A Perspective on Protein Structure Prediction Using Quantum Computers.

Despite the recent advancements by deep learning methods such as AlphaFold2, in silico protein structure prediction remains a challenging problem in biomedical research. With the rapid evolution of quantum computing, it is natural to ask whether quantum computers can offer some meaningful benefits for approaching this problem. Yet, identifying specific problem instances amenable to quantum advantage and estimating the quantum resources required are equally challenging tasks. Here, we share our perspective on how to create a framework for systematically selecting protein structure prediction problems that are amenable for quantum advantage, and estimate quantum resources for such problems on a utility-scale quantum computer. As a proof-of-concept, we validate our problem selection framework by accurately predicting the structure of a catalytic loop of the Zika Virus NS3 Helicase, on quantum hardware.

Prospective comparison of positron emission tomography (PET)/magnetic resonance and PET/computed tomography dosimetry in hepatic malignant neoplastic disease after 90Y radioembolization treatment.

Background: 90Y radioembolization is an established treatment modality for hepatic malignancies. Successful radioembolization requires optimal dose delivery to tumors while minimizing dosages to parenchyma. Post-treatment positron emission tomography (PET)/computed tomography (CT) dosimetry is the established benchmark, whereas PET/magnetic resonance (MR) is an emerging modality. The goal of this study was to assess the intermodality agreement between PET/MR and PET/CT 90Y dosimetry. Methods: In this single-institution study, 18 patients (20 treatment sessions) with a primary or metastatic hepatic malignancy underwent both PET/MR and PET/CT after 90Y radioembolization. Patients were randomized to undergo one modality first, followed by the other. The region of interest was delineated using MR images and tumor and liver dosimetry was calculated. Intermodality agreement was assessed using the Bland-Altman method. A generalized linear model was used to assess the effect of baseline variables on intermodality dose differences. Results: PET/MR underestimated tumor and liver absorbed doses when compared to PET/CT by -3.7% (P=0.042) and -5.8% (P=0.029), respectively. A coverage probability plot demonstrated that 80% and 90% of tumor dose measurements fell within intermodality differences of 11% and 18%, respectively. PET/MR underestimated tumor dose at both low (<1 GBq) and high (>3 GBq) injected activity levels (P<0.001) by -22.3 [standard deviation (SD) =13.5] and -24.3 (SD =18.7), respectively. Conclusions: Although PET/MR significantly underestimated the absorbed dose when compared to PET/CT, the intermodality agreement was high and the degree of underestimation was better than previously reported. Intermodality differences were more pronounced at low and high injected doses. Additional studies are required to assess the clinical implications of these findings.

Blood Cholesterol and Triglycerides Associate with Right Ventricular Function in Pulmonary Hypertension.

Background: Blood lipids are dysregulated in pulmonary hypertension (PH). Lower high-density lipoproteins cholesterol (HDL-C) and low-density lipoproteins cholesterol (LDL-C) are associated with disease severity and death in PH. Right ventricle (RV) dysfunction and failure are the major determinants of morbidity and mortality in PH. This study aims to test the hypothesis that dyslipidemia is associated with RV dysfunction in PH. Methods: We enrolled healthy control subjects (n=12) and individuals with PH (n=30) (age: 18-65 years old). Clinical characteristics, echocardiogram, 2-[18F] fluoro-2-deoxy-D-glucose positron emission tomography (PET) scan, blood lipids, including total cholesterol (TC), triglycerides (TG), lipoproteins (LDL-C and HDL-C), and N-terminal pro-B type Natriuretic Peptide (NT-proBNP) were determined. Results: Individuals with PH had lower HDL-C [PH, 41±12; control, 56±16 mg/dL, p<0.01] and higher TG to HDL-C ratio [PH, 3.6±3.1; control, 2.2±2.2, p<0.01] as compared to controls. TC, TG, and LDL-C were similar between PH and controls. Lower TC and TG were associated with worse RV function measured by RV strain (R=-0.43, p=0.02 and R=-0.37, p=0.05 respectively), RV fractional area change (R=0.51, p<0.01 and R=0.48, p<0.01 respectively), RV end-systolic area (R=-0.63, p<0.001 and R=-0.48, p<0.01 respectively), RV end-diastolic area: R=-0.58, p<0.001 and R=-0.41, p=0.03 respectively), and RV glucose uptake by PET (R=-0.46, p=0.01 and R=-0.30, p=0.10 respectively). NT-proBNP was negatively correlated with TC (R=-0.61, p=0.01) and TG (R=-0.62, p<0.02) in PH. Conclusion: These findings confirm dyslipidemia is associated with worse right ventricular function in PH.

