Lack of repeatability of radiomic features derived from PET scans: Results from a 18 F-DCFPyL test-retest cohort.

OBJECTIVES: PET-based radiomic metrics are increasingly utilized as predictive image biomarkers. However, the repeatability of radiomic features on PET has not been assessed in a test-retest setting. The prostate-specific membrane antigen-targeted compound 18 F-DCFPyL is a high-affinity, high-contrast PET agent that we utilized in a test-retest cohort of men with metastatic prostate cancer (PC). METHODS: Data of 21 patients enrolled in a prospective clinical trial with histologically proven PC underwent two 18 F-DCFPyL PET scans within 7 days, using identical acquisition and reconstruction parameters. Sites of disease were segmented and a set of 29 different radiomic parameters were assessed on both scans. We determined repeatability of quantification by using Pearson's correlations, within-subject coefficient of variation (wCOV), and Bland-Altman analysis. RESULTS: In total, 230 lesions (177 bone, 38 lymph nodes, 15 others) were assessed on both scans. For all investigated radiomic features, a broad range of inter-scan correlation was found (r, 0.07-0.95), with acceptable reproducibility for entropy and homogeneity (wCOV, 16.0% and 12.7%, respectively). On Bland-Altman analysis, no systematic increase or decrease between the scans was observed for either parameter (±1.96 SD: 1.07/-1.30, 0.23/-0.18, respectively). The remaining 27 tested radiomic metrics, however, achieved unacceptable high wCOV (≥21.7%). CONCLUSION: Many common radiomic features derived from a test-retest PET study had poor repeatability. Only Entropy and homogeneity achieved good repeatability, supporting the notion that those image biomarkers may be incorporated in future clinical trials. Those radiomic features based on high frequency aspects of images appear to lack the repeatability on PET to justify further study.

Test-retest repeatability of organ uptake on PSMA-targeted 18 F-DCFPyL PET/CT in patients with prostate cancer.

OBJECTIVES: We evaluated 18 F-DCFPyL test-retest repeatability of uptake in normal organs. METHODS: Twenty-two prostate cancer (PC) patients underwent two 18 F-DCFPyL PET scans within 7 days within a prospective clinical trial (NCT03793543). In both PET scans, uptake in normal organs (kidneys, spleen, liver, and salivary and lacrimal glands) was quantified. Repeatability was determined by using within-subject coefficient of variation (wCOV), with lower values indicating improved repeatability. RESULTS: For SUVmean , repeatability was high for kidneys, spleen, liver, and parotid glands (wCOV, range: 9.0%-14.3%) and lower for lacrimal (23.9%) and submandibular glands (12.4%). For SUVmax , however, the lacrimal (14.4%) and submandibular glands (6.9%) achieved higher repeatability, while for large organs (kidneys, liver, spleen, and parotid glands), repeatability was low (range: 14.1%-45.2%). CONCLUSION: We found acceptable repeatability of uptake on 18 F-DCFPyL PET for normal organs, in particular for SUVmean in the liver or parotid glands. This may have implications for both PSMA-targeted imaging and treatment, as patient selection for radioligand therapy and standardized frameworks for scan interpretation (PROMISE, E-PSMA) rely on uptake in those reference organs.

First-in-human imaging using [11C]MDTC: a radiotracer targeting the cannabinoid receptor type 2.

PURPOSE: We report findings from the first-in-human study of [11C]MDTC, a radiotracer developed to image the cannabinoid receptor type 2 (CB2R) with positron emission tomography (PET). METHODS: Ten healthy adults were imaged according to a 90-min dynamic PET protocol after bolus intravenous injection of [11C]MDTC. Five participants also completed a second [11C]MDTC PET scan to assess test-retest reproducibility of receptor-binding outcomes. The kinetic behavior of [11C]MDTC in human brain was evaluated using tissue compartmental modeling. Four additional healthy adults completed whole-body [11C]MDTC PET/CT to calculate organ doses and the whole-body effective dose. RESULTS: [11C]MDTC brain PET and [11C]MDTC whole-body PET/CT was well-tolerated. A murine study found evidence of brain-penetrant radiometabolites. The model of choice for fitting the time activity curves (TACs) across brain regions of interest was a three-tissue compartment model that includes a separate input function and compartment for the brain-penetrant metabolites. Regional distribution volume (VT) values were low, indicating low CB2R expression in the brain. Test-retest reliability of VT demonstrated a mean absolute variability of 9.91%. The measured effective dose of [11C]MDTC was 5.29 µSv/MBq. CONCLUSION: These data demonstrate the safety and pharmacokinetic behavior of [11C]MDTC with PET in healthy human brain. Future studies identifying radiometabolites of [11C]MDTC are recommended before applying [11C]MDTC PET to assess the high expression of the CB2R by activated microglia in human brain.

