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This study explores the relationship between m6A modification and ferroptosis in intrahepatic cholangiocarcinoma (ICC) and its impact on cisplatin resistance. We established cisplatin-resistant cells. CCK-8 and Transwell assays were conducted to evaluate the effects of METTL3 on drug resistance, migration, and invasion. RT-qPCR and Western blotting were used to measure target gene expression and the effects of overexpression and suppression. RIP, luciferase reporter assay, and other experiments were utilized to investigate the interaction between METTL3 and NRF2. Additionally, rescue experiments were performed to confirm the role of the METTL3/NRF2 axis in tumor drug resistance. METTL3 was found to be highly expressed in cisplatin-resistant cells, enhancing m6A modification levels, stabilizing NRF2 mRNA, and increasing NRF2 protein expression to inhibit ferroptosis. These findings indicate that the METTL3/NRF2 axis inhibits ferroptosis in cisplatin-resistant cells, thereby promoting chemotherapy resistance in ICC. This provides a potential direction for future research and treatment of ICC.

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing in prevalence globally. MASLD is associated with an increased rate of comorbidities, including cardiovascular disease, liver cirrhosis, and hepatocellular carcinoma (HCC). While the link between MASLD and HCC is well known, the potential association with biliary tract cancer, including cholangiocarcinoma (CCA) and gallbladder cancer (GBC), is less certain. To evaluate whether individuals with MASLD are at increased risk of developing CCA compared to the general population, we performed a nationwide cohort study investigating the longitudinal association between MASLD and CCA., Methods: A retrospective cohort study was performed including all patients ≥18 years of age, diagnosed with MASLD, from 1 st of January 1987 to 31 st of December 2020, through the Swedish National Patient Register. For each patient with MASLD, ten individuals, matched to the MASLD patient on year of diagnosis, age, sex, and municipality were selected as reference individuals. The international Classification of Diseases (ICD) codes were used to define MASLD and incident CCA. Incidence rates were calculated, and regression analyses were performed., Results: Out of the 11,940 exposed patients with MASLD, 11 developed CCA (0.1%) out of whom three were diagnosed with iCCA (0.03%), during a median follow-up time of  five years. Out of 112,537 reference individuals, 62 were diagnosed with CCA (0.3%), out of whom 15 were diagnosed with iCCA (0.01%). The rate of GBC was not higher compared to the reference population., Conclusion: This large cohort study found a low incidence of CCA in patients with MASLD, comparable to the general population which can reassure clinicians and patients that no specific vigilance for CCA should be considered in MASLD patients at present.

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.)

Background: Both mutation induction and clonal expansion of mutated cells cause cancer. The probability of cancer development depends on mutations, clonal growth rates, and carcinogenic mechanisms. A recent study showed cases of occupational cholangiocarcinomas that originate multifocally, with higher mutation burden levels than those in common cholangiocarcinomas. This study aimed to identify the effect of clonal expansion on and estimate the risk of occupational and common intrahepatic cholangiocarcinomas (ICCs) using a multistage model modified to include the effect of cell expansion at any carcinogenic stage., Methods: The age-specific incidence of common ICC estimated from the Vital Statistics in Japan and the prognosis of ICC, and mutation frequencies of occupational and common ICC available from the previous report, were applied to a multistage model modified with cell proliferation effects. From the fittest model, the risk after exposure was estimated., Results: The required number of stages for carcinogenesis was estimated to be three based on the incidences and mutation frequencies of occupational and common ICCs. Based on this estimation, the predicted incidence curve under the model was similar to that estimated from the ICC mortality rate, except for older adults. The model indicated a minor effect of clonal expansion on the observed occupational ICC risk. It predicted a rapid decrease in ICC risk after the cessation of occupational exposure, although the time of clinical detection of cancer after the exposure was affected by latency. The model predicted an increase in cancer risk in older adults caused by cell expansion and common background mutations. However, the risk in older adults was overestimated in the case of common ICC; this divergence could influence occupational ICC cases., Conclusions: Three-stage ICC carcinogenesis has been proposed. The high mutation burden levels caused by occupational exposure led to an immediate incidence of cancer. After a long period of relatively low cancer risk, an increased risk in older adults was also predicted., (© 2024. The Author(s).)

Objectives: Endoscopic ultrasound-guided tissue acquisition (EUS-TA) for focal liver lesions has gained attention as an alternative to percutaneous biopsy. Although the outcomes of EUS-TA for focal liver lesions have been reported to be favorable, no studies have focused on small focal liver lesions (≤2 cm). The aim of this study was to evaluate the outcomes of EUS-TA for small focal liver lesions (≤2 cm)., Methods: The details of EUS-TA performed for focal liver lesions between 2016 and 2022 were retrospectively reviewed. The outcomes were compared between cases involving ≤2 cm lesions and those involving >2 cm lesions. The primary outcomes were diagnostic ability and adverse events., Results: EUS-TA for focal liver lesions was performed in 109 cases. Of the 109 cases, 32 (29.3%) involved ≤2 cm lesions and 77 (70.6%) involved >2 cm lesions. Right lobe lesions and transduodenal puncture were significantly fewer in the ≤2 cm group. There were no significant differences in needle gauge, needle type, or number of punctures between the groups. The sensitivity, specificity, and accuracy rates were 96.8%, 100%, and 96.8%, respectively, in the ≤2 cm group and 97.4%, 100%, and 97.4%, respectively, in the >2 cm group, with no significant differences between the groups. There was no difference in adverse events between the groups (0% in the ≤2 cm group and 2.3% in the >2 cm group)., Conclusions: EUS-TA for small focal liver lesions measuring ≤2 cm has favorable outcomes, which are similar to those for lesions measuring >2 cm., Competing Interests: None., (© 2024 The Author(s). DEN Open published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)

Intrahepatic cholangiocarcinoma (ICC), a severe liver cancer, makes up to 20% of all hepatic malignancies and is difficult to diagnose early due to its often asymptomatic nature. This case report documents a rare presentation of ICC with multiple diffuse nodules not previously recorded in medical literature. A 65-year-old man with no significant medical history presented with back pain, anorexia, and significant weight loss. Elevated tumor markers and enlarged lymph nodes were observed, though imaging did not reveal a primary liver mass. Diagnostic efforts, including computed tomography and positron emission tomography scans and biopsies of lymph nodes and bone marrow, suggested adenocarcinoma of unknown primary origin. A definitive diagnosis was only made post-mortem, revealing multiple diffuse nodules in the liver identified as ICC, marking a rare presentation without a primary mass. This case highlights the diagnostic challenges posed by atypical ICC manifestations, where typical imaging does not indicate a primary mass, delaying diagnosis and treatment. The findings emphasize the importance of considering ICC in differential diagnoses in cases of unknown primary adenocarcinoma with liver involvement. The discovery of ICC with diffusely infiltrative nodules underscores the necessity for comprehensive diagnostic evaluations in patients presenting with nonspecific systemic symptoms and abnormal liver findings., (© 2024. Japanese Society of Gastroenterology.)

