Tadashi Ishida

Rebiopsy of non-small cell lung cancer patients with acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitor: Comparison between T790M mutation-positive and mutation-negative populations.

The secondary epidermal growth factor receptor (EGFR) mutation Thr790Met (T790M) accounts for approximately half of acquired resistances to EGFR‐tyrosine kinase inhibitor (TKI). Recent reports have demonstrated that the emergence of T790M predicts a favorable prognosis and indolent progression. However, rebiopsy to confirm T790M status can be challenging due to limited tissue availability and procedural feasibility, and little is known regarding the differences among patients with or without T790M mutation.

Clinical Practice Guidelines for Nursing- and Healthcare-associated Pneumonia (NHCAP) [Complete translation]

Shigeru Kohno, Yoshifumi Imamura, Yuichiro Shindo, Masafumi Seki, Tadashi Ishida, Shinji Teramoto, Junichi Kadota, Kazunori Tomono, Akira Watanabe Unit of Molecular Microbiology and Immunology, Nagasaki University, Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501 Japan Institute for Advanced Research, Nagoya University, and Department of Respiratory Medicine, Nagoya University, Graduate School of Medicine, Japan Division of Infection Control and Prevention, Osaka University Hospital, Japan Department of Respiratory Medicine, Kurashiki Central Hospital, Japan Hitachinaka Medical Education and Research Center, University of Tsukuba, Japan Department of Internal Medicine II, Oita University Faculty of Medicine, Japan Division of Anti-Infective Agents, Institute of Development, Aging and Cancer, Tohoku University, Japan

Erlotinib after gefitinib failure in relapsed non-small cell lung cancer: Clinical benefit with optimal patient selection

BACKGROUNDnRecent reports have suggested that erlotinib therapy after gefitinib failure requires optimal patient selection to obtain clinical benefits in relapsed non-small cell lung cancer (NSCLC). However, insufficient evidence exists to determine which clinical factors best identify patients who benefit from erlotinib therapy.nnnMETHODSnOne hundred twenty-five patients with relapsed NSCLC who had received erlotinib therapy after gefitinib failure were retrospectively evaluated between January 2008 and May 2009.nnnRESULTSnThe response rate (RR), disease control rate (DCR), and median progression-free survival (PFS) for all patients were 9% (95% confidence interval [CI], 5-15%), 44% (95% CI, 35-53%), and 2.0 months (95% CI, 1.4-2.5 months), respectively. The median survival time was estimated to be 11.8 months (95% CI, 6.4-16.0 months). Using multivariate analysis, good performance status (PS), EGFR mutation-positive status, and benefit from prior gefitinib therapy were identified as significant predictive factors for disease control. Using a proportional hazards model, benefit from prior gefitinib therapy, good PS, and insertion of cytotoxic chemotherapies between gefitinib and erlotinib therapies emerged as significant predictive factors for longer PFS. Thirty-two patients with concomitant PS 0/1, benefit from prior gefitinib therapy, and insertion of cytotoxic chemotherapies between gefitinib and erlotinib therapies benefitted more from erlotinib therapy: RR, 25% (95% CI, 12-43%); DCR, 72% (95% CI, 53-86%); and median PFS, 3.4 months (95% CI, 2.4-4.9 months).nnnCONCLUSIONSnHigher efficacy of erlotinib after gefitinib failure can be achieved with proper patient selection criteria, including good PS, benefit from prior gefitinib therapy, and insertion of cytotoxic chemotherapies between gefitinib and erlotinib therapies.

Complex Mutations in the Epidermal Growth Factor Receptor Gene in Non-small Cell Lung Cancer

Introduction: Mutation of the epidermal growth factor receptor (EGFR) gene can predict the efficacy of EGFR-tyrosine kinase inhibitors. Different mutations have been shown to co-occur in a single tumor. However, the frequency of these so-called “complex mutations” and the efficacy of gefitinib in treating patients with these mutations are unclear. Methods: We investigated the frequency of complex mutations in 783 patients with non-small cell lung cancer seen at our institutes between April 2006 and May 2009. Mutational analysis was performed using the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method. Gefitinib efficacy was evaluated in patients found to have complex mutations. Results: EGFR mutations were detected in 318 (41%) patients, with 21 (6.6%) of these individuals having complex mutations. Sixteen of these 21 patients received gefitinib. The response rate (RR) was 67% (95% confidence interval [CI], 35–90%) and median progression-free survival was 12.2 months (95% CI, 1.3 months to undeterminable). Analysis of RR according to mutation type revealed that patients with deletional mutation in exon 19 (Del-19) and a point mutation in exon 21 (L858R) had a better RR (86%, 6 of 7) than those with other complex mutation patterns such as a point mutation in exon 18 (G719S) + L858R (40%, 2 of 5) (p = 0.2222). The median progression-free survival was also longer in these patients (16.5 months; 95% CI, 1.1 months to undeterminable versus 3.8 months; 95% CI, 0.7–10.0 months) (p = 0.0459). Conclusions: Complex EGFR mutations are not rare. Gefitinib has different efficacy according to the type of complex EGFR mutations. Patients with Del-19 and L858R mutations may benefit more from gefitinib than other types of complex mutations.

