Laura H. Thomsen

Results of the Randomized Danish Lung Cancer Screening Trial with Focus on High-Risk Profiling

RATIONALE As of April 2015, participants in the Danish Lung Cancer Screening Trial had been followed for at least 5 years since their last screening. OBJECTIVES Mortality, causes of death, and lung cancer findings are reported to explore the effect of computed tomography (CT) screening. METHODS A total of 4,104 participants aged 50-70 years at the time of inclusion and with a minimum 20 pack-years of smoking were randomized to have five annual low-dose CT scans (study group) or no screening (control group). MEASUREMENTS AND MAIN RESULTS Follow-up information regarding date and cause of death, lung cancer diagnosis, cancer stage, and histology was obtained from national registries. No differences between the two groups in lung cancer mortality (hazard ratio, 1.03; 95% confidence interval, 0.66-1.6; P = 0.888) or all-cause mortality (hazard ratio, 1.02; 95% confidence interval, 0.82-1.27; P = 0.867) were observed. More cancers were found in the screening group than in the no-screening group (100 vs. 53, respectively; P < 0.001), particularly adenocarcinomas (58 vs. 18, respectively; P < 0.001). More early-stage cancers (stages I and II, 54 vs. 10, respectively; P < 0.001) and stage IIIa cancers (15 vs. 3, respectively; P = 0.009) were found in the screening group than in the control group. Stage IV cancers were nonsignificantly more frequent in the control group than in the screening group (32 vs. 23, respectively; P = 0.278). For the highest-stage cancers (T4N3M1, 21 vs. 8, respectively; P = 0.025), this difference was statistically significant, indicating an absolute stage shift. Older participants, those with chronic obstructive pulmonary disease, and those with more than 35 pack-years of smoking had a significantly increased risk of death due to lung cancer, with nonsignificantly fewer deaths in the screening group. CONCLUSIONS No statistically significant effects of CT screening on lung cancer mortality were found, but the results of post hoc high-risk subgroup analyses showed nonsignificant trends that seem to be in good agreement with the results of the National Lung Screening Trial. Clinical trial registered with www.clinicaltrials.gov (NCT00496977).

Smoking habits in the randomised Danish Lung Cancer Screening Trial with low-dose CT: final results after a 5-year screening programme

Background We present the final results of the effect of lung cancer screening with low-dose CT on the smoking habits of participants in a 5-year screening trial. Methods The Danish Lung Cancer Screening Trial (DLCST) was a 5-year screening trial that enrolled 4104 subjects; 2052 were randomised to annual low-dose CT (CT group) and 2052 received no intervention (control group). Participants were current and ex-smokers (≥4 weeks abstinence from smoking) with a tobacco consumption of ≥20 pack years. Smoking habits were determined annually. Missing values for smoking status at the final screening round were handled using two different models. Results There were no statistically significant differences in annual smoking status between the CT group and control group. Overall the ex-smoker rates (CT + control group) significantly increased from 24% (baseline) to 37% at year 5 of screening (p<0.001). The annual point prevalence quit rate increased from 11% to 24% during the five screening rounds; the ex-smokers’ relapse rate remained stable, around 11%, across the same period. Conclusions Screening with low-dose CT had no extra effect on smoking status compared with the control group, but overall the screening programme probably promoted smoking cessation. Clinical Trial Registration: The DLCST is registered in Clinical Trials.gov Protocol Registration System (identification no. NCT00496977).

Predictive Accuracy of the PanCan Lung Cancer Risk Prediction Model -External Validation based on CT from the Danish Lung Cancer Screening Trial

ObjectivesLung cancer risk models should be externally validated to test generalizability and clinical usefulness. The Danish Lung Cancer Screening Trial (DLCST) is a population-based prospective cohort study, used to assess the discriminative performances of the PanCan models.MethodsFrom the DLCST database, 1,152 nodules from 718 participants were included. Parsimonious and full PanCan risk prediction models were applied to DLCST data, and also coefficients of the model were recalculated using DLCST data. Receiver operating characteristics (ROC) curves and area under the curve (AUC) were used to evaluate risk discrimination.ResultsAUCs of 0.826–0.870 were found for DLCST data based on PanCan risk prediction models. In the DLCST, age and family history were significant predictors (p = 0.001 and p = 0.013). Female sex was not confirmed to be associated with higher risk of lung cancer; in fact opposing effects of sex were observed in the two cohorts. Thus, female sex appeared to lower the risk (p = 0.047 and p = 0.040) in the DLCST.ConclusionsHigh risk discrimination was validated in the DLCST cohort, mainly determined by nodule size. Age and family history of lung cancer were significant predictors and could be included in the parsimonious model. Sex appears to be a less useful predictor.Key points• High accuracy in logistic modelling for lung cancer risk stratification of nodules.• Lung cancer risk prediction is primarily based on size of pulmonary nodules.• Nodule spiculation, age and family history of lung cancer are significant predictors.• Sex does not appear to be a useful risk predictor.

