Survival Of Intrahepatic Cholangiocarcinoma Patients Research Articles

Heparanase interacting BCLAF1 to promote the development and drug resistance of ICC through the PERK/eIF2α pathway.

Intrahepatic cholangiocarcinoma (ICC) is a primary epithelial carcinoma known for its aggressive nature, high metastatic potential, frequent recurrence, and poor prognosis. Heparanase (HPSE) is the only known endogenous β-glucuronidase in mammals. In addition to its well-established enzymatic roles, HPSE critically exerts non-catalytic function in tumor biology. This study herein aimed to investigate the non-enzymatic roles of HPSE as well as relevant regulatory mechanisms in ICC. Our results demonstrated that HPSE was highly expressed in ICC and promoted the proliferation of ICC cells, with elevated HPSE levels implicating a poor overall survival of ICC patients. Notably, HPSE interacted with Bcl-2-associated factor 1 (BCLAF1) to upregulate the expression of Bcl-2, which subsequently activated the PERK/eIF2α-mediated endoplasmic reticulum (ER) stress pathway to promote anti-apoptotic effect of ICC. Moreover, our in vivo experiments revealed that concomitant administration of gemcitabine and the Bcl-2 inhibitor navitoclax enhanced the sensitivity of ICC cells with highly expressed HPSE to chemotherapy. In summary, our findings revealed that HPSE promoted the development and drug resistance of ICC via its non-enzymatic function. Bcl-2 may be considered as an effective target with therapeutic potential to overcome ICC chemotherapy resistance induced by HPSE, presenting valuable insights into the development of novel therapeutic strategies against ICC.

Several aspects on the long-term survival of intrahepatic cholangiocarcinoma patients

Patients with intrahepatic cholangiocarcinoma have a poor overall prognosis and a low long-term survival rate. Currently, multimodal treatment is the mainstay of treatment, and surgical resection is the most important treatment for patients with intrahepatic cholangiocarcinoma for a long-term survival. Although the treatment strategies have been constantly updated in recent years to improve survival rates, there are still many controversial issues in the existing treatment strategies. Based on our center's clinical practice and recent research progress, analyzes several issues affecting long-term survival were analyzed based on three aspects: accurate clinical assessment methods, the related decisions making for surgical resection, and the strategies of precision medicine.

MCM6 promotes intrahepatic cholangiocarcinoma progression by upregulating E2F1 and enhancing epithelial-mesenchymal transition.

Minichromosome maintenance complex component 6 (MCM6), a member of the MCM family, plays a pivotal role in DNA replication initiation and genome duplication of proliferating cells. MCM6 is upregulated in multiple malignancies and is considered a novel diagnostic biomarker. However, the functional contributions and prognostic value of MCM6 in intrahepatic cholangiocarcinoma (ICC) remain unexplored. In this study, we investigated the molecular function of MCM6 in ICC. Data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO, GSE107943) indicated an upregulation of MCM6 in tumor tissues. Immunohistochemical analysis performed on 115 cases of ICC samples confirmed the upregulation of MCM6 and further suggested that a high level of MCM6 expression predicted shorter overall and disease-free survival in ICC patients. Functional studies suggested that MCM6 knockdown significantly suppressed cell viability, blocked cell cycle progression and inhibited metastasis, while the enhancement of MCM6 expression promoted the proliferation and migration of ICC cells both in vitro and in vivo. Mechanistically, Gene Set Enrichment Analysis (GSEA) suggested that the epithelial-mesenchymal transition (EMT) and E2F1-correlated genes were enriched in ICC tissues with high MCM6 expression. Further verification indicated that MCM6 promoted the EMT of ICC cells via upregulating E2F1. In addition, E2F1 knockdown partially blocked the pro-malignant effects of MCM6 overexpression. In summary, MCM6 was found to be a novel prognostic and predictive marker for ICC. MCM6 promoted ICC progression via activation of E2F1-mediated EMT.

Dense GM-CSFRα-expressing immune infiltration is allied with longer survival of intrahepatic cholangiocarcinoma patients.

