Impact of alcohol consumption on metabolic dysfunction-associated fatty liver disease development and remission: A longitudinal cohort study.

BACKGROUND: The influence of alcohol intake on metabolic dysfunction-associated fatty liver disease (MAFLD) development and remission remains unclear; thus, we aimed to investigate their longitudinal associations. METHODS: This observational cohort study included 6349 patients who underwent more than two health check-ups over >2 years between April 2013 and March 2021. Generalized estimation equations were used to analyse the longitudinal associations between changes in alcohol intake and MAFLD according to repeated measures at baseline and the most recent stage. RESULTS: The MAFLD development and remission rates were 20.4 and 5.1 and 9.1 and 4.7% in men and women, respectively. Although alcohol consumption was not a significant factor for MAFLD development, consuming 0.1-69.9 g/week (odds ratio [OR]: 0.672, 95% confidence interval [CI]: 0.469-0.964, p < .05) and ≥280 g/week were significant factors for MAFLD development in males (OR: 1.796, 95% CI: 1.009-3.196, p < .05) and females (OR: 16.74, 95% CI: 3.877-72.24, p < .001). Regardless of quantity and frequency, alcohol consumption was not a significant factor for MAFLD remission. Several noninvasive liver fibrosis scores were significantly associated with alcohol intake quantity and frequency in males with MAFLD development and remission (p < .05). The nonalcoholic fatty liver disease fibrosis score differed significantly between males with and without reduced alcohol intake (p < .05) who showed MAFLD remission. CONCLUSIONS: Although the influence of alcohol intake on MAFLD development and remission differed, alcohol consumption was not beneficial for MAFLD remission in either sex. Alcohol intake reduction or cessation is recommended to prevent liver fibrosis, even in those who achieve MAFLD remission.

Association of metabolic dysfunction-associated fatty liver disease with gallstone development: A longitudinal study.

BACKGROUND AND AIM: The influence of metabolic dysfunction-associated fatty liver disease on gallstone development remains unclear. We aimed to investigate the longitudinal association between metabolic dysfunction-associated fatty liver disease and gallstone development in both men and women. METHODS: This observational cohort study included 5398 patients without gallstones who underwent > 2 health check-ups between April 1, 2014, and March 31, 2020. A generalized estimation equation model was used to analyze the association between metabolic dysfunction-associated fatty liver disease and gallstone development according to repeated measures at baseline and most recent stage. RESULTS: After adjustment, the odds ratios of metabolic dysfunction-associated fatty liver disease for gallstone development in men and women were 3.019 (95% confidence interval [CI]: 1.901-4.794) and 2.201 (95% CI: 1.321-3.667), respectively. Among patients aged ≥ 50 years, the odds ratio for gallstone development was significantly enhanced with increasing metabolic dysfunction-associated fatty liver disease component numbers in both sexes; however, no significance was observed in those aged < 50 years. Other significant risk factors for gallstone development were age (odds ratio: 1.093, 95% CI: 1.060-1.126) and waist circumference (odds ratio: 1.048, 95% CI: 1.018-1.079) in men and age (odds ratio: 1.035, 95% CI: 1.003-1.067) and current smoking (odd ratio: 5.465, 95% CI: 1.881-15.88) in women. CONCLUSION: Although the risk factors for gallstone development differed between sexes, metabolic dysfunction-associated fatty liver disease was common. Paying attention to an increase in the number of metabolic dysfunction-associated fatty liver disease components in patients aged ≥ 50 years is important for gallstone prevention.

Association of metabolic dysfunction-associated steatotic liver disease with erosive esophagitis development: a longitudinal observational study.

BACKGROUND AND AIM: Although erosive esophagitis (EE) is associated with fatty liver and metabolic dysregulation, the association between EE and metabolic dysfunction-associated steatotic liver disease (MASLD) remains unclear. Thus, this study aimed to investigate the longitudinal association between MASLD and EE. METHODS: We included 1578 patients without EE at baseline who underwent more than two health checkups over 2 years. Generalized estimation equations were used to analyze associations between MASLD and EE according to repeated measures at baseline and most recent stages. RESULTS: EE development rates in men and women were 14.5% and 7.2%, respectively. After adjusting for lifestyle habits, the odds ratios of MASLD for EE development in men and women were 1.907 (95% confidence interval [CI]: 1.289-2.832, P < 0.005) and 1.483 (95% CI: 0.783-2.811, P = 0.227), respectively. In the subgroup analysis, after adjusting for lifestyle habits, among men and women aged ≥50 years with more than three MASLD components, the odds ratios for EE development were 2.408 (95% CI: 1.505-3.855, P < 0.001) and 2.148 (95% CI: 1.093-4.221, P < 0.05), respectively. After adjusting for various factors, the significant risk factors for EE development were different between men and women. CONCLUSION: The influence of MASLD and other factors on EE development differed by sex and age. Particularly, patients aged ≥50 years with MASLD and with an increased number of MASLD components should be considered at increased risk for EE.

