Protein kinase C delta enhances the diagnostic performance of hepatocellular carcinoma.

BACKGROUND: The conventional markers for hepatocellular carcinoma (HCC), α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP), have several limitations; both have low sensitivity in patients with early-stage HCC; low sensitivity for AFP with HCC after eliminating hepatitis C virus (HCV); low specificity for DCP in patients with non-viral HCC, which is increasing worldwide; low specificity for AFP in patients with liver injury; and low specificity for DCP in patients treated with warfarin. To overcome these issues, the identification of novel biomarkers is an unmet need. OBJECTIVE: This study aimed to assess the usefulness of serum protein kinase C delta (PKCδ) for detecting these HCCs. METHODS: PKCδ levels were measured using a sandwich enzyme-linked immunosorbent assay in 363 chronic liver disease (CLD) patients with and without HCC. RESULTS: In both viral and non-viral CLD, PKCδ can detect HCCs with high sensitivity and specificity, particularly in the very early stages. Notably, the value and sensitivity of PKCδ were not modified by HCV elimination status. Liver injury and warfarin administration, which are known to cause false-positive results for conventional markers, did not modify PKCδ levels. CONCLUSIONS: PKCδ is an enhanced biomarker for the diagnosis of HCC that compensates for the drawbacks of conventional markers.

Kinetics of the hepatitis B core-related antigen and treatment responses in chronic hepatitis B patients treated with tenofovir alafenamide.

AIM: An association between hepatitis B core-related antigen (HBcrAg) kinetics and hepatocarcinogenesis during nucleoside (t)id analog (NA) treatment has recently been reported. HBcrAg kinetics and factors associated with HBcrAg response during tenofovir alafenamide (TAF) administration remain unclear. In this multicenter retrospective study, we aimed to clarify the efficacy and safety of TAF in treatment-naïve patients with chronic hepatitis B, focusing on the reduction in HBcrAg levels. METHODS: Patients were treated with TAF monotherapy for 96 weeks, and the kinetics of HBcrAg during treatment and the factors associated with HBcrAg response (defined as a change in HBcrAg of -1 log IU/mL from baseline) were evaluated. RESULTS: The study population comprised 241 patients, 36.9% of whom were HBeAg-positive. The median baseline HBcrAg level was 4.7 log IU/mL. The median change in HBcrAg from baseline was -1.1 log IU/mL at 96 weeks after treatment. The HBcrAg response rate at 96 weeks was 56.6% (43/76). Multivariate analysis revealed high alanine transaminase level as an independent baseline factor associated with HBcrAg response at 96 weeks of treatment (p = 4.53 × 10-6). No correlation was found between the HBcrAg and hepatitis B surface antigen kinetics in patients treated with TAF monotherapy. CONCLUSIONS: In TAF monotherapy for patients with chronic hepatitis B, HBcrAg levels were significantly decreased and baseline alanine transaminase level is an important factor associated with HBcrAg reduction. As no correlation was found between HBcrAg and reduced hepatitis B surface antigen levels in this study, HBcrAg kinetics in addition to hepatitis B surface antigen may need to be monitored during TAF treatment.

A novel combined C-reactive protein-albumin ratio and modified albumin-bilirubin score can predict long-term outcomes in patients with hepatocellular carcinoma after hepatic resection.

Background: Systemic inflammatory response represented by C-reactive protein and albumin ratio (CAR) and modified albumin-bilirubin (mALBI) grade both have been associated with long-term outcome in patients with hepatocellular carcinoma (HCC). In this study, we investigated the prognostic utility of combined score of CAR and mALBI score to predict the prognosis of HCC patients after hepatic resection. Methods: This study included 214 patients who had undergone primary hepatic resection for HCC between 2008 and 2018. Systemic inflammatory response and mALBI were evaluated preoperatively and patients were classified into three groups based on the combination of CAR and mALBI score: low CAR and low mALBI grade (score 0), either high CAR or high mALBI grade (score 1), and both high CAR and high mALBI grade ≥2b (score 2). Multivariate Cox proportional hazard models were conducted to assess disease-free and overall survival. Results: In multivariate analysis, sex (p < 0.01), HBsAg positivity (p < 0.01), serum AFP level ≥20 ng/mL (p < 0.01), microvascular invasion (p = 0.02), multiple tumors (p < 0.01), type of resection (p < 0.01), and CAR-mALBI score ≥2 (HR 2.19, 95% CI 1.39-3.44, p < 0.01) were independent prognostic factors of disease-free survival, while sex (p = 0.01), HBsAg positivity (p < 0.01), poor tumor differentiation (p = 0.03), multiple tumors (p < 0.01), CAR-mALBI score ≥2 (HR 2.70, 95% CI 1.51-4.83, p < 0.01) were independent prognostic factors of overall survival. Conclusions: CAR-mALBI score is associated with disease-free and overall survival in patients with HCC after hepatic resection, suggesting the importance of evaluating both hepatic functional reserve and host-inflammatory state in the risk assessment of HCC patients.

