Taro Yoneda

Imatinib ameliorates bronchiolitis obliterans via inhibition of fibrocyte migration and differentiation.

BACKGROUND Imatinib, a tyrosine kinase inhibitor, has been proposed as a potential anti-fibrotic agent for fibroproliferative diseases, including bronchiolitis obliterans (BO). However, the underlying anti-fibrotic mechanisms of the agent remain unclear. We evaluated whether bone (BM)-derived progenitor cells, fibrocytes, might be a target of imatinib in the attenuation of BO. METHODS We used a murine BO model induced by heterotopic tracheal transplantation and assessed the origin of fibroblasts by using green fluorescent protein-BM chimeric mice. We also evaluated the effects of imatinib on luminal obstruction and fibrocyte accumulation. The effects of imatinib on fibrocyte migration and differentiation were assessed by culturing fibrocytes in vitro. RESULTS In the murine BO model, tracheal allografts showed epithelial injury and developed complete luminal occlusion 28 days after transplantation. Most of the mesenchymal cells that had accumulated in the tracheal allograft were derived from BM cells. Imatinib treatment ameliorated the airway luminal occlusion and significantly reduced the number of fibrocytes in the allografts. In vitro studies showed that imatinib inhibited migration of cultured blood fibrocytes via the platelet-derived growth factor/platelet-derived growth factor receptor axis. Imatinib also inhibited differentiation of fibrocytes via suppression of c-Abl activity that was essential for the differentiation of monocytes to fibrocytes. CONCLUSIONS Imatinib prevents airway luminal obstruction by inhibiting the migration and differentiation of fibrocytes. Fibrocytes may be a novel target in the prevention and treatment of BO.

Selective gene amplification to detect the T790M mutation in plasma from patients with advanced non-small cell lung cancer (NSCLC) who have developed epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance

Background The epidermal growth factor receptor (EGFR) T790M mutation is associated with resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC). However, tissues for the genotyping of the EGFR T790M mutation can be difficult to obtain in a clinical setting. The aims of this study were to evaluate a blood-based, non-invasive approach to detecting the EGFR T790M mutation in advanced NSCLC patients using the PointMan™ EGFR DNA enrichment kit, which is a novel method for the selective amplification of specific genotype sequences. Methods Blood samples were collected from NSCLC patients who had activating EGFR mutations and who were resistant to EGFR-TKI treatment. Using cell-free DNA (cfDNA) from plasma, EGFR T790M mutations were amplified using the PointMan™ enrichment kit, and all the reaction products were confirmed using direct sequencing. The concentrations of plasma DNA were then determined using quantitative real-time PCR. Results Nineteen patients were enrolled, and 12 patients (63.2%) were found to contain EGFR T790M mutations in their cfDNA, as detected by the kit. T790M mutations were detected in tumor tissues in 12 cases, and 11 of these cases (91.7%) also exhibited the T790M mutation in cfDNA samples. The concentrations of cfDNA were similar between patients with the T790M mutation and those without the mutation. Conclusions The PointMan™ kit provides a useful method for determining the EGFR T790M mutation status in cfDNA.

The measurement of cough response to bronchoconstriction induced by methacholine inhalation in healthy subjects: An examination using the Astograph method

