict the treatment outcomes of patients with advanced ICC and identify the factors most closely related to prognosis.

A total of 5564 patients (CT group, 3632; non-CT group, 1932) were included in the Surveillance Epidemiology and End Results registries between 2000 and 2020. The CODs were compared between the two groups before and after the inverse probability of treatment weighting (IPTW). Furthermore, seven machine learning models were utilized as predictive tools to select variable features, aiming to assess the therapeutic effectiveness in patients with advanced ICC.

After IPTW, the CT group exhibited a lower cumulative incidence of cholangiocarcinoma-related deaths (30%, 49%, and 73% vs. 59%, 66%, and 73%; P < 0.001), secondary malignant neoplasms (8.5%, 13%, and 20% vs. 19%, 22%, and 24%; P < 0.001), and other CODs (1.8%, 2.9%, and 4.4% vs. 4.1%, 4.6%, and 5.4%; P < 0.001) at 0.5-, 1-, and 3- years than the non-CT group, whereas the cumulative incidence of cardiovascular diseases (P = 0.4) was comparable between the two groups. Of the seven machine learning models, the random forest model showed the highest predictive effectiveness. This model verified that variables such as CT, radiotherapy, tumor dimensions, sex, and distant metastasis were strongly correlated with the prognosis of advanced ICC.

CT has improved the therapeutic efficacy of advanced ICC without significantly increasing other CODs. Furthermore, the analysis of various features using machine learning models has confirmed that the random forest model demonstrates the highest predictive performance.

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. 4.08 years, P < 0.001) and after (6.00 vs. 4.08 years, 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.

BackgroundIntrahepatic cholangiocarcinoma (ICC) is an aggressive liver malignancy, and Ki67 is associated with prognosis in patients with ICC and is an attractive therapeutic target.PurposeTo predict Ki67 expression based on multiparametric magnetic resonance imaging (MRI) radiomics multiscale tumor region in patients with ICC.Material and MethodsA total of 191 patients (training cohort, n = 133; validation cohort, n = 58) with pathologically confirmed ICC were enrolled in this retrospective study. All patients underwent baseline abdominal MR scans in our institution. Univariate logistic analysis was conducted of the correlation between clinical and MRI characteristics and Ki67 expression. Radiomics features were extracted from the image of six MRI sequences (T1-weighted imaging, fat-suppression T2-weighted imaging, diffusion-weighted imaging, and 3-phases contrast-enhanced T1-weighted imaging sequences). Using the least absolute shrinkage and selection operator (LASSO) to select Ki67-related radiomics features in four different tumor volumes (VOItumor, VOI+8mm, VOI+10mm, VOI+12mm). The Rad-score was calculated with logistic regression, and models for prediction of Ki67 expression were constructed. The receiver operating curve was used to analyze the predictive performance of each model.ResultsClinical and regular MRI characteristics were independent of Ki67 expression. Four Rad-scores all showed favorable prediction efficiency in both the training and validation cohorts (AUC = 0.849-0.912 vs. 0.789-0.838). DeLong's test showed that there was no significant difference between the AUC of the radiomics scores, while the Rad-score (VOI+10mm) performed the most stable predictive efficiency with △AUC 0.033.ConclusionMultiparametric MRI radiomics based on multiscale tumor regions can help predict the expression status of Ki67 in ICC patients.

This study aimed to develop and validate a predictive model integrating radiomics features and clinical variables to differentiate intrahepatic bile duct stones with cholangitis (IBDS-IL) from intrahepatic cholangiocarcinoma (ICC) preoperatively, as accurate distinction is crucial for determining appropriate treatment strategies.

A total of 169 patients (97 IBDS-IL and 72 ICC) who underwent surgical resection were retrospectively analyzed. Radiomics features were extracted from ultrasound images, and clinical variables with significant differences between groups were identified. Feature selection was performed using LASSO regression and recursive feature elimination (RFE). The radiomics model, clinical model, and combined model were constructed and evaluated using the area under the curve (AUC), calibration curves, decision curve analysis (DCA), and SHAP analysis.

