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Introduction: Atezolizumab plus bevacizumab treatment is highly effective in patients with unresectable hepatocellular carcinoma (HCC). However, progressive disease (PD) occurs in approximately 20% of HCC patients treated with atezolizumab plus bevacizumab, resulting in a poor prognosis. Thus, the prediction and early detection of HCC is crucial. Methods: Patients with unresectable HCC treated with atezolizumab plus bevacizumab and had baseline preserved serum (n = 68) were screened and classified according to their PD, six weeks after treatment initiation (early PD; n = 13). Of these, four patients each with and without early PD were selected for cytokine array and genetic analyses. The identified factors were validated in the validated cohort (n = 60) and evaluated in patients treated with lenvatinib. Results: No significant differences were observed in the genetic alterations in circulating tumor DNA. Cytokine array data revealed that baseline MIG (CXCL9), ENA-78, and RANTES differed substantially between patients with and without early PD. Subsequent analysis in the validation cohort revealed that baseline CXCL9 was significantly lower in patients with early PD than that in patients without early PD, and the best cut-off value of serum CXCL9 to predict early PD was 333 pg/mL (sensitivity: 0.600, specificity: 0.923, AUC = 0.75). In patients with lower serum CXCL9 (< 333 pg/mL), 35.3% (12/34) experienced early PD with atezolizumab plus bevacizumab, while progression-free survival (PFS) was significantly shorter relative to that in patients without (median PFS, 126 days vs 227 days; HR: 2.41, 95% CI: 1.22–4.80, p = 0.0084). While patients with objective response to lenvatinib had significantly lower CXCL9 levels compared with those of patients without. Conclusion: Baseline low serum CXCL9 (< 333 pg/mL) levels may predict early PD in patients with unresectable HCC treated with atezolizumab plus bevacizumab.

Lenvatinib, used for unresectable hepatocellular carcinoma (HCC), causes appetite loss, but the underlying mechanisms, clinical impact, and predictive factors have been unclear. The endocrine factor FGF21 modulates appetite and is involved in cachexia. We evaluated the association between FGF21 level changes during lenvatinib treatment for unresectable HCC and appetite loss. Sixty-three eligible unresectable HCC patients who started lenvatinib treatment between 2018 and 2021 were included. We analyzed FGF21 levels at baseline; 1, 2, and 4 weeks after lenvatinib initiation, and before the onset of appetite loss. Grade ≥ 2 lenvatinib-induced appetite loss led to liver functional reserve deterioration at disease progression and a poor prognosis. Baseline characteristics and serum FGF21 levels were similar between patients with and without appetite loss. However, the serum FGF21 change rate increased significantly at 4 weeks post-lenvatinib initiation in patients with grade ≥ 2 appetite loss, as compared to those without appetite loss. Similar significant increases in the serum FGF21 level change rate were observed prior to grade ≥ 2 appetite loss onset. This suggests that changes in FGF21 levels can be used to predict patients with a greater risk of marked appetite loss and provides insights into the mechanisms underlying lenvatinib-induced appetite loss in patients with HCC.

No prospective study on the efficacy of tenofovir alafenamide (TAF), a novel tenofovir prodrug, in preventing HBV reactivation has yet been reported.This multicenter prospective study enrolled HBV-carriers who received TAF to prevent HBV reactivation before antitumor or immunosuppressive therapy, and patients with resolved HBV infection who experienced HBV-reactivation and received TAF to prevent HBV reactivation-related hepatitis. The efficacy of prophylactic TAF in preventing HBV reactivation and HBV reactivation-related hepatitis was evaluated at 6 and 12 months after initiating TAF.Overall, 110 patients were administered TAF to prevent HBV reactivation or HBV reactivation-related hepatitis. Three patients died owing to primary disease, whereas one patient was transferred to another hospital within 6 months after initiating TAF. Seven patients died due to primary disease, and five patients were transferred to another hospital within 12 months after initiating TAF. Therefore, 106 and 94 (77 patients with HBV infection, 17 with previous-HBV infection) patients were evaluated at 6 and 12 months after initiating TAF, respectively. No patient experienced HBV reactivation, HBV reactivation-related hepatitis, or treatment discontinuation due to HBV reactivation or adverse events of TAF after 6 and 12 months.TAF could effectively prevent HBV reactivation and HBV reactivation-related hepatitis. This article is protected by copyright. All rights reserved.

