Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver tumor and remains a fatal malignancy in most patients. Only 20% to 30% of patients can be treated with potentially curative surgical resection. Local therapies such as radioembolization and hepatic arterial perfusion may be a more effective treatment strategy. The active ingredients of natural plants have aroused wide interest in the treatment of tumors. Triptolide shows toxic effects on a variety of epithelioid carcinoma cells. However, there is currently a lack of suitable delivery system for the treatment of ICC. In this study, organometallic framework material ZIF-8 was chosen to load TP, and then encapsuled in HSA micro-nanoparticles for the perfusion treatment of ICC. The results of SEM, XRD, and FTIR showed that ZIF-8 nanoparticles were encapsuled in HSA micro-nanoparticles. ZIF-8 nanoparticles (57.89 ± 12.24%) and TP@ZIF-8/HSA (36.8 ± 4.71%) micro-nanoparticles could significantly inhibited proliferation of RBE cell. Also, TP@ZIF-8/HSA micro-nanoparticles of all groups exhibited favorable cytocompatibility to L929 cells and hemocompatibility. RT-qPCR and western blot showed that ZIF-8 and TP induced apoptosis in cancer cells through mitochondria-related pathways. The results demonstrated that TP@ZIF-8/HSA was a potential chemotherapy candidate for the treatment of ICC.

Aim. The study aims to explore the expression levels and clinicopathological significance of BRAF V600E and mucin 6 in intrahepatic cholangiocarcinoma. Method. Immunohistochemistry for BRAF V600E and mucin 6 was performed in 110 patients with intrahepatic cholangiocarcinoma. Subsequently, a comprehensive review of medical records and clinicopathological analysis was undertaken. Results. BRAF V600E expression was detected in 11 patients (10%); mucin 6 expression was observed in 19 intrahepatic cholangiocarcinoma specimens (17%). Thereafter, Cox regression models indicated that positive expression of either MUC6 positive (hazard ratio = 0.091, 95% confidence interval = 0.034-0.247, P < .001) and BRAF V600E positive (hazard ratio =0.150, 95% confidence interval = 0.058-0.388, P < .001) was significantly linked with longer overall survival for intrahepatic cholangiocarcinoma patients. Conclusion. The study concludes that positive expression of BRAF V600E and mucin 6 could potentially implied significant survival benefits for patients diagnosed with intrahepatic cholangiocarcinoma.

To investigate the preoperative factors influencing textbook outcomes (TO) in Intrahepatic cholangiocarcinoma (ICC) patients and evaluate the feasibility of an interpretable machine learning model for preoperative prediction of TO, we developed a machine learning model for preoperative prediction of TO and used the SHapley Additive exPlanations (SHAP) technique to illustrate the prediction process.

To analyze the factors influencing textbook outcomes before surgery and to establish interpretable machine learning models for preoperative prediction.

A total of 376 patients diagnosed with ICC were retrospectively collected from four major medical institutions in China, covering the period from 2011 to 2017. Logistic regression analysis was conducted to identify preoperative variables associated with achieving TO. Based on these variables, an EXtreme Gradient Boosting (XGBoost) machine learning prediction model was constructed using the XGBoost package. The SHAP (package: Shapviz) algorithm was employed to visualize each variable's contribution to the model's predictions. Kaplan-Meier survival analysis was performed to compare the prognostic differences between the TO-achieving and non-TO-achieving groups.

Among 376 patients, 287 were included in the training group and 89 in the validation group. Logistic regression identified the following preoperative variables influencing TO: Child-Pugh classification, Eastern Cooperative Oncology Group (ECOG) score, hepatitis B, and tumor size. The XGBoost prediction model demonstrated high accuracy in internal validation (AUC = 0.8825) and external validation (AUC = 0.8346). Survival analysis revealed that the disease-free survival rates for patients achieving TO at 1, 2, and 3 years were 64.2%, 56.8%, and 43.4%, respectively.

Child-Pugh classification, ECOG score, hepatitis B, and tumor size are preoperative predictors of TO. In both the training group and the validation group, the machine learning model had certain effectiveness in predicting TO before surgery. The SHAP algorithm provided intuitive visualization of the machine learning prediction process, enhancing its interpretability.

