Koizumi T

Airway inflammation during stable and acutely exacerbated chronic obstructive pulmonary disease

The aim of this study was to clarify the mechanism of increased airway inflammation during an acute exacerbation. A total of 68 chronic obstructive pulmonary disease patients in a stable phase were enrolled and followed-up for 2–3 yrs. Inflammatory cells were analysed, and interleukin (IL)-8, neutrophil elastase, eotaxin, tryptase and RANTES (regulated on activation, normal T-cell expressed and secreted) were measured in sputum, both in a stable phase and during acute exacerbation. Out of 68 patients, 30 (unstable group) developed an acute exacerbation and expectorated adequate sputum during exacerbation. Thirty-two patients (stable group) did not develop any exacerbation for 2–3 yrs. The number of neutrophils, lymphocytes and eosinophils, and the levels of IL-8, eosinophil cationic protein (ECP), eotaxin and tryptase in sputum obtained from patients in both groups during the stable phase were significantly higher than those from healthy nonsmokers. There were no significant differences in cell analysis and biomarkers between the two groups, but patients in the unstable group showed more severe airflow limitation. In the unstable group, total cells, lymphocytes, neutrophils and eosinophils, and IL-8, neutrophil elastase, ECP and RANTES levels were significantly increased during an exacerbation from values in a stable phase. These findings suggest that exacerbation of chronic obstructive pulmonary disease may associate with additional increases in airway inflammation mediated by neutrophils, lymphocytes, eosinophils, interleukin-8 and RANTES.

Cytokines in bronchoalveolar lavage fluid in patients with high altitude pulmonary oedema at moderate altitude in Japan.

BACKGROUND: The precise mechanism of high altitude pulmonary oedema (HAPE) remains unclear. The purpose of this study was to evaluate the role of cytokines and P-selectin in the development of HAPE which occurred at moderate altitude in Japan. METHODS: The following cellular and biochemical markers and chemotactic cytokines were measured in the bronchoalveolar (BAL) fluid from four patients with HAPE at 2857-3180 m in the Japanese Alps: total proteins, albumin, lactate dehydrogenase (LDH), and interleukin (IL)-1 alpha, IL-1 beta, IL-1 receptor antagonist (ra), IL-6, IL-8, IL-10, tumour necrosis factor (TNF)-alpha, and the soluble form of P-selectin. RESULTS: At admission there were significant increases in the levels of total cells, especially macrophages and neutrophils, total protein, albumin and LDH when compared with 13 healthy individuals. Furthermore, the levels of IL-1 beta, IL-6, IL-8, and TNF-alpha were also considerably increased but returned quickly to the normal ranges or were not detected after recovery. The levels of IL-1 alpha, IL-10, and P-selectin did not change. CONCLUSIONS: These results suggest that an inflammatory process almost identical with acute respiratory distress syndrome (ARDS) may occur in HAPE, but that these changes are transient and are not associated with any increase in P-selectin levels in the BAL fluid.

Endothelin-1 and interleukin-8 in high altitude pulmonary oedema

We present a case of high altitude pulmonary oedema (HAPE) with pulmonary hypertension and polymorphonuclear leucocyte (PMN) accumulation in bronchoalveolar lavage fluid (BALF), which occurred in a 21 year old man. Plasma endothelin-1 (ET-1) and interleukin-8 (IL-8) concentration in BALF were elevated on admission, and returned to normal level at recovery, when the pulmonary artery pressure and the PMN counts in BALF were normal. In addition, E-selectin and intercellular adhesion molecule-1 (ICAM-1) in BALF were also slightly increased on admission. These findings suggest that endothelin-1 is a vasoconstrictor which contributes to the pulmonary hypertension in high altitude pulmonary oedema, and that some of the inflammatory mediators play an important role in chemotaxis and accumulation of polymorphonuclear leucocytes in the development of high altitude pulmonary oedema.

Bronchoscopy-guided radiofrequency ablation as a potential novel therapeutic tool.