Background One of the major complications of gastric endoscopic submucosal dissection (ESD) is delayed bleeding. The treatment of exposed vessels after completed dissection should be effective to avoid delayed bleeding. However, it’s sometimes difficult to detect the detection of exposed blood vessels on ulcers induced by ESD. A recent study reported that red dichromatic imaging (RDI) was useful for detecting exposed vessels. In this study, we aimed to measure the visibility of exposed vessels and the quantitative color difference between the exposed vessels and surrounding tissue on ulcers, as observed using RDI after completed dissection. Methods Sixty-four vessels (14 patients) in gastric ESD-induced ulcers were evaluated using both white light imaging (WLI) and RDI. The Commission Internationale de l’Eclairage 1976 (L*a*b*) color space was used to measure the color difference. The color difference was evaluated by comparing the color values of regions of interest for the point of an exposed vessel and three points surrounding an exposed vessel. The visibility of exposed vessels was evaluated using a visibility scoring system. The primary endpoint was color differences (ΔE) between the exposed vessels and surrounding tissue in each modality. Results The average ΔE values (± SEM) for WLI and RDI were 24.85 (± 1.19) and 31.83(± 1.31), respectively. The ΔE value for RDI was significantly higher than that for WLI (p < 0.01). The visibility score was improved in 54.7% (35/64) of cases. Conclusions The color differences between the exposed vessels and surrounding tissue on gastric ESD-induced ulcers were higher with RDI than with WLI, and RDI improved the visibility of exposed vessels.

Hepatocellular carcinoma (HCC) hemorrhaging/rupture is a rare adverse effect of lenvatinib, and only limited pathological examinations have been reported. This report presents the case of a 69-year-old man who suffered from cardiac arrest and died 7 days after starting lenvatinib treatment for HCC, with an autopsy subsequently performed. Crack and coagulated blood were observed in the largest tumor. Pathologically, the hemorrhaging area was scattered in nearly all of the HCC lesions, regardless of tumor differentiation. This pathological feature is unusual in normal HCC. Thus, it is believed to have been the effect of lenvatinib.

Simple Summary The IMbrave150 trial led to the approval of atezolizumab and bevacizumab for the treatment of unresectable hepatocellular carcinoma (HCC). We performed a retrospective multicenter study including 115 patients with unresectable HCC treated with atezolizumab and bevacizumab, revealing that the combination of atezolizumab and bevacizumab is equally effective for patients meeting the IMbrave150 trial eligibility criteria and for patients not meeting these criteria, generally due to a history of systemic therapy, platelet counts < 75 x 10(9)/L, Child-Pugh B, and 2+ proteinuria. However, liver functional reserve should be carefully monitored in patients not meeting the IMbrave150 trial eligibility criteria. The IMbrave150 trial demonstrated the high efficacy and safety of atezolizumab and bevacizumab for unresectable hepatocellular carcinoma (HCC). In this multicenter study, the efficacy of this combination and its effect on liver functional reserve were evaluated in patients not meeting the eligibility criteria of IMbrave150. Of 115 patients with unresectable HCC treated with atezolizumab and bevacizumab between October 2020 and January 2022, 72 did not meet the eligibility criteria of IMbrave150, most frequently due to a history of systemic therapy (60/72), platelet counts < 75 x 10(9)/L (7/72), Child-Pugh B (9/72), and 2+ proteinuria (8/72). Atezolizumab and bevacizumab therapy was equally effective for patients who did or did not meet the eligibility criteria (PFS, 6.5 vs. 6.9 months, p = 0.765), consistent with subgroup analyses of histories of systemic therapy, platelet counts, Child-Pugh, and proteinuria. Baseline ALBI scores were worse in patients who did not meet the criteria than in those who did and significantly worsened after treatment initiation in patients not meeting the criteria (baseline vs. 12 weeks; 2.35 +/- 0.43 vs. -2.18 +/- 0.54; p = 0.007). Accordingly, atezolizumab plus bevacizumab was effective for patients not meeting the eligibility criteria of IMbrave150, although careful monitoring for changes in liver functional reserve is needed.