A novel PSMA-targeting tracer with highly negatively charged linker demonstrates decreased salivary gland uptake in mice compared to [68Ga]Ga-PSMA-11.

BACKGROUND: The current generation of radiolabeled PSMA-targeting therapeutic agents is limited by prominent salivary gland binding, which results in dose-limiting xerostomia from radiation exposure. JB-1498 is a urea-based small molecule with a highly negatively charged linker targeting prostate specific membrane antigen (PSMA). Prior work on a similar tracer with the same negatively charged linker demonstrated low normal organ/soft tissue background uptake compared to [68Ga]Ga-PSMA-11. The purpose of this study was to investigate if [68Ga]Ga-JB-1498 had reduced salivary gland uptake in mice compared to [68Ga]Ga-PSMA-11. RESULTS: JB-1498 demonstrated high affinity for PSMA binding and tumor uptake in a murine tumor model. In an initial biodistribution study with low molar activity, [68Ga]Ga-JB-1498 demonstrated salivary gland uptake of 0.13 ± 0.01%ID/g. In a second biodistribution study in non-tumor-bearing mice with high molar activity, [68Ga]Ga-JB1498 demonstrated salivary gland uptake of 0.39 ± 0.24% ID/g and kidney activity of 10.12 ± 1.73% ID/g at one hour post IV injection. This salivary gland uptake is significantly less than the published uptake of [68Ga]Ga-PSMA-11. Micro-PET visually confirmed the findings of the biodistribution studies. Dynamic micro-PET imaging demonstrated gradually decreasing [68Ga]Ga-JB1498 activity in salivary glands and kidneys, compared to gradually increasing [68Ga]Ga-PSMA-11 activity in these two organs during the first hour. CONCLUSION: Biodistribution and micro-PET imaging of [68Ga]Ga-JB-1498 demonstrate significantly decreased salivary gland uptake and different pharmacokinetic behavior in kidneys and salivary glands in mice compared to [68Ga]Ga-PSMA-11. Our findings suggest that constructing a PSMA-targeting molecule with a highly negatively charged linker is a promising strategy to reduce salivary gland uptake of GCP-II/PSMA ligands in theranostic applications.

CD6-targeted antibody-drug conjugate as a new therapeutic agent for T cell lymphoma.

T cell lymphomas (TCL) are heterogeneous, aggressive, and have few available targeted therapeutics. In this study, we determined that CD6, an established T cell marker, was expressed at high levels on almost all examined TCL patient specimens, suggesting that CD6 could be a new therapeutic target for this life-threatening blood cancer. We prepared a CD6-targeted antibody-drug conjugate (CD6-ADC) by conjugating monomethyl auristatin E (MMAE), an FDA-approved mitotic toxin, to a high-affinity anti-human CD6 monoclonal antibody (mAb). In contrast to both the unconjugated anti-CD6 mAb, and the non-binding control ADC, CD6-ADC potently and selectively killed TCL cells in vitro in both time- and concentration-dependent manners. It also prevented the development of tumors in vivo in a preclinical model of TCL. More importantly, systemic or local administration of the CD6-ADC or its humanized version, but not the controls, significantly shrank established tumors in the preclinical mouse model of TCL. These results suggest that CD6 is a novel therapeutic target in TCLs and provide a strong rationale for the further development of CD6-ADC as a promising therapy for patients with these potentially fatal lymphoid neoplasms.

Cerebellar deep brain stimulation for chronic post-stroke motor rehabilitation: a phase I trial.

Upper-extremity impairment after stroke remains a major therapeutic challenge and a target of neuromodulation treatment efforts. In this open-label, non-randomized phase I trial, we applied deep brain stimulation to the cerebellar dentate nucleus combined with renewed physical rehabilitation to promote functional reorganization of ipsilesional cortex in 12 individuals with persistent (1-3 years), moderate-to-severe upper-extremity impairment. No serious perioperative or stimulation-related adverse events were encountered, with participants demonstrating a seven-point median improvement on the Upper-Extremity Fugl-Meyer Assessment. All individuals who enrolled with partial preservation of distal motor function exceeded minimal clinically important difference regardless of time since stroke, with a median improvement of 15 Upper-Extremity Fugl-Meyer Assessment points. These robust functional gains were directly correlated with cortical reorganization evidenced by increased ipsilesional metabolism. Our findings support the safety and feasibility of deep brain stimulation to the cerebellar dentate nucleus as a promising tool for modulation of late-stage neuroplasticity for functional recovery and the need for larger clinical trials. ClinicalTrials.gov registration: NCT02835443 .

