MAFLD, patient-centred care, and APASL.

Asian-Pacific nations are home to more than half the world's population and similar to other global super regions, metabolic dysfunction associated fatty liver disease (MAFLD) is the principal cause for chronic liver disease. To address the challenges ahead for tackling the disease at-scale, the Asian Pacific Association for the Study of the Liver (APASL) was the first pan-national society to endorse and lead the process for redefining the disease and adopting the more appropriate term "MAFLD" with its accompanying set of positive diagnostic criteria. As with this initiative, APASL and Hepatology International will continue to strive to lead the field and work with sister societies towards full adoption of MAFLD. This will advance the science and practice of Hepatology and help incorporate MAFLD within multidisciplinary care teams. Ultimately, it will lead to more cogent clinical trials built on innovative design platforms that include patients with any disease related to metabolic dysfunction. For our patients, an outcome of these endeavours will be the provision of holistic person-centred care for this disease that is so common in our region.

PALB2 mutation in a woman with bilateral breast cancer: A case report.

Partner and localizer of breast cancer 2 (PALB2) was identified as a moderate-risk gene of breast and pancreas cancer. The present authors previously reported that no PALB2 germline mutations with a deleterious frameshift or stop codons were identified in 155 Japanese patients with breast and/or ovarian cancer who were estimated to be at risk of hereditary cancer, according to the National Comprehensive Cancer Network (NCCN) criteria. In the present study, one patient with a deleterious mutation of PALB2 (c. 2834+2 T>C) has been identified from a study of an additional 128 cases. Therefore, the prevalence of PALB2 among Japanese patients is now estimated to be 0.35% (1/283). The proband was a 63-year-old woman with bilateral breast cancer, although she had experienced no other cancers. The proband had two elder sisters, the eldest of whom died from pancreatic cancer at 60 years of age. The proband's 40-year-old daughter was affected, but did not show any malignancies. There are only a few reports concerning PALB2 mutations in Japan. To the best of our knowledge, this is the first case study to reveal the significance of DNA-repair genes in the development of malignancies in Japanese patients with breast cancer.

Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial.

PURPOSE: Open-label, phase III trial evaluating whether sunitinib was superior or equivalent to sorafenib in hepatocellular cancer. PATIENTS AND METHODS: Patients were stratified and randomly assigned to receive sunitinib 37.5 mg once per day or sorafenib 400 mg twice per day. Primary end point was overall survival (OS). RESULTS: Early trial termination occurred for futility and safety reasons. A total of 1,074 patients were randomly assigned to the study (sunitinib arm, n = 530; sorafenib arm, n = 544). For sunitinib and sorafenib, respectively, median OS was 7.9 versus 10.2 months (hazard ratio [HR], 1.30; one-sided P = .9990; two-sided P = .0014); median progression-free survival (PFS; 3.6 v 3.0 months; HR, 1.13; one-sided P = .8785; two-sided P = .2286) and time to progression (TTP; 4.1 v 3.8 months; HR, 1.13; one-sided P = .8312; two-sided P = .3082) were comparable. Median OS was similar among Asian (7.7 v 8.8 months; HR, 1.21; one-sided P = .9829) and hepatitis B-infected patients (7.6 v 8.0 months; HR, 1.10; one-sided P = .8286), but was shorter with sunitinib in hepatitis C-infected patients (9.2 v 17.6 months; HR, 1.52; one-sided P = .9835). Sunitinib was associated with more frequent and severe adverse events (AEs) than sorafenib. Common grade 3/4 AEs were thrombocytopenia (29.7%) and neutropenia (25.7%) for sunitinib; hand-foot syndrome (21.2%) for sorafenib. Discontinuations owing to AEs were similar (sunitinib, 13.3%; sorafenib, 12.7%). CONCLUSION: OS with sunitinib was not superior or equivalent but was significantly inferior to sorafenib. OS was comparable in Asian and hepatitis B-infected patients. OS was superior in hepatitis C-infected patients who received sorafenib. Sunitinib-treated patients reported more frequent and severe toxicity.

Factors contributing to the overall survival in patients with hepatocellular carcinoma treated by sorafenib.

