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Aim To evaluate the safety and pharmacokinetics of cotadutide, a dual glucagon-like peptide-1 (GLP-1) and glucagon receptor agonist, in overweight Asian participants with or without type 2 diabetes (T2D). Materials and methods In the phase 1, randomized, blinded, single-ascending dose study, 24 Japanese and eight Chinese healthy adults (body mass index [BMI] 23-40 kg/m2 ) received one subcutaneous dose of cotadutide (50-150 or 100 μg, respectively) or placebo. The primary endpoint was safety. In the phase 2a, randomized, double-blinded, parallel dose-ranging study with forced uptitration, 61 Japanese adults with T2D (BMI 24-40 kg/m2 ; HbA1c 7.0%-10.5%) received cotadutide (100, 200, 300 μg) or placebo for 48 days. Co-primary endpoints were safety/tolerability, change in glucose AUC0-4h and body weight. Results Significant reductions from baseline to day 48 were observed with cotadutide for glucose AUC0-4h (33.6%-42.1% reduction vs. +2.5% with placebo; 95% CIs: 100 μg -45.7%, -33.7%; 200 μg -35.6%, -23.7%; 300 μg -45.0%, -30.8%; placebo 3.4%, 8.3%) and body weight (1.3%-2.5% decrease vs. +0.8% with placebo; 95% CIs: 100 μg -3.4%, -0.8%; 200 μg -4.7%, -2.0%; 300 μg -4.6%, -2.1%; placebo -2.1%, 0.4%). The most common adverse events with cotadutide were mild gastrointestinal symptoms with no serious adverse events. Increased pulse rate with cotadutide versus placebo is consistent with GLP-1 monoagonists. Conclusions Once-daily cotadutide was effective and well tolerated up to 300 μg in overweight Japanese patients with T2D. Further evaluation in Asian populations is warranted.

Aim To examine the long‐term efficacy and safety of dapagliflozin, a sodium‐glucose co‐transporter‐2 (SGLT2) inhibitor used to treat type 1 diabetes, in the Japanese subpopulation of the DEPICT‐2 study. Materials and Methods Patients with type 1 diabetes were randomized to dapagliflozin 5 mg (n = 55), dapagliflozin 10 mg (n = 41) or placebo (n = 58) plus insulin for a 24‐week, double‐blind period followed by a 28‐week, single‐blind extension phase. Results From baseline to 24 weeks, dapagliflozin reduced HbA1c compared with placebo (mean change of −0.58% and −0.80% for 5 and 10 mg, respectively), and an HbA1c reduction was observed up to 52 weeks. Compared with placebo, dapagliflozin 5 and 10 mg increased the proportion of patients achieving HbA1c reductions of 0.5% or more without severe hypoglycaemia events and reduced glycaemic variability assessed via continuous glucose monitoring. Both dapagliflozin doses decreased body weight and total daily insulin dose at 24 weeks compared with placebo; these reductions were maintained up to 52 weeks. Diabetic ketoacidosis occurred in both dapagliflozin groups (one and two cases, respectively) but not with placebo. Conclusions Efficacy and safety results from the Japanese subpopulation of the DEPICT‐2 study were generally consistent with those from the overall population, indicating that long‐term dapagliflozin adjunct to insulin therapy improves glycaemic control without an increased risk of hypoglycaemia but with a risk of diabetic ketoacidosis in Japanese patients with type 1 diabetes.

Aims To investigate the safety and tolerability of 5 and 10 mg dapagliflozin added to insulin therapy over 52 weeks in Japanese patients with inadequately controlled type 1 diabetes mellitus (T1DM). Materials and methods This randomized, open‐label, parallel‐group, multicentre phase III clinical trial was conducted from October 26, 2015 to June 15, 2017. The primary endpoint was the occurrence of adverse events such as hypoglycaemia and diabetic ketoacidosis. Secondary endpoints included changes in glycaemic parameters, total daily insulin dosage and body weight over time. The efficacy of dapagliflozin in patients stratified by body mass index (BMI)

Grapheme-color synesthetes experience graphemes as having a consistent color (e.g., “N is turquoise”). Synesthetes’ specific associations (which letter is which color) are influenced by linguistic properties (letter frequency, phonetic similarity, etc.), and plausibly reveal the characteristics of underlying letter representations. Despite their clear linguistic origin, these influences (termed “Regulatory Factors”, RFs) are almost always studied in a single language, typically English. Here, we measure the influence of three RFs (previously examined only in English) in Dutch, English, Greek, Japanese, Korean, Russian, and Spanish synesthetes. For two RFs, effect size significantly differed between languages. In contrast, an RF which we predicted to be universal (because it is shaped by prelinguistic shape-color associations) did not differ between languages. Our results suggest that monolingual synesthesia studies should be interpreted with caution. Furthermore, they show how synesthetic associations offer an exceptional opportunity to study linguistic and prelinguistic influences on letter representations in different languages.

Background: Immunogenicity and safety of the AZD1222 (ChAdOx1 nCoV-19) vaccine was evaluated in Japanese adults in an ongoing phase 1/2, randomized, double-blind, parallel-group, placebo-controlled, multi-centre trial (NCT04568031). Methods: Adults (n=256, age ≥18 years) seronegative for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) were stratified by age into 18–55- (n=128), 56–69- (n=86) and ≥70-year-old cohorts (n=42), and randomized 3:1 to receive AZD1222 or placebo (two intramuscular injections 4 weeks apart). Immunogenicity and safety were coprimary endpoints. Data collected up to Day 57 are reported. Results: Positive seroresponses to SARS-CoV-2 spike and receptor-binding domain antigens were seen in all 174 participants who received two doses of AZD1222. Neutralizing antibody seroresponses were seen in 67.5%, 60.3% and 50.0% of participants receiving AZD1222 aged 18–55, 56–69 and ≥70 years, respectively. Solicited adverse events (AEs) were typically mild/moderate in severity and included pain and tenderness at the injection site, malaise, fatigue, muscle pain and headache. Common unsolicited AEs included pain and tenderness at the injection site, fatigue and elevated body temperature. No vaccine-related serious AEs or deaths were reported. Conclusions: AZD1222 elicited a strong humoral immune response against SARS-CoV-2, and was well tolerated in Japanese participants, including elderly participants.

