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Background and Aim Reliable predictors for hepatocellular carcinoma (HCC) are urgently needed. The psoas muscle index (PMI) is a simple and rapid method for evaluating muscle atrophy. Furthermore, the neutrophil/lymphocyte ratio (NLR) is a prognostic factor that is easy to calculate in everyday clinical practice. We aimed to investigate the value of the PMI and NLR as prognostic factors for patients receiving nonsurgical HCC therapy, hepatic arterial infusion chemotherapy (HAIC), transcatheter arterial chemoembolization (TACE), or molecular targeted drugs such as sorafenib (SOR) and lenvatinib (LEN). Methods We enrolled 87 patients with HCC who were treated with HAIC, TACE, SOR, or LEN. The primary endpoint was overall survival (OS) with variable PMI or NLR status. For Barcelona Clinic Liver Cancer (BCLC)‐B patients, useful prognostic factors were examined by comparing the OS between stratified groups. Prognostic factors including PMI and NLR were evaluated by univariate and multivariate analysis. Results Analysis of HAIC or TACE (HAIC/TACE) and SOR or LEN (SOR/LEN) patients showed significant differences in OS between low and high PMI. In patients treated with TACE, there was a significant difference in OS between low and high NLR. For BCLC‐B and low PMI, the prognosis was significantly worse for SOR/LEN than for TACE, although there was no difference for high PMI, suggesting that PMI may be useful for treatment selection. In addition, the prognostic formula composed of PMI, NLR, and up‐to‐seven criteria developed in the present study may be useful. Conclusion PMI and NLR are considered to be independent prognostic factors for HCC., Psoas muscle index (PMI) was an independent predictor for all nonsurgical hepatocellular carcinoma (HCC) treatments, and neutrophil/lymphocyte ratio (NLR) was a significant predictor for transcatheter arterial chemoembolization (TACE). In Barcelona Clinic Liver Cancer (BCLC)‐B, if the PMI was low, sorafenib (SOR) or lenvatinib (LEN) was associated with a poor prognosis, and thus PMI may be useful for guiding the choice of treatment. The formula combining PMI and NLR (= 0.555 × [up‐to‐seven out:1, in:0] + 0.161 × NLR − 0.191 × PMI) appears to be useful for predicting the prognosis of HCC.

It is unclear whether there is any difference in the background and prognosis between non-elderly patients who undergo catheter ablation of atrial fibrillation (AF) and common atrial flutter (CAFL).To investigate the difference between the patient background of both CAFL and AF in the non-elderly.In 526 consecutive patients who underwent catheter ablation of clinical paroxysmal/persistent CAFL or AF in our hospital, we enrolled only patients under 60 years old. Cases harboring both AFL and AF were excluded. We analyzed the patient characteristics, echocardiographic findings, electrocardiographic (ECG) abnormalities during sinus rhythm, and clinical course after ablation.In total, 196 patients (Cohort 1: 142 males, 156 AF cases) were analyzed. AFL patients were younger than AF patients (47.4 ± 10.6 vs. 50.2 ± 6.4years, p = 0.031) and organic heart disease (OHD) was significantly more common in AFL patients than AF patients (42.5% vs. 11.5%, p0.001). In 161 patients excluding OHD (Cohort 2), ECG abnormalities were more frequent in AFL than in AF patients (78.3% vs. 39.1%, p = 0.001). There were no significant differences in all-cause death, onset of heart failure, and cerebral strokes. On the other hand, the number of cases that required a pacemaker was significantly higher in the CAFL group than AF group (0.0% vs. 26.1%, p-value0.001). These results suggested that CAFL may reflect occurrence of any atrial myocardial damage, even if it does not lead to heart failure.Our present study suggested that CAFL may be associated with a broader atrial myocardial disorder in non-elderly patients.

Fulminant myocarditis is an inflammatory disease of the cardiac muscle that severely deteriorates cardiac function and often causes haemodynamic collapse in a manner similar to acute coronary syndrome. In rare cases, the myocardium of the right ventricle is dominantly damaged. In cases of lymphocytic myocarditis, a common type of fulminant myocarditis, cardiac function is often recovered after peak myocardial inflammation subsides; however, some cases show irreversible myocardial damage. Herein, we report the case of a 43‐year‐old woman with irreversible, right‐side dominant ventricular myocardial damage; she presented with various cardiopulmonary conditions including complete atrioventricular block, ventricular tachycardia, right heart failure, right ventricular thrombosis, and pulmonary embolism. The patient was successfully treated with medications and a cardiac resynchronization therapy‐defibrillator device.

To date, studies of patients with islet transplantation addressing intermittently scanned continuous glucose monitoring profile and the flexibility of the graft islet function under different doses of insulin administration, both of which reflect the real daily life of patients, are quite limited. Here, we report a case of a 46‐year‐old woman who received islet transplantation after kidney transplantation. The patient was followed up over a period of 2 years after initial islet transplantation. Our results show that intermittently scanned continuous glucose monitoring can be useful for monitoring the reduction of glycemic variability, and suggest the appropriate regulation of insulin secretion from graft islets during mixed‐meal test by using different doses of exogenous insulin administration. Additionally, during the 2‐year observational period, glucagon elevation was detected only at hypoglycemia, whereas the level was within the normal range at normoglycemia or hyperglycemia., Our study shows that intermittently scanned continuous glucose monitoring can be useful for monitoring the reduction of glycemic variability after islet transplantation, and suggests the appropriate regulation of insulin secretion from graft islets during mixed‐meal test by using different doses of exogenous insulin administration. During the 2‐year observation period, glucagon elevation was detected only at hypoglycemia, whereas the level was within the normal range at normoglycemia or hyperglycemia.