Intrahepatic cholangiocarcinoma (iCCA) is a cancer arising from intrahepatic bile duct epithelium. An iCCA incidence is increasing worldwide; however, the outcome of the disease is dismal. The linkage between chronic inflammation and iCCA progression is well established, but the roles of granulocyte-macrophage colony-stimulating factor (GM-CSF) remain unrevealed. Thus, a better understanding of GM-CSF functions in CCA may provide an alternative approach to CCA treatment. Differential GM-CSF and GM-CSFRα mRNA expressions in CCA tissues were investigated by Gene Expression Profiling Interactive Analysis (GEPIA) based on The Cancer Genome Atlas (TCGA) database. The protein expressions and localizations of GM-CSF and its cognate receptor (GM-CSFRα) in iCCA patients' tissues were demonstrated by the immunohistochemistry (IHC) techniques. The survival analyses were performed using Kaplan-Meier survival analysis with log-rank test and Cox proportional hazard regression model for multivariate analysis. The GM-CSF productions and GM-CSFRα expressions on CCA cells were assessed by ELISA and flow cytometry. The effects of GM-CSF on CCA cell proliferation and migration were evaluated after recombinant human GM-CSF treatment. The relationship between GM-CSF or GM-CSFRα level and related immune cell infiltration was analyzed using the Tumor Immune Estimation Resource (TIMER). GEPIA analysis indicated GM-CSF and GM-CSFRα expressions were higher in CCA tissues than in normal counterparts, and high GM-CSFRα was related to the longer disease-free survival of the patients (p < 0.001). IHC analysis revealed that CCA cells differentially expressed GM-CSF, while GM-CSFRα was expressed on cancer-infiltrating immune cells. The patient whose CCA tissue contained high GM-CSF expressed CCA, and moderate to dense GM-CSFRα-expressing immune cell infiltration (ICI) acquired longer overall survival (OS) (p = 0.047), whereas light GM-CSFRα-expressing ICI contributed to an increased hazard ratio (HR) to 1.882 (95% CI [1.077-3.287]; p = 0.026). In non-papillary subtype, an aggressive CCA subtype, patients with light GM-CSFRα-expressing ICI had shorter median OS (181 vs. 351 days; p = 0.002) and the HR was elevated to 2.788 (95% CI [1.299-5.985]; p = 0.009). Additionally, TIMER analysis demonstrated GM-CSFRα expression was positively correlated with neutrophil, dendritic cell, and CD8+ T cell infiltrations, though it was conversely related to M2-macrophage and myeloid-derived suppressor cell infiltration. However, the direct effects of GM-CSF on CCA cell proliferation and migration were not observed in the current study. Light GM-CSFRα-expressing ICI was an independent poor prognostic factor for iCCA patients. Anti-cancer functions of GM-CSFRα-expressing ICI were suggested. Altogether, the benefits of acquired GM-CSFRα-expressing ICI and GM-CSF for CCA treatment are proposed herein and require elucidation.

Genetic heterogeneity of intrahepatic cholangiocarcinoma: Implications for outcome.

595 Background: Intrahepatic cholangiocarcinoma (IHC) is characterized by marked clinical heterogeneity, likely the result of multiple cells of origin and variable driver gene alterations. The hidden-genome classifier is a statistical algorithm that classifies tumors by integrating multi-level genomic features. In this study, we trained the hidden-genome classifier with extrahepatic cholangiocarcinoma (EHC), gallbladder cancer (GBC) and hepatocellular carcinoma (HCC) as extremes of a spectrum to quantify the genetic heterogeneity of IHC with a view toward improved tumor classification. Methods: An IRB approved retrospective review of patients with biopsy confirmed IHC, EHC, GBC and HCC was conducted. All tumors were subjected to MSK-IMPACT to determine the mutational profile. A two-class model was built and internally validated with the genomic data of EHC/GBC as one class and HCC as the other class. IHC tumors were analyzed in the model and classified into three groups based on their proportional genetic resemblance to EHC/GBC (Biliary Class) or HCC (HCC Class), with the remainder as Intermediate Class. The classification thresholds were 90% resemblance to EHC/GBC or HCC and were determined by the inflection point of predicted survival. The survivals of the three groups were analyzed and compared. Results: A total of 1497 patients were included: IHC (733), EHC (208), GBC (258) and HCC (298). 527 IHC tumors with complete metagenetic information were analyzed in the model, showing a continuous spectrum of alterations, ranging from Biliary Class (122 tumors), Intermediate Class (375 tumors) to HCC Class (30 tumor). The biliary-class IHC was characterized by frequent alterations of IDH1 R132C, KRAS, SMAD4, ERBB2 gain, MDM2 gain, and CKDN2A loss, while the HCC-class IHC was primarily characterized by TERT alterations. In patients with unresected IHCs, the median survival ranged from 1 year (CI 0.77, 1.5) in Biliary Class, 1.8 years (CI 1.5, 2.0) in Intermediate Class, to 2 years (CI 0.93, NR) in HCC Class. In patients subjected to resection, the median survival of Biliary Class (2.4 years, CI 2.1, NR) was lower than both the Intermediate Class (5.1 years, CI 4.8, 6.9) and the HCC Class (3.4 years, CI 2.7, NR). Conclusions: By integrating multi-level genomic features, we leveraged the mutational heterogeneity to classify IHC based on its resemblance to EHC/GBC or HCC tumors. We found that the survival in IHC patients appeared to decline with increasing genomic similarity to Biliary Class. The results support a genomic basis for IHC’s variable clinical behavior and point to a role of mutational testing to guide clinical intervention. [Table: see text]

