Search

The purpose of this study was to evaluate predictors of reduction in ammonia levels by occlusion of portosystemic shunts (PSS) in patients with cirrhosis.Forty-eight patients with cirrhosis (21 women, 27 men; mean age, 67.8 years) with PSS underwent balloon-occluded retrograde transvenous obliteration (BRTO) at one institution between February 2008 and June 2014. The causes of cirrhosis were hepatitis B in one case, hepatitis C in 20 cases, alcohol in 15 cases, nonalcoholic steatohepatitis in eight cases, and other conditions in four cases. The Child-Pugh classes were A in 24 cases, B in 23 cases, and C in one case. The indication for BRTO was gastric varices in 40 cases and hepatic encephalopathy in eight cases. Testing was conducted before and 1 month after the procedure. Statistical analyses were performed to identify predictors of a clinically significant decline in ammonia levels after BRTO.Occlusion of PSS resulted in a clinically significant decrease in ammonia levels accompanied by increased portal venous flow and improved Child-Pugh score. Univariate analyses showed that a reduction in ammonia levels due to BRTO was significantly related to lower plasma glucose levels, higher RBC counts, and higher hemoglobin concentration before the treatment. Furthermore, multivariate logistic regression identified preoperative plasma glucose level as the strongest independent predictor of a significant ammonia reduction in response to BRTO. In addition, although BRTO resulted in significantly declined ammonia levels in patients with normal glucose tolerance before the procedure, ammonia levels were not significantly decreased after shunt occlusion in patients with diabetes mellitus or impaired glucose tolerance before BRTO, according to 75-g oral glucose tolerance test results.Preoperative plasma glucose level is a useful predictor of clinically significant ammonia reduction resulting from occlusion of PSS in patients with cirrhosis. Even if PSS are present, control of blood ammonia levels by BRTO alone may be difficult in patients with glucose intolerance.

Liver cirrhosis can disturb circadian rhythms, decreasing patient quality of life. Changes in metabolic products in cirrhosis are poorly understood. We evaluated changes in liver metabolism products using a thioacetamide-induced mouse model of liver cirrhosis exhibiting circadian rhythm disturbance. Principal component analysis indicated that the circular progression found in the control group was disrupted in the thioacetamide group, and Jonckheere-Terpstra-Kendall analysis showed an imbalanced pattern of oscillating metabolic products. In addition to changes in serotonin and other vitamin A-related metabolites, differences in metabolic products associated with energetics, redox homeostasis, bile acid production, inflammation, and other processes were identified. Carbohydrate metabolism showed a reduction in metabolic products associated with the tricarboxylic acid cycle, suggesting up-regulation of glycolysis and reduced mitochondrial activity. Lipid metabolism showed an increase in ω-oxidation products, suggesting decreased β-oxidation. Conclusion: These data will be useful for chronotherapy and modulation of circadian rhythms in patients with liver damage. (Hepatology Communications 2017;1:704-718).

We have been developing a therapy for liver cirrhosis using cultured autologous bone marrow–derived mesenchymal stem cells (BMSCs). Before human clinical trials can be considered, the safety and efficacy of BMSC infusion in medium to large animals must be confirmed; thus, we developed a canine liver fibrosis model. A small amount of bone marrow fluid was aspirated from the canine humerus to assess the characteristics of BMSCs. We implanted a venous catheter in the stomach and a subcutaneous infusion port in the back of the neck of each canine. Repeated injection of CCl4 through the catheter was performed to induce liver cirrhosis. After 10 weeks of CCl4 injection, eight canines were equally divided into two groups: no cell infusion (control group) and autologous BMSC infusion through the peripheral vein (BMSC group). A variety of assays were carried out before and 4 weeks after the infusion. The area of liver fibrosis stained with sirius red was significantly reduced in the BMSC group 4 weeks after BMSC infusion, consistent with a significantly shortened half‐life of indocyanine green and improved liver function. Conclusion: We established a useful canine liver fibrosis model and confirmed that cultured autologous BMSC infusion improved liver fibrosis without adverse effects. (Hepatology Communications 2017;1:691–703)

