Personalized diet and exercise program for steatotic liver disease improved liver function tests, physical findings, glycolipid metabolism markers, and cardiovascular disease risk score. Genetic polymorphism might partially affect treatment efficacy. Further studies should be performed to develop an individualized program for steatotic liver disease, considering genetic polymorphism.

Abstract

Aims

The effects of genetic polymorphism on a personalized diet and exercise program for steatotic liver disease (SLD) are still unclear.

Methods

Participants of this retrospective cohort study were 203 Japanese patients with SLD diagnosed by abdominal ultrasonography. All of them were introduced the personalized diet and exercise treatment. A diet of 25–30 kcal/kg multiplied by ideal body weight (BW) daily and aerobic and resistance exercise (exercise intensity of 4–5 metabolic equivalents daily, respectively) were performed for 6 days. Treatment efficacy was evaluated in terms of the rate of decrease of liver function tests, glycolipid metabolism markers, physical findings, image findings, and cardiovascular disease (CVD) risk score at 6 months compared with baseline. Furthermore, the impact of genetic polymorphism was also investigated.

Results

At 6 months compared with baseline, liver function tests (AST, ALT, γGTP), glycolipid metabolism markers (hemoglobin A1c, triglycerides [TG], low-density lipoprotein cholesterol), physical findings (BW, body mass index), image finding (liver stiffness measurement), and CVD risk score (Suita score) improved significantly. There was no significant difference in treatment efficacy, except for the rates of decrease of TG, according to genotype PNPLA3 rs738409, TM6SF2 rs58542926, and HSD17B13 rs6834314. The rates of decrease of TG with TM6SF2 CT were significantly higher than those with CC or TT, and the rates of TG with HSD17B13 AA were significantly higher than those with AG by multiple comparisons.

Conclusion

Personalized diet and exercise program for SLD improved liver function tests, physical findings, glycolipid metabolism markers, and CVD risk score. Genetic polymorphism might partially affect treatment efficacy. Further studies should be performed to develop an individualized program for SLD, considering genetic polymorphism.

It may be difficult to continue atezolizumab plus bevacizumab (AB) combination therapy for unresectable hepatocellular carcinoma (u-HCC) in patients with severe immune-related adverse events (irAEs), and it may lead to deterioration of their general condition. Therefore, it is important to establish a system for predicting the risk of irAE development before starting AB therapy. Several studies have reported that the presence of autoantibodies at baseline may be associated with irAE development in patients with other types of carcinomas. The present study aimed to determine the association between autoantibodies and irAE development in patients receiving AB therapy for u-HCC. Sixteen percent of patients developed irAEs during the observation period. Autoantibodies at baseline was an independent factor associated with irAE development (hazard ratio: 3.7, p = 0.047). Patients with autoantibodies at baseline are at high risk of irAE development and require cautious follow-up.

Abstract

Aim

Atezolizumab plus bevacizumab (AB) combination therapy is the first-line treatment for unresectable hepatocellular carcinoma (u-HCC). The management of immune-related adverse events (irAEs) is an important issue associated with achieving a good therapeutic response in patients receiving AB therapy. However, few studies have reported irAE development in patients receiving AB therapy. This study focused on the association between irAE development and autoantibodies at baseline in patients receiving AB therapy.

Methods

Sixty-one patients receiving AB therapy were enrolled. For autoantibodies, the following antibodies were tested before the start of AB therapy: antinuclear antibodies, rheumatoid factor (RF), anti-thyroglobulin antibodies, thyroid peroxidase antibodies, anti-thyroid stimulating hormone receptor antibodies, and acetylcholine receptor antibodies. A patient was considered to have pre-existing antibodies if any of the listed antibodies were present at baseline.

Results

Ten patients (16%) developed irAEs during the observation period. The irAEs included liver injury, hypothyroidism, adrenal insufficiency, adrenocorticotropic hormone deficiency, and rhabdomyolysis. Patients with irAE (n = 10) were more likely to be positive for any autoantibody (hazard ratio [HR] 3.7, p = 0.047) and RF at baseline (HR 5.4, p = 0.035) and to achieve complete response (HR 5.8, p = 0.027) than those without. The presence of autoantibodies at baseline was an independent factor associated with irAE development.

