Pim A. de Jong

Surfactant Protein C Mutations Are the Basis of a Significant Portion of Adult Familial Pulmonary Fibrosis in a Dutch Cohort

RATIONALE Familial clustering of adult idiopathic interstitial pneumonias (IIP) suggests that genetic factors might play an important role in disease development. Mutations in the gene encoding surfactant protein C (SFTPC) have been found in children and families with idiopathic pneumonias, whereas cocarriage of a mutation in ATP-binding cassette subfamily A member 3 (ABCA3) was postulated to have a disease-modifying effect. OBJECTIVES To investigate the contribution of SFTPC mutations to adult familial pulmonary fibrosis (FPF) and the disease-modifying effect of mutations in ABCA3 within their families. METHODS Twenty-two unrelated patients with FPF (10%) were identified within our single-center cohort of 229 patients with IIP. SFTPC was sequenced in 20 patients with FPF and 20 patients with sporadic IIP. In patients with an SFTPC mutation, sequencing of ABCA3 was performed. Discovered variants were typed in more than 100 control subjects and 121 additional patients with sporadic IIP. MEASUREMENTS AND MAIN RESULTS In 5/20 unrelated patients with FPF (25%; confidence interval, 10-49) a mutation in SFTPC was detected: M71V, IVS4+2, and three times I73T. No mutations were detected in the sporadic or control cohort. Patients with SFTPC mutations presented with a histopathological pattern of usual interstitial pneumonia and nodular septa thickening and multiple lung cysts in combination with ground glass or diffuse lung involvement on chest high-resolution computed tomography. Two variants in ABCA3 were found in adult patients with FPF but not in affected children. CONCLUSIONS Mutations in SFTPC are a frequent cause of FPF in adult patients in our cohort. Nonclassifiable radiological patterns with cystic changes and histopathological patterns of usual interstitial pneumonia are characteristics of adult SFTPC mutation carriers.

Diagnostic Accuracy of Stress Myocardial Perfusion Imaging Compared to Invasive Coronary Angiography With Fractional Flow Reserve Meta-Analysis

Background—Hemodynamically significant coronary artery disease is an important indication for revascularization. Stress myocardial perfusion imaging is a noninvasive alternative to invasive fractional flow reserve for evaluating hemodynamically significant coronary artery disease. The aim was to determine the diagnostic accuracy of myocardial perfusion imaging by single-photon emission computed tomography, echocardiography, MRI, positron emission tomography, and computed tomography compared with invasive coronary angiography with fractional flow reserve for the diagnosis of hemodynamically significant coronary artery disease. Methods and Results—The meta-analysis adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. PubMed, EMBASE, and Web of Science were searched until May 2014. Thirty-seven studies, reporting on 4721 vessels and 2048 patients, were included. Meta-analysis yielded pooled sensitivity, pooled specificity, pooled likelihood ratios (LR), pooled diagnostic odds ratio, and summary area under the receiver operating characteristic curve. The negative LR (NLR) was chosen as the primary outcome. At the vessel level, MRI (pooled NLR, 0.16; 95% confidence interval [CI], 0.13–0.21) was performed similar to computed tomography (pooled NLR, 0.22; 95% CI, 0.12–0.39) and positron emission tomography (pooled NLR, 0.15; 95% CI, 0.05–0.44), and better than single-photon emission computed tomography (pooled NLR, 0.47; 95% CI, 0.37–0.59). At the patient level, MRI (pooled NLR, 0.14; 95% CI, 0.10–0.18) performed similar to computed tomography (pooled NLR, 0.12; 95% CI, 0.04–0.33) and positron emission tomography (pooled NLR, 0.14; 95% CI, 0.02–0.87), and better than single-photon emission computed tomography (pooled NLR, 0.39; 95% CI, 0.27–0.55) and echocardiography (pooled NLR, 0.42; 95% CI, 0.30–0.59). Conclusions—Stress myocardial perfusion imaging with MRI, computed tomography, or positron emission tomography can accurately rule out hemodynamically significant coronary artery disease and can act as a gatekeeper for invasive revascularization. Single-photon emission computed tomography and echocardiography are less suited for this purpose.

