Publications by authors named "Takumi Kawaguchi"

199 Publications

Evidence-based clinical practice guidelines for Liver Cirrhosis 2020.

J Gastroenterol 2021 Jul 7;56(7):593-619. Epub 2021 Jul 7.

Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan.

The first edition of the clinical practice guidelines for liver cirrhosis was published in 2010, and the second edition was published in 2015 by the Japanese Society of Gastroenterology (JSGE). The revised third edition was recently published in 2020. This version has become a joint guideline by the JSGE and the Japan Society of Hepatology (JSH). In addition to the clinical questions (CQs), background questions (BQs) are new items for basic clinical knowledge, and future research questions (FRQs) are newly added clinically important items. Concerning the clinical treatment of liver cirrhosis, new findings have been reported over the past 5 years since the second edition. In this revision, we decided to match the international standards as much as possible by referring to the latest international guidelines. Newly developed agents for various complications have also made great progress. In comparison with the latest global guidelines, such as the European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Diseases (AASLD), we are introducing data based on the evidence for clinical practice in Japan. The flowchart for nutrition therapy was reviewed to be useful for daily medical care by referring to overseas guidelines. We also explain several clinically important items that have recently received focus and were not mentioned in the last editions. This digest version describes the issues related to the management of liver cirrhosis and several complications in clinical practice. The content begins with a diagnostic algorithm, the revised flowchart for nutritional therapy, and refracted ascites, which are of great importance to patients with cirrhosis. In addition to the updated antiviral therapy for hepatitis B and C liver cirrhosis, the latest treatments for non-viral cirrhosis, such as alcoholic steatohepatitis/non-alcoholic steatohepatitis (ASH/NASH) and autoimmune-related cirrhosis, are also described. It also covers the latest evidence regarding the diagnosis and treatment of liver cirrhosis complications, namely gastrointestinal bleeding, ascites, hepatorenal syndrome and acute kidney injury, hepatic encephalopathy, portal thrombus, sarcopenia, muscle cramp, thrombocytopenia, pruritus, hepatopulmonary syndrome, portopulmonary hypertension, and vitamin D deficiency, including BQ, CQ and FRQ. Finally, this guideline covers prognosis prediction and liver transplantation, especially focusing on several new findings since the last version. Since this revision is a joint guideline by both societies, the same content is published simultaneously in the official English journal of JSGE and JSH.
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http://dx.doi.org/10.1007/s00535-021-01788-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280040PMC
July 2021

Evidence-based clinical practice guidelines for liver cirrhosis 2020.

Hepatol Res 2021 Jul 6;51(7):725-749. Epub 2021 Jul 6.

Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan.

The first edition of the clinical practice guidelines for liver cirrhosis was published in 2010, and the second edition was published in 2015 by the Japanese Society of Gastroenterology (JSGE). The revised third edition was recently published in 2020. This version has become a joint guideline by the JSGE and the Japanese Society of Hepatology (JSH). In addition to the clinical questions (CQs), background questions (BQs) are new items for basic clinical knowledge, and future research questions (FRQs) are newly added clinically important items. Concerning the clinical treatment of liver cirrhosis, new findings have been reported over the past 5 years since the second edition. In this revision, we decided to match the international standards as much as possible by referring to the latest international guidelines. Newly developed agents for various complications have also made great progress. In comparison with the latest global guidelines, such as the European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Diseases (AASLD), we are introducing data based on the evidence for clinical practice in Japan. The flowchart for nutrition therapy was reviewed to be useful for daily medical care by referring to overseas guidelines. We also explain several clinically important items that have recently received focus and were not mentioned in the last editions. This digest version describes the issues related to the management of liver cirrhosis and several complications in clinical practice. The content begins with a diagnostic algorithm, the revised flowchart for nutritional therapy, and refracted ascites, which are of great importance to patients with cirrhosis. In addition to the updated antiviral therapy for hepatitis B and C liver cirrhosis, the latest treatments for non-viral cirrhosis, such as alcoholic steatohepatitis/non-alcoholic steatohepatitis (ASH/NASH) and autoimmune-related cirrhosis, are also described. It also covers the latest evidence regarding the diagnosis and treatment of liver cirrhosis complications, namely gastrointestinal bleeding, ascites, hepatorenal syndrome and acute kidney injury, hepatic encephalopathy, portal thrombus, sarcopenia, muscle cramp, thrombocytopenia, pruritus, hepatopulmonary syndrome, portopulmonary hypertension, and vitamin D deficiency, including BQ, CQ and FRQ. Finally, this guideline covers prognosis prediction and liver transplantation, especially focusing on several new findings since the last version. Since this revision is a joint guideline by both societies, the same content is published simultaneously in the official English journal of JSGE and JSH.
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http://dx.doi.org/10.1111/hepr.13678DOI Listing
July 2021

Phenotypic Characterization by Single-Cell Mass Cytometry of Human Intrahepatic and Peripheral NK Cells in Patients with Hepatocellular Carcinoma.

Cells 2021 Jun 14;10(6). Epub 2021 Jun 14.

Department of Liver Diseases, The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Chiba 272-8516, Japan.

Overall response rates of systemic therapies against advanced hepatocellular carcinoma (HCC) remain unsatisfactory. Thus, searching for new immunotherapy targets is indispensable. NK cells are crucial effectors and regulators in the tumor microenvironment and a determinant of responsiveness to checkpoint inhibitors. We revealed the landscape of NK cell phenotypes in HCC patients to find potential immunotherapy targets. Using single cell mass cytometry, we analyzed 32 surface markers on CD56 and CD56 NK cells, which included Sialic acid-binding immunoglobulin-type lectins (Siglecs). We compared peripheral NK cells between HCC patients and healthy volunteers. We also compared NK cells, in terms of their localizations, on an individual patient bases between peripheral and intrahepatic NK cells from cancerous and noncancerous liver tissues. In the HCC patient periphery, CD160CD56 NK cells that expressed Siglec-7, NKp46, and NKp30 were reduced, while CD49aCD56 NK cells that expressed Siglec-10 were increased. CD160 and CD49a on CD56 NK cells were significantly correlated to other NK-related markers in HCC patients, which suggested that CD160 and CD49a were signature molecules. CD49a CX3CR1 Siglec-10 NK cells had accumulated in HCC tissues. Considering further functional analyses, CD160, CD49a, CX3CR1, and Siglec-10 on CD56 NK cells may be targets for immunotherapies of HCC patients.
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http://dx.doi.org/10.3390/cells10061495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8231799PMC
June 2021

Effects of Mediterranean Diet in Patients with Nonalcoholic Fatty Liver Disease: A Systematic Review, Meta-Analysis, and Meta-Regression Analysis of Randomized Controlled Trials.