Aims To assess the pharmacokinetics/pharmacodynamics (PK/PD) of dapagliflozin, a sodium-glucose co-transporter 2 inhibitor that increases urinary glucose excretion (UGE) and its major metabolite, dapagliflozin-3-O-glucuronide (D3OG), in Japanese patients with type 1 diabetes (T1D) and inadequate glycaemic control (HbA1c 7%-10%). Materials and methods Japanese patients (18-65 years) with inadequately controlled T1D were randomized 1:1:1 to dapagliflozin 5 mg, 10 mg or placebo (n = 14 each) once daily for 7 days, with adjustable insulin. The PK/PD characteristics of dapagliflozin and D3OG were assessed on Day 7. Patients underwent follow-up evaluation on Days 8 and 14. Adverse events (AEs), hypoglycaemic episodes and events of diabetic ketoacidosis (DKA) were recorded over the treatment and follow-up periods. Results A total of 42 randomized patients received dapagliflozin or placebo. PK variables increased in a dose-dependent manner. D3OG was generated rapidly, with a median time to maximum plasma concentration of 2.0 hours (1.0-3.0). The dapagliflozin dose-UGE relationship was attenuated, with larger insulin dose reductions than anticipated. Mean percent (standard error) changes in total daily insulin dose from baseline to Day 7 were - 36.86% (3.32), -39.13% (2.68) and - 4.97% (5.28) for dapagliflozin 5 mg and 10 mg and for placebo, respectively. No DKA was reported. AEs were consistent with the established dapagliflozin safety profile. There was no increase in hypoglycaemia. Conclusions The PK and safety profiles of dapagliflozin in Japanese patients with T1D were consistent with previous studies, but with an unanticipated attenuation of the PD dose-response measured as UGE.

Psychiatric and neurological disorders are afflictions of the brain that can affect individuals throughout their lifespan. Many brain magnetic resonance imaging (MRI) studies have been conducted; however, imaging-based biomarkers are not yet well established for diagnostic and therapeutic use. This article describes an outline of the planned study, the Brain/MINDS Beyond human brain MRI project (FY2018 ∼ FY2023), which aims to establish clinically-relevant imaging biomarkers with multi-site harmonization by collecting data from healthy traveling subjects (TS) at 13 research sites. Collection of data in psychiatric and neurological disorders across the lifespan is also scheduled at 13 sites, whereas designing measurement procedures, developing and analyzing neuroimaging protocols, and databasing are done at three research sites. The Harmonization protocol (HARP) was established for five high-quality 3T scanners to obtain multimodal brain images including T1 and T2-weighted, resting state and task functional and diffusion-weighted MRI. Data are preprocessed and analyzed using approaches developed by the Human Connectome Project. Preliminary results in 30 TS demonstrated cortical thickness, myelin, functional connectivity measures are comparable across 5 scanners, providing high reproducibility and sensitivity to subject-specific connectome. A total of 75 TS, as well as patients with various psychiatric and neurological disorders, are scheduled to participate in the project, allowing a mixed model statistical harmonization. The HARP protocols are publicly available online, and all the imaging, demographic and clinical information, harmonizing database will also be made available by 2024. To the best of our knowledge, this is the first project to implement a rigorous, prospective harmonization protocol with multi-site TS data. It explores intractable brain disorders across the lifespan and may help to identify the disease-specific pathophysiology and imaging biomarkers for clinical practice.

A 65-year-old woman visited our hospital due to right chest pain and dyspnea on exertion. Chest radiography revealed decreased permeability of the right lung. Computed tomography demonstrated a huge mass in the right upper lobe and right pleural effusion. Right pleural effusion cytology yielded a diagnosis of adenocarcinoma and was positive for mutation of epidermal growth factor receptor (EGFR; exon 21 L858R). Afatinib was selected for the initial treatment. Multiple tumors regressed remarkably, but then rapidly progressed 3 months later. We performed re-biopsy to detect the mechanism of resistance to afatinib. Histopathology revealed a mixture of small cell carcinoma (SCC) and adenocarcinoma harboring same EGFR mutation. To the best of our knowledge, this is the first report of transformation to SCC after treatment with afatinib.

A 73-year-old man was referred to our hospital after a 2-week history of bloody sputum and cough. Computed tomography (CT) images of the chest showed a mass grouped with mediastinal lymph nodes, and bronchoscopy showed a projecting mass in the right main bronchus. After a transbronchial biopsy, the patient was diagnosed with squamous cell carcinoma (T4N2M0 stage IIIB). The patient was treated with systemic chemotherapy, consisting of cisplatin (40 mg/m2, days 1 and 8) and docetaxel (30 mg/m2, days 1 and 8), and concurrent thoracic irradiation at a daily dose of 2 Gy. On day 35 of treatment, the patient complained of a sore throat and cough. A CT of the chest showed punctate low-attenuation foci between the esophagus and bronchus. Gastrointestinal endoscopy and bronchoscopy demonstrated a fistula in the middle intrathoracic esophagus and the left main bronchus. The patient’s symptoms gradually improved, and the fistula was closed after the suspension of chemoradiotherapy. Radiotherapy was resumed and completed on day 82. However, on day 108, he developed a fever and cough, and a tumor with fistula was revealed in the right main bronchus. He had an esophageal stent inserted, but he later died of sudden hemoptysis.

