Publications by authors named "Satoru Kakizaki"

187 Publications

Simple Scoring System for Predicting TACE Unsuitable among Intermediate-Stage Hepatocellular Carcinoma Patients in the Multiple Systemic Treatment Era.

Oncology 2021 Nov 29:1-9. Epub 2021 Nov 29.

Real-life Practice Experts for HCC (RELPEC) Study Group, Matsuyama, Japan.

Background/aim: With the development of systemic treatment methods for unresectable hepatocellular carcinoma (uHCC), the concept of unsuitable for transcatheter arterial chemoembolization (TACE) has become important. This study aimed to establish a simple predictive scoring system for determining TACE unsuitable status.

Materials/methods: From 1998 to 2015, 196 patients with intermediate-stage uHCC with Child-Pugh A (score 5:6 = 108:88) and given TACE as the initial treatment were enrolled. At the baseline, tumor burden (Milan criteria-out, up-to-7 in/out, and up-to-11 in/out: 0-2 points) and modified albumin-bilirubin grade 1/2a or 2b (0-1 point) were added to determine the score for TACE unsuitable (CITRUS-MICAN score; low <2 and high ≥2). In addition, a previously reported tumor marker (TM) score, in which alpha-fetoprotein (AFP) was ≥100 ng/mL, fucosylated AFP ≥10%, and des-gamma-carboxy prothrombin ≥100 mAU/mL (each 1 point) (total 0, 1, or ≥2 points), was used for additionally evaluating tumor malignancy potential. Prognosis was retrospectively evaluated based on those scores.

Results: Median survival time (MST) was better for low compared to high CITRUS-MICAN score (42.0 vs. 26.4 months) (p = 0.002). A 2-step evaluation using the combination of CITRUS-MICAN and TM scores showed an MST of 43.2 months for low CITRUS-MICAN/TM score 0/1 (rank-A) and 39.6 months for low CITRUS-MICAN/TM score ≥2 (rank-B2), while it was 46.8 months for high CITRUS-MICAN/TM score 0 (rank-B1), 28.8 months for high CITRUS-MICAN/TM score 1 (rank-B2), and 22.8 months for high CITRUS-MICAN/TM score ≥2 (rank-C). For rank-A cases (n = 51), MST was 43.2 months, while it was 46.8 months for rank-B1 (n = 12), 31.2 months for rank-B2 (n = 82), and 22.8 months for rank-C (n = 51) (p = 0.001).

Conclusion: The results showed that rank-C indicates absolute TACE unsuitable status. For rank-A patients, good prognosis with TACE can be expected, while TACE refractoriness status during the clinical course should be carefully evaluated so as to anticipate the appropriate timing for switching to systemic treatment in rank-B1 and -B2 patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000520292DOI Listing
November 2021

A case of conversion hepatectomy for huge ruptured hepatocellular carcinoma after transarterial embolization and lenvatinib therapy.

Clin J Gastroenterol 2021 Nov 22. Epub 2021 Nov 22.

Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, 36 Takamatsu-cho, Takasaki, Gunma, 370-0829, Japan.

We herein report a successfully treated case of huge ruptured hepatocellular carcinoma (HCC) by conversion hepatectomy after transarterial embolization (TAE) and lenvatinib therapy. A 33-year-old male patient with right hypochondralgia and liver tumor was referred to our hospital. He had a history of surgery for heart malformation. The tumor at the right lobe was 15 cm in diameter with bloody ascites. Right atrial thrombus 4.5 cm in diameter and marked cardiac dilatation were observed. TAE with ethanol suspended in lipiodol and gelatin sponge achieved hemostasis of the ruptured HCC. Although viable HCC remained after TAE, surgical treatment was abandoned because of abdominal wall invasion and his heart function. Lenvatinib and rivaroxaban were then initiated for HCC and atrial thrombus, respectively. Lenvatinib treatment resulted in a reduction in tumor marker levels and the tumor size. First, we planned conversion hepatectomy after 5 months of lenvatinib. However, recurrence of atrial thrombus prompted us to put off the surgery, and lenvatinib was re-administered. After improvement of atrial thrombus, we finally performed conversion hepatectomy 10 months after starting lenvatinib administration. The tumor was completely removed by combined resection of the diaphragm, and the patient has been doing well without any signs of recurrence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12328-021-01558-5DOI Listing
November 2021

Early experience of atezolizumab plus bevacizumab treatment for unresectable hepatocellular carcinoma BCLC-B stage patients classified as beyond up to seven criteria - Multicenter analysis.

Hepatol Res 2021 Nov 19. Epub 2021 Nov 19.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan.

Background/aim: Although systemic therapy is recommended for patients with multiple intermediate stage unresectable hepatocellular carcinoma (u-HCC) classified as beyond the up-to-7 criteria (UT-7 out/multiple) as a transcatheter arterial chemoembolization (TACE) unsuitable condition, few reports have examined the therapeutic efficacy of atezolizumab plus bevacizumab combination therapy (Atez/Bev) in such cases. This study aimed to elucidate the therapeutic response of Atez/Bev in u-HCC patients classified as UT-7 out/multiple.

Material/methods: From September 2020 to September 2021, 95 u-HCC Japanese patients classified as UT-7 out/multiple/Child-Pugh A were enrolled from 21 institutions (median age 76 years, males 73, Child-Pugh 5:6 = 68:27, TNM stage II:III = 17:78). Therapeutic response was retrospectively evaluated using Response Evaluation Criteria in Solid Tumors (RECIST), ver. 1.1 and modified RECIST (mRECIST).

Results: Atez/Bev was given as first-line treatment to 52 (54.7%). Objective response rate (ORR)/disease control rate (DCR) at six weeks of RECIST and mRECIST were 17.7%/84.7% and 42.5%/86.2%, respectively. Median PFS was 8.0 months (median observation period: 6.0 months). Child-Pugh A/modified Albumin-bilirubin grade (mALBI) 1 and 2a at baseline, 3, 6, and 9 weeks, were 100%/69.4%, 89.8%/57.3%, 94.8%/65.3%, and 91.4%/60.0%, respectively. Among adverse events (any-grade, >10%) during the present observation period, general fatigue was most frequent (23.2%), followed by urine protein (21.1%), appetite loss (20.0%), and hypertension (13.7%).

Conclusion: Atez/Bev treatment showed favorable therapeutic response with less influence on hepatic function, suggesting it as a useful therapeutic option for patients with such condition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/hepr.13734DOI Listing
November 2021

Androgen receptor phosphorylated at Ser815: The expression and function in the prostate and tumor-derived cells.