The radiomics model achieved an AUC of 0.962, and the clinical model achieved an AUC of 0.861. The combined model, integrating the Radiomics Score with clinical variables, demonstrated the highest predictive performance with an AUC of 0.988, significantly outperforming the clinical model (p < 0.05). Calibration curves showed excellent agreement between predicted and observed outcomes, and the Hosmer-Lemeshow test confirmed a good model fit (p = 0.998). DCA revealed that the combined model provided the greatest clinical benefit across a wide range of threshold probabilities. SHAP analysis identified the Radiomics Score as the most significant contributor, complemented by abdominal pain and liver atrophy.

The combined model integrating radiomics features and clinical data offers a powerful and reliable tool for preoperative differentiation of IBDS-IL and ICC. Its superior performance and clinical interpretability highlight its potential for improving diagnostic accuracy and guiding clinical decision-making. Further validation in larger, multicenter datasets is warranted to confirm its generalizability.

Intrahepatic cholangiocarcinoma (ICC) is the second most common malignancy of the liver and has the worst prognosis of any tumor arising from the liver, with a 5-year survival as low as 10%. However, whether the rurality of a patient's residence impacts care received and survival has not been well studied. We aimed to assess differences in care patterns associated with the rurality of patient's residences and their impact on survival outcomes, hypothesizing that patients in rural areas would experience lower survival.

Adult patients diagnosed with ICC between 2010 and 2020 were identified in the Iowa Cancer Registry. Chi-square tests were used to compare values categorical variables by rural/urban status. Cox proportional hazards regression was used to determine associations with cancer-specific mortality.

Of 672 patients diagnosed with ICC during the study period, 53%, 27%, and 21% resided in metropolitan, micropolitan, and rural areas, respectively. There were no significant differences in age, sex, stage at diagnosis, the proportion receiving chemotherapy within 12 weeks of diagnosis, and undergoing surgery across all groups. Additionally, the proportion receiving definitive care at a National Cancer Institute (NCI) designated center was comparable across the three groups (37% metro vs. 43% micro vs. 35% rural). However, rural residents had the highest proportion of traveling ≥ 50 miles for definitive care (22% metro vs. 41% micro vs. 56% rural). In multivariable analysis of patients with Stage 1-3 disease, younger age, receipt of chemotherapy, surgery, and definitive care at an NCI center were independently associated with decreased mortality risk. However, rural residence was not significantly associated with survival (HR: 0.64 [95% CI: 0.38-1.06]).

Similar to other complex cancer diagnoses, we found that definitive care at an NCI center was associated with decreased mortality risk for patients with ICC. Although rural residence was not independently associated with survival in this cohort, rural residents traveled significantly longer distances to access definitive care. This highlights a crucial need to improve access to specialized centers for complex cancer care.

Intrahepatic cholangiocarcinoma (ICA) is a highly aggressive primary liver cancer, which originates from the epithelial cells of the bile ducts. The transcriptional profile of metabolic enzymes was investigated at both bulk and single-cell levels in tumor samples from distinct ICA cohorts. In a training cohort (TCGA consortium), 16 genes encoding for metabolic enzymes were found overexpressed in cases with poor survival. A computed metabolic gene expression score was significantly associated with worse ICA prognosis at the univariate level (overall survival [OS] log-rank p = 8.2e-4). After adjusting for Ishak fibrosis score and tumor staging, the metabolic expression remained an independent predictor of poor prognosis (multivariate OS log-rank p = 0.01). Seven genes encoding key enzymes (FH, MAT2B, PLOD2, PLOD1, PDE6D, ALDOC, and NT5DC3) were validated as markers of the proliferative subclass of ICA in the GSE32225 dataset, related to poor prognosis. The metabolic score was significantly different between the inflammatory and proliferative subclasses in the validation cohort (p < 2.2e-16). At the single-cell level, in the tumor microenvironment of 10 ICA patients, these seven enzymes were predominantly expressed by malignant cells. The single-cell metabolic score was thus higher in malignant cells. This study identifies a metabolic transcriptional program linked to poor prognosis in ICA, independent of fibrosis and tumor staging.

A 59-year-old man presented with a mass and pain in the left side of his back for 6 months. 18 F-FDG PET/CT demonstrated increased FDG uptake in the inferior aspect of his left scapula and the left hepatic lobe, highly suggesting the possibility of hepatic malignancy with solitary scapula metastasis. Finally, solitary scapula metastasis from intrahepatic cholangiocarcinoma was confirmed.