Spironolactone and furosemide, which are used to treat ascites associated with decompensated cirrhosis, are ineffective in treating refractory ascites. Hence, combination therapy with tolvaptan, a vasopressin V2 receptor antagonist, has been approved in Japan. Tolvaptan monotherapy and combination therapy with furosemide inhibit fibrosis in cardiac remodeling; hence, we examined these therapies in a rat cirrhotic model, including their usefulness in inhibiting hepatic fibrosis. In the present study, we used a model of hepatic fibrosis induced by a choline-deficient l-amino-acid-defined diet + diethylnitrosamine. Rats were divided into a low-dose furosemide group (15 mg/kg/day), a high-dose furosemide group (100 mg/kg/day), a tolvaptan monotherapy group (10 mg/kg/day), a low-dose furosemide/tolvaptan combination therapy group, and a control group which received neither furosemide nor tolvaptan; we then assessed diuretic effects and hepatic fibrosis. The tolvaptan monotherapy group and the furosemide/tolvaptan combination therapy group demonstrated significantly higher urine volume than the control group and the low-dose furosemide group. In addition, tolvaptan monotherapy and low-dose furosemide/tolvaptan combination therapy were found to inhibit hepatic fibrosis and yield a hepatoprotective effect by an antioxidative mechanism. The results of the present study suggest that tolvaptan monotherapy and low-dose furosemide/tolvaptan combination therapy are highly effective for hepatoprotection and diuresis.

Idiopathic portal hypertension (IPH), causing aberrant portal hemodynamics, is a disease with an as yet unidentified cause and no treatment has been established so far. The Japanese research group on IPH in Japan was set up in 1975 by the Ministry of Health, Labour and Welfare, furthermore extra-hepatic portal obstruction (EHO) and Budd-Chiari syndrome (BCS) have been added to the research subjects and further work has continued. The aims of the research group are to accurately evaluate the current status of the three diseases in Japan, elucidate the disease aetiology and pathogenesis, and develop new treatments. Due to the long-term efforts of the Japanese research group, aberrant portal hemodynamics has been investigated to date in a variety of aspects, from epidemiological and pathological studies to molecular biology analysis. As a result, it has been shown that there are abnormal genes in the liver, specific for IPH. In addition, pathological findings of BCS were internationally compared and the difference in findings between Japan and Western countries has been clarified. Furthermore, it was found that complication rates of hepatocellular carcinoma (HCC) in BCS were higher in Japan. Based on the research, "Diagnosis and treatment of aberrant portal hemodynamics (2001)", including diagnostic criteria for aberrant portal hemodynamics, was published in 2001. In 2013, it was revised to "Diagnosis and treatment guidelines for aberrant portal hemodynamics (2013)" after the incorporation of diagnosis and treatment in accordance with its current status. This article is protected by copyright. All rights reserved.

Aim Loop diuretics and spironolactone are used in patients with hepatic edema, but they are sometimes associated with insufficient responses as well as adverse events. Tolvaptan, a vasopressin type 2 receptor antagonist, was approved for hepatic edema in 2013. A large-scale post-marketing surveillance study has been carried out to evaluate the effectiveness and safety of tolvaptan in real-world clinical settings. Methods Patients with hepatic cirrhosis with insufficient response to conventional diuretics were enrolled. The observational period was up to 6 months. Changes in body weight and clinical symptoms were measured to evaluate effectiveness. The incidence of adverse drug reactions was summarized as a safety measure. Results Of 970 patients enrolled, 463 were included in the safety analysis. Of this group, 340 were included in the effectiveness analysis. Decreases in body weight from baseline were −2.38 kg on day 7 and −3.52 kg on day 14. Ascites and bloated feeling was significantly improved within 14 days. The mean change in body weight depended on estimated glomerular filtration rate levels. The most frequently reported adverse drug reaction was thirst (6.9% of patients). Serum sodium level of ≥146 mEq/L was observed in 12 patients (2.7%). Conclusions In the real-world clinical setting, tolvaptan showed aquaretic effectiveness in patients with cirrhosis. The mean change in body weight depended on renal function. We recommend tolvaptan use for hepatic cirrhosis at a stage in which the renal function is maintained.

