Intrahepatic Cholangiocarcinoma Cohort Research Articles

A single institution’s experience with robotic resections of biliary tract cancers: an analysis of the short-term outcomes and long-term survival

IntroductionPerihilar cholangiocarcinoma, intrahepatic cholangiocarcinoma (IHCC), and gall bladder cancer are difficult malignancies to treat and are characterized by a tendency for local recurrence and a generally unfavorable prognosis. Surgical resection offers the only potential cure, conventionally performed via the open approach. Although minimally invasive approaches show promise, data remain limited. MethodsWith the institutional review board’s approval, we prospectively followed 100 patients between 2013 and 2023 who underwent robotic surgical resection for perihilar, IHCC, and gallbladder cholangiocarcinoma. Data are presented as median (mean ± SD). Significance was accepted at P ≤ .05. ResultsThe median patient age was 70 years, and the median operative duration was 333 min, with an estimated blood loss of 200 mL. Importantly, no unplanned conversions occurred, and only 1 intraoperative complication occurred within the IHCC cohort. The median length of stay was 4 days. There were a total of 19 postoperative complications and 19 readmissions within 30 days. Additionally, there were 3 in-hospital mortalities and 5 90-day mortalities. R0 resection was achieved in 87% of patients and R1 resection in 13%. At a median follow-up of 36 months, 62% of patients demonstrated disease-free survival, whereas 6% continued to live with the disease, and 32% did not survive. ConclusionOur experience demonstrates the feasibility and safety of robotic resection for these complex malignancies, yielding promising short-term outcomes. Further investigation is required to ascertain the long-term oncologic outcomes.

Underexpression of Carbamoyl Phosphate Synthetase I as Independent Unfavorable Prognostic Factor in Intrahepatic Cholangiocarcinoma: A Potential Theranostic Biomarker.

Intrahepatic cholangiocarcinoma (IHCC) is the second most common malignant neoplasm of the liver. In spite of the increasing incidence worldwide, it is relatively rare in Western countries. IHCC is relatively common in Eastern and Southeastern Asia. Patients with IHCC are usually diagnosed at an advanced stage, therefore, the clinical outcome is dismal. Dysregulation of urea cycle metabolic enzyme expression is found in different types of cancers. Nevertheless, a comprehensive evaluation of genes related to the urea cycle (i.e., GO:0000050) has not been conducted in IHCC. By performing a comparative analysis of gene expression profiles, we specifically examined genes associated with the urea cycle (GO:0000050) in a publicly accessible transcriptomic dataset (GSE26566). Interestingly, CPS1 was identified as the second most prominently down-regulated gene in this context. Tumor tissues of 182 IHCC patients who underwent curative-intent hepatectomy were enrolled. The expression level of CPS1 protein in our IHCC cohort was assessed by immunohistochemical study. Subsequent to that, statistical analyses were carried out to examine the expression of CPS1 in relation to various clinicopathological factors, as well as to assess its impact on survival outcomes. We noticed that lower immunoreactivity of CPS1 in IHCC was associated with tumor progression (pT status) with statistical significance (p = 0.003). CPS1 underexpression was not only negatively correlated to overall survival (OS), disease-free survival (DFS), local recurrence-free survival (LRFS) and metastasis-free survival (MeFS) in univariate analysis but also an independent prognosticator to forecast poorer clinical outcome for all prognostic indices (OS, DFS, LRFS and MeFs) in patients with IHCC (all p ≤ 0.001). These results support that CPS1 may play a crucial role in IHCC oncogenesis and tumor progression and serve as a novel prognostic factor and a potential diagnostic and theranostic biomarker.