Clinical differentiation of atypical pneumonia using Japanese guidelines

Background and objective:u2003 Atypical pneumonia occupies an important position in community‐acquired pneumonia. The aim of this study was to examine whether making a diagnosis of atypical pneumonia is possible based upon the Japanese Respiratory Society guidelines.

Genotypes and Related Factors Reflecting Macrolide Resistance in Pneumococcal Pneumonia Infections in Japan

ABSTRACT Although macrolide-resistant Streptococcus pneumoniae strains possessing either the ermB or mefA gene are very common in Japan, clinical and microbial factors in community-acquired pneumonia (CAP) caused by different macrolide resistance genotypes have not been evaluated. A multicenter study of CAP caused by S. pneumoniae was performed in Japan from 2003 to 2005. A total of 156 isolates were tested for susceptibility to antibiotics correlated with ermB and mefA genotyping. Independent relationships between tested variables and possession of either the ermB or the mefA gene were identified. Of 156 isolates, 127 (81.4%) were resistant to erythromycin, with the following distribution of resistance genotypes: ermB alone (50.0%), mefA alone (23.7%), and both ermB and mefA (7.1%). All isolates were susceptible to telithromycin. By multivariate analysis, oxygen saturation of <90% on admission increased the risk for ermB-positive pneumococcal pneumonia (odds ratio [OR] = 11.1; 95% confidence interval [CI] = 1.30 to 95.0; P = 0.03), but there were no associations with mefA or with ermB mefA positivity. Penicillin nonsusceptibility was associated with mefA-positive and with ermB- and mefA-positive isolates (OR = 14.2; 95% CI = 4.27 to 46.9; P < 0.0001 and P < 0.0001, respectively) but not with ermB-positive isolates. The overall patient mortality was 5.1%. Mortality, the duration of hospitalization, and the resolution of several clinical markers were not associated with the different erythromycin resistance genotypes. In Japan, S. pneumoniae with erythromycin resistance or possession of ermB, mefA, or both genes was highly prevalent in patients with CAP. The risk factors for ermB-positive, mefA-positive, and double ermB-mefA-positive pneumococcal pneumonia were different, but the clinical outcomes did not differ.

Differentiation of bacterial and non-bacterial community-acquired pneumonia by thin-section computed tomography

n Abstractn n Background and objectiven The management of community-acquired pneumonia (CAP) depends, in part, on the identification of the causative agents. The objective of this study was to determine the potential of thin-section computed tomography (CT) in differentiating bacterial and non-bacterial pneumonia.n n n Patients and methodsn Thin-section CT studies were prospectively examined in hospitalized CAP patients within 2 days of admission, followed by retrospective assessment by two pulmonary radiologists. Thin-section CT findings on the pneumonias caused by each pathogen were examined, and two types of pneumonias were compared. Using multivariate logistic regression analyses, receiver operating characteristic (ROC) curves were produced.n n n Resultsn Among 183 CAP episodes (181 patients, 125 men and 56 women, mean age±S.D.: 61.1±19.7) examined by thin-section CT, the etiologies of 125 were confirmed (94 bacterial pneumonia and 31 non-bacterial pneumonia). Centrilobular nodules were specific for non-bacterial pneumonia and airspace nodules were specific for bacterial pneumonia (specificities of 89% and 94%, respectively) when located in the outer lung areas. When centrilobular nodules were the principal finding, they were specific but lacked sensitivity for non-bacterial pneumonia (specificity 98% and sensitivity 23%). To distinguish the two types of pneumonias, centrilobular nodules, airspace nodules and lobular shadows were found to be important by multivariate analyses. ROC curve analysis discriminated bacterial pneumonia from non-bacterial pneumonia among patients without underlying lung diseases, yielding an optimal point with sensitivity and specificity of 86% and 79%, respectively, but was less effective when all patients were analyzed together (70% and 84%, respectively).n n n Conclusionn Thin-section CT examination was applied for the differentiation of bacterial and non-bacterial pneumonias. Though showing some potential, this examination at the present time would not be applicable for patients with underlying lung diseases, severe conditions of pneumonia, or immunocompromised conditions.n n

Interstitial lung disease in clinically amyopathic dermatomyositis with and without anti-MDA-5 antibody: to lump or split?