Biochem Pharmacol 2021 Dec 26;194:114794. Epub 2021 Oct 26.

Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan; Department of Clinical Research, National Hospital Organization Takasaki General Medical Center, Takasaki, Gunma 370-0829, Japan.

Androgen is beneficial for the prostate with normal functions but creates a risk for prostate cancer progression. How androgen receptor (AR) mediates these various androgen actions remains elusive. AR conserves a phosphorylation motif within its ligand-binding domain throughout species. Here, we have found AR phosphorylated at Ser815 (P-AR) is expressed in normal tissues of both human and mouse prostates. P-AR begins expression in association with prostatic development and castration decreases its expression levels in the mouse prostate. Functional analysis of AR in prostate cancer PC-3 cells showed ligand-induced AR nuclear translocation and transactivation were disturbed by its phosphorylation at Ser815. Moreover, P-AR suppressed oncogenic AKT signaling suggesting a suppressive function for prostate cancer development. In fact, AR phosphorylation levels progressively decrease in human prostates as cancer worsens. These findings showed androgen might utilize P-AR to self-antagonize oncogenic signals and cancer progression believed to be regulated by non-phosphorylated AR (NonP-AR). By differing its target genes and signal regulations from those of NonP-AR, P-AR co-expression with NonP-AR may be the molecular basis for androgen to balance its actions and to control disease developments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bcp.2021.114794DOI Listing
December 2021

Successful treatment of Japanese hemophilia patient co-infected with HIV and HCV genotype 4a by glecaprevir/pibrentasvir therapy.

Clin J Gastroenterol 2021 Dec 19;14(6):1725-1732. Epub 2021 Oct 19.

Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, 329-0498, Japan.

Although direct-acting antiviral (DAA)-based anti-hepatitis C virus (HCV) therapies are very effective for patients with genotypes 1 and 2, evidence of the efficacy of DAA-based therapy for the special population of patients with genotypes 3-6 is insufficient due to the relatively small number of these subjects in Japan. Human immunodeficiency virus (HIV)/HCV-co-infected patients are recommended to be treated as HCV-mono-infected patients by the latest version of the Japan Society of Hepatology guidelines. However, evidence of efficacy in patients with HIV/HCV genotype 3-6 co-infection is insufficient. Currently, HCV genotypes 3-6 can be treated with two DAA-based therapies, including glecaprevir (GLE)/pibrentasvir (PIB) therapy in Japan. We experienced a relatively rare case of a Japanese hemophilia patient co-infected with HIV/HCV genotype 4a. We evaluated resistance-associated substitutions (RASs) against GLE and PIB before GLE/PIB therapy and found that he had no RASs. He was treated with 12 weeks of GLE/PIB therapy and achieved a sustained virologic response at post-treatment weeks 24. Although the treatment was well tolerated, the patient developed hyper-low-density lipoproteinemia that was probably associated with HCV elimination during the therapy. Additional studies are needed to confirm the efficacy and safety of GLE/PIB therapy for this special population in Japan.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12328-021-01524-1DOI Listing
December 2021

Non-obese non-alcoholic fatty liver disease (NAFLD) in Asia: an international registry study.

Metabolism 2022 Jan 12;126:154911. Epub 2021 Oct 12.

Division of Gastroenterology and Hepatology, National University Health System, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Electronic address:

Background: A significant proportion of the non-alcoholic fatty liver disease (NAFLD) population is non-obese. Prior studies reporting the severity of NAFLD amongst non-obese patients were heterogenous. Our study, using data from the largest biopsy-proven NAFLD international registry within Asia, aims to characterize the demographic, metabolic and histological differences between non-obese and obese NAFLD patients.

Methods: 1812 biopsy-proven NAFLD patients across nine countries in Asia assessed between 2006 and 2019 were pooled into a curated clinical registry. Demographic, metabolic and histological differences between non-obese and obese NAFLD patients were evaluated. The performance of Fibrosis-4 index for liver fibrosis (FIB-4) and NAFLD fibrosis score (NFS) to identify advanced liver disease across the varying obesity subgroups was compared. A random forest analysis was performed to identify novel predictors of fibrosis and steatohepatitis in non-obese patients.

Findings: One-fifth (21.6%) of NAFLD patients were non-obese. Non-obese NAFLD patients had lower proportions of NASH (50.5% vs 56.5%, p = 0.033) and advanced fibrosis (14.0% vs 18.7%, p = 0.033). Metabolic syndrome in non-obese individuals was associated with NASH (OR 1.59, 95% CI 1.01-2.54, p = 0.047) and advanced fibrosis (OR 1.88, 95% CI 0.99-3.54, p = 0.051). FIB-4 performed better than the NFS score (AUROC 81.5% vs 73.7%, p < 0.001) when classifying patients with F2-4 fibrosis amongst non-obese NAFLD patients. Haemoglobin, GGT, waist circumference and cholesterol are additional variables found on random forest analysis useful for identifying non-obese NAFLD patients with advanced liver disease.

Conclusion: A substantial proportion of non-obese NAFLD patients has NASH or advanced fibrosis. FIB-4, compared to NFS better identifies non-obese NAFLD patients with advanced liver disease. Serum GGT, cholesterol, haemoglobin and waist circumference, which are neither components of NFS nor FIB-4, are important biomarkers for advanced liver disease in non-obese patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.metabol.2021.154911DOI Listing
January 2022

Effect of 48-week pemafibrate on non-alcoholic fatty liver disease with hypertriglyceridemia, as evaluated by the FibroScan-aspartate aminotransferase score.

JGH Open 2021 Oct 28;5(10):1183-1189. Epub 2021 Aug 28.

Department of Gastroenterology and Hepatology Gunma University Graduate School of Medicine Maebashi Japan.

Background And Aim: This retrospective study investigated the effect of 48-week pemafibrate therapy in non-alcoholic fatty liver disease (NAFLD) with hypertriglyceridemia, as evaluated by the FibroScan-aspartate aminotransferase (FAST) score.

Methods: A total of 31 NAFLD patients who were treated with pemafibrate in Gunma Saiseikai Maebashi Hospital and Kusunoki Hospital from September 2018 to April 2020 were included in the current study. We used the FAST score, which is a novel index of steatohepatitis that can be calculated based on the AST value, controlled attenuation parameter (CAP), and liver stiffness measurement (LSM), to evaluate the effect of pemafibrate treatment.

