Semi-automated volumetry of pulmonary nodules: Intra-individual comparison of standard dose and chest X-ray equivalent ultralow dose chest CT scans.

PURPOSE: To assess the performance of semi-automated volumetry of solid pulmonary nodules on single-energy tin-filtered ultralow dose (ULD) chest CT scans at a radiation dose equivalent to chest X-ray relative to standard dose (SD) chest CT scans and assess the impact of kernel and iterative reconstruction selection. METHODS: Ninety-four consecutive patients from a prospective single-center study were included and underwent clinically indicated SD chest CT (1.9 ± 0.8 mSv) and additional ULD chest CT (0.13 ± 0.01 mSv) in the same session. All scans were reconstructed with a soft tissue (Br40) and lung (Bl64) kernel as well as with Filtered Back Projection (FBP) and Iterative Reconstruction (ADMIRE-3 and ADMIRE-5). One hundred and forty-eight solid pulmonary nodules were identified and analysed by semi-automated volumetry on all reconstructions. Nodule volumes were compared amongst all reconstructions thereby focusing on the agreement between SD and ULD scans. RESULTS: Nodule volumes ranged from 58.5 (28.8-126) mm3 for ADMIRE-5 Br40 ULD reconstructions to 72.5 (39-134) mm3 for FBP Bl64 SD reconstructions with significant differences between reconstructions (p < 0.001). Interscan agreement of volumes between two given reconstructions ranged from ICC = 0.605 to ICC = 0.999. Between SD and ULD scans, agreement of nodule volumes was highest for FBP Br40 (ICC = 0.995), FBP Bl64 (ICC = 0.939) and ADMIRE-5 Bl64 (ICC = 0.994) reconstructions. ADMIRE-3 reconstructions exhibited reduced interscan agreement of nodule volumes (ICCs from 0.788 - 0.882). CONCLUSIONS: The interscan agreement of node volumes between SD and ULD is high depending on the choice of kernel and reconstruction algorithm. However, caution should be exercised when comparing two image series that were not identically reconstructed.

International Validation of the Canadian Syncope Risk Score : A Cohort Study.

BACKGROUND: The Canadian Syncope Risk Score (CSRS) was developed to predict 30-day serious outcomes not evident during emergency department (ED) evaluation. OBJECTIVE: To externally validate the CSRS and compare it with another validated score, the Osservatorio Epidemiologico della Sincope nel Lazio (OESIL) score. DESIGN: Prospective cohort study. SETTING: Large, international, multicenter study recruiting patients in EDs in 8 countries on 3 continents. PARTICIPANTS: Patients with syncope aged 40 years or older presenting to the ED within 12 hours of syncope. MEASUREMENTS: Composite outcome of serious clinical plus procedural events (primary outcome) and the primary composite outcome excluding procedural interventions (secondary outcome). RESULTS: Among 2283 patients with a mean age of 68 years, the primary composite outcome occurred in 7.2%, and the composite outcome excluding procedural interventions occurred in 3.1% at 30 days. Prognostic performance of the CSRS was good for both 30-day composite outcomes and better compared with the OESIL score (area under the receiver-operating characteristic curve [AUC], 0.85 [95% CI, 0.83 to 0.88] vs. 0.74 [CI, 0.71 to 0.78] and 0.80 [CI, 0.75 to 0.84] vs. 0.69 [CI, 0.64 to 0.75], respectively). Safety of triage, as measured by the frequency of the primary composite outcome in the low-risk group, was higher using the CSRS (19 of 1388 [0.6%]) versus the OESIL score (17 of 1104 [1.5%]). A simplified model including only the clinician classification of syncope (cardiac syncope, vasovagal syncope, or other) variable at ED discharge-a component of the CSRS-achieved similar discrimination as the CSRS (AUC, 0.83 [CI, 0.80 to 0.87] for the primary composite outcome). LIMITATION: Unable to disentangle the influence of other CSRS components on clinician classification of syncope at ED discharge. CONCLUSION: This international external validation of the CSRS showed good performance in identifying patients at low risk for serious outcomes outside of Canada and superior performance compared with the OESIL score. However, clinician classification of syncope at ED discharge seems to explain much of the performance of the CSRS in this study. The clinical utility of the CSRS remains uncertain. PRIMARY FUNDING SOURCE: Swiss National Science Foundation & Swiss Heart Foundation.

