Kazunori Gomi

Severe acute interstitial pneumonia and gefitinib

Gefitinib is an oral selective inhibitor of the epidermal growth factor receptor tyrosine kinase that is an effective treatment for patients with advanced non-small cell lung cancer who do not respond to platinum-based chemotherapy. We assessed four patients who had non-small cell lung cancer causing severe acute interstitial pneumonia in association with gefitinib. Although two patients recovered after treatment with steroids, the other two died from progressive respiratory dysfunction. On the basis of autopsies and bilateral distribution of diffuse ground-glass opacities in chest CTs, we diagnosed diffuse alveolar damage, which was consistent with acute interstitial pneumonia. Patients with interstitial pneumonia also had other pulmonary disorders such as previous thoracic irradiation and poor performance status. Physicians should be aware of the alveolar damage induced by gefitinib, especially for patients with these characteristic features.

Randomized Phase II Trial Comparing Amrubicin With Topotecan in Patients With Previously Treated Small-Cell Lung Cancer: North Japan Lung Cancer Study Group Trial 0402

PURPOSE Amrubicin, a new anthracycline agent, and topotecan are both active for previously treated small-cell lung cancer (SCLC). No comparative study of these agents has been reported. This randomized phase II study was conducted to select amrubicin or topotecan for future evaluation. PATIENTS AND METHODS Patients with SCLC previously treated with platinum-containing chemotherapy were randomly assigned to receive amrubicin (40 mg/m(2) on days 1 through 3) or topotecan (1.0 mg/m(2) on days 1 through 5). Patients were stratified by Eastern Cooperative Oncology Group performance status (0, 1, or 2) and type of relapse (chemotherapy sensitive or refractory). The primary end point was overall response rate (ORR), and secondary end points were progression-free survival (PFS), overall survival, and toxicity profile. RESULTS From February 2004 to July 2007, 60 patients were enrolled, and 59 patients (36 patients with sensitive and 23 patients with refractory relapse) were assessable for efficacy and safety evaluation. Neutropenia was severe, and one treatment-related death owing to infection was observed in the amrubicin arm. ORRs were 38% (95% CI, 20% to 56%) for the amrubicin arm and 13% (95% CI, 1% to 25%) for the topotecan arm. In sensitive relapse, ORRs were 53% for the amrubicin arm and 21% for the topotecan arm. In refractory relapse, ORRs were 17% for the amrubicin arm and 0% for the topotecan arm. Median PFS was 3.5 months for patients in the amrubicin arm and 2.2 months for patients in the topotecan arm. Multivariate analysis revealed that amrubicin has more influence than topotecan on overall survival. CONCLUSION Amrubicin may be superior to topotecan with acceptable toxicity for previously treated patients with SCLC. Further evaluation of amrubicin for relapsed SCLC is warranted.

Dendritic Cells Pulsed with Live and Dead Legionella pneumophila Elicit Distinct Immune Responses

Legionella pneumophila is the causative pathogen of Legionnaires’ disease, which is characterized by severe pneumonia. In regard to the pathophysiology of Legionella infection, the role of inflammatory phagocytes such as macrophages has been well documented, but the involvement of dendritic cells (DCs) has not been clarified. In this study, we have investigated the immune responses that DCs generate in vitro and in vivo after contact with L. pneumophila. Heat- and formalin-killed L. pneumophila, but not live L. pneumophila, induced immature DCs to undergo similar phenotypic maturation, but the secreted proinflammatory cytokines showed different patterns. The mechanisms of the DC maturation by heat- or formalin-killed L. pneumophila depended, at least in part, on Toll-like receptor 4 signaling or on Legionella LPS, respectively. After transfer to naive mice, DCs pulsed with dead Legionella produced serum Ig isotype responses specific for Legionella, leading to protective immunity against an otherwise lethal respiratory challenge with L. pneumophila. The in vivo immune responses required the Ag presentation of DCs, especially that on MHC class II molecules, and the immunity yielded cross-protection between clinical and environmental strains of L. pneumophila. Although the DC maturation was impaired by live Legionella, macrophages were activated by live as well as dead L. pneumophila, as evidenced by the up-regulation of MHC class II. Finally, DCs, but not macrophages, exhibited a proliferative response to live L. pneumophila that was consistent with their cell cycle progression. These findings provide a better understanding of the role of DCs in adaptive immunity to Legionella infection.