Multicenter retrospective study of initial treatment outcome and feasibility of initiating dose reduction of cabozantinib in unresectable hepatocellular carcinoma.

AIM: Cabozantinib (CAB), a multiple kinase inhibitor, has been approved for use in patients with previously treated unresectable hepatocellular carcinoma (uHCC). However, real-world clinical data are lacking, particularly clinical data regarding dose modifications of CAB. We analyzed the clinical outcomes of CAB in uHCC and compared treatment outcomes between the full- and reduced-dose groups. METHODS: This multicenter, observational study included patients with uHCC who were treated with CAB from March 2021 to April 2022. Patient characteristics, efficacy, and safety were compared between the full- and reduced-dose groups. RESULTS: Twenty-six patients from eight institutes were analyzed. Cabozantinib was administered as a third-line or later treatment in 25 (96.2%) patients and postimmunotherapy in 21 (80.5%) patients. There were 15 patients in the full-dose group (60 mg CAB) and 11 in the reduced-dose group (40 or 20 mg CAB). The objective response rate (ORR) and disease control rate (DCR) were not significantly different between the two groups. The ORR was 6.7% for the full-dose group and 9.1% for the reduced-dose group, and the DCR was 53.4% and 81.8%, respectively. Progression-free survival analysis showed no significant differences between the two groups. The incidence of decreased appetite, fatigue, and diarrhea, and the rate of discontinuation and dose reduction, was significantly higher in the full-dose group. CONCLUSIONS: Our study suggests that the efficacy and safety of CAB in real-world clinical practice are comparable to those of the phase III trial (CELESTIAL), and that dose reduction of CAB may be a safer treatment option.

Sequential therapy including regorafenib for unresectable hepatocellular carcinoma: Effect of early relative changes in hepatic functional reserve after regorafenib administration on prognosis.

AIM: Regorafenib is a second-line treatment for unresectable hepatocellular carcinoma after sorafenib-refractory treatment. This study examined the effects of regorafenib administration on hepatic functional reserve and the treatment course after regorafenib discontinuation. METHODS: This retrospective, multicenter study involved 51 patients treated with regorafenib after sorafenib-refractory treatment for u-HCC at seven institutions before March 2021. RESULTS: Fourteen, 13, and 24 patients were classified based on modified albumin-bilirubin (mALBI) grade 1, 2a, and 2b, respectively. The median survival time and progression-free survival were 16.7 and 3.3 months, respectively. Only mALBI grade 2b or 3 was significantly associated with survival rate (hazard ratio, 2.13; 95% confidence interval, 1.01-4.49; p = 0.047). A comparison of median ALBI scores at the initiation of regorafenib (-2.35) with those at 4 weeks (-1.93) revealed a significant relative change (p = 0.0001). After 4 weeks, grade 1 or 2a persisted in 15 patients (Group 1); grade 1 or 2a deteriorated to 2b in 12 patients (Group 2); grade 2b or 3 before regorafenib administration was present in 22 patients (Group 3); and MST was 33.3, 12.8, and 11.3 months in the three groups, respectively (p = 0.05). Patients treated with lenvatinib (LEN) (n = 27, MST = 23.4 months) after regorafenib had a significantly longer survival time from regorafenib initiation than those not treated with LEN (n = 24, 11.8 months; p = 0.043). CONCLUSIONS: Hepatic functional reserve significantly declined after regorafenib administration. During regorafenib treatment, favorable hepatic functional reserve before administration and maintenance of favorable hepatic reserve after administration lead to prolonged prognosis.

Comparison of therapeutic outcomes of sorafenib and lenvatinib as primary treatments for hepatocellular carcinoma with a focus on molecular-targeted agent sequential therapy: A propensity score-matched analysis.

