Faculty Profiles - HIGO Hisao

Papers - HIGO Hisao

Division display >> ／ All the affair displays 1 - 63 of about 63

The Clinical Significance of Interstitial Pneumonia with Autoimmune Features in Cryptogenic Organizing Pneumonia: A Prospective Multicenter Observational Study. International journal

Hisao Higo, Hirohisa Ichikawa, Yukako Arakawa, Yoshihiro Mori, Tomoki Tamura, Shoichi Kuyama, Chiaki Matsumoto, Keisuke Sugimoto, Noboru Hamada, Toshimitsu Suwaki, Junko Itano, Yasushi Tanimoto, Satoru Senoo, Akihiko Taniguchi, Yumi Inukai, Machiko Arita, Satoko Makimoto, Katsuhide Kojima, Takashi Matsushita, Yoshinobu Maeda, Nobuaki Miyahara

Journal of clinical medicine 13 ( 22 ) 2024.11

Language：English Publishing type：Research paper (scientific journal)

Background: There are cases of idiopathic interstitial pneumonias (IIPs) that do not meet the diagnostic criteria for connective tissue disease but have clinical features suggestive of autoimmune process. Interstitial pneumonia with autoimmune features (IPAF) was recently proposed as a research concept for these patients. Although several prospective studies on IPAF have been conducted, its clinical significance in cryptogenic organizing pneumonia (COP) remains unclear. Methods: Patients aged ≥20 years with suspected COP were prospectively enrolled between June 2018 and December 2022. Among the enrolled patients, those diagnosed with COP based on computed tomography (CT) and bronchoalveolar lavage (BAL) findings were compared between the IPAF and non-IPAF groups. Results: A total of 56 patients were enrolled in this study. Of these, 30 were diagnosed with COP and included in the analysis. Clinical and serological features were positive in two and six patients, respectively. Each feature was exclusive, and eight patients (26.7%) were diagnosed with IPAF. There were no differences between the IPAF and non-IPAF groups in terms of clinical features, including BAL findings, laboratory data, CT findings, and clinical course. During the one-year follow-up period, the frequency of COP exacerbation did not differ between the IPAF and non-IPAF groups, and no cases of systemic autoimmune disease or death occurred in either group. Conclusions: The COP characteristics of the IPAF and non-IPAF groups are similar in all aspects, and distinguishing between the two groups may be of little significance.

DOI： 10.3390/jcm13226870

A Prompt Diagnosis and Treatment of a Case of Nuclear Protein of the Testis Carcinoma Characterized by a Bronchial Lesion and High Serum Alpha-fetoprotein Level Following Genomic Testing.

Hiroaki Matsuura, Go Makimoto, Naohiro Oda, Kiichiro Ninomiya, Hisao Higo, Masanori Fujii, Kammei Rai, Eiki Ichihara, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda

Internal medicine (Tokyo, Japan) 63 ( 19 ) 2655 - 2660 2024.10

Language：English Publishing type：Research paper (scientific journal)

Nuclear protein of the testis carcinoma (NUTC) is a rare and aggressive malignancy. We herein report a case of NUTC in the lung characterized by a bronchial lesion and elevated alpha-fetoprotein levels. A 35-year-old Japanese man presented to our institution with suspected advanced lung cancer based on a histological examination. Subsequently, next-generation sequencing (NGS) yielded a positive BRD4-NUTM1 fusion. In addition, positive NUT immunostaining of the lung biopsy specimen confirmed NUTC in the lungs. Systemic chemotherapy and radiotherapy showed a temporary response, with decreased serum alpha-fetoprotein levels. We highlight this case of a prompt diagnosis by NGS of NUTC in a young individual with a rapidly progressing tumor.

DOI： 10.2169/internalmedicine.2938-23

A Case of Single-lung Transplant in a Patient with Mycobacterium avium Pulmonary Disease Successfully Treated with Amikacin Liposome Inhalation Suspension.

Taichi Ozeki, Hisao Higo, Hiroki Omori, Shunta Mori, Shin Tanaka, Go Makimoto, Kiichiro Ninomiya, Akihiko Taniguchi, Masanori Fujii, Kentaro Miyoshi, Kammei Rai, Eiki Ichihara, Kadoaki Ohashi, Seiichiro Sugimoto, Katsuyuki Hotta, Masahiro Tabata, Shinichi Toyooka, Yoshinobu Maeda, Nobuaki Miyahara

Internal medicine (Tokyo, Japan) 2024.9

Language：English Publishing type：Research paper (scientific journal)

A 55-year-old man presented to our hospital with idiopathic pulmonary fibrosis (IPF). He was registered with the Japan Organ Transplant Network the following year due to disease progression. Treatment with clarithromycin, ethambutol, and rifampicin for complications of Mycobacterium avium pulmonary disease was initiated, but sputum conversion could not be achieved. The administration of an amikacin liposome inhalation suspension (ALIS) resulted in sputum conversion, and single-lung transplantation was performed. ALIS therapy was continued after lung transplantation, and no M. avium disease was observed for 15 months. ALIS may cause M. avium pulmonary disease with additional indications for lung transplantation.

DOI： 10.2169/internalmedicine.3854-24

Remission of hypersensitivity pneumonitis after allogeneic hematopoietic stem cell transplantation. International journal

Yumi Inukai Motokura, Hisao Higo, Chiaki Matsumoto, Mari Uno, Kanako Fujiwara, Toshiki Terao, Satoko Makimoto, Fumiyo Higaki, Ken-Ichi Matsuoka, Fumiaki Tokioka, Yoshinobu Maeda, Nobuaki Miyahara

Respiratory investigation 62 ( 5 ) 759 - 761 2024.7

Language：English Publishing type：Research paper (scientific journal)

A 50-year-old man was diagnosed with hypersensitivity pneumonitis caused by the environment of his bar owing to worsening symptoms, laboratory test results, and computed tomography images after an environmental inhalation challenge test. His hypersensitivity pneumonitis exacerbated despite receiving prednisolone 20 mg/day. The patient underwent allogeneic hematopoietic stem cell transplantation (HSCT) from a human leukocyte antigen-matched unrelated donor for myelodysplastic syndrome. No exacerbation of hypersensitivity pneumonitis was observed after HSCT. An environmental inhalation challenge test involving exposure to his bar confirmed the remission of hypersensitivity pneumonitis after HSCT. This case demonstrates that hypersensitivity pneumonitis can be remitted by HSCT.

DOI： 10.1016/j.resinv.2024.06.007

Predictors of exacerbation in Japanese patients with severe asthma: Analysis of the severe asthma research program (Okayama-SARP) cohort. International journal

Hisao Higo, Akihiko Taniguchi, Satoru Senoo, Taichi Ozeki, Naoki Nakamura, Masaki Atokawa, Junko Itano, Naohiro Oda, Ryota Sunami, Yutaro Shiota, Yukako Arakawa, Yoshihiro Mori, Naomi Kunichika, Ichiro Takata, Toshimitsu Suwaki, Norihiko Nakanishi, Yasushi Tanimoto, Arihiko Kanehiro, Yoshinobu Maeda, Katsuyuki Kiura, Nobuaki Miyahara

Respiratory investigation 62 ( 4 ) 695 - 701 2024.7

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Because exacerbation of severe asthma decreases patients' quality of life, this study aimed to identify predictive factors for asthma exacerbation. METHODS: Japanese patients with severe asthma requiring treatment according to the Global Initiative for Asthma (GINA) guidelines ≥ Step 4 between January 2018 and August 2021 were prospectively enrolled and followed up for one year at facilities participating in the Okayama Respiratory Disease Study Group (Okayama Severe Asthma Research Program). RESULTS: A total of 85 patients (29 men and 56 women) were included. The median age was 64 (interquartile range [IQR], 51-72) years. Treatment according to GINA Steps 4 and 5 was required in 29 and 56 patients, respectively, and 44 patients (51.8%) were treated with biologics. The median peripheral-blood eosinophil count, fractional exhaled nitric oxide, IgE level, and percent predicted FEV1 (%FEV1) at enrollment were 204 (IQR, 49-436)/μL, 28 (IQR, 15-43) ppb, 172 (IQR, 56-473) IU/mL, and 80.0 (IQR, 61.1-96.1) %, respectively. Exacerbation during the previous year, asthma control test (ACT) score <20, %FEV1 <60%, and serum IL-10 level >6.7 pg/mL were associated with exacerbation during the observation period. CONCLUSIONS: Exacerbation during the previous year, low ACT score, and low %FEV1 were predictive factors of future exacerbation, even in a cohort with >50% of patients treated with biologics. Furthermore, high serum IL-10 levels might be a new predictive factor.

DOI： 10.1016/j.resinv.2024.05.014

Concomitant osimertinib and antituberculosis therapy in an elderly patient with EGFR-mutated lung cancer and pulmonary tuberculosis: A case report. International journal

Hiroaki Matsuura, Hisao Higo, Tadahiro Kuribayashi, Akihiko Tamaoki, Takamasa Nakasuka, Mari Uno, Go Makimoto, Kiichiro Ninomiya, Masanori Fujii, Kammei Rai, Eiki Ichihara, Katsuyuki Hotta, Nobuaki Miyahara, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura, Kadoaki Ohashi

Thoracic cancer 15 ( 17 ) 1390 - 1394 2024.6

Language：English Publishing type：Research paper (scientific journal)

The concurrent incidence of lung cancer and tuberculosis is expected to escalate due to the projected growth in the older population. Combination therapy with osimertinib and antituberculosis drugs has not been well-established. We report a case of successful treatment involving the concomitant administration of osimertinib and antituberculosis drugs in an older patient, an 89-year-old female, diagnosed with epidermal growth factor receptor (EGFR)-mutant lung cancer and pulmonary tuberculosis. Accumulating evidence is warranted to develop an optimal treatment strategy for patients with lung cancer and tuberculosis.

