Test-Retest Repeatability of Patlak Slopes versus Standardized Uptake Values for Hypermetabolic Lesions and Normal Organs in an Oncologic PET/CT Population.

PURPOSE: We aimed to determine the test-retest repeatability of quantitative metrics based on the Patlak slope (PS) versus the standardized uptake value (SUV) among lesions and normal organs on oncologic [18F]FDG-PET/CT. PROCEDURES: This prospective, single-center study enrolled adults undergoing standard-of-care oncologic [18F]FDG-PET/CTs. Early (35-50 min post-injection) and late (75-90 min post-injection) SUV and PS images were reconstructed from dynamic whole-body PET data. Repeat imaging occurred within 7 days. Relevant quantitative metrics were extracted from lesions and normal organs. Repeatability was assessed via mean test-retest percent changes [T-RT %Δ], within-subject coefficients of variation (wCVs), and intra-class correlation coefficients (ICCs). RESULTS: Nine subjects (mean age, 61.7 ± 6.2 years; 6 females) completed the test-retest protocol. Four subjects collectively had 17 [18F]FDG-avid lesions. Lesion wCVs were higher (i.e., worse repeatability) for PS-early-max (16.2%) and PS-early-peak (15.6%) than for SUV-early-max (8.9%) and SUV-early-peak (8.1%), with similar early metric ICCs (0.95-0.98). Lesion wCVs were similar for PS-late-max (8.5%) and PS-late-peak (6.4%) relative to SUV-late-max (9.7%) and SUV-late-peak (7.2%), with similar late metric ICCs (0.93-0.98). There was a significant bias toward higher retest SUV and PS values in the lesion analysis (T-RT %Δ [95% CI]: SUV-late-max, 10.0% [2.6%, 17.0%]; PS-late-max, 20.4% [14.3%, 26.4%]) but not in the normal organ analysis. CONCLUSIONS: Among [18F]FDG-avid lesions, the repeatability of PS-based metrics is similar to equivalent SUV-based metrics at late post-injection time points, indicating that PS-based metrics may be suitable for tracking response to oncologic therapies. However, further validation is required in light of our study's limitations, including small sample size and bias toward higher retest values for some metrics.

MIRD Pamphlet No. 29: MIRDy90-A 90Y Research Microsphere Dosimetry Tool.

90Y-microsphere radioembolization has become a well-established treatment option for liver malignancies and is one of the first U.S. Food and Drug Administration-approved unsealed radionuclide brachytherapy devices to incorporate dosimetry-based treatment planning. Several different mathematical models are used to calculate the patient-specific prescribed activity of 90Y, namely, body surface area (SIR-Spheres only), MIRD single compartment, and MIRD dual compartment (partition). Under the auspices of the MIRDsoft initiative to develop community dosimetry software and tools, the body surface area, MIRD single-compartment, MIRD dual-compartment, and MIRD multicompartment models have been integrated into a MIRDy90 software worksheet. The worksheet was built in MS Excel to estimate and compare prescribed activities calculated via these respective models. The MIRDy90 software was validated against available tools for calculating 90Y prescribed activity. The results of MIRDy90 calculations were compared with those obtained from vendor and community-developed tools, and the calculations agreed well. The MIRDy90 worksheet was developed to provide a vetted tool to better evaluate patient-specific prescribed activities calculated via different models, as well as model influences with respect to varying input parameters. MIRDy90 allows users to interact and visualize the results of various parameter combinations. Variables, equations, and calculations are described in the MIRDy90 documentation and articulated in the MIRDy90 worksheet. The worksheet is distributed as a free tool to build expertise within the medical physics community and create a vetted standard for model and variable management.

Very-low-density lipoprotein triglyceride and free fatty acid plasma kinetics in women with high or low brown adipose tissue volume and overweight/obesity.

Although a high amount of brown adipose tissue (BAT) is associated with low plasma triglyceride concentration, the mechanism responsible for this relationship in people is not clear. Here, we evaluate the interrelationships among BAT, very-low-density lipoprotein triglyceride (VLDL-TG), and free fatty acid (FFA) plasma kinetics during thermoneutrality in women with overweight/obesity who had a low (<20 mL) or high (≥20 mL) volume of cold-activated BAT (assessed by using positron emission tomography in conjunction with 2-deoxy-2-[18F]-fluoro-glucose). We find that plasma TG and FFA concentrations are lower and VLDL-TG and FFA plasma clearance rates are faster in women with high BAT than low BAT volume, whereas VLDL-TG and FFA appearance rates in plasma are not different between the two groups. These findings demonstrate that women with high BAT volume have lower plasma TG and FFA concentrations than women with low BAT volumes because of increased VLDL-TG and FFA clearance rates. This study was registered at ClinicalTrials.gov (NCT02786251).