Objective: To investigate Sonazoid contrast-enhanced ultrasound (CEUS) features of intrahepatic cholangiocarcinoma (ICC) based on liver backgrounds and tumor sizes., Methods: A retrospective analysis was conducted on patients with histopathologically diagnosed ICC at two centers. Patients underwent Sonazoid CEUS examination at a dose of 0.0165 mL/kg before surgery or biopsy. Continuous imaging was recorded for the first 70 s, followed by intermittent scanning every 15-20 s for 5 min, with a Kupffer phase captured after an 8-min delay. Patients were categorized by liver backgrounds and tumor sizes. Two ultrasound experts evaluated the enhancement patterns of ICCAs during the arterial, portal, delayed, and Kupffer phases according to current guidelines., Results: From February 2019 to July 2022, a total of 85 ICC lesions were included. ICCs were categorized into normal liver (n = 24), chronic liver disease with fibrosis (n = 40), and cirrhosis (n = 21) groups based on different liver backgrounds, and into groups measuring ≤30 mm (n = 22), 31-50 mm (n = 32), and >50 mm (n = 31) based on tumor sizes. Most ICCs in liver fibrosis or liver cirrhosis tended to show non-rim enhancement in arterial phase (p = 0.022) and relatively later washout (39.9 ± 8.5 s vs. 39.7 ± 13.0 s) compared with those on a normal liver background (28.1 ± 5.6 s) (p < 0.001). Based on CEUS Liver Imaging Reporting and Data System, the diagnostic performance of LR-M criteria showed an accuracy of 100% in our high-risk populations. ICCs of ≤30 mm more commonly showed non-rim enhancement in arterial phase (p = 0.003) and relatively later washout (41.3 ± 12.5 s) compared with larger ICCs (p = 0.046). In the Kupffer phase, all ICCs showed marked washout with sharp margin delineation on Sonazoid CEUS, regardless of liver backgrounds and tumor sizes., Conclusion: Sonazoid CEUS features of ICCs differ according to different liver backgrounds and tumor sizes. Arterial phase non-rim enhancement and relatively later washout were more commonly observed in ICCs on liver fibrosis or cirrhosis background or smaller ICCs (≤30 mm)., Competing Interests: Conflict of interest All authors have no conflict of interest related to the manuscript., (Copyright © 2024 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Background: Intrahepatic cholangiocarcinoma (ICC) is a malignant liver tumor that is challenging to treat and manage and current prognostic models for the disease are inefficient or ineffective. Tumor-associated immune cells are critical for tumor development and progression. The main goal of this study was to establish models based on tumor-associated immune cells for predicting the overall survival of patients undergoing surgery for ICC., Aim: To establish 1-year and 3-year prognostic models for ICC after surgical resection., Methods: Immunohistochemical staining was performed for CD4, CD8, CD20, pan-cytokeratin (CK), and CD68 in tumors and paired adjacent tissues from 141 patients with ICC who underwent curative surgery. Selection of variables was based on regression diagnostic procedures and goodness-of-fit tests (PH assumption). Clinical parameters and pathological diagnoses, combined with the distribution of immune cells in tumors and paired adjacent tissues, were utilized to establish 1- and 3-year prognostic models., Results: This is an important application of immune cells in the tumor microenvironment. CD4, CD8, CD20, and CK were included in the establishment of our prognostic model by stepwise selection, whereas CD68 was not significantly associated with the prognosis of ICC. By integrating clinical data associated with ICC, distinct prognostic models were derived for 1- and 3-year survival outcomes using variable selection. The 1-year prediction model yielded a C-index of 0.76 95% confidence interval (95%CI): 0.65-0.87 and the 3-year prediction model produced a C-index of 0.69 (95%CI: 0.65-0.73). Internal validation yielded a C-index of 0.761 (95%CI: 0.669-0.853) for the 1-year model and 0.693 (95%CI: 0.642-0.744) for the 3-year model., Conclusion: We developed Cox regression models for 1-year and 3-year survival predictions of patients with ICC who underwent resection, which has positive implications for establishing a more comprehensive prognostic model for ICC based on tumor immune microenvironment and immune cell changes in the future., Competing Interests: Conflict-of-interest statement: All the authors have nothing to disclose., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Thailand is among countries with the highest global incidence and mortality rates of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). While viral hepatitis and liver fluke infections have been associated with HCC and iCCA, respectively, other environmental risk factors, overall risk factor commonality and combinatorial roles, and effects on survival have not been systematically examined. We conducted a TIGER-LC consortium-based population study covering all high-incidence areas of both malignancies across Thailand: 837 HCC, 1474 iCCA, and 1112 controls (2011-2019) were comprehensively queried on lifelong environmental exposures, lifestyle, and medical history. Multivariate logistic regression and Cox proportional hazards analyses were used to evaluate risk factors and associated survival patterns. Our models identified shared risk factors between HCC and iCCA, such as viral hepatitis infection, liver fluke infection, and diabetes, including novel and shared associations of agricultural pesticide exposure (OR range of 1.50; 95% CI: 1.06-2.11 to 2.91; 95% CI: 1.82-4.63) along with vulnerable sources of drinking water. Most patients had multiple risk factors, magnifying their risk considerably. Patients with lower risk levels had better survival in both HCC (HR 0.78; 95% CI: 0.64-0.96) and iCCA (HR 0.84; 95% CI: 0.70-0.99). Risk factor co-exposures and their common associations with HCC and iCCA in Thailand emphasize the importance for future prevention and control measures, especially in its large agricultural sector. The observed mortality patterns suggest ways to stratify patients for anticipated survivorship and develop plans to support medical care of longer-term survivors, including behavioral changes to reduce exposures., (© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Purpose: The objective of this study was to develop nomograms for predicting outcomes following immunotherapy in patients diagnosed with intrahepatic cholangiocarcinoma (ICC)., Patients and Methods: A retrospective analysis was conducted on data from 75 ICC patients who received immunotherapy at Jinling Hospital and Drum Hospital. The discriminative power, accuracy, and clinical applicability of the nomograms were assessed using the concordance index (C-index), calibration curve, and decision curve analysis (DCA). The predictive performance of the nomograms for overall survival (OS) and progression-free survival (PFS) was evaluated using the area under the receiver operating characteristic (ROC) curve. Kaplan-Meier curves were also generated for validation purposes., Results: Multivariable analysis identified independent prognostic factors for OS, including CA19-9 levels, portal vein tumor thrombus (PVTT) grade, bifidobacteria administration, and surgery. The C-index of the nomogram for OS prediction was 0.722 (95% confidence interval [CI]: 0.661-0.783). Independent prognostic factors for PFS included CA19-9 levels, albumin, and bilirubin, with a C-index of 0.678 (95% CI: 0.612-0.743) for the nomogram predicting PFS. Calibration curves demonstrated strong concordance between predicted and observed outcomes, while DCA and Kaplan-Meier curves further supported the clinical utility of the nomogram., Conclusion: The nomogram developed in this study demonstrated favorable performance in predicting the prognosis of ICC patients undergoing immunotherapy. Additionally, our findings, for the first time, identified probiotics as a potential prognostic marker for immunotherapy. This prognostic model has the potential to enhance patient selection for immunotherapy and improve clinical decision-making., (© 2024. The Author(s).)

This research was intended to compare the clinical efficacy of hepatic arterial infusion chemotherapy (HAIC) in conjunction with lenvatinib and PD1 inhibitors to first-line systemic chemotherapy for advanced intrahepatic cholangiocarcinoma(ICC). The research enrolled advanced ICC patients who underwent HAIC plus lenvatinib and PD1 inhibitor(n = 51) or first-line systemic chemotherapy(cisplatin + gemcitabine, n = 39) between July 2020 to January 2023 in Zhongshan People's Hospital.Their clinical outcomes were assessed through measurement of parameters encompassing objective response rate (ORR), disease control rate (DCR), median overall survival (mOS), median progression-free survival (mPFS), median duration of response (mDOR), and treatment-related adverse events (TRAEs). In accordance with the RECIST1.1, the ORR in the HAIC + L + P and SC groups was 43.1% and 20.5%, while the DCR was 90.2% and 69.2%, respectively (P = 0.04 and = 0.02, respectively). The change in the maximum diameter of intrahepatic target lesions in patients before and after treatment and the diameter of intrahepatic tumors in the HAIC + L + P group were sharply smaller versus the SC group ( P < 0.001). The HAIC + L + P group had prolonged mOS (16.8 months vs. 11.0 months, P = 0.01) and mPFS (12.0 months vs. 6.9 months, P < 0.01) in comparison with the SC group. Compared to first-line systemic chemotherapy(cisplatin + gemcitabine), HAIC plus lenvatinib and PD-1 inhibitors contributes to improvement of tumor response and prolongation of OS and PFS in advanced ICC patients., (© 2024. The Author(s).)

Intrahepatic cholangiocarcinoma (ICC) is a highly heterogeneous malignancy. The reasons behind the global rise in the incidence of ICC remain unclear, and there exists limited knowledge regarding the immune cells within the tumor microenvironment (TME). In this study, a more comprehensive analysis of multi-omics data was performed using machine learning methods. The study found that the immunoactivity of B cells, macrophages, and T cells in the infiltrating immune cells of ICC exhibits a significantly higher level of immunoactivity in comparison to other immune cells. During the immune sensing and response, the effect of antigen-presenting cells (APCs) such as B cells and macrophages on activating NK cells was weakened, while the effect of activating T cells became stronger. Simultaneously, four distinct subpopulations, namely BLp, MacrophagesLp, BHn, and THn, have been identified from the infiltrating immune cells, and their corresponding immune-related marker genes have been identified. The immune sensing and response model of ICC has been revised and constructed based on our current comprehension. This study not only helps to deepen the understanding the heterogeneity of infiltrating immune cells in ICC, but also may provide valuable insights into the diagnosis, evaluation, treatment, and prognosis of ICC.

Tumor budding (TB) has been associated with poor survival in a variety of cancers including intrahepatic cholangiocarcinoma (iCCA). As tumor histomorphological features are significantly altered after neoadjuvant therapy (NAT), our study aims to assess the prognostic significance of TB in iCCA patients before and after NAT, by the modified International Tumor Budding Consensus Conference (ITBCC) criteria. 147 NAT-treated iCCA cases were included in this study. In biopsy specimens obtained before NAT, the TB-positive subgroup had lower overall survival (OS) in univariate analysis (P = 0.010). In resection specimens obtained after NAT, the TB-positive subgroup had reduced OS (P = 0.002) and recurrence-free survival (RFS) (P = 0.013) in univariate analysis. In multivariate analysis including TNM stage, lymphovascular invasion and perineural invasion, TB-positive in post-NAT resection was also found as an independent prognostic factor for both OS and RFS (OS, HR, 3.005; 95% CI, 1.333-6.775, P = 0.008; RFS, HR, 1.748; 95% CI, 1.085-2.816, P = 0.022). In conclusion, assessing the presence of TB by modified ITBCC criteria provides robust prognostic information in the NAT setting of iCCA patients and can be considered to be included in routine pathological reporting., (© 2024. The Author(s).)

