Mitsudomi T.,Aichi Cancer Center Hospital |
Morita S.,Yokohama City University |
Yatabe Y.,Aichi Cancer Center Hospital |
Negoro S.,Hyogo Cancer Center |
And 16 more authors.
The Lancet Oncology | Year: 2010
Background: Patients with non-small-cell lung cancer harbouring mutations in the epidermal growth factor receptor (EGFR) gene respond well to the EGFR-specific tyrosine kinase inhibitor gefitinib. However, whether gefitinib is better than standard platinum doublet chemotherapy in patients selected by EGFR mutation is uncertain. Methods: We did an open label, phase 3 study (WJTOG3405) with recruitment between March 31, 2006, and June 22, 2009, at 36 centres in Japan. 177 chemotherapy-naive patients aged 75 years or younger and diagnosed with stage IIIB/IV non-small-cell lung cancer or postoperative recurrence harbouring EGFR mutations (either the exon 19 deletion or L858R point mutation) were randomly assigned, using a minimisation technique, to receive either gefitinib (250 mg/day orally; n=88) or cisplatin (80 mg/m2, intravenously) plus docetaxel (60 mg/m2, intravenously; n=89), administered every 21 days for three to six cycles. The primary endpoint was progression-free survival. Survival analysis was done with the modified intention-to-treat population. This study is registered with UMIN (University Hospital Medical Information Network in Japan), number 000000539. Findings: Five patients were excluded (two patients were found to have thyroid and colon cancer after randomisation, one patient had an exon 18 mutation, one patient had insufficient consent, and one patient showed acute allergic reaction to docetaxel). Thus, 172 patients (86 in each group) were included in the survival analyses. The gefitinib group had significantly longer progression-free survival compared with the cisplatin plus docetaxel goup, with a median progression-free survival time of 9·2 months (95% CI 8·0-13·9) versus 6·3 months (5·8-7·8; HR 0·489, 95% CI 0·336-0·710, log-rank p<0·0001). Myelosuppression, alopecia, and fatigue were more frequent in the cisplatin plus docetaxel group, but skin toxicity, liver dysfunction, and diarrhoea were more frequent in the gefitinib group. Two patients in the gefitinib group developed interstitial lung disease (incidence 2·3%), one of whom died. Interpretation: Patients with lung cancer who are selected by EGFR mutations have longer progression-free survival if they are treated with gefitinib than if they are treated with cisplatin plus docetaxel. Funding: West Japan Oncology Group (WJOG): a non-profit organisation supported by unrestricted donations from several pharmaceutical companies. © 2010 Elsevier Ltd. All rights reserved.
Hirota T.,RIKEN |
Takahashi A.,RIKEN |
Kubo M.,RIKEN |
Tsunoda T.,RIKEN |
And 24 more authors.
Nature Genetics | Year: 2011
Bronchial asthma is a common inflammatory disease caused by the interaction of genetic and environmental factors. Through a genome-wide association study and a replication study consisting of a total of 7,171 individuals with adult asthma (cases) and 27,912 controls in the Japanese population, we identified five loci associated with susceptibility to adult asthma. In addition to the major histocompatibility complex and TSLP-WDR36 loci previously reported, we identified three additional loci: a USP38-GAB1 locus on chromosome 4q31 (combined P = 1.87×10 -12), a locus on chromosome 10p14 (P = 1.79 ×-10-15) and a gene-rich region on chromosome 12q13 (P = 2.33 ×10 -13). We observed the most significant association with adult asthma at rs404860 in the major histocompatiblity complex region (P = 4.07× 10 -23), which is close to rs2070600, a SNP previously reported for association with FEV 1/FVC in genome-wide association studies for lung function. Our findings offer a better understanding of the genetic contribution to asthma susceptibility. © 2011 Nature America, Inc. All rights reserved.
A phase 3 study of induction treatment with concurrent chemoradiotherapy versus chemotherapy before surgery in patients with pathologically confirmed N2 stage IIIA nonsmall cell lung cancer (WJTOG9903)
Katakami N.,Kobe City Medical Center General Hospital |
Tada H.,Osaka City General Hospital |
Mitsudomi T.,Aichi Cancer Center |
Kudoh S.,Osaka City University |
And 6 more authors.
