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Biliary tract cancers (BTCs) represent a spectrum of malignancies associated with a dismal prognosis. Recent genomic profiling studies have provided a deeper understanding of the complex and heterogenous molecular landscape of BTCs, identifying several actionable genetic alterations, and expanding treatment options. Due to the high number and complexity of genetic alterations which require testing, next-generation sequencing (NGS) is currently the preferred approach over conventional methods (i.e., immunohistochemistry, fluorescence in-situ hybridization and PCR) for molecular profiling of BTCs and should be performed upfront in all BTC patients. However, BTC sampling often yields low tumor cellularity tissue, hampering NGS analysis. Future perspectives to overcome this obstacle include liquid biopsy and optimization of biopsy protocols. In this position paper, the authors discuss the current histopathologic, molecular, and therapeutic landscape of BTCs, provide a critical overview of the available testing methods for molecular diagnostics, and propose a practical diagnostic algorithm for molecular testing of BTC samples., Competing Interests: Declaration of Competing Interest All other authors declare that they have no conflict of interest related to the present work. Conflict of interest statement MF has been involved in consulting/advisory roles in Astellas Pharma, Pierre Fabre, MSD, AstraZeneca, Janssen, GlaxoSmithKline, BMS, Incyte, Amgen, Novartis and Roche, and received research funding from Astellas Pharma, QED Therapeutics, Diaceutics and Macrophage Pharma. NN has been involved in consulting/advisory roles in MSD, Bayer, Biocartis, Illumina, Incyte, Roche, BMS, Merck, Thermofisher, AstraZeneca, Eli Lilly, Novartis; financial support to research projects (institutional grants) from Merck, Thermofisher, QIAGEN, Roche, AstraZeneca, Biocartis, Illumina, Sophia genetics; non-financial interests President of the International Quality Network for Pathology (IQN Path) and Past President of the Italian Cancer Society (SIC). GP has been involved in consulting/advisory roles in Roche, Illumina, Novartis, Lilly, AstraZeneca, Exact Sciences, ADS Biotech. GT has received honoraria from Molteni, Novartis and Pharmamar. AS has received consulting fees from Amgen, AstraZeneca, Basilea, Incyte, and Ipsen and lecture fees from Amgen, Incyte, Ipsen, Merck Serono, Roche, and Sanofi. LR has received consulting fees from AstraZeneca, Basilea, Bayer, BMS, Eisai, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Jazz Pharmaceuticals, MSD, Nerviano Medical Sciences, Roche, Servier, Taiho Oncology, and Zymeworks; lecture fees from AstraZeneca, Bayer, BMS, Eisai, Incyte, Ipsen, Merck Serono, Roche, and Servier; travel expenses from AstraZeneca; and institutional research funding from Agios, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, and Zymeworks. FG has been involved in consulting/advisory roles in MSD and GlaxoSmithKline; lecture fees from MSD, Incyte and GlaxoSmithKline., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: 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)., Methods: 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)., Results: 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., Conclusions: 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., Competing Interests: Disclosure: There are no conflicts of interest., (© 2024. Society of Surgical Oncology.)

The evolving field of liver transplant (LT) oncology calls for tailored immunosuppression protocols to minimize the risk of tumor recurrence. We systematically reviewed the available evidence from inception to May 2023 regarding immunosuppression protocols used in patients undergoing LT for cholangiocarcinoma, neuroendocrine tumors (NET), hepatic-endothelial hemangioendothelioma, and colorectal liver metastases (CRLM) to identify common practices and to evaluate their association with oncological outcomes. Studies not involving humans, case reports, and short case series (ie, n < 10) were excluded. Among 3374 screened references, we included 117 studies involving 6797 patients distributed as follows: cholangiocarcinoma (58.1%), NETs (18.8%), hepatic-endothelial hemangioendothelioma (7.7%), CRLM (6.8%), mixed neoplasms (6.8%), or others (1.7%). Only 41% of the studies disclosed details of the immunosuppression protocol, and 20.8% of studies provided drug trough concentrations during follow-up. The immunosuppression protocols described were heterogeneous and broadly mirrored routine practices for nontumoral indications. The only exception was CRLM, where tacrolimus minimization-or even withdrawal-in combination with inhibitors of the mammalian target of rapamycin (mTORi) were consistently reported. None of the studies evaluated the relationship between the immunosuppression protocol and oncological outcomes. In conclusion, based on low-quality and indirect scientific evidence, patients with tumoral indications for LT should receive the lowest tacrolimus level tolerated under close surveillance. The combination with mTORi titrated to achieve the top therapeutic range of trough concentrations could allow complete tacrolimus withdrawal. This approach may be particularly useful in patients with cholangiocarcinoma and CRLM, in whom tumor recurrence is the main cause of death. We propose a tool for reporting immunosuppression protocols, which could be implemented in future transplant oncology studies., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Liver transplantation (LT) for uncommon tumoral indications has changed across the decades, with impaired results reported in the first historical series mainly for non-tumoral-related causes. Recently, renewed interest in liver transplant oncology has been reported. The study aims to analyze a mono-center experience exploring the evolution and the impact on patient survival of LT in uncommon tumoral indications. A retrospective analysis of 851 LT performed during 1982-2023 was investigated. 33/851 (3.9%) uncommon tumoral indications were reported: hepatocellular carcinoma (HCC) on non-cirrhotic liver (n = 14), peri-hilar (phCCA) (n = 8) and intrahepatic cholangiocarcinoma (i-CCA) (n = 3), metastatic disease (n = 4), hepatic hemangioendothelioma (n = 2), and benign tumor (n = 2). Uncommon tumoral indications were mainly transplanted during the period 1982-1989, with a complete disappearance after the year 2000 and a slight rise in the last years. Poor outcomes were reported: 5-year survival rates were 28.6%, 25.0%, 0%, and 0% in the case of HCC on non-cirrhotic liver, phCCA, i-CCA, and metastases, respectively. However, the cause of patient death was often related to non-tumoral conditions. LT for uncommon oncological diseases has increased worldwide in recent decades. Historical series report poor survival outcomes despite more recent data showing promising results. Hence, the decision to transplant these patients should be under the risk and overall benefit of the patient. The results of the ongoing protocol studies are expected to confirm the validity of the unconventional tumor indications., (© 2024. The Author(s).)

Objectives: This study aimed to determine the methodological quality and evaluate the diagnostic performance of radiomics features in detecting lymph node metastasis on preoperative images in patients with cholangiocarcinoma and gallbladder cancer., Methods: Publications between January 2005 and October 2022 were considered for inclusion. Databases such as Pubmed/Medline, Scopus, Embase, and Google Scholar were searched for relevant studies. The quality of the methodology of the manuscripts was determined using the Radiomics Quality Score and Quality Assessment of Diagnostic Accuracy Studies 2. Pooled results with corresponding 95% confidence intervals (CIs) were calculated using the DerSimonian-Liard method (random-effect model). Forest plots were used to visually represent the diagnostic profile of radiomics signature in each of the data sets pertaining to each study. Fagan plot was used to determine clinical applicability., Results: Overall sensitivity was 0.748 (95% CI, 0.703-0.789). Overall specificity was 0.795 (95% CI, 0.742-0.839). The combined negative likelihood ratio was 0.299 (95% CI, 0.266-0.350), and the positive likelihood ratio was 3.545 (95% CI, 2.850-4.409). The combined odds ratio of the studies was 12.184 (95% CI, 8.477-17.514). The overall summary receiver operating characteristics area under the curve was 0.83 (95% CI, 0.80-0.86). Three studies applied nomograms to 8 data sets and achieved a higher pooled sensitivity and specificity (0.85 [0.80-0.89] and 0.85 [0.71-0.93], respectively)., Conclusions: The pooled analysis showed that predictive models fed with radiomics features achieve good sensitivity and specificity in detecting lymph node metastasis in computed tomography and magnetic resonance imaging images. Supplementation of the models with biological correlates increased sensitivity and specificity in all data sets., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Cholangiocarcinoma (CCA) is a heterogeneous malignancy. The aim of the study was to investigate the regulatory role of long noncoding RNA LINC00844 in CCA progression, explore the underlying molecular mechanisms, and to analyze the potential prognostic value of LINC00844 in CCA patients., Methods: Expression of LINC00844 in CCA cell lines and tissues was examined by reverse transcription-quantitative PCR. Cell counting kit-8 assay was used to assess CCA cell proliferation, and the Transwell assay was used to evaluate tumor cell migration and invasion. miRNAs sponged by LINC00844 were predicted and confirmed using a luciferase reporter assay. Kaplan-Meier survival analysis was performed to evaluate the survival prognosis of CCA patients., Results: The expression levels of LINC00844 were decreased in CCA tissues and cells. Overexpression of LINC00844 inhibited cell proliferation, migration and invasion in CCA cells. miR-19a-5p is directly targeted by LINC00844, mediating the inhibitory effects of LINC00844 on the proliferation, migration and invasion of CCA cells. LINC00844 and miR-19a-5p expression were associated with differentiation and tumor node metastasis stage in CCA patients. CCA patients with low LINC00844 expression or overexpression of miR-19a-5p had worse overall survival., Conclusion: The expression levels of LINC00844 were decreased in both CCA tissues and cells, and high LINC00844 inhibited CCA cell proliferation, migration and invasion through sponging miR-19a-5p. Low LINC00844 and high miR-19a-5p expression were associated with worse overall survival in CCA patients. All the data suggested that the LINC00844/miR-19a-5p axis may provide novel therapeutic targets and prognostic biomarkers for CCA patients., (© 2023. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