ABSTRACT Background: We demonstrated that heightened cough response to bronchoconstriction is a fundamental feature of cough variant asthma (CVA). To evaluate this physiological feature of CVA in daily clinical practice, it is necessary to clarify the cough response to bronchoconstriction in healthy subjects. We evaluated cough response to methacholine (MCh)-induced bronchoconstriction in healthy subjects. A forced oscillometry technique was used to measure airway resistance changes with Mch. Methods: Healthy never-smokers (21 men, 20 women; mean 22.3 ± 3.7 years) participated. None had a >3-week cough history, clinically significant respiratory or cardiovascular disorders, or disorders that might put subjects at risk or influence the study results or the subjects’ ability to participate. Twofold increasing concentrations of Mch chloride diluted in phosphate-buffered saline (0.039 to 160 mg/mL) were inhaled from nebulizers at 1-minute intervals during subjects’ tidal breathing after the baseline respiratory resistance (Rrs) was recorded. Mch inhalation continued until Rrs reached twice the baseline value and forced expiratory volume in 1 second (FEV1) decreased to <90% of baseline value. Spirometry was measured before Mch inhalation and immediately after Rrs had increased twofold. Coughs were counted during and for 30 minutes after Mch inhalation. The cough reflex sensitivity to capsaicin was also examined. Results: The number of coughs was 11.1 ± 14.3 (median, 7.0; range, 0 to 71; reference range, 0 to 39.7). There was no significant difference in the cough response between the sexes. The reproducibility of the cough response to bronchoconstriction was sufficient. No correlation existed between the bronchoconstriction-induced cough response and capsaicin cough-reflex sensitivity. Conclusions: Using the Astograph method, cough response to bronchoconstriction could be measured easily, safely and highly reproducibly in healthy subjects.

Paradoxical reaction to antituberculosis therapy after 6 months of treatment for pulmonary tuberculosis: A case report.

Paradoxical reactions (PRs) to antituberculosis (anti-TB) drugs during treatment are well known phenomena, but a PR presenting as a new pulmonary lesion after completion of treatment is extremely rare, and little is known about the management of such cases. A 44-year-old man was diagnosed with pulmonary TB. His sputum cultures became negative 45 days after the initiation of standard anti-TB treatment. Upon the patients completion of 6 months of anti-TB therapy, computed tomography revealed a new irregularly shaped mass in the lower left pulmonary lobe. A transbronchial lung biopsy (TBLB) revealed caseous necrosis and granulomatosis surrounded by epithelioid and multinucleated giant cells. Cultures of both the TBLB specimen and bronchoalveolar lavage fluid remained negative for TB. The CT shadow disappeared 6 months later without further administration of anti-TB drugs. Careful observation without therapy may be sufficient for a patient treated for TB who develops a PR upon completion of treatment, if the patient has achieved a bacteriological remission.

Postoperative Recurrence of Invasive Thymoma with Cold Agglutinin Disease and Autoimmune Hemolytic Anemia.

A 50-year-old man presented to our hospital in 1995. Invasive thymoma was diagnosed and extended thymectomy and left upper lobe partial resection were performed. In 2013, he complained of dyspnea. Chest computed tomography showed postoperative recurrence of invasive thymoma. Several chemotherapies were administered. Severe anemia and an increase in the total bilirubin level were observed with chemotherapies. In additional, an examination showed that the direct Coombs test was positive. Cold agglutinin was also high. We herein experienced a rare case of postoperative recurrence of invasive thymoma with cold agglutinin disease and autoimmune hemolytic anemia.

Bronchial Carcinoid Associated with Atopic Cough in a 31-year-old Male

Johsuke Hara1*, Tamami Sakai1, Taro Yoneda1, HayatoKoba1, Keigo Saeki2, Mayuko Tani2, Noriyuki Ohkura1, Takashi Sone1, Hideharu Kimura1, Yoshihisa Ishiura3, Kazuo Kasahara1 and Masaki Fujimura4 1Respiratory Medicine, Kanazawa University Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa, Ishikawa, Japan 2Internal Medicine, Keiju Medical Center, Nanao, Ishikawa, Japan 3Respiratory Medicine, Toyama City Hospital, Toyama, Toyama, Japan 4Respiratory Medicine, National Hospital Organization Nanao Hospital, Nanao, Ishikawa, Japan *Corresponding author: Johsuke Hara, Respiratory Medicine, Kanazawa University Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa, Ishikawa, Japan, Tel: +81-76-265-2000; E-mail: hara0728@gmail.com

A case of gingival cancer with pulmonary metastases that developed complete atrioventricular block and ventricular fibrillation as a result of myocardial metastases

We present a rare case of gingival cancer with pulmonary metastases that developed life‐threatening complete atrioventricular block and ventricular fibrillation as a result of myocardial metastases. This case suggests that implantable cardioverter defibrillators significantly improve the quality of life in these patients and maintain their performance status.

