[A case of pulmonary Mycobacterium avium infection presenting multiple nodules with substantial difference in 18F-fluorodeoxyglucose uptake].

A 56-year-old man presented with a chief complaint of chronic cough due to bronchial asthma and pulmonary emphysema in 2001, without any abnormal findings on chest CT. His symptoms improved with high-dose inhaled corticosteroid. In February 2004, multiple nodules without bronchiectasis appeared in the chest CT. Pulmonary Mycobacterium avium infection was diagnosed by bronchial lavage and sputum culture. After multiple nodules appeared and disappeared repeatedly without medication, most nodules vanished after administration of antituberculous drugs. In Feburary 2007, a rapidly growing mass appeared in the right upper lobe, and a new nodule emerged in the left upper lobe the following month. On 18F-fluorodeoxyglucose positron emission tomography (18 FDG-PET), a substantial difference in 18FDG uptake was observed although both lesions were shown to be caused by Mycobacterium avium infection by needle biopsy. The lung specimen of the lesion with high 18FDG uptake demonstrated neutrophil infiltrates, suggesting acute inflammation. On the other hand, neutrophil infiltrates were not observed in the lesion with low uptake. We conclude that the degree of 18FDG uptake is not useful to decide when to initiate therapy and evaluate the efficacy of treatment.

[Usefulness of monitoring plasma voriconazole concentration in patients with chronic necrotizing pulmonary aspergillosis].

We investigated the significance and the usefulness of monitoring plasma voriconazole levels in patients with chronic necrotizing pulmonary aspergillosis associated with underlying chronic respiratory diseases. The average trough level was 2.2 microg/ml and there was no correlation between trough levels and voriconazole doses. Orally administered drug showed no significant difference in trough or peak levels compared with parenteral injection. Six cases with visual adverse events had significantly higher nadirs compared to those without visual disturbance. All three cases who discontinued the drug due to liver dysfunction had plasma trough levels higher than 4.0 microg/ml. Those who failed to respond to the treatment had trough levels lower than 1.4 microg/ml or peak levels lower than 2.8 microg/ml, while some cases with plasma level lower than those levels responded well. Since plasma voriconazole level has a large inter-patient variability, drug monitoring may be beneficial to evaluate the drug efficacy and safety in each individual.

[Outcome of patients with acute exacerbation of idiopathic interstitial fibrosis (IPF) treated with sivelestat and the prognostic value of serum KL-6 and surfactant protein D].

Idiopathic interstitial fibrosis (IPF) is a chronic, usually fatal lung disease of unknown etiology. There are few specific therapies for acute exacerbation of IPF and factors predicting the onset or severity of this syndrome are not clearly understood. A neutrophil elastase inhibitor, sivelestat (ONO-5046) has been commercially available in Japan since 2002. This inhibitor has a potent effect in the treatment of ALI/ARDS. To evaluate the outcome of patients with acute exacerbation of IPF treated with sivelestat and estimate prognostic factors, we investigated 10 patients with acute exacerbation of IPF who were intubated and mechanically ventilated. We analyzed the outcome of patients with acute exacerbation of IPF until day 180 and measured the P/F ratio, PEEP levels, the values of peripheral white blood cell number, and C-reactive protein (CRP) on day 0, 3, 7 after admission. Serum KL-6 and surfactant protein D (SP-D) concentration on day 0 were also analyzed. All patients were treated with sivelestat and methylprednisolone (mPSL) pulse therapy for 3 days from day 0 and maintenance therapy with prednisone (0.5 mg/kg/day) were continued. Of the 10 patients. 4 patients had survived (40%) and 6 patients had died (60%) at day 180 from the onset of acute exacerbation of IPF. In survivors, P/F ratio, PEEP levels, and CRP values significantly improved on day 7 (p<0.05). Serum KL-6 and SP-D were lower in survivors on day 0 (p<0.05). Taken together, serum KL-6 and SP-D may prove valuable as biochemical markers of prognosis in acute exacerbation of IPF. Sivelestat may have potential in the treatment of acute exacerbation of IPF.

[Familial occurrence of bronchiolitis obliterans associated with pulmonary aspergillosis].