[18F]FNDP PET neuroimaging test-retest repeatability and whole-body dosimetry in humans.

PURPOSE: Soluble epoxide hydrolase (sEH) is an enzyme that shapes immune signaling through its role in maintaining the homeostasis of polyunsaturated fatty acids and their related byproducts. [18F]FNDP is a radiotracer developed for use with positron emission tomography (PET) to image sEH, which has been applied to imaging sEH in the brains of healthy individuals. Here, we report the test-retest repeatability of [18F]FNDP brain PET binding and [18F]FNDP whole-body dosimetry in healthy individuals. METHODS: Seven healthy adults (4 men, 3 women, ages 40.1 ± 4.6 years) completed [18F]FNDP brain PET on two occasions within a period of 14 days in a test-retest study design. [18F]FNDP regional total distribution volume (VT) values were derived from modeling time-activity data with a metabolite-corrected arterial input function. Test-retest variability, mean absolute deviation, and intraclass correlation coefficient (ICC) were investigated. Six other healthy adults (3 men, 3 women, ages 46.0 ± 7.0 years) underwent [18F]FNDP PET/CT for whole-body dosimetry, which was acquired over 4.5 h, starting immediately after radiotracer administration. Organ-absorbed doses and the effective dose were then estimated. RESULTS: The mean test-retest difference in regional VT (ΔVT) was 0.82 ± 5.17%. The mean absolute difference in regional VT was 4.01 ± 3.33%. The ICC across different brain regions ranged from 0.92 to 0.99. The organs with the greatest radiation-absorbed doses included the gallbladder (0.081 ± 0.024 mSv/MBq), followed by liver (0.077 ± 0.018 mSv/MBq) and kidneys (0.063 ± 0.006 mSv/MBq). The effective dose was 0.020 ± 0.003 mSv/MBq. CONCLUSION: These data support a favorable test-retest repeatability of [18F]FNDP brain PET regional VT. The radiation dose to humans from each [18F]FNDP PET scan is similar to that of other 18F-based PET radiotracers.

High SUVs Have More Robust Repeatability in Patients with Metastatic Prostate Cancer: Results from a Prospective Test-Retest Cohort Imaged with 18F-DCFPyL.

Objectives: In patients with prostate cancer (PC) receiving prostate-specific membrane antigen- (PSMA-) targeted radioligand therapy (RLT), higher baseline standardized uptake values (SUVs) are linked to improved outcome. Thus, readers deciding on RLT must have certainty on the repeatability of PSMA uptake metrics. As such, we aimed to evaluate the test-retest repeatability of lesion uptake in a large cohort of patients imaged with 18F-DCFPyL. Methods: In this prospective, IRB-approved trial (NCT03793543), 21 patients with history of histologically proven PC underwent two 18F-DCFPyL PET/CTs within 7 days (mean 3.7, range 1 to 7 days). Lesions in the bone, lymph nodes (LN), and other organs were manually segmented on both scans, and uptake parameters were assessed (maximum (SUVmax) and mean (SUVmean) SUVs), PSMA-tumor volume (PSMA-TV), and total lesion PSMA (TL-PSMA, defined as PSMA - TV × SUVmean)). Repeatability was determined using Pearson's correlations, within-subject coefficient of variation (wCOV), and Bland-Altman analysis. Results: In total, 230 pairs of lesions (177 bone, 38 LN, and 15 other) were delineated, demonstrating a wide range of SUVmax (1.5-80.5) and SUVmean (1.4-24.8). Including all sites of suspected disease, SUVs had a strong interscan correlation (R 2 ≥ 0.99), with high repeatability for SUVmean and SUVmax (wCOV, 7.3% and 12.1%, respectively). High SUVs showed significantly improved wCOV relative to lower SUVs (P < 0.0001), indicating that high SUVs are more repeatable, relative to the magnitude of the underlying SUV. Repeatability for PSMA-TV and TL-PSMA, however, was low (wCOV ≥ 23.5%). Across all metrics for LN and bone lesions, interscan correlation was again strong (R 2 ≥ 0.98). Moreover, LN-based SUVmean also achieved the best wCOV (3.8%), which was significantly reduced when compared to osseous lesions (7.8%, P < 0.0001). This was also noted for SUVmax (wCOV, LN 8.8% vs. bone 12.0%, P < 0.03). On a compartment-based level, wCOVs for volumetric features were ≥22.8%, demonstrating no significant differences between LN and bone lesions (PSMA-TV, P =0.63; TL-PSMA, P =0.9). Findings on an entire tumor burden level were also corroborated in a hottest lesion analysis investigating the SUVmax of the most intense lesion per patient (R 2, 0.99; wCOV, 11.2%). Conclusion: In this prospective test-retest setting, SUV parameters demonstrated high repeatability, in particular in LNs, while volumetric parameters demonstrated low repeatability. Further, the large number of lesions and wide distribution of SUVs included in this analysis allowed for the demonstration of a dependence of repeatability on SUV, with higher SUVs having more robust repeatability.

