3D small-scale dosimetry and tumor control of 225Ac radiopharmaceuticals for prostate cancer.

Radiopharmaceutical therapy using α -emitting 225 Ac is an emerging treatment for patients with advanced metastatic cancers. Measurement of the spatial dose distribution in organs and tumors is needed to inform treatment dose prescription and reduce off-target toxicity, at not only organ but also sub-organ scales. Digital autoradiography with α -sensitive detection devices can measure radioactivity distributions at 20-40 µ m resolution, but anatomical characterization is typically limited to 2D. We collected digital autoradiographs across whole tissues to generate 3D dose volumes and used them to evaluate the simultaneous tumor control and regional kidney dosimetry of a novel therapeutic radiopharmaceutical for prostate cancer, [225Ac]Ac-Macropa-PEG4-YS5, in mice. 22Rv1 xenograft-bearing mice treated with 18.5 kBq of [225Ac]Ac-Macropa-PEG4-YS5 were sacrificed at 24 h and 168 h post-injection for quantitative α -particle digital autoradiography and hematoxylin and eosin staining. Gamma-ray spectroscopy of biodistribution data was used to determine temporal dynamics and 213 Bi redistribution. Tumor control probability and sub-kidney dosimetry were assessed. Heterogeneous 225 Ac spatial distribution was observed in both tumors and kidneys. Tumor control was maintained despite heterogeneity if cold spots coincided with necrotic regions. 225 Ac dose-rate was highest in the cortex and renal vasculature. Extrapolation of tumor control suggested that kidney absorbed dose could be reduced by 41% while maintaining 90% TCP. The 3D dosimetry methods described allow for whole tumor and organ dose measurements following 225 Ac radiopharmaceutical therapy, which correlate to tumor control and toxicity outcomes.

The United States Department of Energy and National Institutes of Health Collaboration: Medical Care Advances by Discovery in Radiation Detection.

A National Institutes of Health (NIH) and U.S. Department of Energy (DOE) Office of Science virtual workshop on shared general topics was held in July of 2021 and reported on in this publication in January of 2023. Following the inaugural 2021 joint meeting representatives from the DOE Office of Science and NIH met to discuss organizing a second joint workshop that would concentrate on radiation detection to bring together teams from both agencies and their grantee populations to stimulate collaboration and efficiency. To meet this scientific mission within the NIH and DOE radiation detection space, the organizers assembled workshop sessions covering the state-of-the-art in cameras, detectors, and sensors for radiation external and internal (diagnostic and therapeutic) to human, data acquisition and electronics, image reconstruction and processing, and the application of artificial intelligence. NIH and DOE are committed to continuing the process of convening a joint workshop every 12-24 months. This Special Report recaps the findings of this second workshop. Beyond showing only the innovations and areas of success, important gaps in our knowledge were defined and presented. We summarize by defining four areas of greatest opportunity and need that emerged from the unique, dynamic dialogue the in-person workshop provided the attendees.

A generalization of the maximum likelihood expectation maximization (MLEM) method: Masked-MLEM.

