Michiaki Mishima

Kyoto University, Kioto, Kyōto, Japan

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Publications (359)1208.72 Total impact

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    ABSTRACT: Obesity hypoventilation syndrome (OHS) prevalence was previously estimated at 9% in patients with obstructive sleep apnoea (OSA) in Japan. However, the definition of OSA in that study was based on an apnoea-hypopnoea index (AHI) of ≥ 20/h rather than ≥ 5/h. Therefore, the prevalence of OHS in OSA was not measured in the same way as for Western countries. Our study objectives were to investigate the characteristics of Japanese patients with OHS.
    Respirology 09/2014; · 2.78 Impact Factor
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    American Journal of Respiratory and Critical Care Medicine 08/2014; 190(4):472-4. · 11.04 Impact Factor
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    ABSTRACT: Although obesity has been reported to be a potential risk factor for abdominal aortic dilatation, the impact of obstructive sleep apnea (OSA) on the abdominal aortic diameter remains unknown. We retrospectively reviewed 427 patients aged >45 years who underwent polysomnography and abdominal computed tomography from November 2008 to February 2012. Aortic diameters were measured at 3 locations: upper, infrarenal, and lower abdominal aorta. OSA was defined as non-OSA (apnea-hypopnea index [AHI] <10, n = 58), mild to moderate (AHI 10 to 30, n = 167), and severe (AHI ≥30, n = 202). Adjusted diameter was not significantly different among OSA severity categories at the upper (21.0, 21.3, and 21.4 mm, respectively) and infrarenal aorta (19.5, 20.2, and 19.9 mm, respectively) but was significantly different at the lower abdominal aorta (17.3, 18.2, and 18.2 mm, respectively, p = 0.006) with larger diameters in patients with OSA. Multivariate linear regression analyses revealed that risk profiles for aortic dilatation varied according to the location and gender and that OSA (AHI ≥10) was an independent risk factor for infrarenal and lower abdominal aortic dilatation only in men (β = 0.10 and 0.18, p = 0.049 and 0.001, respectively). In conclusion, OSA may enhance dilatation of the distal abdominal aorta in men.
    The American Journal of Cardiology. 08/2014; 114(4):618–623.
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    ABSTRACT: Since commercial forced oscillation technique (FOT) devices became available, they have been widely used for physiological assessments, mainly of obstructive lung diseases. However, it is not known whether the impedance values measured with different devices are identical. In this study, two FOT devices-the impulse oscillometry system (IOS) and the MostGraph (MG)-were compared using phantom models. The resistance values varied up to 10 % from estimated values in both devices. Additionally, there was a difference in frequency dependence for the resistance between the devices. The reactance values measured with MG were higher than those measured with IOS. The effects of ventilation on the measured impedance values were higher for IOS than for MG, especially at lower frequencies. We concluded that the devices do not always generate identical impedance values. Thus, differences between the devices should be taken into consideration when evaluating clinical data.
    The journal of physiological sciences : JPS. 07/2014;
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    ABSTRACT: Background: Preclinical data indicated that the combination of erlotinib and pemetrexed is synergistic when erlotinib is administered after pemetrexed. Patients and Methods: This was a phase II study of pemetrexed and erlotinib in patients with pretreated advanced non-squamous non-small-cell lung cancer (NSCLC) with wild-type epidermal growth factor receptor (EGFR). Chemotherapy consisted of pemetrexed (500 mg/m(2)) on day 1 and erlotinib (150 mg/body) on days 2-15 every 3 weeks. The protocol treatment was repeated until disease progression or intolerable toxicities occurred. Results: Seventeen patients were enrolled between January 2010 and January 2013, and 15 patients were evaluable for both safety and efficacy. The study was terminated due to slow patient accrual. There was 1 complete response. There was a partial response in 3 patients, stable disease in 4 and progressive disease in 7. The response rate was 27% and disease control rate was 53%. The median progression-free survival and overall survival were 2.5 months and 6.7 months, respectively. Conclusions: Statistical interpretation could not been made due to the early termination of the study. Further studies are needed to clarify the efficacy of this regimen in NSCLC patients without EGFR mutation (UMIN-CTR No. 0000024531). © 2014 S. Karger AG, Basel.
