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Papers - Namkoong, Ho

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Molecular dynamics simulation-guided drug sensitivity prediction for lung cancer with rare EGFR mutations.

Shinnosuke Ikemura, Hiroyuki Yasuda, Shingo Matsumoto, Mayumi Kamada, Junko Hamamoto, Keita Masuzawa, Keigo Kobayashi, Tadashi Manabe, Daisuke Arai, Ichiro Nakachi, Ichiro Kawada, Kota Ishioka, Morio Nakamura, Ho Namkoong, Katsuhiko Naoki, Fumie Ono, Mitsugu Araki, Ryo Kanada, Biao Ma, Yuichiro Hayashi, Sachiyo Mimaki, Kiyotaka Yoh, Susumu S Kobayashi, Takashi Kohno, Yasushi Okuno, Koichi Goto, Katsuya Tsuchihara, Kenzo Soejima

Proceedings of the National Academy of Sciences of the United States of America 116 ( 20 ) 10025 - 10030 2019.05

Accepted

Next generation sequencing (NGS)-based tumor profiling identified an overwhelming number of uncharacterized somatic mutations, also known as variants of unknown significance (VUS). The therapeutic significance of EGFR mutations outside mutational hotspots, consisting of >50 types, in nonsmall cell lung carcinoma (NSCLC) is largely unknown. In fact, our pan-nation screening of NSCLC without hotspot EGFR mutations (n = 3,779) revealed that the majority (>90%) of cases with rare EGFR mutations, accounting for 5.5% of the cohort subjects, did not receive EGFR-tyrosine kinase inhibitors (TKIs) as a first-line treatment. To tackle this problem, we applied a molecular dynamics simulation-based model to predict the sensitivity of rare EGFR mutants to EGFR-TKIs. The model successfully predicted the diverse in vitro and in vivo sensitivities of exon 20 insertion mutants, including a singleton, to osimertinib, a third-generation EGFR-TKI (R2 = 0.72, P = 0.0037). Additionally, our model showed a higher consistency with experimentally obtained sensitivity data than other prediction approaches, indicating its robustness in analyzing complex cancer mutations. Thus, the in silico prediction model will be a powerful tool in precision medicine for NSCLC patients carrying rare EGFR mutations in the clinical setting. Here, we propose an insight to overcome mutation diversity in lung cancer.

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Sitafloxacin-Containing Regimen for the Treatment of Refractory Mycobacterium avium Complex Lung Disease.

Takanori Asakura, Shoji Suzuki, Hanako Fukano, Satoshi Okamori, Tatsuya Kusumoto, Yoshifumi Uwamino, Takunori Ogawa, Matsuo So, Shunsuke Uno, Ho Namkoong, Mitsunori Yoshida, Hirofumi Kamata, Makoto Ishii, Tomoyasu Nishimura, Yoshihiko Hoshino, Naoki Hasegawa

Open forum infectious diseases 6 ( 4 ) ofz108 2019.04

Accepted

Background: Sitafloxacin (STFX) exhibits potent activity against Mycobacterium avium complex (MAC) in both in vitro and in vivo experiments. However, limited data are available for the clinical efficacy and adverse effects of STFX and the susceptibility of refractory MAC lung disease (MAC-LD) to the drug. Therefore, this study was aimed at evaluating the clinical efficacy and safety of an STFX-containing regimen for the treatment of refractory MAC-LD. Methods: We retrospectively evaluated treatment outcomes of 31 patients with refractory MAC-LD, who received an STFX-containing regimen for ≥4 weeks between January 2010 and July 2017. Refractory MAC-LD was defined as persistent positive sputum cultures for >6 months of macrolide-based standard therapy. Results: Clarithromycin resistance (minimum inhibitory concentration [MIC] ≥32 μg/mL) was identified in 15 patients (48%). Twelve months after receiving the STFX-containing regimen, 26% and 19% of patients showed symptomatic and radiological responses, respectively. Although STFX-associated adverse effects were noted in 9 patients, their severity was grade 1 (National Cancer Institute Common Terminology Criteria); only 1 patient discontinued STFX because of suspected gastrointestinal disturbance. Negative sputum culture conversion was achieved in 7 patients (23%). Both univariate and multivariate logistic regression analyses revealed that surgery, low STFX MIC (≤1 μg/mL), and macrolide resistance were significant predictors of negative sputum culture conversion. Conclusions: Our results demonstrate that STFX may be effective in one-fourth of patients with refractory MAC-LD. Prospective larger studies that include the analyses of MAC are needed to determine the clinical efficacy of STFX against refractory MAC-LD.

