Michiaki Mishima

Kyoto University, Kioto, Kyōto, Japan

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Publications (453)1513.96 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: Matrix metalloproteinases (MMPs) are believed to be involved in the pathogenesis of idiopathic pulmonary fibrosis (IPF), and MMP-7 has been described as a useful biomarker for IPF. However, little is known regarding the significance of MMP-10 as a biomarker for IPF. METHODS: This observational cohort study included 57 patients with IPF. Serum MMPs were comprehensively measured in all patients, and the relationships between these markers and both disease severity and prognosis were evaluated. Bronchoalveolar lavage fluid (BALF) MMP-7 and -10 levels were measured in 19 patients to investigate the correlation between these markers and their corresponding serum values. Immunohistochemical staining for MMP-10 was also performed in IPF lung tissue. RESULTS: Serum MMP-7 and -10 levels correlated significantly with both the percentage of predicted forced vital capacity (ρ = -0.31, p = 0.02 and ρ = -0.34, p < 0.01, respectively) and the percentage of predicted diffusing capacity of the lung for carbon monoxide (ρ = -0.32, p = 0.02 and ρ = -0.43, p < 0.01, respectively). BALF MMP-7 and -10 levels correlated with their corresponding serum concentrations. Only serum MMP-10 predicted clinical deterioration within 6 months and overall survival. In IPF lungs, the expression of MMP-10 was enhanced and localized to the alveolar epithelial cells, macrophages, and peripheral bronchiolar epithelial cells. CONCLUSIONS: MMP-10 may be a novel biomarker reflecting both disease severity and prognosis in patients with IPF.
    Respiratory Research 09/2016; 16(1). DOI:10.1186/s12931-015-0280-9 · 3.09 Impact Factor
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    ABSTRACT: Purpose: Acute kidney injury (AKI) is a common and serious adverse effect of cisplatin-based chemotherapy. However, traditional markers of kidney function, such as serum creatinine, are suboptimal, because they are not sensitive measures of proximal tubular injury. We aimed to determine whether the new urinary biomarkers such as kidney injury molecule-1 (KIM-1), monocyte chemotactic protein-1 (MCP-1), and neutrophil gelatinase-associated lipocalin (NGAL) could detect cisplatin-induced AKI in lung cancer patients in comparison with the conventional urinary proteins such as N-acetyl-β-D-glucosaminidase (NAG) and β2-microglobulin. Methods: We measured KIM-1, MCP-1, NGAL, NAG, and β2-microglobulin concentrations in urine samples from 11 lung cancer patients, which were collected the day before cisplatin administration and on days 3, 7, and 14. Subsequently, we evaluated these biomarkers by comparing their concentrations in 30 AKI positive (+) and 12 AKI negative (-) samples and performing receiver operating characteristic (ROC) curve analyses. Results: The urinary levels normalized with urine creatinine of KIM-1 and MCP-1, but not NGAL, NAG, and β2-microglobulin in AKI (+) samples were significantly higher than those in AKI (-) samples. In addition, ROC curve analyses revealed that KIM-1 and MCP-1, but not NGAL, could detect AKI with high accuracy (area under the curve [AUC] = 0.858, 0.850, and 0.608, respectively). The combination of KIM-1 and MCP-1 outperformed either biomarker alone (AUC = 0.871). Conclusions: Urinary KIM-1 and MCP-1, either alone or in combination, may represent biomarkers of cisplatin-induced AKI in lung cancer patients.
