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BACKGROUND: Airway mucus plugs in asthma are associated with exacerbation frequency, increased eosinophilia, and reduced lung function. The relationship between mucus plugs and spatially overlapping ventilation abnormalities observed at hyperpolarized gas MRI has not been assessed quantitatively. PURPOSE: To assess regional associations between CT mucus plugs scored by individual bronchopulmonary segment and corresponding measurements of segmental ventilation defect percentage (VDP) at hyperpolarized helium 3 ((3)He) MRI. MATERIALS AND METHODS: In this secondary analysis of a Health Insurance Portability and Accountability Act–compliant prospective observational cohort, participants in the Severe Asthma Research Program (SARP) III (NCT01760915) between December 2012 and August 2015 underwent hyperpolarized (3)He MRI to determine segmental VDP. Segmental mucus plugs at CT were scored by two readers, with segments scored as plugged only if both readers agreed independently. A linear mixed-effects model controlling for interpatient variability was then used to assess differences in VDP in plugged versus plug-free segments. RESULTS: Forty-four participants with asthma were assessed (mean age ± standard deviation, 47 years ± 15; 29 women): 19 with mild-to-moderate asthma and 25 with severe asthma. Mucus plugs were observed in 49 total bronchopulmonary segments across eight of 44 patients. Segments containing mucus plugs had a median segmental VDP of 25.9% (25th–75th percentile, 7.3%–38.3%) versus 1.4% (25th–75th percentile, 0.1%–5.2%; P < .001) in plug-free segments. Similarly, the model estimated a segmental VDP of 18.9% (95% CI: 15.7, 22.2) for mucus-plugged segments versus 5.1% (95% CI: 3.3, 7.0) for plug-free segments (P < .001). Participants with one or more mucus plugs had a median whole-lung VDP of 11.1% (25th–75th percentile, 7.1%–18.9%) versus 3.1% (25th–75th percentile, 1.1%–4.4%) in those without plugs (P < .001). CONCLUSION: Airway mucus plugging at CT was associated with reduced ventilation in the same bronchopulmonary segment at hyperpolarized helium 3 MRI, suggesting that mucus plugging may be an important cause of ventilation defects in asthma. © RSNA, 2021 Online supplemental material is available for this article.

Incidental respiratory disease-related findings are frequently observed on low-dose CT (LDCT) lung cancer screenings. This study analyzed data from the National Lung Screening Trial (NLST) to assess the relationship between such findings and respiratory disease mortality (RDM), excluding lung cancer.Are incidental respiratory findings on LDCT scanning associated with increased RDM?Subjects in the NLST LDCT arm received three annual screens. Trial radiologists noted findings related to possible lung cancer, as well as respiratory-related incidental findings. Demographic characteristics, smoking history, and medical history were captured in a baseline questionnaire. Kaplan-Meier curves were used to assess cumulative RDM. Multivariate proportional hazards models were used to assess risk factors for RDM; in addition to incidental CT scan findings, variables included respiratory disease history (COPD/emphysema, and asthma), smoking history, and demographic factors (age, race, sex, and BMI).Of 26,722 subjects in the NLST LDCT arm, 25,002 received the baseline screen and a subsequent LDCT screen. Overall, 59% were male, 26.5% were aged ≥ 65 years at baseline, and 10.6% reported a history of COPD/emphysema. Emphysema on LDCT scanning was reported in 30.7% of subjects at baseline and in 44.2% at any screen. Of those with emphysema on baseline LDCT scanning, 18% reported a history of COPD/emphysema. Median mortality follow-up was 10.3 years. There were 3,639 deaths, and 708 were from respiratory diseases. Among subjects with no history of COPD/emphysema, 10-year cumulative RDM ranged from 3.9% for subjects with emphysema and reticular opacities to 1.1% for those with neither condition; the corresponding range among subjects with a COPD/emphysema history was 17.3% (both) to 3.7% (neither). Emphysema on LDCT imaging was associated with a significantly elevated RDM hazard ratio (2.27; 95% CI, 1.92-2.7) in the multivariate model. Reticular opacities (including honeycombing/fibrosis/scar) also had a significantly elevated hazard ratio (1.39; 95% CI, 1.19-1.62).Incidental respiratory disease-related findings observed on NLST LDCT screens were frequent and associated with increased mortality from respiratory diseases.

Rationale: The relative roles of mucus plugs and emphysema in mechanisms of airflow limitation and hypoxemia in smokers with chronic obstructive pulmonary disease (COPD) are uncertain.Objectives: T...

Rationale: Idiopathic pulmonary fibrosis (IPF) is a progressive inflammatory lung disease without effective molecular markers of disease activity or treatment responses. Monocyte and interstitial m...

Quantitative analysis of thin-section CT of the chest has a growing role in the clinical evaluation and management of diffuse lung diseases. This heterogeneous group includes diseases with markedly different prognoses and treatment options. Quantitative tools can assist in both accurate diagnosis and longitudinal management by improving characterization and quantification of disease and increasing the reproducibility of disease severity assessment. Furthermore, a quantitative index of disease severity may serve as a useful tool or surrogate endpoint in evaluating treatment efficacy. The authors explore the role of quantitative imaging tools in the evaluation and management of diffuse lung diseases. Lung parenchymal features can be classified with threshold, histogram, morphologic, and texture-analysis-based methods. Quantitative CT analysis has been applied in obstructive, infiltrative, and restrictive pulmonary diseases including emphysema, cystic fibrosis, asthma, idiopathic pulmonary fibrosis, hypersensitivity pneumonitis, connective tissue-related interstitial lung disease, and combined pulmonary fibrosis and emphysema. Some challenges limiting the development and practical application of current quantitative analysis tools include the quality of training data, lack of standard criteria to validate the accuracy of the results, and lack of real-world assessments of the impact on outcomes. Artifacts such as patient motion or metallic beam hardening, variation in inspiratory effort, differences in image acquisition and reconstruction techniques, or inaccurate preprocessing steps such as segmentation of anatomic structures may lead to inaccurate classification. Despite these challenges, as new techniques emerge, quantitative analysis is developing into a viable tool to supplement the traditional visual assessment of diffuse lung diseases and to provide decision support regarding diagnosis, prognosis, and longitudinal evaluation of disease. ©RSNA, 2019.

Objective Non-calcified nodules (NCNs) associated with false positive low-dose CT (LDCT) lung cancer screens have been attributed to various causes. Some, however, may represent lung cancer precursors. An association of NCNs with long-term lung cancer risk would provide indirect evidence of some NCNs being cancer precursors. Methods LDCT arm participants in the National Lung Screening Trial (NLST) received LDCT screens at baseline and years 1-2. The relationship between NCNs found on LDCT screens and subsequent lung cancer diagnosis over different time periods was examined at the person and lobe level. For the latter, a lobe had a cancer outcome only if the cancer was located in the lobe. Separate analyses were performed on baseline and post-baseline LDCT findings; for the latter, those with baseline NCNs were excluded and only new (non-pre-existing) NCNs examined. Raw and adjusted rate-ratios (RRs) were computed for presence of NCNs and subsequent lung cancer risk; adjusted RRs controlled for demographic and smoking factors. Results 26,309 participants received the baseline LDCT screen. Over median 11.3 years follow-up, 1675 lung cancers were diagnosed. Adjusted RRs for time periods 0–4, 4–8 and 8−12 years following the baseline screen were 5.1 (95 % CI:4.4–5.9), 1.5 (95 % CI:1.3–1.9) and 1.5 (95 % CI:1.2-1.8) at the person-level and 14.7 (95 % CI:12.6–17.2), 2.6 (95 % CI: 2.0–3.4) and 2.2 (95 % CI:1.6–2.9) at the lobe-level. 18,585 participants were included in the post-baseline analysis. Adjusted RRs for periods 0–4, 4–8 and 8−11 years were 5.6 (95 % CI: 4.5–7.0), 1.9 (95 % CI: 1.3–2.7) and 1.6 (95 % CI: 0.9–2.9) at the person-level and 19.6 (95 % CI:14.9–25.3), 2.5 (95 % CI:1.3–4.7) and 3.3 (95 % CI:1.4–7.6) at the lobe-level. Raw RRs were similar. Conclusion NCNs are associated with excess long-term lung cancer risk, suggesting that some may be lung cancer precursors.