Semin Liver Dis 2021 Aug 19;41(3):225-234. Epub 2021 Jun 19.

Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.

We conducted a meta-analysis to investigate the effects of the Mediterranean Diet (Med-Diet) on hepatic steatosis and insulin resistance in patients with nonalcoholic fatty liver disease (NAFLD). Six randomized controlled trials were selected for the meta-analysis (sample size: 250 participants). In the meta-analysis, there was no significant difference in body mass index and waist circumference between the Med-Diet and control groups. Med-Diet significantly reduced fatty liver index (FLI) compared with the control diet (standard mean difference [SMD]: -1.06; 95% CI: -1.95 to -0.17;  = 0.02). Med-Diet significantly reduced homeostasis model assessment of insulin resistance (HOMA-IR) compared with the control diet (SMD: -0.34; 95% CI: -0.65 to -0.03;  = 0.03). Similarly, a meta-regression analysis using age showed that Med-Diet significantly reduced FLI and HOMA-IR (95% CI: -0.956 to -0.237,  = 0.001 and 95% CI: -0.713 to -0.003,  = 0.048, respectively). This meta-analysis demonstrated that Med-Diet improved hepatic steatosis and insulin resistance in patients with NAFLD. Thus, Med-Diet is a beneficial pharmaconutritional therapy in patients with NAFLD.
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http://dx.doi.org/10.1055/s-0041-1723751DOI Listing
August 2021

Electrically Stimulated Eccentric Contractions during Walking Increases Oxygen Uptake.

Kurume Med J 2021 Jul 15;66(2):93-100. Epub 2021 Jun 15.

Division of Rehabilitation, Kurume University Hospital.

Neuromuscular electrical stimulation (NMES) is used to increase not only muscle strength but also whole-body metabolism. A hybrid training system (HTS) in which NMES is synchronized to voluntary exercise by an articular motion sensor may increase exercise load during aerobic walking exercise. We assessed the metabolic cost during walking exercise (5 minutes at 4 km/h and 5.6 km/h) on a treadmill simultaneously combined with HTS (HTSW) or without HTS (CON). We evaluated oxygen uptake ( VO) and heart rate (HR) during HTSW or CON on different days in fifteen subjects. The values ofVO during HTSW at 4 km/h and 5.6 km/h were signifi cantly greater than those during CON (16.6 ± 1.85 ml/min/kg vs 15.3 ± 1.48 ml/min/kg; p < 0.05, 21.0 ± 2.17 ml/min/kg vs 19.4 ± 2.13 ml/min/kg; p < 0.01, respectively). The values of HR during HTSW at 4 km/h, 5.6 km/h were significantly greater than those during CON (106.7 ± 8.1 bpm vs 101.7 ± 10.3 bpm; p < 0.05, 126.5 ± 11.1 bpm vs 121.5 ± 12.5 bpm; p < 0.05, respectively). HTS added significantly to the exercise load by 8.3 ± 12.0% or 9.1 ± 9.9% during aerobic walking exercise at 4 km/h or 5.6 km/h, respectively. HTS might be useful for health promotion by increasing metabolic cost during aerobic walking exercise without increasing the perceived difficulty.
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http://dx.doi.org/10.2739/kurumemedj.MS662008DOI Listing
July 2021

MAFLD better predicts the progression of atherosclerotic cardiovascular risk than NAFLD: Generalized estimating equation approach.

Hepatol Res 2021 Jun 15. Epub 2021 Jun 15.

Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.

Aim: Metabolic associated fatty liver disease (MAFLD) partly overlaps with non-alcoholic fatty liver disease (NAFLD). Thus, using a generalized estimating equation (GEE) approach, we aimed to investigate the difference in worsening of atherosclerotic cardiovascular disease (ASCVD) risk between patients with MAFLD and NAFLD. We also investigated factors related to the difference between the two groups.

Methods: We enrolled 2306 subjects with fatty liver (MAFLD 80.7%, NAFLD 63.4%). Subjects with MAFLD/NAFLD were sub-classified into three groups: NAFLD with no metabolic dysfunction (non-Met NAFLD), overlapping, and MAFLD with moderate alcohol consumption (mod-Alc MAFLD). ASCVD risk was estimated by non-invasive tests, including the Suita score. An event was defined as worsening of these scores from the low-risk to the high-risk group. Independent factors for the event were analyzed by Cox regression analysis with the GEE.

Results: In Cox regression analysis, MAFLD (HR 1.08, 95% CI 1.02-1.15, p = 0.014) and alcohol consumption (20-39 g/day; HR 1.73, 95% CI 1.26-2.36, p = 0.001) were independently associated with worsening of the Suita score. In a subanalysis, the incidence of the event was significantly lower in non-Met NAFLD than in the overlapping group (HR 0.70, 95% CI 0.50-0.98, p = 0.042). However, no significant difference was observed in the incidence between the overlapping and mod-Alc MAFLD group (HR 1.19, 95% CI 0.89-1.58, p = 0.235).

Conclusions: The GEE approach demonstrates that MAFLD better identifies patients with worsening of ASCVD risk than NAFLD. Moreover, the superiority of MAFLD over NAFLD was due to the presence of metabolic dysfunction rather than moderate alcohol consumption.
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http://dx.doi.org/10.1111/hepr.13685DOI Listing
June 2021

Non-Obese MAFLD Is Associated with Colorectal Adenoma in Health Check Examinees: A Multicenter Retrospective Study.

Int J Mol Sci 2021 May 22;22(11). Epub 2021 May 22.

Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan.