Association between Mycobacterial Genotypes and Disease Progression in Mycobacterium avium Pulmonary Infection

Background: Non-tuberculous mycobacterial lung disease, most commonly caused by Mycobacterium avium infection, tends to show variable disease progression, and significant disease predictors have not been adequately established. Methods: Variable numbers of tandem repeats (VNTR) were evaluated in 16 mycobacterial interspersed repetitive unit (MIRU) loci from M avium isolates cultured from respiratory specimens obtained from 2005 to 2007. Specifically, the association between VNTR profiles and disease progression was assessed. Results: Among the 37 subjects who provided positive respiratory cultures for M avium during the 2005–6 period, 15 subjects were treated within 10 months following a microbiological diagnosis of progressive M avium lung disease. Nine subjects underwent long-term follow-up (>24 months) without treatment for stable M avium lung disease. Based on a neighbour-joining cluster analysis used to classify M avium-positive subjects according to the VNTR profile, subjects with progressive versus stable lung disease were found to be grouped together in distinct clusters. Further analysis using logistic regression modelling showed that disease progression was significantly associated with the genetic distance of the M avium isolate from an appropriately selected reference (age-adjusted odds ratio 1.95; 95% confidence interval 1.16 to 3.30; p = 0.01 for the most significant model). A best-fit model could be used to predict the progression of M avium lung disease when subjects from the 2005–6 period were combined with those from 2007 (p = 0.003). Conclusion: Progressive lung disease due to M avium infection is associated with specific VNTR genotypes of M avium.

Combined efficacy of clarithromycin plus cefazolin or vancomycin against Staphylococcus aureus biofilms formed on titanium medical devices

In this study, we investigated the in vitro efficacy of clarithromycin (CLA) combined with cefazolin (CFZ) or vancomycin (VCM) against Staphylococcus aureus biofilms formed on titanium devices in order to confirm the efficacy of eradication therapies against device-related infection. The distribution of CLA in muscle tissue surrounding bone was also investigated by liquid chromatography/tandem mass spectrometry in 10 orthopaedic patients. Biofilm formation and eradication of S. aureus were monitored by scanning electron microscopy and using double-staining dyes, respectively. Although S. aureus biofilms were not eradicated by CLA, CFZ or VCM alone, CLA combined with CFZ or VCM destroyed biofilms, and S. aureus eradication was clearly observed 72 h later. This in vitro study showed that treatment with CLA plus CFZ or VCM destroyed staphylococcal biofilms formed on medical devices and eradicated S. aureus.

Comparative in vitro Activity of S-4661, a New Parenteral Carbapenem, and Other Antimicrobial Agents against Respiratory Pathogens

The activity of S-4661, a new parenteral carbapenem antibiotic, was evaluated against 202 recent clinical isolates of respiratory pathogens. S-4661 was similar to or 2 times more active than imipenem, meropenem, and biapenem, and 8–128 times more active than ceftazidime against gram-positive bacteria. Against gram-negative bacteria, S-4661 was slightly less active than meropenem, but 2–8 times more active than the other agents. In particular, against Pseudomonas aeruginosa S-4661 showed the most potent activity. Thus it was found that S-4661 possesses a potent and well-balanced activity against respiratory pathogens.