Neoadjuvant therapy (NAT) is increasingly used to treat patients with initially unresectable intrahepatic cholangiocarcinoma (iCCA). A histopathologic grading system for residual tumors that can predict patient survival is lacking in the literature. This retrospective study enrolled 151 iCCA patients who received NAT. The percentage of residual viable tumor (%RVT) extent was calculated by RVT surface area/total tumor bed area ×100 and scored in 5% increments. Kaplan-Meier and Cox regression analyses were used to investigate its correlations with recurrence-free survival (RFS) and overall survival (OS). Tumor regression grading by the College of American Pathologists (CAP) and MD Anderson (MDA) methodologies were also validated. A 10% RVT-based tumor regression score (TRS) showed a significant correlation with both OS and RFS. TRS and major pathologic response (mPR) were therefore defined as follows: TRS 1/mPR, tumor with 0 to 10% RVT; TRS 2, more than 10% RVT. Patients graded as TRS 1/mPR had superior OS (P=0.006) and RFS (P<0.001) compared with those with TRS 2 in univariate analysis. In a multivariate analysis including ypTNM stages, lymphovascular invasion, and perineural invasion, TRS 1/mPR was also found to be an independent prognostic factor for both OS (hazard ratio [HR]: 0.226; 95% CI: 0.053-0.966, P=0.045) and RFS (HR: 0.474; 95% CI: 0.231-0.974, P=0.042). As for the CAP and MDA grading methodologies, they were found to correlate with RFS (CAP: P=0.002; MDA: P=0.001), but not with OS (CAP: P=0.181; MDA: P=0.09). Our study revealed that a TRS of ≤10% RVT significantly correlates with longer OS and RFS and can be suggested as an mPR in iCCA. This indicator is easily applicable, prognostically relevant, and could be further validated in future prospective clinical trials.

Cdc2-like kinase 1 (CLK1) has dual-specificity kinase ability to phosphorylate tyrosine and serine/threonine protein residues. CLK1 regulates many physiologic processes and has been shown to contribute to multiple types of cancer. In this study, we investigated the functional role of CLK1 during intrahepatic cholangiocarcinoma (ICC) development. The expression of CLK1 was elevated in ICC tumors, and patients with high expression of CLK1 demonstrated poor prognosis. In hydrodynamically transfected mouse models, CLK1 alone was insufficient to induce ICC, whereas CLK1 cooperated with AKT (AKT/CLK1) to trigger ICC initiation. In addition, overexpression of CLK1 in ICC cells facilitated proliferation in vitro and tumor growth in vivo, whereas loss of CLK1 elicited the opposite effects. Moreover, RNA sequencing analysis indicated that high levels of CLK1 corresponded with activation of the Hippo-Yes-associated protein (YAP) signaling pathway. Consistently, AKT/CLK1 murine tumors displayed upregulation of YAP as well as its downstream targets. Furthermore, loss or pharmacologic inhibition of YAP in ICC cells inhibited CLK1-induced growth, and deletion of Yap completely retarded the induction of AKT/CLK1 tumors. Mechanistically, 4D label-free mass spectrometry and coimmunoprecipitation assays revealed WWC2 as a potential mediator of the CLK1-YAP cascade. Collectively, the current findings identify a critical role for CLK1 in promoting ICC development and indicate that inhibiting YAP might be an effective approach for perturbing CLK1-mediated tumorigenesis. Significance: CLK1 drives intrahepatic cholangiocarcinoma initiation and progression by increasing YAP activity, suggesting that targeting YAP could be a potential strategy for treating and preventing CLK1-driven intrahepatic cholangiocarcinoma.

We aimed to systematically assess the value of radiomics/machine learning (ML) models for diagnosing microvascular invasion (MVI) in patients with cholangiocarcinoma (CCA) using various radiologic modalities.

A systematic search of was conducted on Web of Sciences, PubMed, Scopus, and Embase. All the studies that assessed the value of radiomics models or ML models along with the use of imaging features were included. The Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) criteria and METhodological RadiomICs Score (METRICS) were used for quality assessment. Pooled estimates for the diagnostic performance of radiomics/ML models were calculated. I-squared was used to assess heterogeneity, and sensitivity and subgroup analyses were performed to find the sources of heterogeneity. Deeks' funnel plots were used to assess publication bias.

11 studies were included in the systematic review with only one study being about extrahepatic CCA. According to the METRICS, the mean score was 62.99 %. Meta-analyses were performed on intrahepatic CCA studies. The meta-analysis of the best ML models revealed an AUC of 0.93 in the training cohort and an AUC of 0.85 in the validation cohort. Regarding the best radiomics model, the AUC was 0.85 in the training cohort and 0.81 in the validation cohort.

Radiomics/ML models showed very good diagnostic performance regarding MVI diagnosis in patients with intrahepatic CCA and may provide a non-invasive method for this purpose. However, given the high heterogeneity and low number of the included studies, further multi-center studies with prospective design and robust external validation are essential.

Metachronous biliary tract cancer (BTC) is a rare occurrence after curative resection of primary BTC. The genetic alterations and pathogenesis associated with metachronous BTC remain poorly understood.

We analyzed four patients with metachronous BTC who underwent resection at the Nagoya University Hospital between 2010 and 2024. Gene panel examination was performed on both primary and secondary tumors using next-generation sequencing.

The median interval between resection of the primary tumor and diagnosis of metachronous BTC was 24 months. Genetic alterations were observed in all paired primary and metachronous carcinomas. The number of genetic mutations was higher in metachronous lesions than in primary lesions. CDKN2A and SMAD4 were the most frequently mutated genes in all metachronous lesions. Common genetic mutations between primary and metachronous lesions were confirmed in all four cases, suggesting a common clonal origin.

This study demonstrated that characteristic genetic alterations and their accumulation play important roles in metachronous BTC. This suggests that the increasing burden of gene mutations may play a crucial role in the carcinogenesis of metachronous BTC. Further investigation is required to validate these findings and elucidate the underlying molecular mechanisms.