The prognostic value of preoperative peripheral blood inflammatory biomarkers for intrahepatic cholangiocarcinoma after radical resection

Objective: To explore the value of preoperative peripheral blood inflammatory biomarkers for predicting the prognosis of intrahepatic cholangiocarcinoma (ICC) after radical resection. Methods: A total of 124 patients who underwent radical resection for ICC in the First Affiliated Hospital of Xi'an Jiaotong University from January 2010 to December 2018 were retrospectively analyzed. Receiver operating characteristic (ROC) curve was conducted to determine the best cut-off values of neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), lymphocyte/monocyte ratio (LMR), systemic immune inflammatory index (SII), and systemic inflammatory response index (SIRI). Univariate and multivariate analyses of prognostic factors were performed using Cox proportional hazards regression model. Based on the independent prognostic factors screened by multivariate Cox regression analysis, a nomogram model of overall survival prediction for ICC patients after radical resection was established. Results: Among the 124 patients, 87 patients died and 37 patients survived during the follow-up period. The median overall survival time of the whole patients was 21 months. ROC curve analysis showed that the areas under the curve (AUC) of NLR, PLR, LMR, SII and SIRI for predicting the overall survival of ICC patients after radical resection were 57.86%, 64.21%, 60.61%, 67.57% and 66.03%, respectively. Univariate Cox regression analysis showed that the inflammatory biomarkers of NLR, PLR, SII, and SIRI were associated with overall survival of ICC after radical resection (HR=1.787, 95%CI: 1.165-2.741; HR=1.181, 95% CI: 1.224-2.892; HR=2.412, 95% CI: 1.565-3.717; HR=1.648, 95% CI: 1.081-2.513). Multivariate Cox regression analysis showed that the inflammatory biomarker of SII was an independent prognostic factor of ICC after radical resection (HR=1.863, 95% CI: 1.161-2.989). According to the best cut-off value of SII to predict the overall survival of ICC patients after radical resection (709.86×10(9)/L), the patients were divided into low SII group (SII≤709.86×10(9)/L) and high SII group (SII>709.86×10(9)/L). In the high SII group, the proportions of NLR>3.31, PLR>3.31, SIRI>1.30×10(9)/L, carbohydrate antigen 19-9>39.0 U/ml, Child-Pugh liver function (grade B), hemi-hepatic/extended hepatectomy, combined perineural invasion, N1 stage and TNM stage (ⅢB) were higher than those in the low SII group (P<0.05). Based on the independent prognostic factors screened by multivariate Cox regression analysis, a nomogram model of overall survival prediction for ICC after radical resection was established, the C-index values of the training set and testing set were 0.774 and 0.737, respectively. Conclusions: Preoperative peripheral blood inflammatory marker SII is an independent risk factor for the prognosis of intrahepatic cholangiocarcinoma patients after radical resection. The nomogram model of overall survival prediction established that included SII has a good predictive ability and can be used to evaluate the prognosis of intrahepatic cholangiocarcinoma patients after radical resection.

Dynamic evaluation of postoperative survival in intrahepatic cholangiocarcinoma patients who did not undergo lymphadenectomy: a multicenter study

Background The prognosis of Intrahepatic cholangiocarcinoma (ICC) patients who did not undergo lymphadenectomy is difficult to assess. This study aims to have a dynamic evaluation on the postoperative survival of ICC patients by calculating conditional survival. Methods Relevant data were from patients treated in 12 large-scale hospitals from December 2011 to December 2017. The influence of relevant clinical baseline data on the prognosis of ICC patients was analyzed by Cox regression. Conditional survival (CS) is a method that may predict the prognostic probability dynamically. For a patient with x years of survival, the 1-year CS (CS1) may be calculated as CS1= OS(x + 1)/OS(x). Result A total of 361 patients who met the criteria were included in the study. Conditional survival (CS) means that the patients’ prognosis varies with survival time, meanwhile, relevant factors affecting the prognosis have a time-varying effect. The probability of survival assessed by CS1 increased year by year and the 1,2,3-year survival improved from 68.4% to 87.8%, while the postoperative actuarial OS decreased from 69.4% at 1 years to 36.9% at 3 years. Conclusions In terms of CS, the estimated survival for ICC varies with the increase of survival time after excision. Patients who live longer were likely to live longer. At the same time, with the passage of time, the role of the original adverse factors of the tumor would gradually decrease. Conditional survival allows a more accurate assessment of ICC patients who did not undergo lymphadenectomy.