DOI： 10.1111/1759-7714.15324

肝切除後の難治性気管支胆汁瘻に対してEndobronchial Watanabe Spigotの挿入が感染制御に有効であった1例

宇野真梨, 槇本剛, 藤智和, 大森洋樹, 肥後寿夫, 本倉優美, 田中孝明, 森俊太, 大西桐子, 二宮貴一朗, 頼冠名, 市原英基, 田端雅弘, 宮原信明, 堀田勝幸, 大橋圭明

気管支学 46 ( Suppl. ) S337 - S337 2024.5

重症喘息における増悪予測因子に関する前向き観察研究(Okayama-SARP)

肥後寿夫, 谷口暁彦, 金廣有彦, 荒川裕佳子, 宮原信明

日本職業・環境アレルギー学会雑誌 31 ( 1 ) 89 - 89 2024.4

びまん性肺疾患トピック肺線維症急性増悪におけるS100A8/A9の役割の検討

中村尚季, 肥後寿夫, 妹尾賢, 尾関太一, 角南良太, 山元修成, 板野純子, 谷口暁彦, 田中彩加, 木下理恵, 阪口政清, 前田嘉信, 宮原信明

日本呼吸器学会誌 13 ( 増刊 ) 217 - 217 2024.3

特発性器質化肺炎における自己免疫性疾患の特徴を伴う間質性肺炎(IPAF)の頻度および臨床像の検討

市川裕久, 肥後寿夫, 松岡克浩, 関祥子, 荒川裕佳子, 森由弘, 久山彰一, 松本千晶, 杉本啓介, 濱田昇, 洲脇俊充, 板野純子, 谷口暁彦, 犬飼優美, 有田眞知子, 槇本怜子, 児島克英, 宮原信明

日本呼吸器学会誌 13 ( 増刊 ) 365 - 365 2024.3

Pneumocystis jirovecii pneumonia mortality risk associated with preceding long-term steroid use for the underlying disease: A multicenter, retrospective cohort study. International journal

Kohei Miyake, Satoru Senoo, Ritsuya Shiiba, Junko Itano, Goro Kimura, Tatsuyuki Kawahara, Tomoki Tamura, Kenichiro Kudo, Tetsuji Kawamura, Yasuharu Nakahara, Hisao Higo, Daisuke Himeji, Nagio Takigawa, Nobuaki Miyahara

PloS one 19 ( 2 ) e0292507 2024

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: Long-term steroid use increases the risk of developing Pneumocystis pneumonia (PcP), but there are limited reports on the relation of long-term steroid and PcP mortality. METHODS: Retrospective multicenter study to identify risk factors for PcP mortality, including average steroid dose before the first visit for PcP in non-human immunodeficiency virus (HIV)-PcP patients. We generated receiver operating characteristic (ROC) curves for 90-day all-cause mortality and the mean daily steroid dose per unit body weight in the preceding 10 to 90 days in 10-day increments. Patients were dichotomized by 90-day mortality and propensity score-based stabilized inverse probability of treatment weighting (IPTW) adjusted covariates of age, sex, and underlying disease. Multivariate analysis with logistic regression assessed whether long-term corticosteroid use affected outcome. RESULTS: Of 133 patients with non-HIV-PcP, 37 died within 90 days of initial diagnosis. The area under the ROC curve for 1-40 days was highest, and the optimal cutoff point of median adjunctive corticosteroid dosage was 0.34 mg/kg/day. Past steroid dose, underlying interstitial lung disease and emphysema, lower serum albumin and lower lymphocyte count, higher lactate dehydrogenase, use of therapeutic pentamidine and therapeutic high-dose steroids were all significantly associated with mortality. Underlying autoimmune disease, past immunosuppressant use, and a longer time from onset to start of treatment, were associated lower mortality. Logistic regression analysis after adjusting for age, sex, and underlying disease with IPTW revealed that steroid dose 1-40 days before the first visit for PcP (per 0.1 mg/kg/day increment, odds ratio 1.36 [95% confidence interval = 1.16-1.66], P<0.001), low lymphocyte counts, and high lactate dehydrogenase revel were independent mortality risk factor, while respiratory failure, early steroid, and sulfamethoxazole/trimethoprim for PcP treatment did not. CONCLUSION: A steroid dose before PcP onset was strongly associated with 90-day mortality in non-HIV-PcP patients, emphasizing the importance of appropriate prophylaxis especially in this population.

DOI： 10.1371/journal.pone.0292507

Protracted coronavirus disease 2019 after chimeric antigen receptor-T cell therapy successfully treated with sequential multidrug therapy. International journal

Masahiro Yamashita, Hisao Higo, Nobuharu Fujii, Chiaki Matsumoto, Go Makimoto, Kiichiro Ninomiya, Masanori Fujii, Kammei Rai, Eiki Ichihara, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Nobuaki Miyahara

Respiratory medicine case reports 51 102104 - 102104 2024

Language：English Publishing type：Research paper (scientific journal)

A 56-year-old woman who received CD19 chimeric antigen receptor-T cell therapy for refractory diffuse large B-cell lymphoma developed severe coronavirus disease 2019 (COVID-19) and was treated with nirmatrelvir/ritonavir in April 2022. However, she experienced persistent fatigue and cough and fever in June. Computed tomography revealed bilateral ground-glass opacities (GGO), and the patient was treated with corticosteroids for organizing pneumonia after COVID-19. Partial improvement was observed, but new GGO appeared despite corticosteroid therapy. Genome analysis of severe acute respiratory syndrome coronavirus 2 detected Omicron variant BA.1.1.2, which was prevalent at the time of initial infection. The patient was diagnosed with protracted COVID-19 and was treated with remdesivir, molnupiravir, nirmatrelvir/ritonavir, and tixagevimab/cilgavimab. These treatments appeared to contribute to the improvement of protracted COVID-19.

DOI： 10.1016/j.rmcr.2024.102104

Severe Cytokine Release Syndrome and Immune Effector Cell-associated Neurotoxicity Syndrome in a Man Receiving Immune Checkpoint Inhibitors for Lung Cancer: A Case Report.

Takaaki Tanaka, Masataka Taoka, Go Makimoto, Kiichiro Ninomiya, Hisao Higo, Masanori Fujii, Eiki Ichihara, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda

Internal medicine (Tokyo, Japan) 2023.9

Language：English Publishing type：Research paper (scientific journal)

A 55-year-old man with stage IV lung adenocarcinoma was treated with cisplatin, pemetrexed, nivolumab, and ipilimumab. Approximately 100 days after treatment initiation, he became disoriented and presented to the emergency department with a high fever. Blood tests revealed liver and kidney dysfunctions. Subsequently, the patient developed generalized convulsions that required intensive care. He was clinically diagnosed with cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Organ damage was gradually controlled with immunosuppressive drugs, including steroids, and the patient was discharged. Successful treatment is rare in patients with CRS, including ICANS, during immune checkpoint inhibitor treatment for solid tumors.

DOI： 10.2169/internalmedicine.2429-23

Pulmonary fibrosis and type-17 immunity. International journal

Satoru Senoo, Hisao Higo, Akihiko Taniguchi, Katsuyuki Kiura, Yoshinobu Maeda, Nobuaki Miyahara

Respiratory investigation 61 ( 5 ) 553 - 562 2023.9

Language：English Publishing type：Research paper (scientific journal)

Fibrosis of the lung can occur in idiopathic pulmonary fibrosis, collagen vascular diseases, and hypersensitivity pneumonitis, among other diseases. Transforming growth factor (TGF)-β, vascular epithelial growth factor, fibroblast growth factor, and platelet-derived growth factor contribute to the pathophysiology of fibrosis. TGF-β and other cytokines, including interleukin (IL)-1β, IL-6, and IL-23, activate type-17 immunity, which is involved in pulmonary fibrosis. The components of type-17 immunity include type-17 helper T cells, γδT cells, IL-17A-producing CD8-positive T cells, invariant NKT cells, and group 3 innate lymphoid cells. IL-17A, the main cytokine of type-17 immunity, is able to induce the epithelial-mesenchymal transition in epithelial cells via a production of TGF-β, directly stimulate fibroblasts and fibrocytes, and inhibit autophagy, which otherwise protects against pulmonary fibrosis. IL-23 induces type-17 immunity and plays an important role in the acute exacerbation of pulmonary fibrosis. Clinical studies have also linked type-17 immunity to the pathogenesis of pulmonary fibrosis. Consequently, targeting type-17 immunity may serve as a new therapeutic strategy to prevent the development or exacerbation of pulmonary fibrosis.

DOI： 10.1016/j.resinv.2023.05.005

Switching to Dupilumab from Other Biologics without a Treatment Interval in Patients with Severe Asthma: A Multi-Center Retrospective Study. International journal

Hisao Higo, Hirohisa Ichikawa, Yukako Arakawa, Yoshihiro Mori, Junko Itano, Akihiko Taniguchi, Satoru Senoo, Goro Kimura, Yasushi Tanimoto, Kohei Miyake, Tomoya Katsuta, Mikio Kataoka, Yoshinobu Maeda, Katsuyuki Kiura, Nobuaki Miyahara, Okayama Respiratory Disease Study Group Ordsg

Journal of clinical medicine 12 ( 16 ) 2023.8

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Dupilumab is a fully humanized monoclonal antibody that blocks interleukin-4 and interleukin-13 signals. Several large clinical trials have demonstrated the efficacy of dupilumab in patients with severe asthma. However, few studies have examined a switch to dupilumab from other biologics. METHODS: This retrospective, multi-center observational study was conducted by the Okayama Respiratory Disease Study Group. Consecutive patients with severe asthma who were switched to dupilumab from other biologics without a treatment interval between May 2019 and September 2021 were enrolled. Patients with a treatment interval of more than twice the standard dosing interval for the previous biologic prior to dupilumab administration were excluded. RESULTS: The median patient age of the 27 patients enrolled in this study was 57 years (IQR, 45-68 years). Eosinophilic chronic rhinosinusitis (ECRS)/chronic rhinosinusitis with nasal polyp (CRSwNP) was confirmed in 23 patients. Previous biologics consisted of omalizumab (n = 3), mepolizumab (n = 3), and benralizumab (n = 21). Dupilumab significantly improved FEV1 (median improvement: +145 mL) and the asthma control test score (median improvement: +2). The overall response rate in patients receiving dupilumab for asthma as determined using the Global Evaluations of Treatment Effectiveness (GETE) was 77.8%. There were no significant differences in the baseline characteristics of the GETE-improved group vs. the non-GETE-improved group. ECRS/CRSwNP improved in 20 of the 23 patients (87.0%). Overall, 8 of the 27 patients (29.6%) developed transient hypereosinophilia (>1500/μL), but all were asymptomatic and able to continue dupilumab therapy. CONCLUSIONS: Dupilumab was highly effective for the treatment of severe asthma and ECRS/CRSwNP, even in patients switched from other biologics without a treatment interval.