Abstract 2268: Detection of T790M mutation in EGFR gene, an EGFR-TKI resistant mutation, in tumor samples unexposed to EGFR TKIs

Background: T790M mutation in EGFR gene is the commonest mechanism of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) patients with EGFR mutation. The third-generation EGFR-TKIs are expected to overcome the resistance caused by T790M existence. On the other hand, several reports using highly sensitive detection assays showed a minute amount of T790M mutation alleles was detected in tumor tissues obtained before EGFR-TKI treatment. Aim: To clear whether T790M dominancy in tumor cells before EGFR-TKI treatment reflects between about the EGFR-mutated lung cancer which was not until exposed EGFR TKI therapy and actual resistance mechanism. Methods: We assessed T790M dominancy in tumor cells from 29 NSCLC patients with EGFR mutations, who had not received EGFR-TKIs. T790M mutation and common mutations, such as deletional mutations in exon 19 and L858R, were detected by droplet digital PCR (ddPCR) separately. T790M dominancy was calculated from each level of mutation-alleles about common mutation and T790M mutation. Results: We can detect the T790M mutation in initial biopsy tissues from 21 cases (72%). The mean value of T790M mutation dominancy ratio before EGFR-TKI treatment was 0.48% (0.00-69.09%) and it is not difference between in patients with T790M-positive at resistance and in that with negative (p = 0.87). Conclusions: T790M mutation was detected in most of the tumor tissues unexposed to EGFR TKIs. T790M mutation dominancy calculated by our assays in tumor tissues before EGFR-TKI treatment may not be related to induce T790M resistance to EGFR-TKIs. Citation Format: Hayato Koba, Hideharu Kimura, Shingo Nishikawa, Taro Yoneda, Takashi Sone, Kazuo Kasahara. Detection of T790M mutation in EGFR gene, an EGFR-TKI resistant mutation, in tumor samples unexposed to EGFR TKIs. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2268.

Abstract 2411: Non-invasive analysis for T790M mutations of EGFR using a selective amplification method

Epidermal growth factor receptor (EGFR) T790M mutation is associated with EGFR tyrosine kinase inhibitors (EGFR-TKIs) resistance in non-small cell lung cancer (NSCLC). However, tissue availability limits the genotyping of EGFR T790M mutation in a clinical setting. The aims of this study are to develop a blood-based, non-invasive approach to detecting the EGFRT790M mutation in advanced NSCLC patients, using PointMan™ EGFR DNA Enrichment Kit, which is a novel method for selective amplification of genotype specific sequences. Methods: Blood samples were collected from NSCLC patients with activating EGFR mutations, who were resistant to EGFR-TKIs treatment. EGFR T790M mutations in plasma DNA were detected using the kit. The concentrations of plasma DNA were determined using quantitative real-time PCR. Results: 21 (87.5%) of the patients had EGFR T790M mutations in their plasma DNA as detected using the kit. In all 6 cases detected T790M mutations from tumor tissues, the T790M mutations ware detected also in plasma DNA. The concentrations of plasma DNA were higher in patients with T790M mutations than without the mutations. Conclusions: The PointMan™ is an easily and useful method for determining the plasma EGFR T790M mutation status. Citation Format: Shingo Nishikawa, Hideharu Kimura, Hayato Koba, Taro Yoneda, Takashi Sone, Chris Booth, Andrew Webb, Kazuo Kasahara. Non-invasive analysis for T790M mutations of EGFR using a selective amplification method. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2411. doi:10.1158/1538-7445.AM2015-2411