Aims To evaluate the efficacy and safety of dapagliflozin as add-on to insulin in Japanese patients with type 2 diabetes. Materials and methods Insulin-treated Japanese patients were randomized to 5 mg dapagliflozin or placebo during a 16-week double-blind treatment period. Both groups then received dapagliflozin 5 or 10 mg (the dose was increased at or after week 24 if glycated haemoglobin [HbA1c] at the previous visit was >7.5%) during a 36-week open-label extension period. The exploratory efficacy endpoint was to assess the maintenance efficacy of 5/10 mg dapagliflozin + insulin over 52 weeks of treatment. Safety was assessed in terms of adverse events, laboratory variables and vital signs. Results The changes in HbA1c from baseline to weeks 16 and 52 were −0.62% and −0.74%, respectively, in the dapagliflozin group, vs −0.08% and −0.83%, respectively, in the placebo–dapagliflozin group. Body weight decreased at both time points in the dapagliflozin group and after switching to open-label dapagliflozin in the placebo–dapagliflozin group. The total insulin dose decreased slightly after starting dapagliflozin. Adverse events occurred in 82.9% and 71.7% of patients in the dapagliflozin and placebo–dapagliflozin groups, respectively. Hypoglycaemia occurred in 35.0% and 41.7% of patients in the dapagliflozin and placebo–dapagliflozin groups, respectively, but the incidence was not increased by use of dapagliflozin in either trial period. Genital/urinary tract infections, renal impairment/failure, volume depletion, fracture and hepatic disorders occurred in ≤5% of patients. Conclusion This trial showed that administration of dapagliflozin as an add-on to insulin therapy was effective, was well tolerated and had insulin-sparing effects in Japanese patients with type 2 diabetes.

Highlights • The Brain/MINDS beyond project plans to collect multi-site/scanner brain MRI data. • Prospective harmonization of MRI was achieved by standardizing scanning protocols. • The preliminary data showed moderate reliability of brain connectome data. • Completing traveling subject plan will allow robust statistical harmonization. • Scanning protocols are publicly available and data will also be shared by 2024., Psychiatric and neurological disorders are afflictions of the brain that can affect individuals throughout their lifespan. Many brain magnetic resonance imaging (MRI) studies have been conducted; however, imaging-based biomarkers are not yet well established for diagnostic and therapeutic use. This article describes an outline of the planned study, the Brain/MINDS Beyond human brain MRI project (BMB-HBM, FY2018 ~ FY2023), which aims to establish clinically-relevant imaging biomarkers with multi-site harmonization by collecting data from healthy traveling subjects (TS) at 13 research sites. Collection of data in psychiatric and neurological disorders across the lifespan is also scheduled at 13 sites, whereas designing measurement procedures, developing and analyzing neuroimaging protocols, and databasing are done at three research sites. A high-quality scanning protocol, Harmonization Protocol (HARP), was established for five high-quality 3 T scanners to obtain multimodal brain images including T1 and T2-weighted, resting-state and task functional and diffusion-weighted MRI. Data are preprocessed and analyzed using approaches developed by the Human Connectome Project. Preliminary results in 30 TS demonstrated cortical thickness, myelin, functional connectivity measures are comparable across 5 scanners, suggesting sensitivity to subject-specific connectome. A total of 75 TS and more than two thousand patients with various psychiatric and neurological disorders are scheduled to participate in the project, allowing a mixed model statistical harmonization. The HARP protocols are publicly available online, and all the imaging, demographic and clinical information, harmonizing database will also be made available by 2024. To the best of our knowledge, this is the first project to implement a prospective, multi-level harmonization protocol with multi-site TS data. It explores intractable brain disorders across the lifespan and may help to identify the disease-specific pathophysiology and imaging biomarkers for clinical practice.

Introduction Dapagliflozin treatment when added to insulin therapy in Japanese patients with type 2 diabetes remains to be evaluated. Materials and Methods This was a multicenter, randomized, double-blind, parallel-group, placebo-controlled study to evaluate efficacy (at 16 weeks) and long-term safety (at 52 weeks) of dapagliflozin in addition to insulin therapy. The interim analysis was carried out at week 16 to assess the efficacy and safety profiles. The patients receiving insulin (n = 182) were randomized to either dapagliflozin 5 mg or a placebo at a 2:1 ratio. The primary efficacy end-point was the change in hemoglobin A1c (HbA1c) from baseline at week 16. Results Patients in the dapagliflozin group showed an adjusted decrease in HbA1c of −0.55% from baseline, whereas the placebo showed a marginal increase of 0.05%. The placebo-corrected mean change of HbA1c from baseline to week 16 in dapagliflozin was −0.60% (P < 0.0001). In addition, the placebo-corrected mean change of fasting plasma glucose and bodyweight from baseline to week 16 in the dapagliflozin group was −22.7 mg/dL (P < 0.0001) and −1.21 kg (P < 0.0001), respectively. The placebo-corrected mean daily insulin dose in the dapagliflozin group was numerically decreased (treatment difference: −0.72 IU/day; P = 0.0743). No major episodes or discontinuations as a result of hypoglycemia were reported during the study period. Conclusions Dapagliflozin used as add-on treatment to insulin therapy showed significantly greater reduction of HbA1c, fasting plasma glucose and bodyweight without severe hypoglycemia compared with the placebo at week 16. These results show the clinical benefit of prescribing dapagliflozin for Japanese patients with insufficient glycemic control even with insulin therapy.