The present study investigated the effect of a DNA demethylating agent, decitabine, against Epstein-Barr virus-associated gastric cancer (EBVaGC). Decitabine inhibited cell growth and induced G2/M arrest and apoptosis in EBVaGC cell lines. The expression of E-cadherin was up-regulated and cell motility was significantly inhibited in the cells treated with decitabine. The promoter regions of p73 and RUNX3 were demethylated, and their expression was up-regulated by decitabine. They enhanced the transcription of p21, which induced G2/M arrest and apoptosis through down-regulation of c-Myc. Decitabine also induced the expression of BZLF1 in SNU719. Induction of EBV lytic infection was an alternative way to cause apoptosis of the host cells. This study is the first report to reveal the effectiveness of a demethylating agent in inhibiting tumor cell proliferation and up-regulation of E-cadherin in EBVaGC. J. Med. Virol. 89:508-517, 2017. © 2016 Wiley Periodicals, Inc.

Epstein–Barr virus-associated gastric carcinoma (EBVaGC) can develop in gastric mucosa affected by Helicobacter pylori (H. pylori)-induced atrophic gastritis. However, it is unclear whether EBVaGC can develop in gastric mucosa after successful eradication of H. pylori. We report 3 cases of EBVaGC discovered more than 5 years after successful eradication of H. pylori. All 3 cases are men with a history of smoking. The periods from successful eradication to development of EBVaGC were 18, 8, and 9 years, respectively. Their tumors were mainly depressed lesions located in the gastric corpus. Two patients had intramucosal cancer and the other had advanced gastric cancer. Mucosal atrophy was present in the background gastric mucosa of all of three, and the anti-H. pylori antibody titer in each patient had fallen to

Background: Epstein-Barr virus-associated gastric carcinoma (EBVaGC) is classified as one of the molecular subtypes of gastric cancer. We used droplet digital polymerase chain reaction (ddPCR) to enable highly sensitive and quantitative detection of EBV. Methods: EBV-DNA load was calculated based on the copy number of the BamH1-W fragment of EBV by ddPCR, and the cut-off value of EBV-DNA load was set. We conducted both ddPCR and EBER1 ISH to examine whether their results coincided in 158 gastric cancer specimens of unknown EBV status. We prepared 26 biopsy specimens and 49 serum samples including EBVaGC and assayed them by ddPCR. Results: The median values of EBV-DNA load for EBVaGC and EBV-negative control were 17.0 and 0.00308, respectively. A cut-off value of 0.032 was determined for which the sensitivity was 1. Among the 158 gastric cancer specimens, 14 lesions were judged as EBV-positive by the 0.032 cut-off value determined by ddPCR. The results of ddPCR and EBER1 ISH were in complete agreement. Even when using a biopsy specimen as a sample for ddPCR, the EBV-DNA load of all EBVaGCs was larger than the cut-off value. Conclusions: We established a new method of diagnosing EBVaGC from tissue samples by ddPCR.

The effect of selective transcatheter arterial embolisation (TAE) using trisacryl gelatine microspheres (TGMs) in the normal canine liver was investigated. Selective embolisation was achieved by injecting TGMs into the left hepatic artery through a microcatheter in four healthy dogs. After embolisation, computed tomography (CT), biochemical analysis and histological examination were performed during a 12-week observation period. Embolisation was successful in all four dogs. Postoperative CT revealed consistent embolisation of the artery within the experimental period in three dogs. Hepatic enzyme levels slightly increased after embolisation but tapered to normal ranges. Histological examinations revealed no abnormal changes. Thus, selective TAE with TGMs was well tolerated in normal dogs and may be applicable to canine hepatocellular carcinoma.