Colorectal adenoma is linked to metabolic dysfunction. Metabolic dysfunction-associated fatty liver disease (MAFLD) has a precise definition and three subtypes, including non-obese MAFLD. We aimed to investigate the impact of MAFLD on the prevalence of colorectal adenoma by comparing it to non-alcoholic fatty liver disease (NAFLD) in health check-up examinees. This is a multicenter retrospective study. We enrolled 124 consecutive health check-up examinees who underwent colonoscopy. NAFLD and MAFLD were present in 58 and 63 examinees, respectively. Colorectal adenoma was diagnosed by biopsy. The impact of the MAFLD definition on the prevalence of colorectal adenoma was investigated by logistic regression, decision-tree, and random forest analyses. In logistic regression analysis, MAFLD was identified as the only independent factor associated with the presence of colorectal adenoma (OR 3.191; 95% CI 1.494-7.070; = 0.003). MAFLD was also identified as the most important classifier for the presence of colorectal adenoma in decision-tree and random forest analyses (29 variable importance value). Among the three subtypes of MAFLD, non-obese MAFLD was the sole independent factor associated with the presence of colorectal adenoma (OR 3.351; 95% CI 1.589-7.262; ≤ 0.001). Non-obese MAFLD was also the most important classifier for the presence of colorectal adenoma in decision-tree and random forest analyses (31 variable importance value). MAFLD, particularly non-obese MAFLD, is the most important factor associated with the presence of colorectal adenoma rather than NAFLD. Colonoscopy examination should be considered in patients with MAFLD, especially those who are non-obese.
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http://dx.doi.org/10.3390/ijms22115462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196881PMC
May 2021

Effects of a low-intensity resistance exercise program on serum miR-630, miR-5703, and Fractalkine/CX3CL1 expressions in subjects with No exercise habits: A preliminary study.

Hepatol Res 2021 Jul 2;51(7):823-833. Epub 2021 Jun 2.

Department of Orthopedics, School of Medicine, Kurume University, Kurume, Japan.

Aims: Exercise is effective for the prevention of liver cancer. Exercise exerts biological effects through the regulation of microRNAs (miRNAs) and cytokines/myokines. We aimed to investigate the effects of low-intensity resistance exercise on serum miRNA and cytokine/myokine expressions in subjects with no exercise habits.

Methods: We enrolled seven male subjects with no exercise habits in this prospective before-after study. All subjects performed a low-intensity resistance exercise program (three metabolic equivalents, approximately 20 min/session). Serum miRNA expressions were evaluated using microarrays. We performed Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of differentially expressed miRNAs before and after exercise. Serum cytokine/myokine expressions were evaluated using a multiplex panel.

Results: All subjects completed the exercise program with no adverse events. In the microarray analysis, seven miRNAs showed a significant change between before and after exercise. Of these, microRNA (miR)-630 and miR-5703 showed a >1.5-fold increase (miR-630: 40.7 vs. 69.3 signal intensity, p = 0.0133; miR-5703: 30.7 vs. 55.9 signal intensity, p = 0.0051). KEGG pathway enrichment analysis showed that miR-630- and miR-5703-related genes were enriched in 37 and 5 pathways, including transforming growth factor-beta and Wnt signaling pathways, respectively. In the multiplex analysis, 12 cytokines/myokines showed significant alteration after exercise compared to before exercise. Of these, fractalkine/CX3CL1 showed the most significant up-regulation by exercise (94.5 vs. 109.1 pg/ml, p = 0.0017).

Conclusions: A low-intensity resistance exercise program was associated with upregulation of serum miR-630, miR-5703, and fractalkine/CX3CL1 expressions in subjects with no exercise habits. Thus, even low-intensity exercise may alter miRNA and cytokine/myokine expressions in humans.
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http://dx.doi.org/10.1111/hepr.13670DOI Listing
July 2021

Myostatin as a fibroblast-activating factor impacts on postoperative outcome in patients with hepatocellular carcinoma.

Hepatol Res 2021 Jul 25;51(7):803-812. Epub 2021 May 25.

Department of Liver Disease, The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan.

Aim: In patients with liver cirrhosis, high levels of serum myostatin are associated with poor prognosis. We aimed to clarify the influence of myostatin on the prognosis of patients with non-alcoholic fatty liver disease-hepatocellular carcinoma (NAFLD-HCC) without cirrhosis and on the progression of liver fibrosis.

Methods: Serum myostatin levels were evaluated in 234 patients who underwent primary surgical resection for single HCC. To clarify the impact of myostatin on liver fibrosis, we established human primary liver fibroblasts from resected livers, and cultured them in the presence of myostatin.

Results: The median age was 67.4 years, the median L3 skeletal muscle mass index was 44.4 cm /m , and the median body mass index was 23.4 kg/m . Eighty-two (35.0%) patients had sarcopenia (L3 skeletal muscle mass index: men <42, women <38 cm /m ). The etiologies of liver disease were hepatitis B virus (n = 61), hepatitis C virus (n = 86), and non-B non-C hepatitis (n = 87) including NAFLD (n = 74). High preoperative serum myostatin and vascular invasion were independent predictors of poor overall survival (OS). High serum myostatin was associated with poor OS in patients with no sarcopenia (n = 152). In patients without advanced liver fibrosis (Fibrosis stage, 0-2; n = 58), high levels of serum myostatin were also associated with poor OS, regardless of sarcopenia. Serum myostatin levels were increased with the progression of liver fibrosis. Liver fibroblasts were activated and produced collagen following stimulation with myostatin.

Conclusions: In patients with NAFLD-HCC without advanced liver fibrosis, high levels of serum myostatin were associated with poor OS. Myostatin activated primary fibroblasts and stimulated collagen production.
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http://dx.doi.org/10.1111/hepr.13667DOI Listing
July 2021

Chinese expert consensus on technical recommendations for the standard operation of drug-eluting beads for transvascular embolization.

Ann Transl Med 2021 Apr;9(8):714

Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.

Liver cancer is among the 10 most common tumors globally. In China, liver cancer ranks 4 for prevalence and 3 for mortality among all malignant tumors. With respect to the treatment of primary liver cancer, there are a number of therapies currently available, including surgical resection, liver transplantation, ablation, transarterial chemoembolization (TACE), systemic chemotherapy, radiation therapy, targeted drug therapy and immunotherapy. Clinical practice and research have shown that, compared with conventional TACE (cTACE), drug-eluting bead TACE (DEB-TACE) can achieve a higher response rate and longer survival time in patients with primary liver cancer. Compared with that of cTACE, DEB-TACE has more favorable basic conditions for achieving uniformity, which could facilitate the standardization of operation techniques. China is the country with the highest incidence of primary liver cancer, accounting for more than 50% of the global patients, and its etiology and epidemiology in Chinese patients differ from those in Europeans and Americans. Therefore, experts in China have drafted these technical recommendations for the standard operation of drug-eluting beads for the treatment of liver cancer on the basis of accumulated abundant clinical experience and evidence-based medical data.
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http://dx.doi.org/10.21037/atm-21-1678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106009PMC
April 2021

Type IV Collagen 7S Is the Most Accurate Test For Identifying Advanced Fibrosis in NAFLD With Type 2 Diabetes.

