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The NELSON (Nederlands Leuvens Longkanker Screenings Onderzoek) trial is, with 15,822 participants, the largest European lung cancer computer tomography screening trial. A volumetry-based screening strategy, stringent criteria for a positive screening, and an increasing length of screening interval are particular features of the NELSON trial. To determine the effect of stringent referral criteria and increasing screening interval on the characteristics of screen-detected lung cancers, and to compare this across screening rounds, between sexes, and with other screening trials. All NELSON participants with screen-detected lung cancer in the first three rounds were included. Lung cancer stage at diagnosis, histological subtype, and tumor localization were compared between the screening rounds, the sexes, and with other screening trials. In the first three screening rounds, 200 participants were diagnosed with 209 lung cancers. Of these lung cancers, 70.8% were diagnosed at stage I and 8.1% at stage IIIB-IV, and 51.2% were adenocarcinomas. There was no significant difference in cancer stage, histology, or tumor localization across the screening rounds. Women were diagnosed at a significantly more favorable cancer stage than men. Compared with other trials, the screen-detected lung cancers of the NELSON trial were relatively more often diagnosed at stage I and less often at stage IIIB-IV. Despite stringent criteria for a positive screening, an increasing length of screening interval, and few female participants, the screening strategy of the NELSON trial resulted in a favorable cancer stage distribution at diagnosis, which is essential for the effectiveness of our screening strategy. Clinical trial registered with www.trialregister.nl (ISRCTN63545820).

Low-dose CT screening is recommended for individuals at high risk of developing lung cancer. However, CT screening does not detect all lung cancers: some might be missed at screening, and others can develop in the interval between screens. The NELSON trial is a randomised trial to assess the effect of screening with increasing screening intervals on lung cancer mortality. In this prespecified analysis, we aimed to assess screening test performance, and the epidemiological, radiological, and clinical characteristics of interval cancers in NELSON trial participants assigned to the screening group. Eligible participants in the NELSON trial were those aged 50–75 years, who had smoked 15 or more cigarettes per day for more than 25 years or ten or more cigarettes for more than 30 years, and were still smoking or had quit less than 10 years ago. We included all participants assigned to the screening group who had attended at least one round of screening. Screening test results were based on volumetry using a two-step approach. Initially, screening test results were classified as negative, indeterminate, or positive based on nodule presence and volume. Subsequently, participants with an initial indeterminate result underwent follow-up screening to classify their final screening test result as negative or positive, based on nodule volume doubling time. We obtained information about all lung cancer diagnoses made during the first three rounds of screening, plus an additional 2 years of follow-up from the national cancer registry. We determined epidemiological, radiological, participant, and tumour characteristics by reassessing medical files, screening CTs, and clinical CTs. The NELSON trial is registered at www.trialregister.nl, number ISRCTN63545820. 15 822 participants were enrolled in the NELSON trial, of whom 7915 were assigned to low-dose CT screening with increasing interval between screens, and 7907 to no screening. We included 7155 participants in our study, with median follow-up of 8·16 years (IQR 7·56–8·56). 187 (3%) of 7155 screened participants were diagnosed with 196 screen-detected lung cancers, and another 34 (<1%; 19 [56%] in the first year after screening, and 15 [44%] in the second year after screening) were diagnosed with 35 interval cancers. For the three screening rounds combined, with a 2-year follow-up, sensitivity was 84·6% (95% CI 79·6–89·2), specificity was 98·6% (95% CI 98·5–98·8), positive predictive value was 40·4% (95% CI 35·9–44·7), and negative predictive value was 99·8% (95% CI 99·8–99·9). Retrospective assessment of the last screening CT and clinical CT in 34 patients with interval cancer showed that interval cancers were not visible in 12 (35%) cases. In the remaining cases, cancers were visible when retrospectively assessed, but were not diagnosed because of radiological detection and interpretation errors (17 [50%]), misclassification by the protocol (two [6%]), participant non-compliance (two [6%]), and non-adherence to protocol (one [3%]). Compared with screen-detected cancers, interval cancers were diagnosed at more advanced stages (29 [83%] of 35 interval cancers vs 44 [22%] of 196 screen-detected cancers diagnosed in stage III or IV; p<0·0001), were more often small-cell carcinomas (seven [20%] vs eight [4%]; p=0·003) and less often adenocarcinomas (nine [26%] vs 102 [52%]; p=0·005). Lung cancer screening in the NELSON trial yielded high specificity and sensitivity, with only a small number of interval cancers. The results of this study could be used to improve screening algorithms, and reduce the number of missed cancers. Zorgonderzoek Nederland Medische Wetenschappen and Koningin Wilhelmina Fonds.