Cancer | Year: 2012
BACKGROUND: This study sought to ascertain whether induction-concurrent radiotherapy added to chemotherapy could improve the survival of patients undergoing surgery for stage IIIA N2 nonsmall cell lung cancer (NSCLC). METHODS: Patients with pathologically proven N2 disease were randomized to receive either induction chemotherapy (docetaxel 60 mg/m2 and carboplatin AUC [area under the receiver operating characteristic curve] = 5 for 2 cycles) plus concurrent radiation therapy (40 Gy) followed by surgery (CRS arm) or induction chemotherapy followed by surgery (CS arm). They subsequently underwent pulmonary resection when possible. RESULTS: Sixty patients were randomly assigned between December 2000 and August 2005. The study was prematurely terminated in January 2006 because of slow accrual. The most common toxicity was grade 3 or 4 leukopenia in 92.9% of patients in the CRS arm and 46.4% in the CS arm. Induction therapy was generally well tolerated, and there were no treatment-related deaths in either arm. Downstaging in the CS arm and CRS arm was 21% and 40%, respectively. The progression-free survival (PFS) and overall survival (OS) in the CS arm were 9.7 months and 29.9 months (PFS, hazard ratio [HR] = 0.68, P =.187), and those in the CRS arm were 12.4 months and 39.6 months (OS, HR = 0.77, P =.397), respectively. The PFS with and without downstaging was 55.0 and 9.4 months, respectively (HR = 3.39, P =.001). The OS with and without downstaging was 63.3 and 29.5 months, respectively (HR = 2.62, P =.021). CONCLUSIONS: The addition of radiotherapy to induction chemotherapy conferred better local control without significant adverse events. Tumor downstaging is important for prolonging the OS in patients with stage IIIA (N2) NSCLC. © 2012 American Cancer Society.
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.
Matsumoto T.,Osaka Prefectural Medical Center for Respiratory and Allergic Diseases
Kekkaku : [Tuberculosis] | Year: 2013
Multidrug resistance (MDR) involves resistance to both isoniazid and rifampicin, which makes the treatment of tuberculosis very difficult. Extensive drug resistance (XDR) occurs when, in addition to isoniazid and rifampicin resistance, the microorganisms are resistant to a fluoroquinolone and an injectable agent (e.g., kanamycin, amikacin, or capreomycin). Generally, drug susceptibility testing takes more than 3-4 weeks after the initial cultivation. There is an urgent need to identify methods that can rapidly detect both the presence of Mycobacterium tuberculosis and the status of drug resistance. This study was aimed at evaluating the line probe assay (LiPA; Nipro Co.), for the identification of Mycobacterium species and detection of mutations associated with antituberculous drugs. We found that LiPA enabled the rapid identification of M. tuberculosis, M. avium, M. intracellulare, and M. kansasii. When the results of the LiPA and conventional drug susceptibility tests were compared, there was no difference in the susceptibility to rifampicin, pyrazinamide, and levofloxacin; however, there was a difference in the susceptibility to isoniazid. Thus, LiPA can be used for the rapid identification of Mycobacterium species and the determination of susceptibility to drugs, which can help in the early initiation of appropriate treatment, leading to a reduction in infectiousness.
Kataoka Y.,Osaka Prefectural Medical Center for Respiratory and Allergic Diseases
Journal of Dermatology | Year: 2014
Thymus and activation-regulated chemokine (TARC/CCL17) is a member of the T-helper 2 chemokine family. In Japan, serum TARC level has been commercially measured since 2008. After years of experience, we realized that TARC is an extremely useful clinical biomarker for atopic dermatitis (AD) treatment. Usually, physicians conduct a visual examination to determine whether their treatment has been successful; however, the visual examination results may not always be accurate; in such cases, serum TARC levels should be measured to eliminate any ambiguity regarding the treatment outcome. When the waning and waxing of eczema and fluctuations in the serum TARC levels were considered, we frequently found that AD does not follow a natural course but follows non-regulated inflammatory floating caused by insufficient intermittent topical treatment. Serum TARC is a promising biomarker for remission and can be used for accurately monitoring proactive treatment for long-term control. Abnormally high serum TARC levels indicate accelerated pathogenesis of cutaneous inflammation. Rapid normalization and maintaining normal serum TARC levels using appropriate topical treatment is a reasonable strategy for alleviating inflammation without upregulating cytokine expression. Observing serum TARC levels during early intervention for severe infantile AD is worthwhile to determine initial disease activity and evaluate treatment efficacy. Appropriate control of severe early-onset infantile AD is important for improving prognosis of eczema and for preventing food allergies. Additionally, this biomarker is useful for improving patient adherence. Dermatologists will be able to make great progress in treating AD by adopting biomarkers such as TARC for accurately assessing non-visible subclinical disorders. © 2014 Japanese Dermatological Association.