Intrahepatic cholangiocarcinoma is a rare disease associated with a poor prognosis, primarily due to early recurrence and metastasis. An important feature of this condition is microvascular invasion (MVI). However, current predictive models based on imaging have limited efficacy in this regard. This study employed a random forest model to construct a predictive model for MVI identification and uncover its biological basis. Single-cell transcriptome sequencing, whole exome sequencing, and proteome sequencing were performed. The area under the curve of the prediction model in the validation set was 0.93. Further analysis indicated that MVI-associated tumor cells exhibited functional changes related to epithelial-mesenchymal transition and lipid metabolism due to alterations in the nuclear factor-kappa B and mitogen-activated protein kinase signaling pathways. Tumor cells were also differentially enriched for the interleukin-17 signaling pathway. There was less infiltration of SLC30A1+ CD8+ T cells expressing cytotoxic genes in MVI-associated intrahepatic cholangiocarcinoma, whereas there was more infiltration of myeloid cells with attenuated expression of the major histocompatibility complex II pathway. Additionally, MVI-associated intercellular communication was closely related to the SPP1-CD44 and ANXA1-FPR1 pathways. These findings resulted in a brilliant predictive model and fresh insights into MVI., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Intrahepatic cholangiocarcinoma (IHCC) is highly aggressive primary hepatic malignancy with an increasing incidence., Objective: This study aimed to develop machine learning-based radiomic clustering using F-18 fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) for predicting recurrence-free survival (RFS) and overall survival (OS) in IHCC., Methods: We retrospectively reviewed pretreatment F-18 FDG PET/CT scans of 60 IHCC patients who underwent surgery without neoadjuvant treatment between January 2008 and July 2020. Radiomic features such as first order, shape, and gray level were extracted from the scans of 52 patients and analyzed using unsupervised hierarchical clustering., Results: Of the 60 patients, 36 experienced recurrence and 31 died during follow-up. Eight patients with a negative FDG uptake were classified as Group 0. The unsupervised hierarchical clustering analysis divided the total cohort into three clusters (Group 1: n = 27; Group 2: n = 23; Group 3: n = 2). The Kaplan-Meier curves showed significant differences in RFS and OS among the clusters ( p < 0.0001). Multivariate analyses showed that the PET radiomics grouping was an independent prognostic factor for RFS (hazard ratio (HR) = 3.03, p = 0.001) and OS (HR = 2.39, p = 0.030). Oxidative phosphorylation was significantly activated in Group 1, and the KRAS, P53, and WNT β-catenin pathways were enriched in Group 2., Conclusions: This study demonstrated that machine learning-based PET radiomics clustering can preoperatively predict prognosis and provide valuable information complementing the genomic profiling of IHCC.

Background and Aims: For patients with biliary tract cancer involving the hepatic hilum, major hepatic resection with extrahepatic bile duct resection may be required. In addition to perihilar cholangiocarcinoma (PHCC), the same extent of surgery is used in advanced gallbladder cancer (GBC) and intrahepatic cholangiocarcinoma (IHCC) with hilar involvement. Few studies compare prognostic factors and long-term outcomes across tumor types. This study compared risk characteristics and outcomes after surgery in all subtypes of biliary tract cancer with hilar involvement., Methods: Patients with biliary tract cancer with hilar involvement undergoing major liver resection and extrahepatic bile duct resection between 2011 and 2021 at a single center were retrospectively analyzed. The primary postoperative outcome was overall survival. Secondary outcomes were recurrence-free survival and postoperative complications. Survival analysis was performed with Cox regression analysis and Kaplan-Meier method., Results: One-hundred and eight patients were included. Seventy-three (67%) had PHCC, 24 (22%) had GBC, and 11 (10%) had IHCC. Hilar-invading IHCC and GBC had more adverse histopathological factors like lymph node positivity (p = 0.021), higher number of positive nodes (p = 0.043), and larger tumor size (p < 0.001) compared with PHCC. Peritoneal invasion and lymph node positivity were significant independent predictors for survival (p = 0.011 and p = 0.004, respectively). Median overall survival was 29 months for PHCC, 22 months for GBC and 21 months for IHCC (p = 0.53). IHCC tended to recur earlier (p = 0.046) than GBC and PHCC (6, 15, and 18 months, respectively)., Conclusion: Patients with biliary tract cancer with hilar involvement undergoing major liver resection and resection of extrahepatic bile ducts had similar overall survival regardless of subtype, while IHCC recurred earlier. Peritoneal cancer invasion was common in all subtypes, including PHCC, and was an independent prognostic factor. This finding may support routine reporting of peritoneal invasion-status in resected biliary tract cancer., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Adenosquamous carcinoma (ASC) with the presence of a sarcomatous component is exceptionally uncommon in intrahepatic cholangiocarcinoma (iCCA). We report a case of hepatic ASC with rhabdoid transformation, one variation of sarcomatous change. A 72-year-old man was admitted to our hospital after being diagnosed with a 45 mm-diameter neoplastic lesion in the right hepatic duct on abdominal computed tomography. Laboratory findings showed increases in AST, ALT, ALP, gamma-GT, CA19-9 and DUPAN-II. The patient then underwent an extended right hepatectomy. Histopathologically, the tumor was composed of an ASC component within an abundant fibrous stroma and a sarcomatoid carcinoma component. By immunohistochemistry, keratin 7 and keratin 19 were expressed by all tumor cells. Expression of keratin 5/6, p40 and p63 was restricted to the squamous component. The sarcomatoid component was immunoreactive for vimentin with no loss of INI1 expression. This component also showed a loss of membranous E-cadherin expression and a reduction of membranous β-catenin expression. Staining for desmin, myoglobin and HepPar1 was negative in any tumor cells. The patient died of liver failure 3 months after surgery. This report aims to provide a better understanding of the clinicopathological characteristics and disease progression of the rare variants of iCCA to aid diagnosis and treatment., (© 2024. The Author(s) under exclusive licence to The Japanese Society for Clinical Molecular Morphology.)

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.)

Background: Intrahepatic cholangiocarcinoma (ICC) is the second most common malignancy of the liver and has the worst prognosis of any tumor arising from the liver, with a 5-year survival as low as 10%. However, whether the rurality of a patient's residence impacts care received and survival has not been well studied. We aimed to assess differences in care patterns associated with the rurality of patient's residences and their impact on survival outcomes, hypothesizing that patients in rural areas would experience lower survival., Methods: Adult patients diagnosed with ICC between 2010 and 2020 were identified in the Iowa Cancer Registry. Chi-square tests were used to compare values categorical variables by rural/urban status. Cox proportional hazards regression was used to determine associations with cancer-specific mortality., Results: Of 672 patients diagnosed with ICC during the study period, 53%, 27%, and 21% resided in metropolitan, micropolitan, and rural areas, respectively. There were no significant differences in age, sex, stage at diagnosis, the proportion receiving chemotherapy within 12 weeks of diagnosis, and undergoing surgery across all groups. Additionally, the proportion receiving definitive care at a National Cancer Institute (NCI) designated center was comparable across the three groups (37% metro vs. 43% micro vs. 35% rural). However, rural residents had the highest proportion of traveling ≥ 50 miles for definitive care (22% metro vs. 41% micro vs. 56% rural). In multivariable analysis of patients with Stage 1-3 disease, younger age, receipt of chemotherapy, surgery, and definitive care at an NCI center were independently associated with decreased mortality risk. However, rural residence was not significantly associated with survival (HR: 0.64 [95% CI: 0.38-1.06])., Conclusion: Similar to other complex cancer diagnoses, we found that definitive care at an NCI center was associated with decreased mortality risk for patients with ICC. Although rural residence was not independently associated with survival in this cohort, rural residents traveled significantly longer distances to access definitive care. This highlights a crucial need to improve access to specialized centers for complex cancer care., (© 2024 The Author(s). Journal of Surgical Oncology published by Wiley Periodicals LLC.)

Background: Intrahepatic cholangiocarcinoma (ICC) is a disease with poor prognosis and limited therapeutic options. We investigated the tumor immune microenvironment (TIME) to identify predictors of disease outcome and to explore targets for therapeutic modulation., Methods: Liver tissue samples were collected during 2008-2019 from patients ( n  = 139) diagnosed with ICC who underwent curative intent surgery without neoadjuvant chemotherapy. Samples from the discovery cohort ( n  = 86) were immunohistochemically analyzed on tissue microarrays (TMAs) for the expression of CD68, CD3, CD4, CD8, Foxp3, PD-L1, STAT1, and p-STAT1 in tumor core and stroma areas. Results were digitally analyzed using QuPath software and correlated with clinicopathological characteristics. For validation of TIME-related biomarkers, we performed multiplex imaging mass cytometry (IMC) in a validation cohort ( n  = 53)., Results: CD68+ cells were the predominant immune cell type in the TIME of ICC. CD4+ high T cell density correlated with better overall survival (OS). Prediction modeling together with validation cohort confirmed relevance of CD4+ cells, PD-L1 expression by immune cells in the stroma and N-stage on overall disease outcome. In turn, IMC analyses revealed that silent CD3+CD4+ clusters inversely impacted survival. Among annotated immune cell clusters, PD-L1 was most relevantly expressed by CD4+FoxP3+ cells. A subset of tumors with high density of immune cells ("hot" cluster) correlated with PD-L1 expression and could identify a group of candidates for immune checkpoint inhibition (ICI). Ultimately, higher levels of STAT1 expression were associated with higher lymphocyte infiltration and PD-L1 expression., Conclusions: These results highlight the importance of CD4+ T cells in immune response against ICC. Secondly, a subset of tumors with "hot" TIME represents potential candidates for ICI, while stimulation of STAT1 pathway could be a potential target to turn "cold" into "hot" TIME in ICC., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.)