Lung cancer LDCT screening and mortality reduction - evidence, pitfalls and future perspectives.

In the past decade, the introduction of molecularly targeted agents and immune-checkpoint inhibitors has led to improved survival outcomes for patients with advanced-stage lung cancer; however, this disease remains the leading cause of cancer-related mortality worldwide. Two large randomized controlled trials of low-dose CT (LDCT)-based lung cancer screening in high-risk populations - the US National Lung Screening Trial (NLST) and NELSON - have provided evidence of a statistically significant mortality reduction in patients. LDCT-based screening programmes for individuals at a high risk of lung cancer have already been implemented in the USA. Furthermore, implementation programmes are currently underway in the UK following the success of the UK Lung Cancer Screening (UKLS) trial, which included the Liverpool Health Lung Project, Manchester Lung Health Check, the Lung Screen Uptake Trial, the West London Lung Cancer Screening pilot and the Yorkshire Lung Screening trial. In this Review, we focus on the current evidence on LDCT-based lung cancer screening and discuss the clinical developments in high-risk populations worldwide; additionally, we address aspects such as cost-effectiveness. We present a framework to define the scope of future implementation research on lung cancer screening programmes referred to as Screening Planning and Implementation RAtionale for Lung cancer (SPIRAL).

Accuracy of Conventional and Machine Learning Enhanced Chest Radiography for the Assessment of COVID-19 Pneumonia: Intra-Individual Comparison with CT.

PURPOSE: To evaluate diagnostic accuracy of conventional radiography (CXR) and machine learning enhanced CXR (mlCXR) for the detection and quantification of disease-extent in COVID-19 patients compared to chest-CT. METHODS: Real-time polymerase chain reaction (rt-PCR)-confirmed COVID-19-patients undergoing CXR from March to April 2020 together with COVID-19 negative patients as control group were retrospectively included. Two independent readers assessed CXR and mlCXR images for presence, disease extent and type (consolidation vs. ground-glass opacities (GGOs) of COVID-19-pneumonia. Further, readers had to assign confidence levels to their diagnosis. CT obtained ≤ 36 h from acquisition of CXR served as standard of reference. Inter-reader agreement, sensitivity for detection and disease extent of COVID-19-pneumonia compared to CT was calculated. McNemar test was used to test for significant differences. RESULTS: Sixty patients (21 females; median age 61 years, range 38-81 years) were included. Inter-reader agreement improved from good to excellent when mlCXR instead of CXR was used (k = 0.831 vs. k = 0.742). Sensitivity for pneumonia detection improved from 79.5% to 92.3%, however, on the cost of specificity 100% vs. 71.4% (p = 0.031). Overall, sensitivity for the detection of consolidation was higher than for GGO (37.5% vs. 70.4%; respectively). No differences could be found in disease extent estimation between mlCXR and CXR, even though the detection of GGO could be improved. Diagnostic confidence was better on mlCXR compared to CXR (p = 0.013). CONCLUSION: In line with the current literature, the sensitivity for detection and quantification of COVID-19-pneumonia was moderate with CXR and could be improved when mlCXR was used for image interpretation.

Incidence, characteristics, determinants, and prognostic impact of recurrent syncope.

AIMS: The aim of this study is to characterize recurrent syncope, including sex-specific aspects, and its impact on death and major adverse cardiovascular events (MACE). METHODS AND RESULTS: We characterized recurrent syncope in a large international multicentre study, enrolling patients ≥40 years presenting to the emergency department (ED) with a syncopal event within the last 12 h. Syncope aetiology was centrally adjudicated by two independent cardiologists using all information becoming available during syncope work-up and long-term follow-up. Overall, 1790 patients were eligible for this analysis. Incidence of recurrent syncope was 20% [95% confidence interval (CI) 18-22%] within the first 24 months. Patients with an adjudicated final diagnosis of cardiac syncope (hazard ratio (HR) 1.50, 95% CI 1.11-2.01) or syncope with an unknown aetiology even after central adjudication (HR 2.11, 95% CI 1.54-2.89) had an increased risk for syncope recurrence. Least Absolute Shrinkage and Selection Operator regression fit on all patient information available early in the ED identified >3 previous episodes of syncope as the only independent predictor for recurrent syncope (HR 2.13, 95% CI 1.64-2.75). Recurrent syncope carried an increased risk for death (HR 1.87, 95% CI 1.26-2.77) and MACE (HR 2.69, 95% CI 2.02-3.59) over 24 months of follow-up, however, with a time-dependent effect. These findings were confirmed in a sensitivity analysis excluding patients with syncope recurrence or MACE before or during ED evaluation. CONCLUSION: Recurrence rates of syncope are substantial and vary depending on syncope aetiology. Importantly, recurrent syncope carries a time-dependent increased risk for death and MACE. TRIAL REGISTRATION: BAsel Syncope EvaLuation (BASEL IX, ClinicalTrials.gov registry number NCT01548352).

