Paradigm shift in the treatment options of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is prevalent worldwide with suboptimal therapeutic outcomes. The advancement of therapeutic options and the development of new systemic therapies expand the armamentarium to tackle HCC. Treatment options should be provided based on the hierarchy of efficacy in a multidisciplinary perspective, instead of the traditional stage-guided scheme. In advanced HCC, lenvatinib has a comparable efficacy as sorafenib for the first-line therapy of HCC; while regorafenib, cabozantinib, and ramucirumab have been approved as second-line therapy after the failure of sorafenib. Immune checkpoint inhibitor therapy prolongs response rate and survival and enables long-term cure. Atezolizumab plus bevacizumab is superior to sorafenib as the first-line therapy for advanced HCC. Several emerging regimens by the combination of various systemic therapies are currently under clinical trials. Systemic therapy may be used in the neoadjuvant, adjuvant or even as initial therapy for intermediate-stage HCC. The paradigm shift of HCC treatment will improve patient outcomes.

Iodized oil computed tomography versus ultrasound-guided radiofrequency ablation for early hepatocellular carcinoma.

BACKGROUND AND PURPOSE: Radiofrequency ablation (RFA) is the standard of care for early stage hepatocellular carcinoma (HCC). However, the clinical outcomes of iodized oil computed tomography (IoCT) versus ultrasound (US)-guided RFA for HCC remain unclear. METHODS: We retrospectively analyzed consecutive treatment-naïve patients who received curative RFA for HCC within Milan criteria from January 2016 to December 2018. Patients who underwent either IoCT-guided RFA (IoCT group) or US-guided RFA (US group) were included. Various clinical factors, including tumor location, were adjusted with a 1:1 propensity score matching. Subsequently, the cumulative incidence rates for recurrence and hazard ratios for survival were calculated. RESULTS: We included 184 (37.9%) and 301 (62.1%) patients who received IoCT- and US-guided RFA, respectively. Before propensity score matching, IoCT guidance was significantly associated with multiple tumors, higher body mass index, lower albumin level, and tumors located at S8. After matching, the 1-, 2-, and 3-year local tumor progression rates of the IoCT group were significantly lower than those of the US group (4.4%, 6.9%, and 7.5% vs. 14.4%, 16.3%, and 16.3%, respectively, at p = 0.002, 0.009, and 0.016, respectively). In univariate analyses and multivariate analyses that adjusted for clinical and tumor location-related parameters, the IoCT group had better recurrence-free survival (hazard ratio = 0.581, 95% confidence interval 0.375-0.899) than those with US guidance but not overall survival. CONCLUSION: IoCT-guided RFA had a lower local tumor progression rate and better recurrence-free survival than did US-guided RFA for HCC within the Milan criteria. CT-guide RFA is a safe and effective alternative to US-guided with similar overall survival. IoCT-guided RFA might have a better local tumor control than US-guided. IoCT-guided RFA may be more suitable for male patients, aged < 70 years, a single tumor measuring 2-5 cm, and a tumor located at the subdiaphragmatic/subcardiac region.

The association of vitamin D with hepatitis B virus replication: Bystander rather than offender.

BACKGROUND/PURPOSE: Low vitamin D is frequent in hepatitis B virus (HBV)-infected patients and several studies show an inverse association of serum vitamin D level with HBV viral load. However, the causal relationship remains unclear. METHODS: HBV carriers receiving regular 6-month surveillance without current antiviral treatment or cirrhosis were invited to participate into this trial. The markers of HBV replication included serum HBV DNA and quantitative HBsAg (qHBsAg) levels. Those with undetectable HBV DNA or sufficient vitamin D levels, cancer or electrolyte imbalance were excluded. The eligible subjects were randomized to receive either vitamin D supplement 2000 IU per day for 2 months (vitamin D group) or none (control group). RESULTS: A total of 196 HBV carriers (93 males and 103 females; mean age 51.9 ± 10.0 years) were screened. Of them, 28 patients had undetectable serum HBV DNA levels, which is defined as spontaneous viral clearance. The vitamin D levels were not different between patients with detectable HBV DNA and those without (p = 0.18). After exclusion, 149 patients were randomized to two groups: 75 in vitamin D group and 74 in control group. After 2 months vitamin D supplement, the serum vitamin D levels were significantly higher in the vitamin D group than the control group (p < 0.001). However, the serum qHBsAg and HBV DNA levels were comparable between these two groups. CONCLUSION: There is no causal relationship between vitamin D and HBV replication. The role of liver reserve on serum vitamin D levels in patients with chronic HBV infection needs further investigation.

