Predictive biomarkers of the response of hepatocellular carcinoma (HCC) to Lenvatinib therapy have not yet been clarified. The aim of this study was to identify clinically significant biomarkers of response to Lenvatinib therapy, to target strategies against HCC. Levels of circulating angiogenic factors (CAFs) were analyzed in blood samples collected at baseline and after introducing lenvatinib, from 74 Child-Pugh class A HCC patients who received lenvatinib. As CAF biomarkers, serum vascular endothelial growth factor (VEGF), fibroblast growth factor 19 (FGF19), FGF23, and angiopoietin-2 (Ang-2) were measured using enzyme-linked immunosorbent assays. Results: Significantly increased FGF19 (FGF19-i) levels and decreased Ang-2 (Ang-2-d) levels were seen in Lenvatinib responders as compared to non-responders (ratio of FGF19 level at 4 weeks/baseline in responders vs. non-responders: 2.09 vs. 1.32, respectively, p = 0.0004; ratio of Ang-2 level at four weeks/baseline: 0.584 vs. 0.810, respectively, p = 0.0002). Changes in FGF23 and VEGF levels at four weeks versus baseline, however, were not significantly different in responders versus non-responders. In multivariate analysis, the combination of serum FGF19-i and Ang-2-d was the most independent predictive factor for Lenvatinib response (Odds ratio, 9.143; p = 0.0012). Furthermore, this combination biomarker showed the greatest independent association with progression-free survival (Hazard ratio, 0.171; p = 0.0240). Early changes in circulating FGF19 and Ang-2 levels might be useful for predicting clinical response and progression-free survival in HCC patients on Lenvatinib therapy.

Background: Many studies have investigated the prognosis of nonalcoholic fatty liver disease (NAFLD); however, most studies had a relatively short follow-up. To elucidate the long-term outcome of NAFLD, we conducted a retrospective cohort study of patients with biopsy-proven NAFLD. Methods: We re-evaluated 6080 patients who underwent liver biopsy from 1975 to 2012 and identified NAFLD patients without other etiologies. With follow-up these patients, we evaluated the outcome-associated factors. Results: A total of 223 patients were enrolled, 167 (74.9%) was non-alcoholic steatohepatitis (NASH). The median follow-up was 19.5 (0.5–41.0) years and 4248.3 person-years. The risk of type 2 diabetes mellitus (T2DM) and hypertension was 11.7 (95% confidence interval [CI] 8.70–15.6) and 7.99 (95% CI 6.09–10.5) times higher, respectively, in NAFLD patients than in the general population. Twenty-three patients died, 22 of whom had NASH. Major causes of death were extrahepatic malignancy and cardiovascular disease (21.7%) followed by liver-related mortality (13.0%). All-cause mortality was significantly higher in NASH patients than in nonalcoholic fatty liver patients (P = 0.041). In multivariate analysis, older age (hazard ratio [HR] 1.09 [95% CI 1.05–1.14], P<0.001) and T2DM (HR 2.87 [95% CI 1.12–7.04], P = 0.021) were significantly associated with all-cause mortality. The factors significantly associated with liver-related events were older age, T2DM, milder hepatic steatosis, and advanced liver fibrosis. Body mass index wasn’t associated with either mortality or liver-related events. Conclusions: T2DM was highly prevalent in NAFLD patients and was significantly associated with both all-cause mortality and liver-related events. The lean patients’ prognosis wasn’t necessarily better than that of overweight patients.