Hepatitis C virus (HCV) infection can cause renal dysfunction, expected to improve upon HCV eradication. However, adverse effects of HCV eradication using direct-acting antiviral agents (DAAs) on renal function have been recently reported. This retrospective study aimed to evaluate renal function with glomerular filtration rate (eGFR) estimated using creatinine (eGFRcre) and cystatin C (eGFRcys). Complete clinical information and preserved serum samples were collected from 207 patients with HCV infection treated with interferon-free DAA at baseline and SVR48 (SVR48). Patients who underwent paired computed tomography (CT) at baseline and ≥12 months after DAA were evaluated for changes in skeletal muscle mass using the psoas muscle mass index (PMI). eGFRcre significantly worsened at SVR48, while eGFRcys was similar at baseline and SVR48. At baseline, eGFRcre was significantly higher than eGFRcys; eGFRcre and eGFRcys were similar at SVR48. Multivariate analysis revealed that the presence of liver cirrhosis and low-albumin level, as well as cirrhosis and age, was significantly associated with the overestimation of renal function by eGFRcre at baseline and SVR48, respectively. In the 57 patients who underwent paired CT at baseline and ≥12 months after DAA, relative values of PMI significantly increased after DAA. After DAA, in patients with increased PMI (65% 37/57), eGFRcre significantly worsened but did not change in patients without increased PMI. eGFRcre significantly worsened after DAAs; however, this might not reflect accurate changes in renal function, partially because of changes in skeletal muscle mass. eGFRcys did not change after DAAs, and it is a potential alternative to eGFRcre.

Entecavir and tenofovir–disoproxil–fumarate are first-line nucleos(t)ide analogs (NA) for treatment of hepatitis B virus (HBV) infections; however, their long-term administration can impact extrahepatic organs. Herein, we sought to examine the effect of NA on lipid metabolism while also characterizing the associated mechanism. A retrospective study was performed on HBV patients administered entecavir or tenofovir–disoproxil–fumarate. Patient clinical information, as well as their preserved serum samples obtained at baseline and 6–12 months after treatment initiation, were analyzed. A 1:1 propensity score matching was applied to the assignment of tenofovir–disoproxil–fumarate or entecavir treatment. Changes in serum cholesterol, including oxidized-LDL, were analyzed. Subsequently, in vitro analysis elucidated the mechanism associated with the effect of NAs on lipid metabolism. Administration of tenofovir–disoproxil–fumarate, not entecavir, to chronic HBV patients, decreased serum cholesterol levels, including non-HDL and oxidized-LDL, which are strongly associated with arteriosclerosis. In vitro analysis revealed that tenofovir–disoproxil–fumarate reduced supernatant cholesterol, and upregulated the scavenger receptor, CD36, in hepatocytes. Meanwhile, silencing of hepatic CD36 increased supernatant cholesterol and negated the cholesterol-reducing effect of tenofovir–disoproxil–fumarate in HepG2-cells. Reporter, microarray, and RT-PCR analyses further revealed that tenofovir–disoproxil–fumarate treatment activates PPAR-α-mediated signaling, and upregulates PPAR-α target genes, including CPT1 and CD36. Alternatively, silencing of PPAR-α reversed the effects of tenofovir–disoproxil–fumarate on CD36. Tenofovir–disoproxil–fumarate modulates lipid metabolism by upregulating hepatic CD36 via PPAR-α activation. Since dyslipidemia could be associated with arteriosclerosis and hepatocarcinogenesis, these discoveries provide novel insights into anti-HBV therapies, as well as the associated extrahepatic effects of NA.

Benefits of nucleos(t)ide analogs (NAs) on hepatitis B surface antigen (HBsAg) reduction and interferon-lambda3 (IFN-λ3) induction are still not known. This study aimed to investigate the effects of NAs on HBsAg reduction and association with serum IFN-λ3 levels in chronic hepatitis B (CHB) patients.A total of 91 patients [51 treated with nucleoside analog entecavir hydrate (ETV) and 40 treated with nucleotide analog adefovir dipivoxil (ADV) or tenofovir disoproxil fumarate (TDF)] with clinically evident CHB (chronic hepatitis, 57; liver cirrhosis, 34) were enrolled in this study. Serum IFN-λ3 levels among patients receiving ETV and ADV/TDF were measured before the initiation of therapy and 1, 3, and 5 years post-therapy.The change (mean ± standard deviation) in serum HBsAg levels from baseline to year five was -0.38 ± 0.46 and -0.84 ± 0.64 logNucleotide analog (ADV/TDF) treatment reduced HBsAg levels greater compared with nucleoside analog (ETV) in parallel with IFN-λ3 induction.