Polybromo-1 (PBRM1) serves as a crucial regulator of gene transcription in various tumors, including intrahepatic cholangiocarcinoma (iCCA). However, the exact role of PBRM1 in iCCA and the mechanism by which it regulates downstream target genes remain unclear. This research has revealed that PBRM1 is significantly downregulated in iCCA tissues, and this reduced expression is linked to aggressive clinicopathological features and a poor prognosis. Furthermore, it is demonstrated that PBRM1 can impede iCCA progression, and a gene therapy nanomedicine is developed to treat iCCA in vivo by modulating PBRM1 expression. The heightened expression of PBRM1 induces by the nanomedicine substantially inhibited tumor growth in iCCA. Conversely, the decrease in PBRM1 results in the abnormal activation of the ERK1/2 signaling pathway, a reduction in p16, p53/p21, and cellular senescence, thereby promoting iCCA advancement. Treatment with U0126, an ERK1/2 inhibitor, effectively halted iCCA progression by regulating the PBRM1-ERK1/2-cellular senescence pathway. These findings underscore the significant role of PBRM1 in controlling iCCA progression and predicting prognosis. Targeting the PBRM1-ERK1/2-cellular senescence pathway with U0126 shows promise for clinical applications in treating iCCA.

This study aims to introduce the concept of habitat subregions and construct an accurate prediction model by analyzing refined medical images, to predict lymph node metastasis (LNM) in patients with intrahepatic cholangiocarcinoma (ICC) before surgery, and to provide personalized support for clinical decision-making.

Clinical, radiological, and pathological data from ICC patients were retrospectively collected. Using information from the arterial and venous phases of multisequence CT images, tumor habitat subregions were delineated through the K-means clustering algorithm. Radiomic features were extracted and screened, and prediction models based on different subregions were constructed and compared with traditional intratumoral models. Finally, a lymph node metastasis prediction model was established by integrating the features of several subregional models, and its performance was evaluated.

A total of 164 ICC patients were included in this study, 103 of whom underwent lymph node dissection. The patients were divided into LNM- and LNM + groups on the basis of lymph node status, and significant differences in white blood cell indicators were found between the two groups. Survival analysis revealed that patients with positive lymph nodes had significantly worse prognoses. Through cluster analysis, the optimal number of habitat subregions was determined to be 5, and prediction models based on different subregions were constructed. A comparison of the performance of each model revealed that the Habitat1 and Habitat5 models had excellent performance. The optimal model obtained by fusing the features of the Habitat1 and Habitat5 models had AUC values of 0.923 and 0.913 in the training set and validation set, respectively, demonstrating good predictive ability. Calibration curves and decision curve analysis further validated the superiority and clinical application value of the model.

This study successfully constructed an accurate prediction model based on habitat subregions that can effectively predict the lymph node metastasis of ICC patients preoperatively. This model is expected to provide personalized decision support to clinicians and help to optimize treatment plans and improve patient outcomes.

Intrahepatic cholangiocarcinoma (ICC) presents a significant clinical challenge due to its high fatality rate and limited surgical candidacy. With only 30-40% of patients eligible for surgery upon diagnosis, alternative therapies are imperative. This study assesses the efficacy of Yttrium-90 (Y-90) radioembolization for unresectable ICC patients in a non-university tertiary care center (NUTCC).

A retrospective analysis of 15 unresectable ICC patients treated with Y-90 radioembolization was conducted. Tumor response, survival, and adverse events were evaluated using RECIST criteria.

60% of patients exhibited partial response, and 20% showed stable disease, with notable tumor size reduction and a median survival of 14 months. Minimal adverse effects were observed, indicating Y-90's favorable safety profile.

Y-90 radioembolization shows potential in reducing tumor burden and enhancing survival rates with minimal adverse effects for unresectable ICC. Larger prospective studies are needed to confirm its efficacy and define its role in ICC treatment protocols.

Intrahepatic cholangiocarcinoma (iCCA) is an aggressive liver malignancy that arises from second-order biliary epithelial cells. Its incidence is gradually increasing worldwide. Well-known risk factors have been described, although in many cases, they are not identifiable. Treatment options are continuously expanding, but the prognosis of iCCA remains dismal. R0 liver resection remains the only curative treatment, but only a limited number of patients can benefit from it. Frequently, major hepatectomies are needed to completely remove the tumour. This could contraindicate surgery or increase postoperative morbidity in patients with chronic liver disease and small remnant liver volume. In cases of anticipated inadequate future liver remnant, regenerative techniques may be used to expand resectability. The role and extent of lymphadenectomy in iCCA are still matters of debate. Improvements in iCCA diagnosis and better understanding of genetic profiles might lead to optimized surgical approaches and drug therapies. The role of neoadjuvant and adjuvant therapies is broadening, gaining more and more acceptance in clinical practice. Combining surgery with locoregional therapies and novel drugs, such as checkpoint-inhibitors and molecular-targeted molecules, might improve treatment options and survival rates. Liver transplantation, after very poor initial results, is now receiving attention for the treatment of patients with unresectable very early iCCA (i.e. <2 cm) in cirrhotic livers, showing survival outcomes comparable to those of hepatocellular carcinoma. Ongoing prospective protocols are testing the efficacy of liver transplantation for patients with unresectable, advanced tumours confined to the liver, with sustained response to neoadjuvant treatment. In such a continuously changing landscape, the aim of our work is to review the state-of-the-art in the surgical and medical treatment of iCCA.