Vaccination-associated adenopathy is a frequent imaging finding after administration of COVID-19 vaccines that may lead to a diagnostic conundrum in patients with manifest or suspected cancer, in whom it may be indistinguishable from malignant nodal involvement. To help the medical community address this concern in the absence of studies and evidence-based guidelines, this special report offers recommendations developed by a multidisciplinary panel of experts from three of the leading tertiary care cancer centers in the United States. According to these recommendations, some routine imaging examinations, such as those for screening, should be scheduled before or at least 6 weeks after the final vaccination dose to allow for any reactive adenopathy to resolve. However, there should be no delay of other clinically indicated imaging (eg, for acute symptoms, short-interval treatment monitoring, urgent treatment planning or complications) due to prior vaccination. The vaccine should be administered on the side contralateral to the primary or suspected cancer, and both doses should be administered in the same arm. Vaccination information-date(s) administered, injection site(s), laterality, and type of vaccine-should be included in every preimaging patient questionnaire, and this information should be made readily available to interpreting radiologists. Clear and effective communication between patients, radiologists, referring physician teams, and the general public should be considered of the highest priority when managing adenopathy in the setting of COVID-19 vaccination.

BACKGROUND: There is limited information about survival of stage I lung cancer diagnosed by screening. RESEARCH QUESTION: What was the survival rate of screen-detected stage I lung cancer in the National Lung Screening Trial (NLST), and was it affected by screening method, patient or tumor characteristics, or treatment method? STUDY DESIGN AND METHODS: The study cohort consisted of all NLST participants with screen-detected stage I lung cancer. Lung cancer-specific survival for stage I overall and for IA and IB substages were compared in the low-dose CT and chest radiography (CXR) screening randomization arms and with an analogous cohort from the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute; the cumulative incidence competing risk method was used for analysis. Cox proportional hazards models were used to evaluate the association between lung cancer-specific survival and screening arm, patient factors, primary tumor size, and treatment. RESULTS: There were 324 screen-detected stage I lung cancers in the low-dose CT arm and 125 in the CXR arm. The 10-year survival in the low-dose CT arm was greater than in the CXR arm (73.4% vs 64.6%; P = .05), and both were greater than in the Surveillance, Epidemiology, and End Results cohort (55.6%; P < .001 vs low-dose CT arm, P = .04 vs CXR arm). Proportional hazards models revealed a greater likelihood of survival in the low-dose CT arm (hazard ratio [HR], 0.69; 95% CI, 0.5-0.98) and with primary tumor size below the median of 17 mm (HR, 0.61; 95% CI, 0.42-0.88). There was no survival difference between treatment with limited resection vs full resection (HR, 1.11; 95% CI, 0.6-1.9), whereas nonsurgical treatment was associated with a reduced likelihood of survival compared with full resection (HR, 3.1; 95% CI, 1.6-6.0). INTERPRETATION: Long-term lung cancer-specific survival of stage I lung cancer was greater with low-dose CT imaging than with CXR screening or in the general population, for smaller primary tumor size, and with surgical treatment.

Lung cancer remains the overwhelmingly greatest cause of cancer death in the United States, accounting for more annual deaths than breast, prostate, and colon cancer combined. Accumulated evidence since the mid to late 1990s, however, indicates that low-dose CT screening of high-risk patients enables detection of lung cancer at an early stage and can reduce the risk of dying from lung cancer. CT screening is now a recommended clinical service in the United States, subject to guidelines and reimbursement requirements intended to standardize practice and optimize the balance of benefits and risks. In this review, the evidence on the effectiveness of CT screening will be summarized and the current guidelines and standards will be described in the context of knowledge gained from lung cancer screening studies. In addition, an overview of the potential advances that may improve CT screening will be presented, and the need to better understand the performance in clinical practice outside of the research trial setting will be discussed. © RSNA, 2020.

Idiopathic pulmonary fibrosis (IPF) is a progressive, inflammatory lung disease that is monitored clinically by measures of lung function, without effective molecular markers of disease activity or therapeutic efficacy. Lung immune cells active in the pro-fibrotic process include inflammatory monocyte and interstitial macrophages that express the C-C motif chemokine receptor 2 (CCR2). CCR2+ monocyte lung influx is essential for disease phenotypes in models of fibrosis and identified in lungs from subjects with IPF. Here, we show that our peptide-based radiotracer 64Cu-DOTA-ECL1i identifies CCR2+ inflammatory monocytes and interstitial macrophages in multiple preclinical mouse models of lung fibrosis, using positron emission tomography (PET) imaging. Mice with bleomycin-induced fibrosis treated with blocking antibodies to interleukin-1β, a mediator of fibrosis associated with CCR2+ cell inflammation, or with pirfenidone, an approved anti-fibrotic agent, demonstrated decreased CCR2-dependent interstitial macrophage accumulation and reduced 64Cu-DOTA-ECL1i PET uptake, compared to controls. Lung tissues from patients with fibrotic lung disease demonstrated abundant CCR2+ cells surrounding regions of fibrosis, and an ex vivo tissue-binding assay showed correlation between radiotracer localization and CCR2+ cells. In a phase 0/1 clinical study of 64Cu-DOTA-ECL1i PET, healthy volunteers showed little lung uptake, while subjects with pulmonary fibrosis exhibited increased uptake, notably in zones of subpleural fibrosis, reflecting the distribution of CCR2+ cells in the profibrotic niche. These findings support a pathologic role of inflammatory lung monocytes/macrophages in fibrotic lung disease and the translational use of 64Cu-DOTA-ECL1i PET to track CCR2-specific inflammation for image-guided therapy.One Sentence SummaryPET imaging of CCR2+ cells in lung fibrosis identifies a therapeutic response in mouse models and displays a perifibrotic signal in subjects with IPF.

