Utility of incorporating a gene-based lung cancer risk test on uptake and adherence in a community-based lung cancer screening pilot study.

Based on the results of randomized control trials, screening for lung cancer using computed tomography (CT) is now widely recommended. However, adherence to screening remains an issue outside the clinical trial setting. This study examines the utility of biomarker-based risk assessment on uptake and subsequent adherence in a community screening study. In a single arm pilot study, current or former smokers > 50 years old with 20 + pack year history were recruited following local advertising. One hundred and fifty seven participants volunteered to participate in the study that offered an optional gene-based lung cancer risk assessment followed by low-dose CT according to a standardised screening protocol. All 157 volunteers who attended visit 1 underwent the gene-based risk assessment comprising of a clinical questionnaire and buccal swab. Of this group, 154 subsequently attended for CT screening (98%) and were followed prospectively for a median of 2.7 years. A participant's adherence to screening was influenced by their baseline lung cancer risk category, with overall adherence in those with a positive scan being significantly greater in the "very high" risk group compared to "moderate" and "high" risk categories (71% vs 52%, Odds ratio = 2.27, 95% confidence interval of 1.02-5.05, P = 0.047). Those in the "moderate" risk group were not different to those in the "high" risk group (52% and 52%, P > 0.05). In this proof-of-concept study, personalised gene-based lung cancer risk assessment was well accepted, associated with a 98% uptake for screening and increased adherence for those in the highest risk group.

Airflow limitation and survival after surgery for non-small cell lung cancer: Results from a systematic review and lung cancer screening trial (NLST-ACRIN sub-study).

OBJECTIVE: Lung cancer remains the single greatest cause of cancer mortality where surgery for early stage non-small cell lung cancer achieves the greatest survival. While there is growing optimism for better outcomes with screening using annual computed tomography, the impact of co-existing airflow limitation on survival remains unknown. To compare survival in non-small cell lung cancer patients undergoing surgery stratified according to the presence or absence of pre-surgery airflow limitation. MATERIALS AND METHODS: We undertook a systematic literature search of non-screen lung cancer that encompassed studies reported between January 1946 and January 2017. Full-text articles were identified following eligibility scoring, with data extracted and analysed using a standardised analytical method (PRISMA). The results of this systematic review in non-screen lung cancers were compared to real-world results from a lung cancer screening cohort (N = 10,054), where outcomes following surgery could be compared after stratification according to pre-surgery airflow limitation. RESULTS: In the systematic review, 6899 subjects were included from 10 studies; 7 were retrospective, 3 were prospective. Overall survival was 950 (44%) in 2144 people with COPD and 2597 (55%) from 4755 controls (unadjusted P value <0.001). However, the overall meta-analysed random effects odds ratio for overall survival (N = 10) and 5-year survival (N = 4) comparing those with and without COPD was 0.91 (95% CI = 0.84-1.00) and 0.99 (95% CI = 0.79-1.24) respectively. There were no signs of significant heterogeneity (I2 = 19.1%, P = 0.27) nor publication bias as assessed by funnel plot and Egger's test (P = 0.19). In the lung cancer screening sub-study of 10,054 screening participants we found no difference in 5-year survival in those with and without airflow limitation (84% and 81% respectively, P = 0.64). CONCLUSION: Survival after surgery for non-small cell lung cancer is comparable between those with and without spirometry evidence of airflow limitation. This finding was replicated in lung cancer diagnosed during screening.

Magnetized Disruption of Inertially Confined Plasma Flows.

The creation and disruption of inertially collimated plasma flows are investigated through experiment, simulation, and analytical modeling. Supersonic plasma jets are generated by laser-irradiated plastic cones and characterized by optical interferometry measurements. Targets are magnetized with a tunable B field with strengths of up to 5 T directed along the axis of jet propagation. These experiments demonstrate a hitherto unobserved phenomenon in the laboratory, the magnetic disruption of inertially confined plasma jets. This occurs due to flux compression on axis during jet formation and can be described using a Lagrangian-cylinder model of plasma evolution implementing finite resistivity. The basic physical mechanisms driving the dynamics of these systems are described by this model and then compared with two-dimensional radiation-magnetohydrodynamic simulations. Experimental, computational, and analytical results discussed herein suggest that contemporary models underestimate the electrical conductivity necessary to drive the amount of flux compression needed to explain observations of jet disruption.

Dynamics and genetics of a disease-driven species decline to near extinction: lessons for conservation.

Amphibian chytridiomycosis has caused precipitous declines in hundreds of species worldwide. By tracking mountain chicken (Leptodactylus fallax) populations before, during and after the emergence of chytridiomycosis, we quantified the real-time species level impacts of this disease. We report a range-wide species decline amongst the fastest ever recorded, with a loss of over 85% of the population in fewer than 18 months on Dominica and near extinction on Montserrat. Genetic diversity declined in the wild, but emergency measures to establish a captive assurance population captured a representative sample of genetic diversity from Montserrat. If the Convention on Biological Diversity's targets are to be met, it is important to evaluate the reasons why they appear consistently unattainable. The emergence of chytridiomycosis in the mountain chicken was predictable, but the decline could not be prevented. There is an urgent need to build mitigation capacity where amphibians are at risk from chytridiomycosis.