Purpose: To compare the diagnostic ability between magnetic resonance imaging (MRI) and contrast-enhanced ultrasound (CEUS) in distinguishing intrahepatic cholangiocarcinoma (ICC) from hepatocellular carcinoma (HCC)., Methods: Original studies reporting the diagnostic accuracy of MRI and CEUS in differentiating ICC from HCC were identified in PubMed and EMBASE databases. Histopathological examination was used as the reference standard for tumor diagnosis. Study quality was assessed using QUADAS-2 scale. Data were extracted to calculate the pooled diagnostic sensitivity, specificity, and diagnostic odds ratio (DOR) using a bivariate random-effects model, as well as the area under the curve (AUC). Sensitivity analysis, subgroup analysis, meta-regression, and investigation of publication bias were also performed., Results: A total of 26 studies with 28 data subsets (18 on MRI, 10 on CEUS) were included, consisting of 4169 patients with 1422 ICC lesions and 2747 HCC lesions. Most MRI studies were performed at 3T with hepatobiliary agents, and most CEUS studies used SonoVue as the contrast agent. In MRI, the pooled sensitivity, specificity, DOR, and AUC in distinguishing ICC from HCC were 0.81 (0.79, 0.84), 0.90 (0.88, 0.91), 41.47 (24.07, 71.44), and 0.93 (0.90, 0.96), respectively. The pooled sensitivity, specificity, DOR, and AUC of CEUS were 0.88 (0.84, 0.90), 0.80 (0.78, 0.83), 42.06 (12.38, 133.23), and 0.93 (0.87, 0.99), respectively. Subgroup analysis and meta-regression analysis demonstrated significant heterogeneity among the studies associated with the type of contrast agent in MRI studies. No publication bias was found., Conclusion: Both MRI and CEUS showed excellent diagnostic performance in differentiating ICC from HCC. CEUS showed higher pooled sensitivity and MRI showed higher pooled specificity., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: The high proportion of HCC in CEUS LR-M decreases the sensitivity of LR-5 for the diagnosis of HCC. However, when modifying LR-M criteria to further improve the sensitivity of LR-5, it is also important not to compromise the diagnostic performance (especially sensitivity) of LR-M for non-hepatocellular carcinoma malignancies (non-HCCMs). The purpose of this study was to evaluate the diagnostic performance of CEUS LI-RADS (2017 version) for non-HCCMs and to explore the impact of modified CEUS LI-RADS on the diagnostic performance of LR-M., Methods: In this retrospective study, patients with pathologically confirmed non-HCCMs were evaluated. Two radiologists independently interpreted the major CEUS features and categorized the liver lesions. New LR-M criteria were applied: early washout (< 45 s) or marked washout (< 5 min). The sensitivity values of the current and modified CEUS LR-M were assessed and then compared using a paired χ 2 test. Cohen's κ was used to compare the inter-reader agreement of the LI-RADS categories., Results: A total of 131 non-HCCMs were ultimately selected, including 71 intrahepatic cholangiocarcinomas, 26 combined hepatocellular cholangiocarcinomas, 29 metastases, and 5 other non-HCCMs. The numbers of LR-M, LR-5, LR-4, and LR-3 in liver lesions were 111, 18, 1, and 1, respectively. The inter-reader agreement of the LI-RADS categories for non-HCCMs was 0.59. The sensitivity of the current CEUS LR-M in diagnosing non-HCCMs was 84.7%. By adjusting the early washout time to < 45 s, the sensitivity of LR-M was 80.9%. By adjusting the marked washout time within 5 min, the sensitivity of LR-M was 72.5%., Conclusion: CEUS LR-M has high sensitivity in diagnosing non-HCCMs. For LR-M nodules with nonrim arterial phase hyperenhancement and early washout, advancing the time of early washout to < 45 s has a minimal impact on the sensitivity of LR-M in diagnosing non-HCCMs compared to the condition of increasing the marked washout within 5 min., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Cholangiocarcinoma (CCA) is a highly lethal adenocarcinoma of the hepatobiliary system, which can be classified as intrahepatic, perihilar and distal. Each anatomic subtype has distinct genetic aberrations, clinical presentations and therapeutic approaches. In endemic regions, liver fluke infection is associated with CCA, owing to the oncogenic effect of the associated chronic biliary tract inflammation. In other regions, CCA can be associated with chronic biliary tract inflammation owing to choledocholithiasis, cholelithiasis, or primary sclerosing cholangitis, but most CCAs have no identifiable cause. Administration of the anthelmintic drug praziquantel decreases the risk of CCA from liver flukes, but reinfection is common and future vaccination strategies may be more effective. Some patients with CCA are eligible for potentially curative surgical options, such as resection or liver transplantation. Genetic studies have provided new insights into the pathogenesis of CCA, and two aberrations that drive the pathogenesis of non-fluke-associated intrahepatic CCA, fibroblast growth factor receptor 2 fusions and isocitrate dehydrogenase gain-of-function mutations, can be therapeutically targeted. CCA is a highly desmoplastic cancer and targeting the tumour immune microenvironment might be a promising therapeutic approach. CCA remains a highly lethal disease and further scientific and clinical insights are needed to improve patient outcomes., (© 2021. Springer Nature Limited.)

Hepatocellular carcinoma and intrahepatic cholangiocarcinoma are the two most common primary malignant tumors of the liver. The similarities and variations in imaging characteristics that may aid in distinguishing between these two primary tumors will be discussed and outlined in this review. Knowledge of imaging techniques that are currently available would assist in the differentiation between these primary malignancies., (© 2023 Wiley Periodicals LLC.)

