Public Library of Science Acta Medica Okayama 1932-6203 15 8 2020 Nintedanib can be used safely and effectively for idiopathic pulmonary fibrosis with predicted forced vital capacity <= 50%: A multi-center retrospective analysis e0236935 EN Satoru Senoo Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Nobuaki Miyahara Department of Medical Technology, Okayama University Graduate School of Health Sciences Akihiko Taniguchi Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Naohiro Oda Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Junko Itano Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hisao Higo Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Naofumi Hara Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hiromi Watanabe Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hirohisa Kano Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Toshimitsu Suwaki Department of Respiratory Medicine, Okayama City Hospital Yasuko Fuchimoto Department of Respiratory Medicine, Japan Organization of Occupational Health and Safety Okayama Rosai Hospita Kazuhiro Kajimoto Department of Respiratory Medicine, Japanese Red Cross Kobe Hospita Hirohisa Ichikawa Department of Respiratory Medicine, KKR Takamatsu Hospital Kenichiro Kudo Department of Respiratory Medicine, National Hospital Organization Okayama Medical Center Takuo Shibayama Department of Respiratory Medicine, National Hospital Organization Okayama Medical Center Yasushi Tanimoto Department of Respiratory Medicine, National Hospital Organization Minami-Okayama Medical Center Shoichi Kuyama Department of Respiratory Medicine, National Hospital Organization Iwakuni Clinical Center Arihiko Kanehiro Department of Respiratory Medicine, Japan Organization of Occupational Health and Safety Okayama Rosai Hospital Yoshinobu Maeda Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Katsuyuki Kiura Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama Respiratory Disease Study Group (ORDSG) Background</br> 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%.</br> Methods</br> 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.</br> Results</br> 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.</br> Conclusions</br> 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. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 70 4 2016 Heerfordt’s Syndrome Associated with a High Fever and Elevation of TNF-α 273 277 EN Go Makimoto Department of Respiratory and Allergy Medicine, Okayama University Hospital Nobuaki Miyahara Department of Respiratory and Allergy Medicine, Okayama University Hospital Mao Yoshikawa Department of Respiratory and Allergy Medicine, Okayama University Hospital Akihiko Taniguchi Department of Respiratory and Allergy Medicine, Okayama University Hospital Arihiko Kanehiro Department of Respiratory and Allergy Medicine, Okayama University Hospital Mitsune Tanimoto Department of Respiratory and Allergy Medicine, Okayama University Hospital Katsuyuki Kiura Department of Respiratory and Allergy Medicine, Okayama University Hospital Case Report 10.18926/AMO/54503 Heerfordtʼs syndrome is a rare manifestation of sarcoidosis and is defined as a combination of facial palsy, parotid swelling, and uveitis, associated with a low-grade fever. We report a case of Heerfordtʼs syndrome presenting with a high fever and increased serum tumor necrosis factor alpha (TNF-α) levels. The patient had facial palsy, parotid swelling, uveitis, and swelling of the right supraclavicular and hilar lymph nodes. Corticosteroid therapy was initiated, and her symptoms soon resolved completely, in tandem with a decrease in TNF-α serum levels. No potential conflict of interest relevant to this article was reported.

Biomed Central Ltd Acta Medica Okayama 1465-993X 14 2013 IL-17A is essential to the development of elastase-induced pulmonary inflammation and emphysema in mice EN Etsuko Kurimoto Nobuaki Miyahara Arihiko Kanehiro Koichi Waseda Akihiko Taniguchi Genyo Ikeda Hikari Koga Hisakazu Nishimori Yasushi Tanimoto Mikio Kataoka Yoichiro Iwakura Erwin W. Gelfand Mitsune Tanimoto Background: Pulmonary emphysema is characterized by alveolar destruction and persistent inflammation of the airways. Although IL-17A contributes to many chronic inflammatory diseases, it's role in the inflammatory response of elastase-induced emphysema remains unclear. Methods: In a model of elastase-induced pulmonary emphysema we examined the response of IL-17A-deficient mice, monitoring airway inflammation, static compliance, lung histology and levels of neutrophil-related chemokine and pro-inflammatory cytokines in bronchoalveolar lavage (BAL) fluid. Results: Wild-type mice developed emphysematous changes in the lung tissue on day 21 after elastase treatment, whereas emphysematous changes were decreased in IL-17A-deficient mice compared to wild-type mice. Neutrophilia in BAL fluid, seen in elastase-treated wild-type mice, was reduced in elastase-treated IL-17A-deficient mice on day 4, associated with decreased levels of KC, MIP-2 and IL-1 beta. Elastase-treated wild-type mice showed increased IL-17A levels as well as increased numbers of IL-17A+ CD4 T cells in the lung in the initial period following elastase treatment. Conclusions: These data identify the important contribution of IL-17A in the development of elastase-induced pulmonary inflammation and emphysema. Targeting IL-17A in emphysema may be a potential therapeutic strategy for delaying disease progression. No potential conflict of interest relevant to this article was reported.