Relationship between chronic obstructive pulmonary disease and subclinical coronary artery disease in long-term smokers

AIMS Cardiovascular conditions are reported to be the most frequent cause of death in patients with chronic obstructive pulmonary disease (COPD). However, it remains unsettled whether severity of COPD per se is associated with coronary artery disease (CAD) independent of traditional cardiovascular risk factors. The aim of this study was to examine the relationship between the presence and severity of COPD and the amount of coronary artery calcium deposit, an indicator of CAD and cardiac risk, in a large population of current and former long-term smokers. METHODS AND RESULTS In this cross-sectional study, long-term smokers without clinically manifested CAD were recruited from the Danish Lung Cancer Screening Trial and classified according to lung function by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria. Coronary artery calcium deposit as a measure of subclinical CAD and cardiac risk was evaluated with multi detector computed tomography and the Agatston coronary artery calcium score (CACS). Participants were categorized into five CACS risk classification groups according to the CACS. The population (n = 1535) consisted of 41% participants without COPD, 28% with mild, and 31% with moderate-to-severe COPD (n = 46 with severe COPD). In addition to age, male gender, hypertension, hypercholesterolaemia, and continued smoking, COPD according to GOLD classification were independent predictors of a higher CACS risk classification group in multivariable analysis [odds ratio (OR): 1.28 (1.01-1.63) and OR: 1.32 (1.05-1.67), for mild and moderate-to-severe COPD, respectively, compared with no COPD]. CONCLUSION COPD in long-term smokers is independently correlated with the CACS, while COPD severity per se does not show a dose-response relationship.

A Hierarchical Scheme for Geodesic Anatomical Labeling of Airway Trees

We present a fast and robust supervised algorithm for labeling anatomical airway trees, based on geodesic distances in a geometric tree-space. Possible branch label configurations for a given tree are evaluated based on distances to a training set of labeled trees. In tree-space, the tree topology and geometry change continuously, giving a natural way to automatically handle anatomical differences and noise. The algorithm is made efficient using a hierarchical approach, in which labels are assigned from the top down. We only use features of the airway centerline tree, which are relatively unaffected by pathology.

Visual assessment of early emphysema and interstitial abnormalities on CT is useful in lung cancer risk analysis

AbstractObjectivesScreening for lung cancer should be limited to a high-risk-population, and abnormalities in low-dose computed tomography (CT) screening images may be relevant for predicting the risk of lung cancer. Our aims were to compare the occurrence of visually detected emphysema and interstitial abnormalities in subjects with and without lung cancer in a screening population of smokers.MethodsLow-dose chest CT examinations (baseline and latest possible) of 1990 participants from The Danish Lung Cancer Screening Trial were independently evaluated by two observers who scored emphysema and interstitial abnormalities. Emphysema (lung density) was also measured quantitatively.ResultsEmphysema was seen more frequently and its extent was greater among participants with lung cancer on baseline (odds ratio (OR), 1.8, p = 0.017 and p = 0.002) and late examinations (OR 2.6, p < 0.001 and p < 0.001). No significant difference was found using quantitative measurements. Interstitial abnormalities were more common findings among participants with lung cancer (OR 5.1, p < 0.001 and OR 4.5, p < 0.001).There was no association between presence of emphysema and presence of interstitial abnormalities (OR 0.75, p = 0.499).ConclusionsEven early signs of emphysema and interstitial abnormalities are associated with lung cancer. Quantitative measurements of emphysema—regardless of type—do not show the same association.Key Points• Visually detected emphysema on CT is more frequent in individuals who develop lung cancer.• Emphysema grading is higher in those who develop lung cancer.• Interstitial abnormalities, including discrete changes, are associated with lung cancer. • Quantitative lung density measurements are not useful in lung cancer risk prediction. • Early CT signs of emphysema and interstitial abnormalities can predict future risk.

Emphysema progression is visually detectable in low-dose CT in continuous but not in former smokers

ObjectivesTo evaluate interobserver agreement and time-trend in chest CT assessment of emphysema, airways, and interstitial abnormalities in a lung cancer screening cohort.MethodsVisual assessment of baseline and fifth-year examination of 1990 participants was performed independently by two observers. Results were standardised by means of an electronic score sheet; kappa and time-trend analyses were performed.ResultsInterobserver agreement was substantial in early emphysema diagnosis; highly significant (p < 0.001) time-trends in both emphysema presence and grading were found (higher prevalence and grade of emphysema in late CT examinations). Significant progression in emphysema was seen in continuous smokers, but not in former smokers. Agreement on centrilobular emphysema subtype was substantial; agreement on paraseptal subtype, moderate. Agreement on panlobular and mixed subtypes was only fair. Agreement was fair regarding airway analysis. Interstitial abnormalities were infrequent in the cohort, and agreement on these was fair to moderate. A highly significant time-trend was found regarding interstitial abnormalities, which were more frequent in late examinations.ConclusionsVisual scoring of chest CT is able to characterise the presence, pattern, and progression of early emphysema. Continuous smokers progress; former smokers do not.Key Points• Substantial interobserver consistency in determining early-stage emphysema in low-dose CT.• Longitudinal analyses show clear time-trends for emphysema presence and grading.• For continuous smokers, progression of emphysema was seen in all lung zones.• For former smokers, progression of emphysema was undetectable by visual assessment.• Onset and progression of interstitial abnormalities are visually detectable.