DOI： 10.3390/jcm12165174

抗IL-4受容体抗体他の生物学的製剤からデュピルマブへ切り替えた喘息症例に関する多施設共同後ろ向き観察研究

肥後寿夫, 角南良太, 市川裕久, 荒川裕佳子, 森由弘, 板野純子, 木村五郎, 谷本安, 三宅剛平, 片岡幹男, 木浦勝行, 宮原信明

アレルギー 72 ( 6-7 ) 908 - 908 2023.8

増悪と抑制を司るアレルギーメディエーターダニ抗原による気道過敏性誘発マウスモデルにおけるインターロイキン-22 binding proteinの役割の検討

角南良太, 肥後寿夫, 尾関太一, 中村尚季, 妹尾賢, 谷口暁彦, 前田嘉信, 宮原信明

アレルギー 72 ( 6-7 ) 909 - 909 2023.8

抗IL-4受容体抗体他の生物学的製剤からデュピルマブへ切り替えた喘息症例に関する多施設共同後ろ向き観察研究

肥後寿夫, 角南良太, 市川裕久, 荒川裕佳子, 森由弘, 板野純子, 木村五郎, 谷本安, 三宅剛平, 片岡幹男, 木浦勝行, 宮原信明

アレルギー 72 ( 6-7 ) 908 - 908 2023.8

増悪と抑制を司るアレルギーメディエーターダニ抗原による気道過敏性誘発マウスモデルにおけるインターロイキン-22 binding proteinの役割の検討

角南良太, 肥後寿夫, 尾関太一, 中村尚季, 妹尾賢, 谷口暁彦, 前田嘉信, 宮原信明

アレルギー 72 ( 6-7 ) 909 - 909 2023.8

重症喘息患者の増悪予測因子に関する前向き観察研究(Okayama-SARP)

肥後寿夫, 後川真輝, 谷口暁彦, 板野純子, 小田尚廣, 塩田雄太郎, 荒川裕佳子, 森由弘, 國近尚美, 高田一郎, 洲脇俊充, 中西徳彦, 谷本安, 前田嘉信, 木浦勝行, 宮原信明

日本呼吸器学会誌 12 ( 増刊 ) 315 - 315 2023.3

間質性肺炎急性増悪に対する免疫グロブリン静注療法の効果

市川裕久, 肥後寿夫, 中村尚季, 藤井昌学, 松岡克浩, 関祥子, 和田学政, 須崎規之, 永田拓也, 荒川裕佳子, 宮原信明, 森由弘, 丸川雅臣, 前田嘉信, 木浦勝行

日本呼吸器学会誌 12 ( 増刊 ) 289 - 289 2023.3

Mycobacterium shinjukuense infection successfully treated with clarithromycin, rifampicin, and ethambutol. International journal

Kayo Nakamura, Etsuko Murakami, Daizo Kishino, Shuko Mashimo, Yusuke Kurioka, Yusaku Shibata, Arihiko Taniguchi, Hisao Higo, Yasushi Hiramatsu, Yoshinobu Maeda, Nobuaki Miyahara

Respiratory medicine case reports 45 101894 - 101894 2023

Language：English

We present the case of a 59-year-old woman diagnosed with Mycobacterium shinjukuense infection using mass spectrometry of bronchioalveolar lavage fluid. We initiated treatment with clarithromycin, rifampicin, and ethambutol based on the results of drug susceptibility testing, which improved lung opacities. Most previous cases were treated with the standard regimen for Mycobacterium tuberculosis. However, our regimen may provide a therapeutic option for this rare nontuberculous Mycobacterium infection.

DOI： 10.1016/j.rmcr.2023.101894

Association between early corticosteroid administration and long-term survival in non-infectious pulmonary complications after allogeneic hematopoietic stem cell transplantation.

Yui Kambara, Nobuharu Fujii, Yoshiaki Usui, Akira Yamamoto, Hisao Higo, Hideaki Fujiwara, Noboru Asada, Daisuke Ennishi, Hisakazu Nishimori, Keiko Fujii, Ken-Ichi Matsuoka, Yoshinobu Maeda

International journal of hematology 117 ( 4 ) 578 - 589 2022.12

Language：English Publishing type：Research paper (scientific journal)

Non-infectious pulmonary complications (NIPCs) after allogeneic hematopoietic stem cell transplantation (HSCT) are associated with poor outcomes. It is important to maximize the effectiveness of primary treatment because secondary treatment has not been established. We analyzed data from 393 patients who underwent allogeneic HSCT during a 10-year period. Thirty-seven were diagnosed with NIPCs, which consisted of idiopathic pneumonia syndrome, bronchiolitis obliterans, and interstitial lung disease including cryptogenic organizing pneumonia. Among these, 18 died (Dead group) while 19 remained alive (Alive group) during the study period. The median time between NIPC diagnosis and first administration of ≥ 1 mg/kg/day corticosteroids (prednisolone dose equivalent) was significantly longer in the Dead group than the Alive group, at 9 days versus 4 days (p = 0.01). We further divided these cases into those who received prednisolone within seven days and after 8 days. We found that the ≤ 7 days group were more likely to survive after their NIPC diagnosis compared to the ≥ 8 days group (p = 0.06). Our analysis showed that early initiation of corticosteroid therapy is associated with long-term survival in NIPCs.

DOI： 10.1007/s12185-022-03517-3

Intravenous immunoglobulin for acute exacerbation of fibrotic idiopathic interstitial pneumonias. International journal

Hisao Higo, Hirohisa Ichikawa, Naoki Nakamura, Masanori Fujii, Katsuhiro Matsuoka, Shoko Seki, Takamasa Wada, Noriyuki Suzaki, Takuya Nagata, Yukako Arakawa, Yoshihiro Mori, Masaomi Marukawa, Katsuyuki Kiura, Yoshinobu Maeda, Nobuaki Miyahara

Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG 39 ( 4 ) e2022038 2022.12

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND AND AIM: Acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) is a fatal condition with no established treatment. Intravenous immunoglobulin (IVIG) is a unique therapy with both anti-inflammatory and anti-infective effects. Therefore, we hypothesized that IVIG may have a positive effect on AE of interstitial pneumonia. This study aimed to determine the effect of IVIG in patients with AE of fibrotic idiopathic interstitial pneumonias (IIPs), including IPF. METHODS: We retrospectively analyzed consecutive patients who were diagnosed with AE of fibrotic IIPs and treated with pulse corticosteroid therapy (methylprednisolone 500-1000 mg/day for 3 days) between April 2018 and May 2021 at Kagawa Rosai Hospital and KKR Takamatsu Hospital. RESULTS: This study included 52 patients with AE of fibrotic IIPs (IPF,41; fibrotic IIPs other than IPF,11). Thirteen patients received IVIG (5 g/day for 3-5 days) concurrently with pulse corticosteroid therapy. The remaining 39 patients were assigned to the control group. The survival rate on day 90 was significantly higher in the IVIG group than that in the control group (76.9% vs. 38.5%, p = 0.02). IVIG administration (odds ratio [OR], 0.11; 95% confidence interval [CI], 0.02-0.69; p = 0.02) and C- reactive protein (OR, 1.19; 95% CI, 1.06-1.33, p < 0.01) were independently associated with 90-day mortality. CONCLUSIONS: The results indicate that administration of IVIG may improve the survival of patients with AE of fibrotic IIPs. We are now conducting a prospective study to confirm the effect of IVIG on AE of IPF since May 2022 (jRCT1061220010).

DOI： 10.36141/svdld.v39i4.13682

Fulminant Myocarditis for Non-small-cell Carcinoma of the Lung with Nivolumab and Ipilimumab Plus Chemotherapy: A Case Report.

Tomoka Nishimura, Kiichiro Ninomiya, Mitsutaka Nakashima, Satoshi Akagi, Tadahiro Kuribayashi, Hisao Higo, Katsuyuki Hotta, Yoshinobu Maeda, Hiroshi Ito, Katsuyuki Kiura

Internal medicine (Tokyo, Japan) 62 ( 9 ) 1319 - 1322 2022.9

Language：English Publishing type：Research paper (scientific journal)

A 59-year-old man with a high level of antinuclear antibody received nivolumab and ipilimumab plus chemotherapy for lung cancer. Two weeks after the second course, he was admitted with a fever and severe fatigue. Laboratory studies showed elevated markers of myocardial damage, and a myocardial biopsy showed inflammatory cell infiltration, damaged myocardial fibers. Myocarditis was diagnosed as an immune-related adverse event (irAE), and high-dose corticosteroids were initiated. However, his cardiac function rapidly worsened, and he died on the fifth day after admission. There is no established treatment strategy for fulminant myocarditis as an irAE, and the further exploration of viable treatment strategies is required.