BACKGROUND. The link between mucus plugs and airflow obstruction has not been established in chronic severe asthma, and the role of eosinophils and their products in mucus plug formation is unknown. METHODS. In clinical studies, we developed and applied a bronchopulmonary segment–based scoring system to quantify mucus plugs on multidetector computed tomography (MDCT) lung scans from 146 subjects with asthma and 22 controls, and analyzed relationships among mucus plug scores, forced expiratory volume in 1 second (FEV1), and airway eosinophils. Additionally, we used airway mucus gel models to explore whether oxidants generated by eosinophil peroxidase (EPO) oxidize cysteine thiol groups to promote mucus plug formation. RESULTS. Mucus plugs occurred in at least 1 of 20 lung segments in 58% of subjects with asthma and in only 4.5% of controls, and the plugs in subjects with asthma persisted in the same segment for years. A high mucus score (plugs in ≥ 4 segments) occurred in 67% of subjects with asthma with FEV1 of less than 60% of predicted volume, 19% with FEV1 of 60%–80%, and 6% with FEV1 greater than 80% (P < 0.001) and was associated with marked increases in sputum eosinophils and EPO. EPO catalyzed oxidation of thiocyanate and bromide by H2O2 to generate oxidants that crosslink cysteine thiol groups and stiffen thiolated hydrogels. CONCLUSION. Mucus plugs are a plausible mechanism of chronic airflow obstruction in severe asthma, and EPO-generated oxidants may mediate mucus plug formation. We propose an approach for quantifying airway mucus plugging using MDCT lung scans and suggest that treating mucus plugs may improve airflow in chronic severe asthma. TRIAL REGISTRATION. Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01718197","term_id":"NCT01718197"}}NCT01718197, {"type":"clinical-trial","attrs":{"text":"NCT01606826","term_id":"NCT01606826"}}NCT01606826, {"type":"clinical-trial","attrs":{"text":"NCT01750411","term_id":"NCT01750411"}}NCT01750411, {"type":"clinical-trial","attrs":{"text":"NCT01761058","term_id":"NCT01761058"}}NCT01761058, {"type":"clinical-trial","attrs":{"text":"NCT01761630","term_id":"NCT01761630"}}NCT01761630, {"type":"clinical-trial","attrs":{"text":"NCT01759186","term_id":"NCT01759186"}}NCT01759186, {"type":"clinical-trial","attrs":{"text":"NCT01716494","term_id":"NCT01716494"}}NCT01716494, and {"type":"clinical-trial","attrs":{"text":"NCT01760915","term_id":"NCT01760915"}}NCT01760915. FUNDING. NIH grants P01 HL107201, R01 HL080414, U10 {"type":"entrez-nucleotide","attrs":{"text":"HL109146","term_id":"1051682664"}}HL109146, U10 {"type":"entrez-nucleotide","attrs":{"text":"HL109164","term_id":"1051682685"}}HL109164, U10 {"type":"entrez-nucleotide","attrs":{"text":"HL109172","term_id":"1051682699"}}HL109172, U10 {"type":"entrez-nucleotide","attrs":{"text":"HL109086","term_id":"1051682577"}}HL109086, U10 {"type":"entrez-nucleotide","attrs":{"text":"HL109250","term_id":"1051682815"}}HL109250, U10 {"type":"entrez-nucleotide","attrs":{"text":"HL109168","term_id":"1051682692"}}HL109168, U10 {"type":"entrez-nucleotide","attrs":{"text":"HL109257","term_id":"1051682826"}}HL109257, U10 {"type":"entrez-nucleotide","attrs":{"text":"HL109152","term_id":"1051682671"}}HL109152, and P01 HL107202 and National Center for Advancing Translational Sciences grants UL1TR0000427, UL1TR000448, and KL2TR000428.

As low-dose CT (LDCT) lung cancer screening moves into routine clinical practice, evaluation of nodules identified as new becomes critical. We examine the frequency and clinical outcomes of new lung nodules reported at the two postbaseline annual screening examinations (hereafter referred to as postbaseline time 1 [T1] and time 2 [T2]), compared with those detected at baseline in the National Lung Screening Trial.Radiologists classified nodules detected at T1 and T2 as new or preexisting on the basis of comparison with findings from prior LDCT screening examinations. Subjects were tracked for lung cancer incidence and mortality. We examined the incidence of new nodules and their associated lung cancer risk by nodule size (i.e., mean diameter).A total of 25,002 subjects underwent the baseline LDCT screening examination and either a T1 or T2 LDCT screen. At both T1 and T2, 2.6% of subjects had new solid nodules. Of the new solid nodules, 53.0% were6 mm, 29.5% were 6 to10 mm, and 17.1% were ≥ 10 mm. Lung cancer risk (defined as diagnosis within 2 years of baseline) increased from 1.1% for nodules4 mm to 24.0% for those ≥ 20 mm. Compared with solid nodules detected at baseline, the cancer risk was higher for new solid nodules that were 4 to6 mm (p0.001) and 6 to8 mm (p0.001) but lower for new nodules ≥ 20 mm (p = 0.03). Cancers associated with new nodules had significantly poorer survival than did those associated with baseline nodules and were significantly less likely to be adenocarcinoma.The incidence of new nodules was 2-3% annually, with the cancer risk increasing by nodule size. New nodules may convey differential lung cancer risks by size, compared with baseline nodules.

The National Lung Screening Trial (NLST) demonstrated a reduction in lung cancer and all-cause mortality with low-dose CT (LDCT) screening. The aim of our study was to examine the time to diagnosis (TTD) of lung cancer in the LDCT arm of the NLST and assess its relationship with cancer characteristics and survival. The subjects (N = 462) with a positive baseline screen and subsequent lung cancer diagnosis within 3 years were evaluated by data and image review to confirm the baseline abnormality. The cases were analysed for the relationship between TTD and imaging features, cancer type, stage and survival for 7 years from baseline screen. Cancer was judged to be present at baseline in 397/462 cases. The factors that showed significant association (p value trend less than 0.05) with longer TTD included smaller nodule size, pure ground glass nodules (GGNs), smooth/lobulated margins, stages I/II, adenocarcinoma, and decreasing lung cancer mortality. The logistic regression model for lung cancer death showed significant inverse relationships with size less than 20 mm (OR = 0.32), pure GGNs (OR = 0.24), adenocarcinoma (OR = 0.57) and direct relationship with age (OR = 1.4). TTD after a positive LDCT screen in the NLST showed a strong association with imaging features, stage and mortality. • NLST observed variable time to lung cancer diagnosis from positive baseline screen. • Time to diagnosis was associated with imaging features, cancer type and stage. • In univariate but not multivariate analysis, longer TTD correlated with decreased mortality.

This study retrospectively analyses the screening CT examinations and outcomes of the National Lung Screening Trial (NLST) participants who had interval lung cancer diagnosed within 1 year after a negative CT screen and before the next annual screen.The screening CTs of all 44 participants diagnosed with interval lung cancer (cases) were matched with negative CT screens of participants who did not develop lung cancer (controls). A majority consensus process was used to classify each CT screen as positive or negative according to the NLST criteria and to estimate the likelihood that any abnormalities detected retrospectively were due to lung cancer.By retrospective review, 40/44 cases (91%) and 17/44 controls (39%) met the NLST criteria for a positive screen (P 0.001). Cases had higher estimated likelihood of lung cancer (P 0.001). Abnormalities included pulmonary nodules ≥4 mm (n = 16), mediastinal (n = 8) and hilar (n = 6) masses, and bronchial lesions (n = 6). Cancers were stage III or IV at diagnosis in 32/44 cases (73%); 37/44 patients (84%) died of lung cancer, compared to 225/649 (35%) for all screen-detected cancers (P 0.0001).Most cases met the NLST criteria for a positive screen. Awareness of missed abnormalities and interpretation errors may aid lung cancer identification in CT screening.• Lung cancer within a year of a negative CT screen was rare. • Abnormalities likely due to lung cancer were identified retrospectively in most patients. • Awareness of error types may help identify lung cancer sooner.

