Objectives The aim of this study was to derivate and validate a prediction model for cardiovascular events based on quantification of coronary and aortic calcium volume in lung cancer screening chest ...computed tomography (CT). Background CT-based lung cancer screening in heavy smokers is a very timely topic. Given that the heavily smoking screening population is also at risk for cardiovascular disease, CT-based screening may provide the opportunity to additionally identify participants at high cardiovascular risk. Methods Inspiratory screening CT of the chest was obtained in 3,648 screening participants. Next, smoking characteristics, patient demographics, and physician-diagnosed cardiovascular events were collected from 10 years before the screening CT (i.e., cardiovascular history) until 3 years after the screening CT (i.e., follow-up time). Cox proportional hazards analysis was used to derivate and validate a prediction model for cardiovascular risk. Age, smoking status, smoking history, and cardiovascular history, together with automatically quantified coronary and aortic calcium volume from the screening CT, were included as independent predictors. The primary outcome measure was the discriminatory value of the model. Results Incident cardiovascular events occurred in 145 of 1,834 males (derivation cohort) and 118 of 1,725 males and 2 of 89 females (validation cohort). The model showed good discrimination in the validation cohort with a C-statistic of 0.71 (95% confidence interval: 0.67 to 0.76). When high risk was defined as a 3-year risk of 6% and higher, 589 of 1,725 males were regarded as high risk and 72 of 118 of all events were correctly predicted by the model. Conclusions Quantification of coronary and aortic calcium volumes in lung cancer screening CT images—information that is readily available—can be used to predict cardiovascular risk. Such an approach might prove useful in the reduction of cardiovascular morbidity and mortality and may enhance the cost-effectiveness of CT-based screening in heavy smokers.
Highlights • Exponential growth is assumed for lung cancer but has never been quantified in-vivo. • Growth patterns of 47 screen-detected solid lung cancers were quantified. • Lung cancer growth ...could be described by an exponential function with excellent fit. • Therefore, volume-doubling time can be used to describe growth of pulmonary nodules.
Background Up to 50% of the participants in CT scan lung cancer screening trials have at least one pulmonary nodule. To date, the role of conventional bronchoscopy in the workup of suspicious ...screen-detected pulmonary nodules is unknown. If a bronchoscopic evaluation could be eliminated, the cost-effectiveness of a screening program could be enhanced and the potential harms of bronchoscopy avoided. Methods All consecutive participants with a positive result on a CT scan lung cancer screening between April 2004 and December 2008 were enrolled. The diagnostic sensitivity and negative predictive value were calculated at the level of the suspicious nodules. In 95% of the nodules, the gold standard for the outcome of the bronchoscopy was based on surgical resection specimens. Results A total of 318 suspicious lesions were evaluated by bronchoscopy in 308 participants. The mean ± SD diameter of the nodules was 14.6 ± 8.7 mm, whereas only 2.8% of nodules were > 30 mm in diameter. The sensitivity of bronchoscopy was 13.5% (95% CI, 9.0%-19.6%); the specificity, 100%; the positive predictive value, 100%; and the negative predictive value, 47.6% (95% CI, 41.8%-53.5%). Of all cancers detected, 1% were detected by bronchoscopy only and were retrospectively invisible on both low-dose CT scan and CT scan with IV contrast. Conclusion Conventional white-light bronchoscopy should not be routinely recommended for patients with positive test results in a lung cancer screening program. Trial registration Nederlands Trial Register; No.: ISRCTN63545820; URL: www.trialregister.nl.
Abstract Objective To evaluate the incremental prognostic value of the number and maximum volume of coronary artery calcifications over modified Agatston score strata, age, pack-years, and smoking ...status for predicting cardiovascular events. Methods A total of 3559 male current and former smokers received a CT examination for lung cancer screening. Smoking characteristics, patient demographics, and physician-diagnosed cardiovascular events were collected. Images were acquired without electrocardiography gating on 16-slice CT scanners. The association between the presence of both fatal and nonfatal cardiovascular events and the predictors was quantified using Cox proportional hazard analysis. Results Median follow-up period was 2.9 years. Incident cardiovascular events occurred in 186 participants. Adjusted hazard ratios for modified Agatston score strata of 1 to 10, 11 to 100, 101 to 400, and >400 were 3.39 (95% confidence interval CI, 1.20–9.59), 6.52 (95% CI, 2.73–15.60), 6.58 (95% CI, 2.75–15.78), and 12.58 (95% CI, 5.42–29.16), respectively. Moreover, comparing the models with and without modified Agatston score strata to the model with age, pack-years, and smoking status yielded a significantly better net reclassification improvement (NRI; 27.3%; P < .0001). Adding the number of calcifications to the model with age, pack-years, smoking status, and modified Agatston score strata resulted in a slightly better NRI (1.68%; P = .0490) with a hazard ratio of 1.13 (95% CI, 1.05–1.21) per 10 calcifications. The incremental prognostic information contained in the volume of the largest calcification was not statistically significant (NRI, 0.14%; P = .3458). Conclusion Cardiovascular event rate increased with higher numbers of calcified lesions. The number but not maximum volume of calcifications has independent, although minimal, prognostic value over age, pack-years, smoking status, and modified Agatston score strata in our population.