Regional lymph node metastasis (LNM) assessment is crucial for predicting intrahepatic cholangiocarcinoma (iCCA) prognosis. However, imaging assessment has limitations for identifying LNM.

To investigate the association between MRI radiomics features, regional LNM status, and prognosis in iCCA.

Retrospective.

Two hundred ninety-six patients (male = 197) with surgically confirmed iCCA.

1.5 T and 3.0 T. DWI, T2WI, and contrast-enhanced T1WI.

Clinical information, radiologic, and MRI-based radiomics features associated with LNM status were collected to establish models. Performance of MRI, PET/CT, and the combined LNM models were compared in training (N = 207) and test (N = 89) datasets. Overall survival (OS) was compared based on LNM status.

The independent features were selected by 5-fold cross-validation. The performance of MRI, PET/CT, and the models was evaluated using the area under receiver operating characteristic curve (AUC). Univariable and multivariable Cox regression were used to identify independent variables for OS. Kaplan-Meier curves were compared with the log-rank test between LNM positive and negative groups. P < 0.05 was considered statistically significant.

Intrahepatic duct dilatation, enhancement pattern, and CA19-9 were independent clinicoradiologic features. The radiomics model was constructed by the independent radiomics features extracted from T2WI and delay phase T1WI. The combined LNM model showed AUC of 0.888, 0.884, and 0.811 in training, validation, and test cohorts with a positive net benefit. PET/CT exhibited similar sensitivity to the combined LNM model (0.750 vs. 0.733, P > 0.999) while the combined LNM model showed higher specificity (0.703 vs. 0.630, P = 0.039) in the test cohort. High risk of regional LNM was significantly associated with worse OS (median: 24 months) than low risk (median: 30 months, P < 0.0001).

The combined LNM model has the strongest correlation with LNM status for mass-forming iCCA patients.

3 TECHNICAL EFFICACY: Stage 2.

Intrahepatic cholangiocarcinoma (ICC), a malignancy originating from the epithelial cells of bile ducts, has shown a notable rise in its incidence over the years. It ranks as the second most frequent primary liver cancer after hepatocellular carcinoma. This study investigates how independent prognostic factors, specifically, age and tumor stage, interact to impact mortality in ICC patients. Furthermore, it examines the clinical features, survival rates, and prognostic indicators of ICC cases diagnosed between 2010 and 2017.

Using data from 5083 patients obtained from the Surveillance, Epidemiology, and End Results (SEER) database, this study evaluated demographic and clinical factors alongside overall mortality (OM) and cancer-specific mortality (CSM). Variables achieving a p-value below 0.1 in univariate Cox regression analysis were incorporated into multivariate Cox regression models to identify independent prognostic factors. Hazard ratios (HRs) exceeding 1 were interpreted as markers of poor prognosis. Additionally, this study explored the interaction between age and tumor stage in shaping survival outcomes.

The multivariate Cox proportional hazards analysis indicated higher OM in males (HR = 1.19, 95% CI: 1.12-1.26, p < 0.01) and residents of metropolitan counties with populations exceeding 250,000 (HR = 1.15, 95% CI: 1.01-1.31, p < 0.05). Conversely, lower OM was observed in individuals aged 40-59 years (HR = 0.58, 95% CI: 0.38-0.89, p < 0.05), those aged 60-79 years (HR = 0.65, 95% CI: 0.43-0.98, p < 0.05), and patients who received radiation therapy (HR = 0.78, 95% CI: 0.72-0.85, p < 0.01), chemotherapy (HR = 0.54, 95% CI: 0.51-0.58, p < 0.01), or surgery (HR = 0.29, 95% CI: 0.26-0.31, p < 0.01). For CSM, males exhibited higher risks (HR = 1.17, 95% CI: 1.10-1.25, p < 0.01), as did individuals in metropolitan counties with populations over 250,000 (HR = 1.18, 95% CI: 1.03-1.35, p < 0.05). Reduced CSM was observed in patients aged 40-59 years (HR = 0.52, 95% CI: 0.34-0.79, p < 0.01), those aged 60-79 years (HR = 0.57, 95% CI: 0.38-0.86, p < 0.01), and those undergoing radiation therapy (HR = 0.76, 95% CI: 0.70-0.83, p < 0.01), chemotherapy (HR = 0.55, 95% CI: 0.51-0.59, p < 0.01), or surgery (HR = 0.27, 95% CI: 0.25-0.30, p < 0.01). When examining the interaction between age and tumor stage, higher OM was observed in patients aged 40-59 with tumors involving lymph nodes (HR = 1.26, 95% CI: 1.14-2.67, p < 0.05). Similarly, CSM was elevated in patients aged 40-59 with lymph node involvement alone (HR = 2.60, 95% CI: 1.26-5.36, p < 0.05) or with direct spread (HR = 2.81, 95% CI: 1.04-7.61, p < 0.05). Among those aged 60-79, higher CSM was noted in cases with lymph node involvement only (HR = 2.24, 95% CI: 1.11-4.50, p < 0.05) or lymph node involvement accompanied by direct extension (HR = 2.93, 95% CI: 1.10-7.82, p < 0.05).