There have been significant advancements in the various imaging techniques being used for the evaluation of asthmatic patients, both from a clinical and research perspective. Imaging characteristics can be used to identify specific asthmatic phenotypes and provide a more detailed understanding of endotypes contributing to the pathophysiology of the disease. Computed tomography, magnetic resonance imaging, and positron emission tomography can be used to assess pulmonary structure and function. It has been shown that specific airway and lung density measurements using computed tomography correlate with clinical parameters, including severity of disease and pathology, but also provide unique phenotypes. Hyperpolarized 129Xe and 3He are gases used as contrast media for magnetic resonance imaging that provide measurement of distal lung ventilation reflecting small-airway disease. Positron emission tomography can be useful to identify and target lung inflammation in asthmatic patients. Furthermore, imaging techniques can serve as a potential biomarker and be used to assess response to therapies, including newer biological treatments and bronchial thermoplasty.

Introduction Renal cancer incidence has increased markedly in the United States in recent decades, largely due to incidentally detected tumours from computed tomography imaging. Here, we analyze the potential for low-dose computed tomography lung cancer screening to detect renal cancer. Methods The National Lung Screening Trial randomized subjects to three annual screens with either low-dose computed tomography or chest X-ray. Eligibility criteria included 30 + pack-years, current smoking or quit within 15 years, and age 55–74. Subjects were followed for seven years. Low-dose computed tomography screening forms collected information on lung cancer and non-lung cancer abnormalities, including abnormalities below the diaphragm. A reader study was performed on a sample of National Lung Screening Trial low-dose computed tomography images assessing presence of abnormalities below the diaphragms and abnormalities suspicious for renal cancer. Results There were 26,722 and 26,732 subjects enrolled in the low-dose computed tomography and chest X-ray arms, respectively, and there were 104 and 85 renal cancer cases diagnosed, respectively (relative risk = 1.22, 95% CI: 0.9–1.5). From 75,126 low-dose computed tomography screens, there were 46 renal cancer diagnoses within one year. Abnormalities below the diaphragm rates were 39.1% in screens with renal cancer versus 4.1% in screens without (P Conclusion Low-dose computed tomography screens can potentially detect renal cancers. The benefits to harms tradeoff of incidental detection of renal tumours on low-dose computed tomography is unknown.

The progressive decline of lung function with aging is associated with changes in lung structure at all levels, from conducting airways to acinar airways (alveolar ducts and sacs). While information on conducting airways is becoming available from computed tomography, in vivo information on the acinar airways is not conventionally available, even though acini occupy 95% of lung volume and serve as major gas exchange units of the lung. The objectives of this study are to measure morphometric parameters of lung acinar airways in living adult humans over a broad range of ages by using an innovative MRI-based technique, in vivo lung morphometry with hyperpolarized 3He gas, and to determine the influence of age-related differences in acinar airway morphometry on lung function. Pulmonary function tests and MRI with hyperpolarized 3He gas were performed on 24 healthy nonsmokers aged 19-71 years. The most significant age-related difference across this population was a 27% loss of alveolar depth, h, leading to a 46% increased acinar airway lumen radius, hence, decreased resistance to acinar air transport. Importantly, the data show a negative correlation between h and the pulmonary function measures forced expiratory volume in 1 s and forced vital capacity. In vivo lung morphometry provides unique information on age-related changes in lung microstructure and their influence on lung function. We hypothesize that the observed reduction of alveolar depth in subjects with advanced aging represents a remodeling process that might be a compensatory mechanism, without which the pulmonary functional decline due to other biological factors with advancing age would be significantly larger.

The diaphragm is an unique skeletal muscle separating the thoracic and abdominal cavities with a primary function of enabling respiration. When abnormal, whether by congenital or acquired means, the consequences for patients can be severe. Abnormalities that affect the diaphragm are often first detected on chest radiographs as an alteration in position or shape. Cross-sectional imaging studies, primarily CT and occasionally MRI, can depict structural defects, intrinsic and adjacent pathology in greater detail. Fluoroscopy is the primary radiologic means of evaluating diaphragmatic motion, though MRI and ultrasound also are capable of this function. This review provides an update on diaphragm embryogenesis and discusses current imaging of various abnormalities, including the emerging role of three-dimensional printing in planning surgical repair of diaphragmatic derangements.

OBJECTIVE We reduced the computed tomography (CT)-reconstructed field of view (FOV), increasing pixel density across airway structures and reducing partial volume effects, to determine whether this would improve accuracy of airway wall thickness quantification. METHODS We performed CT imaging on a lung phantom and 29 participants. Images were reconstructed at 30-, 15-, and 10-cm FOV using a medium-smooth kernel. Cross-sectional airway dimensions were compared at each FOV with repeated-measures analysis of variance. RESULTS Phantom measurements were more accurate when FOV decreased from 30 to 15 cm (P < 0.05). Decreasing FOV further to 10 cm did not significantly improve accuracy. Human airway measurements similarly decreased by decreasing FOV (P < 0.001). Percent changes in all measurements when reducing FOV from 30 to 15 cm were less than 3%. CONCLUSIONS Airway measurements at 30-cm FOV are near the limits of CT resolution using a medium-smooth kernel. Reducing reconstructed FOV would minimally increase sensitivity to detect differences in airway dimensions.

After years of assessment through controlled clinical trials, low-dose CT screening for lung cancer is becoming part of clinical practice. As with any cancer screening test, those undergoing lung cancer screening are not being evaluated for concerning signs or symptoms, but are generally in good health and proactively trying to prevent premature death. Given the resultant obligation to achieve the screening aim of early diagnosis while also minimizing the potential for morbidity from workup of indeterminate but ultimately benign screening abnormalities, careful implementation of screening with conformance to currently recognized best practices and a focus on quality assurance is essential. In this review, we address the importance of each component of the screening process to optimize the effectiveness of CT screening, discussing options for quality assurance at each step. We also discuss the potential added advantages, quality assurance requirements and current status of quantitative imaging biomarkers related to lung cancer screening. Finally, we highlight suggestions for improvements and needs for further evidence in evaluating the performance of CT screening as it transitions from the research trial setting into daily clinical practice.

Previous cross-sectional studies have demonstrated that airway wall thickness and air trapping are greater in subjects with severe asthma than in those with mild-to-moderate asthma. However, a better understanding of how airway remodeling and lung density change over time is needed. This study aimed to evaluate predictors of airway wall remodeling and change in lung function and lung density over time in severe asthma.Phenotypic characterization and quantitative multidetector-row computed tomography (MDCT) of the chest were performed at baseline and ∼2.6 years later in 38 participants with asthma (severe n = 24 and mild-to-moderate n = 14) and nine normal controls from the Severe Asthma Research Program.Subjects with severe asthma had a significant decline in postbronchodilator forced expiratory volume in 1 second percent (FEV1%) predicted over time (P.001). Airway wall thickness measured by MDCT was increased at multiple airway generations in severe asthma compared to mild-to-moderate asthma (wall area percent [WA%]: P .05) and normals (P .05) at baseline and year 2. Over time, there was an increase in WA% and wall thickness percent (WT%) in all subjects (P = .030 and .009, respectively) with no change in emphysema-like lung or air trapping. Baseline prebronchodilator FEV1% inversely correlated with WA% and WT% (both P.05). In a multivariable regression model, baseline WA%, race, and health care utilization were predictors of subsequent airway remodeling.Severe asthma subjects have a greater decline in lung function over time than normal subjects or those with mild-to-moderate asthma. MDCT provides a noninvasive measure of airway wall thickness that may predict subsequent airway remodeling.

