Long-Term Survival of Patients With Non-Small Cell Lung Cancer Treated With Immune Checkpoint Inhibitor Monotherapy in Real-World Settings.

BACKGROUND: Immune checkpoint inhibitor (ICI) monotherapy is more effective than cytotoxic chemotherapy in improving overall survival (OS) among patients with advanced-stage non-small cell lung cancer (NSCLC). Recently, chemotherapy combined with ICI has been found to yield good outcomes. However, ICI monotherapy is still considered an important treatment option. Data on long-term progression-free survival (PFS) and OS in real-world settings are limited. PATIENTS AND METHODS: This was a multicenter retrospective observational study. A total of 435 consecutive patients histologically diagnosed with advanced, metastatic, or recurrent NSCLC treated with ICI monotherapy were enrolled in this study from December 2015 to December 2018. Clinical data were collected from electronic medical records and pharmacy databases. RESULTS: The PFS and OS of the patients were 3.4 and 13.0 months, respectively. The objective response and disease control rates were 22.8% and 54.9%, respectively, and the 4-year survival rate was 17.9%. Multivariate analyses revealed that elder patients (>70 years), good Eastern Cooperative Oncology Group Performance Status (ECOG PS) score, programmed death-ligand 1 tumor proportion score (PD-L1 TPS) of ≥ 50%, absence of bone metastasis, and presence of immune-related skin toxicity, which is an immune-related adverse event, were correlated with good PFS. Moreover, good ECOG PS score, PD-L1 TPS of ≥ 50%, absence of bone metastasis, and presence of skin toxicity were correlated with good OS. CONCLUSIONS: The 4-year survival rate was 17.9%. Good ECOG PS score, PD-L1 TPS of ≥ 50%, absence of bone metastasis, and presence of skin toxicity were correlated with good PFS and OS.

Bevacizumab plus chemotherapy in nonsquamous non-small cell lung cancer patients with malignant pleural effusion uncontrolled by tube drainage or pleurodesis: A phase II study North East Japan Study group trial NEJ013B.

BACKGROUND: Pleurodesis is the standard of care for non-small cell lung cancer (NSCLC) patients with symptomatic malignant pleural effusion (MPE). However, there is no standard management for MPE uncontrolled by pleurodesis. Most patients with unsuccessful MPE control are unable to receive effective chemotherapy. Vascular endothelial growth factor (VEGF) plays an important role in the pathogenesis of MPE. This multicenter, phase II study investigated the effects of bevacizumab plus chemotherapy in nonsquamous NSCLC patients with unsuccessful management of MPE. METHODS: Nonsquamous NSCLC patients with MPE following unsuccessful tube drainage or pleurodesis received bevacizumab (15 mg/kg) plus chemotherapy every three weeks. The primary endpoint was pleural effusion control rate (PECR), defined as the percentage of patients without reaccumulation of MPE at eight weeks. Secondary endpoints included pleural progression-free survival (PPFS), safety, and quality of life (QoL). RESULTS: A total of 20 patients (median age: 69 years; 14 males; 20 adenocarcinomas; six epidermal growth factor receptor mutations) were enrolled in nine centers. The PECR was 80% and the primary end point was met. The PPFS and the overall survival (OS) were 16.6 months and 19.6 months, respectively. Patients with high levels of VEGF in the MPE had shorter PPFS (P = 0.010) and OS (P = 0.002). Toxicities of grade ≥ 3 included neutropenia (50%), thrombocytopenia (10%), proteinuria (10%), and hypertension (2%). The cognitive QoL score improved after treatment. CONCLUSIONS: Bevacizumab plus chemotherapy is highly effective with acceptable toxicities in nonsquamous NSCLC patients with uncontrolled MPE, and should be considered as a standard therapy in this setting. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: Bevacizumab plus chemotherapy is highly effective with acceptable toxicities in nonsquamous NSCLC patients with uncontrolled MPE. WHAT THIS STUDY ADDS: Bevacizumab plus chemotherapy should be considered as a standard treatment option for patients with uncontrolled MPE. CLINICAL TRIAL REGISTRATION: UMIN000006868 was a phase II study of efficacy of bevacizumab plus chemotherapy for the management of malignant pleural effusion (MPE) in nonsquamous non-small cell lung cancer patients with MPE unsuccessfully controlled by tube drainage or pleurodesis (North East Japan Study Group Trial NEJ-013B) (http://umin.sc.jp/ctr/).