Abstract Objectives Airway wall thickness (AWT) is affected by changes in lung volume. This study evaluated whether correcting AWT on computed tomography (CT) for differences in inspiration level ...improves measurement agreement, reliability, and power to detect changes over time. Methods Participants of the Dutch-Belgian lung cancer screening trial who underwent 3-month repeat CT for an indeterminate pulmonary nodule were included. AWT on CT was calculated by the square root of the wall area at a theoretical airway with an internal perimeter of 10 mm (Pi10). The scan with the highest lung volume was labelled as the reference scan and the scan with the lowest lung volume was labelled as the comparison scan. Pi10 derived from the comparison scan was corrected by multiplying it with the ratio of CT lung volume of the comparison scan to CT lung volume on the reference scan. Agreement of uncorrected and corrected Pi10 was studied with the Bland-Altman method, reliability with intra-class correlation coefficients (ICC), and power to detect changes over time was calculated. Results 315 male participants were included. Limit of agreement and reliability for Pi10 was −0.61 to 0.57 mm (ICC = 0.87), which improved to −0.38 to 0.37 mm (ICC = 0.94) after correction for inspiration level. To detect a 15% change over 3 months, 71 subjects are needed for Pi10 and 26 subjects for Pi10 adjusted for inspiration level. Conclusions Correcting Pi10 for differences in inspiration level improves reliability, agreement, and power to detect changes over time.
Objectives The purpose of this study was to determine the association of coronary artery calcification (CAC) with incident heart failure in the elderly and examine its independence of overt coronary ...heart disease (CHD). Background Heart failure is often observed as a first manifestation of coronary atherosclerosis rather than a sequela of overt CHD. Although numerous studies have shown that CAC, an established measure of coronary atherosclerosis, is a strong predictor of CHD, the association between CAC and future heart failure has not been studied prospectively. Methods In the Rotterdam Study, a population-based cohort, 1,897 asymptomatic participants (mean age, 69.9 years; 58% women) underwent CAC scoring and were followed for the occurrence of heart failure and CHD. Results During a median follow-up of 6.8 years, there were 78 cases of heart failure and 76 cases of nonfatal CHD. After adjustment for cardiovascular risk factors, increasing CAC scores were associated with heart failure (p for trend = 0.001), with a hazard ratio of 4.1 (95% confidence interval CI: 1.7 to 10.1) for CAC scores >400 compared with CAC scores of 0 to 10. After censoring participants for incident nonfatal CHD, increasing extent of CAC remained associated with heart failure (p for trend = 0.046), with a hazard ratio of 2.9 (95% CI: 1.1 to 7.4) for CAC scores >400. Moreover, adding CAC to cardiovascular risk factors resulted in an optimism-corrected increase in the c -statistic by 0.030 (95% CI: 0.001 to 0.050) to 0.734 (95% CI: 0.698 to 0.770) and substantially improved the risk classification of subjects (continuous net reclassification index = 34.0%). Conclusions CAC has a clear association with the risk of heart failure, independent of overt CHD. Because heart failure is highly prevalent in the elderly, it might be worthwhile to include heart failure as an outcome in future risk assessment programs incorporating CAC.