    Cancer Chemotherapy and Pharmacology 09/2015; DOI:10.1007/s00280-015-2880-y · 2.77 Impact Factor
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    ABSTRACT: Background: Decreased bone mineral density (BMD) has been reported in patients with interstitial lung disease. However, BMD has not been evaluated in steroid-naïve patients with idiopathic pulmonary fibrosis (IPF). We aimed to measure vertebral BMD and investigate its relationship with clinical features in steroid-naïve patients with IPF. Methods: We recruited 55 consecutive male patients with steroid-naïve IPF; 55 male smokers without chronic obstructive pulmonary disease or interstitial lung disease, matched by age, body mass index, and pack-years of smoking (control smokers); and 27 healthy young adults. Thoracic vertebral BMD was measured by computed tomography (CT). We further investigated the relationship of BMD with clinical features and quantitative CT indices of lung density in patients with IPF. Results: The thoracic vertebral BMD of patients with IPF was significantly lower than that of control smokers (139.9 ± 28.5 mg/mL vs 160.9 ± 39.5 mg/mL, p < 0.01). Fifteen patients (27.2%) had BMD more than 2.5 SD below the mean BMD of young adults. In patients with IPF, emphysema volume (EV) and its ratio to total lung volume (EV%) had a significantly negative correlation with BMD (r = -0.28, p = 0.04 and r = -0.39, p < 0.01, respectively). In stepwise multiple regression analysis, EV% was an independent explanatory variable for thoracic vertebral BMD. Conclusion: A substantial percentage of steroid-naïve IPF patients had decreased BMD, and a significant association was observed between the extent of emphysema and BMD in IPF.
    Respiratory medicine 09/2015; 109(9):1181-7. DOI:10.1016/j.rmed.2015.06.014 · 3.09 Impact Factor
  • Young Hak Kim · Michiaki Mishima
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 08/2015; 10(8):e81-2. DOI:10.1097/JTO.0000000000000597 · 5.28 Impact Factor
  • Young Hak Kim · Michiaki Mishima
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 08/2015; 10(8):e76. DOI:10.1097/JTO.0000000000000568 · 5.28 Impact Factor
  • Cancer Research 08/2015; 75(15 Supplement):4669-4669. DOI:10.1158/1538-7445.AM2015-4669 · 9.33 Impact Factor
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    ABSTRACT: Background Quantitative computed tomography (CT) analysis has been proposed as a means of objectively assessing fibrotic interstitial pneumonia (IP) including idiopathic pulmonary fibrosis (IPF). We investigated whether percentages of high-attenuation areas (HAA%) and cystic areas (CA%) quantified from CT images were useful as indices of fibrotic IP. Methods CT images of 74 patients with fibrotic idiopathic interstitial pneumonias (IPF, 36; non-specific interstitial pneumonia, 9; unclassifiable idiopathic interstitial pneumonia, 29) were analyzed via in-house computer software, which automatically calculated HAA%, CA%, mean lung density (MLD), standard deviation of lung density (SD-LD), kurtosis, and skewness from CT attenuation histograms. These indices were compared in each instance with physiologic measures, visual fibrosis score, clinical diagnosis, radiologic CT pattern, and prognosis. Results HAA% correlated significantly with physiologic measures and visual fibrosis score to a moderate extent (%forced vital capacity, rs = −0.59; % carbon monoxide diffusion capacity, rs = −0.43; fibrosis score, rs = 0.23). Densitometric parameters (MLD, SD-LD, kurtosis, and skewness) correlated significantly with physiologic measures and fibrosis score (|rs| = 0.28-0.59). CA% showed no association with pulmonary functions but differed significantly between IPF and other interstitial pneumonias (IPs) (1.50 ± 2.41 % vs. 0.41 ± 0.80 %; P < 0.01) and between the definite usual interstitial pneumonia (UIP) pattern and other patterns (1.48 ± 2.38 % vs. 0.55 ± 1.19 %; P < 0.01). On univariate analysis, HAA%, MLD, SD-LD, kurtosis, skewness, fibrosis score, and definite UIP pattern all correlated with survival, with kurtosis alone identified as a significant predictor of mortality on multivariate analysis (hazard ratio = 0.67; 95 % CI, 0.44-0.96; P = 0.03). Conclusion CA% and HAA% are novel quantitative CT indices with differing properties in fibrotic IP evaluations. HAA% largely reflects physiologic impairments, whereas CA% corresponds with diagnosis and HRCT pattern. Of the CT indices examined, kurtosis constituted the strongest predictor of mortality.