Extraction of Airways From CT (EXACT'09)

This paper describes a framework for establishing a reference airway tree segmentation, which was used to quantitatively evaluate fifteen different airway tree extraction algorithms in a standardized manner. Because of the sheer difficulty involved in manually constructing a complete reference standard from scratch, we propose to construct the reference using results from all algorithms that are to be evaluated. We start by subdividing each segmented airway tree into its individual branch segments. Each branch segment is then visually scored by trained observers to determine whether or not it is a correctly segmented part of the airway tree. Finally, the reference airway trees are constructed by taking the union of all correctly extracted branch segments. Fifteen airway tree extraction algorithms from different research groups are evaluated on a diverse set of twenty chest computed tomography (CT) scans of subjects ranging from healthy volunteers to patients with severe pathologies, scanned at different sites, with different CT scanner brands, models, and scanning protocols. Three performance measures covering different aspects of segmentation quality were computed for all participating algorithms. Results from the evaluation showed that no single algorithm could extract more than an average of 74% of the total length of all branches in the reference standard, indicating substantial differences between the algorithms. A fusion scheme that obtained superior results is presented, demonstrating that there is complementary information provided by the different algorithms and there is still room for further improvements in airway segmentation algorithms.

Detection of lung cancer through low-dose CT screening (NELSON): a prespecified analysis of screening test performance and interval cancers

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.

Identification of chronic obstructive pulmonary disease in lung cancer screening computed tomographic scans.

CONTEXT Smoking is a major risk factor for both cancer and chronic obstructive pulmonary disease (COPD). Computed tomography (CT)-based lung cancer screening may provide an opportunity to detect additional individuals with COPD at an early stage. OBJECTIVE To determine whether low-dose lung cancer screening CT scans can be used to identify participants with COPD. DESIGN, SETTING, AND PATIENTS Single-center prospective cross-sectional study within an ongoing lung cancer screening trial. Prebronchodilator pulmonary function testing with inspiratory and expiratory CT on the same day was obtained from 1140 male participants between July 2007 and September 2008. Computed tomographic emphysema was defined as percentage of voxels less than -950 Hounsfield units (HU), and CT air trapping was defined as the expiratory:inspiratory ratio of mean lung density. Chronic obstructive pulmonary disease was defined as the ratio of forced expiratory volume in the first second to forced vital capacity (FEV(1)/FVC) of less than 70%. Logistic regression was used to develop a diagnostic prediction model for airflow limitation. MAIN OUTCOME MEASURES Diagnostic accuracy of COPD diagnosis using pulmonary function tests as the reference standard. RESULTS Four hundred thirty-seven participants (38%) had COPD according to lung function testing. A diagnostic model with CT emphysema, CT air trapping, body mass index, pack-years, and smoking status corrected for overoptimism (internal validation) yielded an area under the receiver operating characteristic curve of 0.83 (95% CI, 0.81-0.86). Using the point of optimal accuracy, the model identified 274 participants with COPD with 85 false-positives, a sensitivity of 63% (95% CI, 58%-67%), specificity of 88% (95% CI, 85%-90%), positive predictive value of 76% (95% CI, 72%-81%); and negative predictive value of 79% (95% CI, 76%-82%). The diagnostic model showed an area under the receiver operating characteristic curve of 0.87 (95% CI, 0.86-0.88) for participants with symptoms and 0.78 (95% CI, 0.76-0.80) for those without symptoms. CONCLUSION Among men who are current and former heavy smokers, low-dose inspiratory and expiratory CT scans obtained for lung cancer screening can identify participants with COPD, with a sensitivity of 63% and a specificity of 88%.

Automatic classification of pulmonary peri-fissural nodules in computed tomography using an ensemble of 2D views and a convolutional neural network out-of-the-box

In this paper, we tackle the problem of automatic classification of pulmonary peri-fissural nodules (PFNs). The classification problem is formulated as a machine learning approach, where detected nodule candidates are classified as PFNs or non-PFNs. Supervised learning is used, where a classifier is trained to label the detected nodule. The classification of the nodule in 3D is formulated as an ensemble of classifiers trained to recognize PFNs based on 2D views of the nodule. In order to describe nodule morphology in 2D views, we use the output of a pre-trained convolutional neural network known as OverFeat. We compare our approach with a recently presented descriptor of pulmonary nodule morphology, namely Bag of Frequencies, and illustrate the advantages offered by the two strategies, achieving performance of AUC = 0.868, which is close to the one of human experts.

