In vivo brain estrogen receptor density by neuroendocrine aging and relationships with cognition and symptomatology.

17ß-estradiol, the most biologically active estrogen, exerts wide-ranging effects in brain through its action on estrogen receptors (ERs), influencing higher-order cognitive function and neurobiological aging. However, our knowledge of ER expression and regulation by neuroendocrine aging in the living human brain is limited. This in vivo brain 18F-fluoroestradiol (18F-FES) Positron Emission Tomography (PET) study of healthy midlife women reveals progressively higher ER density over the menopause transition in estrogen-regulated networks. Effects were independent of age, plasma estradiol and sex hormone binding globulin, and were highly consistent, correctly classifying all women as being postmenopausal or premenopausal. Higher ER density in target regions was associated with poorer memory performance for both postmenopausal and perimenopausal groups, and predicted presence of self-reported mood and cognitive symptoms after menopause. These findings provide novel insights on brain ER density modulation by female neuroendocrine aging, with clinical implications for women's health.

[1-11C]-Butanol Positron Emission Tomography reveals an impaired brain to nasal turbinates pathway in aging amyloid positive subjects.

BACKGROUND: Reduced clearance of cerebrospinal fluid (CSF) has been suggested as a pathological feature of Alzheimer's disease (AD). With extensive documentation in non-human mammals and contradictory human neuroimaging data it remains unknown whether the nasal mucosa is a CSF drainage site in humans. Here, we used dynamic PET with [1-11C]-Butanol, a highly permeable radiotracer with no appreciable brain binding, to test the hypothesis that tracer drainage from the nasal pathway reflects CSF drainage from brain. As a test of the hypothesis, we examined whether brain and nasal fluid drainage times were correlated and affected by brain amyloid. METHODS: 24 cognitively normal subjects (≥ 65 years) were dynamically PET imaged for 60 min. using [1-11C]-Butanol. Imaging with either [11C]-PiB or [18F]-FBB identified 8 amyloid PET positive (Aß+) and 16 Aß- subjects. MRI-determined regions of interest (ROI) included: the carotid artery, the lateral orbitofrontal (LOF) brain, the cribriform plate, and an All-turbinate region comprised of the superior, middle, and inferior turbinates. The bilateral temporalis muscle and jugular veins served as control regions. Regional time-activity were used to model tracer influx, egress, and AUC. RESULTS: LOF and All-turbinate 60 min AUC were positively associated, thus suggesting a connection between the brain and the nose. Further, the Aß+ subgroup demonstrated impaired tracer kinetics, marked by reduced tracer influx and slower egress. CONCLUSION: The data show that tracer kinetics for brain and nasal turbinates are related to each other and both reflect the amyloid status of the brain. As such, these data add to evidence that the nasal pathway is a potential CSF drainage site in humans. These data warrant further investigation of brain and nasal contributions to protein clearance in neurodegenerative disease.

In vivo Brain Estrogen Receptor Expression By Neuroendocrine Aging And Relationships With Gray Matter Volume, Bio-Energetics, and Clinical Symptomatology.

17ß-estradiol,the most biologically active estrogen, exerts wide-ranging effects in brain through its action on estrogen receptors (ERs), influencing higher-order cognitive function and neurobiological aging. However, our knowledge of ER expression and regulation by neuroendocrine aging in the living human brain is limited. This in vivo multi-modality neuroimaging study of healthy midlife women reveals progressively higher ER density over the menopause transition in estrogen-regulated networks. Effects were independent of age and plasma estradiol levels, and were highly consistent, correctly classifying all women as being post-menopausal or not. Higher ER density was generally associated with lower gray matter volume and blood flow, and with higher mitochondria ATP production, possibly reflecting compensatory mechanisms. Additionally, ER density predicted changes in thermoregulation, mood, cognition, and libido. Our data provide evidence that ER density impacts brainstructure, perfusion and energy production during female endocrine aging, with clinical implications for women's health.

The potential of a medium-cost long axial FOV PET system for nuclear medicine departments.