Hepatol Commun 2021 Apr 16;5(4):559-572. Epub 2020 Nov 16.

Department of Gastroenterology and Hepatology Kyoto Prefectural University of Medicine Kyoto Japan.

This study aimed to examine whether the diagnostic accuracy of four noninvasive tests (NITs) for detecting advanced fibrosis in nonalcoholic fatty liver disease (NAFLD) is maintained or is inferior to with or without the presence of type 2 diabetes. Overall, 874 patients with biopsy-proven NAFLD were enrolled. After propensity-score matching by age, sex, and the prevalence of dyslipidemia, 311 patients were enrolled in each group of with or without diabetes. To evaluate the effect of diabetes, we compared the diagnostic accuracy of the fibrosis-4 (FIB-4) index, the NAFLD fibrosis score (NFS), the aspartate aminotransferase to platelet ratio index (APRI), and type IV collagen 7S (COL4-7S) in patients with NAFLD with and without diabetes. The areas under the receiver operating characteristic curve (AUROC) for identifying advanced fibrosis in patients without diabetes were 0.879 for the FIB-4 index, 0.851 for the NFS, 0.862 for the APRI, and 0.883 for COL4-7S. The AUROCs in patients with diabetes were 0.790 for the FIB-4 index, 0.784 for the NFS, 0.771 for the APRI, and 0.872 for COL4-7S. The AUROC of COL4-7S was significantly larger than that of the other NITs in patients with NAFLD with diabetes than in those without diabetes. The optimal high and low cutoff points of COL4-7S were 5.9 ng/mL and 4.8 ng/mL, respectively. At the low cutoff point, the accuracy of COL4-7S was better than that of the other NITs, especially in patients with diabetes. COL4-7S measurement might be the best NIT for identifying advanced fibrosis in NAFLD, especially in NAFLD with diabetes.
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http://dx.doi.org/10.1002/hep4.1637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034577PMC
April 2021

Tenofovir Alafenamide Rescues Renal Tubules in Patients with Chronic Hepatitis B.

Life (Basel) 2021 Mar 23;11(3). Epub 2021 Mar 23.

Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan.

Nucles(t)ide analogs (NAs) are effective for chronic hepatitis B (CHB). NAs suppress hepatic decompensation and hepatocarcinogenesis, leading to a dramatic improvement of the natural course of patients with CHB. However, renal dysfunction is becoming an important issue for the management of CHB. Renal dysfunction develops in patients with the long-term treatment of NAs including adefovir dipivoxil and tenofovir disoproxil fumarate. Recently, several studies have reported that the newly approved tenofovir alafenamide (TAF) has a safe profile for the kidney due to greater plasma stability. In this mini-review, we discuss the effectiveness of switching to TAF for NAs-related renal tubular dysfunction in patients with CHB.
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http://dx.doi.org/10.3390/life11030263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005189PMC
March 2021

Therapeutic Outcomes and Prognostic Factors of Unresectable Intrahepatic Cholangiocarcinoma: A Data Mining Analysis.

J Clin Med 2021 Mar 2;10(5). Epub 2021 Mar 2.

Division of Gastroenterology, Department of Medicine, School of Medicine, Kurume University, Kurume 830-0011, Japan.

Prognosis of patients with intrahepatic cholangiocarcinoma (ICC) is unsatisfactory. Tumor, host, and treatment factors including hepatic arterial infusion chemotherapy (HAIC) are intricately involved in the progression of ICC. We aimed to identify profiles associated with disease control rate (DCR) and the prognosis of patients with unresectable ICC by decision tree analysis. We analyzed 31 consecutive patients with unresectable ICC (median age, 71 years; the male ratio was 58.1%). Stage IVB occupied 51.6% of patients, and 38.7% and 58.1% of patients were treated with gemcitabine plus cisplatin combination therapy and HAIC, respectively. Profiles associated with prognosis as well as DCR were investigated by decision tree analysis. The median survival time (MST) of the patients was 11.6 months, and the DCR was 70.9%. Multivariate correlation analysis showed that albumin levels and WBC levels were significantly correlated with survival time (albumin, ρ = 0.3572, = 0.0485; WBC, ρ = -0.4008, = 0.0280). In decision tree analysis, WBC level was selected as the initial split variable, and subjects with WBC levels of 6800/μL or less (45.1%) showed a long survival time (MST 476 days). We also demonstrated that the profile associated with the highest DCR was "less than 4.46 mg/dL of CRP levels and treatment with HAIC". We demonstrated a new prognostic profile for ICC patients, which consisted of WBC and CRP levels. Moreover, we demonstrated that HAIC was associated with better disease control in ICC patients with low CPR levels. Thus, these new profiles may be useful for the management of ICC patients.
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http://dx.doi.org/10.3390/jcm10050987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957874PMC
March 2021

Prevalence and profiles of ramucirumab-associated severe ascites in patients with hepatocellular carcinoma.

Mol Clin Oncol 2021 Apr 25;14(4):79. Epub 2021 Feb 25.

Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan.

Severe ascites is an adverse event of ramucirumab (RAM), a second-line treatment for hepatocellular carcinoma (HCC). Ascites can be associated with various factors, including nutritional status and muscle quality. The aim of the present study was to investigate the prevalence and profiles of RAM-associated severe ascites in patients with HCC. This retrospective study enrolled 14 consecutive patients with HCC treated with RAM (median age, 72 years; Barcelona Clinic Liver Cancer stage B/C, 6/8). Nutritional status and muscle quality were evaluated using the controlling nutritional status (CONUT) score and intramuscular adipose tissue (IMAT) content, respectively. Factors associated with severe ascites were evaluated using decision-tree analysis. The median progression-free survival (PFS) time was 2.1 months, and the overall objective response and disease control rates were 14 and 50%, respectively. Severe ascites developed in 57.1% of the patients, and the median onset was 37.5 days (range, 14-61 days) after initiation of RAM treatment. In the decision-tree analysis, the CONUT score and IMAT content were the first and second splitting variables for the development of severe ascites. In patients with a CONUT score ≥5 and IMAT <-0.54, the prevalence of severe ascites was 80 and 100%, respectively. A high incidence of severe ascites was observed in patients treated with RAM. A CONUT score ≥5 and an IMAT <-0.54 were associated with severe ascites. Thus, caution must be taken for severe ascites in patients with HCC treated with RAM, in particular patients with malnutrition and fat infiltration in muscle.
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http://dx.doi.org/10.3892/mco.2021.2241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947949PMC
April 2021

Gut microbiota composition associated with hepatic fibrosis in non-obese patients with non-alcoholic fatty liver disease.