This study evaluated the PK/PD of DAPA, a selective SGLT2 inhibitor, in Japanese T1D patients with poor glycemic control (A1C 7-10%; NCT02582840). Patients were randomized 1:1:1 to DAPA 5 mg, 10 mg or placebo (PBO; n=14 each) once daily for 7 days with adjustable insulin. Mean (SD) age was 39 (10) years, mean (SD) T1D duration was 16 (11) years and mean (SD) A1C was 8.0 (0.7)%. DAPA added to insulin resulted in dose-proportional increase in Cmax and AUCτ (Figure). Mean (SD) changes in 24h urinary glucose excretion (UGE) from baseline (BL) to Day 7 were 96.55 (30.08), 101.28 (20.13) and -6.16 (30.34) g/24h for DAPA 5 mg, 10 mg, and PBO, respectively, consistent with previous DAPA experience but with attenuated dose-response. Mean (SE) changes in total daily insulin dose from BL to Day 7 were larger than expected; -36.86 (3.32), -39.13 (2.68) and -4.97 (5.28)% for DAPA 5 mg, 10 mg and PBO, respectively. This reduction may be responsible for the attenuated glycemic response affecting UGE (explored in a separate abstract); mean (SD) changes in 7-point SMBG values from BL to Day 7 were -1.99 (23.58), -5.68 (40.36) and 6.54 (52.69) mg/dL for DAPA 5 mg, 10 mg and PBO, respectively. No DKA was reported. Adverse events and other laboratory findings were in line with the known DAPA safety profile; there was no increase in hypoglycemia. DAPA may be a clinically relevant adjunctive therapy for patients with T1D. Disclosure H. Watada: Advisory Panel; Self; AstraZeneca. Consultant; Self; Astellas Pharma US, Inc., AstraZeneca, Boehringer Ingelheim GmbH, Daiichi Sankyo Company, Limited, Sumitomo Dainippon Pharma Co., Ltd., Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceuticals America, Inc., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Novartis AG, Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho Co., Ltd., Takeda Development Center Asia, Pte. Ltd.. Research Support; Self; Abbott, Astellas Pharma US, Inc., AstraZeneca, Bayer AG, Benefit One Health Care Co., Ltd., Boehringer Ingelheim GmbH, Bristol-Myers Squibb Company, Daiichi Sankyo Company, Limited, Sumitomo Dainippon Pharma Co., Ltd., Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceuticals America, Inc., Kyowa Hakko Kirin Co., Ltd., Johnson & Johnson Diabetes Institute, LLC., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Nitto Boseki Co., Ltd., Novartis AG, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Pfizer Inc., Sanofi, Sanwa Kagaku Kenkyusho Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Development Center Asia, Pte. Ltd., Terumo Medical Corporation. M. Shiramoto: None. S. Ueda: Employee; Self; AstraZeneca. W. Tang: Employee; Self; AstraZeneca. M. Asano: None. F.A. Thoren: Employee; Self; AstraZeneca. H. Kim: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. T. Yajima: Employee; Self; AstraZeneca. D.W. Boulton: Employee; Self; AstraZeneca. Stock/Shareholder; Self; Bristol-Myers Squibb Company. E. Araki: Speaker's Bureau; Self; Astellas Pharma US, Inc., MSD K.K., Kowa Pharmaceuticals America, Inc., Sanofi, Novo Nordisk Inc.. Research Support; Self; Astellas Pharma US, Inc., MSD K.K., Ono Pharmaceutical Co., Ltd., Shionogi & Co., Ltd., Takeda Pharmaceuticals U.S.A., Inc., Daiichi Sankyo Company, Limited, Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Novo Nordisk Inc., Sanofi, Mitsubishi Tanabe Pharma Corporation, Sumitomo Dainippon Pharma Co., Ltd., Taisho Toyama Pharmaceutical Co..

A 74-year-old man with a history of occupational asbestos exposure in a shipyard was diagnosed with lymphohistiocytoid mesothelioma (LHM). Systemic chemotherapy consisted of cisplatin, and pemetrexed was administered. After six courses of chemotherapy, multiple tumours had regressed. Six months after chemotherapy, the tumours on the pleura exhibited regrowth and partly invaded the liver. Salvage chemotherapies, including irinotecan and vinorelbine, were administered and his disease was stable for several months. Then he suddenly vomited and complained of abdominal pain. Contrast CT showed small intestine intussusception. Partial resection of the small intestine was performed. We found a tumour in the resected small intestine. Review the …

The brain is a rare site of metastasis in malignant pleural mesothelioma (MPM), and its clinical features and prognosis remain unclear. The aim of this study was to investigate the incidence, prognosis, and risk factors for brain metastases (BM) in MPM patients. Between July 1993 and October 2014, 150 patients with histologically proven MPM were included in this retrospective study. The cumulative incidence of BM was estimated with the Kaplan-Meier method, and differences between groups were analyzed by the log-rank test. Multivariate logistic regression analysis was applied to assess risk factors for BM. The median follow-up time was 11 months (range 0-154.0 months). A total of eight patients (5.3 %) developed BM during the course of their illness. Multivariate analysis identified age

