International validation of the Chinese University Prognostic Index for staging of hepatocellular carcinoma: a joint United Kingdom and Hong Kong study

The outcome of hepatocellular carcinoma(HCC) patients significantly differs between western and eastern population centers. Our group previously developed and validated the Chinese University Prognostic Index(CUPI) for the prognostication of HCC among the Asian HCC patient population. In the current study, we aimed to validate the CUPI using an international cohort of patients with HCC and to compare the CUPI to two widely used staging systems, the Barcelona Clinic Liver Cancer(BCLC) classification and the Cancer of the Liver Italian Program(CLIP). To accomplish this goal, two cohorts of patients were enrolled in the United Kingdom(UK; n = 567; 2006-2011) and Hong Kong(HK; n = 517; 2007-2012). The baseline clinical data were recorded. The performances of the CUPI, BCLC, and CLIP were compared in terms of a concordance index(C-index) and were evaluated in subgroups of patients according to treatment intent. The results revealed that the median follow-up durations of the UK and HK cohorts were 27.9 and 29.8 months, respectively. The median overall survival of the UK and HK cohorts were 22.9 and 8.6 months, respectively. The CUPI stratified the patients in both cohorts into three risk subgroups corresponding to distinct outcomes. The median overall survival of the CUPI low-, intermediate-, and high-risk subgroups were 3.15, 1.24, and 0.29 years, respectively, in the UK cohort and were 2.07, 0.32, and 0.10 years, respectively, in the HK cohort. For the patients who underwent curative treatment, the prognostic performance did not differ between the three staging systems, and all were suboptimal. For those who underwent palliative treatment, the CUPI displayed the highest C-index, indicating that this staging system was the most informative for both cohorts. In conclusion, the CUPI is applicable to both western and eastern HCC patient populations. The performances of the three staging systems differed according to treatment intent, and the CUPI was demonstrated to be optimal for those undergoing palliative treatment. A more precise staging system for early-stage disease patients is required.

Aberrant cholesterol metabolic signaling impairs antitumor immunosurveillance through natural killer T cell dysfunction in obese liver

Obesity is a major risk factor for cancers including hepatocellular carcinoma(HCC)that develops from a background of non-alcoholic fatty liver disease(NAFLD).Hypercholesterolemia is a common comorbidity of obesity.Although cholesterol biosynthesis mainly occurs in the liver,its role in HCC development of obese people remains obscure.Using high-fat high-carbohydrate diet-associated orthotopic and spontaneous NAFLD-HCC mouse models,we found that hepatic cholesterol accumulation in obesity selectively suppressed natural killer T(NKT)cell-mediated antitumor immunosurveillance.Transcriptome analysis of human liver revealed aberrant cholesterol metabolism and NKT cell dysfunction in NAFLD patients.Notably,cholesterol-lowering rosuvastatin restored NKT expansion and cytotoxicity to prevent obesogenic diet-promoted HCC development.Moreover,suppression of hepatic cholesterol biosynthesis by a mammalian target of rapamycin(mTOR)inhibitor vistusertib preceded tumor regression,which was abolished by NKT inactivation but not CD8^(+)T cell depletion.Mechanistically,sterol regulatory element-binding protein 2(SREBP2)-driven excessive cholesterol production from hepatocytes induced lipid peroxide accumulation and deficient cytotoxicity in NKT cells,which were supported by findings in people with obesity,NAFLD and NAFLD-HCC.This study highlights mTORC1/SREBP2/cholesterol-mediated NKT dysfunction in the tumor-promoting NAFLD liver microenvironment,providing intervention strategies that invigorating NKT cells to control HCC in the obesity epidemic.