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Efficacy and safety of intermittent maintenance therapy after successful treatment of Mycobacterium avium complex lung disease.

Takanori Asakura, Taku Nakagawa, Shoji Suzuki, Ho Namkoong, Kozo Morimoto, Makoto Ishii, Atsuyuki Kurashima, Tomoko Betsuyaku, Kenji Ogawa, Naoki Hasegawa

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 25 ( 3 ) 218 - 221 2019.03

Accepted

BACKGROUND: The optimal duration of antimicrobial therapy for Mycobacterium avium complex lung disease (MAC-LD) is unknown, and recurrence rates are high after treatment discontinuation. Intermittent therapy is recommended for the initial treatment of non-cavitary nodular/bronchiectatic MAC-LD. We hypothesized that intermittent maintenance therapy (IMT) could effectively prevent recurrence after successful treatment of MAC-LD. METHODS: Adult patients diagnosed with MAC-LD who received IMT after successful daily therapy (DT) between January 1, 2006 and December 31, 2016 were identified from clinical databases at three institutions in Japan. Treatment outcomes were evaluated for all patients. RESULTS: Of 38 patients (median age, 66 years; 29 women; nodular/bronchiectatic form, 29 patients) who received IMT after successful treatment, one was excluded due to death from an unknown cause, 1 month after IMT initiation. Finally, treatment outcomes were evaluated for 37 patients. Twenty-eight (76%) patients had sustained negative culture results over a median follow-up duration of 2.7 (interquartile range [IQR], 1.9-6.0) years, while six (16%) required switching to DT because of clinical deterioration over a median follow-up duration of 2.7 (IQR, 1.6-4.1) years. Favorable clinical outcomes were achieved for all patients who exhibited clinical deterioration. All patients tolerated the antimicrobials without discontinuation, and follow-up drug susceptibility testing showed negative results for clarithromycin-resistant MAC in the patients who experienced clinical deterioration. CONCLUSIONS: IMT after successful treatment may be a feasible option for patients with MAC-LD. Further studies should determine the population that would benefit from this strategy.

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Prognostic values of the Berlin definition criteria, blood lactate level, and fibroproliferative changes on high-resolution computed tomography in ARDS patients.

Tetsuro Kamo, Sadatomo Tasaka, Takeshi Suzuki, Takanori Asakura, Shoji Suzuki, Kazuma Yagi, Ho Namkoong, Makoto Ishii, Hiroshi Morisaki, Tomoko Betsuyaku

BMC pulmonary medicine 19 ( 1 ) 37 - 37 2019.02

Accepted

BACKGROUND: In the Berlin definition, acute respiratory distress syndrome (ARDS) is stratified into three stages according to oxygenation severity at the onset. The relevance between ARDS severity and prognosis varies among published reports and has not been verified, especially in Asian patients. METHODS: In this study, we examined the associations between the Berlin definition criteria and prognosis and clinical parameters, including high-resolution computed tomography (HRCT) scores of fibroproliferative changes of the lungs. One hundred fifty-three patients (45 females; mean age, 67 y/o), who met the Berlin definition and received treatment in our intensive care unit between January 2012 and December 2015, were enrolled. RESULTS: The severity of ARDS was mild in 42 patients, moderate in 71, and severe in 40. The underlying diseases included pneumonia in 56 patients and aspiration in 43. Forty-two (27.5%) patients were deceased within 30 days, and the 30-day mortality was 10% in mild ARDS, 23% in moderate, and 55% in severe, which were significantly different (P < 0.05). In the non-survivors, APACHE II, SOFA, and SAPS II scores were higher than in the survivors (P < 0.001). Multivariate analyses revealed that elevated blood lactate level (≥ 2.0 mmol/L) and increased HRCT scores were significantly associated with weaning failure and 30-day mortality of the patients with ARDS. CONCLUSIONS: These results suggested that the severity criteria in the Berlin definition might be associated with the prognosis of the patients. Blood lactate levels and HRCT score might be predictive of the outcome of patients with ARDS.

