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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background & Aims: Intrahepatic cholangiocarcinoma (iCCA) has two main histological subtypes: large and small duct‐type iCCA, which are characterized by different clinicopathological features. This study was conducted with the purpose of expanding our understanding of their differences in molecular features and immune microenvironment. Methods: We selected 132 patients who underwent radical surgery at our department between 2015 and 2021 for clinical and survival analyses. Whole‐exome sequencing was performed to analyse mutational landscapes. Bulk RNA sequencing and single‐cell RNA sequencing data were used for pathway enrichment and immune infiltration analyses based on differentially expressed genes. The function of PPP1R1B was analysed both in vitro and in vivo and the gene mechanism was further investigated. Results: We found that large duct‐type iCCA had worse overall survival and recurrence‐free survival rates than small duct‐type iCCA. Mutations in ARID1A, DOT1L and ELF3 usually occur in large duct‐type iCCA, whereas mutations in IDH1 and BAP1 occur in small duct‐type iCCA. Among the differentially expressed genes, we found that PPP1R1B was highly expressed in large duct‐type iCCA tumour tissues. Expression of PPP1R1B promoted cell proliferation, migration and invasion and indicated a worse prognosis. A combination of USF2 with the promoter of PPP1R1B can enhance gene expression in iCCA, which may further affect the expression of genes such as AHNAK, C4BPA and activating the PI3K/AKT pathway. Conclusions: Our findings extend our understanding of large and small duct‐type iCCA. In addition, PPP1R1B may serve as a potential marker and therapeutic target for large duct‐type iCCA. [ABSTRACT FROM AUTHOR]

Background: Over recent years, there has been a notable rise in the incidence of intrahepatic cholangiocarcinoma (iCCA), which presents a significant challenge in treatment due to its complex disease characteristics and prognosis. Notably, the identification of fibroblast growth factor receptor 2 (FGFR2) fusion/rearrangement, a potential oncogenic driver primarily observed in iCCA, raises questions about its impact on the prognostic outcomes of patients undergoing surgical intervention or other therapeutic approaches. Methods: A comprehensive search from inception to July 2023 was conducted across PubMed, Embase, Web of Science, and the Cochrane Library databases. The objective was to identify relevant publications comparing the prognosis of FGFR2 alterations and no FGFR2 alterations groups among patients with iCCA undergoing surgical resection or other systemic therapies. The primary outcome indicators, specifically Overall Survival (OS) and Disease‐Free Survival (DFS), were estimated using Hazard Ratios (HRs) with 95% confidence intervals (CIs), and statistical significance was defined as p <.05. Study quality was assessed using the Newcastle‐Ottawa Quality Assessment Scale. Statistical analyses were performed using Review Manager 5.4 software and Stata, version 12.0. Results: Six studies, involving 1314 patients (FGFR2 alterations group n = 173 and no FGFR2 alterations group n = 1141), were included in the meta‐analysis. The analysis revealed that the FGFR2 alterations group exhibited a significantly better OS prognosis compared to the no FGFR2 alterations group, with a fixed‐effects combined effect size HR = 1.31, 95%CI = 1.001–1.715, p =.049. Furthermore, meta‐regression and subgroup analysis showed that the length of the follow‐up period did not introduce heterogeneity into the results. This finding indicates the stability and reliability of the study outcomes. Conclusion: The current study provides compelling evidence that FGFR2 alterations are frequently associated with improved survival outcomes for patients with iCCA undergoing surgical resection or other systemic treatments. Additionally, the study suggests that FGFR2 holds promise as a safe and dependable therapeutic target for managing metastatic, locally advanced or unresectable iCCA. This study offers a novel perspective in the realm of targeted therapy for iCCA, presenting a new and innovative approach to its treatment. [ABSTRACT FROM AUTHOR]

DICER1 syndrome is a tumor predisposition syndrome caused by familial genetic mutations in DICER1. Pathogenic variants of DICER1 have been discovered in many rare cancers, including cystic liver tumors. However, the molecular mechanisms underlying liver lesions induced by these variants remain unclear. In the present study, we sought to gain a better understanding of the pathogenesis of these variants by generating a mouse model of liver‐specific DICER1 syndrome. The mouse model developed bile duct hyperplasia with fibrosis, similar to congenital hepatic fibrosis, as well as cystic liver tumors resembling those in Caroli's syndrome, intrahepatic cholangiocarcinoma, and hepatocellular carcinoma. Interestingly, the mouse model of DICER1 syndrome showed abnormal formation of primary cilia in the bile duct epithelium, which is a known cause of bile duct hyperplasia and cyst formation. These results indicated that DICER1 mutations contribute to cystic liver tumors by inducing defective primary cilia. The mouse model generated in this study will be useful for elucidating the potential mechanisms of tumorigenesis induced by DICER1 variants and for obtaining a comprehensive understanding of DICER1 syndrome. © 2024 The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Background: Tertiary lymphoid structures (TLSs) have prognostic value in intrahepatic cholangiocarcinoma (ICC) patients. Noninvasive tool to preoperatively evaluate TLSs is still lacking. Purpose: To explore the association between TLSs status of ICC and preoperative MRI radiomics analysis. Study Type: Retrospective. Subjects: One hundred and ninety‐two patients with ICC, divided into training (T = 105), internal validation groups (V1 = 46), and external validation group (V2 = 41). Sequence: Coronal and axial single‐shot fast spin‐echo T2‐weighted, diffusion‐weighted imaging, T1‐weighted, and T1WI fat‐suppressed spoiled gradient‐recall echo LAVA sequence at 3.0 T. Assessment: The VOIs were drawn manually within the visible borders of the tumors using ITK‐SNAP version 3.8.0 software in the axial T2WI, DWI, and portal vein phase sequences. Radiomics features were subjected to least absolute shrinkage and selection operator regression to select the associated features of TLSs and construct the radiomics model. Univariate and multivariate analyses were used to identify the clinical radiological variables associated with TLSs. The performances were evaluated by the area under the receiver operator characteristic curve (AUC). Statistical Tests: Logistic regression analysis, ROC and AUC, Hosmer–Lemeshow test, Kaplan–Meier method with the log‐rank test, calibration curves, and decision curve analysis. P < 0.05 was considered statistically significant. Results: The AUCs of arterial phase diffuse hyperenhancement were 0.59 (95% confidence interval [CI], 0.50–0.67), 0.52 (95% CI, 0.43–0.61), and 0.66 (95% CI, 0.52–0.80) in the T, V1, and V2 cohorts. The AUCs of Rad‐score were 0.85 (95% CI, 0.77–0.92), 0.81 (95% CI, 0.67–0.94), and 0.84 (95% CI, 0.71–0.96) in the T, V1, and V2 cohorts, respectively. In cohort T, low‐risk group showed significantly better median recurrence‐free survival (RFS) than that of the high‐risk group, which was also confirmed in cohort V1 and V2. Data Conclusion: A preoperative MRI radiomics signature is associated with the intratumoral TLSs status of ICC patients and correlate significantly with RFS. Level of Evidence: 3 Technical Efficacy: Stage 2 [ABSTRACT FROM AUTHOR]

Aim: Tumor Ki‐67 expression reflects prognosis and cancer grade, and biopsy‐based preoperative assessment of Ki‐67 expression is key to treatment. Apparent diffusion coefficient (ADC) values obtained with this imaging may noninvasively predict Ki‐67 by reflecting tumor cell density and limited water molecule movement from irregular alignment. This study aimed to investigate the ability of ADC values to predict Ki‐67 expression in intrahepatic cholangiocarcinoma (ICC). Method: We retrospectively analyzed 39 cases of ICC confirmed by surgical pathology. All patients had undergone magnetic resonance imaging, and ADC values (mean, minimum, and maximum) were calculated. Ki‐67 expression was assessed by immunohistochemistry, and patients were divided into groups of high (n = 18) and low (n = 21) Ki‐67 expression. To assess the diagnostic performance of the ADC values for Ki‐67 expression, we used the receiver operating characteristic curve and compared the areas under the curve (AUC). Results: The mean and minimum ADC values were significantly lower in the group with high Ki‐67 expression. For predicting high Ki‐67 expression, the AUC values were 0.701 for mean ADC, 0.818 for minimum ADC, and 0.571 for maximum ADC. The diagnostic sensitivity and specificity of the minimum ADC values were 88.9% and 76.2%, respectively. In addition, with ADC values combined, the AUC increased to 0.831. Apparent diffusion coefficient is a useful predictor of Ki‐67 expression level in ICC. Conclusion: Apparent diffusion coefficient values, especially minimum ADC values, can noninvasively predict ICC associated with high Ki‐67 expression. [ABSTRACT FROM AUTHOR]

Background: Intrahepatic cholangiocarcinoma (iCCA) has a poor prognosis and limited treatment options. Aprepitant, a selective NK-1R antagonist, can inhibit the growth of various tumours in vitro and in vivo. However, it remains unclear whether aprepitant has cytotoxic effects on iCCA. Methods: We measured the expression of SP/NK-1R in clinical samples of iCCA by immunohistochemistry. Then, we detected the cytotoxic effects of aprepitant on iCCA cells via MTT, EdU and colony formation assay. We constructed a subcutaneous xenograft model of BALB/c nude mice by using HCCC-9810 and RBE cell lines to explore the effects of aprepitant in vivo. To elucidate the potential mechanisms, we explored the pro-apoptotic effect of aprepitant by flow cytometric, western blotting, ROS detection and JC-1 staining. Furthermore, we detected the autophagic level of HCCC-9810 and RBE by western blotting, mRFP-eGFP-LC3 adenovirus transfection and electron microscope. Results: SP/NK-1R is significantly expressed in iCCA. Aprepitant inhibited human iCCA xenograft growth and dose-dependently decreased the viability of RBE and HCCC-9810 cells. Aprepitant-induced mitochondria-dependent apoptosis through ROS/JNK pathway. Additionally, pretreatment with z-VAD-fmk partly reversed the effect of aprepitant on cell viability, while NAC completely attenuated the cytotoxic effects of aprepitant in vitro. Furthermore, we observed the dynamic changes of au-tophagosome in RBE and HCCC-9810 cells treated with aprepitant. Conclusion: SP/NK-1R signalling is significantly activated in iCCA and promotes the proliferation of iCCA cells. By contrast, aprepitant can induce autophagy and apoptosis in iCCA cells via ROS accumulation and subsequent activation of JNK. [ABSTRACT FROM AUTHOR]

