研究者詳細 - 南宮　湖

論文 - 南宮　湖

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hsa-miR-346 is a potential serum biomarker of Mycobacterium avium complex pulmonary disease activity

T Nishimura, E Tamizu, S Uno, Y Uwamino, H Fujiwara, K Nishio, ...

Journal of infection and chemotherapy 23 (10), 703-708 23 （ 10 ） 703 - 708 2017年10月

査読有り

MicroRNA (miRNA) has been recently recognized as a biomarker of various diseases; however, there are no known miRNAs associated with Mycobacterium avium complex (MAC) pulmonary disease. In addition, there are no known biomarkers to precisely reflect disease activity after the diagnosis of MAC pulmonary disease. Thus, we sought to identify a miRNA which is a candidate biomarker of MAC pulmonary disease activity. Serum hsa-miR-346 concentrations of 16 patients with M. avium pulmonary disease were significantly higher than those of 16 healthy controls (p = 0.047). The secretion of hsa-miR-346 increased in a multiplicity of infection-dependent manner in M. avium-infected macrophages. Serum hsa-miR-346 levels of 5 patients with bacterial conversion at the end of follow-up were significantly lower than those at the beginning of the follow-up (p = 0.043). In addition, the longitudinal change in serum hsa-miR-346 concentration correlated with bacterial load in 2 patients with M. avium pulmonary disease. Based on our results, it is supposed that MAC-infected macrophages in pulmonary lesions produce hsa-miR-346, which is then secreted into the bloodstream. The magnitude of this process could be quantitatively controlled by the bacterial load, suggesting that serum hsa-miR-346 is a potentially useful biomarker of MAC pulmonary disease activity.

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Clinical and radiological characteristics of patients with late-onset severe restrictive lung defect after hematopoietic stem cell transplantation

H Namkoong, M Ishii, T Mori, H Sugiura, S Tasaka, M Sakurai, Y Koda, ...

BMC pulmonary medicine 17 (1), 1-9 17 （ 1 ） 123 - 123 2017年09月

査読有り

BACKGROUND: Late-onset noninfectious pulmonary complications (LONIPCs), which occur more than 3 months after allogeneic hematopoietic stem cell transplantation (HSCT), are major causes of morbidity and mortality after transplantation. Among LONIPCs, we occasionally treat patients with late-onset severe restrictive lung defect after HSCT; however, its clinical features have not been fully elucidated. METHODS: A retrospective chart review of a single center on cases of late-onset severe restrictive lung defect after HSCT was performed. Among 453 patients who survived longer than 100 days after allogeneic HSCT with evaluable spirometry data, 12 patients (2.6%) developed late-onset severe restrictive lung defect (i.e., vital capacity percent of predicted less than 60%). RESULTS: Median duration from transplantation to diagnosis of late-onset severe restrictive lung defect cases was 44.5 months. Major computed tomography (CT) finding was pleuroparenchymal thickening with volume loss, an evidence of fibrosis, predominantly in upper lobes (n = 7), which was consistent with pleuroparenchymal fibroelastosis. The remaining patients showed unclassifiable interstitial pneumonia pattern (n = 2) and airway-predominant pattern (n = 3). The diffusing capacity for carbon oxide tended to decrease, while the residual volume/total lung capacity ratio tended to increase after HSCT. Of 12 patients, 8 patients died and the median month from diagnosis to death was 33.5 months. Seven patients died of pulmonary or systemic infection, and one patient died due to relapse of the primary disease. CONCLUSION: Severe restrictive lung defect could develop in selected cases in the late-phase after HSCT and could be a unique clinical entity with specific radiographical findings.

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The efficacy, safety, and feasibility of inhaled amikacin for the treatment of difficult-to-treat non-tuberculous mycobacterial lung diseases

K Yagi, M Ishii, H Namkoong, T Asami, O Iketani, T Asakura, S Suzuki, ...

