Quantitative implications of the updated EARL 2019 PET-CT performance standards

Purpose Recently, updated EARL specifications (EARL2) have been developed and announced. This study aims at investigating the impact of the EARL2 specifications on the quantitative reads of clinical PET-CT studies and testing a method to enable the use of the EARL2 standards whilst still generating quantitative reads compliant with current EARL standards (EARL1). Methods Thirteen non-small cell lung cancer (NSCLC) and seventeen lymphoma PET-CT studies were used to derive four image datasets-the first dataset complying with EARL1 specifications and the second reconstructed using parameters as described in EARL2. For the third (EARL2F6) and fourth (EARL2F7) dataset in EARL2, respectively, 6 mm and 7 mm Gaussian post-filtering was applied. We compared the results of quantitative metrics (MATV, SUVmax, SUVpeak, SUVmean, TLG, and tumor-to-liver and tumor-to-blood pool ratios) obtained with these 4 datasets in 55 suspected malignant lesions using three commonly used segmentation/volume of interest (VOI) methods (MAX41, A50P, SUV4). Results We found that with EARL2 MAX41 VOI method, MATV decreases by 22%, TLG remains unchanged and SUV values increase by 23-30% depending on the specific metric used. The EARL2F7 dataset produced quantitative metrics best aligning with EARL1, with no significant differences between most of the datasets (p>0.05). Different VOI methods performed similarly with regard to SUV metrics but differences in MATV as well as TLG were observed. No significant difference between NSCLC and lymphoma cancer types was observed. Conclusions Application of EARL2 standards can result in higher SUVs, reduced MATV and slightly changed TLG values relative to EARL1. Applying a Gaussian filter to PET images reconstructed using EARL2 parameters successfully yielded EARL1 compliant data

Quantitative implications of the updated EARL 2019 PET-CT performance standards

Purpose Recently, updated EARL specifications (EARL2) have been developed and announced. This study aims at investigating the impact of the EARL2 specifications on the quantitative reads of clinical PET-CT studies and testing a method to enable the use of the EARL2 standards whilst still generating quantitative reads compliant with current EARL standards (EARL1). Methods Thirteen non-small cell lung cancer (NSCLC) and seventeen lymphoma PET-CT studies were used to derive four image datasets-the first dataset complying with EARL1 specifications and the second reconstructed using parameters as described in EARL2. For the third (EARL2F6) and fourth (EARL2F7) dataset in EARL2, respectively, 6 mm and 7 mm Gaussian post-filtering was applied. We compared the results of quantitative metrics (MATV, SUVmax, SUVpeak, SUVmean, TLG, and tumor-to-liver and tumor-to-blood pool ratios) obtained with these 4 datasets in 55 suspected malignant lesions using three commonly used segmentation/volume of interest (VOI) methods (MAX41, A50P, SUV4). Results We found that with EARL2 MAX41 VOI method, MATV decreases by 22%, TLG remains unchanged and SUV values increase by 23-30% depending on the specific metric used. The EARL2F7 dataset produced quantitative metrics best aligning with EARL1, with no significant differences between most of the datasets (p>0.05). Different VOI methods performed similarly with regard to SUV metrics but differences in MATV as well as TLG were observed. No significant difference between NSCLC and lymphoma cancer types was observed. Conclusions Application of EARL2 standards can result in higher SUVs, reduced MATV and slightly changed TLG values relative to EARL1. Applying a Gaussian filter to PET images reconstructed using EARL2 parameters successfully yielded EARL1 compliant data

Baseline radiomics features and MYC rearrangement status predict progression in aggressive B-cell lymphoma

We investigated whether the outcome prediction of patients with aggressive B-cell lymphoma can be improved by combining clinical, molecular genotype, and radiomics features. MYC, BCL2, and BCL6 rearrangements were assessed using fluorescence in situ hybridization. Seventeen radiomics features were extracted from the baseline positron emission tomography–computed tomography of 323 patients, which included maximum standardized uptake value (SUV(max)), SUV(peak), SUV(mean), metabolic tumor volume (MTV), total lesion glycolysis, and 12 dissemination features pertaining to distance, differences in uptake and volume between lesions, respectively. Logistic regression with backward feature selection was used to predict progression after 2 years. The predictive value of (1) International Prognostic Index (IPI); (2) IPI plus MYC; (3) IPI, MYC, and MTV; (4) radiomics; and (5) MYC plus radiomics models were tested using the cross-validated area under the curve (CV-AUC) and positive predictive values (PPVs). IPI yielded a CV-AUC of 0.65 ± 0.07 with a PPV of 29.6%. The IPI plus MYC model yielded a CV-AUC of 0.68 ± 0.08. IPI, MYC, and MTV yielded a CV-AUC of 0.74 ± 0.08. The highest model performance of the radiomics model was observed for MTV combined with the maximum distance between the largest lesion and another lesion, the maximum difference in SUV(peak) between 2 lesions, and the sum of distances between all lesions, yielding an improved CV-AUC of 0.77 ± 0.07. The same radiomics features were retained when adding MYC (CV-AUC, 0.77 ± 0.07). PPV was highest for the MYC plus radiomics model (50.0%) and increased by 20% compared with the IPI (29.6%). Adding radiomics features improved model performance and PPV and can, therefore, aid in identifying poor prognosis patients