Tumour morphology (tumour burden score (TBS)) and liver function (albumin‐to‐alkaline phosphatase ratio (AAPR)) have been shown to correlate with outcomes in intrahepatic cholangiocarcinoma (ICC). This study aimed to evaluate the combined predictive effect of TBS and AAPR on survival outcomes in ICC patients. We conducted a retrospective analysis using a multicentre database of ICC patients who underwent curative surgery from 2011 to 2018. The Kaplan–Meier method was employed to examine the relationship between a new index (combining TBS and AAPR) and long‐term outcomes. The predictive efficacy of this index was compared to other conventional indicators. A total of 560 patients were included in the study. Based on TBS and AAPR stratification, patients were classified into three groups. Kaplan–Meier curves demonstrated that 124 patients with low TBS and high AAPR had the best overall survival (OS) and recurrence‐free survival (RFS), while 170 patients with high TBS and low AAPR had the worst outcomes (log‐rank p < 0.001). Multivariate analyses identified the combined index as an independent predictor of OS and RFS. Furthermore, the index showed superior accuracy in predicting OS and RFS compared to other conventional indicators. Collectively, this study demonstrated that the combination of liver function and tumour morphology provides a synergistic effect in evaluating the prognosis of ICC patients. The novel index combining TBS and AAPR effectively stratified postoperative survival outcomes in ICC patients undergoing curative resection. [ABSTRACT FROM AUTHOR]

Aim Methods Results Conclusion Cognitive behavioral stress management (CBSM) has been introduced for the postoperative cancer management, but its application in intrahepatic cholangiocarcinoma (ICC) is rare. This current study constructed an offline to online CBSM (OO‐CBSM) program and applying multiple assessing scales, aiming at exploring the benefits of OO‐CBSM regarding anxiety, depression, spiritual well‐being, and quality of life (QoL) in postoperative ICC patients.The study randomly assigned 68 postoperative ICC patients into OO‐CBSM (N = 34) and normal care (NC) (N = 34) groups to undergo 10‐week interventions. Hospital anxiety‐and‐depression scale (HADS), Zung's self‐reporting anxiety scale (SAS), and depression scale (SDS), functional‐assessment of chronic‐illness therapy‐spiritual well‐being scale (FACIT‐Sp), European quality‐of‐life‐5 dimensions (EQ‐5D), and quality‐of‐life questionnaire‐core30 (QLQ‐C30) were assessed within 6 months (M).HADS‐anxiety scores at M3 (P = 0.049) and M6 (P = 0.009), SAS score at M6 (P = 0.028), HADS‐depression score at M3 (P = 0.043), and SDS scores at M3 (P = 0.044) and M6 (P = 0.028), were lower in the OO‐CBSM group versus the NC group. Meanwhile, FACIT‐Sp scores at M1 (P = 0.042) and M6 (P = 0.003) were higher in the OO‐CBSM group over the NC group. Besides, EQ‐5D scores at M3 (P = 0.067) and M6 (P = 0.087) disclosed trends to be lower in the OO‐CBSM group versus the NC group, but not statistically significant. QLQ‐C30‐global‐health scores at M3 (P = 0.049) and M6 (P = 0.033), and QLQ‐C30‐function score at M6 (P = 0.046), were higher in OO‐CBSM group over NC group; but QLQ‐C30‐symptom score was not significantly different at any timepoints between them.OO‐CBSM attenuates anxiety and depression, and advances spiritual well‐being and QoL in postoperative ICC patients, indicating its potency for the ICC postoperative management. [ABSTRACT FROM AUTHOR]

Intrahepatic cholangiocarcinoma (iCCA) is a highly lethal biliary epithelial cancer in the liver. Here, Laminin subunit gamma‐2 (LAMC2) with important oncogenic roles in iCCA is discovered. In a total of 231 cholangiocarcinoma patients (82% of iCCA patients) across four independent cohorts, LAMC2 is significantly more abundant in iCCA tumor tissue compared to normal bile duct and non‐tumor liver. Among 26.3% of iCCA patients, LAMC2 gene is amplified, contributing to its over‐expression. Functionally, silencing LAMC2 significantly blocks tumor formation in orthotopic iCCA mouse models. Mechanistically, it promotes EGFR protein translation via interacting with nascent unglycosylated EGFR in the endoplasmic reticulum (ER), resulting in activated EGFR signaling. LAMC2‐mediated EGFR translation also depends on its interaction with the ER chaperone BiP via their C‐terminus. Together LAMC2 and BiP generate a binding "pocket" of nascent EGFR and facilitate EGFR translation. Consistently, LAMC2‐high iCCA patients have poor prognosis in two iCCA cohorts. LAMC2‐high iCCA cells are highly sensitive to EGFR tyrosine kinase inhibitors (TKIs) treatment both in vitro and in vivo. Together, these data demonstrate LAMC2 as an oncogenic player in iCCA by promoting EGFR translation and an indicator to identify iCCA patients who may benefit from available EGFR‐targeted TKIs therapies. [ABSTRACT FROM AUTHOR]

Background: Cholangiocarcinoma (CCA) is a fatal cancer of the bile duct with a poor prognosis owing to limited therapeutic options. The incidence of intrahepatic CCA (iCCA) is increasing worldwide, and its molecular basis is emerging. Environmental factors may contribute to regional differences in the mutation spectrum of European patients with iCCA, which are underrepresented in systematic genomic and transcriptomic studies of the disease. Methods: We describe an integrated whole‐exome sequencing and transcriptomic study of 37 iCCAs patients in Germany. Results: We observed as most frequently mutated genes ARID1A (14%), IDH1, BAP1, TP53, KRAS, and ATM in 8% of patients. We identified FGFR2::BICC1 fusions in two tumours, and FGFR2::KCTD1 and TMEM106B::ROS1 as novel fusions with potential therapeutic implications in iCCA and confirmed oncogenic properties of TMEM106B::ROS1 in vitro. Using a data integration framework, we identified PBX1 as a novel central regulatory gene in iCCA. We performed extended screening by targeted sequencing of an additional 40 CCAs. In the joint analysis, IDH1 (13%), BAP1 (10%), TP53 (9%), KRAS (7%), ARID1A (7%), NF1 (5%), and ATM (5%) were the most frequently mutated genes, and we found PBX1 to show copy gain in 20% of the tumours. According to other studies, amplifications of PBX1 tend to occur in European iCCAs in contrast to liver fluke‐associated Asian iCCAs. Conclusions: By analyzing an additional European cohort of iCCA patients, we found that PBX1 protein expression was a marker of poor prognosis. Overall, our findings provide insight into key molecular alterations in iCCA, reveal new targetable fusion genes, and suggest that PBX1 is a novel modulator of this disease. [ABSTRACT FROM AUTHOR]

Backgrounds Methods Results Conclusion Liver resection plus lymphadenectomy is essential to ensure precise staging in patients with intrahepatic cholangiocarcinoma (ICC). This study aimed to investigate the influence of the clinical status of lymph nodes on the survival outcomes in ICC patients.Between January 2015 and December 2020, consecutive patients diagnosed with ICC who underwent liver resection plus lymphadenectomy were enrolled. Clinical assessment of lymph node status included positron emission tomography/computed tomography examination by radiologists pre‐operatively, alongside intraoperative abdominal examination by the surgical team. Retrospective collection and analysis of clinical information alongside survival data were performed to assess outcomes.The study included a total of 359 patients, with 291 (81.0%) and 151 (42.1%) displaying clinically and pathologically positive lymph nodes, respectively. The clinical assessment method had a sensitivity of 81.2% and a specificity of 54.3%. Following a median follow‐up period of 32 months, the overall survival (OS) rates at 1, 3, and 5 years were 69.1%, 50.6%, and 41.2%, respectively, while the disease‐free survival (DFS) rates were 60.7%, 42.8%, and 40.1%, respectively, across the cohort. Patients who had clinically positive but pathologically negative lymph nodes recorded the highest median OS (52 months) and median DFS (32 months). Conversely, those who were clinically negative but pathologically positive experienced the lowest median OS (16 months) and median DFS (8 months).The current approach to clinically assessing lymph node status in ICC has a significant rate of false positives. Patients with clinically positive but pathologically negative lymph nodes exhibit the most favourable survival outcomes. [ABSTRACT FROM AUTHOR]

Background: Intrahepatic cholangiocarcinoma (ICC) has a high recurrence rate and a poor prognosis. Thus, the development of effective treatment and prognostic biomarkers is required. High expression of diacylglycerol kinase alpha (DGKα) is a prognostic factor for the recurrence of hepatocellular carcinoma. However, the relationship between DGKα expression and prognosis in ICC has not been reported. Methods: Immunohistochemistry (IHC) with anti‐DGKα antibody was performed on surgical specimens of ICC (n = 69). First, DGKα expression in cancer cells was qualitatively classified into four groups (−, 1+, 2+, 3+) and divided into two groups (DGKα− and DGKα+1 + to 3+). The relationship between clinical features and DGKα expression was analyzed. Second, Ki‐67 expression was evaluated as a cell proliferation marker. The number of Ki‐67‐positive cells was counted, and the relationship with DGKα expression was examined. Results: DGKα IHC divided the patients into a DGKα+ group (1+: n = 15; 2+: n = 5; 3+: n = 5) and a DGKα− group (−: n = 44). In the DGKα+ group, patients were older and had advanced disease. Both overall survival and recurrence‐free survival (RFS) were significantly worse in the DGKα+ patients. DGKα+ was identified as an independent prognostic factor for RFS by multivariate analysis. Furthermore, the number of Ki‐67‐positive cells increased in association with the staining levels of DGKα. Conclusion: Pathological DGKα expression in ICC was a cancer proliferation marker associated with recurrence. This suggests that DGKα may be a potential therapeutic target for ICC. [ABSTRACT FROM AUTHOR]