DOI： 10.2169/internalmedicine.0505-22

IL-5製剤無効気管支喘息症例におけるdupilumabの使用経験

肥後寿夫, 中村尚季, 角南良太, 妹尾賢, 田端雅弘, 木浦勝行, 宮原信明

アレルギー 71 ( 6-7 ) 856 - 856 2022.8

CD8+ T-cell responses are boosted by dual PD-1/VEGFR2 blockade after EGFR inhibition in Egfr-mutant lung cancer. International journal

Kazuya Nishii, Kadoaki Ohashi, Shuta Tomida, Takamasa Nakasuka, Atsuko Hirabae, Sachi Okawa, Jun Nishimura, Hisao Higo, Hiromi Watanabe, Hirohisa Kano, Chihiro Ando, Go Makimoto, Kiichiro Ninomiya, Yuka Kato, Toshio Kubo, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Shinichi Toyooka, Heiichiro Udono, Yoshinobu Maeda, Katsuyuki Kiura

Cancer immunology research 10 ( 9 ) 1111 - 1126 2022.7

Language：English Publishing type：Research paper (scientific journal)

Epidermal growth factor receptor (EGFR) is the most frequently mutated driver oncogene in non-smoking-related, non-small-cell lung cancer (NSCLC). EGFR-mutant NSCLC has a non-inflamed tumor microenvironment (TME), with low infiltration by CD8+ T cells and, thus, immune checkpoint inhibitors, such as anti-programmed cell death-1 (anti-PD-1) have weak anti-tumor effects. Here, we showed that CD8+ T-cell responses were induced by an EGFR-tyrosine kinase inhibitor (TKI) in syngeneic Egfr-mutant NSCLC tumors, which was further pronounced by sequential dual blockade of PD-1 and vascular endothelial growth factor receptor 2 (VEGFR2). However, simultaneous triple blockade had no such effect. PD-1/VEGFR2 dual blockade did not exert tumor-inhibitory effects without pre-treatment with the EGFR-TKI, suggesting that treatment schedule is crucial for efficacy of the dual blockade therapy. Pre-treatment with EGFR-TKI increased the CD8+ T-cell/regulatory T-cell (Treg) ratio, while also increasing expression of immunosuppressive chemokines and chemokine receptors, as well as increasing the number of M2-like macrophages, in the TME. Discontinuing EGFR-TKI treatment reversed the transient increase of immunosuppressive factors in the TME. The subsequent PD-1/VEGFR2 inhibition maintained increased numbers of infiltrating CD8+ T cells and CD11c+ dendritic cells. Depletion of CD8+ T cells in vivo abolished tumor growth inhibition by EGFR-TKI alone and the sequential triple therapy, suggesting that EGFR inhibition is a prerequisite for the induction of CD8+ T-cell responses. Our findings could aid in developing an alternative immunotherapy strategy in patients with cancers that have driver mutations and a non-inflamed TME.

DOI： 10.1158/2326-6066.CIR-21-0751

大量喀血に対して気管支動脈塞栓術と気管支充填術が奏効したALK陽性肺癌の1例

藤岡佑輔, 田岡征高, 槇本剛, 栗林忠弘, 松浦宏昌, 下西惇, 二宮貴一朗, 肥後寿夫, 久保寿夫, 大橋圭明, 堀田勝幸, 宮原信明, 田端雅弘, 木浦勝行

気管支学 44 ( Suppl. ) S307 - S307 2022.5

大量喀血に対して気管支動脈塞栓術と気管支充填術が奏効したALK陽性肺癌の1例

藤岡佑輔, 田岡征高, 槇本剛, 栗林忠弘, 松浦宏昌, 下西惇, 二宮貴一朗, 肥後寿夫, 久保寿夫, 大橋圭明, 堀田勝幸, 宮原信明, 田端雅弘, 木浦勝行

気管支学 44 ( Suppl. ) S307 - S307 2022.5

慢性好酸球性肺炎合併重症喘息に対してBenralizumabを投与した症例

妹尾賢, 谷口暁彦, 藤井昌学, 中村尚季, 角南良太, 肥後寿夫, 前田嘉信, 木浦勝行, 宮原信明

日本呼吸器学会誌 11 ( 増刊 ) 295 - 295 2022.4

Identification of targetable kinases in idiopathic pulmonary fibrosis. International journal

Hisao Higo, Kadoaki Ohashi, Shuta Tomida, Sachi Okawa, Hiromasa Yamamoto, Seiichiro Sugimoto, Satoru Senoo, Go Makimoto, Kiichiro Ninomiya, Takamasa Nakasuka, Kazuya Nishii, Akihiko Taniguchi, Toshio Kubo, Eiki Ichihara, Katsuyuki Hotta, Nobuaki Miyahara, Yoshinobu Maeda, Shinichi Toyooka, Katsuyuki Kiura

Respiratory research 23 ( 1 ) 20 - 20 2022.2

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Tyrosine kinase activation plays an important role in the progression of pulmonary fibrosis. In this study, we analyzed the expression of 612 kinase-coding and cancer-related genes using next-generation sequencing to identify potential therapeutic targets for idiopathic pulmonary fibrosis (IPF). METHODS: Thirteen samples from five patients with IPF (Cases 1-5) and eight samples from four patients without IPF (control) were included in this study. Six of the thirteen samples were obtained from different lung segments of a single patient who underwent bilateral pneumonectomy. Gene expression analysis of IPF lung tissue samples (n = 13) and control samples (n = 8) was performed using SureSelect RNA Human Kinome Kit. The expression of the selected genes was further confirmed at the protein level by immunohistochemistry (IHC). RESULTS: Gene expression analysis revealed a correlation between the gene expression signatures and the degree of fibrosis, as assessed by Ashcroft score. In addition, the expression analysis indicated a stronger heterogeneity among the IPF lung samples than among the control lung samples. In the integrated analysis of the 21 samples, DCLK1 and STK33 were found to be upregulated in IPF lung samples compared to control lung samples. However, the top most upregulated genes were distinct in individual cases. DCLK1, PDK4, and ERBB4 were upregulated in IPF case 1, whereas STK33, PIM2, and SYK were upregulated in IPF case 2. IHC revealed that these proteins were expressed in the epithelial layer of the fibrotic lesions. CONCLUSIONS: We performed a comprehensive kinase expression analysis to explore the potential therapeutic targets for IPF. We found that DCLK1 and STK33 may serve as potential candidate targets for molecular targeted therapy of IPF. In addition, PDK4, ERBB4, PIM2, and SYK might also serve as personalized therapeutic targets of IPF. Additional large-scale studies are warranted to develop personalized therapies for patients with IPF.

DOI： 10.1186/s12931-022-01940-y

Successful and Prompt Treatment with Tepotinib for Lung Adenocarcinoma Harboring MET Exon 14 Skipping Mutation Combined with Lung Abscess Formation: A Case Report. International journal

Go Makimoto, Atsushi Shimonishi, Kadoaki Ohashi, Kiichiro Ninomiya, Hisao Higo, Yuka Kato, Masanori Fujii, Toshio Kubo, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Case reports in oncology 15 ( 2 ) 494 - 498 2022

Language：English

Tepotinib, the novel MET-tyrosine kinase inhibitor, shows an antitumor effect for patients with non-small-cell lung cancer (NSCLC) harboring MET exon 14 skipping mutation. In January 2022, the AmoyDx® Pan Lung Cancer polymerase chain reaction Panel (AmoyDx® panel), which had a shorter turnaround time than the conventional test, was launched in Japan as a tepotinib companion test. We report a patient with an advanced MET-mutant NSCLC promptly diagnosed using the AmoyDx® panel and successfully treated with tepotinib. Although the patient's performance status (PS) worsened due to the rapid tumor progression and lung abscess formation, the tumor shrank immediately after tepotinib treatment with marked PS improvement.

DOI： 10.1159/000524326

Massive hemoptysis in a post-operative patient with recurrent lung cancer successfully treated by the combination therapy of Endobronchial Watanabe Spigot and bronchial artery embolization

Masataka Taoka, Go Makimoto, Noriyuki Umakoshi, Kiichiro Ninomiya, Hisao Higo, Yuka Kato, Masanori Fujii, Toshio Kubo, Eiki Ichihara, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Respiratory Medicine Case Reports 38 101669 - 101669 2022

Indications for SARS-CoV-2 nucleic acid amplification test for areas with low endemicity. International journal

Hisao Higo, Yoshinori Taguchi, Noriyuki Suzaki, Takuya Nagata, Masaomi Marukawa

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 2021.11

Language：English Publishing type：Research paper (scientific journal)

INTRODUCTION: The optimal indication for the nucleic acid amplification test (NAAT) in areas with low endemicity for coronavirus disease 2019 (COVID-19) is unclear. This study aimed to identify patients who should undergo the NAAT for COVID-19 diagnosis. METHODS: We retrospectively analyzed the clinical data of patients with suspected COVID-19 who underwent NAAT between October 5, 2020, and May 31, 2021 in our institution. RESULTS: A total of 1238 patients were enrolled and NAAT positive results were observed in 40 patients (3.2%). The NAAT positivity rate was 34.3% (23/67) in patients with a history of close contact and 1.5% (17/1171) in patients without a history of close contact. Olfactory/gustatory dysfunction and a history of stay in other prefectures were independent risk factors of COVID-19 in patients without a history of close contact. On the other hand, the NAAT positivity rate was only 0.7% (8/1073) in patients without olfactory/gustatory dysfunction and a history of stay in other prefectures. Among them, the group without respiratory symptoms/sign had only one NAAT-positive case (0.1%: 1/1073). CONCLUSIONS: This study revealed that a history of close contact, olfactory/gustatory dysfunction, and a history of stay in other prefectures are key eligibility criteria for NAAT in areas with relatively few patients with COVID-19. On the other hand, NAAT may not be necessary in cases without all of these factors and respiratory symptoms/sign.