We describe a case of a 47-year-old male patient with initially unresectable intrahepatic cholangiocarcinoma of the right liver lobe with tumor thrombi extending from the right bile duct to the common and left bile ducts. Conventional chemotherapy with gemcitabine and cisplatin for 19 months resulted in progressive disease. Subsequently, a comprehensive genome profile revealed fibroblast growth factor receptor 2 rearrangement, and hence, pemigatinib administration was initiated. After 6 months of pemigatinib therapy, significant shrinking of the tumor and disappearance of the tumor thrombi in the common and left bile duct were observed. Subsequently, the patient underwent conversion surgery, resulting in successful radical resection of the tumor. The patient has been disease-free for 7 months., (© 2024. The Author(s).)

Intrahepatic cholangiocarcinoma (iCCA) is a highly heterogeneous and aggressive liver cancer with limited therapeutic options. Precise classification and immunotherapy are perspectives to improve the treatments. We reported the role of septin 9 in apico-basal polarity and epithelial-to-mesenchymal transition (EMT). Here, we aim to elucidate its role in iCCA. We analyzed single-cell transcriptomes from human iCCA tumor cells based on phenotype and cell state. Knockdown of the septin 9 gene (SEPT9) was done using small interfering RNA (siRNA); interferon-γ (IFN-γ) stimulation was performed using different CCA cells; gene expressions were analyzed by reverse transcription and real-time PCR analysis (RT-qPCR); and immunofluorescence, immunoblotting, and flow cytometry were performed to assess the expression of proteins. The differential distributions of SEPT9 and vimentin (VIM) gene expressions allowed us to define specific cellular trajectories of malignant cells and thus identified distinct clusters of iCCA cells. One cluster was enriched in VIM and extracellular-matrix (ECM) remodeling molecules, and another had high expression of SEPT9 and genes from the 'don't eat me' signal involved in immune escape. This antagonism between SEPT9 and VIM was confirmed by in vitro experiments. Notably, SEPT9 and 'don't eat me' gene expressions were inversely correlated to those of vimentin and the EMT markers. SEPT9 expression was upregulated by IFN-γ and SEPT9 knockdown decreased expression of 'don't eat me' signal genes and increased expression of mesenchymal markers. Cancer Cell Line Encyclopedia (CCLE) transcriptome database analyses confirmed that iCCA cells enriched in septin 9 exhibit epithelial-like features. This study revealed septin 9 as a cytoskeleton element of iCCA epithelial-like cells and a regulator of the immune system response. It also brings new insights into the enigmatic relationship between EMT and immune response. Notably, we decoded a potential mechanism that could sensitize patients to immunotherapies., (© 2024 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer and its prognosis remains poor. Although growing numbers of studies have verified the involvement of circular RNAs (circRNAs) in various cancer types, their specific functions in ICC remain elusive. Herein, a circRNA, circUGP2 is identified by circRNA sequencing, which is downregulated in ICC tissues and correlated with patients' prognosis. Moreover, circUGP2 overexpression suppresses tumor progression in vitro and in vivo. Mechanistically, circUGP2 functions as a transcriptional co-activator of PURB over the expression of ADGRB1. It can also upregulate ADGRB1 expression by sponging miR-3191-5p. As a result, ADGRB1 prevents MDM2-mediated p53 polyubiquitination and thereby activates p53 signaling to inhibit ICC progression. Based on these findings, circUGP2 plasmid is encapsulated into a lipid nanoparticle (LNP) system, which has successfully targeted tumor site and shows superior anti-tumor effects. In summary, the present study has identified the role of circUGP2 as a tumor suppressor in ICC through regulating ADGRB1/p53 axis, and the application of LNP provides a promising translational strategy for ICC treatment., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Hepatocyte nuclear factors (HNF) 6 and 4α are master transcriptional regulators of development and maintenance of the liver and pancreaticobiliary tract in mice and humans. However, little is known about the prevalence of HNF6 and HNF4α expression in carcinomas of the hepatobiliary tract and pancreas. We aimed to reveal the diagnostic utility of HNF6 and HNF4α immunolabelling in adenocarcinomas of these organs. We investigated HNF6 and HNF4α expression by immunohistochemistry using a total of 480 adenocarcinomas of the digestive system, including 282 of the hepatobiliary tract and pancreas and 198 of the gastrointestinal tract. HNF6 expression was primarily restricted to intrahepatic cholangiocarcinomas (CCs) (63%, n=80) and gallbladder adenocarcinomas (43%, n=88), among others. Notably, small duct intrahepatic CCs almost invariably expressed HNF6 (90%, n=42), showing stark contrast to a low prevalence in large duct intrahepatic CCs (10%, n=21; p<0.0001). HNF6 expression was infrequent in extrahepatic CCs (9%, n=55) and pancreatic ductal adenocarcinomas (7%, n=58), and it was rare in adenocarcinomas of the gastrointestinal tract [oesophagus/oesophagogastric junction (EGJ) (2%, n=45), stomach (2%, n=86), duodenum (0%, n=25), and colorectum (0%, n=42)]. In contrast, HNF4α was widely expressed among adenocarcinomas of the digestive system, including intrahepatic CCs (88%), extrahepatic CCs (94%), adenocarcinomas of the gallbladder (98%), pancreas (98%), oesophagus/EGJ (96%), stomach (98%), duodenum (80%), and colorectum (100%). HNF6 was frequently expressed in and almost restricted to intrahepatic CCs of small duct type and gallbladder adenocarcinomas, while HNF4α was expressed throughout adenocarcinomas of the digestive system. HNF6 immunolabelling may be useful in distinguishing small duct intrahepatic CCs from other types of CC as well as metastatic gastrointestinal adenocarcinomas., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

The tumorigenesis of intrahepatic cholangiocarcinoma (ICC) has been identified to be exceptionally involved in dysregulated Hippo/Yes-associated protein (YAP) signaling pathway (Hippo/YAP). Hippo/YAP functions as a master regulator engaged in a plethora of physiological and oncogenic processes as well. Therefore, the aberrant Hippo/YAP could serve as an Achilles' heel regarding the molecular therapeutic avenues for ICC patients. Herein, we comprehensively review the recent studies about the underlying mechanism of disrupted Hippo/YAP in ICC, how diagnostic values could be utilized upon the critical genes in this pathway, and what opportunities could be given upon this target pathway., (© 2024 Wiley Periodicals LLC.)

Background & Aims: Intrahepatic cholangiocarcinoma (iCCA) is a fatal malignancy of the biliary system. The lack of a detailed understanding of oncogenic signaling or global gene expression alterations has impeded clinical iCCA diagnosis and therapy. The role of protein lactylation, a newly unraveled post-translational modification that orchestrates gene expression, remains largely elusive in the pathogenesis of iCCA., Methods: Proteomics analysis of clinical iCCA specimens and adjacent tissues was performed to screen for proteins aberrantly lactylated in iCCA. Mass spectrometry, macromolecule interaction and cell behavioral studies were employed to identify the specific lactylation sites on the candidate protein(s) and to decipher the downstream mechanisms responsible for iCCA development, which were subsequently validated using a xenograft tumor model and clinical samples., Results: Nucleolin (NCL), the most abundant RNA-binding protein in the nucleolus, was identified as a functional lactylation target that correlates with iCCA occurrence and progression. NCL was lactylated predominantly at lysine 477 by the acyltransferase P300 in response to a hyperactivity of glycolysis, and promoted the proliferation and invasion of iCCA cells. Mechanistically, lactylated NCL bound to the primary transcript of MAP kinase-activating death domain protein (MADD) and led to efficient translation of MADD by circumventing alternative splicing that generates a premature termination codon. NCL lactylation, MADD translation and subsequent ERK activation promoted xenograft tumor growth and were associated with overall survival in patients with iCCA., Conclusion: NCL is lactylated to upregulate MADD through an RNA splicing-dependent mechanism, which potentiates iCCA pathogenesis via the MAPK pathway. Our findings reveal a novel link between metabolic reprogramming and canonical tumor-initiating events, and uncover biomarkers that can potentially be used for prognostic evaluation or targeted treatment of iCCA., Impact and Implications: Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive liver malignancy with largely uncharacterized pathogenetic mechanisms. Herein, we demonstrated that glycolysis promotes P300-catalyzed lactylation of nucleolin, which upregulates MAP kinase-activating death domain protein (MADD) through precise mRNA splicing and activates ERK signaling to drive iCCA development. These findings unravel a novel link between metabolic rewiring and canonical oncogenic pathways, and reveal new biomarkers for prognostic assessment and targeting of clinical iCCA., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Intrahepatic cholangiocarcinoma (iCCA) is the second most common malignant primary liver cancer. iCCA may develop on an underlying chronic liver disease and its incidence is growing in relation with the epidemics of obesity and metabolic diseases. In contrast, perihilar cholangiocarcinoma (pCCA) may follow a history of chronic inflammatory diseases of the biliary tract. The initial management of CCAs is often complex and requires multidisciplinary expertise. The French Association for the Study of the Liver wished to organize guidelines in order to summarize the best evidence available about several key points in iCCA and pCCA. These guidelines have been elaborated based on the level of evidence available in the literature and each recommendation has been analysed, discussed and voted by the panel of experts. They describe the epidemiology of CCA as well as how patients with iCCA or pCCA should be managed from diagnosis to treatment. The most recent developments of personalized medicine and use of targeted therapies are also highlighted., (© 2024 The Authors. Liver International published by John Wiley & Sons Ltd.)