Plasma extracellular vesicle proteins are associated with stress-induced myocardial ischemia in women presenting with chest pain.

Diagnosing stable ischemic heart disease (IHD) is challenging, especially in females. Currently, no blood test is available. Plasma extracellular vesicles (EV) are emerging as potential biomarker source. We therefore aimed to identify stress induced ischemia due to stable IHD with plasma extracellular vesicle protein levels in chest pain patients. We analyzed 450 patients suspected for stable IHD who were referred for 82Rb PET/CT in the outpatient clinic. Blood samples were collected before PET/CT and plasma EVs were isolated in 3 plasma subfractions named: TEX, HDL, LDL. In total 6 proteins were quantified in each of these subfractions using immuno-bead assays. CD14 and CystatinC protein levels were independent significant predictors of stress-induced ischemia in the LDL and the HDL subfraction and SerpinC1 and SerpinG1 protein levels in the HDL fraction. Subgroup-analysis on sex revealed that these associations were completely attributed to the associations in women. None of the significant EV proteins remained significant in men. Plasma EV proteins levels are associated with the presence of stable IHD in females presenting with chest pain. This finding, if confirmed in larger cohort studies could be a crucial step in improving diagnostic assessment of women with suspected IHD.

High-Sensitivity Troponin-T and Cardiovascular Outcomes in the Community: Differences Between Women and Men.

OBJECTIVE: To evaluate associations of high-sensitivity cardiac troponin-T (cTnT) with cardiovascular disease (CVD), heart failure (HF), and mortality in community-dwelling women and men. PARTICIPANTS AND METHODS: A total of 8226 adults from the Prevention of Renal and Vascular End-stage Disease (PREVEND) cohort (1997-1998) were enrolled in a prospective observational study (mean age: 49 years; 50.2% women). Sex-specific associations of cTnT levels with future clinical outcomes were evaluated using adjusted Cox-regression models. RESULTS: Measurable cTnT levels (≥3 ng/L) were detected in 1102 women (26.7%) and in 2396 men (58.5%). Baseline cTnT levels were associated with a greater risk of developing CVD in women than men [Hazard ratio (HRwomen), 1.48 per unit increase in log2-cTnT; 95% CI, 1.21 to 1.81 vs HRmen, 1.20; 95% CI, 1.07 to 1.35; Pinteraction<.001]. Similar sex-related differences were observed for HF (Pinteraction= .005) and mortality (Pinteraction= .008). Further, compared with referent category (cTnT <3 ng/L), women with cTnT levels greater than or equal to 6 ng/L had a significantly increased risk for CVD (HR, 2.30; 95% CI, 1.45 to 3.64), HF (HR, 2.86; 95% CI, 1.41 to 5.80), and mortality (HR, 2.65; 95% CI, 1.52 to 4.61), whereas men with cTnT levels greater than or equal to 6 ng/L had a significantly increased risk only for CVD (HR, 1.51; 95% CI, 1.07 to 2.13). CONCLUSION: Baseline cTnT levels were associated with future CVD, HF, and mortality in both sexes, and these associations were stronger in women. Future studies are needed to determine the value of cTnT in early diagnosis of CVD, particularly in women.

Reduced Lung-Cancer Mortality with Volume CT Screening in a Randomized Trial.