Introduction: Intrahepatic cholangiocarcinoma (ICC) is characterized by a dismal prognosis with limited therapeutic alternatives. To explore phosphatase and tension homolog (PTEN) as a biomarker for proteasome inhibition in ICC, we conducted a phase II trial to assess the second‐line efficacy of bortezomib in PTEN‐deficient advanced ICC patients. Methods: A total of 130 patients with advanced ICC in our centre were screened by PTEN immunohistochemical staining between 1 July 2017, and 31 December 2021, and 16 patients were ultimately enrolled and treated with single‐agent bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11 of a 21‐day cycle. The primary endpoint was the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors v1.1. Results: The median follow‐up was 6.55 months (95% confidence interval [CI]: 0.7–19.9 months). Among the 16 enrolled patients, the ORR was 18.75% (3/16) and the disease control rate was 43.75% (7/16). The median progress‐free survival was 2.95 months (95% CI: 2.1–5.1 months) and the median overall survival (mOS) was 7.2 months (95% CI: 0.7–21.6 months) in the intent‐to‐treat‐patients. Treatment‐related adverse events of any grade were reported in 16 patients, with thrombopenia being the most common toxicity. Patients with PTEN staining scores of 0 were more likely to benefit from bortezomib than those with staining scores > 0. Conclusions: Bortezomib yielded an encouraging objective response and a favourable OS as a second‐line agent in PTEN‐deficient ICC patients. Our findings suggest bortezomib as a promising therapeutic option for patients with PTEN‐deficient ICC. Highlights: There is a limited strategy for the second‐line option of intrahepatic cholangiocarcinoma (ICC).This investigator‐initiated phase 2 study evaluated bortezomib in ICC patients with phosphatase and tension homology deficiency.The overall response rate was 18.75% and the overall survival was 7.2 months in the intent‐to‐treat cohort.These results justify further developing bortezomib in ICC patients with PTEN deficiency. [ABSTRACT FROM AUTHOR]

Cholangiolocarcinoma (CLC) is a primary liver carcinoma that resembles the canals of Hering and that has been reported to be associated with stem cell features. Due to its rarity, the nature of CLC remains unclear, and its pathological classification remains controversial. To clarify the positioning of CLC in primary liver cancers and identify characteristics that could distinguish CLC from other liver cancers, we performed integrated analyses using whole‐exome sequencing (WES), immunohistochemistry, and a retrospective review of clinical information on eight CLC cases and two cases of recurrent CLC. WES demonstrated that CLC includes IDH1 and BAP1 mutations, which are characteristic of intrahepatic cholangiocarcinoma (iCCA). A mutational signature analysis showed a pattern similar to that of iCCA, which was different from that of hepatocellular carcinoma (HCC). CLC cells, including CK7, CK19, and EpCAM, were positive for cholangiocytic differentiation markers. However, the hepatocytic differentiation marker AFP and stem cell marker SALL4 were completely negative. The immunostaining patterns of CLC with CD56 and epithelial membrane antigen were similar to those of the noncancerous bile ductules. In contrast, mutational signature cluster analyses revealed that CLC formed a cluster associated with mismatch‐repair deficiency (dMMR), which was separate from iCCA. Therefore, to evaluate MMR status, we performed immunostaining of four MMR proteins (PMS2, MSH6, MLH1, and MSH2) and detected dMMR in almost all CLCs. In conclusion, CLC had highly similar characteristics to iCCA but not to HCC. CLC can be categorized as a subtype of iCCA. In contrast, CLC has characteristics of dMMR tumors that are not found in iCCA, suggesting that it should be treated distinctly from iCCA. © 2024 The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Background: Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive malignancy characterized by a poor prognosis and closely linked to tumor stemness. However, the key molecules that regulate ICC stemness remain elusive. Although Y‐box binding protein 1 (YBX1) negatively affects prognosis in various cancers by enhancing stemness and chemoresistance, its effect on stemness and cisplatin sensitivity in ICC remains unclear. Methods: Three bulk and single‐cell RNA‐seq datasets were analyzed to investigate YBX1 expression in ICC and its association with stemness. Clinical samples and colony/sphere formation assays validated the role of YBX1 in stemness and sensitivity to cisplatin. AZD5363 and KYA1979K explored the interaction of YBX1 with the phosphatidylinositol 3‐kinase (PI3K)/protein kinase B (PKB/AKT) and WNT/β‐catenin pathways. Results: YBX1 was significantly upregulated in ICC, correlated with worse overall survival and shorter postoperative recurrence time, and was higher in chemotherapy‐non‐responsive ICC tissues. The YBX1‐high group exhibited significantly elevated stemness scores, and genes linked to YBX1 upregulation were enriched in multiple stemness‐related pathways. Moreover, YBX1 expression is significantly correlated with several stemness‐related genes (SOX9, OCT4, CD133, CD44 and EPCAM). Additionally, YBX1 overexpression significantly enhanced the colony‐ and spheroid‐forming abilities of ICC cells, accelerated tumor growth in vivo and reduced their sensitivity to cisplatin. Conversely, the downregulation of YBX1 exerted the opposite effect. The transcriptomic analysis highlighted the link between YBX1 and the PI3K/AKT and WNT/β‐catenin pathways. Further, AZD5363 and KYA1979K were used to clarify that YBX1 promoted ICC stemness through the regulation of the AKT/β‐catenin axis. Conclusions: YBX1 is upregulated in ICC and promotes stemness and cisplatin insensitivity via the AKT/β‐catenin axis. Our study describes a novel potential therapeutic target for improving ICC prognosis. [ABSTRACT FROM AUTHOR]

Patients with concurrent intrahepatic cholangiocarcinoma (ICC) and hepatolithiasis generally have poor prognoses. Hepatolithiasis is once considered the primary cause of ICC, although recent insights indicate that bacteria in the occurrence of hepatolithiasis can promote the progression of ICC. By constructing in vitro and in vivo ICC models and patient‐derived organoids (PDOs), it is shown that Escherichia coli induces the production of a novel RNA, circGLIS3 (cGLIS3), which promotes tumor growth. cGLIS3 binds to hnRNPA1 and G3BP1, resulting in the assembly of stress granules (SGs) and suppression of hnRNPA1 and G3BP1 ubiquitination. Consequently, the IKKα mRNA is blocked in SGs, decreasing the production of IKKα and activating the NF‐κB pathway, which finally results in chemoresistance and produces metastatic phenotypes of ICC. This study shows that a combination of Icaritin (ICA) and gemcitabine plus cisplatin (GP) chemotherapy can be a promising treatment strategy for ICC. [ABSTRACT FROM AUTHOR]

Background: The diagnosis of intrahepatic cholangiocarcinoma (iCCA) is challenging in hepatitis B virus (HBV)‐infected patients, due to the overlapping clinical manifestations and atypical imaging patterns compared to patients without HBV. Purpose: To investigate the preoperative imaging characteristics of iCCA in patients with HBV in comparison to those without HBV. Study Type: Retrospective. Subjects: 431 patients with histopathologically confirmed iCCA (143 HBV‐positive and 288 HBV‐negative patients) were retrospectively enrolled from three institutes, and patients were allocated to the training (n = 302) and validation (n = 129) cohorts from different institutes or time period; 100 matching HBV‐positive hepatocellular carcinoma (HCC) patients were also enrolled. Field Strength/Sequence: 1.5‐T and 3‐T, including T1‐ and T2‐weighted, diffusion‐weighted and dynamic gadopentetate dimeglumine‐enhanced imaging. Assessment: Clinical and MRI features were analyzed and compared between HBV‐positive and HBV‐negative patients with iCCA, and between HBV‐positive patients with iCCA and HCC. Statistical Tests: Univariate and multivariate logistic regression analyses with odds ratio (OR) to identify independent features for discriminating HBV‐associated iCCA. Diagnostic model generation by incorporating independent features, and the performance for discrimination was evaluated by receiver operating characteristics with the area under the curve (AUC) and 95% confidence interval (CI). AUCs were compared by the DeLong's method. A P‐value <0.05 was considered statistically significant. Results: Compared to patients without HBV, washout or degressive enhancement pattern (OR = 51.837), well‐defined tumor margin (OR = 8.758) and no peritumoral bile duct dilation (OR = 4.651) were independent significant features for discriminating HBV‐associated iCCAs. All these features were also the predominant MRI manifestations for HBV‐associated HCC. The combined index showed an AUC of 0.798 (95% CI 0.748–0.842) in the training cohort and an AUC of 0.789 (95% CI 0.708–0.856) in the validation cohort for discrimination. The sensitivity, specificity, and accuracy were all >70%, which was superior to each single feature alone in both cohorts. [Correction added after first online publication on 29 June 2023. The Field Strength/Sequence has been updated from 5‐T to 1.5‐T.] Data Conclusion: Preoperative MRI may help to discriminate HBV‐associated iCCA. Evidence Level: 3 Technical Efficacy Stage: 2 [ABSTRACT FROM AUTHOR]