Gene by Environment Interaction Linking the Chromosome 15q25 Locus With Cigarette Consumption and Lung Cancer Susceptibility--Are African American Affected Differently?

The majority of lung cancer cases result from complex interactions between smoking exposure, genetic susceptibility and a person's immune response to chronic inflammation or lung remodelling. Epidemiological studies confirm that susceptibility to developing chronic obstructive pulmonary disease (COPD), especially emphysema, is also closely linked to lung cancer susceptibility. Genetic epidemiology studies have consistently reported associations between the chromosome 15q25 locus with lung cancer and COPD. In addition, studies show this locus to be independently associated with cigarette consumption and nicotine addiction in a dose-response manner, primarily at lower levels of cigarette consumption. Studies that measure both cigarette consumption and lung function, together with extensive genotype analysis, will be needed to further unravel these complex relationships.

Observation of the Kibble-Zurek Mechanism in Microscopic Acoustic Crackling Noises.

Characterizing the fast evolution of microstructural defects is key to understanding "crackling" phenomena during the deformation of solid materials. For example, it has been proposed using atomistic simulations of crack propagation in elastic materials that the formation of a nonlinear hyperelastic or plastic zone around moving crack tips controls crack velocity. To date, progress in understanding the physics of this critical zone has been limited due to the lack of data describing the complex physical processes that operate near microscopic crack tips. We show, by analyzing many acoustic emission events during rock deformation experiments, that the signature of this nonlinear zone maps directly to crackling noises. In particular, we characterize a weakening zone that forms near the moving crack tips using functional networks, and we determine the scaling law between the formation of damages (defects) and the traversal rate across the critical point of transition. Moreover, we show that the correlation length near the transition remains effectively frozen. This is the main underlying hypothesis behind the Kibble-Zurek mechanism (KZM) and the obtained power-law scaling verifies the main prediction of KZM.

Clinical applications of gene-based risk prediction for lung cancer and the central role of chronic obstructive pulmonary disease.

Lung cancer is the leading cause of cancer death worldwide and nearly 90% of cases are attributable to smoking. Quitting smoking and early diagnosis of lung cancer, through computed tomographic screening, are the only ways to reduce mortality from lung cancer. Recent epidemiological studies show that risk prediction for lung cancer is optimized by using multivariate risk models that include age, smoking exposure, history of chronic obstructive pulmonary disease (COPD), family history of lung cancer, and body mass index. It has also been shown that COPD predates lung cancer in 65-70% of cases, conferring a four- to sixfold greater risk of lung cancer compared to smokers with normal lung function. Genome-wide association studies of smokers have identified a number of genetic variants associated with COPD or lung cancer. In a case-control study, where smokers with normal lungs were compared to smokers who had spirometry-defined COPD or histology confirmed lung cancer, several of these variants were shown to overlap, conferring the same susceptibility or protective effects on both COPD and lung cancer (independent of COPD status). In this perspective article, we show how combining clinical data with genetic variants can help identify heavy smokers at the greatest risk of lung cancer. Using this approach, we found that gene-based risk testing helped engage smokers in risk mitigating activities like quitting smoking and undertaking lung cancer screening. We suggest that such an approach could facilitate the targeted selection of smokers for cost-effective life-saving interventions.

Chromosome 4q31 locus in COPD is also associated with lung cancer.

Chronic obstructive pulmonary disease (COPD) is the single greatest risk factor for lung cancer in smokers and is found in 50-90% of lung cancer cases. The link between COPD and lung cancer may stem in part from the matrix remodelling and repair processes underlying COPD, and the development of epithelial-mesenchymal transition (EMT) that underlies lung carcinogenesis. The Hedgehog-interacting protein (HHIP), which mediates the epithelial response (EMT) to smoking, has been implicated in COPD and lung cancer. Recent genome-wide and candidate gene studies of COPD implicate genetic variants on the chromosomal 4q31 (HHIP/glycophorin A (GYPA)) locus. In a case-control study of smokers with normal lung function, COPD and lung cancer (subphenotyped for COPD), we show the GG genotype of the rs 1489759 HHIP single-nucleotide polymorphism (SNP) and the CC genotype of the rs 2202507 GYPA SNP confers a "protective" effect on COPD (OR 0.59, p = 0.006 for HHIP and OR = 0.65, p = 0.006 for GYPA) and lung cancer (OR = 0.70 (p = 0.05) for HHIP and OR 0.70 (p = 0.02) for GYPA). This study suggests that, in smokers, genetic variants of the 4q31 locus conferring a protective effect for COPD are also protective in lung cancer. We conclude that genetic susceptibility to lung cancer includes COPD-related gene variants.

A gene-based risk score for lung cancer susceptibility in smokers and ex-smokers.

