Varying impact of lenvatinib or sorafenib therapy on skeletal muscle loss in patients with hepatocellular carcinoma.

BACKGROUND: Lenvatinib and sorafenib are key therapeutic agents for hepatocellular carcinoma. However, there are no useful biomarkers for selecting molecular-targeted agents (MTAs). Skeletal muscle volume is associated with the clinical outcomes in these patients. We investigated the effects of lenvatinib and sorafenib on the skeletal muscles of patients with HCC. METHODS: We evaluated the impact of skeletal muscle changes over a 3-month period for each MTA (n = 117; lenvatinib/sorafenib, 45/72). The skeletal muscle mass index (SMI) was measured at the third lumbar vertebra. Furthermore, we evaluated the direct effect of each MTA on primary human skeletal muscle cells by estimating muscle protein synthesis using western blot analysis. RESULTS: The median change in SMI was -0.7% (p = 0.959) and -5.9% (p <0.001) for the lenvatinib and sorafenib groups, respectively. Sorafenib had a greater effect on skeletal muscle loss than lenvatinib (p < 0.001). Additionally, SMI significantly decreased in the sorafenib group regardless of initial skeletal muscle volume (p < 0.001), whereas no significant differences were observed in the lenvatinib group. Sorafenib therapy (odds ratio [OR], 2.98; p = 0.023) and non-muscle depletion (OR, 3.31; p = 0.009) were associated with a decreased SMI. In vitro analysis showed that sorafenib negatively affected muscle synthesis compared to lenvatinib. CONCLUSIONS: Sorafenib may have a more negative effect on skeletal muscle than lenvatinib.

Early Prediction of Response Focused on Tumor Markers in Atezolizumab plus Bevacizumab Therapy for Hepatocellular Carcinoma.

Despite the promising efficacy of atezolizumab plus bevacizumab (atezo/bev), some patients with unresectable hepatocellular carcinoma (HCC) experience disease progression. This retrospective study, which included 154 patients, aimed to evaluate predictors of treatment efficacy of atezo/bev for unresectable HCC. Factors associated with treatment response were examined, focusing on tumor markers. In the high-alpha-fetoprotein (AFP) group (baseline AFP ≥ 20 ng/mL), a decrease in AFP level > 30% was an independent predictor of objective response (odds ratio, 5.517; p = 0.0032). In the low-AFP group (baseline AFP < 20 ng/mL), baseline des-gamma-carboxy prothrombin (DCP) level < 40 mAU/mL was an independent predictor of objective response (odds ratio, 3.978; p = 0.0206). The independent predictors of early progressive disease were an increase in AFP level ≥ 30% at 3 weeks (odds ratio, 4.077; p = 0.0264) and the presence of extrahepatic spread (odds ratio, 3.682; p = 0.0337) in the high-AFP group and up-to-seven criteria, OUT (odds ratio, 15.756; p = 0.0257) in the low-AFP group. In atezo/bev therapy, focusing on early AFP changes, baseline DCP, and tumor burden of up-to-seven criteria are useful in predicting response to treatment.

Methylated SEPT9 assay-based liquid biopsy as a biomarker in molecular targeted agent-treated hepatocellular carcinoma.

BACKGROUND: The development of molecular targeted agents (MTAs) has changed the treatment strategy for hepatocellular carcinoma (HCC). However, currently, there are no established predictive biomarkers for the treatment efficacy of MTAs. Previously, we developed a novel liquid biopsy test for HCC screening using sensitive methylated DNA testing of septin 9 gene (SEPT9). Here, we hypothesized that SEPT9 could be used as a biomarker for MTA treatment efficacy. METHODS: We enrolled 157 patients receiving sorafenib or lenvatinib as a first-line therapy and allocated 85 and 72 patients to the training and validation cohorts, respectively. For the methylation assay, DNA was treated with methylation-sensitive restriction enzymes, followed by multiplex droplet digital PCR. Various clinical parameters were compared with clinical outcomes. RESULTS: The multivariate analysis revealed Eastern Cooperative Oncology Group performance status (≥ 1; p = 0.048), alpha-fetoprotein (AFP) (≥ 400 ng/mL; p < 0.001), and methylated-septin-9 (m-SEPT9) (≥ 205 copies/mL; p = 0.018) as significant predictors of poor overall survival (OS) in the training cohort. m-SEPT9 was identified as a predictor of poor OS in the validation cohort. We developed a predictive score, called the MTA score, consisting of these three significant OS parameters (two points were added for AFP and one point for each of the other predictors). Patients with MTA scores ≥ 2 showed a significantly poor prognosis compared to those with MTA scores ≤ 1 in both the training and validation cohorts. CONCLUSIONS: m-SEPT9 could be a potential predictive biomarker for survival in patients with HCC treated with MTAs.

Double cancer of primary hepatic angiosarcoma and hepatocellular carcinoma treated with atezolizumab plus bevacizumab.

AIM: Primary hepatic angiosarcoma (PHA) is extremely rare, and its imaging findings are similar to those of other liver tumors including hepatocellular carcinoma (HCC). Here, we report a case of hepatitis C virus (HCV)-related HCC followed by PHA that showed remarkable clinical response to atezolizumab plus bevacizumab (Atezo/Bev) therapy. CASE PRESENTATION: A 78-year-old man with recurrent HCC had a liver tumor with lymphadenopathy. Although considered as HCC recurrence, microscopic examination of the resected liver and lymph node showed PHA. Three months later, a solitary lung nodule was newly detected and subsequently resected. The pathological diagnosis was poorly differentiated HCC. Therefore, the patient was finally diagnosed with double cancer of PHA and HCC. Thereafter, he developed a new liver tumor with lymphadenopathy and received Atezo/Bev therapy. Liver tumor biopsy was carried out before the treatment. The pathological diagnosis was angiosarcoma. The patient showed a partial response after two courses of Atezo/Bev therapy. CONCLUSION: To our best knowledge, this report is the first case to present HCV-related HCC followed by PHA and to show that Atezo/Bev therapy is beneficial for PHA.

