Role of PPARα in inflammatory response of C2C12 myotubes.

Recent studies have shown a role of inflammation in muscle atrophy and sarcopenia. However, no anti-inflammatory pharmacotherapy has been established for the treatment of sarcopenia. Here, we investigate the potential role of PPARα and its ligands on inflammatory response and PGC-1α gene expression in LPS-treated C2C12 myotubes. Knockdown of PPARα, whose expression was upregulated upon differentiation, augmented IL-6 or TNFα gene expression. Conversely, PPARα overexpression or its activation by ligands suppressed 2-h LPS-induced cytokine expression, with pemafibrate attenuating NF-κB or STAT3 phosphorylation. Of note, reduction of PGC-1α gene expression by LPS treatment for 24 hours was partially reversed by fenofibrate. Our data demonstrate a critical inhibitory role of PPARα in inflammatory response of C2C12 myotubes and suggest a future possibility of PPARα ligands as a candidate for anti-inflammatory therapy against sarcopenia.

Clinical performance of Circulating HBV RNA and iTACT-HBcrAg Assays in HBeAg-negative and HBsAg-cleared Chronic Hepatitis B Patients.

Hepatitis B virus (HBV) RNA and hepatitis B core-related antigen (HBcrAg) have been reported to reflect the transcriptional activity of covalently closed circular HBV DNA. We retrospectively investigated the proportions of quantifiable serum HBV RNA and immunoassay for total antigen including complex via pretreatment-hepatitis B core-related antigen (iTACT-HBcrAg) in chronic hepatitis B patients negative for hepatitis B e antigen (HBeAg) and/or with hepatitis B surface antigen (HBsAg) seroclearance. This study included 246 HBeAg-negative HBV-infected patients, who comprised 13 with liver cirrhosis (LC, the LC group), 118 chronic hepatitis (CH, the CH group), and 115 inactive carriers (IC, the IC group), and 44 patients with HBsAg seroclearance. iTACT-HBcrAg and HBV RNA levels were determined using stored serum samples. Higher proportions of the patients had quantifiable iTACT-HBcrAg than HBV RNA in all groups of HBeAg-negative patients (iTACT-HBcrAg: 84.6%, 90.7%, 35.7%, HBV RNA: 23.1%, 26.3%, 14.8%, for the LC, CH, IC groups). With HBsAg seroclearance (HBsAg <0.05 IU/mL), the proportions of quantifiable samples for HBV RNA were also lower than iTACT-HBcrAg (0% for HBV RNA). Thus, iTACT-HBcrAg was more often detectable than circulating HBV RNA in this study population. Further long-term prospective evaluation of iTACT-HBcrAg is desirable for its utilization in clinical practice.

Serum Angiopoietin-2 Levels Predict the Development of Hepatocellular Carcinoma following Hepatitis C Virus Eradication Using Direct-Acting Antiviral Agents.

INTRODUCTION: Our previous studies showed that serum angiopoietin-2 (Ang-2) and C-X-C motif chemokine ligand 10 (CXCL10) levels predicted improvement in liver fibrosis following sustained virological response (SVR) of hepatitis C virus (HCV) obtained with administration of with direct-acting antiviral agents (DAAs). These levels were evaluated retrospectively as predictive indicators of hepatocellular carcinoma (HCC) development following SVR. METHODS: We enrolled individuals from a historical cohort of 89 chronic HCV patients without history of HCC at baseline and with SVR following DAA therapy and had baseline serum levels of Mac-2 binding protein glycosylation isomer ≥2.0 cut-off index (C.O.I.). RESULTS: Multivariate analyses revealed that only the Ang-2 level at 24 weeks following the end of treatment (EOT24W) was significantly related to HCC development (hazard ratio 2.27; p = 0.003). This result was reproduced in individuals without history of HCC and with advanced liver fibrosis (M2BPGi level ≥3.3 C.O.I. at baseline). Time-dependent receiver operating characteristic curve analyses for the future risk of developing HCC within 5 years of follow-up (5y-HCC) showed the best cut-off Ang-2 level at the EOT24W was 2,780 pg/mL, and significantly stratified the cumulative incidence of HCC (≥2,780 vs. < 2,780 pg/mL, 5y-HCC: 45.5 vs. 8.2%, p < 0.001). CONCLUSIONS: At the EOT24W, serum Ang-2 level predicts the likelihood of developing HCC following SVR to DAA therapy.