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First report of hepatobiliary <i>Mycobacterium avium</i> infection developing obstructive jaundice in a patient with neutralizing anti-interferon-gamma autoantibodies.

Namkoong H, Asakura T, Ishii M, Yoda S, Masaki K, Sakagami T, Iwasaki E, Yamagishi Y, Kanai T, Betsuyaku T, Hasegawa N

New microbes and new infections 27 4 - 6 2019.01

Accepted

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Ablation of ADAM17 protects against cigarette smoke-induced emphysema in mice

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

European Respiratory Journal 54 (suppl 63) 2019

Development of lung cancer in patients with nontuberculous mycobacterial lung disease

T Kusumoto, T Asakura, S Suzuki, S Okamori, H Namkoong, H Fujiwara, ...

Respiratory investigation 57 (2), 157-164 2019

Genome-wide association study in patients with pulmonary Mycobacterium avium complex disease

H Namkoong, Y Omae, T Asakura, M Yoshida, S Suzuki, K Morimoto, ...

A18. NTM: HOW, WHERE OR WHY DID I GET IT?, A1031-A1031 2019

First report of hepatobiliary Mycobacterium avium infection developing obstructive jaundice in a patient with neutralizing anti–interferon-gamma autoantibodies

H Namkoong, T Asakura, M Ishii, S Yoda, K Masaki, T Sakagami, ...

New Microbes and New Infections 27, 4-6 2019

Direct Reprogramming of Mouse Fibroblasts into Pulmonary Epithelial-Like Cells

T Kusumoto, M Ishii, M Yotsukura, AE Hegab, F Saito, J Hamamoto, ...

C62. FIBROBLAST BIOLOGY, A5341-A5341 2019

Longitudinal Validity and Prognostic Significance of the St George’s Respiratory Questionnaire in 269 Patients with Pulmonary Mycobacterium Avium Complex Disease

T Ogawa, T Asakura, S Suzuki, S Okamori, T Kusumoto, H Namkoong, ...

A106. NTM: BENCH TO BEDSIDE, A2542-A2542 2019

Retrospective evaluation of natural course in mild cases of Mycobacterium avium complex pulmonary disease.

Yoshifumi Kimizuka, Yoshihiko Hoshino, Tomoyasu Nishimura, Takahiro Asami, Yumi Sakakibara, Kozo Morimoto, Shinji Maeda, Noboru Nakata, Takayuki Abe, Shunsuke Uno, Ho Namkoong, Hiroshi Fujiwara, Yohei Funatsu, Kazuma Yagi, Toshihide Fujie, Makoto Ishii, Naohiko Inase, Satoshi Iwata, Atsuyuki Kurashima, Tomoko Betsuyaku, Naoki Hasegawa

