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Background & Aims: Relationships of serum C-C motif chemokine ligand 5 (CCL5) and C-X-C motif chemokine ligand 10 (CXCL10) levels with hot immune features have been reported in patients with hepatocellular carcinoma (HCC). Therefore, we examined the utility of their levels for predicting the efficacy of atezolizumab plus bevacizumab (Atez/Bev) in patients with HCC., Design: In total, 98 patients with HCC treated with Atez/Bev were enrolled, and their initial responses were evaluated at least once via dynamic computed tomography or magnetic resonance imaging. Serum CCL5 and CXCL10 levels were assessed by enzyme-linked immunosorbent assay before treatment and at the start of the second course of Atez/Bev therapy, and their relationships with treatment efficacy were determined., Results: No analyzed factor was associated with the initial therapeutic response. Among the 56 patients with Barcelona Clinic Liver Cancer (BCLC) stage C, serum CXCL10 levels at the beginning of course two (CXCL10-2c) tended to be higher in responders than in non-responders in the initial evaluation, and its optimal cutoff level of 690 pg/mL could be used to stratify patients regarding overall survival (OS; high vs. low: not reached vs. 17.6 months, p = 0.034) and progression-free survival (high vs. low: 13.6 vs. 5.1 months, p = 0.014). In multivariate analysis, high CXCL10 levels and neutrophil-to-lymphocyte ratios at the start of course two and Child-Pugh stage A at baseline were independent predictive factors of improved OS., Conclusions: Serum CXCL10-2c levels were predictive of Atez/Bev efficacy in patients with BCLC stage C HCC., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Advanced hepatocellular carcinoma (HCC) remains a highly lethal malignancy, although several systemic therapeutic options are available, including sorafenib (SFN), which has been one of the standard treatment agents for almost a decade. As early prediction of response to SFN remains challenging, biomarkers that enable early prediction using a clinically feasible method are needed. Here, we report that the serum secretory form of clusterin (sCLU) protein and its related predictive index are potential beneficial biomarkers for early prediction of SFN response. Using high-throughput screening and subsequent multivariate analysis in the derivation cohort, we found that changes in the concentrations of CLU, vascular cell adhesion molecule-1 (VCAM1), and α-fetoprotein were significantly associated with response to SFN. Furthermore, we confirmed that an increase in CLU serum level 1 month after treatment initiation was significantly associated with shorter progression-free survival. In addition, "NR-index," which comprises these proteins, was evaluated as a tool for accurately predicting the efficacy of SFN and confirmed in the validation cohort. We also established SFN-resistant HepG2 cells (HepG2-SR) and found that sCLU significantly increased in HepG2-SR cells compared with normal HepG2 cells, and confirmed that HepG2-SR cells treated with SFN were resistant to apoptosis. The mechanism underlying activation of sCLU expression in acquired SFN resistance involves aberrant signaling and expression of Akt, mammalian target of rapamycin (mTOR), and a nutrient-related transcription factor, sterol regulatory element binding protein 1c (SREBP-1c). Furthermore, the PI3K and mTOR inhibitor BEZ235 markedly decreased sCLU expression in HepG2-SR cells. Conclusion: These results suggest that measurement of sCLU serum levels and the sCLU-related NR-index are promising clinical tools for the early prediction of SFN response in HCC. Additionally, sCLU-overexpressing HCC might be susceptible to mTOR inhibition., (© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Background: Sarcopenia is a syndrome characterized by progressive and systemic decreases in skeletal muscle mass and muscle strength. The influence or prognosis of various liver diseases in this condition have been widely investigated, but little is known about whether sarcopenia and/or muscle mass loss are related to minimal hepatic encephalopathy (MHE)., Methods: To clarify the relationship between MHE and sarcopenia and/or muscle mass loss in patients with liver cirrhosis., Methods: Ninety-nine patients with liver cirrhosis were enrolled. MHE was diagnosed by a neuropsychiatric test. Skeletal mass index (SMI) and Psoas muscle index (PMI) were calculated by dividing skeletal muscle area and psoas muscle area at the third lumbar vertebra by the square of height in meters, respectively, to evaluate muscle volume., Results: This study enrolled 99 patients (61 males, 38 females). MHE was detected in 48 cases (48.5%) and sarcopenia in 6 cases (6.1%). Patients were divided into two groups, with or without MHE. Comparing groups, no significant differences were seen in serum ammonia concentration or rate of sarcopenia. SMI was smaller in patients with MHE (46.4 cm 2 /m 2 ) than in those without (51.2 cm 2 /m 2 , P = 0.027). Similarly, PMI was smaller in patients with MHE (4.24 cm 2 /m 2 ) than in those without (5.53 cm 2 /m 2 , P = 0.003). Skeletal muscle volume, which is represented by SMI or PMI was a predictive factor related to MHE (SMI ≥ 50 cm 2 /m 2 ; odds ratio 0.300, P = 0.002, PMI ≥ 4.3 cm 2 /m 2 ; odds ratio 0.192, P = 0.001)., Conclusions: Muscle mass loss was related to minimal hepatic encephalopathy, although sarcopenia was not. Measurement of muscle mass loss might be useful to predict MHE.