128 results on '"Akaike, K"'
Search Results
2. The Association of Silica Deposition in the Lung With Acute Respiratory Failure After Lung Surgery
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Hamada, S., primary, Fujino, K., additional, Akaike, K., additional, Okabayashi, H., additional, Masunaga, A., additional, Tomita, Y., additional, Ichiyasu, H., additional, Suzuki, M., additional, and Sakagami, T., additional
- Published
- 2023
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3. Acute coronary syndrome as a possible immune-related adverse event in a lung cancer patient achieving a complete response to anti-PD-1 immune checkpoint antibody
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Tomita, Y, Sueta, D, Kakiuchi, Y, Saeki, S, Saruwatari, K, Sakata, S, Jodai, T, Migiyama, Y, Akaike, K, Hirosako, S, Fujisue, K, Yamamura, S, Miyazaki, S, Takashio, S, Izumiya, Y, Nakamura, K, Tsujita, K, Ichiyasu, H, and Fujii, K
- Published
- 2017
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4. Colchicine protects against cartilage degeneration by inhibiting MMP13 expression via PLC-γ1 phosphorylation
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Takeuchi, K., primary, Ogawa, H., additional, Kuramitsu, N., additional, Akaike, K., additional, Goto, A., additional, Aoki, H., additional, Lassar, A., additional, Suehara, Y., additional, Hara, A., additional, Matsumoto, K., additional, and Akiyama, H., additional
- Published
- 2021
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5. Poster: Polar Dielectrics, Optics, and Ionics
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Jin Kim, Yu, primary, Hyuk Park, Min, additional, Joon Kim, Han, additional, Seok Jeong, Doo, additional, Jiang, Anquan, additional, Seong Hwang, Cheol, additional, Schmelzer, Sebastian, additional, Böttger, Ulrich, additional, Waser, Rainer, additional, Liu, X., additional, Lu, H., additional, Burton, J. D., additional, Wang, Y., additional, Bark, C. W., additional, Zhang, Y., additional, Kim, D. J., additional, Stamm, A., additional, Lukashev, P., additional, Felker, D. A., additional, Folkman, C. M., additional, Gao, P., additional, Rzchowski, M. S., additional, Pan, X. Q., additional, Eom, C. B., additional, Gruverman, A., additional, Tsymbal, E. Y., additional, Politova, E. D., additional, Kaleva, G. M., additional, Mosunov, A. V., additional, Sadovskaya, N. V., additional, Segalla, A. G., additional, Mandal, Dipankar, additional, Henkel, Karsten, additional, Das, Suken, additional, Schmeißer, Dieter, additional, Abdel Halim, K. S., additional, Khedr, M. H., additional, Farghali, A. A., additional, Nasr, M. I., additional, Soliman, N. K., additional, Onbasli, Mehmet, additional, Goto, T., additional, Kim, D. H., additional, Bi, L., additional, Dionne, G. F., additional, Ross, C. A., additional, Schneller, Theodor, additional, Goodwin, Simon, additional, Di Quarto, Francesco, additional, Di Franco, Francesco, additional, Santamaria, Monica, additional, Yuan, Hongtao, additional, Ishida, Y., additional, Koizumi, K., additional, Shimotani, H., additional, Kanai, K., additional, Akaike, K., additional, Kubozono, Y., additional, Tsukazaki, A., additional, Kawasaki, M., additional, Shin, S., additional, Iwasa, Y., additional, De Souza, Roger A., additional, Metlenko, Veronika, additional, Schraknepper, Henning, additional, Ramadan, Amr, additional, Grope, B. O. H., additional, Grieshammer, S., additional, Koettgen, J., additional, Martin, M., additional, Shibuya, Taizo, additional, Yasuoka, Kenji, additional, Mirbt, Susanne, additional, Sanyal, Biplab, additional, Aoki, Yoshitaka, additional, Martin, Manfred, additional, Merkle, R., additional, Shirpour, M., additional, Rahmati, B., additional, Sigle, W., additional, van Aken, P. A., additional, Maier, J., additional, Sobolev, N. A., additional, Azevedo, A. M., additional, Bazarov, V. V., additional, Zhiteytsev, E. R., additional, Khaibullin, R. I., additional, Griesche, David, additional, Otsuka, Yusuke, additional, Pithan, Christian, additional, Dornseiffer, Jürgen, additional, Lustfeld, H., additional, Pithan, C., additional, and Reißel, M., additional
- Published
- 2013
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6. 74P Comprehensive transcriptome analysis of endoplasmic reticulum stress in osteosarcomas
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Suehara, Y., primary, Kurihara, T., additional, Hayashi, T., additional, Sano, K., additional, Sasa, K., additional, Kubota, D., additional, Akaike, K., additional, Okubo, T., additional, Kim, Y., additional, and Saito, T., additional
- Published
- 2020
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7. Prognostic Impact of Pre-Existing Interstitial Lung Disease in Non-HIV Patients with Pneumocystis Pneumonia
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Hamada, S., primary, Ichiyasu, H., additional, Inaba, M., additional, Takahashi, H., additional, Sadamatsu, T., additional, Akaike, K., additional, Masunaga, A., additional, Tashiro, Y., additional, Hirata, N., additional, Yoshinaga, T., additional, and Sakagami, T., additional
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- 2020
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8. Hereditary Low Oxygen Saturation Disease Caused by a Hemoglobin Variant: Hb Iwata
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Tajima, Y., primary, Iyama, S., additional, Naito, D., additional, Akaike, K., additional, Horio, Y., additional, Masunaga, A., additional, Tomita, Y., additional, Saeki, S., additional, Ichiyasu, H., additional, and Sakagami, T., additional
- Published
- 2020
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9. Disorder of Coagulation-Fibrinolysis System: An Emerging Toxicity of Anti-PD-1/PD-L1 Monoclonal Antibodies
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Imamura, K., primary, Sato, R., additional, Sakata, S., additional, Ikeda, T., additional, Horio, Y., additional, Iyama, S., additional, Akaike, K., additional, Hamada, S., additional, Jodai, T., additional, Nakashima, K., additional, Ishizuka, S., additional, Sato, N., additional, Saruwatari, K., additional, Saeki, S., additional, Tomita, Y., additional, Ichiyasu, H., additional, and Sakagami, T., additional
- Published
- 2020
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10. Comparative analysis of protein profiles of prognosis-associated proteins and KIT-related proteins in gastrointestinal stromal tumour
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Suehara, Y., primary, Sasa, K., additional, Okubo, T., additional, Hayashi, T., additional, Sano, K., additional, Kurihara, T., additional, Akaike, K., additional, Ishii, M., additional, Kim, Y., additional, Kaneko, K., additional, and Saito, T., additional
- Published
- 2019
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11. Studies of ion leakage from a Penning trap induced by potential barrier closure
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Akaike, K., primary and Himura, H., additional
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- 2018
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12. Comprehensive mRNA-based screen for tyrosine kinase fusions and a de novo alternative transcription initiation site in soft tissue sarcomas
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Suehara, Y., primary, Kohsaka, S., additional, Kurisaki, A., additional, Akaike, K., additional, Hayashi, T., additional, Mogushi, K., additional, Okubo, T., additional, Kim, Y., additional, Sato, S., additional, Kobayashi, E., additional, Kaneko, K., additional, Mano, H., additional, and Saito, T., additional
- Published
- 2018
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13. P3.15-009 Impact of Interstitial Lung Disease on Clinical Outcomes in Small Cell Lung Cancer Patients
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Akaike, K., primary, Saruwatari, K., additional, Sakamoto, Y., additional, Jodai, T., additional, Sakata, S., additional, Iyama, S., additional, Sato, R., additional, Iriki, T., additional, Tomita, Y., additional, Saeki, S., additional, Ichiyasu, H., additional, and Fujii, K., additional
- Published
- 2017
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14. Anti-tumor activity of tyrosine kinase inhibitors in alveolar soft part sarcoma
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Suehara, Y., primary, Tanabe, Y., additional, Akaike, K., additional, Mogushi, K., additional, Hayashi, T., additional, Kurihara, T., additional, Kaneko, K., additional, and Saito, T., additional
- Published
- 2017
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15. 411P - Comparative analysis of protein profiles of prognosis-associated proteins and KIT-related proteins in gastrointestinal stromal tumour
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Suehara, Y., Sasa, K., Okubo, T., Hayashi, T., Sano, K., Kurihara, T., Akaike, K., Ishii, M., Kim, Y., Kaneko, K., and Saito, T.