We report the familial occurrence of bronchiolitis obliterans (BO) associated with pulmonary aspergillosis. A mother and daughter admitted for dyspnea after taking Sauropus androgynus both had overfiltration of both lungs in chest X-ray and severe obstructive impairment in lung function tests. They were initially diagnosed with severe asthma and treated with high-dose prednisolone (0.5mg/kg/day) for 1 month to no effects. They did not show reversibility in lung function test. They were difinitively diagnosed with BO associated with Sauropus androgynus. Six months later, the mother's symptoms worsened with productive sputum and severe dyspnea, and her chest X-ray showed patty shadow in both upper lung fields. Precipitating antibodies to aspergillus antigen were positive and aspergillus fumigatus was detected from her sputum culture. She was diagnosed with aspergillosis and treatment with Micafungin (MCFG) and Itraconazole (ITCZ) was started. The daughter's symptoms also worsened and her chest tomography showed multiple cavities in both lung fields. Precipitating antibodies to aspergillus were positive. She was diagnosed with Invasive aspergillosis. She was treated unsuccessfully with MCFG and Amphotericin B (AMPH) and ITCZ. Few reports cover BO with aspergillus infection without organ impairment. In these 2 cases, treatment with steroids' or immune suppression of the lung with BO may a trigger aspergillus infection.

[Familial occurrence of bronchiolitis obliterans associated with sauropus androgynus].

We experienced familial occurrence of bronchiolitis obliterans (BO) associated with Sauropus androgynus. The cases were a mother and daughter and both were admitted to our hospital because of dyspnea after taking Sauropus androgynus. Both cases had hyperinflation of both lungs in chest x-ray and lung function test showed severe obstructive impairment. At first, they were given a diagnosis of severe asthma and treated as such. However, neither their symptoms nor lung function improved. They did not show any reversibility on lung function tests. Although we did not perform histological examination of the lung, they were given a diagnosis of BO associated with Sauropus androgynus (SABO), because of the following reasons. Cases of SABO in Taiwan have already been demonstrated in the 1990's, and there were no other reasons to explain their severe airflow obstruction. Neither bronchodilators nor steroid treatment improved airflow obstruction. BO is rare and can mimic asthma and chronic obstructive pulmonary disease (COPD). We should inquire about the intake of food or medication in cases suspected BO.

Phase II trial of amrubicin for treatment of refractory or relapsed small-cell lung cancer: Thoracic Oncology Research Group Study 0301.

PURPOSE: This multicenter, phase II study was conducted to evaluate the activity of amrubicin, a topoisomerase II inhibitor, against refractory or relapsed small-cell lung cancer (SCLC). PATIENTS AND METHODS: SCLC patients with measurable disease who had been treated previously with at least one platinum-based chemotherapy regimen and had an Eastern Cooperative Oncology Group performance status of 0 to 2 were eligible. Two groups of patients were selected: patients who experienced first-line treatment failure less than 60 days from treatment discontinuation (refractory group), and patients who responded to first-line treatment and experienced disease progression > or = 60 days after treatment discontinuation (sensitive group). Amrubicin was administered as a 5-minute daily intravenous injection at a dose of 40 mg/m2 for 3 consecutive days, every 3 weeks. RESULTS: Between June 2003 and December 2004, 60 patients (16 refractory and 44 sensitive) were enrolled. The median number of treatment cycles was four (range, one to eight). Grade 3 or 4 hematologic toxicities comprised neutropenia (83%), thrombocytopenia (20%), and anemia (33%). Febrile neutropenia was observed in three patients (5%). Nonhematologic toxicities were mild. No treatment-related death was observed. The overall response rates were 50% (95% CI, 25% to 75%) in the refractory group, and 52% (95% CI, 37% to 68%) in the sensitive group. The progression-free survival, overall survival, and 1-year survival in the refractory group and the sensitive group were 2.6 and 4.2 months, 10.3 and 11.6 months, and 40% and 46%, respectively. CONCLUSION: Amrubicin exhibits significant activity against SCLC, with predictable and manageable toxicities; this agent deserves to be studied more extensively in additional trials.

[Effectiveness of pneumococcal polysaccharide vaccine in older patients with chronic respiratory diseases].