AIM: The optimal choice between sorafenib (SOR) or lenvatinib (LEN) as the first-line treatment for unresectable hepatocellular carcinoma (u-HCC) remains debatable. Using propensity score matching, this study compares the outcomes of SOR and LEN in the molecular-targeted agent (MTA) sequential treatment of u-HCC patients. METHODS: This retrospective, multicenter, observational study recruited 137 u-HCC patients who underwent primary treatment with LEN (n = 52) or SOR (n = 85) between June 2017 and June 2020 after regorafenib was approved as the secondary treatment for u-HCC. Propensity score matching was used to reduce confounding, resulting in the selection of 104 patients (n = 52 for the SOR and LEN cohorts). RESULTS: The median overall survival was 21.8 months for LEN and 20.4 months for SOR. LEN exhibited significantly greater therapeutic efficacy as compared to SOR (objective response rate: 3.8% [SOR] vs. 42.3% [LEN], p < 0.01; progression-free survival: 10 months [LEN] vs. 5.1 months [SOR], p < 0.01). No significant intergroup differences were noted in the rate of transition to secondary MTA treatments (SOR: 58.7%; LEN: 48.4%), adverse events (SOR: 86%; LEN: 95%), and maintenance of the Child-Pugh (CP) score during treatment. Compared to non-MTA treatments, secondary MTA treatment achieved a greater improvement in survival (4.3  vs. 2.8 months, p = 0.0047). Multivariate analysis demonstrated that the CP score (p < 0.01) and alpha-fetoprotein level (p < 0.01) were independent prognostic factors. CONCLUSIONS: Both SOR and LEN treatments showed a clinically comparable therapeutic efficacy as the first-line treatments for u-HCC patients in an MTA sequential therapy.

Effects of audio and visual distraction on patients' vital signs and tolerance during esophagogastroduodenoscopy: a randomized controlled trial.

BACKGROUND: Esophagogastroduodenoscopy (EGD) provides an indispensable and unambiguous inspection allowing the discovery upper gastrointestinal lesions. However, many patients are anxious about undergoing EGD. Few studies have investigated the influence on patients' vital signs and tolerance during EGD using subjective and objective assessments. This study was a prospective randomized controlled study that investigated the influence of audio and visual distraction on EGD. METHODS: We randomly divided 289 subjects who underwent EGD into 4 groups (control group, audio group, visual group, combination group) and examined their vital signs, heart rate variability (HRV), psychological items, and acceptance of distraction. RESULTS: Pulse rate (PR) at post-distraction and post-EGD in the 3 distraction groups were significantly lower than those of control group (p <  0.001 and p <  0.01, respectively). Blood pressure (BP) during and post-EGD was significantly higher than that at pre-EGD in control group (p <  0.05), but no significant elevation of BP was observed during the latter half of EGD and post-EGD in the 3 distraction groups. BP at post-distraction improved significantly compared to pre-distraction in the 3 distraction groups (p <  0.05). There was a significant difference in the low-frequency (LF) power/ high-frequency (HF) power at post-distraction and post-EGD among the 4 groups (p <  0.001 and p <  0.001, respectively). The LF power/HF power at post-distraction and post-EGD in the 3 distraction groups was significantly lower than that in control group (p <  0.05). Several items of profile of mood states (POMS) and the impression of EGD at post-distraction improved significantly compared to those at pre-distraction among the 3 distraction groups (p <  0.05). Visual analog scale (VAS) of willingness for the next use of distraction in the 3 distraction groups was excellent because VAS was more than 70. CONCLUSIONS: Distractions effectively improved psychological factors, vital signs and some of HRV at pre and post-EGD. Distractions may suppress BP elevation during the latter half of EGD and lead to stability of HRV on EGD. TRIAL REGISTRATION: This prospective trial was registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry as UMIN000029637. Registered on 20 October 2017.

Development of a novel automatic ascites filtration and concentration equipment with multi-ring-type roller pump units for cell-free and concentrated ascites reinfusion therapy.

