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Development and Validation of a Prognostic Score for Intrahepatic Cholangiocarcinoma.

ABSTRACT: Importance:In patients with intrahepatic cholangiocarcinoma (ICC), the oncologic benefit of surgery and perioperative outcomes for large multifocal tumors or tumors with contiguous organ involvement remain to be defined. Objectives:To develop and externally validate a simplified prognostic score for ICC and to determine perioperative outcomes for large multifocal ICCs or tumors with contiguous organ involvement. Design, Setting, and Participants:This study of a contemporary cohort merged data from the California Cancer Registry (January 1, 2004, through December 31, 2011) and the Office of Statewide Health Planning and Development inpatient database. Clinicopathologic variables were compared between tumors that were intrahepatic, small (<7 cm), and solitary (ISS) and those that had extrahepatic extension and were large (?7 cm) and multifocal (ELM). External validation of the prognostic model was performed using an independent data set from the National Cancer Institute's Surveillance, Epidemiology, and End Results database from January 1, 2004, through December 31, 2013. Main Outcomes and Measures:Patient overall survival after hepatectomy. Results:A total of 275 patients (123 men [44.7%] and 152 women [55.3%]; median [interquartile range] age, 65 [55-72] years) met the inclusion criteria. No significant differences in overall complication rate (ISS, 48 [34.5%]; ELM, 37 [27.2%]; P?=?.19) and mortality rate (ISS, 10 [7.2%]; ELM, 6 [4.4%]; P?=?.32) were found. A multivariate Cox proportional hazards model demonstrated that multifocality, extrahepatic extension, grade, node positivity, and age greater than 60 years are independently associated with worse overall survival. These variables were used to develop the MEGNA prognostic score. The prognostic separation/discrimination index was improved with the MEGNA prognostic score (0.21; 95% CI, 0.11-0.33) compared with the staging systems of the American Joint Committee on Cancer sixth (0.17; 95% CI, 0.09-0.29) and seventh (0.18; 95% CI, 0.08-0.30) editions. Conclusions and Relevance:The MEGNA prognostic score allows more accurate and superior estimation of patient survival after hepatectomy compared with current staging systems.

SUBMITTER: Raoof M

PROVIDER: S-EPMC5624806 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Development and Validation of a Prognostic Score for Intrahepatic Cholangiocarcinoma.

Raoof Mustafa M Dumitra Sinziana S Ituarte Philip H G PHG Melstrom Laleh L Warner Susanne G SG Fong Yuman Y Singh Gagandeep G

JAMA surgery 20170517 5

<h4>Importance</h4>In patients with intrahepatic cholangiocarcinoma (ICC), the oncologic benefit of surgery and perioperative outcomes for large multifocal tumors or tumors with contiguous organ involvement remain to be defined.<h4>Objectives</h4>To develop and externally validate a simplified prognostic score for ICC and to determine perioperative outcomes for large multifocal ICCs or tumors with contiguous organ involvement.<h4>Design, setting, and participants</h4>This study of a contemporary ...[more]

PMID: 28297009

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Project description:BackgroundClinical parameter-based nomograms and staging systems provide limited information for the prediction of survival in intrahepatic cholangiocarcinoma (ICC) patients. In this study, we developed a methylation signature that precisely predicts overall survival (OS) after surgery.MethodsAn epigenome-wide study of DNA methylation based on whole-genome bisulfite sequencing (WGBS) was conducted for two independent cohorts (discovery cohort, n=164; validation cohort, n=170) from three hepatobiliary centers in China. By referring to differentially methylated regions (DMRs), we proposed the concept of prognostically methylated regions (PMRs), which were composed of consecutive prognostically methylated CpGs (PMCs). Using machine learning strategies (Random Forest and the least absolute shrinkage and selector regression), a prognostic methylation score (PMS) was constructed based on 14 PMRs in the discovery cohort and confirmed in the validation cohort.ResultsThe C-indices of the PMS for predicting OS in the discovery and validation cohorts were 0.79 and 0.74, respectively. In the whole cohort, the PMS was an independent predictor of OS [hazard ratio (HR) =8.12; 95% confidence interval (CI): 5.48-12.04; P<0.001], and the C-index (0.78) of the PMS was significantly higher than that of the Johns Hopkins University School of Medicine (JHUSM) nomogram (0.69, P<0.001), the Eastern Hepatobiliary Surgery Hospital (EHBSH) nomogram (0.67, P<0.001), American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system (0.61, P<0.001), and MEGNA prognostic score (0.60, P<0.001). The patients in quartile 4 of PMS could benefit from adjuvant therapy (AT) (HR =0.54; 95% CI: 0.32-0.91; log-rank P=0.043), whereas those in the quartiles 1-3 could not. However, other nomograms and staging system failed to do so. Further analyses of potential mechanisms showed that the PMS was associated with tumor biological behaviors, pathway activation, and immune microenvironment.ConclusionsThe PMS could improve the prognostic accuracy and identify patients who would benefit from AT for ICC patients, and might facilitate decisions in treatment of ICC patients.