Efficacy of clarithromycin plus vancomycin in mice with implant-related infection caused by biofilm-forming Staphylococcus aureus

BackgroundStaphylococcal biofilms pose an important problem, especially after orthopedic surgery using foreign implants. Clarithromycin (CAM) eliminates the biofilms formed by a wide variety of aerobic and anaerobic bacteria. In a previous in vitro study, we showed that treatment with CAM and vancomycin (VCM) eradicated staphylococcal biofilms from surgical implants. To investigate the efficacy of this eradication therapy, we assessed its effects against Staphylococcus aureus on titanium plates implanted in mice.MethodsA titanium washer covered with S. aureus biofilms was implanted in the muscular tissue around the femoral bone. Mice were given intravenous injections of CAM and intraperitoneal injections of VCM twice daily beginning 72 h after implantation. To confirm eradication of biofilms and S. aureus strains, the resected washer was examined by scanning electron microscopy.ResultsDense colonization and biofilms were seen on the washer implanted in the control mice that received saline, saline plus CAM, or saline plus VCM. Treatment with CAM plus VCM eliminated the biofilms, indicating an S. aureus eradication effect.ConclusionsStaphylococcal biofilms have demonstrated resistance to most antibiotics, including VCM. Our in vivo data support the hypothesis that combined treatment using CAM plus VCM may effectively eradicate staphylococcal biofilms in patients with implant-related infection.

Mycobacterial hypersensitivity pneumonitis requires TLR9–MyD88 in lung CD11b+ CD11c+ cells

Mycobacteria are among the most common causes of hypersensitivity pneumonitis (HP), but controversy persists with regard to the involvement of the infectious potency of the organism in mycobacterial HP (hot tub lung). This study aimed to establish a mouse model of hot tub lung to clarify its pathophysiology. Mice were exposed intranasally to formalin-killed Mycobacterium avium from a patient with hot tub lung (HP strain) or chronic pulmonary infection (non-HP strain), and bronchoalveolar lavage fluids and lung tissues were evaluated for allergic inflammation. Dead M. avium HP strain, but not non-HP strain, elicited marked HP-like pulmonary inflammation in wild-type mice. Although the inflammation was induced in mice lacking CD4 or CD8, the induction of HP-like responses was prevented in mice lacking myeloid differentiation factor (MyD)88 or Toll-like receptor (TLR)9. Cultured lung CD11c+ cells responded to M. avium in a TLR9-dependent manner, and reconstitution of TLR9-/- mice with lung CD11c+ cells from wild-type mice restored the inflammatory responses. Further investigation revealed that pulmonary exposure to M. avium HP strain increased the number of lung CD11b+ CD11c+ cells (dendritic cells) through TLR9 signalling. Our results provide evidence that hot tub lung develops via the mycobacterial engagement of TLR9–MyD88 signalling in lung CD11b+ dendritic cells independent of the mycobacterial infectious capacity.

Mouse and human cell activation by N -dodecanoyl -DL -homoserine lactone, a Chromobacterium violaceum autoinducer

ABSTRACT Chromobacterium violaceum produces autoinducers, including homoserine lactones (HSLs), for genetic regulation. Among the seven HSLs derived from C. violaceum we evaluated, only C12-HSL stimulated the production of inflammatory cytokines in mammalian monocytic cell lines through the activation of the NF-κB signaling pathway besides their quorum-sensing role, like 3-oxo-C12-HSL from Pseudomonas aeruginosa.

Adenocarcinoma With Epidermal Growth Factor Receptor Gene Mutations in Three Siblings

Sensitivity to an inhibitor of epidermal growth factor receptor (EGFR) kinase strongly correlates with EGFR somatic mutations in non-small cell lung cancer. These mutations are frequently found in patients with adenocarcinoma, never- or light-smokers, women, and East Asians. In this study, we show an aggregation of three non-small cell lung cancer cases with EGFR gene mutations in one family. The subjects were all female, never- or light-smokers with adenocarcinoma. Two of the patients responded to treatment with gefitinib. A genetic study of these cases would be useful in elucidating genetic susceptibility to lung cancer in persons with EGFR mutations.