PURPOSE: Total body positron emission tomography (TB-PET) has recently been introduced in nuclear medicine departments. There is a large interest in these systems, but for many centers, the high acquisition cost makes it very difficult to justify their current operational budget. Here, we propose medium-cost long axial FOV scanners as an alternative. METHODS: Several medium-cost long axial FOV designs are described with their advantages and drawbacks. We describe their potential for higher throughput, more cost-effective scanning, a larger group of indications, and novel research opportunities. The wider spread of TB-PET can also lead to the fast introduction of new tracers (at a low dose), new methodologies, and optimized workflows. CONCLUSIONS: A medium-cost TB-PET would be positioned between the current standard PET-CT and the full TB-PET systems in investment but recapitulate most advantages of full TB-PET. These systems could be more easily justified financially in a standard academic or large private nuclear medicine department and still have ample research options.

Physical performance of adaptive axial FOV PET scanners with a sparse detector block rings or a checkerboard configuration.

Objective.Using Monte-Carlo simulations, we evaluated the physical performance of a hypothetical state-of-the-art clinical PET scanner with adaptive axial field-of-view (AFOV) based on the validated GATE model of the Siemens Biograph VisionTMPET/CT scanner.Approach.Vision consists of 16 compact PET rings, each consisting of 152 mini-blocks of 5 × 5 Lutetium Oxyorthosilicate crystals (3.2 × 3.2 × 20 mm3). The Vision 25.6 cm AFOV was extended by adopting (i) a sparse mini-block ring (SBR) configuration of 49.6 cm AFOV, with all mini-block rings interleaved with 16 mm axial gaps, or (ii) a sparse mini-block checkerboard (SCB) configuration of 51.2 cm AFOV, with all mini-blocks interleaved with gaps of 16 mm (transaxial) × 16 mm (axial) width in checkerboard pattern. For sparse configurations, a 'limited' continuous bed motion (limited-CBM) acquisition was employed to extend AFOVs by 2.9 cm. Spatial resolution, sensitivity, image quality (IQ), NECR and scatter fraction were assessed per NEMA NU2-2012.Main Results.All IQ phantom spheres were distinguishable with all configurations. SBR and SCB percent contrast recovery (% CR) and background variability (% BV) were similar (p-value > 0.05). Compared to Vision, SBR and SCB %CRs were similar (p-values > 0.05). However, SBR and SCB %BVs were deteriorated by 30% and 26% respectively (p-values < 0.05). SBR, SCB and Vision exhibited system sensitivities of 16.6, 16.8, and 15.8 kcps MBq-1, NECRs of 311 kcps @35 kBq cc-1, 266 kcps @25.8 kBq cc-1, and 260 kcps @27.8 kBq cc-1, and scatter fractions of 31.2%, 32.4%, and 32.6%, respectively. SBR and SCB exhibited a smoother sensitivity reduction and noise enhancement rate from AFOV center to its edges. SBR and SCB attained comparable spatial resolution in all directions (p-value > 0.05), yet, up to 1.5 mm worse than Vision (p-values < 0.05).Significance.The proposed sparse configurations may offer a clinically adoptable solution for cost-effective adaptive AFOV PET with either highly-sensitive or long-AFOV acquisitions.

Noise-Based Image Harmonization Significantly Increases Repeatability and Reproducibility of Radiomics Features in PET Images: A Phantom Study.

For multicenter clinical studies, characterizing the robustness of image-derived radiomics features is essential. Features calculated on PET images have been shown to be very sensitive to image noise. The purpose of this work was to investigate the efficacy of a relatively simple harmonization strategy on feature robustness and agreement. A purpose-built texture pattern phantom was scanned on 10 different PET scanners in 7 institutions with various different image acquisition and reconstruction protocols. An image harmonization technique based on equalizing a contrast-to-noise ratio was employed to generate a "harmonized" alongside a "standard" dataset for a reproducibility study. In addition, a repeatability study was performed with images from a single PET scanner of variable image noise, varying the binning time of the reconstruction. Feature agreement was measured using the intraclass correlation coefficient (ICC). In the repeatability study, 81/93 features had a lower ICC on the images with the highest image noise as compared to the images with the lowest image noise. Using the harmonized dataset significantly improved the feature agreement for five of the six investigated feature classes over the standard dataset. For three feature classes, high feature agreement corresponded with higher sensitivity to the different patterns, suggesting a way to select suitable features for predictive models.

Dynamic 68Ga-DOTATATE PET/MRI in the Diagnosis and Management of Intracranial Meningiomas.