Organisms living in temperate regions are sensitive to seasonal variations in the environment; they are known to accumulate energy as fat in their livers during the winter when days are shorter, temperatures are lower, and food is scarce. However, the impact of variations in photoperiod alone on hepatic lipid metabolism has not been well-studied. Therefore, in this study, we analyzed lipid metabolism in the liver of medaka,Oryzias latipes, while varying the length of days at constant temperature. Larger amounts of fatty acids accumulated in the liver after 14 days under short-day conditions than under long-day conditions. Metabolome analysis showed no accumulation of the long-chain unsaturated fatty acids required at low temperatures, but showed a significant accumulation of long-chain saturated fatty acids. Short-day conditions induced decreased levels of succinate, fumarate, and malate in the tricarboxylic acid cycle, decreased expression of PPARα, and decreased accumulation of acylcarnitine, which suggested inhibition of lipolysis. In addition, when a high-fat diet was administered to transparent medaka under short-day conditions, larger amounts of fat accumulated and medaka with fatty liver were efficiently produced. Detailed analysis of the relationship between seasonal changes and hepatic steatosis will be important in the future as hepatic diseases become more prevalent in modern society; the findings obtained in our study will be useful for research studies pertaining to the relationship between photoperiod and disorders such as hepatic steatosis and non-alcoholic steatohepatitis.

Liquid biopsies are not used in practice for hepatocellular carcinoma (HCC). Epi proColon is the first commercial blood‐based test for colorectal cancer screening based on methylated DNA testing of the septin 9 gene (SEPT9). However, Epi proColon has some disadvantages, including the requirement of a large amount of blood and lack of quantitative performance. Therefore, we previously developed a novel liquid biopsy test that can quantitatively detect even a single copy of methylated SEPT9 in a small amount of DNA. In the current study, we evaluated the application potential of this assay for diagnosing HCC. Study subjects included 80 healthy volunteers, 45 patients with chronic liver disease (CLD) without HCC, and 136 patients with HCC (stage 0, 12; stage A, 50; stage B, 31; stage C, 41; and stage D, 2), according to the Barcelona Clinic Liver Cancer staging system. For the assay, DNA was treated with methylation‐sensitive restriction enzymes in two steps, followed by multiplex droplet digital polymerase chain reaction. The median copy number of methylated SEPT9 was 0.0, 2.0, and 6.4 in the healthy control, CLD, and HCC groups, respectively, with significant differences among the groups (HCC vs. healthy control, P, We showed that a novel liquid biopsy test targeting methylated SEPT9 is useful for diagnosing HCC.

Helicobacter pylori can infect the gastric mucosa and cause chronic inflammation, resulting in various diseases, including gastric cancer. Eradication of H. pylori in all infected subjects is recommended; however, the number of H. pylori strains with antibiotic resistance has increased, and the eradication rate has decreased. Vonoprazan, a potassium-competitive acid blocker, produces a stronger acid-inhibitory effect than proton pump inhibitors (PPIs). The H. pylori eradication rate with vonoprazan was found to be higher than that with PPIs. The H. pylori eradication rate with vonoprazan-based triple therapy (vonoprazan, amoxicillin, and clarithromycin) was approximately 90% and had an incidence of adverse events similar to that of PPIs. We review the current situation of H. pylori eradication in Japan, the first country in which vonoprazan was made available.

A questionnaire survey was conducted on the administration of secondary chemotherapy for unresectable or recurrent gastric cancer by 43 doctors involved in gastric cancer treatment in the Yamaguchi prefecture. Seventy-one percent of doctors replied that the secondary chemotherapy transfer rate was more than 60%, and 29% of doctors replied that the secondary chemotherapy transfer rate was less than 60%. The reasons why patients could not be transferred to secondary chemotherapy included inferior performance status, poor general condition, and elderly age, among others. Weekly paclitaxel plus ramucirumab therapy was used as the major regimen of secondary chemotherapy by 95% of doctors. In addition, 93% of doctors indicated that weekly nab-paclitaxel would be an option for gastric cancer secondary chemotherapy. Secondary chemotherapy for gastric cancer in the Yamaguchi prefecture has a standard regimen selection according to guidelines.

In Japan, the primary therapeutic options for refractory ascites include pharmacotherapy with diuretics, paracentesis with albumin infusion, peritoneovenous shunt using Denver shunt, cell-free and concentrated ascites reinfusion therapy (CART), transjugular intrahepatic portosystemic shunt (TIPS), and liver transplantation.