BackgroundInterstitial lung disease (ILD) associated with clinically amyopathic dermatomyositis (CADM-ILD) is often refractory and rapidly progressive. Although the anti-melanoma differentiation-associated gene 5 (anti-MDA-5) antibody is associated with rapidly progressive ILD (RP-ILD), differences in clinical features and prognosis of anti-MDA-5 antibody-positive and -negative CADM-ILD remain unclear.MethodsTo clarify the differences in the clinical features and prognosis between anti-MDA-5 antibody-positive and -negative cases, we retrospectively reviewed the medical records of patients diagnosed with CADM-ILD with and without anti-MDA-5 antibody at Kurashiki Central Hospital from January 2005 to September 2014.ResultsAnti-MDA-5 antibody was found in 10 of 16 patients (63xa0%). The levels of Krebs von den Lungen-6 (KL-6) and surfactant protein D (SP-D) at the first visit were significantly lower in positive patients than in negative patients, whereas the levels of aspartate aminotransferase (AST), γ-glutamyl transpeptidase (γ-GTP), and the CD4+/CD8+ ratio in the bronchoalveolar lavage (BAL) fluid were significantly higher in positive patients than negative patients. Subpleural ground-glass opacity (GGO) or irregular linear opacity was predominant in positive patients. Peribronchovascular consolidation was predominant in negative patients. Positive patients had significantly lower survival rates than negative patients, with all six fatal cases occurring in positive patients who died of refractory ILD within 92xa0days from the first visit despite intensive treatment.ConclusionsThere are clear differences in the clinical features and prognosis of anti-MDA-5 antibody-positive and -negative CADM-ILD. Low serum KL-6 and SP-D levels, high serum AST and γ-GTP levels, high CD4+/CD8+ ratio in BAL fluid, and predominance of subpleural GGO or irregular linear opacity in HRCT may help to discriminate anti-MDA-5 antibody-positive CADM-ILD with poor prognosis.

High prevalence of multidrug-resistant Pneumococcal molecular epidemiology network clones among Streptococcus pneumoniae isolates from adult patients with community-acquired pneumonia in Japan

A total of 141 Streptococcus pneumoniae isolates from patients with community-acquired pneumonia were collected from May 2003 through October 2004. The strains were tested for antimicrobial agent susceptibility, serotype and genotype by multilocus sequence typing (MLST) and the presence of the pilus rlrA islet. MLST analysis identified 49 sequence types (STs), of which 19 were novel. eBURST analysis using the MLST database (3773 STs) grouped the isolates into 27 clonal complexes and three singletons. A total of 92 (65.2%) isolates were related to ten of the 43 international Pneumococcal Molecular Epidemiology Network (PMEN) clones; major clones found were multidrug-resistant Netherlands(3)-31 [clonal complex (CC) 180], Taiwan(19F)-14 (CC271), Taiwan(23F)-15 (CC242), and Colombia(23F)-26 (CC138) (the latter new to Asia). We adopted univariate and multiple logistic regression models to identify factors associated with PMEN CCs. Multivariate analysis showed that multidrug resistance (OR 6.3; 95% CI 2.0-22.9), carriage serogroups (OR 7.2; 95% CI 2.5-23.7), prevalence of rlrA (OR 12.6; 95% CI 3.6-59.7) and central nervous system-related disorders (OR 7.7; 95% CI 1.8-48.4) were independently associated with PMEN CCs. Our data indicate that multidrug-resistant PMEN clones are highly prevalent, contributing to the high frequency of resistance to antimicrobial agents in Japan, and suggest that certain predisposing factors in patients contribute to the high frequency of these clones.

Antimicrobial susceptibilities of Streptococcus pneumoniae isolated from adult patients with community‐acquired pneumonia in Japan

Background and objective:u2003 Streptococcus pneumoniae (S.u2003pneumoniae) is the most common pathogen associated with community‐acquired pneumonia and its resistance to antimicrobials is a worldwide problem. The aim of this study was to investigate the current drug susceptibilities of S.u2003pneumoniae isolated from adult patients with community‐acquired pneumonia in Japan.