A combination of liver stiffness and international normalized ratio is an ideal prognostic predictor of portosystemic shunt occlusion in patients with portal hypertension.

BACKGROUND: We previously reported liver stiffness (LS) as a prognostic predictor of portosystemic shunt (PSS) occlusion. This study aims to reinvestigate the predictive factors of the model for end-stage liver disease-sodium (MELD-Na) score amelioration following balloon-occluded retrograde transvenous obliteration (BRTO) and to evaluate the postoperative prognoses of patients with portal hypertension by using newly identified factors. METHODS: Seventy-five patients who underwent BRTO between 2008 and 2021 were retrospectively enrolled. The MELD-Na scores were calculated preoperatively and one month postoperatively. We monitored long-term outcomes and analyzed postoperative survival. RESULTS: At one month postoperatively, the MELD-Na score decreased in 46 (61.3%) patients. Univariate analyses revealed a significant association of the score amelioration with nine factors, including lower LS levels and a higher international normalized ratio (INR). A multivariate logistic regression analysis with receiver operating characteristic curve analyses identified preoperative LS levels and INR as significant independent predictors of the postoperative MELD-Na score amelioration, with optimal cutoffs of 28.1 kPa and 1.06, respectively. The combination of LS < 28.1 kPa and INR ≥ 1.06 showed a sensitivity and specificity of 84.8% and 75.9% for the prediction of the score amelioration, respectively. For the propensity score model, we matched 24 patients with similar age, sex, MELD-Na score, and concomitant hepatocellular carcinoma. Kaplan-Meier analysis determined significantly higher cumulative survival rates in patients with LS < 28.1 kPa and INR ≥ 1.06 than in other populations. CONCLUSIONS: A combination of LS and INR can predict the MELD-Na score amelioration and prognosis improvement following PSS occlusion.

Drastic Improvement in Hepatitis B/C Virus-induced Decompensated Liver Cirrhosis Treated by Total Management Consisting of Interventional Radiology, Endoscopy, and Pharmacotherapy.

Recent advances in antiviral therapy have enabled control of the hepatitis virus; however, these do not completely eliminate the pathological condition of liver disease, and portal hypertension remains a clinical problem. We herein report a case of hepatitis B virus/hepatitis C virus (HBV/HCV)-induced decompensated liver cirrhosis for which total management consisting of interventional radiology and endoscopy, based on the evidence of our clinical studies, followed by antiviral therapy for co-infection with HBV and HCV was successful. This case clearly indicates the effective timing of total management, suggesting that it prolongs the vital prognosis in addition to improving the hepatic function.

A conserved loop structure of GH19 chitinases assists the enzyme function from behind the core-functional region.

Plant GH19 chitinases have several loop structures, which may define their enzymatic properties. Among these loops, the longest loop, Loop-III, is most frequently conserved in GH19 enzymes. A GH19 chitinase from the moss Bryum coronatum (BcChi-A) has only one loop structure, Loop-III, which is connected to the catalytically important ß-sheet region. Here, we produced and characterized a Loop-III-deleted mutant of BcChi-A (BcChi-A-ΔIII) and found that its stability and chitinase activity were strongly reduced. The deletion of Loop-III also moderately affected the chitooligosaccharide binding ability as well as the binding mode to the substrate-binding groove. The crystal structure of an inactive mutant of BcChi-A-ΔIII was successfully solved, revealing that the remaining polypeptide chain has an almost identical fold to that of the original protein. Loop-III is not necessarily essential for the folding of the enzyme protein. However, closer examination of the crystal structure revealed that the deletion of Loop-III altered the arrangement of the catalytic triad, Glu61, Glu70 and Ser102, and the orientation of the Trp103 side chain, which is important for sugar residue binding. We concluded that Loop-III is not directly involved in the enzymatic activity but assists the enzyme function by stabilizing the conformation of the ß-sheet region and the adjacent substrate-binding platform from behind the core-functional regions.

Candida guilliermondii-induced chorioretinitis in a patient with eating disorder.

Candidemia is a life-threatening fungal infection among patients undergoing long-term intravenous catheterization, hematopoietic stem cell transplantation, or immunosuppressive therapy, as well as patients with severe immunodeficiency or cancer. Endophthalmitis is a rare but severe form of ocular inflammation caused by infection of the intraocular cavity, which can lead to irreversible visual loss if not treated properly and promptly. The initial manifestation typically involves chorioretinitis, which requires early diagnosis and appropriate treatment. Candida guilliermondii is a non-Candida albicans yeast species; its frequency of detection in Japan has increased in recent years, and many drug-resistant and less-chorioretinitis-related strains are known. Here, we describe a 17-year-old girl with an eating disorder who exhibited chorioretinitis because of catheter-related bloodstream infection (CRBSI) caused by C. guilliermondii. The patient was hospitalized with severe weight loss, and she was presumed to develop candidemia because of immunosuppression during central parenteral nutrition therapy with a peripherally inserted central catheter. After onset of CRBSI, the catheter was immediately removed. Antifungal therapy was modified following fundus examination, fungal species confirmation, and drug sensitivity confirmation; thus, the patient recovered without long-term complications. To the best of our knowledge, this is the first report of C. guilliermondii-induced chorioretinitis in a patient with an eating disorder. Prolonged malnutrition and immunosuppression during nutritional therapy create a risk of candidemia in patients with eating disorders. After the onset of CRBSI, early administration and appropriate use of antifungal agents, with respect to specific ocular complications, are important for reduction of both mortality and ocular complications.