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Background: Activation of endothelial cells and platelets in atherothrombosis is characterized by upregulation of P-selectin. As a consequence, P-selectin represents a potential target for molecular imaging to identify thrombosis at an early stage. Fucoidan is a polysaccharide ligand extracted from brown algae with nanomolar affinity for P-selectin. This first-in-human study evaluated in healthy volunteers the safety, whole-body biodistribution, and dosimetry of 99mTc-fucoidan (Good Manufacturing Practices grade). We also investigated whether we could observe binding of 99mTc-fucoidan to human thrombi ex vivo and in vivo. In ten healthy volunteers, conjugate whole-body scans were performed up to 24 h following intravenous injection of 99mTc-fucoidan (370 MBq). Moreover, 99mTc-fucoidan uptake in ex vivo human thrombi (n = 11) was measured by gamma counting. Additionally, three patients with a newly diagnosed deep vein thrombosis (DVT) were subjected to 99mTc-fucoidan SPECT/CT imaging. Results: 99mTc-fucoidan was well tolerated in all participants without any drug-related adverse events. The total-body absorbed dose in males was comparable to females (0.012 ± 0.004 vs. 0.011 ± 0.005 mSv/MBq; p = 0.97). Gamma counting experiments demonstrated binding of tracer to ex vivo human thrombi that was 16% lower after blocking with a natural P-selectin ligand, Sialyl Lewis X. 99mTc-fucoidan demonstrated specific uptake at the thrombus site in one out of three scanned patients with DVT. Conclusions: 99mTc-Fucoidan has a favorable biodistribution and safety profile. 99mTc-fucoidan exhibited specific binding to human thrombi in both in vivo and ex vivo settings. Nonetheless, the in vivo results do not support further clinical investigation of 99mTc-fucoidan as an imaging modality for DVT. Other clinical implementations of a technetium− 99m-labeled P-selectin tracer should be considered. Trial registration: Clinicaltrials,NCT03422055.Registered 01/15/2018. URL: https://clinicaltrials.gov/study/NCT03422055Landelijk Trial Register, NL7739. Registered 4/2/2019. https://onderzoekmetmensen.nl/en/trial/26785 [ABSTRACT FROM AUTHOR]

Quantitative accuracy of single-photon-emission computed tomography (SPECT) images is highly dependent on the photon scatter model used for image reconstruction. Monte Carlo simulation (MCS) is the most general tool for accurate modeling and correction of scatter, but calculations are notoriously slow. Recently, we proposed an efficient strategy for fully three-dimensional (3-D) statistical reconstruction using highly accelerated MCS as a forward projector. We use convolution forced detection (CFD) which accelerates convergence of reprojection by about two orders of magnitude. Here, we investigate how many photon histories during CFD-based MCS need to be calculated to: i) ensure that the noise in the reconstructed image does not increase markedly because of the stochastic nature of MCS reprojections; and ii) to determine the reconstruction time needed. To this end, phantom studies representing Tc-99m cardiac perfusion SPECT, were carried out. We generated reconstructions with different numbers of photon histories during MCS forward projection. Images and profiles were compared for reconstructions with a different number of photon tracks, for reconstructions from different noise realizations using a repeat measurement and for reconstructions with different random seeds for MCS reprojection. We found that [10.sup.5] photon histories per subset is sufficient to produce accurate images; more photons do not show visible improvement. This amount of photons corresponds to a typical reconstruction time below 5 min for a [64.sup.3] volume image on a dual-cpu PC (2.66 GHz), which is sufficiently short to apply such highly accurate reconstruction in clinical routine. Index Terms--Cardiac imaging, image reconstruction, Monte Carlo simulation, scatter, single photon emission computed tomography.