BACKGROUND/AIMS: In both SHARP and Asia-Pacific Study, sorafenib was proved to improve the overall survival of the patients with hepatocellular carcinoma. However, factors contributing to the improvement of overall survival of the patients treated by sorafenib have not been fully evaluated. In this study, patient-derived, background liver disease-derived and tumor-derived factors before treatment were evaluated whether they have contributed to the improvement of the overall survival. METHODOLOGY: Forty-seven cases with HCC treated by sorafenib between Sept 2009 and Feb 2011 were included in this analysis. The survival of these cases was analyzed by Kaplan-Meier Method. Factors used for univariate analysis were two patient-derived parameters, two background liver disease-derived, five tumor-derived. Factors related to the over-all survival were analyzed by multivariate analysis using Cox regression model. RESULTS: In the multivariate analysis, only background liver disease-derived parameter Child-Pugh class A vs. B, (p=0.007, HR=0.21 (0.07-0.65)) was significant. No other parameters including tumor-derived factors were statistically significant by multivariate analysis. CONCLUSIONS: We undertook the statistical analysis on the three categories. Surprisingly, no tumor derived parameter contributed to the overall survival. Background liver disease-derived parameter rather than tumor-derived parameter was found to define the prognosis of patients with advanced HCC treated by sorafenib.

A randomized trial of 24 versus 48 weeks of peginterferon α-2a in patients infected with chronic hepatitis C virus genotype 2 or low viral load genotype 1: a multicenter national study in Japan.

In a country such as Japan with the average age of patients with chronic hepatitis C treated with antivirals sometimes well above 60 years, the standard combination therapy is not well tolerated. In this randomized, prospective, controlled trial, we investigated the efficacy of 24-week peginterferon α monotherapy for easy-to-treat patients. A total of 132 patients chronically infected with hepatitis C virus (HCV) genotype 2 (n = 115) or low viral load HCV genotype 1 (<100 kIU/ml, n = 17) were treated with peginterferon α-2a (180 µg/week). Patients with a rapid virological response (RVR, HCV RNA negative or <500 IU/ml at week 4) were randomized for a total treatment duration of 24 (group A) or 48 (group B) weeks. Patients who did not show RVR (group C) were treated for 48 weeks. Sustained virological response (SVR) was assessed by qualitative reverse-transcription polymerase chain reaction. One hundred eight of 132 (82%) patients with RVR were randomized. SVR rates were 60% (group A), 79% (group B), and 27% (group C), respectively. Similar SVR rates were achieved in patients infected with HCV genotype 2 with low pretreatment viral load (<1000 kIU/ml) in group A (81%) and group B (79%) (P = 0.801), whereas in those with higher viral load (≥1000 kIU/ml), a lower SVR rate was identified in group A (26%) than in group B (67%) (P = 0.041). In conclusion, in patients infected with HCV genotype 2 and pretreatment viral load below 1000 kIU/ml who achieve RVR, 24-week treatment with peginterferon α-2a alone is clinically sufficient. Those who show no RVR or have higher baseline viral load, require alternative therapies.

Efficacy and safety of faropenem in eradication therapy of Helicobacter pylori.

AIMS: While triple therapy with a proton pump inhibitor, amoxicillin, and clarithromycin is the standard therapy for Helicobacter pylori eradication, it is ineffective against clarithromycin-resistant strains. To seek a better regimen for eradication therapy, we assessed the sensitivity of clinical strains seen in Japan to faropenem and then evaluated the efficacy and safety of eradication therapy containing this antibiotic. METHODS: Minimum inhibitory concentrations (MICs) of faropenem were determined in 78 Japanese clinical H. pylori isolates using the agar dilution method. H. pylori-positive patients were consecutively assigned to a 7-day eradication therapy protocol with LAF (lansoprazole 60 mg/day, amoxicillin 2000 mg/day, and faropenem 600 mg/day), and then to a 14-day protocol. The outcomes of the therapies were assessed by (13)C-urea breath tests. RESULTS: All 78 strains showed MICs of faropenem that were equal to or less than 0.2 microg/mL. The eradication rates according to intention-to-treat analyses were 46.5% with the 7-day therapy (n = 43) and 62.5% with the 14-day therapy (n = 32). No special measures were required to treat the adverse events observed in approximately one-third of the patients. CONCLUSIONS: Faropenem was found to have good antimicrobial action against H. pylori in vitro. The 14-day LAF therapy successfully eradicated H. pylori in about two-thirds of the patients although the incidence of adverse events was high.

Cutting edge: The IkappaB kinase (IKK) inhibitor, NEMO-binding domain peptide, blocks inflammatory injury in murine colitis.

