MIRD Pamphlet No. 29: MIRDy90-A 90Y Research Microsphere Dosimetry Tool.

90Y-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 90Y, 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 90Y 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.

Engineering CAR-T cells for radiohapten capture in imaging and radioimmunotherapy applications.

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.

Technical Note: Impact of impurities on Yttrium-90 glass microsphere activity quantitation.

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.

The risk index as a basis for risk/benefit analyses and protocol optimization in diagnostic nuclear 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.

MIRD Pamphlet No. 28, Part 2: Comparative Evaluation of MIRDcalc Dosimetry Software Across a Compendium of Diagnostic Radiopharmaceuticals.

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.

MIRD Pamphlet No. 28, Part 1: MIRDcalc-A Software Tool for Medical Internal Radiation Dosimetry.

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.

Influence of Body Posture on Internal Organ Dosimetry: Radiocesium Exposure Modeling Using Novel Posture-dependent Mesh Computational Phantoms.

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.

Engineered Cells as a Test Platform for Radiohaptens in Pretargeted Imaging and Radioimmunotherapy Applications.

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, [86Y]Y-DOTA-Bn predicted absorbed dose to critical organs with reasonable accuracy for both [177Lu]Lu-DOTA-Bn and [225Ac]Ac-Pr, which highlights the benefit of a dosimetry-based treatment approach.

Technical Note: Patient-morphed mesh-type phantoms to support personalized nuclear medicine dosimetry - a proof of concept study.

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.

Utility of Quantitative SPECT/CT Lymphoscintigraphy in Guiding Sentinel Lymph Node Biopsy in Head and Neck Melanoma.

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.

Modern Radiopharmaceutical Dosimetry Should Include Robust Biodistribution Reporting.

Radiopharmaceutical dosimetry is an important area of nuclear medicine, and its advances have the potential to affect imaging and radiotherapy development and application protocols. Dosimetry is a computationally intensive, assumption-based process, and not all dosimetry is created equal. In this brief communication, we present biodistribution measurements as a valuable part of radiopharmaceutical dosimetry that is worthy of robust documentation. Biodistribution data are routinely collected in every dosimetry case and are integral to the subsequent dosimetry calculations. Standard documentation of these data may help us understand the value and limitations of our dosimetry estimates, identify errors, resolve discrepancies, and enable the reproducibility of results. We may also recognize that the modern digital landscape provides both opportunity and motivation to usher in the evolution of standards in our field. Ultimately, these steps may improve the current generally poor acceptance of dosimetry procedures by clinicians.

Data-driven optimal binning for respiratory motion management in PET.

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.

Frequency based gating: An alternative, conformal, approach to 4D PET data utilization.

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.