Intrahepatic cholangiocarcinoma is a highly malignant tumor with a poor prognosis. Radical surgical resection remains the "gold standard" for improving patient outcomes; however, only a minority of patients qualify for this approach. Intrahepatic cholangiocarcinoma is primarily classified into two major histologic types: small and large ductal cholangiocarcinomas. Nevertheless, rare subtypes with unique diagnostic and prognostic characteristics are increasingly reported. These subtypes often exhibit features such as slow growth, a histologic architecture resembling thyroid tissue, or ductal ectasia, and are associated with a more favorable prognosis. We present the case of a 61-year-old patient with a solitary liver mass initially identified as a hemangioma through imaging studies. Histopathologic examination of the postoperative specimen revealed a thyroid-like structural pattern. Immunohistochemical analysis showed positive staining for CK7 and CK19, confirming the diagnosis of intrahepatic cholangiocarcinoma with a thyroid-like structure. The tumor was completely resected with clear margins, and no evidence of metastasis was found. Consequently, the patient was managed without adjuvant chemotherapy. At 14 months of follow-up, there were no signs of recurrence or metastasis. This clinical case underscores the importance of recognizing novel subtypes of cholangiocarcinoma and exercising vigilance in the management of patients with presumed benign hepatic lesions.

Biliary tract cancers, which are rare and aggressive malignancies, are rich in clinically actionable molecular alterations. A major challenge in the field is the paucity of clinically relevant biliary tract cancer models that recapitulate the diverse molecular profiles of these tumors. The purpose of this study was to curate a collection of patient-derived xenograft (PDX) models that reflect the spectrum of genomic alterations present in biliary tract cancers to create a resource for modeling precision oncology.

PDXs were derived from biliary tract cancer samples collected from surgical resections or metastatic biopsies. Alterations present in the PDXs were identified by whole-exome sequencing and RNA sequencing. PDXs were treated with approved and investigational agents. Efficacy was assessed by change in tumor volume from baseline. Event-free survival was defined as the time to tumor doubling from baseline. Responses were categorized at day 21: >30% decrease in tumor volume = partial response, >20% increase in tumor volume = progressive disease, and any non-partial response/progressive disease was considered stable disease.

Genomic sequencing demonstrated key actionable alterations across this cohort, including alterations in FGFR2, isocitrate dehydrogenase I, ERRB2, PIK3CA, PTEN, and KRAS. RNA sequencing demonstrated fusions and expression of antibody-drug conjugate targets, including TROP2, HER2, and Nectin4. Therapeutic matching revealed objective responses to approved and investigational agents that have been shown to have antitumor activity clinically.

In this study, we developed a catalog of biliary tract cancer PDXs that underwent comprehensive molecular profiling and therapeutic modeling. To date, this is one of the largest collections of biliary tract cancer PDX models and will facilitate the development of personalized treatments for patients with these aggressive malignancies.

Intrahepatic cholangiocarcinoma (iCCA) is a highly malignant tumor of the liver and gallbladder, which is usually diagnosed at an advanced stage and the opportunity for surgery is lost. Therefore, conversion therapy is important to convert the iCCA into a resectable state. In recent years, the conversion protocol of immuno-chemotherapy has been applied for advanced liver cancer. However, little has been reported about iCCA conversion therapy. The aim of this report is to present the results of conversion therapy with Gemcitabine plus S-1 (GS) combined with PD-1 inhibitors (Zimberelimab) in a 74-year-old female IIIB iCCA patient. After 6 cycles of conversion therapy, enhanced CT showed that the patient's tumor had shrunk to nearly half its original size, making radical resection possible. Postoperative pathology showed a complete pathological response. This provides a new way to convert advanced iCCA into resectable state.

To develop ultrasound-based radiomics models and a clinical model associated with inflammatory markers for predicting intrahepatic cholangiocarcinoma (ICC) lymph node (LN) metastasis. Both are integrated for enhanced preoperative prediction.

This study retrospectively enrolled 156 surgically diagnosed ICC patients. A region of interest (ROI) was manually identified on the ultrasound image of the tumor to extract radiomics features. In the training cohort, we performed a Wilcoxon test to screen for differentially expressed features, and then we used 12 machine learning algorithms to develop 107 models within the cross-validation framework and determine the optimal radiomics model through receiver operating characteristic (ROC) curve analysis. Multivariable logistic regression analysis was used to identify independent risk factors to construct a clinical model. The combined model was established by combining ultrasound-based radiomics and clinical parameters. The Delong test and decision curve analysis (DCA) were used to compare the diagnostic efficacy and clinical utility of different models.