Purpose To evaluate dynamic gallium 68 (68Ga) tetraazacyclododecane tetraacetic acid octreotate (DOTATATE) brain PET/MRI as an adjunct modality in meningioma, enabling multiparametric standardized uptake value (SUV) and Patlak net binding rate constant (Ki) imaging, and to optimize static acquisition period. Materials and Methods In this prospective study (ClinicalTrials.gov no. NCT04081701, DOMINO-START), 68Ga-DOTATATE PET/MRI-derived time-activity curves (TACs) were measured in 84 volumes of interest in 19 participants (mean age, 63 years; range, 36-89 years; 13 women; 2019-2021) with meningiomas. Region- and voxel-specific Ki were determined using Patlak analysis with a validated population-based reference tissue TAC model built from an independent data set of nine participants. Mean and maximum absolute and relative-to-superior-sagittal-sinus SUVs were extracted from the entire 50 minutes (SUV50) and last 10 minutes (SUV10) of acquisition. SUV versus Ki Spearman correlation, SUV and Ki meningioma versus posttreatment-change Mann-Whitney U tests, and SUV50 versus SUV10 Wilcoxon matched-pairs signed rank tests were performed. Results Absolute and relative maximum SUV50 demonstrated a strong positive correlation with Patlak Ki in meningioma (r = 0.82, P < .001 and r = 0.85, P < .001, respectively) and posttreatment-change lesions (r = 0.88, P = .007 and r = 0.83, P = .02, respectively). Patlak Ki images yielded higher lesion contrast by mitigating nonspecific background signal. All SUV50 and SUV10 metrics differed between meningioma and posttreatment-change regions (P < .001). Within the meningioma group, SUV10 attained higher mean scores than SUV50 (P < .001). Conclusion Combined SUV and Patlak Ki68Ga-DOTATATE PET/MRI enabled multiparametric evaluation of meningioma, offering the potential to enhance lesion contrast with Ki imaging and optimize the SUV measurement postinjection window. Keywords: Molecular Imaging-Clinical Translation, Neuro-Oncology, PET/MRI, Dynamic, Patlak ClinicalTrials.gov registration no. NCT04081701 © RSNA, 2022.

Decreased CSF clearance and increased brain amyloid in Alzheimer's disease.

BACKGROUND: In sporadic Alzheimer's disease (AD), brain amyloid-beta (Aß) deposition is believed to be a consequence of impaired Aß clearance, but this relationship is not well established in living humans. CSF clearance, a major feature of brain glymphatic clearance (BGC), has been shown to be abnormal in AD murine models. MRI phase contrast and intrathecally delivered contrast studies have reported reduced CSF flow in AD. Using PET and tau tracer 18F-THK5117, we previously reported that the ventricular CSF clearance of the PET tracer was reduced in AD and associated with elevated brain Aß levels. METHODS: In the present study, we use two PET tracers, 18F-THK5351 and 11C-PiB to estimate CSF clearance calculated from early dynamic PET frames in 9 normal controls and 15 AD participants. RESULTS: we observed that the ventricular CSF clearance measures were correlated (r = 0.66, p < 0.01), with reductions in AD of 18 and 27%, respectively. We also replicated a significant relationship between ventricular CSF clearance (18F-THK5351) and brain Aß load (r = - 0.64, n = 24, p < 0.01). With a larger sample size, we extended our observations to show that reduced CSF clearance is associated with reductions in cortical thickness and cognitive performance. CONCLUSIONS: Overall, the findings support the hypothesis that failed CSF clearance is a feature of AD that is related to Aß deposition and to the pathology of AD. Longitudinal studies are needed to determine whether failed CSF clearance is a predictor of progressive amyloidosis or its consequence.

Assessing Bone Marrow Activity with [18F]FLT PET in Patients with Essential Thrombocythemia and Prefibrotic Myelofibrosis: A Proof of Concept.

