Emphysema- and airway-dominant COPD phenotypes defined by standardised quantitative computed tomography.

EvA (Emphysema versus Airway disease) is a multicentre project to study mechanisms and identify biomarkers of emphysema and airway disease in chronic obstructive pulmonary disease (COPD). The objective of this study was to delineate objectively imaging-based emphysema-dominant and airway disease-dominant phenotypes using quantitative computed tomography (QCT) indices, standardised with a novel phantom-based approach.441 subjects with COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages 1-3) were assessed in terms of clinical and physiological measurements, laboratory testing and standardised QCT indices of emphysema and airway wall geometry.QCT indices were influenced by scanner non-conformity, but standardisation significantly reduced variability (p<0.001) and led to more robust phenotypes. Four imaging-derived phenotypes were identified, reflecting "emphysema-dominant", "airway disease-dominant", "mixed" disease and "mild" disease. The emphysema-dominant group had significantly higher lung volumes, lower gas transfer coefficient, lower oxygen (PO2 ) and carbon dioxide (PCO2 ) tensions, higher haemoglobin and higher blood leukocyte numbers than the airway disease-dominant group.The utility of QCT for phenotyping in the setting of an international multicentre study is improved by standardisation. QCT indices of emphysema and airway disease can delineate within a population of patients with COPD, phenotypic groups that have typical clinical features known to be associated with emphysema-dominant and airway-dominant disease.

Endobronchial therapy with a thulium fiber laser (1940 nm).

BACKGROUND: Nd:YAG laser (1064 nm) is standard in bronchology. The thulium fiber laser (1940 nm) has a nearly 1000-fold increased absorption in water, enabling precise tissue ablation with a small margin of coagulation, whereas 1064-nm laser light penetrates deeper into tissue with less controllable effects. OBJECTIVES: To assess the safety, feasibility, and versatility of endobronchial thulium laser therapy in an observational cohort study. METHODS: Endobronchial treatment with the thulium fiber laser was performed in a cohort study of 187 bronchoscopies on 132 consecutive patients with 135 endobronchial lesions amenable to laser resection. RESULTS: The thulium fiber laser produced superficial, precise, and rapid tissue ablation. Eighty-one lesions were completely vaporized; 82 lesions were treated by deep tissue destruction by inserting the fiber into tissue followed by mechanical resection. Tumor bleeding was coagulated with rapid and sustained hemostasis (n = 28). Nitinol stents were removed after resection of severe granulation tissue overgrowth (n = 10). Intact stents were maintained after ablation of in-stent tissue (n = 47). In 11 cases, bleeding occurred during laser treatment (n = 11 of 187). Power settings between 5 and 20 W were found to be safe. CONCLUSIONS: Endobronchial therapy with the thulium laser at 1940 nm seems to be safe, feasible, and highly versatile for treatment of airway stenosis and stent obstruction caused by tissue ingrowth. Further studies are warranted.

The European Respiratory Society spirometry tent: a unique form of screening for airway obstruction.

In order to raise public awareness of the importance of early detection of airway obstruction and to enable many people who had not been tested previously to have their lung function measured, the European Lung Foundation and the European Respiratory Society (ERS) organised a spirometry testing tent during the annual ERS Congresses in 2004-2009. Spirometry was performed during the ERS Congresses in volunteers; all participants answered a simple, brief questionnaire on their descriptive characteristics, smoking and asthma. Portable spirometers were freely provided by the manufacturer. Nurses and doctors from pulmonary departments of local hospitals/universities gave their service for free. Lower limit of normal (LLN) and Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria for diagnosing and grading airway obstruction were used. Of 12,448 participants in six congress cities, 10,395 (83.5%) performed acceptable spirometry (mean age 51.0 ± 18.4 yrs; 25.5% smokers; 5.5% asthmatic). Airway obstruction was present in 12.4% of investigated subjects according to LLN criteria and 20.3% according to GOLD criteria. Through multinomial logistic regression analysis, age, smoking habits and asthma were significant risk factors for airway obstruction. Relative risk ratio and 95% confidence interval for LLN stage I, for example, was 2.9 (2.0-4.1) for the youngest age (≤ 19 yrs), 1.9 (1.2-3.0) for the oldest age (≥ 80 yrs), 2.4 (2.0-2.9) for current smokers and 2.8 (2.2-3.6) for reported asthma diagnosis. In addition to being a useful advocacy tool, the spirometry tent represents an unusual occasion for early detection of airway obstruction in large numbers of city residents with an important public health perspective.