Quantitative assessment of arthritis activity in rheumatoid arthritis patients using [11c]dpa-713 positron emission tomography

Treatment for rheumatoid arthritis (RA) should be started as early as possible to prevent destruction of bone and cartilage in affected joints. A new diagnostic tool for both early diagnosis and therapy monitoring would be valuable to reduce permanent joint damage. Positron emission tomography (PET) imaging of macrophages is a previously demonstrated non-invasive means to visualize (sub)clinical arthritis in RA patients. We developed a kinetic model to quantify uptake of the macrophage tracer [11C]DPA-713 (N,N-diethyl-2-[2-(4-methoxyphenyl)-5,7-dimethylpyrazolo [1,5-a]pyrimidin-3-yl]acetamide) in arthritic joints of RA patients and to assess the performance of several simplified methods. Dynamic [11C]DPA-713 scans of 60 min with both arterial and venous blood sampling were performed in five patients with clinically active disease. [11C]DPA-713 showed enhanced uptake in affected joints of RA patients, with tracer uptake levels corresponding to clinical presence and severity of arthritis. The optimal quantitative model for assessment of [11C]DPA-713 uptake was the irreversible two tissue compartment model (2T3k). Both Ki and standardized uptake value (SUV) correlated with the presence of arthritis in RA patients. Using SUV as an outcome measure allows for a simplified static imaging protocol that can be used in larger cohorts

Combatting the effect of image reconstruction settings on lymphoma [18F]FDG PET metabolic tumor volume assessment using various segmentation methods

Background: [18F]FDG PET-based metabolic tumor volume (MTV) is a promising prognostic marker for lymphoma patients. The aim of this study is to assess the sensitivity of several MTV segmentation methods to variations in image reconstruction methods and the ability of ComBat to improve MTV reproducibility. Methods: Fifty-six lesions were segmented from baseline [18F]FDG PET scans of 19 lymphoma patients. For each scan, EARL1 and EARL2 standards and locally clinically preferred reconstruction protocols were applied. Lesions were delineated using 9 semiautomatic segmentation methods: fixed threshold based on standardized uptake value (SUV), (SUV = 4, SUV = 2.5), relative threshold (41% of SUVmax [41M], 50% of SUVpeak [A50P]), majority vote-based methods that select voxels detected by at least 2 (MV2) and 3 (MV3) out of the latter 4 methods, Nestle thresholding, and methods that identify the optimal method based on SUVmax (L2A, L2B). MTVs from EARL2 and locally clinically preferred reconstructions were compared to those from EARL1. Finally, different versions of ComBat were explored to harmonize the data. Results: MTVs from the SUV4.0 method were least sensitive to the use of different reconstructions (MTV ratio: median = 1.01, interquartile range = [0.96–1.10]). After ComBat harmonization, an improved agreement of MTVs among different reconstructions was found for most segmentation methods. The regular implementation of ComBat (‘Regular ComBat’) using non-transformed distributions resulted in less accurate and precise MTV alignments than a version using log-transformed datasets (‘Log-transformed ComBat’). Conclusion: MTV depends on both segmentation method and reconstruction methods. ComBat reduces reconstruction dependent MTV variability, especially when log-transformation is used to account for the non-normal distribution of MTVs

Sensitivity of an AI method for [18F]FDG PET/CT outcome prediction of diffuse large B-cell lymphoma patients to image reconstruction protocols