A high prevalence of overestimated renal function in patients with liver cirrhosis (LC) has been reported; nonetheless, its impact on prognosis remains unclear. We aimed to evaluate the impact of overestimated renal function on prognosis in patients with LC.An overestimated renal function was defined as a20% increase in the creatinine-based estimated glomerular filtration rate (eGFR), compared with cystatin C-based eGFR. LC patients with conserved serum, who were evaluated for muscle atrophy and had proper clinical information were included, and their prognostic factors were analyzed.A total of 215 consecutive patients with LC were included. The prevalence of overestimated renal function was 29.8% (64/215). Kaplan-Meier survival analysis revealed that patients with overestimated renal function had a poorer prognosis than those without overestimated renal function (hazard ratio [HR]: 2.217 95% confidence interval [CI]: 1.290-3.810; p = 0.001). Subgroup analysis showed that overestimated renal function was a significant prognostic factor, irrespective of sex and the presence of hepatocellular carcinoma (HCC). Multivariate Cox regression analyses revealed that overestimated renal function was a significant and independent factor predictive of poor prognosis in the entire cohort (HR: 2.050; 95% CI: 1.041-4.037; p = 0.038) and in subgroups classified by Child-Pugh class A (HR: 2.131; 95% CI: 1.019-4.458; p = 0.044), Model for End-Stage Liver Disease score ≤9 (HR: 2.303; 95% CI: 1.038-5.109; p = 0.04), and presence of HCC (HR: 2.290; 95% CI: 1.128-4.651; p = 0.022).Overestimated renal function is a significant and independent prognostic factor in patients with LC.

Background Sorafenib and lenvatinib are first‐line systemic therapies for unresectable hepatocellular carcinoma (HCC). However, the criteria for their selection remain unclear. Methods We identified patients with unresectable HCC who were treated with sorafenib or lenvatinib between August 2009 and January 2019 at the Hokkaido University Hospital. Patients who continued treatment for >2 months, underwent evaluation by computed tomography every 2–3 months, and had complete clinical data were included. Responders were patients with objective response (OR) for lenvatinib and patients with stable disease (SD) exceeding 6 months (long‐SD) or OR for sorafenib. The predictive factors for treatment response, including fibroblast growth factor (FGF)19 and 21, angiopoietin 2 (ANG2), hepatocyte growth factor, and vascular endothelial growth factor, were evaluated. Results Overall, 27 and 29 patients treated with lenvatinib and sorafenib, respectively, were included. The responders for lenvatinib and sorafenib were 63% (17/27) and 38% (11/29), respectively. No significant predictive factors for treatment response were identified in patients treated with sorafenib. However, baseline serum FGF19 and ANG2 levels were significantly associated with treatment response to lenvatinib. All (9/9) patients with low baseline ANG2 and FGF19 levels who received lenvatinib achieved OR. Conversely, the OR was low (13%; 1/9) in patients with high baseline ANG2 and FGF19 levels. Responder rate was 40% (2/5) in patients with high baseline ANG2 and FGF19 levels who received sorafenib. Conclusion This study is, to our knowledge, the first to demonstrate that baseline ANG2 and FGF19 levels may aid in selecting optimal systemic therapy for patients with unresectable HCC., The combination of baseline serum ANG2 and FGF19 levels may predict treatment response to lenvatinib in patients with unresectable HCC. An OR was achieved in all patients with low baseline levels of ANG2 and FGF19 treated with lenvatinib (100%, 9/9). Conversely, those with high baseline levels of these markers demonstrated a low OR rate (13%; 1/9). However, in patients with high baseline ANG2 and FGF19 levels, the response to sorafenib was not low (40% 2/5). These findings show, for the first time, that baseline biomarker levels may determine suitability for systemic therapy in patients with unresectable HCC.