Previous studies have shown that the sudden cardiac death (SCD) prediction model proposed by the 2014 European Society of Cardiology (ESC) guideline (5-Year Risk-SCD) was validated in European patients with hypertrophic cardiomyopathy (HCM). However, there are limited data on Asian patients with HCM. We assessed the validity of the estimated 5-Year Risk-SCD in Japanese HCM patients with an implantable cardioverter-defibrillator (ICD) using the2014 ESC guidelines. We retrospectively examined data of 492 consecutive Japanese patients with an ICD. Sixty-two Japanese HCM patients with an ICD were enrolled in this study, and 50 patients (81%) were followed up for ≥ 5 years. We analyzed the characteristics and outcomes of these 50 patients. We investigated the incidence of appropriate ICD therapy as categorized by the ESC guideline and compared the 5-Year Risk-SCD with the 5-year rate of appropriate shock therapies. Based on the 2012 Japanese Circulation Society guideline and the 2011guidelines of the American Heart Association and American College of Cardiology Foundation, 10 and 40 patients met classes I and IIa of the ICD recommendation, respectively. However, only 18 (36%) patients were classified into class I or IIa of the ESC guideline. Among 50 patients followed up for ≥ 5 years after ICD implantation, the incidences of appropriate ICD therapies for classes I, IIa, IIb, and III indications based on the 2014 ESC guideline were 50%, 38%, 17%, and 0%, respectively. Risk stratification for SCD using 5-Year Risk-SCD is valid in Japanese HCM patients with an ICD, and the 2014 ESC guideline might be useful for the indication of ICD implantation in Japan.

SMARCA4‐deficient thoracic sarcoma (SMARCA4‐DTS) is a new clinical entity characterized by SMARCA4 inactivation and has a dismal prognosis because of rapid growth. Effective treatments for SMARCA4‐DTS have not yet been developed. Most recently, anti‐programmed cell death 1 receptor (PD‐1) blockade has been effective for SMARCA4‐deficient lung cancer and malignant rhabdoid tumor‐like tumors. Here, we describe a patient with SMARCA4‐DTC who experienced a marked response to the administration of pembrolizumab. A 70‐year‐old female was referred to our department for treatment of SMARCA4‐DTC. Positron emission tomography‐computed tomography had revealed a left mediastinal tumor, peritoneal dissemination and multiple cutaneous metastases at diagnosis. Immunohistochemical analyses revealed 60% of tumor cells expressed programmed cell death ligand 1 (PD‐L1). The patient was given pembrolizumab as first‐line treatment. Pembrolizumab suppressed tumor growth dramatically, with only one dose leading to a partial response. Our case suggests the immunohistochemical analysis of PD‐L1 expression be undertaken for patients with SMARCA4‐DTS and that pembrolizumab treatment may be a promising strategy for PD‐L1‐positive SMARCA4‐DTS.

Aims/Introduction To investigate the long‐term efficacy and safety of islet transplantation (ITx) compared with multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII). Materials and Methods Among 619 patients diagnosed as insulin‐dependent diabetes mellitus or type 1 diabetes at Kyoto University, Kyoto, Japan, seven patients were selected as the ITx group and 26 age‐matched patients with no endogenous insulin secretion were selected as the MDI/CSII group. Hemoglobin A1c, aspartate aminotransferase/alanine aminotransferase (AST/ALT) and creatinine were assessed retrospectively at 1, 2, 5 and 10 years for both groups; serum C‐peptide immunoreactivity was assessed for the ITx group. Major clinical events were also assessed. Results Hemoglobin A1c improvement in ITx was significant at 1 year (8.4% [7.8–9.9%] at baseline to 7.1% [6.3–7.4%] in ITx vs 8.2% [7.4–9.8%] at baseline to 8.1% [7.3–9.5%] in MDI/CSII, P, This study focuses on the efficacy, possible adverse events and effects on major organ function of islet transplantation during 10‐year follow up, in comparison with conventional insulin therapy. Islet transplantation achieved an improvement in glycemic control corresponding to graft function and a tendency to reduction of severe hypoglycemia, with tolerable, but attention‐requiring, risks, such as transient elevation of transaminase, infectious disease, digestive symptoms and malignancy, and with no mortality.