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- 2019
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16. Intermittent ion leakage from a Penning trap during potential barrier closure
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Himura, H., primary, Kawai, S., additional, Akaike, K., additional, Okada, S., additional, Aoki, J., additional, and Masamune, S., additional
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- 2017
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17. 412P - Comprehensive mRNA-based screen for tyrosine kinase fusions and a de novo alternative transcription initiation site in soft tissue sarcomas
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Suehara, Y., Kohsaka, S., Kurisaki, A., Akaike, K., Hayashi, T., Mogushi, K., Okubo, T., Kim, Y., Sato, S., Kobayashi, E., Kaneko, K., Mano, H., and Saito, T.
- Published
- 2018
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18. 360O Clinicopathological and functional analyses of protein phosphatase 2, regulatory subunit A, alpha mutations in gastrointestinal stromal tumors
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Suehara, Y., primary, Ishii, M., additional, Akaike, K., additional, Mukaihara, K., additional, Kubota, D., additional, Okubo, T., additional, Yao, T., additional, Kaneko, K., additional, and Saito, T., additional
- Published
- 2015
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19. 493P - Anti-tumor activity of tyrosine kinase inhibitors in alveolar soft part sarcoma
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Suehara, Y., Tanabe, Y., Akaike, K., Mogushi, K., Hayashi, T., Kurihara, T., Kaneko, K., and Saito, T.
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- 2017
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20. Fermi level pinning induced electrostatic fields and band bending at organic heterojunctions
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Akaike, K., primary, Koch, N., additional, and Oehzelt, M., additional
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- 2014
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21. Electronic circuit system of high sensitivity mass detection for QCM-biosensor.
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Koyama, M., Akaike, K., Aizawa, H., and Kurosawa, S.
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- 2004
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22. A device for stereotactic transection of fiber bundles in rats
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Imamura, S. i., Tanaka, S., Akaike, K., Tojo, H., Takigawa, M., and Kuratsu, J. i.
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- 2001
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23. Kainic acid-induced dorsal and ventral hippocampal seizures in rats
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Akaike, K., Tanaka, S., Tojo, H., Fukumoto, S. i., Imamura, S. i., and Takigawa, M.
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- 2001
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24. Hippocampal transection attenuates kainic acid-induced amygdalar seizures in rats
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Imamura, S. i., Tanaka, S., Akaike, K., Tojo, H., Takigawa, M., and Kuratsu, J. i.
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- 2001
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25. Farewell Address to Prof. Matsumoto
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Akaike, K, Ishizuka, S, アカイケ, カズマサ, and イシヅカ, シンイチ
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- 2014
26. Negative-predictive value of SUVmax for Ascertaining the efficacy of osimertinib in EGFR mutation-positive non-small cell lung cancer.
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Anai M, Inoue H, Saruwatari K, Oda S, Shiraishi S, Akaike K, Imamura K, Jodai T, Sakata S, Iyama S, Tomita Y, Ichiyasu H, and Sakagami T
- Abstract
Background: Fluorine-
18 2-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography (18 F-FDG PET/CT) is routinely used to stage non-small cell lung cancer (NSCLC). However, whether18 F-FDG accumulation in primary tumors affects the efficacy of osimertinib in patients with epidermal growth factor receptor (EGFR) mutation-positive NSCLC remains unclear., Methods: We retrospectively investigated 74 patients with advanced or postoperative recurrent EGFR mutation-positive NSCLC who underwent18 F-FDG PET/CT and were treated with osimertinib as first-line therapy between September 2018 and March 2023 at Kumamoto University Hospital. The maximum standardized uptake value (SUVmax) of each primary tumor was measured, and the patients were divided into two groups according to the median SUVmax. The effects of SUVmax on progression-free survival (PFS) and overall survival (OS) were assessed using a multivariate Cox proportional hazards model., Results: The median SUVmax was 8.2 (interquartile range: 5.5-11.4). The median PFS in the high SUVmax group (≥8.2) was significantly shorter than that in the low SUVmax group (<8.2). The respective median PFSs were 11.2 months (95% confidence interval [CI]: 3.1-19.3 months) vs. 22.9 months (95% CI: 12.4-33.4 months) (P = 0.015), although the OS values did not differ significantly. Multivariate analysis showed that a high SUVmax was an independent negative predictive factor for PFS in patients treated with osimertinib (hazard ratio, 2.25; 95% CI: 1.15-4.39, P = 0.017)., Conclusions: High primary-lesion SUVmax in patients with EGFR mutation-positive NSCLC correlated with shorter PFS with first-line osimertinib therapy, suggesting that SUVmax is a useful predictive marker for the antitumor efficacy of osimertinib., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)- Published
- 2024
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27. A case of gallbladder neuroendocrine carcinoma complicated by ectopic adrenocorticotropic hormone syndrome and resulting in rapid fetal outcomes due to sepsis.
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Sato K, Suzuki T, Akaike K, Uchihara D, Ichii O, Tai M, Takagi T, Hakozaki H, and Ejiri Y
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- Humans, Female, Middle Aged, Fatal Outcome, Sepsis complications, Sepsis etiology, Disseminated Intravascular Coagulation etiology, Liver Neoplasms secondary, Liver Neoplasms complications, Shock, Septic etiology, Respiratory Distress Syndrome etiology, Gallbladder Neoplasms complications, Carcinoma, Neuroendocrine complications, Carcinoma, Neuroendocrine secondary, ACTH Syndrome, Ectopic etiology, ACTH Syndrome, Ectopic diagnosis
- Abstract
A 52-year-old woman presented to our hospital with chief complaints of upper abdominal bloating and lower leg edema. Computed tomography (CT) revealed liver metastasis from a gallbladder tumor. This tumor was diagnosed as neuroendocrine carcinoma (NEC) on performing a biopsy. Physical examination revealed a moon face. Blood tests revealed hypokalemia and high levels of adrenocorticotropic hormone (ACTH) and cortisol. Dexamethasone suppression test revealed that cortisol secretion was not suppressed, and the patient was diagnosed with gallbladder NEC and ectopic ACTH syndrome (EAS). Metyrapone was administered to suppress cortisol production; however, she developed septic shock due to cellulitis in the lower leg and died on the 16th day of admission. A pathological autopsy was performed, which revealed disseminated intravascular coagulation and acute respiratory distress syndrome as the cause of death. Only a few cases of EAS due to NEC originating from the gallbladder have been reported. The patient reported here succumbed shortly after diagnosis, thereby highlighting the challenges in treating gallbladder NEC complicated by EAS., (© 2024. Japanese Society of Gastroenterology.)
- Published
- 2024
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28. 18 F-FDG accumulation at the early onset of acute exacerbation of idiopathic interstitial pneumonia on 18 F-FDG PET/CT: A case report.
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Akaike K, Saruwatari K, Sakata S, Oda S, Shiraishi S, Iyama S, Masunaga A, Tomita Y, Ichiyasu H, and Sakagami T
- Abstract
Acute exacerbation of idiopathic interstitial pneumonias (AE-IIPs) is a disease associated with a poor prognosis in patients with IIPs. However, the specific characteristics of fluorine-18 2-fluoro-2-deoxy-d-glucose (
18 F-FDG) positron emission tomography/computed tomography (PET/CT) imaging for AE-IIPs remain unclear. Herein, we present the case of a patient with lung cancer combined with IIPs who underwent18 F-FDG PET/CT at the early onset of AE-IIPs. The scan, conducted 18 days post-bronchoscopy for lung cancer evaluation, revealed AE-IIPs before the onset of respiratory failure. New ground-glass opacities appeared, accompanied by significant18 F-FDG accumulation extending beyond these regions. To the best of our knowledge, this report represents the first assessment of18 F-FDG PET/CT images at the early onset of AE-IIPs before respiratory failure in humans. The observed features in this PET image could potentially contribute to our understanding of the pathophysiology of AE-IIPs., Competing Interests: None declared., (© 2024 The Author(s). Respirology Case Reports published by John Wiley & Sons Australia, Ltd on behalf of The Asian Pacific Society of Respirology.)- Published
- 2024
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29. Comparison of nintedanib-induced gastrointestinal adverse events between patients with systemic sclerosis-associated interstitial lung disease and idiopathic interstitial pneumonias.