This retrospective analysis, utilizing data from the SEER database, provides new insights into mortality patterns in intrahepatic cholangiocarcinoma (ICC). This study identifies a significant interplay between two key prognostic factors, emphasizing their collective role in influencing mortality outcomes. Despite the predominance of advanced-stage diagnoses, our analysis underscores the substantial survival benefits associated with treatment interventions, with surgical procedures demonstrating the most pronounced impact. These findings highlight the importance of recognizing patients who may benefit from timely and intensive therapeutic strategies. Furthermore, the results underscore the need for future prospective randomized studies to deepen our understanding of these interactions in ICC, particularly as advancements in precision oncology continue to refine patient care.

Intrahepatic cholangiocarcinoma (ICC) is a primary invasive malignant tumor. This study was conducted to explore the role of methyltransferase-like 3 (METTL3)-mediated m6A modification in ICC cells and provide novel targets for ICC treatment. Levels of METTL3/YTH N6-methyladenosine RNA binding protein 2 (YTHDF2)/Nedd4 family interacting protein 1 (NDFIP1) in cells were determined. Cell viability, proliferation, invasion, and migration were evaluated. The enrichments of METTL3, YTHDF2, and m6A on NDFIP1 mRNA were analyzed. The mRNA stability was determined. Inhibition of YTHDF2 or NDFIP1 was combined with si-METTL3 to confirm the mechanism. The role of METTL3 in vivo was verified. METTL3 was overexpressed in ICC cells. METTL3 silencing suppressed ICC cell malignant behaviors, which were reversed by METTL3 overexpression. METTL3 increased m6A modification on NDFIP1 mRNA, facilitated YTHDF2 recognition of m6A, and promoted NDFIP1 mRNA degradation, thereby suppressing NDFIP1 expression. YTHDF2 inhibition increased NDFIP1 mRNA levels. NDFIP1 downregulation partially reversed the inhibitory effects of si-METTL3 on ICC cell behaviors, while NDFIP1 overexpression partially reversed the promotive effects of METTL3 on ICC cell behaviors. METTL3 downregulation suppressed ICC growth by increasing NDFIP1 expression. In conclusion, METTL3 aggravates ICC cell proliferation, invasion, and migration by promoting the degradation of NDFIP1 mRNA in a YTHDF2-dependent manner.

Cholangiocarcinoma (CCA) is a rare neoplasm, with high mortality, originating in the bile ducts. Its incidence is higher in Eastern countries due to the endemic prevalence of liver parasites. Factors such as metabolic syndrome, smoking, and pro-inflammatory conditions are also linked to the disease. Clinical features include asthenia, abdominal pain, cholestasis, and increased serum levels of CEA and CA19-9.

The aim of this study was to evaluate CCA prevalence, survival, and potential prognostic and therapeutic implications in a patient cohort and assess correlations with clinical laboratory data and possible associated risk factors.

This is a retrospective study of the clinical and histological data of patients diagnosed with CCA at Santa Casa de Misericórdia in Porto Alegre, Brazil, between 2016 and 2021.

There was a 56% prevalence of CCA in women, with intrahepatic localization in 55.4% of cases and unifocality in 85.6% of patients. The mean age of the patients was 63 years (26-89 years), with a mean tumor size of 5.5 cm. The median survival time was 7 months (0 to >50). CA19-9 was altered in 81% of patients, whereas GOT/GPT was altered in 62.5% and gamma-glutamyl transferase/alkaline phosphatase/bilirubin in 69.1% of patients. Mortality was higher among patients with extrahepatic CCA.

