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In nuclear medicine, estimating the number of radioactive decays that occur in a source organ per unit administered activity of a radiopharmaceutical (i.e., the time-integrated activity coefficient [TIAC]) is an essential task within the internal dosimetry workflow. TIAC estimation is commonly derived by least-squares fitting of various exponential models to organ time-activity data (radiopharmaceutical biodistribution). Rarely, however, are methods used to objectively determine the model that best characterizes the data. Additionally, the uncertainty associated with the resultant TIAC is generally not evaluated. As part of the MIRDsoft initiative, MIRDfit has been developed to offer a biodistribution fitting software solution that provides the following essential features and advantages for internal dose assessment: nuclear medicine-appropriate fit functions; objective metrics for guiding best-fit selection; TIAC uncertainty calculation; quality control and data archiving; integration with MIRDcalc software for dose calculation; and a user-friendly Excel-based interface. For demonstration and comparative validation of MIRDfit's performance, TIACs were derived from serial imaging studies involving 18 F-FDG and 177 Lu-DOTATATE using MIRDfit. These TIACs were then compared with TIAC estimates obtained using other software. In most cases, the TIACs agreed within approximately 10% between MIRDfit and the other software. MIRDfit has been endorsed by the MIRD Committee of the Society of Nuclear Medicine and Molecular Imaging and has been integrated into the MIRDsoft suite of free dosimetry software; it is available for download at no user cost (https://mirdsoft.org/)., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Competing Interests: Last year, we organized a gathering of RPT expert physicians and scientists from academia and industry. The objective of the workshop was to propose how to replace existing absorbed dose constraints adopted from EBRT with new constraints and strategies derived from recent RPT experience. We aim to create normal tissue complication probability (NTCP) curves similar to those in Figure 1D for specific toxicities and types of RPT. However, in our examination of the literature, we found that most clinical trial reports unfortunately provide little or no information regarding tissue absorbed doses and insufficient detail regarding toxicities.6,13,23-25 We are actively collecting available patient-level data through data sharing and use agreements with our industry and academic partners, including coauthors and others, and we will analyze the data independently to limit potential bias and conflict of interest. We believe that routine reporting of estimates of absorbed dose delivered to tumors and organs at risk (eg, using single-photon emission computed tomography [SPECT]/computed tomography imaging-based methods) would improve analysis of the factors that might affect the efficacy of RPT agents for a given indication. Beyond this, it would provide the data needed for analysis of absorbed dose versus response or toxicity to better compare different agents and regimens.

Background: Glass 90 Y microspheres are produced with known radionuclide impurities. These impurities are not independently monitored. Clinical instruments, including ionization chamber dose calibrators and positron emmission tomography (PET) cameras, can be much more sensitive in detecting signals from these impurities than to signals from 90 Y itself., Purpose: The "typical" levels of 90 Y impurities have been studied to assess their impact on dosimetry during internal implantation, and for the management of waste. However, unaccounted-for decay spectra of impurities can also have an impact on dose calibrator and PET readings. Thus, even what might be considered negligibly small impurity fractions, can in principle cause substantial overestimates of the amount of 90 Y activity present in a sample. To our knowledge, quantitative effects of radionuclide impurities in glass microspheres on activity measurements have not been documented in the field. As activity quantitation for dosimetry and its correlations with outcome becomes more prevalent, the effects of impurities on measurements may remain unaccounted for in dosimetry studies., Methods: In this letter, we review theoretical and physical considerations that will result in asymmetric errors in quantitation from 90 Y impurities and estimate their typical and potential impact on clinical utilization. Among the common impurities 88 Y is of particular concern for its impact on 90 Y dose measurements because of its decay characteristics, along with other isotopes 91 Y and 46 Sc which can also impact measurements., Results: The typical level of 88 Y impurities reported by the manufacturer should only cause small errors in dose calibrator and PET measurements made within the 12-day label-specified use-by period, up to 2.0% and 1.6%, respectively. However, the product specification max allowable impurity levels, specified by the manufacturer, leave open the potential for much greater bias from within the 12-day use-by period, potentially as high as 13.2% for dose calibrator measurements and 10.6% for PET from the 88 Y impurities., Conclusions: While typical levels of impurities appear to have acceptable impact on patient absorbed dose, it should be noted that they can have adverse effects on 90 Y radioactivity measurements. Furthermore, there is currently minimal independent verification and/or monitoring of impurity levels within the field., (© 2023 American Association of Physicists in Medicine.)

90 Y-microsphere radioembolization has become a well-established treatment option for liver malignancies and is one of the first U.S. Food and Drug Administration-approved unsealed radionuclide brachytherapy devices to incorporate dosimetry-based treatment planning. Several different mathematical models are used to calculate the patient-specific prescribed activity of 90 Y, namely, body surface area (SIR-Spheres only), MIRD single compartment, and MIRD dual compartment (partition). Under the auspices of the MIRDsoft initiative to develop community dosimetry software and tools, the body surface area, MIRD single-compartment, MIRD dual-compartment, and MIRD multicompartment models have been integrated into a MIRDy90 software worksheet. The worksheet was built in MS Excel to estimate and compare prescribed activities calculated via these respective models. The MIRDy90 software was validated against available tools for calculating 90 Y prescribed activity. The results of MIRDy90 calculations were compared with those obtained from vendor and community-developed tools, and the calculations agreed well. The MIRDy90 worksheet was developed to provide a vetted tool to better evaluate patient-specific prescribed activities calculated via different models, as well as model influences with respect to varying input parameters. MIRDy90 allows users to interact and visualize the results of various parameter combinations. Variables, equations, and calculations are described in the MIRDy90 documentation and articulated in the MIRDy90 worksheet. The worksheet is distributed as a free tool to build expertise within the medical physics community and create a vetted standard for model and variable management., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Potential risk associated with low-dose radiation exposures is often expressed using the effective dose (E) quantity. Other risk-related quantities have been proposed as alternatives. The recently introduced risk index (RI) shares similarities with E but expands the metric to incorporate medical imaging-appropriate risks factors including patient-specific size, age, and sex., Purpose: The aim of this work is to examine the RI metric for quantifying stochastic radiation risk and demonstrate its applications in nuclear imaging. The advantages in this improved metric may help the field progress toward stratified risk consideration in the course of patient management, improve efforts for procedure optimization, and support an evolution in the science of radiation risk assessment., Methods: In this study we describe, implement, and calculate RI for various diagnostic nuclear imaging scenarios using reference biokinetics published in ICRP Publication 128 for commonly utilized radiopharmaceuticals. All absorbed dose, E and RI calculations were performed using the freely available MIRDcalc nuclear medicine dosimetry software; the organ specific risk parameters used in the software are also benchmarked in this text. The resulting RI and E values are compared and various trends in RI values identified., Results: E and RI coefficients were calculated for 3016 use cases. Notably RI values vary depending on patient characteristics. Overall, across the population, global trends in RI values can be identified. In general, RI values were 2.15 times higher for females than males, due to higher risk coefficients and activities being distributed in smaller reference masses. The pediatric patients showed higher RIs than adults, as younger patients generally receive higher absorbed doses per administered activity, and are more radiosensitive, and have a longer projected lifespan at risk. A compendium of E and RI values is also provided in table format to serve as a reference for the community., Conclusions: RI is a rational quantity that could be used for justification, risk communication and protocol optimization in medical imaging. It has some advantages when compared to the long-utilized E value with respect to personalization, since accounts for patient size, age, sex, and natural incidence of cancer risk., (© 2023 American Association of Physicists in Medicine.)