BMC infectious diseases 17, 1-9 17 （ 1 ） 558 - 558 2017年08月

査読有り

BACKGROUND: In multidrug regimens, including an intravenous aminoglycoside (e.g. amikacin [AMK]) is recommended for difficult-to-treat non-tuberculous mycobacterial (NTM) lung diseases. We aimed to evaluate the efficacy, safety, and feasibility of inhaled AMK therapy in patients with difficult-to-treat NTM lung diseases in a retrospective chart review. METHODS: The study population consisted of patients with NTM lung diseases who received combination therapy, including inhaled AMK therapy, at Keio University Hospital (Tokyo, Japan), from January 2014 through May 2016. A total of 26 cases, consisting of 23 Mycobacterium avium complex (MAC) and three Mycobacterium abscessus complex (MABC) infections cases, were included in this study. The efficacy, safety, and feasibility of inhaled AMK therapy were retrospectively investigated. The Research Ethics Committee of Keio University Hospital approved this study, and informed consent was obtained from all patients. RESULTS: All 26 patients were culture-positive at enrolment. Twenty-three of the 26 patients (88.5%), including 21/23 MAC patients (91.3%) and 2/3 MABC patients (66.7%), were administered inhaled AMK therapy for >3 months. The proportion of patients who had clinical symptoms, including, cough and sputum, declined after inhalation AMK therapy. Ten of the 23 patients (43.5%) who received AMK inhalation, including 8/21 MAC (38.1%) and 2/2 MABC patients (100%), showed sputum conversion, defined as at least three consecutive negative sputum cultures. Seven of the 23 patients, including, 5/21 MAC and 2/2 MABC patients, showed improvements in high-resolution computed tomography imaging of the chest. In addition, the serum AMK trough levels before the second inhalation were <1.2 μg/mL in all 26 patients, with no occurrence of severe adverse events, such as renal toxicity. One patient (3.8%) experienced auditory toxicity, in the form of tinnitus. However, this symptom was reversible, after temporary interruption of AMK, the patient was able to safely resume the therapy. CONCLUSIONS: Inhaled AMK therapy is an effective and feasible therapy for difficult-to-treat NTM lung disease.

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Long-term outcome of pulmonary resection for nontuberculous mycobacterial pulmonary disease

T Asakura, N Hayakawa, N Hasegawa, H Namkoong, K Takeuchi, ...

Clinical Infectious Diseases 65 (2), 244-251 65 （ 2 ） 244 - 251 2017年07月

査読有り

Background: Pulmonary resection along with multiple antimicrobial therapy has produced favorable outcomes at a few centers. However, little is known regarding the risk factors for long-term survival and microbiological recurrence after pulmonary resection for nontuberculous mycobacterial pulmonary disease (NTMPD). We evaluated the long-term outcomes of pulmonary resection, including microbiological recurrence and survival. Methods: This retrospective cohort study included 125 patients (median age, 60 years) with NTMPD treated by pulmonary resection at two referral centers between January 1994 and August 2015. Results: Postoperative complications occurred in 27 patients (22%). The complication rate after pneumonectomy was significantly higher than those after other types of pulmonary resection (odds ratio, 4.1; 95% confidence interval [CI], 1.6-10.3; P = .005). The median follow-up period was 7.1 years. While 19 patients experienced microbiological recurrence, 26 died. Multivariate analysis revealed pneumonectomy (adjusted hazard ratio [aHR], 0.12; 95% CI, .007-.66; P = .0098) and cavitary lesions after surgery (aHR, 6.73; 95% CI, 1.68-22.7; P = .0095) to be predictors of microbiological recurrence and old age (aHR, 1.06; 95% CI, 1.01-1.13; P = .016), low body mass index (BMI; aHR for every 1-kg/m2 increase, 0.72; 95% CI, .60-.85; P < .0001), pneumonectomy (aHR, 4.38; 95% CI, 1.78-11.3; P = .014), and remnant cavitary lesions (aHR, 3.53; 95% CI, 1.35-9.57; P = .011) to be predictors of poor prognosis. Conclusions: Patients who could benefit from pulmonary resection should be carefully selected considering age, BMI, remnant lesions after surgery, and type of pulmonary resection.

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Disseminated Mycobacterium genavense infection in patient with adult-onset immunodeficiency

T Asakura, H Namkoong, T Sakagami, N Hasegawa, K Ohkusu, ...