Decompensated liver cirrhosis patients with refractory ascites or pleural effusion have a poor prognosis. Tolvaptan has been used for treating water retention associated with cirrhosis. However, despite the short-term response, water retention recurrence is still observed in some cases. This study aimed to clarify the water retention recurrence rate and the relationship between long-term response without recurrence and prognosis. Altogether, 100 patients with decompensated cirrhosis treated with tolvaptan were retrospectively analyzed. Recurrence was evaluated according to the criteria of the EASL clinical practice guideline. The recurrence rate and prognosis of non-responders, patients with recurrence, and long-term responders were analyzed. The baseline factors related to short-term response, recurrence, and long-term response were also evaluated. Approximately 31.0% of the short-term responders had recurrence. Although there was no significant difference in the prognosis by short-term response (p = 0.07), the long-term responders had a significantly better prognosis than those with recurrence and non-responders (p

Background Sarcopenia is associated with poor prognosis in patients with chronic liver disease (CLD). As rapid skeletal muscle wasting predicts worse prognosis and a novel therapy for sarcopenia needs to be evaluated for validation, accurate evaluation methods for relative changes in muscle mass are crucial. Methods We screened CLD patients who had skeletal muscle mass evaluation between June 2015 and December 2017. Patients were included if they had adequate information, were followed for >6 months, and had skeletal muscle mass evaluation by both bioelectrical impedance analysis (BIA) and computed tomography (CT) imaging at baseline and the second evaluation point. We compared BIA and CT imaging in terms of their ability to quantify skeletal muscle mass and identify relative changes in muscle mass in CLD patients. Results Of the screened 447 CLD patients, 110 were included in this study, and 71 (64.5%) were men. The median age was 68 (range 21 to 90) years. In total, 83 (75.5%) and 32 (29.1%) patients had liver cirrhosis and hepatocellular carcinoma, respectively. Of them, 50 (45.5%) patients were liver cirrhosis patients without hepatocellular carcinoma through the observation period. Skeletal muscle mass index (SMI) by BIA, psoas muscle mass index (PMI), and SMI based on CT imaging were significantly correlated at baseline [SMI by simple CT method and SMI by BIA (r = 0.61, P

In hepatocellular carcinoma (HCC), a subset of cells defined by high CD44 and CD133 expression has been reported to possess cancer stem-like cell (CSC) characteristics and to be associated with a poor prognosis. Since the approval of the multikinase inhibitor, lenvatinib, for patients with unresectable HCC, two such inhibitors (sorafenib and lenvatinib) have been employed as first-line systemic chemotherapeutics for these patients. Based on differences in the kinase-affinity profiles between these two drugs, evidence has suggested that both exert different effects on HCC, although these differences are not fully characterized. In this study, using in vitro and a preclinical in vivo xenograft mouse model, we showed that lenvatinib alone (not sorafenib or the cytotoxic agent, 5-fluorouracil) diminished CD44High/CD133High CSCs in HCC. Furthermore, western blotting and reverse transcriptase-polymerase chain reaction analysis revealed that the expression of fibroblast growth factor receptor (FGFR)-1–4 differed between CD44High/CD133High CSCs and control cells. Analysis of the effects of selective FGFR inhibitors and FGFR small interfering RNAs on CSCs in HCC revealed that lenvatinib diminished CSCs in HCC by inhibiting FGFR1–3 signaling, however, FGFR4 signaling was not impacted. Finally, we showed that FGF2 and FGF19 were involved in maintaining CD44High/CD133High CSCs in HCC, potentially, via FGFR1–3. The findings provide novel mechanistic insights into the effects of lenvatinib on CSCs in HCC and provide clues for developing effective targeted therapies against CSCs in HCC.

This study aimed to determine the optimal psoas muscle mass index (PMI) cut-off values for diagnosis of skeletal muscle mass loss. Methods We evaluated PMI in two groups of normal controls: a medical check-up group and a liver donation candidate group. We analyzed two novel PMI cut-off values, one based on the mean - two standard deviations (2SD) and one based on the lower 5%. Skeletal muscle mass index (SMI) evaluations using computed tomography (sliceOmatic; TomoVision) and bioelectrical impedance analysis and PMI evaluation were undertaken simultaneously. We analyzed the correlation between our PMI cut-off values and the Japan Society of Hepatology-defined SMI cut-off values. The prevalence of skeletal muscle mass loss in patients with liver disease was assessed using the novel PMI cut-off values. Results In 504 normal controls aged ≤50 years, the PMI cut-off values based on mean -2SD and the lower 5% were set at 3.30 cm2 /m2 for men and 1.69 cm2 /m2 for women and 3.74 cm2 /m2 for men and 2.29 cm2 /m2 for women, respectively. The PMI cut-off values based on the lower 5% alone showed that skeletal muscle mass loss increased with age. Furthermore, they correlated well with Japan Society of Hepatology-defined SMI (sliceOmatic) cut-off values and showed a significantly higher prevalence of skeletal muscle mass loss in patients with liver cirrhosis than those without liver cirrhosis. Conclusions We propose the following PMI cut-off values: 3.74 cm2 /m2 for male individuals and 2.29 cm2 /m2 for female individuals. These cut-off values can facilitate accurate diagnosis and management of sarcopenia in patients with chronic liver disease.