Rationale: The in vivo dynamics of CAR-T cells remain incompletely understood. Novel methods are urgently needed to longitudinally monitor transferred cells non-invasively for biodistribution, functionality, proliferation, and persistence in vivo and for improving their cytotoxic potency in case of treatment failure. Methods: Here we engineered CD19 CAR-T cells ("Thor"-cells) to express a membrane-bound scFv, huC825, that binds DOTA-haptens with picomolar affinity suitable for labeling with imaging or therapeutic radionuclides. We assess its versatile utility for serial tracking studies with PET and delivery of α-radionuclides to enhance anti-tumor killing efficacy in sub-optimal adoptive cell transfer in vivo using Thor-cells in lymphoma models. Results: We show that this reporter gene/probe platform enables repeated, sensitive, and specific assessment of the infused Thor-cells in the whole-body using PET/CT imaging with exceptionally high contrast. The uptake on PET correlates with the Thor-cells on a cellular and functional level. Furthermore, we report the ability of Thor-cells to accumulate cytotoxic alpha-emitting radionuclides preferentially at tumor sites, thus increasing therapeutic potency. Conclusion: Thor-cells are a new theranostic agent that may provide crucial information for better and safer clinical protocols of adoptive T cell therapies, as well as accelerated development strategies., Competing Interests: Competing Interests: MSK has filed for patent protection on behalf of M.M.D., D.R.V., M.R.M., N.K.C., S.M.C., S.M.L., D.A.S., and S.K. for inventions related to the work described in this paper. S.M.C. was named as an inventor on multiple patents filed by MSK, including those licensed to Y-mAbs Therapeutics. N.K.C. has a financial interest in Abpro-Labs, Biotec Pharmacon, Eureka Therapeutics, and Y-mAbs Therapeutics that may work in areas related to this paper. D.A.S. is an advisor to, or owns equity in, IOVA, ATNM, LNTH, Eureka Therapeutics, CoImmune, Atengen, Repertoire, and PFE, which may work in areas related to this paper. S.M.L. reports receiving commercial research grants from Y-mAbs Therapeutics, Genentech, Inc., WILEX AG, Telix Pharmaceuticals Limited, and Regeneron Pharmaceuticals, Inc.; holding ownership interest/equity in Voreyda Theranostics Inc. and Elucida Oncology Inc., and holding stock in Y-mAbs Therapeutics. S.M.L. is the inventor and owner of issued patents both currently unlicensed and licensed by MSK to Samus Therapeutics, Inc., Y-mAbs Therapeutics Inc., and Elucida Oncology, Inc.; is or has served as a consultant to Cynvec LLC, Eli Lilly & Co., Prescient Therapeutics Limited, Advanced Innovative Partners, LLC, Gerson Lehrman Group, Progenics Pharmaceuticals, Inc., and Janssen Pharmaceuticals, Inc. SK has consulted for Telix Pharmaceuticals Ltd. and acknowledges support for investigator services from RayzeBio. The remaining authors report no competing interests., (© The author(s).)

Radiopharmaceutical dosimetry is usually estimated via organ-level MIRD schema-style formalisms, which form the computational basis for commonly used clinical and research dosimetry software. Recently, MIRDcalc internal dosimetry software was developed to provide a freely available organ-level dosimetry solution that incorporates up-to-date models of human anatomy, addresses uncertainty in radiopharmaceutical biokinetics and patient organ masses, and offers a 1-screen user interface as well as quality assurance tools. The present work describes the validation of MIRDcalc and, secondarily, provides a compendium of radiopharmaceutical dose coefficients obtained with MIRDcalc. Biokinetic data for about 70 currently and historically used radiopharmaceuticals were obtained from the International Commission on Radiological Protection (ICRP) publication 128 radiopharmaceutical data compendium. Absorbed dose and effective dose coefficients were derived from the biokinetic datasets using MIRDcalc, IDAC-Dose, and OLINDA software. The dose coefficients obtained with MIRDcalc were systematically compared against the other software-derived dose coefficients and those originally presented in ICRP publication 128. Dose coefficients computed with MIRDcalc and IDAC-Dose showed excellent overall agreement. The dose coefficients derived from other software and the dose coefficients promulgated in ICRP publication 128 both were in reasonable agreement with the dose coefficients computed with MIRDcalc. Future work should expand the scope of the validation to include personalized dosimetry calculations., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Abstract: Current practice in reference internal dosimetry assumes a fixed upright standing posture is maintained throughout the dose-integration period. Recently, the mesh-type ICRP adult reference computational phantoms were transformed into different body postures (e.g., sitting, squatting) for use in occupational dose reconstruction applications. Here, for the first time, we apply this phantom series to the study of organ dose estimates following radionuclide intake. We consider the specific cases of 137 Cs and 134 Cs ingestion (accidental/occupational intake) with attention to variability in absorbed dose as a function of posture. The ICRP Publication 137 systemic biokinetic model for soluble cesium ingestion was used to compute organ-level time-integrated activity coefficients for reference adults, over a 50-y dose-integration period, for 134 Cs and 137 Cs (and its radioactive progeny 137m Ba). Mean posture time-allocations (h d -1 for standing, sitting, and lying) were taken from published survey data. In accord with modern dosimetry formalisms (e.g., MIRD, ICRP), a posture weighting factor was introduced that accounts for the fraction of time spent within each independent posture. Absorbed dose coefficients were computed using PHITS Monte Carlo simulations. ICRP 103 tissue weighting factors were applied along with the posture weighting factors to obtain committed effective dose per unit intake (Sv Bq -1 ). For 137 Cs ingestion, most organ absorbed dose coefficients were negligibly to marginally higher (< ~3%) for sitting or crouched (lying fetal/semi-fetal) postures maintained over the dose commitment period, relative to the upright standing posture. The committed effective dose coefficients were 1.3 × 10 -8 Sv Bq -1 137 Cs for standing, sitting, or crouched postures; thus, the posture-weighted committed effective dose was not significantly different than the committed effective dose for a maintained upright standing posture. For 134 Cs ingestion, most organ absorbed dose coefficients for the sitting and crouched postures were significantly larger than the standing posture, but the differences were still considered minor (< ~8% for most organs). The committed effective dose coefficients were 1.2 × 10 -8 Sv Bq -1 134 Cs for the standing posture and 1.3 × 10 -8 Sv Bq -1 134 Cs for the sitting or crouched posture. The posture-weighted committed effective dose was 1.3 × 10 -8 Sv Bq -1 134 Cs. Body posture has minor influence on organ-level absorbed dose coefficients and committed effective dose for ingestion of soluble 137 Cs or 134 Cs., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Health Physics Society.)