Non-alcoholic steatohepatitis (NASH)-related HCC is associated with oxidative stress. However, the mechanisms underlying the development of NASH-related HCC is unclear. MUTYH is one of the enzymes that is involved in repair of oxidative DNA damage. The aim of this study was to investigate the association between MUTYH and NASH-related hepatocarcinogenesis. MUTYH wild-type (Mutyh+/+), heterozygous (Mutyh+/−), and MUTYH-null (Mutyh−/−) mice were fed a high-fat high-cholesterol (HFHC) diet or HFHC + high iron diet (20 mice per group) for 9 months. Five of 20 Mutyh−/− mice fed an HFHC + high iron diet developed liver tumors, and they developed more liver tumors than other groups (especially vs. Mutyh+/+ fed an HFHC diet, P = 0.0168). Immunohistochemical analysis revealed significantly higher accumulation of oxidative stress markers in mice fed an HFHC + high iron diet. The gene expression profiles in the non-tumorous hepatic tissues were compared between wild-type mice that developed no liver tumors and MUTYH-null mice that developed liver tumors. Gene Set Enrichment Analysis identified the involvement of the Wnt/β-catenin signaling pathway and increased expression of c-Myc in MUTYH-null liver. These findings suggest that MUTYH deficiency is associated with hepatocarcinogenesis in patients with NASH with hepatic iron accumulation.

The host environment is a crucial factor for considering the transplant of stem cell–derived immature pancreatic cells in patients with type 1 diabetes. Here, we investigated the effect of insulin (INS)-deficient diabetes on the fate of immature pancreatic endocrine cell grafts and the underlying mechanisms. Human induced pluripotent stem cell–derived pancreatic endocrine progenitor cells (EPCs), which contained a high proportion of chromogranin A+ NK6 homeobox 1+ cells and very few INS+ cells, were used. When the EPCs were implanted under the kidney capsule in immunodeficient mice, INS-deficient diabetes accelerated increase in plasma human C-peptide, a marker of graft-derived INS secretion. The acceleration was suppressed by INS infusion but not affected by partial attenuation of hyperglycemia by dapagliflozin, an INS-independent glucose-lowering agent. Immunohistochemical analyses indicated that the grafts from diabetic mice contained more endocrine cells including proliferative INS-producing cells compared with that from nondiabetic mice, despite no difference in whole graft mass between the two groups. These data suggest that INS-deficient diabetes upregulates the INS-secreting capacity of EPC grafts by increasing the number of endocrine cells including INS-producing cells without changing the graft mass. These findings provide useful insights into postoperative diabetic care for cell therapy using stem cell–derived pancreatic cells.

GPR40/FFAR1 is a G-protein-coupled receptor expressed in pancreatic islets and enteroendocrine cells. SCO-267 is a novel full agonist of GPR40 being developed as a treatment for type 2 diabetes and obesity. The efficacy of SCO-267 was investigated in cells and animal models of diabetes and obesity. In animal studies, the efficacy of SCO-267 was compared with that of fasiglifam, a clinically effective GPR40 agonist. SCO-267 treatment activated Gq signaling in both high and low GPR40-expressing CHO cells, stimulated insulin secretion in MIN6 cells, and induced GLP-1 release in GLUTag cells. In rats, SCO-267 increased insulin, glucagon, GLP-1, GIP, and PYY secretion, without hypoglycemia. In the neonatal streptozotocin (N-STZ)-1.5 rat, a diabetic model with impaired beta-cell function, compared to fasiglifam, SCO-267 was more effective in stimulating insulin and GLP-1 secretion, and improving glucose tolerance. In a single dose study using N-STZ-1.5 rats, 0.3 mg/kg SCO-267 (Cmax 0.023 μg/mL) and 3 mg/kg fasiglifam (Cmax 6.2 μg/mL) exhibited similar glucose-lowering efficacies. In a two-week dosing study of N-STZ-1.5 rats, glucose tolerance was more effectively improved by 1 mg/kg SCO-267 (Cmax, 0.139 μg/mL; AUC0-24hr, 0.626 μg h/mL) than by 10 mg/kg fasiglifam (Cmax, 39.8 μg/mL; AUC0-24hr, 254.6 μg h/mL). Diet-induced obese rats treated with SCO-267 for 2 weeks showed elevated plasma GLP-1 and PYY, reduced food intake, and decreased body weight, whereas fasiglifam-treated rats were weight-neutral. The reduction in body weight by SCO-267 was abolished in GPR40 knockout mice. Plasma protein binding of SCO-267 was similar across species (99.6-99.7%), indicating that similar compound exposure may induce therapeutic effects in humans. SCO-267 showed good pharmacokinetic and safety profiles in preclinical studies. These results suggest that SCO-267 treatment may result in effective glycemic and body weight control in patients. Disclosure Y. Moritoh: Employee; Self; SCOHIA PHARMA, Inc. H. Ueno: Employee; Self; Takeda Pharmaceutical Company Limited. R. Ito: Employee; Self; Takeda Pharmaceutical Company Limited. S. Abe: Employee; Self; SCOHIA PHARMA, Inc. H. Miyashita: Employee; Self; Takeda Pharmaceutical Company Limited. H. Ogino: Employee; Self; Takeda Pharmaceutical Company Limited. M. Ookawara: Employee; Self; SCOHIA PHARMA, Inc. Y. Ishimura: Employee; Self; Takeda Pharmaceutical Company Limited. Y. Miyamoto: None. T. Yoshihara: Employee; Self; Takeda Pharmaceutical Company Limited. Employee; Spouse/Partner; Takeda Pharmaceutical Company Limited. Y. Tsujihata: Employee; Self; Takeda Pharmaceutical Company Limited. K. Takeuchi: Employee; Self; Takeda Pharmaceutical Company Limited. N. Nishigaki: Employee; Self; Takeda Pharmaceutical Company Limited. Y. Yamada: Board Member; Self; SCOHIA PHARMA, Inc. M. Watanabe: Employee; Self; SCOHIA PHARMA, Inc. Funding Takeda Pharmaceutical Company Limited; SCOHIA PHARMA, Inc.