Refractory ascites is a complication of decompensated liver cirrhosis and is an indicator of poor prognosis. Portal hypertension and renal sodium retention are involved in the occurrence of refractory ascites. The diagnosis of refractory ascites is based on the criteria advocated by the International Ascites Club (IAC). Exclusion of the conditions that induce transient refractoriness to diuretics is important in the differential diagnosis. In Japan, tolvaptan, an oral arginine vasopressin V2 receptor antagonist, has been used as a new diuretic for ascites in combination with conventional diuretics since the drug was approved in 2013. As the relation between renal dysfunction and poor prognosis has become evident, preservation of renal function should be considered while selecting therapeutic options. An appropriate combination of diuretic therapy using tolvaptan and conventional diuretics may offer the possibility to control ascites without deterioration of renal function. Further investigation to clarify the role of the novel diuretic drug, tolvaptan, in the treatment of cirrhotic refractory ascites is necessary.

Liver cirrhosis is the end stage of chronic liver disease and causes serious complications such as ascites, encephalopathy, and portal hypertension. The only radical treatment currently available is liver transplantation, but issues such as a shortage of donors, long-term immunosuppression, and high lifelong medical costs limit the feasibility of liver transplantation. To overcome these limits to the feasibility of liver transplantation, liver regeneration therapy through cell and stem cell transplantation, bioartificial liver systems, and organ bioengineering are advancing. This chapter will describe the current status and perspective of liver regeneration therapy for liver cirrhosis.

Liver cirrhosis is the end stage of chronic liver disease, and the only radical treatment for decompensated liver cirrhosis is still liver transplantation. Development of effective regenerative therapy for liver cirrhosis is an urgent task. Before human clinical trials can be considered, the safety and efficacy of any planned protocol must be confirmed in medium-to-large animals. Therefore, we have developed a novel canine liver fibrosis model for proof of concept (POC) studies.

Summary Although recent evidence suggests the involvement of iron accumulation in the pathogenesis of nonalcoholic steatohepatitis (NASH), the underlying mechanisms remain poorly understood. Previously, we reported a unique histological structure termed “crown-like structure (CLS),” where liver-resident macrophages (Kupffer cells) surround dead hepatocytes, scavenge their debris, and induce inflammation and fibrosis in NASH. In this study, using magnetic column separation, we show that iron-rich Kupffer cells exhibit proinflammatory and profibrotic phenotypic changes during the development of NASH, at least partly, through activation of MiT/TFE transcription factors. Activation of MiT/TFE transcription factors is observed in Kupffer cells forming CLSs in murine and human NASH. Iron chelation effectively attenuates liver fibrosis in a murine NASH model. This study provides insight into the pathophysiologic role of iron in NASH. Our data also shed light on a unique macrophage subset rich in iron that contributes to CLS formation and serves as a driver of liver fibrosis., Graphical Abstract, Highlights • Kupffer cells are magnetically divided into Fe-hi and Fe-lo fractions in a NASH model • Fe-hi Kupffer cells exert proinflammatory and profibrotic properties in NASH • MiT/TFE transcription factors mediate iron-induced Kupffer cells' phenotypic changes • MiT/TFE transcription factors are activated in Kupffer cells in murine and human NASH, Biological Sciences; Biochemistry; Cell Biology

An 81-year-old woman was brought to our hospital with septic shock due to severe acute cholangitis. Her blood pressure was 61/39 mm Hg, and her SpO2 was 99% with 6 L/min oxygen administration. CT showed common bile duct stones and abscess formation in the liver bed. We decided to perform urgent

Postoperative biliary strictures are usually complications of cholecystectomy. Endoscopic plastic stent prosthesis is generally undertaken for treating benign biliary strictures. Recently, fully covered metal stents have been shown to be effective for treating benign distal biliary strictures. We present the case of a 53-year-old woman with liver injury in which imaging studies showed a common hepatic duct stricture. Endoscopic retrograde cholangiopancreatography also confirmed the presence of a common hepatic duct stricture. Temporally fully covered metal stents with dilated diameters of 6 mm were placed in a side-by-side fashion in the left and right hepatic ducts, respectively. We removed the stents 2 months after their placement. Subsequent cholangiography revealed an improvement in the biliary strictures. Although we were apprehensive about the fully covered metal stents obstructing the biliary side branches, we noted that careful placement of the bilateral metal stents did not cause any complications. Side-by-side deployment of bilateral endoscopic fully covered metal stents can be one of the safe and effective therapies for postoperative biliary stricture.

