Fereidoun Abtin

A one-year, phase I/IIa, open-label pilot trial of imatinib mesylate in the treatment of systemic sclerosis-associated active interstitial lung disease

OBJECTIVE Transforming growth factor β (TGFβ) and platelet-derived growth factor (PDGF) may play a critical role in systemic sclerosis (SSc)-related interstitial lung disease (ILD), and imatinib is a potent inhibitor of TGFβ and PDGF production. In this 1-year, phase I/IIa open-label pilot study of imatinib in patients with SSc-related active ILD, our primary aim was to assess the safety of imatinib; we also explored its efficacy. METHODS We recruited 20 SSc patients with a forced vital capacity (FVC) of <85% predicted, dyspnea on exertion, and presence of a ground-glass appearance on high-resolution computed tomography. Patients received oral therapy with imatinib (up to 600 mg/day) for a period of 1 year. Adverse events were recorded, pulmonary function was tested, and the modified Rodnan skin thickness score (MRSS) was assessed every 3 months. The course of changes in lung function, the Health Assessment Questionnaire (HAQ) disability index (DI), and the MRSS were modeled over the period of study to explore treatment efficacy. RESULTS The majority of patients were female (65%), Caucasian (75%), and had diffuse cutaneous SSc (70%). At baseline, the mean ± SD FVC % predicted was 65.2 ± 14.0 and the mean ± SD MRSS was 18.7 ± 10.1. The mean ± SD dosage of imatinib was 445 ± 125 mg/day. Of the 20 SSc patients, 12 completed the study, 7 discontinued because of adverse events (AEs), and 1 patient was lost to followup. Common AEs (≥20%) included fatigue, facial/lower extremity edema, nausea and vomiting, diarrhea, generalized rash, and new-onset proteinuria. Treatment with imatinib showed a trend toward improvement in the FVC % predicted (1.74%; P not significant) and the MRSS (3.9 units; P < 0.001). CONCLUSION Use of high-dose daily therapy with imatinib (600 mg/day) in SSc patients with ILD was associated with a large number of AEs. Our experience with AEs suggests that dosages of imatinib lower than 600 mg/day may be appropriate and that further dose ranging analysis is needed in order to understand the therapeutic index of imatinib in SSc.

Computed Tomography Screening for Lung Cancer: Has It Finally Arrived? Implications of the National Lung Screening Trial

The National Lung Screening Trial (NLST) has provided compelling evidence of the efficacy of lung cancer screening using low-dose helical computed tomography (LDCT) to reduce lung cancer mortality. The NLST randomized 53,454 older current or former heavy smokers to receive LDCT or chest radiography (CXR) for three annual screens. Participants were observed for a median of 6.5 years for outcomes. Vital status was available in more than 95% of participants. LDCT was positive in 24.2% of screens, compared with 6.9% of CXRs; more than 95% of all positive LDCT screens were not associated with lung cancer. LDCT detected more than twice the number of early-stage lung cancers and resulted in a stage shift from advanced to early-stage disease. Complications of LDCT screening were minimal. Lung cancer-specific mortality was reduced by 20% relative to CXR; all-cause mortality was reduced by 6.7%. The major harms of LDCT are radiation exposure, high false-positive rates, and the potential for overdiagnosis. This review discusses the risks and benefits of LDCT screening as well as an approach to LDCT implementation that incorporates systematic screening practice with smoking cessation programs and offers opportunities for better determination of appropriate risk cohorts for screening and for better diagnostic prediction of lung cancer in the setting of screen-detected nodules. The challenges of implementation are considered for screening programs, for primary care clinicians, and across socioeconomic strata. Considerations for future research to complement imaging-based screening to reduce the burden of lung cancer are discussed.

