Toshiyuki Kita

EGFR Mutation of Tumor and Serum in Gefitinib-Treated Patients with Chemotherapy-Naive Non–small Cell Lung Cancer

Background: The authors evaluate the efficacy and safety of gefitinib monotherapy in chemotherapy-naive patients with advanced non–small-cell lung cancer (NSCLC). A secondary endpoint is to evaluate the relationship between clinical manifestations and epidermal growth factor receptor (EGFR) mutation status. Methods: Japanese chemotherapy-naive NSCLC patients were enrolled. They had measurable lesions, Eastern Cooperative Oncology Group performance status of 0 to 2, and adequate organ and bone marrow function. Patients received 250 mg of oral gefitinib daily. EGFR mutations in exon 18, 19, and 21 of DNA extracted from tumor and serum were analyzed by genomic polymerase chain reaction and direct sequence. Results: All 30 patients were eligible for the assessment of efficacy and safety. An objective response and stable disease were observed in 10 patients (33.3%) and nine patients (30.0%), respectively. The median time to progression was 3.3 months and the median overall survival was 10.6 months. The 1-year survival rate was 43.3%. Grade 3 toxicities were observed in seven patients. EGFR mutation was observed in four of 13 (30.8%) tumors, and two of them achieved partial response. In serum samples, three of 10 patients with EGFR mutations in the serum before treatment had a response to gefitinib. EGFR mutation was observed in 10 of 27 and significantly more frequently observed in the posttreatment samples from patients with a partial response or stable disease than in those from patients with progressive disease (p = 0.006). Conclusions: Gefitinib monotherapy in chemotherapy-naive NSCLC patients was active, with acceptable toxicities. These results warrant further evaluation of gefitinib monotherapy as a first-line therapy. The EGFR mutation in serum DNA may be a biomarker for monitoring the response to gefitinib during treatment.

Blockade of eosinophil migration and airway hyperresponsiveness by cPLA2-inhibition

We examined the role of a cytosolic phospholipase A2 (cPLA2) in antigen-induced eosinophil infiltration of airways and in airway hyperresponsiveness to methacholine. Inhibition of cPLA2, or blockade of the platelet-activating factor (PAF) receptor, blocked antigen-induced airway hyperresponsiveness and suppressed eosinophil infiltration. Neither cyclooxygenase nor 5-lipoxygenase inhibition had either effect. We show here that, in antigen-sensitized guinea pigs, cPLA2 inhibition prevents both eosinophilic infiltration and subsequent airway hyperresponsiveness after antigen challenge. We also show that this effect is mediated by first-step hydrolysis of membrane phospholipid into lysophospholipid rather than by prostanoid or leukotriene metabolites of arachidonate.

Potentiation of allergic bronchoconstriction by repeated exposure to formaldehyde in guinea‐pigs in vivo

Background Indoor formaldehyde (FA) might worsen allergies and be an underlying factor for the increasing incidence and severity of asthma; the exact mechanism, however, remains unclear.

Effect of Pressure Stress Applied to the Airway on Cough-Reflex Sensitivity in Guinea Pigs

RATIONALE We hypothesized that cough stress of the airway wall results in a self-perpetuating cough-reflex cycle in which antigen-induced increase in cough-reflex sensitivity results in pathologic cough, and the cough in turn further amplifies cough-reflex sensitivity. OBJECTIVES To examine cough-reflex sensitivity in an experimental animal model. METHODS We developed an experimental guinea pig model in which airway collapse similar to that in cough was induced by rapid negative pressure applied to the airway of artificially ventilated animals. We examined the influence of this stimulus on cough-reflex sensitivity to inhaled capsaicin and bronchoalveolar lavage (BAL) cell components. After the termination of artificial ventilation, the number of coughs due to capsaicin was measured, and BAL was performed. MEASUREMENTS AND MAIN RESULTS Capsaicin cough-reflex sensitivity and the number of BAL neutrophils were increased 6 hours after stimulus application, decreasing to control levels by 24 hours. Cough-reflex sensitivity or BAL cell components were not changed in the absence of stimulus application. The number of BAL neutrophils correlated significantly with the number of coughs. Hydroxyurea inhibited the stimulus-induced increase in the number of coughs and airway neutrophil accumulation. CONCLUSIONS Our findings suggest that cough itself is a traumatic mechanical stress to the airway wall that induces neutrophilic airway inflammation and cough-reflex hypersensitivity. Cough stress to the airway wall results in a self-perpetuating cough-reflex cycle.

Longitudinal decline in pulmonary function in atopic cough and cough variant asthma

Objective Cough variant asthma and atopic cough are different clinical manifestations of eosinophilic airway inflammation presenting with isolated chronic non‐productive cough. The aim of this study was to examine the longitudinal change in pulmonary function in cough variant asthma and atopic cough.

Effects of suplatast tosilate, a new type of anti‐allergic agent, on airway cough hypersensitivity induced by airway allergy in guinea‐pigs

Background Cough receptor hypersensitivity is a fundamental feature of some conditions presenting with chronic non‐productive cough. Suplatast tosilate, an anti‐allergic agent, is a T helper (Th)2 cytokine inhibitor that inhibits the synthesis of interleukin (IL)‐4, IL‐5, immunoglobulin (Ig)E production, and local eosinophil accumulation.

