Tomoyuki Araya

Evaluation of epidermal growth factor receptor mutation status in serum DNA as a predictor of response to gefitinib (IRESSA).

The aim of this study was to evaluate the usefulness of EGFR mutation status in serum DNA as a means of predicting a benefit from gefitinib (IRESSA) therapy in Japanese patients with non-small cell lung cancer (NSCLC). We obtained pairs of tumour and serum samples from 42 patients treated with gefitinib. EGFR mutation status was determined by a direct sequencing method and by Scorpion Amplification Refractory Mutation System (ARMS) technology. EGFR mutations were detected in the tumour samples of eight patients and in the serum samples of seven patients. EGFR mutation status in the tumours and serum samples was consistent in 39 (92.9%) of the 42 pairs. EGFR mutations were strong correlations between both EGFR mutation status in the tumour samples and serum samples and objective response to gefitinib (P<0.001). Median progression-free survival time was significantly longer in the patients with EGFR mutations than in the patients without EGFR mutations (194 vs 55 days, P=0.016, in tumour samples; 174 vs 58 days, P=0.044, in serum samples). The results suggest that it is feasible to use serum DNA to detect EGFR mutation, and that its potential as a predictor of response to, and survival on gefitinib is worthy of further evaluation.

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.

Usefulness of transesophageal bronchoscopic ultrasound-guided fine-needle aspiration in the pathologic and molecular diagnosis of lung cancer lesions adjacent to the esophagus.

Background:The discovery of driver oncogenes has increased the need to obtain a sufficient amount of tissue specimens for lung cancer diagnosis. Although endoscopic ultrasound (with bronchoscope)-guided fine-needle aspiration (EUS-B-FNA) is reportedly a feasible and well-tolerated modality, additional advantages of EUS-B-FNA are yet to be thoroughly investigated. The purpose of this study was to evaluate the ability of EUS-B-FNA to obtain sufficient tissue specimens for pathologic and molecular diagnoses of lung cancer. Methods:Among lung cancer patients who were diagnosed between December 2010 and December 2012 in our institute, patients who underwent EUS-B-FNA to diagnose lung cancer were enrolled (n=26). EUS-B-FNA was performed when bronchoscopic diagnosis was impossible or difficult to obtain sufficient samples. Epidermal growth factor receptor (EGFR) mutations and echinoderm microtubule-associated protein-like 4 and the anaplastic lymphoma kinase (EML4-ALK) fusion gene were evaluated using EUS-B-FNA samples of non–small cell lung cancer. Results:EUS-B-FNA was performed on 28 lesions in 26 patients. Among the target lesions, 23 were mediastinal lymph nodes including nodal stations 2L, 4L, 7, 8, and 10L. The remaining 5 were intrapulmonary lesions. EUS-B-FNAs were completed without complications in all the patients. The diagnostic yield of EUS-B-FNA in diagnosing lung cancer was 100% (26/26). Additional diagnostic gain of EUS-B-FNA was 69.2% (18/26) as compared to bronchoscopy alone. EGFR mutations and EML4-ALK fusion gene could be evaluated in all patients with non–small cell lung cancer (n=20) using EUS-B-FNA samples. One case with EGFR mutation and 1 case with ALK fusion gene were diagnosed. Six non–small cell carcinomas were also diagnosed by bronchoscopy, but all bronchoscopic samples were insufficient to evaluate mutation analyses. Conclusions:EUS-B-FNA is a practical and feasible method to obtain abundant tumorous tissue samples for pathologic diagnosis and molecular analysis, particularly when the target lesions are inaccessible by other modalities because of their locations or because of the patient’s poor physical condition.

Antitumor effects of inductive hyperthermia using magnetic ferucarbotran nanoparticles on human lung cancer xenografts in nude mice

Background The effects of inductive hyperthermia on lung cancer have yet to be fully investigated. Magnetic nanoparticles used in inductive hyperthermia are made-to-order and expensive. This study was performed to investigate the use of ferucarbotran in inductive hyperthermia and to clarify whether inductive hyperthermia using ferucarbotran promotes antitumor effects in vivo using a lung cancer cell line. Methods We injected A549 cells subcutaneously into the right thighs of BALB/c nu/nu nude mice. Forty mice with A549 xenografts were then classified into three groups. Group 1 was the control group. All mice in groups 2 and 3 had ferucarbotran injected into their tumors, and mice in group 3 were then subjected to alternating magnetic field irradiation. We evaluated tumor temperature during the hyperthermic procedure, the time course of tumor growth, histologic findings in tumors after hyperthermic treatment, and adverse events. Results Intratumor temperature rose rapidly and was maintained at 43°C–45°C for 20 minutes in an alternating magnetic field. Tumor volumes in groups 1 and 2 increased exponentially, but tumor growth in group 3 was significantly suppressed. No severe adverse events were observed. Histologic findings for the tumors in group 3 revealed mainly necrosis. Conclusion Inductive hyperthermia using ferucarbotran is a beneficial and promising approach in the treatment of lung cancer. Ferucarbotran is a novel tool for further development of inductive hyperthermia.