BACKGROUND: There are limited data from randomized trials regarding whether volume-based, low-dose computed tomographic (CT) screening can reduce lung-cancer mortality among male former and current smokers. METHODS: A total of 13,195 men (primary analysis) and 2594 women (subgroup analyses) between the ages of 50 and 74 were randomly assigned to undergo CT screening at T0 (baseline), year 1, year 3, and year 5.5 or no screening. We obtained data on cancer diagnosis and the date and cause of death through linkages with national registries in the Netherlands and Belgium, and a review committee confirmed lung cancer as the cause of death when possible. A minimum follow-up of 10 years until December 31, 2015, was completed for all participants. RESULTS: Among men, the average adherence to CT screening was 90.0%. On average, 9.2% of the screened participants underwent at least one additional CT scan (initially indeterminate). The overall referral rate for suspicious nodules was 2.1%. At 10 years of follow-up, the incidence of lung cancer was 5.58 cases per 1000 person-years in the screening group and 4.91 cases per 1000 person-years in the control group; lung-cancer mortality was 2.50 deaths per 1000 person-years and 3.30 deaths per 1000 person-years, respectively. The cumulative rate ratio for death from lung cancer at 10 years was 0.76 (95% confidence interval [CI], 0.61 to 0.94; P = 0.01) in the screening group as compared with the control group, similar to the values at years 8 and 9. Among women, the rate ratio was 0.67 (95% CI, 0.38 to 1.14) at 10 years of follow-up, with values of 0.41 to 0.52 in years 7 through 9. CONCLUSIONS: In this trial involving high-risk persons, lung-cancer mortality was significantly lower among those who underwent volume CT screening than among those who underwent no screening. There were low rates of follow-up procedures for results suggestive of lung cancer. (Funded by the Netherlands Organization of Health Research and Development and others; NELSON Netherlands Trial Register number, NL580.).

New Fissure-Attached Nodules in Lung Cancer Screening: A Brief Report From The NELSON Study.

INTRODUCTION: In incidence lung cancer screening rounds, new pulmonary nodules are regular findings. They have a higher lung cancer probability than baseline nodules. Previous studies have shown that baseline perifissural nodules (PFNs) represent benign lesions. Whether this is also the case for incident PFNs is unknown. This study evaluated newly detected nodules in the Dutch-Belgian randomized-controlled NELSON study with respect to incidence of fissure-attached nodules, their classification, and lung cancer probability. METHODS: Within the NELSON trial, 7557 participants underwent baseline screening between April 2004 and December 2006. Participants with new nodules detected after baseline were included. Nodules were classified based on location and attachment. Fissure-attached nodules were re-evaluated to be classified as typical, atypical, or non-PFN by two radiologists without knowledge of participant lung cancer status. RESULTS: One thousand four hundred eighty-four new nodules were detected in 949 participants (77.4% male, median age 59 years [interquartile range: 55-63 years]) in the second, third, and final NELSON screening round. Based on 2-year follow-up or pathology, 1393 nodules (93.8%) were benign. In total, 97 (6.5%) were fissure-attached, including 10 malignant nodules. None of the new fissure-attached malignant nodules was classified as typical or atypical PFN. CONCLUSIONS: In the NELSON study, 6.5% of incident lung nodules were fissure-attached. None of the lung cancers that originated from a new fissure-attached nodule in the incidence lung cancer screening rounds was classified as a typical or atypical PFN. Our results suggest that also in the case of a new PFN, it is highly unlikely that these PFNs will be diagnosed as lung cancer.

Prevalence and determinants of exercise-induced left ventricular dysfunction in patients with coronary artery disease.