Objective: Brown adipose tissue (BAT) activity in humans is stimulated by cold and by a limited number of pharmacological agents, including ß3-adrenergic agonists and bile acids. Although thyrotropin-releasing hormone (TRH) is known to activate BAT in several mammals, this has not been reported in humans. Design: A randomized, placebo-controlled, double-blind, cross-over trial. Methods: We investigated the effects of intravenous bolus administration of 400 µg TRH or 2 mL saline on BAT activity in healthy, lean men. BAT activity was measured as standardized 18F-fluorodeoxyglucose (18F-FDG) uptake and glucose metabolic rate (MRglu) using dynamic PET/CT imaging. The first six individuals were studied at room temperature, while subsequently nine were exposed to mild cold (17°C ± 1°C) for 60 min before imaging. During the dynamic scan, blood was withdrawn for measurement of thyroid hormone and catecholamine concentrations. This trial is registered with The Netherlands National Trial Register (number NTR5512). Results: Sixteen participants were recruited. Six men studied at room temperature showed no visible BAT activity during either session. After exposure to mild cold, four of nine men (44.4%) showed clear increase of 18F-FDG uptake after TRH administration compared to placebo. Maximal standardized 18F-FDG uptake showed a trend toward increase after TRH compared to placebo (P = 0.066). MRglu showed a significant increase after TRH administration (P = 0.014). The increase in 18F-FDG uptake was not paralleled by changes in plasma thyroid hormone or catecholamine concentrations. Conclusion: Systemic TRH administration can increase the activity of cold-stimulated BAT in adult men. These findings may assist developing pharmacological strategies for modulating BAT activity in the management of obesity. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Ex vivo storage phosphor imaging rat studies reported increased brain dopamine D2/3 receptor (DRD2/3) availability following treatment with varenicline, a nicotinergic drug. However, ex vivo studies can only be performed using cross-sectional designs. Small-animal imaging offers the opportunity to perform serial assessments. We evaluated whether high-resolution pinhole single photon emission computed tomography (SPECT) imaging in rats was able to reproduce previous ex vivo findings. Methods: Rats were imaged for baseline striatal DRD2/3 availability using ultra-high-resolution pinhole SPECT (U-SPECT-II) and [123I]IBZM as a radiotracer, and randomized to varenicline (n=7; 2 mg/kg) or saline (n=7). Following 2 weeks of treatment, a second scan was acquired. Results: Significantly increased striatal DRD2/3 availability was found following varenicline treatment compared to saline (time⁎treatment effect): posttreatment difference in binding potential between groups corrected for initial baseline differences was 2.039 (P=.022), indicating a large effect size (d=1.48). Conclusions: Ultra-high-resolution pinhole SPECT can be used to assess varenicline-induced changes in DRD2/3 availability in small laboratory animals over time. Future small-animal studies should include imaging techniques to enable repeated within-subjects measurements and reduce the amount of animals. [Copyright &y& Elsevier]

Thallous (201Tl) chloride is a single-photon emission computed tomography (SPECT) tracer mainly used for assessing perfusion and viability of myocardial tissue. 201Tl emits X-rays around 72 keV and gammas at 167 keV, and has a half-life of 73 h. Regulations allow an intrinsic contamination up to 3–5%, which is mainly caused by 200Tl (368 keV; 26 h) and by 202Tl (439 keV; 12.2 days). Contra-intuitive to the low-level percentages in which these contaminants are present, their impact may be significant because of much higher gamma camera sensitivity for these high-energy photon emissions. Therefore, we investigate the effects of the contaminants in terms of detected fractions of photons in projections and contrast degradation in reconstructed images. Acquisitions of a digital thorax phantom filled with thallous (201Tl) chloride were simulated with a validated Monte Carlo tool, thereby, modelling 1% of contamination by 200Tl and 202Tl each. In addition, measurements of a thorax phantom on a dual-headed gamma camera were performed. The product used was contaminated by 0.17% of 200Tl and 0.24% of 202Tl at activity reference time (ART). This ART is specified by the manufacturer, thereby, accounting for the difference in half-lives of 201Tl and its contaminants. These measurements were repeated at different dates associated with various contamination levels. Simulations showed that, with 1% of 200Tl and 202Tl, the total contamination in the 72 keV window can rise up to one out of three detected photons. For the 167keV window, the contamination is even more pronounced: more than four out of five detections in this photopeak window originate from contaminants. Measurements indicate that cold lesion contrast in myocardial perfusion SPECT imaging is at maximum close to ART. In addition to a higher noise level, relative contrast decreases 15% 2 days early to ART, which is explained by an increase in 200Tl contamination. After ART, contrast decreased by 16% when the 202Tl contamination increased to the maximal allowed limit. Contra-intuitive to the low-level percentages in which they are typically present, penetration and downscatter of high-energy photons from 200Tl and 202Tl significantly contribute to thallous (201Tl) chloride images, thereby, reducing contrast and adding noise. These findings may prompt for improved production methods, for updated policies with regard to timing of usage, and they also render the usefulness of adding the high photopeak window (167 keV) questionable. A window-based correction method for this contamination is advisable. [ABSTRACT FROM AUTHOR]

