Background: Lenvatinib is currently available as the first-line treatment for advanced unresectable hepatocellular carcinoma. We evaluated the relationship between its relative dose intensity (RDI) and response in clinical settings. Methods: From March 2018 to May 2019, 93 patients were administered lenvatinib at the Nagasaki University Hospital and its related facilities. Among these, 81 patients (66 men, 15 women, median age 72.0) who received lenvatinib were analyzed retrospectively. Results: Fourteen patients were Child–Pugh grade B, and 15 had received other systemic therapy. According to Response Evaluation Criteria in Solid Tumors (RECIST), the objective response (OR) rate was 17.3%. The overall survival (OS) was significantly better in the OR group (p = 0.011). There was a significant difference in RDI between the OR and non-OR groups (p < 0.05). The area under the receiver operating characteristics curve for OR prediction by the 4, 8, 12, and 16-week RDI were 0.666, 0.747, 0.731, and 0.704, respectively. In the 8-week RDI ≥67.0% group, OS was significantly better than in the 8-week RDI <67.0% group (p = 0.003). Conclusions: Because a sufficient RDI is required to achieve an OR, it is strongly recommended that lenvatinib should be administered to patients with good hepatic function and status.

Background: Atezolizumab plus bevacizumab therapy has high response rates in patients with unresectable hepatocellular carcinoma (HCC). The hepatobiliary phase of gadoxetic acid-enhanced magnetic resonance imaging (EOB-MRI) has been reported to be useful as an imaging biomarker for detecting β-catenin mutations. We evaluated whether the pretreatment of the hepatobiliary phase of EOB-MRI could predict the therapeutic effect of lenvatinib and atezolizumab plus bevacizumab. Methods: This study included 68 patients (lenvatinib group (n = 33) and atezolizumab plus bevacizumab group (n = 35)). The visual assessment and relative enhancement ratio (RER) of the largest HCC lesions were evaluated using the hepatobiliary phase of EOB-MRI. Results: The hyperintensity type (RER ≥ 0.9) was 18.2% in the lenvatinib group and 20.0% in the atezolizumab plus bevacizumab group. In the lenvatinib group, progression-free survival (PFS) was not different between the heterogeneous and homogenous types (p = 0.688) or between the hyperintensity and hypointensity types (p = 0.757). In the atezolizumab plus bevacizumab group, the heterogeneous type had significantly shorter PFS than the homogenous type (p = 0.007), and the hyperintensity type had significantly shorter PFS than the hypointensity type (p = 0.012). Conclusions: The hepatobiliary phase of EOB-MRI was useful for predicting the therapeutic effect of atezolizumab plus bevacizumab therapy on unresectable HCC.

Geranylgeranylacetone (GGA), an anti-ulcer drug widely used in Japan, has attracted interest because of its various therapeutic effects. Therefore, we investigated the effects of GGA on human hepatic stellate cells (HSCs) in vitro and in a mouse model of liver fibrosis. LX2, an immortalized human HSC line, was cultured and treated with GGA at concentrations up to 0.5 mM. After GGA treatment, changes in cellular morphology, apoptosis, and fibrosis-related gene expression were assessed. Male C57BL/6 J mouse model of carbon tetrachloride (CCl₄)-induced liver fibrosis was treated with GGA. Liver fibrosis was evaluated using Sirius red staining and immunohistochemistry for α-smooth muscle actin (SMA). GGA decreased the density of LX2 and primary human hepatic stellate cells but not that of HepG2 cells (a human hepatoma cell line), which was employed as control. In addition, GGA decreased the expression of fibrogenic genes and increased that of C/EBP homologous protein (CHOP). It also induced endoplasmic reticulum (ER) stress and increased apoptosis. CHOP knockdown, however, failed to suppress the GGA-induced decrease in LX2 cell density, suggesting the involvement of additional molecules in ER stress–associated apoptosis. Expression of death receptor 5, mitogen-activated protein kinase, heat shock protein 70, and Akt, all of which affect the activity of stellate cells, was unchanged in relation to LX2 cell fibrogenic activity. In the mouse model of liver fibrosis, GGA decreased the extent of Sirius red staining and SMA expression. GGA attenuated fibrogenic activity and induced apoptosis in cultured human HSCs, and suppressed liver fibrosis in mice, suggesting its potential as an agent for treating liver fibrosis.