Objectives: This study aims to assess the value of FLT-PET as a non-invasive tool to differentiate between patients with ET and Pre-PMF. This study is a pilot study to have a proof of concept only. Methods: This is a prospective, interventional study where a total of 12 patients were included. Each patient underwent FLT PET imaging as well as bone marrow examination (gold standard). In addition, semi-quantitative (SUVmax and SUVmean) measurements of FLT uptake in the liver, spleen, and Lspine, SUVmean, as well as the Total Lesion Glycolysis (TLG) of the Lspine were performed. Results from the two patient cohorts were compared using = Kruskal-Wallis statistical test. A P-value of <.05 is considered to be statistically significant. Results: The differences in FLT SUVmax and SUVmean measurements in the three organs (liver, spleen, and LSpine) between the ET and Pre-PMF patients were not statistically significant (P > .05). In contrast, TLG measurements in the LSpine were statistically different (P = .013), and therefore, compared to gold standard bone marrow results, TLG can separate ET and Pre-PMF patients. Conclusion: This study is a proof of concept about the potential to discriminate between ET and pre-PMF patients in a non-invasive way. TLG of the LSpine in FLT PET images is a potential quantitative parameter to distinguish between ET and pre-PMF patients.

Population-based input function for TSPO quantification and kinetic modeling with [11C]-DPA-713.

INTRODUCTION: Quantitative positron emission tomography (PET) studies of neurodegenerative diseases typically require the measurement of arterial input functions (AIF), an invasive and risky procedure. This study aims to assess the reproducibility of [11C]DPA-713 PET kinetic analysis using population-based input function (PBIF). The final goal is to possibly eliminate the need for AIF. MATERIALS AND METHODS: Eighteen subjects including six healthy volunteers (HV) and twelve Parkinson disease (PD) subjects from two [11C]-DPA-713 PET studies were included. Each subject underwent 90 min of dynamic PET imaging. Five healthy volunteers underwent a test-retest scan within the same day to assess the repeatability of the kinetic parameters. Kinetic modeling was carried out using the Logan total volume of distribution (VT) model. For each data set, kinetic analysis was performed using a patient-specific AIF (PSAIF, ground-truth standard) and then repeated using the PBIF. PBIF was generated using the leave-one-out method for each subject from the remaining 17 subjects and after normalizing the PSAIFs by 3 techniques: (a) Weightsubject×DoseInjected, (b) area under AIF curve (AUC), and (c) Weightsubject×AUC. The variability in the VT measured with PSAIF, in the test-retest study, was determined for selected brain regions (white matter, cerebellum, thalamus, caudate, putamen, pallidum, brainstem, hippocampus, and amygdala) using the Bland-Altman analysis and for each of the 3 normalization techniques. Similarly, for all subjects, the variabilities due to the use of PBIF were assessed. RESULTS: Bland-Altman analysis showed systematic bias between test and retest studies. The corresponding mean bias and 95% limits of agreement (LOA) for the studied brain regions were 30% and ± 70%. Comparing PBIF- and PSAIF-based VT estimate for all subjects and all brain regions, a significant difference between the results generated by the three normalization techniques existed for all brain structures except for the brainstem (P-value = 0.095). The mean % difference and 95% LOA is -10% and ±45% for Weightsubject×DoseInjected; +8% and ±50% for AUC; and +2% and ± 38% for Weightsubject×AUC. In all cases, normalizing by Weightsubject×AUC yielded the smallest % bias and variability (% bias = ±2%; LOA = ±38% for all brain regions). Estimating the reproducibility of PBIF-kinetics to PSAIF based on disease groups (HV/PD) and genotype (MAB/HAB), the average VT values for all regions obtained from PBIF is insignificantly higher than PSAIF (%difference = 4.53%, P-value = 0.73 for HAB; and %difference = 0.73%, P-value = 0.96 for MAB). PBIF also tends to overestimate the difference between PD and HV for HAB (% difference = 32.33% versus 13.28%) and underestimate it in MAB (%difference = 6.84% versus 20.92%). CONCLUSIONS: PSAIF kinetic results are reproducible with PBIF, with variability in VT within that obtained for the test-retest studies. Therefore, VT assessed using PBIF-based kinetic modeling is clinically feasible and can be an alternative to PSAIF.

Comparison of FDG and FMISO uptakes and distributions in head and neck squamous cell cancer tumors.