    BMC Pulmonary Medicine 07/2015; 15(1). DOI:10.1186/s12890-015-0069-0 · 2.40 Impact Factor
  • Journal of clinical sleep medicine: JCSM: official publication of the American Academy of Sleep Medicine 07/2015; · 3.05 Impact Factor
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    ABSTRACT: Alpha-1 antitrypsin (AAT) encoded by SERPINA1 is an acute-phase inflammation marker, and AAT deficiency (AATD) is known as one of the common genetic disorders in European populations. However, no genetic determinants to AAT levels apart from the SERPINA gene clusters have been identified to date. Here we perform a genome-wide association study of serum AAT levels followed by a two-staged replication study recruiting a total of 9,359 Japanese community-dwelling population. Three missense variants of metabolic syndrome-related genes, namely, rs671 in ALDH2, rs1169288 in HNF1A and rs1260326 in GCKR, significantly associate with AAT levels (P≤1.5 × 10(-12)). Previous reports have shown the functional relevance of ALDH2 and HNF1A to AAT. We observe a significant interaction of rs671 and alcohol consumption on AAT levels. We confirm the association between AAT and rs2896268 in SERPINA1, which is independent of known causative variants of AATD. These findings would support various AAT functions including metabolic processes.
    Nature Communications 07/2015; 6:7754. DOI:10.1038/ncomms8754 · 11.47 Impact Factor
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    ABSTRACT: Although sedation is often required for agitated patients undergoing noninvasive ventilation (NIV), reports on its practical use have been few. This study aimed to evaluate the efficacy and safety of sedation for agitated patients undergoing NIV in clinical practice in a single hospital. We retrospectively reviewed sedated patients who received NIV due to acute respiratory failure from May 2007 to May 2012. Sedation level was controlled according to the Richmond Agitation Sedation Scale (RASS). Clinical background, sedatives, failure rate of sedation, and complications were evaluated by 1) sedative methods (intermittent only, switched to continuous, or initially continuous) and 2) code status (do-not-intubate [DNI] or non-DNI). Of 3506 patients who received NIV, 120 (3.4 %) consecutive patients were analyzed. Sedation was performed only intermittently in 72 (60 %) patients, was switched to continuously in 37 (31 %) and was applied only continuously in 11 (9 %). Underlying diseases in 48 % were acute respiratory distress syndrome/acute lung injury/severe pneumonia or acute exacerbation of interstitial pneumonia. In non-DNI patients (n = 39), no patient required intubation due to agitation with continuous sedation, and in DNI patients (n = 81), 96 % of patients could continue NIV treatment. PaCO2 level changes (6.7 ± 15.1 mmHg vs. -2.0 ± 7.7 mmHg, P = 0.028) and mortality in DNI patients (81 % vs. 57 %, P = 0.020) were significantly greater in the continuous use group than in the intermittent use group. According to RASS scores, sedation during NIV in proficient hospitals may be favorably used to potentially avoid NIV failure in agitated patients, even in those having diseases with poor evidence of the usefulness of NIV. However, with continuous use, we must be aware of an increased hypercapnic state and the possibility of increased mortality. Larger controlled studies are needed to better clarify the role of sedation in improving NIV outcomes in intolerant patients.