Introduction Immune checkpoint inhibitors are a promising class of anticancer drugs. The clinical benefits afforded by immune checkpoint inhibitors can be accompanied by immune-related adverse events that affect multiple organs, and endocrine immune-related adverse events include thyroiditis and hypophysitis. Hypophysitis is less frequent and has a less severe clinical presentation in patients treated with other immune checkpoint inhibitors, such as nivolumab, pembrolizumab, and atezolizumab, than in those treated with ipilimumab. However, studies have described isolated adrenocorticotropic hormone deficiency cases associated with nivolumab, pembrolizumab, and atezolizumab therapy, most of which occurred during the course of immune checkpoint inhibitor therapy. We report a rare case of patient with isolated adrenocorticotropic hormone deficiency that occurred after nivolumab therapy. Case presentation A 69-year-old Japanese woman with advanced lung adenocarcinoma developed painless thyroiditis with transient elevations of serum thyroid hormones during 3 months of cancer treatment with nivolumab and began thyroid hormone replacement therapy for subsequent primary hypothyroidism. Four months after nivolumab therapy was discontinued, she developed isolated adrenocorticotropic hormone deficiency; corticosteroid replacement therapy relieved her secondary adrenal insufficiency symptoms, such as anorexia and fatigue. Human leukocyte antigen typing revealed the presence of DRB1*04:05-DQB1*04:01-DQA1*03:03 and DRB1*09:01-DQB1*03:03-DQA1*03:02 haplotypes, which increase susceptibility to autoimmune polyendocrine syndrome associated with thyroid and pituitary disorders in the Japanese population. Conclusions Our patient developed thyroiditis during cancer treatment with nivolumab and subsequently exhibited isolated adrenocorticotropic hormone deficiency 4 months after discontinuing the drug. Administration of nivolumab in combination with a genetic predisposition to polyglandular autoimmunity probably caused both the thyroiditis and hypophysitis, resulting in primary hypothyroidism and isolated adrenocorticotropic hormone deficiency, respectively, in our patient. The present case highlights the need for physicians to be aware that endocrine immune-related adverse events, including hypophysitis, can occur more than several months after discontinuing a drug.

The GPR40/FFA1 receptor is a G-protein-coupled receptor expressed in the pancreatic islets and enteroendocrine cells. Here, we report the pharmacological profiles of (3S)-3-cyclopropyl-3-{2-[(1-{2-[(2,2-dimethylpropyl)(6-methylpyridin-2-yl)carbamoyl]-5-methoxyphenyl}piperidin-4-yl)methoxy]pyridin-4-yl}propanoic acid (SCO-267), a novel full agonist of GPR40. Ca2+ signaling and insulin and glucagon-like peptide-1 (GLP-1) secretion were evaluated in GPR40-expressing CHO, MIN6, and GLUTag cells. Hormone secretions and effects on fasting glucose were tested in rats. Single or repeated dosing effects were evaluated in neonatally streptozotocin-induced diabetic rats (N-STZ-1.5 rats), diet-induced obese (DIO) rats, and GPR40-knockout (Ffar1-/- ) mice. Treatment with SCO-267 activated Gq signaling in both high- and low-FFAR1-expressing CHO cells, stimulated insulin secretion in MIN6 cells, and induced GLP-1 release in GLUTag cells. When administered to normal rats, SCO-267 increased insulin, glucagon, GLP-1, glucose-dependent insulinotropic peptide, and peptide YY (PYY) secretions under nonfasting conditions. These results show the full agonistic property of SCO-267 against GPR40. Hypoglycemia was not induced in SCO-267-treated rats during the fasting condition. In diabetic N-STZ-1.5 rats, SCO-267 was highly effective in improving glucose tolerance in single and 2-week dosing studies. DIO rats treated with SCO-267 for 2 weeks showed elevated plasma GLP-1 and PYY levels, reduced food intake, and decreased body weight. In wild-type mice, SCO-267 induced GLP-1 secretion, food intake inhibition, and body weight reduction; however, these effects were abolished in Ffar1-/- mice, indicating a GPR40-dependent mechanism. In conclusion, SCO-267 stimulated islet and gut hormone secretion, improved glycemic control in diabetic rats, and decreased body weight in obese rats. These data suggest the therapeutic potential of SCO-267 for the treatment of diabetes and obesity.