Risk factors such as smoking, cholecystectomy, cirrhosis, intrahepatic lithiasis, and transplantation should be considered individually by the attending physician for radiological monitoring and incidental discovery of the neoplasm. Lack of timely identification by the attending physician can delay diagnosis, increasing mortality.

N7-methylguanosine (m7G) modification is one of the most prevalent forms of chemical modification in RNA molecules, which plays an important role in biological processes such as RNA stability, translation regulation and ribosome recognition. Methyl-transferation of m7G modification is catalyzed by the enzyme complex of methyltransferase-like 1 (METTL1) and WD repeat domain 4 (WDR4), and Quaking (QKI) recognizes internal m7G methylated mRNA and regulates mRNA translation and stabilization. Recent studies have found that m7G modification - related enzymes are associated with the onset and progression of digestive cancer, such as colorectal cancer, liver cancer, and other digestive diseases such as ulcerative colitis. This review will focus on the latest research progress on the roles of m7G methyltransferase METTL1/WDR4 and recognized enzyme QKI in digestive diseases.

Major hepatectomy (MH) can increase the risk of adverse events (AEs) owing to impaired drug metabolism due to decreased liver volume and surgical injury. Thus, we performed this subgroup analysis using data from JCOG1113, a phase III trial comparing gemcitabine plus S-1 (GS) and gemcitabine plus cisplatin (GC) in patients with advanced and recurrent biliary tract cancer (BTC), to evaluate the effect of MH on the safety and efficacy of GC and GS regimens in patients with recurrent BTC.

Of the 354 patients with advanced BTC enrolled in JCOG1113, 76 patients with postoperative recurrence (30 in the MH group and 46 in the non-MH group) were analyzed.

Grade ≥ 3 platelet count decreased in both arms was more frequent in the MH group than in non-MH group (GC, 0.0 vs. 17.6%; GS, 3.9 vs. 15.4%). However, in the MH group, the white blood cell decreased (GC, 55.0 vs. 38.5%; GS, 23.1 vs. 7.7%) and anemia (GC, 15.0 vs. 11.8%; GS, 23.1 vs. 7.7%) were less common than in the non-MH group. The MH and non-MH groups showed no significant difference in overall survival (OS) in both GC [median OS, 23.0 in MH vs. 16.9 months in non-MH (hazard ratio, 0.857; 95% CI 0.387-1.899)], and GS [median OS, 21.5 vs. 14.9 months (hazard ratio, 0.670; 95% CI 0.310-1.447)] arms.

The safety and efficacy of gemcitabine-based chemotherapy were comparable between patients who underwent MH and those who underwent other surgeries.

To improve the prognosis of advanced intrahepatic cholangiocarcinoma (iCCA), the authors retrospectively compared the effect and safety of combined hepatic arterial infusion chemotherapy (HAIC), targeted therapy, and immunotherapy with systemic chemotherapy (SC) in unresectable iCCA patients.

The authors retrospectively enrolled 202 advanced iCCA patients treated with SC or targeted therapy, immunotherapy, and FOLFOX-HAIC combined between March 2015 and June 2023 at our institution. Two hundred two patients were divided into two groups based on the therapeutic regimens. Baseline characteristics and prognosis were reviewed and analyzed.

After 1-to-1 propensity score matching, 76 patients were included in each group. The triple combination therapy group demonstrated longer median overall survival (OS, 20.77 vs. 14.83 months, P =0.047), progression-free survival (PFS, 9.07 vs. 6.23 months, P <0.001), intrahepatic PFS (11.03 vs. 6.73 months, P <0.001), extrahepatic PFS (11.37 vs. 7.13 months, P =0.0064), and a higher objective response rate (35.5% vs. 14.5%, P =0.003) than the SC group. Fever, thrombocytopenia, elevated ALT, elevated AST, hypoalbuminemia, and hyperbilirubinemia were more common adverse events (AEs) in the triple combination therapy group, while fatigue and anemia were more prevalent in the SC group ( P <0.05). For grades 3-4 AEs, the rates of elevated ALT were higher in the triple combination group ( P =0.028).