Automated classification of lung bronchovascular anatomy in CT using AdaBoost

Lung CAD systems require the ability to classify a variety of pulmonary structures as part of the diagnostic process. The purpose of this work was to develop a methodology for fully automated voxel-by-voxel classification of airways, fissures, nodules, and vessels from chest CT images using a single feature set and classification method. Twenty-nine thin section CT scans were obtained from the Lung Image Database Consortium (LIDC). Multiple radiologists labeled voxels corresponding to the following structures: airways (trachea to 6th generation), major and minor lobar fissures, nodules, and vessels (hilum to peripheral), and normal lung parenchyma. The labeled data was used in conjunction with a supervised machine learning approach (AdaBoost) to train a set of ensemble classifiers. Each ensemble classifier was trained to detect voxels part of a specific structure (either airway, fissure, nodule, vessel, or parenchyma). The feature set consisted of voxel attenuation and a small number of features based on the eigenvalues of the Hessian matrix (used to differentiate structures by shape). When each ensemble classifier was composed of 20 weak classifiers, the AUC values for the airway, fissure, nodule, vessel, and parenchyma classifiers were 0.984+/-0.011, 0.949+/-0.009, 0.945+/-0.018, 0.953+/-0.016, and 0.931+/-0.015, respectively. The strong results suggest that this could be an effective input to higher-level anatomical based segmentation models with the potential to improve CAD performance.

Radiofrequency Ablation of Lung Tumors: Imaging Features of the Postablation Zone

Radiofrequency ablation (RFA) is used to treat pulmonary malignancies. Although preliminary results are suggestive of a survival benefit, local progression rates are appreciable. Because a patient can undergo repeat treatment if recurrence is detected early, reliable post-RFA imaging follow-up is critical. The purpose of this article is to describe (a) an algorithm for post-RFA imaging surveillance; (b) the computed tomographic (CT) appearance, size, enhancement, and positron emission tomographic (PET) metabolic activity of the ablation zone; and (c) CT, PET, and dual-modality imaging with PET and CT (PET/CT) features suggestive of partial ablation or tumor recurrence and progression. CT is routinely used for post-RFA follow-up. PET and PET/CT have emerged as auxiliary follow-up techniques. CT with nodule densitometry may be used to supplement standard CT. Post-RFA follow-up was divided into three phases: early (immediately after to 1 week after RFA), intermediate (>1 week to 2 months), and late (>2 months). CT and PET imaging features suggestive of residual or recurrent disease include (a) increasing contrast material uptake in the ablation zone (>180 seconds on dynamic images), nodular enhancement measuring more than 10 mm, any central enhancement greater than 15 HU, and enhancement greater than baseline anytime after ablation; (b) growth of the RFA zone after 3 months (compared with baseline) and definitely after 6 months, peripheral nodular growth and change from ground-glass opacity to solid opacity, regional or distant lymph node enlargement, and new intrathoracic or extrathoracic disease; and (c) increased metabolic activity beyond 2 months, residual activity centrally or at the ablated tumor, and development of nodular activity.

Diagnostic performance comparison of the Chartis System and high-resolution computerized tomography fissure analysis for planning endoscopic lung volume reduction

Endobronchial valve (EBV) therapy is optimized in patients who demonstrate little or no collateral ventilation (CV). The accuracy of the Chartis System and visual assessment of high‐resolution computerized tomography (HRCT) fissure completeness by a core radiology laboratory for classifying CV status was compared by evaluating the relationship of each method with target lobe volume reduction (TLVR) after EBV placement.

Brief report: effect of ambrisentan treatment on exercise-induced pulmonary hypertension in systemic sclerosis: a prospective single-center, open-label pilot study.

OBJECTIVE Exercise-induced pulmonary hypertension (ePH) may represent an early, clinically relevant phase in the spectrum of pulmonary vascular disease. The purpose of this pilot study was to describe the changes in hemodynamics and exercise capacity in patients with systemic sclerosis (SSc) spectrum-associated ePH treated with open-label daily ambrisentan. METHODS Patients were treated with ambrisentan, 5 mg or 10 mg once daily, for 24 weeks. At baseline and 24 weeks, patients with SSc spectrum disorders exercised in a supine position, on a lower extremity cycle ergometer. All patients had normal hemodynamics at rest. We defined baseline ePH as a mean pulmonary artery pressure of >30 mm Hg with maximum exercise and a transpulmonary gradient (TPG) of >15 mm Hg. The primary end point was change in pulmonary vascular resistance (PVR) with exercise. Secondary end points included an improvement from baseline in 6-minute walking distance, health-related quality of life assessments, and cardiopulmonary hemodynamics. RESULTS Of the 12 enrolled patients, 11 completed the study. At 24 weeks there were improvements in mean exercise PVR (85.8 dynes × second/cm(5) ; P = 0.003) and mean distance covered during 6-minute walk (44.5 meters; P = 0.0007). Improvements were also observed in mean exercise cardiac output (1.4 liters/minute; P = 0.006), mean pulmonary artery pressure (-4.1 mm Hg; P = 0.02), and total pulmonary resistance (-93.0 dynes × seconds/cm(5) ; P = 0.0008). Three patients developed resting pulmonary arterial hypertension during the 24 weeks. CONCLUSION Exercise hemodynamics and exercise capacity in patients with SSc spectrum-associated ePH improved over 24 weeks with exposure to ambrisentan. Placebo-controlled studies are needed to confirm whether this is a drug-related effect and to determine optimal therapeutic regimens for patients with ePH.