Hepatitis B and C virus, Opisthorchis viverrini and Clonorchis sinensis, are all individually known to put a person at increased risk for cholangiocarcinoma and hepatocellular carcinoma. This paper seeks to determine if there is any interaction between liver flukes and hepatitis virus infection that are known to put a person at an increased risk for cholangiocarcinoma and hepatocellular carcinoma collectively. This paper seeks to determine whether there is any publicly available articles in English that determine if having a hepatitis viral co-infection along with liver flukes would influence the risk of developing liver cancer. We followed PRISMA systematic review guidelines to conduct a literature review. Three manuscripts fit the search criteria. Two presented evidence in support of a synergistic relationship between liver fluke and viral hepatitis infection while the other found no relationship. One manuscript determined that the interaction between hepatitis B and C. sinensis did not have any significant risk of liver cancer. Studies found that HBV affected progression of co-infection to liver cancer but may have its own disease state worsened by presence of liver flukes. Only one paper was found that presented data on HCV, therefore no conclusion can be drawn due to the lack of evidence discovered. Of the studies, the conclusions and strength of the data were mixed. However, the stronger studies suggested a synergistic relationship between liver flukes and HBV to increase the risk of progressing to liver cancer. [ABSTRACT FROM AUTHOR]

Background and Objectives: The National Comprehensive Cancer Network recommends a second-line treatment of pemigatinib for patients with intrahepatic cholangiocarcinoma with fibroblast growth factor receptor 2 (FGFR2) fusions/rearrangements and modified FOLFOX (mFOLFOX) for those without FGFR2 alterations. However, these regimens are not yet covered by Taiwa's National Health Insurance. This cost-effectiveness analysis evaluated the cost-effectiveness of the pemigatinib/mFOLFOX regimen as the second-line treatment for advanced intrahepatic cholangiocarcinoma based on FGFR2 status in comparison with the regimen of fluorouracil chemotherapy and provided a cost-effectiveness analysis-based reference price for pemigatinib., Methods: A three-state partitioned survival model with a 5-year time horizon was constructed for patients with advanced intrahepatic cholangiocarcinoma who did not respond to first-line therapy. Overall and progression-free survival functions of pemigatinib, mFOLFOX, and fluorouracil were estimated from the FIGHT-202, ABC-06, and NIFTY trials, respectively. The utility of health states and disutility of adverse events were obtained from the literature. The genetic testing fee and price of pemigatinib were set as the market price. Other costs related to advanced intrahepatic cholangiocarcinoma were calculated using National Health Insurance claims data. The willingness-to-pay threshold was three times the gross domestic product per capita in 2021 (NT$2,889,684). A 3% discount rate was applied to quality-adjusted life-years and costs. Scenario analyses included a gradual price reduction of pemigatinib, alternative survival models, application of a National Health Insurance payment conversion factor to non-medication costs, and consideration of life-years as effectiveness. A deterministic sensitivity analysis, probabilistic sensitivity analysis, and a value of information analysis were performed., Results: The new regimen provided an incremental 0.13 quality-adjusted life-years, with incremental costs of NT$459,697, yielding an incremental cost-effectiveness ratio of NT$3,411,098 per quality-adjusted life-year and an incremental net monetary benefit of - NT$70,268. The new regimen was found to be 53.2% cost effective in the probabilistic sensitivity analysis. The expected value of uncertainty measured by the expected value of perfect information was NT$80,695/person. In scenario analyses, the incremental net monetary benefit was positive when the price of pemigatinib was reduced by 40% or more. When applying a conversion factor to non-medical costs, the probability of the new regimen being cost effective was slightly increased from 53.2 to 56.5% compared with the base-case analysis. The utility and the cost of the new regimen were the main drivers of uncertainty., Conclusions: Although the new second-line genetic-based and biomarker-driven regimen of pemigatinib/mFOLFOX appears not cost effective for patients with advanced intrahepatic cholangiocarcinoma in the base-case analysis, our analysis suggests it is highly likely to be cost effective in the case of a 40% price reduction on pemigatinib., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

It is known that Opisthorchis viverrini (OV) is the most significant risk factor for the development of cholangiocarcinoma (CCA); hence, it is also known as carcinogenic parasite. Effective control and elimination of OV infection should significantly reduce O. viverrini-related CCA. This chapter includes details of the three recently developed innovative tools, namely the Isan cohort database software, an OV-RDT for screening of O. viverrini, and an ultrasound telecommunication system. Past and current control programs, i.e., education, medication, and sanitation were discussed and stressed the need for a comprehensive control program which encompasses primary, secondary, and tertiary patient care programs for confirmation and management of suspected CCA cases. The approach of mathematical modeling for control of OV and CCA was also briefly described. Additionally, we highlighted the current progress toward control of OV and CCA in Thailand and potential for expansion into nearby countries in Southeast Asia., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

This chapter details all aspects of the general principles of palliative care for advanced stage cholangiocarcinoma patients. These include symptoms management, communication guide, advance care planning, and management for bereavement. Surgical and intervention techniques of palliative biliary drainage are described in detail for patients with obstructive jaundice with advanced stage CCA. Additionally, details are provided regarding the establishment of a multidisciplinary palliative care team which is critical to provide the most appropriate multimodal treatment for good quality of life and survival of patients., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Background: This study aimed to investigate whether preoperative muscle mass is associated with the recurrence of distal cholangiocarcinoma after pancreatoduodenectomy (PD)., Methods: We retrospectively examined 88 patients who had undergone PD for distal cholangiocarcinoma. The preoperative psoas muscle mass index (PMI) was measured using computed tomography as an index of muscle mass. We performed multivariate analysis of factors influencing early recurrence and developed a prognostic survival model using independent risk factors for recurrence., Results: The cut-off PMI values for recurrence within 1 year of surgery, determined from the receiver operating characteristic curve, were 5.90 cm 2 /m 2 in males and 3.98 cm 2 /m 2 in females. Multivariate analysis of effects associated with early recurrence within 1 year indicated that low PMI (odds ratio [OR] 9.322; 95% confidence interval [CI] 2.832 - 30.678; p = 0.0002) and lymph node metastasis (OR 5.474; 95% CI 1.620 - 18.497; p = 0.0062) were independent risk factors, and the median recurrence-free survival (RFS) of the low and high PMI groups were 21.6 and 81.0 months, respectively (p = 0.0214). The median RFS for zero, one, and two risk factors of low PMI and lymph node metastasis were as follows: zero variables, median not reached; one variable, 15.3 months; two variables: 6 months., Conclusions: Low preoperative PMI may be a risk factor for distal cholangiocarcinoma recurrence after PD., Trial Registration: The Institutional Review Board of St. Marianna University School of Medicine approved this study prior to commencement of data collection and analysis on October 9, 2020 (IRB no. 5006) and waived the informed consent requirement., (© 2022. The Author(s).)

Purpose: To eliminate the effects of field strength in determining the diagnostic performance of the LI-RADS version 2018 (LI-RADS v2018) in differentiating hepatocellular carcinoma (HCC) from non-HCC primary liver malignancy in high-risk patients., Methods: Patients who were pathologically confirmed intrahepatic cholangiocarcinoma (iCCA) or combined hepatocellular-cholangiocarcinoma (cHCC-CCA) were retrospectively reviewed. Patients with HCC were matched to the iCCA or cHCC-CCA patients on age, tumor size, MR scanner, and number of tumors. Two readers independently evaluated the lesions according to LI-RADS v2018. Diagnostic performance of LI-RADS v2018 in differentiating HCC from non-HCC primary liver malignancy were analyzed., Results: A total of 198 patients with 204 lesions (102 HCCs, 78 iCCAs, and 24 cHCC-CCAs) were enrolled. The sensitivity and specificity of LR-5 or LR-TIV (definitely due to HCC) in diagnosing HCC were 68.63% and 85.29%, respectively. LR-M or LR-TIV (may be due to non-HCC malignancy) had a sensitivity of 72.55% and a specificity of 86.27% in diagnosing non-HCC malignancy. The sensitivity of LR-M or LR-TIV (may be due to non-HCC malignancy) for iCCA and cHCC-CCA was 82.05% and 41.67%, respectively. Nearly half (11/24, 45.83%) of cHCC-CCAs were categorized as LR-5. Three tesla MR showed higher sensitivity than 1.5 T in diagnosing HCC (80.00% vs 57.69%, P = 0.015)., Conclusion: When the effect of field strength was eliminated, LI-RADS v2018 demonstrated high specificity but suboptimal sensitivity in distinguishing HCC from non-HCC primary liver carcinomas. Most iCCAs were categorized as LR-M or LR-TIV (may be due to non-HCC malignancy). However, nearly half of cHCC-CCAs were assigned as LR-5.