The NCCN Guidelines for Occult Primary tumors provide recommendations for the evaluation, workup, management, and follow-up of patients with occult primary tumors (cancers of unknown primary). These NCCN Guidelines Insights summarize major discussion points of the 2014 NCCN Occult Primary panel meeting. The panel discussed gene expression profiling (GEP) for the identification of the tissue of origin and concluded that, although GEP has a diagnostic benefit, a clinical benefit has not been demonstrated. The panel recommends against GEP as standard management, although 20% of the panel believes the diagnostic benefit of GEP warrants its routine use. In addition, the panel discussed testing for actionable mutations (eg, ALK) to help guide choice of therapy, but declined to add this recommendation.

Obtaining information on transplanted lung microstructure is an important part of the current care for monitoring transplant recipients. However, until now this information was only available from invasive lung biopsy. The objective of this study was to evaluate the use of an innovative non-invasive technique, in vivo lung morphometry with hyperpolarized ³He MRI-to characterize lung microstructure in the pediatric lung transplant population. This technique yields quantitative measurements of acinar airways' (alveolar ducts and sacs) parameters, such as acinar airway radii and alveolar depth. Six pediatric lung transplant recipients with cystic fibrosis underwent in vivo lung morphometry MRI, pulmonary function testing, and quantitative CT. We found a strong correlation between lung lifespan and alveolar depth-patients with more shallow alveoli were likely to have a negative outcome sooner than those with larger alveolar depth. Combining morphometric results with CT, we also determined mean alveolar wall thickness and found substantial increases in this parameter in some patients that negatively correlated with DLCO. In vivo lung morphometry uniquely provides previously unavailable information on lung microstructure that may be predictive of a negative outcome and has a potential to aid in lung selection for transplantation.

Background Quantitative computed tomographic (QCT) biomarkers of airway morphology hold potential for understanding and monitoring regional airway remodeling in asthmatic patients. Objective We sought to determine whether the change in airway lumen area between total lung capacity (TLC) and functional residual capacity (FRC) lung volumes measured from CT imaging data was correlated with severe outcomes in asthmatic patients. Methods We studied 152 asthmatic patients (90 female and 62 male patients) and 33 healthy subjects (12 female and 21 male subjects) using QCT. Postprocessing of airways at generations 1 to 5 (1 = trachea) was performed for wall area percentage, wall thickness percentage (WT%), lumen area at baseline total lung capacity (LA TLC ), lumen area at baseline functional residual capacity (LA FRC ), and low attenuation area at FRC. A new metric (reflecting remodeling, distal air trapping, or both), Delta Lumen, was determined as follows: Percentage difference in lumen area (LA TLC − LA FRC )/LA TLC × 100. Results Postprocessing of 4501 airway segments was performed (3681 segments in the 152 patients with asthma and 820 segments in the 33 healthy subjects; range, 17-28 segments per subject). Delta Lumen values were negatively correlated with WT% and low attenuation area ( P P Conclusion Reduced Delta Lumen value in the central airways measured by using QCT is a promising exploratory biomarker of unstable refractory asthma that warrants further study.

To characterize the variability in radiologists' interpretations of computed tomography (CT) studies in the National Lung Screening Trial (NLST) (including assessment of false-positive rates [FPRs] and sensitivity), to examine factors that contribute to variability, and to evaluate trade-offs between FPRs and sensitivity among different groups of radiologists.The HIPAA-compliant NLST was approved by the institutional review board at each screening center; all participants provided informed consent. NLST radiologists reported overall screening results, nodule-specific findings, and recommendations for diagnostic follow-up. A noncalcified nodule of 4 mm or larger constituted a positive screening result. The FPR was defined as the rate of positive screening examinations in participants without a cancer diagnosis within 1 year. Descriptive analyses and mixed-effects models were utilized. The average odds ratio (OR) for a false-positive result across all pairs of radiologists was used as a measure of variability.One hundred twelve radiologists at 32 screening centers each interpreted 100 or more NLST CT studies, interpreting 72 160 of 75 126 total NLST CT studies in aggregate. The mean FPR for radiologists was 28.7% ± 13.7 (standard deviation), with a range of 3.8%-69.0%. The model yielded an average OR of 2.49 across all pairs of radiologists and an OR of 1.83 for pairs within the same screening center. Mean FPRs were similar for academic versus nonacademic centers (27.9% and 26.7%, respectively) and for centers inside (25.0%) versus outside (28.7%) the U.S. "histoplasmosis belt." Aggregate sensitivity was 96.5% for radiologists with FPRs higher than the median (27.1%), compared with 91.9% for those with FPRs lower than the median (P = .02).There was substantial variability in radiologists' FPRs. Higher FPRs were associated with modestly higher sensitivity.

Background Lung cancer is the largest contributor to mortality from cancer. The National Lung Screening Trial (NLST) showed that screening with low-dose helical computed tomography (CT) rather than with chest radiography reduced mortality from lung cancer. We describe the screening, diagnosis, and limited treatment results from the initial round of screening in the NLST to inform and improve lung-cancer-screening programs. Methods At 33 U.S. centers, from August 2002 through April 2004, we enrolled asymptomatic participants, 55 to 74 years of age, with a history of at least 30 pack-years of smoking. The participants were randomly assigned to undergo annual screening, with the use of either low-dose CT or chest radiography, for 3 years. Nodules or other suspicious findings were classified as positive results. This article reports findings from the initial screening examination. Results A total of 53,439 eligible participants were randomly assigned to a study group (26,715 to low-dose CT and 26,724 to chest radiography); 26,309 participants (98.5%) and 26,035 (97.4%), respectively, underwent screening. A total of 7191 participants (27.3%) in the low-dose CT group and 2387 (9.2%) in the radiography group had a positive screening result; in the respective groups, 6369 participants (90.4%) and 2176 (92.7%) had at least one follow-up diagnostic procedure, including imaging in 5717 (81.1%) and 2010 (85.6%) and surgery in 297 (4.2%) and 121 (5.2%). Lung cancer was diagnosed in 292 participants (1.1%) in the low-dose CT group versus 190 (0.7%) in the radiography group (stage 1 in 158 vs. 70 participants and stage IIB to IV in 120 vs. 112). Sensitivity and specificity were 93.8% and 73.4% for low-dose CT and 73.5% and 91.3% for chest radiography, respectively. Conclusions The NLST initial screening results are consistent with the existing literature on screening by means of low-dose CT and chest radiography, suggesting that a reduction in mortality from lung cancer is achievable at U.S. screening centers that have staff experienced in chest CT. (Funded by the National Cancer Institute; NLST ClinicalTrials.gov number, NCT00047385.).

OBJECTIVE The aim of this study was to compare the performance of 2- (2D) and 3-dimensional (3D) quantitative computed tomography (CT) methods for classifying lung nodules as lung cancer, metastases, or benign. METHODS Using semiautomated software and computerized analysis, we analyzed more than 50 quantitative CT features of 96 solid nodules in 94 patients, in 2D from a single slice and in 3D from the entire nodule volume. Multivariable logistic regression was used to classify nodule types. Model performance was assessed by the area under the receiver operating characteristic curve (AUC) using leave-one-out cross-validation. RESULTS The AUC for distinguishing 53 primary lung cancers from 18 benign nodules and 25 metastases ranged from 0.79 to 0.83 and was not significantly different for 2D and 3D analyses (P = 0.29-0.78). Models distinguishing metastases from benign nodules were statistically significant only by 3D analysis (AUC = 0.84). CONCLUSIONS Three-dimensional CT methods did not improve discrimination of lung cancer, but may help distinguish benign nodules from metastases.

Despite strong supportive evidence on and professional society endorsement of CT screening for lung cancer, there is minimal demand from patients or physicians.