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Imai M, Okabayashi H, Akaike K, Hamada S, Masunaga A, Ichiyasu H, and Sakagami T
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- Humans, Retrospective Studies, Diarrhea chemically induced, Nausea chemically induced, Nausea epidemiology, Lung Diseases, Interstitial etiology, Lung Diseases, Interstitial complications, Idiopathic Interstitial Pneumonias complications, Scleroderma, Systemic complications, Scleroderma, Systemic drug therapy, Indoles
- Abstract
Background: Gastrointestinal symptoms, such as diarrhea and nausea, are common adverse events associated with nintedanib. Systemic sclerosis is associated with a high prevalence of gastrointestinal symptoms that may increase with nintedanib administration. In clinical practice, we aimed to determine whether patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) experience more adverse gastrointestinal events associated with nintedanib than patients with idiopathic interstitial pneumonias (IIPs)., Methods: We retrospectively examined the clinical records of patients with SSc-ILD and IIPs newly treated with nintedanib at Kumamoto University Hospital between January 2020 and September 2022 and compared adverse events., Results: In total, 27 patients with SSc-ILD and 34 with IIPs were enrolled. No significant differences were observed in the duration of nintedanib treatment. The most frequent adverse event in both groups was diarrhea, which was more frequent in the SSc-ILD group (81.5 % vs. 61.8 %, p = 0.157). Nausea was significantly more frequent in the SSc-ILD group than in the IIPs group (37.0 % vs. 11.8 %, p = 0.031). The permanent discontinuation rate of nintedanib during the study period between the two groups was not different (40.7 % vs. 32.4 %, p = 0.595). However, the most common reasons for discontinuation varied. The most frequent reason in the SSc-ILD group was nausea, due to the progression of ILD in the IIPs group., Conclusions: Patients with SSc-ILD experienced significantly more nintedanib-induced nausea than those with IIPs. Gastrointestinal adverse events are often the reason for discontinuation of nintedanib in the SSc-ILD group, which requires better management of gastrointestinal symptoms., Competing Interests: Declaration of competing interest The authors have no conflicts of interest., (Copyright © 2024 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)
- Published
- 2024
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30. The impact of factor Xa inhibitors on bleeding risk in patients with respiratory diseases.
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Hamada S, Muramoto K, Akaike K, Okabayashi H, Masunaga A, Tomita Y, Ichiyasu H, and Sakagami T
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- Humans, Anticoagulants adverse effects, Retrospective Studies, Rivaroxaban adverse effects, Atrial Fibrillation complications, Atrial Fibrillation drug therapy, Factor Xa Inhibitors adverse effects, Hemorrhage chemically induced, Hemorrhage complications, Respiration Disorders complications, Respiration Disorders drug therapy, Respiratory Tract Diseases complications
- Abstract
It is unclear which factor Xa (FXa) inhibitors are associated with higher bleeding risk in patients with respiratory diseases, and there are no studies on the association between prothrombin time-international normalized ratio (PT-INR) and bleeding risk. We conducted a retrospective cohort study comparing 1-year-outcomes and PT-INR between patients with respiratory diseases treated with rivaroxaban (R group, n = 82) or edoxaban (E group, n = 138) for atrial fibrillation or venous thromboembolism from 2013 to 2021. The most frequent event of all bleeding discontinuations was respiratory bleeding in both groups (7.3 and 4.3%, respectively). The cumulative incidence of bleeding discontinuation was significantly higher in the R group (25.6%) than in the E group (14.4%) (hazard ratio [HR], 2.29; 95% confidence interval [CI] 1.13-4.64; P = 0.023). PT-INR after initiation of therapy significantly increased and was higher in the R group than in the E group (median value, 1.4 and 1.2, respectively; P < 0.001). Multivariate analysis using Cox proportional hazards and Fine-Gray models revealed that PT-INR after initiation of therapy was an independent risk factor of bleeding discontinuation events (HR = 4.37, 95% CI 2.57-7.41: P < 0.001). Respiratory bleeding occasionally occurs in patients receiving FXa inhibitors, and monitoring the PT-INR may need to ensure safety., (© 2024. The Author(s).)
- Published
- 2024
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31. NTRK2 expression in gastrointestinal stromal tumors with a special emphasis on the clinicopathological and prognostic impacts.
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Sasa K, Son R, Oguchi A, Ashizawa K, Hasegawa N, Kubota D, Suehara Y, Takagi T, Okubo T, Akaike K, Sugimoto K, Takahashi M, Sakamoto K, Hashimoto T, Mine S, Fukunaga T, Ishijima M, Hayashi T, Yao T, Murakawa Y, and Saito T
- Subjects
- Humans, Prognosis, Receptor Protein-Tyrosine Kinases, Proto-Oncogenes, Proto-Oncogene Proteins c-kit, Gastrointestinal Stromal Tumors genetics
- Abstract
Gastrointestinal stromal tumors (GISTs) are typically characterized by activating mutations of the KIT proto-oncogene receptor tyrosine kinase (KIT) or platelet-derived growth factor receptor alpha (PDGFRA). Recently, the neurotrophic tyrosine receptor kinase (NTRK) fusion was reported in a small subset of wild-type GIST. We examined trk IHC and NTRK gene expressions in GIST. Pan-trk immunohistochemistry (IHC) was positive in 25 (all 16 duodenal and 9 out of 16 small intestinal GISTs) of 139 cases, and all pan-trk positive cases showed diffuse and strong expression of c-kit. Interestingly, all of these cases showed only trkB but not trkA/trkC expression. Cap analysis of gene expression (CAGE) analysis identified increased number of genes whose promoters were activated in pan-trk/trkB positive GISTs. Imbalanced expression of NTRK2, which suggests the presence of NTRK2 fusion, was not observed in any of trkB positive GISTs, despite higher mRNA expression. TrkB expression was found in duodenal GISTs and more than half of small intestinal GISTs, and this subset of cases showed poor prognosis. However, there was not clear difference in clinical outcomes according to the trkB expression status in small intestinal GISTs. These findings may provide a possible hypothesis for trkB overexpression contributing to the tumorigenesis and aggressive clinical outcome in GISTs of duodenal origin., (© 2024. The Author(s).)
- Published
- 2024
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32. Association of Clostridium butyricum Therapy Using the Live Bacterial Product CBM588 with the Survival of Patients with Lung Cancer Receiving Chemoimmunotherapy Combinations.
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Tomita Y, Sakata S, Imamura K, Iyama S, Jodai T, Saruwatari K, Hamada S, Akaike K, Anai M, Fukusima K, Takaki A, Tsukamoto H, Goto Y, Motozono C, Sugata K, Satou Y, Ueno T, Ikeda T, and Sakagami T
- Abstract
The gut microbiota has emerged as a key regulator of immune checkpoint inhibitor (ICI) efficacy. Therapeutic approaches aimed at manipulating the microbiota through targeted reconstitution to enhance cancer treatment outcomes have garnered considerable attention. A single live microbial biotherapeutic bacterium, Clostridium butyricum MIYAIRI 588 strain (CBM588), has been shown to enhance the effects of ICI monotherapy in patients with advanced lung cancer. However, whether CBM588 affects the outcomes of chemoimmunotherapy combinations in lung cancer remains unknown. We hypothesized that CBM588 augments the effect of chemoimmunotherapy combinations and restores diminished effectiveness in patients with non-small cell lung cancer (NSCLC) receiving dysbiosis-inducing drugs. To validate this hypothesis, we retrospectively analyzed 106 patients with stage IV or recurrent metastatic NSCLC consecutively treated with chemoimmunotherapy combinations. A survival analysis was performed employing univariate and multivariate Cox proportional hazard models with inverse probability of treatment weighting (IPTW) using propensity scores. Forty-five percent of patients received Clostridium butyricum therapy. CBM588 significantly extended overall survival in patients with NSCLC receiving chemoimmunotherapy. The favorable impact of CBM588 on the efficacy of chemoimmunotherapy combinations varied based on tumor-programmed cell death ligand 1 (PD-L1) expression. The survival benefit of CBM588 in the PD-L1 <1% cohort was higher than that in the PD-L1 1-49% and PD-L1 ≥ 50% cohorts. Furthermore, CBM588 was associated with improved overall survival in patients receiving proton pump inhibitors and/or antibiotics. CBM588-induced manipulation of the commensal microbiota holds the potential to enhance the efficacy of chemoimmunotherapy combinations, warranting further exploration of the synergy between CBM588 and immunotherapy.