Intrahepatic cholangiocarcinoma (ICC) is a highly malignant and aggressive cancer whose incidence and mortality continue to increase, whereas its prognosis remains dismal. Tumor‐associated macrophages (TAMs) promote malignant progression and immune microenvironment remodeling through direct contact and secreted mediators. Targeting TAMs has emerged as a promising strategy for ICC treatment. Here, we revealed the potential regulatory function of immune responsive gene 1 (IRG1) in macrophage polarization. We found that IRG1 expression remained at a low level in M2 macrophages. IRG1 overexpression can restrain macrophages from polarizing to the M2 type, which results in inhibition of the proliferation, invasion, and migration of ICC, whereas IRG1 knockdown exerts the opposite effects. Mechanistically, IRG1 inhibited the tumor‐promoting chemokine CCL18 and thus suppressed ICC progression by regulating STAT3 phosphorylation. The intervention of IRG1 expression in TAMs may serve as a potential therapeutic target for delaying ICC progression. [ABSTRACT FROM AUTHOR]

Background and Aims: To measure the impact of socio-economic environment on the incidence of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Method: The study used data from the French Network of Cancer Registries (FRANCIM) between 2006 and 2016. Classification of patients into HCC and iCCA was performed according to the topographical and morphological codes of the 3rd edition of the International Classification of Diseases for Oncology. Patient addresses were geolocalized and assigned to an IRIS, the smallest French geographic unit. Socio-economic environment was assessed by the European Deprivation Index (EDI). Sex- and age-standardized incidence rates with 95% confidence intervals (CI) were estimated per 100 000 inhabitants, by national quintiles, for each IRIS, sex and age group. Quintile 1 (Q1) characterized the most affluent areas. A Poisson regression was performed to model the impact of deprivation. Results: We included 22 249 cases (79.64% HCC, 16.97% iCCA). Incidence rates were 11.46 and 2.39 per 100 000 person-years for HCC and iCCA, respectively. There was an over-incidence of HCC in quintiles 2, 3, 4 and 5 compared to quintile 1: Q1 10.28 [9.9--10.66] per 100 000 person-years, Q2 11.43 [10.48--12.47] (p < .0001), Q3 11.81 [10.82--12.89] (p < .0001), Q4 12.26 [11.25--13.37] (p < .001) and Q5 11.53 [10.57-- 12.57] (p < .0001). By contrast, there was no difference for iCCa. Deprivation was significantly associated with HCC in men (p = .0018) and women (p = .0009), but not with iCCA (p = .7407). Conclusion: The incidence of HCC is related to socio-economic environment, unlike iCCA. HCC and iCCA should be studied separately in epidemiological studies. [ABSTRACT FROM AUTHOR]

Background and Aims: Sarcopenia is associated with poor prognosis, but its role in older patients with intrahepatic cholangiocarcinoma (ICC) is unclear. We aimed to evaluate the impact of sarcopenia on the prognosis of older patients with ICC undergoing hepatectomy. Methods: A total of 363 patients with ICC following hepatectomy from 2015 to 2021 were retrospectively reviewed at five institutions. Sarcopenia was evaluated using skeletal muscle index by computed tomography images. Patients were divided into four subgroups according to sarcopenia and age. Postoperative outcomes including complication, overall survival (OS) and recurrence‐free survival (RFS) were evaluated. Risk factors were identified through univariate and multivariate Cox regression analyses. Results: 302 patients were included in the analysis. The median age was 63 years and there were 128 patients (42.4%) aged over 65 years. 192 patients (63.6%) were diagnosed with sarcopenia, while 180 patients (59.6%) experienced myosteatosis. Older patients experienced a higher incidence of sarcopenia and myosteatosis, and worse postoperative outcomes than younger patients. In the subgroup of patients with sarcopenia, older patients experienced a significant shorter OS than younger patients, which was not observed in patients without sarcopenia. According to the multivariate Cox regression analysis, lymphatic metastasis (p <.001), blood transfusion (p =.004), low serum albumin (p =.051), sarcopenia (p =.024), and myosteatosis (p =.004) were identified as independent risk factors of OS in older patients, meanwhile tumour size (p =.013) and lymphatic metastasis (p <.001) were independent risk factors of RFS. Conclusions: Sarcopenia and myosteatosis have a significant adverse impact on postoperative outcomes in older patients with ICC undergoing hepatectomy. [ABSTRACT FROM AUTHOR]

TP53‐induced glycolysis and apoptosis regulator (TIGAR) is an important gene that encodes a regulatory enzyme of glycolysis and reactive oxygen species (ROS) detoxification and is associated with worse prognosis in various cancers. Ferroptosis is a recently identified type of programmed cell death that is triggered by iron‐dependent lipid peroxidation. There are no reports on the prognostic impact of TIGAR on intrahepatic cholangiocarcinoma (ICC), and its role in ferroptosis is unclear. Ninety ICC patients who had undergone hepatic resection were enrolled. Immunohistochemical staining for TIGAR was performed. The regulation of malignant activity by TIGAR and the association between ferroptosis and TIGAR were investigated in vitro. Twenty‐two (24.4%) patients were categorized into TIGAR‐high and ‐low groups by immunohistochemical staining. There were no noticeable differences in background factors between the two groups, but TIGAR positivity was an independent prognostic factor in disease‐free survival (hazard ratio [HR], 2.00; 95% confidence interval [CI], 1.04–3.85, p = 0.0378) and overall survival (HR, 2.10; 95% CI, 1.03–4.30, p = 0.00422) in a multivariate analysis. In vitro, TIGAR knockdown (KD) decreased cell motility (cell proliferation/migration/invasion/colony‐forming capabilities) and elevated ROS and lipid peroxidation. This indicated that TIGAR KD induced ferroptosis. TIGAR KD‐induced ferroptosis was suppressed using liproxstatin. TIGAR KD decreased the expression of glutathione peroxidase 4, known as factor‐suppressing ferroptosis. The combination of TIGAR KD with cisplatin significantly induced more ferroptosis. In conclusion, TIGAR is associated with poor outcomes in ICC patients and resistance to ferroptosis. [ABSTRACT FROM AUTHOR]

Aim: The prognosis of patients with resected intrahepatic cholangiocarcinoma (ICC) is still unsatisfactory, with a high recurrence rate. We aimed to evaluate risks of recurrence changing over time and the survival benefit of resection for recurrent ICC. Methods: This study included patients who underwent hepatectomy for ICC during 1995–2020. Risk factors for recurrence‐free survival (RFS) in patients undergoing initial resection and overall survival (OS) in patients who developed recurrence after initial resection were analyzed. Conditional cumulative incidence of recurrence was assessed. Results: A total of 169 patients were included in the study and 114 patients (67.5%) developed recurrence. Cumulative analyses showed that the 5‐year recurrence rate was 69.3% at the time of initial resection but decreased to 24.8% in patients free from recurrence at 2 years after initial resection and 2.6% in patients free from recurrence at 4 years. Re‐resection was carried out in 26 (22.8%) of 114 patients who developed recurrence. Multivariable Cox proportional hazards model analysis indicated re‐resection (hazard ratio [HR] 0.19; 95% confidence interval [CI] 0.11–0.40, p < 0.001), microvascular invasion (MVI) (HR 2.39; 95% CI 1.05–5.40, p = 0.037), and disease‐free interval (months) (HR 0.97; 95% CI 0.95–1.00, p = 0.067) were significantly associated with longer OS after recurrence. Conclusions: Although the rate of recurrence remains high, conditional cumulative recurrence rate analysis showed that the rate of recurrence decreased by disease‐free interval. Resection of recurrent ICC was associated with improved OS, particularly among patients with longer disease‐free interval and absence of MVI after initial hepatectomy. [ABSTRACT FROM AUTHOR]

Intrahepatic cholangiocarcinoma (ICC) is characterized by its dense fibrotic microenvironment and highly malignant nature, which are associated with chemotherapy resistance and very poor prognosis. Although circRNAs have emerged as important regulators in cancer biology, their role in ICC remains largely unclear. Herein, a circular RNA, cPKM is identified, which is upregulated in ICC and associated with poor prognosis. Silencing cPKM in ICC cells reduces TGFB1 release and stromal fibrosis, inhibits STMN1 expression, and suppresses ICC growth and metastasis, moreover, it also leads to overcoming paclitaxel resistance. This is regulated by the interactions of cPKM with miR‐199a‐5p or IGF2BP2 and by the ability of cPKM to stabilize STMN1/TGFB1 mRNA. Based on these findings, a Trojan horse nanotherapy strategy with co‐loading of siRNA against cPKM (si‐cPKM) and paclitaxel (PTX) is developed. The siRNA/PTX co‐loaded nanosystem (Trojan horse) efficiently penetrates tumor tissues, releases si‐cPKM and paclitaxel (soldiers), promotes paclitaxel sensitization, and suppresses ICC proliferation and metastasis in vivo. Furthermore, it alleviates the fibrosis of ICC tumor stroma and reopens collapsed tumor vessels (opening the gates), thus enhancing the efficacy of the standard chemotherapy regimen (main force). This novel nanotherapy provides a promising new strategy for ICC treatment. [ABSTRACT FROM AUTHOR]

For the 23rd Nationwide Follow‐up Survey of Primary Liver Cancer in Japan, data from 20 889 newly registered patients and 42 274 previously registered follow‐up patients were compiled from 516 institutions over a 2‐year period from January 1, 2014 to December 31, 2015. Basic statistics compiled for patients newly registered in the 23rd survey were cause of death, past medical history, clinical diagnosis, imaging diagnosis, treatment‐related factors, pathological diagnosis, recurrence status, and autopsy findings. Compared with the previous 22nd survey, the population of patients with hepatocellular carcinoma (HCC) was older at the time of clinical diagnosis, had more female patients, had more patients with non‐B non‐C HCC, had smaller tumor diameter, and was more frequently treated with hepatectomy. Cumulative survival rates were calculated for HCC, intrahepatic cholangiocarcinoma, and combined hepatocellular cholangiocarcinoma (combined HCC and intrahepatic cholangiocarcinoma) by treatment type and background characteristics for patients newly registered between 2004 and 2015 whose final outcome was survival or death. The median overall survival and cumulative survival rates for HCC were calculated by dividing patients by combinations of background factors (number of tumors, tumor diameter, Child–Pugh grade, or albumin‐bilirubin grade) and by treatment type (hepatectomy, radiofrequency ablation therapy, transcatheter arterial chemoembolization, hepatic arterial infusion chemotherapy, and systemic therapy). The same values were also calculated according to registration date by dividing patients newly registered between 1978 and 2015 into five time period groups. The data obtained from this nationwide follow‐up survey are expected to contribute to advancing clinical research and treatment of primary liver cancer in the world. [ABSTRACT FROM AUTHOR]