Compared with SC, triple combination therapy comprising HAIC, targeted therapy and immunotherapy appears to be an effective and safe treatment for advanced iCCA.

This study aimed to develop and validate clinical nomograms for predicting progression-free survival (PFS) and overall survival (OS) in unresectable ICC patients.

Patients with ICC between 1 January 2018 and 31 May 2023 were selected and randomized into a training set and an internal validation set as a 7:3 ratio. Data analysis and modeling were conducted through R software. The univariate and multivariate Cox regression models were used to analyze the prognosis factors affecting OS and PFS. Survival analysis was conducted using the Kaplan-Meier (KM) method, and comparisons were made using the Log rank test. Then, two nomogram models were constructed to predict OS and PFS, respectively. The nomogram was evaluated and calibrated using the Harrell's C-index, receiver operating characteristic curve (ROC), and calibration plots, and the decision curve analysis (DCA) was conducted to assess its clinical utility.

A total of 110 patients were enrolled in this study, with 77 to the training set and 33 to the validation set. In the entire population, the OS rates at 6 and 12 months were 75.5% and 35.5%, respectively, while the PFS rates at 6 and 12 months were 47.3% and 20%, respectively. Cox regression analyses showed that ECOG, Tumor volume, HBsAg and AFP were the prognosis factors of OS, and the predictors in the model of PFS included Gender, Stage of tumor, CDC20 expression and AFP. The nomograms were constructed based on the predictors above. The C-index for predicting OS was 0.802 (0.755, 0.849) in the training set, 0.813 (0.764, 0.862) in the internal validation set; the C-index for predicting PFS was 0.658 (0.568, 0.748) in the training set, and 0.795 (0.705, 0.885) in the internal validation set. Finally, calibration curves and DCA indicated that two nomograms showed favorable performance.

Two practical and effective prognostic nomograms were developed to assist clinicians in evaluating OS and PFS in patients with unresectable ICC.

Increasing evidence highlights that fibroblast growth factor receptor 2 (FGFR2) fusion/rearrangement shows important therapeutic value for patients with intrahepatic cholangiocarcinoma (ICC). This study aims to explore the association of FGFR2 status with the prognosis and immune cell infiltration profiles of patients with ICC. A total of 226 ICC tissue samples from patients who received surgery at the Department of Liver Surgery at Zhongshan Hospital, Fudan University, were collected retrospectively and assigned to a primary cohort (n = 152) and validation cohort (n = 74) group. Fluorescence in situ hybridization was performed to determine FGFR2 status. Multiplex immunofluorescence (mIF) staining and immunohistochemistry were performed to identify immune cells. Thirty-two (14.2%) ICC tissues presented with FGFR2 fusion/rearrangement. FGFR2 fusion/rearrangement was associated with low levels of carcinoembryonic antigen (CEA, P = .026) and gamma glutamyl transferase (γ-GGT, P = .003), low TNM (P = .012), CNLC (P = .008) staging as well as low tumor cell differentiation (P = .016). Multivariate COX regression analyses revealed that FGFR2 fusion/rearrangement was an independent protective factor for both overall survival (OS) and relapse-free survival in patients with ICC. Furthermore, correlation analysis revealed that an FGFR2 fusion/rearrangement was associated with low levels of Tregs and N2 neutrophils and high levels of N1 neutrophils infiltrating into tumors but not with CD8+ T-cell or macrophage tumor infiltration. FGFR2 fusion/rearrangement may exert a profound impact on the prognosis of ICC patients and reprogram the tumor microenvironment to be an immune-activated state. FGFR2 status may be used for ICC prognostic stratification and as an immunotherapeutic target in patients with ICC.

Several locoregional treatments approaches, including thermoablation, have been tested for the treatment of intrahepatic cholangiocarcinoma (ICC) and have shown encouraging results. However, data are heterogeneous in terms of tumor number, size, and ablation technique.

The aim of this study was to investigate the efficacy and prognostic factors in ICC treated by monopolar radiofrequency (RF) or microwave ablation (MW).

This was a retrospective study including patients treated with RF or MW for ICC in six participating centers. DFS and OS were evaluated by the Kaplan-Meier method and prognostic factors by log-rank test and Cox modeling.

