Search

Purpose: To evaluate cystic fibrosis (CF) subjects over 4 years using (3) He magnetic resonance imaging (MRI), pulmonary function tests, and track hospitalization and physician visits., Materials and Methods: Five CF adults provided written informed consent to an approved protocol and underwent MRI, spirometry, and plethysmography at baseline, 7 days, and 4 ± 1 years later. (3) He MRI ventilation defect percent (VDP) was generated for all subjects and timepoints., Results: After 4 years, mean forced expiratory volume in 1 second / forced vital capacity (FEV1 /FVC) was lower (P = 0.01) in all subjects and there were no other pulmonary function test changes. Two CF adults showed significantly elevated (worse) (3) He VDP at baseline and after 4 years they had significantly greater (worsened) VDP (P = 0.02), without a significant FEV1 decline (P = 0.06) but with a greater number of exacerbations (P < 0.05). Baseline VDP strongly correlated with FEV1 (r(2)  = 0.98, P = 0.0007) at 4-year follow-up., Conclusion: For two CF subjects, VDP was significantly worse at baseline and worsened over 4 years, which was in agreement with a greater number of hospitalizations and clinic visits. These results are limited by the very small sample size, but the strong VDP correlation with longitudinal changes in FEV1 generates the hypothesis that abnormal VDP may temporally precede FEV1 decline in CF subjects; this must be tested in a larger CF study., (© 2014 Wiley Periodicals, Inc.)

Objective: In this prospectively planned interim-analysis, the prevalence of chronic obstructive lung disease (COPD) phenotypes was determined using magnetic resonance imaging (MRI) and X-ray computed tomography (CT) in non-small-cell-lung-cancer (NSCLC) patients., Materials and Methods: Stage-III-NSCLC patients provided written informed consent for pulmonary function tests, imaging and the 6-min-walk-test. Ventilation defect percent (VDP) and CT lung density (relative-of-CT-density-histogram <-950, RA950) were measured. Patients were classified into three subgroups based on qualitative and quantitative COPD and tumour-specific imaging phenotypes: (1) tumour-specific ventilation defects (TSD), (2) tumour-specific and other ventilation defects without emphysema (TSDV), and, (3) tumour-specific and other ventilation defects with emphysema (TSDVE)., Results: Seventeen stage-III NSCLC patients were evaluated (68 ± 7 years, 7 M/10 F, mean FEV1 = 77%pred) including seven current and 10 ex-smokers and eight patients with a prior lung disease diagnosis. There was a significant difference for smoking history (p = .02) and FEV1/FVC (p = .04) for subgroups classified using quantitative imaging. Patient subgroups classified using qualitative imaging findings were significantly different for emphysema (RA950, p < .001). There were significant relationships for whole-lung VDP (p < .05), but not RECIST or tumour-lobe VDP measurements with pulmonary function and exercise measurements. Preliminary analysis for non-tumour burden ventilation abnormalities using Reader-operator-characteristic (ROC) curves reflected a 94% classification rate for smoking pack-years, 93% for FEV1/FVC and 82% for RA950. ROC sensitivity/specificity/positive/negative likelihood ratios were also generated for pack-years, (0.92/0.80/4.6/0.3), FEV1/FVC (0.92/0.80/4.6/0.3), RA950 (0.92/0.80/4.6/0.3) and RECIST (0.58/0.80/2.9/1.1)., Conclusions: In this prospectively planned interim-analysis of a larger clinical trial, NSCLC patients were classified based on COPD imaging phenotypes. A proof-of-concept evaluation showed that FEV1/FVC and smoking history identified NSCLC patients with ventilation abnormalities appropriate for functional lung avoidance radiotherapy.

Background: To evaluate ultra-short-echo-time (UTE) MRI pulmonary signal-intensity measurements and reproducibility in chronic obstructive pulmonary disease (COPD)., Methods: A two-dimensional sequence (echo-time = 0.05 ms; acquisition-time = 13 s) with interleaved half-pulse excitation and radial ramp-sampling was used with compressed-sensing to reconstruct UTE images from under-sampled data. Five healthy volunteers and 15 subjects with COPD provided written informed consent to imaging and pulmonary-function-tests. Healthy volunteers underwent MRI at four lung volumes: full-expiration, functional-residual-capacity (FRC), FRC+1L, and full-inhalation; COPD patients underwent computed-tomography (CT) and MRI at FRC+1L. Three-week reproducibility was evaluated and the relative area of the density histogram ≤ -950 HU (RA950 ) was compared with mean MRI signal-intensity. The 15th percentile of signal-intensity-histogram (SI15 ) was compared with the 15th percentile of the CT-density-histogram (HU15 )., Results: In healthy subjects, signal-intensity correlated with the inverse of lung volume (r = 0.99; P = 0.007). Contrast-to-noise and signal-to-noise ratios were significantly improved for 32-channel UTE (P < 0.01). The coefficient of variation for 3-week repeated measurements was 4%. There were significant correlations for signal-intensity with RA950 (r = -0.71; P = 0.005), FEV1 /FVC (r = 0.59; P = 0.02), and for SI15 with HU15 (r = 0.62; P = 0.01)., Conclusion: Pulmonary signal-intensity is reproducible and related to tissue density. In COPD subjects with and without bronchiectasis, signal-intensity was also related to pulmonary function and CT measurements., (© 2014 Wiley Periodicals, Inc.)

Rationale and Objectives: In this proof-of-concept demonstration, we aimed to quantitatively and qualitatively compare pulmonary ventilation abnormalities derived from Fourier decomposition of free-breathing (1)H magnetic resonance imaging (FDMRI) to hyperpolarized (3)He MRI in subjects with chronic obstructive pulmonary disease (COPD) and bronchiectasis., Materials and Methods: All subjects provided written informed consent to a protocol approved by a local research ethics board and Health, Canada, and they underwent MRI, computed tomography (CT), spirometry, and plethysmography during a single 2-hour visit. Semiautomated segmentation was used to generate ventilation defect measurements derived from FDMRI and (3)He MRI, and these were compared using analysis of variance and Pearson correlations., Results: Twenty-six subjects were evaluated including 12 COPD subjects (67 ± 9 years) and 14 bronchiectasis subjects (70 ± 11 years). For COPD subjects, FDMRI and (3)He MRI ventilation defect percent (VDP) was 7 ± 6% and 24 ± 14%, respectively (P < .001; bias = -16 ± 9%). In COPD subjects, FDMRI was significantly correlated with (3)He MRI VDP (r = .88; P = .0001), (3)He MRI apparent diffusion coefficient (r = .71; P < .05), airways resistance (r = .60; P < .05), and RA950 (r = .80; P < .01). In subjects with bronchiectasis, FDMRI VDP (5 ± 3%) and (3)He MRI VDP (18 ± 9%) were significantly different (P < .001) and not correlated (P > .05). The Dice similarity coefficient (DSC) for FDMRI and (3)He MRI ventilation was 86 ± 7% for COPD and 86 ± 4% for bronchiectasis subjects (P > .05); the DSC for FDMRI ventilation defects and CT RA950 was 19 ± 20% in COPD and 2 ± 3% in bronchiectasis subjects (P < .01)., Conclusions: FDMRI and (3)He MRI VDP were strongly related in COPD but not in bronchiectasis subjects. In COPD only, FDMRI ventilation defects were spatially related with (3)He ventilation defects and emphysema., (Copyright © 2015 AUR. Published by Elsevier Inc. All rights reserved.)

Congenital lobar emphysema is mainly diagnosed in infants, although rare cases are reported in adults. A 20-yr-old female with acute dyspnea, chest pain and left upper lobe (LUL) chest x-ray hyperlucency underwent 3He magnetic resonance imaging (MRI) for ventilation and apparent diffusion coefficient (ADC) measurements, as well as CT for emphysema and airway wall measurements. Forced expiratory volume in 1s, residual volume, and airways-resistance were abnormal, but there was normal carbon-monoxide-diffusing-capacity. The LUL relative area of the density histogram <-950 HU and airway morphology were highly abnormal compared with the other lobes and coincident with highly abnormal MRI-derived acinar duct dimensions. CT also identified bronchial atresia and congenital lobar emphysema as the source of symptoms in this case where there was also functional imaging evidence of collateral ventilation from the fissure (and not the abnormally terminated airway) into the emphysematous LUL.

It is well-established that COPD patients have a burden of vascular disease that cannot be fully-explained by smoking history but the mechanistic links between atherosclerosis and pulmonary disease in COPD patients are not well-understood. Moreover, in ex-smokers without symptoms or other evidence of COPD, subclinical pulmonary and vascular disease, although potentially present, has not been described or evaluated. Hence our aim was to use sensitive three-dimensional (3D) pulmonary and carotid imaging to quantify pulmonary airway/parenchyma abnormalities and atherosclerosis in ex-smokers without airflow limitation or symptoms consistent with COPD. We evaluated 61 subjects without airflow limitation including 34 never- (72 ± 6 years) and 27 ex-smokers (73 ± 9 years), who provided written informed consent to spirometry, plethysmography, (3)He magnetic resonance imaging (MRI) and carotid ultrasound (US) and, for ex-smokers alone, thoracic X-ray computed tomography (CT). Ex-smokers had significantly greater (3)He ventilation defect percent (VDP = 7%, p = 0.001) and carotid total plaque volume (TPV = 250 mm(3), p = 0.002) than never-smokers, although there were no significant differences for spirometry or plethysmography, and CT airway and emphysema measurements were normal. There were univariate relationships for (3)He VDP with carotid intima media thickness (IMT, r = 0.42, p = 0.004), TPV (r = 0.41, p = 0.006) and vessel wall volume (VWV, r = 0.40, p = 0.007). Multivariate models that included age, BMI, FEV1, DLCO and VDP showed that only VDP significantly predicted IMT (β = 0.41, p = 0.001), VWV (β = 0.45, p = 0.003) and TPV (β = 0.38, p = 0.005). In summary, there was imaging evidence of mild airways disease and carotid plaque burden that were related and significantly greater in ex-smokers without airflow limitation than in never-smokers.