Background: Surgical resection for Bismuth-Corlette type IV (BC-IV) hilar cholangiocarcinomas, also termed Klatskin tumours are technically challenging and were once considered unresectable tumours. Following advances in hepatobiliary imaging and surgical techniques, emerging evidence suggests that surgical resection is a viable avenue for long-term survival. We aimed to identify factors affecting survival outcomes of hepatic resections for BC-IV cholangiocarcinomas., Method: A systematic review was performed across multiple databases and several clinical trial registries. Two reviewers independently screened and selected papers that contained survival data on BC-IV cholangiocarcinoma after hepatic resections., Results: Of 13 499 papers from our search result, 21 papers satisfied the inclusion criteria. The median post-operative survival was 30.8 months. The average 1- and 5-year post-operative survivals were 61.6 and 33.3%, respectively. Predictors of long-term survival included achievement of R0 margins, minimisation of operative time and reduction intra-operative blood loss., Conclusion: Our analysis demonstrates improving post-operative outcomes and survival in surgical resection of BC-IV cholangiocarcinoma and suggests that radical surgical resection is a valid treatment option for the disease., (© 2019 Royal Australasian College of Surgeons.)

The COVID-19 pandemic brought into prominence several emergent medical and surgical entities, but, also, it served as trigger and contributor for numerous apparently unrelated ailments such as arterial and venous thromboembolic complications. Additional risk factors for these thrombotic traits may be concurrent (known or unknown) malignancies, including at hepatic level. Among these, cholangiocarcinoma (CCA), a rare cancer of intra- and extra-hepatic biliary ducts, represents a very aggressive condition that typically associates local and distant advanced stages on first presentation requiring a prompt diagnosis and a stratified management. This neoplasia has been reported to present a large spectrum of paraneoplastic syndromes in terms of dermatologic, renal, systemic, neurologic, endocrine, and cardiovascular settings, that, overall, are exceptional in their epidemiologic impact when compared to other cancers. Our aim was to introduce a most unusual case of CCA-associated distant thrombosis in a male adult who initially was considered to experience COVID-19-related thrombotic features while having a history of obesity and bariatric surgery. This is a hybrid type of paper: this clinical vignette is accompanied by two distinct sample-focused analyses as a basis for discussion; they each had different methods depending on their current level of statistical evidence. We only included English-published articles in PubMed, as follows: Firstly, we conducted a search of reports similar to the present case, regarding distant vein thrombosis in CCA, from inception until the present time. We performed a literature search using the keywords "cholangiocarcinoma", "thrombosis", and "Trousseau's syndrome" and identified 20 cases across 19 original papers; hence, the current level of evidence remains very low Secondly, we searched for the highest level of statistical evidence concerning the diagnosis of venous thrombosis/thromboembolism in patients who underwent COVID-19 infection (key search terms were "COVID-19", alternatively, "coronavirus", and "SARS-CoV-2", and "thrombosis", alternatively, "thromboembolism") and included the most recent systematic reviews and meta-analyses that were published in 2024 (from 1 January 2024 until 8 July 2024). After excluding data on vaccination against coronavirus or long COVID-19 syndrome, we identified six such articles. To conclude, we presented a probably unique case of malignancy with an initial manifestation consisting of recurrent superficial vein thrombosis under anticoagulation therapy, with no gastrointestinal manifestations, in a patient with a notable history for multiple episodes of SARS-CoV-2 infection and a prior endocrine (gastric) surgery. To our knowledge, this is the first identification of a CCA under these specific circumstances. [ABSTRACT FROM AUTHOR]

Simple Summary: Rare diseases represent a significant health problem since patients face difficulty obtaining a rapid diagnosis and a proper treatment. An inflammatory pseudotumor of the liver (IPTL) is a rare and benign entity in which reaching a correct preoperative diagnosis can be challenging since it is similar to the worst form of liver cancer, intrahepatic cholangiocarcinoma (ICC). Our paper aims to report our experience and to review the available literature on this topic, thus summarizing previous experiences and central issues to point out a prompt road map of treatment that still needs to be standardized. IPTL is not associated with substantial risk factors and presents with faint symptoms. Imaging data via MRI and CT scan are not specific, thus often requiring ultrasound (US)-guided biopsy. Proper and widely accepted gold standard treatment does not exist; conservative strategies represent an accepted option, while the decision for surgery still exists where there is a suspicion of malignancy. An inflammatory pseudotumor of the liver is a rare tumor-like lesion composed of polymorphous inflammatory cell infiltrates and variable amounts of fibrosis that can often mimic a malignant liver neoplasm. The etiology of inflammatory pseudotumors of the liver is unknown; symptoms are faint and imaging non-specific. Thus, it is often hard to make a diagnosis preoperatively and it is not so rare to over-treat patients with this disease or vice versa. Thus, more profound knowledge is necessary to plan appropriate disease management. We reported our two cases and systematically searched the literature regarding IPTL. We selected articles published in English from four databases, PubMed, Scopus, Web of Science and Google Scholar, and we included only articles with consistent data. Twenty nine papers fulfilling criteria for the review were selected. The analysis of 69 cases published from 1953 confirmed that the risk factors are unclear, the imaging data is not specific, and biopsy is crucial but not so widely used in clinical practice due to the procedure's related risks, and relatively low effectiveness and improvement in imaging analysis. Regarding treatment, surgeons have moved towards a more conservative attitude over the years due to better imaging quality and patient surveillance. However, surgery remains the modality of choice for most cases with an indeterminate diagnosis. Even if an inflammatory pseudotumor of the liver is a benign tumor with a good prognosis, not requiring any treatment in most cases, sometimes it remains challenging to differentiate it from ICC; therefore, there is a solid recommendation to manage this condition with a multidisciplinary team. [ABSTRACT FROM AUTHOR]