Results: The median age was 64.0 (interquartile range [IQR] 55.0-75.0) years and 14 patients (45.2%) were male. Median body mass index was 26.8 (IQR 23.8-28.8). Hypertension and diabetes mellitus were detected in 14 (45.2%) and five (16.1%) patients, respectively. Fasting triglyceride and high-density lipoprotein cholesterol were significantly improved ( < 0.001 and 0.013, respectively) and the AST, alanine aminotransferase (ALT), alkaline phosphatase, and γ-glutamyl transpeptidase values were significantly decreased during pemafibrate treatment ( = 0.041, <0.001, <0.001, and <0.001, respectively). While the LSM value and CAP value did not differ to a statistically significant extent ( = 0.19 and 0.140, respectively), the FAST score was significantly improved during pemafibrate treatment ( = 0.029). The delta FAST score was found to be correlated with the variations of ALT (r = 0.504,  = 0.005), which represents the effect of pemafibrate.

Conclusions: Pemafibrate improved the FAST score due to the hepatic anti-inflammatory effect, indicating that pemafibrate may prevent disease progression in NAFLD patients with hypertriglyceridemia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jgh3.12650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8485409PMC
October 2021

Follow-up after Direct-acting Antiviral Treatment for Chronic Hepatitis C Virus Infection: Most Patients Are Followed Appropriately.

Intern Med 2021 1;60(19):3061-3070. Epub 2021 Oct 1.

Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Japan.

Objective Chronic hepatitis C virus (HCV) infection carries a residual risk of hepatocarcinogenesis even after viral elimination, so appropriate follow-up is necessary. The present study investigated the current hospital visits and hepatocarcinogenesis status of patients who received daclatasvir plus asunaprevir treatment (DCV+ASV) to determine whether or not appropriate follow-up was being performed. Methods We retrospectively analyzed hepatocarcinogenesis, the overall survival, and the length of hospital visits in 442 patients who applied for the medical expense subsidy system for viral hepatitis and received DCV+ASV treatment in Gunma Prefecture between October 2014 and December 2015. This also included 61 patients who had a history of hepatocellular carcinoma (HCC). Results Among 442 patients, 388 achieved a sustained viral response (SVR) by DCV+ASV therapy (87.8%), and 95.9% achieved an SVR if additional treatment was included. HCC was found in 75 cases (17.0%). A history of HCC, the FIB-4 index and the treatment effect SVR were determined to be factors affecting the incidence of HCC. Regarding the follow-up rate, 89.9% of patients continued to regularly visit the hospital after 5 years of treatment. However, patients ≤60 years old had significantly lower persistence rates than older patients. The persistence rate of hospital visits to the same institution was 67.7% over a 5-year period, which was significantly better in small and medium-sized institutions than in large, specialized institutions (71.7% vs. 63.9%, p=0.039). Conclusion Patients with direct-acting antiviral treatment generally received adequate follow-up, but younger patients had a slightly higher rate of follow-up interruption and were considered to need support.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2169/internalmedicine.6591-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8545640PMC
October 2021

Guillain-Barré syndrome after SARS-CoV-2 infection.

J Gen Fam Med 2021 Jul 9. Epub 2021 Jul 9.

Department of Clinical Research National Hospital Organization Takasaki General Medical Center Takasaki Japan.

We herein report a case of Guillain-Barré syndrome (GBS) after SARS-CoV-2 infection. The patient was a close contact with a SARS-CoV-2 patient. Initially, she did not have any symptoms and quarantined at a hotel. Dysgeusia and olfactory abnormality appeared at day 6 after testing positive for infection and disappeared by day 9. Subsequently, the patient developed numbness of the arms and legs, difficulty walking, and dyspnea and was referred to our hospital. Her clinical examination showed generalized weakness and hyporeflexia. A cerebrospinal fluid analysis showed albuminocytological dissociation. Her nerve conduction studies were consistent with demyelinating polyneuropathy. Intravenous immunoglobulin was administered based on a diagnosis of GBS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jgf2.481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426991PMC
July 2021

Lenvatinib for Hepatocellular Carcinoma Patients with Nonviral Infection Who Were Unlikely to Respond to Immunotherapy: A Retrospective, Comparative Study.

Oncology 2021 10;99(10):641-651. Epub 2021 Aug 10.

Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Maebashi, Japan.

Aim: Atezolizumab plus bevacizumab (atezo + bev) shows a good overall survival (OS) in advanced hepatocellular carcinoma (HCC) patients. However, the OS of patients with nonviral infection is quite worse than that in those with viral infection. The present study investigated the efficacy and safety of lenvatinib in patients with nonviral infection, who were unlikely to obtain benefit from atezo + bev.

Methods: We conducted a multicenter retrospective study that included 139 advanced HCC patients treated with lenvatinib between March 2018 and September 2020.

Results: The median age was 72 years, and 116 patients (83.5%) were male. Based on the etiology of liver disease, 84 (60.4%) and 55 patients (39.6%) were assigned to the viral infection and nonviral infection groups, respectively. The significant extents in patient characteristics were not observed in both groups. The objective response rate per mRECIST and progression-free survival (PFS) did not differ significantly between the viral infection and nonviral infection groups (36.0 vs. 33.0%, p = 0.85; and 7.6 vs. 7.5 months, p = 0.94, respectively). The 1-year survival rates were 68.7% (95% confidence interval [CI] 57.7-79.7%) in the viral infection group and 59.5% (95% CI 45.2-73.8%) in the nonviral infection group. The viral infection group was not a significant factor associated with the PFS or OS in a multivariate analysis.

Conclusions: Lenvatinib shows no significant difference in response between patients with and without viral infection. Treatment strategies based on the etiology of liver disease may lead to good clinical outcome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000517494DOI Listing
September 2021

The first reported case of Noonan syndrome complicated with hepatocellular carcinoma.

Clin Case Rep 2021 Jul 9;9(7):e04317. Epub 2021 Jul 9.

Department of Gastroenterology and Hepatology Gunma University Graduate School of Medicine Maebashi Japan.

Noonan syndrome is a genetic multisystem disorder and is associated with mutation of genes encoding the proteins in the RAS-MAPK pathway. We reported the first case of Noonan syndrome complicated with hepatocellular carcinoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ccr3.4317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8271263PMC
July 2021

Impact of M2BPGi on the Hepatocarcinogenesis after the Combination Therapy with Daclatasvir and Asunaprevir for Hepatitis C.

Biomedicines 2021 Jun 8;9(6). Epub 2021 Jun 8.

Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.