Background: Although radiotherapy is a key component of curative-intent treatment for locally advanced, unresectable non-small cell lung cancer (NSCLC), it can be associated with substantial pulmonary toxicity in some patients. Current radiotherapy planning techniques aim to minimize the radiation dose to the lungs, without accounting for regional variations in lung function. Many patients, particularly smokers, can have substantial regional differences in pulmonary ventilation patterns, and it has been hypothesized that preferential avoidance of functional lung during radiotherapy may reduce toxicity. Although several investigators have shown that functional lung can be identified using advanced imaging techniques and/or demonstrated the feasibility and theoretical advantages of avoiding functional lung during radiotherapy, to our knowledge this premise has never been tested via a prospective randomized clinical trial., Methods/design: Eligible patients will have Stage III NSCLC with intent to receive concurrent chemoradiotherapy (CRT). Every patient will undergo a pre-treatment functional lung imaging study using hyperpolarized 3He MRI in order to identify the spatial distribution of normally-ventilated lung. Before randomization, two clinically-approved radiotherapy plans will be devised for all patients on trial, termed standard and avoidance. The standard plan will be designed without reference to the functional state of the lung, while the avoidance plan will be optimized such that dose to functional lung is as low as reasonably achievable. Patients will then be randomized in a 1:1 ratio to receive either the standard or the avoidance plan, with both the physician and the patient blinded to the randomization results. This study aims to accrue a total of 64 patients within two years. The primary endpoint will be a pulmonary quality of life (QOL) assessment at 3 months post-treatment, measured using the functional assessment of cancer therapy-lung cancer subscale. Secondary endpoints include: pulmonary QOL at other time-points, provider-reported toxicity, overall survival, progression-free survival, and quality-adjusted survival., Discussion: This randomized, double-blind trial will comprehensively assess the impact of functional lung avoidance on pulmonary toxicity and quality of life in patients receiving concurrent CRT for locally advanced NSCLC., Trial Registration: Clinicaltrials.gov identifier: NCT02002052.

Purpose: To evaluate the predictive value of imaging and clinical and physiological measurements of chronic obstructive pulmonary disease ( COPD chronic obstructive pulmonary disease ) in patients monitored for more than 5 years for pulmonary exacerbations that required hospitalization., Materials and Methods: Exacerbations requiring hospitalization were monitored over 5 years in 91 subjects who provided written informed consent. Study was local research ethics board and Health Canada approved and HIPAA compliant. Subjects with COPD chronic obstructive pulmonary disease underwent spirometry, plethysmography, diffusing capacity of carbon monoxide, St George's Respiratory Questionnaire, 6-minute walk test, and imaging. Computed tomographic (CT) wall area and relative area with attenuation values less than -950 HU ( RA950 relative area with attenuation values less than -950 HU ), helium 3 ((3)He) magnetic resonance (MR) imaging ventilation defect percentage ( VDP ventilation defect percentage ), and apparent diffusion coefficient were generated. Zero-inflated Poisson model was used to compare number of hospitalizations with lung function and imaging measurements., Results: Twenty-four subjects were hospitalized 58 times and had significantly worse forced expiratory volume in 1 second ( FEV1 forced expiratory volume in 1 second ) (P < .0001), CT RA950 relative area with attenuation values less than -950 HU (P = .02), and (3)He VDP ventilation defect percentage (P < .0001) than values in 67 subjects who were not hospitalized. In mild to moderate COPD chronic obstructive pulmonary disease , nine hospitalized subjects had significantly worse FEV1 forced expiratory volume in 1 second (P = .02) and (3)He VDP ventilation defect percentage (P = .02) than values in 52 subjects who were not hospitalized. (3)He VDP ventilation defect percentage was quantitatively related to CT airway morphology (r = 0.26, P = .01) and quantitatively (r = 0.61, P < .0001) and spatially related to emphysema; this spatial relationship was significantly greater for hospitalized patients with COPD chronic obstructive pulmonary disease than unhospitalized patients (P = .0006). For all subjects, number of prior hospitalizations (P < .0001), 6-minute walk test distance (P < .0001), CT RA950 relative area with attenuation values less than -950 HU (P = .03), and (3)He VDP ventilation defect percentage (P = .002) were significantly related to number of hospitalizations. For 61 subjects with mild to moderate COPD chronic obstructive pulmonary disease , only (3)He VDP ventilation defect percentage was significantly associated with COPD chronic obstructive pulmonary disease exacerbations (P = .01)., Conclusion: (3)He MR imaging VDP ventilation defect percentage represents a mixed airways-emphysema phenotype and helps identify subjects with mild to moderate COPD chronic obstructive pulmonary disease who are at risk for exacerbation that requires hospitalization., (© RSNA, 2014.)

Rationale and Objectives: Hyperpolarized (3)He magnetic resonance imaging (MRI) previously revealed the temporal and spatial heterogeneity of ventilation defects in asthmatics, but these findings have not been used in treatment studies or to guide personalized therapy. Our objective was to exploit the temporal and spatial information inherent to (3)He MRI and develop image processing methods to generate pulmonary ventilation temporal-spatial maps that could be used to measure, optimize, and guide asthma therapy., Materials and Methods: In this proof-of-concept study, seven asthmatics provided written informed consent to an approved protocol and underwent spirometry and (3)He MRI on three occasions, each 5 ± 2 days apart. A registration and segmentation pipeline was developed to generate three-dimensional, temporal-spatial, pulmonary function maps. Briefly, (3)He ventilation images were segmented to generate ventilation masks that were coregistered and voxels classified according to their temporal behavior. This enabled the regional mapping of temporally persistent and intermittent ventilation defects that were normalized to the (1)H MRI thoracic cavity volume to generate persistent ventilation defect percent (VDPP) and intermittent ventilation defect percent (VDPI)., Results: (3)He temporal-spatial pulmonary function maps identified temporally persistent and intermittent ventilation defects. VDP(I) was significantly greater in the posterior (P = .04) and inferior (P = .04) lung as compared to the anterior and superior lung. Persistent and intermittent ventilation defect percent were strongly correlated with forced expiratory volume in one second/forced vital capacity (VDP(P): r = -0.87, P = .01; VDP(I): r = -0.96, P = .0008)., Conclusions: Temporal-spatial pulmonary maps generated from (3)He MRI can be used to quantify temporally persistent and intermittent ventilation defects as asthma intermediate end points and targets for therapy., (Copyright © 2014 AUR. Published by Elsevier Inc. All rights reserved.)

Although the human and societal burden and cost of COPD is staggering, there are few clinical tools that provide earlier diagnoses or a means to regionally monitor disease in a way that might lead to improved therapies and outcomes. In acknowledgement of the current gaps in COPD therapy, the objective of the Thoracic Imaging Network of Canada (TINCan) is to improve COPD patient phenotyping through imaging, to provide methods and imaging-based intermediate endpoints for the development of new treatments, and to evaluate disease progression and patient-based outcomes in COPD patients and those at risk of COPD. Here we summarize and outline the TINCan study protocol and describe our objectives. TINCan is a prospective study that aims to identify and quantify novel COPD phenotypes from thoracic computed tomography (CT) and thoracic hyperpolarized noble gas magnetic resonance imaging (MRI) in 200 ex-smokers, 50 years of age or greater, including asymptomatic ex-smokers with normal pulmonary function and Global initiative for chronic Obstructive Lung Disease (GOLD) Unclassified (U) , and GOLD stages I-IV patients. Baseline and 2-year follow-up measurements will be acquired using spirometry, plethysmography, diffusing capacity of the lung for carbon monoxide (DL CO ), St. George's Respiratory Questionnaire (SGRQ), 6-minute walk test (6MWT), thoracic CT and hyperpolarized helium-3 ( 3 He) and xenon 129 ( 129 Xe) MRI. TINCan provides a unique opportunity to quantify and compare novel lung structure-function measurements and investigate their relationship with well-established clinical measurements and outcomes. Such intermediate endpoints of COPD may be used to stratify patients for personalized treatments and to develop new treatments to improve outcomes, a long-standing clinical goal., Competing Interests: M. Kirby gratefully acknowledges support from the Canadian Institute of Health Research (CIHR) Bisby Post-doctoral Scholarship, the CIHR Integrated and Mentored Pulmonary and Cardiovascular Training program (IMPACT) and the Michael Smith Foundation for Health Research. D. D Sin holds a Tier 1 Canada Research Chair in COPD. H.O. Coxson is supported by a Roberta R. Miller Fellowship in Thoracic Imaging from the British Columbia Lung Association and a service contract with GlaxoSmithKline Inc. for the quantitative analysis of CT data not related to this study. G. Parraga gratefully acknowledges support from a CIHR New Investigator Award. Ongoing research funding from CIHR Team Grant CIF# 97687 (Thoracic Imaging Network of Canada, TINCan) and support from the Canadian Respiratory Research Network (CRRN), also funded by CIHR, is gratefully acknowledged. The authors are solely responsible for the writing of this article and none have conflicts in relation to the study described here.