18F-fluciclovine PET/CT to distinguish radiation necrosis from tumor progression for brain metastases treated with radiosurgery: results of a prospective pilot study.

PURPOSE: Distinguishing radiation necrosis from tumor progression among patients with brain metastases previously treated with stereotactic radiosurgery represents a common diagnostic challenge. We performed a prospective pilot study to determine whether PET/CT with 18F-fluciclovine, a widely available amino acid PET radiotracer, repurposed intracranially, can accurately diagnose equivocal lesions. METHODS: Adults with brain metastases previously treated with radiosurgery presenting with a follow-up tumor-protocol MRI brain equivocal for radiation necrosis versus tumor progression underwent an 18F-fluciclovine PET/CT of the brain within 30 days. The reference standard for final diagnosis consisted of clinical follow-up until multidisciplinary consensus or tissue confirmation. RESULTS: Of 16 patients imaged from 7/2019 to 11/2020, 15 subjects were evaluable with 20 lesions (radiation necrosis, n = 16; tumor progression, n = 4). Higher SUVmax statistically significantly predicted tumor progression (AUC = 0.875; p = 0.011). Lesion SUVmean (AUC = 0.875; p = 0.018), SUVpeak (AUC = 0.813; p = 0.007), and SUVpeak-to-normal-brain (AUC = 0.859; p = 0.002) also predicted tumor progression, whereas SUVmax-to-normal-brain (p = 0.1) and SUVmean-to-normal-brain (p = 0.5) did not. Qualitative visual scores were significant predictors for readers 1 (AUC = 0.750; p < 0.001) and 3 (AUC = 0.781; p = 0.045), but not for reader 2 (p = 0.3). Visual interpretations were significant predictors for reader 1 (AUC = 0.898; p = 0.012) but not for reader 2 (p = 0.3) or 3 (p = 0.2). CONCLUSIONS: In this prospective pilot study of patients with brain metastases previously treated with radiosurgery presenting with a contemporary MRI brain with a lesion equivocal for radiation necrosis versus tumor progression, 18F-fluciclovine PET/CT repurposed intracranially demonstrated encouraging diagnostic accuracy, supporting the pursuit of larger clinical trials which will be necessary to establish diagnostic criteria and performance.

Novel Depiction of Collateral Flow in Chronic Thromboembolic Pulmonary Hypertension Using 4D Dynamic 82 Rb PET/CT.

ABSTRACT: CT pulmonary angiogram and ventilation-perfusion scintigraphy are the 2 primary imaging modalities for evaluating patients with CTEPH (chronic thromboembolic pulmonary hypertension). PET/CT and MRI currently have a limited role in the evaluation of acute or chronic pulmonary embolism. We present incidentally captured dynamic pulmonary perfusion images in a patient with history of CTEPH who underwent 82 Rb myocardial perfusion PET/CT for evaluation of chest pain. Analysis of the PET data revealed delayed perfusion of the affected lobes suggesting collateralization, highlighting a potentially new imaging paradigm for assessment of pulmonary perfusion.

Metabolic endophenotype associated with right ventricular glucose uptake in pulmonary hypertension.

Alterations in metabolism and bioenergetics are hypothesized in the mechanisms leading to pulmonary vascular remodeling and heart failure in pulmonary hypertension (PH). To test this, we performed metabolomic analyses on 30 PH individuals and 12 controls. Furthermore, using 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography, we dichotomized PH patients into metabolic phenotypes of high and low right ventricle (RV) glucose uptake and followed them longitudinally. In support of metabolic alterations in PH and its progression, the high RV glucose group had higher RV systolic pressure (p < 0.001), worse RV function as measured by RV fractional area change and peak global longitudinal strain (both p < 0.05) and may be associated with poorer outcomes (33% death or transplantation in the high glucose RV uptake group compared to 7% in the low RV glucose uptake group at five years follow-up, log-ranked p = 0.07). Pathway enrichment analysis identified key metabolic pathways including fructose catabolism, arginine-nitric oxide metabolism, tricarboxylic acid cycle, and ketones metabolism. Integrative human protein-protein interactome network analysis of metabolomic and transcriptomic data identified key pathobiological pathways: arginine biosynthesis, tricarboxylic acid cycle, purine metabolism, hypoxia-inducible factor 1, and apelin signaling. These findings identify a PH metabolomic endophenotype, and for the first time link this to disease severity and outcomes.