The clinical significance of mac-2 binding protein glycosylation isomer (M2BPGi) levels based on virological responses due to antiviral therapy has not been fully evaluated. We compared the change before and 24 weeks after the therapy with daclatasvir and asunaprevir (DCV+ASV) of M2BPGi levels with those of other fibrosis markers in 73 chronic hepatitis C cases. Moreover, we examined the association between M2BPGi levels and hepatocarcinogenesis in sustained virological response (SVR) and non-SVR cases. M2BPGi levels were significantly improved at post-treatment week 24 (PTW24) in SVR but not non-SVR cases, whereas the changes of other fibrosis markers showed the same tendency in both SVR and non-SVR cases. M2BPGi levels were well correlated with other fibrosis markers at baseline but not PTW24. The incidence of hepatocellular carcinoma (HCC) was significantly associated with M2BPGi levels at PTW24. The achievement of SVR significantly affected the improvement of M2BPGi levels that best reflected the effect of direct-acting antivirals among the fibrosis markers. Furthermore, M2BPGi levels at PTW24 were also associated with the incidence of HCC in only SVR cases. However, the rapid decrease of M2BPGi levels might reflect the amelioration of liver inflammation rather than the improvement of liver fibrosis, which should be further elucidated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/biomedicines9060660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8227298PMC
June 2021

Nutritional intervention after an early assessment by a flexible endoscopic evaluation of swallowing is associated with a shorter hospital stay for patients with acute cerebral infarction: A retrospective study.

Asia Pac J Clin Nutr 2021 Jun;30(2):199-205

Nutrition Support Team, National Hospital Organization Takasaki General Medical Center, Takasaki, Gunma, Japan. Email:

Background And Objectives: It is important to evaluate the swallowing function of patients with acute cerebral infarction. The effects of nutritional intervention after an early assessment by a flexible endoscopic evaluation of swallowing (FEES) were evaluated.

Methods And Study Design: This retrospective study included 274 patients who were hospitalized for acute cerebral infarction and underwent a FEES between 2016 and 2018. The effects of early nutritional intervention after an assessment by a FEES within 48 h from admission were evaluated. The patients were divided into a shorter hospital stay group (<30 days) and a longer group (≥30 days). A multivariate analysis was performed to identify the predictive factors for a shorter hospital stay.

Results: The overall patient characteristics were as follows: 166 men; median age, 81 years old; and median body mass index (BMI), 21.1 kg/m2. No significant differences in the age, sex, or BMI were found between the shorter and longer hospital stay groups. A FEES within 48 h of admission (odds ratio [OR], 2.040; 95% confidence interval [CI], 1.120-3.700; p=0.019), FILS level ≥6 at admission (OR, 2.300; 95% CI, 1.190-4.440; p=0.013), and an administered energy dose of ≥18.5 kcal/kg on hospital day 3 (OR, 2.360; 95% CI, 1.180-4.690; p=0.015) were independently associated with a hospital stay <30 days.

Conclusions: Patients with acute cerebral infarction are more likely to have a shorter hospital stay (<30 days) if they undergo a FEES early after admission and receive optimal nutritional intervention.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.6133/apjcn.202106_30(2).0003DOI Listing
June 2021

An Autopsy Case of Multicentric Castleman Disease Presenting with Severe Jaundice.

Intern Med 2021 Nov 5;60(22):3615-3620. Epub 2021 Jun 5.

¹Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Japan.

A 70-year-old man with multicentric Castleman disease (MCD) was admitted to our hospital with jaundice and ascites. Elevations in his bilirubin and interleukin-6 levels were noted, and computed tomography revealed hepatic atrophy and portal vein and bile duct disorders. Steroid therapy was started for MCD, but he died of hepatic failure. An autopsy revealed that the MCD activity was mild, but advanced fibrosis and cholestasis were observed in the liver. Mild infiltration of interleukin-6-positive plasma cells was noted in the highly fibrotic area of the liver. Although rare, liver and biliary tract damage may be also considered organ disorders of MCD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2169/internalmedicine.6835-20DOI Listing
November 2021

Efficacy of Zinc Acetate Treatment for Patients with Decompensated Liver Cirrhosis Complicated by Hypozincemia.

Biol Trace Elem Res 2021 Apr 29. Epub 2021 Apr 29.

Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Maebashi, Japan.

The aim of this study was to evaluate the efficacy of zinc acetate treatment for patients with decompensated liver cirrhosis complicated by hypozincemia. We retrospectively analyzed 49 patients with decompensated liver cirrhosis complicated by hypozincemia who received zinc acetate treatment from August 2017 to March 2020. The relationships between serum zinc levels and several parameters including the prognosis, sarcopenia, and immunity were evaluated. Serum zinc levels measured at 3 months post-treatment and the incidence of adverse events were also determined. The median age was 69.0 years (IQR:59.5-78.8) and the male to female ratio was 29:20. Twenty-seven patients had a Child-Pugh classification of B and 22 had a Child-Pugh classification of C; the median Child-Pugh score was 9.0 (IQR, 8.0-11.0). The median serum zinc levels measured at 3 months post-treatment (74.7 (IQR, 50.0-101.0) μg/dL) were significantly elevated in comparison to the pre-treatment levels (43.0 (IQR, 34.0-51.0) μg/dL, P < 0.0001). The overall survival of patients with pre-treatment serum zinc levels of ≥60 μg/dL was significantly better than that of those with pre-treatment serum zinc levels of <60 μg/dL (P = 0.013). The survival of patients with zinc levels of ≥70 μg/dL at 3 months post-treatment was significantly better than those with levels of <70 μg/dL (P = 0.013). The serum albumin level, Child-Pugh score, albumin-bilirubin (ALBI) score and model for end-stage liver disease (MELD) score were identified as factors predicting a good response at 3 months post-treatment. There were no significant relations between the pretreatment serum zinc levels and skeletal muscle mass, lymphocyte count, and neutrophil lymphocyte ratio. There were no obvious problematic adverse events in patients who received zinc acetate treatment. The patients with higher basal zinc levels and good responders to zinc acetate treatment had a better prognosis. Zinc acetate was useful and safe for patients with decompensated liver cirrhosis complicated by hypozincemia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12011-021-02675-5DOI Listing
April 2021

Therapeutic efficacy of lenvatinib as third-line treatment after regorafenib for unresectable hepatocellular carcinoma progression.

Hepatol Res 2021 Aug 5;51(8):880-889. Epub 2021 May 5.

Department of Gastroenterology, Okayama City Hospital, Okayama, Japan.

Aim: Multiple molecular agents have been developed for treating unresectable hepatocellular carcinoma. This study aimed to elucidate the clinical efficacy of sequential treatment with lenvatinib after regorafenib failure.

Methods: From June 2017 to October 2020, 63 patients with Child-Pugh A and treated with regorafenib followed by sorafenib were enrolled (median age 71 years, 52 men, Barcelona Clinic Liver Cancer B:C = 23:40). They were divided into two groups, those treated with lenvatinib after regorafenib treatment (R-L group, n = 47) and those who did not receive lenvatinib after regorafenib (non-R-L group, n = 16). Prognostic factors were retrospectively analyzed after adjustment with inverse probability weighting.