Joint regional uptake quantification of Thorium-227 and Radium-223 using a multiple-energy-window projection-domain quantitative SPECT method.

Thorium-227-based alpha-particle radiopharmaceutical therapies ({\alpha}-RPTs) are being investigated in several clinical and pre-clinical studies. After administration, Thorium-227 decays to Radium-223, another alpha-particle-emitting isotope, which redistributes within the patient. Reliable dose quantification of both Thorium-227 and Radium-223 is clinically important, and SPECT may perform this quantification as these isotopes also emit X- and gamma-ray photons. However, reliable quantification is challenged by the orders-of-magnitude lower activity compared to conventional SPECT, resulting in a very low number of detected counts, the presence of multiple photopeaks, substantial overlap in the emission spectra of these isotopes, and the image-degrading effects in SPECT. To address these issues, we propose a multiple-energy-window projection-domain quantification (MEW-PDQ) method that jointly estimates the regional activity uptake of both Thorium-227 and Radium-223 directly using the SPECT projection from multiple energy windows. We evaluated the method with realistic simulation studies using anthropomorphic digital phantoms, in the context of imaging patients with bone metastases of prostate cancer and treated with Thorium-227-based {\alpha}-RPTs. The proposed method yielded reliable (accurate and precise) regional uptake estimates of both isotopes and outperformed state-of-the-art methods across different lesion sizes and contrasts, in a virtual imaging trial, as well as with moderate levels of intra-regional heterogeneous uptake and with moderate inaccuracies in the definitions of the support of various regions. Additionally, we demonstrated the effectiveness of using multiple energy windows and the variance of the estimated uptake using the proposed method approached the Cram\'er-Rao-lower-bound-defined theoretical limit.

An automatic pipeline for PET/MRI attenuation correction validation in the brain.

PURPOSE: Challenges in PET/MRI quantitative accuracy for neurological uses arise from PET attenuation correction accuracy. We proposed and evaluated an automatic pipeline to assess the quantitative accuracy of four MRI-derived PET AC methods using analytically simulated PET brain lesions and ROIs as ground truth for PET activity. METHODS: Our proposed pipeline, integrating a synthetic lesion insertion tool and the FreeSurfer neuroimaging framework, inserts simulated spherical and brain ROIs into PET projection space, reconstructing them via four PET MRAC techniques. Utilizing an 11-patient brain PET dataset, we compared the quantitative accuracy of four MRACs (DIXON, DIXONbone, UTE AC, and DL-DIXON) against the gold standard PET CTAC, evaluating MRAC to CTAC activity bias in spherical lesions and brain ROIs with and without background activity against original (lesion free) PET reconstructed images. RESULTS: The proposed pipeline yielded accurate results for spherical lesions and brain ROIs, adhering to the MRAC to CTAC pattern of original brain PET images. Among the MRAC methods, DIXON AC exhibited the highest bias, followed by UTE, DIXONBone, and DL-DIXON showing the least. DIXON, DIXONbone, UTE, and DL-DIXON showed MRAC to CTAC biases of - 5.41%, - 1.85%, - 2.74%, and 0.08% respectively for ROIs inserted in background activity; - 7.02%, - 2.46%, - 3.56%, and - 0.05% for lesion ROIs without background; and - 6.82%, - 2.08%, - 2.29%, and 0.22% for the original brain PET images' 16 FreeSurfer brain ROIs. CONCLUSION: The proposed pipeline delivers accurate results for synthetic spherical lesions and brain ROIs, with and without background activity consideration, enabling the evaluation of new attenuation correction approaches without utilizing measured PET emission data. Additionally, it offers a consistent method to generate realistic lesion ROIs, potentially applicable in assessing further PET correction techniques.

Chemokine Receptor 2 Is A Theranostic Biomarker for Abdominal Aortic Aneurysms.

