Grace Parraga

Regional pulmonary response to a methacholine challenge using hyperpolarized (3)He magnetic resonance imaging.

Background and objective:  Spirometry is insensitive to small airway abnormalities in asthma. Our objective was to evaluate regional lung structure and function using hyperpolarized 3He magnetic resonance imaging (MRI) before, during and after a methacholine challenge (MCh).

Mapping and quantifying hyperpolarized 3He magnetic resonance imaging apparent diffusion coefficient gradients

We measured hyperpolarized 3He magnetic resonance imaging (MRI) apparent diffusion coefficients (ADC) and quantified ADC gradients in each three-by-three voxel region of interest (ROI). Such local ADC gradients can be represented in vector maps showing the magnitude (|G3x3|) and direction of ADC gradients, providing a qualitative visualization tool and quantitative measurement of airway and air space heterogeneity. Twenty-four subjects (15 male, mean age=67+/-7 yr) with global initiative for chronic obstructive lung disease (GOLD) stage II (n=9, mean age 68+/-6 yr), GOLD stage III chronic obstructive pulmonary disease (COPD; n=7, mean age 67+/-8 yr), and age-matched healthy volunteers (n=8, mean age 67+/-6 yr) were enrolled based on their age and spirometry results. Hyperpolarized 3He MRI was performed on a whole body 3.0 Tesla system. Mean 3He ADC and ADC standard deviation were calculated for the center coronal slice, and the mean magnitude and direction of the ADC gradient vectors were calculated for each three-by-three voxel matrix (|G3x3|). While the 3He ADC standard deviation was not significantly different, mean |G3x3| was significantly different between subjects with stage II (0.14+/-0.03 cm/s) and stage III COPD (0.19+/-0.03 cm/s; P<0.005) and between healthy subjects (0.12+/-0.03 cm/s) and those with stage II COPD (P<0.02). The second order statistic |G3x3| may provide a sensitive measure of ADC heterogeneity for ROI representing 9.4x9.4x30 mm or 2.6 cm3 of lung tissue.

A pilot randomised clinical trial of mepolizumab in COPD with eosinophilic bronchitis.

Airflow limitation in chronic obstructive pulmonary disease (COPD) is associated with influx of various inflammatory cells (e.g. eosinophils, neutrophils, lymphocytes, macrophages) into the airways. Approximately one-third of stable COPD patients and one in five COPD exacerbations are associated with eosinophilic bronchitis that usually responds to inhaled or ingested corticosteroids [1]. Specific anti-eosinophil agents like mepolizumab, a humanised monoclonal antibody against interleukin 5 (IL-5), reduce severe asthma exacerbations and improve lung function [2–4]. The improvement in forced expiratory volume in 1 s (FEV1) is also associated with a decrease in biomarkers of airway remodelling, such as sputum hyaluronan and versican, over a 6-month treatment period [5]. It is not known if the same benefits are observed in patients with COPD and eosinophilia in whom the airflow obstruction is due to cigarette smoke-related bronchitis and emphysema. Eosinophils may not directly contribute to luminal obstruction in COPD although they may predict steroid response http://ow.ly/b3Au308wA0m

Mild chronic obstructive pulmonary disease: why spirometry is not sufficient!

ABSTRACT Introduction: Chronic obstructive pulmonary disease (COPD) – an inflammatory disease of the airways, alveoli and lung microvasculature – is a leading cause of death worldwide. Smokers with milder airway obstruction constitute the majority of patients with this disease. Many studies have shown increased morbidity, activity-related dyspnea, exercise intolerance and mortality in such patients, compared with age-matched healthy populations. Clinical evaluation of symptomatic smokers with ostensibly mild airway obstruction poses a challenge in clinical practice as spirometry can obscure extensive heterogeneous pathophysiological impairment. Areas covered: A detailed review of the evidence for complex biological, physiological and radiological abnormalities in smokers who barely fit arbitrary spirometric criteria for COPD diagnosis. A brief discussion of the debate about current diagnostic spirometric criteria for COPD that can lead to diagnostic confusion and, in-some-instances, to inappropriate management. Finally, we provide a review of the clinical implications of these structural and functional abnormalities and try to build a solid rationale for earlier detection and effective, timely management. Expert commentary: The prevalence of mild COPD among smokers is high, yet under-diagnosis remains a major problem and there is lack of evidence-based management recommendations for this sub-population. Further tests beyond spirometry are useful in uncovering patho-physiological derangements that are clinically relevant.