Background and Aim Immune checkpoint inhibitors (ICI) have revolutionized anti-malignancy therapy and thus have been increasingly used. Although ICI may cause immune-related adverse events (irAE) in various organs, including the liver, the prevalence and predictive factors of irAE have not been clarified. Methods In this retrospective study, consecutive patients who had malignancies and were treated with ICI without other chemotherapeutic agents at Hokkaido University Hospital between 2014 and 2019 were screened. Patients were excluded if they were Of the 233 patients screened, 202 patients met the inclusion criteria and were included in the analysis. The patients were aged 25-92 years, and 60.9% were male. The patients received nivolumab (n = 137), pembrolizumab (n = 45), ipilimumab (n = 17), atezolizumab (n = 2), and avelumab (n = 1). The prevalence of any grade and grade >= 3 irAE hepatitis was 8.4% (17/202) and 4.0% (8/202), respectively. irAE hepatitis occurred at a median duration of 42 days in any grade and 36 days in grade >= 3 after ICI initiation. The clinical course of grade >= 3 irAE hepatitis was generally favorable; however, 50% required corticosteroid treatment and two patients required additional mycophenolate mofetil. Female sex and history of ICI treatment were significantly associated with the incidence of grade >= 3 irAE hepatitis. Conclusions Grade >= 3 irAE hepatitis was observed in 4.0% of the patients who were treated with ICI. Female sex and history of ICI treatment were significantly associated with the incidence of grade >= 3 irAE hepatitis.

Aim Factors associated with improvement of liver fibrosis after successful hepatitis C virus (HCV) eradication by interferon (IFN)-free direct-acting antiviral agents (DAAs) have been not clarified well. Angiopoietin-2 (Ang2) is reported to be associated with vascular leak and inflammation observed in patients with advanced liver fibrosis. Methods In this retrospective study, patients treated with IFN-free DAAs who underwent transient elastography before and at 24-weeks post-treatment and achieved sustained viral response were enrolled. Baseline serum Ang2 was measured, and its relationship with other clinical factors was analyzed. Liver fibrosis stage was defined based on liver stiffness according to a previous report. Predictive factors for regression of liver fibrosis stage after DAA therapy were evaluated. Results Overall, 116 patients were analyzed. Baseline serum Ang2 levels were significantly associated with liver stiffness, spleen index, and liver stiffness-based liver fibrosis stage. Moreover, 75% of patients experienced regression of liver fibrosis stage after DAA therapy. Multivariate analysis revealed that advanced liver fibrosis stage and Ang2 levels were significantly associated with regression of liver fibrosis stage after DAA therapy. In patients with advanced liver fibrosis (F3/4), baseline Ang2 level alone could predict regression of liver fibrosis stage. A baseline Ang2 cut-off value (354 pg/ML) could predict regression of liver fibrosis stage after DAA therapy with high accuracy (sensitivity 0.882, specificity 0.733). Conclusions Evaluation of serum Ang2 levels before DAA therapy is important. Our results provide a novel mechanistic insight into non-regression of liver stiffness after DAA therapy. Long-term and larger studies are required.