Automatic Detection of Subsolid Pulmonary Nodules in Thoracic Computed Tomography Images

Subsolid pulmonary nodules occur less often than solid pulmonary nodules, but show a much higher malignancy rate. Therefore, accurate detection of this type of pulmonary nodules is crucial. In this work, a computer-aided detection (CAD) system for subsolid nodules in computed tomography images is presented and evaluated on a large data set from a multi-center lung cancer screening trial. The paper describes the different components of the CAD system and presents experiments to optimize the performance of the proposed CAD system. A rich set of 128 features is defined for subsolid nodule candidates. In addition to previously used intensity, shape and texture features, a novel set of context features is introduced. Experiments show that these features significantly improve the classification performance. Optimization and training of the CAD system is performed on a large training set from one site of a lung cancer screening trial. Performance analysis on an independent test from another site of the trial shows that the proposed system reaches a sensitivity of 80% at an average of only 1.0 false positive detections per scan. A retrospective analysis of the output of the CAD system by an experienced thoracic radiologist shows that the CAD system is able to find subsolid nodules which were not contained in the screening database.

Observer Variability for Classification of Pulmonary Nodules on Low-Dose CT Images and Its Effect on Nodule Management

PURPOSE To examine the factors that affect inter- and intraobserver agreement for pulmonary nodule type classification on low-radiation-dose computed tomographic (CT) images, and their potential effect on patient management. MATERIALS AND METHODS Nodules (n = 160) were randomly selected from the Dutch-Belgian Lung Cancer Screening Trial cohort, with equal numbers of nodule types and similar sizes. Nodules were scored by eight radiologists by using morphologic categories proposed by the Fleischner Society guidelines for management of pulmonary nodules as solid, part solid with a solid component smaller than 5 mm, part solid with a solid component 5 mm or larger, or pure ground glass. Inter- and intraobserver agreement was analyzed by using Cohen κ statistics. Multivariate analysis of variance was performed to assess the effect of nodule characteristics and image quality on observer disagreement. Effect on nodule management was estimated by differentiating CT follow-up for ground-glass nodules, solid nodules 8 mm or smaller, and part-solid nodules smaller than 5 mm from immediate diagnostic work-up for solid nodules larger than 8 mm and part-solid nodules 5 mm or greater. RESULTS Pair-wise inter- and intraobserver agreement was moderate (mean κ, 0.51 [95% confidence interval, 0.30, 0.68] and 0.57 [95% confidence interval, 0.47, 0.71]). Categorization as part-solid nodules and location in the upper lobe significantly reduced observer agreement (P = .012 and P < .001, respectively). By considering all possible reading pairs (28 possible combinations of observer pairs × 160 nodules = 4480 possible agreements or disagreements), a discordant nodule classification was found in 36.4% (1630 of 4480), related to presence or size of a solid component in 88.7% (1446 of 1630). Two-thirds of these discrepant readings (1061 of 1630) would have potentially resulted in different nodule management. CONCLUSION There is moderate inter- and intraobserver agreement for nodule classification by using current recommendations for low-radiation-dose CT examinations of the chest. Discrepancies in nodule categorization were mainly caused by disagreement on the size and presence of a solid component, which may lead to different management in the majority of cases with such discrepancies. (©) RSNA, 2015.

CT and 18F-FDG PET for noninvasive detection of splenic involvement in patients with malignant lymphoma.

