Masayuki Mizuguchi

Comparative analysis of epidermal growth factor receptor mutations and gene amplification as predictors of gefitinib efficacy in Japanese patients with nonsmall cell lung cancer

Because the investigation of epidermal growth factor receptor gene (EGFR) status as a predictor of gefitinib efficacy in Japanese patients has shown promise, the authors evaluated EGFR mutations and gene amplification in biopsy specimens from Japanese patients with nonsmall cell lung cancer (NSCLC) who received treatment with gefitinib to analyze the correlation between EGFR gene status and clinical outcome.

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.

Involvement of NK2 receptors rather than NK1 receptors in bronchial hyperresponsiveness induced by allergic reaction in guinea‐pigs

1 In this study, the role of neuropeptides in antigen‐induced bronchoconstriction and bronchial responsiveness in guinea‐pigs was evaluated by use of phosphoramidon, the inhibitor of neutral endopeptidases (NEP), the NK1 receptor antagonist, FK888, and the dual NK1/NK2 receptor antagonist, FK224. The role of endogenous tachykinins in bronchial hyperresponsiveness induced by inhaled capsaicin was also observed with FK888 and FK224. 2 Allergic bronchoconstriction and bronchial responsiveness was evoked by inhalation of ovalbumin (OA), and increasing doses of methacholine were inhaled at 5‐min intervals for 30 min after OA challenge in passively sensitized and artificially ventilated guinea‐pigs. Animals were treated with a 30 s inhalation of phosphoramidon (10−3m) or saline 10 min before the OA challenge. FK888 (1.0 or 10 mg kg−1) or FK224 (1.0 or 10 mg kg−1) was administered intravenously 5 min before the OA challenge. 3 Treatment with phosphoramidon did not alter the increase in the lateral pressure at the tracheal tube (Pao) caused by OA inhalation or the increase in bronchial response to methacholine following the allergic reaction. Pretreatment with FK224 did not inhibit the increase in Pao after antigen provocation but did significantly inhibit antigen‐induced bronchial hyperresponsiveness in a dose‐dependent manner, while FK888 did not affect either allergic bronchoconstriction or post‐allergic bronchial hyperresponsiveness. 4 Histamine, 25, 50, 100 or 200 μ ml−1 was inhaled for 20 s at 5‐min intervals in non‐sensitized guinea‐pigs which were pretreated with inhalation of subthreshold dose of capsaicin (10−7 m). FK888 or FK224, each at a dose of 0.1 or 1.0 mg kg−1, or vehicle was given to guinea‐pigs intravenously 3 min before inhalation of capsaicin. The capsaicin inhalation significantly potentiated bronchial responsiveness to histamine, compared with control. The capsaicin‐induced bronchial hyperresponsiveness was completely blocked by FK224 in a dose‐dependent manner but not by FK888. 5 These results suggest that NK2 receptors rather than NK1 receptors may play an important role in bronchial hyperresponsiveness induced by antigen challenge as well as capsaicin while tachykinins do not play a primary role in the acute bronchospasm elicited by antigen challenge in passively sensitized guinea‐pigs.

Addition of a 2-month low-dose course of levofloxacin to long-term erythromycin therapy in sinobronchial syndrome

Background: We previously reported that a 6‐month low‐dose course of ofloxacin combined with long‐term low‐dose erythromycin therapy (EM therapy) was superior to EM therapy alone for sinobronchial syndrome (SBS), especially during the initial 2 months of treatment. However, there was no data as to whether discontinuation of low‐dose ofloxacin after 2 months results in symptom relapse. This study was designed to clarify this issue.

Bronchial Asthma Showing Reduction in FEV1 after Inhalation of Qvar

The administration of Qvar (a hydrofluoroalkane-134a beclomethasone dipropionate; HFA-BDP) is highly useful for the treatment of patients with asthma. However, we found in a case of bronchial asthma that replacing the prior inhaled corticosteroids with Qvar resulted in temporary dyspnea and reduction in forced expiratory volume in 1 second (FEV1). Qvar contains beclomethasone dipropionate combined with absolute ethanol and an alternative to fluorocarbon. The patient had complicated alcohol-induced asthma. FEV1 decreased markedly and immediately after Qvar inhalation. The Qvar placebo is free of beclomethasone but contains other ingredients (ethanol and fluorocarbon). FEV1 did not decrease after the Qvar placebo, Aldecin inhalation, and Qvar inhalation orally treated with atropine before inhalation of Qvar™. It seems unlikely that the components of Qvar (except beclomethasone) are responsible for the reduction in FEV1 observed immediately after inhalation of Qvar. These findings would be noteworthy when using Qvar for Japanese patients with asthma known to have a relatively high frequency of the complication of alcohol-induced asthma.