Cell-free and concentrated ascites reinfusion therapy (CART) is an effective therapy for refractory ascites. However, CART is difficult to perform as ascites filtration and concentration is a complicated procedure. Moreover, the procedure requires the constant assistance of a clinical engineer or/and the use of an expensive equipment for the multi-purpose blood processing. Therefore, we developed a CART specialized equipment (mobility CART [M-CART]) that could be used safely with various safety measures and automatic functions such as automatic washing of clogged filtration filter and self-regulation of the concentration ratio. Downsizing, lightning of the weight, and automatic processing in M-CART required the use of newly developed multi-ring-type roller pump units. This equipment was approved under Japanese regulations in 2018. In performing 41 sessions of CART (for malignant ascites, 22 sessions; and hepatic ascites, 19 sessions) using this equipment in 17 patients, no serious adverse event occurred. An average of 4494 g of ascites was collected and the total amount of ascites was processed in all the sessions without any trouble. The mean weight of the processed ascites was 560 g and the mean concentration ratio was 8.0. The ascites were processed at a flow rate of 50 mL/min. The mean ascites processing time was 112.5 minutes and a 106.5-minutes (95.2%) ascites processing was performed automatically. The operator responded to alarms or support information 3.2 times on average (3.1 minutes, 2.1% of ascites processing time). Human errors related to ascites processing were detected by M-CART at 0.4 times per session on average and were appropriately addressed by the operator. The frequencies of automatic washing of clogged filtration filter and self-regulation of the concentration ratio were 31.7% and 53.7%, respectively. The mean recovery rates (recovery dose) of protein, albumin, and immunoglobulin G were 72.9%, 72.9%, and 71.2% (65.9 g, 34.9 g, and 13.2 g), respectively. Steroids were administered in 92.7% of the sessions to prevent fever and the mean increase in body temperature was 0.53°C. M-CART is a compact and lightweight automatic CART specialized equipment that can safely and easily process a large quantity of ascites without the constant assistance of an operator.

APOB codon 4311 polymorphism is associated with hepatitis C virus infection through altered lipid metabolism.

BACKGROUND: It has been reported that some single-nucleotide polymorphisms (SNPs) in lipid regulators such as apolipoproteins and cell surface molecules for hepatitis C virus (HCV) entry into hepatocytes are associated with HCV infection. However, it is unknown how HCV infection is affected by altered lipid metabolism resulting from the SNPs. We investigated the relationship between these SNPs and HCV infection status, and also analyzed the mechanism by which these SNPs mediate HCV infection via lipid metabolism alterations. METHODS: Serum lipid and apolipoprotein profiles were tested in 158 HCV-positive and 220 HCV-negative subjects. We selected 22 SNPs in five lipid regulator genes which were related to HCV entry into hepatocytes and to lipid metabolism (APOA1, APOB, SR-B1, LDLR, and APOE), and their polymorphisms were analyzed using the PCR-sequence-specific oligonucleotide probe-Luminex method. RESULTS: An APOB N4311S (g.41553a > g) SNP, rs1042034, was significantly associated with HCV positivity; the HCV positivity rate for the minor allele AA genotype was significantly higher than for genotype AG + GG (P = 0.016). Other SNPs except for APOB P2712L SNP rs676210, which is in linkage disequilibrium with rs1042034, showed no significant difference in genotype distribution. The serum level of low density lipoprotein-cholesterol (LDL-C) in the genotype AA group was significantly lower than in the genotype non-AA group (P = 0.032), whereas the triglyceride (TG) level was significantly higher (P = 0.007). CONCLUSION: An APOB SNP, rs1042034, is closely associated with HCV infection through lipid metabolism alteration. The minor allele AA genotype might contribute to facilitating serum LDL uptake into hepatocytes via LDLR by modifying their affinity and interaction and may have an influence on HCV infection by their entry to the liver through the LDLR.

Poly-(ADP-Ribose) Polymerase-1 Promotes Prothrombin Gene Transcription and Produces Des-Gamma-Carboxy Prothrombin in Hepatocellular Carcinoma.

BACKGROUND AND AIM: Although des-gamma-carboxy prothrombin (DCP) is a well-known tumor marker for hepatocellular carcinoma (HCC), the mechanism of DCP production is unclear. This study aimed to investigate the mechanism how DCP is produced in HCC cells. METHODS: Levels of mRNA and DCP were analyzed by real-time polymerase chain reaction and electro-chemiluminescence immunoassay respectively. Secreted alkaline phosphatase (SEAP) expression vectors including deletion mutants of the prothrombin gene promoter were constructed for reporter gene assay. The transcription factors bound to DNA fragments were analyzed by mass spectrometry. An electrophoretic mobility shift assay (EMSA) was performed using a biotin end-labeled DNA. RESULTS: The prothrombin mRNA levels in all 5 DCP producing cell lines were appreciably high. However, those in 2 DCP non-producing cell lines were below detectable levels. A SEAP vector with -2985 to +27 showed a very high transcription activity in DCP-producing Huh-1 cells. However, transcription abruptly decreased when the vector with -2955 to +27 was transfected, and then remained at the similar levels with larger deletion mutants, indicating the existence of a cis-element at -2985 to -2955 (31-bp). Mass spectrometry analysis identified the protein that bound to the 31-bp DNA as poly-(ADP-ribose) polymerase-1 (PARP-1). Knockdown of the PARP-1 gene by small interfering RNA in Huh-1 cells induced marked inhibition of prothrombin gene transcription. The EMSA clearly showed that PARP-1 specifically binds to the 31-bp DNA fragment in the prothrombin gene promoter. CONCLUSIONS: Our data suggest that PARP-1 activates prothrombin gene transcription and that the excessive prothrombin gene transcription induces DCP production in DCP-producing HCC cells.

