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Background: Current molecular breast imaging (MBI) images are limited to qualitative evaluation, not absolute measurement, of 99mTc uptake in benign and malignant breast tissues. Purpose: This work assesses the accuracy of previously‐published and newly‐proposed tumor and normal breast tissue 99mTc uptake MBI measurements using simulations of a commercial dual‐headed planar MBI system under typical clinical and acquisition protocols. Methods: Quantification techniques were tested in over 4000 simulated acquisitions of spherical and ellipsoid tumors with clinically relevant uptake conditions using a validated Monte Carlo application of the GE Discovery NM750b system. The evaluated techniques consisted of four tumor total activity methodologies (two single‐detector‐based and two geometric‐mean‐based), two tumor MBI volume methodologies (diameter‐based and ROI‐based), and two normal tissue activity concentration methodologies (single‐detector‐based and geometric‐mean‐based). The most accurate of these techniques were then used to estimate tumor activity concentrations and tumor to normal tissue relative activity concentrations (RC). Results: Single‐detector techniques for tumor total activity quantification achieved mean (standard deviation) relative errors of 0.2% (4.3%) and 1.6% (4.4%) when using the near and far detector images, respectively and were more accurate and precise than the measured 8.1% (5.8%) errors of a previously published geometric‐mean technique. Using these activity estimates and the true tumor volumes resulted in tumor activity concentration and RC errors within 10% of simulated values. The precision of tumor activity concentration and RC when using only MBI measurements were largely driven by the errors in estimating tumor MBI volume using planar images (± 30% inter‐quartile range). Conclusions: Planar MBI images were shown to accurately and reliably be used to estimate tumor total activities and normal tissue activity concentrations in this simulation study. However, volumetric tumor uptake measurements (i.e., absolute and relative concentrations) are limited by inaccuracies in MBI volume estimation using two‐dimensional images, highlighting the need for either tomographic MBI acquisitions or anatomical volume estimates for accurate three‐dimensional tumor uptake estimates. [ABSTRACT FROM AUTHOR]

Background: Yttrium-90 (90Y) radioembolization is increasingly being utilized with curative intent. While single-compartment doses with respect to the perfused volume for the complete pathologic necrosis (CPN) of tumors have been reported, the actual doses delivered to the tumor and at-risk margins that leads to CPN have hitherto not been estimated. We present an ablative dosimetry model that calculates the dose distribution for tumors and at-risk margins based on numerical mm-scale dose modeling and the available clinical CPN evidence and report on the necessary dose metrics needed to achieve CPN following 90Y-radioembolization. Methods: Three-dimensional (3D) activity distributions (MBq/voxel) simulating spherical tumors were modeled with a 121 × 121 × 121 mm3 soft tissue volume (1 mm3 voxels). Then, 3D dose distributions (Gy/voxel) were estimated by convolving 3D activity distributions with a 90Y 3D dose kernel (Gy/MBq) sized 61 × 61 × 61 mm3 (1 mm3 voxels). Based on the published data on single-compartment segmental doses for the resected liver samples of HCC tumors showing CPN after radiation segmentectomy, the nominal voxel-based mean tumor dose ( D m e a n C P N ), point dose at tumor rim ( D r i m C P N ), and point dose 2 mm beyond the tumor boundary ( D 2 m m C P N ), which are necessary to achieve CPN, were calculated. The single-compartment dose prescriptions to required achieve CPN were then analytically modeled for more general cases of tumors with diameters d t = 2, 3, 4, 5, 6, and 7 cm and with tumor-to-normal-liver uptake ratios T : N = 1:1, 2:1, 3:1, 4:1, and 5:1. Results: The nominal case defined to estimate the doses needed for CPN, based on the previously published clinical data, was a single hyperperfused tumor with a diameter of 2.5 cm and T : N = 3:1, treated with a single-compartment segmental dose of 400 Gy. The voxel-level doses necessary to achieve CPN were 1053 Gy for the mean tumor dose, 860 Gy for the point dose at the