Recurrence and prognosis in intrahepatic cholangiocarcinoma patients with different etiology after radical resection: a multi-institutional study

ObjectiveWe aimed to evaluate the prognosis and adjuvant chemotherapy (ACT) in intrahepatic cholangiocarcinoma (ICC) patients with different etiology after radical resection.MethodsA total of 448 patients with ICC who underwent radical resection between 2010 and 2018 at ten Chinese tertiary hospitals were analyzed in the study. These patients were divided into conventional ICC (Con-ICC, n = 261, 58.2%), hepatitis B virus ICC (HBV-ICC, n = 102, 22.8%) and hepatolithiasis (Stone-ICC, n = 85,19.0%) subtypes according to different etiology. Propensity score matching (PSM) was conducted to mitigate the baseline differences between Con-ICC and HBV-ICC, Con-ICC and Stone-ICC, HBV-ICC and Stone-ICC subtypes.ResultsUnivariate and multivariate analysis showed that different etiology was a prognostic factor for overall survival and relapse-free survival, and different etiology was an independent risk factor for overall survival in ICC patients, respectively (P < 0.05). In addition, there was a statistical difference for overall survival in early recurrence patients among the three etiological subtypes (P < 0.05). After PSM, the overall survival of patients with Stone-ICC was worse than those of Con-ICC and HBV-ICC subtypes (P < 0.05), while the relapse-free survival of patients with Stone-ICC was equivalent to patients with Con-ICC and HBV-ICC (P > 0.05). In Stone-ICC patients, the median overall survival was 16.0 months and 29.7 months, and the median relapse-free survival was 9.0 months and 20.0 months for non-ACT and ACT patients, respectively (P < 0.05).ConclusionThe prognosis of Stone-ICC patients was significantly worse than those of Con-ICC and HBV-ICC patients. Interestingly, postoperative adjuvant chemotherapy can improve the prognosis of Stone-ICC patients effectively.

Hepatic stellate cells promote intrahepatic cholangiocarcinoma progression via NR4A2/osteopontin/Wnt signaling axis.

Intrahepatic cholangiocarcinoma (ICC) is a highly fatal malignancy characterized by a vast amount of intra-tumoral fibroblasts. These fibroblasts are potentially implicated in maintaining the high aggressiveness of ICC, whereas its pro-cancer mechanisms remain scarcely reported. Here, by establishing co-culture models of ICC cells and hepatic stellate cells (HSCs), we identified that HSCs triggered the expression of nuclear receptor family 4 subgroup A member 2 (NR4A2), a transcription factor previously reported as a molecular switch between inflammation and cancer, in ICC cells. Functionally, NR4A2 promotes tumor proliferation, metastatic potentiality and represents an independent prognostic indicator for overall survival in ICC patients. Mechanistically, NR4A2 upregulates osteopontin (OPN) expression through transcriptional activation and thereby augments the activity of Wnt/β-catenin signaling. Intriguingly, in the context of co-culture, vascular endothelial growth factor (VEGF), a previously proved NR4A2 stimulus, not only enhances NR4A2 expression, but also can be blunted by the interference of the NR4A2-OPN axis. Altogether, this study suggests the NR4A2/OPN/Wnt signaling axis to be a pivotal executor of HSC-instigated cancer-promoting roles in ICC, and the NR4A2/OPN/VEGF positive feedback loop may help to reinforce the effect.

Preoperatively elevated RDW-SD and RDW-CV predict favorable survival in intrahepatic cholangiocarcinoma patients after curative resection

BackgroundRecent studies suggest red blood cell distribution width (RDW) was a prognostic factor in various types of cancer patients, although the results are controversial. The objective of this study was to investigate the significance of RDW in patients with intrahepatic cholangiocarcinoma (ICC) after radical resection.MethodThe relationship between the preoperative serum RDW value and clinic pathological characteristics was analyzed in 157 ICC patients between January 2012 and June 2018 who underwent curative resection. X-tile software was used to determine 40.2 fl, 12.6% as the optimal cut-off value for RDW-SD and RDW-CV respectively. 153 patients were classified into the low RDW-SD (≤ 40.2, n = 53) group and the high RDW-SD (> 40.2, n = 104) group, low RDW-CV (≤ 12.6, n = 94) group and the high RDW-CV (> 12.6, n = 63). Based on the RDW-SD combined with RDW-CV (SCC), classified into SCC = 0, 1 and 2 group. Kaplan–Meier survival analysis and Cox proportional hazard models were used to examine the effect of RDW on survival.ResultsKaplan–Meier curve analysis showed that Patients with RDW-SD > 40.2 were significantly associated with better OS (P = 0.004, median OS: 68.0 months versus 17.0 months). Patients with RDW-CV > 12.6 were significantly associated with better OS (p = 0.030, median OS: not reach versus 22.0 months). Compared with a SCC = 0 or SCC = 1, SCC = 2 was significantly associated with better OS (p < 0.001, median OS: not reach versus 33.0 months versus 16, respectively). In the multivariate analysis, RDW-SD > 40.2 fl (HR = 0.446, 95% CI: 0.262–0.760, p = 0.003), RDW-CV > 12.6% (HR = 0.425, 95%CI: 0.230–0.783, p = 0.006), SCC = 2 (HR = 0.270, 95%CI: 0.133–0.549, p < 0.001) were associated with favorable OS. The multivariate analysis showed RDW-SD, RDW-CV and SCC level were not independent prognostic factors for DFS.ConclusionsPreoperative low levels of RDW are associated with poor survival in ICC after curative resection. This provides a new way for predicting the prognosis of ICC patients and more targeted intervention measures.