Results: Serum albumin level at the start of regorafenib and reasons for discontinuation of regorafenib were significantly different between the R-L and non-R-L groups, whereas the albumin-bilirubin score, Child-Pugh class, and tumor burden were not. Progression-free survival was also not significantly different (median 4.1 vs. 3.8 months, p = 0.586). As for overall survival, the R-L group showed better prognosis after introducing regorafenib and after introducing sorafenib, following inverse probability weighting adjustment (MST 19.7 vs. 10.3 months, 33.8 vs. 15.3 months, p < 0.001 and p = 0.022, respectively). Modified albumin-bilirubin grade 2b (score >-2.27) at the start of regorafenib (HR 2.074, p = 0.041) and the presence of lenvatinib treatment after regorafenib failure (HR 0.355, p = 0.004) were found to be significant prognostic factors in Cox proportional hazards multivariate analysis, after inverse probability weighting adjustment.

Conclusion: These results show that lenvatinib is a good sequential treatment option after progression under regorafenib therapy in unresectable hepatocellular carcinoma patients with better hepatic reserve function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/hepr.13644DOI Listing
August 2021

Impact of Pemafibrate in Patients with Hypertriglyceridemia and Metabolic Dysfunction-associated Fatty Liver Disease Pathologically Diagnosed with Non-alcoholic Steatohepatitis: A Retrospective, Single-arm Study.

Intern Med 2021 Jul 22;60(14):2167-2174. Epub 2021 Feb 22.

Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Japan.

Objective The therapeutic effect of pemafibrate on metabolic dysfunction-associated fatty liver disease (MAFLD) remains unknown. This retrospective, single-arm study investigated the efficacy and safety of pemafibrate in MAFLD patients with hypertriglyceridemia. Methods A total of 10 patients who received pemafibrate (oral, 0.1 mg, twice a day) at Gunma Saiseikai Maebashi Hospital between September 2018 and September 2019 were included. All patients underwent a liver biopsy, and the disease grade and stage were pathologically assessed based on the FLIP algorithm. Results The median age was 66.0 (53.8-74.8) years old, and 5 patients (50.0%) were men. All patients were diagnosed with non-alcoholic steatohepatitis (NASH). The fasting and non-fasting triglyceride (TG) levels were 175 (149-247) mg/dL and 228 (169-335) mg/dL, respectively. The AST and ALT values at 6 months were significantly lower than at baseline [AST: 28.0 (22.0-33.8) U/L vs. 43.5 (24.0-55.0) U/L, p=0.008, ALT: 23.0 (14.8-26.5) U/L vs. 51.5 (23.0-65.3) U/L, p=0.005, respectively], especially in NASH patients with significant activity and advanced fibrosis (p=0.040 and 0.014, respectively). Fasting TG levels were significantly lower and HDL-C levels significantly higher at 6 months than at baseline (p=0.005 and 0.032, respectively). At six months, FIB-4, the aspartate aminotransferase-to-platelet ratio index, and the macrophage galactose-specific lectin-2 binding protein glycosylation isomer level were significantly improved compared with baseline (p=0.041, 0.005 and 0.005, respectively). Treatment-related adverse events were not observed. Conclusion Pemafibrate treatment may be safe and effective for MAFLD patients with hypertriglyceridemia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2169/internalmedicine.6574-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8355409PMC
July 2021

Imatinib and nutritional support can make successful treatment for a case of huge liver metastasis of duodenal gastrointestinal stromal tumor that initially showed jaundice and cachexia.

Clin J Gastroenterol 2021 Apr 28;14(2):570-576. Epub 2021 Jan 28.

Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, 36 Takamatsu-cho, Takasaki, Gunma, 370-0829, Japan.

It is very difficult to treat patients with liver metastasis presenting with jaundice or cachexia. We herein report a successfully treated case of huge liver metastasis of gastrointestinal stromal tumor (GIST) that initially showed jaundice and cachexia. The patient was a woman in her early 40 s. She had a history of duodenal GIST 4 years before this admission. She was admitted to our hospital for abdominal fullness and anorexia. Abdominal computed tomography revealed huge liver metastasis of GIST. She showed jaundice and cancer cachexia with a modified Glasgow Prognostic Score of 2. After applying nutritional support, 400 mg of imatinib was administered. Although leg edema transiently worsened, the withdrawal of imatinib and administration of diuretics improved it. Imatinib was re-administered, and nutritional support was continued. The total bilirubin level decreased, and the serum albumin level increased. The tumor gradually decreased in size. Finally, she received surgical resection after 16 months of treatment with imatinib. Although adjuvant imatinib administration was continued after surgery, and no recurrence was observed as of 18 months after surgery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12328-021-01340-7DOI Listing
April 2021

Prognosis of late elderly patients with chronic hepatitis C after achieving a sustained viral response by direct-acting antivirals.

JGH Open 2021 Jan 23;5(1):122-127. Epub 2020 Nov 23.

Department of Gastroenterology and Hepatology Gunma University Graduate School of Medicine Maebashi Japan.

Background And Aim: We investigated the prognosis of late elderly patients (≥75 years old) after the achievement of a sustained viral response (SVR) by direct-acting antivirals (DAAs).

Methods: One hundred and four late elderly patients and 251 young patients (≤74 years old) who had achieved an SVR were included. We compared the cumulative hepatocellular carcinoma (HCC) incidence rates and survival rates after DAA administration. Furthermore, the factors associated with HCC incidence and the causes of death after DAA administration were also investigated.

Results: The cumulative HCC incidence rates for 1 and 3 years were 2.9% and 11.7% in the late elderly patients and 2.4% and 5.4% in the young patients, respectively. The cumulative survival rates for 1 and 3 years were 100% and 95.6% in the late elderly patients and 100% and 96.4% in the young patients, respectively, with no significant differences in those rates noted ( = 0.133, = 0.322, respectively). In the late elderly patients, only a history of HCC was a significant factor associated with HCC incidence after DAA administration. Five late elderly patients died after achieving an SVR, and malignant liver tumor was the cause of death in three of those patients.

Conclusions: The prognosis did not differ markedly between late elderly patients and young patients. The factor most strongly influencing the prognosis of late elderly patients was likely liver disease, including HCC. DAAs should be introduced even in late elderly patients who can be expected to have a relative long-term survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jgh3.12459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812467PMC
January 2021

Lenvatinib for Hepatocellular Carcinoma: A Literature Review.