Medical internal radiation dosimetry constitutes a fundamental aspect of diagnosis, treatment, optimization, and safety in nuclear medicine. The MIRD committee of the Society of Nuclear Medicine and Medical Imaging developed a new computational tool to support organ-level and suborgan tissue dosimetry (MIRDcalc, version 1). Based on a standard Excel spreadsheet platform, MIRDcalc provides enhanced capabilities to facilitate radiopharmaceutical internal dosimetry. This new computational tool implements the well-established MIRD schema for internal dosimetry. The spreadsheet incorporates a significantly enhanced database comprising details for 333 radionuclides, 12 phantom reference models (International Commission on Radiological Protection), 81 source regions, and 48 target regions, along with the ability to interpolate between models for patient-specific dosimetry. The software also includes sphere models of various composition for tumor dosimetry. MIRDcalc offers several noteworthy features for organ-level dosimetry, including modeling of blood source regions and dynamic source regions defined by user input, integration of tumor tissues, error propagation, quality control checks, batch processing, and report-preparation capabilities. MIRDcalc implements an immediate, easy-to-use single-screen interface. The MIRDcalc software is available for free download (www.mirdsoft.org) and has been approved by the Society of Nuclear Medicine and Molecular Imaging., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Aims: Clinical radiographic imaging is seated upon the principle of differential keV photon transmission through an object. At clinical x-ray energies the scattering of photons causes signal noise and is utilized solely for transmission measurements. However, scatter - particularly Compton scatter, is characterizable. In this work we hypothesized that modern radiation sources and detectors paired with deep learning techniques can use scattered photon information constructively to resolve superimposed attenuators in planar x-ray imaging., Methods: We simulated a monoenergetic x-ray imaging system consisting of a pencil beam x-ray source directed at an imaging target positioned in front of a high spatial- and energy-resolution detector array. The setup maximizes information capture of transmitted photons by measuring off-axis scatter location and energy. The signal was analyzed by a convolutional neural network, and a description of scattering material along the axis of the beam was derived. The system was virtually designed/tested using Monte Carlo processing of simple phantoms consisting of 10 pseudo-randomly stacked air/bone/water materials, and the network was trained by solving a classification problem., Results: From our simulations we were able to resolve traversed material depth information to a high degree, within our simple imaging task. The average accuracy of the material identification along the beam was 0.91±0.01, with slightly higher accuracy towards the entrance/exit peripheral surfaces of the object. The average sensitivity and specificity was 0.91 and 0.95, respectively., Conclusions: Our work provides proof of principle that deep learning techniques can be used to analyze scattered photon patterns which can constructively contribute to the information content in radiography, here used to infer depth information in a traditional 2D planar setup. This principle, and our results, demonstrate that the information in Compton scattered photons may provide a basis for further development. The work was limited by simple testing scenarios and without yet integrating complexities or optimizations. The ability to scale performance to the clinic remains unexplored and requires further study.

177 Lu-DOTATATE (Lutathera ® ) enables targeted radionuclide therapy of neuroendocrine tumors expressing somatostatin receptor type 2. Though patient-specific dosimetry estimates may be clinically important for predicting absorbed dose-effect relationships, there are multiple relevant dosimetry paradigms which are distinct in terms of clinical effort, numerical output and added-value. This work compares three different approaches for 177 Lu-DOTATATE dosimetry, including 1) an organ-level approach based on reference phantom MIRD S-values scaled to patient-specific organ masses (MIRDcalc), 2) an organ-level approach based on Monte Carlo simulation in a patient-specific mesh phantoms (PARaDIM), and 3) a 3D approach based on Monte Carlo simulation in patient-specific voxel phantoms. Method . Serial quantitative SPECT/CT images for two patients receiving 177 Lu-DOTATATE therapy were obtained from archive in the Deep Blue database. For each patient, the serial CT images were co-registered to the first time point CT using a deformable registration technique aided by virtual landmarks placed in the kidney pelves and the lesion foci. The co-registered SPECT images were integrated voxel-wise to generate time-integrated activity maps. Lesions, kidneys, liver, spleen, lungs, compact bone, spongiosa, and rest of body were segmented at the first imaging time point and overlaid on co-registered integrated activity maps. The resultant segmentation was used for three purposes: 1) to generate patient-specific phantoms, 2) to determine organ-level time-integrated activities, and 3) to generate dose volume histograms from 3D voxel-based calculations. Results . Mean absorbed doses were computed for lesions and 48 tissues with MIRDcalc software. Mean organ absorbed doses and dose volume histograms were obtained for lesions and 6 tissues with the voxel Monte Carlo approach. Lesion- and organ-level absorbed dose estimates agreed within ±26% for the lesions and ±13% for the critical organs, among the different methods tested. Overall good agreement was observed with the dosimetry estimates from the NETTER-1 trial. Conclusions . For personalized 177 Lu-DOTATATE dosimetry, a combined approach was determined to be valuable, which utilized two dose calculation methods supported by a single image processing workflow. In the absence of quantitative imaging limitations, the voxel Monte Carlo method likely provides valuable information to guide treatment by considering absorbed dose non-uniformity in lesions and organs at risk. The patient-scaled reference phantom method also provides valuable information, including absorbed dose estimates for non-segmented organs, and more accurate dose estimates for complex radiosensitive organs including the active marrow., (© 2021 IOP Publishing Ltd.)