Assessment of the Outcomes of Intrahepatic Cholangiocarcinoma After Ultrasound-Guided Percutaneous Microwave Ablation Based on Albumin-Bilirubin Grade.

To determine whether albumin-bilirubin (ALBI) grade could be used to predict the outcomes of patients with intrahepatic cholangiocarcinoma (ICC) who underwent ultrasound-guided percutaneous microwave ablation (MWA). This retrospective study was approved by the institutional review board, and the requirement for informed consent was waived. We studied 52 treatment-naïve patients with 74 ICC lesions according to the Milan criteria who subsequently underwent MWA from April 2011 to March 2018. Overall survival (OS) and recurrence-free survival (RFS) were compared in groups classified by Child-Pugh score and ALBI grade, which were statistically analyzed with the log-rank test. Cox proportional hazard regression analyses were used to determine the prognostic factors for survival in patients with ICC. The median follow-up time was 21.2months (3.2-78.7months). Seventeen patients died during this period. After MWA, the cumulative 1-, 3-, and 5-year OS rates were 87.4%, 51.4%, and 35.2%, respectively, and the cumulative 1-, 3-, and 5-year RFS rates were 68.9%, 56.9%, and 56.9%, respectively. The major complication rate was 3.8% (2/52). Stratified according to ALBI grade, the cumulative 1-, 3-, and 5-year OS rates were 95.5%, 72.4%, and 72.4% for patients with ALBI grade 1 and 62.5%, 40.6%, and 36.3% for patients with ALBI grade 2, respectively, showing a significant difference (P = 0.006). Multivariate analysis results showed that older age (hazard ratio [HR]: 1.67, 95% confidence interval [CI]: 1.11-2.82; P = 0.002), tumor size ≥ 3cm in diameter (HR: 11.33, CI: 2.24-34.52; P = 0.021) and ALBI grade (HR: 8.23, CI: 1.58-58.00; P = 0.004) may be predictors of poor OS. ALBI grade was validated as a significant biomarker for predicting survival in ICC patients within the Milan criteria who underwent MWA.

Identification of prognostic factors for intrahepatic cholangiocarcinoma using long non-coding RNAs-associated ceRNA network

BackgroundAccumulating amount of evidence has highlighted the important roles of long non-coding RNAs (lncRNAs) acting as competing endogenous RNAs (ceRNAs) in tumor pathogenesis. However, the roles of long non coding RNAs (lncRNAs) in the lncRNA-related ceRNA network of intrahepatic cholangiocarcinoma (ICC) still remain enigmatic. The current study aims to identify prognostic factors in the lncRNA-related ceRNA network of ICC.MethodsThe transcriptome sequencing data of lncRNAs, messenger RNA (mRNA) and microRNA (miR) were downloaded from the SRA and TCGA databases. Differentially expressed lncRNAs (DElncRNAs), DEmiRs and DEmRNAs were identified and adopted to construct an lncRNA-miR-mRNA ceRNA network. ICC-associated DEmRNAs were adopted to construct the protein–protein interaction (PPI) network. The expression of the top 6 genes in the hub module was validated with mRNA transcriptome sequencing data and ICC-related gene expression dataset GSE45001, followed by GO and KEGG pathway enrichment analysis. The relationship between the hub gene-associated ceRNA network and the overall survival of patients with ICC was predicted by conducting a Kaplan–Meier survival analysis.ResultsSixty co-expressed DEmRNAs were identified in the ceRNA network. The top 6 hub genes consisted of downregulated FOS, IGF2, FOXO1 and NTF3, upregulated IGF1R, and insignificantly downregulated HGF in ICC tissues, when compared to that of normal adjacent tissues, followed by the successful construction of lncRNA-miR-hub network consisting of 86 ceRNA modules. MME-AS1 and hsa-miR-182 were associated with overall survival in ICC patients. FOS, IGF1R, IGF2, FOXO1, and NTF3 might target “TGF-β signaling pathway”, “the hedgehog signaling pathway”, “retinol metabolism”, or “type II diabetes mellitus” pathways respectively.ConclusionThese results indicate that FOS, IGF1R, IGF2, FOXO1, and NTF3 were useful prognostic factors in determining the prognosis of patients with ICC.