The aim of this study was to evaluate whether a computer-aided diagnosis (CAD) system improves interobserver agreement in the interpretation of lung nodules at low-dose computed tomography (CT) screening for lung cancer.Baseline low-dose screening CT examinations from 134 participants enrolled in the National Lung Screening Trial were reviewed by 7 chest radiologists. All participants consented to the use of their deidentified images for research purposes. Screening results were classified as positive when noncalcified nodules larger than 4 mm in diameter were present. Follow-up evaluation was recommended according to the nodule diameter: 4 mm or smaller, more than 4 to 8 mm, and larger than 8 mm. When multiple nodules were present, recommendations were based on the largest nodule. Readers initially assessed the nodule presence visually and measured the average nodule diameter manually. Revision of their decisions after reviewing the CAD marks and size measurement was allowed. Interobserver agreement evaluated using multirater κ statistics was compared between initial assessment and that with CAD.Multirater κ values for the positivity of the screening results and follow-up recommendations were improved from moderate (κ = 0.53-0.54) at initial assessment to good (κ = 0.66-0.67) after reviewing CAD results. The average percentage of agreement between reader pairs on the positivity of screening results and follow-up recommendations per case was also increased from 77% and 72% at initial assessment to 84% and 80% with CAD, respectively.Computer-aided diagnosis may improve the reader agreement on the positivity of screening results and follow-up recommendations in the assessment of low-dose screening CT.

To measure reader variability related to the evaluation of screening chest radiographs (CXRs) for findings of primary lung cancer.From the National Lung Screening Trial (NLST), 100 cases were randomly selected from baseline CXR examinations for retrospective interpretation by 9 NLST radiologists; images with noncalcified lung nodules (NCNs) or other abnormalities suspicious for lung cancer as determined by the original NLST reader were oversampled. Agreement on the presence of pulmonary nodules and abnormalities suspicious for cancer and recommendations for follow-up were assessed by the multirater κ statistic.The multirater κ statistic for interreader agreement on the presence of at least 1 NCN was 0.38. Rates at which readers reported the presence of at least 1 NCN ranged from 32% to 63% (mean, 41%); among 16 subjects with NCN and a cancer diagnosis within 1 year of the CXR examination, an average of 87% (range, 81% to 94%) of cases were classified as suspicious for cancer across all readers. The multirater κ for agreement on follow-up recommendations was 0.34; pairwise κ values ranged from 0.15 to 0.64 (mean, 0.36). For all subjects, readers recommended a follow-up procedure classified as high level (computed tomography, fluorodeoxyglucose-positron emission tomography, or biopsy) 42% of the time on average (range, 30% to 67%); this increased to 84% (range, 52% to 100%) when readers reported an NCN and 88% (range, 82% to 94%) for subjects with cancer.Reader agreement for screening CXR interpretation and follow-up recommendations is fair overall but is high for malignant lesions.

Purpose: To mathematically model the relationship between CT measurements of emphysema obtained from imagesreconstructed using different section thicknesses and kernels and to evaluate the accuracy of the models for converting measurements to those of a reference reconstruction. Methods: CT raw data from the lung cancer screening examinations of 138 heavy smokers were reconstructed at 15 different combinations of section thickness and kernel. An emphysema index was quantified as the percentage of the lung with attenuation below −950 HU (EI950). Linear, quadratic, and power functions were used to model the relationship between EI950 values obtained with a reference 1 mm, medium smooth kernel reconstruction and values from each of the other 14 reconstructions. Preferred models were selected using the corrected Akaike information criterion (AICc), coefficients of determination (R 2), and residuals (conversion errors), and cross-validated by a jackknife approach using the leave-one-out method. Results: The preferred models were power functions, with modelR 2 values ranging from 0.949 to 0.998. The errors in converting EI950 measurements from other reconstructions to the 1 mm, medium smooth kernel reconstruction in leave-one-out testing were less than 3.0 index percentage points for all reconstructions, and less than 1.0 index percentage point for five reconstructions. Conversion errors were related in part to imagenoise, emphysema distribution, and attenuation histogram parameters. Conversion inaccuracy related to increased kernel sharpness tended to be reduced by increased section thickness. Conclusions: Imagereconstruction-related differences in quantitative emphysema measurements were successfully modeled using power functions.

Matrix metalloprotease (MMP)-9 is an elastolytic endopeptidase produced by activated macrophages that may be involved in the development of human pulmonary emphysema and could be inhibited with existing compounds. Mouse models have demonstrated that excess MMP-9 production can result in permanent alveolar destruction.To determine if MMP-9 causes cigarette smoke-induced emphysema using MMP-9 knockout mice and human samples.Mouse lungs were analyzed for inflammation and airspace enlargement using a mainstream smoke-exposure model. Human macrophage mRNA was isolated from subjects with emphysema by laser capture microdissection. Human blood monocyte mRNA was isolated from subjects with greater than 30 pack-year smoking history. Human gene expression was determined by quantitative polymerase chain reaction and compared with emphysema severity determined by automated computed tomography analysis. Plasma Clara cell secretory protein and surfactant protein-D were quantified to measure ongoing lung injury.Mice deficient in MMP-9 develop the same degree of cigarette smoke-induced inflammation and airspace enlargement as strain-matched controls. Macrophages are the predominant source of MMP-9 production in human emphysema specimens and similar quantities of macrophage MMP-9 mRNA is present in areas of lung with and without emphysema. Circulating monocytes produce more MMP-9 in individuals with advanced emphysema severity despite no correlation of MMP-9 with markers of ongoing lung damage.These results suggest that MMP-9 in humans who smoke is similar to smoke-exposed mice, where MMP-9 is present in emphysematous lung but not correlated with the emphysema. To the degree that the mechanisms of emphysema in humans who smoke resemble the mouse model, these data suggest specific inhibition of MMP-9 is unlikely to be an effective therapy for cigarette smoke-induced emphysema. Clinical trial registered with www.clinicaltrials.gov (NCT 00757120).

The National Lung Screening Trial (NLST) is a randomized multicenter study comparing low-dose helical computed tomography (CT) with chest radiography in the screening of older current and former heavy smokers for early detection of lung cancer, which is the leading cause of cancer-related death in the United States. Five-year survival rates approach 70% with surgical resection of stage IA disease; however, more than 75% of individuals have incurable locally advanced or metastatic disease, the latter having a 5-year survival of less than 5%. It is plausible that treatment should be more effective and the likelihood of death decreased if asymptomatic lung cancer is detected through screening early enough in its preclinical phase. For these reasons, there is intense interest and intuitive appeal in lung cancer screening with low-dose CT. The use of survival as the determinant of screening effectiveness is, however, confounded by the well-described biases of lead time, length, and overdiagnosis. Despite previous attempts, no test has been shown to reduce lung cancer mortality, an endpoint that circumvents screening biases and provides a definitive measure of benefit when assessed in a randomized controlled trial that enables comparison of mortality rates between screened individuals and a control group that does not undergo the screening intervention of interest. The NLST is such a trial. The rationale for and design of the NLST are presented.