The InSPira HD system, a novel brain-dedicated SPECT scanner, allows for imaging with a high spatial resolution. Here, we tested whether this scanner can be used to image the dopamine transporter adequately. Therefore, striatal phantom and patient data acquired on the InSPira were compared head-to-head with the well-validated brain-dedicated NeuroFocus system. A striatal phantom filled with [123I] and 14 subjects (after [123I]FP-CIT injection) were scanned on both systems. [123I]FP-CIT SPECT scans were visually assessed. Striatal binding ratios were calculated automatically using the software package BRASS. Striatal phantom and patient data showed strong correlations with respect to striatal ratios (R = 0.99 and R = 0.92; p < 0.05 and p < 0.01, respectively). Slightly higher ratios were found for the NeuroFocus patient data, probably due to differences in system performance. Visual assessment of [123I]FP-CIT scans showed agreement between systems in 13 of the 14 cases. We conclude that [123I]FP-CIT SPECT imaging can be performed adequately on the new InSPira system. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the potential of magnetic resonance imaging (MRI) for accurate assessment of the three-dimensional 166Ho activity distribution to estimate radiation-absorbed dose distributions in 166Ho-loaded poly (L-lactic acid) microsphere (166Ho-PLLA-MS) liver radioembolization. Methods and Materials: MRI, computed tomography (CT), and single photon emission CT (SPECT) experiments were conducted on an anthropomorphic gel phantom with tumor-simulating gel samples and on an excised human tumor-bearing liver, both containing known amounts of 166Ho-PLLA-MS. Three-dimensional radiation-absorbed dose distributions were estimated at the voxel level by convolving the 166Ho activity distribution, derived from quantitative MRI data, with a 166Ho dose point-kernel generated by MCNP (Monte Carlo N-Particle transport code) and from Medical Internal Radiation Dose Pamphlet 17. MRI-based radiation-absorbed dose distributions were qualitatively compared with CT and autoradiography images and quantitatively compared with SPECT-based dose distributions. Both MRI- and SPECT-based activity estimations were validated against dose calibrator measurements. Results: Evaluation on an anthropomorphic phantom showed that MRI enables accurate assessment of local 166Ho-PLLA-MS mass and activity distributions, as supported by a regression coefficient of 1.05 and a correlation coefficient of 0.99, relating local MRI-based mass and activity calculations to reference values obtained with a dose calibrator. Estimated MRI-based radiation-absorbed dose distributions of 166Ho-PLLA-MS in an ex vivo human liver visually showed high correspondence to SPECT-based radiation-absorbed dose distributions. Quantitative analysis revealed that the differences in local and total amounts of 166Ho-PLLA-MS estimated by MRI, SPECT, and the dose calibrator were within 10%. Excellent agreement was observed between MRI- and SPECT-based dose–volume histograms. Conclusions: Quantitative MRI was demonstrated to provide accurate three-dimensional 166Ho-PLLA-MS activity distributions, enabling localized intrahepatic radiation-absorbed dose estimation by convolution with a 166Ho dose point-kernel for liver radioembolization treatment optimization and evaluation. [Copyright &y& Elsevier]

Objective: Brown adipose tissue (BAT) activity in humans is stimulated by cold and by a limited number of pharmacological agents, including β3-adrenergic agonists and bile acids. Although thyrotropin-releasing hormone (TRH) is known to activate BAT in several mammals, this has not been reported in humans., Design: A randomized, placebo-controlled, double-blind, cross-over trial., Methods: We investigated the effects of intravenous bolus administration of 400 µg TRH or 2 mL saline on BAT activity in healthy, lean men. BAT activity was measured as standardized 18 F-fluorodeoxyglucose ( 18 F-FDG) uptake and glucose metabolic rate (MRglu) using dynamic PET/CT imaging. The first six individuals were studied at room temperature, while subsequently nine were exposed to mild cold (17°C ± 1°C) for 60 min before imaging. During the dynamic scan, blood was withdrawn for measurement of thyroid hormone and catecholamine concentrations. This trial is registered with The Netherlands National Trial Register (number NTR5512)., Results: Sixteen participants were recruited. Six men studied at room temperature showed no visible BAT activity during either session. After exposure to mild cold, four of nine men (44.4%) showed clear increase of 18 F-FDG uptake after TRH administration compared to placebo. Maximal standardized 18 F-FDG uptake showed a trend toward increase after TRH compared to placebo ( P  = 0.066). MRglu showed a significant increase after TRH administration ( P  = 0.014). The increase in 18 F-FDG uptake was not paralleled by changes in plasma thyroid hormone or catecholamine concentrations., Conclusion: Systemic TRH administration can increase the activity of cold-stimulated BAT in adult men. These findings may assist developing pharmacological strategies for modulating BAT activity in the management of obesity., (© 2018 European Society of Endocrinology.)