Emerging Infectious Diseases 23 (7), 1208 23 （ 7 ） 1208 - 1210 2017年07月

査読有り

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Impact of cavity and infiltration on pulmonary function and health-related quality of life in pulmonary Mycobacterium avium complex disease: A 3-dimensional computed tomographic analysis.

Takanori Asakura, Yoshitake Yamada, Ho Namkoong, Shoji Suzuki, Yuki Niijima, Hirofumi Kamata, Yohei Funatsu, Kazuma Yagi, Satoshi Okamori, Hiroaki Sugiura, Makoto Ishii, Masahiro Jinzaki, Tomoko Betsuyaku, Naoki Hasegawa

Respiratory medicine 126 9 - 16 2017年05月

査読有り

BACKGROUND AND OBJECTIVES: Pulmonary Mycobacterium avium complex (pMAC) disease manifests as various types of lesions, such as infiltrates, nodules, cavities, and bronchiectasis. However, the important determinants for clinical parameters in lung involvement are poorly understood. The objective of this study was to obtain quantitative parameters by 3-dimensional CT, and investigate the relationship between these parameters and the pulmonary function tests (PFTs) and health-related quality of life. MATERIAL AND METHODS: Quantitative analysis using CT was performed in 67 pMAC patients. The relationship between new quantitative parameters for evaluating lung involvement using 3-dimensional CT and PFTs or St George's Respiratory Questionnaire (SGRQ) was evaluated. RESULTS: The ratio of infiltration to total lung volume showed significant correlation with the PFT results, especially the percent-predicted forced vital capacity (%FVC; ρ = -0.52), residual volume (ρ = -0.51), and total lung capacity (ρ = -0.59). The cavity volume was strongly correlated with the %FVC (ρ = -0.78) in the cavity group, while the ratio of infiltration to total lung volume was strongly correlated with the %FVC (ρ = -0.53) in the non-cavity group. The ratio of infiltration to total lung volume was significantly correlated with all SGRQ parameters (ρ = 0.41-0.52) in the non-cavity group. CONCLUSIONS: Infiltration was an important parameter for the PFTs and SGRQ in pMAC patients according to the 3-dimensional CT analysis. Moreover, cavity volume was an important parameter of the PFTs in the cavity group. Therefore, infiltration and cavity volume are key features for the management of pMAC disease.

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Effects of the common polymorphism in the human aldehyde dehydrogenase 2 (ALDH2) gene on the lung

A Kuroda, AE Hegab, G Jingtao, S Yamashita, N Hizawa, T Sakamoto, ...

Respiratory research 18, 1-18 18 （ 1 ） 69 - 69 2017年04月

査読有り

BACKGROUND: Aldehyde dehydrogenases (ALDHs) play a major role in detoxification of aldehydes. High expression of ALDHs is a marker for stem cells of many organs including the lungs. A common polymorphism in ALDH2 gene (ALDH2*2) results in inactivation of the enzyme and is associated with alcohol flushing syndrome and increased risk for cardiovascular and Alzheimer's diseases and some cancers. The effect of this ALDH2 polymorphism on the lung and its stem cells has not been thoroughly examined. METHODS: We examined the association between the ALDH2*2 allele and lung function parameters in a population of healthy individuals. We also examined its association with the incidence of asthma and COPD in patient cohorts. We used the in vitro colony forming assay to detect the effect of the polymorphism on lung epithelial stem cells from both primary human surgical samples and Aldh2*2 transgenic (Tg) and Aldh2 -/- mice. Response to acute and chronic lung injuries was compared between wild type (WT), Aldh2*2 Tg and Aldh2 -/- mice. RESULTS: In humans, the ALDH2*2 allele was associated with lower FEV1/FVC in the general population, but not with the development of asthma or COPD. Both the bronchial and lung epithelium carrying the ALDH2*2 allele showed a tendency for lower colony forming efficiency (CFE) compared to ALDH2 allele. In mice, the tracheal epithelial thickness, nuclear density, and number of basal stem cells were significantly lower in Aldh2 -/- and Aldh2*2 Tg adult mice than in WT. Electron microscopy showed significantly increased number of morphologically abnormal mitochondria in the trachea of Aldh2 -/- mice. Aldh2 -/- tracheal and lung cells showed higher ROS levels and fewer functional mitochondria than those from WT mice. No significant differences were detected when tracheal and lung epithelial stem cells were examined for their in vitro CFE. When exposed to chronic cigarette smoke, Aldh2*2 Tg mice were resistant to emphysema development, whereas influenza infection caused more epithelial damage in Aldh2 -/- mice than in WT mice. CONCLUSIONS: ALDH2 polymorphism has several subtle effects on the lungs, some of which are similar to changes observed during normal aging, suggesting a "premature lung aging" effect.