Summary: Background: Immune checkpoint inhibitor (ICI) combination therapy offers a new option for treatment of unresectable intrahepatic cholangiocarcinoma (uICC). Aim: To compare the effect of different anti‐PD‐1 combination therapies as the first‐line treatments for uICC. Methods: This study included 318 patients who received chemotherapy alone (Chemo), anti‐PD‐1 plus chemotherapy (ICI‐chemo), anti‐PD‐1 plus targeted therapy (ICI‐target) or anti‐PD‐1 plus targeted therapy and chemotherapy (ICI‐target‐chemo) as first line for uICC from 22 centres in China. The primary endpoint was progression‐free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR) and safety. Results: Patients with ICI‐chemo (median PFS [mPFS], 6.3 months; HR: 0.61, 95% CI: 0.42–0.88; p = 0.008; median OS [mOS], 10.7 months; HR: 0.61, 95% CI: 0.39–0.94; p = 0.026), ICI‐target (7.2 months; HR: 0.54, 95% CI: 0.36–0.80; p = 0.002; 15.8 months; HR: 0.54, 95% CI: 0.35–0.84; p = 0.006) or ICI‐target‐chemo (6.9 months; HR: 0.65, 95% CI: 0.47–0.90; p = 0.009; 14.4 months; HR: 0.47, 95% CI: 0.31–0.70; p < 0.001) achieved better clinical outcomes than those with Chemo (3.8 months; 9.3 months). ICI‐target was not inferior to ICI‐chemo in survival outcomes (HR for PFS: 0.88, 95% CI: 0.55–1.42; p = 0.614; HR for OS: 0.89, 95% CI: 0.51–1.55; p = 0.680). ICI‐target‐chemo yielded similar prognoses as ICI‐chemo (HR for PFS: 1.07, 95% CI: 0.70–1.62; p = 0.764; HR for OS: 0.77, 95% CI: 0.45–1.31; p = 0.328) and ICI‐target (HR for PFS: 1.20, 95% CI: 0.77–1.88; p = 0.413; HR for OS: 0.86, 95% CI: 0.51–1.47; p = 0.583) but resulted in more adverse events (p < 0.001; p = 0.010). Multivariable and propensity score analyses supported these findings. Conclusions: Among patients with uICC, ICI‐chemo or ICI‐target provided more survival benefits than Chemo while achieving comparable prognoses and fewer adverse events than ICI‐target‐chemo. [ABSTRACT FROM AUTHOR]

Aims: Given that bile duct adenoma was significantly more prevalent in the liver with small duct type intrahepatic cholangiocarcinoma (small duct iCCA), compared to other primary liver carcinomas, we examined the possibility of bile duct adenoma as a precursor of small duct iCCA by analysing genetic alterations and other features in bile duct adenomas. Methods and results: Subjects included 33 bile duct adenomas and 17 small‐sized (up to 2 cm in diameter) small duct iCCAs. Genetic alterations were examined by direct sequencing for hot‐spot regions and immunohistochemical staining. The expression of p16INK4a, EZH2 and IMP3 and stromal and inflammatory components were also examined. Genetic alterations examined including BRAF were not detected in bile duct adenomas, whereas genetic alterations of p53 (47%), ARID1A (41%), PBRM1 (12%), MTAP (12%), IDH1 (6%), KRAS (6%) and TERT promoter (6%) were detected in 16 small‐sized small duct iCCA (94%) (P < 0.01). The expression of IMP3 and EZH2 was not detected in bile duct adenomas, whereas it was detected in most small duct iCCA (94%) (P < 0.01). Immature stroma and neutrophilic infiltration were significantly more prevalent in small duct iCCA, compared to bile duct adenoma (P < 0.01). Conclusion: Bile duct adenomas and small‐sized small duct iCCAs show distinct differences in genetic alterations, expression of IMP3 and EZH2 and stromal and inflammatory components. There was no evidence suggesting that bile duct adenoma is a precursor of small duct iCCA. Immunohistochemical staining for IMP3, EZH2, p53, ARID1A and MTAP may be useful for differential diagnosis between bile duct adenomas and small duct iCCAs. [ABSTRACT FROM AUTHOR]

Key Clinical Message: The liquid CGP was useful for detecting FGFR2 fusion and the patient experienced typical side effects (nail disorders, hyperphosphatemia, and taste disorders) of pemigatinib that required treatment. [ABSTRACT FROM AUTHOR]

Aims: The fibroblast growth factor receptor 2 (FGFR2) fusion gene is frequently found as a genetic abnormality in the FGFR pathway in patients with intrahepatic cholangiocarcinoma (ICC). The FGFR fusion protein, produced from the FGFR fusion gene, is thought to cause tumor cell growth. To date, there have been few reports on the relationship between pathologic FGFR2 expression and prognosis in patients who have undergone hepatectomy for ICC, and on the relationship between FGFR2 and tumor‐infiltrating lymphocytes (TILs). Methods and Results: We enrolled 92 patients who underwent hepatectomy for ICC and performed immunohistochemical staining for FGFR2 and cluster of differentiation 8, and hematoxylin and eosin staining for evaluating TILSs. The relationships between the FGFR2 and clinicopathological characteristics and outcomes were analyzed, and patients were classified into positive (n = 18) and negative (n = 74) FGFR2 groups. The FGFR2‐positive group contained more men (p < 0.0001) and had lower serum albumin (p = 0.0355) and higher carcinoembryonic antigen (p = 0.0099). Furthermore, multivariable analyses revealed that the FGFR2‐positive group had worse disease‐free survival (DFS) (p = 0.0002). Multivariate analysis showed that the independent prognostic factors for DFS were maximum tumor size (≥5 cm) (p = 0.0011), tumor localization (perihilar type) (p = 0.0180), and FGFR2 positivity (p = 0.0029). There was no significant difference in TILs count between the two groups. Conclusion: We showed that FGFR2 high expression was an independent prognostic factor for recurrence of resected ICC. [ABSTRACT FROM AUTHOR]

Aims: Lymph node metastases (LNM) are associated with lethal prognosis in intrahepatic cholangiocarcinoma (ICC). Lymphadenectomy is crucial for accurate staging and hopes of possible oncological treatment. However, the therapeutic implications and optimal extent of lymphadenectomy remain contentious. Methods: To clarify the prognostic value and optimal extent of lymphadenectomy, the therapeutic index (TI) for each lymph node was analyzed for 279 cases that had undergone lymphadenectomy in a multi‐institutional database. Tumor localization was divided into hilar lesions (n = 130), right peripheral lesions (n = 60), and left peripheral lesions (n = 89). In addition, the lymph node station was classified as Level 1 (LV1: hepatoduodenal ligament node), Level 2 (LV2: postpancreatic or common hepatic artery nodes), or Level 3 (LV3: gastrocardiac, left gastric artery, or celiac artery nodes). Results: Lymph node metastases were confirmed in 109 patients (39%). Five‐y survival rates were 45.3% for N0 disease, 27.1% for LV1‐LNM, 22.9% for LV2‐LNM, and 7.3% for LV3‐LNM (P < 0.001). LV3‐LNM were the most frequent and earliest recurrence outcome, including multisite recurrence, followed by LV2, LV1, and N0 disease. The 5‐year TI (5year‐TI) for lymphadenectomy was 7.2 for LV1, 5.5 for LV2, and 1.9 for LV3. Regarding tumor location, hilar lesions showed 5‐year TI >5.0 in LV1 and LV2, whereas bilateral peripheral lesions showed 5‐year TI > 5.0 in LV1. Conclusion: The implications and extent of lymphadenectomy for ICC appear to rely on tumor location. In the peripheral type, the benefit of lymphadenectomy would be limited and dissection beyond LV1 should be avoided, while in the hilar type, lymphadenectomy up to LV2 could be recommended. [ABSTRACT FROM AUTHOR]

Background: The role of carbonic anhydrase II (CAII) in intrahepatic cholangiocarcinoma (ICC) was investigated and a novel prognostic system combining CAII and preoperative carbohydrate antigen 19‐9 (CA19‐9) was established to predict the survival of patients with ICC after curative resection. Methods: A total of 110 patients who underwent curative‐intent resection for ICC between 2012 and 2020 were retrospectively analyzed. CAII in tumor and peritumor regions was examined by immunohistochemistry, and the relationships between clinicopathological factors and the prognostic value of CAII and CA19‐9 were analyzed. Results: CAII was frequently downregulated in ICC tissues (p <.001). Multivariate analyses indicated that showed that both low CAII expression level and preoperative CA19‐9 ≥236 U/ml were independent risk factors for overall survival (OS) and recurrence‐free survival (RFS) in patients with ICC after radical resection. Survival analysis revealed that patients with high CAII and low CA19‐9 were significantly associated with a better OS and RFS (p <.001). The time‐dependent receiver operating characteristic curves showed that CAII + CA19‐9 had better prognostic predictive ability than CAII or CA19‐9 alone. The nomogram constructed on independent factors including T stage, lymph node metastasis, CA19‐9 (continuous variable), and CAII achieved C‐indexes of 0.754 (95% CI, 0.701–0.807) and 0.730 (0.674–0.785) for OS and RFS, respectively. The calibration curve revealed acceptable agreement between actual and predicted OS and RFS. Conclusions: The combination of CAII and preoperative CA19‐9 is a novel and useful prognostic tool for predicting the survival of patients with ICC after curative resection and guiding clinical decisions. Plain Language Summary: Carbonic anhydrase II (CAII) was frequently downregulated in intrahepatic cholangiocarcinoma (ICC) tissues.Survival analysis revealed that CAII is a novel independent factor for prognosis in patients with ICC after curative resection. CAII could be a useful prognostic marker for patients with ICC after surgery.The combination of CAII and preoperative carbohydrate antigen 19‐9 is a novel and useful prognostic tool for predicting the survival of patients with ICC after curative resection and guiding clinical decisions. Carbonic anhydrase II (CAII) is a novel independent factor for prognosis in patients with intrahepatic cholangiocarcinoma (ICC) after curative resection. Combining CAII and preoperative carbohydrate antigen 19‐9 can more effectively predict the survival of patients with ICC after curative resection, which could influence decision‐making regarding the possible benefit of surgery or other treatment strategies. [ABSTRACT FROM AUTHOR]