Impact of liver fibrosis score on prognosis after common therapies for intrahepatic cholangiocarcinoma: a propensity score matching analysis

BackgroundLiver fibrosis or cirrhosis is associated with the dismal prognosis of hepatocellular carcinoma (HCC), and it might also be involved in intrahepatic cholangiocarcinoma (ICC). The effect of hepatic fibrosis on the survival of ICC patients is still unclear. This study aims to explore whether liver fibrosis impacts the overall survival (OS) and disease-specific survival (DSS) of ICC patients.MethodsData of 729 eligible ICC patients receiving different therapies from the Surveillance, Epidemiology, and End Results database (2004–2015) were analyzed. Unmatched, propensity score-matched, and propensity score-weighted cohorts were used to investigate the relationships of different fibrosis scores (low fibrosis score vs. high fibrosis score) and survival. A Cox regression and Kaplan–Meier curves were used to explore the influence of fibrosis score on patients’ survival. Stratified analyses based on treatment modality were conducted to compare the survival difference in ICC patients with different fibrosis scores.ResultsBefore matching, the one-, three-, and five-year OS were 50.9, 28.0, and 16.1% in the low fibrosis score group (n = 465) and 39.3, 20.1, and 8.0% in the high fibrosis score group (n = 264) (P < 0.001), respectively. After propensity score matching, the one-, three-, and five-year OS were 45.0, 26.0, and 10.2% in the low fibrosis score group and 36.0, 8.1, and 2.3% in the high fibrosis score group (P = 0.008), respectively. The multivariate Cox regression results showed that a high fibrosis score was an independent risk factor of OS. Additionally, patients with high fibrosis scores achieved low DSS after matching (P = 0.032). The survival benefits of the low fibrosis score group were consistent across treatment cohorts.ConclusionsHigh fibrosis scores were associated with poor clinical outcomes of ICC patients receiving different common therapies.

Age-adjusted Charlson Comorbidity Index predicts survival in intrahepatic cholangiocarcinoma patients after curative resection.

BackgroundComorbidity among cancer patients is prevalent and influential to prognosis after operation. Limited data are available on comorbidity evaluations in patients with intrahepatic cholangiocarcinoma (ICC). This study aimed to assess the comorbidity distribution in ICC patients and to adapt the Charlson Comorbidity Index (CCI) or the age-adjusted CCI (ACCI) for survival prediction.MethodsThe study cohort included 268 ICC patients treated with curative surgery from January 2000 to December 2007 at the Department of Liver Surgery, Zhongshan Hospital. The association between the comorbidity index and overall survival (OS) or disease-free survival (DFS). was analyzed by the Kaplan-Meier method. Multivariable analysis was established to select the determinant parameters.ResultsMajor comorbid conditions of ICC patients included liver disease, hypertension, diabetes and ulcer. The median follow-up time was 25.5 months in the whole data set. Among the entire cohort, the 1-, 3- and 5-year OS rates were 55.3%, 26.0% and 15.6%, respectively. In multivariate analysis, the ACCI correlated with OS, and higher scores were associated with poorer prognosis (hazard ratio =1.134, 95% confidence interval: 1.015–1.267 and P value =0.026). CCI was not an independent predictive factor for OS or DFS.ConclusionsIn contrast to CCI, ACCI was a more promising model to accurately predict OS in ICC patients who underwent liver resection. Further research should be focused on the impact of comorbidity therapies.

The combination of preoperative D-dimer and CA19-9 predicts lymph node metastasis and survival in intrahepatic cholangiocarcinoma patients after curative resection.

BackgroundTo investigate the predictive role of D-dimer and its combination of preoperative CA19-9 for lymph node metastasis (LNM) and prognosis in intrahepatic cholangiocarcinoma (ICC) patients who underwent curative-intent resection.MethodsOne hundred and seventy-three patients admitted to our hospital between April 2012 and December 2018 were included. The combination of preoperative D-dimer and CA19-9 (CPDC) was scored as 0 (decreased D-dimer levels with decreased CA19-9 levels), 2 (elevated D-dimer levels with elevated CA19-9 levels), or 1 (all other combinations). Multivariate logistic regression analysis was performed to identify independent factors. Cox proportional hazard regression was adopted for the multivariate survival analysis.ResultsThe CPDC score was an independent predictor of LNM and overall survival (OS) in the multivariate analyses. For the prediction of LNM, the area under the curve (AUC) for the CPDC score was 0.722 (95% CI: 0.613–0.831, P<0.001), and for the prediction of survival, the AUC for the CPDC score was 0.756 (95% CI: 0.658–0.854, P<0.001). The predictive capacity of the CPDC score was higher than that of D-dimer or CA19-9. Kaplan-Meier curve analysis revealed that a CPDC =2 was significantly associated with a worse OS (P<0.001, median OS: 8.00 versus 19.00 months versus not reached) and shorter progression-free survival (PFS) (P<0.001, median PFS: 4.00 versus 11.00 versus 15.00 months) than a CPDC =1 or CPDC =0 in ICC patients. There were significant differences in the OS comparisons between any two groups. Decreased preoperative CPDC was associated with worse OS and PFS in all subgroups except in the HBsAg (+) group. In the cirrhosis, HBsAg (−) and tumour size ≥5 cm subgroups, there were significant differences in the OS and PFS comparisons between any two groups.ConclusionsThe preoperative CPDC score is a convenient and powerful prognostic biomarker to predict LNM and OS for ICC patients after curative resection. Especially for radiologically-negative metastatic lymph node in ICC patients, CPDC could be helpful to assess the extent of lymph node dissection and make follow-up plans.