Kataoka Y.,Osaka Prefectural Medical Center for Respiratory and Allergic Diseases
Skin Research | Year: 2013
More than ten years has passed after publication of Japanese guideline for atopic dermatitis treatment. However there are still considerable numbers of patients who suffer from severe symptoms which deteriorate their quality of life. In the author's view this is because atopic dermatitis is a tricky disease that has several pitfalls which traps even medical personnel. Three pitfalls are described and the way of solution and importance of appropriate anti-inflammatory treatment is emphasized. 1. Pitfall for therapeutic goal: Considerable numbers of patients loose the way of treatment because of obscure therapeutic goal and indefinite therapeutic schedule. They should be obvious. 2. Pitfall for situation of aggravating factor elimination and anti-inflammatory treatment: Persistent cutaneous inflammation induces more aggravating factors to fall into vicious circle. Management for emotional stress without anti-inflammatory treatment achieves no goal. Allergen specific IgE is not only a cause but product of skin inflammation. 3. Pitfall of topical corticosteroid treatment: Topical corticosteroid application method should be reconsidered precisely and scientifically. Several clinical evidences and practical benefit reveal that the concept of treatment strategy should be "tight control" which achieves early complete remission and long-term maintenance of scarce inflammation even subclinical. Precise procedures of adequate topical corticosteroid application based on "proactive therapy" acompanied with educational support to accomplish the treatment goal were proposed.
Matsuno O.,Osaka Prefectural Medical Center for Respiratory and Allergic Diseases
Respiratory Research | Year: 2012
Drug-induced interstitial lung disease (DILD) is not uncommon and has many clinical patterns, ranging from benign infiltrates to life-threatening acute respiratory distress syndrome. There are two mechanisms involved in DILD, which are probably interdependent: one is direct, dose-dependent toxicity and the other is immune-mediated. Cytotoxic lung injury may result from direct injury to pneumocytes or the alveolar capillary endothelium. Drugs can induce all types of immunological reactions described by Gell and Coombs; however, most reactions in immune-mediated DILD may be T cell-mediated.DILD can be difficult to diagnose; diagnosis is often possible by exclusion alone. Identifying the causative drug that induces an allergy or cytotoxicity is essential for preventing secondary reactions.One method to confirm the diagnosis of a drug-induced disease is re-exposure or re-test of the drug. However, clinicians are reluctant to place patients at further risk of illness, particularly in cases with severe drug-induced diseases. Assessment of cell-mediated immunity has recently increased, because verifying the presence or absence of drug-sensitized lymphocytes can aid in confirmation of drug-induced disease. Using peripheral blood samples from drug-allergic patients, the drug-induced lymphocyte stimulation test (DLST) and the leukocyte migration test (LMT) can detect the presence of drug-sensitized T cells. However, these tests do not have a definite role in the diagnosis of DILD. This study explores the potential of these new tests and other similar tests in the diagnosis of DILD and provides a review of the relevant literature on this topic. © 2012 Matsuno; licensee BioMed Central Ltd.
Kadota Y.,Osaka Prefectural Medical Center for Respiratory and Allergic Diseases
Kyobu geka. The Japanese journal of thoracic surgery | Year: 2012
Autoimmune diseases arise from an inappropriate immune response against substances and tissues normally present in the body. Although the pathogenesis are still unclear, several autoimmune diseases, such as dermatomyositis, systemic sclerosis, have a higher incidence of thoracic neoplasm. Also in the mediastinum several autoimmune diseases are known to associate thymoma. While the manifestations of the disease diverse, administration of immunosuppressant are commonly used for the management of aberrant immune response. Immunosuppressive therapies likely to increase susceptibility to infections and associate other side-effects, which could increase the risk of surgery and complicate the perioperative management. In this article we discuss the autoimmune diseases which are known to associate with thoracic and mediastinal neoplasms, and the perioperative management of thoracic surgery in patients with autoimmune diseases.
Kataoka Y.,Osaka Prefectural Medical Center for Respiratory and Allergic Diseases
Skin Research | Year: 2014
Topical corticosteroid is well known as the most effective topical anti-inflammatory agents for atopic dermatitis at this time. However considerable numbers of patients are suffering from persistent refractory severe dermatitis as a result of inappropriate topical corticosteroid treatment. In such cases there seems to be several pitfalls that prevent physicians to reach the treatment goal such as insufficient comprehension of significance of anti-inflammatory effect, misevaluation of treatment outcome or ignorance of patient's low adherence. To solve those problems topical corticosteroid treatment strategy with conscious of time course to reach the goal was proposed. It is accurate proactive treatment combined with monitoring serum biomarker thymus and activation-regulated chemokine (TARC). This strategy is composed of remission induction followed by control of subclinical inflammation with tapering of topical application frequency. In the treatment schedule of atopic dermatitis physicians should recognize the two-step strategic goal. First step is to induce and maintain remission with anti-inflammatory agent; second step is the final goal of long term remission with minimal anti-inflammatory agent.