The role of hypoxia in the tumor microenvironment of intrahepatic cholangiocarcinoma (iCCA) remains unclear. Here, we generated a comprehensive atlas of the entire tumor microenvironment and delineated the multifaceted cell-cell interactions to decipher hypoxia-induced pro-tumor immune suppression. We discovered hypoxia is significantly associated with iCCA progression via the activation of HIF1A expression. Moreover, hypoxia-dependent PPARγ-mediated fatty acid oxidation in APOE + TAMs promoted M2 macrophage polarization by activating the HIF1A-PPARG-CD36 axis. These polarized APOE + TAMs recruited Treg cell infiltration via the CCL3-CCR5 pair to form an immunosuppressive microenvironment. APOE + TAMs tended to co-localize spatially with Treg cells in the malignant tissue based on spatial transcriptome data and immunofluorescence analysis results. We identified tumor-reactive CXCL13 + CD8-PreTex with specific high expression of ENTPD1 and ITGAE, which acted as precursors of CD8-Tex and had higher cytotoxicity, lower exhaustion, and more vigorous proliferation. Consequently, CXCL13 + CD8-PreTex functioned as a positive regulator of antitumor immunity by expressing the pro-inflammatory cytokines IFNG and TNF, associated with a better survival outcome. Our study reveals the mechanisms involved in hypoxia-induced immunosuppression and suggests that targeting precursor-exhausted CXCL13 + CD8 + T cells might provide a pratical immunotherapeutic approach., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024. Published by Elsevier B.V.)

Introduction: Hepatocellular carcinoma is the most common form of primary liver cancer. Intrahepatic cholangiocarcinoma and fibrolamellar carcinoma make up most other cases. The vast majority of intrahepatic cholangiocarcinoma's are adenocarcinoma in nature. Few reports have indicated pure squamous cell or mixed squamous glandular histopathology., Presentation of Case: We present the case of a 35-year-old female whose preoperative diagnosis indicated primary keratinizing squamous cell carcinoma (SCC) of the liver. However, histological analysis of surgical resections later confirmed intrahepatic cholangiocarcinoma composed of 95 % squamous and 5 % glandular features., Discussion: The change in diagnosis post-operatively is indicative of the pre-operative diagnostic difficulties associated with these newly classified variants. While adenomatous differentiation is the most common form of intrahepatic cholangiocarcinoma, a squamous and mixed histology can be observed., Conclusion: Surgeons must be aware of new histological variants of cholangiocarcinoma, potential differentials, and direct further research to improve their poor prognosis., Competing Interests: Conflict of interest statement The authors have no conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: N-acetyltransferase 10 (NAT10) plays a crucial role in the occurrence and development of various tumors. However, the current regulatory mechanism of NAT10 in tumors is limited to its presence in tumor cells. Here, we aimed to reveal the role of NAT10 in intrahepatic cholangiocarcinoma (ICC) and investigate its effect on macrophage polarization in the tumor microenvironment (TME)., Methods: The correlation between NAT10 and ICC clinicopathology was analyzed using tissue microarray (TMA), while the effect of NAT10 on ICC proliferation was verified in vitro and in vivo. Additionally, the downstream target of NAT10, C-C motif chemokine ligand 2 (CCL2), was identified by Oxford Nanopore Technologies full-length transcriptome sequencing, RNA immunoprecipitation-quantitative polymerase chain reaction, and coimmunoprecipitation experiments. It was confirmed by co-culture that ICC cells could polarize macrophages towards M2 type through the influence of NAT10 on CCL2 protein expression level. Through RNA-sequencing, molecular docking, and surface plasmon resonance (SPR) assays, it was confirmed that berberine (BBR) can specifically bind CCL2 to inhibit ICC development., Results: High expression level of NAT10 was associated with poor clinicopathological manifestations of ICC. In vitro, the knockdown of NAT10 inhibited the proliferative activity of ICC cells and tumor growth in vivo, while its overexpression promoted ICC proliferation. Mechanically, by binding to CCL2 messenger RNA, NAT10 increased CCL2 protein expression level in ICC and their extracellular matrix, thereby promoting the proliferation of ICC cells and M2-type polarization of macrophages. BBR can target CCL2, inhibit ICC proliferation, and reduce M2-type polarization of macrophages., Conclusions: NAT10 promotes ICC proliferation and M2-type polarization of macrophages by up-regulating CCL2, whereas BBR inhibits ICC proliferation and M2-type polarization of macrophages by inhibiting CCL2., (© 2024. The Author(s).)

Rationale and Objectives: Identifying intrahepatic cholangiocarcinoma (iCCA) patients who are at high risk for early recurrence (ER) can guide personalized treatment strategy and improve survival. This study aimed to investigate the value of preoperative MRI, especially diffusion-weighted imaging, in predicting ER, including in patients receiving neoadjuvant therapy., Materials and Methods: This study included 175 pathologically-confirmed iCCA patients who underwent curative resection (114 men, 61 women; mean age 59.0 ± 9.56 years). MRI features, particularly apparent diffusion coefficient (ADC), were analyzed and compared between ER and non-ER cases. Survival analyses of ER were evaluated using Cox regression and Kaplan-Meier analysis., Results: ER occurred in 54.3% (95/175) of patients. Multivariate logistic regression analysis identified tumor ADC as the only independent predictor of ER (odds ratio = 0.034, P < 0.001), with AUCs of 0.758 (95%CI 0.664, 0.836) in the testing cohort and 0.779 (95%CI 0.622, 0.893) in the validation cohort. The optimal ADC threshold was 1.273 × 10 -3 mm 2 /s. Tumor ADC was comparable to the AJCC 8th staging system in predicting ER (AUC 0.758 vs 0.650 in testing cohort and 0.779 vs 0.661 in validation cohort). Multivariate Cox analysis identified high tumor burden score (HR = 1.109, P = 0.009), non-smooth margin (HR = 2.265, P = 0.008) and tumor ADC (HR = 0.111, P < 0.001) as independent risk factors for ER. Lower ADC values were linked to shorter RFS in both testing and validation cohorts (P < 0.001 and 0.0219), as well as in patients receiving neoadjuvant therapy (P = 0.003)., Conclusion: Preoperative MRI, particularly ADC, can help predict ER in iCCA, regardless of the application of neoadjuvant therapy, comparable to the AJCC 8th staging system., 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 Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Background: Several inflammatory indicators have been reported to have predictive value in many types of malignant cancer. This research was aimed to explore the ability of the monocyte-to-lymphocyte ratio (MLR) to predict prognosis in patients with intrahepatic cholangiocarcinoma (ICC) who subjected to curative hepatectomy., Methods: This retrospective analysis included 196 patients with ICC who underwent curative hepatectomy between May 2018 and April 2023. The predictive abilities of the preoperative MLR in assessing overall survival (OS) and disease-free survival (DFS) in those patients were compared with other inflammation-based scores, including monocyte-to-white ratio, neutrophil-to-lymphocyte ratio, neutrophil-to-white ratio, platelet-to-lymphocyte ratio, platelet-to-white ratio, and systemic immune-inflammation index, as well as tumor markers, like carcinoembryonic antigen (CEA) and carbohydrate antigen 19 - 9 (CA19-9)., Results: The area under the time-dependent receiver operating characteristic curve indicated that the preoperative MLR had higher predictive efficiency in contrast with other inflammation-based scores and tumor markers in assessing OS and DFS. Stratifying patients according to the optimal cut-off value for the preoperative MLR, the data showed that both OS and DFS in the high MLR group were significantly worse than those in the low MLR group (p < 0.05 for all). Univariable and multivariable Cox analyses revealed that the preoperative MLR was an independent risk factor for OS and DFS in patients with ICC. In addition to predicting OS in patients with high CEA levels and predicting DFS in patients with high CA19-9 levels, patients with different CEA and CA19-9 levels were divided into completely different OS and DFS subgroups based on the risk stratification of the preoperative MLR., Conclusions: Our results demonstrated that the preoperative MLR was a good prognosis indicator to predict DFS and OS following curative hepatectomy in patients with ICC., (© 2024. The Author(s).)

Background/aims: Extended hepatectomy combined with caudate lobe resection has been approved for the radical resection of hilar cholangiocarcinoma. There was a lack of credible research on the clinical value of caudate lobectomy (CL) for intrahepatic cholangiocarcinoma involving the hepatic hilus when combined with hepatectomy. We aimed to compare the short-term and long-term outcomes of the combined procedure with those of only CL for curative resection of intrahepatic cholangiocarcinoma involving the hepatic hilus., Methods: This single-center retrospective cohort study of patients with hilar cholangiocarcinoma was conducted from January 2007 to December 2021. Patients who underwent radical resection were enrolled in this study. The short-term and long-term clinical outcomes of the groups were compared before and after propensity score matching (PSM)., Results: A total of 282 patients were included. There were no statistically significant differences in perioperative clinical outcomes between the CL group and the non-CL group before and after PSM. Compared to patients in the non-CL group, patients in the CL group had significantly longer overall survival before and after PSM (p=0.007 before PSM, p=0.033 after PSM). Moreover, compared to the non-CL group, the CL group had longer disease-free survival before and after PSM (p<0.001 before PSM, p=0.019 after PSM)., Conclusions: The postoperative complications of the CL group were comparable to those of the non-CL group. CL improved the long-term survival of patients with intrahepatic cholangiocarcinoma involving the hepatic hilus when combined with hepatectomy. Therefore, hepatectomy combined with caudate lobe resection should be performed for patients with hilar cholangiocarcinoma.