Background and Purpose: Carotid ultrasound atherosclerosis measurements, including those of the arterial wall and plaque, provide a way to monitor patients at risk of vascular events. Our objective was to examine carotid ultrasound plaque texture measurements and the change in carotid plaque texture during 1 year in patients at risk of events and to compare these with measurements of plaque volume and other risk factors as predictors of vascular events., Methods: We evaluated 298 patients with carotid atherosclerosis using 3-dimensional (3D) ultrasound at baseline and after 1 year and measured carotid plaque volume and 376 measures of plaque texture. Patients were followed up to 5 years (median [range], 3.12 [0.77-4.66]) for myocardial infarction, transient ischemic attack, and stroke. Sparse Cox regression was used to select the most predictive plaque texture measurements in independent training sets using a 10-fold cross-validation, repeated 5×, to ensure unbiased results., Results: Receiver operator curves and Kaplan-Meier analysis showed that changes in texture and total plaque volume combined provided the best predictor of vascular events. In multivariate Cox regression, changes in plaque texture (median hazard ratio, 1.4; P<0.001) and total plaque volume (median hazard ratio, 1.5 per 100 mm(3); P<0.001) were both significant predictors, whereas the Framingham risk score was not., Conclusions: Changes in both plaque texture and volume are strongly predictive of vascular events. In high-risk patients, 3D ultrasound plaque measurements should be considered for vascular event risk prediction., (© 2014 American Heart Association, Inc.)

Hyperpolarized (3)He MRI previously revealed spatially persistent ventilation defects in healthy, older compared with healthy, younger never-smokers. To understand better the physiological consequences and potential relevance of (3)He MRI ventilation defects, we evaluated (3)He-MRI ventilation-defect percent (VDP) and the effect of deep inspiration (DI) and salbutamol on VDP in older never-smokers. To identify the potential determinants of ventilation defects in these subjects, we evaluated dyspnea, pulmonary function, and cardiopulmonary exercise test (CPET) measurements, as well as occupational and second-hand smoke exposure. Fifty-two never-smokers (71 ± 6 yr) with no history of chronic respiratory disease were evaluated. During a single visit, pulmonary function tests, CPET, and (3)He MRI were performed and the Burden of Obstructive Lung Disease questionnaire administered. For eight of 52 subjects, there was spirometry evidence of airflow limitation (Global Initiative for Chronic Obstructive Lung Disease-Unclassified, I, and II), and occupational exposure was reported in 13 of 52 subjects. In 13 of 52 (25%) subjects, there were no ventilation defects and in 39 of 52 (75%) subjects, ventilation defects were observed. For those subjects with ventilation defects, six of 39 showed a VDP response to DI/salbutamol. Ventilation heterogeneity and VDP were significantly greater, and forced expiratory volume in 1 s (FEV1)/forced vital capacity was significantly lower (P < 0.05) for subjects with ventilation defects with a response to DI/salbutamol than subjects with ventilation defects without a response to DI/salbutamol and subjects without ventilation defects. In a step-wise, forward multivariate model, FEV1, inspiratory capacity, and airway resistance significantly predicted VDP (R(2) = 0.45, P < 0.001). In conclusion, most never-smokers had normal spirometry and peripheral ventilation defects not reversed by DI/salbutamol; such ventilation defects were likely related to irreversible airway narrowing/collapse but not to dyspnea and decreased exercise capacity., (Copyright © 2014 the American Physiological Society.)

Noble gas pulmonary magnetic resonance imaging (MRI) is transitioning away from (3)He to (129)Xe gas, but the physiological/clinical relevance of (129)Xe apparent diffusion coefficient (ADC) parenchyma measurements is not well understood. Therefore, our objective was to generate (129)Xe MRI ADC for comparison with (3)He ADC and with well-established measurements of alveolar structure and function in older never-smokers and ex-smokers with chronic obstructive pulmonary disease (COPD). In four never-smokers and 10 COPD ex-smokers, (3)He (b = 1.6 sec/cm(2)) and (129)Xe (b = 12, 20, and 30 sec/cm(2)) ADC, computed tomography (CT) density-threshold measurements, and the diffusing capacity for carbon monoxide (DLCO) were measured. To understand regional differences, the anterior-posterior (APG) and superior-inferior (∆SI) ADC differences were evaluated. Compared to never-smokers, COPD ex-smokers showed greater (3)He ADC (P = 0.006), (129)Xe ADCb12 (P = 0.006), and ADCb20 (P = 0.006), but not for ADCb30 (P > 0.05). Never-smokers and COPD ex-smokers had significantly different APG for (3)He ADC (P = 0.02), (129)Xe ADCb12 (P = 0.006), and ADCb20 (P = 0.01), but not for ADCb30 (P > 0.05). ∆SI for never- and ex-smokers was significantly different for (3)He ADC (P = 0.046), but not for (129)Xe ADC (P > 0.05). There were strong correlations for DLCO with (3)He ADC and (129)Xe ADCb12 (both r = -0.95, P < 0.05); in a multivariate model (129)Xe ADCb12 was the only significant predictor of DLCO (P = 0.049). For COPD ex-smokers, CT relative area <-950 HU (RA950) correlated with (3)He ADC (r = 0.90, P = 0.008) and (129)Xe ADCb12 (r = 0.85, P = 0.03). In conclusion, while (129)Xe ADCb30 may be appropriate for evaluating subclinical or mild emphysema, in this small group of never-smokers and ex-smokers with moderate-to-severe emphysema, (129)Xe ADCb12 provided a physiologically appropriate estimate of gas exchange abnormalities and alveolar microstructure., (© 2014 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.)

FEV1, measured using spirometry, provides a straightforward, widely available, and inexpensive global measurement of airflow limitation and lung function. For decades, FEV1 has remained the main intermediate endpoint used in research studies and for the development of new chronic obstructive pulmonary disease (COPD) therapies. Not surprisingly, treatments that acutely improve FEV1 dominate as COPD therapies. However, in patients with COPD, the relationship of FEV1 with symptoms and outcomes such as exacerbations and mortality is weak, and, importantly, FEV1 does not take into account the heterogeneity of COPD or its different phenotypes. Thoracic imaging provides a way to quantify airway remodeling, emphysematous destruction, regional ventilation abnormalities (ventilation defects), and gas trapping in ex-smokers in whom FEV1 may be normal and in patients with COPD with very modest lung function deterioration. In individual patients and in COPD cohort studies, thoracic imaging using X-ray computed tomography, and magnetic resonance imaging (conventional (1)H as well as hyperpolarized noble gases such as (129)Xe, (3)He, and inhaled O2 and (19)F) can be used to directly visualize the structural and functional consequences of COPD and thus provide a clearer picture of COPD mechanisms, disease progression, and response to therapy. We briefly describe pulmonary imaging methods that provide a way to visualize and quantify, with high spatial and temporal resolution, regional ventilation abnormalities, gas trapping, emphysema, and airway remodeling in COPD. Finally, we discuss the implications of recent imaging findings and their impact on future biomarker and therapy research aimed at improving COPD outcomes.

Background and Purpose: Previous studies have shown the presence of ulceration in atherosclerotic plaque either by categorizing the plaque as complex (irregular morphology with ulcers) or smooth or by quantifying the number of ulcers observed in a specific region of interest. The aim of this study was to quantify carotid total ulcer volume by 3-dimensional ultrasound to investigate the relationship of total ulcer volume to vascular events (strokes, transient ischemic attack, myocardial infarction, revascularization, or death because of cardiovascular reasons)., Methods: In total, 349 at-risk subjects provided written informed consent to carotid 3-dimensional ultrasound and were analyzed for ulcerations. Ulcer volume was defined as a distinct discontinuity in an atherosclerotic plaque, with a volume≥1.00 mm3 as measured using manual segmentation. The sum of the volumes of all ulcers seen in both carotids was the total ulcer volume. Participants were monitored for ≤5 years for outcomes, including cardiovascular events and death., Results: Kaplan-Meier survival analysis showed that subjects with total ulcer volume≥5 mm3 experienced a significantly higher risk of developing stroke, transient ischemic attack, or death (P=0.009) and of developing stroke/transient ischemic attack/death/myocardial infarction/revascularization (P=0.017). Lower ulcer volumes did not predict events nor did ulcer depth., Conclusions: Volume of carotid ulceration on 3-dimensional ultrasound predicts cardiovascular events. In addition to improving risk stratification, ulceration is a potential therapeutic target.

Background: Hyperpolarised (3)He MRI provides a way to visualise regional pulmonary functional abnormalities that in asthma are thought to be related to airway morphological abnormalities. However, the exact aetiology of ventilation defects in asthma is not well understood., Objective: To better understand the determinants of ventilation defects in asthma, we evaluated well-established clinical as well as (3)He MRI and X-ray CT airway measurements in healthy subjects and subjects with asthma., Methods: Thirty-four subjects (n=26 subjects with asthma, n=8 healthy volunteers) underwent MRI, spirometry, plethysmography, fraction of exhaled nitric oxide analysis, methacholine challenge and CT for a region-of-interest proximal to ventilation defects. For subjects who consented to CT (n=18 subjects with asthma, n=5 healthy volunteers), we evaluated 3(rd) to 5th generation airway wall area and wall thickness per cent and lumen area., Results: Seventeen subjects with asthma (17/26=65%) had visually obvious evidence of (3)He ventilation defects prior to bronchoprovocation and nine subjects with asthma had no ventilation defects prior to bronchoprovocation (9/26=35%). Subjects with asthma with defects were older (p=0.01) with worse forced expiratory volume in 1 s (FEV1)/forced vital capacity (p=0.0003), airways resistance (p=0.004), fraction of exhaled nitric oxide (p=0.03), greater bronchoprovocation concentration of methacholine that reduced FEV1 by 20% (p=0.008) and wall thickness per cent (p=0.02) compared with subjects with asthma without defects. There was a moderate correlation for wall area per cent with ventilation defect per cent (r=0.43, p=0.04)., Conclusions: Subjects with asthma with (3)He ventilation defects were older with significantly worse airway hyper-responsiveness, inflammation and airway remodelling but similar FEV1 as subjects with asthma without defects; hyperpolarised (3)He ventilation abnormalities were spatially and quantitatively related to abnormally remodelled airways.

