<b><i>Introduction:</i></b> We evaluated the efficacy and safety of lenvatinib-transcatheter arterial chemoembolization (LEN-TACE) sequential therapy for patients (<i>n</i> = 88) with intermediate-stage hepatocellular carcinoma (HCC). <b><i>Methods:</i></b> Eighty-eight patients who obtained tumor control by LEN treatment were analyzed; 30 received LEN followed by TACE (LEN-TACE sequential therapy), and 58 received LEN monotherapy. Propensity score matching was performed, and the outcomes of 19 patients in the LEN-TACE group and 19 patients in the LEN-alone group were compared. Objective response rate (ORR), progression-free survival (PFS), overall survival (OS), incidence of adverse events (AEs), and change in albumin-bilirubin (ALBI) score were evaluated. <b><i>Results:</i></b> After matching, baseline characteristics were similar between the groups. The ORR was 63.2% with LEN-TACE group and 63.2% with the LEN-alone group. Multivariate analysis showed that addition of TACE during LEN treatment (hazard ratio [HR] 0.264, 95% confidence interval [CI] 0.087–0.802, <i>p</i> =  0.019) and Child-Pugh score 5 (HR 0.223, 95% CI 0.070–0.704, <i>p</i> = 0.011) were the significant factors for PFS. Median PFS was 11.6 months with LEN-TACE and 10.1 months with LEN-alone. The survival rate of the LEN-TACE group was significantly higher than that of the LEN-alone group (median survival time; not reached vs. 16.9 months, <i>p</i> = 0.007). The incidence of common LEN-associated AEs was similar between groups. Although elevated aspartate aminotransferase/alanine aminotransferase and fever were more frequent with LEN-TACE group, these events were manageable. <b><i>Conclusion:</i></b> For patients with intermediate-stage HCC, LEN-TACE sequential therapy may provide a deep response and favorable prognosis.

<b><i>Aim:</i></b> This study investigated early tumor marker response and treatment response in patients with advanced hepatocellular carcinoma (HCC) treated with lenvatinib. <b><i>Methods:</i></b> Twenty patients with advanced HCC who received lenvatinib were enrolled in this retrospective study. α-Fetoprotein (AFP) and des-γ-carboxyprothrombin (DCP) levels were measured before treatment as well as 2 and 4 weeks after treatment. The objective response rate was evaluated by mRECIST at 6 weeks. <b><i>Results:</i></b> The response rate was 30% (complete response/partial response/stable disease/progressive disease: <i>n</i> = 0/6/6/8 cases) by mRECIST. At 4 weeks, the AFP levels of 12 patients (80%) were lower than at baseline. The AFP levels of 9 patients (60%) continued decreasing from 2 weeks to 4 weeks (sustained-reduction group). In this group, the response rate was 67%. The median AFP change rate was –39% at 4 weeks. In imaging responders, the AFP change rate significantly decreased (<i>p</i> = 0.02). The DCP change rate had no significant correlation with imaging response. The AFP-sustained-reduction group had significantly higher adherence to lenvatinib than the non-sustained-reduction group (<i>p</i> = 0.02). <b><i>Conclusion:</i></b> With lenvatinib therapy for HCC, the AFP levels of most patients had declined at 2 weeks, and at 4 weeks the AFP-sustained-reduction group demonstrated a higher objective response.