Purpose: To comprehensively investigate the implications of lymph node dissection (LND) and the prognostic impact of the number of lymph node (LN) metastases on survival in intrahepatic cholangiocarcinoma (ICC) using a large‐scale study. Methods: Patients who underwent surgical resection for ICC between 2004 and 2018 were identified from the Surveillance, Epidemiology, and End Results (SEER) registries. The Kaplan–Meier and log‐rank tests were used to compare cancer‐specific survival (CSS) and overall survival (OS) between different groups. Propensity score matching (PSM) and subgroup analyses were performed to balance potential confounding factors. A multivariate Cox proportional hazards regression model was used to identify prognostic factors of survival outcomes. Restricted cubic splines fitted in the Cox proportional hazard regression models were also conducted to examine associations between continuous variables and outcomes. Results: In all, 1028 patients were enrolled. There were 652 (63.4%) patients undergoing LND, with lymph node metastasis (LNM) confirmed in 212 (32.5%) cases. Patients receiving LND did not show better survival outcomes than those receiving non‐LND (NLND). We divided the LND group into two subgroups: patients with LNM (+) and those without LNM (−). Among these three groups, patients with LNM experienced the worst CSS and OS, while NLND patients had similar survival times to LNM (−) patients. Restricted cubic spline analysis indicated that an increased number of LNM was associated with a decreased chance of survival (p < 0.001). Patients who received LND were further categorized as having no nodal metastasis (N0), 1–2 LNM (N1), or ≥3 LNM (N2) according to the number of LNM. The Kaplan–Meier curves showed that the mortality risk of patients with N0, N1, and N2 disease (median CSS, N0 50.0 vs. N1 22.0 vs. N2 14.0 months; median OS, N0 46.0 vs. N1 21.0 vs. N2 14.0 months, all p < 0.01) increased significantly, except for patients who had <6 LNs harvested. On multivariable survival analysis, a higher nodal stage (N1 vs. N0: CSS, hazard ratio [HR] 2.135, 95% CI 1.636–2.788, p < 0.001; OS, HR 2.100, 95% CI 1.624–2.717, p < 0.001; N2 vs. N0: CSS, HR 4.027, 95% CI 2.791–5.811, p < 0.001; OS, HR 3.678, 95% CI 2.561–5.282, p < 0.001) was an independent prognostic risk factor for survival. Conclusions: Despite the lack of a clear survival benefit of LND in patients with ICC, a significant positive association between the number of LNM and poor outcomes was observed. We still suggest adequate LND by examining at least six LNs to ensure precise staging. On this basis, the recently proposed nodal classification of N0, N1, and N2 stages may also allow better prognostic stratification of ICC patients. [ABSTRACT FROM AUTHOR]

Background: Intrahepatic cholangiocarcinoma (iCCA) is a highly lethal malignancy characterized by massive fibrosis and has ineffective adjuvant therapies. Here, we demonstrate the potential of angiotensin receptor blockers (ARBs) in targeting iCCA. Methods: Masson's trichrome staining was used to assess the effect of ARBs in iCCA specimens, CCK8 and gel contraction assays in vitro and in xenograft models in vivo. RNA‐seq and ATAC‐seq were used for mechanistic investigations. Results: Patients with iCCA who were administered ARBs had a better prognosis and a lower proportion of tumour stroma, indicating alleviated fibrosis. The presence of AGTR1, the ARBs receptor, is associated with a poor prognosis of iCCA and is highly expressed in tumour tissues and cancer‐associated fibroblasts (CAFs). The ARBs strongly attenuated the viability of AGTR1+CAFs in vitro and retarded tumour progression and fibrosis in xenograft models of co‐cultured CAFs and iCCA cells. Still, they did not have a significant effect on AGTR1−CAFs. Moreover, ARBs decreased the secretion of AGTR1+CAF‐derived MFAP5 via the Hippo pathway, weakened the interaction between CAFs and iCCA cells, and impaired the aggressiveness of iCCA cells by attenuating the activation of the Notch1 pathway in iCCA cells. Conclusions: ARBs exhibit anti‐fibrotic function by inhibiting the viability of AGTR1+CAFs. These findings support using ARBs as a novel therapeutic option for targeting iCCA. [ABSTRACT FROM AUTHOR]

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver tumor and remains a fatal malignancy in the majority of patients. Approximately 20%–30% of patients are eligible for resection, which is considered the only potentially curative treatment; and, after resection, a median survival of 53 months has been reported when sequenced with adjuvant capecitabine. For the 70%–80% of patients who present with locally unresectable or distant metastatic disease, systemic therapy may delay progression, but survival remains limited to approximately 1 year. For the past decade, doublet chemotherapy with gemcitabine and cisplatin has been considered the most effective first‐line regimen, but results from the recent use of triplet regimens and even immunotherapy may shift the paradigm. More effective treatment strategies, including those that combine systemic therapy with locoregional therapies like radioembolization or hepatic artery infusion, have also been developed. Molecular therapies, including those that target fibroblast growth factor receptor and isocitrate dehydrogenase, have recently received US Food and Drug Administration approval for a defined role as second‐line treatment for up to 40% of patients harboring these actionable genomic alterations, and whether they should be considered in the first‐line setting is under investigation. Furthermore, as the oncology field seeks to expand indications for immunotherapy, recent data demonstrated that combining durvalumab with standard cytotoxic therapy improved survival in patients with ICC. This review focuses on the current and future strategies for ICC treatment, including a summary of the primary literature for each treatment modality and an algorithm that can be used to drive a personalized and multidisciplinary approach for patients with this challenging malignancy. [ABSTRACT FROM AUTHOR]

The association between tumor microenvironment (TME) and cancer‐associated fibroblasts (CAFs) in intrahepatic cholangiocarcinoma (ICC) progression is poorly understood. This study aimed to reveal whether specific microRNAs (miRNAs) in extracellular vesicles (EVs) derived from CAFs were involved in ICC progression. Conditioned medium (CM) and EVs in the CM of CAFs and normal fibroblasts (NFs) derived from ICC specimens were used to investigate the effects on tumor cell lines. miRNA microarray assay was used to examine the miRNAs of EVs derived from CAFs and NFs in ICC, and the effects of miR‐493‐5p on tumor cell lines were examined. Additionally, databases were used to identify miR‐493‐5p targets, and the relationship between prognosis of ICC patients and cocaine‐ and amphetamine‐regulated transcript propeptide (CARTPT), one of the targets of miR‐493‐5p, expression in ICC tissues was retrospectively analyzed. Compared with NF‐derived CM and EVs, CAF‐derived CM and EVs promoted cell lines in proliferation, scratch, migration, and invasion assays. miRNA microarray analysis revealed that miR‐493‐5p was significantly increased in CAF‐derived EVs compared to NF‐derived EVs. Tumor cell lines transfected with miR‐493‐5p were promoted in proliferation and scratch assays. Immunohistochemical staining was performed on 76 ICC specimens; both overall and recurrence‐free survival rates were significantly worse in the CARTPT‐negative group. Univariate and multivariate analyses showed that low CARTPT expression was an independent poor prognostic factor for overall and recurrence‐free survival. Overall, our data suggest that CAFs in the ICC TME suppress CARTPT in tumor cells and promote tumor cells via miR‐493‐5p in EVs. [ABSTRACT FROM AUTHOR]

Background: The Liver Imaging Reporting and Data System (LI‐RADS) is a comprehensive system for standardizing the terminology and interpretation of liver imaging. The association between the LI‐RADS category and tumor recurrence in patients with intrahepatic cholangiocarcinomas (iCCAs) has not yet been evaluated in a multicenter study. Purpose: To retrospectively investigate the preoperative clinical and imaging features associated with recurrence‐free survival (RFS) after curative resection of iCCAs and to identify the role of the LI‐RADS category in at‐risk patients. Study Type: Retrospective, multicenter. Subjects: A total of 113 patients (mean age: 61.1 years; 74 men, 39 women) who underwent preoperative contrast‐enhanced MRI and curative surgical resection for a single treatment‐naive iCCA between 2008 and 2021. Filed Strength/Sequence: A 3 T dual gradient‐echo T1WI with in‐ and opposed‐phase, turbo spin‐echo T2WI, diffusion‐weighted echo‐planar images, and three‐dimensional gradient‐echo T1WI before and after administration of contrast agent. Assessment: MR imaging features were evaluated and assigned for each lesion using LI‐RADS version 2018. RFS was calculated from the date of surgery to tumor recurrence or the last imaging date without evidence of recurrence. Factors affecting RFS were evaluated using clinical and imaging features. Statistical Tests: Cox proportional hazards model, Kaplan–Meier method, and log‐rank test. A P‐value of <0.05 was considered statistically significant. Results: A total of 93 (82.3%) were categorized as LR‐M and 20 (17.7%) were categorized as LR‐4 or 5. In the multivariable analysis, LR‐M category (hazard ratio [HR], 8.035; 95% confidence interval [CI], 1.096–58.931) and a tumor size >3 cm on MRI (HR, 2.690; 95% CI, 1.319–5.487) were independent factors for poor RFS. The 5‐year RFS rate was significantly higher in patients with iCCA categorized as LR‐4 or 5 than in those categorized as LR‐M (94.4% vs. 51.9%, respectively). Data Conclusion: Patients with iCCA categorized as LR‐4 or 5 may have a better RFS than those categorized as LR‐M. Evidence Level: 3 Technical Efficacy: Stage 2 [ABSTRACT FROM AUTHOR]