Src-homology protein tyrosine phosphatase-1 agonist, SC-43, reduces liver fibrosis.

This study aimed to investigate the role of src-homology protein tyrosine phosphatase-1 (SHP-1)-signal transducer and activator of transcription 3 (STAT3) pathway in liver fibrogenesis and the anti-fibrotic effect of SHP-1 agonist. The antifibrotic activity of SC-43, a sorafenib derivative with an enhanced SHP-1 activity, was evaluated in two fibrosis mouse models by carbon tetrachloride induction and bile duct ligation. Rat, human, and primary mouse hepatic stellate cells (HSCs) were used for mechanistic investigations. The results showed that SHP-1 protein primarily localized in fibrotic areas of human and mouse livers. SC-43 treatment reduced the activated HSCs and thus effectively prevented and regressed liver fibrosis in both fibrosis mouse models and improved mouse survival. In vitro studies revealed that SC-43 promoted HSC apoptosis, increased the SHP-1 activity and inhibited phospho-STAT3. The enhanced SHP-1 activity in HSCs significantly inhibited HSC proliferation, whereas SHP-1 inhibition rescued SC-43-induced HSC apoptosis. Furthermore, SC-43 interacted with the N-SH2 domain of SHP-1 to enhance the activity of SHP-1 as its antifibrotic mechanism. In conclusion, the SHP-1-STAT3 pathway is crucial in fibrogenesis. SC-43 significantly ameliorates liver fibrosis through SHP-1 upregulation. A SHP-1-targeted antifibrotic therapy may represent a druggable strategy for antifibrotic drug discovery.

A pilot study of add-on oral hypoglycemic agents in treatment-naïve genotype-1 chronic hepatitis C patients receiving peginterferon alfa-2b plus ribavirin.

BACKGROUND/PURPOSE: Insulin resistance (IR) affects sustained virological response (SVR) to peginterferon alfa plus ribavirin (PR) in patients with chronic hepatitis C (CHC). Whether add-on oral hypoglycemic agents (OHAs) to PR improve SVR remains unclear; therefore, we conducted a prospective, randomized pilot trial on 23 consecutive patients with genotype 1 CHC and IR in Taiwan. METHODS: Patients were randomized to receive acarbose (Arm A; n = 7) or metformin (Arm B; n = 6) or pioglitazone (Arm C; n = 5) in addition to peginterferon alfa-2b (1.5 µg/kg/week) plus ribavirin (1000-1200 mg/day) or just PR (Arm D; n = 5). The primary end point was SVR, and secondary end points were viral clearance at Weeks 17, 29, and 53. There were no differences among all arms at baseline. RESULTS: Using intent-to-treat analysis, SVR was observed in 66.7% (4/6), 83.3% (5/6), 66.7% (4/6), and 60% (3/5) in Arms A, B, C, and D, respectively. SVR was higher in female patients receiving OHA [90% (9/10)] than in male patients [50% (4/8)]. Results of per protocol analysis showed that SVR was 80.0% (4/5) in Arm A, 100% (5/5) in Arm B, 66.7% (4/6) in Arm C, and 60% (3/5) in Arm D. Patients receiving OHA had a higher rapid virologic response: 11/18 (61%) versus 2/5 (40%). Complete early virologic response was comparable between patients receiving OHA and PR [15/18 (83%) vs. 4/5 (80%)]. CONCLUSION: Our preliminary data show add-on OHAs to PR might achieve better early viral kinetics and SVR. However, further larger studies are needed to confirm these findings.