Attenuating effect of H+K+ATPase inhibitors on airway cough hypersensitivity induced by allergic airway inflammation in guinea‐pigs

Background Gastrooesophageal reflux (GER) is a frequent cause of chronic cough. Several investigators have indicated that inhibitors of H+K+ATPase (proton pump inhibitors; PPIs) could relieve coughing via inhibition of acid reflux. However, we considered that PPIs might directly inhibit increased cough reflex sensitivity.

Bronchoprotective effects of KF-19514 and cilostazol in guinea pigs in vivo

It has been shown that inhibitors of cyclic nucleotide phosphodiesterase III and IV have a bronchodilator effect. We compared the effects of a selective phosphodiesterase III inhibitor, 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quin olinone (cilostazol) and a phosphodiesterase I/IV inhibitor, 5-phenyl-3-(3-pyridil) methyl-3H-imidazo[4,5-c][1,8]naphthyridin-4(5H)-one (KF-19514) on antigen- and histamine-induced bronchoconstriction in guinea pigs in vivo. Intravenous administration of cilostazol and KF-19514 inhibited histamine- and antigen-induced bronchoconstriction in a dose-dependent manner. When assessing the resulting ED50 values, the activity of KF-19514 against antigen-induced bronchoconstriction was stronger than its antagonism of histamine-induced bronchoconstriction (0.004 vs. 0.056 mg/kg). while those of cilostazol were contrary (0.835 vs. 0.031 mg/kg). These results suggest that although both inhibitors of phosphodiesterase III and phosphodiesterase IV have a bronchodilator or bronchoprotective effect, phosphodiesterase IV inhibitors such as KF-19514 may be more useful for asthma treatment because KF-19514 had an anti-allergic effect in addition to the functional bronchodilator activity.

Effects of KF19514, a Phosphodiesterase 4 and 1 Inhibitor, on Bronchial Inflammation and Remodeling in a Murine Model of Chronic Asthma

BACKGROUND Phosphodiesterase 4 selective inhibitor may prevent airway inflammation and remodeling. OBJECTIVE The aim of this study was to investigate the effects of KF19514, a phosphodiesterase 4 and 1 dual inhibitor, on chronic airway inflammation and remodeling following chronic exposure to aerosolized antigen in mice. METHODS Ovalbumin (OVA) was administered intraperitoneally to BALB/c mice on days 0 and 14, and the mice were then exposed to aerosolized OVA daily for 4 weeks. Twenty-four hours following the final inhalation, bronchial responsiveness to acetylcholine was measured, and histologic examination and hydroxyproline content of the lung were evaluated. RESULTS Bronchial responsiveness to acetylcholine, number of inflammatory cells and eosinophils in the lamina propria, thickness of epithelial and subepithelial collagen layers, and hydroxyproline content of the lung increased following chronic exposure to OVA for 7 weeks. KF19514 significantly prevented all of these changes. CONCLUSIONS Phosphodiesterase 4 and 1 inhibitors such as KF19514 may help prevent bronchial hyperresponsiveness and chronic asthma-induced airway remodeling.

Sputum Eosinophilia, Airway Hyperresponsiveness and Airway Narrowing in Young Adults with Former Asthma

BACKGROUND 30-80% of outgrown asthma subjects develop symptoms again later in life. We investigated inflammation and function of lower airway in adolescents with former asthma. METHODS 326 never-smoking young adults (mean age 24.0 years) were interviewed with special emphasis on history of asthma. Diagnosis of asthma was based on GINA guidelines. Former asthma subjects consisted of ones with a history of physician-diagnosed childhood asthma, who had been free of asthma symptoms without the use of medication for at least 10 years prior to the study. Provocative concentration of methacholine causing a 20% fall in forced expiratory volume in 1 second (FEV(1))(PC(20)) and eosinophil percentage in induced sputum were measured. RESULTS 31 subjects were former asthma subjects (FBA), 11 subjects were current asthma subjects (CBA) and 284 subjects had no history of asthma (non-BA). PC(20) and FEV(1)/FVC ratio were significantly lower in the FBA group than in the non-BA group (P < 0.01). Maximal mid-expiratory flow (MMF) was significantly lower in the FBA group than in the non-BA group (P < 0.05). Sputum eosinophil percentage was significantly increased in the FBA group compared with the non-BA group (P < 0.01). PC(20) was significantly lower in the CBA group than in the FBA and non-BA groups (P < 0.01). FEV(1), FEV(1)/FVC ratio and MMF were significantly lower in the CBA group than in the FBA group (P < 0.05, P < 0.05 and P < 0.05, respectively) and the non-BA group (P < 0.01, P < 0.01 and P < 0.05, respectively). Sputum eosinophils were significantly higher in the CBA group than in the FBA and non-BA groups (P < 0.01). CONCLUSIONS This study shows that subjects with long-term outgrown asthma continue to have airway eosinophilic inflammation, airway hyperresponsiveness and airway narrowing.