Shigenori Kyoh

Phase II study of docetaxel and carboplatin in elderly patients with advanced non-small cell lung cancer.

Background: Mainly single-agent chemotherapy has been considered as standard treatment for elderly patients with non-small cell lung cancer (NSCLC). Docetaxel monotherapy is regarded as a standard treatment for elderly patients with advanced NSCLC, and recent subset analyses have suggested that platinum-based chemotherapy can be safely used in the elderly. This phase II study was conducted to evaluate the efficacy and safety of docetaxel and carboplatin in elderly patients with advanced NSCLC. Methods: Patients enrolled in this study had stage IIIB or IV NSCLC with measurable disease, no prior chemotherapy, Eastern Cooperative Oncology Group performance status of 0–2, and were 70 years or older. Treatment consisted of docetaxel at a dose of 60 mg/m2 and carboplatin at area under the curve of 5 mg/ml/min on day 1 every 3 weeks. Results: From October 2003 to April 2006, 30 patients were enrolled. One complete response and 13 partial responses were observed, for an overall response rate of 46.7% (95% confidence interval: 28.8–64.6%). Median progression-free survival and overall survival periods were 4.4 months and 9.9 months, respectively. One-year survival rate was 43.3%. Major grade 3 and 4 hematological toxicities included neutropenia (86.7%), leucopenia (80.0%) and febrile neutropenia (16.7%). Major grade 3 nonhematological toxicities were anorexia (30.0%) and diarrhea (13.3%). There were no grade 4 nonhematological toxicities or treatment-related deaths. Conclusions: Docetaxel combined with carboplatin was an active treatment with manageable toxicity for the treatment of elderly patients with chemotherapy-naive NSCLC.

Increased levels of angiopoietin-2 in induced sputum from smoking asthmatic patients

Background Active cigarette smoking has detrimental effects on asthma morbidity and severity. Angiopoietin‐1 has been shown to protect the microvessels against plasma leakage, whereas angiopoietin‐2 enhances vascular permeability and subsequently induces airway mucosal oedema. Therefore, it is recently thought that angiopoietin‐2 may contribute to the pathophysiology of asthma.

Potential roles of pentosidine in age-related and disease-related impairment of pulmonary functions in patients with asthma

BACKGROUND Pentosidine is well established as an intermolecular cross-linking type of advanced glycation end products, and it accumulates with aging in various connective tissues. OBJECTIVE To determine whether pentosidine contributes to age-related and disease-related impairment of pulmonary functions in patients with asthma. METHODS We measured pentosidine levels in induced sputum from young to elderly patients with asthma and assessed the slope of the nitrogen (N(2)) alveolar plateau (delta N(2)), closing volume (CV), and closing capacity (CC) from a nitrogen washout curve in a single breath. RESULTS Pentosidine levels in induced sputum were significantly higher in patients with asthma than in normal controls (patients with asthma: median, 20.1, interquartile range, 16.7-26.5 ng/mL; normal controls: median, 3.0, interquartile range, 0.7-7.5 ng/mL; P < .001). The levels were closely correlated with age in both normal controls and patients with asthma. However, the slope of age-related increase in pentosidine levels was markedly steeper in patients with asthma than in normal controls. CV/vital capacity, CC/total lung capacity, and delta N(2) increased with aging in both normal controls and patients with asthma. Moreover, in each range of age (21-40, 41-60, 61-80 years), CV/vital capacity, CC/total lung capacity, and delta N(2) were significantly higher in patients with asthma than in normal controls. In addition, pentosidine levels in patients with asthma were closely correlated with each of these variables. CONCLUSION Our results demonstrated the association between sputum levels of pentosidine and age-related small airways function in both normal controls and patients with asthma. Moreover, the age-related increase in pentosidine levels was more pronounced in patients with asthma. These findings will herald new era in the pathophysiology of elderly asthma.

A technological advance comparing epithelial lining fluid from different regions of the lung in smokers.