Lower Leptin/Adiponectin Ratio and Risk of Rapid Lung Function Decline in Chronic Obstructive Pulmonary Disease

RATIONALE The rate of annual change in FEV1 is highly variable among patients with chronic obstructive pulmonary disease (COPD). Reliable blood biomarkers are needed to predict prognosis. OBJECTIVES To explore plasma biomarkers associated with an annual change in FEV1 in patients with COPD. METHODS Plasma samples of 261 subjects, all Japanese, with COPD from the 5-year Hokkaido COPD cohort study were analyzed as a hypothesis-generating cohort, and the results were validated using data of 226 subjects with and 268 subjects without airflow limitation, mainly white, from the 4-year COPD Quantification by Computed Tomography, Biomarkers, and Quality of Life (CBQ) study conducted in Denmark. The plasma samples were measured using Human CardiovascularMAP (Myriad RBM, Austin, TX), which could analyze 50 biomarkers potentially linked with inflammatory, metabolic, and tissue remodeling pathways, and single ELISAs were used to confirm the results. MEASUREMENTS AND MAIN RESULTS Higher plasma adiponectin levels and a lower leptin/adiponectin ratio at enrollment were significantly associated with an annual decline in FEV1 even after controlling for age, sex, height, and body mass index in the Hokkaido COPD cohort study (P = 0.003, P = 0.004, respectively). A lower plasma leptin/adiponectin ratio was also significantly associated with an annual decline in FEV1 in subjects with airflow limitation in the CBQ study (P = 0.014), the patients of which had largely different clinical characteristics compared with the Hokkaido COPD cohort study. There were no significant associations between lung function decline and adipokine levels in subjects without airflow limitation. CONCLUSIONS A lower leptin/adiponectin ratio was associated with lung function decline in patients with COPD in two independent Japanese and Western cohort studies of populations of different ethnicity. Measure of systemic adipokines may provide utility in predicting patients with COPD at higher risk of lung function decline.

Analysis of FEV1 Decline in Relatively Healthy Heavy Smokers: Implications of Expressing Changes in FEV1 in Relative Terms

Abstract Progressive decline in lung function has been widely accepted as the hallmark of chronic obstructive pulmonary disease (COPD); however, recent evidence indicates that the rate of decline measured as decline in forced expiratory volume in one second (FEV1) is higher in mild to moderate COPD than in severe COPD. Usually changes in FEV1 are measured in ml that is “absolute”; however, changes can also be measured “relative” as a percentage of the actual FEV1. We hypothesize that relative measurements could be more appropriate than absolute measurements for describing changes in lung function. We analyzed data from 3,218 relatively healthy heavy smokers who participated in the Danish Lung Cancer Screening Trial. The influences of age, sex, height, body mass index, smoking, and severity of airflow limitation on FEV1 were analyzed in mixed effects models. In absolute terms those with the best lung function consistently showed the steepest decline, whereas in relative terms most fast decliners are found among those with low lung function. Measuring changes in relative terms implied statistically significant acceleration of decline with advancing age, smoking (pack-years) and severity of airflow limitation. Relative measurements may lead to a better understanding of changes in lung function. Smoking and severity of airflow limitation speed up the loss of lung function, and this emphasizes the importance of abstaining from smoking the sooner the better. Measuring changes in relative terms could have important implications for the interpretation of results from clinical trials where FEV1 is the primary outcome. DLCST; www.ClinicalTrials.org, registration number: NCT00496977.

Geodesic Atlas-Based Labeling of Anatomical Trees: Application and Evaluation on Airways Extracted From CT

We present a fast and robust atlas-based algorithm for labeling airway trees, using geodesic distances in a geometric tree-space. Possible branch label configurations for an unlabeled airway tree are evaluated using distances to a training set of labeled airway trees. In tree-space, airway tree topology and geometry change continuously, giving a natural automatic handling of anatomical differences and noise. A hierarchical approach makes the algorithm efficient, assigning labels from the trachea and downwards. Only the airway centerline tree is used, which is relatively unaffected by pathology. The algorithm is evaluated on 80 segmented airway trees from 40 subjects at two time points, labeled by three medical experts each, testing accuracy, reproducibility and robustness in patients with chronic obstructive pulmonary disease (COPD). The accuracy of the algorithm is statistically similar to that of the experts and not significantly correlated with COPD severity. The reproducibility of the algorithm is significantly better than that of the experts, and negatively correlated with COPD severity. Evaluation of the algorithm on a longitudinal set of 8724 trees from a lung cancer screening trial shows that the algorithm can be used in large scale studies with high reproducibility, and that the negative correlation of reproducibility with COPD severity can be explained by missing branches, for instance due to segmentation problems in COPD patients. We conclude that the algorithm is robust to COPD severity given equally complete airway trees, and comparable in performance to that of experts in pulmonary medicine, emphasizing the suitability of the labeling algorithm for clinical use.