Objective: The aim of this study was to quantitatively evaluate the relationship between short echo time pulmonary (1)H magnetic resonance imaging (MRI) signal intensity (SI) and (3)He MRI apparent diffusion coefficients (ADC), high-resolution computed tomography (CT) measurements of emphysema, and pulmonary function measurements., Materials and Methods: Nine healthy never-smokers and 11 COPD subjects underwent same-day plethysmography, spirometry, short echo time ((TE)=1.2ms) (1)H and diffusion-weighted hyperpolarized (3)He MRI (b=1.6s/cm(2)) at 3.0T. In addition, for COPD subjects only, CT densitometry was also performed., Results: Mean (1)H SI was significantly greater for never-smokers (12.1 ± 1.1 arbitrary units (AU)) compared to COPD subjects (10.9 ± 1.3 AU, p=0.04). The (1)H SI AP-gradient was also significantly greater for never-smokers (0.40 AU/cm, R(2)=0.94) compared to COPD subjects (0.29 AU/cm, R(2)=0.968, p=0.05). There was a significant correlation between (1)H SI and (3)He ADC (r=-0.58, p=0.008) and significant correlations between (1)H MR SI and CT measurements of emphysema (RA950, r=-0.69, p=0.02 and HU15, r=0.66, p=0.03)., Conclusions: The significant and moderately strong relationship between (1)H SI and (3)He ADC, as well as between (1)H SI and CT measurements of emphysema suggests that these imaging methods and measurements may be quantifying similar tissue changes in COPD and that pulmonary (1)H SI may be used to monitor emphysema as a complement to CT and noble gas MRI., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To compare hyperpolarized helium-3 ((3) He) and xenon-129 ((129) Xe) MRI in asthmatics before and after salbutamol inhalation., Materials and Methods: Seven asthmatics provided written informed consent and underwent spirometry, plethysmography, and MRI before and after salbutamol inhalation. (3) He and (129) Xe ventilation defect percent (VDP) and ventilation coefficient of variation (COV) were measured. To characterize the airways spatially related to ventilation defects, wall area percent (WA%) and lumen area (LA) were evaluated for two subjects who had thoracic x-ray computed tomography (CT) acquired 1 year before MRI., Results: Before salbutamol inhalation, (129) Xe VDP (8 ± 5%) was significantly greater than (3) He VDP (6 ± 5%, P = 0.003). Post-salbutamol, there was a significant improvement in both (129) Xe (5 ± 4%, P < 0.0001) and (3) He (4 ± 3%, P = 0.001) VDP, and the improvement in (129) Xe VDP was significantly greater (P = 0.008). (129) Xe MRI COV (Pre: 0.309 ± 0.028, Post: 0.296 ± 0.036) was significantly greater than (3) He MRI COV (Pre: 0.282 ± 0.018, Post: 0.269 ± 0.024), pre- (P < 0.0001) and post-salbutamol (P < 0.0001) and the decrease in COV post-salbutamol was significant ((129) Xe, P = 0.002; (3) He, P < 0.0001). For a single asthmatic, a sub-segmental (129) Xe MRI ventilation defect that was visible only before salbutamol inhalation but not visible using (3) He MRI was spatially related to a remodeled fourth generation sub-segmental airway (WA% = 78%, LA = 2.9 mm(2) )., Conclusion: In asthma, hyperpolarized (129) Xe MRI may help reveal ventilation abnormalities before bronchodilation that are not observed using hyperpolarized (3) He MRI., (Copyright © 2013 Wiley Periodicals, Inc.)

Purpose: The goal of this work was to investigate lung morphological changes associated with chronic obstructive pulmonary disease (COPD) using hyperpolarized (129) Xe diffusion-weighted MRI., Methods: Hyperpolarized (129) Xe MRI was performed at three different nonzero diffusion sensitizations (b-value = 12, 20, and 30 s/cm(2) ) in the lungs of four subjects with COPD and four healthy volunteers. The image signal intensities were fit as a function of b-value to obtain anisotropic diffusion coefficient maps for all subjects. The image signal intensities were also fit to a morphological model allowing extraction of length scales associated with the terminal airways: external radius (R), internal radius (r), mean airspace chord length (Lm ), and depth of alveolar sleeve (h)., Results: Longitudinal (DL ) and transverse (DT ) anisotropic diffusion coefficients were both significantly increased (both P= 0.004) in the COPD subjects (0.102 ± 0.02 cm(2) /s and 0.072 ± 0.02 cm(2) /s, respectively) compared with the healthy subjects (0.083 ± 0.011 cm(2) /s and 0.046 ± 0.017 cm(2) /s, respectively). Significant morphological differences were observed between the COPD subjects and healthy volunteers, specifically decreases in h (68 ± 36 µm vs. 95 ± 710 µm, respectively, P = 0.019) and increases in Lm (352 ± 57 µm vs. 253 ± 37 µm, respectively, P = 0.002) consistent with values obtained previously using hyperpolarized (3) He MRI in similar subjects., Conclusions: Diffusion-weighted hyperpolarized (129) Xe MRI is a promising technique for mapping changes in human lung morphology and may be useful for early detection of emphysema associated with COPD., (Copyright © 2013 Wiley Periodicals, Inc.)

Background: It is still not known how patients who are post-transient ischemic attack (TIA) or post-stroke might benefit from prospectively planned comprehensive cardiac rehabilitation (CCR). In this pilot evaluation of a larger ongoing randomized-controlled-trial, we evaluated ultrasound (US) measurements of carotid atherosclerosis in subjects following TIA or mild non-disabling stroke and their relationship with risk factors before and after 6-months of CCR., Methods: Carotid ultrasound (US) measurements of one-dimensional intima-media-thickness (IMT), two-dimensional total-plaque-area (TPA), three-dimensional total-plaque-volume (TPV) and vessel-wall-volume (VWV) were acquired before and after 6-months CCR for 39 subjects who had previously experienced a TIA and provided written informed consent to participate in this randomized controlled trial. We maintained blinding for this ongoing study by representing treatment and control groups as A or B, although we did not identify which of A or B was treatment or control. Carotid IMT, TPA, TPV and VWV were measured before and after CCR as were changes in body mass index (BMI), total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides (TG), systolic blood pressure (SBP) and diastolic blood pressure (DBP)., Results: There were no significant differences in US measurements or risk factors between groups A and B. There was no significant change in carotid ultrasound measurements for group A (IMT, p = .728; TPA, p = .629; TPV, p = .674; VWV, p = .507) or B (IMT, p = .054; TPA, p = .567; TPV, p = .773; VWV, p = .431) at the end of CCR. There were significant but weak-to-moderate correlations between IMT and VWV (r = 0.25, p = .01), IMT and TPV (r = 0.21, p = .01), TPV and TPA (r = 0.60, p < .0001) and VWV and TPV (r = 0.22, p = .02). Subjects with improved TC/HDL ratios showed improved carotid VWV although, this was not statistically significant., Conclusion: In this preliminary evaluation, there were no significant differences in carotid US measurements in the control or CCR group; a larger sample size and/or longer duration is required to detect significant changes in US or other risk factor measurements.

Rationale and Objectives: In this review, we summarize our experience evaluating pulmonary function in 330 different subjects using hyperpolarized noble gas magnetic resonance imaging (MRI) after enrollment and screening of >1100 subjects with and without respiratory disease during the period February 1, 2006, through November 1, 2012., Materials and Methods: We discuss the feasibility of hyperpolarized gas MRI research in a small nonhospital research unit and provide an overview of our experience since we initiated patient-based studies. We also discuss the importance of infrastructure support, collaboration, research trainees, and a large and willing patient population that helped to advance the research and technological deliverables. A summary of patient safety and tolerability, key feasibility, and research milestones is provided, as well as a roadmap for future studies., Results: Hyperpolarized (3)He and (129)Xe gas MRI is feasible at smaller centers without significant human resources for large and small longitudinal studies by virtue of its excellent patient safety and tolerability, the speed with which images can be acquired and quantitatively analyzed and the high spatial-temporal dynamics of the method that allows for acute and chronic therapy studies., Conclusions: The hyperpolarized noble gas MRI community's highly collaborative efforts and motivation to further the development and application of this tool has resulted in a moment-of-opportunity to translate the method clinically to provide an improved understanding of pulmonary disease. There are, as well, new and unprecedented opportunities for the evaluation of disease progression and to help develop the new treatments and interventions critically required for chronic pulmonary disease., (Copyright © 2013 AUR. Published by Elsevier Inc. All rights reserved.)