tumor boundary, and 561 Gy for the point dose at 2 mm beyond the tumor edge. The single-compartment segmental doses necessary to satisfy the criteria for CPN in terms of the mean tumor dose, point dose at the tumor boundary, and the point dose at 2 mm beyond the tumor edge were tabulated for a range of tumor diameters and tumor-to-normal-liver uptake ratios. Conclusions: The analytical functions that describe the relevant dose metrics for CPN and, more importantly, the single-compartment dose prescriptions for the perfused volume needed to achieve CPN are reported for a large range of conditions in terms of tumor diameters (1–7 cm) and T : N uptake ratios (2:1–5:1). [ABSTRACT FROM AUTHOR]

Background: Molecular breast imaging (MBI) of 99mTc‐sestamibi is an emerging adjunct qualitative tool in the detection and diagnosis of breast cancer. Purpose: This work outlines the development and performance evaluation of a methodology to absolutely quantify tumor 99mTc activity uptake using a commercially available dual‐headed MBI system by implementing corrections for background, scatter, attenuation, and detector characteristics. Methods: A validated Monte Carlo application of a commercial MBI system was used to simulate over 7000 unique acquisitions of spherical and ellipsoidal tumors in breast tissue. Tumor absolute activity was calculated following background, scatter, and attenuation corrections of tumor region of interest counts. The methodology was first optimized using a set of high‐uptake spherical tumors, and its accuracy and precision was then assessed in a set of spherical tumors with clinical uptake conditions. Finally, the performance of the activity methodology was evaluated under various bias and uncertainty conditions to better characterize the technique under expected clinical measurement conditions. Results: In a test set of images with clinically relevant contrast and noise conditions, the mean ± standard deviation relative error in total tumor activity was 0.5% ± 6.5% (n = 2363) under ideal measurement conditions. Allowing for variability in tumor and background contours and in estimated tumor depths, the expected accuracy of the methodology in clinical practice was 0.5% ± 11.1% (n = 2363), with minimal loss of accuracy for ellipsoidal tumors. Conclusions: Planar MBI photopeak images acquired with standard‐of‐care protocols can be used to accurately quantify absolute tumor 99mTc activity with an accuracy and precision of 0.5% ± 11.1%. The reported precision was based on a comprehensive evaluation of random errors and systematic biases. [ABSTRACT FROM AUTHOR]

Influenza-A virus (IAV) infects yearly an estimated one billion people worldwide, resulting in 300,000-650,000 deaths. Preventive vaccination programs and antiviral medications represent the mainstay of therapy, but with unacceptably high morbidity and mortality rates, new targeted therapeutic approaches are urgently needed. Since inflammatory processes are commonly associated with measurable changes in the cell membrane potential (Em), we investigated whether Em hyperpolarization via TREK-1 (K2P2.1) K+ channel activation can protect against influenza-A virus (IAV)-induced pneumonia. We infected mice with IAV, which after 5 days caused 10-15% weight loss and a decrease in spontaneous activity, representing a clinically relevant infection. We then started a 3-day intratracheal treatment course with the novel TREK-1 activating compounds BL1249 or ML335. We confirmed TREK-1 activation with both compounds in untreated and IAV-infected primary human alveolar epithelial cells (HAECs) using high-throughput fluorescent imaging plate reader (FLIPR) assays. In mice, TREK-1 activation with BL1249 and ML335 counteracted IAV-induced histological lung injury and decrease in lung compliance and improved BAL fluid total protein levels, cell counts, and inflammatory IL-6, IP-10/CXCL-10, MIP-1α, and TNF-α levels. To determine whether these anti-inflammatory effects were mediated by activation of alveolar epithelial TREK-1 channels, we studied the effects of BL1249 and ML335 in IAV-infected HAEC, and found that TREK-1 activation decreased IAV-induced inflammatory IL-6, IP-10/CXCL10, and CCL-2 secretion. Dissection of TREK-1 downstream signaling pathways and construction of protein-protein interaction (PPI) networks revealed NF-κB1 and retinoic acid-inducible gene-1 (RIG-1) cascades as the most likely targets for TREK-1 protection. Therefore, TREK-1 activation may represent a novel therapeutic approach against IAV-induced lung injury. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the accuracy and biases of predicted lung shunt fraction (LSF) and lung dose (LD) calculations via 99mTc‐macro‐aggregated albumin (99mTc‐MAA) planar imaging for treatment planning of 90Y‐microsphere radioembolization. Methods and materials: LSFs in 52 planning and LDs in 44 treatment procedures were retrospectively calculated, in consecutive radioembolization patients over a 2 year interval, using 99mTc‐MAA planar and SPECT/CT imaging. For each procedure, multiple planar LSFs and LDs were calculated using different: (1) contours, (2) views, (3) liver 99mTc‐MAA shine‐through compensations, and (4) lung mass estimations. The accuracy of each planar‐based LSF and LD methodology was determined by calculating the median (range) absolute difference from SPECT/CT‐based LSF and LD values, which have been demonstrated in phantom and patient studies to more accurately and reliably quantify the true LSF and LD values. Results: Standard‐of‐care LSF using geometric mean of lung and liver contours had median (range) absolute over‐estimation of 4.4 percentage points (pp) (0.9 to 11.9 pp) from SPECT/CT LSF. Using anterior views only decreased LSF errors (2.4 pp median, −1.1 to +5.7 pp range). Planar LD over‐estimations decreased when using single‐view versus geometric‐mean LSF (1.3 vs. 2.6 Gy median and 7.2 vs. 18.5 Gy maximum using 1000 g lung mass) but increased when using patient‐specific versus standard‐man lung mass (2.4 vs. 1.3 Gy median and 11.8 vs. 7.2 Gy maximum using single‐view LSF). Conclusions: Calculating planar LSF from lung and liver contours of a single view and planar LD using that same LSF and 1000 g lung mass was found to improve accuracy and minimize bias in planar lung dosimetry. [ABSTRACT FROM AUTHOR]

Purpose: There are no published data on organ doses following intra‐hepatic‐arterial administration of 99mTc‐macroaggregated‐albumin (IHA 99mTc‐MAA) routinely used in 90Y‐radioembolization treatment planning to assess intra‐ and extra‐hepatic depositions and calculate lung‐shunt‐fraction (LSF). We propose a method to model the organ doses following IHA 99mTc‐MAA that incorporates three in vivo constituent biodistributions, the 99mTc‐MAA that escape the liver due to LSF, and the 99mTc‐MAA dissociation fraction (DF). Methods: The potential in vivo biodistributions for IHA 99mTc‐MAA are: Liver‐Only MAA with all activity sequestered in the liver (LSF = 0&DF = 0), Intravenous MAA with all activity transferred intravenously as 99mTc‐MAA (LSF = 1&DF = 0), and Intravenous Pertechnetate with all activity is transferred intravenously as 99mTc‐pertechnetate (LSF = 0&DF = 1). Organ doses for Liver‐Only MAA were determined using OLINDA/EXM 2.2, where liver was modeled as the source organ containing 99mTc‐MAA, while those for Intravenous MAA and Intravenous Pertechnetate were from ICRP 128. Organ doses for the general case can be determined as a weighted‐linear‐combination of the three constituent biodistributions depending on the LSF and DF. The maximum‐dose scenario was modeled by selecting the highest dose rate for each organ amongst the three constituent cases. Results: For Liver‐Only MAA, the liver as source organ received the highest dose at 98.6 and 126 mGy/GBq for the adult male and adult female phantoms, respectively; all remaining organs received <27 and <32 mGy/GBq. For Intravenous MAA, the lung as source organ received the highest dose at 66 and 97 mGy/GBq; all remaining organs received <16 and <21 mGy/GBq. The organ with the highest dose for Intravenous Pertechnetate was the upper‐large‐intestinal wall at 56 and 73 mGy/GBq; all remaining organs received <26 and <34 mGy/GBq. The liver and lung doses for the maximum‐dose scenario with 5 mCi (185 MBq) 99mTc‐MAA were estimated at 18.2 and 12.2 mGy, and 23.3 and 17.9 mGy, for the adult male and adult female phantoms, respectively. Conclusion: Organ dose estimates following IHA 99mTc‐MAA based on constituent biodistribution models and patient‐specific LSF and DF values have been derived. Liver and lung were the organs with highest dose, receiving at most 15–25 mGy in the maximum‐dose scenario, following 5 mCi IHA 99mTc‐MAA. [ABSTRACT FROM AUTHOR]