Aim: Worldwide, hepatocellular cancer (HCC) is the fourth leading cause of cancer death and occurs 3 times more commonly in males than females. Current surveillance practices do not fully address gender differences in HCC. Methods: Clinical characteristics and survival were compared between males and females using a prospectively collected database of HCC patients. Results: In a cohort of 1206 patients, 307 (25%) were female who presented with older age, more non-alcoholic fatty liver disease/steatohepatitis (NAFLD/NASH), family history of HCC, and hypertension. Males (75%) were more likely to use alcohol and cigarettes. Females were more likely to undergo HCC surveillance, have smaller tumor size at diagnosis, and less vascular involvement. Males who met Milan criteria were more likely to undergo liver transplant than women who met the criteria. Median/mean survival was similar between the genders. Multivariate analysis showed that NAFLD/NASH was predictive of mortality for both males and females, age and smoking were predictive of mortality for males, and transplant was predictive of survival for males. Conclusion: Gender differences in HCC appear related to both behavioral risk factors and biologic factors. Older females with HCC have more NAFLD/NASH and may be overlooked by current surveillance guidelines. These gender disparities may lend support to future studies of gender-based HCC screening.

PurposeHexokinase-2 (HK2) and more recently choline kinase alpha (CKA) expression has been correlated with clinical outcomes in several major cancers. This study examines the protein expression of HK2 and CKA in hepatocellular carcinoma (HCC) in association with patient survival and other clinicopathologic parameters.MethodsImmunohistochemical analysis for HK2 and CKA expression was performed on a tissue microarray of 157 HCC tumor samples. Results were analyzed in relation to clinicopathologic data from Surveillance, Epidemiology, and End-Results Program registries. Mortality rates were assessed by Kaplan-Meier estimates and compared using log-rank tests. Predictors of overall survival were assessed using proportional hazards regression. RESULTS: Immunohistochemical expression of HK2 and CKA was detected in 71 (45%) and 55 (35%) tumor samples, respectively. Differences in tumor HK2 expression were associated with tumor grade (p = 0.008) and cancer stage (p = 0.001), while CKA expression differed significantly only across cancer stage (p = 0.048). Increased mortality was associated with tumor HK2 expression (p = 0.003) as well as CKA expression (p = 0.03) with hazard ratios of 1.86 (95% confidence interval (CI) 1.23–2.83) and 1.59 (95% CI 1.04–2.41), respectively. Similar effects on overall survival were noted in a subset analysis of early stage (I and II) HCC. Tumor HK2 expression, but not CKA expression, remained a significant predictor of survival in multivariable analyses.ConclusionHK2 and CKA expression may have biologic and prognostic significance in HCC, with tumor HK2 expression being a potential independent predictor of survival.

BackgroundHepatocellular carcinoma (HCC) is one of the most common cancers and frequently presents with an advanced disease at diagnosis. There is only limited knowledge of genome-scale methylation changes in HCC.Methods and FindingsWe performed genome-wide methylation profiling in a total of 47 samples including 27 HCC and 20 adjacent normal liver tissues using the Illumina HumanMethylation450 BeadChip. We focused on differential methylation patterns in the promoter CpG islands as well as in various less studied genomic regions such as those surrounding the CpG islands, i.e. shores and shelves. Of the 485,577 loci studied, significant differential methylation (DM) was observed between HCC and adjacent normal tissues at 62,692 loci or 13% (p<1.03e-07). Of them, 61,058 loci (97%) were hypomethylated and most of these loci were located in the intergenic regions (43%) or gene bodies (33%). Our analysis also identified 10,775 differentially methylated (DM) loci (17% out of 62,692 loci) located in or surrounding the gene promoters, 4% of which reside in known Differentially Methylated Regions (DMRs) including reprogramming specific DMRs and cancer specific DMRs, while the rest (10,315) involving 4,106 genes could be potential new HCC DMR loci. Interestingly, the promoter-related DM loci occurred twice as frequently in the shores than in the actual CpG islands. We further characterized 982 DM loci in the promoter CpG islands to evaluate their potential biological function and found that the methylation changes could have effect on the signaling networks of Cellular development, Gene expression and Cell death (p = 1.0e-38), with BMP4, CDKN2A, GSTP1, and NFATC1 on the top of the gene list.ConclusionSubstantial changes of DNA methylation at a genome-wide level were observed in HCC. Understanding epigenetic changes in HCC will help to elucidate the pathogenesis and may eventually lead to identification of molecular markers for liver cancer diagnosis, treatment and prognosis.