To evaluate effectiveness of pneumococcal polysaccharide vaccine, we recommended 1378 outpatients aged over 60 with chronic respiratory diseases to be vaccinated from August to October 2002, and 647 patients were vaccinated from August to November 2002. In the 1229 patients without respiratory failure, the incidence of antimicrobial treatment for bacterial respiratory infections in 547 vaccinated patients significantly decreased from 7.9% in the 2001/02 winter season to 5.7% in the 2002/03 winter season, although that in the 682 unvaccinated patients increased from 3.8% to 5.7%. The incidence of antimicrobial treatment for bacterial respiratory infections in 229 vaccinated patients with pneumococcal and influenza vaccines together significantly decreased from 10.5% in the 2001/02 winter season to 5.2% in 2002/03 winter season although that in 110 subjects vaccinated with influenza vaccine only increased from 2.7% to 7.2%. These findings suggest the effectiveness of the pneumococcal polysaccharide vaccine for the prevention of bacterial respiratory infections and the additive effectiveness of pneumococcal and influenza vaccines together.

[Gefitinib as a first-line therapy in patients with advanced non-small cell lung cancer].

BACKGROUND: The objective of this study was to evaluate the efficacy and toxicity of gefitinib as a first-line therapy in patients with advanced non-small cell lung cancer (NSCLC). METHODS: We analyzed 19 patients with advanced NSCLC retrospectively, who were treated with gefitinib as a first-line therapy. These patients were not considered for systemic chemotherapy secondary to co-morbid conditions, poor performance status (PS) or refusal of chemotherapy. RESULTS: Median age 68 years, male/female 10/9, stage III/IV 7/12, smoker/non-smoker 12/7, adenocarcinoma/non-adeno 13/6, PS 0/1/2/3/4 0/4/7/5/3. Four patients had a partial response and the overall response rate was 21.0%. The median survival time was 6.8 months and 1-year survival was 27%. Overall toxicities were mild. Grade (G) 3 diarrhea was observed in one patient and G1 interstitial pneumonia in one. CONCLUSIONS: These results demonstrate that gefitinib is active as a first-line therapy in patients with advanced NSCLC.

Adenovirus-mediated transfer and overexpression of heme oxygenase 1 cDNA in lungs attenuates elastase-induced pulmonary emphysema in mice.

Heme oxygenase 1 (HO-1) is an inducible enzyme that catalyzes heme to generate bilirubin, ferritin, and carbon monoxide. Because enhanced expression of HO-1 provides an anti-inflammatory effect and confers cytoprotection, we examined whether HO-1 overexpression induced by inoculation of mice with an adenovirus encoding HO-1 (Ad.HO-1) in the lung would prevent pulmonary emphysema induced by porcine pancreatic elastase (PPE). Pretreatment with Ad.HO-1, which upregulated production of HO-1 in the lung, attenuated the PPE-induced increase of neutrophils in bronchoalveolar lavage fluid (BALF) and enlargement of alveoli. It also reduced PPE-induced elevated levels of tumor necrosis factor alpha, interleukin (IL)-6, and keratinocyte-derived chemokine, and increased the level of anti-inflammatory cytokine IL-10 in BALF. These results suggest that Ad.HO-1-induced HO-1 overexpression suppressed PPE-induced emphysema by attenuating neutrophilic inflammation via modulating cytokine and chemokine profiles in mouse lungs.

Cigarette smoke increases mucosal permeability in guinea pig trachea via tachykinin NK2 receptor activation.

We investigated whether exposure to cigarette smoke increases the mucosal permeability in guinea pig trachea and if this effect could be mediated by tachykinin NK2 receptor activation. Guinea pigs were exposed to either three different doses of cigarette smoke or room air. Mucosal permeability was measured by monitoring the rate of appearance in the circulation of horseradish peroxidase (HRP) that had been instilled into the isolated tracheal segment. Exposure to 20 and 30 puffs but not 10 puffs of cigarette smoke increased the tracheal mucosal permeability. Pretreatment with the tachykinin NK2 receptor antagonist SR48,968 [(S)-N-methyl-N[4-(4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl)butyl]benzamide] completely inhibited the increase in the permeability of the tracheal mucosa induced by exposure to cigarette smoke, whereas the tachykinin NK1 receptor antagonist SSR240,600 [(R)-2-(1-{2-[4-{2-[3,5-bis(trifluoromethyl)phenyl]acetyl}-2-(3,4-dichlorophenyl)-2-morpholinyl]ethyl}-4-piperidinyl)-2-methylpropanamide] and the tachykinin NK3 receptor antagonist SR142,801 [(S)-(N)-(1-[3-(1-benzoyl-3(3,4-dichlorophenyl)piperidine-3-yl)propyl]-4-phenylpiperidin-4-yl)-N-methyl-acetamide] had no effect. It is concluded that endogenous tachykinins via NK2 receptor activation mediate the increase in the permeability of the tracheal mucosa induced by exposure to cigarette smoke in guinea pigs.