PURPOSE: Glycolysis is increased by hypoxia, suggesting a possible correlation between the accumulation of 2-[18F]fluoro-2-deoxy-D-glucose (FDG) in malignant tumors and regional hypoxia defined by 1H-1-(3-[18F]fluoro-2-hydroxypropyl)-2-nitroimidazole (FMISO) PET. The aim of this study is to investigate the intra-tumoral spatial distribution and quantitative relationship between FDG and FMISO in a cohort of head and neck squamous cell cancer (HNSCC) patients. METHODS: Twenty HNSCC patients with 20 primary tumors and 19 metastatic lymph nodes (LNs) underwent FDG and FMISO PET within 1 week. The metabolic target volume (MTV) was defined on the FDG PET images using a region growing algorithm. The hypoxic volume (HV) was defined by the volume of voxels in an FMISO image within the MTV that satisfy a tumor-to-blood ratio (T/B) greater than 1.2. FDG and FMISO lesions were co-registered, and a voxel-by-voxel correlation between the two datasets was performed. FDG and FMISO TVs' SUVs were also compared as well as the intra-tumoral homogeneity of the two radiotracers. Separate analysis was performed for the primary tumors and LNs. RESULTS: Twenty-six percent of the primary tumors and 15% of LNs showed a strong correlation (R > 0.7) between FDG and FMISO intra-tumor distributions when considering the MTV. For the HV, only 19% of primary tumors and 12% of LN were strongly correlated. A weak and moderate correlation existed between the two markers SUVavg, and SUVmax in the case of the primary tumors, respectively. However, this was not the case for the LNs. Good concordances were also observed between the primary tumor's and LNs HV SUVavgs as well as between the corresponding hypoxic fractions (HF's). CONCLUSIONS: A moderate correlation between FDG and hypoxia radiotracer distribution, as measured by FMISO, seems to exist for primary tumors. However, discordant results were found in the case of LNs. Hypoxia appears to be the dominant driver of high FDG uptake in selected tumors only, and therefore FDG PET images cannot be used as a universal surrogate to identify or predict intra-tumor hypoxia.

A study of 18F-FLT positron emission tomography/computed tomography imaging in cases of prefibrotic/early primary myelofibrosis and essential thrombocythemia.

The objectives of this research project are to study in patients with primary myelofibrosis (PMF) and Essential Thrombocythemia (ET); (1) the uptake patterns of FLT-PET (FLT-PET) and its value in diagnosing, staging, and treatment response monitoring of malignant hematopoiesis, (2) compare imaging findings from FLT-PET with bone marrow biopsy (standard of care), and (3) associate FLT-PET uptake patterns with genetic makeup such as JAK2 (Janus kinase 2), CALR (Calreticulin), MPL (myeloproliferative leukemia protein), Triple negative disease, and allele burden.This trial is registered in ClinicalTrials.gov with number NCT03116542. Protocol version: Mar 2017.

A pilot study of 13N-ammonia cardiac PET imaging to assess subacute cardiotoxicity following adjuvant intensity-modulated radiotherapy for locally advanced breast cancer.

OBJECTIVE: (1) Assess the feasibility of 13 N-ammonia cardiac PET (13 N-ammonia-PET) imaging in radiotherapy (RT) treatment position in locally-advanced breast cancer (LABC) patients. (2) Correlate pre-/post-RT changes in myocardial flow reserve (MFR) with the corresponding radiation heart dose. METHODS: Ten left-sided LABC patients undergoing Volumetric Modulated-Arc-Therapy (VMAT) to chest wall and regional lymph nodes underwent a rest/stress 13 N-ammonia-PET at baseline and (median) 13 months post-RT. Changes in cardiac functions and coronary artery Ca2+ scoring between baseline and follow-up were correlated with average RT dose to the myocardium,3 coronary territories, and 17 myocardial segments. RESULTS: Eight (of 10) patients successfully completed the study. The average rest (stress) global MBF (ml.g-1.min-1) for baseline (follow-up) were 0.83 ± 0.25 (2.4 ± 0.79) and 0.92 ± 0.30 (2.76 ± 0.71), respectively. Differences in MBF, heart rate, blood pressure, and rate-pressure product (RPP) between baseline and follow-up were insignificant (P > 0.1).Strong (R = 0.79; P < 0.01) and moderate (R = 0.53; P = 0.37) correlation existed between MBF Rest and MBF Stress, and RPP respectively. Four patients showed a reduction in MFR of up to ~41% in follow-up studies, increasing to ~52% in myocardial segments close to high-radiation isodose lines in 5/8 patients. Agatston Ca + 2 scoring were zero in both baseline and follow-up in six patients; two patients exhibited mild increase in Ca + 2 on follow-ups (range:10-20).Rest and stress LVEF's were normal (>50) for all patients in both studies. CONCLUSION: The feasibility of 13 N-ammonia-PET imaging in treatment position of LABC patients was demonstrated. MFR at 1-year post-irradiation of the heart decreased in 50% of the patients. MFR may be a potential index for early detection of cardiotoxicity in BC patients receiving RT to the chest wall.