Aim: The 123I-metaiodobenzylguanidine (123I-MIBG) late heart-to-mediastinum ratio (H/M) is a well-established prognostic parameter in patients with chronic heart failure (CHF). However, 123I presents imaging problems owing to high-energy photon emission leading to penetration of collimator septa and subsequent reduction in image quality. Most likely this affects the H/M ratio and may subsequently lead to incorrect patient risk classification. In this prospective study we assessed the intrapatient variation in late H/M ratio between low-energy high-resolution (LEHR) and medium-energy (ME) collimators in patients with CHF., Materials and Methods: Fifty-three patients with CHF (87% male, age 63±8.3 years, left ventricular ejection fraction 29±7.8) referred for 123I-MIBG scintigraphy were enrolled in the study. In each patient, after the administration of 185 MBq I-MIBG, early (15 min after injection) and late (4 h after injection) planar anterior thoracic images were acquired with both LEHR and ME collimators. Early and late H/M ratios were calculated on the basis of the mean count densities from the manually drawn regions of interest (ROIs) over the left ventricle and a predefined fixed ROI placed in the upper mediastinum. Additional ROIs were drawn over the liver and lungs. Liver/lung to myocardium and liver/lung to mediastinal ratios were calculated to estimate the effect of collimator septa penetration from liver and lung activity on the myocardial and mediastinal ROIs., Results: The mean LEHR collimator-derived parameters were lower compared with those from the ME collimator (late H/M 1.41±0.18 vs. 1.80±0.41, P<0.001). Moreover, Bland-Altman analysis showed that with increasing late H/M ratios the difference between the ratios from the two collimator types increased (R2=0.73, P=0.001). Multivariate regression analysis showed that almost 90% of the variation in the difference between ME and LEHR late H/M ratios could be explained by scatter from the liver in both the mediastinal and myocardial ROIs (R2=0.90, P=0.001). Independent predictors for the difference in the late H/M between ME and LEHR were the liver-to-heart ratio and the liver-to-mediastinum ratio assessed by ME (standardized coefficient of -1.69 and 1.16, respectively) and LEHR (standardized coefficient of 1.24 and -0.90, respectively) (P<0.001 for all)., Conclusion: Intrapatient comparison in H/M between the ME and LEHR collimators in patients with CHF showed that with increasing H/M the difference between the ratios increased in favour of the ME collimator. These differences could be explained by septal penetration of high-energy photons from both the liver and the lung in the mediastinum and myocardium, being lowest when using the ME collimator. These results strengthen the importance of the recommendation to use ME collimators in semiquantitative 123I-MIBG studies.

Unlabelled: (201)Tl-Chloride ((201)Tl) is a myocardial perfusion SPECT agent with excellent biochemical properties commonly used for assessing tissue viability. However, cardiac (201)Tl SPECT images are severely degraded by photons scattered in the thorax. Accurate correction for this scatter is complicated by the nonuniform density and varied sizes of thoraxes, by the additional attenuation and scatter caused by female patients' breasts, and by the energy spectrum of (201)Tl. Monte Carlo simulation is a general and accurate method well suited to modeling this scatter., Methods: Statistical reconstruction that includes Monte Carlo modeling of scatter was compared with statistical reconstruction algorithms not corrected for scatter. In the ADS method, corrections for attenuation, detector response, and scatter (Monte Carlo-based) were implemented simultaneously via the dual-matrix ordered-subset expectation maximization algorithm with a Monte Carlo simulator as part of the forward projector. The ADS method was compared with the A method (ordered-subset expectation maximization with attenuation correction) and with the AD method (a method like the A method but with detector response modeling added). A dual-head SPECT system equipped with two (153)Gd scanning line sources was used for simultaneously acquiring transmission and emission data. Four clinically realistic phantom configurations (a large thorax and a small thorax, each with and without breasts) with a cardiac insert containing 2 cold defects were used to evaluate the proposed reconstruction algorithms. We compared the performance of the different algorithms in terms of noise properties, contrast-to-noise ratios, the contrast separability of perfusion defects, uniformity, and robustness to anatomic variations., Results: The ADS method provided images with clearly better visual defect contrast than did the other methods. The contrasts achieved with the ADS method were 10%-24% higher than those achieved with the AD method and 11%-37% higher than those achieved with the A method. For a typical contrast level, the ADS method exhibited noise levels around 27% lower than the AD method and 34% lower than the A method. Compared with the other 2 algorithms, the ADS reconstructions were less sensitive to anatomic variations and had better image uniformity in the homogeneously perfused myocardium. Finally, we found that the improvements that can be achieved with Monte Carlo-based scatter correction are stronger for (201)Tl than for (99m)Tc imaging., Conclusion: Our results indicate that Monte Carlo-based scatter correction is suitable for (201)Tl cardiac imaging and that such correction simultaneously improves several image-quality metrics.