- Published
- 2023
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33. Spontaneous orientation polarization of flavonoids.
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Akaike K, Hosokai T, Ono Y, Tsuruta R, and Yamada Y
- Abstract
Spontaneous orientation polarization (SOP) is macroscopic electric polarization that is attributed to a constant orientational degree of dipole moments of polar molecules on average. The phenomenon has been found in small molecules like H
2 O at low temperatures and π-conjugated molecules employed in organic light-emitting diodes. In this study, we demonstrate that a thin film of baicalein, a flavonoid compound found in natural products, exhibits SOP and resultant giant surface potential (GSP) exceeding 5500 mV at a film thickness of 100 nm. Vacuum-deposition of baicalein under high vacuum results in smooth and amorphous films, which enables the generation of GSP with a slope of 57 mV/nm in air, a value comparable to the representative of an organic semiconductor showing GSP, tris(8-hydroxyquinoline)aluminum(III) (Alq3 ). We also found the superior photostability of a baicalein film compared to an Alq3 film. These findings highlight the potential of baicalein in new applications to organic electronics., (© 2023. The Author(s).)- Published
- 2023
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34. Interstitial Lung Disease in Adulthood Associated with Surfactant Protein C Gene Mutation in a Patient with a History of Lipoid Pneumonia in Infancy.
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Furukawa T, Akaike K, Iyama S, Masunaga A, Tomita Y, Saeki S, Ichiyasu H, and Sakagami T
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- Humans, Infant, Mutation, Protein C genetics, Pulmonary Surfactant-Associated Protein C genetics, Surface-Active Agents, Lung Diseases, Interstitial diagnostic imaging, Lung Diseases, Interstitial genetics, Pneumonia, Lipid, Pulmonary Fibrosis
- Abstract
Mutations in the surfactant protein C gene (SFTPC) are responsible for hereditary interstitial lung disease (ILD), which is a rare disease. We herein report a patient with a clinical history of endogenous lipoid pneumonia in infancy who developed diffuse progressive pulmonary fibrosis in adulthood associated with SFTPC mutations. A surgical lung biopsy and genetic sequencing revealed fibrotic interstitial pneumonia and two SFTPC mutations (c.215G>A and c.578C>A). Based on these findings, we diagnosed the series of lung diseases as sporadic ILD caused by SFTPC mutations. Physicians should suggest genetic sequencing in patients with early-onset ILD.
- Published
- 2023
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35. Disentangling Origins of Adhesive Bonding at Interfaces between Epoxy/Amine Adhesive and Aluminum.
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Akaike K, Shimoi Y, Miura T, Morita H, Akiyama H, and Horiuchi S
- Abstract
Joining metals by adhesive bonding is essential in widespread fields such as mobility, dentistry, and electronics. Although adhesive technology has grown since the 1920s, the roles of interfacial phenomena in adhesive bonding are still elusive, which hampers the on-demand selection of surface treatment and adhesive types. In the present study, we clarified how chemical interactions and mechanical interlocking governed adhesive bonding by evaluating adhesion properties at the interfaces between epoxy/amine adhesive and two kinds of Al adherends: a flat aluminum hydroxide (Al
x Oy Hz ) and technical Al plate with roughness. Spectroscopic and microscopical data demonstrate that the protonation of the amino groups in an amine hardener converts Al(OH)3 on the Alx Oy Hz surface to AlO(OH). The interfacial protonation results in an interfacial dipole layer with positive charges on the adhesive side, whose electrostatic interaction increases the interfacial fracture energy. The double cantilever beam tests for the flat Alx Oy Hz and technical Al substrates clarify that the mechanical interlocking originating from the surface roughness further increases the fracture energy. This study disentangles the roles of the chemical interactions and mechanical interlocking occurring at the epoxy adhesive/Al interface in the adhesion mechanism.- Published
- 2023
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36. Oral formulation of bendamustine hydrochloride for patients with advanced solid tumors; a phase 1 study.
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Shimizu T, Nakagawa K, Hayashi H, Iwasa T, Kawakami H, Watanabe S, Yamamoto N, Yonemori K, Koyama T, Sato J, Tamura K, Kikuchi K, Akaike K, Takeda S, and Takeda M
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- Humans, Bendamustine Hydrochloride adverse effects, Maximum Tolerated Dose, Neoplasms drug therapy, Neoplasms pathology
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To determine the maximum tolerated dose (MTD) and recommended dose (RD) of orally-administered bendamustine in Japanese patients with advanced solid tumors. The optimal dosing schedule, safety, pharmacokinetics, and preliminary antitumor effects were also evaluated. A multicenter, open-label trial with a standard 3 + 3 design and dose escalation by dose-limiting toxicity (DLT) was conducted. The treatment schedules were once daily for 7, 14, and 21 days every 3 weeks as one cycle. The total dose per cycle was increased from 175 to 840 mg/m
2 . Eighteen patients were enrolled in this study. DLT occurred in one of six patients at 75 mg/m2 /day × 7 days, and one of three patients at 37.5 mg/m2 /day × 14 days and 25 mg/m2 /day × 21 days. However, the delayed recovery from a decrease in neutrophil or platelet count hampered the start of subsequent treatment cycles, and the trend was more prominent at 37.5 mg/m2 /day × 14 days and 25 mg/m2 /day × 21 days than in 75 mg/m2 /day × 7 days. MTD was determined as 75 mg/m2 /day × 7 days to allow acceptable hematologic recovery. The pharmacokinetics of orally-administered bendamustine were generally dose-dependent; however, the inter-individual variability is relatively large. The major adverse events were hematologic toxicities; gastrointestinal disorders were generally mild. Adverse drug reactions did not lead to the discontinuation of the drug. A partial response was observed in two of six patients (prostatic small cell carcinoma and thymic carcinoma) at 75 mg/m2 /day × 7 days. The RD and optimal dosing schedule of orally-administered bendamustine was 75 mg/m2 once daily for 7 days every 3 weeks for the treatment of advanced solid tumors. (Trial registration number ClinicalTrials.gov NCT03604679. Registration date July 27, 2018)., (© 2022. The Author(s).)- Published
- 2023
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37. Clinical Implications and Molecular Characterization of Drebrin-Positive, Tumor-Infiltrating Exhausted T Cells in Lung Cancer.
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Imamura K, Tomita Y, Sato R, Ikeda T, Iyama S, Jodai T, Takahashi M, Takaki A, Akaike K, Hamada S, Sakata S, Saruwatari K, Saeki S, Ikeda K, Suzuki M, and Sakagami T
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- Humans, CD8-Positive T-Lymphocytes metabolism, Neoplasm Recurrence, Local, Lung Neoplasms genetics, Neuropeptides metabolism, Carcinoma, Non-Small-Cell Lung genetics
- Abstract
T cells express an actin-binding protein, drebrin, which is recruited to the contact site between the T cells and antigen-presenting cells during the formation of immunological synapses. However, little is known about the clinical implications of drebrin-expressing, tumor-infiltrating lymphocytes (TILs). To address this issue, we evaluated 34 surgical specimens of pathological stage I-IIIA squamous cell lung cancer. The immune context of primary tumors was investigated using fluorescent multiplex immunohistochemistry. The high-speed scanning of whole-slide images was performed, and the tissue localization of TILs in the tumor cell nest and surrounding stroma was automatically profiled and quantified. Drebrin-expressing T cells were characterized using drebrin
+ T cells induced in vitro and publicly available single-cell RNA sequence (scRNA-seq) database. Survival analysis using the propensity scores revealed that a high infiltration of drebrin+ TILs within the tumor cell nest was independently associated with short relapse-free survival and overall survival. Drebrin+ T cells induced in vitro co-expressed multiple exhaustion-associated molecules. The scRNA-seq analyses confirmed that the exhausted tumor-infiltrating CD8+ T cells specifically expressed drebrin. Our study suggests that drebrin-expressing T cells present an exhausted phenotype and that tumor-infiltrating drebrin+ T cells affect clinical outcomes in patients with resectable squamous cell lung cancer.- Published
- 2022
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38. Clinical impact of SUV max of interstitial lesions in lung cancer patients with interstitial lung disease who underwent pulmonary resection.