Background Persons with Chronic Obstructive Pulmonary Disease (COPD), performing some level of regular physical activity, have a lower risk of both COPD-related hospital admissions and mortality. COPD patients of all stages seem to benefit from exercise training programs, thereby improving with respect to both exercise tolerance and symptoms of dyspnea and fatigue. Physical inactivity, which becomes more severe with increasing age, is a point of concern in healthy older adults. COPD might worsen this scenario, but it is unclear to what degree. This literature review aims to present the extent of the impact of COPD on objectively-measured daily physical activity (DPA). The focus is on the extent of the impact that COPD has on duration, intensity, and counts of DPA, as well as whether the severity of the disease has an additional influence on DPA. Results A literature review was performed in the databases PubMed [MEDLINE], Picarta, PEDRO, ISI Web of Knowledge and Google scholar. After screening, 11 studies were identified as being relevant for comparison between COPD patients and healthy controls with respect to duration, intensity, and counts of DPA. Four more studies were found to be relevant to address the subject of the influence the severity of the disease may have on DPA. The average percentage of DPA of COPD patients vs. healthy control subjects for duration was 57%, for intensity 75%, and for activity counts 56%. Correlations of DPA and severity of the disease were low and/or not significant. Conclusions From the results of this review, it appears that patients with COPD have a significantly reduced duration, intensity, and counts of DPA when compared to healthy control subjects. The intensity of DPA seems to be less affected by COPD than duration and counts. Judging from the results, it seems that severity of COPD is not strongly correlated with level of DPA. Future research should focus in more detail on the relation between COPD and duration, intensity, and counts of DPA, as well as the effect of disease severity on DPA, so that these relations become more understandable.

Objective To determine inter-observer and inter-examination variability of manual attenuation measurements of the vertebrae in low-dose unenhanced chest computed tomography (CT). Methods Three hundred and sixty-seven lung cancer screening trial participants who underwent baseline and repeat unenhanced low-dose CT after 3 months because of an indeterminate lung nodule were included. The CT attenuation value of the first lumbar vertebrae (L1) was measured in all CTs by one observer to obtain inter-examination reliability. Six observers performed measurements in 100 randomly selected CTs to determine agreement with limits of agreement and Bland-Altman plots and reliability with intraclass correlation coefficients (ICCs). Reclassification analyses were performed using a threshold of 110 HU to define osteoporosis. Results Inter-examination reliability was excellent with an ICC of 0.92 ( p  < 0.001). Inter-examination limits of agreement ranged from -26 to 28 HU with a mean difference of 1 ± 14 HU. Inter-observer reliability ICCs ranged from 0.70 to 0.91. Inter-examination variability led to 11.2 % reclassification of participants and inter-observer variability led to 22.1 % reclassification. Conclusions Vertebral attenuation values can be manually quantified with good to excellent inter-examination and inter-observer reliability on unenhanced low-dose chest CT. This information is valuable for early detection of osteoporosis on low-dose chest CT. Key Points • Vertebral attenuation values can be manually quantified on low-dose unenhanced CT reliably. • Vertebral attenuation measurements may be helpful in detecting subclinical low bone density. • This could become of importance in the detection of osteoporosis.

There is an urgent medical need to differentiate active tuberculosis (ATB) from latent tuberculosis infection (LTBI) and prevent undertreatment and overtreatment. The aim of this study was to identify biomarker profiles that may support the differentiation between ATB and LTBI and to validate these signatures. The discovery cohort included adult individuals classified in four groups: ATB (n = 20), LTBI without prophylaxis (untreated LTBI; n = 20), LTBI after completion of prophylaxis (treated LTBI; n = 20), and healthy controls (HC; n = 20). Their sera were analyzed for 40 cytokines/chemokines and activity of adenosine deaminase (ADA) isozymes. A prediction model was designed to differentiate ATB from untreated LTBI using sparse partial least squares (sPLS) and logistic regression analyses. Serum samples of two independent cohorts (national and international) were used for validation. sPLS regression analyses identified C-C motif chemokine ligand 1 (CCL1), C-reactive protein (CRP), C-X-C motif chemokine ligand 10 (CXCL10), and vascular endothelial growth factor (VEGF) as the most discriminating biomarkers. These markers and ADA(2) activity were significantly increased in ATB compared to untreated LTBI (p ≤ 0.007). Combining CCL1, CXCL10, VEGF, and ADA2 activity yielded a sensitivity and specificity of 95% and 90%, respectively, in differentiating ATB from untreated LTBI. These findings were confirmed in the validation cohort including remotely acquired untreated LTBI participants. The biomarker signature of CCL1, CXCL10, VEGF, and ADA2 activity provides a promising tool for differentiating patients with ATB from non-treated LTBI individuals.