Pharmaceuticals (Basel) 2021 Jan 6;14(1). Epub 2021 Jan 6.

Department of Clinical Research, National Hospital Organization Takasaki General Medical Center, 36 Takamatsucho, Takasaki, Gunma 370-0829, Japan.

Lenvatinib, which is an oral multikinase inhibitor, showed non-inferiority to the sorafenib in terms of overall survival (OS) and a higher objective response rate (ORR) and better progression-free survival (PFS) in patients with hepatocellular carcinoma (HCC). A good liver function and Barcelona Clinic Liver Cancer (BCLC) intermediate stage were the key factors in achieving therapeutic efficacy. The management of adverse events plays an important role in continuing lenvatinib treatment. While sequential therapies contributed to prolonging overall survival, effective molecular targeted agents for the administration after lenvatinib have not been established. Repeated transcatheter arterial chemoembolization (TACE) was associated with a decline in the liver function and poor therapeutic response in BCLC intermediate patients. Recently, the Asia-Pacific Primary Liver Cancer Expert (APPLE) Consensus Statement proposed the criteria for TACE unsuitability. Upfront systemic therapy may be better for the BCLC intermediate stage HCC patients with a high tumor burden, while selective TACE will be recommended for obtaining a curative response in patients with a low tumor burden. This article reviews the therapeutic response, management of adverse events, post-progression treatment after Lenvatinib, and treatment strategy for BCLC intermediate stage HCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ph14010036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825021PMC
January 2021

The influence of the long-term chemical activation of the nuclear receptor pregnane X receptor (PXR) on liver carcinogenesis in mice.

Arch Toxicol 2021 03 4;95(3):1089-1102. Epub 2021 Jan 4.

Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan.

Pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are nuclear receptors that are highly expressed in the liver and activated by numerous chemicals. While CAR activation by its activators, such as phenobarbital (PB), induces hepatocyte proliferation and liver carcinogenesis in rodents, it remains unclear whether PXR activation drives liver cancer. To investigate the influence of PXR activation on liver carcinogenesis, we treated mice with the PXR activator pregnenolone 16α-carbonitrile (PCN) with or without PB following tumor initiation with diethylnitrosamine (DEN). After 20 weeks of treatment, preneoplastic lesions detected by immunostaining with an anti-KRT8/18 antibody were observed in PB-treated but not PCN-treated mice, and PCN cotreatment augmented the formation of preneoplastic lesions by PB. After 35 weeks of treatment, macroscopic observations indicated that PB-treated and PB/PCN-cotreated mice had increased numbers of liver tumors compared to control and PCN-treated mice. In the pathological analyses of liver sections, all the mice in the PB and PB/PCN groups developed carcinoma and/or eosinophilic adenoma, but in the PB/PCN group, the multiplicity of carcinoma and eosinophilic adenoma was significantly reduced and the size of carcinoma showed a tendency to decrease. No mouse in the control or PCN-treated group developed such tumors. Differentially expressed gene (DEG) and gene set enrichment analyses in combination with RNA sequencing suggested the increased expression of genes related to epithelial-mesenchymal transition (EMT) in mice cotreated with PCN and PB compared to those treated with PB alone. Changes in the hepatic mRNA levels of epithelial marker genes supported the results of the transcriptome analyses. In conclusion, the present results suggest that PXR activation does not promote hepatocarcinogenesis in contrast to CAR and rather attenuates CAR-mediated liver cancer development by suppressing the EMT of liver cancer cells in rodents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00204-020-02955-4DOI Listing
March 2021

Carbon ion radiotherapy for patients with hepatocellular carcinoma in the caudate lobe carbon ion radiotherapy for hepatocellular carcinoma in caudate lobe.

Hepatol Res 2021 Mar 22;51(3):303-312. Epub 2021 Feb 22.

Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.

Aim: The treatment of hepatocellular carcinoma in the caudate lobe (HCCCL) is technically challenging. We aimed to investigate the efficacy and toxicity of carbon ion radiotherapy (C-ion RT) for HCCCL.

Methods: Patients with HCCCL treated with C-ion RT at our hospital between January 2011 and December 2018 were evaluated. The total dose was 52.8 or 60 Gy (relative biological effectiveness) in four or 12 fractions depending on the distance between the tumor and the gastrointestinal tract. The survival outcome, the presence or absence of recurrence (local recurrence, intrahepatic recurrence outside the irradiation field, or extrahepatic recurrence), and acute/late adverse events were evaluated.

Results: Nine patients were included. The median tumor size was 3.4 cm, and the median follow-up duration was 18.3 months for all patients. No patient developed local recurrence during follow-up. Five patients subsequently developed intrahepatic recurrence outside the irradiation field and two had extrahepatic metastasis. Five patients died of hepatocellular carcinoma. No acute adverse events of grade ≥2 were observed. Two patients experienced grade 2 or 3 late adverse events, including obstructive jaundice, hepatic encephalopathy, ascites, and edema.

Conclusion: Carbon ion radiotherapy for HCCCL achieved excellent local control with acceptable adverse events and can thus be a curative treatment option for HCCCL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/hepr.13606DOI Listing
March 2021

The Role of the Albumin-Bilirubin Score for Predicting the Outcomes in Japanese Patients with Advanced Hepatocellular Carcinoma Treated with Ramucirumab: A Real-World Study.

Oncology 2021 4;99(4):203-214. Epub 2020 Dec 4.

Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine​, Maebashi, Japan.

Aim: The aim of this retrospective study was to investigate the efficacy and safety of ramucirumab treatment under real-world conditions and to clarify the role of albumin-bilirubin (ALBI) score in predicting outcomes.

Methods: Between June 2019 and May 2020, a total of 16 patients with advanced hepatocellular carcinoma (HCC) treated with ramucirumab in Gunma Saiseikai Maebashi Hospital and its affiliated hospitals was included.

Results: The median age was 71 (interquartile range [IQR] 65-74) years old, and 12 patients (75.0%) were male. The modified ALBI (mALBI) grade was 1, 2a, and 2b at baseline in 4 (25.0%), 3 (18.8%), and 9 patients (56.3%), respectively. The Barcelona Clinic Liver Cancer stage was intermediate and advanced stage in 1 (6.3%) and 15 patients (93.8%), respectively. The serum α-fetoprotein at baseline was 4,911 (IQR 2,091-17,377) ng/mL. The disease control rate in patients with mALBI grade1 + 2a was significantly higher than in those with mALBI grade 2b (100 vs. 28.6%, p = 0.028). The patients with mALBI grade 1 + 2a had a significantly better overall survival (OS) and longer progression-free survival (PFS) than those with mALBI grade 2b (median OS 6.7 vs. 3.0 months; p = 0.036, median PFS 7.5 vs. 1.4 months; p = 0.002). The number of cycles of ramucirumab treatment was significantly correlated with the ALBI score (r = -0.452, p = 0.030). The patients with mALBI grade 1 + 2a showed a low incidence of adverse events (AEs) and discontinuation due to AEs.