Intrahepatic cholangiocarcinoma (iCCA) is a hepatobiliary malignancy which accounts for approximately 5-10 % of primary liver cancers and has a high mortality rate. The diagnosis of iCCA remains significant challenges owing to the lack of specific and sensitive diagnostic tests available. Hence, improved methods are needed to detect iCCA with high accuracy. In this study, we evaluated the efficacy of serum amino acid profiling combined with machine learning modeling for the diagnosis of iCCA. A comprehensive analysis of 28 circulating amino acids was conducted in a total of 140 blood samples from patients with iCCA and normal individuals. We screened out 6 differentially expressed amino acids with the criteria of |Log 2 (Fold Change, FC)| > 0.585, P-value < 0.05, variable importance in projection (VIP) > 1.0 and area under the curve (AUC) > 0.8, in which amino acids L-Asparagine and Kynurenine showed an increasing tendency as the disease progressed. Five frequently used machine learning algorithms (Logistic Regression, Random Forest, Supporting Vector Machine, Neural Network and Naïve Bayes) for diagnosis of iCCA based on the 6 circulating amino acids were established and validated with high sensitivity and good overall accuracy. The resulting models were further improved by introducing a clinical indicator, gamma-glutamyl transferase (GGT). This study introduces a new approach for identifying potential serum biomarkers for the diagnosis of iCCA with high accuracy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Abnormal antioxidant capacity in cancer cells is intimately linked to tumor aggressiveness. Modulating oxidative stress status and inhibiting ferroptosis represents a novel anticancer therapeutic strategy. STAM Binding Protein Like 1 (STAMBPL1), a deubiquitinase, is implicated in various malignancies, yet its function in inhibiting ferroptosis and therapeutic potential for cholangiocarcinoma (CCA) remains unexplored., Purpose: This study elucidates STAMBPL1's function in ferroptosis and evaluates liquidambaric acid (LDA) as its inhibitor for therapeutic applications., Methods: Using bioinformatics, WB, IHC, the expression and prognostic value of STAMBPL1 in CCA tissue was detected. The carcinogenic capacity of STAMBPL1 and LDA were assessed through CCK-8, EdU, cloning, transwell, scratch, apoptosis, and cell cycle assays. Flow cytometry and fluorescence microscopy, as well as transmission electron microscopy (TEM), examines the effects of STAMBPL1 and LDA on intracellular reactive oxygen species (ROS) and changes in mitochondrial membrane potential. The tumorigenic ability of STAMBPL1 and LDA in vivo was evaluated through subcutaneous tumor model and lung metastasis model. The underlying mechanism of STAMBPL1 was explored using immunoprecipitation coupled with Mass spectrometry (IP/MS), Co-immunoprecipitation (Co-IP), GST pull-down, DNA pull-down, and Dual-luciferase reporter assays. Molecular docking simulations, SPR, DARTS and CETSA predict the putative binding site of LDA on STAMBPL1 protein. Rescue experiments further confirmed the above conclusions., Results: This study unveils the upregulation and oncogenic role of STAMBPL1 in CCA. Functionally, STAMBPL1 notably enhances CCA cell proliferation and metastasis while impeding ferroptosis. STAMBPL1 stabilizes NRF2, a pivotal regulator of antioxidant enzymes, through K63 deubiquitination. Elevated NRF2, stabilized by STAMBPL1 overexpression, triggers GPX4 activation and reactive oxygen species (ROS) elimination. Particularly, sites 251-436 of STAMBPL1 interact with sites 228-605 of NRF2, facilitating DUB activity and eliminating ubiquitin molecules attached to NRF2, thus protecting it from proteasome-mediated degradation. Moreover, NRF2, acting as a transcription factor, binds to the promoter region of STAMBPL1 and activates its transcription, thus forming STAMBPL1/NRF2 positive feedback loop and regulating redox homeostasis. Molecular docking and in vitro/in vivo experiments identified that LDA binds to and inhibits STAMBPL1, thereby disrupting the STAMBPL1/NRF2 positive feedback loop, consequently suppressing CCA progression., Conclusion: This study firstly reveals that STAMBPL1 promotes cholangiocarcinoma progression by upregulating NRF2, indicating that targeting the STAMBPL1/NRF2 axis is a novel therapeutic strategy. Additionally, our findings firstly suggest that LDA can bind to STAMBPL1, inhibiting NRF2 deubiquitination and offering significant therapeutic potential., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Metabolomics intends to maximize the quantity of available metabolites for the global metabolome, which largely depends on sample pretreatment protocols. However, there are few studies that comprehensively examined the effects of extraction and reconstitution solvents on metabolome coverage of adherent mammalian cells. In this study, the human cholangiocarcinoma TFK-1 cells were chosen as a cell model, and eight extraction solvents and five reconstitution solvents were used for the pretreatment based on ultrahigh performance liquid chromatography coupled with mass spectrometry (UPLC/MS). The coverage, reproducibility, and stability of the data were norms to evaluate the effectiveness of different extraction solvents and reconstitution solvents. Based on the number of metabolites, the mean Euclidean distance (ED MEAN ) in the principal component analysis (PCA) 3D score plots and the relative standard deviation (RSD) distribution of metabolites, it was demonstrated that MeOH-CHCl 3 -H 2 O (8:1:1, v/v/v) was the optimal extraction solvent and MeOH-H 2 O (1:1, v/v) or H 2 O was superior to other reconstitution solvents for RP column analysis, and the extraction solvent MeOH-ACN-H 2 O (2:2:1, v/v/v) and the reconstitution solvents ACN-H 2 O (4:1, v/v) or MeOH-H 2 O (1:1, v/v) provide the best performance for HILIC column analysis. The optimized pretreatment methods explored in this study expand the coverage of polar and non-polar metabolites and improve the reproducibility and stability of the metabolic data, which can be applied to UPLC/MS-based global metabolomics study on cholangiocarcinoma cells, potentially providing better extraction solvents and reconstitution solvents for other adherent mammalian cells with similar chemical and physical properties., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive cancer of the peripheral bile ducts and is recognized by the abundance of cancer stem-like cells (CSCs) within the tumor mass. While CSC markers in iCCA are well-defined, the molecular vulnerabilities of this subpopulation remain elusive., Methods: The 96-well, three dimensional (3D) tumorsphere culture was adapted from a well-established CSC model, validated for CSC markers through gene expression analysis. Kinase library screening was then conducted to reveal potential oncogenic vulnerable pathways. RNA interference was utilized to stably silence the candidate gene in three iCCA cell lines and its impact on iCCA cell proliferation and tumorsphere formation efficiency (TFE) was evaluated., Results: Kinase inhibitor library screening identified the top 50 kinase inhibitors crucial for tumorsphere viability, with 11 inhibitors targeting the IGF-1R/PI3K/AKT axis. Further dose-dependent analysis of the top 'hit' inhibitors confirmed IGF-1R as the candidate molecule. Upon stably silencing of IGF-1R, all three iCCA cell lines exhibited decreased AKT activation, impeded proliferation and reduced TFE, indicating a decline in CSC subpopulations., Conclusions: IGF-1R plays a critical role in maintaining iCCA-stem like cell populations., General Significance: Our data highlight the potential utility of IGF-1R as a prognostic marker of iCCA and a therapeutic target for eliminating its CSC subpopulation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In the past 20 years, targeted therapy for cholangiocarcinoma has attracted certain attention. There is a significant upward in papers focusing on this field. In this study, we used bibliometric and visual methods to explore the current status and future directions in cholangiocarcinoma-targeted therapy research. A total of 1057 papers published in English from 2003 to 2022 were extracted from the Web of Science Core Collection SCI-expanded database. Furthermore, Citespace, Vosviewer, and Excel 2016 were utilized to conduct bibliometric and visual analysis. The volume of annual publications has steadily increased over the past two decades. The USA has published the largest number of publications, and the Mayo Clinic acted as the dominant institution. Cancers, Frontiers in Oncology, and Hepatology were the prolific resources in this research field. Moreover, the co-cited reference analysis uncovered the landmark paper in this field. With regard to research hotspots and frontiers, the burst keywords analysis showed that growth factor receptors and pathogenesis might become the hot topics of future research. To sum up, our study displays the current research status and future directions in the targeted therapy for cholangiocarcinoma. More comprehensive and in-depth investigations should focus on critical genetic mutations and their molecular mechanisms to prompt the molecular-targeted therapy. [ABSTRACT FROM AUTHOR]

Despite the growing adoption of laparoscopic hepatectomy (LH) for intrahepatic cholangiocarcinoma (ICC), there is no scoring system available designed to evaluate its surgical complexity. This paper aims to introduce a novel difficulty scoring system (DSS), designated as the Wei-DSS, exclusively tailored to assess the surgical difficulty of pure LH for ICC. We retrospectively collected clinical data from ICC patients who underwent pure LH at our institution, spanning from November 2018 to May 2024. Patients were categorized into two levels of Wei-DSS scores (low-difficulty [5-6], and high-difficulty [7-10]) determined by tumor characteristics, liver texture, resection extent and tumor marker levels. A total of 104 patients were enrolled in this study including a low-difficulty (LD) group comprising 47 patients and a high-difficulty (HD) group comprising 57 patients. Perioperative comparisons indicated that the HD group was significantly associated with a longer operation time (318.14 ± 125.89 min vs. 222.83 ± 119.03 min, P < 0.001), higher rates of intraoperative blood transfusions (59.6% vs. 27.7%, P = 0.001), and increased rates of postoperative complications (84.2% vs. 48.9%, P < 0.001) compared to the LD group. The receiver operating characteristic (ROC) curve analysis indicated that the Wei-DSS demonstrated superior predictive accuracy over the Major/Minor Classification for predicting postoperative complication rates (area under the curve [AUC] 0.702 vs. 0.622) and operating time (AUC 0.720 vs. 0.604 ). The Wei-DSS score may have the potential to assist surgeons in categorizing ICC patients with varying levels of surgical difficulty of LH, though it warrants further validations across multiple centers to solidify its efficacy and reliability., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics approval and consent to participate statement: The study adhered to the principles of the Declaration of Helsinki and gathered data from retrospective data. The study obtained approval from the Institutional Review Board of Zhejiang Provincial People’s Hospital. Due to the retrospective nature of the study, the Institutional Review Board of Zhejiang Provincial People’s Hospital waived the need of obtaining informed consent., (© 2024. The Author(s).)