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Clinical prediction of advanced hepatic fibrosis (HF) and cirrhosis has long been challenging due to the gold standard, liver biopsy, being an invasive approach with certain limitations. Less invasive blood test tandem with a cutting-edge machine learning algorithm shows promising diagnostic potential. In this study, we constructed and compared machine learning methods with the FIB-4 score in a discovery dataset ( n = 490) of hepatitis B virus (HBV) patients. Models were validated in an independent HBV dataset ( n = 86). We further employed these models on two independent hepatitis C virus (HCV) datasets ( n = 254 and 230) to examine their applicability. In the discovery data, gradient boosting (GB) stably outperformed other methods as well as FIB-4 scores ( p < .001) in the prediction of advanced HF and cirrhosis. In the HBV validation dataset, for classification between early and advanced HF, the area under receiver operating characteristic curves (AUROC) of GB model was 0.918, while FIB-4 was 0.841; for classification between non-cirrhosis and cirrhosis, GB showed AUROC of 0.871, while FIB-4 was 0.830. Additionally, GB-based prediction demonstrated good classification capacity on two HCV datasets while higher cutoffs for both GB and FIB-4 scores were required to achieve comparable specificity and sensitivity. Using the same parameters as FIB-4, the GB-based prediction system demonstrated steady improvements relative to FIB-4 in HBV and HCV cohorts with different cutoff values required in different etiological groups. A user-friendly web tool, LiveBoost, makes our prediction models freely accessible for further clinical studies and applications.

Malignant tumors in the prostate gland can be localized based on a standardized regional measurement of F FCH uptake. PET with F FCH is potentially useful for staging and localizing prostate cancer.

Biliary atresia (BA) is a severe chronic cholestasis disorder of infants that leads to death if not treated on time. Neonatal hepatitis syndrome (NHS) is another leading cause of neonatal cholestasis confounding the diagnosis of BA. Recent studies indicate that altered bile acid metabolism is closely associated with liver injury and cholestasis. In this study, we systematically measured the bile acid metabolome in plasma of BA, NHS, and healthy controls. Liver bile acids were also measured using biopsy samples from 48 BA and 16 NHS infants undergoing operative cholangiography as well as 5 normal adjacent nontumor liver tissues taken from hepatoblastoma patients as controls. Both BA and NHS samples had significantly elevated bile acid levels in plasma compared to normal controls. BA patients showed a distinct bile acid profile characterized by the higher taurochenodeoxycholic acid (TCDCA) level and lower chenodeoxycholic acid (CDCA) level than those in NHS patients. The ratio of TCDCA to CDCA in plasma was significantly higher in BA compared to healthy infants (p < 0.001) or NHS (p < 0.001). The area under receiver operating characteristic curve for TCDCA/CDCA to differentiate BA from NHS was 0.923 (95% CI: 0.862-0.984). These findings were supported by significantly altered expression levels of bile acid transporters and nuclear receptors in liver including farnesoid X receptor (FXR), small heterodimer partner (SHP), bile salt export pump (BSEP), and multidrug resistant protein 3 (MDR3) in BA compared to NHS. Taken together, the plasma bile acid profiles are distinct in BA, NHS, and normal infants, as characterized by the ratio of TCDCA/CDCA differentially distributed among the three groups of infants.

This study investigates the prognostic significance of metabolically active tumor volume (MATV) measurements applied to fluorine-18 fluorocholine (FC) PET/CT in castrate-resistant prostate cancer (CRPC). Methods FC PET/CT imaging was performed in 30 patients with CRPC. Metastatic disease was quantified on the basis of maximum standardized uptake value (SUVmax), MATV, and total lesion activity (TLA = MATV × mean SUV). Tumor burden indices derived from whole-body summation of PET tumor volume measurements (ie. net MATV and net TLA) were evaluated as variables in Cox regression and Kaplan-Meier survival analyses. Results Net MATV ranged from 0.12 cm3 to 1543.9 cm3 (median 52.6 cm3). Net TLA ranged from 0.40g to 6688.7g (median 225.1g). PSA level at the time of PET correlated significantly with net MATV (Pearson r = 0.65, p = 0.0001) and net TLA (r = 0.60, p = 0.0005) but not highest lesional SUVmax of each scan. Survivors were followed for a median 23 months (range 6 – 38 months). On Cox regression analyses, overall survival was significantly associated with net MATV (p = 0.0068), net TLA (p = 0.0072), and highest lesion SUVmax (p = 0.0173), and borderline associated with PSA level (p = 0.0458). Only net MATV and net TLA remained significant in univariate-adjusted survival analyses. Kaplan-Meier analysis demonstrated significant differences in survival between groups stratified by median net MATV (log-rank P = 0.0371), net TLA (log-rank P = 0.0371), and highest lesion SUVmax (log-rank P = 0.0223). Conclusions Metastatic prostate cancer detected by FC PET/CT can be quantified based on volumetric measurements of tumor metabolic activity. The prognostic value of FC PET/CT may stem from this capacity to assess whole-body tumor burden. With further clinical validation, FC PET-based indices of global disease activity and mortality risk could prove useful in patient-individualized treatment of CRPC.