M6A RNA methylation-mediated upregulation of HLF promotes intrahepatic cholangiocarcinoma progression by regulating the FZD4/β-catenin signaling pathway

Hepatic leukemia factor (HLF) is aberrantly expressed in human malignancies. However, its role in regulating intrahepatic cholangiocarcinoma (ICC) remains unclear. This study aimed to define the role of HLF in ICC progression. Here, we showed that HLF expression is upregulated in ICC and predicts the poor prognosis in patients. Mechanistically, HLF activation in ICC is mediated by METTL3-dependent m6A methylation of the HLF mRNA. As per the results from the loss- or gain-of-function experiments, HLF promoted the self-renewal, tumorigenicity, proliferation and metastasis of ICC cells. RNA-seq and CUT&Tag analyses showed that frizzled-4 (FZD4) and forkhead box Q1 (FOXQ1) are target genes of HLF. Moreover, FOXQ1 transcriptionally activates METTL3 expression, forming a positive feedback loop, which subsequently activates WNT/β-catenin signaling and downstream tumor stemness. Furthermore, HLF expression was positively correlated with METTL3, IGF2BP3, FZD4 and FOXQ1 expression in ICC tissues in a large ICC cohort. The combined IHC panels exhibited a better prognostic value for patients with ICC than any of these components alone. In conclusions, these findings demonstrated that the METTL3/HLF/FOXQ1 regulatory circuit drove FZD4-mediated WNT/β-catenin activation in ICC progression, suggesting that targeting this axis could be novel therapeutic strategy for ICC.

Integrative Analysis of ceRNA Network Reveals Functional lncRNAs in Intrahepatic Cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) is the second most common lethal liver cancer worldwide. Currently, despite the latest developments in genomics and transcriptomics for ICC in recent years, the molecular pathogenesis promoting ICC remains elusive, especially in regulatory mechanisms of long noncoding RNAs (lncRNAs), which acts as competing endogenous RNA (ceRNA). In order to elucidate the molecular mechanism of functional lncRNA, expression profiles of lncRNAs, microRNAs (miRNAs), and messenger RNAs (mRNAs) were obtained from The Cancer Genome Atlas (TCGA) database and an integrative analysis of the ICC-associated ceRNA network was performed. Moreover, gene oncology enrichment analyses for the genes in the ceRNA network were implemented and novel prognostic biomarker lncRNA molecules were identified. In total, 6,738 differentially expressed mRNAs (DEmRNAs), 2,768 lncRNAs (DElncRNAs), and 173 miRNAs (DEmiRNAs) were identified in tumor tissues and adjacent nontumor ICC tissues with the thresholds of adjusted P < 0.01 and |logFC| > 2. An ICC-specific ceRNA network was successfully constructed with 30 miRNAs, 16 lncRNAs, and 80 mRNAs. Gene oncology enrichment analyses revealed that they were associated with the adaptive immune response, T cell selection and positive regulation of GTPase activity categories. Among the ceRNA networks, DElncRNAs ARHGEF26-AS1 and MIAT were found to be hub genes in underexpressed and overexpressed networks, respectively. Notably, univariate Cox regression analysis indicated that DElncRNAs HULC significantly correlated with overall survival (OS) in ICC patients (P value < 0.05), and an additional survival analysis for HULC was reconfirmed in an independent ICC cohort from the Gene Expression Omnibus (GEO) database. These findings contribute to a more comprehensive understanding of the ICC-specific ceRNA network and provide novel strategies for subsequent functional studies of lncRNAs in ICC.

Role of nonalcoholic steatohepatitis as a risk factor for intrahepatic cholangiocarcinoma and its role in patients’ prognosis: A case-control study.