PloS one 14 ( 4 ) e0216034 2019

Accepted

BACKGROUND: There is no proven management for mild cases of Mycobacterium avium complex (MAC) pulmonary disease, who do not immediately receive treatment and are managed with observation alone, because its long term-natural course, factors predictive of deterioration, and the effect of treating the disease remain unclear. Thus, we sought to investigate the natural course of mild cases of MAC pulmonary disease. METHODS: We conducted a multicenter retrospective study. Sixty-five patients with mild MAC pulmonary disease in whom treatment was withheld for at least 6 months after diagnosis were retrospectively recruited after a review of 747 medical records. Longitudinal changes in clinical features were evaluated by using a mixed effects model. RESULTS: Mean follow-up was 6.9 ± 5.7 years. During the follow-up period, 15 patients (23%) required treatment and 50 (77%) were managed with observation alone. At diagnosis, 65 patients had nodular bronchiectatic disease without fibrocavitary lesions. Among clinical features, mean body mass index (BMI), forced expiratory volume in 1 second as percent of forced vital capacity (%FEV1), nodular lung lesions, and bronchiectasis worsened significantly in the observation group during follow-up. In the treatment group, BMI, and %FEV1 were stable, but bronchiectasis significantly worsened. At diagnosis, the polyclonal MAC infection rate in the treatment group was higher than that in the observation group. Other microbiological factors, such as insertion sequences, did not differ significantly between the groups. CONCLUSIONS: Mild MAC pulmonary disease progresses slowly but substantially without treatment. Treatment prevents the deterioration of the disease but not the progression of bronchiectasis. Polyclonal MAC infection is a predictor of disease progression.

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Mycobacterium abscessus pulmonary disease: individual patient data meta-analysis

N Kwak, MP Dalcolmo, CL Daley, G Eather, R Gayoso, N Hasegawa, ...

European Respiratory Journal 54 (1) 2019

Quantitative assessment of erector spinae muscles in patients with Mycobacterium avium complex lung disease.

Takanori Asakura, Yoshitake Yamada, Shoji Suzuki, Ho Namkoong, Satoshi Okamori, Tatsuya Kusumoto, Yuki Niijima, Akihiko Ozaki, Masahiro Hashimoto, Kazuma Yagi, Hirofumi Kamata, Yohei Funatsu, Makoto Ishii, Masahiro Jinzaki, Tomoko Betsuyaku, Naoki Hasegawa

Respiratory medicine 145 66 - 72 2018.12

Accepted

BACKGROUND AND OBJECTIVE: No reports exist regarding skeletal muscle involvement in patients with Mycobacterium avium complex lung disease (MAC-LD). The cross-sectional area of the erector spinae muscles (ESMCSA) reflects physical activity and can be assessed by computed tomography (CT). We investigated the relationship between ESMCSA and physiological parameters and prognosis in MAC-LD patients. MATERIAL AND METHODS: In this prospective observational study, the ESMCSA was measured on single-slice axial CT images. MAC-LD patients and sex- and age-matched controls (non-MAC-LD participants) were evaluated. We evaluated the relationship between the ESMCSA and physiological parameters and prognosis. RESULTS: A total of 260 patients (209 female; median age, 69 years; 190 with nodular/bronchiectatic disease; 74 with cavitary lesions) were enrolled. The ESMCSA was not different between MAC-LD patients and controls. In MAC-LD patients, the ESMCSA was significantly associated with age, body mass index (BMI), pulmonary function, CT severity, and health-related quality of life (HRQL). Multivariate Cox proportional hazards analyses revealed that an ESMCSA < -1 standard derivation (hazards ratio [HR], 2.76; P = 0.047) was significantly associated with all-cause mortality, along with BMI < 18.5 kg/m2 (HR, 3.67; P = 0.02) and presence of cavitary lesions (HR, 5.84; P = 0.001). However, the ESMCSA was not significantly associated with all-cause mortality when current treatment status, % predicted functional vital capacity, and forced expiratory volume in 1 s were added to the analyses. CONCLUSIONS: Although the prognostic impact was limited, ESMCSA was significantly associated with HRQL and prognostic physiological parameters, such as BMI and pulmonary function.

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Sphingosine 1-phosphate receptor modulator ONO-4641 stimulates CD11b+Gr-1+ cell expansion and inhibits lymphocyte infiltration in the lungs to ameliorate murine pulmonary emphysema.