A method for the automatic quantification of the completeness of pulmonary fissures: evaluation in a database of subjects with severe emphysema

AbstractObjectivesTo propose and evaluate a technique for automatic quantification of fissural completeness from chest computed tomography (CT) in a database of subjects with severe emphysema.MethodsNinety-six CT studies of patients with severe emphysema were included. The lungs, fissures and lobes were automatically segmented. The completeness of the fissures was calculated as the percentage of the lobar border defined by a fissure. The completeness score of the automatic method was compared with a visual consensus read by three radiologists using boxplots, rank sum tests and ROC analysis.ResultsThe consensus read found 49% (47/96), 15% (14/96) and 67% (64/96) of the right major, right minor and left major fissures to be complete. For all fissures visually assessed as being complete the automatic method resulted in significantly higher completeness scores (mean 92.78%) than for those assessed as being partial or absent (mean 77.16%; all p values <0.001). The areas under the curves for the automatic fissural completeness were 0.88, 0.91 and 0.83 for the right major, right minor and left major fissures respectively.ConclusionsAn automatic method is able to quantify fissural completeness in a cohort of subjects with severe emphysema consistent with a visual consensus read of three radiologists.Key Points• Lobar fissures are important for assessing the extent and distribution of lung disease • Modern CT allows automatic lobar segmentation and assessment of the fissures • This segmentation can also assess the completeness of the fissures. • Such assessment is important for decisions about novel therapies (eg for emphysema).

Classification of parenchymal abnormality in scleroderma lung using a novel approach to denoise images collected via a multicenter study.

RATIONALE AND OBJECTIVES Computerized classification techniques have been developed to offer accurate and robust pattern recognition in interstitial lung disease using texture features. However, these techniques still present challenges when analyzing computed tomographic (CT) image data from multiprotocols because of disparate acquisition protocols or from standardized, multicenter clinical trials because of noise variability. Our objective is to investigate the utility of denoising thin section CT image data to improve the classification of scleroderma disease patterns. The patterns are lung fibrosis (LF), groundglass (GG), honeycomb (HC), or normal lung (NL) within small regions of interest (ROIs). METHODS High-resolution CT images were scanned in a multicenter clinical trial for the Scleroderma Lung Study. A thoracic radiologist contoured a training set (38 patients) consisting of 148 ROIs with 46 LF, 85 GG, 4 HC, and 13 NL patterns and contoured a test set (33 new patients) consisting of 132 ROIs with 44 LF, 72 GG, 4 HC, and 12 NL patterns. The corresponding CT slices of a contoured ROI were denoised using Aujols mathematic partial differential equation algorithm. The algorithms noise parameter was estimated as the standard deviation of grey-level signal (in Hounsfield units) in a homogeneous, non-lung region: the aorta. Within each contoured ROI, every pixel within a 4 x 4 neighborhood was sampled (4 x 4 grid sampling). All sampled pixels from a contoured ROI were assumed to be the same disease pattern as labeled by the radiologist. 5,690 pixels (3,009 LF, 1,994 GG, 348 HC, and 339 NL) and 5,045 pixels (2,665 LF, 1,753 GG, 291 HC, and 336 NL) were sampled in training and test sets, respectively. Next, 58 texture features from the original and denoised image were calculated for each pixel. Using a multinomial logistic model, subsets of features (one from original and another from denoised images) were selected to classify disease patterns. Finally, pixels were classified into disease patterns using a support vector machine procedure. RESULTS From the training set, multinomial logistic model selected 45 features from the original images and 38 features from denoised images to classify disease patterns. Using the test set, the overall pixel classification rate by SVM increased from 87.8% to 89.5% with denoising. The specific classification rates (original/denoised) were 96.3/96.4% for LF, 88.8/89.4% for GG, 21.3/28.9% for HC, and 73.5/88.4% for NL. Denoising significantly improved the NL and overall classification rates (P = .037 and P = .047 respectively) at ROI level. CONCLUSIONS Analyzing multicenter data using a denoising approach led to more parsimonious classification models with increasing accuracy. This approach offers a novel alternate classification strategy for heterogeneous technical and disease components. Furthermore, the model offers the potential to discriminate the multiple patterns of scleroderma disease correctly.