Abstract Background Convolutional neural networks (CNNs), applied to baseline [18F]-FDG PET/CT maximum intensity projections (MIPs), show potential for treatment outcome prediction in diffuse large B-cell lymphoma (DLBCL). The aim of this study is to investigate the robustness of CNN predictions to different image reconstruction protocols. Baseline [18F]FDG PET/CT scans were collected from 20 DLBCL patients. EARL1, EARL2 and high-resolution (HR) protocols were applied per scan, generating three images with different image qualities. Image-based transformation was applied by blurring EARL2 and HR images to generate EARL1 compliant images using a Gaussian filter of 5 and 7 mm, respectively. MIPs were generated for each of the reconstructions, before and after image transformation. An in-house developed CNN predicted the probability of tumor progression within 2 years for each MIP. The difference in probabilities per patient was then calculated between both EARL2 and HR with respect to EARL1 (delta probabilities or ΔP). We compared these to the probabilities obtained after aligning the data with ComBat using the difference in median and interquartile range (IQR). Results CNN probabilities were found to be sensitive to different reconstruction protocols (EARL2 ΔP: median = 0.09, interquartile range (IQR) = [0.06, 0.10] and HR ΔP: median = 0.1, IQR = [0.08, 0.16]). Moreover, higher resolution images (EARL2 and HR) led to higher probability values. After image-based and ComBat transformation, an improved agreement of CNN probabilities among reconstructions was found for all patients. This agreement was slightly better after image-based transformation (transformed EARL2 ΔP: median = 0.022, IQR = [0.01, 0.02] and transformed HR ΔP: median = 0.029, IQR = [0.01, 0.03]). Conclusion Our CNN-based outcome predictions are affected by the applied reconstruction protocols, yet in a predictable manner. Image-based harmonization is a suitable approach to harmonize CNN predictions across image reconstruction protocols

Interobserver agreement in automated metabolic tumor volume measurements of Deauville score 4 and 5 lesions at interim 18F-FDG PET in DLBCL

Introduction: Metabolic tumor volume (MTV) on interim-PET (I-PET) is a potential prognostic biomarker for diffuse large B-cell lymphoma (DLBCL). Implementation of MTV on I-PET requires consensus which semi-automated segmentation method delineates lesions most successfully with least user interaction. Methods used for baseline PET are not necessarily optimal for I-PET due to lower lesional standardized uptake values (SUV) at I-PET. Therefore, we aimed to evaluate which method provides the best delineation quality of Deauville-score (DS) 4-5 DLBCL lesions on I-PET at best interobserver agreement on delineation quality and, secondly, to assess the effect of lesional SUVmax on delineation quality and performance agreements. Methods: DS4-5 lesions from 45 I-PET scans were delineated using six semi-automated methods i) SUV 2.5, ii) SUV 4.0, iii) adaptive threshold [A50%peak], iv) 41% of maximum SUV [41%max], v) majority vote including voxels detected by ≥2 methods [MV2] and vi) detected by ≥3 methods [MV3]. Delineation quality per MTV was rated by three independent observers as acceptable or non-acceptable. For each method, observer scores on delineation quality, specific agreements and MTV were assessed for all lesions, and per category of lesional SUVmax (10). Results: In 60 DS4-5 lesions on I-PET, MV3 performed best, with acceptable delineation in 90% of lesions, with a positive agreement (PA) of 93%. Delineation quality scores and agreements per method strongly depended on lesional SUV: the best delineation quality scores were obtained using MV3 in lesions with SUVmax10, were comparable after excluding visually failed MV3 contouring. For lesions with SUVmax<10, MTVs using different methods correlated poorly. Conclusion: On I-PET, MV3 performed best and provided the highest interobserver agreement regarding acceptable delineations of DS4-5 DLBCL lesions. However, delineation method preference strongly depended on lesional SUV. Therefore, we suggest to explore an approach that identifies the optimal delineation method per lesion as function of tumor FDG uptake characteristics, i.e. SUVmax

Interobserver agreement in automated metabolic tumor volume measurements of Deauville score 4 and 5 lesions at interim 18F-FDG PET in DLBCL