Multisite Technical and Clinical Performance Evaluation of Quantitative Imaging Biomarkers from 3D FDG PET Segmentations of Head and Neck Cancer Images.

Quantitative imaging biomarkers (QIBs) provide medical image-derived intensity, texture, shape, and size features that may help characterize cancerous tumors and predict clinical outcomes. Successful clinical translation of QIBs depends on the robustness of their measurements. Biomarkers derived from positron emission tomography images are prone to measurement errors owing to differences in image processing factors such as the tumor segmentation method used to define volumes of interest over which to calculate QIBs. We illustrate a new Bayesian statistical approach to characterize the robustness of QIBs to different processing factors. Study data consist of 22 QIBs measured on 47 head and neck tumors in 10 positron emission tomography/computed tomography scans segmented manually and with semiautomated methods used by 7 institutional members of the NCI Quantitative Imaging Network. QIB performance is estimated and compared across institutions with respect to measurement errors and power to recover statistical associations with clinical outcomes. Analysis findings summarize the performance impact of different segmentation methods used by Quantitative Imaging Network members. Robustness of some advanced biomarkers was found to be similar to conventional markers, such as maximum standardized uptake value. Such similarities support current pursuits to better characterize disease and predict outcomes by developing QIBs that use more imaging information and are robust to different processing factors. Nevertheless, to ensure reproducibility of QIB measurements and measures of association with clinical outcomes, errors owing to segmentation methods need to be reduced.

Physical performance of a long axial field-of-view PET scanner prototype with sparse rings configuration: A Monte Carlo simulation study.

PURPOSE: There is a growing interest in extending the axial fields-of-view (AFOV) of PET scanners. One major limitation for the widespread clinical adoption of such systems is the multifold increase in the associated material costs. In this study, we propose a cost-effective solution to extend the PET AFOV using a sparse detector rings configuration. The corresponding physical performance was validated using Monte Carlo simulations. METHODS: Monte Carlo model of the Siemens BiographTM mCT PET/CT, with a 21.8 cm AFOV and a set of compact rings of LSO crystals was developed as a gold standard. The mCT configuration was then modified by interleaving the LSO crystals in the axial direction within each detector block with 4 mm physical gaps (equivalent to the LSO crystal axial dimension) thus extending the AFOV to 43.6 cm (Ex-mCT). The physical performances of the two MC models were assessed and then compared using NEMA NU 2-2007 standards. RESULTS: Ex-mCT showed <0.2 mm difference in transaxial spatial resolution, and, 0.8 mm and 0.3 mm deterioration in axial spatial resolution, compared to the mCT, at 1 and 10 cm off-center of the transaxial field-of-view respectively. The system sensitivities for the mCT and Ex-mCT models were 9.4 ± 0.2 and 10.75 ± 0.2 cps/kBq respectively. The higher sensitivity of Ex-mCT was due to four additional detector rings required to double the mCT AFOV. PET images of the NEMA Image Quality (IQ) phantom showed no artifacts due to detector rings sparsity, and all spheres were visible in both configurations. Ex-mCT achieved percent contrast recoveries within 5.6% of those of the mCT for all spheres and a maximum of 36% higher background variability at the center of the AFOV. The Ex-mCT, however, showed a more uniform noise distribution over an axial range of almost twice the length of the mCT AFOV. CONCLUSIONS: Using the proposed sparse detector-ring configuration, the AFOV of current generation PET systems can be doubled while maintaining the original number and volume of detector crystal elements, and without jeopardizing the system's overall physical performance. Despite an increase in the noise level, the Ex-mCT exhibited an improved noise uniformity.

Carotid Plaque Positron Emission Tomography Imaging and Cerebral Ischemic Disease.