A total of 1239 radiomics features were extracted from the ROIs of tumors. Among the 107 prediction models, the model (Stepglm + LASSO) utilizing 10 radiomics features ultimately yielded the highest average area under the receiver operating characteristic curve (AUC) of 0.872, with an AUC of 0.916 in the training cohort and 0.827 in the validation cohort. The combined model, which incorporates the optimal radiomics score, clinical N stage, and platelet-to-lymphocyte ratio (PLR), achieved an AUC of 0.882 in the validation cohort, significantly outperforming the clinical model with an AUC of 0.687 (P = 0.009). According to the DCA analysis, the combined model also showed better clinical benefits.

The combined model incorporating ultrasound-based radiomics features and the PLR marker offers an effective, noninvasive intelligence-assisted tool for preoperative LN metastasis prediction in ICC patients.

Not applicable.

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.

The term cholangiocarcinoma (CCA) includes a group of malignant tumors that develop in the efferent bile ducts and are characterized by a high degree of heterogeneity. These differences between intrahepatic, perihilar and distal CCAs run through all aspects of the disease including the etiology, pathogenesis, symptoms, diagnostics and treatment. This review article presents the current developments in this field of diseases. We highlight surgical innovations in the clinical routine and the application of new systemic forms of treatment to augment the oncological radicality of surgery.

The incidence of intrahepatic cholangiocarcinoma (ICC) is steadily rising, and it is associated with a high mortality rate. Clinical samples were collected to detect the expression of HSPB8 and BAG3 in ICC tissues. ICC cells were cultured and transfected with plasmids that overexpressed or silenced specific genes to investigate the impact of gene expression alterations on cell function. qPCR and Western blot techniques were utilized to measure gene and protein expression levels. A wound healing assay was conducted to assess cell migration ability. The Transwell assay was used to assess cell invasion ability. Co-IP was used to verify the binding relationship between HSPB8 and BAG3. The effects of HSPB8 and BAG3 on lung metastasis of tumors in vivo were verified by constructing a metastatic tumor model. Through the above experiments, we discovered that the expressions of HSPB8 and BAG3 were up-regulated in ICC tissues and cells, and their expressions were positively correlated. The metastatic ability of ICC cells could be promoted or inhibited by upregulating or downregulating the expression of BAG3. Furthermore, the HSPB8-BAG3 chaperone complex resulted in the abnormal degradation of Filamin A by activating autophagy. Increased expression of Filamin A inhibits the migration and invasion of ICC cells. Overexpression of HSPB8 and BAG3 in vivo promoted the lung metastasis ability of ICC cells. The HSPB8-BAG3 chaperone complex promotes ICC cell migration and invasion by regulating CASA-mediated degradation of Filamin A, offering insights for enhancing ICC therapeutic strategies.

Intrahepatic cholangiocarcinoma (iCCA) is a highly lethal hepatobiliary malignancy with an increasing incidence annually. Extensive research has elucidated the existence of a reciprocal interaction between platelets and cancer cells, which promotes tumor proliferation and metastasis. This study aims to investigate the function and mechanism underlying iCCA progression driven by the interplay between platelets and tumor cells, aiming to provide novel therapeutic strategies for iCCA.

The associations between platelets and cancer development were investigated by analyzing the peripheral blood platelet count, degree of platelet activation and infiltration in the microenvironment of patients with iCCA. By co-culturing tumor cells with platelets, the influence of platelet stimulation on the epithelial-mesenchymal transition (EMT), proliferation, and metastasis of iCCA cells was assessed through in vitro and in vivo experiments. Quantitative proteomic profiling was conducted to identify key downstream targets that were altered in tumor cells following platelet stimulation. The RNA interference technique was utilized to investigate the impacts of gene silencing on the malignant biological behaviors of tumor cells.

Compared with healthy adults, patients with iCCA presented significantly higher levels of peripheral blood platelet counts, platelet activation and infiltration degrees, which were also found to be correlated with patient prognosis. Platelet stimulation greatly facilitated the EMT of iCCA cells, leading to enhanced proliferative and metastatic capabilities. Mechanistically, proteomic profiling identified a total of 67 up-regulated and 40 down-regulated proteins in iCCA cells co-cultured with platelets. Among these proteins, two elevated targets ILK and ITGB3, were further demonstrated to be partially responsible for platelet-induced iCCA progression, which might depend on their regulatory effects on FAK/PI3K/AKT signaling transduction.

Our data revealed that platelet-related indices were abnormally ascendant in iCCA patients compared to healthy adults. Co-culturing with platelets enhanced the progression of EMT, and the motility and viability of iCCA cells in vitro and in vivo. Proteomic profiling discovered that platelets promoted the development of iCCA through FAK/PI3K/AKT pathway by means of elevating the expression of ILK and ITGB3, indicating that both proteins are promising therapeutic targets for iCCA with the guidance of platelet-related indices.