Biomed Central Ltd Acta Medica Okayama 1465-993X 14 2013 Inhibition of neutrophil elastase attenuates airway hyperresponsiveness and inflammation in a mouse model of secondary allergen challenge: neutrophil elastase inhibition attenuates allergic airway responses EN Hikari Koga Nobuaki Miyahara Yasuko Fuchimoto Genyo Ikeda Koichi Waseda Katsuichiro Ono Yasushi Tanimoto Mikio Kataoka Erwin W. Gelfand Mitsune Tanimoto Arihiko Kanehiro Background: Chronic asthma is often associated with neutrophilic infiltration in the airways. Neutrophils contain elastase, a potent secretagogue in the airways, nonetheless the role for neutrophil elastase as well as neutrophilic inflammation in allergen-induced airway responses is not well defined. In this study, we have investigated the impact of neutrophil elastase inhibition on the development of allergic airway inflammation and airway hyperresponsiveness (AHR) in previously sensitized and challenged mice. Methods: BALB/c mice were sensitized and challenged (primary) with ovalbumin (OVA). Six weeks later, a single OVA aerosol (secondary challenge) was delivered and airway inflammation and airway responses were monitored 6 and 48 hrs later. An inhibitor of neutrophil elastase was administered prior to secondary challenge. Results: Mice developed a two-phase airway inflammatory response after secondary allergen challenge, one neutrophilic at 6 hr and the other eosinophilic, at 48 hr. PAR-2 expression in the lung tissues was enhanced following secondary challenge, and that PAR-2 intracellular expression on peribronchial lymph node (PBLN) T cells was also increased following allergen challenge of sensitized mice. Inhibition of neutrophil elastase significantly attenuated AHR, goblet cell metaplasia, and inflammatory cell accumulation in the airways following secondary OVA challenge. Levels of IL-4, IL-5 and IL-13, and eotaxin in BAL fluid 6 hr after secondary allergen challenge were significantly suppressed by the treatment. At 48 hr, treatment with the neutrophil elastase inhibitor significantly reduced the levels of IL-13 and TGF-beta 1 in the BAL fluid. In parallel, in vitro IL-13 production was significantly inhibited in spleen cells from sensitized mice. Conclusion: These data indicate that neutrophil elastase plays an important role in the development of allergic airway inflammation and hyperresponsiveness, and would suggest that the neutrophil elastase inhibitor reduced AHR to inhaled methacholine indicating the potential for its use as a modulator of the immune/inflammatory response in both the neutrophil-and eosinophil-dominant phases of the response to secondary allergen challenge. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 65 6 2011 Successful Extracorporeal Life Support for Life-threatening Hypercapnia with Bronchiolitis Obliterans after Allogeneic Hematopoietic Stem Cell Transplantation 403 406 EN Koichi Waseda Yasushi Tanimoto Shingo Ichiba Nobuaki Miyahara Toshi Murakami Nobuaki Ochi Michihisa Terado Osamu Nagano Yoshinobu Maeda Arihiko Kanehiro Yoshihito Ujike Mitsune Tanimoto Case Report 10.18926/AMO/47266 Bronchiolitis obliterans (BO) is a disease with a poor prognosis, and a key factor that limits long-term survival after allogeneic hematopoietic stem cell transplantation (HSCT). We here report a case of a 31-year woman with acute lymphatic leukemia, which was treated by chemotherapy and HSCT, and consequently developed BO 2 years after HSCT. A non-tuberculous mycobacterial infection occurred and showed gradual exacerbation. She started taking anti-mycobacterial drugs, but lost appetite, felt tired and finally lost consciousness one month after beginning medication. Arterial blood gas revealed marked hypercapnia. Using extracorporeal life support (ECLS), the carbon dioxide concentration was reduced and her consciousness recovered. To our knowledge, this is the first case in which ECLS was successfully used for hypercapnia in a patient with BO. No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 123 3 2011 新型インフルエンザウイルス（A/H1N1）感染後にARDSを来たした1例 221 225 EN Akihiko Taniguchi Nobuaki Miyahara Atsushi Nakahara Saburo Takata Ryo Sakugawa Osamu Nagano Yasushi Tanimoto Arihiko Kanehiro Katsuyuki Kiura Yoshito Ujike Mitsune Tanimoto A 28-year-old man with a history of mental retardation was admitted to our hospital because of dyspnea, cough and high fever. His SpO(2) level at room-environmental conditions was in the eighties, and his chest radiograph showed diffuse infiltrates in both lungs. He was diagnosed as suffering from influenza A by a rapid influenza virus antigen test. The echocardiogram showed no evidence of left cardiac failure; therefore, his symptoms were consistent with acute respiratory distress syndrome (ARDS). Oseltamivir was started, and antibiotics were also given because of the possibility of secondary bacterial infection. Due to respiratory failure and low blood pressure, which suggested septic shock, intensive treatments including mechanical ventilation were performed. Corticosteroid therapy was started for ARDS and sepsis, and these therapies improved his respiratory condition. Polymerase chain reaction of his pharyngeal swab revealed that he had influenza A (H1N1). This is the first case of ARDS following infection by influenza A (H1N1) virus in Japan. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 65 3 2011 Churg-Strauss Syndrome with Necrosis of Toe Tips 215 218 EN Koichi Waseda Yasushi Tanimoto Kenjiro Hasegawa Nobuaki Miyahara Daisuke Nojima Genyo Ikeda Arihiko Kanehiro Chiharu Okada Yoshihiro Kimata Mitsune Tanimoto Case Report 10.18926/AMO/46635 Churg-Strauss syndrome (CSS) is a granulomatous necrotizing vasculitis of unknown etiology associated with bronchial asthma. Despite affecting small to medium-sized vessels, necrosis of the digits due to vasculitis is extremely rare. We report a case of CSS with necrosis of the toe tips. A 37-year-old woman with asthma, who had been diagnosed with CSS 2 years ago, was admitted to our hospital with an exacerbation of CSS. The patient had a high grade fever and complained of abdominal pain and numbness of the lower extremities. Blood examination revealed marked eosinophilia. The fever pattern, abdominal pain and blood eosinophilia showed improvement by combination treatment with prednisolone and cyclophosphamide. However, the color of her right toe tips changed, and necrosis finally resulted despite antithrombotic therapy. Arteriography showed narrowing of the dorsalis pedis artery and of the more peripheral arteries of her right leg. Stump plasty with negative pressure dressing therapy for the toe tips, but not amputation, was done to preserve the leg function. While numbness of the extremities remained, no recurrence of necrosis was seen. Clinicians need to be aware that rare complications of CSS, including necrosis of the digits, can occur. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 64 3 2010 Interstitial Lung Disease during Trimethoprim/Sulfamethoxazole Administration 181 187 EN Syota Yuzurio Naokatsu Horita Yutaro Shiota Arihiko Kanehiro Mitsune Tanimoto Original Article 10.18926/AMO/40010 We studied clinical and radiographic features of interstitial lung disease (ILD) during trimethoprim/sulfamethoxazole (TMP/SMX) administration. Ten patients who had received prednisolone treatment for underlying diffuse pulmonary disease showed various ILDs after introduction of TMP/SMX. The radiographic features of the ILDs were not consistent with infectious disease or exacerbation of the underlying disease, and these diagnoses were excluded radiographically and on clinical grounds during the differential diagnosis of the ILDs. These ILDs emerged relatively early after introduction of TMP/SMX, which is consistent with the former case report of drug-induced ILD (DI-ILD) caused by TMP/SMX. Therefore DI-ILDs caused by TMP/SMX were suspected in these cases. In most of these cases, the ILDs were clinically mild and disappeared immediately although administration of TMP/SMX was continued. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 64 2 2010 Experimental Pulmonary Granuloma Mimicking Sarcoidosis Induced by Propionibacterium acnes in Mice 75 83 EN Kouji Iio Tomoe Ueno Iio Yuhei Okui Hirohisa Ichikawa Yasushi Tanimoto Nobuaki Miyahara Arihiko Kanehiro Mitsune Tanimoto Yasunari Nakata Mikio Kataoka Original Article 10.18926/AMO/32852 <p>Propionibacterium acnes has been implicated as an etiologic agent of sarcoidosis since the isolation of this bacterium from sarcoid lesions. We experimentally produced a murine pulmonary granuloma model using P. acnes with several features that simulate sarcoidosis. Mice were sensitized with heat-killed P. acnes and complete Freund's adjuvant and were subsequently challenged with heat-killed P. acnes at 2-week intervals. P. acnes-challenged mice developed epitheloid cell granulomas in the lungs. These mice showed a pulmonary immune response characterized by an increased number of T-lymphocytes, especially CD4 cells, and the ratio of CD4/CD8 in bronchoalveolar lavage (BAL) fluid also increased. Furthermore, significant elevations in both angiotensin-converting enzyme (ACE) serum levels and antibody titers against P. acnes were observed. Mice sensitized with P. acnes without complete Freund's adjuvant were capable of forming pulmonary granulomas, which appeared to be caused by indigenous P. acnes. The genome of P. acnes was found in the lungs, BAL cells, hilar lymph nodes, liver, and spleen in non-sensitized mice, which were thought to be germ-free. These results suggest that the immune response against indigenous P. acnes may play an important role in the pathogenesis of granuloma formation in a murine model.