Background Atrial fibrillation (AF) is the most common type of arrhythmia. The definition of AF in patients with cardiac implantable electronic devices (CIEDs) is not clear, and the appropriate treatment guideline for patients with episodes of AF has not been established yet. Additionally, little is known about the incidence of AF and embolic stroke events in Japanese patients with CIEDs. The purposes of this study were to identify the incidence of embolic stroke events in Japanese patients with and without AF events detected by CIEDs and to examine the risk factors of embolic stroke events. Methods We retrospectively analyzed the database of our CIED clinic. Every 6 months, episodes of AF were checked by CIEDs. Using univariate (Student's t-test and Fisher's exact test) and multivariate analyses, we examined the characteristics and incidence of embolic stroke events and investigated the relationship between episodes of AF and the incidence of embolic stroke events. Results In this study, we enrolled 348 consecutive patients who had no prior history of AF and were not administering anticoagulants (follow-up period, 65 ± 58 months; age, 70 ± 16 years; male sex, 64%; implantable cardioverter defibrillator, 55%). The mean CHADS2 and CHA2DS2-VASc scores were 1.7 ± 1.1 and 2.8 ± 1.5 points, respectively. Fifty-five patients (16%) had AF events detected by CIEDs that lasted for ≥30 s, and 23 patients (6.6%) had embolic stroke during the follow-up period. Multivariate analysis demonstrated that independent predictors for embolic stroke were a left atrial diameter ≥40 mm [odds ratio (OR) 3.1, 95% confidence interval (CI) 1.2–7.9, p = 0.016] and episodes of AF (OR 5.3, 95% CI 2.2–13, p = 0.0003). Conclusions Embolic stroke events are common in Japanese patients with CIEDs. AF events lasting ≥30 s and an enlarged left atrium are the risk factors of embolic stroke in this population.

Patient: Female, 39-year-old Final Diagnosis: Anaplastic carcinoma of the pancreas • pancreatic cancer Symptoms: Epigastralgia • jaundice Medication: — Clinical Procedure: — Specialty: Gastroenterology and Hepatology • Oncology Objective: Rare disease Background: Anaplastic carcinoma of the pancreas (ACP) is a rare type of cancer with an extremely poor prognosis. Hereditary pancreatitis is a rare autosomal-dominant disease. It progresses to chronic pancreatitis at a young age, increasing the risk of pancreatic cancer. Case Report: A 39-year-old woman was diagnosed with chronic pancreatitis at the age of 18 years. The patient was referred to our hospital for epigastralgia and jaundice. We identified a tumor mass at the head of the pancreas using contrast computed tomography (CT) and endoscopic ultrasound (EUS) of the abdomen. Tissue biopsy revealed ACP of the spindle cell type. We started the patient on combination chemotherapy using gemcitabine and nanoparticle albumin-bound (nab) -paclitaxel, but she died 1 month after her first visit. An autopsy revealed a mixture of tubular adenocarcinoma and anaplastic carcinoma. We performed genetic analysis using DNA samples from the biopsy tissues but did not find mutations in the PRSS1 and SPINK1 genes associated with hereditary pancreatitis. Conclusions: The risk of pancreatic cancer generally increases in patients with hereditary pancreatitis after 50 years of age. However, in this case, the development of pancreatic cancer occurred at a younger age, suggesting the importance of early detection in such cases. Furthermore, this case suggests that EUS is a useful method for monitoring patients with hereditary pancreatitis and the diagnosis of ACP.

A 70-year-old man, treated for asthma for 2 years and chronic sinusitis for several months, presented with fever, numbness in the lower limbs, heaviness in the head, gross hematuria, and black stools. He also had eosinophilia, elevated serum IgG4 levels, high levels of myeloperoxidase-anti-neutrophil cytoplasmic antibodies (MPO-ANCA), and pulmonary infiltrative shadows. Bronchoscopy revealed multiple white flattened lesions (white moss) on the airway mucosa, suggesting mycobacterial infection or malignancy. A biopsy from tracheal mucosa revealed airway inflammation with marked eosinophil infiltration. The patient was diagnosed with eosinophilic granulomatosis with polyangiitis (EGPA) and treated with steroids, and all findings improved. However, a year and a half after the initiation of treatment, eosinophils and IgE gradually increased; subjective symptoms, such as asthma symptoms and numbness in the lower limbs, worsened; and ANCA, which had been negative, turned positive. Therefore, we suspected disease relapse and anti-IL-5 antibody (mepolizumab) treatment was initiated. Thereafter, ANCA turned negative again, eosinophils and IgE normalized, and subjective symptoms decreased. The presence of airway mucosal lesions in EGPA is relatively rare, and we report this case as a valuable case owing to the interesting bronchoscopic findings that are worth comprehending as a respiratory physician.