Conclusion

In the real world, 16% of patients receiving AB therapy for u-HCC developed irAEs. Patients with autoantibodies at baseline are at high risk of developing irAEs and require cautious follow-up.

Metabolic dysfunction-associated fatty liver disease (MAFLD), along with drinking and smoking, is an independent risk factor for the recurrence of esophageal squamous cell carcinoma after endoscopic treatment. Decision tree and random-forest analyses revealed MAFLD as the second most important classifier for recurrence, followed by drinking. Acyclic graphs revealed that MAFLD directly contributes to the recurrence. Moreover, the cumulative incidence of recurrence was significantly higher in the non-obese than that in the obese MAFLD group among abstainers/non-drinkers.

Abstract

Aim

Metabolic dysfunction is a risk factor for esophageal squamous cell carcinoma (ESCC). We investigated the impact of the recently proposed metabolic dysfunction-associated fatty liver disease (MAFLD) and its subtypes on ESCC recurrence after endoscopic treatment.

Methods

This multicenter observational cohort study enrolled consecutive patients newly diagnosed with ESCC after endoscopic treatment. Patients were classified into MAFLD or non-MAFLD groups. The MAFLD group was further classified into non-obese and obese MAFLD groups with a body mass index cutoff value of 25 kg/m². The impact of MAFLD on the recurrence of ESCC was evaluated using a decision tree algorithm and random forest analysis.

Results

A total of 147 patients (average age, 69 years; male: female, 127:20; observational period, 2.4 years) were enrolled. The 1-, 3-, and 5-year recurrence rates were 2.0%, 21.1%, and 33.7%, respectively. Independent risk factors for the recurrence of ESCC were MAFLD (HR, 2.2812; 95% CI, 1.0497–4.9571; p=0.0373), drinking status, and smoking status. MAFLD was identified as the second most important classifier for recurrence followed by drinking status. The cumulative incidence of ESCC recurrence was higher in the MAFLD group than in the non-MAFLD group. In a sub-analysis, the cumulative incidence of recurrence was significantly higher in the non-obese than in the obese MAFLD group among abstainers/non-drinkers. Directed acyclic graphs revealed that MAFLD directly contributes to ESCC recurrence.

Conclusions

MAFLD was independently and directly associated with ESCC recurrence after endoscopic treatment; a high recurrence rate was observed in patients with non-obese MAFLD. MAFLD may identify patients at high risk for ESCC recurrence.

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1. CircPIP5K1A regulates ARHGAP1 expression by sponging miR-101-3p. 2. CircPIP5K1A and ARHGAP1 are carcinogenic factors in liver cancer. 3. circPIP5K1A/miR-101-3p/ARHGAP1 axis governs tumor progression in liver cancer.

Abstract

Aim

There has been an increased focus on regulating cell function with Rho family GTPases, including proliferaton, migration/invasion, polarity and adhesion. Due to the challenges involved in targeting Rho family GTPases directly, it may be more effective to target their regulators, such as ARHGAP1. This present research was performed to define the clinical significance of ARHGAP1 expression as well as its regulatory mechanisms in hepatocellular carcinoma (HCC).

Methods

ARHGAP1 and miR-101-3p expression of liver cancer patients and their relevance with clinicopathological characteristics and prognosis were analyzed by the Cancer Genome Atlas sequencing data and verified using samples of HCC patients. The interactions between miR-101-3p and ARHGAP1 or circPIP5K1A were validated by bioinformatic analyses as well as confirmed by qRT-PCR, western blotting and dual-luciferase reporter analysis. Plate clonality assays, cell adhesion and migration experiments and proliferation experiments were used for assessing the participation of circPIP5K1A /miR-101-3p/ARHGAP1 pathway in cell proliferation and motility.