Objective: We developed a semi-automated tool to quantify emphysema from thoracic X-ray multi-detector (64-slice) computed tomography (CT) for training purposes and multi-reader studies., Materials and Methods: Thoracic X-ray CT was acquired in 93 ex-smokers, who were evaluated by six trainees with little or no expertise (trainees) and a single experienced thoracic radiologist (expert). A graphic user interface (GUI) was developed for emphysema quantification based on the percentile of lung where a score of 0=no abnormalities, 1=1-25%, 2=26-50%, 3=51-75% and 4=76-100% for each lung side/slice. Trainees blinded to subject characteristics scored randomized images twice; accuracy was determined by comparison to expert scores, density histogram 15th percentile (HU 15), relative area at -950 HU (RA(950)), low attenuation clusters at -950 HU (LAC(950)), -856 HU (LAC(856)) and the diffusing capacity for carbon monoxide (DL(CO%pred)). Intra- and inter-observer reproducibility was evaluated using coefficients-of-variation (COV), intra-class (ICC) and Pearson correlations., Results: Trainee-expert correlations were significant (r=0.85-0.97, p<0.0001) and a significant trainee bias (0.15 ± 0.22) was observed. Emphysema score was correlated with RA(950) (r=0.88, p<0.0001), HU 15 (r=-0.77, p<0.0001), LAC(950) (r=0.76, p<0.0001), LAC(856) (r=0.74, p=0.0001) and DLCO%pred (r=-0.71, p<0.0001). Intra-observer reproducibility (COV=4-27%; ICC=0.75-0.94) was moderate to high for trainees; intra- and inter-observer COV were negatively and non-linearly correlated with emphysema score., Conclusion: We developed a GUI for rapid and interactive emphysema scoring that allows for comparison of multiple readers with clinical and radiological standards., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

A better understanding of the anatomic structure and physiological function of the lung is fundamental to understanding the pathogenesis of pulmonary disease and how to design and deliver better treatments and measure response to intervention. Magnetic resonance imaging (MRI) with the hyperpolarised noble gases helium-3 ((3)He) and xenon-129 ((129)Xe) provides both structural and functional pulmonary measurements, and because it does not require the use of x-rays or other ionising radiation, offers the potential for intensive serial and longitudinal studies in paediatric patients. These facts are particularly important in the evaluation of chronic lung diseases such as asthma and cystic fibrosis- both of which can be considered paediatric respiratory diseases with unmet therapy needs. This review discusses MRI-based imaging methods with a focus on hyperpolarised gas MRI. We also discuss the strengths and limitations as well as the future work required for clinical translation towards paediatric respiratory disease., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: The functional effects of abnormal diffusing capacity for carbon monoxide (DLCO) in ex-smokers without chronic obstructive pulmonary disease (COPD) are not well understood., Objective: We aimed to evaluate and compare well established clinical, physiological and emerging imaging measurements in ex-smokers with normal spirometry and abnormal DLCO with a group of ex-smokers with normal spirometry and DLCO and ex-smokers with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I COPD., Methods: We enrolled 38 ex-smokers and 15 subjects with stage I COPD who underwent spirometry, plethysmography, St George's Respiratory Questionnaire (SGRQ), 6 min Walk Test (6MWT), x-ray CT and hyperpolarised helium-3 ((3)He) MRI. The 6MWT distance (6MWD), SGRQ scores, (3)He MRI apparent diffusion coefficients (ADC) and CT attenuation values below -950 HU (RA950) were evaluated., Results: Of 38 ex-smokers without COPD, 19 subjects had abnormal DLCO with significantly worse ADC (p=0.01), 6MWD (p=0.008) and SGRQ (p=0.01) but not RA950 (p=0.53) compared with 19 ex-smokers with normal DLCO. Stage I COPD subjects showed significantly worse ADC (p=0.02), RA950 (p=0.0008) and 6MWD (p=0.005), but not SGRQ (p=0.59) compared with subjects with abnormal DLCO. There was a significant correlation for (3)He ADC with SGRQ (r=0.34, p=0.02) and 6MWD (r=-0.51, p=0.0002)., Conclusions: In ex-smokers with normal spirometry and CT but abnormal DLCO, there were significantly worse symptoms, 6MWD and (3)He ADC compared with ex-smokers with normal DLCO, providing evidence of the impact of mild or early stage emphysema and a better understanding of abnormal DLCO and hyperpolarised (3)He MRI in ex-smokers without COPD.

Background and Purpose: Carotid ultrasound evaluation of intima-media thickness (IMT) and plaque burden has been used for risk stratification and for evaluation of antiatherosclerotic therapies. Increasing evidence indicates that measuring plaque burden is superior to measuring IMT for both purposes. We compared progression/regression of IMT, total plaque area (TPA), and total plaque volume (TPV) as predictors of cardiovascular outcomes., Methods: IMT, TPA, and TPV were measured at baseline in 349 patients attending vascular prevention clinics; they had TPA of 40 to 600 mm(2) at baseline to qualify for enrollment. Participants were followed up for ≤5 years (median, 3.17 years) to ascertain vascular death, myocardial infarction, stroke, and transient ischemic attacks. Follow-up measurements 1 year later were available in 323 cases for IMT and TPA, and in 306 for TPV., Results: Progression of TPV predicted stroke, death or TIA (Kaplan-Meier logrank P=0.001), stroke/death/MI (P=0.008) and Stroke/Death/TIA/Myocardial infarction (any Cardiovascular event) (P=0.001). Progression of TPA weakly predicted Stroke/Death/TIA (P=0.097) but not stroke/death/MI (P=0.59) or any CV event (P=0.143); likewise change in IMT did not predict Stroke/Death/MI (P=0.13) or any CV event (P=0.455 ). In Cox regression, TPV progression remained a significant predictor of events after adjustment for coronary risk factors (P=0.001) but change in TPA did not. IMT change predicted events in an inverse manner; regression of IMT predicted events (P=0.004)., Conclusions: For assessment of response to antiatherosclerotic therapy, measurement of TPV is superior to both IMT and TPA.

Rationale and Objectives: High-resolution computed tomography (CT) measurements of emphysema typically use Hounsfield unit (HU) density histogram thresholds or observer scores based on regions of low x-ray attenuation. Our objective was to develop an automated measurement of emphysema using principal component analysis (PCA) of the CT density histogram., Materials and Methods: Ninety-seven ex-smokers, including 53 subjects with chronic obstructive pulmonary disease (COPD) and 44 asymptomatic subjects (AEs), provided written informed consent to imaging as well as plethysmography and spirometry. We applied PCA to the CT density histogram to generate whole lung and regional density histogram principal components including the first and second components and the sum of both principal components (density histogram principal component score [DHPCS]). Significant relationships for DHPCS with single HU thresholds, pulmonary function measurements, an expert's emphysema score, and hyperpolarized (3)He magnetic resonance imaging apparent diffusion coefficients (ADCs) were determined using linear regression and Pearson coefficients. Receiver operator characteristics analysis was performed using forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) as the independent diagnostic., Results: There was a significant difference (P < .0001) between AE and COPD subjects for DHPCS; FEV1/FVC; diffusing capacity of lung for carbon monoxide%predicted; attenuation values below -950, -910, and -856 HU; and (3)He ADCs. There were significant correlations for DHPCS with FEV1/FVC (r = -0.85, P < .0001); diffusing capacity of lung for carbon monoxide%predicted (r = -0.67, P < .0001); attenuation values below -950/-910/-856 HU (r = 0.93/0.96/0.76, P < .0001); and (3)He ADCs (r = 0.85, P < .0001). Receiver operator characteristics analysis showed a 91% classification rate for DHPCS., Conclusions: We generated an automated emphysema score using PCA of the CT density histogram with a 91% COPD classification rate that showed strong and significant correlations with pulmonary function tests, single HU thresholds, and (3)He magnetic resonance imaging ADCs., (Copyright © 2013 AUR. Published by Elsevier Inc. All rights reserved.)

Purpose: Three-dimensional ultrasound (3DUS) vessel wall volume (VWV) provides a 3D measurement of carotid artery wall remodeling and atherosclerotic plaque and is sensitive to temporal changes of carotid plaque burden. Unfortunately, although 3DUS VWV provides many advantages compared to measurements of arterial wall thickening or plaque alone, it is still not widely used in research or clinical practice because of the inordinate amount of time required to train observers and to generate 3DUS VWV measurements. In this regard, semiautomated methods for segmentation of the carotid media-adventitia boundary (MAB) and the lumen-intima boundary (LIB) would greatly improve the time to train observers and for them to generate 3DUS VWV measurements with high reproducibility., Methods: The authors describe a 3D algorithm based on a modified sparse field level set method for segmenting the MAB and LIB of the common carotid artery (CCA) from 3DUS images. To the authors' knowledge, the proposed algorithm is the first direct 3D segmentation method, which has been validated for segmenting both the carotid MAB and the LIB from 3DUS images for the purpose of computing VWV. Initialization of the algorithm requires the observer to choose anchor points on each boundary on a set of transverse slices with a user-specified interslice distance (ISD), in which larger ISD requires fewer user interactions than smaller ISD. To address the challenges of the MAB and LIB segmentations from 3DUS images, the authors integrated regional- and boundary-based image statistics, expert initializations, and anatomically motivated boundary separation into the segmentation. The MAB is segmented by incorporating local region-based image information, image gradients, and the anchor points provided by the observer. Moreover, a local smoothness term is utilized to maintain the smooth surface of the MAB. The LIB is segmented by constraining its evolution using the already segmented surface of the MAB, in addition to the global region-based information and the anchor points. The algorithm-generated surfaces were sliced and evaluated with respect to manual segmentations on a slice-by-slice basis using 21 3DUS images., Results: The authors used ISD of 1, 2, 3, 4, and 10 mm for algorithm initialization to generate segmentation results. The algorithm-generated accuracy and intraobserver variability results are comparable to the previous methods, but with fewer user interactions. For example, for the ISD of 3 mm, the algorithm yielded an average Dice coefficient of 94.4% ± 2.2% and 90.6% ± 5.0% for the MAB and LIB and the coefficient of variation of 6.8% for computing the VWV of the CCA, while requiring only 1.72 min (vs 8.3 min for manual segmentation) for a 3DUS image., Conclusions: The proposed 3D semiautomated segmentation algorithm yielded high-accuracy and high-repeatability, while reducing the expert interaction required for initializing the algorithm than the previous 2D methods.