Sulfonylureas (SUs) are widely used insulin secretagogues, but they have adverse effects including hypoglycemia and secondary failure. Fasiglifam/TAK-875, a selective GPR40 agonist, enhances glucose-stimulated insulin secretion and improves hyperglycemia. In the present study, we compared the in vivo glucose-lowering effects of fasiglifam with SUs. The risk of secondary failure of fasiglifam and the efficacy in rats desensitized to SUs were also evaluated. Moreover, we assessed whether fasiglifam was effective when combined with SUs. In diabetic neonatally streptozotocin-induced rats 1.5 days after birth (N-STZ-1.5), oral administrations of fasiglifam (3-30 mg/kg) dose dependently improved glucose tolerance; the effect was greater than that of glibenclamide at maximal effective doses (glucose AUC: fasiglifam, -37.6%; glibenclamide, -12.3%). Although the glucose-lowering effects of glibenclamide (10 mg/kg/day) were completely diminished in N-STZ-1.5 rats after 4 weeks of treatment, effects were maintained in rats receiving fasiglifam (10 mg/kg/day), even after 15 weeks. Fasiglifam (3-10 mg/kg) was still effective in two models desensitized to SUs: 15-week glibenclamide-treated N-STZ-1.5 rats and aged Zucker diabetic fatty (ZDF) rats. Acute administration of fasiglifam (3 mg/kg) and glimepiride (10 mg/kg) in combination additively decreased glucose AUC (fasiglifam, -25.3%; glimepiride, -20.0%; combination, -43.1%). Although glimepiride (10 mg/kg) decreased plasma glucose below normal in nonfasted control rats, fasiglifam (3 mg/kg) maintained normoglycemia, and no further exaggeration of hypoglycemia was observed with combination treatment. These results indicate that GPR40 agonists could be more effective and durable than SUs. Our results also provide new insights into GPR40 pharmacology and rationale for the use of GPR40 agonists in diabetic patients with SU failure.

The aim of this study is to determine which indicator of chronic kidney disease most closely correlates with 10-year Framingham coronary heart disease (CHD) risk among serum creatinine, serum cystatin C (S-CysC), urine albumin-creatinine ratio (UACR), estimated creatinine-based GFRs (eGFRcre), and estimated CysC-based GFRs (eGFRcys) in patients with obesity and diabetes. Serum creatinine, S-CysC, UACR, and cardio-ankle vascular index (CAVI) were examined in 468 outpatients with obesity and type 2 diabetes, free of severe renal dysfunction or previous history of cardiovascular disease, as a cross-sectional survey using baseline data from the multi-centered Japan Diabetes and Obesity Study. S-CysC and eGFRcys had significantly stronger correlations with the 10-year Framingham CHD risk than serum creatinine, eGFRcre, and UACR (creatinine, ρ = 0.318; S-CysC, ρ = 0.497; UACR, ρ = 0.174; eGFRcre, ρ = -0.291; eGFRcys, ρ = -0.521; P < 0.01 by Fisher's z-test). S-CysC and eGFRcys had significantly stronger correlations with CAVI than serum creatinine, eGFRcre, and UACR (creatinine, ρ = 0.198; S-CysC, ρ = 0.383; UACR, ρ = 0.183; eGFRcre, ρ = -0.302; eGFRcys, ρ = -0.444; P < 0.05 by Fisher's z-test). The receiver operating characteristic curves to distinguish the high-risk patients for CHD revealed significantly larger areas under the curve of S-CysC and eGFRcys than those of serum creatinine, UACR, and eGFRcre (serum creatinine, 0.64; S-CysC, 0.75; UACR, 0.56; eGFRcre, 0.63; eGFRcys, 0.76; P < 0.01). The data suggested that eGFRcys can be more predictive of the 10-year CHD risk than eGFRcre in Japanese patients with obesity and diabetes.

Aim Previous epidemiological studies demonstrated that the ratio of n-6 to n-3 polyunsaturated fatty acids is associated with cardiovascular diseases. We herein investigated whether the beneficial effect of highly purified eicosapentaenoic acid(EPA) on arterial stiffness is associated with changes in the ratio of polyunsaturated fatty acids, such as EPA, docosahexaenoic acid(DHA) and dihomo-γ-linolenic acid(DGLA), relative to arachidonic acid(AA), in obese Japanese patients with dyslipidemia. Methods The EPA/AA, DHA/AA and DGLA/AA ratios were compared between obese patients with(n=94) and without (n=31) dyslipidemia. Among the former group, 88 patients received either highly purified EPA treatment(1.8g daily, n=45) or treatment without EPA(control, n=43). Results At baseline, the ratios of DHA/AA and DGLA/AA were significantly(P＜0.05) higher in obese patients with dyslipidemia than in those without, while the EPA/AA ratio was similar between patients with and without dyslipidemia. EPA significantly reduced the hemoglobin A1c, total cholesterol, triglycerides, CRP, cardio-ankle vascular index(CAVI)(an index of arterial stiffness) and the DGLA/AA ratio relative to the control at three months after the treatment. On the other hand, EPA significantly increased the adiponectin level and EPA/AA ratio(P＜0.05). A multivariate regression analysis revealed that only age, an increase in the EPA/AA ratio and a decrease in the CRP level were significant determinants of a reduction of the CAVI by EPA. Conclusion These findings suggest that EPA improves the arterial stiffness in association with an increase in the EPA/AA ratio and a decrease in inflammation in obese patients with dyslipidemia.