Drug-eluting beads transarterial chemoembolization with CalliSpheres microspheres for treatment of unresectable intrahepatic cholangiocarcinoma.

Objective: This study aimed to evaluate the efficacy and safety of doxorubicin-loaded drug-eluting beads transarterial chemoembolization (DEB-TACE) with CalliSpheres microspheres (CSM) in treating unresectable intrahepatic cholangiocarcinoma (ICC).Methods: 88 unresectable ICC patients who received DEB-TACE treatment with CSM were retrospectively enrolled in this study. Information about treatment response, survival and adverse events were collected. The Kaplan-Meier curve was used to evaluate progression-free survival (PFS) and overall survival (OS), and factors affecting OS were determined by Cox's proportional hazards regression model.Results: Tumor response of the whole sample of 88 patients was partial response (PR) in 58 (65.9%) patients, stable disease (SD) in 19 (21.6%) and progressive disease (PD) in 11 (12.5%) at one month after therapy, with no complete responses (CR). The median PFS and OS were 3.0 months and 9.0 months respectively. Cox's proportional hazards regression analysis disclosed that subsequent treatment was an independent favorable prognostic factor, while cholangiectasis, extensive intrahepatic tumor burden and extrahepatic metastasis were the three prognostic factors associated with poor survival in ICC patients. Besides, common adverse events included nausea/vomiting, abdominal pain and transient elevation of liver transaminase in patients treated by DEB-TACE with CSM.Conclusion: DEB-TACE with CSM is safe and well-tolerated for unresectable ICC patients, with a low complication rate and a relative benefit in terms of survival. Subsequent treatments including systemic/loco-regional treatments is an independent favorable prognostic factor, but cholangiectasis, extensive intrahepatic tumor burden and extrahepatic metastases are the three prognostic factors associated with poor survival.

Loss of ARID1A induces a stemness gene ALDH1A1 expression with histone acetylation in the malignant subtype of cholangiocarcinoma.

Genomic analyses have recently discovered the malignant subtype of human intrahepatic cholangiocarcinoma (ICC) characterized by frequent mutations of chromatin remodeling gene ARID1A; however, the biological and molecular functions still remain obscure. We here examined the clinical and biological significances of ARID1A deficiency in human ICC. Immunohistochemical analysis demonstrated that the loss of ARID1A was an independent prognostic factor for overall survival of ICC patients (P = 0.023). We established ARID1A-knockout (KO) cells by using the CRISPR/Cas9 system from two human cholangiocarcinoma cell lines. ARID1A-KO cells exhibited significantly enhanced migration, invasion, and sphere formation activity. Microarray analysis revealed that ALDH1A1, a stemness gene, was the most significantly elevated genes in ARID1A-KO cells. In addition, ALDH enzymatic activity as a hallmark of cancer stem cells was markedly high in the KO cells. ARID1A and histone deacetylase 1 were directly recruited to the ALDH1A1 promoter region in cholangiocarcinoma cells with undetectable ALDH1A1 expression by chromatin immunoprecipitation assay. The histone H3K27 acetylation level at the ALDH1A1 promoter region was increased in cells when ARID1A was disrupted (P < 0.01). Clinically, inverse correlation between ARID1A and ALDH1A1 expression was also identified in primary ICC (P = 0.018), and ARID1A-negative and ALDH1A1-positve ICCs showed worse prognosis than only ARID1A-negative cases (P = 0.002). In conclusion, ARID1A may function as a tumor suppressor in ICC through transcriptional downregulation of ALDH1A1 expression with decreasing histone H3K27 acetylation. Our studies provide the basis for the development of new epigenetic approaches to ARID1A-negative ICC. Immunohistochemical loss of ARID1A is an independent prognostic factor in intrahepatic cholangiocarcinoma patients. ARID1A recruits HDAC1 to the promoter region of ALDH1A1, a stemness gene, and epigenetically suppresses ALDH1A1 expression with decreasing histone H3K27 acetylation in cholangiocarcinoma cells.