J Gastroenterol Hepatol 2021 Mar 11. Epub 2021 Mar 11.

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

Background And Aim: Gut microbiota composition is associated with the pathogenesis of non-alcoholic fatty liver disease. However, the association between gut microbiota composition and non-alcoholic fatty liver disease in non-obese patients remains unclear. We compared clinical parameters and gut microbiota profiles of healthy controls and non-obese and obese patients with non-alcoholic fatty liver disease.

Methods: We examined the clinical parameters and gut microbiota profiles by 16S rRNA sequences and short-chain fatty acid levels in fecal samples from 51 non-obese patients with non-alcoholic fatty liver disease (body mass index <25 kg/m ) and 51 obese patients with non-alcoholic fatty liver disease (body mass index ≥30 kg/m ) who underwent pathological examination and 87 controls at five hospitals in Japan.

Results: Although no significant differences between the non-obese and other groups were observed in alpha diversity, a significant difference was found in beta diversity. We observed a significant decrease in serum alanine aminotransferase levels, Eubacterium population, and butyric acid levels in non-obese patients with non-alcoholic fatty liver disease compared with those in obese patients with non-alcoholic fatty liver disease. A significant negative correlation was found between the stage of hepatic fibrosis and Eubacterium abundance in non-obese patients with non-alcoholic fatty liver disease.

Conclusions: The decrease in the abundance of Eubacterium that produces butyric acid may play an important role in the development of non-alcoholic fatty liver disease in non-obese individuals. This study was registered at the University Hospital Medical Information Network clinical trial registration system (UMIN000020917).
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http://dx.doi.org/10.1111/jgh.15487DOI Listing
March 2021

FIB-4 First in the Diagnostic Algorithm of Metabolic-Dysfunction-Associated Fatty Liver Disease in the Era of the Global Metabodemic.

Life (Basel) 2021 Feb 14;11(2). Epub 2021 Feb 14.

Japan Strategic Medical Administration Research Center (J-SMARC), Nagoya, Aichi 460-0011, Japan.

The prevalence of obesity or metabolic syndrome is increasing worldwide (globally metabodemic). Approximately 25% of the adult general population is suffering from nonalcoholic fatty liver disease (NAFLD), which has become a serious health problem. In 2020, global experts suggested that the nomenclature of NAFLD should be updated to metabolic-dysfunction-associated fatty liver disease (MAFLD). Hepatic fibrosis is the most significant determinant of all cause- and liver -related mortality in MAFLD. The non-invasive test (NIT) is urgently required to evaluate hepatic fibrosis in MAFLD. The fibrosis-4 (FIB-4) index is the first triaging tool for excluding advanced fibrosis because of its accuracy, simplicity, and cheapness, especially for general physicians or endocrinologists, although the FIB-4 index has several drawbacks. Accumulating evidence has suggested that vibration-controlled transient elastography (VCTE) and the enhanced liver fibrosis (ELF) test may become useful as the second step after triaging by the FIB-4 index. The leading cause of mortality in MAFLD is cardiovascular disease (CVD), extrahepatic malignancy, and liver-related diseases. MAFLD often complicates chronic kidney disease (CKD), resulting in increased simultaneous liver kidney transplantation. The FIB-4 index could be a predictor of not only liver-related mortality and incident hepatocellular carcinoma, but also prevalent and incident CKD, CVD, and extrahepatic malignancy. Although NITs as milestones for evaluating treatment efficacy have never been established, the FIB-4 index is expected to reflect histological hepatic fibrosis after treatment in several longitudinal studies. We here review the role of the FIB-4 index in the management of MAFLD.
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http://dx.doi.org/10.3390/life11020143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917687PMC
February 2021

Eradication of hepatitis C virus with direct-acting antivirals improves glycemic control in diabetes: A multicenter study.

JGH Open 2021 Feb 19;5(2):228-234. Epub 2020 Dec 19.

Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences Hiroshima University Hiroshima Japan.

Background And Aim: Hepatitis C virus (HCV) infection causes insulin resistance and diabetes as extrahepatic manifestations. We aimed to analyze the effect of HCV eradication by direct-acting antiviral (DAA) agents on glucose tolerance.

Methods: The hemoglobin A1c (HbA1c) of 272 patients with HCV infection who achieved a sustained virologic response (SVR) was analyzed at baseline before DAA treatment, at the end of DAA therapy (ETR), and 12 weeks after therapy (Post12W).

Results: There were no significant differences in HbA1c between baseline, ETR, and Post12W in the overall patients. When the data were stratified according to the presence or absence of diabetes, median HbA1c significantly decreased from baseline (7.2%) to ETR (6.8%) and Post12W (6.8%) in the 55 patients with diabetes, whereas there were no significant changes in the patients without diabetes. Basal HbA1c, fasting plasma glucose, and age were independently associated with the changes in HbA1c according to multivariate analysis, and the predictive formula for changes in HbA1c was found to be ΔHbA1c (%) = 1.449-0.4* HbA1c (%) + 0.012 × Age (year). There were no changes in body mass in diabetic or nondiabetic patients. In diabetic patients taking medication, 63.4% of patients needed less medication.

Conclusions: Eradication of HCV improves glycemic control, indicated by a 0.4% decrease in HbA1c in diabetes.
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http://dx.doi.org/10.1002/jgh3.12474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857302PMC
February 2021

Prediction of Nonalcoholic Fatty Liver Disease Using Noninvasive and Non-Imaging Procedures in Japanese Health Checkup Examinees.

Diagnostics (Basel) 2021 Jan 16;11(1). Epub 2021 Jan 16.

Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan.