Pretargeted imaging and radioimmunotherapy approaches are designed to have superior targeting properties over directly targeted antibodies but impose more complex pharmacology, which hinders efforts to optimize the ligands prior to human applications. Human embryonic kidney 293T cells expressing the humanized single-chain variable fragment (scFv) C825 (huC825) with high-affinity for DOTA-haptens (293T-huC825) in a transmembrane-anchored format eliminated the requirement to use other pretargeting reagents and provided a simplified, accelerated assay of radiohapten capture while offering normalized cell surface expression of the molecular target of interest. Using binding assays, ex vivo biodistribution, and in vivo imaging, we demonstrated that radiohaptens based on benzyl-DOTA and a second generation "Proteus" DOTA-platform effectively and specifically engaged membrane-bound huC825, achieving favorable tumor-to-normal tissue uptake ratios in mice. Furthermore, [ 86 Y]Y-DOTA-Bn predicted absorbed dose to critical organs with reasonable accuracy for both [ 177 Lu]Lu-DOTA-Bn and [ 225 Ac]Ac-Pr, which highlights the benefit of a dosimetry-based treatment approach.

Despite the known influence of anatomic variability on internal dosimetry, dosimetry for 18 F-FDG and other diagnostic radiopharmaceuticals is routinely derived using reference phantoms, which embody population-averaged morphometry for a given age and sex. Moreover, phantom format affects dosimetry estimates to varying extent. Here, we applied newly developed mesh format reference phantoms and a patient-dependent phantom library to assess the impact of height, weight, and body contour variation on dosimetry of 18 F-FDG. We compared the mesh reference phantom dosimetry estimates with corresponding estimates from common software to identify differences related to phantom format or software implementation. Our study serves as an example of how more precise patient size-dependent dosimetry methodology could be performed. Methods: Absorbed dose coefficients were computed for the adult mesh reference phantoms and derivative patient-dependent phantom series by Monte Carlo simulation using the PHITS radiation transport code within PARaDIM software. The dose coefficients were compared with reference absorbed dose coefficients obtained from ICRP Publication 128, or generated using software including OLINDA 2.1, OLINDA 1.1, and IDAC-dose 2.1. Results: Differences in dosimetry arising from anatomical variations were shown to be significant, with detriment-weighted dose coefficients for the percentile-specific phantoms varying by up to ±40% relative to the corresponding reference phantom effective dose coefficients, irrespective of phantom format. Similar variations were seen in the individual organ absorbed dose coefficients for the percentile-specific phantoms relative to the reference phantoms. The effective dose coefficient for the mesh reference adult was 0.017 mSv/MBq, which was 5% higher than estimated by a corresponding voxel phantom, and 10% lower than estimated by the stylized phantom format. Conclusion: We observed notable variability in 18 F-FDG dosimetry across morphometrically different patients, supporting the use of patient-dependent phantoms for more accurate dosimetric estimations relative to standard reference dosimetry. These data may help in optimizing imaging protocols and research studies, in particular when longer-lived isotopes are employed., (Copyright © 2021 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Purpose: Current standard practice for clinical radionuclide dosimetry utilizes reference phantoms, where defined organ dimensions represent population averages for a given sex and age. Greater phantom personalization would support more accurate dose estimations and personalized dosimetry. Tailoring phantoms is traditionally accomplished using operator-intensive organ-level segmentation of anatomic images. Modern mesh phantoms provide enhanced anatomical realism, which has motivated their integration within Monte Carlo codes. Here, we present an automatable strategy for generating patient-specific phantoms/dosimetry using intensity-based deformable image registration between mesh reference phantoms and patient CT images. This work demonstrates a proof-of-concept personalized dosimetry workflow, presented in comparison to the manual segmentation approach., Methods: A linear attenuation coefficient phantom was generated by resampling the PSRK-Man reference phantom onto a voxel grid and defining organ regions with corresponding Hounsfield unit (HU) reference values. The HU phantom was co-registered with a patient CT scan using Plastimatch B-spline deformable registration. In parallel, major organs were manually contoured to generate a "ground truth" patient-specific phantom for comparisons. Monte Carlo derived S-values, which support nuclear medicine dosimetry, were calculated using both approaches and compared., Results: Application of the derived B-spline transform to the polygon vertices comprising the PSRK-Man yielded a deformed variant more closely matching the patient's body contour and most organ volumes as-evaluated by Hausdorff distance and Dice metrics. S-values computed for fluorine-18 for the deformed phantom using the Particle and Heavy Ion Transport code System showed improved agreement with those derived from the patient-specific analog., Conclusions: Deformable registration techniques can be used to create a personalized phantom and better support patient-specific dosimetry. This method is shown to be easier and faster than manual segmentation. Our study is limited to a proof-of-concept scope, but demonstrates that integration of personalized phantoms into clinical dosimetry workflows can reasonably be achieved when anatomical images (CT) are available., (© 2021 American Association of Physicists in Medicine.)

Purpose: To investigate the use of advanced SPECT/CT quantification in guiding surgical selection of positive sentinel lymph nodes (SLNs) in head and neck melanoma., Methods: We retrospectively reviewed data from patients with cutaneous head and neck melanoma who underwent lymphoscintigraphy with SPECT/CT prior to SLN biopsy (SLNB). Quantification of radiotracer uptake from SPECT/CT data was performed using in-house segmentation software. SLNs identified using SPECT/CT were compared to SLNs identified surgically using an intraoperative γ-probe. A radioactivity count threshold using SPECT/CT for detecting a positive SLN was calculated., Results: One hundred and five patients were included. Median number of SLNs detected was 3/patient with SPECT/CT and 2/patient with intraoperative γ-probe. The hottest node identified by SPECT/CT and intraoperative γ-probe were identical in 85% of patients. All 20 histologically positive SLNs were identified by SPECT/CT and γ-probe. On follow-up, all nodal recurrences occurred at lymph node levels with the hottest node identified by SPECT/CT and either the hottest or second hottest node identified by γ-probe during SLNB. Using our data, a SPECT/CT radioactivity count threshold of 20% would eliminate the unnecessary removal of 11% of SPECT/CT identified nodes and 12% of intraoperatively detected nodes., Conclusion: Utilizing SPECT/CT quantification, we propose that a radioactivity count threshold can be developed to help guide the selective removal of lymph nodes in head and neck SLNB. Furthermore, the nodal level containing the hottest node identified by SPECT/CT quantification must be thoroughly investigated for SLNs and undergo careful follow-up and surveillance for recurrence.

