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Gler M.T.,Makati Medical Center | Skripconoka V.,State Agency of Tuberculosis and Lung Diseases | Sanchez-Garavito E.,Hospital Nacional Sergio E. Bernales | Xiao H.,Shanghai Pulmonary Hospital | And 16 more authors.
New England Journal of Medicine | Year: 2012

BACKGROUND: Delamanid (OPC-67683), a nitro-dihydro-imidazooxazole derivative, is a new anti-tuberculosis medication that inhibits mycolic acid synthesis and has shown potent in vitro and in vivo activity against drug-resistant strains of Mycobacterium tuberculosis. METHODS: In this randomized, placebo-controlled, multinational clinical trial, we assigned 481 patients (nearly all of whom were negative for the human immunodeficiency virus) with pulmonary multidrug-resistant tuberculosis to receive delamanid, at a dose of 100 mg twice daily (161 patients) or 200 mg twice daily (160 patients), or placebo (160 patients) for 2 months in combination with a background drug regimen developed according to World Health Organization guidelines. Sputum cultures were assessed weekly with the use of both liquid broth and solid medium; sputum-culture conversion was defined as a series of five or more consecutive cultures that were negative for growth of M. tuberculosis. The primary efficacy end point was the proportion of patients with sputum-culture conversion in liquid broth medium at 2 months. RESULTS:Among patients who received a background drug regimen plus 100 mg of delamanid twice daily, 45.4% had sputum-culture conversion in liquid broth at 2 months, as compared with 29.6% of patients who received a background drug regimen plus placebo (P = 0.008). Likewise, as compared with the placebo group, the group that received the background drug regimen plus 200 mg of delamanid twice daily had a higher proportion of patients with sputum-culture conversion (41.9%, P = 0.04). The findings were similar with assessment of sputum-culture conversion in solid medium. Most adverse events were mild to moderate in severity and were evenly distributed across groups. Although no clinical events due to QT prolongation on electrocardiography were observed, QT prolongation was reported significantly more frequently in the groups that received delamanid. CONCLUSIONS: Delamanid was associated with an increase in sputum-culture conversion at 2 months among patients with multidrug-resistant tuberculosis. This finding suggests that delamanid could enhance treatment options for multidrug-resistant tuberculosis. (Funded by Otsuka Pharmaceutical Development and Commercialization; ClinicalTrials. gov number, NCT00685360.) Copyright © 2012 Massachusetts Medical Society.

Hamamoto S.,Osaka City University | Okuma T.,National Hospital Organization Kinki chuo Chest Medical Center | Yamamoto A.,Osaka City University | Kageyama K.,Osaka City University | And 5 more authors.
Radiology | Year: 2013

Purpose: To evaluate whether antitumor immunity is enhanced systemically by combining radiofrequency ablation (RFA) and local injection of an immunostimulant, OK-432. Materials and Methods: Experiments were approved by the institutional animal care committee. Experimental Japanese rabbits inoculated with VX2 tumors in the lung and the auricle were randomized into four groups of eight: control (supportive care), RFA (RFA of lung tumor), OK-432 (direct injection of OK-432 into lung tumor), and combination therapy (lung RFA and direct OK-432 injection into lung tumor). All procedures were performed 1 week after implantation of VX2 tumors (week 1). In addition, a VX2 tumor rechallenge test was performed in the RFA and combination therapy groups. Survival time was evaluated by means of the Kaplan-Meier method and by using the log-rank test for intergroup comparison. Mean auricle tumor volumes were calculated every week. Specific growth rates (SGRs) were calculated and compared by using the Mann-Whitney test. Results: The median survival times of the control, RFA, OK-432, and combination therapy groups were 23, 36.5, 46.5, and 105 days, respectively. Survival was significantly prolonged in the combination therapy group when compared with the other three groups (P < .05). The mean auricle tumor volume decreased only in the combination therapy group. The mean auricle tumor volumes of the combination therapy group from week 1 to week 7 were 205, 339, 264, 227, 143, 127, and 115 mm3. SGR in the combination therapy group became significantly smaller than those in the other three groups (P < .05). In the rechallenge test, the volume of all reimplanted tumors decreased. Conclusion: Combining RFA with local injection of immunostimulant OK-432 may lead to indirectly activation of systemic antitumor immunity. © RSNA, 2013.