Computational approaches to detect small lesions in 18 F-FDG PET/CT scans.

PURPOSE: When physicians interpret 18 F-FDG PET/CT scans, they rely on their subjective visual impression of the presence of small lesions, the criteria for which may vary among readers. Our investigation used physical phantom scans to evaluate whether image texture analysis metrics reliably correspond to visual criteria used to identify lesions and accurately differentiate background regions from sub-centimeter simulated lesions. METHODS: Routinely collected quality assurance test data were processed retrospectively for 65 different 18 F-FDG PET scans performed of standardized phantoms on eight different PET/CT systems. Phantoms included 8-, 12-, 16-, and 25-mm diameter cylinders embedded in a cylindrical water bath, prepared with 2.5:1 activity-to-background ratio emulating typical whole-body PET protocols. Voxel values in cylinder regions and background regions were sampled to compute several classes of image metrics. Two experienced physicists, blinded to quantified image metrics and to each other's readings, independently graded cylinder visibility on a 5-level scale (0 = definitely not visible to 4 = definitely visible). RESULTS: The three largest cylinders were visible in 100% of cases with a mean visibility score of 3.3 ± 1.2, while the smallest 8-mm cylinder was visible in 58% of cases with a significantly lower mean visibility score of 1.5±1.1 (P < 0.0001). By ROC analysis, the polynomial-fit signal-to-noise ratio was the most accurate at discriminating 8-mm cylinders from the background, with accuracy greater than visual detection (93% ± 2% versus 76% ± 4%, P = 0.0001), and better sensitivity (94% versus 58%, P < 0.0001). CONCLUSION: Image texture analysis metrics are more sensitive than visual impressions for detecting sub-centimeter simulated lesions. Therefore, image texture analysis metrics are potentially clinically useful for 18 F-FDG PET/CT studies.

Pilot Study of F18-Florbetapir in the Early Evaluation of Cardiac Amyloidosis.

Background: Cardiac amyloidosis is an increasingly recognized etiology of heart failure, in part due to the rise of non-invasive nuclear bone scintigraphy. Molecular imaging using positron emission tomography (PET) has promised the direct visualization of cardiac amyloid fibrils. We sought to assess the performance of F18-florbetapir PET in patients with a potential for cardiac amyloidosis in order to identify early disease. Methods: We performed a pilot study of 12 patients: one with asymptomatic transthyretin cardiac amyloidosis, seven with a potential for developing cardiac amyloidosis (two smoldering myeloma and five with extracardiac biopsy demonstrating transthyretin amyloid deposits and negative technetium pyrophosphate scans), and four controls. Patients were imaged with PET/CT in listmode 10-20 min after receiving F18-florbetapir. Static images were created from this acquisition, and mean standardized uptake values (SUVs) of the left ventricular myocardium, blood pool, paraspinal muscles, and liver were calculated. Results: All 12 patients demonstrated radiotracer uptake in the myocardium with mean SUV of 2.3 ± 0.4 and blood pool SUV of 0.8 ± 0.1. The patient with cardiac amyloidosis had SUV of 3.3, while mean SUV for patients at risk was 2.3 ± 0.4 and for controls was 2.2 ± 0.3. After 3 years of follow-up, one patient with SUV below the mean was subsequently diagnosed with ATTR cardiac amyloidosis. Conclusion: In this cohort, PET with F18-florbetapir demonstrated non-specific radiotracer uptake in the myocardium in all patients using a static image protocol; though, the highest values were noted in a patient with ATTR cardiac amyloidosis. There was no difference in the intensity of F18-florbetapir uptake in at-risk patients and controls. Future studies should continue to investigate metabolic PET tracers and protocols in cardiac amyloidosis, including in early disease.

Comparison and validation of automated scoring of SPECT phantom cold rod visibility.