Chronic inflammation plays a key role in the pathogenesis of malignant pleural mesothelioma (MPM) as a result of asbestos exposure. Several inflammation-based prognostic scores including the lymphocyte-to-monocyte ratio (LMR), Glasgow Prognostic Score (GPS), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) reportedly predict survival in many malignancies, while the role of LMR in MPM remains unclear. The aim of this study was to evaluate the clinical value of LMR and to compare the prognostic value of these inflammation-based scores in predicting overall survival (OS) in MPM.One hundred and fifty patients with histologically proven MPM were included in this retrospective study. Kaplan-Meier curves and multivariate Cox-regression analyses were calculated for OS. The area under the receiver operating characteristics curve (AUC) was calculated to compare the discriminatory ability of each scoring system.An elevated LMR was significantly associated with prolonged OS. Patients with LMR2.74 had significantly poor survival compared with LMR ≥2.74 (median, 5.0 versus 14.0 months; p=0.000). The LMR consistently had a higher AUC value at 6 months (0.722), 12 months (0.712), and 24 months (0.670), compared with other scores. Multivariate analysis showed that the LMR was independently associated with OS.The LMR is an independent prognostic marker for OS in patients with MPM and is superior to other inflammation-based prognostic scores with respect to prognostic ability.

We report a very rare case of primary endobronchial peripheral T-cell lymphoma (PTCL) not otherwise specified (NOS), which presented as an endobronchial tumor obstructing the main airway. An 81-year-old man was referred to our hospital for a 1-month history of productive cough and wheeze. Computed tomography revealed chronic pyothorax with calcified foci in the right lung and a mass inside the bronchus intermedius. Flexible bronchoscopy identified an endobronchial tumor obstructing the bronchus intermedius. The biopsy specimen showed an infiltration composed predominantly of small atypical lymphocytes. Immunohistochemical analyses demonstrated that the proliferating cells were positive for CD3, CD4, and CD5 and negative for CD8 and CD20. Pathological tests confirmed that the case was PTCL-NOS. PTCL-NOS should be considered in the differential diagnosis of endobronchial tumors.

An 81-year-old woman visited a local clinic due to chest pain and a skin induration on the right precordia. She had a history of right breast cancer, and she had undergone a mastectomy and radiation therapy 10 years prior. Computed tomography (CT) imaging of the chest demonstrated a lobular mass that involved the right anterior thoracic wall and partially extruded from the thoracic cavity into the subcutaneous tissue. The tumor was surgically excised, and pathological analyses yielded a diagnosis of angiosarcoma. Five months after the operation, CT imaging showed multiple masses on the right pleura, indicating a local relapse and pleural dissemination of the angiosarcoma. Systemic chemotherapy composed of nanoparticle albumin-bound paclitaxel (nab-PTX) (80 mg/m(2)) was delivered weekly. After 4 courses of chemotherapy, the tumors regressed remarkably. Nab-PTX may be an effective treatment option for recurrent or metastatic angiosarcoma.

A 76-year-old woman came to us because of staggering, fever, dysarthria, and appetite loss. Magnetic resonance imaging (MRI) of the brain revealed multiple masses with surrounding edema. Chest X-ray and computed tomography demonstrated a mass-like lesion in the left lung and left pleural effusion. Lung cancer and multiple brain metastases were suspected. However, the brain lesions demonstrated a high intensity through diffusion-weighted MRI. The finding was an important key to differentiate brain abscesses from lung cancer metastases.

We examined linear and curvilinear correlations of gray matter volume and density in cortical and subcortical gray matter with age using magnetic resonance images (MRI) in a large number of healthy children. We applied voxel‐based morphometry (VBM) and region‐of‐interest (ROI) analyses with the Akaike information criterion (AIC), which was used to determine the best‐fit model by selecting which predictor terms should be included. We collected data on brain structural MRI in 291 healthy children aged 5–18 years. Structural MRI data were segmented and normalized using a custom template by applying the diffeomorphic anatomical registration using exponentiated lie algebra (DARTEL) procedure. Next, we analyzed the correlations of gray matter volume and density with age in VBM with AIC by estimating linear, quadratic, and cubic polynomial functions. Several regions such as the prefrontal cortex, the precentral gyrus, and cerebellum showed significant linear or curvilinear correlations between gray matter volume and age on an increasing trajectory, and between gray matter density and age on a decreasing trajectory in VBM and ROI analyses with AIC. Because the trajectory of gray matter volume and density with age suggests the progress of brain maturation, our results may contribute to clarifying brain maturation in healthy children from the viewpoint of brain structure. Hum Brain Mapp, 2013. © 2012 Wiley Periodicals, Inc.

Determinants of synesthetic color choice for Japanese phonetic characters were studied in six Japanese synesthetes. The study used Hiragana and Katakana characters, which represent the same set of syllables although their visual forms are dissimilar. From a palette of 138 colors, synesthetes selected a color corresponding to each character. Results revealed that synesthetic color choices for Hiragana characters and those for their Katakana counterparts were remarkably consistent, indicating that color selection depended on character-related sounds and not visual form. This Hiragana–Katakana invariance cannot be regarded as the same phenomenon as letter case invariance, usually reported for English grapheme-color synesthesia, because Hiragana and Katakana characters have different identities whereas upper and lower case letters have the same identity. This involvement of phonology suggests that cross-activation between an inducer (i.e., letter/character) brain region and that of the concurrent (i.e., color) area in grapheme-color synesthesia is mediated by higher order cortical processing areas.