Background and Aims: Observational epidemiology studies suggested a relationship between the gut microbiome and primary liver cancer. However, the causal relationship remains unclear because of confounding factors and reverse causality. We aimed to explore the causal role of the gut microbiome in the development of primary liver cancer, including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Methods: Mendelian randomization (MR) study was conducted using summary statistics from genome‐wide association studies (GWAS) of the gut microbiome and liver cancer, and sequencing data from a case–control study validated the findings. A 5‐cohort GWAS study in Germany (N = 8956) served as exposure, whilst the UK biobank GWAS study (N = 456 348) served as an outcome. The case–control study was conducted at the First Affiliated Hospital of Wenzhou Medical University from December 2018 to October 2020 and included 184 HCC patients, 63 ICC patients and 40 healthy controls. Results: A total of 57 features were available for MR analysis, and protective causal associations were identified for Family_Ruminococcaceae (OR = 0.46 [95% CI, 0.26–0.82]; p =.009) and Genus_Porphyromonadaceae (OR = 0.59 [95% CI, 0.42–0.83]; p =.003) with HCC, and for Family_Porphyromonadaceae (OR = 0.36 [95% CI, 0.14–0.94]; p =.036) and Genus_Bacteroidetes (OR = 0.55 [95% CI, 0.34–0.90]; p =.017) with ICC respectively. The case–control study results showed that the healthy controls had a higher relative abundance of Family_Ruminococcaceae (p =.00033), Family_Porphyromonadaceae (p =.0055) and Genus_Bacteroidetes (p =.021) than the liver cancer patients. Conclusions: This study demonstrates that Ruminococcaceae, Porphyromonadaceae and Bacteroidetes are related to a reduced risk of liver cancer (HCC or ICC), suggesting potential significance for the prevention and control of liver cancer. [ABSTRACT FROM AUTHOR]

Background: Biliary tract cancers (BTCs), encompassing cholangiocarcinoma (CCA), gallbladder (GBC), and ampulla of Vater cancers (AVC), are common hepatobiliary cancer after hepatocellular carcinoma with a high mortality rate. As there is no effective chemopreventive agent to prevent BTCs, this study aimed to explore the role of statins on the risk of BTCs. Methods: PubMed, Embase, and Cochrane Library from inception until 24 April 2020 were searched according to the Meta‐Analyses of Observational Studies in Epidemiology (MOOSE) guidelines. The adjusted risk ratios (aRRs) of BTCs and individual cancer were pooled using a random‐effects model. Results: Eight observational studies (3 cohort and 5 case–control studies) were included with 10,485,231 patients. The median age was 68.0 years (IQR: 67.0–71.5) and 48.3% were male. Statins were associated with a lower risk of all BTCs (aRR: 0.67; 95% CI: 0.51–0.87). The pooled aRR for CCA was 0.60 (95% CI: 0.38–0.94) and GBC was 0.78 (95% CI: 0.68–0.90). There was only one study on AVC with aRR of 0.96 (95% CI: 0.66–1.41). The pooled aRR for lipophilic and hydrophilic statins was 0.78 (95% CI: 0.69–0.88) and 0.70 (95% CI: 0.61–0.80), respectively. The effects were attenuated in studies that adjusted for aspirin and/or non‐steroidal anti‐inflammatory drugs (aRR: 0.80, 95% CI: 0.72–0.89) and metformin (aRR: 0.80, 95% CI: 0.72–0.90). Conclusions: Statins, both lipophilic and hydrophobic, were associated with a lower risk of BTCs, particularly CCA and GBC. [ABSTRACT FROM AUTHOR]

Background: The prognostic value of preoperative systemic inflammatory markers, including the neutrophil‐to‐lymphocyte ratio (NLR), platelet‐to‐lymphocyte ratio (PLR), and lymphocyte‐to‐monocyte ratio (LMR), remains controversial in patients with intrahepatic cholangiocarcinoma (ICC). Therefore, this meta‐analysis aimed to investigate the prognostic value of preoperative NLR, PLR, and LMR in patients with ICC who underwent hepatic resection. Methods: We conducted a comprehensive search of four electronic databases. Two researchers assessed the quality of the available data using the Newcastle–Ottawa Scale. We selected overall survival (OS) as the primary outcome and recurrence‐free survival (RFS) and disease‐free survival (DFS) as secondary outcomes. Hazard ratios (HRs) and 95% confidence intervals (CIs) were merged to evaluate the associations between inflammatory markers and ICC patient prognosis. Results: Fifteen studies (18 cohorts) with 4123 cases were included in this meta‐analysis. The results revealed that a high preoperative NLR was associated with short OS and RFS (HR = 1.04, 95% CI: 1.01–1.07, and HR = 1.29, 95% CI: 1.04–1.60, respectively) in patients with ICC. However, the association between PLR or LMR and ICC prognosis was not statistically significant. In addition, the publication bias and sensitivity analyses demonstrated that the results were reliable and stable. Conclusion: Our meta‐analysis revealed that preoperative NLR may be a useful prognostic predictor for patients with ICC. [ABSTRACT FROM AUTHOR]

Background: SQSTM1/p62 is a selective autophagy receptor that regulates multiple signaling pathways participating in the initiation and progression of tumors. Metastasis is still the main cause for intrahepatic cholangiocarcinoma (ICC)‐associated mortality. Hence, this study aimed to explore the mechanism of p62 promoting the progression of ICC. Methods: Western blotting and immunohistochemical analyses were conducted to detect the expression level of protein p62 in ICC tissues and its correlation with prognosis. Subsequently, the loss‐of‐function experiments in vitro and in vivo were performed to define the role of p62 in ICC cell proliferation, invasion, and metastasis. Then, the effect of p62 knockdown on mitochondrial function and mitophagy was evaluated by measuring the oxygen consumption rate, and using immunofluorescence and western blotting analyses. Results: The expression of p62 was significantly upregulated in ICC specimens compared with normal tissues. We further illustrated that p62 expression positively correlated with lymph node metastasis and poor prognosis. The loss‐of‐function assays revealed that p62 not only promoted ICC cell proliferation, migration, and invasive capacities in vitro, but also induced lung metastasis in the xenograft mouse model. Mechanistically, high expression of p62‐induced epithelial–mesenchymal transition (EMT) with the upregulation of Snail, vimentin, N‐cadherin, and downregulation of E‐cadherin. Moreover, the autophagy‐dependent function of p62 might play a vital role in maintaining the mitochondrial function of ICC by mitophagy which might further promote EMT. Conclusion: These data provided new evidence for the mechanism by which abundant p62 expression promoted ICC progression, suggesting a promising therapeutic target for antimetastatic strategies in patients with ICC. [ABSTRACT FROM AUTHOR]

Purpose: This retrospective study evaluated our hypothesis that high tumor budding (≥10 buds) may help determine the appropriate T category for more accurate staging of intrahepatic cholangiocarcinoma (ICC). Methods: We analyzed the clinical and histopathologic data of 235 consecutive patients with histologically confirmed ICC following hepatectomy at five university hospitals in the Kansai region of Japan between January 2009 and December 2020. ICC staging was based on the Liver Cancer Study Group of Japan (LCSGJ) staging system, 6th edition. Results: Patients with ICC with high budding showed significantly shorter disease‐specific survival (DSS) and disease‐free survival (DFS) than patients with low/intermediate budding. Cox proportional hazards regression analysis showed a hazard ratio of 2.2‐2.3 (P < 0.05) for high budding. Based on these results, we modified the T category of ICC in the LCSGJ staging system by adding severity of tumor budding as a fourth determinant. This proposed staging system for ICC has significantly improved the prognostic accuracy for both DSS and DFS (both: P < 0.05). Conclusions: High tumor budding is a new candidate for an additional determinant of the T category in staging ICC. An LCSGJ staging system containing an additional evaluation of tumor budding may lead to improved staging accuracy. [ABSTRACT FROM AUTHOR]

Cholangiocarcinoma (CCA) is a group of tumors that arise along the human biliary duct tree, ranking second in primary hepatic malignancies. Intrahepatic CCA (iCCA) represents about 10%–20% of CCAs. There is an increasing body of evidence suggesting that iCCAs' incidence and mortality have been increasing globally over the past few decades. In this study, we found that the EIF3H expression level in iCCA tissues was significantly increased compared to the adjacent non‐cancerous tissues by immunohistochemistry analysis (IHC). A similar tendency of EIF3H mRNA and protein level was confirmed in iCCA cell lines using RT‐qPCR and Western blot. EIF3H has been identified as a critical molecule that plays a pro‐neoplasmic role in iCCA both in vivo and in vitro, such as proliferation, migration, and anti‐apoptosis. Mechanistically, we found that EIF3H knockdown can promote the degradation of CCND1 and the proteolysis of CCND1 is mediated by ubiquitin‐proteasome system (UPS). Thus, we come to the conclusion that EIF3H promotes proliferation and migration of iCCAs, inhibiting apoptosis of iCCA cells at the same time by stabilizing the CCND1 protein structure. Our findings provide insights into the mechanism of tumorigenesis role of EIF3H in iCCAs and a potential therapeutic target for iCCA treatment. [ABSTRACT FROM AUTHOR]