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Akaike K, Saruwatari K, Matsushima R, Fujino K, Morinaga J, Oda S, Takahashi H, Shiraishi S, Okabayashi H, Hamada S, Tomita Y, Masunaga A, Saeki S, Ikeda K, Ichiyasu H, Suzuki M, and Sakagami T
- Abstract
Background: Acute exacerbation of interstitial lung disease often causes fatal respiratory deterioration in lung cancer patients with interstitial lung disease. Here, we examined whether the maximum standardized uptake value of a contralateral interstitial lesion was a predictive factor of acute exacerbation of interstitial lung disease within 30 days postoperatively in lung cancer patients with interstitial lung disease who underwent pulmonary resection., Methods: Overall, 117 consecutive lung cancer patients with interstitial lung disease who underwent pulmonary resection between August 2010 and April 2019 at the Kumamoto University Hospital were retrospectively analysed for the association between the maximum standardized uptake value of the contralateral interstitial lesions and interstitial lung disease parameters., Results: The median maximum standardized uptake value of contralateral interstitial lesions was 1.61, which was regarded as the cut-off point predictive of the incidence of acute exacerbation of interstitial lung disease. Eight patients developed postoperative acute exacerbation of interstitial lung disease. There was no significant association between the maximum standardized uptake value of the contralateral interstitial lesions and postoperative acute exacerbation of interstitial lung disease. The maximum standardized uptake value was weakly but significantly associated with lactate dehydrogenase levels (r=0.211, P=0.022), Krebs von den Lungen-6 (r=0.208, P=0.028), and % diffusing capacity for carbon monoxide (r=-0.290, P=0.002). Moreover, seven patients developed acute exacerbation of the interstitial lung disease during the clinical course after 30 postoperative days, and the incidence rate of acute exacerbation of interstitial lung disease was significantly higher in the high maximum standardized uptake value group (≥1.61) than in the low maximum standardised uptake value group (<1.61) (12.7% vs. 0%, P=0.002, Gray's test)., Conclusions: Maximum standardized uptake value was not a predictor of postoperative acute exacerbation of interstitial lung disease in lung cancer patients with interstitial lung disease after pulmonary resection, but could be a predictive tool of an association with interstitial lung disease severity and activity markers., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-604/coif). The authors have no conflicts of interest to declare., (2022 Journal of Thoracic Disease. All rights reserved.)
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- 2022
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39. Chemical reactions of graphitic carbon nitride films with glass surfaces and their impact on photocatalytic activity.
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Akaike K, Hosokai A, Nagashima H, Wei Q, and Hosokai T
- Abstract
Thin films of graphitic carbon nitride (g-CN), a visible-light-driven photocatalyst, have recently attracted interest for application in photoelectrochemical cells for water splitting and high-throughput photocatalysis. In typical syntheses, g-CN films are formed by heating the nitrogen-rich precursor and substrate to 500-600 °C. The heated substrate should affect the polycondensation of the precursor and thereby alter the properties of the g-CN film. In this paper, we demonstrate that soda-lime glass, such as commercial glass slides, modifies the chemical structure of g-CN. The terminal amino groups of g-CN are partially substituted with cyanamide and hydroxyl groups. The electron-withdrawing groups provide the energy offsets of the frontier orbitals between the modified and unmodified molecules, facilitating exciton dissociation. After alkali metals are removed, the modified g-CN film exhibits a faster photodegradation of methyl orange compared with a melon film. The simple protocol to activate a g-CN film without co-catalysts paves a new way to enhance photocatalytic activity via selections of substrates, including waste glass.
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- 2022
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40. Bicyclic-ring base doping induces n-type conduction in carbon nanotubes with outstanding thermal stability in air.
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Horike S, Wei Q, Akaike K, Kirihara K, Mukaida M, Koshiba Y, and Ishida K
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The preparation of air and thermally stable n-type carbon nanotubes is desirable for their further implementation in electronic and energy devices that rely on both p- and n-type material. Here, a series of guanidine and amidine bases with bicyclic-ring structures are used as n-doping reagents. Aided by their rigid alkyl functionality and stable conjugate acid structure, these organic superbases can easily reduce carbon nanotubes. n-Type nanotubes doped with guanidine bases show excellent thermal stability in air, lasting for more than 6 months at 100 °C. As an example of energy device, a thermoelectric p/n junction module is constructed with a power output of ca. 4.7 μW from a temperature difference of 40 °C., (© 2022. The Author(s).)
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- 2022
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41. Clostridium butyricum therapy restores the decreased efficacy of immune checkpoint blockade in lung cancer patients receiving proton pump inhibitors.
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Tomita Y, Goto Y, Sakata S, Imamura K, Minemura A, Oka K, Hayashi A, Jodai T, Akaike K, Anai M, Hamada S, Iyama S, Saruwatari K, Saeki S, Takahashi M, Ikeda T, and Sakagami T
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- Humans, Immune Checkpoint Inhibitors pharmacology, Immune Checkpoint Inhibitors therapeutic use, Neoplasm Recurrence, Local, Proton Pump Inhibitors adverse effects, Retrospective Studies, Carcinoma, Non-Small-Cell Lung drug therapy, Clostridium butyricum, Lung Neoplasms drug therapy
- Abstract
Oral microbiota is associated with human diseases including cancer. Emerging evidence suggests that proton pump inhibitors (PPIs), which allow the oral microbiome to translocate into the gut, negatively influence the efficacy of immune checkpoint blockade (ICB) in cancer patients. However, currently there is no effective treatment that restores the decreased efficacy. To address this issue, we retrospectively evaluated 118 advanced or recurrent non-small cell lung cancer (NSCLC) patients treated with ICB and analyzed 80 fecal samples of patients with lung cancer by 16S metagenomic sequencing. Clostridium butyricum therapy using C. butyricum MIYAIRI 588 (CBM588), a live biotherapeutic bacterial strain, was shown to improve the ICB efficacy in lung cancer. Thus, we investigated how CBM588 affects the efficacy of ICB and the gut microbiota of lung cancer patients undergoing PPI treatment. We found that PPI treatment significantly decreased the efficacy of ICB in NSCLC patients, however, CBM588 significantly restored the diminished efficacy of ICB and improved survival. In addition, CBM588 prolonged overall survival in patients receiving PPIs and antibiotics together. The fecal analysis revealed that PPI users had higher abundance of harmful oral-related pathobionts and lower abundance of beneficial gut bacteria for immunotherapy. In contrast, patients who received CBM588 had lesser relative abundance of potentially harmful oral-related bacteria in the gut. Our research suggests that manipulating commensal microbiota by CBM588 may improve the therapeutic efficacy of ICB in cancer patients receiving PPIs, highlighting the potential of oral-related microbiota in the gut as a new therapeutic target for cancer immunotherapy., Competing Interests: Takuro Sakagami received research funding from Miyarisan Pharmaceutical Co., Ltd. to his institution. Ayaka Minemura, Kentaro Oka, Atsushi Hayashi, and Motomichi Takahashi are employees of Miyarisan Pharmaceutical Co., Ltd. Yusuke Tomita received fundings from the JSPS KAKENHI (Grant Number 18K15928 and 22K08256). Shinya Sakata received funding from the JSPS KAKENHI (Grant Number 20K16449). The other authors have no conflicts of interest to declare., (© 2022 The Author(s). Published with license by Taylor & Francis Group, LLC.)
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- 2022
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42. Retraction Note to: IRE1α-XBP1 but not PERK inhibition exerts anti-tumor activity in osteosarcoma.