Cigarette smoking causes inflammatory responses in the airways. However, not all smokers exhibit the development of airflow limitation. This study was designed to determine the implications of small airways inflammation in the development of airflow limitation in smokers by our newly explored method. Twenty-eight smokers (15 smokers without airflow limitation and 13 with airflow limitation) were included in this study. Levels of interleukin-8 (IL-8) and 8-isoprostane were measured in epithelial lining fluid (ELF) from central and peripheral airways separately collected using a bronchoscopic microsampling technique. 8-isoprostane levels in ELF from central or peripheral airways did not significantly differ between the two groups. However, these levels were markedly higher in peripheral than in central airways. Similarly, IL-8 levels in ELF from central airways did not significantly differ between the two groups. In smokers without airflow limitation, IL-8 levels were not higher in peripheral than in central airways. In contrast, in smokers with airflow limitation, IL-8 levels were significantly higher in peripheral airways. Moreover, in smokers with airflow limitation, 8-isoprostane levels in central or peripheral airways were not significantly correlated with FEV(1). However, IL-8 levels in peripheral airways were inversely correlated with FEV(1), though those levels in central airways were not. Thus our technique provides a novel method for ELF sampling from central or peripheral airways separately, and the preliminary evidence that support differences in oxidative stress and neutrophil chemotactic stimulus in these two locations.

Role of vascular endothelial growth factor in pulmonary endothelial cell injury by exercise challenge in asthmatic patients

This study was designed to examine the role of vascular endothelial growth factor (VEGF) in pulmonary endothelial cell injury by exercise in asthmatics. Post-exercise circulating thrombomodulin (TM) levels were significantly increased in asthmatics. Moreover, the increase in TM levels with exercise was significantly correlated with VEGF level in induced sputum from asthmatics (r = 0.80, p = 0.0007). After inhaled steroid therapy, post-exercise TM levels were significantly decreased, but the increase in TM levels with exercise was also correlated with VEGF level (r = 0.60, p = 0.01). Thus, pulmonary endothelial cells stimulated by VEGF in asthmatic airways may be sensitive to exercise challenge.

Plasma concentration of amrubicinol in plateau phase in patients treated for 3 days with amrubicin is correlated with hematological toxicities.

Amrubicinol (AMR-OH) is an active metabolite of amrubicin (AMR), a novel synthetic 9-aminoanthracycline derivative. The time–concentration profile of AMR-OH exhibits a continuous long plateau slope in the terminal phase. To determine the relationships between the steady-state plasma concentration of AMR-OH and treatment effects and toxicities associated with AMR therapy, we carried out a pharmacokinetic/pharmacodynamic study in patients treated with AMR alone or the combination of AMR+cisplatin (CDDP). AMR was given at a dose of 30 or 40 mg/m2 on days 1–3. Plasma samples were collected 24 h after the third injection (day 4). Plasma concentrations of AMR-OH or total CDDP were determined by a high-performance liquid chromatography or an atomic absorption spectrometry. Percent change in neutrophil count (dANC) and the plasma concentration of AMR-OH were evaluated using a sigmoid Emax model. A total of 35 patients were enrolled. Significant relationships were observed between AMR-OH on day 4 and the toxicity grades of leukopenia, neutropenia, and anemia (P=0.018, P=0.012, and P=0.025, respectively). Thrombocytopenia grade exhibited a tendency toward relationship with AMR-OH on day 4 (P=0.081). The plasma concentration of AMR-OH on day 4 was positively correlated with dANC in the group of all patients, as well as in patients treated with AMR alone and in patients coadministered with CDDP. In conclusion, the plasma concentration of AMR-OH on day 4 was correlated with hematological toxicities in patients treated with AMR. The assessment of plasma concentration of AMR-OH at one timepoint might enable the prediction of hematological toxicities.

Nε-(Carboxymethyl)Lysine, a Major Advanced Glycation End Product in Exhaled Breath Condensate as a Biomarker of Small Airway Involvement in Asthma

Nε -(Carboxymethyl)Lysine (CML) expression is selectively present in the lower respiratory tract. We compared CML levels in exhaled breath condensate (EBC) between 19 asthmatics and 10 normal control subjects and its levels before and after tiotropium therapy in 11 non-smoking asthmatics and 10 smoking asthmatics. CML levels were significantly lower in asthmatics than in normal control subjects. Moreover, low CML level was associated with small airway dysfunction. After tiotropium therapy, CML level in non-smoking asthmatics was unchanged, while that in smoking asthmatics was significantly increased. Therefore, CML level in EBC is a non-invasive biomarker for evaluating small airway involvements in asthma.