224 Background: The prevalence of intrahepatic cholangiocarcinoma (ICC) is rising worldwide. The current epidemics of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) might be partly responsible for this trend. Methods: Case control study investigating the prevalence of histology-confirmed NASH in peritumoral liver of resected ICC patients and controls (pre-explant biopsies of liver donors). Controls were matched for age and sex in a 2:1 fashion. Correlates between NASH, tumor characteristics and overall survival (OS) were also explored in the ICC cohort. Results: Between 2006 and 2017, 84 ICCs were resected in our Institution. Sixty-two (74%) had no apparent risk factors for ICC. Amongst this group, the prevalence of NAFLD and NASH was 45.2% and 24.2%,respectively, compared to 44.3 and 8.9% in the 124 matched liver donors (p = 1.000 and p = 0.007, respectively). The 5-year OS rate was 20.0% in NASH and 57.4% in ICC without either NASH and other risk factors (p = 0.017). Main tumor size, sex and NASH (hazard ratio 2.618 , 95% confidence interval 1.140-6.013, p = 0.023) were independent predictors of the OS at the multivariate Cox regression. Conclusions: NASH (but not NAFLD) acts as a risk factor for ICC and may affect its long-term outcome. A collaborative multicenter approach could confirm and strengthen these data.

Racial disparities in the survival time of patients with hepatocellular carcinoma and intrahepatic cholangiocarcinoma between Chinese patients and patients of other racial groups: A population-based study from 2004 to 2013.

The aim of the present study was to investigate the racial disparities in the presentation, treatment and survival time of patients with hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICC) between Chinese and other racial groups from the Surveillance, Epidemiology, and End Results (SEER) database between January 1st 2004, and December 31st 2013. Key covariates, including clinical presentation, treatment and survival time, were recorded and compared, demonstrating the racial differences. Kaplan-Meier analysis and Cox regression models were performed to identify these disparities in survival time. A total of 30,954 patients were identified in the SEER database. Among these, 27,767 (89.7%) had HCC and 3,187 (10.3%) had ICC. In the HCC cohort, Chinese patients had the highest survival time. Compared with the mortality risk of Chinese patients, the mortality risk of Other Asian, non-Hispanic white, Hispanic and African-American patients increased by 16.8, 35.1, 28.3 and 33.3%, respectively. Compared with other groups, Chinese patients were more likely to present with localized stage, and without vascular invasion, adjacent invasion and metastasis. In the ICC cohort, the Chinese group had improved survival time, compared with the other groups following univariate analysis, although no significant differences were observed between Chinese and Other Asian and Hispanic patients following adjusting for contributing factors. Furthermore, there was no significant differences in the presentation between the groups, which differed from the HCC analysis. In conclusion, race/ethnicity was a significant independent prognostic factor in the HCC cohort, whereas it was not significant in the ICC cohort. The synergistic effect of contributing factors, including demographic, socioeconomic, biological and treatment differences, caused the racial disparity observed in primary liver cancer survival time.

Enhancer of zeste homolog 2 (EZH2) regulates tumor angiogenesis and predicts recurrence and prognosis of intrahepatic cholangiocarcinoma

BackgroundEnhancer of zeste homolog 2 (EZH2) is the catalytic subunit of the polycomb repressive complex 2 (PRC2) and regulates tumor malignancy by gene silencing via histone methylation. In this study we investigate the role of EZH2 in angiogenesis of intrahepatic cholangiocarcinoma (ICC). MethodsThe influence of EZH2 on tumor angiogenesis was examined by bioinformatics analysis of a public database. We also assessed the correlation between EZH2 and vasohibin 1 (VASH1) expression in 47 patients with ICC by immunohistochemical (IHC) staining and in vitro gene silencing assays. The prognostic significance of EZH2 and VASH1 expression by IHC was also examined in the ICC cohort. ResultsBioinformatics analysis showed that EZH2 was associated with several angiogenesis gene sets in the public database. EZH2 suppressed VASH1 expression in in vitro assays and IHC studies. EZH2-high/VASH1-low status was independently associated with poor disease-free survival (P = 0.019) and poor overall survival (P = 0.0055). ConclusionThe current study demonstrated that high EZH2 expression was associated with activation of tumor angiogenesis, and activation of the EZH2-mediated angiogenesis pathway predicted the prognosis of patients with ICC.