Although various noninvasive markers and prediction formulas for nonalcoholic steatohepatitis (NASH) have been reported, they are of value only in the diagnosis of the advanced fibrosis stage of NASH. In this study, we evaluated soluble CD14 (sCD14) as a diagnostic marker for discriminating NASH from nonalcoholic fatty liver disease (NAFLD) using an animal model and clinical specimens.Serum sCD14 levels were measured in samples derived from mice with diet-induced NASH and patients using an enzyme-linked immunosorbent assay. Our cohort enrolled 126 patients with liver needle biopsy-proven NAFLD.The intestinal defense mechanism in NASH model mice was altered as a consequence of the unique gut environment. Elevated serum levels of sCD14 were observed in mice with diet-induced NASH, and the condition of the liver was exacerbated as a result of exposure to gut-derived endotoxin. We confirmed that the serum sCD14 levels in NAFL patients significantly differed from those in NASH patients. The area under the curve for distinguishing between NAFL and NASH was 0.891. Moreover, we found that serum sCD14 levels were weakly correlated with the inflammation grade based on the NAFLD activity score (NAS), the grade of fibrosis according to the Brunt fibrosis classification, and a positive correlation with the grade of ballooning based on NAS in patients with NAFLD.sCD14 could be a useful pathophysiological marker and diagnostic adjunct distinguishing NASH from NAFLD. The use of sCD14 may allow the screening and identification of high-risk groups for NASH development and support early therapeutic interventions.

Simple Summary The possible mechanisms of resistance to atezolizumab/bevacizumab for unresectable HCC and the subsequent response to these therapies remain underexplored. The sequential changes in serum growth factors, including VEGF-A, VEGF-C, VEGF-D, ANG-2, FGF-19, HGF, and EGF during atezolizumab/bevacizumab for unresectable HCC were evaluated in 46 patients. Of 32 patients with disease control, 28 experienced PD after CR, PR, or SD with atezolizumab/bevacizumab. Growth factor changes between the baseline and best overall response points (BOR) for patients with disease control showed that FGF-19 significantly increased and ANG2 significantly decreased at the BOR. Growth factor changes between the BOR and the PD point in 28 patients who experienced PD after disease control showed that VEGF-D and ANG2 significantly increased at the PD point compared with that at the BOR. Summarily, increased serum VEGF-D and ANG-2 levels might contribute to developing resistance to atezolizumab/bevacizumab for unresectable HCC and might be target molecules in subsequent salvage therapies. The possible mechanisms of resistance to atezolizumab/bevacizumab for unresectable HCC, and the subsequent response to these therapies, remain underexplored. The sequential changes in serum growth factors, including VEGF-A, VEGF-C, VEGF-D, ANG-2, FGF-19, HGF, and EGF during atezolizumab/bevacizumab for unresectable HCC were evaluated in 46 patients. Patients who experienced PD after CR, PR, or SD to atezolizumab/bevacizumab were evaluated. A total of 4, 9, 19, and 14 patients showed CR, PR, SD, and PD, respectively. Of 32 patients with disease control, 28 experienced PD after CR, PR, or SD with atezolizumab/bevacizumab. Baseline growth factor levels were similar between patients with or without disease control and those with or without an objective response. Growth factor changes between the baseline and the best overall response points (BOR) for patients with disease control showed that FGF-19 significantly increased and ANG2 significantly decreased at the BOR. Growth factor changes between the BOR and the PD point in 28 patients who experienced PD after disease control showed that VEGF-D and ANG2 significantly increased at the PD point compared with that at the BOR. Summarily, increased serum VEGF-D and ANG-2 levels might contribute to developing resistance to atezolizumab/bevacizumab for unresectable HCC and might be target molecules in subsequent salvage therapies.

We aimed to evaluate factors associated with changes in skeletal muscle mass in hepatitis C virus (HCV)-infected patients after treatment with direct-acting antivirals (DAAs). Consecutive HCV-infected patients after treatment with DAA were recruited into the study. Patients who achieved sustained virological response (SVR); and had complete clinical information, preserved serum samples at baseline and SVR48, and skeletal muscle mass evaluations based on the psoas muscle mass index (PMI) on computed tomography at baseline and ≥ 12 months were included. Altogether, 70.7% of patients (41/58) showed increased PMI after DAA therapy, and mean relative PMI was significantly higher after DAA therapy than at baseline. There were no significant associations between baseline clinical factors routinely examined in clinical practice and increased PMI. Among factors reported to be associated with skeletal muscle loss in patients with chronic liver disease, serum zinc levels and total and free carnitine levels increased significantly after DAA therapy and only changes in serum free carnitine levels were significantly associated with an increased PMI (r = 0305, P = 0.020). In conclusion, increased skeletal muscle mass after successful HCV eradication by DAAs was significantly associated with increased serum-free carnitine levels. l-carnitine supplementation may be beneficial in patients with low skeletal muscle mass after DAA.