BACKGROUND: The phenomenon of exercise-induced left ventricular dysfunction (LVD) is incompletely understood. Better understanding of its prevalence and determinants might help to address the current potential oversimplification of the relation between physical activity and cardiac health in patients with coronary artery disease (CAD). METHODS: We prospectively assessed the prevalence and determinants of exercise-induced LVD in patients with stable CAD and normal LV function at rest undergoing bicycle rest/stress myocardial perfusion imaging single-photon emission computed tomography (MPI-SPECT). Exercise-induced LVD was defined as a relevant (5% or more) drop in left ventricular ejection fraction after maximal exercise. High-sensitivity cardiac troponin I/T (Hs-cTnI/T) and N-terminal probrain natriuretic peptide (NT-proBNP) concentrations were measured before exercise to quantify cardiomyocyte injury and hemodynamic cardiac stress, respectively. RESULTS: Among 317 patients, exercise-induced LVD was present in 83 (26%) patients. Exercise-induced LVD was associated with the extent of exercise-inducible myocardial ischaemia as well as transient ischaemic dilatation. Still, 43% of patients developing exercise-induced LVD did not have functionally relevant CAD. Neither baseline characteristics, nor the quantification of the extent of cardiomyocyte injury and hemodynamic cardiac stress using hs-cTnI/T and NT-proBNP concentrations, respectively, allowed predicting exercise-induced LVD. CONCLUSION: One out of four patients with stable CAD develops exercise-induced LVD after bicycle exercise test. While the extent of exercise-inducible myocardial ischaemia is a predictor, other still unrecognized mechanisms also seem to play a major role, as nearly half of all patients with exercise-induced LVD do not have functionally relevant CAD.

Persisting new nodules in incidence rounds of the NELSON CT lung cancer screening study.

BACKGROUND: The US guidelines recommend low-dose CT (LDCT) lung cancer screening for high-risk individuals. New solid nodules after baseline screening are common and have a high lung cancer probability. Currently, no evidence exists concerning the risk stratification of non-resolving new solid nodules at first LDCT screening after initial detection. METHODS: In the Dutch-Belgian Randomized Lung Cancer Screening (NELSON) trial, 7295 participants underwent the second and 6922 participants the third screening round. We included participants with solid nodules that were registered as new or <15 mm³ (study detection limit) at previous screens and received additional screening after initial detection, thereby excluding high-risk nodules according to the NELSON management protocol (nodules ≥500 mm3). RESULTS: Overall, 680 participants with 1020 low-risk and intermediate-risk new solid nodules were included. A total of 562 (55%) new solid nodules were resolving, leaving 356 (52%) participants with a non-resolving new solid nodule, of whom 25 (7%) were diagnosed with lung cancer. At first screening after initial detection, volume doubling time (VDT), volume, and VDT combined with a predefined ≥200 mm3 volume cut-off had high discrimination for lung cancer (VDT, area under the curve (AUC): 0.913; volume, AUC: 0.875; VDT and ≥200 mm3 combination, AUC: 0.939). Classifying a new solid nodule with either ≤590 days VDT or ≥200 mm3 volume positive provided 100% sensitivity, 84% specificity and 27% positive predictive value for lung cancer. CONCLUSIONS: More than half of new low-risk and intermediate-risk solid nodules in LDCT lung cancer screening resolve. At follow-up, growth assessment potentially combined with a volume limit can be used for risk stratification. TRIAL REGISTRATION NUMBER: ISRCTN63545820; pre-results.

Relationship between the number of new nodules and lung cancer probability in incidence screening rounds of CT lung cancer screening: The NELSON study.

BACKGROUND: New nodules are regularly found after the baseline round of low-dose computed tomography (LDCT) lung cancer screening. The relationship between a participant's number of new nodules and lung cancer probability is unknown. METHODS: Participants of the ongoing Dutch-Belgian Randomized Lung Cancer Screening (NELSON) Trial with (sub)solid nodules detected after baseline and registered as new by the NELSON radiologists were included. The correlation between a participant's new nodule count and the largest new nodule size was assessed using Spearman's rank correlation. To evaluate the new nodule count as predictor for new nodule lung cancer together with largest new nodule size, a multivariable logistic regression analysis was performed. RESULTS: In total, 705 participants with 964 new nodules were included. In 48% (336/705) of participants no nodule had been found previously during baseline screening and in 22% (154/705) of participants >1 new nodule was detected (range 1-12 new nodules). Eventually, 9% (65/705) of the participants had lung cancer in a new nodule. In 100% (65/65) of participants with new nodule lung cancer, the lung cancer was the largest or only new nodule at initial detection. The new nodule lung cancer probability did not differ significantly between participants with 1 (10% [56/551], 95%CI 8-13%) or >1 new nodule (6% [9/154], 95%CI 3-11%, P = .116). An increased number of new nodules positively correlated with a participant's largest nodule size (P < 0.001, Spearman's rho 0.177). When adjusted for largest new nodule size, the new nodule count had a significant negative association with lung cancer (odds ratio 0.59, 0.37-0.95, P = .03). CONCLUSION: A participant's new nodule count alone only has limited association with lung cancer. However, a higher new nodule count correlates with an increased largest new nodule size, while the lung cancer probability remains equivalent, and may improve lung cancer risk prediction by size only.