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Erlotinib as second- or third-line treatment in elderly patients with advanced non-small cell lung cancer: Keio Lung Oncology Group Study 001 (KLOG001).

Masayoshi Miyawaki, Katsuhiko Naoki, Satoshi Yoda, Sohei Nakayama, Ryosuke Satomi, Takashi Sato, Shinnosuke Ikemura, Keiko Ohgino, Kota Ishioka, Daisuke Arai, Ho Namkoong, Kengo Otsuka, Masaki Miyazaki, Tetsuo Tani, Aoi Kuroda, Makoto Nishino, Hiroyuki Yasuda, Ichiro Kawada, Hidefumi Koh, Morio Nakamura, Takeshi Terashima, Fumio Sakamaki, Koichi Sayama, Tomoko Betsuyaku, Kenzo Soejima

Molecular and clinical oncology 6 （ 3 ） 409 - 414 2017年03月

査読有り

The aim of this study was to assess the efficacy and safety of erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), as second- or third-line treatment for elderly Japanese patients with non-small-cell lung cancer (NSCLC). The patients eligible for this phase II trial were aged ≥70 years, had stage III/IV or recurrent NSCLC, and had previously received 1 or 2 chemotherapy regimens that did not include EGFR-TKIs. The patients received erlotinib at a dose of 150 mg/day. The primary endpoint was overall response rate (ORR), and the secondary endpoints were progression-free survival (PFS), overall survival (OS) and toxicity. A total of 38 patients with a median age of 76 years were enrolled. The majority of the patients were men (66%), had an Eastern Cooperative Oncology Group performance status of 1 (58%), stage IV disease (66%) and adenocarcinoma (74%). Of the 35 patients, 13 (34%) had tumors with EGFR mutations. The ORR was 26.3% (95% confidence interval: 12.1-40.5%) and the disease control rate was 47.4%. The median PFS was 3.7 months and the median OS was 17.3 months. The grade 3 adverse events observed included rash (13%), diarrhea (5%), interstitial pneumonitis (5%), anorexia (3%) and gastrointestinal bleeding (3%). Grade 4 or 5 adverse events were not observed. The median OS did not differ significantly between patients aged <75 years (14.9 months) and those aged ≥75 years (19.0 months; P=0.226). Therefore, erlotinib was found to be effective and well-tolerated in elderly patients with previously treated NSCLC.

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A laboratory-based analysis of nontuberculous mycobacterial lung disease in Japan from 2012 to 2013

K Morimoto, N Hasegawa, K Izumi, H Namkoong, K Uchimura, ...

Annals of the American Thoracic Society 14 (1), 49-56 （American Thoracic Society） 14 （ 1 ） 49 - 56 2017年01月