Parametric response mapping (PRM) of paired CT lung images has been shown to improve the phenotyping of COPD by allowing for the visualization and quantification of non-emphysematous air trapping component, referred to as functional small airways disease (fSAD). Although promising, large variability in the standard method for analyzing PRM fSAD has been observed. We postulate that representing the 3D PRM fSAD data as a single scalar quantity (relative volume of PRM fSAD ) oversimplifies the original 3D data, limiting its potential to detect the subtle progression of COPD as well as varying subtypes. In this study, we propose a new approach to analyze PRM. Based on topological techniques, we generate 3D maps of local topological features from 3D PRM fSAD classification maps. We found that the surface area of fSAD (S fSAD ) was the most robust and significant independent indicator of clinically meaningful measures of COPD. We also confirmed by micro-CT of human lung specimens that structural differences are associated with unique S fSAD patterns, and demonstrated longitudinal feature alterations occurred with worsening pulmonary function independent of an increase in disease extent. These findings suggest that our technique captures additional COPD characteristics, which may provide important opportunities for improved diagnosis of COPD patients.

The main challenge in CT screening for lung cancer is the high prevalence of pulmonary nodules and the relatively low incidence of lung cancer. Management protocols use thresholds for nodule size and growth rate to determine which nodules require additional diagnostic procedures, but these should be based on individuals' probabilities of developing lung cancer. In this prespecified analysis, using data from the NELSON CT screening trial, we aimed to quantify how nodule diameter, volume, and volume doubling time affect the probability of developing lung cancer within 2 years of a CT scan, and to propose and evaluate thresholds for management protocols. Eligible participants in the NELSON trial were those aged 50–75 years, who have smoked 15 cigarettes or more per day for more than 25 years, or ten cigarettes or more for more than 30 years and were still smoking, or had stopped smoking less than 10 years ago. Participants were randomly assigned to low-dose CT screening at increasing intervals, or no screening. We included all participants assigned to the screening group who had attended at least one round of screening, and whose results were available from the national cancer registry database. We calculated lung cancer probabilities, stratified by nodule diameter, volume, and volume doubling time and did logistic regression analysis using diameter, volume, volume doubling time, and multinodularity as potential predictor variables. We assessed management strategies based on nodule threshold characteristics for specificity and sensitivity, and compared them to the American College of Chest Physicians (ACCP) guidelines. The NELSON trial is registered at www.trialregister.nl, number ISRCTN63545820. Volume, volume doubling time, and volumetry-based diameter of 9681 non-calcified nodules detected by CT screening in 7155 participants in the screening group of NELSON were used to quantify lung cancer probability. Lung cancer probability was low in participants with a nodule volume of 100 mm3 or smaller (0·6% [95% CI 0·4–0·8]) or maximum transverse diameter smaller than 5 mm (0·4% [0·2–0·7]), and not significantly different from participants without nodules (0·4% [0·3–0·6], p=0·17 and p=1·00, respectively). Lung cancer probability was intermediate (requiring follow-up CT) if nodules had a volume of 100–300 mm3 (2·4% [95% CI 1·7–3·5]) or a diameter 5–10 mm (1·3% [1·0–1·8]). Volume doubling time further stratified the probabilities: 0·8% (95% CI 0·4–1·7) for volume doubling times 600 days or more, 4·0% (1·8–8·3) for volume doubling times 400–600 days, and 9·9% (6·9–14·1) for volume doubling times of 400 days or fewer. Lung cancer probability was high for participants with nodule volumes 300 mm3 or bigger (16·9% [95% CI 14·1–20·0]) or diameters 10 mm or bigger (15·2% [12·7–18·1]). The simulated ACCP management protocol yielded a sensitivity and specificity of 90·9% (95% CI 81·2–96·1), and 87·2% (86·4–87·9), respectively. A diameter-based protocol with volumetry-based nodule diameter yielded a higher sensitivity (92·4% [95% CI 83·1–97·1]), and a higher specificity (90·0% [89·3–90·7). A volume-based protocol (with thresholds based on lung cancer probability) yielded the same sensitivity as the ACCP protocol (90·9% [95% CI 81·2–96·1]), and a higher specificity (94·9% [94·4–95·4]). Small nodules (those with a volume <100 mm3 or diameter <5 mm) are not predictive for lung cancer. Immediate diagnostic evaluation is necessary for large nodules (≥300 mm3 or ≥10 mm). Volume doubling time assessment is advocated only for intermediate-sized nodules (with a volume ranging between 100–300 mm3 or diameter of 5–10 mm). Nodule management protocols based on these thresholds performed better than the simulated ACCP nodule protocol. Zorgonderzoek Nederland Medische Wetenschappen and Koningin Wilhelmina Fonds.