PURPOSE: Evaluation of phantom image quality is an integral component of the quality assurance of SPECT systems. This evaluation often is done by visual assessment of the resolution of known structures of a specified size, such as arrays of cold rods in a warm background. Although this method is rapid and convenient, it is qualitative and is subject to inter- and intraobserver variability. Thus an automated quantitative analysis would be preferable. Several metrics of cold rod visibility have been developed, although their suitability for SPECT quality assurance depends on how well they correspond to visual scoring by experienced observers. METHODS: Various metrics of cold rod visibility, derived from either texture analysis or template-based analysis, were investigated. The texture analysis methods measured the normalized gray-level co-occurrence matrix (GLCM) energy ("Energy%") and entropy ("Entropy%") of each region and an associated combination of the two ("EnergyEntropy%"). One template-based method measured the rods-to-background contrast ("Contrast") and an associated visibility index (Contrast × area = "Contrast Visibility"). Another template-based method performed binary classification (BC) of the rods and background to compute the area under curve (AUC) of its receiver operating characteristics (ROC) curve ("BC-AUC") and the corresponding signal-to-noise ratio ("BC-SNR"). All these metrics were computed for 90 SPECT acquisitions of the standard American College of Radiology ("Jaszczak") phantom. Cold rod visibility was scored independently by two experienced nuclear medicine physicists on both dichotomous and 5-point scales. Scoring was performed twice by each observer to evaluate variability. RESULTS: Interobserver agreement (Cohen's kappa statistic) was 0.78, and intraobserver reproducibility was 0.86 and 0.88, respectively, for each observer. Mean and median scores differed significantly between observers. Accuracy of each metric was assessed according to AUC of ROC analysis with respect to mean dichotomous score. The binary classification metrics had the highest accuracy (BC-AUC = 0.995, BC-SNR = 0.994), above that of the texture analysis metrics (Entropy% = 0.992, Energy% = 0.988, EnergyEntropy% = 0.992) and conventional template analysis (Contrast = 0.984, Contrast Visibility = 0.989). The metrics were similar in terms of rank correlation to mean visibility score. BC-AUC correlated linearly with mean visibility score (R2  = 0.95) and consistently performed among the highest of the metrics vs rod diameter and count level. CONCLUSIONS: Automated quantitative analysis of SPECT phantom cold rods correlated well with visual scoring. The metrics based on binary classification performed particularly well for this task, across the range of rod diameters and count levels. The suboptimal interobserver agreement highlights the importance of developing automated algorithms for evaluating scanner performance.

MCLENA-1: A Phase II Clinical Trial for the Assessment of Safety, Tolerability, and Efficacy of Lenalidomide in Patients with Mild Cognitive Impairment Due to Alzheimer's Disease.

With the general population reaching higher ages, a surge in Alzheimer's disease (AD) incidence will happen in the coming decades, putting a heavy burden on families and healthcare systems Worldwide. This emphasizes the pressing need for AD therapeutic interventions. Accumulating evidence indicates that inflammation is prominent both in the blood and central nervous system of AD sufferers. These data suggest that systemic inflammation plays a crucial role in the cause and effects of AD neuropathology. Capitalizing on our experience from a previous clinical trial with thalidomide, we hypothesize that modulating inflammation via the pleiotropic immunomodulator lenalidomide may alter AD if administered during a proper time window in the course of the disease. Thus, in this Phase II, proof-of mechanism study, 30 amnestic mild cognitive impairment (aMCI) subjects will be treated with lenalidomide at 10 mg/day for 12 months on a 1:1 ratio, followed by a 6 months washout period. The primary objective of this study is to investigate the effect of lenalidomide on cognition, which is assessed at regular intervals. The secondary objective is to assess the safety and tolerability of lenalidomide in aMCI patients evaluated through adverse events, vital signs, clinical biochemistry, and physical and neurological examinations. Tertiary objectives are to analyze the effects of lenalidomide on brain amyloid loads (Florbetapir PET imaging) and neurodegeneration (volumetric MRI) by comparing pre- and post-dosing data. Finally, exploratory objectives will investigate whether blood inflammatory markers can serve as surrogate markers of therapeutic efficacy. Our study should determine whether lenalidomide is safe in AD subjects and whether it can alter the clinical progression of AD when administered before dementia onset. If effective, lenalidomide would become the first drug capable of delaying the trajectory of AD, which could lead the way to find additional, less toxic treatments in the near future.