査読有り

RATIONALE: Since 2010, mycobacterial examination results have been used widely to survey nontuberculous mycobacteria (NTM) lung disease. OBJECTIVES: To reveal the clinical and epidemiological status of NTM lung disease in Japan. METHODS: All data on the isolation and identification of mycobacteria in 2012 and 2013 were obtained from three dominant commercial laboratories in Japan. Pulmonary NTM disease was defined on the basis of bacteriological diagnostic criteria issued by the American Thoracic Society/Infectious Diseases Society of America. The coverage population was estimated using the ratio between national tuberculosis registration data and laboratory results for each of the eight regions of Japan. MEASUREMENTS AND MAIN RESULTS: A total of 113,313 mycobacterial specimens from 4,710 institutes were collected, and specimens from 26,059 patients tested positive for NTM cultures at least once. Among patients with positive cultures, 7,167 (27.5%) satisfied the American Thoracic Society/Infectious Diseases Society of America criteria for NTM lung disease, resulting in a 2-year prevalence rate of 24.0 per 100,000. Mycobacterium avium complex (MAC) was the most commonly isolated species (93.3%), and 29.0% of the patients from whom MAC was isolated satisfied the criteria for NTM lung disease. Individuals older than 70 years of age accounted for the majority of cases, and 65.5% of cases involved females. After MAC, Mycobacterium kansasii and Mycobacterium abscessus exhibited the highest (43.6%) and second-highest (37.1%) incidence per isolation, respectively. The prevalence of M. kansasii was highest in the Kinki region (P < 0.05), and M. abscessus had the greatest prevalence in the Kyushu-Okinawa region (P < 0.005). The proportion of Mycobacterium intracellulare in MAC cases was higher in the southwestern part of Japan than in other regions. The period prevalence was highest in the southwestern part of Japan, and the standardized prevalence ratio was highest in central regions. Evaluations of clarithromycin susceptibility revealed a clear binomial distribution. CONCLUSIONS: This investigation is the first laboratory-based study in which a large number of NTM isolated from clinical samples in Japan have been assessed. Although the calculated prevalence of NTM disease might be underestimated, the approach may prove useful for monitoring relative epidemiological data for NTM lung disease.

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Glycoprotein nanotube traps influenza virus

S Yuge, M Akiyama, M Ishii, H Namkoong, K Yagi, Y Nakai, R Adachi, ...

Chemistry Letters 46 (1), 95-97 （CHEMICAL SOC JAPAN） 46 （ 1 ） 95 - 97 2017年01月

査読有り, ISSN 0366-7022

We report the synthesis, structure, and influenza A virus trapping capability of protein nanotubes with an internal wall of fetuin glycoprotein. The nanotubes were fabricated via the alternating layer-by-layer assembly of human serum albumin (HSA), poly-L-arginine (PLA), and fetuin into a track-etched polycarbonate (PC) membrane (pore size, 800 nm), followed by dissolution of the PC template. In an aqueous medium, the (PLA/HSA) 5PLA/fetuin nanotubes captured influenza A virus PR8 (H1N1) efficiently, as revealed by ELISA measurements.

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非結核性抗酸菌症の疾患感受性遺伝子

南宮湖, 長谷川直樹, 別役智子

日本臨床免疫学会会誌（日本臨床免疫学会） 40 （ 1 ） 60 - 67 2017年

査読有り, ISSN 0911-4300

非結核性抗酸菌（Nontuberculous Mycobacteria: NTM）による感染症は日本・世界で患者数が増加している．NTM症はその臨床像により播種性NTM症と肺NTM症に分類され，その発症メカニズムは病態により大きく異なることが予想される．播種性NTM症については，IFN-γ/IL-12軸を中心とするTh1型細胞性免疫の先天的シグナル伝達異常により発症することが分子レベルで詳細に解明されている．また，最近はIFN-γに対する自己抗体を介した後天的免疫異常による播種性NTM症が注目されている．肺NTM症は軽快と増悪を繰り返しながら徐々に進行するが，その経過には宿主・病原菌両者の関与が推察され，宿主の疾患感受性遺伝子の存在が疑われている．肺NTM症の疾患感受性遺伝子に関して，Single Nucleotide Polymorphism（SNP）解析やマイクロサテライトマーカーを用いた解析が行われてきたが，その再現性や生物学的意義など今後検討，検証すべき課題は多い．次世代シークエンサーの登場により，網羅的解析技術が急速に発展している現在，肺NTM症の疾患感受性遺伝子に関する新たな発見が期待される．

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A Case Of Cutis Laxa With Juvenile Emphysema Arising From Frameshift Mutations In Exon 30 Of The Elastin Gene (eln)

H Namkoong, M Ishii, K Yagi, S Chubachi, A Tsuji, K Kosaki, T Betsuyaku

C48. COPD: CASE REPORTS I, A5704-A5704 2017年

D18 WHO DOES WHAT IN COPD: THE CELLULAR ORIGINS: S1p Receptor Modulation Expands Cd11b+ gr-1+ Cells And Inhibits Lymphocyte Infiltration In The Lungs And Ameliorate Murine …

T Asakura, M Ishii, H Namkoong, S Suzuki, S Kagawa, T Komiya, K Yagi, ...