Direct Comparison of Cardiac Troponin T and I Using a Uniform and a Sex-Specific Approach in the Detection of Functionally Relevant Coronary Artery Disease.

BACKGROUND: We aimed to directly compare high-sensitivity cardiac troponin I (hs-cTnI) and high-sensitivity cardiac troponin T (hs-cTnT) in the detection of functionally relevant coronary artery disease (fCAD). METHODS: Consecutive patients referred with clinical suspicion of fCAD and no structural heart disease other than coronary artery disease were included. The presence of fCAD was based on rest/stress myocardial perfusion single-photon emission computed tomography/computed tomography and coronary angiography. hs-cTnI and hs-cTnT concentrations were measured in a blinded fashion. Diagnostic accuracy was quantified using the area under the ROC curve (AUC) and evaluated both for uniform use in all patients and for sex-specific use in women and men separately. The prognostic end point was major adverse cardiac events (MACEs; cardiovascular death or myocardial infarction) within 2 years. For the prognostic performance, we used a multivariable model comparison with the Akaike information criterion (AIC). RESULTS: fCAD was detected in 613 of 2062 patients (29.7%) overall, 112 of 664 of women (16.9%), and 501 of 1398 of men (35.8%). hs-cTnI and hs-cTnT had comparable diagnostic accuracy when assessed for uniform use in all patients (AUC, 0.68 vs 0.66; P = 0.107) and separately in women (AUC, 0.68 vs 0.63; P = 0.068) and men (AUC, 0.65 vs 0.64; P = 0.475). However, women required lower rule-out cutoffs to achieve high sensitivity, and men needed higher rule-in cutoffs to achieve high specificity. hs-cTnI and hs-cTnT were strongly and independently associated with MACE within 2 years (P < 0.001), with comparable prognostic accuracies by the AIC. CONCLUSIONS: hs-cTnI and hs-cTnT provide moderate and comparable diagnostic accuracy. Sex-specific cutoffs may be preferred. The prognostic utility of both troponins is comparable.

New Subsolid Pulmonary Nodules in Lung Cancer Screening: The NELSON Trial.

INTRODUCTION: Low-dose computed tomography (LDCT) lung cancer screening is recommended in the United States. While new solid nodules after baseline screening have a high lung cancer probability at small size and require lower size cutoff values than baseline nodules, there only is limited evidence on management of new subsolid nodules. METHODS: Within the Dutch-Belgian randomized controlled LDCT lung cancer screening trial (NELSON), 7557 participants underwent baseline screening between April 2004 and December 2006. Participants with new subsolid nodules detected after the baseline screening round were included. RESULTS: In the three incidence screening rounds, 60 new subsolid nodules (43 [72%] part-solid, 17 [28%] nonsolid) not visible in retrospect were detected in 51 participants, representing 0.7% (51 of 7295) of participants with at least one incidence screening. Eventually, 6% (3 of 51) of participants with a new subsolid nodule were diagnosed with (pre-)malignancy in such a nodule. All (pre-)malignancies were adenocarcinoma (in situ) and diagnostic workup (referral 950, 364, and 366 days after first detection, respectively) showed favorable staging (stage I). Overall, 67% (33 of 49) of subsolid nodules with an additional follow-up screening were resolving. CONCLUSIONS: Less than 1% of participants in LDCT lung cancer screening presents with a new subsolid nodule after baseline. Contrary to new solid nodules, data suggest that new subsolid nodules may not require a more aggressive follow-up.

Characteristics of new solid nodules detected in incidence screening rounds of low-dose CT lung cancer screening: the NELSON study.