To investigate the differences of combined hepatocellular carcinoma-cholangiocarcinoma (cHCC-CCA) patients with a cholangiocarcinoma (CCA) component ≥ 30% or < 30% versus intrahepatic cholangiocarcinoma (iCCA) patients in recurrence-free survival (RFS) and overall survival (OS) prognoses.

Patients with cHCC-CCA and iCCA after surgery were recruited. All cHCC-CCA patients were divided into two subgroups (CCA components ≥ 30% and < 30%). Then, Kaplan-Meier survival analysis and Cox regression analysis were used to investigate and compare the differences of cHCC-CCAs with a CCA component ≥ 30% or < 30% versus iCCAs in RFS and OS prognoses, respectively. The differences of MRI features between cHCC-CCAs with a CCA component ≥ 30% and < 30% were also compared.

One hundred sixty-four cHCC-CCAs and 146 iCCAs were enrolled. Compared with iCCAs, cHCC-CCAs with a CCA component < 30% had better OS prognosis (HR: 2.888, p = 0.045). However, Cox regression analysis revealed that cHCC-CCAs with a CCA component ≥ 30% had poorer RFS (HR: 0.503, p < 0.001) and OS (HR: 0.58, p = 0.033) prognoses than iCCAs. In addition, rim APHE (OR = 0.286, p < 0.001), targetoid diffusion restriction (OR = 0.316, p = 0.019), corona enhancement (OR = 0.481, p = 0.033), delayed enhancement (OR = 0.251, p = 0.001), and LR-M (OR = 1.586, p < 0.001) were significant factors associated with cHCC-CCAs with a CCA component ≥ 30%. Multivariable regression analyses showed that only LR-M (OR = 1.522, p = 0.042) was a significantly independent predictor for cHCC-CCAs with a CCA component ≥ 30%.

cHCC-CCAs with a CCA component ≥ 30% had worse prognoses than iCCAs. Therefore, we suggest that the postoperative treatment of cHCC-CCAs with a CCA component ≥ 30% can be based on the treatment strategy for iCCAs.

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.

Intrahepatic cholangiocarcinoma (iCCA) was considered a contraindication for liver transplantation. However, recent studies have shown that highly selected cases of patients with a good response to neoadjuvant therapy may achieve acceptable survival rates when following liver transplantation.

To present two cases of patients with iCCA, without extrahepatic disease, who underwent living donor liver transplantation after receiving neoadjuvant chemotherapy.

Two cases of patients with histopathological diagnosis of locally advanced iCCA, ineligible for resection and without evidence of extrahepatic disease, are presented.

These patients underwent at least nine sessions of neoadjuvant chemotherapy, including Gemcitabine and Cisplatin, with or without the addition of immunobiological agents, resulting in a radiological tumor response. They subsequently underwent living donor liver transplantation. The average follow-up time was 15 months, with no clinical or radiological signs of disease.

In well-selected patients without extrahepatic disease, living donor liver transplantation represents a potential therapeutic option for iCCA.

Liver resection plus lymphadenectomy is essential to ensure precise staging in patients with intrahepatic cholangiocarcinoma (ICC). This study aimed to investigate the influence of the clinical status of lymph nodes on the survival outcomes in ICC patients.

Between January 2015 and December 2020, consecutive patients diagnosed with ICC who underwent liver resection plus lymphadenectomy were enrolled. Clinical assessment of lymph node status included positron emission tomography/computed tomography examination by radiologists pre-operatively, alongside intraoperative abdominal examination by the surgical team. Retrospective collection and analysis of clinical information alongside survival data were performed to assess outcomes.

The study included a total of 359 patients, with 291 (81.0%) and 151 (42.1%) displaying clinically and pathologically positive lymph nodes, respectively. The clinical assessment method had a sensitivity of 81.2% and a specificity of 54.3%. Following a median follow-up period of 32 months, the overall survival (OS) rates at 1, 3, and 5 years were 69.1%, 50.6%, and 41.2%, respectively, while the disease-free survival (DFS) rates were 60.7%, 42.8%, and 40.1%, respectively, across the cohort. Patients who had clinically positive but pathologically negative lymph nodes recorded the highest median OS (52 months) and median DFS (32 months). Conversely, those who were clinically negative but pathologically positive experienced the lowest median OS (16 months) and median DFS (8 months).

The current approach to clinically assessing lymph node status in ICC has a significant rate of false positives. Patients with clinically positive but pathologically negative lymph nodes exhibit the most favourable survival outcomes.

CCA has a poor prognosis. Different anatomical subtypes are characterized by distinct clinical features, surgical options, and prognoses, which can potentially impact survival outcomes following radical resection. In addition to the malignancy of CCA itself, clinical staging and treatment methods are the main factors that can affect survival. This study aims to update a more reliable prediction model for the prognosis of CCA based on different anatomical locations.

A total of 1172 CCA patients (305 iCCA, 467 pCCA, and 400 dCCA) who underwent surgical resection between 2015 and 2022 were included in the analysis. The covariates included in the analysis were age, sex, tumor diameter, differentiation grade, T stage, N stage, M stage, neural invasion, cancer thrombus, history of hepatitis B or biliary calculi, and receipt of adjuvant chemotherapy. The data were randomly divided into training (80 %) and validation cohort (20 %).