Background: Curative surgical treatments afford the best prognosis for patients with intrahepatic cholangiocarcinoma (iCCA); however, the comparative effectiveness of treatment options and factors associated with curative treatment receipt for early stage iCCA remain unknown.Methods: The authors identified patients who were diagnosed with early stage iCCA, defined as a unifocal tumor <3 cm, during 2004-2018 from the National Cancer Database. Multivariable logistic and Cox regression analyses were used to identify the factors associated with curative treatment and overall survival (OS), respectively.Results: The proportion of patients with early stage iCCA increased from 4.5% in 2004 to 7.3% in 2018, with the odds of early stage detection increasing by 3.1% per year (odds ratio [OR], 1.031; 95% CI, 1.015-1.049). Of 1093 patients who had early stage iCCA, 464 (42.5%) underwent resection, 113 (10.3%) underwent ablation, 62 (5.7%) underwent liver transplantation, and 454 (41.5%) received noncurative treatments. Hispanic patients (adjusted OR [aOR], 0.57; 95% CI, 0.33-0.97) and Black patients (aOR, 0.47; 95% CI, 0.28-0.77) were less likely to receive curative treatments than White patients. Compared with patients who underwent surgical resection, those who underwent liver transplantation had a trend toward improved OS (adjusted hazard ratio [aHR], 0.63; 95% CI, 0.37-1.08), whereas those who underwent local ablation (aHR, 1.39; 95% CI, 1.01-1.92) and noncurative treatments (aHR, 3.97; 95% CI, 3.24-4.88) experienced worse OS.Conclusions: More than one third of patients with early stage iCCA did not receive curative treatment, with Hispanic and Black patients being less likely to receive curative treatments than White patients. Surgical resection and liver transplantation were associated with improved survival compared with local ablation. Future studies should investigate disparities in curative treatment receipt and outcomes for early stage iCCA. [ABSTRACT FROM AUTHOR]

Background: Assessment of microvascular invasion (MVI) in intrahepatic cholangiocarcinoma (ICC) by using a noninvasive method is an unresolved issue. Deep learning (DL) methods based on multiparametric fusion of MR images have the potential of preoperative assessment of MVI. Purpose: To investigate whether a multiparametric fusion DL model based on MR images can be used for preoperative assessment of MVI in ICC. Study type: Retrospective. Population: A total of 519 patients (200 females and 319 males) with a single ICC were categorized as a training (n = 361), validation (n = 90), and an external test cohort (n = 68). Field strength/Sequence: A 1.5 T and 3.0 T; axial T2‐weighted turbo spin‐echo sequence, diffusion‐weighted imaging with a single‐shot spin‐echo planar sequence, and dynamic contrast‐enhanced (DCE) imaging with T1‐weighted three‐dimensional quick spoiled gradient echo sequence. Assessment: DL models of multiparametric fusion convolutional neural network (CNN) and late fusion CNN were both constructed for evaluating MVI in ICC. Gradient‐weighted class activation mapping was used for visual interpretation of MVI status in ICC. Statistical Tests: The DL model performance was assessed through the receiver operating characteristic curve (ROC) analysis, and the area under the ROC curve (AUC) with the accuracy, sensitivity, and specificity were measured. P value < 0.05 was considered as statistical significance. Results: In the external test cohort, the proposed multiparametric fusion DL model achieved an AUC of 0.888 with an accuracy of 86.8%, sensitivity of 85.7%, and specificity of 87.0% for evaluating MVI in ICC, and the positive predictive value and negative predictive value were 63.2% and 95.9%, respectively. The late fusion DL model achieved a lower AUC of 0.866, with an accuracy of 83.8%, sensitivity of 78.6%, specificity of 85.2% for evaluating MVI in ICC. Data Conclusion: Our DL model based on multiparametric fusion of MRI achieved a good diagnostic performance in the evaluation of MVI in ICC. Level of Evidence: 3 Technical Efficacy: Stage 2 [ABSTRACT FROM AUTHOR]

Background: The clinical outcomes of patients with intrahepatic cholangiocarcinoma (ICC) after partial hepatectomy remain suboptimal. Identifying patients with poor outcomes before surgery is urgently required. Purpose: To develop a multiparametric magnetic resonance imaging (MRI)‐based radiomic signature to evaluate overall survival (OS) preoperatively and to investigate its incremental value for disease stratification. Study Type: Retrospective. Subjects: One hundred and sixty‐three patients with pathologically defined ICC, divided into training (N = 115) and validation sets (N = 48). Sequence: Three‐dimensional T1‐weighted gradient‐echo sequence with and without contrast agent, T2‐weighted fast spin‐echo sequence, and diffusion‐weighted imaging with single‐shot echo‐planar sequence at 1.5 T or 3.0 T. Assessment: OS was defined as the time from the date of surgery to death or last contact. The radiomic signature was built based on the least absolute shrinkage and selection operator regression model. A clinicopathologic‐radiographic (CPR) model and a combined model integrating radiomic signature with CPR factors were developed with multivariable Cox regression models. Statistical Tests: Harrell's concordance index (C‐index) was used to compare the discrimination of different models. Net reclassification index (NRI) and integrated discrimination improvement (IDI) were used to quantify the improvement of prognostic accuracy after adding radiomic signature. Results: The high‐risk patients of death defined by the radiomic signature showed significantly lower OS compared with low‐risk patients in validation set (3‐year OS 17.1% vs. 56.4%, P < 0.001). Integrating radiomic signature into tumor, node, and metastasis (TNM) staging system significantly improved the prognostic accuracy compared with TNM stage alone (validation set C‐index 0.745 vs. 0.649, P = 0.039, NRI improvement 39.9%–43.8%, IDI improvement 16.1%–19.4%). The radiomic signature showed no significant difference of C‐index with postoperative CPR model (validation set, 0.698 vs. 0.674, P = 0.752). Incorporating the radiomic signature into CPR model significantly improved prognostic accuracy (NRI improvement 32.5%–34.3%, IDI improvement 8.1%–12.9%). Data Conclusion: Multiparametric MRI‐based radiomic signature is a potential biomarker for preoperative prognostic evaluation of ICC patients. Level of Evidence: 4 Technical Efficacy: Stage 4 [ABSTRACT FROM AUTHOR]

Objective: To compare the treatment efficacy and safety of tyrosine kinase inhibitors (TKIs) and anti‐programmed cell death 1 (PD‐1) immunotherapy combined with transarterial chemoembolization (TACE) or hepatic arterial infusion chemotherapy (HAIC) for patients with unresectable intrahepatic cholangiocarcinoma (ICC). Methods: Patients with unresectable ICC received TKIs and anti‐PD‐1 immunotherapy combined with HAIC (HTP group) or TACE (TTP group) were included. The clinicopathological characteristics, treatment efficacy, and adverse events (AEs) were compared between the two groups. The factors associated with response rate to the treatments were evaluated. Results: A total of 58 patients were enrolled, with 39 in the HTP group and 19 in the TTP group. Patients in the HTP group exhibited a better objective response rate (ORR; Response Evaluation Criteria in Solid Tumors [RECIST] 48.7% vs 15.8%, P = 0.02; modified RECIST [mRECIST] 61.5% vs 21.1%, P = 0.004) and disease control rate (DCR; 82.1% vs 36.8%, P = 0.001) compared to the TTP group. The median progression‐free survival (PFS) rate was not reached and the 1‐year PFS rate was 61.9% in the HTP group, whereas the median PFS was 11.0 months and the 1‐year PFS rate was 31.6% in the TTP group. The type of treatment and tumor size were significant factors for the response rate. More patients in the HTP group presented rash, abdominal pain and hand‐foot syndrome, but all AEs were relieved after symptomatic treatment, and no treatment‐related death occurred. Conclusions: For unresectable ICC, treatment with a combination of HAIC with TKIs and anti‐PD‐1 immunotherapy was effective and safe. Tumor size might serve as a significant factor for the response rate following treatment for unresectable ICC. [ABSTRACT FROM AUTHOR]

Background and Aim: Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive disease with the underlying mechanisms poorly understood. YTHDF1, an N6‐methyladenosine (m6A) reader protein, has important physiological functions in regulation of tumor development. However, the effect of YTHDF1 on ICC progression remains unknown yet. Methods: The expression level of YTHDF1 in human ICC tissue was examined in The Cancer Genome Atlas database and our cohort. The role of YTHDF1 was detected using two human ICC cell lines in vitro. An ICC tumorigenesis mouse model was established via hydrodynamic transfection of AKT/YAP plasmids. m6A sequencing, RNA immunoprecipitation sequencing, and RNA sequencing were carried out to explore the mechanism of YTHDF1 modulating ICC progression. Results: Here, we find that YTHDF1 is upregulated in ICC and associated with shorter survival of ICC patients. Depletion of YTHDF1 inhibits cell proliferation, migration, and invasion, while overexpression of wild‐type YTHDF1, but not m6A reader domain mutant YTHDF1, significantly enhances tumor cell growth and aggressive abilities in vitro. Moreover, overexpression of YTHDF1 promotes the AKT/YAP transfection‐induced orthotopic ICC tumorigenesis and progression in vivo. Mechanistically, we identify that YTHDF1 regulates the translation of epidermal growth factor receptor (EGFR) mRNA via binding m6A sites in the 3′‐UTR of EGFR transcript, thus leading to aberrant activities of downstream signal pathways that impact tumor progression. Conclusions: Our data uncover the oncogenic function and m6A reader‐dependent mechanism of YTHDF1 in regulation of ICC progression. Restricting abnormal oncogenic mRNA translation by targeting YTHDF1 may be a novel and promising strategy for ICC treatment. [ABSTRACT FROM AUTHOR]