Conclusions: Advanced HCC patients with mALBI grade 1 + 2a may be a good indication for ramucirumab treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000511734DOI Listing
April 2021

The development of broncho-biliary fistula after treatment for hepatocellular carcinoma: a report of two cases.

Clin J Gastroenterol 2021 Feb 24;14(1):229-237. Epub 2020 Oct 24.

Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan.

Broncho-biliary fistula (BBF) is a rare but severe disorder defined as abnormal communication between the biliary system and bronchial tree. Cases of BBF have occasionally been reported, but no standard treatment has been established. We report two cases of BBF that developed after the treatment of hepatocellular carcinoma (HCC) and reviewed the relevant literature. Case 1, a man in his early eighties was diagnosed with BBF 4 months after undergoing surgical resection for HCC (diameter, 7 cm; location, segments 4 and 5). Percutaneous drainage and endoscopic nasobiliary drainage (ENBD) improved BBF without recurrence for more than a year. Case 2, a woman in her late sixties was diagnosed with BBF after percutaneous radiofrequency ablation for HCC. Although the BBF was treated with ENBD, bronchial occlusion, and percutaneous transhepatic portal vein embolization, these treatments were unsuccessful and the patient died. Although non-invasive treatments have been developed, refractory BBF still exists. The prediction of BBF and the development of more effective treatments are necessary to improve outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12328-020-01264-8DOI Listing
February 2021

Successfully Treated Case of Cholangiolocellular Carcinoma with a Poor Hepatic Functional Reserve Reporting with Various Imaging Findings.

Intern Med 2021 Mar 14;60(6):873-881. Epub 2020 Oct 14.

Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Japan.

Cholangiolocellular carcinoma (CoCC) is a rare primary liver cancer that is difficult diagnose due to a lack of specific imaging findings. We herein report a case of CoCC accompanied by severe alcoholic cirrhosis. Dynamic computed tomography showed a low-density tumor with a faint surrounding enhancement. Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging revealed iso-intensity in the hepatobiliary phase and a maximum tumor diameter of 53 mm. F-fluoro-2-deoxyglucose position-emission tomography was moderately positive (maximum standardized uptake value: 4.3). CoCC was diagnosed based on the pathological findings, including immunohistochemistry. We discuss the diagnostic imaging findings and review previous reports.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2169/internalmedicine.5891-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024949PMC
March 2021

Liver Function Changes in Patients with Hepatocellular Carcinoma Treated with Lenvatinib: Predictive Factors of Progression to Child-Pugh Class B, the Formation of Ascites and the Candidates for the Post-Progression Treatment.

Cancers (Basel) 2020 Oct 10;12(10). Epub 2020 Oct 10.

Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, 3-39-15 Showa, Maebashi, Gunma 371-8511, Japan.

The aim of this multicenter retrospective study was to assess the change in liver function in patients with hepatocellular carcinoma treated with lenvatinib. Among 139 consecutive patients receiving lenvatinib treatment between March 2018 and July 2019, 28 patients with Child-Pugh class B and one patient with inadequate patient information were excluded. Remaining 110 patients with Child-Pugh class A were analyzed. The median age of 110 patients was 73 years (IQR 66.7-80) and 88 patients (80.0%) were men. Child-Pugh score was 5 (CP5A) and 6 (CP6A) in 58 (52.7%) and 52 patients (47.3%), and ALBI grade was 1 and 2 in 38 (34.5%) and 72 patients (65.5%), respectively. The deterioration to Child-Pugh class B was found in 43 patients (39.1%) during the lenvatinib treatment. The favorable factors related to preserving liver function were significantly shown to be male, ALBI grade 1, CP5A and BCLC early or intermediate stage in the multivariate analysis. The formation of ascites was found in 32 patients (28.6%). The significant unfavorable factors associated with the formation of ascites were found to be low platelet count and CP6A. Among the 79 patients, there were 36 (45.6%) and 11 patients (13.9%) who fulfilled the criteria for candidate for the post-progression treatment and ramucirumab treatment, respectively. The predictive factors of the post-progression treatment were shown to be ALBI grade 1 and CP5A in multivariate analysis. In conclusion, male, ALBI grade 1, CP5A and BCLC early or intermediate stage were favorable factors related to sustaining liver function and the patients with ALBI grade 1 and CP5A were eligible for the post-progression treatment. Careful screening for ascites was needed in patients with low platelet count and CP6A.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12102906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601832PMC
October 2020

Real-world efficacy and safety of 12-week sofosbuvir/velpatasvir treatment for patients with decompensated liver cirrhosis caused by hepatitis C virus infection.

Hepatol Res 2021 Jan 20;51(1):51-61. Epub 2020 Oct 20.

Department of Medicine, Division of Gastroenterology, Jichi Medical University, Shimotsuke, Japan.

Aim: This study aimed to evaluate the real-world efficacy and safety of 12-week sofosbuvir/velpatasvir (SOF/VEL) treatment for patients with decompensated liver cirrhosis caused by hepatitis C virus (HCV) infection.

Methods: A total 72 of patients with Child-Pugh (CP) class B or C were enrolled. We evaluated the sustained virologic response at 12 weeks after the end of treatment (SVR12), adverse events (AEs), and changes in the liver function.

Results: All participants had genotype 1 or 2 HCV infection. At baseline, the numbers of patients with CP class B and C were 59 and 13, respectively. The overall SVR12 rate was 95.8% (69/72); 94.9% (56/59) in CP class B and 100% (13/13) in CP class C. The serum albumin level, prothrombin time and ascites were significantly improved (P < 0.01); however, the serum bilirubin level and encephalopathy did not improve. Among patients who achieved SVR12, 75.0% showed an improvement in their CP score, while 5.9% showed a worsening. The presence of large portosystemic shunt (diameter ≥6 mm) and hyperbilirubinemia (≥2.0 mg/dL) were independent factors that interfered with the improvement in the CP score (P < 0.05). The most common AEs were encephalopathy (15.3%) and skin symptoms (7.9%). Two patients discontinued SOF/VEL due to AEs.