The QIBA Profile for FDG PET/CT as an Imaging Biomarker Measuring Response to Cancer Therapy.

The Quantitative Imaging Biomarkers Alliance (QIBA) Profile for fluorodeoxyglucose (FDG) PET/CT imaging was created by QIBA to both characterize and reduce the variability of standardized uptake values (SUVs). The Profile provides two complementary claims on the precision of SUV measurements. First, tumor glycolytic activity as reflected by the maximum SUV (SUVmax) is measurable from FDG PET/CT with a within-subject coefficient of variation of 10%-12%. Second, a measured increase in SUVmax of 39% or more, or a decrease of 28% or more, indicates that a true change has occurred with 95% confidence. Two applicable use cases are clinical trials and following individual patients in clinical practice. Other components of the Profile address the protocols and conformance standards considered necessary to achieve the performance claim. The Profile is intended for use by a broad audience; applications can range from discovery science through clinical trials to clinical practice. The goal of this report is to provide a rationale and overview of the FDG PET/CT Profile claims as well as its context, and to outline future needs and potential developments.

Dynamic whole-body PET imaging: principles, potentials and applications.

PURPOSE: In this article, we discuss dynamic whole-body (DWB) positron emission tomography (PET) as an imaging tool with significant clinical potential, in relation to conventional standard uptake value (SUV) imaging. BACKGROUND: DWB PET involves dynamic data acquisition over an extended axial range, capturing tracer kinetic information that is not available with conventional static acquisition protocols. The method can be performed within reasonable clinical imaging times, and enables generation of multiple types of PET images with complementary information in a single imaging session. Importantly, DWB PET can be used to produce multi-parametric images of (i) Patlak slope (influx rate) and (ii) intercept (referred to sometimes as "distribution volume"), while also providing (iii) a conventional 'SUV-equivalent' image for certain protocols. RESULTS: We provide an overview of ongoing efforts (primarily focused on FDG PET) and discuss potential clinically relevant applications. CONCLUSION: Overall, the framework of DWB imaging [applicable to both PET/CT(computed tomography) and PET/MRI (magnetic resonance imaging)] generates quantitative measures that may add significant value to conventional SUV image-derived measures, with limited pitfalls as we also discuss in this work.

Comparison of two software systems for quantification of myocardial blood flow in patients with hypertrophic cardiomyopathy.