Akira M.,National Hospital Organization Kinki chuo Chest Medical Center
European Journal of Radiology | Year: 2014

Lung injury caused by chemicals includes bronchitis, bronchiolitis, chemical pneumonitis, pulmonary edema, acute respiratory distress syndrome, organizing pneumonia, hypersensitivity pneumonitis, acute eosinophilic pneumonia, and sarcoid-like granulomatous lung disease. Each chemical induces variable pathophysiology and the situation resembles to the drug induced lung disease. The HRCT features are variable and nonspecific, however HRCT may be useful in the evaluation of the lung injuries and so we should know about HRCT features of lung parenchymal abnormalities caused by chemicals. © 2014 Elsevier Ireland Ltd.

Yoshimura N.,Osaka City University | Okishio K.,National Hospital Organization Kinki chuo Chest Medical Center | Mitsuoka S.,Osaka City University | Kimura T.,Osaka City University | And 7 more authors.
Journal of Thoracic Oncology | Year: 2013

INTRODUCTION: Patients with epidermal growth factor receptor (EGFR) mutation positive non-small-cell lung cancer exhibited marked response to gefitinib or erlotinib. In most cases, however, the patients showed disease progression after EGFR-tyrosine kinase inhibitor (TKI) treatment. We evaluated the efficacy and safety of pemetrexed in combination with EGFR-TKI in patients with disease progression. METHODS: Patients with EGFR-mutant stage IIIB or IV non-small-cell lung cancer that progressed during gefitinib or erlotinib therapy were administered pemetrexed with the continuation of EGFR-TKI treatment. Pemetrexed was administered on day 1 at a dose of 500 mg/m, and EGFR-TKI was sequentially administered on days 2 to 16. This treatment was repeated every 3 weeks until disease progression. The primary endpoint was disease control rate. RESULTS: Twenty-seven patients were enrolled in this study. The median number of treatment cycles was six. Overall response rate was 25.9% (95% confidence interval, 9.4%-42.4%) and disease control rate was 77.8% (95% confidence interval, 62.1%-93.5%). Grade 3/4 hematological toxicities were neutropenia (22.2%), leukopenia (14.8%), and anemia (7.4%). Grade 4 nonhematological toxicities were not observed. Major grade 3 nonhematological toxicities were anorexia (14.8%), infection (14.8%), and fatigue (11.1%). The median progression-free survival was 7.0 months, and median survival time was 11.4 months. No treatment-related deaths occurred. CONCLUSIONS: Pemetrexed in combination with erlotinib or gefitinib after disease progression shows favorable response and acceptable toxicity. Copyright © 2012 by the International Association for the Study of Lung Cancer.

Asami K.,National Hospital Organization Kinki chuo Chest Medical Center | Atagi S.,National Hospital Organization Kinki chuo Chest Medical Center
World Journal of Clinical Oncology | Year: 2014

First-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), including gefitinib and erlotinib, have proven to be highly effective agents for advanced non-small cell lung cancer (NSCLC) in patients harboring an activating EGFR mutation such as the exon 19 deletion mutation and L858R. Although those reversible small molecular targeted agents provide a significant response and survival benefit, all responders eventually acquire resistance. Secondgeneration EGFR-targeting agents, such as irreversible EGFR/HER2 tyrosine kinase inhibitors and pan-HER TKIs, may improve survival further and be useful for patients who acquired resistance to ?rst-generation EGFR- TKIs. This review discusses novel therapeutic strategies for EGFR-mutated advanced NSCLC using first- and second-generation EGFR-TKIs. © 2014 Baishideng Publishing Group Inc. All rights reserved.

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