Lenvatinib, which is an oral multikinase inhibitor, showed non-inferiority to the sorafenib in terms of overall survival (OS) and a higher objective response rate (ORR) and better progression-free ...survival (PFS) in patients with hepatocellular carcinoma (HCC). A good liver function and Barcelona Clinic Liver Cancer (BCLC) intermediate stage were the key factors in achieving therapeutic efficacy. The management of adverse events plays an important role in continuing lenvatinib treatment. While sequential therapies contributed to prolonging overall survival, effective molecular targeted agents for the administration after lenvatinib have not been established. Repeated transcatheter arterial chemoembolization (TACE) was associated with a decline in the liver function and poor therapeutic response in BCLC intermediate patients. Recently, the Asia-Pacific Primary Liver Cancer Expert (APPLE) Consensus Statement proposed the criteria for TACE unsuitability. Upfront systemic therapy may be better for the BCLC intermediate stage HCC patients with a high tumor burden, while selective TACE will be recommended for obtaining a curative response in patients with a low tumor burden. This article reviews the therapeutic response, management of adverse events, post-progression treatment after Lenvatinib, and treatment strategy for BCLC intermediate stage HCC.
Nuclear receptors (NR) collectively regulate several biological functions in various organs. While NRs can be characterized by activation of the transcription of their signature genes, they also have ...other diverse roles. Although most NRs are directly activated by ligand binding, which induces cascades of events leading to gene transcription, some NRs are also phosphorylated. Despite extensive investigations, primarily focusing on unique phosphorylation of amino acid residues in different NRs, the role of phosphorylation in the biological activity of NRs in vivo has not been firmly established. Recent studies on the phosphorylation of conserved phosphorylation motifs within the DNA- and ligand-binding domains confirmed has indicated the physiologically relevance of NR phosphorylation. This review focuses on estrogen and androgen receptors, and highlights the concept of phosphorylation as a drug target.
Transarterial chemoembolization (TACE) has been standard treatment for intermediate-stage hepatocellular carcinoma (HCC). However, all intermediate-stage HCC patients did not benefit from TACE ...treatment because intermediate-stage HCC encompasses a wide variety of HCCs. Owing to remarkable progress in systemic therapy, including molecular-targeted therapy for advanced-stage HCC, the standard treatment of HCC has recently shifted to systemic therapy. However, it remains controversial as to which treatment should be initially performed for intermediate-stage HCC. In addition, although curative treatment can be considered when the tumor shrinks, the timing of conversion therapy remains uncertain. This review summarizes the advances of HCC treatment and discusses treatment strategies for intermediate-stage HCC.
•We investigated the feasibility of high-dose hypo-fractionated carbon ion radiotherapy (C-ion RT) for patients with hepatocellular carcinoma.•C-ion RT using 60 Gy (RBE) in four fractions was safe ...and achieved promising local tumor control.•The beneficial effect of C-ion RT using 60 Gy (RBE) in four fractions should be evaluated in further prospective trials.
To evaluate the safety of carbon-ion radiotherapy (C-ion RT) using 60 Gy (relative biological effectiveness, RBE) in four fractions for patients with hepatocellular carcinoma (HCC).
The primary outcome was acute toxicities within 90 days. The secondary outcomes were late toxicities, local control, and progression-free survival and overall survival rates. The key inclusion criteria were as follows: (1) 3 cm or larger HCC without major vascular invasion and not adjacent to the alimentary tract; (2) Child–Pugh’s grade A/B; and (3) without extrahepatic metastasis.
A total of 21 cases were analyzed between October 2012 and April 2016. The median follow-up period among the 17 survivors was 24.2 (range: 6.3–43.7) months. Grade 3 or higher acute toxicity was not observed, while three (14.3%) of the 21 patients experienced grade 3 late toxicities. The 1- and 2-year local control, progression-free survival, and overall survival rates were 100% and 92.3%, 81.0% and 50.0%, and 90.5% and 80.0%, respectively.
C-ion RT using 60 Gy (RBE) in four fractions was safe and achieved promising local tumor control.
Transcatheter arterial chemoembolization (TACE) is widely accepted as a treatment for patients with hepatocellular carcinoma (HCC) in the intermediate stage according to the Barcelona Clinic Liver ...Cancer (BCLC) guidelines. Recently, balloon-occluded TACE (B-TACE) was developed in Japan. Despite the lack of a clear definition, B-TACE is generally defined as the infusion of emulsion of chemotherapeutic agents with lipiodol followed by gelatin particles under the occlusion of feeding arteries by a microballoon catheter, which leads to the dense lipiodol emulsion (LE) accumulation in HCC nodules. This phenomenon cannot be explained only by the prevention of proximal migration and leakage of embolization materials; it further involves causing local changes in the hemodynamics of the surrounding occlusion artery and targeted HCC nodules. Balloon-occluded arterial stump pressure plays an important role in the dense LE accumulation in targeted HCC nodules. Although randomized controlled trials comparing the therapeutic effect and the prognosis of B-TACE to those of the other TACE procedures, such as conventional-TACE and drug-eluting beads TACE, are still lacking, B-TACE is thought to be a promising treatment. The purpose of this review is to summarize the mechanism, therapeutic effect, indication, prognosis and complications of B-TACE.
Pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are nuclear receptors that are highly expressed in the liver and activated by numerous chemicals. While CAR activation by its ...activators, such as phenobarbital (PB), induces hepatocyte proliferation and liver carcinogenesis in rodents, it remains unclear whether PXR activation drives liver cancer. To investigate the influence of PXR activation on liver carcinogenesis, we treated mice with the PXR activator pregnenolone 16α-carbonitrile (PCN) with or without PB following tumor initiation with diethylnitrosamine (DEN). After 20 weeks of treatment, preneoplastic lesions detected by immunostaining with an anti-KRT8/18 antibody were observed in PB-treated but not PCN-treated mice, and PCN cotreatment augmented the formation of preneoplastic lesions by PB. After 35 weeks of treatment, macroscopic observations indicated that PB-treated and PB/PCN-cotreated mice had increased numbers of liver tumors compared to control and PCN-treated mice. In the pathological analyses of liver sections, all the mice in the PB and PB/PCN groups developed carcinoma and/or eosinophilic adenoma, but in the PB/PCN group, the multiplicity of carcinoma and eosinophilic adenoma was significantly reduced and the size of carcinoma showed a tendency to decrease. No mouse in the control or PCN-treated group developed such tumors. Differentially expressed gene (DEG) and gene set enrichment analyses in combination with RNA sequencing suggested the increased expression of genes related to epithelial–mesenchymal transition (EMT) in mice cotreated with PCN and PB compared to those treated with PB alone. Changes in the hepatic mRNA levels of epithelial marker genes supported the results of the transcriptome analyses. In conclusion, the present results suggest that PXR activation does not promote hepatocarcinogenesis in contrast to CAR and rather attenuates CAR-mediated liver cancer development by suppressing the EMT of liver cancer cells in rodents.
Hepatitis E is a zoonosis caused by hepatitis E virus (HEV), which was first discovered 40 years ago. Twenty million HEV infections worldwide are estimated each year. Most hepatitis E cases are ...self-limiting acute hepatitis, but the virus has been recognized to cause chronic hepatitis. Following the first case report of chronic hepatitis E (CHE) in a transplant recipient, CHE has recently been identified as associated with chronic liver damage induced by HEV genotypes 3, 4, and 7-usually in immunocompromised patients such as transplant recipients. In addition, patients infected with HIV and those receiving chemotherapy for malignancy, along with patients with rheumatic disease and COVID-19, have recently been reported as having CHE. CHE can be easily misdiagnosed by usual diagnostic methods of antibody response, such as anti-HEV IgM or IgA, because of the low antibody response in the immunosuppressive condition. HEV RNA should be evaluated in these patients, and appropriate treatments-such as ribavirin-should be given to prevent progression to liver cirrhosis or liver failure. While still rare, cases of CHE in immunocompetent patients have been reported, and care must be taken not to overlook these instances. Herein, we conduct an overview of hepatitis E, including recent research developments and management of CHE, in order to improve our understanding of such cases. The early diagnosis and treatment of CHE should be performed to decrease instances of hepatitis-virus-related deaths around the world.
Objective The therapeutic effect of pemafibrate on metabolic dysfunction-associated fatty liver disease (MAFLD) remains unknown. This retrospective, single-arm study investigated the efficacy and ...safety of pemafibrate in MAFLD patients with hypertriglyceridemia. Methods A total of 10 patients who received pemafibrate (oral, 0.1 mg, twice a day) at Gunma Saiseikai Maebashi Hospital between September 2018 and September 2019 were included. All patients underwent a liver biopsy, and the disease grade and stage were pathologically assessed based on the FLIP algorithm. Results The median age was 66.0 (53.8-74.8) years old, and 5 patients (50.0%) were men. All patients were diagnosed with non-alcoholic steatohepatitis (NASH). The fasting and non-fasting triglyceride (TG) levels were 175 (149-247) mg/dL and 228 (169-335) mg/dL, respectively. The AST and ALT values at 6 months were significantly lower than at baseline AST: 28.0 (22.0-33.8) U/L vs. 43.5 (24.0-55.0) U/L, p=0.008, ALT: 23.0 (14.8-26.5) U/L vs. 51.5 (23.0-65.3) U/L, p=0.005, respectively, especially in NASH patients with significant activity and advanced fibrosis (p=0.040 and 0.014, respectively). Fasting TG levels were significantly lower and HDL-C levels significantly higher at 6 months than at baseline (p=0.005 and 0.032, respectively). At six months, FIB-4, the aspartate aminotransferase-to-platelet ratio index, and the macrophage galactose-specific lectin-2 binding protein glycosylation isomer level were significantly improved compared with baseline (p=0.041, 0.005 and 0.005, respectively). Treatment-related adverse events were not observed. Conclusion Pemafibrate treatment may be safe and effective for MAFLD patients with hypertriglyceridemia.
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