Background and study aims: Light-emitting diodes (LEDs) are used widely for their high luminous efficiency and durability. We developed a novel prototype high definition endoscope with white LEDs and evaluated the image quality it produced against a commercial endoscope with conventional light source. Patients and methods: The specifications of both colonoscopes were identical, except for the LED light source at the tip of the prototype. We examined 20 patients with rectal or sigmoid colon lesions and the image quality was evaluated in 40 images (one image from the LED colonoscope and one from the conventional colonoscope for each lesion) by three endoscopists. We additionally evaluated the 17 videos recorded with the LED colonoscope that were available. Image quality, mucosal and vascular color, and luminous distribution and intensity were scored on a 5-point scale. Results: The mean score for vascular color given by one evaluator was significantly higher using the LED colonoscope than using the conventional colonoscope. The mean scores for mucosal color and luminous intensity from another evaluator were significantly lower with the LED colonoscope than with the conventional colonoscope. There were no significant differences in the luminous distribution scores for any of the evaluators. The image quality of the videos was evaluated as being similar with both colonoscopes. Conclusions: Image quality from the LED and conventional colonoscopes were similar, although the luminous intensity of the LEDs is inferior to that of the conventional light source at the present time.

A 64-year-old man was found to have a nodule in his right lung. He also complained of nausea and abdominal pain during the clinical course. Esophagogastroduodenoscopy revealed a duodenal ulcer associated with severe stenosis and a suspicion of malignancy. However, three subsequent biopsies revealed no evidence of malignancy. The fourth biopsy showed scattered large eosinophilic cells with an eccentric nucleus, leading to a diagnosis of Russell body duodenitis (RBD). RBD is an extremely rare disease, and little is known about its etiology and clinical course. The pathogenesis of RBD is discussed based on our experience with this case.

The Japanese Society of Gastroenterology revised the evidence-based clinical practice guidelines for liver cirrhosis in 2015. Eighty-three clinical questions were selected, and a literature search was performed for the clinical questions with use of the MEDLINE, Cochrane, and Igaku Chuo Zasshi databases for the period between 1983 and June 2012. Manual searching of the latest important literature was added until August 2015. The guidelines were developed with use of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. This digest version in English introduces selected clinical questions and statements related to the management of liver cirrhosis and its complications. Branched-chain amino acids relieve hypoalbuminemia and hepatic encephalopathy and improve quality of life. Nucleoside analogues and peginterferon plus ribavirin combination therapy improve the prognosis of patients with hepatitis B virus related liver cirrhosis and hepatitis C related compensated liver cirrhosis, respectively, although the latter therapy may be replaced by direct-acting antivirals. For liver cirrhosis caused by primary biliary cirrhosis and active autoimmune hepatitis, urosodeoxycholic acid and steroid are recommended, respectively. The most adequate modalities for the management of variceal bleeding are the endoscopic injection sclerotherapy for esophageal varices and the balloon-occluded retrograde transvenous obliteration following endoscopic obturation with cyanoacrylate for gastric varices. Beta-blockers are useful for primary prophylaxis of esophageal variceal bleeding. The V2 receptor antagonist tolvaptan is a useful add-on therapy in careful diuretic therapy for ascites. Albumin infusion is useful for the prevention of paracentesis-induced circulatory disturbance and renal failure. In addition to disaccharides, the nonabsorbable antibiotic rifaximin is useful for the management of encephalopathy. Anticoagulation therapy is proposed for patients with acute-onset or progressive portal vein thrombosis.