Malignant pleural mesothelioma (MPM) is a highly aggressive neoplasm primarily arising from surface serosal cells of the pleura and is strongly associated with asbestos exposure. Patients with MPM often develop pleural fluid as initial presentation. However, cytological diagnosis using pleural fluid is usually difficult and has limited utility. A useful molecular marker for differential diagnosis particularly with lung cancer (LC) is urgently needed. The aim of the present study was to investigate the diagnostic value of soluble mesothelin-related protein (SMRP) in pleural fluid. Pleural fluids were collected from 23 patients with MPM, 38 with LC, 26 with benign asbestos pleurisy (BAP), 5 with tuberculosis pleurisy (TP) and 4 with chronic heart failure (CHF), and the SMRP concentration was determined. All data were analyzed by using non-parametric two-sided statistical tests. The median concentration of SMRP in MPM, LC, BAP, TP and CHF were 11.5 (range 0.90-82.80), 5.20 (0.05-36.40), 6.65 (1.45-11.25), 3.20 (1.65-6.50) and 2.03 (1.35-2.80) nmol/l, respectively. The SMRP concentration was significantly higher in MPM than in the other diseases (P=0.001). The area under the ROC curve (AUC) values of the MPM diagnosis was 0.75 for the differential diagnosis from the other groups. Based on the cut-off value of 8 nmol/l, the sensitivity and specificity for diagnosis of MPM were 70.0 and 68.4%, respectively. These results indicate that the SMRP concentration in pleural fluid is a useful marker for the diagnosis of MPM.

The Rapid Appearance and Disappearance of Dendriform Pulmonary Ossification after Diffuse Alveolar Hemorrhage Tomoko Yamagishi, Nobukazu Fujimoto, Yosuke Miyamoto, Naofumi Hara, Michiko Asano, Yasuko Fuchimoto, Sae Wada, Kenichi Kitamura, Shinji Ozaki, Hideyuki Nishi, and Takumi Kishimoto Department of Respiratory Medicine, Department of Medical Oncology, Department of Surgery, and Department of Internal Medicine, Okayama Rosai Hospital, Okayama, Japan

A 59-year-old man was referred to our hospital because of left pleural effusion detected at a regular medical checkup. A chest X-ray showed left pleural effusion. A thoracoscopic pleural biopsy specimen from the left side gave a pathological diagnosis of malignant pleural mesothelioma (MPM), epithelioid type. Then thoracoscopic exploration of the right pleura was performed because of fluorodeoxyglucose accumulation along the right dorsal pleura. Thoracoscopic exploration of the right indicated no visible tumor formation, but a pleural biopsy specimen revealed epithelioid MPM. In this case, MPM in each thorax was confined to the parietal pleura and was classified as stage I. We therefore suggest that MPM may develop simultaneously in both thoraxes.

A 59-year-old man who was diagnosed with small cell lung cancer (SCLC), achieved a complete response to the induction chemoradiotherapy and received prophylactic cranial irradiation (PCI) (25 Gy at 250 cGy per fraction) in October 2008. Three months later, he complained of anorexia, weight loss, fatigue, and short-term memory loss and developed dementia and systemic muscle weakness. Magnetic resonance imaging in April and July 2009 revealed the progression of the diffuse brain atrophy without evidence of the metastasis of SCLC. Paraneoplastic neurological syndrome was suspected because anti-Hu antibody was detected in his serum and cerebrospinal fluid, but the adverse effects of chemotherapy and/or radiotherapy were also suspected as the cause of his neurological disorder.

Recent progress in grapheme-color synesthesia research has revealed that certain regularities, as well as individual differences, figure into grapheme-color associations. Although several factors are known to regulate grapheme-color associations, the impact of factors, including their interrelationships, on synesthesia remains unclear. We investigated determinants of synesthetic color for graphemes (characters, letters) of Hiragana, a phonetic script in the Japanese language, and the English alphabet. Results revealed that grapheme ordinality was the strongest predictor of synesthetic colors for Hiragana characters, followed by character sound, and visual shape. Ordinality and visual shapes also significantly predicted synesthetic colors for English alphabet letters, however, sounds did not. The relative impact of grapheme properties on grapheme-color associations and the differences between these two writing systems are accounted for by considering the way graphemes are processed in the brain and introduced during an individual's development. A new model is proposed which takes into account the developmental process of grapheme learning. The model provides comprehensive explanation of synesthetic grapheme-color association determination processes, including the differences across writing systems.

Background We retrospectively analyzed hyaluronic acid (HA) concentrations in pleural fluid and evaluated its utility for the differential diagnosis of malignant pleural mesothelioma (MPM). Methods Pleural fluid HA concentrations were measured in 334 patients, including 50, 48, 85, 18, 86, 6, and 41 patients with MPM, benign asbestos pleurisy (BAP), lung cancer (LC), other malignant conditions (OMCs), infectious pleuritis (IP), collagen disease (CD), and other conditions, respectively. Results The median (range) HA concentrations in pleural fluid were 78,700 (7920–2,630,000)ng/ml in the MPM group, 35,950 (900–152,000)ng/ml in the BAP group, 19,500 (2270–120,000)ng/ml in the LC group, 14,200 (900–101,000)ng/ml in the OMC group, 23,000 (900–230,000)ng/ml in the IP group, 24,600 (9550–80,800)ng/ml in the CD group, and 8140 (900–67,800)ng/ml in the other diseases group. HA levels were significantly higher in the MPM group than in the other groups. Receiver operating characteristic (ROC) analysis revealed an area under the ROC curve value of 0.832 (95% confidence interval, 0.765–0.898) for the differential diagnosis of MPM. With a cutoff value of 100,000ng/ml, the sensitivity and specificity were 44.0 and 96.5%, respectively. In the MPM group, HA values were significantly higher for the epithelioid subtype than for the sarcomatous subtype ( p =0.007), and higher in earlier stages (I and II) than in advanced stages (III and IV) ( p =0.007). Conclusions A diagnosis of MPM should be strongly considered in patients with pleural fluid HA concentrations exceeding 100,000ng/ml.