Takanori Asakura, Makoto Ishii, Ho Namkoong, Shoji Suzuki, Shizuko Kagawa, Kazuma Yagi, Takaki Komiya, Takafumi Hashimoto, Satoshi Okamori, Hirofumi Kamata, Sadatomo Tasaka, Akio Kihara, Ahmed E Hegab, Naoki Hasegawa, Tomoko Betsuyaku

Mucosal immunology 11 ( 6 ) 1606 - 1620 2018.11

Accepted

Sphingolipids play a pivotal role in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, little is known about the precise roles of sphingosine-1-phosphate (S1P), a bioactive sphingolipid metabolite, and its receptor modulation in COPD. In this study, we demonstrated that the S1P receptor modulator ONO-4641 induced the expansion of lung CD11b+Gr-1+ cells and lymphocytopenia in naive mice. ONO-4641-expanded CD11b+Gr-1+ cells showed higher arginase-1 activity, decreased T cell proliferation, and lower IFN-γ production in CD3+ T cells, similar to the features of myeloid-derived suppressor cells. ONO-4641 treatment decreased airspace enlargement in elastase-induced and cigarette smoke-induced emphysema models and attenuated emphysema exacerbation induced by post-elastase pneumococcal infection, which was also associated with an increased number of lung CD11b+Gr-1+ cells. Adoptive transfer of ONO-4641-expanded CD11b+Gr-1+ cells protected against elastase-induced emphysema. Lymphocytopenia observed in these models likely contributed to beneficial ONO-4641 effects. Thus, ONO-4641 attenuated murine pulmonary emphysema by expanding lung CD11b+Gr-1+ cell populations and inducing lymphocytopenia. The S1P receptor might be a promising target for strategies aimed at ameliorating pulmonary emphysema progression.

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Panton-Valentine leukocidin-positive methicillin-resistant Staphylococcus aureus infection of the lip.

Ayaka Chaya, Masataka Sato, Ho Namkoong, Naoko Wada

International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases 75 80 - 81 2018.10

Accepted

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Association between six-minute walk test parameters and the health-related quality of life in patients with pulmonary Mycobacterium avium complex disease.

Kazuma Yagi, Takanori Asakura, Ho Namkoong, Shoji Suzuki, Takahiro Asami, Satoshi Okamori, Tatsuya Kusumoto, Yohei Funatsu, Hirofumi Kamata, Tomoyasu Nishimura, Makoto Ishii, Tomoko Betsuyaku, Naoki Hasegawa

BMC pulmonary medicine 18 ( 1 ) 114 - 114 2018.07

Accepted

BACKGROUND: Pulmonary Mycobacterium avium complex (pMAC) disease is a chronic, slowly progressive disease. The aim of the present study was to determine the association of six-minute walk test (6MWT) parameters with pulmonary function and the health-related quality of life (HRQL) in patients with pMAC disease. METHODS: This cross-sectional study included adult patients with pMAC and was conducted at Keio University Hospital. We investigated the relationship of 6MWT parameters with clinical parameters, including pulmonary function, and HRQL, which was assessed using the 36-Item Short Form Health Survey (SF-36) and St. George's Respiratory Questionnaire (SGRQ). RESULTS: In total, 103 consecutive patients with pMAC participated in 6MWT (median age, 64 years; 80 women) and completed SF-36 and SGRQ. The six-minute walk distance (6MWD) showed significant negative and positive correlations with all SGRQ domain scores [ρ = (- 0.54)-(- 0.32)] and the physical component summary (PCS) score (ρ = 0.39) in SF-36, respectively; the opposite was observed for the final Borg scale (FBS) score (all SGRQ scores, ρ = 0.34-0.58; PCS score, ρ = - 0.50). The distance-saturation product showed significant negative and positive correlations with all SGRQ scores [ρ = (- 0.29)-(- 0.55)] and the PCS score (ρ = 0.40), respectively. Multivariate analysis revealed that 6MWD and the FBS score were significant predictors of HRQL. CONCLUSIONS: Our findings suggest that 6MWD and the FBS score are useful parameters for evaluating HRQL in patients with pMAC. Further studies should investigate the impact of 6WMT parameters on disease progression, treatment responses, and prognosis.