Assessment of PET and SPECT phantom image quality through automated binary classification of cold rod arrays.

PURPOSE: Evaluation of positron emission tomography (PET) or single photon emission computed tomography (SPECT) performance often involves qualitative assessment of phantom images, namely the visibility of hot or cold structures in a warm background. Structure-to-background contrast is a quantitative measure of scanner performance; however, contrast measurements do not account for image noise and its effect on task performance. Although task-based performance could be evaluated over an ensemble of phantom scans, a more practical approach is desired. METHODS: Repeated structures, such as the cold rod arrays of the American College of Radiography (ACR) PET and SPECT phantoms, offer an opportunity to evaluate image quality based on statistical decision theory. Images are co-registered to a digital template for placement of numerous regions of interest (ROIs) in multiple thick slices centered on each cold rod and on each midpoint between rods. The assumption is made that each ROI corresponds to a statistically independent measurement, known to be of either a cold rod or the background. A receiver operating characteristic (ROC) curve then is generated for each cold rod sector of the phantom. The area under the ROC curve (AUC) provides a quantitative measure of cold rod visibility. In addition, signal-to-noise ratio (SNR) is calculated, under the assumption that the rod and background ROI measurements are distributed normally. RESULTS: Using this approach, data from PET and SPECT phantom studies from prior annual physics surveys were analyzed retrospectively. Rod and background ROI measurements had nearly normal (PET) or approximately normal (SPECT) distributions. Resultant ROC curves illustrated the varying degrees of overlap between rod and background histograms vs cold rod diameter. Both AUC and SNR correlated well with visual image assessment and had high consistency between phantom studies, demonstrating the quantitative accuracy of the automated analysis. AUC reliably quantified cases where cold rods were partially or mostly resolved, while SNR provided further characterization when cold rods were completely resolved. In comparison, contrast measurements often mirrored AUC and SNR but were inconsistent in cases of varying noise. CONCLUSIONS: Automated analysis of phantom cold rod arrays using binary classification provides informative quantitative measures of image quality and is practical for routine use. This approach avoids observer dependencies associated with visual assessment and potentially can benefit quality assurance, physics surveys, laboratory accreditation, and harmonization of multicenter image quality.

Automated Quantitative Analysis of American College of Radiology PET Phantom Images.

Evaluation of PET image quality is central to annual physics surveys, quality assurance, and laboratory accreditation. A common method is to image the American College of Radiology (ACR) PET phantom, which contains hot and cold structures of various sizes in a warm background. Performance evaluation involves qualitative assessment of hot and cold structure visibility and overall image quality. Some criteria are quantitative and rely on manually drawn regions of interest (ROIs) to measure SUV. Fully automated scoring of ACR PET phantom images would improve efficiency, avoid observer-related dependencies, and possibly provide more robust evaluation of image quality. Methods: Software was developed to coregister PET images to a phantom template and to compute ROI measurements of hot vial activity (SUVmax) and background activity (SUVmean) automatically. In addition, 3-dimensional volumes of interest (VOIs) were generated to measure hot vial activity (SUVvial), background activity, and cold rod contrast. Consistency of the ROI-based and VOI-based methods was evaluated using phantom data from a total of 17 annual physics surveys of 3 PET/CT scanners with the same PET detector design. Results: The automated software processed all PET phantom datasets successfully. SUV consistency for hot vials was improved through use of cylindric VOIs and through normalization with respect to assayed activities and dilution volumes used in phantom preparation. Average vial SUV SD improved from 8.0% for standard SUVmax to 3.2% for normalized SUVvial Similarly, the SD for the SUV ratio of 16- to 25-mm vials improved from 5.0% for SUVmax to 3.2% for SUVvial Background SUVmean had a similar consistency between the ROI and VOI methods. Cold rod contrast was highly consistent, offering a potential alternative to qualitative visual assessment of low-contrast performance. Conclusion: Automated quantitative scoring of the ACR PET phantom is feasible and offers the advantages of more efficient, consistent, and thorough performance characterization. Acceptance ranges for SUVs and ratios likely can be tightened if normalized VOI measurements are used. Further testing with phantom data from a variety of PET scanners is necessary to establish suitable quantitative thresholds for acceptable performance.

Texture analysis for automated evaluation of Jaszczak phantom SPECT system tests.