Access to imaging is limited for diagnosing nonalcoholic fatty liver disease (NAFLD) in general populations. This study evaluated the diagnostic performance of noninvasive and nonimaging indexes to predict NAFLD in the general Japanese population. Health checkup examinees without hepatitis virus infection or habitual alcohol drinking were included. Fatty liver was diagnosed by ultrasonography. The hepatic steatosis index (HSI), Zhejiang University (ZJU) index, and fatty liver index (FLI) were determined, and risk of advanced liver fibrosis was evaluated by the fibrosis-4 index. NAFLD was diagnosed in 1935 (28.0%) of the 6927 subjects. The area under the receiver operating characteristic (AUROC) curve of the HSI, ZJU index, and FLI was 0.874, 0.886, and 0.884, respectively. The AUROC of the ZJU index ( < 0.001) and FLI ( = 0.002) was significantly greater than that for the HSI. In subjects with a high risk of advanced fibrosis, the sensitivity of the HSI, ZJU index, and FLI were 88.8%, 94.4%, and 83.3% with a low cut-off value and the specificity was 98.5%, 100%, and 100% with a high cut-off value. In conclusion, all indexes were useful to diagnose NAFLD in the general Japanese population and in subjects with potentially advanced liver fibrosis.
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http://dx.doi.org/10.3390/diagnostics11010132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830542PMC
January 2021

Alternating Lenvatinib and Trans-Arterial Therapy Prolongs Overall Survival in Patients with Inter-Mediate Stage HepatoCellular Carcinoma: A Propensity Score Matching Study.

Cancers (Basel) 2021 Jan 5;13(1). Epub 2021 Jan 5.

Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan.

We aimed to evaluate the impact of alternating lenvatinib (LEN) and trans-arterial therapy (AT) in patients with intermediate-stage hepatocellular carcinoma (HCC) after propensity score matching (PSM). This retrospective study enrolled 113 patients with intermediate-stage HCC treated LEN. Patients were classified into the AT ( = 41) or non-AT group ( = 72) according to the post LEN treatment. Overall survival (OS) was calculated using the Kaplan-Meier method and analyzed using a log-rank test after PSM. Factors associated with AT were evaluated using a decision tree analysis. After PSM, there were no significant differences in age, sex, etiology, or albumin-bilirubin (ALBI) score/grade between groups. The survival rate of the AT group was significantly higher than that of the non-AT group (median survival time; not reached vs. 16.3 months, = 0.01). Independent factors associated with OS were AT and ALBI grade 1 in the Cox regression analysis. In the decision tree analysis, age and ALBI were the first and second splitting variables for AT. In this study, we show that AT may improve prognosis in patients with intermediate-stage HCC. Moreover, alternating LEN and trans-arterial therapy may be recommended for patients below 70 years of age with ALBI grade 1.
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http://dx.doi.org/10.3390/cancers13010160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796435PMC
January 2021

Effects of In-Hospital Exercise on Frailty in Patients with Hepatocellular Carcinoma.

Cancers (Basel) 2021 Jan 7;13(2). Epub 2021 Jan 7.

Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan.

Frailty including physical inactivity is associated with the survival of patients with hepatocellular carcinoma (HCC). We aimed to investigate the effects of in-hospital exercise on frailty in patients with HCC. This was a multi-center observational study. Patients with HCC were classified into exercise ( = 114) and non-exercise ( = 67) groups. The exercise group was treated with a mixture of aerobic and resistance exercises (20-40 min/day, median four days). Frailty was assessed using the liver frailty index (LFI). Factors for changes in LFI were examined by multivariate and decision-tree analyses. The factors were also examined after propensity score matching. During hospitalization, LFI was significantly improved in the exercise group compared to the non-exercise group (ΔLFI -0.17 vs. -0.02, = 0.0119). In multivariate analysis, exercise (odds ratio (OR) 2.38, 95% confidence interval (CI) 1.240-4.570, = 0.0091) and females (OR 2.09; 95%CI, 1.062-4.109; = 0.0328) were identified as independent factors for the improvement of LFI. In the decision-tree analysis, exercise was identified as an initial classifier associated with the improvement of LFI. Similar findings were also seen in the propensity score matching analyses. We demonstrated that in-hospital exercise improved frailty in patients with HCC. Thus, in-hospital exercise may be beneficial for improving physical function in patients with HCC.
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http://dx.doi.org/10.3390/cancers13020194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826707PMC
January 2021

Hepatocellular carcinoma development in diabetic patients: a nationwide survey in Japan.

J Gastroenterol 2021 Mar 11;56(3):261-273. Epub 2021 Jan 11.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

Background: Although type 2 diabetes mellitus (T2DM) is a known risk factor for hepatocellular carcinoma (HCC) development, the annual incidence in diabetes patients is far below the threshold of efficient surveillance. This study aimed to elucidate the risk factors for HCC in diabetic patients and to determine the best criteria to identify surveillance candidates.

Methods: The study included 239 patients with T2DM who were diagnosed with non-viral HCC between 2010 and 2015, with ≥ 5 years of follow-up at diabetes clinics of 81 teaching hospitals in Japan before HCC diagnosis, and 3277 non-HCC T2DM patients from a prospective cohort study, as controls. Clinical data at the time of and 5 years before HCC diagnosis were collected.

Results: The mean patient age at HCC diagnosis was approximately 73 years, and 80% of the patients were male. The proportion of patients with insulin use increased, whereas the body mass index (BMI), proportion of patients with fatty liver, fasting glucose levels, and hemoglobin A1c (HbA1c) levels decreased significantly in 5 years. In the cohort study, 18 patients developed HCC during the mean follow-up period of 4.7 years with an annual incidence of 0.11%. Multivariate logistic regression analyses showed that the FIB-4 index was an outstanding predictor of HCC development along with male sex, presence of hypertension, lower HbA1c and albumin levels, and higher BMI and gamma-glutamyl transpeptidase levels. Receiver-operating characteristic analyses showed that a FIB-4 cut-off value of 3.61 could help identify high-risk patients, with a corresponding annual HCC incidence rate of 1.1%.

Conclusion: A simple calculation of the FIB-4 index in diabetes clinics can be the first step toward surveillance of HCC with a non-viral etiology.
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http://dx.doi.org/10.1007/s00535-020-01754-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7932951PMC
March 2021

Effects of In-Hospital Physical Therapy on Activities of Daily Living in Patients with Hepatocellular Carcinoma.

Int J Environ Res Public Health 2020 12 6;17(23). Epub 2020 Dec 6.

Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan.