BACKGORUND: Quantification of myocardial blood flow (MBF) by positron emission tomography (PET) is important for investigation of angina in hypertrophic cardiomyopathy (HCM). Several software programs exist for MBF quantification, but they have been mostly evaluated in patients (with normal cardiac geometry), referred for evaluation of coronary artery disease (CAD). Software performance has not been evaluated in HCM patients who frequently have hyperdynamic LV function, LV outflow tract (LVOT) obstruction, small LV cavity size, and variation in the degree/location of LV hypertrophy. AIM: We compared results of MBF obtained using PMod, which permits manual segmentation, to those obtained by FDA-approved QPET software which has an automated segmentation algorithm. METHODS: 13N-ammonia PET perfusion data were acquired in list mode at rest and during pharmacologic vasodilation, in 76 HCM patients and 10 non-HCM patients referred for evaluation of CAD (CAD group.) Data were resampled to create static, ECG-gated and 36-frame-dynamic images. Myocardial flow reserve (MFR) and MBF (in ml/min/g) were calculated using QPET and PMod softwares. RESULTS: All HCM patients had asymmetric septal hypertrophy, and 50% had evidence of LVOT obstruction, whereas non-HCM patients (CAD group) had normal wall thickness and ejection fraction. PMod yielded significantly higher values for global and regional stress-MBF and MFR than for QPET in HCM. Reasonably fair correlation was observed for global rest-MBF, stress-MBF, and MFR using these two softwares (rest-MBF: r = 0.78; stress-MBF: r = 0.66.; MFR: r = 0.7) in HCM patients. Agreement between global MBF and MFR values improved when HCM patients with high spillover fractions (> 0.65) were excluded from the analysis (rest-MBF: r = 0.84; stress-MBF: r = 0.72; MFR: r = 0.8.) Regionally, the highest agreement between PMod and QPET was observed in the LAD territory (rest-MBF: r = 0.82, Stress-MBF: r = 0.68) where spillover fraction was the lowest. Unlike HCM patients, the non-HCM patients (CAD group) demonstrated excellent agreement in MBF/MFR values, obtained by the two softwares, when patients with high spillover fractions were excluded (rest-MBF: r = 0.95; stress-MBF: r = 0.92; MFR: r = 0.95). CONCLUSIONS: Anatomic characteristics specific to HCM hearts contribute to lower correlations between MBF/MFR values obtained by PMod and QPET, compared with non-HCM patients. These differences indicate that PMod and QPET cannot be used interchangeably for MBF/MFR analyses in HCM patients.

Correction to: Comparison of two software systems for quantification of myocardial blood flow in patients with hypertrophic cardiomyopathy.

The following information is missing from the Funding footnote on the first page of the published article: "This study was partly funded by NIH RO1 HL092985." The last/corresponding author is incorrectly listed on the first page of the published article: The correct name is Abraham MR.

Imager-4D: New Software for Viewing Dynamic PET Scans and Extracting Radiomic Parameters from PET Data.

Extensive research is currently being conducted into dynamic positron emission tomography (PET) acquisitions (including dynamic whole-body imaging) as well as extraction of radiomic features from imaging modalities. We describe a new PET viewing software known as Imager-4D that provides a facile means of viewing and analyzing dynamic PET data and obtaining associated quantitative metrics including radiomic parameters. The Imager-4D was programmed in the Java language utilizing the FX extensions. It is executable on any system for which a Java w/FX compliant virtual machine is available. The software incorporates the ability to view and analyze dynamic data acquired with different types of dynamic protocols. For image display, the program maintains a built-in library of 62 different lookup tables with monochromatic and full-color distributions. The Imager-4D provides multiple display layouts and can display fused images. Multiple methods of volume-of-interest (VOI) selection are available. Dynamic analysis features, such as image summation and full Patlak analysis, are also available. The user interface includes window width and level, blending, and zoom functionality. VOI sizes are adjustable and data from VOIs can either be displayed numerically or graphically within the software or exported. An example case of a 50-year-old woman with metastatic colorectal cancer and thyroiditis is included and demonstrates the steps for a user to obtain standard PET parameters, dynamic data, and radiomic features using selected VOIs. The Imager-4D represents a novel PET viewer that allows the user to view dynamic PET data, to derive dynamic and radiomic parameters from that data, and to combine dynamic data with radiomics ("dynomics"). The Imager-4D is available as a free download. This software has the potential to speed the adoption of advanced analysis of dynamic PET data into routine clinical use.

Feasibility of state of the art PET/CT systems performance harmonisation.

PURPOSE: The objective of this study was to explore the feasibility of harmonising performance for PET/CT systems equipped with time-of-flight (ToF) and resolution modelling/point spread function (PSF) technologies. A second aim was producing a working prototype of new harmonising criteria with higher contrast recoveries than current EARL standards using various SUV metrics. METHODS: Four PET/CT systems with both ToF and PSF capabilities from three major vendors were used to acquire and reconstruct images of the NEMA NU2-2007 body phantom filled conforming EANM EARL guidelines. A total of 15 reconstruction parameter sets of varying pixel size, post filtering and reconstruction type, with three different acquisition durations were used to compare the quantitative performance of the systems. A target range for recovery curves was established such that it would accommodate the highest matching recoveries from all investigated systems. These updated criteria were validated on 18 additional scanners from 16 sites in order to demonstrate the scanners' ability to meet the new target range. RESULTS: Each of the four systems was found to be capable of producing harmonising reconstructions with similar recovery curves. The five reconstruction parameter sets producing harmonising results significantly increased SUVmean (25%) and SUVmax (26%) contrast recoveries compared with current EARL specifications. Additional prospective validation performed on 18 scanners from 16 EARL accredited sites demonstrated the feasibility of updated harmonising specifications. SUVpeak was found to significantly reduce the variability in quantitative results while producing lower recoveries in smaller (≤17 mm diameter) sphere sizes. CONCLUSIONS: Harmonising PET/CT systems with ToF and PSF technologies from different vendors was found to be feasible. The harmonisation of such systems would require an update to the current multicentre accreditation program EARL in order to accommodate higher recoveries. SUVpeak should be further investigated as a noise resistant alternative quantitative metric to SUVmax.