Survival Analysis for Patients with ALK Rearrangement-Positive Non-Small Cell Lung Cancer and a Poor Performance Status Treated with Alectinib: Updated Results of Lung Oncology Group in Kyushu 1401.

LESSONS LEARNED: Alectinib confers a pronounced survival benefit in patients with ALK rearrangement-positive non-small cell lung cancer and a poor performance status. Survival benefit of alectinib for patients with a poor performance status was consistent regardless of the presence of central nervous system metastases. BACKGROUND: We previously reported a marked objective response rate (ORR) and safety for alectinib treatment in patients with ALK rearrangement-positive non-small cell lung cancer (NSCLC) and a poor performance status (PS) in the Lung Oncology Group in Kyushu (LOGiK) 1401 study. It remained unclear, however, whether alectinib might also confer a long-term survival benefit in such patients. METHODS: Eighteen patients with ALK rearrangement-positive advanced NSCLC and a PS of 2, 3, or 4 (n = 12, 5, and 1, respectively) were enrolled in LOGiK1401 between September 2014 and December 2015 and received alectinib. We have now updated the survival data for the study. RESULTS: The median follow-up time for all patients was 27.3 months. The median progression-free survival (PFS) was 16.2 months (95% confidence interval [CI], 7.1-30.8 months), and the median survival time (MST) and the 3-year overall survival rate were 30.3 months (95% CI, 11.5 months to not reached) and 43.8% (95% CI, 20.8-64.7%), respectively. This survival benefit was similarly manifest in patients with a PS of 2 (MST, 20.5 months) and those with a PS of ≥3 (MST, not reached). PFS did not differ between patients with or without central nervous system (CNS) metastases at baseline (median of 17.5 and 16.2 months, respectively, p = .886). CONCLUSION: Alectinib showed a pronounced survival benefit for patients with ALK rearrangement-positive NSCLC and a poor PS regardless of the presence of CNS metastases, a patient population for which chemotherapy is not indicated.

A phase II study of bevacizumab with carboplatin-pemetrexed in non-squamous non-small cell lung carcinoma patients with malignant pleural effusions: North East Japan Study Group Trial NEJ013A.

BACKGROUND: Vascular endothelial growth factor (VEGF) plays a pivotal role in the pathogenesis of malignant pleural effusion (MPE). Here, a multicenter phase II trial to evaluate bevacizumab in non-squamous non-small cell lung carcinoma patients with MPE was conducted. METHODS: Patients having MPE with no prior treatment and performance status of 0-2 received carboplatin (area under the curve: AUC 6; up to 6 cycles) and pemetrexed (500mg/m(2)) with bevacizumab (15mg/kg) every 3 weeks. The primary endpoint was the control rate of MPE without pleurodesis at 8 weeks after treatment. VEGF levels in plasma and MPE were measured by enzyme immunoassay. RESULTS: Of 30 patients entered (median 66 years; 24 males; adenocarcinoma; 4 epidermal growth factor receptor: EGFR mutations), 28 patients (2 withdrawn patients) were given a median of 4 cycles of carboplatin, and 68% of the patients received maintenance pemetrexed with bevacizumab (median 8 cycles). At eight weeks, MPE was controlled without pleurodesis in 93% of treated patients (95% confidence interval: 77-99%). At the median follow-up time of 12.8 months, 78.6% of the cases required no pleurodesis. Response rate was 46%, and median progression-free survival (PFS) and overall survival (OS) were 8.2 months and 18.6 months, respectively. Toxicities of grade ≥3 included neutropenia (28.6%), thrombocytopenia (28.6%), proteinuria (3.6%), and hypertension (3.6%). Assessment of VEGF levels before treatment indicated that patients with low VEGF (<1000pg/ml) in MPE frequently needed pleurodesis (p=0.011), and that high VEGF (≥100pg/ml) in plasma was indicative of poor prognosis in the context of PFS (p=0.012). CONCLUSION: The combination of bevacizumab with carboplatin and pemetrexed demonstrated efficacy with acceptable toxicities in patients with MPE.

Paradoxical reaction to antituberculosis therapy after 6 months of treatment for pulmonary tuberculosis: A case report.