The aim of the current study was to assess the safety of bronchoscopy-guided radiofrequency ablation (RFA) and compare the effectiveness between new internal cooled-RFA and standard noncooled-RFA. Normal lungs from sheep were used (n = 6). Internal cooled-RFA and standard noncooled-RFA were set to assess the most suitable RFA conditions, such as power output, flow rate and ablation time. Internal cooled-RFA was then applied under the most optimal conditions of power output and flow rate for 15, 30, 60 and 120 s, and two water temperatures either room temperature (RT) water or cold water. Criteria for the most appropriate conditions were set over 15 s of ablation time and 50°C of the tips temperature. Internal cooled-RFA had no complications. Standard noncooled-RFA was complicated with bronchial bleeding after RFA. On the basis of the histological findings, average temperature and average output, the most appropriate conditions of the cooled-RFA were a power output of 30 W and flow rate of 30 or 40 mL·min−1. The cooled-RFA using cold water caused a smaller, more discrete, lesion compared with that using RT water. Bronchoscopy-guided internal cooled-radiofrequency ablation was an effective, safe and feasible procedure that could become a potential therapeutic tool in managing lung pathology.

Different efficacy of CT screening for lung cancer according to histological type: Analysis of Japanese-smoker cases detected using a low-dose CT screen

The efficacy of CT screening for lung cancers is still a controversial issue, although one of the recently publicized large randomized controlled trials of this methodology, the National Lung Screening Trial (NLST), reported a decrease in the lung cancer-specific mortality for heavy smokers. We here performed case-matched comparative analyses, as a retrospective study, of three lung cancer arms detected by CT screen, X-ray screen, and by individual analysis of the clinicopathological features and outcomes in smokers from a symptomatic-prompted group of patients. We also considered the impacts of various potential biases in this cohort. The total study cohort comprised 136 patients in the CT screen group, 263 in the X-ray screen group and 254 in the symptomatic-prompted group. The ratio of stage IA cancers in the CT screen group was 67.7% and the ratio of advanced cases (i.e. stages IIIB+IV) was 12.5%. The percentage of bronchioloalveolar carcinoma (BAC) was 28.7% in the CT screen group. The 5-year survival rates were 82.4% in the CT screen group, 38.0% in the X-ray screen group and 17.8% in the symptomatic-prompted group. CT screening was found to be an independent prognostic factor for lung cancer even when BAC cases were eliminated (HR 0.35, P<0.01). Based on our sub-analysis by individual histological sub-type, CT screen lung cancer cases had a better survival rate than non-screened patients, which included adenocarcinoma, squamous cell carcinoma and large/small cell carcinoma. However, by multi-variant analysis a CT scan would not be expected to reduce the risk of lung cancer mortality in patients with large/small cell carcinoma, although would be expected to reduce the risk of lung cancer death by 80% in cases of both adenocarcinoma and squamous cell carcinoma. In conclusion, our current findings indicate that CT screening for lung cancer is an effective strategy for smokers and that patients with adenocarcinoma and squamous cell carcinoma of all variant histological types may benefit from this test. In this regard, early stage large/small cell carcinomas are insufficiently detected by the existing annual screening system.

Efficacy of CT screening for lung cancer in never-smokers: Analysis of Japanese cases detected using a low-dose CT screen