Combined model-based and patient-specific dosimetry for 18F-DCFPyL, a PSMA-targeted PET agent.

PURPOSE: Prostate-specific membrane antigen (PSMA), a type-II integral membrane protein highly expressed in prostate cancer, has been extensively used as a target for imaging and therapy. Among the available PET radiotracers, the low molecular weight agents that bind to PSMA are proving particularly effective. We present the dosimetry results for 18F-DCFPyL in nine patients with metastatic prostate cancer. METHODS: Nine patients were imaged using sequential PET/CT scans at approximately 1, 12, 35 and 70 min, and a final PET/CT scan at approximately 120 min after intravenous administration of 321 ± 8 MBq (8.7 ± 0.2 mCi) of18F-DCFPyL. Time-integrated-activity coefficients were calculated and used as input in OLINDA/EXM software to obtain dose estimates for the majority of the major organs. The absorbed doses (AD) to the eye lens and lacrimal glands were calculated using Monte-Carlo models based on idealized anatomy combined with patient-specific volumes and activity from the PET/CT scans. Monte-Carlo based models were also developed for calculation of the dose to two major salivary glands (parotid and submandibular) using CT-based patient-specific gland volumes. RESULTS: The highest calculated mean AD per unit administered activity of 18F was found in the lacrimal glands, followed by the submandibular glands, kidneys, urinary bladder wall, and parotid glands. The S-values for the lacrimal glands to the eye lens (0.42 mGy/MBq h), the tear film to the eye lens (1.78 mGy/MBq h) and the lacrimal gland self-dose (574.10 mGy/MBq h) were calculated. Average S-values for the salivary glands were 3.58 mGy/MBq h for the parotid self-dose and 6.78 mGy/MBq h for the submandibular self-dose. The resultant mean effective dose of 18F-DCFPyL was 0.017 ± 0.002 mSv/MBq. CONCLUSIONS: 18F-DCFPyL dosimetry in nine patients was obtained using novel models for the lacrimal and salivary glands, two organs with potentially dose-limiting uptake for therapy and diagnosis which lacked pre-existing models.

Combination of the histone deacetylase inhibitor vorinostat with bevacizumab in patients with clear-cell renal cell carcinoma: a multicentre, single-arm phase I/II clinical trial.

BACKGROUND: Class II histone deacetylase (HDAC) inhibitors induce hypoxia-inducible factor-1 and -2α degradation and have antitumour effects in combination with vascular endothelial growth factor (VEGF) inhibitors. In this study, we tested the safety and efficacy of the HDAC inhibitor vorinostat and the VEGF blocker bevacizumab in metastatic clear-cell renal cell carcinoma (ccRCC) patients previously treated with different drugs including sunitinib, sorafenib, axitinib, interleukin-2, interferon, and temsirolimus. METHODS: Patients with up to two prior regimens were eligible for treatment, consisting of vorinostat 200 mg orally two times daily × 2 weeks, and bevacizumab 15 mg kg-1 intravenously every 3 weeks. The primary end points were safety and tolerability, and the proportion of patients with 6 months of progression-free survival (PFS). Correlative studies included immunohistochemistry, FDG PET/CT scans, and serum analyses for chemokines and microRNAs. RESULTS: Thirty-six patients were enrolled, with 33 evaluable for toxicity and efficacy. Eighteen patients had 1 prior treatment, 13 patients had 2 prior treatments, and 2 patients were treatment naïve. Two patients experienced grade 4 thrombocytopenia and three patients had grade 3 thromboembolic events during the course of exposure. We observed six objective responses (18%), including one complete response and five partial responses. The proportion of patients with PFS at 6 months was 48%. The median PFS and overall survival were 5.7 months (confidence interval (CI): 4.1-11.0) and 13.9 months (CI: 9.8-20.7), respectively. Correlative studies showed that modulation of specific chemokines and microRNAs were associated with clinical benefit. CONCLUSIONS: The combination of vorinostat with bevacizumab as described is relatively well tolerated. Response rate and median PFS suggest clinical activity for this combination strategy in previously treated ccRCC.