Results

Elevated ARHGAP1 and reduced miR-101-3p expression are related to poorer survival. MiR-101-3p targets ARHGAP1 to suppress HCC cell colony formation and invasion, while miR-101-3p inhibitor reverses liver cancer proliferation and metastasis suppression caused by ARHGAP1 knockdown. In addition, circPIP5K1A, which is mainly distributed in the cytosol, showed carcinogenic effects by sponging miR-101-3p, thus regulating ARHGAP1 expression.

Conclusions

ARHGAP1 serves as an oncogenic gene in liver cancer and the expression thereof is regulated by CircPIP5K1A through sponging miR-101-3p.

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Patients with nonalcoholic fatty liver disease in high-risk groups (F3–4 of fibrosis stage, rule-in [IN] of Agile 3+, and IN of Agile 4) showed a stepwise increase of liver-related events. Hazard ratios of the high-risk groups were much higher in Agile 3+ and Agile 4 than fibrosis, compared to their counterparts.

Abstract

Aim

The noninvasive tests (NITs) Agile 3+ and Agile 4 effectively identify patients with nonalcoholic fatty liver disease (NAFLD) complicated with advanced fibrosis (F3–4) and cirrhosis (F4), respectively. Little information is available on associations between Agile scores and intra-/extrahepatic events. The aim of this study was to determine the predictive performance of Agile scores for intra-/extrahepatic events in Asian patients with biopsy-proven NAFLD.

Methods

We undertook a retrospective multicenter cohort study to investigate associations between intra-/extrahepatic events and two Agile scores, Agile 3+ and Agile 4. The scores were obtained by combining clinical parameters and liver stiffness measurement using transient elastography.

Results

Among 403 enrolled patients, 11 had liver-related events (LREs), including seven with hepatocellular carcinoma (HCC). The incidence of LREs and HCC showed a stepwise increase in the advanced fibrosis group (F3–4), Agile 3+ rule-in (F3–4, highly suspected), and Agile 4 rule-in (F4, highly suspected) groups, compared to their counterparts. Hazard ratios for LREs in the advanced fibrosis group, Agile 3+ rule-in, and Agile 4 rule-in groups were 4.05 (p = 0.03), 23.5 (p = 0.003), and 45.5 (p < 0.001), respectively. The predictive performance results for Agile 3+ and Agile 4 were 0.780 and 0.866, respectively, which were higher than for fibrosis (0.595). Unlike for LREs, Agile scores failed to identify patients with extrahepatic events, including cardiovascular events and extrahepatic cancer.

Conclusions

Agile 3+ and Agile 4 scores are excellent NITs for predicting LREs in patients with NAFLD, possibly without histological assessment.

Abstract

Aim

This study was undertaken to investigate the utility of the fatty liver index (FLI) as a noninvasive tool for predicting hepatic steatosis based on alcohol consumption and sex in a large Asian population.

Methods

We carried out a single-center observational cohort study at the HITO Medical Center in Japan and enrolled 1976 Asian subjects. The subjects were categorized into nondrinkers and light drinkers (0–19 g/day) and moderate drinkers (20–59 g/day) based on their self-reported alcohol intake. We used physical examinations, laboratory tests, and a questionnaire to collect information on various factors related to the FLI, including body mass index, waist circumference, and levels of γ-glutamyl transferase and triglycerides.

Results

The diagnostic accuracy of the FLI was assessed by calculating the area under the receiver operating characteristic curve (AUROC), and optimal cut-off values were determined using Youden's index. The FLI had an acceptable performance index of >0.7 both overall and in all subgroups, with an overall AUROC of 0.844. The AUROCs were higher in women and moderate drinkers of both sexes. We also compared the cut-off values obtained in the present study with the previously reported values of 30 and 60. Optimal cut-off values for the FLI were calculated for the total population and subgroups and were found to differ from the previously established values in other countries.

Conclusions

Our study suggests that the FLI is a useful noninvasive marker for predicting hepatic steatosis in a large Asian population, irrespective of alcohol consumption and sex.