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Sasa K, Saito T, Kurihara T, Hasegawa N, Sano K, Kubota D, Akaike K, Okubo T, Hayashi T, Takagi T, Yao T, Ishijima M, and Suehara Y
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- 2022
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43. Establishment of Rapid and Accurate Screening System for Molecular Target Therapy of Osteosarcoma.
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Sasa K, Saito T, Kurihara T, Hasegawa N, Sano K, Kubota D, Akaike K, Okubo T, Hayashi T, Takagi T, Ishijima M, and Suehara Y
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- Humans, Retrospective Studies, DNA Copy Number Variations, Molecular Targeted Therapy
- Abstract
Introduction Comprehensive analyses using clinical sequences subcategorized osteosarcoma (OS) into several groups according to the activated signaling pathways. Mutually exclusive co-occurrences of gene amplification ( PDGFRA/KIT/KDR, VEGFA/CCND3, and MDM2/CDK4 ) have been identified in approximately 40% of OS, representing candidate subsets for clinical evaluation of additional therapeutic options. Thus, it would be desirable to evaluate the specific gene amplification before starting therapy in patients with OS. Materials and Methods This is a retrospective study. We examined 13 cases of clinical OS samples using NanoString-based copy number variation (CNV) analysis. Decalcification and chemotherapeutic effects on this analysis were also assessed. Results First, the accuracy of this system was validated by showing that amplification/deletion data obtained from this system using various types of cancer cell lines almost perfectly matched to that from the Cancer Cell Line Encyclopedia (CCLE). We identified potentially actionable alterations in CDK4/MDM2 amplification in 10% of samples and potential additional therapeutic targets ( PDGFRA/KIT/KDR and VEGFA/CCND3 ) in 20% of samples, which is consistent with the reported frequencies. Furthermore, this assay could identify these potential therapeutic targets regardless of the sample status (frozen vs formalin-fixed paraffin-embedded [FFPE] tissues). Conclusion We established a NanoString-based rapid and cost-effective method with a short turnaround time (TAT) to examine gene amplification status in OS. This CNV analysis using FFPE samples is recommended where the histological evaluation of viable tumor cells is possible, especially for tumors after chemotherapy with higher chemotherapeutic effects.
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- 2022
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44. IRE1α-XBP1 but not PERK inhibition exerts anti-tumor activity in osteosarcoma.
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Sasa K, Saito T, Kurihara T, Hasegawa N, Sano K, Kubota D, Akaike K, Okubo T, Hayashi T, Takagi T, Yao T, Ishijima M, and Suehara Y
- Abstract
Osteosarcoma (OS) is the most common primary malignant bone tumor. However, the therapeutic results of the advanced cases at the first visit were still extremely poor. Therefore, more effective therapeutic options based on molecular profiling of OS are needed. In this study, we investigated the functions of endoplasmic reticulum (ER) stress activities in OS and elucidated whether ER stress inhibitors could exert antitumor effects. The expression of 84 key genes associated with unfolded protein response (UPR) was assessed in four OS cells (143B, MG63, U2OS and KHOS) by RT2 Profiler PCR Arrays. Based on results, we performed both siRNA and inhibitor assays focusing on IRE1α-XBP1 and PERK pathways. All OS cell lines showed resistance to PERK inhibitors. Furthermore, ATF4 and EIF2A inhibition by siRNA did not affect the survival of OS cell lines. On the other hand, IRE1α-XBP1 inhibition by toyocamycin suppressed OS cell growth (IC50: < 0.075 μM) and cell viability was suppressed in all OS cell lines by silencing XBP1 expression. The expression of XBP1s and XBP1u in OS cell lines and OS surgical samples were confirmed using qPCR. In MG63 and U2OS, toyocamycin decreased the expression level of XBP1s induced by tunicamycin. On the other hand, in 143B and KHOS, stimulation by toyocamycin did not clearly change the expression level of XBP1s induced by tunicamycin. However, morphological apoptotic changes and caspase activation were observed in these two cell lines. Inhibition of the IRE1α-XBP1s pathway is expected to be a promising new target for OS., (© 2021. The Author(s).)
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- 2021
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45. Identification of a Novel MAN1A1-ROS1 Fusion Gene Through mRNA-based Screening for Tyrosine Kinase Gene Aberrations in a Patient with Leiomyosarcoma.
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Suehara Y, Kohsaka S, Hayashi T, Akaike K, Kurisaki-Arakawa A, Sato S, Kobayashi E, Mizuno S, Ueno T, Morii T, Okuma T, Kurihara T, Hasegawa N, Sano K, Sasa K, Okubo T, Kim Y, Mano H, and Saito T
- Subjects
- 3T3 Cells, Adult, Aged, Aged, 80 and over, Animals, Antineoplastic Agents pharmacology, Crizotinib pharmacology, Female, Gene Expression Profiling, Humans, Leiomyosarcoma drug therapy, Leiomyosarcoma enzymology, Leiomyosarcoma pathology, Male, Mice, Mice, Inbred BALB C, Mice, Nude, Middle Aged, Protein Kinase Inhibitors pharmacology, RNA, Messenger genetics, Reverse Transcriptase Polymerase Chain Reaction, Sequence Analysis, RNA, Soft Tissue Neoplasms drug therapy, Soft Tissue Neoplasms enzymology, Soft Tissue Neoplasms pathology, Tumor Burden, Biomarkers, Tumor genetics, Gene Fusion, Leiomyosarcoma genetics, Mannosidases genetics, Protein-Tyrosine Kinases genetics, Proto-Oncogene Proteins genetics, Soft Tissue Neoplasms genetics
- Abstract
Background: Soft tissue sarcomas are a heterogeneous group of rare malignant tumors. Advanced soft tissue sarcomas have a poor prognosis, and effective systemic therapies have not been established. Tyrosine kinases are increasingly being used as therapeutic targets for a variety of cancers and soft tissue sarcomas. Although complex karyotype sarcomas typically tend to carry more potentially actionable genetic alterations than do translocation-associated sarcomas (fusion gene sarcomas), based on our database review, we found that leiomyosarcoma and malignant peripheral nerve sheath tumors have lower frequencies of potential targets than other nontranslocation soft tissue sarcomas. We theorized that both leiomyosarcoma and malignant peripheral nerve sheath tumors might be included in any unique translocations. Furthermore, if tyrosine kinase imbalances, especially fusion genes, occur in patients with leiomyosarcomas and malignant peripheral nerve sheath tumors, tyrosine kinase inhibitors might be a drug development target for this sarcoma. In this study, we used a tyrosine kinase screening system that could detect an imbalance in mRNA between 5'- and 3'-sides in tyrosine kinase genes to identify potential novel therapeutic tyrosine kinase targets for soft tissue sarcomas., Questions/purposes: (1) Are there novel therapeutic tyrosine kinase targets in tumors from patients with soft tissue sarcomas that are detectable using mRNA screening focusing on imbalance expressions between the 5' and 3' end of the kinase domain? (2) Can potential targets be verified by RNA sequencing and reverse transcription PCR (RT-PCR)? (3) Will potential fusion gene(s) transform cells in in vitro assays? (4) Will tumors in mice that have an identified fusion gene respond to treatment with a therapeutic drug directed at that target?, Methods: We used mRNA screening to look for novel tyrosine kinase targets that might be of therapeutic potential. Using functional assays, we verified whether the identified fusion genes would be good therapeutic candidates for soft tissue sarcomas. Additionally, using in vivo assays, we assessed whether suppressing the fusion's kinase activity has therapeutic potential. Study eligibility was based on a patient having high-grade spindle cell and nontranslocation sarcomas, including leiomyosarcoma, malignant peripheral nerve sheath tumor, and high-grade myxofibrosarcoma. Between 2015 and 2019, of the 172 patients with soft tissue sarcomas treated with surgical resection at Juntendo University Hospital, 72 patients had high-grade nontranslocation sarcomas. The analysis was primarily for leiomyosarcoma and malignant peripheral nerve sheath tumors, and there was a limitation of analysis size (reagent limitations) totaling 24 samples at the start of the study. We collected additional samples from a sample bank at the Tokyo Medical and Dental University to increase the number of sarcomas to study. Therefore, in this study, a total of 15 leiomyosarcoma samples, five malignant peripheral nerve sheath tumors samples, and four high-grade myxofibrosarcoma samples were collected to achieve the sample size of 24 patients. To identify tyrosine kinase fusion genes, we designed a NanoString-based assay (NanoString Technologies Inc, Seattle, WA, USA) to query the expression balances regarding transcripts of 90 tyrosine kinases at two points: the 5' end of the kinase domain and within the kinase domain or 3' end of the kinase domain. The tumor's RNA was hybridized to the NanoString probes and analyzed for the expression ratios of outliers from the 3' to 5' end of the kinase domain. Presumed novel fusion events in these positive tumors that were defined by NanoString-based assays were confirmed tyrosine kinase fusion genes by RNA sequencing and confirmatory RT-PCR. Functional analyses consisting of in vitro and in vivo assays were also performed to elucidate whether the identified tyrosine kinase gene fusions were associated with oncogenic abilities and drug responses., Results: We identified aberrant expression ratios regarding the 3' to 5' end of the kinase domain ratios in ROS1 transcripts in a leiomyosarcoma in a 90-year-old woman. A novel MAN1A1-ROS1 fusion gene was identified from her thigh tumor through RNA sequencing, which was confirmed with real-time PCR. In functional assays, MAN1A1-ROS1 rearrangement revealed strong transforming potential in 3T3 cells. Moreover, in an in vivo assay, crizotinib, a ROS1 inhibitor, markedly inhibited the growth of MAN1A1-ROS1 rearrangement-induced transformed cells in a dose-dependent manner., Conclusion: We conducted tyrosine kinase screening to identify new therapeutic targets in soft tissue sarcomas. We found a novel MAN1A1-ROS1 fusion gene that may be a therapeutic target in patients with leiomyosarcoma. This study demonstrates that the mRNA screening system may aid in the development of useful therapeutic options for soft tissue sarcomas., Clinical Relevance: If novel tyrosine fusions such as MAN1A1-ROS1 fusion can be found in sarcomas from other patients, they could offer avenues for new molecular target therapies for sarcomas that currently do not have effective chemotherapeutic options. Therefore, the establishment of a screening system that includes both genomic and transcript analyses in the clinical setting is needed to verify our discoveries and take the developmental process of treatment to the next step., Competing Interests: All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request. Each author certifies that neither he nor she, nor any member of his or her immediate family, has funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article., (Copyright © 2020 by the Association of Bone and Joint Surgeons.)