DOI： 10.1016/j.jiac.2021.10.029

Triple therapy with osimertinib, bevacizumab and cetuximab in EGFR-mutant lung cancer with HIF-1α/TGF-α expression. International journal

Kazuya Nishii, Kadoaki Ohashi, Hiromi Watanabe, Go Makimoto, Takamasa Nakasuka, Hisao Higo, Kiichiro Ninomiya, Yuka Kato, Toshio Kubo, Kammei Rai, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Oncology letters 22 ( 3 ) 639 - 639 2021.9

Language：English Publishing type：Research paper (scientific journal)

Osimertinib, a third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is the standard treatment for patients with lung cancer harboring EGFR T790M; however, acquired resistance is inevitable due to genetic and epigenetic changes in cancer cells. In addition, a recent randomized clinical trial revealed that the combination of osimertinib and bevacizumab failed to exhibit superior progression-free survival compared with osimertinib alone. The present study aimed to investigate the effect of triple therapy with osimertinib, bevacizumab and cetuximab in xenograft tumors with different initial tumor volumes (conventional model, 200 mm3 and large model, 500 mm3). The results demonstrated that osimertinib significantly inhibited tumor growth in both the conventional and large models; however, maximum tumor regression was attenuated in the large model in which hypoxia-inducible factor-1α (HIF-1α) and transforming growth factor-α (TGF-α) expression levels increased. Although the combination of osimertinib and bevacizumab exerted a greater inhibitory effect on tumor growth compared with osimertinib in the conventional model, the effect of this combination therapy was attenuated in the large model. TGF-α attenuated sensitivity to osimertinib in vitro; however, this negative effect was counteracted by the combination of osimertinib and cetuximab, but not osimertinib and bevacizumab. In the large xenograft tumor model, the triple therapy induced the greatest inhibitory effect on tumor growth compared with osimertinib alone and its combination with bevacizumab. Clinical trials of the triple therapy are required for patients with lung cancer with EGFR mutations and HIF-1α/TGF-α.

DOI： 10.3892/ol.2021.12900

非感染性移植後肺合併症診断後1週間以内の大量ステロイドの投与は予後を改善し得る(High-dose steroids within 7 days after diagnosis may improve prognosis of NIPC post HSCT)

神原由依, 藤井伸治, 碓井喜明, 山本晃, 肥後寿夫, 藤原英晃, 淺田騰, 遠西大輔, 西森久和, 藤井敬子, 松岡賢市, 前田嘉信

日本血液学会学術集会 83回 OS3 - 1 2021.9

VEGFR2 blockade augments the effects of tyrosine kinase inhibitors by inhibiting angiogenesis and oncogenic signaling in oncogene-driven non-small-cell lung cancers. International journal

Hiromi Watanabe, Eiki Ichihara, Hiroe Kayatani, Go Makimoto, Kiichiro Ninomiya, Kazuya Nishii, Hisao Higo, Chihiro Ando, Sachi Okawa, Takamasa Nakasuka, Hirohisa Kano, Naofumi Hara, Atsuko Hirabae, Yuka Kato, Takashi Ninomiya, Toshio Kubo, Kammei Rai, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Cancer science 112 ( 5 ) 1853 - 1864 2021.5

Language：English Publishing type：Research paper (scientific journal)

Molecular agents targeting the epidermal growth factor receptor (EGFR)-, anaplastic lymphoma kinase (ALK)- or c-ros oncogene 1 (ROS1) alterations have revolutionized the treatment of oncogene-driven non-small-cell lung cancer (NSCLC). However, the emergence of acquired resistance remains a significant challenge, limiting the wider clinical success of these molecular targeted therapies. In this study, we investigated the efficacy of various molecular targeted agents, including erlotinib, alectinib, and crizotinib, combined with anti-vascular endothelial growth factor receptor (VEGFR) 2 therapy. The combination of VEGFR2 blockade with molecular targeted agents enhanced the anti-tumor effects of these agents in xenograft mouse models of EGFR-, ALK-, or ROS1-altered NSCLC. The numbers of CD31-positive blood vessels were significantly lower in the tumors of mice treated with an anti-VEGFR2 antibody combined with molecular targeted agents compared with in those of mice treated with molecular targeted agents alone, implying the antiangiogenic effects of VEGFR2 blockade. Additionally, the combination therapies exerted more potent antiproliferative effects in vitro in EGFR-, ALK-, or ROS1-altered NSCLC cells, implying that VEGFR2 inhibition also has direct anti-tumor effects on cancer cells. Furthermore, VEGFR2 expression was induced following exposure to molecular targeted agents, implying the importance of VEGFR2 signaling in NSCLC patients undergoing molecular targeted therapy. In conclusion, VEGFR2 inhibition enhanced the anti-tumor effects of molecular targeted agents in various oncogene-driven NSCLC models, not only by inhibiting tumor angiogenesis but also by exerting direct antiproliferative effects on cancer cells. Hence, combination therapy with anti-VEGFR2 antibodies and molecular targeted agents could serve as a promising treatment strategy for oncogene-driven NSCLC.

DOI： 10.1111/cas.14801

Invasion of small cell lung cancer into the limbic system from leptomeningeal metastases. International journal

Hisao Higo, Takuro Igawa, Katsuhiro Matsuoka, Hiromichi Kawaji, Noriyuki Suzaki, Takuya Nagata, Masako Nagayama, Masaomi Marukawa

Respiratory medicine case reports 33 101417 - 101417 2021

Language：English

The diagnosis of leptomeningeal metastases is sometimes difficult when the cytology of cerebrospinal fluid is negative. We report a rare case of leptomeningeal metastases that required differentiation from paraneoplastic limbic encephalitis. A 67-year-old man with extensive-stage small cell lung cancer was admitted for a sudden decrease in the level of consciousness. He suffered memory disturbances that began the day before admission. Diffusion-weighted and fluid-attenuated inversion recovery images of brain magnetic resonance imaging (MRI) showed bilateral symmetric areas of hyperintensity in the hippocampus, amygdala, insular cortex, and medial temporal lobe; contrast enhancement was positive. Cytology of the cerebrospinal fluid (CSF) was negative. Anti-N-methyl-d-aspartate receptor antibody and herpes simplex virus DNA were not detected in the CSF. Paraneoplastic Limbic encephalitis was suspected due to his symptoms and brain MRI scan. The patient developed generalized seizures after admission. High-dose methylprednisolone and intravenous immune globulin were administered, but his condition did not improve. Uncontrollable seizures persisted and he died in the hospital at day 13. Autopsy revealed leptomeningeal metastasis and invasion of cancer cells into the limbic system. Contrast-enhanced MRI should be performed even if limbic encephalitis is suspected, and leptomeningeal metastases should be suspected if the lesions are enhanced.

DOI： 10.1016/j.rmcr.2021.101417

Detection of epidermal growth factor receptor mutations in exhaled breath condensate using droplet digital polymerase chain reaction. International journal

Kazuya Nishii, Kadoaki Ohashi, Tomoki Tamura, Kiichiro Ninomiya, Takehiro Matsubara, Satoru Senoo, Hirohisa Kano, Hiromi Watanabe, Naohiro Oda, Go Makimoto, Hisao Higo, Yuka Kato, Takashi Ninomiya, Toshio Kubo, Hiromasa Yamamoto, Shuta Tomida, Katsuyuki Hotta, Masahiro Tabata, Shinichi Toyooka, Yoshinobu Maeda, Katsuyuki Kiura

Oncology letters 20 ( 6 ) 393 - 393 2020.12

Language：English Publishing type：Research paper (scientific journal)

The detection of certain oncogenic driver mutations, including those of epidermal growth factor receptor (EGFR), is essential for determining treatment strategies for advanced non-small cell lung cancer (NSCLC). The current study assessed the feasibility of testing exhaled breath condensate (EBC) for EGFR mutations by droplet digital PCR (ddPCR). Samples were collected from 12 patients with NSCLC harboring EGFR mutations that were admitted to Okayama University Hospital between June 1, 2014 and December 31, 2017. A total of 21 EBC samples were collected using the RTube™ method and EGFR mutations (L858R, exon 19 deletions or T790M) were assessed through ddPCR analysis (EBC-ddPCR). A total of 3 healthy volunteer samples were also tested to determine a threshold value for each mutation. Various patient characteristics were determined, including sex (3 males and 9 females), age (range 54-81 years; median, 66 years), smoking history (10 had never smoked; 2 were former smokers), histology (12 patients exhibited adenocarcinoma), clinical stage (9 patients were stage IV; 3 exhibited post-operative recurrence) and EGFR mutation type (4 had L858R; 8 had exon 19 deletions; 8 had T790M). EBC-ddPCR demonstrated positive droplets in 8 of the 12 patients. The sensitivity and specificity of each mutation was as follows: 27.3 and 80.0% for EGFR L858R, 30.0 and 90.9% for EGFR Ex19del, and 22.2 and 100% for EGFR T790M. EBC-ddPCR analysis of EGFR mutations exhibited modest sensitivity and acceptable specificity. EBC-ddPCR is a minimally invasive and replicable procedure and may be a complementary method for EGFR testing in patients where blood or tissue sampling proves difficult.

DOI： 10.3892/ol.2020.12256

Beneficial effect of erlotinib and trastuzumab emtansine combination in lung tumors harboring EGFR mutations. International journal

Hiroe Kayatani, Kadoaki Ohashi, Kiichiro Ninomiya, Go Makimoto, Kazuya Nishii, Hisao Higo, Hiromi Watanabe, Hirohisa Kano, Yuka Kato, Takashi Ninomiya, Toshio Kubo, Kammei Rai, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Biochemical and biophysical research communications 532 ( 3 ) 341 - 346 2020.11

Language：English Publishing type：Research paper (scientific journal)

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is the standard therapy for non-small cell lung cancer (NSCLC) harboring EGFR mutations, but the resistance is inevitable. The drug-tolerant persister cancer cells are thought to be involved in the resistance. We recently reported that HER2 expression had a negative impact on time-to-treatment-failure in patients with EGFR mutant NSCLC. In this study, we hypothesized that HER2 might be a potential target for alternative combination therapy in NSCLC harboring EGFR mutations. In vitro study showed that the level of HER2 expression had no correlation with the sensitivity to EGFR-TKI, erlotinib but showed some correlation with HER2-inhibitor, ado-trastuzumab emtansine (T-DM1) in multiple EGFR-mutant lung cancer cell lines. In addition, HER2 expression was increased in persister cancer cells in 11-18 cell line harboring EGFR L858R or HCC827 cell line harboring EGFR exon 19 deletion after the exposure to erlotinib in vitro and in vivo. The combination of erlotinib and T-DM1 showed a superior inhibitory effect on cell proliferation compared with those of the erlotinib or T-DM1 alone in either 11-18 or HCC827 cells in vitro. The combination therapy also induced a significantly greater inhibitory effect on tumor growth in xenograft model in mice transplanted with either 11-18 or HCC827 cells compared with erlotinib alone or T-DM1 alone. No body weight loss was observed in these mice. These results suggested that the combination therapy with EGFR-TKI and T-DM1 might be a potentially promising strategy for treating lung cancer harboring EGFR mutations.