Potential role of pentosidine on susceptibility to small airway closure in elderly and smoking asthma

BACKGROUND Small airway closure in asthma is determined by a complex interaction of structural and functional characteristics including lung elastic recoil. Recently, we determined that loss of elastic recoil might be attributable to pentosidine level in the airways. This study was designed to investigate the influences of aging and smoking on small airway closure in asthma. METHODS Sixty-one patients with asthma (20 non-smoking young adult, 23 non-smoking elderly, and 18 smoking young adult) and 36 control subjects (12 non-smoking young adult, 11 non-smoking elderly, and 13 smoking young adult) were included. We assessed airway responses during methacholine provocation and calculated the closing index. In addition, we measured pentosidine levels in induced sputum from all study subjects. RESULTS Pentosidine levels in induced sputum were markedly higher in asthmatic patients than in controls. In control subjects, the intergroup differences in pentosidine level among 3 subgroups were significant. Similarly, pentosidine levels were significantly higher in non-smoking elderly and smoking young adult asthmatics than in non-smoking young adult asthmatics. There was no significant difference in pentosidine levels between non-smoking elderly and smoking young adult asthmatics. The closing index was also significantly higher in non-smoking elderly and smoking young adult asthmatics than in non-smoking young adult asthmatics. Moreover, pentosidine levels in non-smoking elderly and smoking young adult asthmatics were closely correlated with closing index. CONCLUSIONS We determined the correlation of pentosidine level with susceptibility to small airway closure in elderly and smoking asthmatics. Our results might facilitate the understanding of elderly and smoking asthma.

Measurement of soluble perforin, a marker of CD8+ T lymphocyte activation in epithelial lining fluid.

BACKGROUND CD8(+) T lymphocytes in the peripheral airways have been suggested to be involved in the pathogenesis of COPD. However, the significance of CD8(+) T lymphocyte activation in COPD is not well understood. A biomarker of CD8(+) T lymphocyte activation in patients with COPD is required. METHODS Thirty COPD patients and twenty-one healthy controls (eleven ex-smokers and ten who had never smoked or were light ex-smokers) were included in this study. We separately obtained epithelial lining fluid (ELF) from central and peripheral airways using a bronchoscopic microsampling technique. Levels of perforin in ELF were measured and we examined correlations between its values and patients characteristics including pulmonary function. RESULTS Perforin levels in both the central and peripheral airways in COPD patients were significantly higher than those in the healthy control groups. In the healthy control groups, there was no significant difference in perforin levels between central and peripheral airways. However, in COPD patients, perforin levels in peripheral airways were significantly higher than those in central airways. Perforin levels in peripheral airways were significantly correlated with FEV(1) (percent predicted), FEV(1)/FVC, and DLco (percent predicted) in COPD patients. CONCLUSION The microsampling technique is safe and useful for separately obtaining ELF from central and peripheral airways. Levels of perforin in ELF from peripheral airways were significantly increased and correlated with the degree of pulmonary dysfunction. Perforin might reflect inflammation involving CD8(+) T-lymphocytes. This novel biomarker might enable better understanding of the pathogenesis of COPD.

Validity of Measurement of Two Specific Biomarkers for the Assessment of Small Airways Inflammation in Asthma

Background: Small airways inflammation in asthma has been supposed to contribute to instability of the disease and therapy resistance. This study was designed to determine the validity of measurement of Nε-(carboxymethyl)lysine (CML) levels in induced sputum and alveolar concentrations of nitric oxide (NO) for the assessment of small airways inflammation in asthma. Methods: The authors measured CML levels in induced sputum and the bronchial flux (Jno) and alveolar concentration (Calv) of NO in 37 asthmatic patients and 15 normal controls. After initial analysis, all asthmatics were randomly assigned to receive inhaled fluticasone propionate (FP; 400 μg/day, n = 21) or hydrofluoroalkane–beclomethasone dipropionate (HFA-BDP; 400 μg/day, n = 16) for 12 weeks. And then the determination of exhaled NO level and sputum induction was performed after the treatment period. Results. CML levels in induced sputum were significantly higher in asthmatics than in normal controls (median [interquartile range], asthmatics: 53.0 [44.8–64.3] μg/ml, normal controls: 22.0 [14.8–28.3] μg/ml; p < .01). Similarly, Jno and Calv were also higher in asthmatics. Moreover, CML level was closely correlated with Calv but not with Jno in asthmatics (r = .47, p = .005). Jno was significantly correlated with forced expiratory volume in one second/forced vital capacity (FEV1/FVC), and CML level and Calv were correlated with forced expiratory flow between 25% and 75% of FVC (FEF25–75), an index of small airways obstruction. After FP treatment, the decrease in CML level and Calv were very small. In contrast, these levels were markedly decreased after HFA-BDP treatment. Moreover, even after FP or HFA-BDP treatment, CML level was significantly correlated with Calv. Conclusions: This novel, noninvasive technique of measurement of CML levels in induced sputum and Calv may prove to be important not only in the evaluation of small airways inflammation but also in helping us move toward a better understanding of the roles of the small airways in the pathogenesis of asthma.