PURPOSE: Routine quarterly quality assurance (QA) assessment of single photon emission computed tomography (SPECT) systems includes analysis of multipurpose phantoms containing spheres and rods of various sizes. When evaluated by accreditation agencies, criteria applied to assess image quality are largely subjective. Determining a quantified image characteristic metric that emulates human reader impressions of image quality could be quite useful. Our investigation was conducted to ascertain whether image texture analysis metrics, such as those applied to PET scans to detect neoplasms, could prove helpful in linking qualitative statements of phantom sphere and rod visibility to quantified parameters. Because it is not obvious whether it is preferable to submit reconstructions to accrediting agencies performed using typical clinical (CLIN) protocol processing parameters or to follow agencies' filtered backprojection (FBP) suggestions, we applied texture analysis metrics to determine the degree to which these choices affect equipment capability assessment. METHODS AND MATERIALS: Data were processed retrospectively for 125 different Tc-99 m SPECT scans of standardized phantoms for 14 rotating Anger detector systems as part of routine quarterly QA. Algorithms were written to compute several classes of image metrics: quantile curve metrics, image texture analysis gray-level co-occurrence matrix (GLCM) metrics, contrast metrics, and count histogram metrics. For qualitative image scores, two experienced physicists independently graded sphere and rod visibility on a 5-level scale and assigned dichotomous visibility scores, without knowledge of quantified texture analysis metrics or each other's readings. The same phantom was used to collect 15 additional data sets with two dual-detector SPECT/CT systems, reconstructed both by FBP parameters that have been suggested by accrediting agencies and by manufacturers' default settings for CLIN SPECT/CT bone imaging protocols by ordered subsets expectation maximization (OSEM), incorporating attenuation correction using the CT scan. Image characteristics metrics were compared for FBP and CLIN reconstructions. RESULTS: For spheres, the metric with the strongest rank correlation with 5-level scale readings was the quantile curve slope (ρ = 0.83, P < 0.0001), while for rods it was GLCM Energy normalized to the maximum GLCM Energy value (EnergyNorm) (ρ = -0.88, P < 0.0001). Compared to dichotomous readings, the metric with the highest ROC area under curve (AUC) for spheres was the quantile curve slopes (AUC = 96 ± 1%, sensitivity = 91%, specificity = 90%), and for rods was EnergyNorm (AUC = 98 ± 1%, sensitivity = 92%, specificity = 95%). Image contrast was higher for all sphere sizes and rod EnergyNorm was lower for sectors of intermediate-sized rods for FBP compared to CLIN reconstructions, in agreement with more rods judged to be visible from FBP than CLIN reconstructions (47% vs 33%, P = 0.002). CONCLUSIONS: When preparing to submit quality assurance images of standardized phantoms to accrediting agencies, a reliable gauge of sphere and rod visibility can be predicted accurately using quantified reader-independent image texture analysis metrics, which also provide a useful basis for choosing among alternative image reconstruction options.

Loss of dihydrotestosterone-inactivation activity promotes prostate cancer castration resistance detectable by functional imaging.

Androgens such as testosterone and dihydrotestosterone are a critical driver of prostate cancer progression. Cancer resistance to androgen deprivation therapies ensues when tumors engage metabolic processes that produce sustained androgen levels in the tissue. However, the molecular mechanisms involved in this resistance process are unclear, and functional imaging modalities that predict impending resistance are lacking. Here, using the human LNCaP and C4-2 cell line models of prostate cancer, we show that castration treatment-sensitive prostate cancer cells that normally have an intact glucuronidation pathway that rapidly conjugates and inactivates dihydrotestosterone and thereby limits androgen signaling, become glucuronidation deficient and resistant to androgen deprivation. Mechanistically, using CRISPR/Cas9-mediated gene ablation, we found that loss of UDP glucuronosyltransferase family 2 member B15 (UGT2B15) and UGT2B17 is sufficient to restore free dihydrotestosterone, sustained androgen signaling, and development of castration resistance. Furthermore, loss of glucuronidation enzymatic activity was also detectable with a nonsteroid glucuronidation substrate. Of note, glucuronidation-incompetent cells and the resultant loss of intracellular conjugated dihydrotestosterone were detectable in vivo by 18F-dihydrotestosterone PET. Together, these findings couple a mechanism with a functional imaging modality to identify impending castration resistance in prostate cancers.