DOI： 10.1016/j.bbrc.2020.07.055

Characteristics and prognosis of interstitial pneumonias complicated with pneumomediastinum. International journal

Shojiro Minomo, Toru Arai, Hisao Higo, Taisuke Tsuji, Kazunobu Tachibana, Masanori Akira, Yoshikazu Inoue

Respiratory investigation 58 ( 4 ) 262 - 268 2020.7

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: The clinical characteristics and prognostic impact of complication with pneumomediastinum in patients with interstitial pneumonias (IPs) are not well studied due to the relatively limited nature of available reports. The purpose of this study was to clarify the characteristics and prognostic factors of IPs complicated with pneumomediastinum. METHODS: Consecutive patients with IPs complicated with pneumomediastinum detected by computed tomography (CT) between July 1, 2011, and April 30, 2014 were retrospectively reviewed. Clinical data including symptoms associated with pneumomediastinum, laboratory data, lung function tests, treatments, and mortality were collected from medical records. RESULTS: Forty-five patients (25 males, 20 females), including 32 with idiopathic IP (IIPs) and 13 connective tissue disease-associated interstitial lung diseases (CTD-ILDs) were identified. The median age of onset of pneumomediastinum was 72 years (interquartile range [IQR] 68-79 years). The most common symptom associated with occurrence of pneumomediastinum was appearance or worsening of dyspnoea. No specific treatment was performed for most (84%) of the cases. The median period between occurrence and improvement of pneumomediastinum was 29 days (IQR 5-69 days). Multivariate analysis revealed that IIPs and no improvement of pneumomediastinum were associated with poor prognosis. CONCLUSIONS: Patients with IIPs complicated with pneumomediastinum and those without improvement of pneumomediastinum had poor prognosis.

DOI： 10.1016/j.resinv.2020.02.007

Deterioration of high-resolution computed tomography findings predicts disease progression after initial decline in forced vital capacity in idiopathic pulmonary fibrosis patients treated with pirfenidone. International journal

Hisao Higo, Nobuaki Miyahara, Akihiko Taniguchi, Satoru Senoo, Junko Itano, Hiromi Watanabe, Naohiro Oda, Hiroe Kayatani, Hirohisa Ichikawa, Takuo Shibayama, Kazuhiro Kajimoto, Yasushi Tanimoto, Arihiko Kanehiro, Yoshinobu Maeda, Katsuyuki Kiura

Respiratory investigation 58 ( 3 ) 185 - 189 2020.5

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Pirfenidone suppresses the decline of forced vital capacity (FVC) in patients with idiopathic pulmonary fibrosis (IPF). However, IPF progresses in some patients despite treatment. We analyzed patients with meaningful FVC declines during pirfenidone treatment and explored the factors predictive of disease progression after FVC decline. METHODS: This study was a retrospective, multicenter, observational study conducted by the Okayama Respiratory Disease Study Group. We defined initial decline in %FVC as 5% or greater per 6-month period during pirfenidone treatment. IPF patients who were treated with pirfenidone and experienced an initial decline from December 2008 to September 2017 were enrolled. RESULTS: We analyzed 21 patients with IPF. After the initial decline, 4 (19.0%) patients showed improvement in disease, 11 (52.4%) showed stable disease, and 6 (28.6%) showed progressive disease. There was no significant correlation between %FVC reduction on initial decline and subsequent %FVC change (p = 0.475). Deterioration of high-resolution computed tomography (HRCT) findings on initial decline was observed significantly more often in the progressive versus improved/stable disease groups (100% vs 20.0%, p = 0.009). CONCLUSIONS: We revealed that deterioration of HRCT findings may predict disease progression after the initial decline in %FVC in IPF patients treated with pirfenidone.

DOI： 10.1016/j.resinv.2019.12.007

Pulmonary lymphangitic carcinomatosis from gallbladder cancer mimicking diffuse alveolar haemorrhage. International journal

Hisao Higo, Noriyuki Suzaki, Takuya Nagata, Taro Togami, Nobuya Ohara, Masaomi Marukawa

Respirology case reports 8 ( 3 ) e00540 2020.4

Language：English

Diagnosis in cases with pulmonary lymphangitic carcinomatosis as a primary manifestation is difficult due to unawareness of the cancer. An 81-year-old man was admitted due to a one-week history of dyspnoea and haemoptysis. Chest computed tomography showed diffuse bilateral ground-grass opacity and partial consolidation. We suspected diffuse alveolar haemorrhage. High-dose methylprednisolone and cyclophosphamide did not improve his condition and he died from respiratory failure. Autopsy revealed pulmonary lymphangitic carcinomatosis of whole lungs and primary gallbladder cancer. We should consider pulmonary lymphangitic carcinomatosis in the differential diagnosis of patients with haemoptysis and diffuse lung opacity of unknown origin.

DOI： 10.1002/rcr2.540

Successful Re-administration of Osimertinib in Osimertinib-induced Interstitial Lung Disease with an Organizing Pneumonia Pattern: A Case Report and Literature Review.

Junko Itano, Hisao Higo, Kadoaki Ohashi, Go Makimoto, Kazuya Nishii, Katsuyuki Hotta, Nobuaki Miyahara, Yoshinobu Maeda, Katsuyuki Kiura

Internal medicine (Tokyo, Japan) 59 ( 6 ) 823 - 828 2020.3

Language：English Publishing type：Research paper (scientific journal)

Osimertinib is the standard therapy for epidermal-growth-factor-receptor (EGFR)-mutant lung cancers. We herein report a case of osimertinib-induced interstitial lung disease (OsiILD) with an organizing pneumonia (OP) pattern and provide a literature-based review. Six months after osimertinib administration, a 75-year-old woman with right pleural carcinomatosis developed ILD with an OP pattern. After salvage chemotherapy, osimertinib with corticosteroid was successfully re-administered. A literature review suggested that 1) OsiILD with an OP pattern was rare but should be recognized, and 2) re-administration of osimertinib in OsiILD was successful in select patients. A criterion that determines whether a patient would benefit from re-administration is warranted.

DOI： 10.2169/internalmedicine.3689-19

Nintedanib can be used safely and effectively for idiopathic pulmonary fibrosis with predicted forced vital capacity ≤ 50%: A multi-center retrospective analysis. International journal

Satoru Senoo, Nobuaki Miyahara, Akihiko Taniguchi, Naohiro Oda, Junko Itano, Hisao Higo, Naofumi Hara, Hiromi Watanabe, Hirohisa Kano, Toshimitsu Suwaki, Yasuko Fuchimoto, Kazuhiro Kajimoto, Hirohisa Ichikawa, Kenichiro Kudo, Takuo Shibayama, Yasushi Tanimoto, Shoichi Kuyama, Arihiko Kanehiro, Yoshinobu Maeda, Katsuyuki Kiura

PloS one 15 ( 8 ) e0236935 2020

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Nintedanib is a multi-kinase inhibitor approved for idiopathic pulmonary fibrosis (IPF); however, its efficacy and safety for patients with IPF and restricted pulmonary function remain unclear. Therefore, the objective of this study was to determine the efficacy and safety of nintedanib for patients with IPF and forced vital capacity (FVC) ≤ 50%. METHODS: This was a multi-center retrospective study performed by the Okayama Respiratory Disease Study Group. Patients were allocated into FVC ≤ 50% and FVC > 50% groups based on their predicted FVC. The primary endpoints were FVC changes from baseline after 6 and 12 months. RESULTS: 45 patients were eligible for the study. 18 patients had FVC ≤ 50%, and 27 patients had FVC > 50%. Overall, 31 and 19 patients underwent pulmonary function tests at 6 and 12 months after initiating nintedanib, respectively. FVC changes from baseline at 6 and 12 months after initiating nintedanib were comparable between the two groups. Adverse events were seen in all patients, and the rates of patients who discontinued nintedanib were also comparable (38.9% vs. 37.0%, p = 1.000). Multiple regression analysis showed that age and forced expiratory volume in 1 second (FEV1)/FVC were negatively correlated with changes in FVC at 6 months after initiating nintedanib. CONCLUSIONS: Our data suggest that nintedanib can be a useful agent for IPF patients, including those with a low FVC, and that age and FEV1/FVC are predictive markers for changes in FVC following nintedanib treatment.

DOI： 10.1371/journal.pone.0236935

Rapid Acquisition of Alectinib Resistance in ALK-Positive Lung Cancer With High Tumor Mutation Burden. International journal

Go Makimoto, Kadoaki Ohashi, Shuta Tomida, Kazuya Nishii, Takehiro Matsubara, Hiroe Kayatani, Hisao Higo, Kiichiro Ninomiya, Akiko Sato, Hiromi Watanabe, Hirohisa Kano, Takashi Ninomiya, Toshio Kubo, Kammei Rai, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Shinichi Toyooka, Minoru Takata, Yoshinobu Maeda, Katsuyuki Kiura

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 14 ( 11 ) 2009 - 2018 2019.11

Language：English Publishing type：Research paper (scientific journal)

INTRODUCTION: The highly selective ALK receptor tyrosine kinase (ALK) inhibitor alectinib is standard therapy for ALK-positive lung cancers; however, some tumors quickly develop resistance. Here, we investigated the mechanism associated with rapid acquisition of resistance using clinical samples. METHODS: Autopsied samples were obtained from lung, liver, and renal tumors from a 51-year-old male patient with advanced ALK-positive lung cancer who had acquired resistance to alectinib in only 3 months. We established an alectinib-resistant cell line (ABC-14) from pleural effusion and an alectinib/crizotinib-resistant cell line (ABC-17) and patient-derived xenograft (PDX) model from liver tumors. Additionally, we performed next-generation sequencing, direct DNA sequencing, and quantitative real-time reverse transcription polymerase chain reaction. RESULTS: ABC-14 cells harbored no ALK mutations and were sensitive to crizotinib while also exhibiting MNNG HOS transforming gene (MET) gene amplification and amphiregulin overexpression. Additionally, combined treatment with crizotinib/erlotinib inhibited cell growth. ABC-17 and PDX tumors harbored ALK G1202R, and PDX tumors metastasized to multiple organs in vivo, whereas the third-generation ALK-inhibitor, lorlatinib, diminished tumor growth in vitro and in vivo. Next-generation sequencing indicated high tumor mutation burden and heterogeneous tumor evolution. The autopsied lung tumors harbored ALK G1202R (c. 3604 G>A) and the right renal metastasis harbored ALK G1202R (c. 3604 G>C); the mutation thus comprised different codon changes. CONCLUSIONS: High tumor mutation burden and heterogeneous tumor evolution might be responsible for rapid acquisition of alectinib resistance. Timely lorlatinib administration or combined therapy with an ALK inhibitor and other receptor tyrosine-kinase inhibitors might constitute a potent strategy.