Activities of daily living (ADL) are frequently impaired in patients with hepatocellular carcinoma (HCC). In this retrospective study, we aimed to investigate the effects of physical therapy on ADLs in patients with HCC during hospitalization for cancer treatment. Nineteen patients with HCC were enrolled. During hospitalization, patients performed a combination of resistance training, stretching, and aerobic exercise (20-60 min/day). ADLs were assessed using the functional independence measure (FIM). Changes in FIM were evaluated by before-after analysis. No significant difference was seen in Child-Pugh class before and after physical therapy. The bilateral knee extension strength and chair stand test were significantly increased after physical therapy compared with before physical therapy ( = 0.001 and = 0.008, respectively). The total FIM score was significantly increased after physical therapy compared with that before physical therapy ( = 0.0156). Among the 18 indexes of FIM, the stairs index was significantly improved after physical therapy compared with that before physical therapy (5.9 vs. 6.4 points, = 0.0241). We demonstrated that physical therapy improved muscle strength without worsening liver function. Furthermore, physical therapy improved FIM, especially in the stairs index, in patients with HCC. Thus, physical therapy may be beneficial in patients with HCC during cancer treatment.
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http://dx.doi.org/10.3390/ijerph17239098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730642PMC
December 2020

Impact of Immune Reconstitution-Induced Hepatic Flare on Hepatitis B Surface Antigen Loss in Hepatitis B Virus/Human Immunodeficiency Virus-1 Coinfected Patients.

J Infect Dis 2021 Jun;223(12):2080-2089

AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan.

Background: Hepatitis B surface antigen (HBsAg) loss is an ideal goal for chronic hepatitis B patients. Antiretroviral therapy (ART) in hepatitis B virus/human immunodeficiency virus-1 (HBV/HIV-1)-coinfected patients can lead to hepatic flare (HF) caused by immune reconstitution-induced inflammatory syndrome (IRIS). Here, we investigated the impact of IRIS-HF on HBsAg loss.

Methods: This was a retrospective study of 58 HBV/HIV-1-coinfected subjects HBsAg-positive for ≥6 months before ART initiation and followed for ≥1 year (median 9.9 years) after ART initiation. We examined humoral factors in sera from healthy volunteers, HIV-monoinfected patients, and HBV/HIV-1-coinfected patients with IRIS-HF or acute hepatitis B infection.

Results: During ART, HBsAg loss was observed in 20 of 58 HBV/HIV-1-coinfected patients (34.5%). Of the 58 patients, 15 (25.9%) developed IRIS-HF within 12 months of ART initiation. HBsAg loss was more frequent among patients who developed IRIS-HF (11/15, 73.3%) than those who did not (9/43, 20.9%). Multivariate analysis showed IRIS-HF was an independent predictor of subsequent HBsAg loss. Younger age and higher baseline HBV DNA titer were associated with IRIS-HF. Elevation of sCD163, not CXCL9, CXC10, CXCXL11, or CXCL13, was observed at IRIS-HF.

Conclusions: IRIS-HF was associated with HBsAg loss in HBV/HIV-1-coinfected patients.
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http://dx.doi.org/10.1093/infdis/jiaa662DOI Listing
June 2021

The Asian Pacific Association for the Study of the Liver clinical practice guidelines for the diagnosis and management of metabolic associated fatty liver disease.

Hepatol Int 2020 Dec 1;14(6):889-919. Epub 2020 Oct 1.

Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Westmead, NSW, 2145, Australia.

Metabolic associated fatty liver disease (MAFLD) is the principal worldwide cause of liver disease and affects nearly a quarter of the global population. The objective of this work was to present the clinical practice guidelines of the Asian Pacific Association for the Study of the Liver (APASL) on MAFLD. The guidelines cover various aspects of MAFLD including its epidemiology, diagnosis, screening, assessment, and treatment. The document is intended for practical use and for setting the stage for advancing clinical practice, knowledge, and research of MAFLD in adults, with specific reference to special groups as necessary. The guidelines also seek to improve patient care and awareness of the disease and assist stakeholders in the decision-making process by providing evidence-based data. The guidelines take into consideration the burden of clinical management for the healthcare sector.
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http://dx.doi.org/10.1007/s12072-020-10094-2DOI Listing
December 2020

MAFLD identifies patients with significant hepatic fibrosis better than NAFLD.

Liver Int 2020 12;40(12):3018-3030

Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.

Background & Aims: Diagnostic criteria for metabolic associated fatty liver disease (MAFLD) have been proposed, but not validated. We aimed to compare the diagnostic accuracy of the MAFLD definition vs the existing NAFLD criteria to identify patients with significant fibrosis and to characterize the impact of mild alcohol intake.

Methods: We enrolled 765 Japanese patients with fatty liver (median age 54 years). MAFLD and NAFLD were diagnosed in 79.6% and 70.7% of patients respectively. Significant fibrosis was defined by FIB-4 index ≥1.3 and liver stiffness ≥6.6 kPa using shear wave elastography. Mild alcohol intake was defined as <20 g/day. Factors associated with significant fibrosis were analysed by logistic regression and decision-tree analyses.

Results: Liver stiffness was higher in MAFLD compared to NAFLD (7.7 vs 6.8 kPa, P = .0010). In logistic regression, MAFLD (OR 4.401; 95% CI 2.144-10.629; P < .0001), alcohol intake (OR 1.761; 95% CI 1.081-2.853; P = .0234), and NAFLD (OR 1.721; 95%CI 1.009-2.951; P = .0463) were independently associated with significant fibrosis. By decision-tree analysis, MAFLD, but not NAFLD or alcohol consumption was the initial classifier for significant fibrosis. The sensitivity for detecting significant fibrosis was higher for MAFLD than NAFLD (93.9% vs 73.0%). In patients with MAFLD, even mild alcohol intake was associated with an increase in the prevalence of significant fibrosis (25.0% vs 15.5%; P = .0181).

Conclusions: The MAFLD definition better identifies a group with fatty liver and significant fibrosis evaluated by non-invasive tests. Moreover, in patients with MAFLD, even mild alcohol consumption is associated with worsening of hepatic fibrosis measures.
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http://dx.doi.org/10.1111/liv.14675DOI Listing
December 2020

Hybrid Training System Improves Insulin Resistance in Patients with Nonalcoholic Fatty Liver Disease: A Randomized Controlled Pilot Study.

Tohoku J Exp Med 2020 09;252(1):23-32

Division of Rehabilitation, Kurume University Hospital.