Sensitive three-dimensional ultrasound assessment of carotid atherosclerosis by weighted average of local vessel wall and plaque thickness change

Purpose: Vitamin B deficiency has been identified as a risk factor for vascular events. However, the reduction of vascular events was not shown in large randomized controlled trials evaluating B‐Vitamin therapy. There is an important requirement to develop sensitive biomarkers to be used as efficacy targets for B‐Vitamin therapy as well as other dietary treatments and lifestyle regimes that are being developed. Carotid vessel‐wall‐plus‐plaque thickness change (VWT‐Change) measured from 3D ultrasound has been shown to be sensitive to atorvastatin therapies in previous studies. However, B‐Vitamin treatment is expected to confer a smaller beneficial effect in carotid atherosclerosis than the strong dose of atorvastatin. This paper introduces a sensitive atherosclerosis biomarker based on the weighted mean VWT‐Change measurement from 3D ultrasound with a purpose to detect statistically significant effect of B‐Vitamin therapy. Methods: Of the 56 subjects analyzed in this study, 27 were randomized to receive a B‐Vitamin tablet daily and 29 received a placebo tablet daily. Participants were scanned at baseline and 1.9 ± 0.8 yr later. The 3D VWT map at each scanning session was computed by matching the outer wall and lumen surfaces on a point‐by‐point basis. The 3D annual VWT‐Change maps were obtained by first registering the 3D VWT maps obtained at the baseline and follow‐up scanning sessions, and then taking the point‐wise difference in VWT and dividing the result by the years elapsed from the baseline to the follow‐up scanning session. The 3D VWT‐Change maps constructed for all patients were mapped to a 2D carotid template to adjust for the anatomic variability of the arteries. A weight at each point of the carotid template was assigned based on the degree of correlation between the VWT‐Change measurements exhibited at that point and the treatment received (i.e., B‐Vitamin or placebo) quantified by mutual information. The weighted mean of VWT‐Change for each patient, denoted by Symbol, was computed according to this weight. T‐tests were performed to compare the sensitivity of Symbol with existing biomarkers in detecting treatment effects. These biomarkers included changes in intima‐media thickness (IMT), total plaque area (TPA), vessel wall volume (VWV), unweighted average of VWT‐Change (Symbol) and a previously described biomarker, denoted by Symbol, that quantifies the mean VWT‐Change specific to regions of interest identified by a feature selection algorithm. Symbol. No Caption available. Symbol. No Caption available. Symbol. No Caption available. Symbol. No Caption available. Results: Among the six biomarkers evaluated, the effect of B Vitamins was detected only by Symbol in this cohort (Symbol). The sample sizes per treatment group required to detect an effect as large as exhibited in this study were 139, 178, 41 for ΔVWV, Symbol and Symbol respectively. Symbol. No Caption available. Symbol. No Caption available. Symbol. No Caption available. Symbol. No Caption available. Conclusion: The proposed weighted mean of VWT‐Change is more sensitive than existing biomarkers in detecting treatment effects. This measurement tool will allow for many proof‐of‐principal studies to be performed for various novel treatments before a more costly study involving a larger population is held to validate the results.

Two and three-dimensional segmentation ofhyperpolarized 3 He magnetic resonance imaging ofpulmonary gas distribution

A semi-automated method for generating hyperpolarized helium-3 (3He) measurements of individual slice (2D) or whole lung (3D) gas distribution was developed. 3He MRI functional images were segmented using two-dimensional (2D) and three-dimensional (3D) hierarchical K-means clustering of the 3He MRI signal and in addition a seeded region-growing algorithm was employed for segmentation of the 1H MRI thoracic cavity volume. 3He MRI pulmonary function measurements were generated following two-dimensional landmark-based non-rigid registration of the 3He and 1H pulmonary images. We applied this method to MRI of healthy subjects and subjects with chronic obstructive lung disease (COPD). The results of hierarchical K-means 2D and 3D segmentation were compared to an expert observers manual segmentation results using linear regression, Pearson correlations and the Dice similarity coefficient. 2D hierarchical K-means segmentation of ventilation volume (VV) and ventilation defect volume (VDV) was strongly and significantly correlated with manual measurements (VV: r=0.98, p<.0001; VDV: r=0.97, p<.0001) and mean Dice coefficients were greater than 92% for all subjects. 3D hierarchical K-means segmentation of VV and VDV was also strongly and significantly correlated with manual measurements (VV: r=0.98, p<.0001; VDV: r=0.64, p<.0001) and the mean Dice coefficients were greater than 91% for all subjects. Both 2D and 3D semi-automated segmentation of 3He MRI gas distribution provides a way to generate novel pulmonary function measurements.

3D Ultrasound System for Analysis of Carotid Plaque Progression and Regression

Morphological characterization of carotid plaques has been used for risk stratification and evaluation of response to therapy, evaluation of new risk factors, genetic research, and for quantifying effects of new anti-atherosclerotic therapies. We developed a 3D US system that allows detailed studies of carotid plaques in 3D. Our software includes 3D reconstruction, viewing, and manual and semi-automated segmentation of carotid plaques. We evaluated our plaque quantification software by examining plaque volume measurement accuracy, variability, and plaque surface morphology. Our results indicate that our approach is sensitive tool and can be used in studies of atherosclerotic plaque progression and regression.