DOI： 10.1016/j.jtho.2019.07.017

EGFR-TKI acquired resistance in lung cancers harboring EGFR mutations in immunocompetent C57BL/6J mice. International journal

Hisao Higo, Kadoaki Ohashi, Go Makimoto, Kazuya Nishii, Kenichiro Kudo, Hiroe Kayatani, Hiromi Watanabe, Hirohisa Kano, Kiichiro Ninomiya, Katsuyuki Hotta, Yoshinobu Maeda, Katsuyuki Kiura

Lung cancer (Amsterdam, Netherlands) 136 86 - 93 2019.10

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVES: Lung cancers harboring epidermal growth factor receptor (EGFR) mutations inevitably develop resistance to EGFR tyrosine-kinase inhibitors (EGFR-TKIs). Therefore, we sought to establish clinically relevant lung-cancer mouse models to achieve deep remission of cancers. MATERIALS AND METHODS: We previously established two transgenic lung-cancer mouse models harboring human EGFR exon 21 L858R substitution (hLR) and mouse Egfr exon 19 deletion (mDEL) in the C57BL/6 J background. Lung tumors from these two transgenic mouse strains were transplanted subcutaneously into BALB/c-nunu mice or C57BL/6 J mice. RESULTS: The transplanted tumors developed the ability to grow on the subcutaneous tissue, peritoneum, or lung of C57BL/6 J mice. While hLR tumors could grow only in C57BL/6 J mice carrying the transgene, mDEL tumors could grow in wild-type C57BL/6 J mice. The tumors maintained EGFR-dependency, and, thus, the EGFR-TKI gefitinib inhibited tumor growth; however, similar to human lung cancers, hLR and mDEL tumors acquired resistance in 60 and 200 days, respectively, following gefitinib administration. Secondary EGFR T790 M mutation in hLR tumors and secondary Egfr T792I mutation in mDEL tumors developed; however, no MET activation was detected. Accordingly, the third-generation EGFR-TKI osimertinib effectively inhibited gefitinib-resistant tumors in vivo. Furthermore, gefitinib-resistant tumors developed resistance to osimertinib in 100 days. CONCLUSION: These syngeneic lung-cancer mouse models harboring EGFR mutations are suitable for studying the drug-resistance mechanisms and the role of the tumor microenvironment. Further investigation with these mouse models is warranted for developing next-generation treatment strategies for lung cancer.

DOI： 10.1016/j.lungcan.2019.08.019

Cause of pleuroparenchymal fibroelastosis following allogeneic hematopoietic stem cell transplantation. International journal

Hisao Higo, Nobuaki Miyahara, Akihiko Taniguchi, Yoshinobu Maeda, Katsuyuki Kiura

Respiratory investigation 57 ( 4 ) 321 - 324 2019.7

Language：English Publishing type：Research paper (scientific journal)

Late-onset noninfectious pulmonary complications (LONIPCs) are life-threatening complications after hematopoietic stem cell transplantation (HSCT). Pleuroparenchymal fibroelastosis (PPFE) is a LONIPC, but its etiology remains elusive. Chronic graft-versus-host disease (cGVHD) and alkylating agents used for conditioning have been considered possible causes of PPFE. Therefore, to investigate the primary cause of PPFE in allogeneic HSCT, we compared three secondary PPFE groups, namely, the post-lung-transplantation, post-autologous-HSCT or chemotherapy-alone, and post-allogeneic-HSCT groups, and focused on the coexistence of bronchiolitis obliterans (BO), a typical phenotype of cGVHD. We found a trend towards higher rates of PPFE with BO in the post-allogeneic-HSCT and post-lung-transplantation groups (71% and 90%, respectively) than in the post-autologous-HSCT or chemotherapy-alone group (25%). The incidence of BO following allogeneic HSCT is reportedly <10%. If PPFE in the post-allogeneic-HSCT group has no association with BO and is induced by alkylating agents rather than cGVHD, the incidence of BO in PPFE in this group is estimated to be <10%, which is inconsistent with our data (71%). Thus, this study suggests that PPFE following allogeneic HSCT could be mainly induced by cGVHD because the majority of cases are associated with BO, a typical phenotype of cGVHD.

DOI： 10.1016/j.resinv.2019.04.003

Chemoradiotherapy for locally advanced lung cancer patients with interstitial lung abnormalities. International journal

Hisao Higo, Toshio Kubo, Satoko Makimoto, Go Makimoto, Hiroki Ihara, Yoshihisa Masaoka, Takashi Ninomiya, Eiki Ichihara, Kadoaki Ohashi, Akiko Sato, Katsuyuki Hotta, Masahiro Tabata, Nagio Takigawa, Yoshinobu Maeda, Katsuyuki Kiura

Japanese journal of clinical oncology 49 ( 5 ) 458 - 464 2019.5

Language：English Publishing type：Research paper (scientific journal)

INTRODUCTION: Although chemoradiotherapy for locally advanced lung cancer has the potential for cure, treatment is avoided in patients with interstitial lung disease because of the risk for severe radiation pneumonitis. Interstitial lung abnormalities (ILA) can be evaluated using high-resolution computed tomography (HRCT) to assess interstitial changes. In this study, we retrospectively examined the feasibility and efficacy of chemoradiotherapy for locally advanced lung cancer patients with ILA. METHODS: Patients who underwent chemoradiotherapy for locally advanced lung cancer at Okayama University Hospital between 2012 and 2015 were reviewed retrospectively. HRCT prior to treatment was evaluated by one pulmonologist and two radiologists using a sequential reading method. RESULTS: Of the 77 patients enrolled in this study, ILA was present in 25 (32.5%) and indeterminate ILA in 24 patients; 28 patients did not have ILA. Desaturation at rest (SpO2 < 95%) and honeycombing on HRCT were not observed in ILA patients. Only one patient with ILA had a low vital capacity (%VC < 80%). Severe radiation pneumonitis (≥Grade 2) occurred in 36.0% of the patients with ILA, but it was controllable; Grade 4 or 5 was not observed. Multivariate analysis showed that >25% of the lung volume receiving >20 Gy was risk factors of severe radiation pneumonitis, but ILA was not. The 2-year survival rates of patients with and without ILA were 56.8% and 74.1%, respectively, but the difference was not significant (P = 0.33). CONCLUSIONS: Chemoradiotherapy was feasible and effective in some patient population with ILA without desaturation, low VC and honeycombing on HRCT.

DOI： 10.1093/jjco/hyz016

Lung transplant candidates with idiopathic pulmonary fibrosis and long-term pirfenidone therapy: Treatment feasibility influences waitlist survival. International journal

Shin Tanaka, Kentaroh Miyoshi, Hisao Higo, Takeshi Kurosaki, Shinji Otani, Seiichiro Sugimoto, Masaomi Yamane, Katsuyuki Kiura, Shinichi Toyooka, Takahiro Oto

Respiratory investigation 57 ( 2 ) 165 - 171 2019.3

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronically progressive lung disease with exceptionally poor prognosis. While lung transplantation (LTx) is considered the last-resort therapeutic option, dismal waitlist mortality still hampers the salvage of patients with IPF. Pirfenidone, originally designed for IPF treatment, has increasingly been utilized. This study aimed to evaluate whether Pirfenidone could influence outcomes of patients with IPF on the Japanese LTx waitlist. METHODS: This retrospective single-center cohort study included 25 consecutive patients with IPF who were registered as LTx candidates at our institution between July 1999 and August 2016. Patients with a history of pretransplant Pirfenidone therapy (Pirfenidone group) were compared with those with no history (non-Pirfenidone group). RESULTS: In total, 6 (24%) patients received Pirfenidone as pretransplant therapy for 45.2 (range, 18.6-66.8) months. During the treatment period, the Pirfenidone group achieved a significant reduction in the decline rate of the forced vital capacity (-6.2% vs. -0.3%, p = 0.04) and a lower lung allocation score (31 vs. 41, p = 0.013) compared with the non-Pirfenidone group. The Pirfenidone group exhibited 100% waitlist survival three years after registration that was comparable to other indications, and 66% of the patients were still alive at the time of organ availability. No patient in the Pirfenidone group developed Pirfenidone-related surgical complications postoperatively. CONCLUSIONS: Patients with IPF successfully managed with long-term Pirfenidone therapy achieved favorable outcomes after LTx registration, comparable to other patients with LTx indications. The tolerability to antifibrotic therapy can be a predictor of waitlist survival.