Background: Older patients with advanced cholangiocarcinoma lack systemic therapy standards. These people have a high risk of chemotherapy, accompanied by adverse reactions and even discontinuation of treatment., Case Presentation: We report a 78-year-old female subject with advanced intrahepatic cholangiocarcinoma presenting with unresectable lesions involving the hepatic veins, along with extensive metastatic lymph nodes. After the geriatric assessment, capecitabine was utilized for only one cycle owing to adverse events (AEs). Next, a combination of low-dose lenvatinib and tislelizumab was administrated as a second-line treatment, which resulted in remarkable early tumor shrinkage. The following individual lenvatinib taper enabled a manageable safety profile and durable deep response. A near-complete response was achieved, with the primary tumor significantly reducing from 5.6 cm × 4.7 cm to nearly complete disappearance, accompanied by complete regression of lymph nodes, and both progression-free survival and overall survival exceeding 24 months., Conclusion: The case provides valuable insights that could influence future treatment strategies for older patients with advanced cholangiocarcinoma who are unsuitable for chemotherapy. The dose-individualized chemotherapy-free regime of lenvatinib and tislelizumab might be used in similar cases to improve their outcomes., 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 Zhang, Wang, Li, Li, Cheng and Cao.)

Celastrol (Cel) is a monomer from a famous traditional Chinese medicine named Tripterygium wilfordii Hook. f. Cel has shown great potential in treating intrahepatic cholangiocarcinoma (ICC) but still faces problems, including poor water solubility, high toxicity, and lack of targeting ability. Thus, the present work constructed a drug-delivery system using black fungus polysaccharide self-assembled -nanotubes (BFP). Cel-loaded nanotubes (BFP-Cel) were confirmed to have a high loading content of Cel (38 %), liver targeting, and enzyme-controlled release abilities. Moreover, BFP carriers could significantly increase the uptake efficiency of Cel by tumor cells. In vivo experiments showed that BFP-Cel could effectively inhibit tumor growth and reduce the physiological toxicity of Cel. Furthermore, BFP, as a carrier, could regulate the immune microenvironment in the liver through the activation of macrophages and play an immunomodulatory role. In summary, the BFP nanotube carrier could achieve detoxification and efficacy enhancement of Cel in treating ICC by increasing the targetability, controlled release ability, cell-uptake effect, and regulation of the immune microenvironment., 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.)

Primary liver cancer, including hepatocellular carcinoma and intrahepatic cholangiocarcinoma was the sixth leading cause of cancer death in the United States in 2023. Hispanic people constitute approximately 19% of the nation's total population according to the US Census. Hispanic patients have the highest relative incidence rates of liver cancer compared to non-Hispanic Whites and non-Hispanic Blacks, a disparity frequently overlooked in cancer research. In this study, our primary objective was to analyze the potential underrepresentation of Hispanic individuals in liver cancer research databases. We identified databases that had liver cancer-specific studies and be population-based in the United States. Our search yielded 7 cancer genomic databases, which were analyzed according to incidence percentages across ethnicity and race categories. Our study included 3104 patients; ethnic data was not reported for 13.1% (n = 406) of the patients. Samples were predominantly from individuals who identified as Not Hispanic (81.0%), Hispanic individuals represented 5.9%. Race was reported as follows: non-Hispanic Whites (61.0%), Asians (22.0%), non-Hispanic Blacks (5.4%), Other (3.1%), Native American/American Indian/Alaska Native (0.4%), Pacific Islander/Native Hawaiian (0.2%) and not reported (7.9%). These findings collectively underscore significant disparities in the representation of ethnic and racial groups, particularly Hispanics. Given the present racial and ethnic demographics of the US population and the projected surge in the Hispanic population in forthcoming years, it becomes imperative to address health disparities that may worsen without efforts to enhance proper inclusion in cancer research., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Intrahepatic bile duct mucinous adenocarcinoma (IHBDMAC) is a rare pathological subtype of intrahepatic cholangiocarcinoma (IHCC), and its tumor biological features and survival outcomes have rarely been explored, especially when compared to the most common subtype, intrahepatic bile duct adenocarcinoma (IHBDAC). Therefore, the aim of this study was to explore the clinical features and survival outcomes of IHBDAC and IHBDMAC using the Surveillance, Epidemiology, and End Results (SEER) database from 2000 to 2021. A total of 1,126 patients were included, with 1,083 diagnosed with IHBDAC and 43 diagnosed with IHBDMAC. Patients with IHBDMAC presented with a more advanced T stage (55.8% vs. 36.9%, P = 0.012) and higher rate of lymph node metastasis (37.2% vs. 24.9%, P = 0.070). Cox regression identified advanced T stage, lymph node metastasis, and distant metastasis as poor survival predictors, while chemotherapy and surgery were protective factors. Survival analyses revealed significantly worse overall survival (OS) and cancer-specific survival (CSS) for IHBDMAC compared to IHBDAC (P < 0.05). Even after matching, patients with IHBDMAC still had a worse prognosis than those with IHBDAC. These findings highlight the aggressive nature of IHBDMAC and the need for tailored therapeutic strategies. Future research should focus on prospective studies and molecular insights to develop targeted treatments for IHBDMAC.

Background: The impact of age on the causes of death (CODs) in patients with early-stage intrahepatic cholangiocarcinoma (ICC) who had undergone surgery was analyzed in this study., Methods: A total of 1555 patients (885 in the older group and 670 in the younger group) were included in this study. Before and after applying inverse probability of treatment weighting (IPTW), the different CODs in the 2 groups were further investigated. Additionally, 7 different machine learning models were used as predictive tools to identify key variables, aiming to evaluate the therapeutic outcome in early ICC patients undergoing surgery., Results: Before (5.92 vs. 4.08 years, P < 0.001) and after (6.00 vs. 4.08 years, P < 0.001) IPTW, the younger group consistently showed longer overall survival (OS) compared with the older group. Before IPTW, there were no significant differences in cholangiocarcinoma-related deaths (CRDs, P = 0.7) and secondary malignant neoplasms (SMNs, P = 0.78) between the 2 groups. However, the younger group had a lower cumulative incidence of cardiovascular disease (CVD, P = 0.006) and other causes (P < 0.001) compared with the older group. After IPTW, there were no differences between the 2 groups in CRDs (P = 0.2), SMNs (P = 0.7), and CVD (P = 0.1). However, the younger group had a lower cumulative incidence of other CODs compared with the older group (P < 0.001). The random forest (RF) model showed the highest C-index of 0.703. Time-dependent variable importance bar plots showed that age was the most important factor affecting the 2-, 4-, and 6-year survival, followed by stage and size., Conclusions: Our study confirmed that younger patients have longer OS compared with older patients. Further analysis of the CODs indicated that older patients are more likely to die from CVDs. The RF model demonstrated the best predictive performance and identified age as the most important factor affecting OS in early ICC patients undergoing surgery., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Multiple studies have shown that tumor-associated macrophages (TAMs) promote cancer initiation and progression. However, the reprogramming of macrophages in the tumor microenvironment (TME) and the cross-talk between TAMs and malignant subclones in intrahepatic cholangiocarcinoma (iCCA) has not been fully characterized, especially in a spatially resolved manner. Deciphering the spatial architecture of variable tissue cellular components in iCCA could contribute to the positional context of gene expression containing information pathological changes and cellular variability., Methods: Here, we applied spatial transcriptomics (ST) and digital spatial profiler (DSP) technologies with tumor sections from patients with iCCA., Results: The results reveal that spatial inter- and intra-tumor heterogeneities feature iCCA malignancy, and tumor subclones are mainly driven by physical proximity. Tumor cells with TME components shaped the intra-sectional heterogenetic spatial architecture. Macrophages are the most infiltrated TME component in iCCA. The protein trefoil factor 3 (TFF3) secreted by the malignant subclone can induce macrophages to reprogram to a tumor-promoting state, which in turn contributes to an immune-suppressive environment and boosts tumor progression., Conclusions: In conclusion, our description of the iCCA ecosystem in a spatially resolved manner provides novel insights into the spatial features and the immune suppressive landscapes of TME for iCCA., (© 2024. The Author(s).)