Abdominal aortic aneurysm (AAA) is a degenerative vascular disease impacting aging populations with a high mortality upon rupture. There are no effective medical therapies to prevent AAA expansion and rupture. We previously demonstrated the role of the monocyte chemoattractant protein-1 (MCP-1) / C-C chemokine receptor type 2 (CCR2) axis in rodent AAA pathogenesis via positron emission tomography/computed tomography (PET/CT) using CCR2 targeted radiotracer 64 Cu-DOTA-ECL1i. We have since translated this radiotracer into patients with AAA. CCR2 PET showed intense radiotracer uptake along the AAA wall in patients while little signal was observed in healthy volunteers. AAA tissues collected from individuals scanned with 64 Cu-DOTA-ECL1i and underwent open-repair later demonstrated more abundant CCR2+ cells compared to non-diseased aortas. We then used a CCR2 inhibitor (CCR2i) as targeted therapy in our established male and female rat AAA rupture models. We observed that CCR2i completely prevented AAA rupture in male rats and significantly decreased rupture rate in female AAA rats. PET/CT revealed substantial reduction of 64 Cu-DOTA-ECL1i uptake following CCR2i treatment in both rat models. Characterization of AAA tissues demonstrated decreased expression of CCR2+ cells and improved histopathological features. Taken together, our results indicate the potential of CCR2 as a theranostic biomarker for AAA management.

Synthetic PET via Domain Translation of 3-D MRI.

Historically, patient datasets have been used to develop and validate various reconstruction algorithms for PET/MRI and PET/CT. To enable such algorithm development, without the need for acquiring hundreds of patient exams, in this article we demonstrate a deep learning technique to generate synthetic but realistic whole-body PET sinograms from abundantly available whole-body MRI. Specifically, we use a dataset of 56 18F-FDG-PET/MRI exams to train a 3-D residual UNet to predict physiologic PET uptake from whole-body T1-weighted MRI. In training, we implemented a balanced loss function to generate realistic uptake across a large dynamic range and computed losses along tomographic lines of response to mimic the PET acquisition. The predicted PET images are forward projected to produce synthetic PET (sPET) time-of-flight (ToF) sinograms that can be used with vendor-provided PET reconstruction algorithms, including using CT-based attenuation correction (CTAC) and MR-based attenuation correction (MRAC). The resulting synthetic data recapitulates physiologic 18F-FDG uptake, e.g., high uptake localized to the brain and bladder, as well as uptake in liver, kidneys, heart, and muscle. To simulate abnormalities with high uptake, we also insert synthetic lesions. We demonstrate that this sPET data can be used interchangeably with real PET data for the PET quantification task of comparing CTAC and MRAC methods, achieving ≤ 7.6% error in mean-SUV compared to using real data. These results together show that the proposed sPET data pipeline can be reasonably used for development, evaluation, and validation of PET/MRI reconstruction methods.

A list-mode multi-energy window low-count SPECT reconstruction method for isotopes with multiple emission peaks.

SPECT provides a mechanism to perform absorbed-dose quantification tasks for $\alpha$-particle radiopharmaceutical therapies ($\alpha$-RPTs). However, quantitative SPECT for $\alpha$-RPT is challenging due to the low number of detected counts, the complex emission spectrum, and other image-degrading artifacts. Towards addressing these challenges, we propose a low-count quantitative SPECT reconstruction method for isotopes with multiple emission peaks. Given the low-count setting, it is important that the reconstruction method extract the maximal possible information from each detected photon. Processing data over multiple energy windows and in list-mode (LM) format provide mechanisms to achieve that objective. Towards this goal, we propose a list-mode multi-energy window (LM-MEW) OSEM-based SPECT reconstruction method that uses data from multiple energy windows in LM format, and includes the energy attribute of each detected photon. For computational efficiency, we developed a multi-GPU-based implementation of this method. The method was evaluated using 2-D SPECT simulation studies in a single-scatter setting conducted in the context of imaging [$^{223}$Ra]RaCl${_2}$. The proposed method yielded improved performance on the task of estimating activity uptake within known regions of interest in comparison to approaches that use a single energy window or use binned data. The improved performance was observed in terms of both accuracy and precision and for different sizes of the region of interest. Results of our studies show that the use of multiple energy windows and processing data in LM format with the proposed LM-MEW method led to improved quantification performance in low-count SPECT of isotopes with multiple emission peaks. These results motivate further development and validation of the LM-MEW method for such imaging applications, including for $\alpha$-RPT SPECT.

An automatic pipeline for PET/MRI attenuation correction validation in the brain.