BACKGROUND: Epidemiological and family studies suggest that lung cancer results from the combined effects of age, smoking and genetic factors. Chronic obstructive pulmonary disease (COPD) is also an independent risk factor for lung cancer and coexists in 40-60% of lung cancer cases. METHODS: In a two-stage case-control association study, genetic markers associated with either susceptibility or protection against lung cancer were identified. In a test cohort of 439 Caucasian smokers or ex-smokers, consisting of healthy smokers and lung cancer cases, 157 candidate single nucleotide polymorphisms (SNPs) were screened. From this, 30 SNPs were identified, the genotypes (codominant or recessive model) of which were associated with either the healthy smokers (protective) or lung cancer (susceptibility) phenotype. After genotyping of this 30-SNP panel in a second validation cohort of 491 subjects and using the same protective and susceptibility genotypes from our test cohort, a 20-SNP panel was selected on the basis of independent univariate analyses. RESULTS: Using multivariate logistic regression, including the 20 SNPs, it was also found that age, history of COPD, family history of lung cancer and gender were significantly and independently associated with lung cancer. CONCLUSIONS: When numeric scores were assigned to both the SNP and demographic data, and sequentially combined by a simple algorithm in a risk model, the composite score was found to be linearly related to lung cancer risk with a bimodal distribution. Genetic data may therefore be combined with other risk variables from smokers or ex-smokers to identify individuals who are most susceptible to developing lung cancer.

Potential benefits of statins on morbidity and mortality in chronic obstructive pulmonary disease: a review of the evidence.

Studies show reduced forced expiratory volume in 1 s (FEV(1)) in patients with chronic obstructive pulmonary disease (COPD) is an important independent predictor of cardiovascular death and is characterised by both pulmonary and systemic inflammation. Evidence shows statins have important anti-inflammatory effects in both the lungs and arteries. Although randomised control trials are yet to be reported, non-randomised studies have consistently shown benefit in COPD patients taking statins compared with those not. These include reductions in both cardiovascular and respiratory morbidity/mortality. Other potential benefits include a reduced decline in FEV(1) and reduced risk of lung cancer. It is argued that confounding by a "healthy user effect" is unlikely to explain the observed benefit. Given the undisputed benefit of statins in high risk populations and the growing body of data suggesting statins may benefit patients with COPD, the question arises "Should statins be considered more often in patients with COPD?".

COPD prevalence is increased in lung cancer, independent of age, sex and smoking history.

Chronic obstructive pulmonary disease (COPD) is a common comorbid disease in lung cancer, estimated to affect 40-70% of lung cancer patients, depending on diagnostic criteria. As smoking exposure is found in 85-90% of those diagnosed with either COPD or lung cancer, coexisting disease could merely reflect a shared smoking exposure. Potential confounding by age, sex and pack-yr smoking history, and/or by the possible effects of lung cancer on spirometry, may result in over-diagnosis of COPD prevalence. In the present study, the prevalence of COPD (pre-bronchodilator Global Initiative for Chronic Obstructive Lung Disease 2+ criteria) in patients diagnosed with lung cancer was 50% compared with 8% in a randomly recruited community control group, matched for age, sex and pack-yr smoking exposure (n = 602, odds ratio 11.6; p<0.0001). In a subgroup analysis of those with lung cancer and lung function measured prior to the diagnosis of lung cancer (n = 127), we found a nonsignificant increase in COPD prevalence following diagnosis (56-61%; p = 0.45). After controlling for important variables, the prevalence of COPD in newly diagnosed lung cancer cases was six-fold greater than in matched smokers; this is much greater than previously reported. We conclude that COPD is both a common and important independent risk factor for lung cancer.

Pharmacological actions of statins: potential utility in COPD.

Chronic obstructive pulmonary disease (COPD) is characterised by minimally reversible airflow limitation and features of systemic inflammation. Current therapies for COPD have been shown to reduce symptoms and infective exacerbations and to improve quality of life. However, these drugs have little effect on the natural history of the disease (progressive decline in lung function and exercise tolerance) and do not improve mortality. The anti-inflammatory effects of statins on both pulmonary and systemic inflammation through inhibition of guanosine triphosphatase and nuclear factor-κB mediated activation of inflammatory and matrix remodelling pathways could have substantial benefits in patients with COPD due to the following. 1) Inhibition of cytokine production (tumour necrosis factor-α, interleukin (IL)-6 and IL-8) and neutrophil infiltration into the lung; 2) inhibition of the fibrotic activity in the lung leading to small airways fibrosis and irreversible airflow limitation; 3) antioxidant and anti-inflammatory (IL-6 mediated) effects on skeletal muscle; 4) reduced inflammatory response to pulmonary infection; and 5) inhibition of the development (or reversal) of epithelial-mesenchymal transition, a precursor event to lung cancer. This review examines the pleiotropic pharmacological action of statins which inhibit key inflammatory and remodelling pathways in COPD and concludes that statins have considerable potential as adjunct therapy in COPD.