Protein Kinase C Delta Is a Novel Biomarker for Hepatocellular Carcinoma.

Backgrounds and Aims: Hepatocellular carcinoma (HCC) is the most common cancer with a poor prognosis. Identification of an alternative biomarker that can detect early-stage and conventional tumor marker-negative HCC is urgently needed. We found that protein kinase C delta (PKCδ) is specifically secreted from HCC cell lines into extracellular space and contributes to tumor development and that its serum levels were elevated in HCC patients. This study aimed to assess the practical usefulness of serum PKCδ for detecting HCC in chronic liver disease (CLD) patients. Methods: Serum PKCδ levels in 313 CLD patients with and without HCC (n = 187 and 126, respectively) were measured using a sandwich enzyme-linked immunosorbent assay. The diagnostic performance of PKCδ for HCC was evaluated using the receiver operating characteristic curve analysis and was compared with that of conventional markers, α-fetoprotein (AFP), and des-γ-carboxy prothrombin (DCP). Results: Serum PKCδ levels in HCC patients were significantly higher than those in CLD patients without HCC. PKCδ distinguished HCC patients from CLD patients without HCC, with high sensitivity and specificity. Subgroup analyses revealed that the diagnostic performance of PKCδ for HCC was comparable to that of AFP and DCP, and that approximately 40% of AFP/DCP double-negative HCC patients were positive for PKCδ. PKCδ yielded better diagnostic performance for detecting solitary small-sized (ie, very early stage) HCC than AFP and DCP. There was no significant correlation between serum PKCδ and AFP/DCP levels. Conclusion: Serum PKCδ is a novel HCC biomarker, which is independent of and complementary to conventional markers. Specifically, PKCδ may be useful for detecting very early-stage or AFP/DCP double-negative HCC.

The Impact of Cirrhosis and History of Hepatocellular Carcinoma on All-Cause Mortality After Eradication of Hepatitis C Virus in Patients With Chronic Hepatitis C.

Backgrounds and Aims: Cirrhosis and hepatocellular carcinoma (HCC) are potentially fatal complications of chronic hepatitis C virus (HCV) infection. We investigated how compensated cirrhosis and a history of curatively treated HCC influenced patient mortality after HCV eradication, that is, sustained virologic response (SVR). Methods: We studied 5458 patients with confirmed SVR who were prospectively followed up for more than 1 year after SVR achieved with direct-acting antivirals. Mortality and the incidence of HCC development after SVR were analyzed based on the presence or absence of compensated cirrhosis or a history of curatively treated HCC before the start of therapy. Results: Mortality and the incidence of post-SVR HCC were significantly higher in patients with compensated cirrhosis and those with a history of curatively treated HCC than in those without these complications. Multivariate analysis showed that a history of HCC was associated with high mortality after SVR. In patients with no history of HCC, cirrhosis was associated with high mortality. Although both liver-related and nonliver-related mortality rates were significantly higher in patients with a history of HCC or cirrhosis, nonliver-related mortality did not differ based on HCC history, and liver-related and nonliver-related mortality were comparable regardless of cirrhosis after propensity score matching with age, gender, alcohol intake, and comorbidities. Conclusion: Mortality after SVR was significantly higher in patients with compensated cirrhosis or a history of HCC. While a history of HCC significantly increased mortality after SVR, even following curative treatment, the impact of pre-SVR compensated cirrhosis on post-SVR mortality was modest.