    BMC Pulmonary Medicine 07/2015; 15(1):71. DOI:10.1186/s12890-015-0072-5 · 2.40 Impact Factor
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    ABSTRACT: Associations between obstructive sleep apnea (OSA) and liver fat accumulation have been frequently investigated because both morbidities are common. Visceral fat was reported to be closely related to OSA and liver fat accumulation. Recently, sex differences in the association between OSA and mortality have gained much attention. To investigate the associations among OSA, liver fat accumulation as determined by computed tomography, and visceral fat area and their sex differences. Studied were 188 males and 62 females who consecutively underwent polysomnography and computed tomography. Although the apnea-hypopnea index was positively correlated with liver fat accumulation in the total males, none of the OSA-related factors was independently associated with liver fat accumulation in either the total male or female participants in the multivariate analyses. When performing subanalyses using a specific definition for Japanese of obesity or visceral obesity (body mass index (BMI) ≥25 kg/m2 or visceral fat area ≥100 cm2), in only males without visceral obesity, percent sleep time with oxygen saturation <90%, in addition to BMI, insulin resistance, and serum triglyceride values, was independently correlated with liver fat accumulation (R2 = 15.1%, P<0.001). In males, percent sleep time of oxygen saturation <90% was also a determining factor for alanine aminotransferase values regardless of visceral fat area. In contrast, OSA was not associated with liver fat accumulation or alanine aminotransferase values in females whether or not visceral obesity was absent. Sex differences in the visceral fat-dependent impact of OSA on liver fat accumulation existed. Although the mechanisms are not known and ethnic differences may exist in addition to the specific criteria of visceral obesity in Japan, the treatment of male patients with OSA might be favorable from the viewpoint of preventing liver fat accumulation and liver dysfunction even in patients without obvious visceral fat accumulation.
    PLoS ONE 06/2015; 10(6):e0129513. DOI:10.1371/journal.pone.0129513 · 3.23 Impact Factor
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    ABSTRACT: Airway remodelling in bronchial asthma (BA) and COPD has been quantitatively assessed by analysing the airway wall area and the luminal area on cross-sectional CT images. To date, there have been no reports on assessment of the longitudinal structure of the airway lumen. Quantitative airway analysis using CT was performed on three groups consisting of 29 patients with BA, 58 patients with COPD and 59 healthy controls. To assess the longitudinal shape irregularity of the airway lumen, new quantitative CT parameters, validated by a phantom study, were established. The internal radii of imaginary inscribed spheres in the airway lumen were measured as a function of distance from the level of the carina to the fifth-order branches of the right posterior basal bronchus. The gaps of these radii from the regression line were calculated as parameters to reflect the longitudinal airway lumen shape irregularity. These new parameters were compared among the study groups as well as with the conventional parameters of airway wall thickening and luminal area. Longitudinal airway lumen shape irregularity was significantly greater in patients with COPD than in those with BA and healthy controls. Wall thickening was significantly greater, and luminal area smaller, in patients with BA than in those with COPD and healthy controls. These results were consistent even among the BA and COPD subgroups with similar airflow limitation. The combination of cross-sectional and longitudinal airway structure analyses using CT images may suggest differences in the characteristics of airway remodelling between COPD and asthma. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
    Thorax 05/2015; 70(8). DOI:10.1136/thoraxjnl-2014-206651 · 8.29 Impact Factor
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    ABSTRACT: Pulmonary spindle cell carcinoma (SpCC) is a rare subtype of non-small-cell lung cancer (NSCLC) and, in general, is chemoresistance. A sixty-five year-old male patient with metastatic pulmonary SpCC was initially treated with cisplatin and docetaxel, but his disease progressed. Then, he received a combination chemotherapy with carboplatin and nab-PTX followed by maintenanced chemotherapy with nab-PTX. Fluorodeoxyglucose (FDG) positron-emission CT revealed a substantial decrease of FDG accumulation in the primary tumor, and the response continued for more than 7 months. Preclinical models suggested that nab-PTX may reach the tumor microenvironment more efficiently than solvent-based paclitaxel (sb-PTX) and be preferentially taken up by cancer cells. Considering that there is no effective treatment for patients with pulmonary SpCC, nab-PTX may merit further investigation in patients with pulmonary SpCC.