Prognostic Nutritional Index after Introduction of Atezolizumab with Bevacizumab Predicts Prognosis in Advanced Hepatocellular Carcinoma: A Multicenter Study.

INTRODUCTION: Atezolizumab plus bevacizumab (Atez/Bev) is the preferred treatment for advanced hepatocellular carcinoma (HCC). However, biomarkers of therapeutic efficacy have remained unclear. We took a retrospective approach to explore the role of prognostic nutritional index (PNI) for predicting the outcomes of Atez/Bev treatment. METHODS: One hundred 25 HCC patients were enlisted; these patients received Atez/Bev treatment and underwent dynamic computerized tomography/magnetic resonance imaging to determine the treatment response on at least one occasion between October 2020 and January 2023, and their PNI before treatment and at the beginning of the second cycle (PNI-2c) was evaluated. RESULTS: During the initial evaluation, 2 (2%), 28 (22%), 70 (56%), and 25 (20%) patients exhibited a complete response, partial response, stable disease, and progressive disease (PD), respectively. Patients with non-PD tended to have higher PNI at baseline and PNI-2c than those with PD (p = 0.245 and 0.122, respectively), with optimal baseline PNI and PNI-2c cut-off values of 42.6 and 40.4, respectively. PNI at baseline could not be used to predict overall survival (OS) or progression-free survival (PFS). However, PNI-2c predicted OS and PFS (PNI-2c ≥ 40.4 vs. < 40.4: 25.3 vs. 16.2 months, p = 0.008 for OS; 12.7 vs. 8.4 months, p = 0.036 for PFS). A multivariate analysis showed a significant association between PNI-2c and OS. CONCLUSIONS: PNI-2c is a predictor of prognosis in HCC patients treated with Atez/Bev therapy.

Factors affecting the sodium-glucose cotransporter 2 inhibitors-related initial decline in glomerular filtration rate and its possible effect on kidney outcome in chronic kidney disease with type 2 diabetes: The Japan Chronic Kidney Disease Database.

AIM: Sodium-glucose cotransporter 2 (SGLT2) inhibitors often cause a transient decrease in glomerular filtration rate (GFR) shortly after the initiation, referred to as the 'initial drop'. However, the clinical significance of this initial drop in real-world practice remains unclear. MATERIALS AND METHODS: Using the nationwide Japan Chronic Kidney Disease Database, we examined factors that affected the initial drop, in patients with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM). We also evaluated the effects of the initial drop on a composite kidney outcome (a decline in GFR of ≥50% or progression to end-stage kidney disease). RESULTS: Data from 2053 patients with CKD and T2DM newly prescribed an SGLT2 inhibitor were analysed. The follow-up period after SGLT2 inhibitor administration was 1015 days (interquartile range: 532, 1678). Multivariate linear regression models revealed that the concomitant use of the renin-angiotensin system inhibitors and diuretics, urinary protein levels ≥2+, and changes in GFR before the initiation of the SGLT2 inhibitor were associated with a larger initial GFR decline (ß = -0.609, p = .039; ß = -2.298, p < .001; ß = -0.936, p = .048; ß = -0.079, p < .001, respectively). Patients in the quartile with the largest initial GFR decline experienced a higher incidence of the subsequent composite kidney outcome than those in the other quartiles (p < .001). CONCLUSIONS: The concomitant use of renin-angiotensin system inhibitors and diuretics, higher urine protein levels and pre-treatment GFR changes were associated with a larger initial GFR decline. Of these factors, the use of a diuretic had the largest effect. Furthermore, patients with CKD and T2DM experiencing an excessive initial GFR drop might be at a higher risk of adverse kidney outcomes.

Efficacy of antiviral therapy for the prevention of mother-to-child transmission of hepatitis B virus and the risk of postpartum hepatitis flare after discontinuation of antiviral therapy.