Early onset lung cancer, cigarette smoking and the SNP309 of the murine double minute-2 (MDM2) gene.

The polymorphism SNP309 (rs2279744) in the promoter region of the MDM2 gene has been shown to alter protein expression and may play a role in the susceptibility to lung cancer. The MDM2 protein is a key inhibitor of p53 and several mechanisms of MDM2/p53 interactions are presently known: modulating DNA-repair, cell-cycle control, cell growth and apoptosis.We used 635 Caucasian patients diagnosed with lung cancer before 51 years of age and 1300 healthy gender and age frequency matched population Caucasian controls to investigate the association between the MDM2 SNP309 and the risk of developing early onset lung cancer. Conditional logistic models were applied to assess the genotype-phenotype association, adjusted for smoking. Compared to the GG genotype, the adjusted ORs for the TG and TT genotype were 0.9 (95% CI: 0.7-1.5) and 1.0 (95% CI: 0.7-1.5), respectively. Also no association was found for histological subtypes of lung cancer. The strength of this study is that within young cases the genetic component to develop lung cancer may be greater. Our results indicate that the MDM2 SNP309 is not significantly associated with lung carcinogenesis but point towards gender-specific differences.

Seizure 6-like (SEZ6L) gene and risk for lung cancer.

DNA pooling in combination with high-throughput sequencing was done as a part of the Sequenom-Genefinder project. In the pilot study, we tested 83,715 single nucleotide polymorphisms (SNP), located primarily in gene-based regions, to identify polymorphic susceptibility variants for lung cancer. For this pilot study, 369 male cases and 287 controls of both sexes (white Europeans of Southern German origin) were analyzed. The study identified a candidate region in 22q12.2 that contained numerous SNPs showing significant case-control differences and that coincides with a region that was shown previously to be frequently deleted in lung cancer cell lines. The candidate region overlies the seizure 6-like (SEZ6L) gene. The pilot study identified a polymorphic Met430Ile substitution in the SEZ6L gene (SNP rs663048) as the top candidate for a variant modulating risk of lung cancer. Two replication studies were conducted to assess the association of SNP rs663048 with lung cancer risk. The M. D. Anderson Cancer Center study included 289 cases and 291 controls matched for gender, age, and smoking status. The Liverpool Lung Project (a United Kingdom study) included 248 cases and 233 controls. Both replication studies showed an association of the rs663048 with lung cancer risk. The homozygotes for the variant allele had more than a 3-fold risk compared with the wild-type homozygotes [combined odds ratio (OR), 3.32; 95% confidence interval (95% CI), 1.81-7.21]. Heterozygotes also had a significantly elevated risk of lung cancer from the combined replication studies with an OR of 1.15 (95% CI, 1.04-1.59). The effect remained significant after adjusting for age, gender, and pack-years of tobacco smoke. We also compared expression of SEZ6L in normal human bronchial epithelial cells (n = 7), non-small cell lung cancer (NSCLC; n = 52), and small cell lung cancer (SCLC; n = 22) cell lines by using Affymetrix HG-U133A and HG-U133B GeneChips. We found that the average expression level of SEZ6L in NSCLC cell lines was almost two times higher and in SCLC cell lines more than six times higher when compared with normal lung epithelial cell lines. Using the National Center for Biotechnology Information Gene Expression Omnibus database, we found a approximately 2-fold elevated and statistically significant (P = 0.004) level of SEZ6L expression in tumor samples compared with normal lung tissues. In conclusion, the results of these studies representing 906 cases compared with 811 controls indicate a role of the SEZ6L Met430Ile polymorphic variant in increasing lung cancer risk.

Inhalative vaccination with pneumococcal polysaccharide in patients with chronic obstructive pulmonary disease.