Paradoxical reactions (PRs) to antituberculosis (anti-TB) drugs during treatment are well known phenomena, but a PR presenting as a new pulmonary lesion after completion of treatment is extremely rare, and little is known about the management of such cases. A 44-year-old man was diagnosed with pulmonary TB. His sputum cultures became negative 45 days after the initiation of standard anti-TB treatment. Upon the patient's completion of 6 months of anti-TB therapy, computed tomography revealed a new irregularly shaped mass in the lower left pulmonary lobe. A transbronchial lung biopsy (TBLB) revealed caseous necrosis and granulomatosis surrounded by epithelioid and multinucleated giant cells. Cultures of both the TBLB specimen and bronchoalveolar lavage fluid remained negative for TB. The CT shadow disappeared 6 months later without further administration of anti-TB drugs. Careful observation without therapy may be sufficient for a patient treated for TB who develops a PR upon completion of treatment, if the patient has achieved a bacteriological remission.

Primary A (H1N1) pdm09 Influenza Pneumonia Diagnosed on Reverse Transcription-polymerase Chain Reaction (RT-PCR) of Bronchoalveolar Lavage Fluid but not Rapid Tests with Nasopharyngeal Swabs.

A 47-year-old man with a fever was highly suspected of having influenza A infection since his wife and son who lived with him had been diagnosed with influenza A. Although repeated rapid tests with a nasopharyngeal swab showed negative findings, the patient developed bilateral pneumonia and reverse transcription polymerase chain reaction (PCR) for A (H1N1) pdm09 virus in the bronchoalveolar lavage fluid was positive. We therefore diagnosed him with primary influenza pneumonia and initiated treatment with peramivir plus corticosteroids, which rapidly improved his condition. During the influenza season, sample collection from the lower airway and PCR should be considered for the definitive diagnosis of primary influenza viral pneumonia.

(18)F-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.

Successful treatment with a combination of electrocautery using wire snares and gefitinib in patients with EGFR-mutant lung cancer and central airway obstruction.

One-third of lung cancer patients present with life-threatening central airway obstruction (CAO). Two elderly patients were referred to our institution with symptoms caused by CAO. In each case, thoracic computed tomography and a bronchoscopic examination revealed a tumor obstructing the central airway. The tumors were resected endoscopically, and the patients' respiratory and performance status remarkably improved. Both patients were diagnosed with an advanced stage of lung adenocarcinoma harboring epidermal growth factor receptor (EGFR) mutations. They received gefitinib monotherapy, with partial responses sustained for more than 12 months. Combination therapy with endoscopic tumor resection and gefitinib is beneficial in patients with EGFR-mutant lung cancer and CAO.

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.

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.

Pulmonary veno-occlusive disease following reduced-intensity allogeneic bone marrow transplantation for acute myeloid leukemia.

We report a case of pulmonary veno-occlusive disease (PVOD) following allogeneic bone marrow transplantation (BMT) for the treatment of acute myeloid leukemia (AML) from an HLA mismatched mother using a reduced-intensity conditioning (RIC) regimen including gemtuzumab ozogamicin. The patient was a 21-year-old male who complained of dyspnea with hypoxemia followed by loss of consciousness. The abnormalities in chest CT and echocardiography were compatible with a diagnosis of PVOD. Treatment with 1 mg/kg of oral prednisolone resolved dyspnea and hypoxemia within a few days, and chest CT abnormalities disappeared in a week. This report is the first to describe PVOD following RIC stem cell transplantation.

[Endobronchial ultrasonic-guided transbronchial needle aspiration (EBUS-TBNA) for lung cancer diagnosis].

BACKGROUND: Although bronchoscopy has an important role in the diagnosis of lung cancer, more invasive procedures, such as CT-guided biopsy or surgery, are needed when transbronchial approaches fail. OBJECTIVE: We investigated the usefulness of endobronchial ultrasonic-transbronchial needle aspiration (EBUS-TBNA) for lung cancer diagnosis. SUBJECTS AND METHODS: We retrospectively evaluated 122 cases who were finally diagnosed to have lung cancer from among 388 cases who underwent bronchoscopy because of abnormal shadows on their chest X-ray or CT. When bronchoscopic approaches were possible, conventional transbronchial lung biopsy or cytology (conventional approaches) were done. EBUS-TBNA was added whenever mediastinal or hilar lymph nodes enlarged to more than 1 cm in diameter, or if there were lesions attached to the lower respiratory tract. The diagnostic accuracy of conventional approaches and EBUS-TBNA were assessed. RESULTS: The number of cases diagnosed as lung cancer by conventional approaches was 79 cases (64.8%) among the 122 cases examined. Of the 43 cases undiagnosed by these procedures, 27 cases were diagnosed as lung cancer by EBUS-TBNA. Thus, 106 cases (86.9%) were diagnosed as lung cancer using conventional approaches plus EBUS-TBNA. No severe complications were observed in all the subjects. CONCLUSION: EBUS-TBNA is a safe and useful approach for the diagnosis of lung cancer together with staging.