Background: Fluorine-18 fluorodeoxyglucose ([ 18 F]FDG) positron emission tomography/computed tomography (PET/CT) has some limitations in diagnosis of Intrahepatic cholangiocarcinoma (ICC)., Materials and Methods: Patients with histologically confirmed ICC who underwent both [ 18 F]FDG and 18 F-labeled fibroblast-activation protein inhibitors ([ 18 F]FAPI)-04 PET/CT were prospectively analyzed. The maximum standard uptake value (SUV max ), tumor-to-background ratio (TBR), metabolic tumor volume (MTV), total lesion glycolysis (TLG), [ 18 F]FAPI-avid tumor volume (FTV), total lesion fibroblast activation protein expression (TLF) were compared between the two modalities by paired Wilcoxon signed-rank test and Mann-Whitney U test, and McNemar's test was used to assess the diagnostic accuracy between the two techniques., Results: In total, 23 patients with 389 lesions were included. Compared to [ 18 F]FDG, [ 18 F]F-FAPI-04 PET/CT demonstrated a higher detection rate for intrahepatic lesions (86.3% vs. 78.2% P = 0.040), lymph node metastases (85.2% vs. 68.2%, P = 0.007), peritoneal metastases (100% vs. 93.8%), and bone metastases (100% vs. 70.5%, P < 0.001). [ 18 F]FAPI-04 PET showed higher SUV max , TBR and greater tumor burden values than [ 18 F]FDG PET in non-cholangitis intrahepatic lesions (SUV max : 8.7 vs. 6.4, P < 0.001; TBR: 8.0 vs. 3.5, P < 0.001; FTV vs. MTV: 41.3 vs. 12.4, P < 0.001; TLF vs. TLG: 223.5 vs. 57.0, P < 0.001), lymph node metastases (SUV max : 6.5 vs. 5.5, P = 0.042; TBR: 5.4 vs. 3.9, P < 0.001; FTV vs. MTV: 2.0 vs. 1.5, P = 0.026; TLF vs. TLG: 9.0 vs. 7.8 P = 0.024), and bone metastases (SUV max : 9.7 vs. 5.25, P < 0.001; TBR: 10.8 vs. 3.0, P < 0.001; TLF vs. TLG: 9.8 vs. 4.2, P < 0.001). However, [ 18 F]FDG showed higher radiotracer uptake (SUV max : 14.7 vs. 8.4, P < 0.001; TBR: 7.4 vs. 2.8, P < 0.001) than [ 18 F]FAPI-04 PET/CT for 6 patients with obstructive cholangitis. [ 18 F]FAPI-04 PET/CT yielded a change in planned therapy in 6 of 23 (26.1%) patients compared with [ 18 F]FDG., Conclusions: [ 18 F]FAPI-04 PET/CT had higher detection rate and radiotracer uptake than [ 18 F]FDG PET/CT in intrahepatic lesions, lymph node metastases, and distant metastases, especially in bone. Therefore, [ 18 F]FAPI-04 PET/CT may be a promising technique for diagnosis and staging of ICC., Trial Registration: Clinical Trials, NCT05485792. Registered 1 August 2022, retrospectively registered, https//clinicaltrials.gov/study/NCT05485792?cond=NCT05485792&rank=1., (© 2024. The Author(s).)

Background: Racial and sex disparities in the incidence and outcomes of patients with intrahepatic cholangiocarcinoma (iCCA) exist, yet potential genomic variations of iCCA based on race and sex that might be contributing to disparate outcomes have not been well studied., Methods: Data from the American Association for Cancer Research Project GENIE registry (version 15.0) were analyzed to assess genetic variations in iCCA. Adult patients (age >18 years) with histologically confirmed iCCA who underwent next-generation sequencing were included in the analytic cohort. Racial and sex variations in genomic profiling of iCCA were examined., Results: The study enrolled 1068 patients from 19 centers (White, 71.9%; Black, 5.1%; Asian, 8.4%, other, 14.6%). The male-to-female ratio was 1:1. The majority of the patients had primary tumors (73.7%), whereas 23.0% had metastatic disease sequenced. While IDH1 mutations occurred more frequently in White versus Black patients (20.8% vs. 5.6%; p = 0.021), FGFR2 mutations tended to be more common among Black versus White populations (27.8% vs. 16.1%; p = 0.08). Males were more likely to have TP53 mutations than females (24.3% vs. 18.2%, p = 0.016), whereas females more frequently had IDH1 (23.3% vs 16.0 %), FGFR2 (21.0% vs. 11.3%), and BAP1 (23.4% vs. 14.5%) mutations than males (all p < 0.05). Marked variations in the prevalence of other common genomic alterations in iCCA were noted across different races and sexes., Conclusion: Distinct genomic variations exist in iCCA across race and sex. Differences in mutational profiles of iCCA patients highlight the importance of including a diverse patient population in iCCA clinical trials as well as the importance of recognizing different genetic drivers that may be targetable to treat distinct patient cohorts., (© 2024. The Author(s).)

Background: Intrahepatic cholangiocarcinoma (ICC) is an aggressive and highly lethal cancer with an increasing incidence worldwide that lacks effective treatment regimens. Hypocrellin A (HA), a natural small compound isolated from S. bambusicola, has multiple biomedical activities, including antitumor activity., Purpose: We intended to investigate the therapeutic effects of HA on ICC and its potential mechanisms., Methods: RBE and HuccT1 cell lines were utilized for in vitro experiments. CCK8 assay, colony formation analysis, RTCA, and immunofluorescence staining of ki67 were employed to evaluate the suppression effects of HA on proliferation. The inhibitory effects of HA on cell migration and invasion were evaluate through transwell and wound healing assays, and Hoechst 33,258 staining was performed to evaluate apoptosis. Additionally, we performed transcriptome sequencing and molecular docking for targeting identification, and immunoblotting and immunofluorescence of key molecules for validation. Two in vivo models, HuccT1 xenografts, and the primary ICC model (KRAS/P19/SB) established via hydrodynamic tail-vein injection were implemented. Multiplex immunohistochemistry (mIHC) was used to illustrate the multi-target inhibitory effects of HA., Results: The IC50 values of HA against RBE and HuccT1 cells were 4.612 μM and 10.01 μM for 24 h, as determined through the CCK8 assay. Our results confirmed that HA significantly repressed the proliferation, migration, invasion, and promoted the apoptosis of ICC cells at low concentrations. Moreover, HA exerted its anti-cancer effects through multi-target inhibition of the PI3K-AKT-mTOR, MAPK, and STAT3 signaling pathways. This inhibitory effect was rescued by Recilisib, an activator of the PI3K-AKT-mTOR pathway. Bioinformatics analysis of a multi-center RNA-Seq cohort (n = 90) demonstrated significant associations between these target pathways and the occurrence and poor prognosis of ICC. Animal studies suggested that HA strongly inhibited tumor growth in xenograft ICC models, and repressed the tumor number and size in the liver of primary ICC models by suppressing these three crucial pathways., Conclusion: HA, a novel natural small molecule, demonstrated promising therapeutic efficacy against ICC through its multi-target inhibitory effects on the PI3K-AKT-mTOR, MAPK, and STAT3 signaling pathways. Moreover, it exhibited notable therapeutic benefits in a primary ICC model (KRAS/P19/SB), positioning it as a novel therapeutic agent for ICC., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

The tumour microenvironment (TME) of intrahepatic cholangiocarcinoma (iCCA) is complex and plays a role in prognosis and resistance to treatments. We aimed to decipher the iCCA TME phenotype using multiplex sequential immunohistochemistry (MS-IHC) to investigate which cell types and their spatial location may affect its prognosis. This was a retrospective study of 109 iCCA resected samples. For all cases, we used an open-source software to analyse a panel of markers (αSMA, FAP, CD8, CD163) by MS-IHC for characterize the different TME cells and their location. RNA sequencing was performed to determine the main iCCA transcriptomic classes. The association of the TME composition with overall survival (OS) was assessed by univariate and multivariate analyses. A high proportion of activated fibroblasts (FAP +) was significantly associated with poor OS (HR = 2.33, 95%CI = 1.43-3.81, p = 0.001). CD8 T lymphocytes excluded from the epithelial compartment were significantly associated with worse OS (HR = 1.86, 95% CI = 1.07-3.22, p = 0.014). The combination of a high proportion of FAP + fibroblasts and CD8 T lymphocytes excluded from the epithelial compartment, observed in 21 cases (19%), was significantly associated with poor OS on univariate (HR = 2.49, 95% CI = 1.44-4.28, p = 0.001) and multivariate analyses (HR = 2.77, 95% CI = 1.56-4.92, p < 0.001). In these cases, CD8 T lymphocytes were predominantly located at the tumour/non-tumour interface (19/21, 90%), and an association with the transcriptomic inflammatory stroma class was observed (10/21, 48%). Our results confirm the TME prognostic role in iCCA, highlighting the impact in the process of spatial heterogeneity, especially cell colocalization of immune and fibroblastic cells creating a peritumoural fibro-immune interface., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Intrahepatic cholangiocarcinoma (iCCA) is one of the most lethal malignancies and highly heterogeneous. We thus aimed to identify and characterize iCCA cell subpopulations with severe malignant features., Methods: Transcriptomic datasets from three independent iCCA cohorts (iCCA cohorts 1-3, n = 382) and formalin-fixed and paraffin-embedded tissues from iCCA cohort 4 (n = 31) were used. An unbiased global screening strategy was established, including the transcriptome analysis with the activated malignancy/stemness (MS) signature in iCCA cohorts 1-3 and the mass spectrometry analysis of the sorted stemness reporter-positive iCCA cells. A group of cellular assays and subcutaneous tumor xenograft assay were performed to investigate functional roles of the candidate. Immunohistochemistry was performed in iCCA cohort 4 to examine the expression and localization of the candidate. Molecular and biochemical assays were used to evaluate the membrane localization and functional protein domains of the candidate. Cell sorting was performed and the corresponding cellular molecular assays were utilized to examine cancer stem cell features of the sorted cells., Results: The unbiased global screening identified RRM2 as the top candidate, with a significantly higher level in iCCA patients with the MS signature activation and in iCCA cells positive for the stemness reporter. Consistently, silencing RRM2 significantly suppressed iCCA malignancy phenotypes both in vitro and in vivo. Moreover, immunohistochemistry in tumor tissues of iCCA patients revealed an unreported cell membrane localization of RRM2, in contrast to its usual cytoplasmic localization. RRM2 cell membrane localization was then confirmed in iCCA cells via immunofluorescence with or without cell membrane permeabilization, cell fractionation assay and cell surface biotinylation assay. Meanwhile, an unclassical signal peptide and a transmembrane domain of RRM2 were revealed experimentally. They were essential for RRM2 trafficking to cell membrane via the conventional endoplasmic reticulum (ER)-Golgi secretory pathway. Furthermore, the membrane RRM2-positive iCCA cells were successfully sorted. These cells possessed significant cancer stem cell malignant features including cell differentiation ability, self-renewal ability, tumor initiation ability, and stemness/malignancy gene signatures. Patients with membrane RRM2-positive iCCA cells had poor prognosis., Conclusions: RRM2 had an alternative cell membrane localization. The membrane RRM2-positive iCCA cells represented a malignant subpopulation with cancer stem cell features., (© 2024. The Author(s).)