In order to determine the feasibility of inhalative vaccination with polysaccharide antigen in patients with chronic obstructive pulmonary disease (COPD), we used controlled inhalation of a defined dose of Pneumovax in a randomized 3-arm study. The vaccine was either deposited in the alveoli (alveolar vaccination) or in the large airways (bronchial vaccination) and these were compared to standard intramuscular vaccination. Adverse effects were minor and never exceeded WHO grade 2. There was frequent cough, headache and shivering in the bronchial vaccination group, frequent fatigue only in the alveolar vaccination group and no frequent adverse effects in the intramuscular vaccination group. Specific serum IgG antibody was measured before and at 4 and 12 weeks after vaccination. At 12 weeks there was a greater than twofold rise in 7 out of 10 individuals in every vaccination group. Mean antibody levels of responders at 12 weeks were 278 mg/l for alveolar vaccination, 238 mg/l for bronchial vaccination and 737 mg/l for standard intramuscular vaccination. The data show that polysaccharide vaccine can be safely administered by controlled inhalation in COPD patients and that it can induce a rapid serum antibody response.

Association of the PDCD5 locus with lung cancer risk and prognosis in smokers.

PURPOSE: Whole-genome scan association analysis was carried out to identify genetic variants predictive of lung cancer risk in smokers and to confirm the identified variants in an independent sample. PATIENTS AND METHODS: A case-control study was performed using two pools consisting of DNA from 322 German smoking lung cancer patients and 273 healthy smoking controls, respectively. A replication study was carried out using 254 Italian lung adenocarcinoma (ADCA) patients and 235 healthy controls. RESULTS: Patients with genotypes GG or CG for the rs1862214 single nucleotide polymorphism, 5' upstream of the programmed cell death 5 (PDCD5) gene, compared with those with the common genotype CC showed an increased risk of lung cancer (odds ratio, 1.6; 95% CI, 1.2 to 2.1) and a higher incidence of poor clinical stage disease (hazard ratio [HR], 1.9; 95% CI, 1.1 to 3.4; P = .023), nodal involvement (HR, 1.9; 95% CI, 1.1 to 3.6; P = .033), and short-term survivorship (HR, 1.8; 95% CI, 1.2 to 2.6, P = .003). PDCD5 mRNA expression levels were approximately 2.4-fold lower in lung ADCA as compared to normal lung tissue. Human NCI-H520 cancer cells transfected with PDCD5 cDNA showed decreased colony-forming ability. CONCLUSION: These results suggest that the rs1862214 polymorphism in PDCD5 is predictive for lung cancer risk and prognosis, and that PDCD5 may represent a novel tumor suppressor gene influencing lung cancer.

Inhalative vaccination with pneumococcal polysaccharide in healthy volunteers.

In order to determine the feasibility of inhalative vaccination with polysaccharide antigen, we used controlled inhalation of a defined dose of Pneumovax in a randomized 3-arm study. The vaccine was either deposited in the alveoli (alveolar vaccination) or in the large airways (bronchial vaccination) and this was compared to standard intra-muscular vaccination. Adverse effects were minor and never exceeded WHO grade 2. There was frequent cough in the inhalative groups and frequent local pain at the injection site in the intra-muscular group. Specific serum IgG antibody measured before, and 4 and 12 weeks after, vaccination showed a greater than 2-fold rise in 4 out of 10 individuals after alveolar vaccination and in 6 out of 10 individuals after bronchial vaccination as compared to 10 out of 10 in the intra-muscular vaccination group. Average antibody levels of responders at 12 weeks were 350 microg/ml for alveolar vaccination, 200 microg/ml for bronchial vaccination and 1010 microg/ml for standard intra-muscular vaccination. Analysis of antibodies for 9 specific serotypes showed a more than 3-fold rise to 7-9 of the serotypes in the intra-muscular group. In both the bronchial and the alveolar group, all subjects responded but this was restricted to 2-4 of the 9 serotypes. The data show that polysaccharide vaccine can be safely administered by controlled inhalation and that it can induce good, albeit lower, serum antibody responses.