Rationale and Objectives Airway wall dimensions can be determined in vivo using transverse computed tomographic (CT) images, but the measurement of airway phantoms shows that the wall thickness is consistently overestimated for small airways. This phantom study was performed to derive and test corrections to the measurements on the basis of consideration of partial volume averaging and tilt effects. Materials and Methods A lung phantom with six polycarbonate tubes embedded in foam was scanned, and the cross-sectional dimensions of the tubes were determined using the full width at half maximum, zero crossing, and phase congruency edge detection methods. Equations were derived using the reported wall intensity to correct for partial volume averaging. Corrections for the overestimation of the wall thickness due to the tilt of the tube with respect to the CT z-axis were also derived. Results All three methods (full width at half maximum, zero crossing, and phase congruency) overestimated the wall thickness of the small polycarbonate tubes. It was verified that two sources of error were partial volume averaging and tilt that was introduced when the phantom was positioned with tube axes at an angle to the CT z-axis. The corrections were applied to the measured tube wall dimensions and substantially reduced the deviation of the CT measurements from the true values. Conclusions Correcting for partial volume effects and airway tilt greatly increases the accuracy of simulated airway wall measurements in transverse CT images.

Objective: To evaluate the use of inflation-fixed lung tissue for emphysema quantification with CT and 3He MR diffusion imaging. Methods: Fourteen subjects representing a range of chronic obstructive pulmonary disease severity who underwent complete or lobar lung resection were studied. CT measurements of lung attenuation and MR measurements of the hyperpolarized 3He apparent diffusion coefficient (ADC) in resected specimens fixed in inflation with heated formalin vapor were compared with measurements obtained before fixation. Results: The mean CT emphysema index was 56% ± 17% before and 58% ± 19% after fixation (P=0.77;R=0.76). Index differences correlated with differences in lung volume (R2=0.47). The mean 3He ADC was 0.40 ± 0.15 cm2/sec before and 0.39 ± 0.14 cm2/sec after fixation (P=0.03, R=0.98). The CT emphysema index and the 3He ADC were correlated before (R=0.89) and after fixation (R=0.79). Conclusion: Concordance of CT and 3He MR imaging measurements in unfixed and inflation-fixed lungs supports the use of inflation-fixed lungs for quantitative imaging studies in emphysema.

Rationale and Objectives Computed tomography (CT) section thickness and reconstruction kernel each influence CT measurements of emphysema. This study was performed to assess whether their effects are related to the magnitude of the measurement. Materials and Methods Low-radiation-dose multidetector CT was performed in 21 subjects representing a wide range of emphysema severity. Images were reconstructed using 20 different combinations of section thickness and reconstruction kernel. Emphysema index values were determined as the percentage of lung pixels having attenuation lower than multiple thresholds ranging from −960 HU to −890 HU. The index values obtained from the different thickness-kernel combinations were compared by repeated measures analysis of variance and Bland-Altman plots of mean versus difference in all subjects, and correlated with quantitative histology (mean linear intercept, Lm) in a subset of resected lung specimens. Results The effects of section thickness and reconstruction kernel on the emphysema index were significant ( P r = 0.55–0.68 ( P = .007–.03). Conclusion The effects of CT section thickness and kernel on emphysema index values varied systematically with the magnitude of the emphysema index. All reconstruction techniques provided significant correlations with quantitative histology.

To quantify regional gas trapping in the lung by using computed tomographic (CT)-determined specific gas volume and hyperpolarized helium 3 ((3)He) magnetic resonance (MR) imaging in a porcine model of airway obstruction.Four porcine lungs were removed after sacrifice for unrelated cardiac experiments, for which animal studies approval was obtained. Dynamic expiratory thin-section CT and (3)He MR imaging were performed during passive deflation from total lung capacity after obstructions were created with inverted one-way endobronchial exit valves in segmental or lobar bronchi to produce identifiable regions of trapped gas. Changes in specific gas volume were assessed from CT data for defined regions of interest within and outside of obstructed segments and for entire lobes. Helium 3 data were analyzed according to the corresponding regional signal reduction during expiration, compared with the total magnetic moment at each time point.In 4.5 seconds of free collapse, volume decreased by 6% +/- 2 (standard error) and 53% +/- 3, respectively, in trapped-gas lobes and in unobstructed regions (P.0001). Specific gas volume changed by 6% +/- 2 in areas of trapped gas and decreased by 56% +/- 3 in unobstructed regions, from 3.4 mL/g +/- 0.2 to 1.5 mL/g +/- 0.1 (P.0001). The (3)He signal intensity decreased by 25% +/- 6 and 71% +/- 3, respectively, in trapped-gas and normal regions (P = .0008). In unobstructed regions, the percentage decreases in specific gas volume and (3)He signal intensity were not statistically different from one another (P = .89).The results obtained from the model of gas trapping demonstrate that CT-determined specific gas volume and (3)He MR imaging can help identify and quantify the extent of regional trapped gas in explanted porcine lungs.

To characterize the effect of diffusion time on short-range hyperpolarized (3)He magnetic resonance imaging (MRI) diffusion measurements across a wide range of emphysema severity.(3)He diffusion MRI was performed on 19 lungs or lobes resected from 18 subjects with varying degrees of emphysema using three diffusion times (1.6 msec, 5 msec, and 10 msec) at constant b value. Emphysema severity was quantified as the mean apparent diffusion coefficient (ADC) and as the percentage of pixels with ADC higher than multiple thresholds from 0.30-0.55 cm(2)/sec (ADC index). Quantitative histology (mean linear intercept) was obtained in 10 of the lung specimens from 10 of the subjects.The mean ADCs with diffusion times of 1.6, 5.0, and 10.0 msec were 0.46, 0.40, and 0.37 cm(2)/sec, respectively (P0.0001, analysis of variance [ANOVA]). There was no relationship between the ADC magnitude and the effect of diffusion time on ADC values. The mean linear intercept correlated with ADC (r = 0.91-0.94, P0.001) and ADC index (r = 0.78-0.92, P0.01) at all diffusion times.Decreases in ADC with longer diffusion time were unrelated to emphysema severity. The strong correlations between the ADC at all diffusion times tested and quantitative histology demonstrate that ADC is a robust measure of emphysema.

Alveolar elastic fibres are key targets of proteases during the pathogenesis of chronic obstructive pulmonary disease (COPD). In the current study, we hypothesised that a response to injury leads to enhanced alveolar elastin gene expression in very severe COPD. Lung samples obtained from 43 patients, including 11 with very severe COPD (stage 4), 10 donors, 10 with moderate/severe COPD (stage 2-3) and 12 non-COPD subjects, were analysed for elastin mRNA expression by real-time RT-PCR and in situ hybridisation. Alveolar elastic fibres were visualised using Hart's staining of sections of frozen inflated lungs obtained from 11 COPD stage 4 patients and three donor lungs. Compared with donors, non-COPD and stage 2-3 COPD, elastin mRNA expression was significantly increased in very severe COPD lungs (12-fold change), and localised in situ hybridisation induced elastin expression to alveolar walls. Compared with donors, alveolar elastic fibres also comprised a greater volume fraction of total lung tissue in very severe COPD lungs (p

Oxidative stress is a key element in the pathogenesis of emphysema, but oxidation of nucleic acids has been largely overlooked. The aim of this study was to investigate oxidative damage to nucleic acids in severe emphysematous lungs.Thirteen human severe emphysematous lungs, including five with alpha(1)-antitrypsin deficiency (AATD), were obtained from patients receiving lung transplantation. Control lung tissue was obtained from non-COPD lungs (n = 8) and donor lungs (n = 8). DNA and RNA oxidation were investigated by immunochemistry. Morphometry (mean linear intercept [Lm] and CT scan) and immunostaining for CD68 and neutrophil elastase also were performed.Nucleic acid oxidation was increased in alveolar wall cells in emphysematous lungs compared to non-COPD and donor lungs (p0.01). In emphysematous lungs, oxidative damage to nucleic acids in alveolar wall cells was increased in the more severe emphysematous areas assessed by histology (Lm,0.5 mm; p0.05) and CT scan (-950 Hounsfield units; p0.05). Compared to classic emphysema, AATD lungs exhibited higher levels of nucleic acid oxidation in macrophages (p0.05) and airway epithelial cells (p0.01). Pretreatments with DNase and RNase demonstrated that RNA oxidation was more prevalent than DNA oxidation in alveolar wall cells.We demonstrated for the first time that nucleic acids, especially RNA, are oxidized in human emphysematous lungs. The correlation between the levels of oxidative damage to nucleic acids in alveolar wall cells and the severity of emphysema suggest a potential role in the pathogenesis of emphysema.