The effect of regadenoson on the integrity of the human blood-brain barrier, a pilot study.

Regadenoson is an FDA approved adenosine receptor agonist which increases blood-brain barrier (BBB) permeability in rodents. Regadenoson is used clinically for pharmacologic cardiac stress testing using SPECT or CT imaging agents that do not cross an intact BBB. This study was conducted to determine if standard doses of regadenoson transiently disrupt the human BBB allowing higher concentrations of systemically administered imaging agents to enter the brain. Patients without known intracranial disease undergoing clinically indicated pharmacologic cardiac stress tests were eligible for this study. They received regadenoson (0.4 mg) followed by brain imaging with either 99mTc-sestamibi for SPECT or visipaque for CT imaging. Pre- and post-regadenoson penetration of imaging agents into brain were quantified [SPECT: radioactive counts, CT: Hounsfield units (HU)] and compared using a matched-pairs t-test. Twelve patients (33% male, median 60 yo) were accrued: 7 SPECT and 5 CT. No significant differences were noted in pre- and post-regadenoson values using mean radionuclide counts (726 vs. 757) or HU (29 vs. 30). While animal studies have demonstrated that regadenoson transiently increases the permeability of the BBB to dextran and temozolomide, we were unable to document changes in the penetration of contrast agents in humans with intact BBB using the FDA approved doses of regadenoson for cardiac evaluation. Further studies are needed exploring alternate regadenoson dosing, schedules, and studies in patients with brain tumors; as transiently disrupting the BBB to improve drug entry into the brain is critical to improving the care of patients with CNS malignancies.

Practical PERCIST: A Simplified Guide to PET Response Criteria in Solid Tumors 1.0.

Positron Emission Tomography (PET) Response Criteria in Solid Tumors (PERCIST 1.0) describes in detail methods for controlling the quality of fluorine 18 fluorodeoxyglucose PET imaging conditions to ensure the comparability of PET images from different time points to allow quantitative expression of the changes in PET measurements and assessment of overall treatment response in PET studies. The steps for actual application of PERCIST are summarized. Several issues from PERCIST 1.0 that appear to require clarification, such as measurement of size and definition of unequivocal progression, also are addressed. (©) RSNA, 2016.

Absolute myocardial flow quantification with (82)Rb PET/CT: comparison of different software packages and methods.

PURPOSE: In clinical cardiac (82)Rb PET, globally impaired coronary flow reserve (CFR) is a relevant marker for predicting short-term cardiovascular events. However, there are limited data on the impact of different software and methods for estimation of myocardial blood flow (MBF) and CFR. Our objective was to compare quantitative results obtained from previously validated software tools. METHODS: We retrospectively analyzed cardiac (82)Rb PET/CT data from 25 subjects (group 1, 62 ± 11 years) with low-to-intermediate probability of coronary artery disease (CAD) and 26 patients (group 2, 57 ± 10 years; P=0.07) with known CAD. Resting and vasodilator-stress MBF and CFR were derived using three software applications: (1) Corridor4DM (4DM) based on factor analysis (FA) and kinetic modeling, (2) 4DM based on region-of-interest (ROI) and kinetic modeling, (3) MunichHeart (MH), which uses a simplified ROI-based retention model approach, and (4) FlowQuant (FQ) based on ROI and compartmental modeling with constant distribution volume. RESULTS: Resting and stress MBF values (in milliliters per minute per gram) derived using the different methods were significantly different: using 4DM-FA, 4DM-ROI, FQ, and MH resting MBF values were 1.47 ± 0.59, 1.16 ± 0.51, 0.91 ± 0.39, and 0.90 ± 0.44, respectively (P<0.001), and stress MBF values were 3.05 ± 1.66, 2.26 ± 1.01, 1.90 ± 0.82, and 1.83 ± 0.81, respectively (P<0.001). However, there were no statistically significant differences among the CFR values (2.15 ± 1.08, 2.05 ± 0.83, 2.23 ± 0.89, and 2.21 ± 0.90, respectively; P=0.17). Regional MBF and CFR according to vascular territories showed similar results. Linear correlation coefficient for global CFR varied between 0.71 (MH vs. 4DM-ROI) and 0.90 (FQ vs. 4DM-ROI). Using a cut-off value of 2.0 for abnormal CFR, the agreement among the software programs ranged between 76 % (MH vs. FQ) and 90 % (FQ vs. 4DM-ROI). Interobserver agreement was in general excellent with all software packages. CONCLUSION: Quantitative assessment of resting and stress MBF with (82)Rb PET is dependent on the software and methods used, whereas CFR appears to be more comparable. Follow-up and treatment assessment should be done with the same software and method.