Patients with chronic renal failure have increased cardiac calcium loads. Previous studies have investigated the prevalence and quantitative extent of aortic valve calcium (AVC) and coronary artery ...calcium (CAC) in patients with various stages of chronic kidney disease (CKD). However, the impact of preexisting atherosclerosis on the calcification burden has not been clarified. Therefore, this study was conducted to examine the effect of CKD stage as well as the primary cause of renal failure (atherosclerotic vs nonatherosclerotic) on AVC and CAC. Twenty-two, 13, and 28 patients with stage 3, 4, and 5 CKD, respectively, were included, of whom 24 had atherosclerotic CKD. Patients underwent electron-beam computed tomography to assess AVC and CAC. AVC was present in 27% of patients with stage 3 CKD, in 38% of patients with stage 4 CKD, and in 43% of patients with stage 5 CKD. CAC was present in 77% of patients with stage 3 CKD, in 54% of patients with stage 4 CKD, and in 64% of patients with stage 5 CKD. There was no correlation between CKD stage and the quantitative extent of AVC and CAC. AVC was more frequent (58% vs 23%, p <0.01) and more extensive (median score 43 range 0 to 494 vs 0 range 0 to 8, p <0.01) in patients with CKD caused by atherosclerotic renal disease than in patients with nonatherosclerotic causes of CKD. CAC was more frequent (83% vs 56%, p <0.05) and more extensive (median score 437 range 61 to 1,565 vs 31 range 0 to 155, p <0.001) in patients with atherosclerotic causes of CKD than in patients with CKD caused by nonatherosclerotic renal disease. In conclusion, the prevalence as well as the severity of AVC and CAC did not vary between patients with stage 3, 4, and 5 CKD. Cardiac calcification, both AVC and CAC, were more frequent and more severe in patients with atherosclerotic causes of renal failure. These results suggest that cardiac calcium is related to atherosclerotic burden rather than to the severity of CKD.
Objectives The purpose of this study was to examine the effect of coronary artery calcium (CAC) on the classification of 10-year hard coronary heart disease (CHD) risk and to empirically derive ...cut-off values of the calcium score for a general population of elderly patients. Background Although CAC scoring has been found to improve CHD risk prediction, there are limited data on its impact in clinical practice. Methods The study comprised 2,028 asymptomatic participants (age 69.6 ± 6.2 years) from the Rotterdam Study. During a median follow-up of 9.2 years, 135 hard coronary events occurred. Persons were classified into low (<10%), intermediate (10% to 20%), and high (>20%) 10-year coronary risk categories based on a Framingham refitted risk model. In a second step, the model was extended by CAC, and reclassification percentages were calculated. Cutoff values of CAC for persons in the intermediate-risk category were empirically derived based on 10-year hard CHD risk. Results Reclassification by means of CAC scoring was most substantial in persons initially classified as intermediate risk. In this group, 52% of men and women were reclassified, all into more accurate risk categories. CAC values above 615 or below 50 Agatston units were found appropriate to reclassify persons into high or low risk, respectively. Conclusions In a general population of elderly patients at intermediate CHD risk, CAC scoring is a powerful method to reclassify persons into more appropriate risk categories. Empirically derived CAC cutoff values at which persons at intermediate risk reclassified to either high or low risk were 615 and 50 Agatston units, respectively.
To quantitatively assess coronary atherosclerotic plaque composition in patients with acute non-ST elevation myocardial infarction (NSTEMI) and patients with stable coronary artery disease (CAD) by ...coronary computed tomography angiography (cCTA) correlated with virtual histology intravascular ultrasound (VH-IVUS).
Sixty patients (35 with NSTEMI) were included. Corresponding plaques were assessed by dual-source cCTA and VH-IVUS regarding volumes and percentages of fatty, fibrous, and calcified component; overall plaque burden; and maximal percent area stenosis. Possible differences between patient groups were investigated. Concordance between cCTA and VH-IVUS measurements was validated by Bland-Altman analysis.
Forty corresponding plaques (22 of patients with NSTEMI) were finally analyzed by cCTA and VH-IVUS. cCTA plaque analysis revealed no significant differences between plaques of patients with NSTEMI and stable CAD regarding absolute and relative amounts of any plaque component (fatty: 20 mm³/13% versus 17 mm³/14%; fibrous: 81 mm³/63% versus 80 mm³/53%; calcified: 16 mm³/14% versus 26 mm³/26%; all P > .05) or overall plaque burden (153 mm³ versus 165 mm³; P > .05), nor did VH-IVUS plaque analysis. VH-IVUS measured a higher area stenosis in patients with NSTEMI compared to patients with stable CAD (76% versus 68%, P = .01; in cCTA 69% versus 65%, P = .2). Volumes of fatty component were measured systematically lower in cCTA, whereas calcified and fibrous volumes were higher. No significant bias was observed comparing volumes of overall noncalcified component and overall plaque burden.
Plaques of patients with acute NSTEMI and of patients with stable CAD cannot be differentiated by quantification of plaque components. cCTA and VH-IVUS differ in plaque component analysis.
Summary Background 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. Methods 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. Findings 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). Interpretation 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. Funding Zorgonderzoek Nederland Medische Wetenschappen and Koningin Wilhelmina Fonds.
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