The use of nucleos(t)ide analogs (NAs) is recommended for mothers with a high viral load of hepatitis B virus (HBV) during the second or third trimester of pregnancy. However, postpartum hepatitis flares can occur in some cases. We examined the efficacy of NA administration for the prevention of mother-to-child transmission of hepatitis B virus, and evaluated the risk of postpartum hepatitis flares in mothers after NA discontinuation. Nine pregnant women with a high viral load (HBV DNA ≥5.3 log IU/mL) received tenofovir disoproxil fumarate (TDF) at approximately 28 weeks of gestation, and TDF was discontinued at 4-10 weeks after delivery. We evaluated the virological and biochemical parameters in mothers after TDF discontinuation. Hepatitis flares in mothers were defined as alanine transaminase level ≥60 U/L. None of the infants developed any congenital anomaly or acquired HBV infection during infancy. Hepatitis flares occurred within 6 months after TDF discontinuation in five of seven cases, whereas two cases were lost to follow-up. Furthermore, three cases required the resumption of NA use. NA administration was highly effective against mother-to-child-transmission of HBV in pregnant women with high HBV DNA levels. However, hepatitis flares were commonly observed after NA discontinuation in the postpartum period. Patients should be followed up carefully after NA discontinuation, and NA resumption should be considered based on a comprehensive assessment of virological and biochemical parameters.

Serum inducible protein 10 kDa/C-X-C motif chemokine 10 levels predict regression of M2BPGi-based liver fibrosis after hepatitis C virus eradication by direct-acting antiviral agents.

AIM: It is desirable to identify predictors of regression of liver fibrosis after achieving sustained virological response by anti-hepatitis C virus (anti-HCV) therapy. We retrospectively investigated the serum interferon-γ inducible protein 10 kDa (IP-10) level as a predictive indicator of regression of liver fibrosis after successful hepatitis C virus eradication by direct-acting antiviral agents (DAAs) therapy. METHODS: The study participants were recruited from a historical cohort of 116 chronically hepatitis C virus-infected patients who had achieved sustained virological response by DAAs therapy and whose serum Mac-2 binding protein glycosylation isomer (M2BPGi) levels at baseline (before DAAs therapy) were ≥2.0 cut-off index. We defined patients with M2BPGi levels <1.76 and ≥1.76 cut-off index at 2 years after the end of treatment (EOT) as the regression (n = 71) and non-regression (n = 45) groups, respectively. RESULTS: Multivariate analyses revealed that the albumin-bilirubin score at baseline, and albumin-bilirubin score, Fibrosis-4 index at 24 weeks after the EOT, and serum IP-10 change from baseline to 24 weeks after the EOT (IP-10 change) were significantly associated with regression of M2BPGi-based liver fibrosis. In addition, IP-10 change was significantly associated with regression of M2BPGi-based liver fibrosis by a multivariate analysis, even when the serum M2BPGi levels were aligned by propensity score matching and in patients with advanced M2BPGi-based liver fibrosis: M2BPGi levels ≥3.3 cut-off index at baseline. CONCLUSIONS: Serum IP-10 change from baseline to 24 weeks after the EOT is a feasible predictor of regression of M2BPGi-based liver fibrosis after achieving sustained virological response with DAA therapy.

A prospective cohort study of a new electrosurgical unit for preventing colorectal post-endoscopic submucosal dissection coagulation syndrome.

BACKGROUND AND AIM: Post-endoscopic submucosal dissection coagulation syndrome (PECS) is a recognized complication of colorectal endoscopic submucosal dissection (ESD); however, there is a lack of interventions for preventing PECS. We therefore conducted a prospective study to evaluate the utility of maXium, a novel electrosurgical unit, for preventing PECS. METHODS: This single-center, prospective cohort study prospectively enrolled patients undergoing colorectal ESD. The voltage and power of the electrosurgical units were measured. PECS was defined as a visual analog scale (VAS) ≥ 30 mm, an increase of VAS ≥ 20 mm from baseline, body temperature ≥ 37.5°C, or white blood cell count ≥ 10 000/µL after ESD. PECS was classified into type I (without extra-luminal air) and type II (with peri-luminal air). The primary endpoint was the incidence of PECS. A sample size of 92 patients was required to ensure the upper limit of the 90% CI for the incidence of PECS was less than 15%. RESULTS: At resistances greater than 400 Ω, the maXium unit allowed submucosal dissection with lower power than with the VIO300D unit. Ninety-one patients meeting the inclusion criteria were included in the final study analysis. The incidence of PECS was 16% (90% CI, 10-23%), comprising type I (11%) and type II (5%) PECS. Simple extra-luminal air without PECS was observed in 7% of patients. CONCLUSION: Use of the maXium electrosurgical unit did not reduce the incidence of PECS after colorectal ESD; however, the maXium unit had equivalent performance to a conventional electrosurgical unit used for colorectal ESD.