Comparison of Multiple Segmentation Methods for Volumetric Delineation of Primary Prostate Cancer with Prostate-Specific Membrane Antigen-Targeted 18F-DCFPyL PET/CT.

This study aimed to assess the accuracy of intraprostatic tumor volume measurements on prostate-specific membrane antigen-targeted 18F-DCFPyL PET/CT made with various segmentation methods. An accurate understanding of tumor volumes versus segmentation techniques is critical for therapy planning, such as radiation dose volume determination and response assessment. Methods: Twenty-five men with clinically localized, high-risk prostate cancer were imaged with 18F-DCFPyL PET/CT before radical prostatectomy. The tumor volumes and tumor-to-prostate ratios (TPRs) of dominant intraprostatic foci of uptake were determined using semiautomatic segmentation (applying SUVmax percentage [SUV%] thresholds of SUV30%-SUV70%), adaptive segmentation (using adaptive segmentation percentage [A%] thresholds of A30%-A70%), and manual contouring. The histopathologic tumor volume (TV-Histo) served as the reference standard. The significance of differences between TV-Histo and PET-based tumor volume were assessed using the paired-sample Wilcoxon signed-rank test. The Spearman correlation coefficient was used to establish the strength of the association between TV-Histo and PET-derived tumor volume. Results: Median TV-Histo was 2.03 cm3 (interquartile ratio [IQR], 1.16-3.36 cm3), and median TPR was 10.16%. The adaptive method with an A40% threshold most closely determined the tumor volume, with a median difference of +0.19 (IQR, -0.71 to +2.01) and a median relative difference of +7.6%. The paired-sample Wilcoxon test showed no significant difference in PET-derived tumor volume and TV-Histo using A40%, A50%, SUV40%, and SUV50% threshold segmentation algorithms (P > 0.05). For both threshold-based segmentation methods, use of higher thresholds (e.g., SUV60% or SUV70% and A50%-A70%) resulted in underestimation of tumor volumes, and use of lower thresholds (e.g., SUV30% or SUV40% and A30%) resulted in overestimation of tumor volumes relative to TV-Histo and TPR. Manual segmentation overestimated the tumor volume, with a median difference of +2.49 (IQR, 0.42-4.11) and a median relative difference of +130%. Conclusion: Segmentation of intraprostatic tumor volume and TPR with an adaptive segmentation approach most closely approximates TV-Histo. This information might be used to guide the primary treatment of men with clinically localized, high-risk prostate cancer.

Dynamic 18F-Pretomanid PET imaging in animal models of TB meningitis and human studies.

Pretomanid is a nitroimidazole antimicrobial active against drug-resistant Mycobacterium tuberculosis and approved in combination with bedaquiline and linezolid (BPaL) to treat multidrug-resistant (MDR) pulmonary tuberculosis (TB). However, the penetration of these antibiotics into the central nervous system (CNS), and the efficacy of the BPaL regimen for TB meningitis, are not well established. Importantly, there is a lack of efficacious treatments for TB meningitis due to MDR strains, resulting in high mortality. We have developed new methods to synthesize 18F-pretomanid (chemically identical to the antibiotic) and performed cross-species positron emission tomography (PET) imaging to noninvasively measure pretomanid concentration-time profiles. Dynamic PET in mouse and rabbit models of TB meningitis demonstrates excellent CNS penetration of pretomanid but cerebrospinal fluid (CSF) levels does not correlate with those in the brain parenchyma. The bactericidal activity of the BPaL regimen in the mouse model of TB meningitis is substantially inferior to the standard TB regimen, likely due to restricted penetration of bedaquiline and linezolid into the brain parenchyma. Finally, first-in-human dynamic 18F-pretomanid PET in six healthy volunteers demonstrates excellent CNS penetration of pretomanid, with significantly higher levels in the brain parenchyma than in CSF. These data have important implications for developing new antibiotic treatments for TB meningitis.