Background: Intrahepatic cholangiocarcinoma (iCCA) is a lethal primary liver tumor characterized by clinical aggressiveness, poor prognosis, and scarce therapeutic possibilities. Therefore, new treatments are urgently needed to render this disease curable. Since cumulating evidence supports the oncogenic properties of the Heat Shock Factor 1 (HSF1) transcription factor in various cancer types, we investigated its pathogenetic and therapeutic relevance in iCCA., Methods: Levels of HSF1 were evaluated in a vast collection of iCCA specimens. The effects of HSF1 inactivation on iCCA development in vivo were investigated using three established oncogene-driven iCCA mouse models. In addition, the impact of HSF1 suppression on tumor cells and tumor stroma was assessed in iCCA cell lines, human iCCA cancer-associated fibroblasts (hCAFs), and patient-derived organoids., Results: Human preinvasive, invasive, and metastatic iCCAs displayed widespread HSF1 upregulation, which was associated with a dismal prognosis of the patients. In addition, hydrodynamic injection of a dominant-negative form of HSF1 (HSF1dn), which suppresses HSF1 activity, significantly delayed cholangiocarcinogenesis in AKT/NICD, AKT/YAP, and AKT/TAZ mice. In iCCA cell lines, iCCA hCAFs, and patient-derived organoids, administration of the HSF1 inhibitor KRIBB-11 significantly reduced proliferation and induced apoptosis. Cell death was profoundly augmented by concomitant administration of the Bcl-xL/Bcl2/Bcl-w inhibitor ABT-263. Furthermore, KRIBB-11 reduced mitochondrial bioenergetics and glycolysis of iCCA cells., Conclusions: The present data underscore the critical pathogenetic, prognostic, and therapeutic role of HSF1 in cholangiocarcinogenesis., (© 2024. The Author(s).)

Background: This study aims to investigate preoperative prognostic factors available for intrahepatic cholangiocarcinoma (ICC) patients and propose a new preoperative prognostic scoring system for ICC that combines CA19-9 and neutrophil/lymphocyte ratio (NLR)., Methods: In this retrospective analysis, 1728 patients diagnosed with ICC and undergoing curative liver resections were studied. This study employed univariate and multivariate Cox regression to find factors affecting recurrence and overall survival (OS), and furthermore assessed how preoperative models influenced tumor traits and postoperative recurrence., Results: The results of the multivariate Cox regression analysis indicated that two preoperative variables, NLR and Ca19-9, were independent risk factors affecting postoperative recurrence and OS in ICC patients. Based on this data, assigning a score of 0 (NLR ≤ 2.4 and Ca19-9 ≤ 37U/ml) or 1 (NLR > 2.4 and Ca19-9 > 37U/ml) to these two factors, a preoperative prognostic score was derived. According to the scoring model, patients were divided into three groups: 0 points (low-risk group), 1 point (intermediate-risk group), and 2 points (high-risk group). The 5-year recurrence and OS rates for the three groups were 56.6%, 68.2%, 77.8%, and 56.8%, 40.6%, 27.6%, respectively, with all P values < 0.001. Furthermore, high-risk group patients were more prone to early recurrence (early recurrence rates for high-, intermediate-, and low-risk groups were 56.8%, 51.5%, and 37.1%, respectively, P < 0.001) and extrahepatic metastasis (extrahepatic metastasis rates for high-, intermediate-, and low-risk groups were 31.7%, 26.4%, and 15.4%, respectively, P < 0.001). In terms of tumor characteristics, high-risk group patients had larger tumor diameters and were more likely to experience microvascular invasion, lymph node metastasis, and perineural invasion., Conclusions: The predictive capacity of postoperative recurrence and OS rates in ICC patients is effectively captured by the preoperative scoring system incorporating NLR and CA19-9 levels., (© 2024. The Author(s).)

Introduction: Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver cancer after hepatocellular carcinoma. Through data mining of publicly available iCCA transcriptomic datasets from the Gene Expression Omnibus, we identified SFN as the most significantly up-regulated gene in iCCA compared to normal tissue, focusing on the Gene Ontology term "cell proliferation" (GO:0008283). SFN encodes the 14-3-3σ protein, also known as stratifin, which plays crucial roles in various cellular processes., Materials and Methods: Immunohistochemistry was used to assess stratifin expression in 182 patients with localized iCCAs undergoing surgical resection. Patients were divided into low and high expression groups, and the association between stratifin expression and clinicopathological features was analyzed. Univariate and multivariate survival analyses were performed to assess overall survival (OS), disease-specific survival (DSS), local recurrence-free survival (LRFS), and metastasis-free survival (MeFS)., Results: Elevated stratifin expression in iCCAs was significantly associated with the absence of hepatitis, positive surgical margins, advanced primary tumor stages, and higher histological grades (all p ≤ 0.011). Survival analyses demonstrated a significant negative association between stratifin expression and all prognostic indicators, including OS, DSS, LRFS, and MeFS (all p ≤ 0.0004). Multivariate analysis revealed that stratifin overexpression was significantly correlated with poorer outcomes in terms of DSS, LRFS, and MeFS (all p < 0.001)., Conclusions: These findings suggest that stratifin may play a crucial role in iCCA oncogenesis and tumor progression, serving as a potential novel prognostic biomarker., (Copyright © 2024 Asian Surgical Association and Taiwan Society of Coloproctology. Published by Elsevier B.V. All rights reserved.)

Recent advancements in proteomics have shown promise in identifying biomarkers for various cancers. Our study is the first to compare the serum proteomes of intrahepatic cholangiocarcinoma (iCCA) with cirrhosis (CIR), primary sclerosing cholangitis (PSC), and hepatocellular carcinoma (HCC), aiming to identify a proteomic signature that can effectively distinguish among these conditions. Utilizing high-throughput mass spectrometry on serum samples, we identified 845 proteins, of which 646 were suitable for further analysis. Unique clustering patterns were observed among the five groups, with significant proteomic differences. Our key findings include: S100 calcium-binding protein A9 (S100A9) and haptoglobin (HP) were more abundant in iCCA, while intercellular adhesion molecule 2 (ICAM2) was higher in HCC. Serum amyloid A1 (SAA1) and A4 (SAA4) emerged as potential biomarkers, with SAA1 significantly different in the iCCA vs healthy controls (HC) comparison, and SAA4 in the HCC vs HC comparison. Elevated levels of vascular cell adhesion molecule 1 (VCAM-1) in HCC suggested its potential as a differentiation and diagnostic marker. Angiopoietin-1 receptor (TEK) also showed discriminatory and diagnostic potential in HCC. ELISA validation corroborated mass spectrometry findings. Our study underscores the potential of proteomic profiling in distinguishing iCCA from other liver conditions and highlights the need for further validation to establish robust diagnostic biomarkers., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Mocan, Grapa, Crăciun, Pralea, Uifălean, Soporan, Mureșan, Iacobescu, Al Hajjar, Mihu, Spârchez, Mocan and Iuga.)

Background and Aims: Intrahepatic cholangiocarcinoma (iCC) is an aggressive tumor, usually detected at an advanced stage. Our aim was to investigate the potential of body composition analysis (BCA) derived from presurgical staging computed tomography (CT) in predicting perisurgical complications., Methods: In this retrospective cohort study, we enrolled 86 patients who underwent CT imaging prior to liver surgery. Cox and logistic regression were performed to assess risk factors for prolonged hospital and intensive care unit (ICU) stays, as well as the occurrence of various complications. BCA parameters served as covariates besides conventional risk factors., Results: Postoperative complications after resection of iCC significantly prolonged the overall length of hospitalization (p < .001). Presence of sarcopenia was associated with longer ICU stays. Complications were common, with 62.5% classified as Clavien-Dindo grade IIIa or lower and 37.5% as more severe. Subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) were identified as risk factors for complications, including bile leakage (in 24 cases, p = .025), pleural effusions (in 26 cases, p = .025), and intra-abdominal abscess formation (in 24 cases, p = .043). SAT was associated with severe complications requiring interventional therapy, whereas VAT was correlated with abscess formation. Despite normal prevalence of obesity (22%), body mass index (BMI) did not have an impact on the development of perioperative complications., Conclusion: BCA is a useful tool for preoperative risk stratification in patients with iCC and is superior to BMI assessment. Increased SAT and VAT were associated with the risk of perisurgical complications, prolonging hospitalization. Therefore, BCA derived from routine staging CT should be considered in the preoperative assessment of patients with iCC., (© 2024 The Authors. Cancer Reports published by Wiley Periodicals LLC.)