American Journal of Respiratory and Critical Care Medicine 195 2017年

Impact of cavity and infiltration on pulmonary function and health-related quality of life in pulmonary Mycobacterium avium complex disease: a 3-dimensional computed …

T Asakura, Y Yamada, H Namkoong, S Suzuki, Y Niijima, H Kamata, ...

Respiratory Medicine 126, 9-16 2017年

Erlotinib as second‑or third‑line treatment in elderly patients with advanced non‑small cell lung cancer: Keio Lung Oncology Group Study 001 (KLOG001)

M Miyawaki, K Naoki, S Yoda, S Nakayama, R Satomi, T Sato, S Ikemura, ...

Molecular and Clinical Oncology 6 (3), 409-414 2017年

Protective role of a disintegrin and metalloprotease 17 (ADAM17) in elastase-induced emphysema in mice

S Suzuki, M Ishii, T Asakura, H Namkoong, S Okamori, K Yagi, H Kamata, ...

C73. NEW MECHANISMS AND THERAPIES IN COPD, A6273-A6273 2017年

The Critical Role Of A Disintegrin And Metalloprotease (adam) 10 During Severe Influenza Virus Infection In Vivo And In Vitro

S Okamori, M Ishii, T Asakura, S Suzuki, H Kamata, H Namkoong, K Yagi, ...

B19. HOST RESPONSES TO INFLUENZA, A2921-A2921 2017年

Susceptibility genes for nontuberculous mycobacterial disease.

H Namkoong, N Hasegawa, T Betsuyaku

Nihon Rinsho Men'eki Gakkai Kaishi= Japanese Journal of Clinical Immunology … 2017年

S1p Receptor Modulation Expands Cd11b+ gr-1+ Cells And Inhibits Lymphocyte Infiltration In The Lungs And Ameliorate Murine Pulmonary Emphysema

T Asakura, M Ishii, H Namkoong, S Suzuki, S Kagawa, T Komiya, K Yagi, ...

D18. WHO DOES WHAT IN COPD: THE CELLULAR ORIGINS, A7042-A7042 2017年

Macrolide-Resistant Mycobacterium avium Complex Lung Disease: Analysis of 102 Consecutive Cases

K Morimoto, H Namkoong, N Hasegawa, T Nakagawa, E Morino, ...

Annals of the American Thoracic Society 13 (11), 1904-1911 （American Thoracic Society） 13 （ 11 ） 1904 - 1911 2016年11月

査読有り

RATIONALE: The management of macrolide-resistant Mycobacterium avium complex (MR-MAC) pulmonary disease is difficult and is thought to be analogous to that of multidrug-resistant tuberculosis (MDR-TB). OBJECTIVES: This study aimed to clarify the cause of MR-MAC, to see how its management affected outcome, and to compare its prognosis with that of MDR-TB. METHODS: The medical records of 102 consecutive cases with MR-MAC pulmonary disease at three tertiary hospitals for mycobacteriosis in metropolitan Tokyo and one in Aichi prefecture from 2005 to 2014 were reviewed. The data of 311 consecutive cases with MDR-TB were extracted from the medical data at Fukujuji Hospital. MEASUREMENTS AND MAIN RESULTS: Of the 90 patients who met the criteria, 53 (58.9%) received inappropriate first-line treatment, and 28 (31.1%) deviated from the standard treatment because of the adverse effects of ethambutol. The survival rates for MR-MAC disease and MDR-TB were not significantly different (P = 0.6). Multivariate analysis showed that the combination of aminoglycoside and surgery resulted in the best treatment outcome (P = 0.02), although neither of the two factors reached significance by themselves. The continuation of clarithromycin and the addition of fluoroquinolones did not improve the outcome for the treatment of disease caused by MR-MAC. CONCLUSIONS: Inappropriate prescription patterns and deviations from the standard treatment because of adverse drug reactions appeared to be the main causes of macrolide resistance in this patient series. Drug sensitivity testing should be performed at diagnosis to identify macrolide resistance and patients who may benefit from other therapy.

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