Influence of light alcohol consumption on lifestyle-related diseases: a predictor of fatty liver with liver enzyme elevation in Japanese females with metabolic syndrome.

BACKGROUND: Although heavy drinking is known to lead to liver injury, some recent studies have reported that light alcohol consumption (LAC) may play a protective role against fatty liver in the general population, and may even play a protective role against non-alcoholic fatty liver disease (NAFLD) in males with metabolic syndrome (MS). However, the association between LAC and fatty liver with liver enzyme elevation in females with MS is unclear. METHODS: Participants of this study were 20,853 females who underwent a regular health check-up between April 2008 and March 2012 at our hospital. Enrolled subjects were 1141 females with MS, who underwent all necessary tests and drank less than 20 g/day of alcohol. We investigated the presence of fatty liver with liver enzyme elevation, defined in this study as alanine aminotransferase (ALT) levels ≧31 IU/I, and the association between LAC and fatty liver with ALT elevation. RESULTS: There was no significant difference in the prevalence of fatty liver and ALT between light drinkers and non-drinkers. The prevalence of individuals receiving a treatment for dyslipidemia and impaired glucose tolerance (IGT) was significantly lower in light drinkers than in non-drinkers. Body mass index (BMI), waist circumference (WC), diastolic blood pressure (DBP), triglyceride (TG), uric acid (UA), IGT, and visceral fat type MS (V-type MS) were significant predictors of the prevalence of fatty liver with ALT elevation in logistic regression analysis. The odds ratio [OR] (95 % confidence interval [CI], p value) for fatty liver with ALT elevation were as follows: BMI, 2.181 (1.445-3.293, p <0.001); WC, 1.853 (1.280-2.684, p <0.01); DBP, 1.604 (1.120-2.298, p <0.05); TG, 2.202 (1.562-3.105, p <0.001); UA, 2.959 (1.537-5.698, p <0.01); IGT, 1.692 (1.143-2.506, p <0.01); and V-type MS, 3.708 (2.529-5.437, p <0.001). CONCLUSIONS: There was no significant difference in the prevalence of fatty liver with ALT elevation in females with MS between light drinkers and non-drinkers, suggesting that other factors such as BMI, WC, V-type MS, and lifestyle-related disease may be more important than LAC for the prevalence of fatty liver with ALT elevation.

Light alcohol consumption plays a protective role against non-alcoholic fatty liver disease in Japanese men with metabolic syndrome.

BACKGROUND & AIMS: Although excess alcohol consumption has been believed to cause liver injury, light alcohol consumption (LAC) has been reported to play a protective role against fatty liver in recent studies. However, the association between non-alcoholic fatty liver disease (NAFLD) and LAC in men with metabolic syndrome (MS) is unclear. The aim of this study was to examine the association between NAFLD and LAC in men with MS. METHODS: Subjects were 1055 men with MS who underwent a regular health check-up and drank less 20 g/day of alcohol. A distinction was made between non-drinkers and light drinkers and the association between NAFLD and LAC in men with MS was elucidated. NAFLD was referred as fatty liver with alanine aminotransferase (ALT) levels ≧31 IU/L in this study. RESULTS: Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and the prevalence of NAFLD were significantly lower in light drinkers than in non-drinkers. Logistic regression analysis showed body mass index (BMI), waist circumference (WC), uric acid (UA), haemoglobin A1c (HbA1c), visceral fat type MS and LAC (odds ratios: 0.654; 95% confidence intervals: 0.473-0.906; <0.05) were significant predictors of the prevalence of NAFLD. CONCLUSION: The prevalence of NAFLD in light drinkers was significantly lower than in non-drinkers, and supporting previous reports studying the general population, LAC is one of the significant predictors of a decreased prevalence of NAFLD in men with MS.