CT-screening for lung cancer is fairly widely used for both smokers and never-smokers in East Asia because the mortality rate for never-smokers due to this cancer is relatively high in this region. We performed comparative analyses, as a retrospective study, on three lung cancer arms detected by CT-screen, X-ray-screen, and via analysis of clinicopathological features and outcomes in never-smokers from a symptomatic-prompted group of patients. The total study cohort comprised 218 patients in CT group, 160 in X-ray group, and 82 in symptomatic-prompted group. The percentage of bronchioloalveolar carcinoma (BAC) was 65.1% in CT-screen group. The ratio of stage IA tumors in CT-screen group was 88.5% and the ratio of advanced cases (i.e. stages IIIB+IV) was 2.3%. The 5-year-survival rates were 95.0% in CT-screen, 73.0% in X-ray-screen and 40.0% in symptomatic-prompted group. We performed further sub-analysis which excluded pure BACs (i.e. Noguchi types A and B) or pure GGOs within a 10mm diameter because this is indicative of a very favorable prognosis. Based on this sub-analysis the number of the subjects in each group became 76 in CT group; 140 in X-ray group and 77 in symptomatic-prompted group. The principal characteristics of the patients such as age and sex became almost even in the three arms. In CT-screen subgroup, the ratio of stage IA cancer was 69.7% and of advanced cases was 6.6%. This advanced ratio was lower than both X-ray-screen (22.1%) and symptomatic-prompted (61.9%) groups. The 5-year-survival rates were 89.9% among CT-screen group patients, 72.6% for X-ray screen cases and 39.1% in symptomatic-prompted group. A CT-screen was found to be one of the independent prognostic factors for lung cancer (HR, 0.28; 95% CI, 0.12-0.72) and based on this would be expected to reduce the risk of lung cancer death by 78% compared with non-screened cases. In conclusion, CT will improve the survival rate and decrease the rate of advanced cancers in never-smokers via the existing annual screening system. CT-screening is also an independent prognostic improvement factor in never-smokers, and will therefore reduce the risk of lung cancer death.

Phase I trial of nedaplatin and paclitaxel for patients with non-small cell lung cancer

Abstract A phase I study was conducted to evaluate the maximum tolerated dose and feasibility of combination with nedaplatin (NDP) and paclitaxel in patients with nonsmall cell lung cancer (NSCLC). Fifteen patients under 75 years old, with unresectable NSCLC who had not previously received chemotherapy or radiotherapy, with a performance status of 0-1, were enrolled. The dose escalation levels (NDP/Paclitaxel; mg/m2 day 1) were 80/150 (level 1), 80/180 (level 2), 90/180 (level 3) and repeated every 28 days. All patients receiving level 3 had dose-limiting toxicity. One patient developed grade 4 neutropenia with infection, two had incomplete recovery of neutropenia and thrombocytopenia by the 28th day after the first cycle of chemotherapy. Non-hematologic toxicities, including nephrotoxicity, nausea/vomiting, alopecia, and hypersensitivity reaction, were tolerated. Three of the 15 patients achieved partial responses. We concluded that the recommended dose was paclitaxel 180 and NDP 80 mg/m2 due to the hematologic toxicity.

Serial pentamidine levels in bronchial epithelial lining fluid after aerosol administration.

Background: There is no information on serial pharmacokinetic assessment in the lungs after administration of aerosolized pentamidine. Objective: The present study was performed to evaluate the elimination of aerosolized pentamidine from bronchial airways following inhalation. Methods: We used 4 sheep with tracheotomies in the present study. Pentamidine (300 mg) was administered by inhalation to each animal. Serial bronchial washing to obtain epithelial lining fluid (ELF) was performed 1, 7, 10, 14, 21 and 28 days after administration of aerosolized pentamidine in each animal. The pentamidine concentration in the supernatant of ELF was measured by high-performance liquid chromatography. Results: The maximal pentamidine level on the first day (12 h after inhalation) was 616.5 ± 238.2 ng/ml (mean ± SE) in ELF. The pentamidine levels rapidly decreased within 2 weeks (8.9 ± 1.2 ng/ml at 14 days), followed by slow elimination (8.9 ± 0.8 ng/ml at 28 days). Thus, inhaled pentamidine showed a rapid clearance from the bronchial wall within the first 2 weeks. Conclusions: These findings may be useful in designing and interpreting future studies of aerosolized pentamidine in patients who are receiving inhaled pentamidine, especially for those with failure of prophylaxis for Pneumocystis carinii pneumonia.