    Respiratory Medicine Case Reports 05/2015; 30. DOI:10.1016/j.rmcr.2015.05.003
  • Young Hak Kim · Michiaki Mishima
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 05/2015; 10(5):e35. DOI:10.1097/JTO.0000000000000513 · 5.28 Impact Factor
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    ABSTRACT: Computed tomography (CT) assessment of air trapping has been considered useful as a measure of small airway disease. Mean lung density (MLD) and the percentage of the lung field occupied by low attenuation area (LAA%) can be evaluated automatically, and their expiratory/inspiratory (E/I) ratios correlate with asthma severity and spirometry parameters. However, mosaic attenuation, another indicator of air trapping, has been assessed visually, and its functional relevance remains controversial. This retrospective study was conducted to correlate mosaic attenuation, which was assessed visually and automatically, and the E/I ratios of MLD and LAA% (defined as areas <-960 Hounsfield units) with clinical and physiological variables, including impulse oscillometry (IOS) indices. In 36 nonsmoking patients with stable asthma, the lungs were scanned at full inspiration and full expiration. Mosaic attenuation was measured visually and automatically, by counting areas with CT values higher than the surrounding areas. MLD and LAA% were measured using our validated method. Spirometry, IOS, exhaled NO and the sputum eosinophil count were evaluated. The automatic results and visual scores of mosaic attenuation correlated well on expiratory scans (r = 0.894) and to a lesser degree on inspiratory scans (r = 0.629; p < 0.0001 for both). However, only the E/I ratios of MLD and LAA% correlated with forced expiratory volume in 1 s/forced vital capacity of spirometry and the IOS indices of resistance from 5 to 20 Hz and the integrated area of low-frequency reactance. Our automatic method for analysis of mosaic attenuation is likely useful, but the results themselves may not be reflecting small airway involvement of asthma, unlike the E/I ratios of MLD and LAA%. © 2015 S. Karger AG, Basel.
    Respiration 04/2015; 89(6). DOI:10.1159/000381553 · 2.59 Impact Factor
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    ABSTRACT: No studies have addressed the relationship between obstructive sleep apnea (OSA) and abdominal aortic calcification (AAC), a marker for subclinical atherosclerosis and future cardiovascular events. To investigate 1) the association between OSA severity and AAC, and 2) whether OSA can impact the extent of AAC independent of comorbid atherogenic risk factors. 390 participants aged 40-70 years underwent polysomnography and abdominal computed tomography. AAC was separately quantified in the upper and lower abdominal aorta using the modified Agatston scoring method, and the total AAC score was calculated as a sum of the two scores. OSA was defined as none/mild (apnea-hypopnea index [AHI] <15, n = 87), moderate (AHI 15-30, n = 129), and severe (AHI ≥30, n = 174). Log-transformed total AAC score adjusted for age and body mass index (BMI) was greater in participants with an elevated AHI (3.4 for none/mild OSA, 3.7 for moderate OSA, and 4.2 for severe OSA, p = 0.04). Multivariate linear regression analysis including age and BMI as covariates showed that severe OSA was associated with higher scores for the lower and total AAC (β = 0.15 and 0.14, p = 0.01 and 0.01, respectively). The association did not persist after additionally adjusting for traditional atherogenic risk factors including visceral fat, smoking, hypertension, dyslipidemia, and diabetes. Severe OSA was associated with a greater extent of AAC, which was dependent on coexisting atherogenic risk factors. Comorbid cardiometabolic disorders may largely mediate the association of OSA with subclinical atherosclerosis. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Atherosclerosis 04/2015; 241(1):6-11. DOI:10.1016/j.atherosclerosis.2015.04.801 · 3.99 Impact Factor