Advancements in antiviral drugs have enabled control of viral hepatitis; yet, many patients with liver cirrhosis (LC) are awaiting liver transplants. Liver transplantation yields dramatic therapeutic effects, but problems such as shortage of donors, surgical invasiveness, immunological rejection and costs, limit the number of transplantations. Advances in liver regeneration therapy through cell transplantation as a non-invasive treatment for cirrhosis will supplement these restrictions to the number of liver transplants. Clinical trials for LC have included hematopoietic stem cell mobilization by administration of granulocyte colony-stimulating factor, infusion of autologous bone marrow cells, and administration of autologous mesenchymal stem cells derived from bone marrow or umbilical cord. Several recently reported randomized controlled studies have shown the effectiveness of these approaches. However, to promote implementation of new liver regeneration therapies, it is important to develop a system whereby cell therapies with ensured safety can be approved quickly.

Previous studies have reported prognostic factors for hepatocellular carcinoma (HCC) patients receiving lenvatinib, however, no studies have evaluated the effects of both handgrip strength and skeletal muscle mass on the clinical outcomes. Therefore, this retrospective study investigated the individual effect of handgrip strength, skeletal muscle mass, and sarcopenia on clinical outcomes of 53 HCC patients treated with lenvatinib. Before receiving lenvatinib, handgrip strength and skeletal muscle index (SMI) were measured. Low handgrip strength and muscle depletion were defined as &lt, 26 and &lt, 18 kg and SMI &lt, 42 and SMI &lt, 38 cm2/m2 in men and women, respectively. Sarcopenia was defined as having low handgrip strength and muscle depletion. Multivariate analysis identified modified albumin&ndash, bilirubin grade 1&ndash, 2a (p = 0.010), Barcelona Clinic Liver Cancer stage A&ndash, B (p = 0.011), and absence of low handgrip strength (p = 0.015) as favorable prognostic factors for survival. Furthermore, sarcopenia was an independent significant prognostic factor for survival. Time to treatment failure was associated with handgrip strength and sarcopenia. Our findings suggest that handgrip strength may be a useful marker of clinical outcomes in HCC patients treated with lenvatinib.

Introduction We have reported previously that fecal DNA testing of TWIST1 methylation in combination with the fecal immunochemical test for hemoglobin (FIT) (combination test) is useful for colorectal neoplasia screening. In this study, using larger sample sizes, we studied the clinical performance of the combination test for the detection of colorectal neoplasia and, especially, advanced colorectal adenoma. Methods We performed a prospective study in which FIT, fecal DNA testing of TWIST1 methylation, and colonoscopy were performed on 372 patients with colorectal neoplasia and 71 subjects without colorectal neoplasia. We assessed the individual clinical performance of each of FIT and fecal DNA testing of TWIST1 methylation and of the combination test for the detection of colorectal neoplasia including advanced adenoma based on morphologic subtypes. Results The FIT alone had a sensitivity of 7.5% (3/40) for nonadvanced adenoma, 32.3% (41/127) for advanced adenoma, and 93.7% (192/205) for colorectal cancer and a specificity of 87.3% (62/71). The combination test had a sensitivity of 35.0% (14/40) for nonadvanced adenoma, 68.5% (87/127) for advanced adenoma, and 95.6% (196/205) for colorectal cancer and a specificity of 80.3% (57/71). For morphological subtypes of advanced adenoma, the sensitivity of FIT was only 28.2% (20/71) for polypoid type and 16.1% (5/31) for nonpolypoid type, whereas the combination test increased the sensitivities to 64.8% (46/71) and 71.0% (22/31), respectively. Discussion The combination of the fecal DNA test with FIT seemed to be useful to detect colorectal neoplasia and, especially, advanced adenoma of the nonpolypoid type.

Management of multinodular hepatocellular carcinoma (HCC) in the intermediate Barcelona Clinic Liver Cancer (BCLC)-B stage is controversial. The aim of the present study as to identify the subgroup of patients with BCLC-B HCC who could benefit from liver resection. The present study retrospectively analyzed the outcomes of 65 patients (training cohort) who underwent liver resection for multinodular BCLC-B HCC. Cox's regression analysis was conducted to identify the independent prognostic factors for overall survival and to develop the prognostic score. As some authors have reported that maximum tumor size (cm) plus tumor number (N+S) is a prognostic factor in patients with BCLC-B HCC who undergo chemoembolization, the usefulness of this factor in patients who underwent liver resection was also evaluated. Subsequently, the validity of the prognostic score was assessed in an independent validation cohort (n=132). Multivariate analysis revealed that positivity for hepatitis C virus antibody (HCV-ab), platelet count ≤1010/l, N+S >8, and des-γ-carboxy prothrombin (DCP) >400 mAU/ml were independent prognostic factors for overall survival. The prognostic score differentiated two groups (≤2, ≥3) with distinct outcomes (median survival time 68.3 months vs. 29.1 months; P