Purpose: The increasing interest and availability of non-standard positron-emitting radionuclides has heightened the relevance of radionuclide choice in the development and optimization of new positron emission tomography (PET) imaging procedures, both in preclinical research and clinical practice. Differences in achievable resolution arising from positron range can largely influence application suitability of each radionuclide, especially in small-ring preclinical PET where system blurring factors due to annihilation photon acollinearity and detector geometry are less significant. Some resolution degradation can be mitigated with appropriate range corrections implemented during image reconstruction, the quality of which is contingent on an accurate characterization of positron range., Procedures: To address this need, we have characterized the positron range of several standard and non-standard PET radionuclides (As-72, F-18, Ga-68, Mn-52, Y-86, and Zr-89) through imaging of small-animal quality control phantoms on a benchmark preclinical PET scanner. Further, the Particle and Heavy Ion Transport code System (PHITS v3.02) code was utilized for Monte Carlo modeling of positron range-dependent blurring effects., Results: Positron range kernels for each radionuclide were derived from simulation of point sources in ICRP reference tissues. PET resolution and quantitative accuracy afforded by various radionuclides in practicable imaging scenarios were characterized using a convolution-based method based on positron annihilation distributions obtained from PHITS. Our imaging and simulation results demonstrate the degradation of small animal PET resolution, and quantitative accuracy correlates with increasing positron energy; however, for a specific "benchmark" preclinical PET scanner and reconstruction workflow, these differences were observed to be minimal given radionuclides with average positron energies below ~ 400 keV., Conclusion: Our measurements and simulations of the influence of positron range on PET resolution compare well with previous efforts documented in the literature and provide new data for several radionuclides in increasing clinical and preclinical use. The results will support current and future improvements in methods for positron range corrections in PET imaging.

Purpose: Respiratory gating has been used in PET imaging to reduce the amount of image blurring caused by patient motion. Optimal binning is an approach for using the motion-characterized data by binning it into a single, easy to understand/use, optimal bin. To date, optimal binning protocols have utilized externally driven motion characterization strategies that have been tuned with population-derived assumptions and parameters. In this work, we are proposing a new strategy with which to characterize motion directly from a patient's gated scan, and use that signal to create a patient/instance-specific optimal bin image., Methods: Two hundred and nineteen phase-gated FDG PET scans, acquired using data-driven gating as described previously, were used as the input for this study. For each scan, a phase-amplitude motion characterization was generated and normalized using principle component analysis. A patient-specific "optimal bin" window was derived using this characterization, via methods that mirror traditional optimal window binning strategies. The resulting optimal bin images were validated by correlating quantitative and qualitative measurements in the population of PET scans., Results: In 53% (n = 115) of the image population, the optimal bin was determined to include 100% of the image statistics. In the remaining images, the optimal binning windows averaged 60% of the statistics and ranged between 20% and 90%. Tuning the algorithm, through a single acceptance window parameter, allowed for adjustments of the algorithm's performance in the population toward conservation of motion or reduced noise-enabling users to incorporate their definition of optimal. In the population of images that were deemed appropriate for segregation, average lesion SUV max were 7.9, 8.5, and 9.0 for nongated images, optimal bin, and gated images, respectively. The Pearson correlation of FWHM measurements between optimal bin images and gated images were better than with nongated images, 0.89 and 0.85, respectively. Generally, optimal bin images had better resolution than the nongated images and better noise characteristics than the gated images., Discussion: We extended the concept of optimal binning to a data-driven form, updating a traditionally one-size-fits-all approach to a conformal one that supports adaptive imaging. This automated strategy was implemented easily within a large population and encapsulated motion information in an easy to use 3D image. Its simplicity and practicality may make this, or similar approaches ideal for use in clinical settings., (© 2017 American Association of Physicists in Medicine.)

Radionuclide absorbed-dose dosimetry is an active area of development and has the potential to positively impact molecular radiotherapies. At present, many of the operations required to perform dosimetry calculations are unstandardized and unestablished. While the current methodology allows reasonable dosimetry estimates to be derived and published, it can be difficult to understand, and reproduce, each others' work. To help alleviate this we have identified the collection of biodistribution information as a key step in all internal dosimetry calculations, and present a template that can be used to standardize its documentation and reporting. A generalized biodistribution template entitled the IAEA Radiotracer Biodistribution Template (IAEA RaBiT) has been built and distributed for users performing biodistribution measurements in the community. The template enables robust recording of dosimetry-relevant information through standardization of details and their format. It has been designed to be simple and easy to use, and establish a structured recording of a common reference point in dosimetry operations - biodistribution data documentation. Improved documentation procedures may benefit organization of in house data, or be used to disseminate details throughout the community - for example to supplement dosimetry related publications. The standard format information may also enable the creation of new dosimetry related tools and protocols and support robust population databases. As dosimetry in nuclear medicine becomes more routinely applied in clinical applications, we need to develop the infrastructure for robustly handling large amounts of these data. Our IAEA RaBiT can be used as a standard format structure for data collection, organization, and dissemination., (Copyright © 2017 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

Purpose To assess the performance of hardware- and software-gating technologies in terms of qualitative and quantitative characteristics of respiratory motion in positron emission tomography (PET) imaging. Materials and Methods Between 2010 and 2013, 219 fluorine 18 fluorodeoxyglucose PET examinations were performed in 116 patients for assessment of pulmonary nodules. All patients provided informed consent in this institutional review board-approved study. Acquisitions were reconstructed as respiratory-gated images by using hardware-derived respiratory triggers and software-derived signal (via an automated postprocessing method). Asymmetry was evaluated in the joint distribution of reader preference, and linear mixed models were used to evaluate differences in outcomes according to gating type. Results In blind reviews of reconstructed gated images, software was selected as superior 16.9% of the time (111 of 657 image sets; 95% confidence interval [CI]: 14.0%, 19.8%), and hardware was selected as superior 6.2% of the time (41 of 657 image sets; 95% CI: 4.4%, 8.1%). Of the image sets, 76.9% (505 of 657; 95% CI: 73.6%, 80.1%) were judged as having indistinguishable motion quality. Quantitative analysis demonstrated that the two gating strategies exhibited similar performance, and the performance of both was significantly different from that of nongated images. The mean increase ± standard deviation in lesion maximum standardized uptake value was 42.2% ± 38.9 between nongated and software-gated images, and lesion full width at half maximum values decreased by 9.9% ± 9.6. Conclusion Compared with vendor-supplied respiratory-gating hardware methods, software gating performed favorably, both qualitatively and quantitatively. Fully automated gating is a feasible approach to motion correction of PET images. (©) RSNA, 2016 Online supplemental material is available for this article.