Inflammatory mediators such as TNF-alpha, IL-6, and IL-1 are important in the pathogenesis of inflammatory bowel diseases and are regulated by the activation of NF-kappaB. The aim of the present study was to investigate whether the NF-kappaB essential modulator (NEMO)-binding domain (NBD) peptide, which has been shown to block the association of NEMO with the IkappaB kinasebeta subunit (IKKbeta) and inhibit NF-kappaB activity, reduces inflammatory injury in mice with colitis. Two colitis models were established by the following: 1) inclusion of dextran sulfate sodium salt (DSS) in the drinking water of the mice; and 2) a trinitrobenzene sulfonic acid enema. Marked NF-kappaB activation and expression of proinflammatory cytokines were observed in colonic tissues. The NBD peptide ameliorated colonic inflammatory injury through the down-regulation of proinflammatory cytokines mediated by NF-kappaB inhibition in both models. These results indicate that an IKKbeta-targeted NF-kappaB blockade using the NBD peptide could be an attractive therapeutic approach for inflammatory bowel disease.

Efficacy of peppermint oil as an antispasmodic during endoscopic retrograde cholangiopancreatography.

BACKGROUND: During endoscopic retrograde cholangiopancreatography (ERCP), hyoscine-N-butylbromide (Buscopan) or glucagon is used to inhibit duodenal motility. However, they may cause adverse effects. Peppermint oil has an antispasmodic effect and is used as a less hazardous antispasmodic during colonoscopy and upper gastrointestinal endoscopy. The purpose of the present paper was therefore to investigate peppermint as an antispasmodic for ERCP. METHODS: Forty patients were enrolled prospectively. They were assigned to four groups according to the peppermint oil concentration and site of administration: group 1, 20 mL of 1.6% solution around duodenal papilla; group 2, 20 mL of 1.6% solution both to the antrum of the stomach and around the duodenal papilla; group 3, 20 mL of 3.2% solution around the duodenal papilla; and group 4, 3.2% solution both to the antrum and around the duodenal papilla. Glucagon or hyoscine-N-butylbromide was added when duodenal peristalsis was not adequately diminished. Sixteen patients undergoing ERCP with glucagon were employed as historical controls. RESULTS: The ERCP was attempted in all except one patient in group 2 who had bleeding from invaded tumor to the duodenum. Peppermint administration equally reduced duodenal motility in the groups. Duodenal movement was none or mild in 69.2% of patients. The ERCP was successfully performed with peppermint alone in 91.4% of patients (37/39). Glucagon or hyoscine-N-butylbromide was needed in one patient each in groups 1 and 4. Serious complications related to peppermint oil did not occur. Inhibitory effect of peppermint appears to be identical to that of glucagon. CONCLUSION: Duodenal relaxation was obtained with 20 mL of 1.6% peppermint oil solution in the duodenum, but additional administration may be required. Peppermint oil is useful as an antispasmodic agent for ERCP.

Prospective cohort study of transarterial chemoembolization for unresectable hepatocellular carcinoma in 8510 patients.

BACKGROUND & AIMS: To elucidate the survival of the patients with unresectable hepatocellular carcinoma (HCC) who underwent transcatheter arterial lipiodol chemoembolization (TACE) and to analyze the factors affecting the survivals. METHODS: During the last 8 years, a nationwide prospective cohort study was performed in 8510 patients with unresectable HCC who underwent TACE using emulsion of lipiodol and anticancer agents followed by gelatin sponge particles as an initial treatment. Exclusion criteria were extrahepatic metastases and/or any previous treatment prior to the present TACE. The primary end point was survival. The survival rates were calculated by the Kaplan-Meier method. The multivariate analyses for the factors affecting survival were evaluated by the Cox proportional hazard model. The mean follow-up period was 1.77 years. RESULTS: For overall survival rates by TACE, median and 1-, 3-, 5-, and 7-year survivals were 34 months, 82%, 47%, 26%, and 16%, respectively. Both the degree of liver damage and the tumor-node-metastasis (TNM) system proposed by the Liver Cancer Study Group of Japan demonstrated good stratification of survivals (P = .0001). The multivariate analyses showed significant difference in degree of liver damage (P = .0001), alpha-fetoprotein value (P = .0001), maximum tumor size (P = .0001), number of lesions (P = .0001), and portal vein invasion (P = .0001). The last 3 factors could be replaced by TNM stage. The TACE-related mortality rate after the initial therapy was .5%. CONCLUSIONS: TACE showed safe therapeutic modality with a 5-year survival of 26% for unresectable HCC patients. The degrees of liver damage, TNM stage, and alpha-fetoprotein values were independent risk factors for patient survival.

The herbal medicine inchin-ko-to (TJ-135) induces apoptosis in cultured rat hepatic stellate cells.