Bronchoconstriction-triggered cough is impaired in typical asthmatics.

BACKGROUND AND OBJECTIVE: Cough is an essential innate protective behavior, which is experienced by even healthy individuals. The mechanism of cough triggered by bronchoconstriction is not yet clear. The aim of this study was to investigate the relation between bronchoconstriction and cough caused by methacholine (Mch) inhalation in typical asthmatics and normal healthy subjects. METHODS: We measured bronchial responsiveness to Mch and counted the number of coughs induced by Mch inhalation in 15 typical asthmatics and 20 normal subjects. RESULTS: After inhalation of Mch at the concentration causing 20% or more decrease in forced expiratory volume in 1 second (FEV(1)) (PC(20)-FEV(1)), coughs were provoked in normal subjects (number of cough: 22.5/32 min, range: 3.3-45). Conversely, coughs were hardly provoked in typical asthmatics (median number of cough: 2/32 min, range: 0-4). CONCLUSIONS: Although typical asthmatics have increased airway responsiveness, their cough response to bronchoconstriction is impaired.

Bronchodilator effect of deep inspiration and bronchoconstriction-triggered cough.

BACKGROUND: Cough in the patients with cough variant asthma is triggered by bronchoconstriction, which responds to bronchodilator therapy. Following airway narrowing induced by inhaled methacholine, deep inspiration (DI) causes dilation of the airways in both asthmatic and non-asthmatic subjects. The aim of the present study was to investigate the relationship between bronchodilator effect of DI and bronchoconstriction-triggered cough. METHODS: We measured airway responsiveness to methacholine using partial and full flow-volume curves in 28 healthy adults. The expiratory flow at 40% above residual volume from the full forced vital capacity (MEF40) was obtained and the volume was used as the reference volume to determine the isovolume flow from the partial curve (PEF40). Coughs were counted for 32 min during and following the inhalation of methacholine at the provocative concentration which produced a 20% fall or more in FEV1from the post-saline value (PC20-FEV1). The bronchodilator effect of DI on bronchoconstriction induced by methacholine at the PC20-FEV1 concentration was expressed as the ratio of (MEF40-PEF40)/PEF40 (DI index). RESULTS: The number of coughs for 32 min during and following the inhalation of PC20-FEV1 concentration of methacholine was 39.3 +/- 29.7 (mean +/- SD)/32 min. The number of coughs during and following the inhalation was correlated with DI index (r = 0.57, p = 0.0015), but not with PC20-FEV1 or change in FEV1 or PEF40 by inhalation of the PC20-FEV1 concentration of methacholine. CONCLUSION: We found that methacholine-induced cough was associated with the bronchodilator effect of DI on methacholine induced-bronchoconstriction in normal subjects.

Effect of montelukast in a guinea pig model of cough variant asthma.

Cough variant asthma is known as a major cause of chronic cough. Fundamental features of cough variant asthma are prolonged non-productive cough responding to bronchodilator therapy, no history of wheezing or dyspnea attack, normal cough sensitivity and slightly increased bronchial responsiveness. Recently, we reported the animal model of cough variant asthma. The aim of this study was to clarify the involvement of cysteinyl leukotrienes (cysLTs) in this model by using a specific leukotriene receptor antagonist, montelukast. Cough number and specific airway resistance (sRaw) were measured during the antigen inhalation (1.5 min) and following 18.5 min, which was carried out 72 h after the first antigen inhalation in actively sensitized guinea pigs, and then total cell number and cell differentials in bronchoalveolar lavage fluid (BALF) were measured. Montelukast significantly reduced the antigen re-inhalation-induced cough, increase in sRaw, and increase in total cell number in BALF. In conclusion, cysLTs may play an important part in antigen-induced cough associated with bronchoconstriction and airway inflammation in cough variant asthma.

[Longitudinal decline of forced expiratory volume in one second in non-smoking Japanese women].

We prospectively studied 1,696 clinically healthy non-smoking women to assess the influence of aging on longitudinal decline in forced expiratory volume in one second (FEV10). All the subjects took an annually medical examination involving a pulmonary function test from 1995 to 2001. The mean value of annual decrease in FEV10 (slope) was 19.6 mL/year. Multiple regression analysis revealed that initial age, height, and FEV10 were significant parameters determining the slope. This study clearly showed the aging-related longitudinal decline in pulmonary function in non-smoking Japanese women.

Predictors for typical asthma onset from cough variant asthma.