Purpose: Respiratory gating is a strategy for overcoming image degradation caused by patient motion in Positron Emission Tomography (PET) imaging. Traditional methods for sorting data, namely, phase-based gating or amplitude-based gating, come with an inherent trade-off between resolution improvements and added noise present in the subjugated data. If the goal of motion correction in PET is realigned from creating 4D images that attempt to mimic nongated images, towards ideal utilization of the information available, then new paths for data management emerge. In this work, the authors examine the application of a method in a new class of frequency based data subjugation algorithms, termed gating +. This strategy utilizes data driven information to locally adapt signal to its optimal segregation, thereby creating a new approach to 4D data utilization PET., Methods: 189 (18)F-fluorodeoxyglucose (FDG) PET scans were acquired at a single bed position centered on the thorax region. 4D gated image sets were reconstructed using data driven gating. The gating+ signal optimization algorithm, previously presented in small animal PET images and simulations, was used to segregate data in frequency space to generate optimized 4D images in the population-the first application and analysis of gating+ in human PET scans. The nongated, phase gated, and gating+ representations of the data were compared using FDG uptake analysis in the identified lesions and noise measurements from background regions., Results: Optimized processing required less than 1 min per scan on a standard PC (plus standard reconstruction time), and yielded entire 4D optimized volumes plus motion maps. Optimized scans had noise characteristics similar to nongated images, yet also contained much of the resolution and motion information found in the gated images. The average SUVmax increase in the lesion sample between gated/nongated and gating+/nongated (±SD in population) was 35.8% ± 34.6% and 28.6% ± 27.9%, respectively. The average percent standard deviation (%SD ± SD in population) in liver volumes of interest (VOIs) across the sample for the nongated, gated, and gating+ scans was 6.7% ± 2.4%, 13.6% ± 3.3%, and 7.1% ± 2.5%, respectively. In all cases, the noise in the gating+ liver VOIs was closer to the nongated measurements than to the gated., Conclusions: The gating+ algorithm introduces the notion of conforming 4D data segregation to the local information and statistics that support it. By segregating data in frequency space, the authors are able to generate low noise motion information rich image sets, derived solely from selective use of raw data. Their work shows that the gating+ algorithm can be robustly applied in populations, and across varying qualities of motion and scans statistics, and be integrated as part of a fully automated motion correction workflow. Furthermore, the idea of smart signal utilization underpins a new concept of low risk or even risk-free motion correction application in PET.

Positron emission tomography (PET) is increasingly used for the detection, characterization, and follow-up of tumors located in the thorax. However, patient respiratory motion presents a unique limitation that hinders the application of high-resolution PET technology for this type of imaging. Efforts to transcend this limitation have been underway for more than a decade, yet PET remains for practical considerations a modality vulnerable to motion-induced image degradation. Respiratory motion control is not employed in routine clinical operations. In this article, we take an opportunity to highlight some of the recent advancements in data-driven motion control strategies and how they may form an underpinning for what we are presenting as a fully automated data-driven motion control framework. This framework represents an alternative direction for future endeavors in motion control and can conceptually connect individual focused studies with a strategy for addressing big picture challenges and goals.

Background: Respiratory gating and gate optimization strategies present solutions for overcoming image degradation caused by respiratory motion in PET and traditionally utilize hardware systems and/or employ complex processing algorithms. In this work, we aimed to advance recently emerging data-driven gating methods and introduce a new strategy for optimizing the four-dimensional data based on information contained in that data. These algorithms are combined to form an automated motion correction workflow., Methods: Software-based gating methods were applied to a nonspecific population of 84 small-animal rat PET scans to create respiratory gated images. The gated PET images were then optimized using an algorithm we introduce as 'gating+' to reduce noise and optimize signal; the technique was also tested using simulations. Gating+ is based on a principle of only using gated information if and where it adds a net benefit, as evaluated in temporal frequency space. Motion-corrected images were assessed quantitatively and qualitatively., Results: Of the small-animal PET scans, 71% exhibited quantifiable motion after software gating. The mean liver displacement was 3.25 mm for gated and 3.04 mm for gating+ images. The (relative) mean percent standard deviations measured in background ROIs were 1.53, 1.05, and 1.00 for the gated, gating+, and ungated values, respectively. Simulations confirmed that gating+ image voxels had a higher probability of being accurate relative to the corresponding ungated values under varying noise and motion scenarios. Additionally, we found motion mapping and phase decoupling models that readily extend from gating+ processing., Conclusions: Raw PET data contain information about motion that is not currently utilized. In our work, we showed that through automated processing of standard (ungated) PET acquisitions, (motion-) information-rich images can be constructed with minimal risk of noise introduction. Such methods have the potential for implementation with current PET technology in a robust and reproducible way.

Purpose: Respiratory gating in PET is an approach used to minimize the negative effects of respiratory motion on spatial resolution. It is based on an initial determination of a patient's respiratory movements during a scan, typically using hardware based systems. In recent years, several fully automated databased algorithms have been presented for extracting a respiratory signal directly from PET data, providing a very practical strategy for implementing gating in the clinic. In this work, a new method is presented for extracting a respiratory signal from raw PET sinogram data and compared to previously presented automated techniques., Methods: The acquisition of respiratory signal from PET data in the newly proposed method is based on rebinning the sinogram data into smaller data structures and then analyzing the time activity behavior in the elements of these structures. From this analysis, a 1D respiratory trace is produced, analogous to a hardware derived respiratory trace. To assess the accuracy of this fully automated method, respiratory signal was extracted from a collection of 22 clinical FDG-PET scans using this method, and compared to signal derived from several other software based methods as well as a signal derived from a hardware system., Results: The method presented required approximately 9 min of processing time for each 10 min scan (using a single 2.67 GHz processor), which in theory can be accomplished while the scan is being acquired and therefore allowing a real-time respiratory signal acquisition. Using the mean correlation between the software based and hardware based respiratory traces, the optimal parameters were determined for the presented algorithm. The mean/median/range of correlations for the set of scans when using the optimal parameters was found to be 0.58/0.68/0.07-0.86. The speed of this method was within the range of real-time while the accuracy surpassed the most accurate of the previously presented algorithms., Conclusions: PET data inherently contains information about patient motion; information that is not currently being utilized. We have shown that a respiratory signal can be extracted from raw PET data in potentially real-time and in a fully automated manner. This signal correlates well with hardware based signal for a large percentage of scans, and avoids the efforts and complications associated with hardware. The proposed method to extract a respiratory signal can be implemented on existing scanners and, if properly integrated, can be applied without changes to routine clinical procedures.