Serum interleukin-6 levels at the start of the second course of atezolizumab plus bevacizumab therapy predict therapeutic efficacy in patients with advanced hepatocellular carcinoma: a multicenter analysis.

BACKGROUND AND AIM: Serum interleukin-6 (IL-6) before the administration of atezolizumab plus bevacizumab (Atez + Bev) is a prognostic biomarker in patients with hepatocellular carcinoma (HCC) treated with Atez + Bev. We previously revealed that the neutrophil-to-lymphocyte ratio and serum chemokine levels during treatment with Atez + Bev were more useful as prognostic biomarkers. Therefore, we examined the predictive ability of serum IL-6 for the efficacy of Atez + Bev in patients with HCC. METHODS: We enrolled 94 patients with HCC who received treatment with Atez + Bev. Initial responses were assessed through dynamic computed tomography or magnetic resonance imaging. The levels of IL-6 in serum were measured before and at the initiation of the second course of Atez + Bev. Subsequently, the relationship of IL-6 levels with treatment efficacy was evaluated. RESULTS: IL-6 levels at the initiation of the second course tended to be higher in patients with progressive disease versus those with non-progressive disease in the initial evaluation (P = 0.054). Moreover, the cutoff value (7.4 pg/mL) was useful in stratifying patients by overall survival (i.e. low vs high: not reached vs 21.4 months, respectively, P = 0.001) and progression-free survival (low vs high: 11.9 vs 5.2 months, respectively, P = 0.004). This result was reproduced in patients with HCC who received Atez + Bev as first-line therapy. In the multivariate analyses, IL-6 levels at the initiation of the second course were independent predictive factors for progression-free and overall survival. CONCLUSIONS: Serum levels of IL-6 at the initiation of the second course of treatment may predict Atez + Bev efficacy and prognosis in HCC.

Salvage radiotherapy for locoregional recurrence of esophageal cancer after surgery.

OBJECTIVE: There is no consensus on the optimal treatment for patients with locoregional recurrence of esophageal cancer after surgery. The objective of this study was to investigate the outcomes and prognostic factors associated with salvage radiotherapy in patients with locoregional recurrence of esophageal cancer after surgery. METHODS: We reviewed 80 patients with locoregional recurrence of esophageal cancer after surgery who were treated with radiotherapy. The median dose was 60 Gy, and 29 patients (36%) received elective nodal irradiation. Fifty-three patients (66%) received concurrent chemotherapy (mostly 5-fluorouracil and cisplatin) during radiotherapy. Overall survival, progression-free survival and in-field recurrence rate were assessed. RESULTS: The median follow-up period was 17 months. Two-year overall survival, progression-free survival and in-field recurrence rate were 50.3%, 23.5% and 41.3%, respectively. On multivariate analysis, a maximum diameter of locoregional recurrence lesions <30 mm was associated with higher overall survival (P = 0.044). Disease-free interval between surgery and locoregional recurrence >14 months was associated with higher PFS (P = 0.003). Late grade 3 toxicities occurred in three patients (3.8%). No grade 4 or higher toxicity was observed. CONCLUSIONS: Salvage radiotherapy demonstrated efficacy in achieving in-field control with acceptable toxicity. However, the high rate of out-of-field metastases led to poor progression-free survival and overall survival, particularly in cases involving large lesions and a short disease-free interval. A prospective study is warranted to establish a treatment strategy, particularly considering the combined use of effective anti-cancer drugs.