Ho-166 is a combined beta-gamma emitter of which the betas can be used therapeutically. From the 81 keV gammas of Ho-166, SPECT images can be obtained, which give opportunities to guide Ho-166 therapy. Accurate reconstruction of Ho-166 images is currently hampered by photopeak-scatter in the patient, down-scatter in the detector, collimator and patient caused by the 1.4 MeV photons and by bremsstrahlung. We developed and validated a method for quantitative SPECT of Ho-166 that involves correction for both types of scatter plus non-uniform attenuation correction using attenuation maps. Photopeak-scatter (S) is compensated for by a rapid 3D Monte Carlo (MC) method that is incorporated in ordered subset (OS) reconstruction of the emission data, together with simultaneous correction for attenuation (A) and detector response (D); this method is referred to as OS-ADS. Additionally, for correction of down-scatter, we use a 14 keV wide energy window centred at 118 keV (OS-ADSS). Due to a limited number of available energy windows, the same 118 keV energy window was used for down-scatter correction of the simultaneously acquired Gd-153 transmission data. Validations were performed using physical phantom experiments carried out on a dual-head SPECT system; Gd-153 transmission line sources were used for acquiring attenuation maps. For quantitative comparison of OS-ADS and OS-ADSS, bottles filled with Ho-166 were placed in both a cylindrical phantom and an anthropomorphic thorax phantom. Both OS-ADS and OS-ADSS were compared with an ordered subset reconstruction without any scatter correction (OS-AD). Underestimations of about 20% in the attenuation map were reduced to a few per cent after down-scatter correction. The average deviation from the true activity contained in the bottles was +72% with OS-AD. Using OS-ADS, this average overestimation was reduced to +28% and with OS-ADSS the deviation was further reduced to 16%. With OS-AD and OS-ADS, these numbers were more sensitive to the choice of volumes of interest than with OS-ADSS. For the reconstructed activity distributions, erroneous background activity found with OS-AD was reduced by a factor of approximately 2 by applying OS-ADS and reduced by a factor of approximately 4 by applying OS-ADSS. The combined attenuation, photopeak-scatter and down-scatter correction framework proposed here greatly enhanced the quantitative accuracy of Ho-166 imaging, which is of the uppermost importance for image-guided therapies. It is expected that the method, with adapted window settings, also can be applied to other isotopes with high energy peaks that contaminate the photopeak data, such as I-131 or In-111.

Unlabelled: Cardiac SPECT images are degraded by photons scattered in the thorax. Accurate correction for scatter is complicated by the nonuniform density and varied sizes of thoraxes and by the additional attenuation and scatter caused by female patients' breasts. Monte Carlo simulation is a general and accurate method for detailed modeling of scatter. Hence, for 99mTc we compared statistical reconstruction based on Monte Carlo modeling of scatter with statistical reconstruction that incorporates the more commonly used triple-energy-window scatter correction. Both of these scatter correction methods were used in conjunction with attenuation correction and resolution recovery., Methods: Simultaneous attenuation, detector response, and Monte Carlo-based scatter correction were implemented via the dual-matrix ordered-subset expectation maximization algorithm with a Monte Carlo simulator as part of the forward projector (ADS-MC). ADS-MC was compared to (i) ordered-subset expectation maximization with attenuation correction and with detector response modeling (AD); (ii) like (i) but with scatter correction added using the triple-energy-window method (ADS-TEW). A dual-detector SPECT system equipped with 2 153Gd scanning line sources was used for acquiring 99mTc emission data and attenuation maps. Four clinically realistic phantom configurations (a large thorax and a small thorax, each with and without breasts) with a cardiac insert containing 2 cold defects were used to evaluate the proposed reconstruction algorithms. In these phantom configurations, we compared the performance of the algorithms in terms of noise properties, contrast-to-noise ratios, contrast separability of cold defects, and robustness to anatomic variation., Results: Noise was found to be approximately 14% lower in the ADS-MC images than in the ADS-TEW and AD images. Typically, the contrast obtained with the ADS-MC algorithm was 10%-20% higher than that obtained with the other 2 methods. Furthermore, compared with the other 2 algorithms, the ADS-MC method was less sensitive to anatomic variations., Conclusion: Our results indicate that the imaging performance of 99mTc SPECT can be improved more by Monte Carlo-based scatter correction than by window-based scatter correction.