K-ras Mutation is Strongly Associated with Perineural Invasion and Represents an Independent Prognostic Factor of Intrahepatic Cholangiocarcinoma after Hepatectomy

Unsatisfying long-term survival of intrahepatic cholangiocarcinoma (ICC) triggers the clinicians searching for molecular markers, such as K-ras mutation, to tailor management strategy. Additionally, emergence of tyrosine kinase inhibitors (TKIs) brings new hope to palliate advanced ICC; whether the efficacy of TKIs is influenced by k-ras mutation is largely unknown. This study was designed to determine the prevalence of k-ras mutation and its clinical significance in ICC, as well as to pave the reference for future application of TKIs. A total of 86 patients with ICC who underwent hepatectomy were retrospectively recruited. K-ras mutation was determined by using laser capture microdissection and direct sequencing method. Association among clinicopathological variables and K-ras mutation was analyzed. Prognostic factors of ICC after hepatectomy also were determined. Nineteen (22%) patients exhibited K-ras mutations. Seventeen had their K-ras mutations occurring at codon 12, and the remaining two occurring at codon 13 and codon 61 in one each. Perineural invasion was exclusively the variable associated with K-ras mutation (odds ratio, 6.9) using logistic regression analysis. Multivariate analysis demonstrated that resection margin, T-status, nodal metastasis, and K-ras mutation were independent prognostic factors. The median survival of ICC patients with K-ras mutation was 5.7 months compared with 19.0 months in those without K-ras mutation (P = 0.002). The prevalence of K-ras mutations in a considerably large cohort of ICC was 22%. K-ras mutation is strongly associated with perineural invasion phenotypically. K-ras mutation is an independent prognostic factor of ICC after hepatectomy.

Comments on Minimizing Misdiagnosis of Hepatocellular Carcinoma from Magnetic Resonance Imaging†

We appreciate the interest of Yun Ku Cho in our article entitled “Cholangiocarcinoma in Cirrhosis: Absence of Contrast Washout in Delayed Phases by MR Avoids Misdiagnosis of Hepatocellular Carcinoma.”1 As we stated in the article, our main goal was to assess the magnetic resonance features of intrahepatic cholangiocarcinoma (ICC) in the setting of cirrhosis. This entity is a risk factor for both ICC and hepatocellular carcinoma (HCC), and it is critical to accurately distinguish them before the determination of therapy (i.e., liver transplantation). Our data show that the application of the American Association for the Study of Liver Diseases guidelines prevents a false-positive diagnosis of ICC in cirrhosis. Small ICC may display an early enhancement (partial or total) in the arterial phase. This is similar to the HCC pattern, but because we have not observed washout in delayed phases, this finding is confirmed to be specific for HCC2, 3 and critical for nodule diagnosis. We focused our analysis on ICC arising within a cirrhotic liver; this constituted most of the cases detected in the setting of a surveillance program for early HCC diagnosis. The majority of the published series evaluating the computed tomography and magnetic resonance imaging features of ICC did not restrict the analysis to only patients with cirrhosis, and most of the cases were detected in the presence of symptoms, so the lesions usually were larger. We already acknowledged in the discussion that the number of patients recruited was limited, but even so, this is the largest cohort of ICC in cirrhosis. More importantly, more than two-thirds of the nodules were smaller than 3 cm, and the challenge of imaging characterization lies in small nodules. Regarding the previously reported delayed washout in ICC,4 we have to stress again that the reported “washout” of ICC cannot be confused with the typical washout of HCC in delayed phases. The former still enhances more than the hepatic parenchyma, whereas the latter typically has lower enhancement in delayed phases with respect to the liver. In conclusion, our data show that small ICC may mimic the pattern of HCC in the arterial phases of magnetic resonance imaging, but this tumor does not show washout in the delayed venous phase. This is specific for HCC and may allow a noninvasive HCC diagnosis, but if it is not observed, diagnostic biopsy should be mandatory, as already recommended in the American Association for the Study of Liver Diseases guidelines. Jordi Rimola M.D.*, Alejandro Forner M.D. , Carmen Ayuso Ph.D.*, Jordi Bruix Ph.D. , * Radiology Department, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain, Liver Unit, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain.