Karwoski, Ronald A.

Abstract Rationale Quantitative computed tomographic (CT) measures of baseline disease severity might identify patients with idiopathic pulmonary fibrosis (IPF) with an increased mortality risk. We evaluated whether quantitative CT variables could act as a cohort enrichment tool in future IPF drug trials. Objectives To determine whether computer-derived CT measures, specifically measures of pulmonary vessel–related structures (VRSs), can better predict functional decline and survival in IPF and reduce requisite sample sizes in drug trial populations. Methods Patients with IPF undergoing volumetric noncontrast CT imaging at the Royal Brompton Hospital, London, and St. Antonius Hospital, Utrecht, were examined to identify pulmonary function measures (including FVC) and visual and computer-derived (CALIPER [Computer-Aided Lung Informatics for Pathology Evaluation and Rating] software) CT features predictive of mortality and FVC decline. The discovery cohort comprised 247 consecutive patients, with validation of results conducted in a separate cohort of 284 patients, all fulfilling drug trial entry criteria. Measurements and Main Results In the discovery and validation cohorts, CALIPER-derived features, particularly VRS scores, were among the strongest predictors of survival and FVC decline. CALIPER results were accentuated in patients with less extensive disease, outperforming pulmonary function measures. When used as a cohort enrichment tool, a CALIPER VRS score greater than 4.4% of the lung was able to reduce the requisite sample size of an IPF drug trial by 26%. Conclusions Our study has validated a new quantitative CT measure in patients with IPF fulfilling drug trial entry criteria—the VRS score—that outperformed current gold standard measures of outcome. When used for cohort enrichment in an IPF drug trial setting, VRS threshold scores can reduce a required IPF drug trial population size by 25%, thereby limiting prohibitive trial costs. Importantly, VRS scores identify patients in whom antifibrotic medication prolongs life and reduces FVC decline.

ABSTRACT Background and objective This study evaluated whether patients with combined pulmonary fibrosis and emphysema (CPFE) have an increased likelihood of pulmonary hypertension (PHT) when compared with idiopathic pulmonary fibrosis (IPF) patients without emphysema. Methods Two consecutive IPF populations having undergone transthoracic echocardiography were examined ( n = 223 and n = 162). Emphysema and interstitial lung disease (ILD) extent were quantified visually; ILD extent was also quantified by a software tool, CALIPER. Echocardiographic criteria categorized PHT risk. Results The prevalence of an increased PHT likelihood was 29% and 31% in each CPFE cohort. Survival at 12 months was 60% across both CPFE cohorts with no significantly worsened outcome identified when compared with IPF patients without emphysema. Using logistic regression models in both cohorts, total computed tomography (CT) disease extent (ILD and emphysema) predicted the likelihood of PHT. After adjustment for total disease extent, CPFE had no stronger association with PHT likelihood than IPF patients without emphysema. Conclusion Our findings indicate that the reported association between CPFE and PHT is explained by the summed baseline CT extents of ILD and emphysema. Once baseline severity is taken into account, CPFE is not selectively associated with a malignant microvascular phenotype, when compared with IPF patients without emphysema.

Purpose: Fibrotic interstitial lung diseases presenting with nonspecific and overlapping radiologic findings may be difficult to diagnose without surgical biopsy. We hypothesized that baseline quantifiable radiologic features and their short-term interval change may be predictive of underlying histologic diagnosis as well as long-term survival in idiopathic pulmonary fibrosis (IPF) presenting without honeycombing versus nonspecific interstitial pneumonia (NSIP). Materials and Methods: Forty biopsy-confirmed IPF and 20 biopsy-confirmed NSIP patients with available high-resolution chest computed tomography 4 to 24 months apart were studied. CALIPER software was used for the automated characterization and quantification of radiologic findings. Results: IPF subjects were older (66 vs. 48; P<0.0001) with lower diffusion capacity for carbon monoxide and higher volumes of baseline reticulation (193 vs. 83 mL; P<0.0001). Over the interval period, compared with NSIP, IPF patients experienced greater functional decline (forced vital capacity, −6.3% vs. −1.7%; P=0.02) and radiologic progression, as noted by greater increase in reticulation volume (24 vs. 1.74 mL; P=0.048), and decrease in normal (−220 vs. −37.7 mL; P=0.045) and total lung volumes (−198 vs. 58.1 mL; P=0.03). Older age, male gender, higher reticulation volumes at baseline, and greater interval decrease in normal lung volumes were predictive of IPF. Both baseline and short-term changes in quantitative radiologic findings were predictive of mortality. Conclusions: Baseline quantitative radiologic findings and assessment of short-term disease progression may help characterize underlying IPF versus NSIP in those with difficult to differentiate clinicoradiologic presentations. Our study supports the possible utility of assessing serial quantifiable high-resolution chest computed tomographic findings for disease differentiation in these 2 entities.

Abstract This study assessed the inter-user reproducibility of Computer-Aided Nodule Assessment and Risk Yield (CANARY), a novel analytical tool that risk stratifies lung adenocarcinomas (ADCs) according to defined computed tomography (CT) structural characteristics. CANARY detects nine distinct voxel signatures in ADCs based on standard CT imaging, thereby defining nodule characteristics correlating with patient outcomes, and corresponding to invasion or lepidic growth histologically. A software user segments the borders of each ADC prior to voxel analysis, introducing potential variability into the assessment. While CANARY is a promising method, it requires validation of the analytical variability between users and prediction of accuracy in an independent cohort. To evaluate the reproducibility of CANARY analysis, three independent users who are not part of the CANARY development team segmented and analyzed 50 biopsy-confirmed primary lung ADCs from Vanderbilt University Medical Center. The CT scans of ADCs were selected retrospectively based on the following criteria: ADC-histology proven on biopsy, diagnosed between 2009-2015, less than 3cm in greatest diameter, and stages IA-IV. Users followed a standard operating procedure established at the Mayo Clinic, and were blinded to clinical characteristics and patient outcomes. Results: To measure inter-user variability of ADC voxel composition, the intraclass correlation coefficient (ICC) was calculated based upon the percentage of each voxel subtype within the whole ADC. An ICC of 1 reflects high reproducibility between users. Amongst all 50 ADCs, the average ICC for all nine voxel types was 0.828 (95% CI 0.76, 0.895). The ICC of the four voxel types associated with invasive features on CT was 0.865 (95% CI 0.805, 0.924). ICCs were also calculated using a logarithmic transformation for data normalization, generating an ICC of 0.745 (95% CI 0.663, 0.826) for all nine voxel types, and an ICC of 0.995 (95% CI 0.993, 0.997) for the four voxel types associated with invasion. Conclusions: (1) CANARY analysis of lung ADC voxel signatures appears to be reproducible amongst users, making it a reliable tool for the evaluation of ADC voxel density. (2) Correlation of invasive signatures associated with more aggressive ADCs was nearly perfect amongst users. Additional validation metrics for CANARY with larger datasets are being evaluated, including the accuracy of tumor prognostic predictions between users and analysis of ADC datasets from other institutions. Citation Format: Erica C. Nakajima, Michael P. Frankland, Tucker Johnson, Sanja L. Antic, Ronald A. Karwoski, Bennett Landman, Heidi Chen, Ronald C. Walker, Brian J. Bartholmai, Tobias Peikert, Srinivasan Rajagopalan, Pierre P. Massion, Fabien Maldonado. Assessing the reproducibility of computer-aided nodule assessment and risk yield (CANARY) method to characterize lung adenocarcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3723. doi:10.1158/1538-7445.AM2017-3723

ABSTRACTBackground and objectiveTo determine whether computer‐based quantification (CALIPER software) is superior to visual computed tomography (CT) scoring in the identification of CT patterns indicative of restrictive and obstructive functional indices in hypersensitivity pneumonitis (HP).MethodsA total of 135 consecutive HP patients had CT parenchymal patterns evaluated quantitatively by both visual scoring and CALIPER. Results were evaluated against: forced vital capacity (FVC), total lung capacity (TLC), diffusing capacity for carbon monoxide (DLCO) and a composite physiological index (CPI) to identify which CT scoring method better correlated with functional indices.ResultsCALIPER‐derived scores of total interstitial lung disease extent correlated more strongly than visual scores: FVC (CALIPER R = 0.73, visual R = 0.51); DLCO (CALIPER R = 0.61, visual R = 0.48); and CPI (CALIPER R = 0·70, visual R = 0·55). The CT variable that correlated most strongly with restrictive functional indices was CALIPER pulmonary vessel volume (PVV): FVC R = 0.75, DLCO R = 0.68 and CPI R = 0.76.Ground‐glass opacity quantified by CALIPER alone demonstrated strong associations with restrictive functional indices: CALIPER FVC R = 0.65; DLCO R = 0.59; CPI R = 0.64; and visual = not significant. Decreased attenuation lung quantified by CALIPER was a better morphological measure of obstructive lung disease than equivalent visual scores as judged by relationships with TLC (CALIPER R = 0.63 and visual R = 0.12). All results were maintained on multivariate analysis.ConclusionCALIPER improved on visual scoring in HP as judged by restrictive and obstructive functional correlations. Decreased attenuation regions of the lung quantified by CALIPER demonstrated better linkages to obstructive lung physiology than visually quantified CT scores. A novel CALIPER variable, the PVV, demonstrated the strongest linkages with restrictive functional indices and could represent a new automated index of disease severity in HP.

Purpose: The aim of the study was to determine whether a novel computed tomography (CT) postprocessing software technique (CALIPER) is superior to visual CT scoring as judged by functional correlations in idiopathic pulmonary fibrosis (IPF). Materials and Methods: A total of 283 consecutive patients with IPF had CT parenchymal patterns evaluated quantitatively with CALIPER and by visual scoring. These 2 techniques were evaluated against: forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), diffusing capacity for carbon monoxide (DLco), carbon monoxide transfer coefficient (Kco), and a composite physiological index (CPI), with regard to extent of interstitial lung disease (ILD), extent of emphysema, and pulmonary vascular abnormalities. Results: CALIPER-derived estimates of ILD extent demonstrated stronger univariate correlations than visual scores for most pulmonary function tests (PFTs): (FEV1: CALIPER R 2=0.29, visual R 2=0.18; FVC: CALIPER R 2=0.41, visual R 2=0.27; DLco: CALIPER R 2=0.31, visual R 2=0.35; CPI: CALIPER R 2=0.48, visual R 2=0.44). Correlations between CT measures of emphysema extent and PFTs were weak and did not differ significantly between CALIPER and visual scoring. Intriguingly, the pulmonary vessel volume provided similar correlations to total ILD extent scored by CALIPER for FVC, DLco, and CPI (FVC: R 2=0.45; DLco: R 2=0.34; CPI: R 2=0.53). Conclusions: CALIPER was superior to visual scoring as validated by functional correlations with PFTs. The pulmonary vessel volume, a novel CALIPER CT parameter with no visual scoring equivalent, has the potential to be a CT feature in the assessment of patients with IPF and requires further exploration.

Abstract Rationale Screening for lung cancer using low-dose computed tomography (CT) reduces lung cancer mortality. However, in addition to a high rate of benign nodules, lung cancer screening detects a large number of indolent cancers that generally belong to the adenocarcinoma spectrum. Individualized management of screen-detected adenocarcinomas would be facilitated by noninvasive risk stratification. Objectives To validate that Computer-Aided Nodule Assessment and Risk Yield (CANARY), a novel image analysis software, successfully risk stratifies screen-detected lung adenocarcinomas based on clinical disease outcomes. Methods We identified retrospective 294 eligible patients diagnosed with lung adenocarcinoma spectrum lesions in the low-dose CT arm of the National Lung Screening Trial. The last low-dose CT scan before the diagnosis of lung adenocarcinoma was analyzed using CANARY blinded to clinical data. Based on their parametric CANARY signatures, all the lung adenocarcinoma nodules were risk stratified into three groups. CANARY risk groups were compared using survival analysis for progression-free survival. Measurements and Main Results A total of 294 patients were included in the analysis. Kaplan-Meier analysis of all the 294 adenocarcinoma nodules stratified into the Good, Intermediate, and Poor CANARY risk groups yielded distinct progression-free survival curves (P &lt; 0.0001). This observation was confirmed in the unadjusted and adjusted (age, sex, race, and smoking status) progression-free survival analysis of all stage I cases. Conclusions CANARY allows the noninvasive risk stratification of lung adenocarcinomas into three groups with distinct post-treatment progression-free survival. Our results suggest that CANARY could ultimately facilitate individualized management of incidentally or screen-detected lung adenocarcinomas.