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    ABSTRACT: Chronic obstructive pulmonary disease (COPD) is characterized by a mixture of emphysema and airway disease. The forced oscillation technique (FOT) has been applied to COPD patients to clarify changes in respiratory mechanics; dynamic changes in respiratory resistance (Rrs) during breathing (within-breath changes in Rrs, ΔRrs) are characteristic of COPD. However, the pathophysiological significance of these changes is unknown. The aim of this study was to assess how emphysema and airway disease influence ΔRrs in COPD patients. In this cross-sectional study, stable COPD patients were recruited and underwent respiratory impedance measurements with a commercially available FOT device. Rrs was recorded during tidal breathing and then analyzed as whole-breath Rrs (Rrs at 5 Hz, R5; Rrs at 20 Hz, R20; and their difference, R5-R20) or as ΔRrs, the difference between the expiratory and inspiratory Rrs (ΔR5, ΔR20 and ΔR5-R20). The percentage of the low attenuation area (LAA%) and airway wall area (WA%) was quantified by computed tomography analysis, and their contributions to ΔRrs were examined. Seventy-five COPD patients were recruited. LAA% was negatively correlated with ΔR5 and ΔR5-R20 (P = 0.0002 and P = 0.0033, respectively); meanwhile, WA% in B(10) was positively correlated with ΔR5 and ΔR5-R20 (P = 0.0057 and P < 0.0001, respectively). Multivariate analysis revealed that the contribution of both LAA% and WA% in B(10) to ΔRrs was independent of the severity of airflow limitations. This study shows that emphysema suppresses ΔRrs in COPD patients, while airway disease increases ΔRrs in these patients. © 2015 Asian Pacific Society of Respirology.
    Respirology 03/2015; 20(5). DOI:10.1111/resp.12535 · 3.35 Impact Factor
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    ABSTRACT: Visceral obesity, low adiponectin, and severe obstructive sleep apnea (OSA) are associated with cardiovascular diseases, but the interactions among these factors on endothelial dysfunction are not well known.Methods and Results:Endothelial function in 133 patients after polysomnography was evaluated as reactive hyperemia index (RHI) on reactive hyperemia peripheral arterial tonometry. Visceral obesity was defined as visceral fat area ≥100 cm(2)on computed tomography. RHI was significantly correlated with apnea hypopnea index (AHI), visceral fat area, and serum adiponectin (r=-0.24, P=0.0055, r=-0.19, P=0.031, and r=0.20, P=0.019, respectively). RHI in patients with visceral obesity was significantly decreased in the presence of severe OSA (AHI ≥30; P=0.042). On multivariate regression analysis, only severe OSA remained as an independent predictive factor of RHI (P=0.024, R(2)=5.4%). RHI in patients with severe OSA (n=44) was significantly improved after 3 months of continuous positive airway pressure (CPAP) treatment (1.78±0.40 before CPAP vs. 2.00±0.53 after CPAP, P=0.013), similarly to those with AHI <30 (P=0.45). Severe OSA, but not visceral fat area or serum adiponectin, was independently associated with endothelial function according to RHI. In addition, impaired endothelial function was reversible following 3 months of CPAP treatment.
    Circulation Journal 03/2015; 79(6). DOI:10.1253/circj.CJ-14-1303 · 3.94 Impact Factor

Publication Stats

6k Citations
1,513.96 Total Impact Points


  • 1993–2015
    • Kyoto University
      • • Department of Respiratory Medicine
      • • Primate Research Institute
      Kioto, Kyōto, Japan
  • 2013
    • Khon Kaen University
      • Centre for Research and Development of Medical Diagnostic Laboratories
      Kawn Ken, Khon Kaen, Thailand
  • 2011
    • Hospital Universitari Germans Trias i Pujol
      Badalona, Catalonia, Spain
  • 2010
    • Chiba University
      • Department of Respirology
      Chiba-shi, Chiba-ken, Japan
  • 2006
    • Nagai Internal Medicine Clinic
      Okayama, Okayama, Japan
  • 2005
    • Kyoto Sangyo University
      Kioto, Kyōto, Japan
  • 1992
    • Hyogo Prefectural Amagasaki Hospital
      Amagasaki, Hyōgo, Japan