Changes in right heart haemodynamics and echocardiographic function in an advanced phenotype of pulmonary hypertension and right heart dysfunction associated with pulmonary fibrosis

Background Pulmonary hypertension (PH)-targeted therapy in the setting of pulmonary fibrosis (PF) is controversial; the main clinical concern is worsening of systemic hypoxaemia. We sought to determine the effects of gentle initiation and chronic administration of parenteral treprostinil on right heart function in patients with PF associated with an advanced PH phenotype. Methods Open-label, prospective analysis of patients with PF-PH referred for lung transplantation (LT). Advanced PH was defined as mean pulmonary artery pressure (mPAP) ≥35 mm Hg. We compared haemodynamics, Doppler echocardiography (DE), oxygenation, dyspnoea and quality of life indices, and 6 min walk distance (6MWD) before and 12 weeks after parenteral treprostinil. Results 15 patients were recruited in the study. After therapy, there were significant improvements in right heart haemodynamics (right atrial pressure (9.5 ± 3.4 vs 6.0 ± 3.7); mPAP (47 ± 8 vs 38.9 ± 13.4); CI (2.3 ± 0.5 vs 2.7 ± 0.6); pulmonary vascular resistance (698 ± 278 vs 496 ± 229); transpulmonary gradient (34.7 ± 8.7 vs 28.5 ± 10.3); mvO2 (65 ± 7.2 vs 70.9 ± 7.4); and stroke volume index (29.2 ± 6.7 vs 33 ± 7.3)) and DE parameters reflecting right heart function (right ventricular (RV) end diastolic area (36.4 ± 5.2 vs 30.9 ± 8.2 cm2), left ventricular eccentricity index (1.7 ± 0.6 vs 1.3 ± 0.5), tricuspid annular planar systolic excursion (1.6 ± 0.5 vs 1.9 ± 0.2 cm)). These changes occurred without significant alteration in systemic oxygenation, heart rate, or mean systemic arterial pressure. In addition, improvements were seen in 6MWD (171 ± 93 vs 230 ± 114), 36-Item Short Form Health Survey Mental Component Summary aggregate (38 ± 11 vs 44.2 ± 10.7), University of California, San Diego Shortness of Breath Questionnaire (87 ± 17.1 vs 73.1 ± 21), and brain natriuretic peptide (558 ± 859 vs 228 ± 340). Conclusions PH-targeted therapy may improve right heart haemodynamics and echocardiographic function without affecting systemic oxygen saturation in an advanced PH phenotype associated with RV dysfunction in the setting of PF.

Prevalence of Tracheal Collapse in an Emphysema Cohort as Measured With End-expiration CT

RATIONALE AND OBJECTIVES To retrospectively investigate the prevalence of tracheal collapse in an emphysema cohort. The occurrence of a large degree of tracheal collapse may have important implications for the clinical management of respiratory symptoms and air trapping in patients with emphysema. MATERIALS AND METHODS Paired full-inspiratory and end-expiratory thin-section volumetric computed tomographic scans were available for 1071 long-term smokers with clinically and physiologically confirmed emphysema. The percentage reduction in the cross-sectional tracheal luminal area from full-inspiration to end-expiration was automatically computed at 2.5-mm intervals along the centerline of the trachea using customized software. RESULTS Maximal tracheal collapse did not follow a normal distribution in the emphysema cohort (P < .0001, skewness/kurtosis tests for normality); the median collapse was 18% (intraquartile range, 11%-30%). Statistically significant differences were found in the distribution of maximal collapse by gender (P < .005, Wilcoxon rank sum test). Overall, 10.5% of men and 17.1% of women showed evidence of tracheomalacia on the basis of the criterion of a reduction of 50% or greater in cross-sectional tracheal luminal area at end-expiration. CONCLUSION This study offers insights into the prevalence of tracheal collapse in a cohort of patients with emphysema; future work is needed to determine the possible relationship between tracheal collapse and air trapping in subjects with emphysema.