Po-Thur Eve General-24: Non-Invasive Imaging Phenotypes of Carotid Atherosclerosis in Subjects: MRI, B-mode and 3D Ultrasound Measurements

Atherosclerosis is a chronic inflammatory disease, characterized by the accumulation of lipids and fibrous elements within the inner‐most layer of the artery wall. Vulnerable atherosclerotic plaques may eventually rupture, resulting in emboli that can obstruct blood flow and result in stroke or myocardial infarction. Direct measurements of atherosclerosis include non‐invasive imaging phenotypes such as MRI and 3DUS derived plaque and wall volume measurements and B‐mode US measurements of the intima media thickness (IMT). Here we report the first comparison of IMT with 3D Ultrasound and MRI‐derived atherosclerosis phenotypes measured in five subjects with moderate carotid atherosclerosis . Five research subjects with carotid plaque area ⩾ 0.5 cm2 were studied and all subjects were undergoing treatment for hyperlipidemia. Mean age was 66 yrs with no significant difference between males and females. Subjects underwent MRI, 3DUS and 2D B‐mode US of the left and right carotid arteries. A single observer carried out 3DUS vessel wall volume measurements (VWV) in 10 subject images at both time points, a second observer measured MRI vessel wall volume; a third observer measured IMT. Both 3DUS VWV and MRI VWV measurements were repeated five times to determine intra‐observer variability and variability between time points. At baseline 3DUS and MRI VWV measurements were not significantly different. No significant differences was observed for mean 3DUS VWV and MRI VWV at test and retest. No significant difference between mean IMT at test and retest was found. IMT measurements had the highest intra‐class correlation coefficients and the lowest coefficient of variation values.

Pulmonary MRI in Clinical Trials

Until very recently, pulmonary MRI has played a limited clinical role for patients with chronic lung diseases such as COPD and asthma. The reasons for this are numerous and complex; yet, because of a concerted effort of a number of key research sites, pulmonary MRI endpoints are increasingly being used as research tools and biomarkers in clinical trials. A number of previous landmark studies focused on the development and validation of biomarkers to provide a better understanding of structural and functional information. These biomarkers are now being applied in emerging cohort studies to forge a better understanding of lung disease in cross-sectional and longitudinal evaluations and in the evaluation of localized treatment and regional treatment responses. Pulmonary MRI biomarker use has certainly been increasing, but gaps remain between the research bench and clinical workflows to patient care. Advancing pulmonary MRI toward clinical implementation will require the concerted, globally collaborative development and validation of clinically relevant biomarkers in multinational cohort studies and clinical trials.

WE-FG-206-08: Pulmonary Functional Imaging Biomarkers of NSCLC to Guide and Optimize Functional Lung Avoidance Radiotherapy

PURPOSE Functional lung avoidance radiotherapy promises optimized therapy planning by minimizing dose to well-functioning lung and maximizing dose to the rest of the lung. Patients with NSCLC commonly present with co-morbid COPD and heterogeneously distributed ventilation abnormalities stemming from emphysema, airways disease, and tumour burden. We hypothesized that pulmonary functional imaging methods may be used to optimize radiotherapy plans to avoid regions of well-functioning lung and significantly improve outcomes like quality-of-life and survival. To ascertain the utility of functional lung avoidance therapy in clinical practice, we measured COPD phenotypes in NSCLC patients enrolled in a randomized-controlled-clinical-trial prior to curative intent therapy. METHODS Thirty stage IIIA/IIIB NSCLC patients provided written informed consent to a randomized-controlled-clinical-trial (https://clinicaltrials.gov/ct2/show/NCT02002052) comparing outcomes in patients randomized to standard or image-guided radiotherapy. Hyperpolarized noble gas MRI ventilation-defect-percent (VDP) (Kirby et al, Acad Radiol, 2012) as well as CT-emphysema measurements were determined. Patients were stratified based on quantitative imaging evidence of ventilation-defects and emphysema into two subgroups: 1) tumour-specific ventilation defects only (TSD), and, 2) tumour-specific and other ventilation defects with and without emphysema (TSDVE ). Receiver-operating-characteristic (ROC) curves were used to characterize the performance of clinical measures as predictors of the presence of non-tumour specific ventilation defects. RESULTS Twenty-one out of thirty subjects (70%) had non-tumour specific ventilation defects (TSDVE ) and nine subjects had ONLY tumour-specific defects (TSD). Subjects in the TSDVE group had significantly greater smoking-history (p=.006) and airflow obstruction (FEV1 /FVC) (p=.001). ROC analysis demonstrated an 87% classification rate for smoking pack-years, 90% for FEV1 /FVC, and 56% for tumour RECIST measurements for identifying patients with non-tumour and tumour-specific ventilation abnormalities. CONCLUSION 70% of NSCLC patients had ventilation abnormalities stemming from emphysema, airways disease and tumour burden. Smoking-history and airflow obstruction, but not RECIST, identified NSCLC patients with ventilation abnormalities appropriate for functional lung avoidance therapy.