18F-FDG uptake predicts diagnostic yield of transbronchial biopsy in peripheral lung cancer

OBJECTIVES Recent advances in endobronchial ultrasonography with a guide sheath (EBUS-GS) have enabled better visualization of distal airways, while virtual bronchoscopic navigation (VBN) has been shown useful as a guide to navigate the bronchoscope. However, indications for utilizing VBN and EBUS-GS are not always clear. To clarify indications for a bronchoscopic examination using VBN and EBUS-GS, we evaluated factors that predict the diagnostic yield of a transbronchial biopsy (TBB) procedure for peripheral lung cancer (PLC) lesions. METHODS We retrospectively reviewed the charts of 194 patients with 201 PLC lesions (≤3cm mean diameter), and analyzed the association of diagnostic yield of TBB with [(18)F]-fluoro-2-deoxy-d-glucose ((18)F-FDG) positron emission tomography and chest computed tomography (CT) findings. RESULTS The diagnostic yield of TBB using VBN and EBUS-GS was 66.7%. High maximum standardized uptake value (SUVmax), positive bronchus sign, and ground-glass opacity component shown on CT were all significant predictors of diagnostic yield, while multivariate analysis showed only high (18)F-FDG uptake (SUVmax ≥2.8) and positive bronchus sign as significant predictors. Diagnostic yield was higher for PLC lesions with high (18)F-FDG uptake (SUVmax ≥2.8) and positive bronchus sign (84.6%) than for those with SUVmax <2.8 and negative bronchus sign (33.3%). High (18)F-FDG uptake was also correlated with tumor invasiveness. CONCLUSIONS High (18)F-FDG uptake predicted the diagnostic yield of TBB using VBN and EBUS-GS for PLC lesions. (18)F-FDG uptake and bronchus sign may indicate for the accurate application of bronchoscopy with those modalities for diagnosing PLC.

IgG4-Related Pleuritis With No Other Organ Involvement

A 65-year-old man was admitted for productive cough and dyspnea. Bilateral pleural effusions were observed on chest X-ray. Although the bilateral pleural effusions were exudative with an increased number of lymphocytes, bacterial culture and polymerase chain reaction analysis for Mycobacterium tuberculosis were negative. Immunological examinations showed high levels of immunoglobulin G4 (IgG4) in both serum and pleural effusion fluid. Pathologic evaluation of a left pleural biopsy specimen using hematoxylin and eosin staining and immunohistochemical staining showed fibrosis-associated lymphoplasmacytic infiltration, 50 IgG4-positive plasma cells per high-power field, and an IgG4/IgG ratio of 40%. Thus, a diagnosis of IgG4-related pleuritis without other systemic manifestations was established. The bilateral pleural effusion improved following corticosteroid therapy. This is a rare case of IgG4-related pleuritis with no other organ involvement.

Successful treatment with erlotinib of severe neutropenia induced by gefitinib in a patient with advanced non-small cell lung cancer

Neutropenia is a rare side effect of gefitinib and was scarcely reported in many large-scale randomized phase III trials using gefitinib monotherapy as first-line treatment. A 77-year-old female was referred to our institution due to abnormal shadow of the right lung, diagnosed by CT scan and biopsy histopathology as adenocarcinoma of the lung (cT3N1M1b). Mutation analysis with PCR-Invader assay of tumor DNA samples revealed short in-frame deletion in exon 19. Based on the diagnosis, first-line treatment was initiated using oral gefitinib (250 mg, daily). During the initial 27 days of gefitinib therapy, the only side effect was a mild skin rash. After 28 days, there was marked tumor shrinkage, indicative of a partial response to gefitinib; however, grade 4 neutropenia was also detected. The patient was switched to the oral erlotinib monotherapy (150 mg/day) as second-line chemotherapy with careful monitoring of neutropenia. Discontinuation of the gefitinib, without the need for granulocyte colony-stimulating factor support, was successful in allowing the neutrophils and leukocytes counts to recover to normal by day 47. The patient continued oral erlotinib for more than 9 months and there has been no evidence of neutropenia, leukopenia, or disease progression. Clinicians should be aware that gefitinib-induced neutropenia in patients with non-small cell lung cancer can be treated successful by switching to erlotinib.

Plasma EGFR and Her2 levels in non-small cell lung cancer patients treated with gefitinib

19007 Background: Although EGFR mutation is a strong predictive factor of EGFR-TKI, it is difficult to obtain tumor tissue which is suitable to examine EGFR mutations in patients (pts) with metasta...