Purpose: PET/MRI quantitative accuracy for neurological applications is challenging due to accuracy of the PET attenuation correction. In this work, we proposed and evaluated an automatic pipeline for assessing the quantitative accuracy of four different MRI = based attenuation correction (PET MRAC) approaches. Methods: The proposed pipeline consists of a synthetic lesion insertion tool and the FreeSurfer neuroimaging analysis framework. The synthetic lesion insertion tool is used to insert simulated spherical, and brain regions of interest (ROI) into the PET projection space and reconstructed with four different PET MRAC techniques, while FreeSurfer is used to generate brain ROIs from T1 weighted MRI image. Using a cohort of 11 patients' brain PET dataset, the quantitative accuracy of four MRAC(s), which are: DIXON AC, DIXONbone AC, UTE AC, and Deep learning trained with DIXON AC, named DL-DIXON AC, were compared to the PET-based CT attenuation correction (PET CTAC). MRAC to CTAC activity bias in spherical lesions and brain ROIs were reconstructed with and without background activity and compared to the original PET images. Results: The proposed pipeline provides accurate and consistent results for inserted spherical lesions and brain ROIs inserted with and without considering the background activity and following the same MRAC to CTAC pattern as the original brain PET images. As expected, the DIXON AC showed the highest bias; the second was for the UTE, then the DIXONBone, and the DL-DIXON with the lowest bias. For simulated ROIs inserted in the background activity, DIXON showed a -4.65% MRAC to CTAC bias, 0.06% for the DIXONbone, -1.70% for the UTE, and - 0.23% for the DL-DIXON. For lesion ROIs inserted without background activity, DIXON showed a -5.21%, -1% for the DIXONbone, -2.55% for the UTE, and - 0.52 for the DL-DIXON. For MRAC to CTAC bias calculated using the same 16 FreeSurfer brain ROIs in the original brain PET reconstructed images, a 6.87% was observed for the DIXON, -1.83% for DIXON bone, -3.01% for the UTE, and - 0.17% for the DL-DIXON. Conclusion: The proposed pipeline provides accurate and consistent results for synthetic spherical lesions and brain ROIs inserted with and without considering the background activity; hence a new attenuation correction approach can be evaluated without using measured PET emission data.

A simplified method to correct saturation of arterial input function for cardiac magnetic resonance first-pass perfusion imaging: validation with simultaneously acquired PET.

BACKGROUND: First-pass perfusion imaging in magnetic resonance imaging (MRI) is an established method to measure myocardial blood flow (MBF). An obstacle for accurate quantification of MBF is the saturation of blood pool signal intensity used for arterial input function (AIF). The objective of this project was to validate a new simplified method for AIF estimation obtained from single-bolus and single sequence perfusion measurements. The reference MBF was measured simultaneously on 13N-ammonia positron emission tomography (PET). METHODS: Sixteen patients with clinically confirmed myocardial ischemia were imaged in a clinical whole-body PET-MRI system. PET perfusion imaging was performed in a 10-min acquisition after the injection of 10 mCi of 13N-ammonia. The MRI perfusion acquisition started simultaneously with the start of the PET acquisition after the injection of a 0.075 mmol/kg gadolinium contrast agent. Cardiac stress imaging was initiated after the administration of regadenoson 20 s prior to PET-MRI scanning. The saturation part of the MRI AIF data was modeled as a gamma variate curve, which was then estimated for a true AIF by minimizing a cost function according to various boundary conditions. A standard AHA 16-segment model was used for comparative analysis of absolute MBF from PET and MRI. RESULTS: Overall, there were 256 segments in 16 patients, mean resting perfusion for PET was 1.06 ± 0.34 ml/min/g and 1.04 ± 0.30 ml/min/g for MRI (P = 0.05), whereas mean stress perfusion for PET was 2.00 ± 0.74 ml/min/g and 2.12 ± 0.76 ml/min/g for MRI (P < 0.01). Linear regression analysis in MBF revealed strong correlation (r = 0.91, slope = 0.96, P < 0.001) between PET and MRI. Myocardial perfusion reserve, calculated from the ratio of stress MBF over resting MBF, also showed a strong correlation between MRI and PET measurements (r = 0.82, slope = 0.81, P < 0.001). CONCLUSION: The results demonstrated the feasibility of the simplified AIF estimation method for the accurate quantification of MBF by MRI with single sequence and single contrast injection. The MRI MBF correlated strongly with PET MBF obtained simultaneously. This post-processing technique will allow easy transformation of clinical perfusion imaging data into quantitative information.

A list-mode multi-energy window low-count SPECT reconstruction method for isotopes with multiple emission peaks.