DOI： 10.1016/j.resinv.2018.12.002

MET or NRAS amplification is an acquired resistance mechanism to the third-generation EGFR inhibitor naquotinib. International journal

Kiichiro Ninomiya, Kadoaki Ohashi, Go Makimoto, Shuta Tomida, Hisao Higo, Hiroe Kayatani, Takashi Ninomiya, Toshio Kubo, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Scientific reports 8 ( 1 ) 1955 - 1955 2018.1

Language：English Publishing type：Research paper (scientific journal)

As a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), osimeritnib is the standard treatment for patients with non-small cell lung cancer harboring the EGFR T790M mutation; however, acquired resistance inevitably develops. Therefore, a next-generation treatment strategy is warranted in the osimertinib era. We investigated the mechanism of resistance to a novel EGFR-TKI, naquotinib, with the goal of developing a novel treatment strategy. We established multiple naquotinib-resistant cell lines or osimertinib-resistant cells, two of which were derived from EGFR-TKI-naïve cells; the others were derived from gefitinib- or afatinib-resistant cells harboring EGFR T790M. We comprehensively analyzed the RNA kinome sequence, but no universal gene alterations were detected in naquotinib-resistant cells. Neuroblastoma RAS viral oncogene homolog (NRAS) amplification was detected in naquotinib-resistant cells derived from gefitinib-resistant cells. The combination therapy of MEK inhibitors and naquotinib exhibited a highly beneficial effect in resistant cells with NRAS amplification, but the combination of MEK inhibitors and osimertinib had limited effects on naquotinib-resistant cells. Moreover, the combination of MEK inhibitors and naquotinib inhibited the growth of osimertinib-resistant cells, while the combination of MEK inhibitors and osimertinib had little effect on osimertinib-resistant cells. Clinical assessment of this novel combination (MEK inhibitors and naquotinib) is worth considering in osimertinib-resistant lung tumors.

DOI： 10.1038/s41598-018-20326-z

Clinical characteristics of Japanese candidates for lung transplant for interstitial lung disease and risk factors for early death while on the waiting list. International journal

Hisao Higo, Takeshi Kurosaki, Eiki Ichihara, Toshio Kubo, Kentaroh Miyoshi, Shinji Otani, Seiichiro Sugimoto, Masaomi Yamane, Nobuaki Miyahara, Katsuyuki Kiura, Shinichiro Miyoshi, Takahiro Oto

Respiratory investigation 55 ( 4 ) 264 - 269 2017.7

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Lung transplants have produced very favorable outcomes for patients with interstitial lung disease (ILD) in Japan. However, because of the severe donor lung shortage, patients must wait approximately 2.5 years before they can undergo transplantation and many candidates die before allocation. We reveal the clinical characteristics of Japanese patients with ILD who are candidates for lung transplants and the risk factors for early death while on the waiting list. METHODS: We retrospectively reviewed the clinical data of patients registered in the Japan Organ Transplant Network from Okayama University Hospital who are candidates for cadaveric lung transplants for ILD between 1999 and 2015. RESULTS: Fifty-three patients with ILD were included (24 patients with idiopathic pulmonary fibrosis and 29 others). They had severe pulmonary dysfunction and low exercise tolerability. The median waiting time for transplantation was 462 days, and 22 patients died before allocation. Patients who died before 462 days without undergoing transplantation had more severe dyspnea, shorter 6-minute walk distance (6MWD), and lower performance status than those who waited ≥462 days. CONCLUSIONS: Japanese candidates for cadaveric lung transplants for ILD have severe pulmonary dysfunction. Severe dyspnea, short 6MWD, and low performance status are risk factors for early death while on the waiting list.

DOI： 10.1016/j.resinv.2017.03.002

Triplet therapy with afatinib, cetuximab, and bevacizumab induces deep remission in lung cancer cells harboring EGFR T790M in vivo. International journal

Kenichiro Kudo, Kadoaki Ohashi, Go Makimoto, Hisao Higo, Yuka Kato, Hiroe Kayatani, Yasuko Kurata, Yoichiro Takami, Daisuke Minami, Takashi Ninomiya, Toshio Kubo, Eiki Ichihara, Akiko Sato, Katsuyuki Hotta, Tadashi Yoshino, Mitsune Tanimoto, Katsuyuki Kiura

Molecular oncology 11 ( 6 ) 670 - 681 2017.6

Language：English Publishing type：Research paper (scientific journal)

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have changed the treatment strategy for EGFR-mutant lung cancers; however, resistance usually occurs due to a secondary mutation, T790M, in EGFR. Combination therapy using afatinib and cetuximab has had good results in lung tumors harboring EGFRT790M mutations in clinical trials. The effect of bevacizumab, an antivascular endothelial growth factor (VEGF) antibody, combined with EGFR-TKIs has also been investigated. We hypothesized that the dose of afatinib and cetuximab could be reduced by combination with bevacizumab and that the triplet therapy may result in better tumor inhibition with tolerable toxicity. Using a xenograft mouse model with H1975-harboring EGFRL858R+T790M and RPC-9-harboring EGFR19DEL+T790M , we tested the efficacy of the triplet therapy with a modified dose of afatinib, cetuximab, and bevacizumab, and compared this therapy to single and double therapies. Triplet therapy with afatinib, cetuximab, and bevacizumab induced pathological complete remission in xenograft tumors with H1975 and RPC-9 cells versus tumors treated with single or double therapies. We saw no body weight loss in the mice. The triple therapy induced a significant reduction in CD31-positive vascular endothelial cells and increased cleaved caspase-3-positive cells in the tumors. This suggests that one mechanism underlying the deep remission could be suppression of neovascularization and induction of apoptosis by intensive inhibition of driver oncoproteins and VEGF. These results highlight the potential of afatinib, cetuximab, and bevacizumab to induce deep remission in tumors harboring EGFRT790M mutations. Therefore, clinical trials of this combination therapy are warranted.

DOI： 10.1002/1878-0261.12063

ガイドシース併用気管支腔内超音波断層法の肺癌診断への導入効果

南大輔, 瀧川奈義夫, 二宮貴一朗, 小田尚廣, 豊田容輔, 槙本剛, 肥後寿夫, 久保寿夫, 大橋圭明, 佐藤晃子, 堀田勝幸, 宮原信明, 金廣有彦, 田端雅弘, 谷本光音, 木浦勝行

肺癌 54 ( 5 ) 534 - 534 2014.10

Diffuse parenchymal pulmonary amyloidosis showing an objective response to bortezomib-based chemotherapy.

Hisao Higo, Keiichi Fujiwara, Hiromi Watanabe, Go Makimoto, Nobuhisa Kameyama, Mizuho Matsushita, Kammei Rai, Ken Sato, Tomoko Inomata, Kazutaka Sunami, Takuo Shibayama

Internal medicine (Tokyo, Japan) 53 ( 16 ) 1809 - 12 2014

Language：English Publishing type：Research paper (scientific journal)

A 77-year-old woman was admitted because of bilateral hand numbness and dyspnea on exertion. Her serum IgG was increased, and a bone marrow aspiration analysis supported a diagnosis of multiple myeloma. Additionally, computed tomography scans of the chest showed bilateral ground glass attenuations, linear opacities, and consolidations. Transbronchial lung biopsy revealed Congo Red-positive amorphous eosinophilic deposits. She was therefore diagnosed with diffuse parenchymal pulmonary amyloidosis accompanied by multiple myeloma. Following combination chemotherapy including bortezomib, her serum monoclonal protein levels were normalized, and pulmonary function and oxygenation improved.

脊髄横断症状にて発症した原発性肺癌症例の検討

時政雄平, 松尾潔, 槇本剛, 肥後寿夫, 亀山伸久, 松下瑞穂, 佐藤賢, 藤原慶一, 米井敏郎, 佐藤利雄

日本呼吸器学会誌 2 ( 4 ) 321 - 326 2013.7

高周波スネアにて切除した気管原発MALTリンパ腫の1例

太田徹, 松尾潔, 槇本剛, 肥後寿夫, 時政雄平, 亀山伸久, 萱谷紘枝, 松下瑞穂, 佐藤賢, 藤原慶一, 米井敏郎, 佐藤利雄

呼吸と循環 61 ( 4 ) 379 - 382 2013.4

A case of tracheal mucosa-associated lymphoid tissue lymphoma successfully treated using a high-frequency electrosurgical snare

Toru Ota, Kiyoshi Matsuo, Gou Makimoto, Hisao Higo, Yuhei Tokimasa, Nobuhisa Kameyama, Hiroe Kayatani, Mizuho Matsushita, Ken Sato, Keiichi Fujiwara, Toshiro Yonei, Toshio Sato

Respiration and Circulation 61 ( 4 ) 379 - 382 2013.4

胸腺カルチノイド5例の臨床的検討

肥後寿夫, 松尾潔, 槇本剛, 亀山伸久, 時政雄平, 佐藤賢, 藤原慶一, 米井敏郎, 佐藤利雄

肺癌 52 ( 5 ) 781 - 781 2012.10

当院における進行非小細胞肺癌に対するBevacizumabの使用経験

亀山伸久, 藤原慶一, 槇本剛, 時政雄平, 肥後寿夫, 松下瑞穂, 佐藤賢, 米井敏郎, 佐藤利雄

肺癌 52 ( 5 ) 553 - 553 2012.10

当院で治療された胸腺癌11症例の臨床的検討

肥後寿夫, 藤原慶一, 槇本剛, 時政雄平, 亀山伸久, 萱谷紘枝, 松下瑞穂, 佐藤賢, 米井敏郎, 安藤陽夫, 佐藤利雄

日本癌治療学会誌 47 ( 3 ) 2130 - 2130 2012.10

21.気管支内腔に小隆起性病変を多数呈したサルコイドーシスの1例(第19回日本呼吸器内視鏡学会中国四国支部会)

萱谷紘枝, 時政雄平, 肥後寿夫, 工藤健一郎, 藤原慶一, 松尾潔, 米井敏郎, 佐藤利雄

気管支学 33 ( 3 ) 199 - 199 2011

14.高周波スネアにて切除した気管原発悪性リンパ腫の1例(第19回日本呼吸器内視鏡学会中国四国支部会)

太田徹, 松尾潔, 肥後寿夫, 時政雄平, 萱谷紘枝, 工藤健一郎, 藤原慶一, 米井敏郎, 佐藤利雄

気管支学 33 ( 3 ) 198 - 198 2011

　 PREV - NEXT 　

1