A chronic obstructive pulmonary disease (COPD) exsmoker underwent pulmonary function tests and hyperpolarized helium-3 ((3) He) magnetic resonance imaging (MRI) serially over 4 years, twice prior to and twice following an acute exacerbation (AE). About 2.5 years pre-AE, (3) He ventilation defect percent (VDP) was 16%, the apparent diffusion coefficient (ADC) was 0.34 cm(2) /s, and forced expiratory volume in 1 sec (FEV1 ) was 41%pred . Six months pre-AE, VDP and ADC were worse (29% and 0.38 cm(2) /s, respectively) without worsening FEV1 (47%pred ). After hospitalization and AE treatment, VDP was 20%, whereas FEV1 did not improve (45%pred ); 16 months post-AE, both VDP and ADC remained improved and similar to 4 years prior., (Copyright © 2012 Wiley Periodicals, Inc.)

In subjects with chronic obstructive pulmonary disease (COPD), hyperpolarized xenon-129 ((129)Xe) magnetic resonance imaging (MRI) reveals significantly greater ventilation defects than hyperpolarized helium-3 ((3)He) MRI. The physiological and/or morphological determinants of ventilation defects and the differences observed between hyperpolarized (3)He and (129)Xe MRI are not yet understood. Here we aimed to determine the structural basis for the differences in ventilation observed between (3)He and (129)Xe MRI in subjects with COPD using apparent diffusion coefficients (ADC) and computed tomography (CT). Ten COPD ex-smokers provided written, informed consent and underwent MRI, CT, spirometry, and plethysmography. (3)He and (129)Xe MRI ventilation volume was generated using semiautomated segmentation, and ADC maps were registered to generate ADC values for lung regions of interest ventilated by both gases (ADCHX) and by (3)He gas only (ADCHO). CT wall area percentage and the lowest 15th percentile point of the CT lung density histogram (HU15%) were also evaluated. For lung regions accessed by (3)He gas only, mean (3)He ADCHO was significantly greater than for regions accessed by both gases (ADCHO = 0.503 ± 0.119 cm(2)/s, ADCHX = 0.470 ± 0.125 cm(2)/s, P < 0.0001). The difference between (3)He and (129)Xe ventilation volume was significantly correlated with CT HU15% (r = -65, P = 0.04) and (3)He ADCHO (r = 0.70, P = 0.02), but not CT wall area percentage (r = -0.34, P = 0.33). In conclusion, in this small study in COPD subjects, we observed significantly decreased (129)Xe MRI ventilation compared with (3)He MRI, and these regions of decreased (129)Xe ventilation were spatially and significantly correlated with regions of increased pulmonary emphysema, but not airway wall thickness.

Rationale and Objectives: Pulmonary functional imaging using four-dimensional x-ray computed tomographic (4DCT) imaging and hyperpolarized (3)He magnetic resonance imaging (MRI) provides regional lung function estimates in patients with lung cancer in whom pulmonary function measurements are typically dominated by tumor burden. The aim of this study was to evaluate the quantitative spatial relationship between 4DCT and hyperpolarized (3)He MRI ventilation maps., Materials and Methods: Eleven patients with lung cancer provided written informed consent to 4DCT imaging and MRI performed within 11 ± 14 days. Hyperpolarized (3)He MRI was acquired in breath-hold after inhalation from functional residual capacity of 1 L hyperpolarized (3)He, whereas 4DCT imaging was acquired over a single tidal breath of room air. For hyperpolarized (3)He MRI, the percentage ventilated volume was generated using semiautomated segmentation; for 4DCT imaging, pulmonary function maps were generated using the correspondence between identical tissue elements at inspiratory and expiratory phases to generate percentage ventilated volume., Results: After accounting for differences in image acquisition lung volumes ((3)He MRI: 1.9 ± 0.5 L ipsilateral, 2.3 ± 0.7 L contralateral; 4DCT imaging: 1.2 ± 0.3 L ipsilateral, 1.3 ± 0.4 L contralateral), there was no significant difference in percentage ventilated volume between hyperpolarized (3)He MRI (72 ± 11% ipsilateral, 79 ± 12% contralateral) and 4DCT imaging (74 ± 3% ipsilateral, 75 ± 4% contralateral). Spatial correspondence between 4DCT and (3)He MRI ventilation was evaluated using the Dice similarity coefficient index (ipsilateral, 86 ± 12%; contralateral, 88 ± 12%)., Conclusions: Despite rather large differences in image acquisition breathing maneuvers, good spatial and significant quantitative agreement was observed for ventilation maps on hyperpolarized (3)He MRI and 4DCT imaging, suggesting that pulmonary regions with good lung function are similar between modalities in this small group of patients with lung cancer., (Copyright © 2012 AUR. Published by Elsevier Inc. All rights reserved.)

Background and Objective: Spirometry is insensitive to small airway abnormalities in asthma. Our objective was to evaluate regional lung structure and function using hyperpolarized (3)He magnetic resonance imaging (MRI) before, during and after a methacholine challenge (MCh)., Methods: Twenty-five asthmatics (mean age = 34 ± 11 years) and eight healthy volunteers (HV) (mean age = 33 ± 11 years) underwent spirometry, plethysmography and hyperpolarized (3)He MRI prior to a MCh. MRI was repeated following the MCh and again 25 min after salbutamol administration. (3)He MRI gas distribution was quantified using semiautomated segmentation of the ventilation defect percent (VDP). Tissue microstructure was measured using the (3)He apparent diffusion coefficient (ADC). Analysis of variance with repeated measures was used to evaluate changes at each time point as well as to determine interactions between regions of interest (ROI) and subject group. Pearson's correlations were performed to evaluate associations between (3)He MRI measurements and established clinical measures., Results: In asthmatics, but not HV, whole-lung ADC was increased post-MCh (P < 0.01). In asthmatics only, ADC was increased post-MCh in posterior ROI (P < 0.01) and all ROI in the superior-inferior direction (P < 0.01). VDP was increased in posterior and inferior ROI (P < 0.001). There was a correlation between VDP and specific airway resistance (r = 0.74, P < 0.0001), dyspnoea score (r = 0.66, P < 0.01) and fractional exhaled nitric oxide (r = 0.45, P < 0.05)., Conclusions: We evaluated the regional pulmonary response to methacholine and salbutamol using (3)He MRI and showed heterogeneous VDP and ADC consistent with bronchoconstriction and gas trapping, respectively, post-MCh. These regional alterations resolved post-salbutamol., (© 2012 The Authors. Respirology © 2012 Asian Pacific Society of Respirology.)

Purpose: To quantitatively compare hyperpolarized helium 3 (3He) and xenon 129 (129Xe) magnetic resonance (MR) images obtained within 5 minutes in healthy volunteers and patients with chronic obstructive pulmonary disease (COPD) and to evaluate the correlations between 3He and 129Xe MR imaging measurements and those from spirometry and plethysmography., Materials and Methods: This study was approved by an ethics board and compliant with HIPAA. Written informed consent was obtained from all subjects. Eight healthy volunteers and 10 patients with COPD underwent MR imaging, spirometry, and plethysmography. Ventilation defect percentages (VDPs) at 3He and 129Xe imaging were obtained by using semiautomated segmentation. Apparent diffusion coefficients (ADCs) were calculated from 3He (b=1.6 sec/cm2) and 129Xe (b=12 sec/cm2) diffusion-weighted images. VDPs at hyperpolarized 3He and 129Xe imaging were compared with a two-tailed Wilcoxon signed rank test and analysis of variance; Pearson correlation coefficients were used to evaluate the relationships among measurements., Results: 129Xe VDP was significantly greater than 3He VDP for patients with COPD (P<.0001) but not for healthy volunteers (P=.35), although 3He and 129Xe VDPs showed a significant correlation for all subjects (r=0.91, P<.0001). The forced expiratory volume in 1 second (FEV1) showed a similar and significant correlation with 3He VDP (r=-0.84, P<.0001) and 129Xe VDP (r=-0.89, P<.0001), although the correlation between the FEV1/forced vital capacity (FVC) ratio and 129Xe VDP (r=-0.95, P<.0001) was significantly greater (P=.01) than that for FEV1/FVC and 3He VDP (r=-0.84, P<.0001). A significant correlation was also observed for 3He and 129Xe ADC (r=0.97, P<.0001); 129Xe ADC was significantly correlated with diffusing capacity of lung for carbon monoxide (r=-0.79, P=.03) and computed tomographic emphysema measurements (areas with attenuation values in the 15th percentile: r=-0.91, P=.0003; relative areas with attenuation values of less than -950 HU: r=0.87, P=.001)., Conclusion: In patients with COPD, the VDP obtained with hyperpolarized 29Xe MR imaging was significantly greater than that with 3He MR imaging, suggesting incomplete or delayed filling of lung regions that may be related to the different properties of 129Xe gas and physiologic and/or anatomic abnormalities in COPD., (© RSNA, 2012)

This review provides a summary of pulmonary functional imaging approaches for determining pulmonary ventilation, with a specific focus on multi-detector x-ray computed tomography and magnetic resonance imaging (MRI). We provide the important functional definitions of pulmonary ventilation typically used in medicine and physiology and discuss the fact that some of the imaging literature describes gas distribution abnormalities in pulmonary disease that may or may not be related to the physiological definition or clinical interpretation of ventilation. We also review the current state-of-the-field in terms of the key physiological questions yet unanswered related to ventilation and gas distribution in lung disease. Current and emerging imaging research methods are described, including their strengths and the challenges that remain to translate these methods to more wide-spread research and clinical use. We also examine how computed tomography and MRI might be used in the future to gain more insight into gas distribution and ventilation abnormalities in pulmonary disease.