    Chemotherapy 07/2014; 59(6):414-419. · 2.07 Impact Factor
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    ABSTRACT: Omalizumab, a humanized anti-IgE monoclonal antibody, is reportedly an effective treatment for severe allergic asthma. However, there have been few comprehensive analyses of its efficacy, including assessments of small airways or airway remodeling.
    Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology 07/2014; · 3.45 Impact Factor
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    ABSTRACT: Bacteria and viruses are major causes of COPD exacerbations. Molecular components of these pathogens are recognized by pattern-recognition receptors (PRRs) expressed by various cells in the airway, which leads to initiation of inflammatory processes. Expression levels of PRRs in airway inflammatory cells are expected to affect susceptibility to COPD exacerbation.
    The Clinical Respiratory Journal 06/2014; · 1.66 Impact Factor
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    ABSTRACT: There is a need for agents that suppress inflammation and progression of chronic obstructive pulmonary disease. p38 mitogen-activated protein kinase (p38 MAPK) has been associated with this disorder, and several inhibitors of this cascade are in clinical trials for its treatment, but their efficacy and utility are unknown. This study evaluated the relationship between p38 MAPK activation and susceptibility to cigarette smoke (CS)-induced emphysema, and whether its inhibition ameliorated the lung inflammation and injury in murine models of cigarette smoke exposure.
    BMC Pulmonary Medicine 05/2014; 14(1):79. · 2.76 Impact Factor
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    ABSTRACT: Patients with asthma show a steeper age-related decline in pulmonary function than healthy subjects, which is often alleviated after the initiation of treatment with inhaled corticosteroids (ICS). However, there still are patients who develop irreversible airflow limitations despite receiving adequate ICS treatment. The identification of the characteristics of such patients and biomarkers of progression for airflow limitation, a functional consequence of airway remodeling, is considered important in the management of asthma. A variety of biomarkers are associated with the forced expiratory volume in 1s (FEV1) in asthma in a cross-sectional fashion. However, few biomarkers are known to reflect the decline in pulmonary function, particularly in patients with asthma who receive ICS treatment. Recently periostin, a matricellular protein that prolongs Th2/eosinophilic inflammation and reflects airway remodeling, was reported to be detected in serum. In a Kinki Hokuriku Airway disease Conference multicenter cohort study, we demonstrated that among several serum markers, high serum periostin level, particularly ≥95ng/mL, was the only marker associated with a greater annual decline in FEV1 and a decline in FEV1 of ≥30mL·yr-1. A variant (rs9603226) of the POSTN gene that encodes periostin was also involved in the frequency of a decline in FEV1 of ≥30mL·yr-1. Our results suggest that the serum periostin level is a useful marker reflecting pulmonary function decline in patients with asthma receiving ICS.
    Allergology International 04/2014;
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    ABSTRACT: To identify druggable oncogenic fusions in invasive mucinous adenocarcinoma (IMA) of the lung, a malignant type of lung adenocarcinoma in which KRAS mutations frequently occur. From an IMA cohort of 90 cases, consisting of 56 cases (62%) with KRAS mutations and 34 cases without (38%), we conducted whole-transcriptome sequencing of 32 IMAs, including 27 cases without KRAS mutations. We used the sequencing data to identify gene fusions, and then performed functional analyses of the fusion gene products. We identified oncogenic fusions that occurred mutually exclusively with KRAS mutations: CD74-NRG1, SLC3A2-NRG1, EZR-ERBB4, TRIM24-BRAF, and KIAA1468-RET. NRG1 fusions were present in 17.6% (6/34) of KRAS-negative IMAs. The CD74-NRG1 fusion activated HER2:HER3 signaling, whereas the EZR-ERBB4 and TRIM24-BRAF fusions constitutively activated the ERBB4 and BRAF kinases, respectively. Signaling pathway activation and fusion-induced anchorage-independent growth/tumorigenicity of NIH3T3 cells expressing these fusions were suppressed by tyrosine kinase inhibitors approved for clinical use. Oncogenic fusions act as driver mutations in IMAs without KRAS mutations, and thus represent promising therapeutic targets for the treatment of such IMAs.