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- 2021
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46. Decrease in hemoglobin level predicts increased risk for severe respiratory failure in COVID-19 patients with pneumonia.
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Anai M, Akaike K, Iwagoe H, Akasaka T, Higuchi T, Miyazaki A, Naito D, Tajima Y, Takahashi H, Komatsu T, Masunaga A, Kishi H, Fujii K, Fukuda K, Tomita Y, Saeki S, Ichiyasu H, and Sakagami T
- Subjects
- Adult, Aged, Aged, 80 and over, Biomarkers blood, COVID-19 therapy, COVID-19 virology, Female, Humans, Male, Middle Aged, Pneumonia, Viral therapy, Pneumonia, Viral virology, Predictive Value of Tests, Respiration, Artificial, Respiratory Insufficiency therapy, Retrospective Studies, Risk, Serum Albumin analysis, Severity of Illness Index, Time Factors, Young Adult, COVID-19 complications, Hemoglobins analysis, Pneumonia, Viral complications, Respiratory Insufficiency diagnosis, Respiratory Insufficiency etiology, SARS-CoV-2
- Abstract
Background: In December 2019, the coronavirus disease (COVID-19), caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), emerged in Wuhan, China, and has since spread throughout the world. This study aimed to investigate the association between the change in laboratory markers during the three days after pneumonia diagnosis and severe respiratory failure in COVID-19 patients., Methods: Data of 23 COVID-19 patients with pneumonia, admitted to the Kumamoto City Hospital between February and April 2020 were retrospectively analyzed., Results: Among the 23 patients, eight patients received mechanical ventilation (MV) (MV group), and the remaining 15 comprised the non-MV group. The levels of hemoglobin (Hb) and albumin (Alb) decreased in the MV group during the three days after pneumonia diagnosis more than in the non-MV group (median Hb: 1.40 vs. -0.10 g/dL, P = 0.015; median Alb: 0.85 vs. -0.30 g/dL, P = 0.020). Univariate logistic regression analysis showed that the decrease in Hb was associated with receiving MV care (odds ratio: 0.313, 95% confidence interval: 0.100-0.976, P = 0.045). Receiver operating characteristic curve analyses showed that the optimal cut-off value for the decrease in Hb level was -1.25 g/dL, with sensitivity and specificity values of 0.867 and 0.750, respectively., Conclusions: The decrease in Hb level during the short period after pneumonia diagnosis might be a predictor of worsening pneumonia in COVID-19 patients., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest., (Copyright © 2020 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)
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- 2021
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47. Validation of a breath-holding test as a screening test for exercise-induced hypoxemia in chronic respiratory diseases.
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Ideguchi H, Ichiyasu H, Fukushima K, Okabayashi H, Akaike K, Hamada S, Nakamura K, Hirosako S, Kohrogi H, Sakagami T, and Fujii K
- Subjects
- Dyspnea diagnosis, Dyspnea etiology, Humans, Hypoxia diagnosis, Hypoxia etiology, Oxygen, Pilot Projects, Walk Test, Exercise Test, Pulmonary Disease, Chronic Obstructive
- Abstract
The detection of exercise-induced hypoxemia is important for evaluating disease status in patients with chronic respiratory diseases. The 6-min walk test (6MWT) is useful for detecting exercise-induced hypoxemia. This pilot study aimed to validate the breath-holding test (BHT) as a screening for exercise-induced hypoxemia and compare its utility with that of the 6MWT in patients with chronic respiratory diseases. Fifty-nine patients with chronic respiratory diseases underwent BHTs lasting 10, 15, and 20 s. Percutaneous oxygen saturation (SpO
2 ), pulse rate, and severity of dyspnoea were measured. The participants also underwent a 6MWT, a pulmonary function test, and analysis of arterial blood gas at rest. Multivariate linear regression analysis was performed to identify significant predictors of desaturation in the 6MWT. The minimum SpO2 during the BHT (all durations) and 6MWT were significantly correlated. Receiver operating characteristic analysis revealed the optimal cut-off for predicting SpO2 < 90% during the 6MWT as a minimum SpO2 ≤ 94% during the 15-s BHT. Perceived dyspnoea and maximum pulse rate were significantly lower during the 15-s BHT than during the 6MWT. In the multivariate linear regression analysis, the minimum SpO2 during the 15-s BHT (β, 0.565, p < 0.001) and %DLco (β, 0.255, p < 0.028) were independent predictors of desaturation in the 6MWT. The minimum SpO2 during the 15-s BHT may be a useful measure for screening for exercise-induced hypoxemia in patients with chronic respiratory diseases. The BHT is easier to perform, more readily available, and better tolerated than the 6MWT.- Published
- 2021
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48. Assessment of Predictive Biomarkers of the Response to Pazopanib Based on an Integrative Analysis of High-grade Soft-tissue Sarcomas: Analysis of a Tumor Sample from a Responder and Patients with Other Soft-tissue Sarcomas.