Use of herbal remedies in the treatment of various diseases has a long tradition in Eastern medicine and the liver diseases are not an exception. In their use, lack of elucidation of mechanism(s) as well as randomized, placebo-controlled clinical trials has been a problem. Recently, we and others reported that inchin-ko-to (TJ-135), one of herbal remedies, suppressed hepatic fibrosis in animal models. In the course of clarifying the mechanism, we directed our focus on hepatic stellate cells (HSCs), playing a pivotal role in hepatic fibrosis, and found that rat HSCs cultured with TJ-135 changed their morphology to star-like configuration with thin, slender and dendritic processes with fewer stress fibers, which might be the features in apoptosis. In fact, TJ-135 induced HSC apoptosis in a time- and concentration-dependent manner as judged by the nuclear morphology, quantitation of cytoplasmic histone-associated DNA oligonucleosome fragments and caspase 3 activity. In HSCs treated with TJ-135, increased expression of p53 and decreased expression of Bcl-2 and phosphorylated Akt and Bad were determined. HSC apoptosis is shown to be involved in the mechanisms of spontaneous resolution of rat hepatic fibrosis and the agent which induces HSC apoptosis has been shown to reduce experimental hepatic fibrosis in rats. Thus, the induction of HSC apoptosis could be the mechanism how TJ-135 works on the resolution of hepatic fibrosis. Our current data may shed light on the novel effect of the herbal remedy.

Branched-chain amino acids, hepatocyte growth factor and protein production in the liver.

Although the functions associated with differentiation are thought to be suppressed when cells proliferate, recent studies have shown that several mitogens can stimulate functions such as protein production under certain physiological conditions. Hepatocyte growth factor (HGF) is now considered to be a pluripotent factor and has been shown to stimulate the differentiated functions of hepatocytes, as well as their proliferation. The use of HGF for the treatment of liver disease, especially hepatic failure, has been suggested. Because patients with decompensated liver cirrhosis have decreased plasma concentrations of branched-chain amino acids (BCAAs), many investigations in laboratory animals and patients have been designed to demonstrate the benefits of supplementation of BCAAs on the hepatic metabolism of proteins. However, the mechanisms involved in the specific actions of BCAAs remain to be elucidated. Amino acids are molecules that modulate numerous cellular functions. BCAAs are known to influence gene expression, cellular metabolism, amino acid transport, and protein turnover. In this paper, we show the potential of BCAAs for stimulating HGF synthesis in the liver and discuss the possibility that BCAAs stimulate protein production by hepatocytes through the induction of HGF.

Vitamin K2 inhibits the growth and invasiveness of hepatocellular carcinoma cells via protein kinase A activation.

Hepatocellular carcinoma (HCC) is a common human malignancy. Its high mortality rate is mainly a result of high intrahepatic recurrence and portal venous invasion (PVI). We previously reported that the development of PVI is related to levels of des-gamma-carboxy prothrombin (DCP), a serum protein that increases at a notably higher rate in patients with HCC. Because DCP is produced by a vitamin K shortage, we examined the biological effects of extrinsic supplementation of vitamin K(2) in HCC cells in vitro and in vivo. Consequently, vitamin K(2) inhibits the growth and invasion of HCC cells through the activation of protein kinase A, which modulates the activities of several transcriptional factors and inhibits the small GTPase Rho, independent of suppression of DCP. In addition, administration of vitamin K(2) to nude mice inoculated with liver tumor cells reduced both tumor growth and body weight loss. In conclusion, similar to an acyclic retinoid--which was previously reported to prevent the recurrence of HCC--vitamin K(2), another lipid-soluble vitamin, may be a promising therapeutic means for the management of HCC.

Significance of branched chain amino acids as possible stimulators of hepatocyte growth factor.

Amino acids can serve as regulatory molecules that modulate numerous cellular functions. Branched chain amino acids (BCAAs) are known to exert influences on cellular metabolism, amino acid transport, protein turn over, and gene expression. However, the mechanisms involved in the specific effect of BCAAs have not been clarified. BCAA supplementation therapy is a current treatment for patients with liver cirrhosis, therefore, specific BCAA activities should be examined. Hepatocyte growth factor (HGF) is considered to be a pleiotropic factor, and is reported to modulate gene expression and to stimulate the proliferation and functions of many cell types, including hepatocytes. A potential application of HGF for several types of diseases has been postulated. Here, we describe the potential of BCAAs as a therapeutic agent that acts through the induction of HGF production in the liver.

Structural and functional characterization of gastric mucosa and central nervous system in histamine H2 receptor-null mice.