From January 2015 to October 2023, 24 patients with 31 nodules were treated with RFA or MW. Overall, 70% had chronic liver disease, with 50% at cirrhosis stage. The median size of lesions was 17 mm (6-35 mm). After a median follow-up of 33 months (5-85), the median DFS was 10.5 months. The median OS was 40.8 months. On univariate and multivariate analysis, only lesion size > 17 mm was associated with a poor OS (HR 3.09; IC [1.02; 9.37] (p = 0.04).

Monopolar radiofrequency or microwave ablation is an alternative to surgery for small ICCs. Tumors < 17 mm were associated with better OS.

Intrahepatic cholangiocarcinoma (iCCA) is a lethal primary liver tumor characterized by clinical aggressiveness, poor prognosis, and scarce therapeutic possibilities. Therefore, new treatments are urgently needed to render this disease curable. Since cumulating evidence supports the oncogenic properties of the Heat Shock Factor 1 (HSF1) transcription factor in various cancer types, we investigated its pathogenetic and therapeutic relevance in iCCA.

Levels of HSF1 were evaluated in a vast collection of iCCA specimens. The effects of HSF1 inactivation on iCCA development in vivo were investigated using three established oncogene-driven iCCA mouse models. In addition, the impact of HSF1 suppression on tumor cells and tumor stroma was assessed in iCCA cell lines, human iCCA cancer-associated fibroblasts (hCAFs), and patient-derived organoids.

Human preinvasive, invasive, and metastatic iCCAs displayed widespread HSF1 upregulation, which was associated with a dismal prognosis of the patients. In addition, hydrodynamic injection of a dominant-negative form of HSF1 (HSF1dn), which suppresses HSF1 activity, significantly delayed cholangiocarcinogenesis in AKT/NICD, AKT/YAP, and AKT/TAZ mice. In iCCA cell lines, iCCA hCAFs, and patient-derived organoids, administration of the HSF1 inhibitor KRIBB-11 significantly reduced proliferation and induced apoptosis. Cell death was profoundly augmented by concomitant administration of the Bcl-xL/Bcl2/Bcl-w inhibitor ABT-263. Furthermore, KRIBB-11 reduced mitochondrial bioenergetics and glycolysis of iCCA cells.

The present data underscore the critical pathogenetic, prognostic, and therapeutic role of HSF1 in cholangiocarcinogenesis.

Organoids refer to 3D cultures established to recapitulate histology, pathology, architecture, and genetic traits of various organs and tissues in the body, thereby replacing 2D cell cultures, xenograft, and animal models. Organoids form a 3D in vitro mimic of original tissues like the liver and are derived from embryonic or adult tissue stem cells. Liver and bile duct tumor organoids, also called, tumoroids capture genetic diversity, cellular, and pathophysiological properties of original tumors. Moreover, co-culture techniques along with genetic modulation of organoids allow for using tumoroids in liver and bile duct cancer research and drug screening/testing. Therefore, tumoroids are promising platforms for studying liver and bile duct cancer, which paves the way for the new era of personalized therapies. In the current review, we aimed to discuss liver and bile duct organoids with special emphasis on tumoroids and their applications, advantages, and shortcomings.

Intrahepatic cholangiocarcinoma (ICC) is the 2nd most common primary liver malignancy. For nonsurgical candidates, the primary treatment option is systemic chemotherapy, which can be combined with locoregional therapies to enhance local control. Common intra-arterial locoregional therapies include transarterial hepatic embolization, conventional transarterial chemoembolization, drug-eluting bead transarterial chemoembolization, transarterial radioembolization with Yttrium-90 microspheres, and hepatic artery infusion. This article aims to review the latest literature on intra-arterial locoregional therapies for treating ICC.

A literature search was conducted on PubMed using keywords: intrahepatic cholangiocarcinoma, intra-arterial locoregional therapy, embolization, chemoembolization, radioembolization, hepatic artery infusion, and immunotherapy. Articles from 2008 to 2024 were reviewed. Survival data from retrospective and prospective studies, meta-analyses, and clinical trials were evaluated.

Although no level I evidence supports the superiority of any specific intra-arterial therapy, there has been a shift toward favoring radioembolization. In our expert opinion, radioembolization may offer superior outcomes when performed by skilled operators with meticulous planning and personalized dosimetry, particularly for radiation segmentectomy or treating lobar/bilobar disease in appropriate candidates.