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.

First-in-human imaging with [89Zr]Zr-DFO-SC16.56 anti-DLL3 antibody in patients with high-grade neuroendocrine tumors of the lung and prostate.

Background: Delta-like ligand 3 (DLL3) is aberrantly expressed on the cell surface in many neuroendocrine cancers including small cell lung cancer (SCLC) and neuroendocrine prostate cancer (NEPC). Several therapeutic agents targeting DLL3 are in active clinical development. Molecular imaging of DLL3 would enable non-invasive diagnostic assessment to inform the use of DLL3-targeting therapeutics or to assess disease treatment response. Methods: We conducted a first-in-human immuno-positron emission tomography (immunoPET) imaging study of [89Zr]Zr-DFO-SC16.56, composed of the anti-DLL3 antibody SC16.56 conjugated to desferrioxamine (DFO) and the positron-emitting radionuclide zirconium-89, in 18 patients with neuroendocrine cancers. An initial cohort of three patients received 1-2 mCi of [89Zr]Zr-DFO-SC16.56 at a total mass dose of 2·5 mg and underwent serial PET and computed tomography (CT) imaging over the course of one week. Radiotracer clearance, tumor uptake, and radiation dosimetry were estimated. An expansion cohort of 15 additional patients were imaged using the initial activity and mass dose. Retrospectively collected tumor biopsies were assessed for DLL3 by immunohistochemistry (IHC) (n = 16). Findings: Imaging of the initial 3 SCLC patients demonstrated strong tumor-specific uptake of [89Zr]Zr-DFO-SC16.56, with similar tumor: background ratios at days 3, 4, and 7 post-injection. Serum clearance was bi-phasic with an estimated terminal clearance half-time of 119 h. The sites of highest background tracer uptake were blood pool and liver. The normal tissue receiving the highest radiation dose was liver; 1·8 mGy/MBq, and the effective dose was 0.49 mSv/MBq. Tumoral uptake varied both between and within patients, and across anatomic sites, with a wide range in SUVmax (from 3·3 to 66·7). Tumor uptake by [89Zr]Zr-DFO-SC16.56 was associated with protein expression in all cases. Two non-avid DLL3 NEPC cases by PET scanning demonstrated the lowest DLL3 expression by tumor immunohistochemistry. Only one patient had a grade 1 allergic reaction, while no grade ≥2 adverse events noted. Interpretation: DLL3 PET imaging of patients with neuroendocrine cancers is safe and feasible. These results demonstrate the potential utility of [89Zr]Zr-DFO-SC16.56 for non-invasive in vivo detection of DLL3-expressing malignancies. Funding: Supported by NIH R01CA213448 (JTP), R35 CA263816 (CMR), U24 CA213274 (CMR), R35 CA232130 (JSL), and a Prostate Cancer Foundation TACTICAL Award (JSL), Scannell foundation. The Radiochemistry and Molecular Imaging Probes Core Facility is supported by NIH P30 CA08748.

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.

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.

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.

Yttrium-90 Activity Quantification in PET/CT-Guided Biopsy Specimens from Colorectal Hepatic Metastases Immediately after Transarterial Radioembolization Using Micro-CT and Autoradiography.

PURPOSE: To evaluate the yttrium-90 (90Y) activity distribution in biopsy tissue samples of the treated liver to quantify the dose with higher spatial resolution than positron emission tomography (PET) for accurate investigation of correlations with microscopic biological effects and to evaluate the radiation safety of this procedure. MATERIALS AND METHODS: Eighty-six core biopsy specimens were obtained from 18 colorectal liver metastases (CLMs) immediately after 90Y transarterial radioembolization (TARE) with either resin or glass microspheres using real-time 90Y PET/CT guidance in 17 patients. A high-resolution micro-computed tomography (micro-CT) scanner was used to image the microspheres in part of the specimens and allow quantification of 90Y activity directly or by calibrating autoradiography (ARG) images. The mean doses to the specimens were derived from the measured specimens' activity concentrations and from the PET/CT scan at the location of the biopsy needle tip for all cases. Staff exposures were monitored. RESULTS: The mean measured 90Y activity concentration in the CLM specimens at time of infusion was 2.4 ± 4.0 MBq/mL. The biopsies revealed higher activity heterogeneity than PET. Radiation exposure to the interventional radiologists during post-TARE biopsy procedures was minimal. CONCLUSIONS: Counting the microspheres and measuring the activity in biopsy specimens obtained after TARE are safe and feasible and can be used to determine the administered activity and its distribution in the treated and biopsied liver tissue with high spatial resolution. Complementing 90Y PET/CT imaging with this approach promises to yield more accurate direct correlation of histopathological changes and absorbed dose in the examined specimens.

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.

Dosimetry in Radiopharmaceutical Therapy.

The application of radiopharmaceutical therapy for the treatment of certain diseases is well established, and the field is expanding. New therapeutic radiopharmaceuticals have been developed in recent years, and more are in the research pipeline. Concurrently, there is growing interest in the use of internal dosimetry as a means of personalizing, and potentially optimizing, such therapy for patients. Internal dosimetry is multifaceted, and the current state of the art is discussed in this continuing education article. Topics include the context of dosimetry, internal dosimetry methods, the advantages and disadvantages of incorporating dosimetry calculations in radiopharmaceutical therapy, a description of the workflow for implementing patient-specific dosimetry, and future prospects in the field.

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.

Patient Size-Dependent Dosimetry Methodology Applied to 18F-FDG Using New ICRP Mesh Phantoms.

Despite the known influence of anatomic variability on internal dosimetry, dosimetry for 18F-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 18F-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 18F-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.

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.