    Clinical Cancer Research 04/2014; · 7.84 Impact Factor
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    ABSTRACT: In steroid-naive patients with asthma, several gene variants are associated with a short-term response to inhaled corticosteroid (ICS) treatment; this has mostly been observed in Caucasians. However, not many studies have been conducted for other ethnicities. Here, we aimed to determine the relationship between the annual decline in forced expiratory flow volume in one second (FEV1 ) and the variant of the glucocorticoid-induced transcript 1 gene (GLCCI1) in Japanese patients with asthma receiving long-term ICS treatment, taking into account the effect of high serum periostin levels, a known association factor of pulmonary function decline and a marker of refractory eosinophilic/Th2 inflammation. In this study, 224 patients with asthma receiving ICS treatment for at least 4 years were enrolled. The effects of single-nucleotide polymorphisms (SNPs) in GLCCI1, stress-induced phosphoprotein 1 (STIP1), and T gene on the decline in FEV1 of 30 ml/year or greater were determined. Besides the known contributing factors, that is, the most intensive treatment step, ex-smoking, and high serum periostin levels (≥95 ng/ml), the GG genotype of GLCCI1 rs37973, and not other SNPs, was independently associated with a decline in FEV1 of 30 ml/year or greater. When patients were stratified according to their serum periostin levels, the GG genotype of rs37973 was significantly associated with blood eosinophilia (≥250/μl) in the high serum periostin group. A GLCCI1 variant is a risk factor of pulmonary function decline in Japanese patients with asthma receiving long-term ICS treatment. Thus, GLCCI1 may be associated with response to ICS across ethnicities.
    Allergy 03/2014; · 5.88 Impact Factor
  • Isao Ito, Michiaki Mishima
    American Journal of Respiratory and Critical Care Medicine 03/2014; 189(6):756-7. · 11.04 Impact Factor
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    ABSTRACT: Surgical lung biopsy (SLB) by videothoracoscopy for diffuse interstitial lung diseases is recommended for detailed diagnosis. Because substantial mortality and morbidity are associated with this procedure, its safety and diagnostic yield should be validated. Sixty-four patients with diffuse interstitial lung disease who received SLB by videothoracoscopy between 2007 and 2013 were retrospectively analyzed for mortality, surgical complication, and diagnosis. Criteria for the procedure included patients <70-year old, who had at least 60 % vital capacity and at least 40 % diffusion capacity. Patients with radiologically definite usual interstitial pneumonia were not eligible. One conversion from the 3-port approach to thoracotomy due to bleeding occurred. Mean operation and anesthesia times were 63 and 133 min, respectively. The mean hospital stay was 6 days. Only 10 patients (16 %) received prophylactic steroid and/or elastase inhibitor administration. Neither deaths nor acute exacerbations of interstitial pneumonia occurred within 60 days after surgery. Pneumothorax occurred in four cases (6 %) after discharge, which was associated with lower % vital capacity and intraoperative steroid administration. Prolonged air leak and postoperative pneumonia were observed in 2 and 1 patients, respectively. Postoperative diagnosis was obtained in all patients. A group of connective tissue disease-related interstitial pneumonia (n = 15) and chronic hypersensitivity pneumonitis (n = 18) were the major diagnoses. Discordance between pre- and postoperative diagnoses was observed among usual interstitial pneumonia, non-specific interstitial pneumonia, and chronic hypersensitivity pneumonia. Surgical lung biopsy for diffuse interstitial lung diseases is safe under appropriate inclusion criteria and provides definite diagnosis.
    General Thoracic and Cardiovascular Surgery 03/2014;
  • The Journal of allergy and clinical immunology 02/2014; · 12.05 Impact Factor
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    ABSTRACT: To the Editor:Neutrophil gelatinase-associated lipocalin (NGAL) is a 25 kD lipocalin that is covalently bound to matrix metalloproteinase (MMP)-9 produced by neutrophils (1). NGAL in blood or bronchoalveolar lavage fluid (BALF) may reflect neutrophilic inflammation in the lungs (2, 3), and it is highly induced in injured epithelial cells, including those in the lung (4). Possible roles for neutrophilic inflammation and epithelial injury have been reported in idiopathic pulmonary fibrosis (IPF). Thus, we hypothesised that NGAL may be associated with the pathogenesis of IPF. To investigate the roles of NGAL in IPF, we used immunohistochemical staining for lung specimens and measured plasma and BALF NGAL levels. Our study was approved by the Ethics Committee of Kyoto University (approval No. E438), and written informed consent was obtained from all study participants.First, we immunohistochemically stained the lung tissue specimens of six IPF patients, two nonspecific interstitial pneumonia (NSIP) patients, and a control (normal area distant from the lesion of surgically diagnosed organising pneumonia) for NGAL using a conventional method (5). We also performed sequential immunofluorescent staining for NGAL and MMP-9. Immunohistochemical staining showed that NGAL was abundantly expressed in airway epithelial cells that covered the honeycomb cysts in IPF (fig. 1a and b). Further, histologically.