Unlabelled: Transgenic mouse models of human cancers represent one of the most promising approaches to elucidate clinically relevant mechanisms of action and provide insights into the treatment efficacy of new antitumor drugs. The use of Trp53 transgenic mice (Trp53 knockout [Trp53(-/-)] mice) for these kinds of studies is, so far, restricted by limitations in detecting developing tumors and the lack of noninvasive tools for monitoring tumor growth, progression, and treatment response., Methods: We hypothesized that quantitative small-animal PET with (18)F-FDG was able to detect the onset and location of tumor development, follow tumor progression, and monitor response to chemotherapy. To test these hypotheses, C57BL/6J Trp53(-/-) mice underwent longitudinal small-animal PET during lymphoma development and gemcitabine treatment. Trp53 wild-type (Trp53(+/+)) mice were used as controls, and histology after full necropsy served as the gold standard., Results: In Trp53(+/+) mice, the thymic standardized uptake value (SUV) did not exceed 1.0 g/mL, with decreasing (18)F-FDG uptake over time. Conversely, all Trp53(-/-) mice that developed thymic lymphoma showed increasing thymic glucose metabolism, with a mean SUV doubling time of 9.0 wk (range, 6.0-17.5 wk). Using an SUV of 3.0 g/mL as a criterion provided a sensitivity of 78% and a specificity of 100% for the detection of thymic lymphoma. Treatment monitoring with (18)F-FDG PET correctly identified all histologic responses and relapses to gemcitabine., Conclusion: (18)F-FDG small-animal PET can be used to visualize onset and progression of thymic lymphomas in Trp53(-/-) mice and monitor response to chemotherapy. Thus, (18)F-FDG small-animal PET provides an in vivo means to assess intervention studies in the Trp53 transgenic mouse model.

Purpose: We evaluated the usefulness of small animal brain positron emission tomography (PET) imaging with the amyloid-beta (A beta) probe 2-(1-{6-[(2-[(18)F]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malonitrile ([(18)F]FDDNP) and with 2-deoxy-2-[F-18]fluoro-D-glucose (FDG) for detection and quantification of pathological changes occurring in a transgenic mouse model of Alzheimer's disease (Tg2576 mice)., Procedures: [(18)F]FDDNP (n = 6) and FDG-PET scans (n = 3) were recorded in Tg2576 mice (age 13-15 months) and age-matched wild-type litter mates. Brain volumes of interest were defined by co-registration of PET images with a 3D MOBY digital mouse phantom. Regional [(18)F]FDDNP retention in mouse brain was quantified in terms of the relative distribution volume (DVR) using Logan's graphical analysis with cerebellum as a reference region., Results: Except for a lower maximum brain uptake of radioactivity in transgenic animals, the regional brain kinetics as well as DVR values of [(18)F]FDDNP appeared to be similar in both groups of animals. Also for FDG, regional radioactivity retention was almost identical in the brains of transgenic and control animals., Conclusions: We could not detect regionally increased [(18)F]FDDNP binding and regionally decreased FDG binding in the brains of Tg2576 transgenic versus wild-type mice. However, small group differences in signal might have been masked by inter-animal variability. In addition, technical limitations of the applied method (partial volume effect, spatial resolution) for measurements in such small organs as mouse brain have to be taken into consideration.

Introduction: Radiation dosimetry assessment often begins with measuring pharmaceutical biodistribution in rodents. The traditional approach to dosimetry in rodents involves a radioassay ex vivo of harvested organs at different time points following administration of the radiopharmaceutical. The emergence of small-animal positron emission tomography (PET) presents the opportunity for an alternative method for making radiodosimetry estimates previously employed only in humans and large animals. In the current manuscript, normal-tissue absorbed dose estimates for the 18F-labeled chemotherapy agent [18F]5-fluorouracil ([18F]5-FU) were derived by PET imaging- and by tissue harvesting-based methods in rats., Methods: Small-animal PET data were acquired dynamically for up to 2 h after injection of [18F]5-FU in anesthetized rats (n=16). Combined polynomial and exponential functions were used to model the harvesting-based and imaging-based time-activity data. The measured time-activity data were extrapolated to modeled (i.e., Standard Man) human organs and human absorbed doses calculated., Results: Organ activities derived by imaging-based and by harvesting-based methods were highly correlated (r>0.999) as were the projected human dosimetry estimates across organs (r=0.998) obtained with each method. The tissues calculated to receive highest radiation dose by both methods were related to routes of excretion (bladder wall, liver, and intestines). The harvesting-based and imaging-based methods yielded effective dose (ED) of 2.94E-2 and 2.97E-2 mSv/MBq, respectively., Conclusions: Small-animal PET presents an opportunity for providing radiation dose estimates with statistical and logistical advantages over traditional tissue harvesting-based methods.

The utility of PET for monitoring responses to radiation therapy have been complicated by metabolically active processes in surrounding normal tissues. We examined the time-course of [18F]FDG uptake in normal tissues using small animal-dedicated PET during the 2 month period following external beam radiation. Four mice received 12 Gy of external beam radiation, in a single fraction to the left half of the body. Small animal [18F]FDG-PET scans were acquired for each mouse at 0 (pre-radiation), 1, 2, 3, 4, 5, 8, 12, 19, 24, and 38 days following irradiation. [18F]FDG activity in various tissues was compared between irradiated and non-irradiated body halves before, and at each time point after irradiation. Radiation had a significant impact on [18F]FDG uptake in previously healthy tissues, and time-course of effects differed in different types of tissues. For example, liver tissue demonstrated increased uptake, particularly over days 3-12, with the mean left to right uptake ratio increasing 52% over mean baseline values (p < 0.0001). In contrast, femoral bone marrow uptake demonstrated decreased uptake, particularly over days 2-8, with the mean left to right uptake ratio decreasing 26% below mean baseline values (p = 0.0005). Significant effects were also seen in lung and brain tissue. Radiation had diverse effects on [18F]FDG uptake in previously healthy tissues. These kinds of data may help lay groundwork for a systematically acquired database of the time-course of effects of radiation on healthy tissues, useful for animal models of cancer therapy imminently, as well as interspecies extrapolations pertinent to clinical application eventually.