BACKGROUND: Single-photon emission computed tomography (SPECT) provides a mechanism to perform absorbed-dose quantification tasks for [Formula: see text]-particle radiopharmaceutical therapies ([Formula: see text]-RPTs). However, quantitative SPECT for [Formula: see text]-RPT is challenging due to the low number of detected counts, the complex emission spectrum, and other image-degrading artifacts. Towards addressing these challenges, we propose a low-count quantitative SPECT reconstruction method for isotopes with multiple emission peaks. METHODS: Given the low-count setting, it is important that the reconstruction method extracts the maximal possible information from each detected photon. Processing data over multiple energy windows and in list-mode (LM) format provide mechanisms to achieve that objective. Towards this goal, we propose a list-mode multi energy window (LM-MEW) ordered-subsets expectation-maximization-based SPECT reconstruction method that uses data from multiple energy windows in LM format and include the energy attribute of each detected photon. For computational efficiency, we developed a multi-GPU-based implementation of this method. The method was evaluated using 2-D SPECT simulation studies in a single-scatter setting conducted in the context of imaging [[Formula: see text]Ra]RaCl[Formula: see text], an FDA-approved RPT for metastatic prostate cancer. RESULTS: The proposed method yielded improved performance on the task of estimating activity uptake within known regions of interest in comparison to approaches that use a single energy window or use binned data. The improved performance was observed in terms of both accuracy and precision and for different sizes of the region of interest. CONCLUSIONS: Results of our studies show that the use of multiple energy windows and processing data in LM format with the proposed LM-MEW method led to improved quantification performance in low-count SPECT of isotopes with multiple emission peaks. These results motivate further development and validation of the LM-MEW method for such imaging applications, including for [Formula: see text]-RPT SPECT.

DEMIST: A deep-learning-based task-specific denoising approach for myocardial perfusion SPECT.

There is an important need for methods to process myocardial perfusion imaging (MPI) SPECT images acquired at lower radiation dose and/or acquisition time such that the processed images improve observer performance on the clinical task of detecting perfusion defects. To address this need, we build upon concepts from model-observer theory and our understanding of the human visual system to propose a Detection task-specific deep-learning-based approach for denoising MPI SPECT images (DEMIST). The approach, while performing denoising, is designed to preserve features that influence observer performance on detection tasks. We objectively evaluated DEMIST on the task of detecting perfusion defects using a retrospective study with anonymized clinical data in patients who underwent MPI studies across two scanners (N = 338). The evaluation was performed at low-dose levels of 6.25%, 12.5% and 25% and using an anthropomorphic channelized Hotelling observer. Performance was quantified using area under the receiver operating characteristics curve (AUC). Images denoised with DEMIST yielded significantly higher AUC compared to corresponding low-dose images and images denoised with a commonly used task-agnostic DL-based denoising method. Similar results were observed with stratified analysis based on patient sex and defect type. Additionally, DEMIST improved visual fidelity of the low-dose images as quantified using root mean squared error and structural similarity index metric. A mathematical analysis revealed that DEMIST preserved features that assist in detection tasks while improving the noise properties, resulting in improved observer performance. The results provide strong evidence for further clinical evaluation of DEMIST to denoise low-count images in MPI SPECT.

Ultrasmall, elementary and highly translational nanoparticle X-ray contrast media from amphiphilic iodinated statistical copolymers.

To expand the single-dose duration over which noninvasive clinical and preclinical cancer imaging can be conducted with high sensitivity, and well-defined spatial and temporal resolutions, a facile strategy to prepare ultrasmall nanoparticulate X-ray contrast media (nano-XRCM) as dual-modality imaging agents for positron emission tomography (PET) and computed tomography (CT) has been established. Synthesized from controlled copolymerization of triiodobenzoyl ethyl acrylate and oligo(ethylene oxide) acrylate monomers, the amphiphilic statistical iodocopolymers (ICPs) could directly dissolve in water to afford thermodynamically stable solutions with high aqueous iodine concentrations (>140 mg iodine/mL water) and comparable viscosities to conventional small molecule XRCM. The formation of ultrasmall iodinated nanoparticles with hydrodynamic diameters of ca. 10 nm in water was confirmed by dynamic and static light scattering techniques. In a breast cancer mouse model, in vivo biodistribution studies revealed that the 64Cu-chelator-functionalized iodinated nano-XRCM exhibited extended blood residency and higher tumor accumulation compared to typical small molecule imaging agents. PET/CT imaging of tumor over 3 days showed good correlation between PET and CT signals, while CT imaging allowed continuous observation of tumor retention even after 10 days post-injection, enabling longitudinal monitoring of tumor retention for imaging or potentially therapeutic effect after a single administration of nano-XRCM.