Risk Factors and Outcomes of Early Relapse After Curative Resection of Intrahepatic Cholangiocarcinoma.

Early relapse after hepatectomy for intrahepatic cholangiocarcinoma (ICC) has a tremendous influence on the long-term survival outcomes of ICC patients. The purpose of our study was to investigate risk factors for early tumor relapse and confirm whether early relapse was correlated with ICC patients' long-term survival outcomes. Three hundred and twenty-two consecutive ICC patients undergoing partial hepatectomy at Liver Surgery Department of Zhongshan Hospital (Fudan University, Shanghai, China) between January 2005 and December 2011 were included in this retrospectively study. The definition of early relapse had been described as tumor relapse within 24 months after hepatectomy in ICC patients. We identified a total of 168 ICC patients with early relapse and 23 ICC patients with late relapse after hepatectomy. From the time of relapse, the long-term survival outcomes were worse among patients who had early vs. late relapse (median OS 16.5 vs. 44.7 months, respectively; P < 0.0001). The overall survival of the early relapse group was lower than that of the late relapse group (P < 0.0001). Multivariate Cox regression analysis indicated that multiple tumors (hazard ratio [HR], 1.951; 95% CI, 1.382–2.755; P < 0.001), lymphonodus metastasis (HR, 1.517; 95% CI, 1.061–2.168; P = 0.022), and higher serum CA19-9 levels (HR, 1.495; 95% CI, 1.095–2.039; P = 0.011) were independent risk factors of early relapse. Moreover, multiple tumors (HR, 1.641; 95% CI, 1.120–2.406; P = 0.011), lymphonodus metastasis (HR, 2.008; 95% CI, 1.367–2.949; P < 0.001), elevated NLR (HR, 1.921; 95% CI, 1.331–2.774; P < 0.001) and higher serum CA19-9 levels (HR, 1.990; 95% CI, 1.409–2.812; P < 0.001) were independent predictors of overall survival for ICC patients with early relapse. Collectively, our findings demonstrated that multiple tumors, lymphonodus metastasis, and higher serum CA19-9 levels were associated with the increased risks of early relapse and worse prognoses of ICC after curative-intent resection.

Perihepatic lymph node dissection of resectable intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinoma (ICC) is a primary malignant tumor derived from epithelial cell of the subbranches of the intrahepatic bile ducts, which has characteristics of atypical clinical symptom, high misdiagnosis rate and poor prognosis. Radical surgery in early stage is considered as the only effective measure to cure ICC. Nowadays, it has been a focus and still remains debatable that whether perihepatic lymph node dissection (LND) could improve the long-time survival for ICC patients in consideration of that ICC is easy to migrate via lymphatic system. Therefore, for standardization of surgical treatment of ICC and improvement of patients′ survival, it is quite important to evaluate the necessity of LND in radical resection and benefits of LND in patients highly suspected lymph node metastasis or without lymph node metastasis preoperatively and intraoperatively. Based on the current situation of the global clinical research of LND in ICC, along with the clinical practice experience in authors′ clinical center, this paper focused on the safety and effectiveness of LND aiming to provide some evidences for the indication of LND in ICC patients. Key words: Intrahepatic cholangiocarcinoma; Perihepatic lymph node dissection; Survival rate; Lymph node metastasis; Postoperative recurrence

The Prognostic Prediction Role of Preoperative Serum Albumin Level in Patients with Intahepatic Cholangiocarcinoma Following Hepatectomy

Background: There is little information regarding the role of preoperative serum albumin (ALB) in intrahepatic cholangiocarcinoma (ICC) patients who underwent liver resection. Methods: Clinicopathological characteristics and survival rate of 91 ICC patients who underwent surgery between 2009 and 2013 were included in this study. The optimal cut-off for ALB were determined by plotting the receiver operating characteristics curves of ALB in predicting overall survival (OS) and utilizing the Youden index. Long-term outcome was calculated by Kaplan-meire method. Results: The pathological characteristics were similar in both groups. The 1- and 3-year disease-free survival (DFS) rates between the high ALB group and the lower ALB group were 62.7 vs. 25.5% and 27.0 vs. 11.1% respectively (p < 0.001). The 1- and 3-year OS rates between the high ALB group and the lower ALB group were 78.4 vs. 57.5% and 42.6 vs. 6.7% respectively (p < 0.001). The ALB level as continuous variable in multivariate analysis remained a favorable factor for DFS and OS (p < 0.05). Furthermore, ALB could distinguish the prognoses in non-cirrhotic patients. Multivariate analysis showed other pathological risk factors like lymph node involvement, positive surgical margin, satellite lesions, and carbohydrate antigen 19-9 were associated with DFS and OS (p < 0.05 for all). Conclusions: A higher preoperative serum ALB level is associated with better long-term survival in ICC patients.