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Asakura T, Ishii M, Ishii K, Suzuki S, Namkoong H, Okamori S, Kamata H, Yagi K, Funatsu Y, Betsuyaku T, Hasegawa N

International Journal of Tuberculosis and Lung Disease 22 ( 6 ) 695 - 703 2018.06

Accepted, ISSN 1027-3719

BACKGROUND: Little is known about the clinical characteristics and health-related quality of life (HQOL) of elderly patients with pulmonary Mycobacterium avium complex (pMAC) disease. OBJECTIVES: To evaluate HQOL using the 36-Item Short-Form Health Survey and St George's Respiratory Questionnaire (SGRQ) and to investigate the predictors of HQOL changes among elderly patients with pMAC disease. METHODS: This prospective cohort registry was conducted at Keio University Hospital, Tokyo, Japan, between May 2012 and July 2015 and included 84 patients with pMAC disease aged 75 years who had completed the HQOL questionnaire and 48 patients with pMAC disease who had been followed up and completed the HQOL questionnaire in cross-sectional and longitudinal analyses, respectively. RESULTS: In cross-sectional analyses, elderly patients with pMAC disease had significantly lower role-physical, general health, vitality, social functioning, role-emotional and role/social component scores than the general Japanese elderly population. Analysis of covariance revealed that patients with cavitary lesions had significantly worse physical functioning and SGRQ scores (P < 0.05). Longitudinal analysis showed that under-treatment, short duration of disease and positive sputum smear at baseline were predictors of worse HQOL at 12 months. CONCLUSIONS: Elderly patients with pMAC disease have reduced HQOL. Further large studies on HQOL are required to refine the use of this parameter in the treatment of these patients.

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Aspergillus precipitating antibody in patients with Mycobacterium avium complex lung disease: A cross-sectional study.

Shoji Suzuki, Takanori Asakura, Ho Namkoong, Satoshi Okamori, Kazuma Yagi, Hirofumi Kamata, Yoshifumi Uwamino, Yohei Funatsu, Yasushi Nakano, Tomoyasu Nishimura, Makoto Ishii, Tamotsu Ebihara, Tomoko Betsuyaku, Naoki Hasegawa

Respiratory medicine 138 1 - 6 2018.05

Accepted

RATIONALE: Little is known about the role of Aspergillus precipitating antibody (APAb) in patients with Mycobacterium avium complex lung disease (MAC-LD). OBJECTIVES: We investigated the clinical characteristics of patients with MAC-LD positive for APAb. METHODS: We conducted a cross-sectional study targeting patients with MAC-LD. APAb was checked in all participants. Clinical variables included laboratory data, pulmonary function, high-resolution computed tomography findings, and health-related quality of life. RESULTS: We analyzed 109 consecutive patients. Their median age was 68 years, and the median duration of MAC-LD was 4.8 years. Twenty (18.3%) patients tested positive for APAb. APAb-positive patients had significantly longer duration of MAC-LD (9.4 vs. 4.0 years, P = 0.017), more severe bronchiectasis evaluated by modified Reiff score (6.5 vs. 4, P = 0.0049), and lower forced expiratory volume in 1 s (%FEV1) (75.1% vs. 86.2%, P = 0.013) than APAb-negative patients. Analysis of covariance adjusted for background factors and underlying pulmonary disease revealed that %FEV1 was also significantly lower in patients with APAb (P = 0.045). Ten patients were newly diagnosed with chronic pulmonary aspergillosis (N = 5) or allergic bronchopulmonary aspergillosis (N = 5). CONCLUSIONS: APAb is associated with lower pulmonary function, and observed especially in patients with longer duration of MAC-LD and severe bronchiectasis, even in the absence of cavitary lesions.

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Clinical features of Mycoplasma pneumoniae pneumonia in older adults.

Naoki Kawakami, Ho Namkoong, Takanori Ohata, Shinji Sakaguchi, Fumitake Saito, Hideki Yuki

Geriatrics & gerontology international 18 ( 5 ) 814 - 816 2018.05

Accepted

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