An increase in intra-abdominal fat area (IAFA) is an essential component of metabolic syndrome (MetS). Waist circumference (WC) is not a precise measure of IAFA, and computed tomography (CT) is unsuitable for frequent monitoring. Here, we examined utility of a dual bioelectrical impedance analysis (Dual BIA) for measuring IAFA in obese patients during weight reduction. Fat distribution was measured by Dual BIA and CT in 100 obese outpatients. All fat areas including total, IAFA, and subcutaneous fat by Dual BIA were more closely correlated with those by CT than WC. Estimated IAFA by Dual BIA was significantly correlated with number of MetS components as well as CT, but WC was not. Furthermore, in 61 obese patients who received 6-month weight reduction therapy, estimated IAFA by Dual BIA showed an earlier and greater decrease as well as that by CT than WC and BMI. In addition, decrease in estimated IAFA by Dual BIA through weight reduction had a higher correlation with decrease in IAFA by CT, than WC. This study is the first to demonstrate that the change in estimated IAFA by Dual BIA was highly correlated with that in IAFA by CT during weight reduction therapy. Our findings also indicate that estimated IAFA by Dual BIA is, potentially, a better indicator of severity of MetS, cardiovascular risk factors, and effectiveness of weight reduction than WC, and equal to IAFA by CT. Estimated IAFA by Dual BIA may be useful for monitoring the effectiveness of weight reduction therapy in obese patients.

Background and Purpose TAK-875, a selective GPCR40/free fatty acid receptor 1 agonist, improves glycaemic control by increasing glucose-dependent insulin secretion. Metformin is a first-line drug for treatment of type 2 diabetes that improves peripheral insulin resistance. Based on complementary mechanism of action, combining these agents is expected to enhance glycaemic control. Here, we evaluated the chronic effects of TAK-875 monotherapy and combination therapy with metformin in diabetic rats. Experimental Approach Long-term effects on glycaemic control and β-cell function were evaluated using Zucker diabetic fatty (ZDF) rats, which develop diabetes with hyperlipidaemia and progressive β-cell dysfunction. Key Results Single doses of TAK-875 (3–10 mg·kg−1) and metformin (50–150 mg·kg−1) significantly improved both postprandial and fasting hyperglycaemia, and additive improvements were observed in their combination. Six-week treatment with TAK-875 (10 mg·kg−1, b.i.d.) significantly decreased glycosylated Hb (GHb) by 1.7%, and the effect was additively enhanced by combination with metformin (50 mg·kg−1, q.d.; GHb: −2.4%). This improvement in glycaemic control in the combination group was accompanied by significant 3.2-fold increase in fasting plasma insulin levels. Pancreatic insulin content was maintained at a level comparable to that in normal rats by combination treatment (vehicle: 26, combination: 67.1; normal lean: 69.1 ng·mg−1 pancreas) without affecting pancreatic glucagon content. Immunohistochemical analyses revealed normal morphology, enhanced pancreas duodenum homeobox-1 expression and increased PCNA-positive cells in islets of the combination group. Conclusion and Implications Our results indicate that combination therapy with TAK-875 and metformin could be a valuable strategy for glycaemic control and β-cell preservation in type 2 diabetes.

G protein-coupled receptor 40/free fatty acid receptor 1 (GPR40/FFA(1)) is highly expressed in pancreatic β cells and mediates free fatty acid-induced insulin secretion. This study examined the pharmacological effects and potential for avoidance of lipotoxicity of [(3S)-6-({2',6'-dimethyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}meth-oxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid hemi-hydrate) (TAK-875), a novel, orally available, selective GPR40 agonist. Insulinoma cell lines and primary rat islets were used to assess the effects of TAK-875 in vitro. The in vivo effects of TAK-875 on postprandial hyperglycemia, fasting hyperglycemia, and normoglycemia were examined in type 2 diabetic and normal rats. In rat insulinoma INS-1 833/15 cells, TAK-875 increased intracellular inositol monophosphate and calcium concentration, consistent with activation of the Gqα signaling pathway. The insulinotropic action of TAK-875 (10 μM) in INS-1 833/15 and primary rat islets was glucose-dependent. Prolonged exposure of cytokine-sensitive INS-1 832/13 to TAK-875 for 72 h at pharmacologically active concentrations did not alter glucose-stimulated insulin secretion, insulin content, or caspase 3/7 activity, whereas prolonged exposure to palmitic or oleic acid impaired β cell function and survival. In an oral glucose tolerance test in type 2 diabetic N-STZ-1.5 rats, TAK-875 (1-10 mg/kg p.o.) showed a clear improvement in glucose tolerance and augmented insulin secretion. In addition, TAK-875 (10 mg/kg, p.o.) significantly augmented plasma insulin levels and reduced fasting hyperglycemia in male Zucker diabetic fatty rats, whereas in fasted normal Sprague-Dawley rats, TAK-875 neither enhanced insulin secretion nor caused hypoglycemia even at 30 mg/kg. TAK-875 enhances glucose-dependent insulin secretion and improves both postprandial and fasting hyperglycemia with a low risk of hypoglycemia and no evidence of β cell toxicity.