AIM A clinical trial (IMbrave150) indicated the efficacy and safety of atezolizumab plus bevacizumab for patients with unresectable hepatocellular carcinoma (HCC). In this study, we evaluated this therapeutic combination in a real-world setting, with a focus on patients who did not meet the IMbrave150 eligibility criteria. METHODS In this multicenter study, patients with unresectable HCC treated with atezolizumab plus bevacizumab between October 2020 and May 2021 were screened. In patients who did not meet IMbrave150 eligibility criteria, treatment responses and safety at 6 and 12 weeks were evaluated. RESULTS Atezolizumab plus bevacizumab was initiated in 64 patients, including 46 patients (71.9%) who did not meet IMbrave150 eligibility criteria. Most of these patients had a history of systemic therapy (44/46). The objective response rate and disease control rate observed using Response Evaluation Criteria in Solid Tumors 1.1 were 5.2% and 82.8% at 6 weeks and 10.0% and 84.0% at 12 weeks, respectively; these rates were similar between patients who met and did not meet the IMbrave150 criteria. Ten patients experienced progressive disease (PD) at 6 weeks. Portal vein tumor thrombosis was significantly associated with PD (p = 0.039); none of the 15 patients with hepatitis B virus-related HCC experienced PD (p = 0.050). The most common adverse events of grade 3 or higher were aspartate aminotransferase elevation (n = 8, 13.8%) and the safety profile was similar between patients who met and did not meet the IMbrave150 criteria. CONCLUSION Most patients treated with atezolizumab plus bevacizumab did not meet the IMbrave150 criteria; however, the combination therapy showed good safety and efficacy at the early treatment phase.

Renal dysfunction and sarcopenia are important prognostic factors in patients with chronic liver disease (CLD). Muscle atrophy can cause the overestimation of renal function based on serum creatinine. However, the frequency of overestimated renal function in Japanese patients with CLD and its relationship with sarcopenia are unclear. In present study, we evaluated the frequency of overestimated renal function, defined as a &gt, 20% higher eGFR using creatinine than using cystatin C, in 307 patients with CLD as well as its relationship with indicators of sarcopenia. In total, 24.8% of patients had overestimated renal function. In a multivariate regression analysis, liver cirrhosis (p = 0.004) and psoas muscle mass index (p = 0.049) were significantly associated with overestimated renal function. Loss of skeletal muscle mass was significantly more frequent in both male and female patients with overestimated renal function than without. In males, the loss of muscle strength and rate of sarcopenia, defined as loss of muscle mass and strength, were significantly higher in patients with than without overestimated renal function. The high frequency of overestimated renal function in Japanese patients suggests that indicators of renal function should be carefully considered, furthermore, monitoring and interventions for both renal function and sarcopenia are needed in patients with CLD.

AIMS Development of direct-acting antivirals (DAAs) has made antihepatitis C virus (HCV) treatment highly safe and effective. However, the emergence of resistant-associated variants (RAVs) after failure of DAA therapy affects retreatment outcomes. In particular, genotype 1 HCV with P32 deletion has been reported to be highly resistant to all approved non-structural protein (NS)5A inhibitors. However, analysis of RAVs in genotype 2 HCV has been limited. Accordingly, in this study, we evaluated the roles of genotype 2 HCV variants in antiviral drug efficacy. METHODS We utilized HCV-2b/2a (JFH-1) chimeric virus (genotype 2a), which replicates more robustly than JFH-1. We constructed various genotype 2a JFH-1-based HCV cell culture systems with NS3 (D168E), NS5A (F28S, F28S/M31I, P32 deletion, and Y93H), and NS5B (S282 T) RAVs and analyzed the replication ability and sensitivity to various anti-HCV reagents. RESULTS Genotype 2a-based HCV with NS5A-P32 deletion could not replicate even in long-term cultures. Genotype 2a-based HCV with NS5A-F28S/M31I showed significantly higher replication ability than the wild-type strain, and replication could not be suppressed, even with high concentrations of NS5A inhibitors, including pibrentasvir and velpatasvir (