PURPOSE: New nodules after baseline are regularly found in low-dose CT lung cancer screening and have a high lung cancer probability. It is unknown whether morphological and location characteristics can improve new nodule risk stratification by size. METHODS: Solid non-calcified nodules detected during incidence screening rounds of the randomised controlled Dutch-Belgian lung cancer screening (NELSON) trial and registered as new or previously below detection limit (15 mm3) were included. A multivariate logistic regression analysis with lung cancer as outcome was performed, including previously established volume cut-offs (<30 mm3, 30-<200 mm3 and ≥200 mm3) and nodule characteristics (location, distribution, shape, margin and visibility <15 mm3 in retrospect). RESULTS: Overall, 1280 new nodules were included with 73 (6%) being lung cancer. Of nodules ≥30 mm3 at detection and visible <15 mm3 in retrospect, 22% (6/27) were lung cancer. Discrimination based on volume cut-offs (area under the receiver operating characteristic curve (AUC): 0.80, 95% CI 0.75 to 0.84) and continuous volume (AUC: 0.82, 95% CI 0.77 to 0.87) was similar. After adjustment for volume cut-offs, only location in the right upper lobe (OR 2.0, P=0.012), central distribution (OR 2.4, P=0.001) and visibility <15 mm3 in retrospect (OR 4.7, P=0.003) remained significant predictors for lung cancer. The Hosmer-Lemeshow test (P=0.75) and assessment of bootstrap calibration curves indicated adequate model fit. Discrimination based on the continuous model probability (AUC: 0.85, 95% CI 0.81 to 0.89) was superior to volume cut-offs alone, but when stratified into three risk groups (AUC: 0.82, 95% CI 0.78 to 0.86), discrimination was similar. CONCLUSION: Contrary to morphological nodule characteristics, growth-independent characteristics may further improve volume-based new nodule lung cancer prediction, but in a three-category stratification approach, this is limited. TRIAL REGISTRATION NUMBER: ISRCTN63545820; pre-results.

Influence of lung nodule margin on volume- and diameter-based reader variability in CT lung cancer screening.

OBJECTIVE:: To evaluate the influence of nodule margin on inter- and intrareader variability in manual diameter measurements and semi-automatic volume measurements of solid nodules detected in low-dose CT lung cancer screening. METHODS:: 25 nodules of each morphological category (smooth, lobulated, spiculated and irregular) were randomly selected from 93 participants of the Dutch-Belgian Randomized Lung Cancer Screening Trial (NELSON). Semi-automatic volume measurements were performed using Syngo LungCARE® software (Version Somaris/5 VB10A-W, Siemens, Forchheim, Germany). Three radiologists independently measured mean diameters manually. Impact of nodule margin on interreader variability was evaluated based on systematic error and 95% limits of agreement. Interreader variability was compared with the nodule growth cut-off as used in Lung CT Screening Reporting and Data System (LungRADS; +1.5-mm diameter) and the Dutch-Belgian Randomized Lung Cancer Screening Trial(acronym: NELSON) /British Thoracic Society (+25% volume). RESULTS:: For manual diameter measurements, a significant systematic error (up to 1.2 mm) between readers was found in all morphological categories. For semi-automatic volume measurements, no statistically significant systematic error was found. The interreader variability in mean diameter measurements exceeded the 1.5-mm cut-off for nodule growth for all morphological categories [smooth: ±1.9 mm (+27%), lobulated: ±2.0 mm (+33%), spiculated: ±3.5 mm (+133%), irregular: ±4.5 mm (+200%)]. The 25% vol growth cut-off was exceeded slightly for spiculated [28% (+12%)] and irregular [27% (+8%)] nodules. CONCLUSION:: Lung nodule sizing based on manual diameter measurement is affected by nodule margin. Interreader variability increases especially for nodules with spiculated and irregular margins, and causes substantial misclassification of nodule growth. This effect is almost neglectable for semi-automated volume measurements. Semi-automatic volume measurements are superior for both size and growth determination of pulmonary nodules. ADVANCES IN KNOWLEDGE:: Nodule assessment based on manual diameter measurements is susceptible to nodule margin. This effect is almost neglectable for semi-automated volume measurements. The larger interreader variability for manual diameter measurement results in inaccurate lung nodule growth detection and size classification.

Disagreement of diameter and volume measurements for pulmonary nodule size estimation in CT lung cancer screening.