The purpose of our study was to evaluate the performance of a computer-aided program that performs automated matching of pulmonary nodules imaged in three serial screening chest MDCT studies.Forty subjects with pulmonary nodules depicted in three annual (T0, T1, T2) low-dose MDCT screening studies for lung cancer were selected from the National Lung Screening Trial database at a single institution. All CT images were reevaluated by two radiologists in consensus. One hundred forty-three nodules were identified and characterized by type (solid parenchymal, juxtavascular, juxtapleural, and ground-glass opacity) and size (or = 4 mm, 4-6 mm, 6-8 mm, and8 mm). Using an automated program, nodules at T0 were matched to nodules at T1, and the same nodules at T1 were matched to nodules at T2. Associations between nodule matching rate (i.e., number of nodules matched by the program divided by the number of nodules determined to match by radiologists) and nodule type or size were analyzed.The combined matching rate of the nodules was 92.7% (T0 vs T1, 91.6%; T1 vs T2, 93.7%). By nodule type, the matching rate was 94.6% (parenchymal), 98.4% (juxtavascular), 85.8% (juxtapleural), and 100% (ground-glass opacity), with the rate significantly lower for juxtapleural nodules (p0.01). Matching rates were not significantly influenced by nodule size (p = 0.67).The automated matching rate for pulmonary nodules in screening MDCT scans was high (92.7%) and was not affected by the nodule size but was slightly lower with nodules at juxtapleural locations.

Objective Widespread application of computed tomographic scans has increased detection of asymptomatic pulmonary nodules. A dedicated clinic was established to encourage referral and manage large numbers of patients with such nodules. Methods Patients were evaluated periodically by a nurse practitioner with surgeon oversight, and follow-up imaging was centralized. Patients were rescanned at intervals on the basis of radiologist recommendation. Results A total of 414 patients, 189 male and 225 female with a median age of 60.2 years (20.7–84.1 years), were evaluated since April 2000. Median follow-up was 1.51 years (0–6.65 years). Thirty-seven percent (153/414) were older than 60 years with at least 10 pack-years of tobacco use, whereas 30% (123/414) had never smoked. A total of 286 patients completed at least 2 years of follow-up computed tomographic evaluation. After 2 years, 24.2% (69/286) were deemed in stable condition and were discharged from further follow-up, whereas 22.4% (64/286) of patients were followed up longer than 2 years owing to the development of new nodules. Forty-five percent (127/286) of patients did not complete their recommended follow-up at our clinic. Overall, 3% (13/414) of our patients have been shown to have a malignant tumor. Only 5 patients underwent curative resection of a primary lung cancer. Conclusion In a population of patients with indeterminate nodules in routine clinical practice, few patients required intervention and few cancers were detected. Although the benefits of a "nodule" clinic may include patient reassurance and convenience to referring physicians, a significant number of patients did not complete their follow-up in our clinic.

From 2002-2004, the Lung Screening Study (LSS) of the National Lung Screening Trial (NLST) enrolled 34,614 participants, aged 55-74 years, at increased risk for lung cancer due to heavy cigarette smoking. Participants, randomized to standard chest X-ray (CXR) or computed tomography (CT) arms at ten screening centers, received up to three imaging screens for lung cancer at annual intervals. Participant medical histories and radiologist-interpreted screening results were transmitted to the LSS coordinating center, while all images were retained at local screening centers. From 2005-2007, all CT exams were uniformly de-identified and delivered to a central repository, the CT Image Library (CTIL), on external hard drives (94%) or CD/DVD (5.9%), or over a secure Internet connection (0.1%). Of 48,723 CT screens performed, only 176 (0.3%) were unavailable (lost, corrupted, compressed) while 48,547 (99.7%) were delivered to the CTIL. Described here is the experience organizing, implementing, and adapting the clinical-trial workflow surrounding the image retrieval, de-identification, delivery, and archiving of available LSS-NLST CT exams for the CTIL, together with the quality assurance procedures associated with those collection tasks. This collection of CT exams, obtained in a specific, well-defined participant population under a common protocol at evenly spaced intervals, and its attending demographic and clinical information, are now available to lung-disease investigators and developers of computer-aided-diagnosis algorithms. The approach to large scale, multi-center trial CT image collection detailed here may serve as a useful model, while the experience reported should be valuable in the planning and execution of future equivalent endeavors.

Rationale and Objectives The hyperpolarized 3 He long-range diffusion coefficient (LRDC) in lungs is sensitive to changes in lung structure due to emphysema, reflecting the increase in collateral paths resulting from tissue destruction. However, no clear understanding of LRDC in healthy lungs has emerged. Here we compare LRDC measured in healthy lungs with computer simulations of diffusion along the airway tree with no collateral connections. Materials and Methods Computer simulations of diffusion of spatially modulated spin magnetization were performed in computer-generated, symmetric-branching models of lungs and compared with existing LRDC measurements in canine and human lungs. Results The simulations predict LRDC values of order 0.001 cm 2 /sec, approximately 20 times smaller than the measured LRDC. We consider and rule out possible mechanisms for LRDC not included in the simulations: incomplete breath hold, cardiac motion, and passage of dissolved 3 He through airway walls. However, a very low density of small (micron) holes in the airways is shown to account for the observed LRDC. Conclusion It is proposed that LRDC in healthy lungs is determined by small collateral pathways.

To evaluate agreement among radiologists on the interpretation of pulmonary findings at low-dose computed tomographic (CT) screening examinations for lung cancer.Institutional review board approval and informed consent were obtained. HIPAA guidelines were followed. Sixteen radiologists from the 10 National Lung Screening Trial screening centers of the National Cancer Institute's Lung Screening Study network reviewed image subsets from 135 baseline low-dose screening CT examinations in 135 trial participants (89 men, 46 women; mean age, 62.7 years +/- 5.4 [standard deviation]). Interpretations were classified into one of four of the following categories: noncalcified nodule 4 mm or larger in greatest transverse dimension (positive screening result); noncalcified nodule smaller than 4 mm in greatest transverse dimension (negative screening result); calcified, benign nodule (negative screening result); or no nodule (negative screening result). A recommendation for follow-up evaluation was obtained for each case. Interobserver agreement was evaluated by using the multirater kappa statistic and by using response frequencies and descriptive statistics.Multirater kappa values ranged from 0.58 (for agreement among all four classifications; 95% confidence interval: 0.55, 0.61) to 0.64 (for agreement on classification as a positive or negative screening result; 95% confidence interval: 0.62, 0.65). The average percentage of reader pairs in agreement on the screening result per case (percentage agreement) was 82%. There was wide variation in the total number of abnormalities detected and classified as pulmonary nodules, with differences of up to more than twofold among radiologists. For cases classified as positive, multirater kappa for follow-up recommendations was 0.35.Interobserver agreement was moderate to substantial; potential for considerable improvement exists. Clinical trial registration no. NCT00047385.