Co-Clinical Imaging Metadata Information (CIMI) for Cancer Research to Promote Open Science, Standardization, and Reproducibility in Preclinical Imaging.

Preclinical imaging is a critical component in translational research with significant complexities in workflow and site differences in deployment. Importantly, the National Cancer Institute's (NCI) precision medicine initiative emphasizes the use of translational co-clinical oncology models to address the biological and molecular bases of cancer prevention and treatment. The use of oncology models, such as patient-derived tumor xenografts (PDX) and genetically engineered mouse models (GEMMs), has ushered in an era of co-clinical trials by which preclinical studies can inform clinical trials and protocols, thus bridging the translational divide in cancer research. Similarly, preclinical imaging fills a translational gap as an enabling technology for translational imaging research. Unlike clinical imaging, where equipment manufacturers strive to meet standards in practice at clinical sites, standards are neither fully developed nor implemented in preclinical imaging. This fundamentally limits the collection and reporting of metadata to qualify preclinical imaging studies, thereby hindering open science and impacting the reproducibility of co-clinical imaging research. To begin to address these issues, the NCI co-clinical imaging research program (CIRP) conducted a survey to identify metadata requirements for reproducible quantitative co-clinical imaging. The enclosed consensus-based report summarizes co-clinical imaging metadata information (CIMI) to support quantitative co-clinical imaging research with broad implications for capturing co-clinical data, enabling interoperability and data sharing, as well as potentially leading to updates to the preclinical Digital Imaging and Communications in Medicine (DICOM) standard.

A Projection-Domain Low-Count Quantitative SPECT Method for α-Particle-Emitting Radiopharmaceutical Therapy.

Single-photon emission-computed tomography (SPECT) provides a mechanism to estimate regional isotope uptake in lesions and at-risk organs after administration of α-particle-emitting radiopharmaceutical therapies (α-RPTs). However, this estimation task is challenging due to the complex emission spectra, the very low number of detected counts (~20 times lower than in conventional SPECT), the impact of stray-radiation-related noise at these low counts, and the multiple image-degrading processes in SPECT. The conventional reconstruction-based quantification methods are observed to be erroneous for α-RPT SPECT. To address these challenges, we developed a low-count quantitative SPECT (LC-QSPECT) method that directly estimates the regional activity uptake from the projection data (obviating the reconstruction step), compensates for stray-radiation-related noise, and accounts for the radioisotope and SPECT physics, including the isotope spectra, scatter, attenuation, and collimator-detector response, using a Monte Carlo-based approach. The method was validated in the context of 3-D SPECT with 223Ra, a commonly used radionuclide for α-RPT. Validation was performed using both realistic simulation studies, including a virtual clinical trial, and synthetic and 3-D-printed anthropomorphic physical-phantom studies. Across all studies, the LC-QSPECT method yielded reliable regional-uptake estimates and outperformed the conventional ordered subset expectation-maximization (OSEM)-based reconstruction and geometric transfer matrix (GTM)-based post-reconstruction partial-volume compensation methods. Furthermore, the method yielded reliable uptake across different lesion sizes, contrasts, and different levels of intralesion heterogeneity. Additionally, the variance of the estimated uptake approached the Cramér-Rao bound-defined theoretical limit. In conclusion, the proposed LC-QSPECT method demonstrated the ability to perform reliable quantification for α-RPT SPECT.

Need for objective task-based evaluation of deep learning-based denoising methods: A study in the context of myocardial perfusion SPECT.