Background and Purpose- The clinical utility of positron emission tomography (PET) imaging in evaluating carotid artery plaque vulnerability remains unclear. Two tracers of recent interest for carotid plaque imaging are 18F-fluorodeoxyglucose (18F-FDG) and 18F-sodium fluoride (18F-NaF). We performed a systematic review and meta-analysis evaluating the association between carotid artery 18F-FDG or 18F-NaF uptake and recent or future cerebral ischemic events. Methods- A systematic review of Ovid MEDLINE, Ovid EMBASE, and the Cochrane library was conducted from inception to December 2017 for articles evaluating PET tracer uptake in recently symptomatic versus asymptomatic carotid arteries, and articles evaluating carotid uptake in relation to future ischemic events. Cerebral ischemic events were defined as ipsilateral strokes, transient ischemic attacks, or amaurosis fugax. We quantitatively pooled studies by a random-effects model when 3 or more studies were amenable for analysis. We assessed the standardized mean difference between tracer uptake in the symptomatic versus asymptomatic carotid artery using Cohen's d metric. Results- After screening 4144 unique articles, 13 prospective cohort studies assessing carotid artery 18F-FDG uptake in patients with recent cerebral ischemia were eligible for review. Eleven cohorts of 290 subjects scanned with 18F-FDG were eligible for meta-analysis. We found that carotid arteries ipsilateral to recent ischemic events had significantly higher 18F-FDG uptake than asymptomatic arteries (Cohen's d =0.492; CI=0.130-0.855; P=0.008) as well as significant heterogeneity (Cochran's Q =31.5; P=0.0005; I2=68.3%). Meta-regression was not performed due to the limited number of studies in the analysis. Only 2 studies investigating 18F-NaF PET imaging, and another 2 articles investigating ischemic event recurrence were found. Conclusions- Recent ipsilateral cerebral ischemia may be associated with increased carotid 18F-FDG uptake on PET imaging regardless of degree of carotid stenosis, although significant heterogeneity was found, and these results should be interpreted with caution. Emerging evidence suggests a similar association may be present with 18F-NaF plaque uptake. More studies are warranted to provide definitive conclusions on the utility of 18F-FDG or 18F-NaF in carotid plaque evaluation before investigating carotid PET as a diagnostic tool for cerebral ischemic events.

Erratum: Measuring temporal stability of positron emission tomography standardized uptake value bias using long-lived sources in a multicenter network.

[This corrects the article DOI: 10.1117/1.JMI.5.1.011016.].

Inter-operator variability in compartmental kinetic analysis of 18F-fluoromisonidazole dynamic PET.

PURPOSE: To assess the inter-operator variability in compartment analysis (CA) of dynamic-FMISO (dyn-FMISO) PET. METHODS: Study-I: Five investigators conducted CA for 23 NSCLC dyn-FMISO tumor time-activity-curves. Study-II: Four operators performed CA for four NSCLC dyn-FMISO datasets. Repeatability of Kinetic-Rate-Constants (KRCs) was assessed. RESULTS: Study-I: Strong correlation (ICC > 0.9) and interchangeable results among operators existed for all KRCs. Study-II: Up to 103% variability in tumor segmentation, and weaker ICC in KRCs (ICC-VB = 0.53; ICC-K1 = 0.91; ICC-K1/k2 = 0.25; ICC-k3 = 0.32; ICC-Ki = 0.54) existed. All KRCs were repeatable among the different operators. CONCLUSIONS: Inter-operator variability in CA of dyn-FMISO was shown to be within statistical errors.

Measuring temporal stability of positron emission tomography standardized uptake value bias using long-lived sources in a multicenter network.

Positron emission tomography (PET) is a quantitative imaging modality, but the computation of standardized uptake values (SUVs) requires several instruments to be correctly calibrated. Variability in the calibration process may lead to unreliable quantitation. Sealed source kits containing traceable amounts of [Formula: see text] were used to measure signal stability for 19 PET scanners at nine hospitals in the National Cancer Institute's Quantitative Imaging Network. Repeated measurements of the sources were performed on PET scanners and in dose calibrators. The measured scanner and dose calibrator signal biases were used to compute the bias in SUVs at multiple time points for each site over a 14-month period. Estimation of absolute SUV accuracy was confounded by bias from the solid phantoms' physical properties. On average, the intrascanner coefficient of variation for SUV measurements was 3.5%. Over the entire length of the study, single-scanner SUV values varied over a range of 11%. Dose calibrator bias was not correlated with scanner bias. Calibration factors from the image metadata were nearly as variable as scanner signal, and were correlated with signal for many scanners. SUVs often showed low intrascanner variability between successive measurements but were also prone to shifts in apparent bias, possibly in part due to scanner recalibrations that are part of regular scanner quality control. Biases of key factors in the computation of SUVs were not correlated and their temporal variations did not cancel out of the computation. Long-lived sources and image metadata may provide a check on the recalibration process.