A 68-year-old woman presented with severe bowel obstruction and was subsequently diagnosed with stage IV gastric cancer with peritoneal dissemination. She was immediately stabilized in the hospital with the placement of a nasointestinal tube. Abdominal computed tomography showed multiple intraperitoneal nodules consistent with peritoneal dissemination of the gastric cancer. The patient's inability to tolerate oral intake was a contraindication to using S-1 chemotherapy, currently one of the most effective medications used for gastric cancer in Japan. Therefore, she was initially treated with octreotide acetate (OA). Her bowel obstruction was sufficiently attenuated on the seventh day after the initiation of treatment with OA to permit the initiation of oral S-1, along with low-dose cisplatin (CDDP) and radiation. S-1 was orally administered at a dose of 100 mg/day per body (80 mg/m(2) per day) on days 1-28, and CDDP was infused at a dose of 7.8 mg/day per body (6 mg/m(2) per day) on days 1-5, 8-12, and 15-19. Radiation therapy (2 Gy/day for 5 days/week) was performed with the chemotherapy. Despite no change being shown on her imaging findings with the chemotherapy, the patient's bowel obstruction resolved and she was able to tolerate both liquids and solid food orally. She was discharged 2 months after admission. Seven months after beginning the chemotherapy, she was still doing well on outpatient chemotherapy with S-1 and CDDP, and had no decline in her quality of life or progression of her disease.

The level of hypohydration at which power output during intermittent exercise performance starts to decrease is not fully understood. The purpose of this study was to investigate the effects of 2% hypohydration without hyperthermia on intermittent exercise performance. Eight collegiate amateur boxers completed 2 exercise tests. On day 1, subjects hypohydrated by 2% of body mass by exercising in a hot environment, and on day 2, subjects performed intermittent exercise (4 × 2 minute per round [R] separated by 1-minute recovery) under a randomly assigned condition of with (HYP) or without (EUH) hypohydration. Each bout consisted of 8 × 5 seconds of maximal cycling exercise (0.05 kp × body mass) separated by 10 seconds of passive recovery. Mean power output per kilogram (MPO), total power output per kilogram (TPO), energy system relative contribution, and core rectal temperature (Tre) were measured. Changes in body mass before the exercise tests were -2.25 ± 0.18% (HYP) and -0.17 ± 0.19% (EUH) (p < 0.001). Mean power output, TPO, and each energy contribution ratio were not significantly different between the trials, and pre- and postexercise test Tre did not differ significantly between trials. Results demonstrated that approximately 2% hypohydration lies below the point at which power output during intermittent exercise starts to decline.

8569Background: Thymic carcinoma is a rare neoplasm. Minimal information exists regarding second-line chemotherapy efficacy in patients with previously treated advanced thymic carcinoma. Methods: W...

Introduction. It was reported that 25-hydroxyvitamin D level was independently associated with anemia in chronic kidney diseases, but the relation between vitamin D and anemia in diabetes mellitus is not still certain. We analyzed the relation between plasma 25-hydroxyvitamin D level and hemoglobin concentration.Materials and Methods. A cross-sectional study in male patients with type 2 diabetes was performed. Correlation coefficients and standardized partial regression coefficient for the hemoglobin concentration were evaluated.Results. Hemoglobin concentration was positively correlated with body mass index, HbA1c, estimated glomerular filtration rate, cholinesterase, and 25-hydroxyvitamin D level and negatively correlated with age, duration of diabetes mellitus, serum creatinine, and urinary albumin creatinine ratio. Multiple regression analysis revealed the independent relation of 25-hydroxyvitamin D to hemoglobin concentration.Conclusions. Plasma circulating form of vitamin D is significantly associated with hemoglobin concentration in diabetes mellitus independent of the clinical markers for kidney function or nutrition.

Six cases of rectal leiomyoma, measuring less than 10 mm in diameter, are reported. The color of the overlying mucosa was similar to that of the surrounding mucosa. No central depression or ulceration was observed endoscopically in any of the six cases. In five cases, the tumors were sessile or semipedunculated and mobile, and were thus snare polypectomised. In the remaining case, the tumor was flat-elevated and immobile, and removed surgically by transanal wedge-resection. All six cases were benign leiomyoinas without malignant changes such as cellular atypia or mitosis.

Two cases of familial adenomatous polyposis (FAP) with mental retardation, in a 40-year-old female and a 46-year-old male, are reported. Their IQs were 40 and 31, respectively. The cause of mental retardation, in both cases, was most likely to have been congenital. There have been six cases of FAP with mental retardation reported in the literature. Recent investigations have revealed an interstitial deletion of the long arm of chromosome 5 in FAP as well as in mental retardation. These case reports of FAP with mental retardation, and the cytogenetic studies, strongly suggest that mental retardation is a further feature of FAP.

注腸検査で,enema tube balloonの過伸展により直腸に生じたbarium granulomaを合併した潰瘍性大腸炎の1例を報告した,症例は60歳女性.約3年半前に発症した全大腸炎型潰瘍性大腸炎で,腹部単純X線写真で小骨盤腔内に3.5×2.5cmの陽性陰影があり,内視鏡検査では潰瘍性大腸炎の所見に加えて,肛門輪より4cm口側,4時方向に黄白色の斑状模様をみとめ,同部からの生検組織で淡黄緑色の結晶物質を貪食した多数のmacrophageがみられた.前医での注腸X線写真の検討から,enema tube balloonの過伸展が粘膜を損傷し発生した直腸barium granulomaと考えられた.わが国における直腸barium granulomaの報告は著者らが調べた限り8例と稀で,とくに潰瘍性大腸炎で起こった報告は本例のみである.なお,報告例8例のうち,診断確定のため,あるいはBorrmann IIまたはIII様の悪性像などと判定されたため4例に外科的処置が加えられている.