Multi institutional quantitative phantom study of yttrium-90 PET in PET/MRI: the MR-QUEST study.

BACKGROUND: Yttrium-90 (90Y) radioembolization involves the intra-arterial delivery of radioactive microspheres to treat hepatic malignancies. Though this therapy involves careful pre-treatment planning and imaging, little is known about the precise location of the microspheres once they are administered. Recently, there has been growing interest post-radioembolization imaging using positron-emission tomography (PET) for quantitative dosimetry and identifying lesions that may benefit from additional salvage therapy. In this study, we aim to measure the inter-center variability of 90Y PET measurements as measured on PET/MRI in preparation for a multi-institutional prospective phase I/II clinical trial. Eight institutions participated in this study and followed a standardized phantom filling and imaging protocol. The NEMA NU2-2012 body phantom was filled with 3 GBq of 90Y chloride solution. The phantom was imaged for 30 min in listmode on a Siemens Biograph mMR non-TOF PET/MRI scanner at five time points across 10 days (0.3-3.0 GBq). Raw PET data were sent to a central site for image reconstruction and data analysis. Images were reconstructed with optimal parameters determined from a previous study. Volumes of interest (VOIs) matching the known sphere diameters were drawn on the vendor-provided attenuation map and propagated to the PET images. Recovery coefficients (RCs) and coefficient of variation of the RCs (COV) were calculated from these VOIs for each sphere size and activity level. RESULTS: Mean RCs ranged from 14.5 to 75.4%, with the lowest mean RC coming from the smallest sphere (10 mm) on the last day of imaging (0.16 MBq/ml) and the highest mean RC coming from the largest sphere (37 mm) on the first day of imaging (2.16 MBq/ml). The smaller spheres tended to exhibit higher COVs. In contrast, the larger spheres tended to exhibit lower COVs. COVs from the 37 mm sphere were < 25.3% in all scans. For scans with ≥ 0.60 MBq/ml, COVs were ≤ 25% in spheres ≥ 22 mm. However, for all other spheres sizes and activity levels, COVs were usually > 25%. CONCLUSIONS: Post-radioembolization dosimetry of lesions or other VOIs ≥ 22 mm in diameter can be consistently obtained (< 25% variability) at a multi-institutional level using PET/MRI for any clinically significant activity for 90Y radioembolization.

Technical Note: Automated quantitative analysis of planar scintigraphic resolution with the ACR SPECT phantom.

PURPOSE: Evaluating gamma camera image quality is a routine task required for annual physics surveys and laboratory accreditation. A common method is visual assessment of a planar view of the American College of Radiology (ACR) phantom, for which a satisfactory result is to resolve 7.9 mm diameter cold rods with high contrast. The objective was to investigate an automated quantitative measure of planar image quality for more precise evaluation of gamma camera performance. METHODS: Planar images were automatically co-registered to a template of the phantom's cold rod pattern. Contrast-to-noise ratio (CNR) was measured for each cold rods sector by automatic placement of regions of interests on each rod and on each gap between rods. A quadratic fit to CNR vs. rod diameter yielded the Minimum Detectable Rod Diameter (MDRD) corresponding to a CNR threshold of 4. This methodology was applied to planar images acquired on a variety of gamma cameras according to ACR guidelines and also to planar images generated by Monte Carlo simulation. RESULTS: The automated MDRD analysis had reproducibility of 0.1 mm in repeat phantom scans with random repositioning between scans. The MDRD was 5.8 mm for modern fully digital gamma cameras and 6.2 mm for an older analog gamma camera, whereas visual assessment was identical for all cameras. Simulated Monte Carlo images had MDRD of 5.6 mm using the following parameters: 3.5 mm FWHM intrinsic detector resolution, LEHR collimators, 9.0% FWHM energy resolution, and 15% energy window. Further simulations revealed that collimator design and detector resolution have a substantial impact on MDRD but that energy window width and energy resolution have a minor or negligible impact. The small difference between the Monte Carlo simulations and the modern fully digital gamma cameras was attributed to nonlinearities associated with event positioning and depth-of-interaction effects, which were not modeled in the simulations. CONCLUSIONS: Automated MDRD analysis of planar phantom images is a robust technique that provides more precise and meaningful evaluation of camera performance than visual assessment. MDRD is a suitable measure for quality assurance and for annual physics surveys of gamma cameras.