Project description:Background: Previous studies have shown that cellular senescence is strongly associated with tumorigenesis and the tumor microenvironment. Accordingly, we developed a novel prognostic signature for intrahepatic cholangiocarcinoma (ICCA) based on senescence-associated long non-coding RNAs (SR-lncRNAs) and identified a lncRNA-miRNA-mRNA axis involving in ICCA. Methods: Based on the 197 senescence-associated genes (SRGs) from Genacards and their expression in Fu-ICCA cohort, we identified 20 lncRNAs as senescence-associated lncRNAs (SR-lncRNAs) through co-expression and cox-regression analysis. According to 20 SR-lncRNAs, patients with ICCA were classified into 2 molecular subtypes using unsupervised clustering machine learning approach and to explore the prognostic and functional heterogeneity between these two subtypes. Subsequently, we integrated 113 machine learning algorithms to develop senescence-related lncRNA signature, ultimately identifying 11 lncRNAs and constructing prognostic models and risk stratification. The correlation between the signature and the immune landscape, immunotherapy response as well as drug sensitivity are explored too. Results: We developed a novel senescence related signature. The predictive model and risk score calculated by the signature exhibited favorable prognostic predictive performance, which is a suitable independent risk factor for the prognosis of patients with ICCA based on Kaplan-Meier plotter, nomogram and receiving operating characteristic (ROC) curves. The results were validated using external datasets. Estimate, ssGSEA (single sample gene set enrichment analysis), IPS (immunophenotype score) and TIDE (tumor immune dysfunction and exclusion) algorithms revealed higher immune infiltration, higher immune scores, lower immune escape potential and better response to immunotherapy in the high-risk group. In addition, signature identifies eight chemotherapeutic agents, including cisplatin for patients with different risk levels, providing guidance for clinical treatment. Finally, we identified a set of lncRNA-miRNA-mRNA axes involved in ICCA through regulation of senescence. Conclusion: SR-lncRNAs signature can favorably predict the prognosis, risk stratification, immune landscape and immunotherapy response of patients with ICCA and consequently guide individualized treatment.

Project description:ObjectivesTo establish a nomogram based on preoperative laboratory study variables using least absolute shrinkage and selection operator (LASSO) regression for differentiating combined hepatocellular cholangiocarcinoma (cHCC) from intrahepatic cholangiocarcinoma (iCCA).MethodsWe performed a retrospective analysis of iCCA and cHCC patients who underwent liver resection. Blood signatures were established using LASSO regression, and then, the clinical risk factors based on the multivariate logistic regression and blood signatures were combined to establish a nomogram for a differential preoperative diagnosis between iCCA and cHCC. The differential accuracy ability of the nomogram was determined by Harrell's index (C-index) and decision curve analysis, and the results were validated using a validation set. Furthermore, patients were categorized into two groups according to the optimal cut-off values of the nomogram-based scores, and their survival differences were assessed using Kaplan-Meier curves.ResultsA total of 587 patients who underwent curative liver resection for iCCA or cHCC between January 2008 and December 2017 at West China Hospital were enrolled in this study. The cHCC score was based on the personalized levels of the seven laboratory study variables. On multivariate logistic analysis, the independent factors for distinguishing cHCC were age, sex, biliary duct stones, and portal hypertension, all of which were incorporated into the nomogram combined with the cHCC-score. The nomogram had a good discriminating capability, with a C-index of 0.796 (95% CI, 0.752-0.840). The calibration plot for distinguishing cHCC from iCCA showed optimal agreement between the nomogram prediction and actual observation in the training and validation sets. The decision curves indicated significant clinical usefulness.ConclusionThe nomogram showed good accuracy for the differential diagnosis between iCCA and cHCC preoperatively, and therapeutic decisions would improve if it was applied in clinical practice.

Project description:Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver cancer. It is defined by cholangiocytic differentiation and has poor prognosis. Recently, epigenetic processes have been shown to play an important role in cholangiocarcinogenesis. We performed an integrative analysis on 52 iCCAs using both genetic and epigenetic data with a specific focus on DNA methylation components. We found recurrent isocitrate dehydrogenase 1 (IDH1) and IDH2 (28%) gene mutations, recurrent arm-length copy number alterations (CNAs), and focal alterations such as deletion of 3p21 or amplification of 12q15, which affect BRCA1 Associated Protein 1, polybromo 1, and mouse double minute 2 homolog. DNA methylome analysis revealed excessive hypermethylation of iCCA, affecting primarily the bivalent genomic regions marked with both active and repressive histone modifications. Integrative clustering of genetic and epigenetic data identified four iCCA subgroups with prognostic relevance further designated as IDH, high (H), medium (M), and low (L) alteration groups. The IDH group consisted of all samples with IDH1 or IDH2 mutations and showed, together with the H group, a highly disrupted genome, characterized by frequent deletions of chromosome arms 3p and 6q. Both groups showed excessive hypermethylation with distinct patterns. The M group showed intermediate characteristics regarding both genetic and epigenetic marks, whereas the L group exhibited few methylation changes and mutations and a lack of CNAs. Methylation-based latent component analysis of cell-type composition identified differences among these four groups. Prognosis of the H and M groups was significantly worse than that of the L group. Conclusion: Using an integrative genomic and epigenomic analysis approach, we identified four major iCCA subgroups with widespread genomic and epigenomic differences and prognostic implications. Furthermore, our data suggest differences in the cell-of-origin of the iCCA subtypes.

Dataset Information

Development and Validation of a Prognostic Score for Intrahepatic Cholangiocarcinoma.

Publications

Development and Validation of a Prognostic Score for Intrahepatic Cholangiocarcinoma.

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