Rationale and Objectives: The objective of this study was to evaluate the tolerability of hyperpolarized (129)Xe gas inhaled from functional residual capacity and magnetic resonance imaging in healthy subjects and those with pulmonary disease., Materials and Methods: Twelve healthy volunteers (mean age, 59 ± 17 years), seven subjects with asthma (mean age, 47 ± 7 years), 10 subjects with chronic obstructive pulmonary disease (mean age, 74 ± 4 years), three subjects with cystic fibrosis (mean age, 27 ± 10 years), and a single subject with radiation-induced lung injury (age, 66 years) were enrolled and evaluated over 43 visits with 136 anoxic inhalations of 500 mL (129)Xe gas mixed with 500 mL (4)He gas. Oxygen saturation and heart rate were monitored during the breath-hold and imaging; subjects were queried for adverse events (AEs) before and immediately following gas inhalation and for 24 hours after the last dose., Results: No subjects withdrew from the study or reported serious, hypoxic, or severe AEs. Over the course of 136 dose administrations, two mild AEs (1%) were reported in two different subjects (two of 33 [6%]). One of these AEs (light-headedness) was temporally related and judged as possibly related to (129)Xe administration and resolved without treatment within 2 minutes. Statistically significant but clinically insignificant changes in oxygen saturation and heart rate were observed after inhalation (P < .001), and both resolved 1 minute later, with no difference between subject groups., Conclusions: Inhalation of hyperpolarized (129)Xe gas and subsequent magnetic resonance imaging were well tolerated in healthy subjects and ambulatory subjects with obstructive and restrictive pulmonary disease., (Copyright © 2012 AUR. Published by Elsevier Inc. All rights reserved.)

Objective: To synthesise the association of shift work with major vascular events as reported in the literature., Data Sources: Systematic searches of major bibliographic databases, contact with experts in the field, and review of reference lists of primary articles, review papers, and guidelines., Study Selection: Observational studies that reported risk ratios for vascular morbidity, vascular mortality, or all cause mortality in relation to shift work were included; control groups could be non-shift ("day") workers or the general population., Data Extraction: Study quality was assessed with the Downs and Black scale for observational studies. The three primary outcomes were myocardial infarction, ischaemic stroke, and any coronary event. Heterogeneity was measured with the I(2) statistic and computed random effects models., Results: 34 studies in 2,011,935 people were identified. Shift work was associated with myocardial infarction (risk ratio 1.23, 95% confidence interval 1.15 to 1.31; I(2)=0) and ischaemic stroke (1.05, 1.01 to 1.09; I(2)=0). Coronary events were also increased (risk ratio 1.24, 1.10 to 1.39), albeit with significant heterogeneity across studies (I(2)=85%). Pooled risk ratios were significant for both unadjusted analyses and analyses adjusted for risk factors. All shift work schedules with the exception of evening shifts were associated with a statistically higher risk of coronary events. Shift work was not associated with increased rates of mortality (whether vascular cause specific or overall). Presence or absence of adjustment for smoking and socioeconomic status was not a source of heterogeneity in the primary studies. 6598 myocardial infarctions, 17,359 coronary events, and 1854 ischaemic strokes occurred. On the basis of the Canadian prevalence of shift work of 32.8%, the population attributable risks related to shift work were 7.0% for myocardial infarction, 7.3% for all coronary events, and 1.6% for ischaemic stroke., Conclusions: Shift work is associated with vascular events, which may have implications for public policy and occupational medicine.

Purpose: Radiation-induced lung injury (RILI) is the primary dose-limiting toxicity for radiation therapy of the lung, and although the effects of radiation dose on RILI development have been well characterized, the influence of chronic obstructive pulmonary disease (COPD) on the development of RILI and other outcomes is not well understood. The purpose of this small pilot study was to evaluate the relationship between hyperpolarized (3)He magnetic resonance imaging (MRI) measurements of COPD with RILI and 12-month survival in lung cancer patients undergoing radical radiotherapy and to evaluate the feasibility of pulmonary functional MRI as an image guidance∕planning tool for radiation therapy., Methods: Fifteen non-small cell and small cell lung cancer patients underwent pulmonary function tests, x-ray computed tomography (CT), and hyperpolarized (3)He MRI prior to radical radiation therapy (≥60 Gy). Conventional thoracic (1)H and hyperpolarized (3)He MRI were acquired to generate ventilation defect percent and the apparent diffusion coefficient for the ipsilateral and contralateral lungs independently. CT was acquired postradiation therapy and qualitatively evaluated for radiological evidence of RILI and 12-month survival was reported., Results: Hyperpolarized (3)He MRI measurements of COPD classified 10∕15 subjects with contralateral lung COPD (CLC), and five subjects without COPD [contralateral lung normal (CLN)]. Of the 10 subjects with CLC, only four had a previous clinical diagnosis of COPD. CT images were acquired postradiation therapy for 13 subjects, and for eight (62%) of these there was qualitative evidence of RILI, including 5∕9 CLC and 3∕4 CLN subjects. The one-year survival was 2∕10 for CLC and 3∕5 for CLN subjects., Conclusions: In this small pilot study, we report the use of (3)He MRI to stratify lung cancer patients based on MRI evidence of COPD and showed that comorbid COPD was present in the majority of lung cancer subjects stratified for radiation therapy. Lung cancer patients with imaging evidence of COPD did not have an increased incidence of RILI compared to patients without COPD. However, preliminary data presented here indicated that one-year survival in COPD subjects was lower than expected based on previously published survival rates, which may have implications for radiation therapy in lung cancer patients with comorbid COPD.

The relationship of three-dimensional ultrasound (3DUS)-derived carotid vessel wall volume (VWV) was evaluated with respect to age and sex. B-mode and 3DUS images were acquired for 316 subjects from diverse groups including obese primary prevention, diabetic nephropathy, renal transplant and rheumatoid arthritis populations. The relationship for intima-media thickness (IMT) and VWV with age and sex were determined using Pearson-product-moment correlations. Mean IMT (r = 0.18, p = 0.001) and VWV (r = 0.24, p < 0.01) correlated modestly with age. There were modest correlations in males (IMT, r = 0.19, p = 0.003; VWV, r = 0.34, p < 0.001) and in females for IMT and age (r = 0.30, p = 0.007) but not between 3DUS VWV and age in females (r = 0.10, p = 0.4). Significant associations between plaque and VWV (r = 0.36, p = 0.001) but not IMT suggest different correlations in females that may be attributed to plaque., (Copyright © 2012 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Dynamic imaging methods such as four-dimensional computed tomography (4DCT) and static imaging methods such as noble gas magnetic resonance imaging (MRI) deliver direct and regional measurements of lung function even in lung cancer patients in whom global lung function measurements are dominated by tumour burden. The purpose of this study was to directly compare quantitative measurements of gas distribution from static hyperpolarized 3 He MRI and dynamic 4DCT in a small group of lung cancer patients. MRI and 4DCT were performed in 11 subjects prior to radiation therapy. MRI was performed at 3.0T in breath-hold after inhalation 1L of hyperpolarized 3 He gas. Gas distribution in 3 He MRI was quantified using a semi-automated segmentation algorithm to generate percent-ventilated volume (PVV), reflecting the volume of gas in the lung normalized to the thoracic cavity volume. 4DCT pulmonary function maps were generated using deformable image registration of six expiratory phase images. The correspondence between identical tissue elements at inspiratory and expiratory phases was used to estimate regional gas distribution and PVV was quantified from these images. After accounting for differences in lung volumes between 3 He MRI (1.9±0.5L ipsilateral, 2.3±0.7 contralateral) and 4DCT (1.2±0.3L ipsilateral, 1.3±0.4L contralateral) during image acquisition, there was no statistically significant difference in PVV between 3 He MRI (72±11% ipsilateral, 79±12% contralateral) and 4DCT (74±3% ipsilateral, 75±4% contralateral). Our results indicate quantitative agreement in the regional distribution of inhaled gas in both static and dynamic imaging methods. PVV may be considered as a regional surrogate measurement of lung function or ventilation., (© 2012 American Association of Physicists in Medicine.)

Measurements of lung function, including spirometry and body plethesmography, are easy to perform and are the current clinical standard for assessing disease severity. However, these lung functional techniques do not adequately explain the observed variability in clinical manifestations of disease and offer little insight into the relationship of lung structure and function. Lung imaging and the image-based assessment of lung disease has matured to the extent that it is common for clinical, epidemiologic and genetic investigation to have a component dedicated to image analysis. There are several exciting imaging modalities currently being used for the non-invasive study of lung anatomy and function. In this review, we will focus on two of them; X-ray computed tomography and magnetic resonance imaging. Following a brief introduction of each method, we detail some of the most recent work being done to characterize smoking-related lung disease and the clinical applications of such knowledge., (© 2011 The Authors. Respirology © 2011 Asian Pacific Society of Respirology.)