We studied 2240 indeterminate solid nodules (volume 50-500mm3) to determine the correlation of diameter and semi-automated volume measurements for pulmonary nodule size estimation. Intra-nodular diameter variation, defined as maximum minus minimum diameter through the nodule's center, varied by 2.8 mm (median, IQR:2.2-3.7 mm), so above the 1.5 mm cutoff for nodule growth used in Lung CT Screening Reporting and Data System (Lung-RADS). Using mean or maximum axial diameter to assess nodule volume led to a substantial mean overestimation of nodule volume of 47.2% and 85.1%, respectively, compared to semi-automated volume. Thus, size of indeterminate nodules is poorly represented by diameter. TRIAL REGISTRATION NUMBER: Pre-results, ISRCTN63545820.

Prospective Validation of a Biomarker-Based Rule Out Strategy for Functionally Relevant Coronary Artery Disease.

BACKGROUND: This study aimed to prospectively advance a rule-out strategy for functionally significant coronary artery disease (CAD) by use of high-sensitivity cardiac troponin I (hs-cTnI) from bench to bedside, by application of a 3-step approach: validation in serum, correlation in plasma, and application on a clinical platform. METHODS: Patients without known CAD referred for rest/stress myocardial perfusion single-photon emission tomography/computer tomography (MPI-SPECT/CT) were assigned to 3 consecutive cohorts: validation, correlation, and application. Functionally relevant CAD was adjudicated with the use of expert interpretation of MPI-SPECT/CT and, if available, coronary angiography. In the validation cohort resting hs-cTnI was measured in serum before stress testing with the research Erenna system, in serum and plasma in the correlation cohort with the research Erenna system, and in plasma in the application cohort with the clinical Clarity system. RESULTS: Overall, functionally relevant CAD was adjudicated in 21% (304/1478) of patients. In the validation cohort (n = 613), hs-cTnI concentrations were significantly higher in patients with functionally relevant CAD (median 2.8 ng/L vs 1.9 ng/L, P < 0.001) as compared to patients without functionally relevant CAD and allowed a rule out with 95% sensitivity in 14% of patients. In the correlation cohort (n = 606), hs-cTnI concentrations in serum and plasma strongly correlated (Spearman r = 0.921) and had similar diagnostic accuracy as quantified by the area under the receiver operating characteristic curve (0.686 vs 0.678, P = 0.425). In the application cohort (n = 555), very low hs-cTnI plasma concentrations (< 0.5 ng/L) ruled out functionally relevant CAD with 95% sensitivity in 10% of patients. CONCLUSIONS: A single resting plasma hs-cTnI measurement can safely rule out functionally relevant CAD in around 10% of patients without known CAD.

Relationship between nodule count and lung cancer probability in baseline CT lung cancer screening: The NELSON study.

OBJECTIVES: To explore the relationship between nodule count and lung cancer probability in baseline low-dose CT lung cancer screening. MATERIALS AND METHODS: Included were participants from the NELSON trial with at least one baseline nodule (3392 participants [45% of screen-group], 7258 nodules). We determined nodule count per participant. Malignancy was confirmed by histology. Nodules not diagnosed as screen-detected or interval cancer until the end of the fourth screening round were regarded as benign. We compared lung cancer probability per nodule count category. RESULTS: 1746 (51.5%) participants had one nodule, 800 (23.6%) had two nodules, 354 (10.4%) had three nodules, 191 (5.6%) had four nodules, and 301 (8.9%) had>4 nodules. Lung cancer in a baseline nodule was diagnosed in 134 participants (139 cancers; 4.0%). Median nodule count in participants with only benign nodules was 1 (Inter-quartile range [IQR]: 1-2), and 2 (IQR 1-3) in participants with lung cancer (p=NS). At baseline, malignancy was detected mostly in the largest nodule (64/66 cancers). Lung cancer probability was 62/1746 (3.6%) in case a participant had one nodule, 33/800 (4.1%) for two nodules, 17/354 (4.8%) for three nodules, 12/191 (6.3%) for four nodules and 10/301 (3.3%) for>4 nodules (p=NS). CONCLUSION: In baseline lung cancer CT screening, half of participants with lung nodules have more than one nodule. Lung cancer probability does not significantly change with the number of nodules. Baseline nodule count will not help to differentiate between benign and malignant nodules. Each nodule found in lung cancer screening should be assessed separately independent of the presence of other nodules.