Background and Objective Sodium glucose co-transporter 2 inhibitors increase urinary glucose excretion and reduce visceral adiposity and body weight, but their efficacy on patients with nonalcoholic fatty liver disease has not been sufficiently investigated. The aim of this study was to assess the effect of sodium glucose co-transporter 2 inhibitors on liver fat mass and body composition in patients with nonalcoholic fatty liver disease and type 2 diabetes mellitus. Methods We retrospectively analyzed 17 patients with nonalcoholic fatty liver disease and type 2 diabetes who received sodium glucose co-transporter 2 inhibitors between November 2016 and July 2017. Changes in liver fat, subcutaneous and visceral fat, body composition, and liver function-related parameters were assessed after 24 weeks of sodium glucose co-transporter 2 inhibitor treatment and compared to baseline values. Results Ten patients received dapagliflozin at 5 mg/day and seven patients received canagliflozin at 100 mg/day for 24 weeks. All patients completed the study without any serious adverse effects and achieved body weight loss and improved glycated hemoglobin levels. Liver fat mass evaluated by proton magnetic resonance spectroscopy was significantly reduced (19.1% vs. 9.2%, p < 0.01), and so were both subcutaneous and visceral fat mass. The body fat/body weight ratio decreased, whereas the skeletal muscle mass/body weight ratio increased. Liver function (aspartate aminotransferase, alanine aminotransferase, and γ-glutamyl transpeptidase) improved significantly. Conclusions Sodium glucose co-transporter 2 inhibitor treatment not only improved glycemic control but also reduced liver fat mass in patients with nonalcoholic fatty liver disease and type 2 diabetes. Body weight loss was primarily attributable to a reduction in fat mass, especially visceral fat. Thus, sodium glucose co-transporter 2 inhibitors could potentially serve as a therapeutic agent for patients with nonalcoholic fatty liver disease and type 2 diabetes.

Patients with advanced hepatocellular carcinoma (HCC) undergoing molecular targeted therapy often experience non-negligible adverse events (AEs). Paradoxically, certain AEs are reportedly associated with a good prognosis. We aimed to identify factors predictive of treatment duration and overall survival (OS) in patients with HCC undergoing lenvatinib therapy. Forty-six consecutive patients with advanced HCC who received lenvatinib therapy from April 2018 to November 2019 were prospectively followed until November 2019. Treatment efficacy was assessed according to the modified Response Evaluation Criteria in Solid Tumors for 2–3 months after therapy initiation. The disease control rate (DCR) was defined as the percentage of patients with a complete response, partial response, or stable disease. The DCR was 65.2%, with a median survival of 10.2 months. Grade 2/3 hypoalbuminemia resulted in shorter treatment duration. Factors predictive of longer OS were a Child-Pugh score of 5 at baseline and the occurrence of Grade 2/3 hypothyroidism. Conversely, Grade 2/3 hypoalbuminemia was associated with a poorer prognosis. An AE of Grade 2/3 hypothyroidism was associated with a better prognosis in patients receiving lenvatinib treatment for advanced HCC. Continuing anticancer therapy with appropriate thyroid hormone replacement may contribute to longer OS.

This study aimed to identify the health-related quality of life (HRQOL) domains associated with prognosis by assessing longitudinal alterations in HRQOL in patients with advanced hepatocellular carcinoma receiving sorafenib. We prospectively assessed HRQOL by administering the SF-36 questionnaire 3-monthly to consecutive patients with advanced hepatocellular carcinoma receiving sorafenib. We evaluated the impact of HRQOL on their overall survival and duration of treatment with sorafenib using Cox's proportional hazards model. There were 54 participants: 42 (78 %) were male, the median age was 71 years, 24 (44 %) had hepatitis C virus infection, 33 (61 %) had Child-Pugh scores of 5, and 30 (56 %) had TNM stage IV hepatocellular carcinoma. The median overall survival and treatment duration were 9 and 5 months, respectively, and 40 patients (74 %) died. Thirteen patients receiving sorafenib over a 1-year period maintained all domain scores >40, without a significant decline during the treatment period. In contrast, physical functioning, physical role, and vitality scores declined continuously and significantly in the year before death (in the 40 patients who died). Previous curative treatment and physical functioning scores ≥40 at baseline were significantly associated with longer overall survival by multivariate analysis. Social functioning scores ≥40, absence of vascular invasion, and lower DCP value were significant predictors of longer treatment duration. HRQOL was not significantly impaired in those patients who were able to complete a 1-year course of sorafenib treatment. Baseline physical functioning scores ≥40 and social functioning scores ≥40 were significantly associated with longer overall survival and longer treatment duration, respectively. Thus, HRQOL could be a valuable marker to predict the clinical course of patients with advanced hepatocellular carcinoma receiving sorafenib.