BACKGROUND: Artificial intelligence-based methods have generated substantial interest in nuclear medicine. An area of significant interest has been the use of deep-learning (DL)-based approaches for denoising images acquired with lower doses, shorter acquisition times, or both. Objective evaluation of these approaches is essential for clinical application. PURPOSE: DL-based approaches for denoising nuclear-medicine images have typically been evaluated using fidelity-based figures of merit (FoMs) such as root mean squared error (RMSE) and structural similarity index measure (SSIM). However, these images are acquired for clinical tasks and thus should be evaluated based on their performance in these tasks. Our objectives were to: (1) investigate whether evaluation with these FoMs is consistent with objective clinical-task-based evaluation; (2) provide a theoretical analysis for determining the impact of denoising on signal-detection tasks; and (3) demonstrate the utility of virtual imaging trials (VITs) to evaluate DL-based methods. METHODS: A VIT to evaluate a DL-based method for denoising myocardial perfusion SPECT (MPS) images was conducted. To conduct this evaluation study, we followed the recently published best practices for the evaluation of AI algorithms for nuclear medicine (the RELAINCE guidelines). An anthropomorphic patient population modeling clinically relevant variability was simulated. Projection data for this patient population at normal and low-dose count levels (20%, 15%, 10%, 5%) were generated using well-validated Monte Carlo-based simulations. The images were reconstructed using a 3-D ordered-subsets expectation maximization-based approach. Next, the low-dose images were denoised using a commonly used convolutional neural network-based approach. The impact of DL-based denoising was evaluated using both fidelity-based FoMs and area under the receiver operating characteristic curve (AUC), which quantified performance on the clinical task of detecting perfusion defects in MPS images as obtained using a model observer with anthropomorphic channels. We then provide a mathematical treatment to probe the impact of post-processing operations on signal-detection tasks and use this treatment to analyze the findings of this study. RESULTS: Based on fidelity-based FoMs, denoising using the considered DL-based method led to significantly superior performance. However, based on ROC analysis, denoising did not improve, and in fact, often degraded detection-task performance. This discordance between fidelity-based FoMs and task-based evaluation was observed at all the low-dose levels and for different cardiac-defect types. Our theoretical analysis revealed that the major reason for this degraded performance was that the denoising method reduced the difference in the means of the reconstructed images and of the channel operator-extracted feature vectors between the defect-absent and defect-present cases. CONCLUSIONS: The results show the discrepancy between the evaluation of DL-based methods with fidelity-based metrics versus the evaluation on clinical tasks. This motivates the need for objective task-based evaluation of DL-based denoising approaches. Further, this study shows how VITs provide a mechanism to conduct such evaluations computationally, in a time and resource-efficient setting, and avoid risks such as radiation dose to the patient. Finally, our theoretical treatment reveals insights into the reasons for the limited performance of the denoising approach and may be used to probe the effect of other post-processing operations on signal-detection tasks.

Need for Objective Task-based Evaluation of Deep Learning-Based Denoising Methods: A Study in the Context of Myocardial Perfusion SPECT.

Artificial intelligence-based methods have generated substantial interest in nuclear medicine. An area of significant interest has been using deep-learning (DL)-based approaches for denoising images acquired with lower doses, shorter acquisition times, or both. Objective evaluation of these approaches is essential for clinical application. DL-based approaches for denoising nuclear-medicine images have typically been evaluated using fidelity-based figures of merit (FoMs) such as RMSE and SSIM. However, these images are acquired for clinical tasks and thus should be evaluated based on their performance in these tasks. Our objectives were to (1) investigate whether evaluation with these FoMs is consistent with objective clinical-task-based evaluation; (2) provide a theoretical analysis for determining the impact of denoising on signal-detection tasks; (3) demonstrate the utility of virtual clinical trials (VCTs) to evaluate DL-based methods. A VCT to evaluate a DL-based method for denoising myocardial perfusion SPECT (MPS) images was conducted. The impact of DL-based denoising was evaluated using fidelity-based FoMs and AUC, which quantified performance on detecting perfusion defects in MPS images as obtained using a model observer with anthropomorphic channels. Based on fidelity-based FoMs, denoising using the considered DL-based method led to significantly superior performance. However, based on ROC analysis, denoising did not improve, and in fact, often degraded detection-task performance. The results motivate the need for objective task-based evaluation of DL-based denoising approaches. Further, this study shows how VCTs provide a mechanism to conduct such evaluations using VCTs. Finally, our theoretical treatment reveals insights into the reasons for the limited performance of the denoising approach.

Observer-study-based approaches to quantitatively evaluate the realism of synthetic medical images.