Although the effect of levocarnitine (L‐carnitine) on hyperammonemia has been reported in patients with liver cirrhosis (LC), its effect on sarcopenia remains to be elucidated. We assessed the effects of L‐carnitine on sarcopenia in patients with LC. We retrospectively evaluated 52 patients with LC who were treated with L‐carnitine for more than 3 months between February 2013 and June 2017. Computed tomography was used to measure the cross‐sectional area of the skeletal muscles at the level of the third lumbar vertebra. The relative change in skeletal muscle index (SMI) per year (ΔSMI/year) was computed in each patient. We evaluated the relationship between ΔSMI/year and various parameters, such as age, sex, liver functional reserve, and dose of L‐carnitine. The median ΔSMI/year for all patients was −0.22%. The ΔSMI/year values in Child‐Pugh classes A, B, and C were not significantly different among the three groups. There was no significant relationship between ΔSMI/year and sex, age, body mass index, and sarcopenia. Multivariate analysis showed that only a high dose of L‐carnitine (odds ratio [OR], 4.812; 95% confidence interval [CI], 1.233‐18.784; P = 0.024) was associated with increased muscle mass. The L‐carnitine high‐dose group included a significantly larger number of patients with increased muscle mass compared with the low‐dose group (OR, 3.568; 95% CI, 1.138‐11.185; P = 0.027). Administration of L‐carnitine led to a significant and gradual reduction in serum ammonia levels. Conclusion: L‐carnitine seems to suppress the progression of sarcopenia dose dependently, and this was noted to be associated with the improvement of hyperammonemia in patients with LC.

The aim of this study was to investigate the early tumor response and safety of atezolizumab plus bevacizumab for patients with unresectable hepatocellular carcinoma in real-world practice. Forty patients with Child-Pugh class A liver function and eastern cooperative oncology group performance status 0 or 1 were enrolled. The objective response rate (ORR) at six weeks after the start of treatment, changes in α-fetoprotein (AFP) and des-γ-carboxyprothrombin, incidence of adverse events (AEs), and changes in albumin-bilirubin (ALBI) score and serum ammonia level, were evaluated. Among 40 patients, 24 had histories of prior molecular targeted agents (MTAs). The ORR was 22.5% based on mRECIST. Multivariate analysis showed that an AFP ratio <1.0 at three weeks (odds ratio 39.2, 95% confidence interval CI 2.37–649.0, p = 0.0103) was the only significant factor for predicting early response. There was no significant difference in the frequency of AEs between patients receiving first-line treatments and others. Fatigue, proteinuria, and ascites were more frequent in patients who experienced prior treatment. No decrease in ALBI score or increase in serum ammonia level was observed. Our study demonstrated that AFP may be useful in assessing early response and that this treatment is safe, including in patients with prior MTA treatments.

OBJECTIVES: Biomarkers for optimizing the outcome of treatment with lenvatinib in patients with advanced hepatocellular carcinoma remain to be established despite intensive and comprehensive genomic research. Lenvatinib is characterized by its prominent inhibitory potency for fibroblast growth factor receptor (FGFR) 4 compared with earlier tyrosine kinase inhibitors. Thus, in this study, we focused on simplified quantification of FGFR4 in tumors as a potential predictive indicator. METHODS: According to The Cancer Genome Atlas data set curation, FGFR4 messenger RNA is broadly overexpressed in hepatocellular carcinoma in the absence of gene alteration. Gene set enrichment analysis revealed that the aggressiveness of the tumor was closely related to the FGFR4 level. To confirm the relationship between the benefits of lenvatinib and tumor addiction to the FGFR4 pathway, we analyzed protein levels in tumors and peripheral blood obtained from 57 prospectively registered patients treated with lenvatinib. RESULTS: Positive immunohistochemistry (>10% of tumor cells) for FGFR4 in biopsy samples before treatment was associated with a longer progression-free survival (2.5 vs 5.5 months, P = 0.01) and a favorable objective response rate (31% vs 81%, P = 0.006). By contrast, the concentration of soluble FGFR4 in peripheral blood as measured by an enzyme-linked immunosorbent assay was not associated with survival outcomes, because its fluctuations reflect hepatic fibrosis. Additional RNA sequencing analysis using archival surgical specimens (n = 90) suggested that alternative RNA splicing of FGFR4 in cancer may also explain this discrepancy. DISCUSSION: The tumor FGFR4 level was an independent predictor of response to lenvatinib.