Background Lung cancer screening CT scans might provide valuable information about air trapping as an early indicator of smoking-related lung disease. We studied which of the currently suggested measures is most suitable for detecting functionally relevant air trapping on low-dose computed tomography (CT) in a population of subjects with early-stage disease. Methods This study was ethically approved and informed consent was obtained. Three quantitative CT air trapping measures were compared against a functional reference standard in 427 male lung cancer screening participants. This reference standard for air trapping was derived from the residual volume over total lung capacity ratio (RV/TLC) beyond the 95th percentile of predicted. The following CT air trapping measures were compared: expiratory to inspiratory relative volume change of voxels with attenuation values between −860 and −950 Hounsfield Units (RVC −860 to −950 ), expiratory to inspiratory ratio of mean lung density (E/I-ratio MLD ) and percentage of voxels below −856 HU in expiration (EXP −856 ). Receiver operating characteristic (ROC) analysis was performed and area under the ROC curve compared. Results Functionally relevant air trapping was present in 38 (8.9 %) participants. E/I-ratio MLD showed the largest area under the curve (0.85, 95 % CI 0.813–0.883), which was significantly larger than RVC −860 to −950 (0.703, 0.657–0.746; p  < 0.001) and EXP −856 (0.798, 0.757–0.835; p  = 0.002). At the optimum for sensitivity and specificity, E/I-ratio MLD yielded an accuracy of 81.5 %. Conclusions The expiratory to inspiratory ratio of mean lung density (E/I-ratio MLD ) is most suitable for detecting air trapping on low-dose screening CT and performs significantly better than other suggested quantitative measures.

Participants who were at an increased risk for lung cancer were enrolled in a trial to determine whether CT screening reduces mortality from lung cancer. In this study, volume measurements and volume doubling times were used to evaluate the noncalcified lung nodules that were detected by CT scanning at baseline and at years 1, 2, and 4 of the trial. With the use of these volumetric methods, the authors found that the chances of finding lung cancer by CT scanning 1 and 2 years after a negative baseline test were 1 in 1000 and 3 in 1000, respectively. With the use of volumetric methods, the authors found that the chances of finding lung cancer by CT scanning 1 and 2 years after a negative baseline test were 1 in 1000 and 3 in 1000, respectively. The use of multidetector computed tomography (CT) has increased the chance of finding noncalcified pulmonary nodules, 1 , 2 and as a result, clinicians often face the problem of deciding on the best course of action with respect to such nodules when they are found in asymptomatic subjects who have an increased risk for lung cancer. 3 This difficulty is especially evident in CT-based screening programs for lung cancer. The current practice is to refer participants in these programs for additional diagnostic evaluation if they have a noncalcified nodule that is larger than 5 mm in diameter. 4 – 9 In designing the Dutch–Belgian randomized . . .

Background: Microbial exposures in both childhood and adult life are protective against atopy, allergic rhinitis and atopic asthma. In adults, this protective effect is paralleled by an increased prevalence of non-atopic asthma. This study was undertaken to investigate associations between occupational endotoxin exposure and atopic sensitization and bronchial hyperresponsiveness to methacholine (BHR) in agricultural workers. In addition, the role of atopy in endotoxin-related respiratory effects was studied. Methods: Data were available for 427 farmers and agricultural industry workers, for whom airborne endotoxin exposure levels were estimated by 249 personal exposure measurements. Atopy was assessed as specific serum IgE to common inhalant allergens, and respiratory symptoms and personal characteristics by standardized questionnaires. BHR was determined in a subset of 113 subjects. Associations were adjusted for age, sex, smoking and living on a farm during childhood. Results: Endotoxin exposure was positively associated with BHR and wheeze (p < 0.05). In contrast, endotoxin exposure was inversely associated with atopy and IgE to grass pollen (p < 0.001). The proportions of wheeze and BHR that were attributable to atopy were only 16.6 and 32.8%, respectively. Conclusions: High endotoxin exposure is a risk factor for BHR and wheeze, which were characterized by a predominantly non-atopic phenotype. At the same time, endotoxin exposure is related to a reduced risk of atopy and IgE to grass pollen in adults. It is unlikely that this is entirely a result of healthy worker selection, as significant inverse associations between endotoxin and IgE to grass pollen were found regardless of reported allergic symptoms.