Metabolic tumor volume (MTV) on interim-PET (I-PET) is a potential prognostic biomarker for diffuse large B-cell lymphoma (DLBCL). Implementation of MTV on I-PET requires consensus which semi-automated segmentation method delineates lesions most successfully with least user interaction. Methods used for baseline PET are not necessarily optimal for I-PET due to lower lesional standardized uptake values (SUV) at I-PET. Therefore, we aimed to evaluate which method provides the best delineation quality of Deauville-score (DS) 4-5 DLBCL lesions on I-PET at best interobserver agreement on delineation quality and, secondly, to assess the effect of lesional SUVmax on delineation quality and performance agreements. Methods: DS4-5 lesions from 45 I-PET scans were delineated using six semi-automated methods i) SUV 2.5, ii) SUV 4.0, iii) adaptive threshold [A50%peak], iv) 41% of maximum SUV [41%max], v) majority vote including voxels detected by ≥2 methods [MV2] and vi) detected by ≥3 methods [MV3]. Delineation quality per MTV was rated by three independent observers as acceptable or non-acceptable. For each method, observer scores on delineation quality, specific agreements and MTV were assessed for all lesions, and per category of lesional SUVmax (10). Results: In 60 DS4-5 lesions on I-PET, MV3 performed best, with acceptable delineation in 90% of lesions, with a positive agreement (PA) of 93%. Delineation quality scores and agreements per method strongly depended on lesional SUV: the best delineation quality scores were obtained using MV3 in lesions with SUVmax10, were comparable after excluding visually failed MV3 contouring. For lesions with SUVmax<10, MTVs using different methods correlated poorly. Conclusion: On I-PET, MV3 performed best and provided the highest interobserver agreement regarding acceptable delineations of DS4-5 DLBCL lesions. However, delineation method preference strongly depended on lesional SUV. Therefore, we suggest to explore an approach that identifies the optimal delineation method per lesion as function of tumor FDG uptake characteristics, i.e. SUVmax

18F-FDG PET improves baseline clinical predictors of response in diffuse large B-cell lymphoma: The HOVON-84 study

We aimed to determine the added value of baseline metabolic tumor volume (MTV) and interim positron emission tomography (I-PET) to age-adjusted international prognostic index (aaIPI) to predict 2- year progression-free survival (PFS) in diffuse large B-cell lymphoma (DLBCL). Secondary objectives were to investigate optimal I-PET response criteria (using Deauville score (DS) - or quantitative change in maximum Standardized Uptake Value (ΔSUVmax) between baseline and I-PET). Methods: Observational I-PET scans were performed after four cycles R(R)-CHOP14 (I-PET4) in the HOVON-84 randomized clinical trial (EudraCT 2006-005174-42), and centrally reviewed using DS (cut-off 4-5). Additionally, ΔSUVmax (prespecified cut-off 70%) and baseline MTV were measured. Multivariable hazard ratios (HR), positive (PPV), and negative predictive values (NPV) were obtained for 2-year PFS. Results: 513 I-PET4 scans were reviewed according to DS, and ΔSUVmax and baseline MTV were available for 367 and 296 patients. NPV of I-PET ranged between 82% and 86% for all PET response criteria. Univariate HR and PPV were optimal for ΔSUVmax (4·8 and 53%, respectively) compared to DS (3·1 and 38%, respectively). AaIPI and ΔSUVmax independently predicted 2-year PFS (HRs 3·2 and 5·0, respectively); adding MTV slightly improved this. Low/low-intermediate aaIPI combined with ΔSUVmax >70% (37% of patients) yielded a NPV of 93%, and the combination of high-intermediate/high aaIPI and ΔSUVmax=70% a PPV of 65%. Conclusion: In this DLBCL study, I-PET after four cycles R(R)-CHOP14 added predictive value to aaIPI for 2-year PFS, and both were independent response biomarkers in a multivariable Cox model. We externally validated that ΔSUVmax outperformed Deauville score in 2-year PFS prediction

An artificial intelligence method using FDG PET to predict treatment outcome in diffuse large B cell lymphoma patients

Abstract Convolutional neural networks (CNNs) may improve response prediction in diffuse large B-cell lymphoma (DLBCL). The aim of this study was to investigate the feasibility of a CNN using maximum intensity projection (MIP) images from 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) baseline scans to predict the probability of time-to-progression (TTP) within 2 years and compare it with the International Prognostic Index (IPI), i.e. a clinically used score. 296 DLBCL 18F-FDG PET/CT baseline scans collected from a prospective clinical trial (HOVON-84) were analysed. Cross-validation was performed using coronal and sagittal MIPs. An external dataset (340 DLBCL patients) was used to validate the model. Association between the probabilities, metabolic tumour volume and Dmaxbulk was assessed. Probabilities for PET scans with synthetically removed tumors were also assessed. The CNN provided a 2-year TTP prediction with an area under the curve (AUC) of 0.74, outperforming the IPI-based model (AUC = 0.68). Furthermore, high probabilities (> 0.6) of the original MIPs were considerably decreased after removing the tumours (< 0.4, generally). These findings suggest that MIP-based CNNs are able to predict treatment outcome in DLBCL