Unlabelled: In mice bearing human breast cancer xenografts, we examined the biodistribution of (18)F-fluorocyclophosphamide ((18)F-F-CP) to evaluate its potential as a noninvasive prognostic tool for predicting the resistance of tumors to cyclophosphamide therapy., Methods: (18)F-F-CP was synthesized as we recently described, and PET data were acquired after administration of (18)F-F-CP in mice bearing human breast cancer xenografts (MCF-7 cells). Tracer biodistribution in reconstructed images was quantified by region-of-interest analysis. Distribution was also assessed by harvesting dissected organs, tumors, and blood, determining (18)F content in each tissue with a gamma-well counter. The mice were subsequently treated with cyclophosphamide, and tumor size was monitored for at least 3 wk after chemotherapy administration., Results: The distribution of harvested activity correlated strongly with distribution observed in PET images. Target organs were related to routes of metabolism and excretion. (18)F-F-CP uptake was highest in kidneys, lowest in brain, and intermediate in tumors, as determined by both image-based and tissue-based measurements. (18)F-F-CP uptake was not inhibited by coadministration of an approximately x700 concentration of unlabeled cyclophosphamide. PET measures of (18)F-F-CP uptake in tumor predicted the magnitude of the response to subsequent administration of cyclophosphamide., Conclusion: Noninvasive assessment of (18)F-F-CP uptake using PET may potentially be helpful for predicting the response of breast tumors to cyclophosphamide before therapy begins.

Unlabelled: Paclitaxel is used as a chemotherapy drug for the treatment of various malignancies, including breast, ovarian, and lung cancers. To evaluate the potential of a noninvasive prognostic tool for specifically predicting the resistance of tumors to paclitaxel therapy, we examined the tumoral uptake of (18)F-fluoropaclitaxel ((18)F-FPAC) in mice bearing human breast cancer xenografts by using small-animal-dedicated PET and compared (18)F-FPAC uptake with the tumor response to paclitaxel treatment., Methods: PET data were acquired after tail vein injection of approximately 9 MBq of (18)F-FPAC in anesthetized nude mice bearing breast cancer xenografts. Tracer uptake in reconstructed images was quantified by region-of-interest analyses and compared with the tumor response, as measured by changes in tumor volume, after treatment with paclitaxel., Results: Mice with tumors that progressed demonstrated lower tumoral uptake of (18)F-FPAC than mice with tumors that did not progress or that regressed (r = 0.55, P < 0.02; n = 19), indicating that low (18)F-FPAC uptake was a significant predictor of chemoresistance. Conversely, high (18)F-FPAC uptake predicted tumor regression. This relationship was found for mice bearing xenografts from cell lines selected to be either sensitive or intrinsically resistant to paclitaxel in vitro., Conclusion: PET data acquired with (18)F-FPAC suggest that this tracer holds promise for the noninvasive quantification of its distribution in vivo in a straightforward manner. In combination with approaches for examining other aspects of resistance, such quantification could prove useful in helping to predict subsequent resistance to paclitaxel chemotherapy of breast cancer.

Unlabelled: The objective of the work reported here was to develop and test automated methods to calculate biodistribution of PET tracers using small-animal PET images., Methods: After developing software that uses visually distinguishable organs and other landmarks on a scan to semiautomatically coregister a digital mouse phantom with a small-animal PET scan, we elastically transformed the phantom to conform to those landmarks in 9 simulated scans and in 18 actual PET scans acquired of 9 mice. Tracer concentrations were automatically calculated in 22 regions of interest (ROIs) reflecting the whole body and 21 individual organs. To assess the accuracy of this approach, we compared the software-measured activities in the ROIs of simulated PET scans with the known activities, and we compared the software-measured activities in the ROIs of real PET scans both with manually established ROI activities in original scan data and with actual radioactivity content in immediately harvested tissues of imaged animals., Results: PET/atlas coregistrations were successfully generated with minimal end-user input, allowing rapid quantification of 22 separate tissue ROIs. The simulated scan analysis found the method to be robust with respect to the overall size and shape of individual animal scans, with average activity values for all organs tested falling within the range of 98% +/- 3% of the organ activity measured in the unstretched phantom scan. Standardized uptake values (SUVs) measured from actual PET scans using this semiautomated method correlated reasonably well with radioactivity content measured in harvested organs (median r = 0.94) and compared favorably with conventional SUV correlations with harvested organ data (median r = 0.825)., Conclusion: A semiautomated analytic approach involving coregistration of scan-derived images with atlas-type images can be used in small-animal whole-body radiotracer studies to estimate radioactivity concentrations in organs. This approach is rapid and less labor intensive than are traditional methods, without diminishing overall accuracy. Such techniques have the possibility of saving time, effort, and the number of animals needed for such assessments.

Unlabelled: Paclitaxel (PAC) is widely used as a chemotherapy drug in the treatment of various malignancies, including breast, ovarian, and lung cancers. We examined the biodistribution of (18)F-fluoropaclitaxel ((18)F-FPAC) in mice with and without human breast cancer tumor xenografts by use of small-animal-dedicated PET (microPET) and clinically practical semiquantitative methods. We compared the PET data to data derived from direct harvesting and analysis of blood, organs, and breast carcinoma xenografts., Methods: PET data were acquired after tail vein injection of (18)F-FPAC in nude mice. Tracer biodistribution in reconstructed images was quantified by region-of-interest analysis. Biodistribution also was assessed by harvesting and analysis of dissected organs, tumors, and blood after coadministration of (18)F-FPAC and (3)H-PAC. (18)F content in each tissue was assessed with a gamma-well counter, and (3)H content was quantified by scintillation counting of solubilized tissue after (18)F radioactive decay., Results: The distributions of (18)F-FPAC and (3)H-PAC were very similar, with the highest concentrations in the small intestine, the lowest concentrations in the brain, and intermediate concentrations in tumor. Uptake in these and other tissues was not inhibited by the presence of more pharmacologic doses of unlabeled PAC. Administration of the P-glycoprotein modulator cyclosporine doubled the uptake of both (18)F-FPAC and (3)H-PAC into tumor., Conclusion: PET studies with (18)F-FPAC can be used in conjunction with clinically practical quantification methods to yield estimates of PAC uptake in breast cancer tumors and normal organs noninvasively.