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Suehara Y, Kohsaka S, Yamaguchi S, Hayashi T, Kurihara T, Sano K, Sasa K, Akaike K, Ueno T, Kojima S, Ikegami M, Mizuno S, Okubo T, Kim Y, Kaneko K, Saito T, Kato S, and Mano H
- Subjects
- Adult, Aged, Angiogenesis Inhibitors therapeutic use, Biomarkers metabolism, Female, Humans, Male, Middle Aged, Sarcoma genetics, Exome Sequencing, Indazoles therapeutic use, Pyrimidines therapeutic use, Sarcoma drug therapy, Sulfonamides therapeutic use
- Abstract
Background: Soft-tissue sarcomas are a rare group of malignant tumors that usually are treated with surgical excision and radiation therapy, but recently, pazopanib, an oral tyrosine kinase inhibitor, has been used in patients with metastases who do not respond to standard chemotherapy regimens. Based on patients with advanced soft-tissue sarcomas who had received prior chemotherapy, several clinical studies have reported the survival and sensitivity (approximately 5% to 10% sensitive) of patients with soft-tissue sarcomas treated with pazopanib. Recently, next-generation sequencing (NGS) technologies have been used to provide a wide genetic information and to develop personalized medicine in cancer treatment. However, there are few reports and no genetic analyses of patients with soft-tissue sarcomas who had a complete response (CR) to pazopanib., Questions/purposes: We described the clinicopathologic features of a patient with a rare, advanced soft-tissue sarcoma who achieved a CR to pazopanib treatment. Furthermore, integrative analyses using NGS and arrays were performed to elucidate characteristic alterations, including gene mutations, copy number changes, and protein expression that were associated with response to pazopanib. Additionally, functional analyses consisting of in vitro and in vivo assays were also performed to elucidate whether the identified alterations were associated with oncogenic abilities and drug responses., Methods: In a sample from a 70-year-old woman with an advanced soft-tissue sarcoma treated for 1 month with 800 mg of oral pazopanib daily, CT scans demonstrated a CR to treatment. To our knowledge, there have been no patients with soft-tissue sarcomas among several clinical trials of pazopanib that have achieved a CR and therefore, our patient is considered to be extremely rare. We performed an integrative analysis including whole-exome sequencing, transcriptome sequencing, and phosphorylation profiling of receptor tyrosine kinases (RTK) using tumor samples from a patient with a CR matched to normal samples. From here on we will refer to this patient as having a CR, although a short term high-grade partial response may be more accurate. These analyses were performed using NGS and the phosphoreceptor tyrosine kinase (phospho-RTK) array. As a validation study, we also performed target sequencing using three samples from patients with long-term stable disease and two samples from patients with progressive disease who responded to pazopanib treatment. In addition, characteristic gene alterations that were identified according to the response to pazopanib in one patient with a CR, in three patients with long-term stable disease, and in 27 patients with high-grade soft-tissue sarcomas with different histologic subtypes and different responses to pazopanib were verified by quantitative real-time polymerase chain reaction. We conducted a focus formation assay to evaluate the transforming activities of these genomic alterations., Results: In the patient with a CR to pazopanib, we identified several somatic mutations including Fms related receptor tyrosine kinase 1 (FLT1) p.G38S, platelet-derived growth factor receptor alpha (PDGFRA) p.T83S, and platelet-derived growth factor receptor beta (PDGFRB) exon 13 skipping. Amplification at chromosome 12q13-14 encompassing GLI family zinc finger 1 (GLI1) and cyclin-dependent kinase-4 (CDK4) was also detected. Furthermore, an elevated PDGFRB phosphorylation level was observed in the tumor. In target sequencing analyses in five patients, one of three patients with long-term stable disease had 12q13-14 amplification. The mRNA expression of GLI1, CDK4, and pazopanib targets including PDGFRA, PDGFRB, vascular endothelial growth factor receptor (VEGFR)1-3, and stem cell factor receptor (KIT) in samples from the patient with a CR, and 27 patients with high-grade soft-tissue sarcomas was verified. The expression of GLI1 was characteristically increased in the patient with a CR and in those with long-term stable disease relative to other patients with soft-tissue sarcomas. Overexpression of GLI1 showed strong transforming potential in 3T3 cells. Moreover, the overexpression of GLI1 upregulated the expression of the PDGFRB protein and promoted phosphorylation, which was dose-dependently inhibited by pazopanib. However, inhibition of GLI1-induced transformation by pazopanib was limited in the focus formation assay; therefore, mechanisms other than PDGFRB activation may contribute to transformation., Conclusions: We identified several gene alterations that might be associated with a CR and long-term stable disease in patients who received pazopanib for advanced soft-tissue sarcomas. We therefore believe that this distinct molecular profile warrants further investigation to identify predictive biomarkers of the response to pazopanib., Clinical Relevance: Our findings identify molecular mechanisms that possibly explain the high sensitivity of soft-tissue sarcomas to pazopanib and may lead to the development of predictive biomarkers and novel therapies in patients with this and other types of soft-tissue sarcomas.
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- 2020
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49. Nanostring-based screening for tyrosine kinase fusions in inflammatory myofibroblastic tumors.
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Kurihara T, Suehara Y, Akaike K, Hayashi T, Kohsaka S, Ueno T, Hasegawa N, Takagi T, Sasa K, Okubo T, Kim Y, Mano H, Yao T, Kaneko K, and Saito T
- Subjects
- Adult, Aged, Antibodies chemistry, Female, Fibronectins genetics, Humans, Immunohistochemistry, In Situ Hybridization, Fluorescence, Inflammation, Male, Middle Aged, Protein-Tyrosine Kinases genetics, Proto-Oncogene Mas, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins c-ets genetics, Receptor, trkC genetics, Repressor Proteins genetics, Young Adult, ETS Translocation Variant 6 Protein, Myofibroblasts enzymology, Nanotechnology methods, Neoplasms enzymology, Protein-Tyrosine Kinases metabolism
- Abstract
Gene expression imbalances were measured for tyrosine kinase (TK) genes using Nanostring in 19 samples of inflammatory myofibroblastic tumor (IMT). All cases were immunohistochemically stained with anaplastic lymphoma kinase (ALK) and pan-tropomyosin-related-kinase (pan-Trk) antibodies. Five cases with imbalanced ALK expression, reported with Nanostring, were tested using fluorescence in situ hybridization (FISH); two cases with imbalanced neurotrophic tyrosine receptor kinase 3 (NTRK3) expression were tested using reverse transcription-polymerase chain reaction (RT-PCR). One case with imbalanced expression for ROS proto-oncogene 1 (ROS1) was tested using RNA sequencing and RT-PCR. TK fusions were detected in all cases with imbalanced TK expression. RNA sequencing detected a FN1-ROS1 fusion gene in an adult IMT case. IMT with ALK rearrangement showed myofibroblast-dominant features. IMT with ETV6-NTRK3 fusion showed prominent lymphoplasmacytic infiltration with scattered myofibroblasts. Pan-Trk IHC revealed only scattered positively stained cells in IMT with ETV6-NTRK3 fusion gene. ROS1-positive IMT showed myofibroblast-dominant features.
- Published
- 2020
- Full Text
- View/download PDF
50. Association of Probiotic Clostridium butyricum Therapy with Survival and Response to Immune Checkpoint Blockade in Patients with Lung Cancer.
- Author
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Tomita Y, Ikeda T, Sakata S, Saruwatari K, Sato R, Iyama S, Jodai T, Akaike K, Ishizuka S, Saeki S, and Sakagami T
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Humans, Immune Checkpoint Inhibitors pharmacology, Lung Neoplasms mortality, Male, Middle Aged, Probiotics pharmacology, Survival Analysis, Clostridium butyricum pathogenicity, Immune Checkpoint Inhibitors therapeutic use, Lung Neoplasms drug therapy, Probiotics therapeutic use
- Abstract
Gut dysbiosis caused by antibiotics impairs response to immune checkpoint blockade (ICB). Gut microbiota is becoming an attractive therapeutic target for cancer. The Clostridium butyricum MIYAIRI 588 strain is a probiotic therapy used to improve symptoms related to antibiotic-induced dysbiosis in Japan. We hypothesized that probiotic Clostridium butyricum therapy (CBT) may affect the therapeutic efficacy of ICBs. We retrospectively evaluated 118 patients with advanced non-small cell lung cancer treated with ICBs at Kumamoto University Hospital (Kumamoto-shi, Kumamoto, Japan). Survival analysis comparing patients given CBT before and/or after ICB was conducted using univariate analyses and Cox proportional hazards regression models using propensity score. Propensity score analyses confirmed that probiotic CBT significantly prolonged progression-free survival (PFS) and overall survival (OS). Probiotic CBT significantly associated with longer PFS and OS even in patients who received antibiotic therapy. This study suggests that probiotic CBT may have a positive impact on therapeutic efficacy of ICB in patients with cancer. See articles by Hakozaki et al., p. 1243, and Peng et al., p. 1251 ., (©2020 American Association for Cancer Research.)
- Published
- 2020
- Full Text
- View/download PDF
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