</p> No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 60 5 2006 Severe Interstitial Pneumonia Induced by Paclitaxel in a Patient with Adenocarcinoma of the Lung 295 298 EN Noriyuki Suzaki Akio Hiraki Nagio Takigawa Hiroshi Ueoka Yasushi Tanimoto Toshiyuki Kozuki Masahiro Tabata Arihiko Kanehiro Katsuyuki Kiura Mitsune Tanimoto Article 10.18926/AMO/30737 A 71-year-old Japanese man with adenocarcinoma of the lung developed interstitial pneumonia after treatment with paclitaxel. The patient had acute chills and fever on the fourth day after the second exposure to paclitaxel, rapidly got worse despite empiric therapies, and developed prolonged respiratory failure requiring mechanical ventilation. Four months later, he died of respiratory failure due to progression of both interstitial pneumonia and lung cancer. This is the first case developing fatal paclitaxel-induced pulmonary toxicity to date. Interstitial pneumonia should be considered one of the possible life-threatening complications during treatment with paclitaxel. No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 104 7-8 1992 難治性喘息の病態と治療に関する研究　第2編　難治性喘息における細胞反応型アレルギーに対する選択的 Thromboxane A(2) 合成酵素阻害剤の抑制機序について 735 746 EN Arihiko Kanehiro The specific thromboxane A(2) (TXA(2)) synthetase inhibitor (OKY-046) seems to be a useful drug in the treatment of intractable asthmatics. In this study, to clarify the action mechanism of OKY-046 and the relationship between TXA(2) and prostaglandin E(2) (PGE(2)) in cell-mediated allergy, the effect of the TXA(2) receptor antagonist (AA-2414), TXA2 analogue (STA(2)) and PGE(2) for peripheral blood mononuclear cells in adult intractable asthmatics was studied. OKY-046 significantly suppressed TXB(2) production and increased PGE(2) production from the peripheral blood mononuclear cells stimulated by PHA and Candida antigen, but AA-2414 had no effect. AA-2414 suppressed lymphocyte blastgenesis, but did not suppress significantly interleukin-2 (IL-2) or neutrophil chemotactic factor (NCF) production. Furthermore, STA(2) increased lymphocyte blastgenesis stimulated by Candida antigen partially, but not dose-dependently. On the other hand, PGE(2) suppressed significantly lymphocyte blastgenesis and IL-2 and NCF production in a dose-dependent manner. These findings suggest that the action mechanism of OKY-046 is a suppressive effect of cell-mediated allergy, and that TXA(2) and PGE(2) play an important role in the mechanism of intractable asthma. No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 104 7-8 1992 難治性喘息の病態と治療に関する研究　第1編　難治性喘息患者のリンパ球および好中球機能に及ぼす選択的 Thromboxane A(2) 合成酵素阻害剤の効果 721 733 EN Arihiko Kanehiro To clarify whether thromboxane A(2) (TXA(2)) is involved in type III and IV allergy, so-called "cell-mediated allergy", the effects of a specific TXA(2) synthetase inhibitor, sodium ozagrel (OKY-046) on peripheral blood mononuclear cells and neutrophils in adult intractable asthmatics were studied. Lymphocyte blastogenesis and interleukin-2 (IL-2) production from peripheral blood mononuclear cells stimulated by PHA and Candida antigen in intractable asthmatics was significantly suppressed dose-dependently by OKY-046. The neutrophil chemotactic factor (NCF) and eosinophil chemotactic factor (ECF) from peripheral blood nomonuclear cells stimulated by Candida antigen in intractable asthmatics tended to be suppressed by OKY-046. Furthermore, leukotriene C(4) (LTC(4)) and superoxide (O(2)(-)) production from peripheral blood neutrophils in intractable asthmatics was significantly suppressed dose-dependently by OKY-046. These findings suggest that TXA(2) plays an important role in the development of intractable asthma and OKY-046, which has a suppressive effect on type IV allergy caused by lymphocyte activation and on mediator release from neutrophils, might be a useful drug in the treatment of intractalbe asthmatics. No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 115 1 2005 重度急性呼吸器症候群SARS 63 68 EN No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 115 2 2005 気管支喘息 155 159 EN No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 118 1 2006 アレルギー疾患総論とアナフィラキシーについて 47 52 EN No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 1992 難治性喘息の病態と治療に関する研究 第1編 難治性喘息患者のリンパ球および好中球機能に及ぼす選択的 Thromboxane A2 合成酵素阻害剤の効果 第2編 難治性喘息における細胞反応型アレルギーに対する選択的 Thromboxane A2 合成酵素阻害剤の抑制機序について EN No potential conflict of interest relevant to this article was reported.