Pseudomonas aeruginosa-induced neutrophilic lung inflammation is attenuated by adenovirus-mediated transfer of the heme oxygenase 1 cDNA in mice.

Heme oxygenase (HO) is well known as the rate-limiting enzyme in the oxidative degradation of heme to biliverdin, carbon monoxide (CO), and iron. Based on recent evidence that overexpression of HO-1 confers protection against various types of cell and tissue injury by regulating apoptotic cell death or cytokine expression profiles, the present study was performed to examine whether the transfer of exogenous HO-1 cDNA in the lung would provide therapeutic effect in a murine model of lung inflammation induced by Pseudomonas aeruginosa. HO-1 overexpression clearly attenuated neutrophil influx and decreased numbers of apoptotic bronchial epithelial cells. Interestingly, the overexpression of Bcl-2, a known antiapoptotic factor, was observed and thought to be the mechanism that inhibits bronchial epithelial cellular apoptosis. It is thus suggested that HO-1 overexpression is useful for treating P. aeruginosa-associated lung inflammation by attenuating neutrophil influx and apoptotic cell death.

[A case of lung infection due to Mycobacterium abscessus].

We report a case of lung infection due to Mycobacterium abscessus (M. abscessus). A 60 year-old woman was admitted to our hospital because of an abnormal shadow found on chest radiography and a bloody sputum. Chest radiography revealed infiltrative and linear shadows in the middle and lower fields of both lungs. The sputum smears were negative for acid-fast bacilli, but sputum culture was positive. Rapidly growing mycobacteria were detected. The patient was treated with clarithromycin. Since M. abscessus was identified from repeated cultures of the sputa, the patient was treated with Imipenem/Cilastatin and Amikacin for four weeks, during which the chest radiography improved. After discharge, the treatment with clarithromycin and minocycline was continued for ten months, and the chest radiography improved further. Our treatment for M. abscessus may be a useful choice for drug treatment of such cases.

[Hypogammaglobulinemia associated with thymoma (Good syndrome) similar to diffuse panbronchiolitis].

A 65-year-old woman complained of dyspnea and a productive cough after surgical treatment and irradiation therapy for thymoma. Chest radiography and high-resolution computed tomography showed small nodules in centrilobular lesions in all of both lung fields, but predominantly in the lower fields. In addition, blood tests showed hypogammaglobulinemia. Chronic sinusitis, mild hypoxemia, severe obstructive impairment and the pathological findings of bronchiolitis led to a diagnosis of sinobronchial syndrome caused by Good syndrome. Treatment with oral erythromycin 600 mg/day was started. After 6 months, the patient improved both clinically and radiologically. Low-dose, long-term treatment with erythromycin was effective against sinobronchial syndrome caused by Good syndrome.

[Acute lung injury caused by inhalation of waterproofing spray].

A 55-year-old man was admitted to our hospital because of severe dyspnea 30 minutes after inhalation of waterproofing spray. He had used the spray outdoors and had then smoked a cigarette with spray-contaminated fingers. Chest radiography and computed tomography (CT) revealed diffuse ground glass opacities in both lungs. In pulmonary function tests, the lungs showed a moderately decreased diffusing capacity and there was slight hypoxemia. Transbronchial lung biopsy specimens demonstrated extensive alveolitis and marked eosinophil migration. Without any specific treatment, the patient recovered clinically in 4 days. We speculated that acute lung injury in this patient may have been induced by not only direct inhalation of the waterproofing spray itself, but also by inhalation of spray by-products resulting from decomposition due to heat. When waterproofing spray is used, precautions should be taken to avoid both inhalation and heating of the fumes.