We developed a nomogram of the sensitive model and calculated concordance indices of different constructed prognostic survival models. Meanwhile, we validated the effectiveness of the nomogram model and compared it with the TNM system through decision curve analysis (DCA) and internal cohort validation. The nomogram model had a better net benefit than the TNM system at any given threshold for iCCA, pCCA, and dCCA, regardless of their location.

We have updated the prognostic model for OS in CCA patients who underwent radical resection according to the different tumor locations. This model can effectively predict OS and has the potential to facilitate individual clinical decision-making.

Cholangiocarcinoma (CCA) represents a global health challenge, with rising incidence and mortality rates. This study aimed to elucidate the clinical course and practices of CCA in Latin America.

This observational cohort study investigated individuals diagnosed with CCA between 2010 and 2023 at five referral centres across Latin America. Demographic, biochemical, and clinical data were analysed.

A total of 309 patients were enrolled, demonstrating a balanced distribution of CCA subtypes (intrahepatic, perihilar, and distal), with Hispanics and Caucasians as the predominant ethnic groups, followed by Africans. Major risk factors identified included age, diabetes, obesity, MASLD, bile duct stones, and cholecystitis. Disparities in overweight/obesity prevalence were noted among CCA subtypes and ethnicities, with higher rates in extrahepatic CCA and among Hispanics and Caucasians. At diagnosis, 72% of patients had ECOG-PS scores of 0-1, with disease presentations ranging from localized (47%) to locally advanced (19%) and metastatic (34%). Patients who did not receive any anti-cancer therapy exhibited a median survival of 2.3 months. Survival rates significantly improved across treatment modalities, with surgery yielding the longest (34 months), followed by chemotherapy (8 months). Notably, Africans presented with worse ECOG-PS scores and more advanced disease, while Hispanics were less frequently treated with chemotherapy for advanced disease, contributing to lower survival rates (8.3 and 6 months, respectively) compared to Caucasians (12.6 months).

The high prevalence of late-stage CCA diagnosis in Latin America, particularly among individuals of African ethnicity, coupled with a significant proportion of Hispanic patients not receiving chemotherapy, underscores the dismal prognosis for these patients. These findings reveal structural challenges in cancer screening and healthcare access among diverse ethnic backgrounds and lower socioeconomic statuses in the region. Urgent measures are needed, including the identification of preventable risk factors, raising awareness among high-risk populations, and establishing equitable health coverage to address these disparities.

European Union's Horizon 2020 R&I Program, Incyte Bioscience International Sàrl, and European Association for the Study of the Liver (EASL).

Lymph node metastasis (LNM) in patients with intrahepatic cholangiocarcinoma (iCCA) affects treatment strategies and prognosis. However, preoperative imaging is not reliable enough for identifying LNM.

To develop and validate a radiomics nomogram based on dynamic contrast enhanced (DCE)-MR images for identifying LNM and prognosis in iCCA.

Retrospective.

Two hundred four patients with pathologically proven iCCA who underwent curative-intent resection and lymphadenectomy (training cohort: N = 107, internal test cohort: N = 46, and external test cohort: N = 51).

T1- and T2-weighted imaging, diffusion-weighted imaging and DCE imaging at 1.5 T or 3.0 T.

Radiomics features were extracted from intra- and peri-tumoral regions on preoperative DCE-MR images. Imaging features were evaluated by three radiologists, and significant variables in univariable and multivariable regression analysis were included in clinical model. The best-performing radiomics signature and clinical characteristics (intrahepatic duct dilatation, MRI-reported LNM) were combined to build a nomogram. Patients were divided into high-risk and low-risk groups based on their nomogram scores (cutoff = 0.341). Patients were followed up for 1-102 months (median 12) after surgery, the overall survival (OS) and recurrence-free survival (RFS) were calculated.

Receiver operating characteristic (ROC) curve, calibration, decision curve, Delong test, Kaplan-Meier curves, log rank test. Two tailed P < 0.05 was considered statistically significant.

The nomogram incorporating intra- and peri-tumoral radiomics features, intrahepatic duct dilatation and MRI-reported LNM obtained the best discrimination for LNM, with areas under the ROC curves of 0.946, 0.913, and 0.859 in the training, internal, and external test cohorts. In the entire cohort, high-risk patients had significantly lower RFS and OS than low-risk patients. High-risk of LNM was an independent factor of unfavorable OS and RFS.

The nomogram integrating intra- and peri-tumoral radiomics signatures has potential to identify LNM and prognosis in iCCA.

3 TECHNICAL EFFICACY: Stage 2.

The value of liver enzymes, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT), in predicting the prognosis of intrahepatic cholangiocarcinoma (ICC) patients who underwent curative resection has not been elucidated. Therefore, we aimed to construct prognostic nomograms for surgically treated ICC patients.