OBJECTIVE The purpose of this study was to determine the sensitivity and specificity of (18)F-FDG PET, CT, and combined PET/CT in the detection of splenic involvement at initial staging of lymphoma. MATERIALS AND METHODS A retrospective longitudinal analysis was performed on the records of 111 patients with proven lymphoma who had undergone PET and CT before and after treatment. CT scans were evaluated independently by two radiologists, and PET scans by two nuclear medicine physicians. Abnormal CT findings were defined as low-attenuation nodules or a splenic index greater than 725 cm(3) (> 2 SDs above the mean in 100 controls). An abnormal PET finding was defined as splenic uptake greater than hepatic uptake. True splenic involvement was defined retrospectively on the basis of the treatment response assessed with criteria revised in the International Harmonization Project on lymphoma. Observer agreement and sensitivity and specificity values were calculated. RESULTS Observer agreement for CT splenic index and PET findings was good. For initial splenic staging, the sensitivity and specificity of CT, PET, and PET/CT were 91% and 96%, 75% and 99%, and 100% and 95%. CONCLUSION For initial staging of splenic involvement in malignant lymphoma, the sensitivity and specificity of PET/CT can reach 100% and 95%. The sensitivity of the combined approach is higher than that of either technique alone.

Computed tomographic screening for lung cancer: an opportunity to evaluate other diseases

THE RESULTS OF THE NATIONAL LUNG SCREENING TRIAL (NLST) have led to renewed interest in lung cancer screening. The NLST demonstrated that lung cancer screening using computed tomography (CT) reduces lung cancer–specific mortality by more than 20% and overall mortality by 7%. Although the discussion about false-positive findings is unsettling and cost-effectiveness analysis and confirmation by other large randomized trials are still being awaited, guidelines have been released by major organizations in the United States recommending lung cancer screening for patients who meet the inclusion criteria of the NLST. The approach used in the NLST is based on low-dose non– contrast-enhanced chest CT scanning. As such, not only pulmonary nodules but a host of other imaging findings may be assessed as well, all of which are associated with increased morbidity and mortality. Because this assessment does not require additional scans but only systematic evaluation of data already acquired, it appears logical to extend evaluation to quantification of coronary calcium and signs of chronic obstructive pulmonary disease (COPD). Lung cancer screening therefore can evolve into chest screening, including 3 major diseases: lung cancer, cardiovascular disease, and COPD. That this is possible has been shown in several recent studies. In addition, the concept of comprehensive screening may be extended to osteoporosis and various other diseases that may be asymptomatic but can be detected by noncontrast CT. Coronary calcium scoring using electrocardiography (ECG)-synchronized CT has been shown to be an independent predictor of cardiovascular risk. However, lung cancer screening CT is not ECG-synchronized, resulting in suboptimal display of the coronary arteries due to motion artifacts. Nevertheless, although a nonsynchronized technique cannot exclude coronary heart disease, this approach is useful for demonstrating serious coronary heart disease. Recently, investigators from the Dutch-Belgian lung cancer screening trial and the Italian lung cancer screening trial showed that coronary calcium scoring can be performed using lung cancer screening CT, and results are highly predictive of cardiovascular events and overall mortality. Relative to individuals with no or minimal detected calcium, hazard ratios greater than 9 were seen for all-cause mortality in the highest quartile of coronary calcium scores. Appropriate treatment of patients at high risk for coronary heart disease has substantially reduced cardiovascular morbidity and mortality in the past decades. Therefore, the information derived from chest CT screening might help provide more appropriate care for asymptomatic individuals with an increased risk profile. Chronic obstructive pulmonary disease is characterized by chronic airflow limitation, caused by pulmonary emphysema, large airways disease, and inflammation with remodeling of the smallest conducting airways, each contributing in varying degrees. Clinical diagnosis of COPD is usually late in the course of the disease, when patients become symptomatic. Today, the disease components can be quantified automatically using automated CT analysis tools, and recently screening CT has been shown to be useful for detecting early stages of COPD. External validation is still needed, but adding other quantitative markers, such as airway wall dimensions, may enable even better diagnostic performance. These other CT markers may also help separate various phenotypes of COPD: predominant emphysema, involvement of the large bronchi, or small airways disease. Detection of early stages of the disease together with a better characterization may become an important step toward developing more tailored treatments based on disease phenotype. Moreover, the diagnosis of COPD or emphysema is associated with an increased incidence of lung cancer independent of cumulative smoking history, which suggests that stricter screening regimens may be warranted. Evaluation of other diseases visible on CT may be added to the evaluation of lung cancer in screening CT. Osteopenia/