Rationale and Objectives: To improve intra- and interobserver variability and enable the use of functional magnetic resonance imaging (MRI) for multicenter, multiobserver studies, we generated a semiautomated segmentation method for hyperpolarized helium-3 ((3)He) MRI. Therefore the objective of this study was to compare the reproducibility and spatial agreement of manual and semiautomated segmentation of (3)He MRI ventilation defect volume (VDV) and ventilation volume (VV) in subjects with asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF)., Materials and Methods: The multistep semiautomated segmentation method we developed employed hierarchical K-means clustering to classify (3)He MRI pixel intensity values into five user-determined clusters ranging from signal void to hyperintense. A seeded region-growing algorithm was also used to segment the (1)H MRI thoracic cavity for coregistration to the (3)He cluster-map, generating VDV and VV., Results: We compared manual segmentation performed by an expert observer and semiautomated measurements of (3)He MRI VDV and observed strong significant correlations between the volumes generated using each method (asthma, n = 5, r = 0.89, P < .0001; COPD, n = 5, r = 0.84, P < .0001; CF, n = 5, r = 0.89, P < .0001). Semiautomated VDV had high interobserver reproducibility (coefficient of variation [CV] = 7%, intraclass correlation coefficient [ICC] = 0.96); intraobserver reproducibility was significantly higher for semiautomated (CV = 5%, ICC = 1.00) compared to manual VDV (CV = 12%, ICC = 0.98). Spatial agreement for VV determined using the Dice coefficient (D) was also high for all disease states (asthma, D = 0.95; COPD, D = 0.88; CF, D = 0.90)., Conclusions: Semiautomated segmentation (3)He MRI provides excellent inter- and intraobserver precision with high spatial and quantitative agreement with manual measurements enabling its use in longitudinal studies., (Copyright © 2012 AUR. Published by Elsevier Inc. All rights reserved.)

The objective of this study was to evaluate the regional effects of bronchodilator administration in chronic obstructive pulmonary disease (COPD) using hyperpolarized helium-3 ((3)He) MRI apparent diffusion coefficient (ADC). Ten COPD ex-smokers provided written, informed consent and underwent diffusion-weighted, hyperpolarized (3)He MRI, spirometry, and plethysmography before and 25 ± 2 min after bronchodilator administration. Pre- and postsalbutamol whole-lung (WL) ADC maps were generated and registered together to identify the lung regions containing the (3)He signal at both time points, and mean ADC within those regions of interest (ROI) was determined for a measurement of previously ventilated ROI ADC (ADC(P)). Lung ROI with (3)He signal at both time points was used as a binary mask on postsalbutamol WL ADC maps to obtain an ADC measurement for newly ventilated ROI (ADC(N)). Postsalbutamol, no significant differences were detected in WL ADC (P = 0.516). There were no significant differences between ADC(N) and ADC(P) postsalbutamol (P = 1.00), suggesting that the ADC(N) lung regions were not more emphysematous than the lung ROI participating in ventilation before bronchodilator administration. Postsalbutamol, a statistically significant decrease in ADC(P) (P = 0.01) was detected, and there were significant differences between ADC(P) in the most anterior and most posterior image slices (P = 0.02), suggesting a reduction in regional gas trapping following bronchodilator administration. Regional evaluation of tissue microstructure using hyperpolarized (3)He MRI ADC provides insights into lung alterations that accompany improvements in regional (3)He gas distribution after bronchodilator administration.

Purpose: Manual segmentation of lung tumors is observer dependent and time-consuming but an important component of radiology and radiation oncology workflow. The objective of this study was to generate an automated lung tumor measurement tool for segmentation of pulmonary metastatic tumors from x-ray computed tomography (CT) images to improve reproducibility and decrease the time required to segment tumor boundaries., Methods: The authors developed an automated lung tumor segmentation algorithm for volumetric image analysis of chest CT images using shape constrained Otsu multithresholding (SCOMT) and sparse field active surface (SFAS) algorithms. The observer was required to select the tumor center and the SCOMT algorithm subsequently created an initial surface that was deformed using level set SFAS to minimize the total energy consisting of mean separation, edge, partial volume, rolling, distribution, background, shape, volume, smoothness, and curvature energies., Results: The proposed segmentation algorithm was compared to manual segmentation whereby 21 tumors were evaluated using one-dimensional (1D) response evaluation criteria in solid tumors (RECIST), two-dimensional (2D) World Health Organization (WHO), and 3D volume measurements. Linear regression goodness-of-fit measures (r(2) = 0.63, p < 0.0001; r(2) = 0.87, p < 0.0001; and r(2) = 0.96, p < 0.0001), and Pearson correlation coefficients (r = 0.79, p < 0.0001; r = 0.93, p < 0.0001; and r = 0.98, p < 0.0001) for 1D, 2D, and 3D measurements, respectively, showed significant correlations between manual and algorithm results. Intra-observer intraclass correlation coefficients (ICC) demonstrated high reproducibility for algorithm (0.989-0.995, 0.996-0.997, and 0.999-0.999) and manual measurements (0.975-0.993, 0.985-0.993, and 0.980-0.992) for 1D, 2D, and 3D measurements, respectively. The intra-observer coefficient of variation (CV%) was low for algorithm (3.09%-4.67%, 4.85%-5.84%, and 5.65%-5.88%) and manual observers (4.20%-6.61%, 8.14%-9.57%, and 14.57%-21.61%) for 1D, 2D, and 3D measurements, respectively., Conclusions: The authors developed an automated segmentation algorithm requiring only that the operator select the tumor to measure pulmonary metastatic tumors in 1D, 2D, and 3D. Algorithm and manual measurements were significantly correlated. Since the algorithm segmentation involves selection of a single seed point, it resulted in reduced intra-observer variability and decreased time, for making the measurements.

Asthma is a variable disease with changes in symptoms and airway function over many time scales. Airway resistance (Raw) is variable and thought to reflect changes in airway smooth muscle activity, but just how variation throughout the airway tree and the influence of gas distribution abnormalities affect Raw is unclear. We used a multibranch airway lung model to evaluate variation in airway diameter size, the role of coherent regional variation, and the role of gas distribution abnormalities on mean Raw (Raw) and variation in Raw as described by the SD (SDRaw). We modified an anatomically correct airway tree, provided by Merryn Tawhai (The University of Auckland, New Zealand), consisting of nearly 4,000 airways, to produce temporal and spatial heterogeneity. As expected, we found that increasing the diameter variation by twofold, with no change in the mean diameter, increased SDRaw more than fourfold. Perhaps surprisingly, Raw was proportional to SDRaw under several conditions-when either mean diameter was fixed, and its SD varied or when mean diameter varied, and SD was fixed. Increasing the size of a regional absence in gas distribution (ventilation defect) also led to a proportionate increase in both Raw and SDRaw. However, introducing regional dependence of connected airways strongly increased SDRaw by as much as sixfold, with little change in Raw. The model was able to predict previously reported Raw distributions and correlation of SDRaw on Raw in healthy and asthmatic subjects. The ratio of SDRaw to Raw depended most strongly on interairway coherent variation and only had a slight dependence on ventilation defect size. These findings may explain the linear correlation between variation and mean values of Raw but also suggest that regional alterations in gas distribution and local coordination in ventilation amplify any underlying variation in airway diameters throughout the airway tree.

A 73-year-old exsmoker with Global initiative for chronic Obstructive Lung Disease stage III chronic obstructive pulmonary disease underwent airway bypass (AB) as part of the Exhale Airway Stents for Emphysema (EASE) trial, and was the only EASE subject to undergo hyperpolarized 3He magnetic resonance imaging for evaluation of lung function pre- and post-AB. 3He magnetic resonance imaging was acquired twice previously (32 and eight months pre-AB) and twice post-AB (six and 12 months post-AB). Six months post-AB, his increase in forced vital capacity was <12% predicted, and he was classified as an AB nonresponder. However, post-AB, he also demonstrated improvements in quality of life scores, 6 min walk distance and improvements in 3He gas distribution in the regions of stent placement. Given the complex relationship between well-established pulmonary function and quality of life measurements, the present case provides evidence of the value-added information functional imaging may provide in chronic obstructive pulmonary disease interventional studies.

Rationale and Objectives: We evaluated the accuracy and reproducibility of three-dimensional (3D) measurements of lung phantoms and patient tumors from x-ray computed tomography (CT) and compared these to one-dimensional (1D) and two-dimensional (2D) measurements., Materials and Methods: CT images of three spherical and three irregularly shaped tumor phantoms were evaluated by three observers who performed five repeated measurements. Additionally, three observers manually segmented 29 patient lung tumors five times each. Follow-up imaging was performed for 23 tumors and response criteria were compared. For a single subject, imaging was performed on nine occasions over 2 years to evaluate multidimensional tumor response. To evaluate measurement accuracy, we compared imaging measurements to ground truth using analysis of variance. For estimates of precision, intraobserver and interobserver coefficients of variation and intraclass correlations (ICC) were used. Linear regression and Pearson correlations were used to evaluate agreement and tumor response was descriptively compared., Results: For spherical shaped phantoms, all measurements were highly accurate, but for irregularly shaped phantoms, only 3D measurements were in high agreement with ground truth measurements. All phantom and patient measurements showed high intra- and interobserver reproducibility (ICC >0.900). Over a 2-year period for a single patient, there was disagreement between tumor response classifications based on 3D measurements and those generated using 1D and 2D measurements., Conclusion: Tumor volume measurements were highly reproducible and accurate for irregular, spherical phantoms and patient tumors with nonuniform dimensions. Response classifications obtained from multidimensional measurements suggest that 3D measurements provide higher sensitivity to tumor response., (Copyright © 2011 AUR. Published by Elsevier Inc. All rights reserved.)