The impact of liver enzymes on overall survival (OS) and recurrence-free survival (RFS) was analysed using Kaplan-Meier analysis and evaluated by univariate and multivariate analyses. Nomograms were constructed for predicting the probability of 1-, 3-, and 5-year OS and RFS and evaluated by receiver operating characteristic (ROC) curves, calibration curves and decision curve analysis (DCA).

High ALT, AST, ALP and GGT levels were associated with worse prognoses in surgically treated ICC patients. Nomograms for OS and RFS were constructed based on five prognostic factors: number of high liver enzyme (No. HLE), CA19-9 ≥ 37 U/mL, multiple tumours, lymph node invasion and microvascular invasion (MVI). Compared with 8th edition TNM stage, these nomograms showed better predictive value. The C-index and 1-, 3- and 5-year areas under the curve (AUCs) of the nomograms for OS and RFS in the discovery and validation cohorts were higher than those of the 8th TNM stage. The calibration plots indicated that there was good agreement between the actual observations and predictions.

Preoperative ALT, AST, ALP and GGT levels could predict prognosis in surgically treated ICC patients. The nomograms showed good predictive ability for predicting the survival of ICC patients.

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic malignancy after hepatocellular carcinoma, with poor prognosis and limited treatment options. The genomic features of ICC in Chinese patients remain largely unknown. In this study, we perform deep whole-exome sequencing of 204 Chinese primary ICCs and characterize genomic alterations and clonal evolution, and reveal their associations with patient outcomes. We identify six mutational signatures, including Signatures A and F, which are highly similar to previously described signatures linked to aristolochic acid and aflatoxin exposures, respectively. We also identify 13 significantly mutated genes in the ICC samples, including SAV1. We find that SAV1 was mutated in 2.9% (20/672) of 672 ICC samples. SAV1 mutation is associated with lower SAV1 protein levels, higher rates of tumor recurrence, and shorter overall patient survival. Biofunctional investigations reveal a tumor-suppressor role of SAV1: its inactivation suppresses Hippo signaling, leading to YAP activation, thereby promoting tumor growth and metastasis. Collectively, our results delineate the genomic landscape of Chinese ICCs and identify SAV1 as a potential driver of ICC.

The prognostic role of the fibrosis-4 (FIB-4) index relative to intrahepatic cholangiocarcinoma (ICC) after hepatectomy remains unclear. This study sought to characterize the impact of the FIB-4 index and tumor burden score (TBS) on recurrence and overall survival (OS).

ICC patients undergoing hepatectomy (2000-2020) were identified using a multi-institutional database. Patients were categorized as low (low TBS/low FIB-4 index), intermediate (low TBS/high FIB-4 index or high TBS/low FIB-4 index), and high (high TBS/high FIB-4 index).

Among 1168 patients in different TBS and FIB-4 index cohorts, 3-year recurrence varied considerably. For instance, among the patients with low TBS, individuals with a high FIB-4 index had a greater risk of recurrence than patients with a low FIB-4 index (59.9 vs. 47.7%; P = 0.01). Among patients with a high TBS, individuals with a high versus a low FIB-4 index had a higher incidence of recurrence (76.8 vs. 69.0%; P = 0.04). A similar pattern was observed among patients with both a low FIB-4 index (low [47.7%] vs. high [69.0%] TBS) and a high FIB-4 index (low [59.9%] vs. high [76.8%] TBS; both P < 0.001). Patients with a high [27.5%] versus a low [48.8%] TBS; P < 0.001) and patients with a high [34.2%] versus a low [43.5%] FIB-4 index; P = 0.01) had a worse OS. The multivariable analysis demonstrated an increasing risk of recurrence in the intermediate-index (hazard ratio [HR], 1.61; 95% confidence interval [CI], 1.20-2.16; P = 0.001) and high-index (HR, 2.13; 95% CI 1.45-3.13; P < 0.001) groups versus the low-index group.

Both tumor-related and non-tumorous characteristics should be used to predict risk of recurrence and survival more accurately among patients with ICC following hepatic resection.

To evaluate the safety and effectiveness of the combination of drug-eluting microsphere (DEM) transcatheter arterial chemoembolization (TACE) with those of chemotherapy in treating unresectable intrahepatic cholangiocarcinoma (ICC).

Seventy patients diagnosed with unresectable ICC between January 2016 and December 2020 were retrospectively included in this study. Of these, 39 patients received DEM-TACE and first-line chemotherapy (TACE+Chemo group) and 31 received chemotherapy alone (Chemo group). Propensity score matching was performed to reduce selection bias between the TACE+Chemo and the Chemo groups. Differences in tumor response, progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs) were compared between 2 groups.

The patients in the TACE+Chemo group had better median OS (18.6 vs 11.9 months; P = .018), median PFS (11.9 vs 6.9 months, P = .033), and objective response rates (56.8% vs 13.3%; P < .001) than those in the Chemo group. TRAEs showed a higher incidence of transient elevation of transaminase and abdominal pain in the TACE+Chemo group than in the Chemo group (P < .001).

Compared with chemotherapy alone, DEM-TACE combined with first-line chemotherapy may be a viable and safe treatment option for unresectable ICC.