Background and aim The goals of the study were to identify an effective treatment for ascites and to examine the influence of tolvaptan on outcomes by investigating non-responders to tolvaptan and comparing outcomes of hepatic cirrhosis in patients treated with and without tolvaptan. Methods In Study 1, of 145 patients with hepatic cirrhosis who were treated with tolvaptan between September 2013 and March 2018, 45 who did not achieve weight loss of ≥1.5 kg within one week were investigated. In Study 2, 83 patients who received tolvaptan for ascites between September 2013 and March 2017 were compared with 131 patients who were treated for ascites without use of tolvaptan between January 2006 and January 2012. Results In Study 1, the 45 patients were divided into three groups based on changes in dosing of diuretics. Renal function was retained in the dose reduction group compared with that in the other groups, and the rate of discharge with remission and the outcomes were also favorable in patients with dose reduction. In Study 2, survival was significantly more favorable in patients treated with tolvaptan. Conclusions Dose reduction of diuretics may be effective for patients with reduced renal function for whom tolvaptan is ineffective or the effect is insufficient and may also improve outcomes of patients with hepatic cirrhosis by preventing a decline in renal function caused by an increased dose of diuretics.

Fatty liver, which has been continuously becoming more common in a number of patients, is the most common liver disease. For detailed analysis, a useful model for fatty liver is needed and fish are considered as a potential candidate. We assessed through direct observation of the liver, which is the most conventional method for non-invasive analysis of progression in fatty liver. By using transparent medaka (Oryzias latipes), we were able to observe changes in fat deposition in the liver. An analysis of the progression of fatty liver using ultrasound showed a significant increase in echo intensity, which indicates that this is a useful examination method. In addition, we clarified a metabolite profile in the medaka liver fed a high-fat diet (HFD), which had not previously been shown in detail. This medaka model, allowing non-invasive and repetitive assessment, is a useful model for the analysis of diseases that cause fatty liver in which changes in detailed metabolites are identified., Summary: Our medaka model allows for non-invasive and repetitive assessment and is useful in the analysis of fatty liver in which changes in detailed metabolites are identified.

Epstein–Barr virus (EBV) is an oncogenic human herpesvirus involved in the development of around 10% of gastric cancers. The overexpression of PD-L1 is one of the features of EBV-associated gastric cancer (EBVaGC); however, the function of PD-L1 has not been studied in EBVaGC. We used three EBVaGC cell lines, SNU719 cells, NCC24 cells, and YCCEL1 cells, to evaluate the PD-L1 expression and function in EBVaGC. Jurkat T-lymphocytes expressing PD-1 were co-cultured with NCC24 and YCCEL1 cells and the cell cycles were analyzed. To study the regulatory mechanism for PD-L1 expression, the 3′UTR of PD-L1 was sequenced, and the effect of inhibitors of the IFN-γ signaling pathway was evaluated. All of the EBVaGC cell lines expressed PD-L1, and its expression was further enhanced by stimulation with IFN-γ. In Jurkat T-cells co-cultured with IFN-γ-stimulated NCC24 and YCCEL1 cells, the number of cells in the G0/G1 phase was significantly increased. This G0/G1 arrest was partially released by administration of anti-PD-L1 antibody. We found SNPs in PD-L1 3′UTR nucleotide sequences that were located at seed regions for microRNAs. Treatment of EBVaGC cell lines with JAK2-inhibitor, PI3K-inhibitor, and mTOR inhibitor reduced the level of PD-L1 expression to the same level as cells without IFN-γ stimulation. EBVaGC cells expressing high levels of PD-L1 suppress T-cell proliferation, and the IFN-γ signaling pathway is involved in the expression of PD-L1.