Cholangiocarcinoma (CCA) is a highly lethal malignant tumor originating from the bile duct, and its underlying mechanisms are not fully understood. In order to identify key genes in CCA, we downloaded gene expression data from public GSE76297, GSE26566 and TCGA-CHOL datasets. CARD9 was selected as a CCA-related gene from the datasets. Its expression was identified in the CCA tissues via PCR, western blot and immunohistochemistry assays. The loss-and-gain function assay of CARD9 was conducted in CCA cell lines (QBC939 and RBE) and nude mice. This study found a significant upregulation of CARD9 in CCA tissues, which is associated with poor prognosis in patients. Overexpression of CARD9 promotes proliferation and invasion of QBC939 and RBE cells, enhances the growth and development in CCA mouse models, and reduces sensitivity to chemotherapy drugs for CCA. Mechanistically, CARD9 activates the NF-κB and NLRP3 inflammatory signaling pathways, induces excessive release of various inflammatory factors, and triggers a cascade reaction of interleukin-17 (IL-17A). IL-17A promotes the stability of IHH mRNA by regulating HuR, enhances IHH transcription, and activates the Hedgehog signaling pathway to accelerate the progression of CCA. In addition, CARD9 promotes proliferation and invasion of CCA cells by interacting with THEM4, thereby facilitating AKT and mTOR phosphorylation, and accelerating the progression of CCA. Overall, these data suggest that CARD9 is involved in the progression of CCA by regulating the IL-17A/Hedgehog and the THEM4/AKT/mTOR signaling pathways. Therefore, CARD9 may serve as a novel therapeutic target for CCA treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Traditional chemotherapy and immunotherapy-based systemic treatments for locally advanced or metastatic cholangiocarcinoma have been associated with poor clinical outcomes driven partly by molecular heterogeneity promoting early treatment resistance and a higher toxicity profile associated with these regimens. Few patients are eligible for upfront surgical resection and clinical studies have been traditionally difficult to conduct due to the orphan nature of this disease. However, increasing use of genomic profiling in clinical practice have led to active investigations of aberrant albeit promising mechanistic therapeutic targets such as IDH-1, FGFRs, BRAF V600E , HER-2 and NTRK. This review article aims to highlight the complex genomic landscape of this difficult-to-treat disease, followed by a discussion of evidence-based biological mechanisms that can be actioned using targeted agents. We explore the clinical rationale behind a targeted therapeutic strategy, the role of liquid biopsies in guiding clinical decisions and future treatment pathways for cholangiocarcinoma management. We also discuss the challenges and opportunities originating from recent clinical trials evaluating targeted treatments and our own institutional experience at UCLH that have aimed to address some of these biological complexities and have translated into improved patient outcomes via effective molecularly driven patient selection strategies. We also provide perspectives on emerging novel, next generation targeted inhibitors overcoming treatment resistance to previous targeted agents with demonstrated clinical value in a challenging patient population., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: The advanced lung cancer inflammation index (ALI), which combines inflammation and nutrition data, was recently proposed as a prognostic biomarker. We assessed the impact of ALI on overall survival (OS) among patients undergoing surgery for intrahepatic cholangiocarcinoma (ICC)., Methods: Patients who underwent surgery for ICC were identified from an international cohort. ALI was calculated as body-mass index (BMI)∗albumin/neutrophil-to-lymphocyte ratio; patients were categorized into "low-" and "high-ALI" using log-rank statistics. The impact of ALI on OS was compared against other inflammatory markers (i.e., neutrophil-to-lymphocyte ratio [NLR], platelet-to-lymphocyte ratio [PLR], systemic immune inflammation index [SII = platelets∗NLR]) using Harrell's Concordance index (C-index) and the Akaike Information Criterion (AIC). To minimize intergroup differences, propensity score matching was employed., Results: Among 1045 patients, more than one-half of individuals underwent major hepatectomy (n = 582, 55.7 %), median tumor size was 5.5 cm (IQR, 3.8-7.8), and median ALI was 38.9 (IQR 26.5-57.2). On multivariate analysis, low ALI was an independent risk factor for worse OS (HR 1.21, 95 % CI 1.01-1.46; p = 0.04). Patients with low ALI had worse 5-year OS (36.9 % vs. 49.9 %; p < 0.001), which remained significant after PSM (36.9 % vs. 41.3 %; p = 0.039). ALI had a comparable discriminatory ability compared with NLR, PLR, and SII (C-index: 0.646 vs. 0.644 vs. 0.640 vs. 0.641, respectively), yet had a lower AIC (5475.31 vs. 5546.80 vs. 5550.45 vs. 5548.62, respectively) suggesting slightly better model fit and accuracy., Conclusions: ALI was an independent predictor of OS among patients undergoing surgery for ICC. Nutritional and inflammatory markers should be incorporated into predictive models to improve prognostic stratification., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: Cholangiocarcinoma (CCA) is a malignant tumor of the gastrointestinal tract with a poor prognosis. Immunotherapy plays an important role in the treatment of CCA. This study aimed to investigate the research hotspots and trends in immunotherapy for CCA., Methods: The Web of Science Core Collection was searched for literature related to CCA immunotherapy research from January 1, 2014, to December 31, 2023, and features such as country, institution, authors, references, and keywords in the included literature were quantitatively and visually analyzed using the VOS viewer and CiteSpace software., Results: A total of 252 English publications published between 2014 and 2023 were included. The publications were mainly from China and the United States, with Fudan University being the institution that published the most papers. The highest number of publications came from Frontiers in Oncology. The most prolific authors were Jia Fan, Jian Zhou from China and Pa-Thai Yenchitsomanus from Thailand, while the Journal of Clinical Oncology ranked first in the number of citations among the co-cited journals. In recent years, the focus of research has shifted from "immune checkpoint" and "chemotherapy" to "immunotherapy combined therapy." Currently, the research frontiers are "microenvironment," "immune cells," and "macrophages.", Conclusion: Our study analyzes the research hotspots and trends in CCA to provide a knowledge map of immunotherapy research, which will serve as a reference and direction for future research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Qu, Wang, Zhu, Liang, Long, Wu, Jiang, Liu, Dai and Zhu.)