Older children are more successful at producing unfamiliar, non-native speech sounds than younger children during the initial stages of learning. To reveal the neuronal underpinning of the age-related increase in the accuracy of non-native speech production, we examined the developmental changes in activation involved in the production of novel speech sounds using functional magnetic resonance imaging. Healthy right-handed children (aged 6–18 years) were scanned while performing an overt repetition task and a perceptual task involving aurally presented non-native and native syllables. Productions of non-native speech sounds were recorded and evaluated by native speakers. The mouth regions in the bilateral primary sensorimotor areas were activated more significantly during the repetition task relative to the perceptual task. The hemodynamic response in the left inferior frontal gyrus pars opercularis (IFG pOp) specific to non-native speech sound production (defined by prior hypothesis) increased with age. Additionally, the accuracy of non-native speech sound production increased with age. These results provide the first evidence of developmental changes in the neural processes underlying the production of novel speech sounds. Our data further suggest that the recruitment of the left IFG pOp during the production of novel speech sounds was possibly enhanced due to the maturation of the neuronal circuits needed for speech motor planning. This, in turn, would lead to improvement in the ability to immediately imitate non-native speech. Hum Brain Mapp 35:4079–4089, 2014. © 2014 Wiley Periodicals, Inc.

We present two cases of relapsed adenocarcinoma of the lung: a 50-year-old male and a 67-year-old male. Both patients had previously been treated with platinum-containing systemic chemotherapy. In both cases, significant clinical efficacy was demonstrated with combination chemotherapy consisting of pemetrexed, carboplatin, and bevacizumab as salvage treatment. Adverse events were mild. This regimen might be a viable therapeutic option even after heavy treatment such as platinum-containing chemotherapy, especially for patients with preserved organ function and good performance status.

YOSHIDA, M. and ASANO, M. Direct Compression by Megadolichobasilar Anomaly as a Cause of Trigeminal Neuralgia, A Case Diagnosed by MRI. Tohoku J. Exp. Med., 1994, 172 (4), 327-332 A 49 year-old man with trigeminal neuralgia caused by megadolichobasilar anomaly was described. The patient having neuralgic attacks in the second branch of the right trigeminal nerve for two and a half years showed the angiographic evidence of a tortuous and elongated vertebrobasilar artery and MRI of the brain clearly visualized the root entry zone of the nerve having been compressed by the main trunk of ectatic basilar artery. Cases of trigeminal neuralgia due to the compression by the basilar artery itself have been rarely described previously. In order to evaluate trigeminal neuralgia, MRI is essential to determine the relationship of the involvedsite of nerve to the pathogenic artery.

Two experiments explored rapid extraction of gist from a visual text and its influence on word recognition. In both, a short text (sentence) containing a target word was presented for 200 ms and was followed by a target recognition task. Results showed that participants recognized contextually anomalous word targets less frequently than contextually consistent counterparts (Experiment 1). This context effect was obtained when sentences contained the same semantic content but with disrupted syntactic structure (Experiment 2). Results demonstrate that words in a briefly presented visual sentence are processed in parallel and that rapid extraction of sentence gist relies on a primitive representation of sentence context (termed protocontext) that is semantically activated by the simultaneous presentation of multiple words (i.e., a sentence) before syntactic processing.

To investigate gender differences in brain perfusion, this study utilized pulsed arterial spin-labeling magnetic resonance imaging (MRI) in a large number of healthy children. Data on structural and perfusion MRI in the brain were collected from 202 healthy children aged 5–18 years. Gender differences in brain perfusion using partial volume correction (PVC), which was calculated by dividing the normalized perfusion MRI by the normalized gray-matter segments, were analyzed by applying voxel-based analysis and region-of-interest (ROI) analysis. Girls showed significantly higher brain perfusion with PVC in the bilateral medial aspect of the parietal lobes, including the posterior cingulate cortex and precuneus, as compared to boys using voxel-based analysis. In addition, brain perfusion with PVC in the bilateral posterior cingulate cortex, bilateral precuneus, and left thalamus was significantly higher in girls than in boys in the ROI analysis. In contrast, no regions were seen in which boys exhibited higher brain perfusion with PVC than girls in both analyses. The findings showed significant differences between boys and girls in brain perfusion with PVC, and these differences may contribute to gender differences in the cognitive ability of healthy children.

We examined the correlation between brain perfusion and age using pulsed arterial spin‐labeling (ASL) magnetic resonance images (MRI) in a large number of healthy children. We collected data on brain structural and ASL perfusion MRI in 202 healthy children aged 5–18 years. Structural MRI data were segmented and normalized, applying a voxel‐based morphometric analysis. Perfusion MRI was normalized using the normalization parameter of the corresponding structural MRI. We calculated brain perfusion with an adjustment for gray matter density (BP‐GMD) by dividing normalized ASL MRI by normalized gray matter segments in 22 regions. Next, we analyzed the correlation between BP‐GMD and age in each region by estimating linear, quadratic, and cubic polynomial functions, using the Akaike information criterion. The correlation between BP‐GMD and age showed an inverted U shape followed by a U‐shaped trajectory in most regions. In addition, age at which BP‐GMD was highest was different among the lobes and gray matter regions, and the BP‐GMD association with age increased from the occipital to the frontal lobe via the temporal and parietal lobes. Our results indicate that higher order association cortices mature after the lower order cortices, and may help clarify the mechanisms of normal brain maturation from the viewpoint of brain perfusion. Hum Brain Mapp, 2011. © 2011 Wiley‐Liss, Inc.