Objective.Synthetic images generated by simulation studies have a well-recognized role in developing and evaluating imaging systems and methods. However, for clinically relevant development and evaluation, the synthetic images must be clinically realistic and, ideally, have the same distribution as that of clinical images. Thus, mechanisms that can quantitatively evaluate this clinical realism and, ideally, the similarity in distributions of the real and synthetic images, are much needed.Approach.We investigated two observer-study-based approaches to quantitatively evaluate the clinical realism of synthetic images. In the first approach, we presented a theoretical formalism for the use of an ideal-observer study to quantitatively evaluate the similarity in distributions between the real and synthetic images. This theoretical formalism provides a direct relationship between the area under the receiver operating characteristic curve, AUC, for an ideal observer and the distributions of real and synthetic images. The second approach is based on the use of expert-human-observer studies to quantitatively evaluate the realism of synthetic images. In this approach, we developed a web-based software to conduct two-alternative forced-choice (2-AFC) experiments with expert human observers. The usability of this software was evaluated by conducting a system usability scale (SUS) survey with seven expert human readers and five observer-study designers. Further, we demonstrated the application of this software to evaluate a stochastic and physics-based image-synthesis technique for oncologic positron emission tomography (PET). In this evaluation, the 2-AFC study with our software was performed by six expert human readers, who were highly experienced in reading PET scans, with years of expertise ranging from 7 to 40 years (median: 12 years, average: 20.4 years).Main results.In the ideal-observer-study-based approach, we theoretically demonstrated that the AUC for an ideal observer can be expressed, to an excellent approximation, by the Bhattacharyya distance between the distributions of the real and synthetic images. This relationship shows that a decrease in the ideal-observer AUC indicates a decrease in the distance between the two image distributions. Moreover, a lower bound of ideal-observer AUC = 0.5 implies that the distributions of synthetic and real images exactly match. For the expert-human-observer-study-based approach, our software for performing the 2-AFC experiments is available athttps://apps.mir.wustl.edu/twoafc. Results from the SUS survey demonstrate that the web application is very user friendly and accessible. As a secondary finding, evaluation of a stochastic and physics-based PET image-synthesis technique using our software showed that expert human readers had limited ability to distinguish the real images from the synthetic images.Significance.This work addresses the important need for mechanisms to quantitatively evaluate the clinical realism of synthetic images. The mathematical treatment in this paper shows that quantifying the similarity in the distribution of real and synthetic images is theoretically possible by using an ideal-observer-study-based approach. Our developed software provides a platform for designing and performing 2-AFC experiments with human observers in a highly accessible, efficient, and secure manner. Additionally, our results on the evaluation of the stochastic and physics-based image-synthesis technique motivate the application of this technique to develop and evaluate a wide array of PET imaging methods.

First-in-Humans Evaluation of Safety and Dosimetry of 64Cu-LLP2A for PET Imaging.

There remains an unmet need for molecularly targeted imaging agents for multiple myeloma (MM). The integrin very late antigen 4 (VLA4), is differentially expressed in malignant MM cells and in pathogenic inflammatory microenvironmental cells. [64Cu]Cu-CB-TE1A1P-LLP2A (64Cu-LLP2A) is a VLA4-targeted, high-affinity radiopharmaceutical with promising utility for managing patients diagnosed with MM. Here, we evaluated the safety and human radiation dosimetry of 64Cu-LLP2A for potential use in MM patients. Methods: A single-dose [natCu]Cu-LLP2A (Cu-LLP2A) tolerability and toxicity study was performed on CD-1 (Hsd:ICR) male and female mice. 64Cu-LLP2A was synthesized in accordance with good-manufacturing-practice-compliant procedures. Three MM patients and six healthy participants underwent 64Cu-LLP2A-PET/CT or PET/MRI at up to 3 time points to help determine tracer biodistribution, pharmacokinetics, and radiation dosimetry. Time-activity curves were plotted for each participant. Mean organ-absorbed doses and effective doses were calculated using the OLINDA software. Tracer bioactivity was evaluated via cell-binding assays, and metabolites from human blood samples were analyzed with analytic radio-high-performance liquid chromatography. When feasible, VLA4 expression was evaluated in the biopsy tissues using 14-color flow cytometry. Results: A 150-fold mass excess of the desired imaging dose was tolerated well in male and female CD-1 mice (no observed adverse effect level). Time-activity curves from human imaging data showed rapid tracer clearance from blood via the kidneys and bladder. The effective dose of 64Cu-LLP2A in humans was 0.036 ± 0.006 mSv/MBq, and the spleen had the highest organ uptake, 0.142 ± 0.034 mSv/MBq. Among all tissues, the red marrow demonstrated the highest residence time. Image quality analysis supports an early imaging time (4-5 h after injection of the radiotracer) as optimal. Cell studies showed statistically significant blocking for the tracer produced for all human studies (82.42% ± 13.47%). Blood metabolism studies confirmed a stable product peak (>90%) up to 1 h after injection of the radiopharmaceutical. No clinical or laboratory adverse events related to 64Cu-LLP2A were observed in the human participants. Conclusion: 64Cu-LLP2A exhibited a favorable dosimetry and safety profile for use in humans.