Background: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is poorly understood, while the predictive value of the staging in which it is included is controversial., Methods: Patients with cHCC-CCA underwent radical hepatectomy in two medical centers in China were enrolled and staged based on optimal cut-off values of tumor burden score (TBS), determined using the X-Tile. The association between TBS and prognosis was evaluated by Cox proportional hazard models and Kaplan-Meier curves with Log-rank test. TBS model and primary liver cancer (PLC) stages were compared by discrimination, consistency, and clinical utility, which were further validated by a 5-folds cross-validation., Results: A total of 192 patients were stratified into low, medium, and high TBS, comprising 92, 51 and 49 patients, respectively. Prognoses worsened with elevated TBS in both the training and validation cohorts. TBS was not only an independent prognostic indicator in univariate and multivariate cox regression, but also a stable risk factor in subgroup analysis according to baseline variables. TBS exhibited best discrimination within these predictive models, as evidenced by the highest c-index and area under curve values of time-dependent receiver operating curves within 5 years post-surgery. TBS calibration plots revealed favorable consistency between prediction and observation. Decision curve analysis suggested higher net benefits for TBS. A 5-folds cross-validation revealed consistent results., Conclusions: TBS could be applied to stratify cHCC-CCA patients after surgery into groups with statistically different prognoses. Moreover, TBS exhibited optimal prognostic value over all available PLC stages and may inform clinical decisions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Cholangiocarcinoma (CCA) is an oxidative stress-driven liver cancer with bile duct epithelial cell phenotypes and currently lacks effective treatments, making targeted drug therapy urgently needed. Oxidative stress plays a critical role in CCA carcinogenesis, involving cells with oxidative stress resistance via upregulation of the PI3K and MEKK3 signaling pathways. In this study, we investigated the antineoplastic efficacy of a PI3K inhibitor (buparlisib) and a multi-tyrosine kinase inhibitor (ponatinib) on CCA. The cytotoxicity of the drug combination was studied in vitro using CCA cell lines and in vivo using CCA xenograft models. It was found that the drug combination suppressed growth, colony formation, and migration abilities of CCA cells and induced oxidative damage, cell cycle arrest, and autophagy by suppressing MEKK3 and YAP1 through inhibition of insulin receptor substrate 1 (IRS1) signaling. Moreover, the drugs would potentially bind to the IRS1 protein, significanly decreasing IRS1 phosphorylation. Additionally, the drug combination significantly diminished the expression of YAP1, the cell proliferation marker and an antioxidant regulator, and increased oxidative stress-responsive markers in the xenograft model. In conclusion, targeting oxidative stress resistance with combined buparlisib and ponatinib suppressed tumor growth and migration by repressing IRS1-related pathways and ultimately inducing oxidative damage, suggesting the potential for targeted therapy and clinical trials in CCA patients over the use of a single drug., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Aims: Drug export through ABC proteins hinders cancer response to chemotherapy. Here, we have evaluated the relevance of MRP3 (ABCC3) in cholangiocarcinoma (CCA) as a potential target to overcome drug resistance., Methods: Gene expression was analyzed in silico using the TCGA-CHOL database and experimentally (mRNA and protein) in resected CCA tumors. The effect of manipulating MRP3 function/expression was evaluated in vitro and in vivo., Results: High MRP3 expression at the plasma membrane of human CCA cells was found. MRP3 overexpression in HEK293T cells selectively impaired the cytotoxic effect of etoposide, cisplatin, SN-38, and mitoxantrone. Reduced MRP3 activity with shRNAs or pan-MRP blockers enhanced the sensitivity to these drugs. MRP3 interaction with natural and semisynthetic compounds (≈40,000) was evaluated by virtual drug screening and molecular docking. Two identified potential MRP3 inhibitors (EM-114, EM-188), and sorafenib impaired MRP3 transport activity and enhanced sensitivity of CCA cells to etoposide and cisplatin. The antitumor effect of cisplatin in the mouse xenograft model was enhanced by co-treatment with sorafenib, which was accompanied by a higher intratumor accumulation of cisplatin., Conclusions: Genetic and pharmacological MRP3 inhibition enhances the anti-CCA effect of several drugs, which constitutes a promising strategy to improve the response to chemotherapy in CCA patients., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jose J.G. Marin reports financial support was provided by Carlos III Health Institute. Jose J.G. Marin reports financial support was provided by Spanish Ministry of Science and Innovation. Jose J.G. Marin reports financial support was provided by Junta de Castilla y León, Consejería de Educación. Jose J.G. Marin reports financial support was provided by Spanish Association Against Cancer Scientific Foundation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Purpose: To assess the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) of gemcitabine and oxaliplatin (GEMOX) plus systemic gemcitabine chemotherapy (GEM-SYS) in combination with lenvatinib and programmed cell death protein-1 (PD-1) inhibitor for patients with large unresectable intrahepatic cholangiocarcinoma (uICC)., Methods: From November 2019 to December 2022, 21 large uICC patients who underwent GEMOX-HAIC (Day 1) and GEM-SYS (Day 8) (3w/cycle) combined with lenvatinib and PD-1 inhibitor were retrospectively enrolled. Local tumor response, progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were analyzed. Tumor response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. AEs were evaluated by the common terminology criteria for adverse events (CTCAE) version 5.0., Results: After a median follow-up duration of 16.0 months (range 5-43.5 months), 17 patients had died. The median OS was 19.5 months (range 9-43.5 months), and the median PFS was 6.0 months (range 2.5-38.5 months). The 1-, 2-, and 3-year OS rates were 71.4 %, 42.9 %, and 19.0 %, respectively. The 1-, 2-, and 3-year PFS rates were 33.3 %, 19.0 %, and 9.5 %, respectively. Complete response, partial response, stable disease, and progressive disease were observed in 0 (0 %), 11 (52.3 %), 5 (23.8 %), and 5 (23.8 %) patients, respectively. The disease control rate and objective response rate were 76.1 % and 52.3 %, respectively. None of the enrolled patients experienced grade 5 AEs., Conclusions: GEMOX-HAIC plus GEM-SYS in combination with lenvatinib and PD-1 inhibitor was effective and well tolerated for patients with large uICC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In this paper we present a deep learning segmentation approach to classify and quantify the two most prevalent primary liver cancers - hepatocellular carcinoma and intrahepatic cholangiocarcinoma - from hematoxylin and eosin (H&E) stained whole slide images. While semantic segmentation of medical images typically requires costly pixel-level annotations by domain experts, there often exists additional information which is routinely obtained in clinical diagnostics but rarely utilized for model training. We propose to leverage such weak information from patient diagnoses by deriving complementary labels that indicate to which class a sample cannot belong to. To integrate these labels, we formulate a complementary loss for segmentation. Motivated by the medical application, we demonstrate for general segmentation tasks that including additional patches with solely weak complementary labels during model training can significantly improve the predictive performance and robustness of a model. On the task of diagnostic differentiation between hepatocellular carcinoma and intrahepatic cholangiocarcinoma, we achieve a balanced accuracy of 0.91 (CI 95%: 0.86-0.95) at case level for 165 hold-out patients. Furthermore, we also show that leveraging complementary labels improves the robustness of segmentation and increases performance at case level., (© 2024. The Author(s).)