Serum diamine oxidase activity as a predictor of gastrointestinal toxicity and malnutrition due to anticancer drugs.

BACKGROUND AND AIM: Objective evaluation of intestinal mucosal damage due to anticancer drugs is generally difficult. Serum diamine oxidase (DAO) activity is reported to reflect the integrity and maturity of the small intestinal mucosa. Therefore, we investigated whether serum DAO activity is an indicator of gastrointestinal toxicity or nutritional status in patients receiving chemotherapy. METHODS: We prospectively enrolled 20 patients with unresectable metastatic gastric cancer who received oral S-1 (80 mg/m(2) ) on days 1-14, and intravenous cisplatin (60 mg/m(2) ) and docetaxel (50 mg/m(2) ) on day 8 every 3 weeks. Serum DAO activity was measured by colorimetry. Gastrointestinal toxicity was evaluated by Common Toxicity Criteria for Adverse Events version 4.0. Endoscopic examination and biopsy of duodenal mucosa assessed mucosal damage. Malnutrition was evaluated by measuring serum total protein and albumin levels. RESULTS: Serum DAO activity decreased step-by-step significantly during anticancer drug treatment and recovered after drug holidays. In all 14 patients who experienced diarrhea, serum DAO activity significantly decreased prior to diarrhea onset. Percent decrease in DAO activity was significantly correlated with severity of diarrhea. Significant correlation was observed between percent decrease in DAO activity and percent decrease in duodenal villus height or surface area from baseline. There were also significant correlations between percent decrease in serum DAO activity at day 14 and percent decrease in serum total protein or albumin levels at day 21 from baseline. CONCLUSION: Serum DAO activity sensitively indicates gastrointestinal damage prior to symptom onset and can be a useful predictor of intestinal mucosal damage and nutritional status in patients receiving chemotherapy.

Acanthopanax senticosus ameliorates steatohepatitis through HNF4 alpha pathway activation in mice.

Non-alcoholic fatty liver disease is a common liver disease worldwide, and is associated with dysregulation of lipid metabolism, leading to inflammation and fibrosis. Acanthopanax senticosus Harms (ASH) is widely used in traditional medicine as an adaptogen food. We examined the effect of ASH on steatohepatitis using a high-fat diet mouse model. Mice were fed a choline-deficient, L-amino acid-defined, high-fat diet with ASH extract (ASHE). After 6 weeks, liver RNA transcriptome sequencing (RNA-Seq) was performed, followed by Ingenuity Pathway Analysis (IPA). Our findings revealed that mice fed a high-fat diet with 5% ASHE exhibited significantly reduced liver steatosis. These mice also demonstrated alleviated inflammation and reduced fibrosis in the liver. IPA of RNA-Seq indicated that hepatocyte nuclear factor 4 alpha (HNF4 alpha), a transcription factor, was the activated upstream regulator (P-value 0.00155, z score = 2.413) in the liver of ASHE-fed mice. Adenosine triphosphate binding cassette transporter 8 and carboxylesterase 2, downstream targets of HNF4 alpha pathway, were upregulated. Finally, ASHE-treated HepG2 cells exposed to palmitate exhibited significantly decreased lipid droplet contents. Our study provides that ASHE can activate HNF4 alpha pathway and promote fat secretion from hepatocytes, thereby serving as a prophylactic treatment for steatohepatitis in mice.

Skill Proficiency, Efficacy, and Safety of the Transradial Approach in Transarterial Treatments for Hepatocellular Carcinoma.

Introduction Abdominal angiography procedures such as transarterial chemoembolization (TACE) are essential for hepatocellular carcinoma treatment. One method commonly used is transfemoral access (TFA). However, issues associated with this method, which include postoperative compression of the puncture site and long periods of bed rest, can affect patient satisfaction. Thus, transradial access (TRA), a minimally invasive treatment method that improves treatment quality, was developed for TACE. This retrospective, multicenter study aimed to investigate the efficacy and safety of abdominal angiography using the radial artery approach. Methods In total, 1,601 patients underwent abdominal angiography using TRA and received treatment (radial access for visceral intervention (RAVI)) at 14 institutions in Japan. The treatment time, procedure completion rate, patient satisfaction, and complications were investigated. Results The success rate of RAVI was 99.4%, and the complication rate was 1.2%. Approximately 98.2% of the patients requested the radial artery approach again. There were no significant differences in the success rate of RAVI and the incidence of complications based on the operator's years of experience or the patient's age. Some patients developed minor complications such as puncture site bleeding, hematoma, vascular pain, and vasospasm. Further, serious complications (cerebral infarction (n = 1), cerebellar infarction (n = 1), and aortic dissection (n = 1)) were observed. Conclusion Similar to the conventional TFA, RAVI helped in facilitating peritoneal angiography safely. In abdominal angiography, this method can reduce patient burden and can be widely used in the future from the perspective of clinical benefit.