Prospective Within-Patient Assessment of the Impact of an Unlabeled Octreotide Pre-dose on the Biodistribution and Tumor Uptake of 68Ga DOTATOC as Assessed by Dynamic Whole-body PET in Patients with Neuroendocrine Tumors: Implications for Diagnosis and Therapy.

PURPOSE: Gastroenteropancreatic neuroendocrine tumors (GEP NETs) are often associated with high expression of somatostatin receptors (SSTRs) which allows for PET/CT imaging with radiolabeled somatostatin analogs such as 68Ga-DOTATOC. The interplay between 68Ga-DOTATOC and the synthetic somatostatin analogs commonly used to manage patient symptoms may lead to competition between the labelled and unlabeled peptides for receptor binding sites and current product labelling recommends patients be taken off somatostatin analogs before imaging. In this study, we prospectively investigated in human patients the effect of a pre-dose of octreotide, a short-acting somatostatin analog, on the distribution of 68Ga-DOTATOC in GEP NETs and normal organs. PROCEDURE: Research participants with GEP NETs were studied on two occasions using dynamic whole-body 68Ga-DOTATOC PET/CT. The two imaging studies were performed within 21 days of each other, using an identical acquisition protocol except for the administration of 50 µg of short-acting octreotide (pre-dose) immediately before the second PET/CT. Paired t-tests were used to compare tracer uptake with and without octreotide, for tumor and various normal organs. RESULTS: Seven participants with a mean age of 53 ± 10 years were studied. Octreotide pre-dosing decreased radiotracer uptake in the normal liver and spleen by 25 % (p = 0.04) and 47 % (p = 0.05) respectively but did not significantly change uptake in tumor (p = 0.53), red marrow (p = 0.12), kidneys (p =0.57), or pituitary gland (p = 0.27). CONCLUSIONS: Our data indicate SSTR imaging can be improved with a pre-dose of unlabeled octreotide given just prior to injection of the radiotracer. These data suggest there may be no need to discontinue somatostatin analog therapy prior to PET/CT with 68Ga-DOTATOC, allowing for a simpler, less disruptive patient protocol. This approach warrants further study in a variety of settings.

Measurement of PET Quantitative Bias In Vivo.

Quantitative imaging biomarkers are widely used in PET for both research and clinical applications, yet bias in the underlying image data has not been well characterized. In the absence of a readily available reference standard for in vivo quantification, bias in PET images has been inferred using physical phantoms, even though arrangements of this sort provide only a poor approximation of the imaging environment in real patient examinations. In this study, we used data acquired from patient volunteers to assess PET quantitative bias in vivo. Image-derived radioactivity concentrations in the descending aorta were compared with blood samples counted on a calibrated γ-counter. Methods: Ten patients with prostate cancer were studied using 2-(3-(1-carboxy-5-[(6-18F-fluoro-pyridine-3-carbonyl)-amino]-pentyl)-ureido)-pentanedioic acid PET/CT. For each patient, 3 whole-body PET/CT image series were acquired after a single administration of the radiotracer: shortly after injection as well as approximately 1 and 4 h later. Venous blood samples were obtained at 8 time points over an 8-h period, and whole blood was counted on a NaI γ-counter. A 10-mm-diameter, 20-mm-long cylindric volume of interest was positioned in the descending thoracic aorta to estimate the PET-derived radioactivity concentration in blood. A triexponential function was fit to the γ-counter blood data and used to estimate the radioactivity concentration at the time of each PET acquisition. Results: The PET-derived and γ-counter-derived radioactivity concentrations were linearly related, with an R2 of 0.985, over a range of relevant radioactivity concentrations. The mean difference between the PET and γ-counter data was 4.8% ± 8.6%, with the PET measurements tending to be greater. Conclusion: Human image data acquired on a conventional whole-body PET/CT system with a typical clinical protocol differed by an average of around 5% from blood samples counted on a calibrated γ-counter. This bias may be partly attributable to residual uncorrected scatter or attenuation correction error. These data offer an opportunity for the assessment of PET bias in vivo and provide additional support for the use of quantitative imaging biomarkers.