Background: Intrahepatic cholangiocarcinoma (ICC) remains a significant challenge in cancer therapy, especially due to its resistance to established treatments like Gemcitabine, necessitating novel therapeutic approaches., Methods: This study utilized Gemcitabine-resistant cell lines, patient-derived organotypic tumor spheroids (PDOTs), and patient-derived xenografts (PDX) to evaluate the effects of Saikosaponin-a (SSA) on ICC cellular proliferation, migration, apoptosis, and its potential synergistic interaction with Gemcitabine. Techniques such as transcriptome sequencing, Luciferase reporter assays, and molecular docking were employed to unravel the molecular mechanisms., Results: SSA exhibited antitumor effects in both in vitro and PDX models, indicating its considerable potential for ICC treatment. SSA markedly inhibited ICC progression by reducing cellular proliferation, enhancing apoptosis, and decreasing migration and invasion. Crucially, it augmented Gemcitabine's efficacy by targeting the p-AKT/BCL6/ABCA1 signaling pathway. This modulation led to the downregulation of p-AKT and suppression of BCL6 transcriptional activity, ultimately reducing ABCA1 expression and enhancing chemosensitivity to Gemcitabine. Additionally, ABCA1 was validated as a predictive biomarker for drug resistance, with a direct correlation between ABCA1 expression levels and the IC50 values of various small molecule drugs in ICC gene profiles., Conclusion: This study highlights the synergistic potential of SSA combined with Gemcitabine in enhancing therapeutic efficacy against ICC and identifies ABCA1 as a key biomarker for drug responsiveness. Furthermore, the introduction of the novel PDOTs microfluidic model provides enhanced insights into ICC research. This combination strategy may provide a novel approach to overcoming treatment challenges in ICC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Background: Cholangiocarcinoma (CCA) is a highly aggressive and invasive malignant tumor of the bile duct, with a poor prognosis and a high mortality rate. Currently, there is a lack of effective targeted treatment methods and reliable biomarkers for prognosis., Methods: We downloaded RNA-seq and clinical data of CCA from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases as training and test sets. The apoptosis-related genes were obtained from the Molecular Signatures Database (MsigDB) database. We used univariate/multivariate Cox regression and Lasso regression analyses to construct a riskscore prognostic model. Based on the median riskscore, we clustered the patients into high-risk (HR) and low-risk (LR) groups. We carried out Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of differentially expressed genes (DEGs) in HR and LR groups. The single sample gene set enrichment analysis (ssGSEA) was employed to analyze the immune infiltration of the HR and LR groups. The CellMiner database was utilized to predict drugs and perform molecular docking on drugs and target proteins., Results: We identified 8 genes with prognostic significance to construct a prognostic model. Results of GO and KEGG demonstrated that DEGs were mainly enriched in biological functions such as fatty acid metabolic processes and pathways such as the cAMP signaling pathway. Results of ssGSEA uncovered that immune cells such as DCs and Macrophages in the HR group, as well as immune functions such as Check-point and Parainflammation, were considerably higher than those in the LR group. Drug sensitivity prediction and results of molecular docking revealed that Rigosertib targeted the prognostic genes MAP3K1. HYPOTHEMYCIN and AMG900 effectively targeted JUN., Conclusion: Our project suggested that the prognostic model with apoptotic features can effectively predict prognosis in CCA patients, proffering prognostic biomarkers and potential therapeutic targets for CCA patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Cholangiocarcinoma (CCA) is an aggressive and fatal cancer. The prognosis is very poor and no optimal chemotherapy has been established. Human epidermal growth factor receptor 2 (HER2, neu, and erbB2) is highly-expressed in breast cancer and is expressed in many other tumors but poorly expressed in CCA. The anti-HER2 antibody, trastuzumab, has been used for the treatment of HER2-positive breast and gastric cancer. In this study, we examined the surface expression of HER2 on seven Thai liver-fluke-associated CCA cell lines by flow cytometry, and found all of these CCA cells were weakly positive for HER2. MTT assay revealed that trastuzumab directly suppressed the growth of CCA. By using FcR-bearing recombinant Jurkat T-cell-expressing firefly luciferase gene under the control of NFAT response elements, we defined the activities of antibody-dependent cytotoxicity (ADCC) and antibody-dependent cell phagocytosis (ADCP). ADCC was confirmed by using expanded NK cells. ADCP was confirmed by using mouse peritoneal macrophages and human monocyte-derived macrophages as effector cells. Rabbit serum was administered to test the complement-dependent cytotoxicity (CDC) activity of trastuzumab. Finally, we evaluated the efficacy of trastuzumab in in vivo patient-derived cell xenograft and patient-derived xenograft (PDX) models. Our results showed that a distinct population of CCA (liver-fluke-associated CCA) expressed HER2. Trastuzumab demonstrated a potent inhibitory effect on even HER2 weakly positive CCA both in vitro and in vivo via multiple mechanisms. Thus, HER2 is a promising target in anti-CCA therapy, and trastuzumab can be considered a promising antibody immunotherapy agent for the treatment of CCA., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The prognosis for Cholangiocarcinoma (CCA) is unfavorable, necessitating the development of new therapeutic approach such as magnetic hyperthermia therapy (MHT) which is induced by magnetic nano-particle (MNPs) drug to bridge the treatment gap. Given the deep location of CCA within the abdominal cavity and proximity to vital organs, accurately predict the individualized treatment effects and safety brought by the distribution of MNPs in tumor will be crucial for the advancement of MHT in CCA. The Mimics software was used in this study to conduct three-dimensional reconstruction of abdominal computed tomography (CT) and magnetic reso-nance imaging images from clinical patients, resulting in the generation of a realistic digital geometric model representing the human biliary tract and its adjacent structures. Subsequently, The COMSOL Multiphysics software was utilized for modeling CCA and calculating the heat transfer law resulting from the multi-regional distribution of MNPs in CCA. The temperature within the central region of irregular CCA measured approximately 46°C, and most areas within the tumor displayed temperatures surpassing 41°C. The temperature of the inner edge of CCA is only 39 ∼ 41℃, however, it can be ameliorated by adjusting the local drug concentration through simulation system. For CCA with diverse morphologies and anatomical locations, the multi-regional distribution patterns of intratumoral MNPs and a slight overlap of drug distribution areas synergistically enhance intratumoral temperature while ensuring treatment safety. The present study highlights the practicality and imperative of incorporating personalized intratumoral MNPs distribution strategy into clinical practice for MHT, which can be achieved through the development of an integrated simulation system which incorporates medical image data and numerical calculations., Competing Interests: Declaration of Competing Interest The authors state that they have no competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The challenge of drug resistance in intrahepatic cholangiocarcinoma (ICC) is intricately linked with lipid metabolism reprogramming. The hepatic lipase (HL) and the membrane receptor CD36 are overexpressed in BGJ398-resistant ICC cells, while they are essential for lipid uptake, further enhancing lipid utilization in ICC. Herein, a metal-organic framework-based drug delivery system (OB@D-pMOF/CaP-AC, DDS), has been developed. The specifically designed DDS exhibits a successive targeting property, enabling it to precisely target ICC cells and their mitochondria. By specifically targeting the mitochondria, DDS produces reactive oxygen species (ROS) through its sonodynamic therapy effect, achieving a more potent reduction in ATP levels compared to non-targeted approaches, through the impairment of mitochondrial function. Additionally, the DDS strategically minimizes lipid uptake through the incorporation of the anti-HL drug, Orlistat, and anti-CD36 monoclonal antibody, reducing lipid-derived energy production. This dual-action strategy on both mitochondria and lipids can hinder energy utilization to restore drug sensitivity to BGJ398 in ICC. Moreover, an orthotopic mice model of drug-resistant ICC was developed, which serves as an exacting platform for evaluating the multifunction of designed DDS. Upon in vivo experiments with this model, the DDS demonstrated exceptional capabilities in suppressing tumor growth, reprogramming lipid metabolism and improving immune response, thereby overcoming drug resistance. These findings underscore the mitochondria-targeted DDS as a promising and innovative solution in ICC drug resistance., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Simple Summary: Fibroblast growth factors (FGFs) and their receptors (FGFRs) play a crucial role in cancer development. However, due to their diverse cellular functions, the mechanisms by which they drive cancer are complex. In this review, we discuss the mechanisms of action of FGFs and FGFRs, as well as how the dysregulation of FGF signaling contributes to cancer in various tumor types. The complexity of FGF signaling is partly explained by the large number of FGF isoforms and FGFR receptor types. We provide a classification of FGF ligands based on their signaling modes and binding specificity to FGFRs. Additionally, we explore promising therapeutic strategies being developed to target FGF signaling in oncology, including small molecules, ligand traps, and monoclonal antibody-based inhibitors. Fibroblast growth factors (FGFs) have diverse functions in the regulation of cell proliferation and differentiation in development, tissue maintenance, wound repair, and angiogenesis. The goal of this review paper is to (i) deliberate on the role of FGFs and FGF receptors (FGFRs) in different cancers, (ii) present advances in FGF-targeted cancer therapies, and (iii) explore cell signaling mechanisms that explain how FGF expression becomes dysregulated during cancer development. FGF is often mutated and overexpressed in cancer and the different FGF and FGFR isoforms have unique expression patterns and distinct roles in different cancers. Among the FGF members, the FGF 15/19 subfamily is particularly interesting because of its unique protein structure and role in endocrine function. The abnormal expression of FGFs in different cancer types (breast, colorectal, hepatobiliary, bronchogenic, and others) is examined and correlated with patient prognosis. The classification of FGF ligands based on their mode of action, whether autocrine, paracrine, endocrine, or intracrine, is illustrated, and an analysis of the binding specificity of FGFs to FGFRs is also provided. Moreover, the latest advances in cancer therapeutic strategies involving small molecules, ligand traps, and monoclonal antibody-based FGF inhibitors are presented. Lastly, we discuss how the dysregulation of FGF and FGFR expression affects FGF signaling and its role in cancer development. [ABSTRACT FROM AUTHOR]

Histopathological image analysis plays an important role in the diagnosis and treatment of cholangiocarcinoma. This time-consuming and complex process is currently performed manually by pathologists. To reduce the burden on pathologists, this paper proposes a histopathological image classification method for cholangiocarcinoma based on spatial-channel feature fusion convolutional neural networks. Specifically, the proposed model consists of a spatial branch and a channel branch. In the spatial branch, residual structural blocks are used to extract deep spatial features. In the channel branch, a multiscale feature extraction module and some multi-level feature extraction modules are designed to extract channel features in order to increase the representational ability of the model. The experimental results of the Multidimensional Choledoch Database show that the proposed method performs better than other classical CNN classification methods. [ABSTRACT FROM AUTHOR]