    European Respiratory Journal 02/2014; · 6.36 Impact Factor
  • Toru Oga, Kazuo Chin, Michiaki Mishima
    European Respiratory Journal 02/2014; 43(2):322-4. · 6.36 Impact Factor
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    ABSTRACT: Rationale: Difference in mortality from obstructive sleep apnea (OSA) by sex is an important issue. Visceral fat, a significant risk factor for cardiovascular disease (CVD), was reported to be closely related to OSA. Objectives: To assess the different associations between OSA and visceral fat area (VFA) by sex, which might account for the different prognosis in men and women with OSA. Methods: Participants were 271 men and 100 women consecutively hospitalized for examination of OSA from October 2008 to December 2010. Among the 371 participants, relationships were analyzed between fat areas by computed tomography, comorbidity, polysomnographic data, arterial blood gas, pulmonary function and venous blood data. Multiple regression analyses were performed to identify variables independently associated with VFA and subcutaneous fat area (SFA) for each sex. Measurements and Main Results: Despite similar body mass index (BMI) and waist circumference, men had larger VFA, more severe OSA and more severe dyslipidemia than women. Multiple regression analyses revealed that in men, not only age and BMI but also minimum oxygen saturation (contribution rate (R²) = 4.6%) during sleep, and alveolar-arterial oxygen difference (R² = 7.6%) were independently associated with VFA. Conversely, VFA was only associated with BMI in women. Conclusions: Only in men OSA was independently associated with VFA. The lesser associations between OSA and visceral fat in women might account for OSA's lower impact on CVD or mortality in women.
    Annals of the American Thoracic Society. 01/2014;
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    ABSTRACT: Rationale: Both periodic limb movements during sleep (PLMS) and obstructive sleep apnea (OSA) are major causes of sleep disorders and have been associated with systemic inflammation and cardiovascular events. However, it is uncertain whether in combination they promote a higher inflammatory response and greater risk of cardiovascular events than each condition alone. Objectives: To investigate whether the presence of PLMS is associated with increased inflammation in patients suspected of having OSA. Methods: In 342 patients who underwent polysomnography to diagnose OSA, plasma C-reactive protein (CRP) and fibrinogen levels were measured. Measurements and Main Results: OSA was found in 254 patients, with 46 also having PLMS. Among the 88 patients who did not have OSA, 8 had PLMS. Plasma CRP and fibrinogen levels in the group with both PLMS and OSA were higher than in patients with neither OSA nor PLMS and in patients with OSA only (CRP: 0.20±0.48 vs. 0.09±0.15 vs. 0.13±0.18 mg/dl, p=0.03; fibrinogen: 298.2±76.1 vs. 269.0±57.1 vs. 270.0±52.6 mg/dl, p <0.01) Multivariate analysis showed that the presence of PLMS was associated with higher plasma CRP levels (β=0.1401, p<0.01) and fibrinogen levels (β=0.1359, p=0.01) independently from other clinical variables such as body mass index and the severity of OSA. Conclusions: PLMS were positively associated with plasma CRP and fibrinogen levels in patients suspected of having OSA. Since plasma levels of these proteins have been established as predictive factors of future cardiovascular events, the presence of PLMS may be a useful clinical sign to identify OSA patients at high risk of cardiovascular events.