Association of variabilities in body mass index and waist circumference with newly achieved remission of metabolic dysfunction-associated fatty liver disease.

AIMS: Although body weight reduction is recommended to ameliorate nonalcoholic fatty liver disease, the effects of body mass index (BMI) and waist circumference (WC) variability on newly achieved remission of metabolic dysfunction-associated fatty liver disease (MAFLD) remain unclear. We aimed to investigate the longitudinal association between BMI and WC variabilities and newly achieved MAFLD remission in both sexes. METHODS: Among 26,952 patients, 1823 with MAFLD diagnosed by ultrasonography and with >2 health checkups over >2 years from April 2014 to March 2021 were included in this observational cohort study. A generalized estimation equation model analyzed the association between BMI and WC and newly achieved MAFLD remission according to repeated measures at baseline and the most recent stage. RESULTS: Rates of MAFLD remission in male and female patients were 7.4 % and 6.0 %, respectively. Regarding decreased BMI variability, newly achieved MAFLD remission prevalence among the subgroups differed significantly between sexes (p < 0.001). In male patients, a decrease in BMI variability of ≥1.5 kg/m2 and WC variability of ≥4.2 cm had adjusted odds ratios (ORs) of 5.215 and 2.820, respectively, for newly achieved MAFLD remission. Among female patients, regular exercise and breakfast consumption were accelerating factors for newly achieved MAFLD remission. Non-invasive liver fibrosis scores significantly differed between MAFLD and newly achieved MAFLD remission, including in the subgroups (p < 0.01 and p < 0.001, respectively). CONCLUSIONS: Reducing BMI and WC variabilities in male patients and improving lifestyle habits in female patients may accelerate MAFLD remission.

Novel des-γ-carboxy prothrombin in serum for the diagnosis of hepatocellular carcinoma.

BACKGROUND AND AIM: Serum des-γ-carboxy prothrombin (DCP) levels using a newly developed electrochemiluminescence immunoassay (ECLIA, novel DCP [NX-DCP]) were measured, and the utility of NX-DCP and DCP/NX-DCP ratio for the diagnosis of hepatocellular carcinoma (HCC) was investigated. Antigenic differences in DCP between HCC and non-HCC patients were elucidated. METHODS: The subjects included 170 patients with HCC, 61 with benign liver disease, 12 with obstructive jaundice, and 10 warfarin users. NX-DCP was quantitated by sandwich ECLIA employing novel anti-DCP monoclonal antibodies, P11 and P16. Conventional DCP was quantitated by standard ECLIA. DCP extracted from serum by affinity-chromatography was analyzed by Western blotting. RESULTS: Conventional serum DCP levels were high in patients with HCC and obstructive jaundice, and in warfarin users, consistent with previous reports. Serum NX-DCP levels were high only in warfarin users and obstructive jaundice patients (vitamin K-deficient patients) but not in HCC patients. The DCP/NX-DCP ratio was significantly higher in the HCC group than in the benign liver disease, obstructive jaundice, and warfarin groups (P < 0.001). Receiver operating characteristic analysis showed significant superiority of the DCP/NX-DCP ratio over conventional DCP as a marker for HCC diagnosis (P < 0.05). Western blot analysis showed that P11 and P16 reacted strongly with DCP from a warfarin user and an obstructive jaundice patient but very faintly with DCP from an HCC patient. Immunohistochemistry on HCC samples and autopsied normal liver tissues from warfarin users showed similar results. CONCLUSIONS: The DCP/NX-DCP ratio is very useful for diagnosing HCC. DCP in HCC patients is distinct from that in vitamin K-deficient patients.

A case of complete response with rechallenge-lenvatinib plus transcatheter arterial chemoembolization for unresectable hepatocellular carcinoma refractory to multiple molecular-targeted agent treatments.