Insulin resistance is associated with the progression of nonalcoholic fatty liver disease (NAFLD). Insulin resistance is regulated by various cytokines, including interleukin-6 (IL-6), a proinflammatory myokine, and selenoprotein P (SeP), a liver-derived secretory hepatokine. High levels of IL-6 and/or SeP have been shown to contribute to insulin resistance, and exercise is a first-line therapy for NAFLD. We have developed a hybrid training system (HTS): a neuromuscular electrical stimulation device to enhance exercise results. We aimed to investigate the effects of HTS on insulin resistance as well as serum IL-6 and SeP in patients with NAFLD. This is a randomized, single-blind (assessor), controlled trial. Subjects with NAFLD walked on a treadmill with or without HTS (9 subjects each) for 30 minutes three times a week for six weeks (HTS vs. control group; median age 45 vs. 45; male/female 5/4 vs. 6/3). We examined subjects before the first session and at the end of the final session. Serum SeP levels were measured by ELISA which measures the fragment of SeP. In the HTS group, HOMA-IR values were significantly reduced compared to the control group (Δ-0.71 vs. Δ0.05; P < 0.05). IL-6 and SeP levels in serum were also significantly reduced compared to that of the control group (IL-6; Δ-0.6 vs. Δ0.29 pg/mL; P < 0.05, SeP; Δ-1288.5 vs. Δ-435.4 ng/mL; P < 0.05, respectively). In conclusion, we propose that HTS improves insulin resistance by reducing serum IL-6 and SeP levels in patients with NAFLD.
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http://dx.doi.org/10.1620/tjem.252.23DOI Listing
September 2020

Surveillance of Hepatocellular Carcinoma in Nonalcoholic Fatty Liver Disease.

Diagnostics (Basel) 2020 Aug 10;10(8). Epub 2020 Aug 10.

Japan Strategic Medical Administration Research Center (J-SMARC), Nagoya, Aichi 460-0011, Japan.

Nonalcoholic fatty liver disease (NAFLD) is becoming the leading cause of hepatocellular carcinoma (HCC), liver-related mortality, and liver transplantation. There is sufficient epidemiological cohort data to recommend the surveillance of patients with NAFLD based upon the incidence of HCC. The American Gastroenterology Association (AGA) expert review published in 2020 recommends that NAFLD patients with cirrhosis or advanced fibrosis estimated by non-invasive tests (NITs) consider HCC surveillance. NITs include the fibrosis-4 (FIB-4) index, the enhanced liver fibrosis (ELF) test, FibroScan, and MR elastography. The recommended surveillance modality is abdominal ultrasound (US), which is cost effective and noninvasive with good sensitivity. However, US is limited in obese patients and those with NAFLD. In NAFLD patients with a high likelihood of having an inadequate US, or if an US is attempted but inadequate, CT or MRI may be utilized. The GALAD score, consisting of age, gender, AFP, the lens culinaris-agglutinin-reactive fraction of AFP (AFP-L3), and the protein induced by the absence of vitamin K or antagonist-II (PIVKA-II), can help identify a high risk of HCC in NAFLD patients. Innovative parameters, including a Mac-2 binding protein glycated isomer, type IV collagen 7S, free apoptosis inhibitor of the macrophage, and a combination of single nucleoside polymorphisms, are expected to be established. Considering the large size of the NAFLD population, optimal screening tests must meet several criteria, including high sensitivity, cost effectiveness, and availability.
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http://dx.doi.org/10.3390/diagnostics10080579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7459689PMC
August 2020

Lenvatinib prolongs the progression-free survival time of patients with intermediate-stage hepatocellular carcinoma refractory to transarterial chemoembolization: A multicenter cohort study using data mining analysis.

Oncol Lett 2020 Sep 19;20(3):2257-2265. Epub 2020 Jun 19.

Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan.

Tyrosine kinase inhibitors are considered for use in patients with hepatocellular carcinoma (HCC) refractory to transarterial chemoembolization (TACE). The aim of the present retrospective study was to identify factors associated with progression-free survival (PFS) and to evaluate the indications for lenvatinib treatment in patients with intermediate-stage HCC refractory to TACE using a data-mining analysis. A total of 171 patients with intermediate-stage HCC refractory to TACE were included. All patients were classified into three groups according to their HCC treatment: Lenvatinib (n=45), sorafenib (n=53) and TACE (n=73) groups. PFS time was calculated using the Kaplan-Meier method and analyzed using a log-rank test. Factors associated with PFS time were evaluated using multivariate and decision-tree analyses. The median PFS time was 5.8, 3.2 and 2.4 months in the lenvatinib, sorafenib and TACE groups, respectively (P<0.001). In the Cox regression analysis, lenvatinib treatment and being within the up-to-seven criteria were identified as independent factors for PFS (lenvatinib, P<0.0001; within up-to-seven, P=0.001). The decision-tree analysis revealed that patients beyond the up-to-seven criteria, treated with lenvatinib and with albumin-bilirubin (ALBI) grade 1 had a longer PFS time (245.2±107.9 days) than patients beyond the up-to-seven criteria, treated with lenvatinib and with ALBI grade 2 (147.1±78.6 days). Additionally, lenvatinib was independently associated with longer PFS time in patients with intermediate-stage HCC refractory to TACE. Therefore, lenvatinib may be recommended for patients who have intermediate-stage HCC refractory to TACE, ALBI grade 1 and who are within the up-to-seven criteria.
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http://dx.doi.org/10.3892/ol.2020.11758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400966PMC
September 2020

Clinical Significance of Adverse Events for Patients with Unresectable Hepatocellular Carcinoma Treated with Lenvatinib: A Multicenter Retrospective Study.

Cancers (Basel) 2020 Jul 11;12(7). Epub 2020 Jul 11.

Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan.

We sought to investigate the clinical profile(s) associated with the discontinuation of lenvatinib (LEN) due to severe adverse events (DLSAE) in patients with unresectable hepatocellular carcinoma (HCC). This retrospective study enrolled 177 patients with HCC treated with LEN. Independent factors associated with DLSAE were advanced age, albumin-bilirubin (ALBI) grade 2, fatigue grade ≥ 3, and appetite loss ≥ 2. The overall survival (OS) in the group that did not require DLSAE was significantly longer compared to the group that did require DLSAE (median survival time (MST): not reached vs. 12.8 months, < 0.001). Moreover, advanced age was the most important variable for DLSAE in a decision tree analysis. Hypertension and hand-foot-skin-reaction (HFSR) were also significantly associated with longer survival, and the occurrence of hypertension was the earliest predictor for improved prognosis, while appetite loss and development of grade ≥ 3 fatigue were predictive of a poor prognosis. We concluded that the appearance of hypertension has potential as an early surrogate marker to predict improved prognosis. Moreover, careful management to avoid discontinuation of treatment leads to longer survival in patients receiving LEN.
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http://dx.doi.org/10.3390/cancers12071867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408786PMC
July 2020
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