    Annals of the American Thoracic Society. 01/2014;
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    ABSTRACT: Autoantibodies to aminoacyl-tRNA synthetases (ARSs) are useful in the diagnosis of idiopathic inflammatory myopathy (IIM) with interstitial pneumonia (IP). We developed an enzyme-linked immunosorbent assay (ELISA) system using a mixture of recombinant ARS antigens and tested its utility in a multicenter study. Methods: We prepared six recombinant ARSs: GST-Jo-1, His-PL-12, His-EJ and GST-KS expressed in Escherichia coli, and His-PL-7 and His-OJ expressed in Hi-5 cells. After confirming their antigenic activity, with the exception of His-OJ, we developed our ELISA system in which the five recombinant ARSs (without His-OJ) were mixed. Efficiency was confirmed using the sera from 526 Japanese patients with connective tissue disease (CTD) (IIM n = 250, systemic lupus erythematosus n = 91, systemic sclerosis n = 70, rheumatoid arthritis n = 75, Sjögren's syndrome n = 27 and other diseases n = 13), 168 with idiopathic interstitial pneumonia (IIP) and 30 healthy controls collected from eight institutes. IIPs were classified into two groups; idiopathic pulmonary fibrosis (IPF) (n = 38) and non-IPF (n = 130). Results were compared with those of RNA immunoprecipitation. Results: Sensitivity and specificity of the ELISA were 97.1% and 99.8%, respectively when compared with the RNA immunoprecipitation assay. Anti-ARS antibodies were detected in 30.8% of IIM, 2.5% of non-myositis CTD, and 10.7% of IIP (5.3% of IPF and 12.3% of non-IPF). Anti-ARS-positive non-IPF patients were younger and more frequently treated with glucocorticoids and/or immunosuppressants than anti-ARS-negative patients. Conclusion: A newly established ELISA detected anti-ARS antibodies as efficiently as RNA immunoprecipitation. This system will enable easier and wider use in the detection of anti-ARS antibodies in patients with IIM and IIP.
    PLoS ONE 01/2014; 9(1):e85062. · 3.53 Impact Factor
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    ABSTRACT: Background Comprehensive studies of the pathophysiologic characteristics of elderly asthma, including predominant site of disease, airway inflammation profiles, and airway hyperresponsiveness, are scarce despite their clinical importance. Objective To clarify the pathophysiologic characteristics of elderly patients with asthma. Methods Patients older than 65 years (elderly; n = 45) vs those no older than 65 years (nonelderly; n = 67) were retrospectively analyzed by spirometry, computed tomographic indices of large airway wall thickness and small airway involvement (air trapping), impulse oscillation measurements, exhaled nitric oxide levels, blood and induced sputum cell differentials, methacholine airway responsiveness, and total and specific serum IgE levels. Results Elderly patients with asthma had significantly lower values for forced expiration volume in 1 second, mid-forced expiratory flow (percentage predicted), and ratio of forced expiration volume in 1 second to forced vital capacity than nonelderly patients with asthma (median 81.2% vs 88.8%, P = .02; 50.9% vs 78.6%, P = .03; 0.72 vs 0.78, P = .001, respectively). In computed tomographic measurements, elderly patients with asthma had significantly greater airway wall thickening and air trapping than nonelderly patients. Impulse oscillation measurements indicated that elderly patients with asthma showed significantly greater resistance at 5 Hz (used as an index of total airway resistance), greater decrease in resistance from 5 to 20 Hz, a higher ratio of decrease in resistance from 5 to 20 Hz to resistance at 5 Hz, higher integrated area between 5 Hz and frequency of resonance, greater frequency of resonance, and lower reactance at a frequency of 5 Hz (potential markers of small airway disease) than nonelderly patients. There were no significant differences in blood or sputum cell differentials, exhaled nitric oxide, or methacholine airway responsiveness between the 2 groups. Total serum IgE levels and positive rates of specific IgE antibodies against several allergens were significantly lower in elderly than in nonelderly patients with asthma. Conclusion Based on spirometric, computed tomographic, and impulse oscillation analyses, elderly patients with asthma have greater involvement of small and large airways than nonelderly patients with asthma.
    Annals of Allergy, Asthma & Immunology. 01/2014;

Publication Stats

4k Citations
1,208.72 Total Impact Points


  • 1991–2014
    • Kyoto University
      • • Department of Respiratory Medicine
      • • Primate Research Institute
      Kioto, Kyōto, Japan
  • 2011
    • Kyoto Medical Center
      Kioto, Kyōto, Japan
  • 2010
    • Chiba University
      • Department of Respirology
      Chiba-shi, Chiba-ken, Japan
  • 2008
    • Kurashiki Central Hospital
      Kurasiki, Okayama, Japan
  • 2006
    • Nagai Internal Medicine Clinic
      Okayama, Okayama, Japan
  • 2004
    • Shiga University of Medical Science
      Ōtu, Shiga, Japan
  • 1992
    • Hyogo Prefectural Amagasaki Hospital
      Amagasaki, Hyōgo, Japan