Conclusions: Treatment with SOF/VEL for 12 weeks was relatively safe and effective for patients with decompensated cirrhosis. An SVR provided an improvement of the liver function in the majority of patients. However, large portosystemic shunt and hyperbilirubinemia were independent factors that interfered with the improvement in the CP score.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/hepr.13576DOI Listing
January 2021

Hepatitis C virus-associated decompensated liver cirrhosis with refractory hepatic encephalopathy successfully treated by balloon-occluded retrograde transvenous obliteration after sofosbuvir/velpatasvir.

Clin J Gastroenterol 2020 Dec 10;13(6):1303-1309. Epub 2020 Sep 10.

Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebashi, Gunma, 371-8511, Japan.

Sofosbuvir/velpatasvir (SOF/VEL) is expected to be highly effective, even in patients with decompensated liver cirrhosis. However, portal hypertension can be problematic after achieving a sustained viral response (SVR), especially in patients with hepatic encephalopathy (HE) associated with large portal-systemic shunt. Although balloon-occluded retrograde transvenous obliteration (BRTO) is a useful option, whether BRTO or SOF/VEL therapy should be initially performed in patients with a poor liver function reserve is controversial. We herein report a case of refractory HE caused by decompensated liver cirrhosis due to hepatitis C virus (HCV) classified as Child-Pugh class C that was treated by BRTO after SVR with SOF/VEL. A 64-year-old woman with HCV-associated decompensated cirrhosis developed refractory HE. Dynamic contrast-enhanced computed tomography (CT) revealed large portal-systemic shunt. We treated the patient with 12 weeks of SOF/VEL, and she achieved SVR. Although the serum albumin level, edema, and ascites were improved, intractable HE remained. Her general condition had been improved after SVR, so HE was suspected to have been caused by portal-systemic shunting. We, therefore, treated the patient by BRTO. On dynamic contrast-enhanced CT, partial obstruction of the shunt vessel was confirmed after BRTO. Thereafter, her serum ammonia level rapidly improved, and HE did not recur. Interventional radiology such as BRTO following SOF/VEL therapy may be a useful option even in patients with decompensated HCV-associated cirrhosis accompanied by portal-systemic shunt.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12328-020-01229-xDOI Listing
December 2020

Ipragliflozin-induced improvement of liver steatosis in obese mice may involve sirtuin signaling.

World J Hepatol 2020 Jul;12(7):350-362

Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Maebashi 371-8511, Gunma, Japan.

Background: Sodium glucose cotransporter 2 (SGLT2) inhibitors are newly developed oral antidiabetic drugs. SGLT2 is primarily expressed in the kidneys and reabsorbs approximately 90% of the glucose filtered by the renal glomeruli. SGLT2 inhibitors lower glucose levels independently of insulin action by facilitating urinary glucose excretion. The SGLT2 inhibitor ipragliflozin has reportedly improved liver steatosis in animal models and clinical studies. However, the mechanisms by which SGLT2 inhibitors improve liver steatosis are not fully understood.

Aim: To investigate the ameliorative effects of ipragliflozin on liver steatosis and the mechanisms of these effects in obese mice.

Methods: We analyzed 8-wk-old male obese () mice that were randomly divided into a group receiving a normal chow diet and a group receiving a normal chow diet supplemented with ipragliflozin (3 mg/kg or 10 mg/kg) for 4 wk. We also analyzed their lean sex-matched littermates receiving a normal chow diet as another control group. Body weight and liver weight were evaluated, and liver histology, immunoblotting, and reverse transcription-polymerase chain reaction analyses were performed.

Results: Hepatic lipid accumulation was significantly ameliorated in mice treated with 10 mg/kg ipragliflozin compared to untreated mice irrespective of body weight changes. Ipragliflozin had no appreciable effects on hepatic oxidative stress-related gene expression levels or macrophage infiltration, but significantly reduced hepatic interleukin-1β (IL-1β) mRNA expression levels. Ipragliflozin increased both the mRNA and protein expression levels of sirtuin 1 (SIRT1) in the liver. The hepatic mRNA levels of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), peroxisome proliferator-activated receptor α (PPARα), and fibroblast growth factor-21 (FGF21) were also significantly higher in ipragliflozin-treated mice than in untreated mice.

Conclusion: Our study suggests that the liver steatosis-ameliorating effects of ipragliflozin in mice may be mediated partly by hepatic SIRT1 signaling, possibly through the PGC-1α/PPARα-FGF21 pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4254/wjh.v12.i7.350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407917PMC
July 2020

Features of resistance-associated substitutions after failure of multiple direct-acting antiviral regimens for hepatitis C.

JHEP Rep 2020 Oct 18;2(5):100138. Epub 2020 Jun 18.

Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino, Tokyo, Japan.

Background & Aims: We aimed to clarify the features of resistance-associated substitutions (RASs) after failure of multiple interferon (IFN)-free regimens in HCV genotype 1b infections.

Methods: A total of 1,193 patients with HCV for whom direct-acting antiviral (DAA) treatment had failed were enrolled from 67 institutions in Japan. The RASs in non-structural protein (NS)3, NS5A, and NS5B were determined by population sequencing.

Results: Failure of 1, 2, and 3 regimens was observed in 1,101; 80; and 12 patients, respectively. Among patients with failure of 1 regimen, Y56H and D168V in NS3 were more frequently detected after failure of paritaprevir, whereas D168E was more frequently detected after failure of regimens including asunaprevir. R30H and L31-RAS in NS5A were frequently detected after failure of regimens including daclatasvir. The prevalence of Y93-RAS was high irrespective of the regimen. S282T RAS in NS5B was detected in 3.9% of ledipasvir/sofosbuvir failures. The prevalence of D168-RAS increased significantly according to the number of failed regimens ( <0.01), which was similar to that seen with L31-RAS and Y93-RAS. The prevalence of patients with RASs in either NS3 or NS5A, or in both, increased significantly with increasing numbers of failed regimens. The P32del, which is unique to patients for whom DAA had failed, was linked to the absence of Y93H, the presence of L31F, and previous exposure to IFN plus protease inhibitor regimens.

Conclusions: Failure of multiple DAA regimens can lead to the generation of multiple RASs in the NS3 and NS5A regions of the HCV 1b genome. These mutations contribute to viral resistance to multiple treatment regimens and, therefore, should be considered during decision making for treatment of chronic HCV.

Lay Summary: Resistance-associated substitutions (RAS) in the genome of the hepatitis C virus are 1 of the major causes for failed treatment. We investigated RASs after failure of various treatments for chronic hepatitis C, and found that more complicated RASs accumulated in the viral genome with successive failed treatments. The highly resistant P32del RAS at NS5A region was uniquely found in patients for whom DAA treatments had failed, and was linked to the presence and absence of specific RASs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhepr.2020.100138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424232PMC
October 2020
-->