To examine the physiological role of the histamine H(2) receptor, histamine H(2) receptor-null mice were generated by homologous recombination. Histamine H(2) receptor-null mice, which developed normally and were fertile and healthy into adulthood, exhibited markedly enlarged stomachs and marked hypergastrinemia. The former was due to hyperplasia of gastric gland cells (small-sized parietal cells, enterochromaffin-like cells and mucous neck cells which were rich in mucin), but not of gastric surface mucous cells, which were not increased in number as compared with those in wild-type mice despite the marked hypergastrinemia. Basal gastric pH was slightly but significantly higher in histamine H(2) receptor-null mice. Although carbachol but not gastrin induced in vivo gastric acid production in histamine H(2) receptor-null mice, gastric pH was elevated by both muscarinic M(3) and gastrin antagonists. Thus, both gastrin and muscarinic receptors appear to be directly involved in maintaining gastric pH in histamine H(2) receptor-null mice. Interestingly, gastric glands from wild-type mice treated with an extremely high dose of subcutaneous lansoprazole (10 mg/kg body weight) for 3 months were very similar to those from histamine H(2) receptor-null mice. Except for hyperplasia of gastric surface mucous cells, the findings for gastric glands from lansoprazole-treated wild-type mice were almost identical to those from gastric glands from histamine H(2) receptor-null mice. Therefore, it is possible that the abnormal gastric glands in histamine H(2) receptor-null mice are secondary to the severe impairment of gastric acid production, induced by the histamine H(2) receptor disruption causing marked hypergastrinemia. Analyses of the central nervous system (CNS) of histamine H(2) receptor-null mice revealed these mice to be different from wild-type mice in terms of spontaneous locomotor activity and higher thresholds for electrically induced convulsions. Taken together, these results suggest that (1) gastrin receptors are functional in parietal cells in histamine H(2) receptor-null mice, (2) abnormal gastric glands in histamine H(2) receptor-null mice may be secondary to severe impairment of gastric acid production and secretion and (3) histamine H(2) receptors are functional in the central nervous system.

Effect of cervical vagal nerve stimulation on defibrillation energy: a possible adjunct to efficient defibrillation.

The efficacy of electrical defibrillation is considered to be related to the autonomic status. In search of a possible adjunct to enhance the therapeutic performance of an implantable cardioverter-defibrillator. we investigated whether parasympathetic manipulation by cervical vagal nerve stimulation (VNS) increases defibrillation efficacy. The effects of VNS on transcardiac defibrillation threshold (DFT) were assessed in 55 anesthetized dogs. In neurally intact dogs, right and left unilateral VNS at 10 mA for 7 seconds significantly decreased the DFT after 10 seconds of ventricular fibrillation (control: 3.1 +/- 0.9 J, right: 2.1 +/- 0.9 J [delta-35 +/- 12%, P < 0.0001], left: 2.2 +/- 0.8 J [delta-31 +/- 11%, P < 0.0005]), while bilateral VNS did not (2.8 +/- 1.0 J). In dogs with decentralized vagus nerves, both unilateral and bilateral VNS decreased the DFT. The extent of the VNS-induced decrease in DFT was dependent on the current and the duration of stimulation. We conclude that unilateral VNS decreases the DFT, while bilateral VNS paradoxically has no effect on the DFT unless the vagi are decentralized.

A novel mitochondrial Ca2+-dependent solute carrier in the liver identified by mRNA differential display.

Pancreatic AR42J cells have the feature of pluripotency of the precursor cells of the gut endoderm. Dexamethasone converts them to exocrine cells or liver cells. Using mRNA differential display techniques, we have identified a novel Ca2+-dependent member of the mitochondrial solute carrier superfamily, which is expressed during the course of differentiation, and have designated it MCSC. The corresponding cDNA comprises an open reading frame of 1407 base pairs encoding a polypeptide of 469 amino acids. The carboxyl-terminal-half of MCSC has high similarity with other mitochondrial carriers, and the amino-terminal-half has three canonical elongation factor-hand motifs and has calcium binding capacity. The deduced amino acid sequence revealed 79.1% homology to the rabbit peroxisomal Ca2+-dependent member of the mitochondrial superfamily, but the subcellular localization of the protein was exclusively mitochondrial, not peroxisomal. Northern blot and Western blot analyses revealed its predominant expression in the liver and the skeletal muscle. In the liver, the expression level of MCSC was higher in the adult stage than in the fetal stage, and MCSC was highly up-regulated in dexamethasone-treated AR42J cells before the expression of albumin. Taken together, MCSC may play an important role in regulating the function of hepatocytes rather than in differentiation in vivo.