Positron Emission Tomography/Computed Tomography-Based Assessments of Androgen Receptor Expression and Glycolytic Activity as a Prognostic Biomarker for Metastatic Castration-Resistant Prostate Cancer.

IMPORTANCE: Androgen receptor-signaling inhibitor (ARSi) drugs prolong life in metastatic castration-resistant prostate cancer (mCRPC), but such tumors eventually become resistant and progress. Comprehensive positron emission tomography/computed tomography (PET/CT) imaging using fluoro-2-D-deoxyglucose F 18 ([18F]-FDG) for glycolysis (Glyc) and fluorodihydrotestosterone F 18 ([18F]-FDHT) for androgen receptor (AR) expression determine heterogeneity of imaging phenotypes, which may be useful in distinguishing patients who will benefit from ARSi drugs from those who need alternative treatments. OBJECTIVE: To test the hypothesis that PET/CT-based assessments of AR expression and glycolytic activity would reveal heterogeneity affecting prognosis. DESIGN, SETTING, AND PARTICIPANTS: Between April 6, 2007, and October 4, 2012, patients with mCRPC underwent imaging with both [18F]-FDG and [18F]-FDHT at Memorial Sloan Kettering Cancer Center. The patients were naive to ARSi treatment with enzalutamide or abiraterone acetate and were referred during documented disease progression. Image-directed biopsy determined the presence or absence of prostate cancer at positive imaging sites. INTERVENTIONS: PET/CT imaging was performed with [18F]-FDHT and [18F]-FDG; select individual lesions were biopsied to correlate imaging phenotype with histologic findings. MAIN OUTCOMES AND MEASURES: All metabolically active lesions were interpreted as [18F]-FDHT-positive (AR1) or [18F]-FDHT-negative (AR0) and as [18F]-FDG-positive (Glyc1) or [18F]-FDG-negative (Glyc0). Correlation was performed with overall survival for both individual lesion imaging phenotype as well as patient-specific imaging phenotype. RESULTS: The mean (SD) age of the 133 patients was 68 (8.6) years. Imaging phenotypes of 2405 PET/CT-positive lesions (median, 12.0 per patient) included 1713 (71.2%) AR1Glyc1, 386 (16.0%) AR1Glyc0, and 306 (12.7%) AR0Glyc1. On multivariate analysis, each phenotype had an independent negative impact effect on survival, most pronounced for AR0Glyc1 lesions (hazard ratio [HR], 1.11; 95% CI, 1.05-1.16; P < .001), followed by AR1Glyc1 lesions (HR, 1.05; 95% CI, 1.03-1.06; P < .001) and AR1Glyc0 lesions (HR, 1.03; 95% CI, 1.00-1.05; P = .048). When sorted by lesion type, 4 patient-specific groups emerged: (1) concordant, with all AR1Glyc1 (34 patients [25.6%]); (2) AR predominant, with AR1Glyc1 and varying numbers of AR1Glyc0 (33 [24.8%]); (3) Glyc predominant, with AR1Glyc1 and varying numbers of AR0Glyc1 (40 [30.1%]); and (4) mixed, with AR1Glyc1 plus a mixture of varying numbers of AR1Glyc0 and AR0Glyc1 (26 [19.5%]). CONCLUSIONS AND RELEVANCE: Heterogeneity of PET/CT imaging phenotype has clinical relevance on a lesion and individual patient level. With regard to mCRPC lesions, most express ARs, consistent with initial benefit of ARSi drugs. On a patient basis, 49% (groups 3 and 4) had at least 1 AR0Glyc1 lesion-the imaging phenotype with the most negative effect on survival, possibly due to ARSi resistance.