The efficacy of lenvatinib (LEN) plus transcatheter arterial chemoembolization (LEN-TACE) has been reported, but its effect on unresectable hepatocellular carcinoma (HCC) refractory to LEN therapy has not been demonstrated. We report a case of HCC refractory to multiple molecular-targeted agents (MTA) treatments, including LEN, that was successfully treated with LEN-TACE. A 59-year-old man was referred to our department with multiple HCCs and a background of hepatitis B virus infection. TACE was the initial treatment. However, he was determined to be TACE-refractory, and multitargeted therapy was initiated. LEN was started at 12 mg/day but resulted in progressive disease (PD) after 13 months of the administration. The response to second-line sorafenib was PD after 2 months. Third-line therapy with atezolizumab + bevacizumab was stopped after one course because of an immune-related adverse event (i.e., dermatitis). The response to fourth-line regorafenib was PD at 2 months, and the response to fifth-line cabozantinib was PD after 6 months. The efficacy of LEN-TACE was recently reported; therefore, we decided to attempt LEN-TACE therapy as a salvage line. After obtaining the patient's consent to repeat LEN and TACE, treatment was initiated. The tumor markers levels markedly reduced after LEN-TACE therapy. After three additional TACE treatments with continued LEN administration, the tumor marker levels normalized, and complete response was determined based on RECIST guidelines. LEN-TACE therapy may effectively treat unresectable advanced HCC in the LEN-rechallenge setting and may be a treatment option as a last-line therapeutic option.

Initial therapeutic results of atezolizumab plus bevacizumab for unresectable advanced hepatocellular carcinoma and the importance of hepatic functional reserve.

AIM: We analyzed the association between the modified albumin-bilirubin (mALBI) grade and therapeutic efficacy of atezolizumab plus bevacizumab (Atezo+Bev) for the treatment of unresectable hepatocellular carcinoma (u-HCC). METHODS: In this retrospective observational study, we included 71 u-HCC patients treated with Atezo+Bev between September 2020 and September 2021. Patients were grouped corresponding to the mALBI grade at the start of treatment (mALBI 1+2a or mALBI 2b+3) and analyzed for therapeutic effect and the transition rate to secondary treatment. RESULTS: According to the Response Evaluation Criteria in Solid Tumors, the overall response rate was significantly higher for the mALBI 1+2a group, than for the mALBI 2b+3 group, with 26.2% and 3.4%, respectively. The progression-free survival (PFS) was significantly longer in the mALBI 1+2a group (10.5 months) than in the mALBI 2b+3 group (3.0 months). In the multivariate analysis, an mALBI of 1+2a was found to be an independent factor of PFS. The rate of second-line treatment with multi-targeted agents was also significantly higher in the mALBI 1+2a group. CONCLUSIONS: In real-world practice, Atezo+Bev treatment might have higher therapeutic efficacy in u-HCC patients with mALBI 1+2a.

Clinical Features and Outcomes of Conversion Therapy in Patients with Unresectable Hepatocellular Carcinoma.

This retrospective multicenter study analyzed 244 patients with unresectable hepatocellular carcinoma treated with lenvatinib (LEN) and atezolizumab + bevacizumab (Atezo + Bev) to examine the characteristics, treatment courses, and prognoses. The cases of patients who could achieve HCC downstaging from Barcelona Clinic Liver Cancer (BCLC) stage B or C to A or zero indicated the need for conversion therapy. The patients' prognoses with and without conversion therapy were compared. Of the 244 patients, 12 (4.9%) underwent conversion therapy, six out of 131 (4.6%) were treated with LEN, and six out of 113 (5.3%) were treated with Atezo + Bev. Eleven patients (91.7%) with a modified albumin bilirubin (mALBI) grade 1 or 2a and BCLC-B stage showed significantly higher rates of transition during conversion therapy (p < 0.05). The patients undergoing conversion therapy had a significantly longer median overall survival rate than those receiving chemotherapy alone (1208 [1064-NA] vs. 569 [466-704] days, p < 0.01). A comparison of the patients who achieved a partial response with and without conversion was evaluated using propensity score matching to reduce the confounding factors, showing a significant survival benefit in the conversion group (1208 [1064-NA] vs. 665 days, p < 0.01). Among the patients with u-HCC who were treated with LEN and Atezo + Bev, those with mALBI 1 + 2a and BCLC-B were likely to achieve conversion therapy with downstaging.