Cough variant asthma is recognized to be a precursor of asthma or preasthmatic state because nearly 30% patients with cough variant asthma develop typical asthma within several years. However, predictors for risk of typical asthma onset from cough variant asthma are unknown. Forty-one patients with cough variant asthma (median age 50 years, 13 men and 28 women), who had undertaken spirometry, bronchial reversibility test, methacholine provocation test, measurements of peripheral blood eosinophil count, serum total IgE, and specific IgE to common allergens, and induced sputum eosinophil count at presentation, were followed up with special emphasis on typical asthma onset during 1 year or more (median 4 years, range 1-12.4). Long-term inhaled corticosteroids (ICS) were taken in 27 patients. Univariate and multivariate logistic analyses were performed to determine the predictors for typical asthma onset. Asthma onset was recognized in 7 patients. Bronchial hyperresponsiveness, peripheral blood eosinophil count, and no use of ICS were significant predictors for the typical asthma onset by univariate analysis. However, only bronchial hyperresponsiveness was the significant predictor when multivariate analysis was used (adjusted OR 0.028, 95% CI 0.001-0.783, p = 0.0355). Bronchial hyperresponsiveness may be the most important predictor for risk of typical asthma onset from cough variant asthma.

A guinea pig model for cough variant asthma and role of tachykinins.

Cough variant asthma is known as a major cause of chronic cough. Fundamental features of cough variant asthma are prolonged nonproductive cough responding to bronchodilator therapy, no history of wheezing or dyspnea attack, normal cough sensitivity, and slightly increased bronchial responsiveness. Animal model of cough variant asthma has not been reported. The aim of this study was to establish an animal model for studying detailed pathophysiology of cough variant asthma. Bronchial responsiveness to methacholine and cough reflex sensitivity to capsaicin were measured 72 hours after antigen (ovalbumin, OA) inhalation in actively sensitized guinea pigs. Next, cough number and specific airway resistance (sRaw) were measured during 20 minutes following reinhalation of OA solution, which was carried out 72 hours after the first OA inhalation, and then total cell number and cell differentials in bronchoalveolar lavage fluid (BALE) were measured. Bronchial responsiveness to methacholine, but not cough reflex sensitivity to capsaicin, was significantly increased 72 hours after the first inhalation of OA solution. Number of coughs, sRaw and total cell number in BALF increased significantly by the OA reinhalation, and the cough number and the increase in sRaw were significantly suppressed by beta2 agonist, procaterol. FK224, a specific neurokinin (NK) receptor antagonist, did not significantly influence the OA reinhalation-induced cough and increase in sRaw and total cell number in BALF in this model In conclusion, pathophysiologic feature of this animal model is similar to that of clinical cough variant asthma. Tachykinins may not play an important part in antigen-induced cough associated with bronchoconstriction and airway inflammation in cough variant asthma.

[Influence of smoking on longitudinal decline in one-second forced expiratory volume in clinically healthy Japanese men: a longitudinal study].

We prospectively studied 2140 clinically healthy men to assess the influence of smoking on longitudinal decline in one-second forced expiratory volume (FEV1.0). All the subjects had annual medical checks including pulmonary function tests from 1995 to 1999. The mean values +/- standard deviations of annual decreases in FEV1.0 (slope) were 22 +/- 49 mL/year in non-smokers, 26 +/- 52 mL/year in former smokers, and 33 +/- 57 mL/year in current smokers (p < 0.01; non-smokers vs. current smokers). The adjusted slope (slope divided by predicted value of FEV1.0, per year) in current smokers was also greater than that in non-smokers (p < 0.01). Multiple regression analysis revealed that initial age, height, FEV1.0, and smoking status were significant parameters for determining the slope. This study clearly showed that smoking is an important risk factor foracceleration of the aging-related longitudinal decline in pulmonary function in Japanese men.

[A case of broncho-pulmonary aspergillosis complicated by bronchial asthma attack].

A 55-year-old man was hospitalized for the treatment of severe asthma. However, his condition improved with steroid chemotherapy under artificial ventilation, but high fever and multiple patchy shadows of the lung that were not responsive to antibiotics appeared. We detected aspergillus hyphae, probably inhaled with a quantity of dust in the attic of his workplace, in the sputum. We diagnosed invasive broncho-pulmonary aspergillosis complicated with allergic broncho-pulmonary aspergillosis. His condition improved with anti-fungal drug treatment. We consider that the causes of invasive broncho-pulmonary aspergillosis in this case were massive inhalation of aspergillus conidia, artifical ventilation and steroid chemotherapy.