Abstract

Aim

We evaluated the safety and efficacy of vascular endothelial growth factor receptor (VEGFR)-targeted peptide vaccines for the immunization of patients with unresectable hepatocellular carcinoma (HCC) who had responded to transarterial chemoembolization.

Methods

Twenty-two patients were randomized 1:1 to receive VEGFR-targeted peptides or placebo. The primary end-point was the safety assessment of the immunization. The secondary end-points were evaluation of immunological responses and clinical outcomes.

Results

No severe adverse events were induced by the study agents. Among the 12 patients in the vaccine group, a VEGFR1-specific cytotoxic T lymphocyte (CTL) response was induced in eight (66.7%) patients and a VEGFR2-specific CTL response was induced in 10 (83.3%). The median progression-free survival (PFS) and overall survival (OS) rates were 4.8 and 52.0 months, respectively, in the vaccine group, and 2.7 and 21.8 months, respectively, in the placebo group. No statistically significant differences were found between the two groups (PFS p = 0.925, OS p = 0.190). When divided into two groups according to immunoreactivity, the median PFS of patients with and without a strong immune response to VEGFR1 were 7.4 and 2.7 months, and that to VEGFR2 were 10.6 and 2.7 months, respectively; there were significant differences according to the immune response.

Conclusions

Immunotherapy with peptide vaccines targeting VEGFR1 and VEGFR2 was well tolerated with no serious adverse events. It also effectively induced peptide-specific CTLs in patients with unresectable HCC.

Abstract

Aim

It remains unclear whether the newly defined concept of metabolic dysfunction-associated steatotic liver disease (MASLD) appropriately includes patients with nonalcoholic fatty liver disease with significant liver fibrosis.

Methods

A total of 4112 patients in whom nonalcoholic fatty liver disease was diagnosed by ultrasonography during medical checkups were enrolled. We defined a fibrosis-4 index ≥1.3 in patients aged <65 years and ≥2.0 in patients aged ≥65 years as significant liver fibrosis.

Results

The numbers of patients with a low, intermediate, and high probability of advanced fibrosis based on the fibrosis-4 index were 3360 (81.7%), 668 (16.2%), and 84 (2.0%). There were 3828 (93.1%) and 284 (6.9%) patients diagnosed with MASLD and non-MASLD. The non-MASLD group, compared with the MASLD group, was significantly younger (44 vs. 55 years) and had a higher percentage of women (62.3% vs. 27.7%). Significant fibrosis, defined based on the fibrosis-4 index, was present in 18.5% of the MASLD group and 15.5% of the non-MASLD group. In a multivariable analysis, female sex (OR 6.170, 95% CI 3.180–12.000; p < 0.001) was independently associated with non-MASLD in patients with a significant fibrosis. Among non-MASLD patients with a significant fibrosis (n = 44), body mass index was significantly lower in females than in males (p < 0.001). In a multivariable analysis of patients aged <65 years, female sex (OR, 7.700; 95% CI, 3.750–15.800; p < 0.001) remained independently associated with non-MASLD in patients with a significant fibrosis.

Conclusions

MASLD may inappropriately exclude patients with significant fibrosis, especially lean females with nonalcoholic fatty liver disease.

The number of hepatocellular carcinoma-related general medical practices decreased during the first state of emergency. However, there were no major significant delays leading to hepatocellular carcinoma stage progression for patients newly diagnosed with hepatocellular carcinoma due to the coronavirus disease 2019 pandemic.

Abstract

Aim

Coronavirus disease 2019 emerged in December 2019 and spread worldwide. This study aimed to clarify the impact of the coronavirus disease 2019 pandemic on the diagnosis and treatment of hepatocellular carcinoma (HCC) in Japan.

Methods

First, we collected the monthly numbers of HCC-related general medical practices from January 2019 to December 2021 at liver disease-specific medical institutions in Japan. Next, we collected individual clinical information from patients with newly diagnosed HCC during this period.

Results

There was a decrease in the number of HCC-related medical practices, including referrals, enhanced abdominal ultrasonography and radiofrequency ablation, in Japan's first state of emergency (SOE; April–May 2020) compared with 2019. Fewer patients were diagnosed with new HCC during the first SOE than before or after it. There was no difference in tumor diameter, number of tumors or Barcelona Clinic Liver Cancer stage between patients diagnosed before the first SOE and those diagnosed during or after the first SOE. The median waiting times for treatment of patients diagnosed during and after the first SOE were 31 and 37 days, which were significantly shorter and not longer than that of patients diagnosed before the first SOE (36 days), respectively.

Conclusion

The number of HCC-related general medical practices decreased during the first SOE. However, the coronavirus disease 2019 pandemic did not lead to HCC progression by diagnostic delays or cause HCC treatment delays in Japan.

We performed a cost-effectiveness analysis of living-donor liver transplantation (LDLT) compared to conservative management (CM) for adult patients using the Japanese nationwide database of the Diagnostic Procedure Combination research group. LDLT compared with CM for patients with Child–Pugh class C was cost-effective, with an incremental cost-effectiveness ratio (ICER) of 2.08 million JPY/QALY (20,708 USD/QALY), whereas LDLT versus CM for patients with Child–Pugh class B was not cost-effective, with an ICER of 5.24 million JPY/QALY (52,153 USD/QALY).

Abstract

Aim

Living-donor liver transplantation (LDLT) is a highly effective life-saving procedure; however, it requires substantial medical resources, and the cost-effectiveness of LDLT versus conservative management (CM) for adult patients with end-stage liver disease (ESLD) remains unclear in Japan.

Methods

We performed a cost-effectiveness analysis using the Diagnostic Procedure Combination (DPC) data from the nationwide database of the DPC research group. We selected adult patients (18 years or older) who were admitted or discharged between 2010 and 2021 with a diagnosis of ESLD with Child–Pugh class C or B. A decision tree and Markov model were constructed, and all event probabilities were computed in 3-month cycles over a 10-year period. The willingness-to-pay per quality-adjusted life-year (QALY) was set at 5 million Japanese yen (JPY) (49,801 US dollars [USD]) from the perspective of the public health-care payer.

Results

After propensity score matching, we identified 1297 and 111,849 patients in the LDLT and CM groups, respectively. The incremental cost-effectiveness ratio for LDLT versus CM for Child–Pugh classes C and B was 2.08 million JPY/QALY (20,708 USD/QALY) and 5.24 million JPY/QALY (52,153 USD/QALY), respectively. The cost-effectiveness acceptability curves showed the probabilities of being below the willingness-to-pay of 49,801 USD/QALY as 95.4% in class C and 48.5% in class B. Tornado diagrams revealed all variables in class C were below 49,801 USD/QALY while their ranges included or exceeded 49,801 USD/QALY in class B.

Conclusions

Living-donor liver transplantation for adult patients with Child–Pugh class C was cost-effective compared with CM, whereas LDLT versus CM for class B patients was not cost-effective in Japan.

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.

This article is protected by copyright. All rights reserved.