We report a case with a history of occupational asbestos exposure in which malignant pleural mesothelioma (MPM) was suspected clinically and diagnosed postmortem as pleural involvement of extrapulmonary small cell carcinoma (SCC). An 85-year-old man with a 65 pack-year history of smoking was referred to our hospital in June 2011. The patient had been exposed to asbestos in the iron production industry over the course of 30 years, and an irregular thickening of the right pleura was observed on chest CT at a medical check-up. The patient had a history of chronic hepatitis C and had been undergone transurethral resection for urothelial bladder cancer five times since 2006. Chest CT revealed neoplastic thickening of the right pleura, which had grown over 6 months (figure 1). The CT scan demonstrated bilateral pleural plaques, but no mass-like lesion in other organs, including the lungs, or mediastinal lymphadenopathy. The patient was suspected as having MPM and scheduled for thoracoscopic pleural biopsy, but his general condition worsened rapidly and he …

Background —It has been suggested that intracellular Ca 2+ overload in cardiac myocytes leads to the development of diabetic cardiomyopathy. Troglitazone, an insulin-sensitizing agent, is a promising therapeutic agent for diabetes and has been shown to prevent diabetes-induced myocardial changes. To elucidate the underlying mechanism of troglitazone action on cardiac myocytes, the effects of troglitazone on voltage-dependent Ca 2+ currents were examined and compared with classic Ca 2+ antagonists (verapamil and nifedipine). Methods and Results —Whole-cell voltage-clamp techniques were applied in single guinea pig atrial myocytes. Under control conditions with CsCl internal solution, the voltage-dependent Ca 2+ currents consisted of both T-type ( I Ca,T ) and L-type ( I Ca,L ) Ca 2+ currents. Troglitazone effectively reduced the amplitude of I Ca,L in a concentration-dependent manner. Troglitazone also suppressed I Ca,T , but the effect of troglitazone on I Ca,T was less potent than that on I Ca,L . The current-voltage relationships for I Ca,L and the reversal potential for I Ca,L were not altered by troglitazone. The half-maximal inhibitory concentration of troglitazone on I Ca,L measured at a holding potential of −40 mV was 6.3 μmol/L, and 30 μmol/L troglitazone almost completely inhibited I Ca,L . Troglitazone 10 μmol/L did not affect the time courses for inactivation of I Ca,L and inhibited I Ca,L mainly in a use-independent fashion, without shifting the voltage-dependency of inactivation. This effect was different from those of verapamil and nifedipine. Troglitazone also reduced isoproterenol- or cAMP-enhanced I Ca,L . Conclusions —These results demonstrate that troglitazone inhibits voltage-dependent Ca 2+ currents (T-type and L-type) and then antagonizes the effects of isoproterenol in cardiac myocytes, thus possibly playing a role in preventing diabetes-induced intracellular Ca 2+ overload and subsequent myocardial changes.

The present study was performed to evaluate the effects of physical exercise at altitudes on serum vascular endothelial growth factor (VEGF) levels. Eight subjects underwent intensive swimming training for 21 days at 1886 m. After altitude training commenced, red blood cell (RBC) counts and erythropoietin levels increased, but both haemoglobin and haematocrit levels did not change significantly. The serum level of VEGF, measured by means of a highly sensitive chemiluminescence (ELISA), showed a transient decrease 10 days after start of the altitude training, thereafter increasing significantly to reach a peak level 19 days later, rising from 23.0 +/- 5.3 to 46.0 +/- 14.6 pg mL-1 (P < 0.05 vs. before). On return to low altitude in Japan, the level of VEGF decreased, and 1 month later had returned to initial levels. Endurance training at altitudes increases serum VEGF levels; this could be an adaptive reaction to hypoxic conditions. This result suggests that VEGF may provide a new physiological parameter for hypoxic stress imposed by high altitude training.

The acute effects of a newly synthesized thromboxane dual blocker (KDI-792), a combined thromboxane synthase inhibitor and receptor antagonist, on lower limb circulation were examined using two-dimensional color and pulse Doppler ultrasonography and laser Doppler flowmetry. A randomized single-masked, placebo-controlled trial was performed on 36 type 2 diabetic patients with minimally impaired baseline flow. The anatomical cross-sectional area (CSA), maximum flow velocity (MFV) and flow volume index (FVI) in the right dorsal pedis artery (DPA) and right femoral artery (FA) were determined by Doppler ultrasonography before and 45 and 90 minutes after the administration of either 100 or 200 mg of KDI-792 to the dose groups or placebo to the control group. Periflux blood flow (PBF) in the right foot was determined simultaneously by laser Doppler flowmetry. Both CSA and MFV in the dose groups were significantly increased in both the FA and DPA. FVI was markedly increased from 21.4 +/- 3.7 to 68.3 +/- 26.8 in the DPA (M +/- SD, P0.01) and from 365.4 +/- 35.3 to 771.7 +/- 75.7 in the FA (P0.01) in the 200 mg dose group. In the 100 mg dose group, FVI was markedly increased from 20.0 +/- 8.7 to 68.3 +/- 26.8 (P0.01) in the DPA and from 372.5 +/- 130.0 to 677.5 +/- 187.8 (P0.01) in the FA. PBF was also increased in both dose groups (from 4.15 +/- 1.4 to 7.0 +/- 4.0 ml/min/100 g tissue in the 200 mg dose group, P0.01), whereas there were no significant changes in either measurement in the control group. There were no significant changes in pulse rate or blood pressure after administration in either the dosage group or the placebo group. These and previous findings indicate that a single administration of KDI-792 markedly increases lower limb blood flow and might have a more potent vasodilating effect than that of prostaglandin I2 derivatives.