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Rationale: We aimed to test the interscan variation of semi-automatic volumetry of subsolid nodules (SSNs), as growth evaluation is important for SSN management., Methods: From a lung cancer screening trial all SSNs that were stable over at least 3 months were included (N = 44). SSNs were quantified on the baseline CT by two observers using semi-automatic volumetry software for effective diameter, volume, and mass. One observer also measured the SSNs on the second CT 3 months later. Interscan variation was evaluated using Bland-Altman plots. Observer agreement was calculated as intraclass correlation coefficient (ICC). Data are presented as mean (± standard deviation) or median and interquartile range (IQR). A Mann-Whitney U test was used for the analysis of the influence of adjustments on the measurements., Results: Semi-automatic measurements were feasible in all 44 SSNs. The interscan limits of agreement ranged from -12.0 % to 9.7 % for diameter, -35.4 % to 28.6 % for volume and -27.6 % to 30.8 % for mass. Agreement between observers was good with intraclass correlation coefficients of 0.978, 0.957, and 0.968 for diameter, volume, and mass, respectively., Conclusion: Our data suggest that when using our software an increase in mass of 30 % can be regarded as significant growth., Key Points: • Recently, recommendations regarding subsolid nodules have stressed the importance of growth quantification. • Volumetric measurement of subsolid nodules is feasible with good interscan agreement. • Increase of mass of 30 % can be regarded as significant growth.

Objective: To determine whether semiautomatic volumetric software can differentiate part-solid from nonsolid pulmonary nodules and aid quantification of the solid component., Methods: As per reference standard, 115 nodules were differentiated into nonsolid and part-solid by two radiologists; disagreements were adjudicated by a third radiologist. The diameters of solid components were measured manually. Semiautomatic volumetric measurements were used to identify and quantify a possible solid component, using different Hounsfield unit (HU) thresholds. The measurements were compared with the reference standard and manual measurements., Results: The reference standard detected a solid component in 86 nodules. Diagnosis of a solid component by semiautomatic software depended on the threshold chosen. A threshold of -300 HU resulted in the detection of a solid component in 75 nodules with good sensitivity (90%) and specificity (88%). At a threshold of -130 HU, semiautomatic measurements of the diameter of the solid component (mean 2.4 mm, SD 2.7 mm) were comparable to manual measurements at the mediastinal window setting (mean 2.3 mm, SD 2.5 mm [p = 0.63])., Conclusion: Semiautomatic segmentation of subsolid nodules could diagnose part-solid nodules and quantify the solid component similar to human observers. Performance depends on the attenuation segmentation thresholds. This method may prove useful in managing subsolid nodules., Key Points: • Semiautomatic segmentation can accurately differentiate nonsolid from part-solid pulmonary nodules • Semiautomatic segmentation can quantify the solid component similar to manual measurements • Semiautomatic segmentation may aid management of subsolid nodules following Fleischner Society recommendations • Performance for the segmentation of subsolid nodules depends on the chosen attenuation thresholds.

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., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: 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., Methods: 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., Findings: 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 mm(3) 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 mm(3) (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 mm(3) 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])., Interpretation: Small nodules (those with a volume <100 mm(3) or diameter <5 mm) are not predictive for lung cancer. Immediate diagnostic evaluation is necessary for large nodules (≥300 mm(3) or ≥10 mm). Volume doubling time assessment is advocated only for intermediate-sized nodules (with a volume ranging between 100-300 mm(3) or diameter of 5-10 mm). Nodule management protocols based on these thresholds performed better than the simulated ACCP nodule protocol., Funding: Zorgonderzoek Nederland Medische Wetenschappen and Koningin Wilhelmina Fonds., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Evaluation of: National Lung Screening Trial Research Team, Church TR, Black WC, Aberle DR et al. Results of initial low-dose computed tomographic screening for lung cancer. N. Engl. J. Med. 368, 1980-1991 (2013). In 2011, the US NLST trial demonstrated that mortality from lung cancer can be reduced by using low-dose computed tomography (LDCT) screening rather than chest x-ray (CXR) screening. This paper from the US NLST research team focuses on the results of the initial round of LDCT for lung cancer. A total of 53,439 participants were included and randomly assigned to LDCT screening (n = 26,715) or CXR screening (n = 26,724). In total, 27.3% of the participants in the LDCT group and 9.2% in the CXR group had a positive screening result. As a result, 3.8% (LDCT group) and 5.7% (CXR group) of these subjects were diagnosed with lung cancer. The sensitivity (93.8%) and specificity (73.4%) for lung cancer were higher for LDCT compared with CXR screening; 73.5 and 91.3%, respectively.

Disease-specific mortality is the final outcome of a lung cancer screening trial, therefore cause of death verification is crucial. The use of death certificates for this purpose is debated because of bias, inaccurate completion and incorrect ante mortem diagnoses. A cause of death evaluation process was designed to ensure a uniform and unbiased determination of the graduation of certainty that lung cancer was the underlying cause of death. An independent clinical expert committee will review the medical files of all deceased participants once diagnosed with lung cancer and will make use of a flow chart and predetermined criteria. A pilot study of fifty cases was conducted to determine the performance of this process and to compare the outcome with the official death certificates. The independent review has shown an agreement of 90% (kappa 0.65), which demonstrates a uniform classification. The sensitivity and specificity of the death certificates for lung cancer specific mortality were 95.2 and 62.5%. This demonstrates a limited distinctive character of the death certification process in lung cancer patients. Our results imply that the final outcome of a lung cancer screening trial cannot reliably be established without predetermined criteria and an independent review of blinded cases., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

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.