Objective.In our previous work on image reconstruction for single-layer collimatorless scintigraphy, we developed the min-min weighted robust least squares (WRLS) optimization algorithm to address the challenge of reconstructing images when both the system matrix and the projection data are uncertain. Whereas the WRLS algorithm has been successful in two-dimensional (2D) reconstruction, expanding it to three-dimensional (3D) reconstruction is difficult since the WRLS optimization problem is neither smooth nor strongly-convex. To overcome these difficulties and achieve robust image reconstruction in the presence of system uncertainties and projection noise, we propose a generalized iterative method based on the maximum likelihood expectation maximization (MLEM) algorithm, hereinafter referred to as the Masked-MLEM algorithm.Approach.In the Masked-MLEM algorithm, only selected subsets ('masks') from the system matrix and the projection contribute to the image update to satisfy the constraints imposed by the system uncertainties. We validate the Masked-MLEM algorithm and compare it to the standard MLEM algorithm using experimental data obtained from both collimated and uncollimated imaging instruments, including parallel-hole collimated SPECT, 2D collimatorless scintigraphy, and 3D collimatorless tomography. Additionally, we conduct comprehensive Monte Carlo simulations for 3D collimatorless tomography to further validate the effectiveness of the Masked-MLEM algorithm in handling different levels of system uncertainties.Main results.The Masked-MLEM and standard MLEM reconstructions are similar in cases with negligible system uncertainties, whereas the Masked-MLEM algorithm outperforms the standard MLEM algorithm when the system matrix is an approximation. Importantly, the Masked-MLEM algorithm ensures reliable image reconstruction across varying levels of system uncertainties.Significance.With a good choice of system uncertainty and without requiring accurate knowledge of the actual system matrix, the Masked-MLEM algorithm yields more robust image reconstruction than the standard MLEM algorithm, effectively reducing the likelihood of erroneously reconstructing higher activities in regions without radioactive sources.

Coded aperture and Compton imaging for the development of 225 Ac-based radiopharmaceuticals.

BACKGROUND: Targeted alpha-particle therapy (TAT) has great promise as a cancer treatment. Arguably the most promising TAT radionuclide that has been proposed is 225 Ac. The development of 225 Ac-based radiopharmaceuticals has been hampered due to the lack of effective means to study the daughter redistribution of these agents in small animals at the preclinical stage. PURPOSE: The ability to directly image the daughters, namely 221 Fr and 213 Bi, via their gamma-ray emissions would be a boon for preclinical studies. That said, conventional medical imaging modalities, including single photon emission computed tomography (SPECT) based on nonmultiplexed collimation, cannot be employed due to sensitivity limitations. METHODS: As an alternative, we propose the use of both coded aperture and Compton imaging with the former modality suited to the 218-keV gamma-ray emission of 221 Fr and the latter suited to the 440-keV gamma-ray emission of 213 Bi. RESULTS: This work includes coded aperture images of 221 Fr and Compton images of 213 Bi in tumor-bearing mice injected with 225 Ac-based radiopharmaceuticals. CONCLUSIONS: These results are the first demonstration of visualizing and quantifying the 225 Ac daughters in small animals through the application of coded aperture and Compton imaging.

Simultaneous Imaging of Ga-DOTA-TATE and Lu-DOTA-TATE in Murine Models of Neuroblastoma.

68Ga-DOTA-TATE and 177Lu-DOTA-TATE are radiolabeled somatostatin analogs used to detect or treat neuroendocrine tumors. They are administered separately for either diagnostic or therapeutic purposes but little experimental data for their biokinetics are measured simultaneously in the same biological model. By co-administering 68Ga-DOTA-TATE and 177Lu-DOTA-TATE in three laboratory mice bearing two IMR32 tumor xenografts expressing different levels of somatostatin receptors (SSTRs) on their shoulders and imaging both 68Ga and 177Lu simultaneously, we investigated the relationship between the uptake of 68Ga-DOTA-TATE and 177Lu-DOTA-TATE in organs and tumors. In addition, using the percent of injected activity (%IA) values of 68Ga-DOTA-TATE at 0 hr and 4 hr, we investigated the correlation between 68Ga-DOTA-TATE %IA and the time-integrated activity coefficients (TIACs) of 177Lu-DOTA-TATE to estimate the organ-based and tumor-based doses of 177Lu-DOTA-TATE. The results showed that the extrapolated clearance time of 68Ga-DOTA-TATE linearly correlated with the TIACs of 177Lu-DOTA-TATE in the IMR32-SSTR2 tumor, kidneys, brain, heart, liver, stomach and remainder body. The extrapolated %IA value at 0 hr of 68Ga-DOTA-TATE linearly correlated with the TIACs of 177Lu-DOTA-TATE in the IMR32 tumor and lungs. In our murine study, both kidneys and lungs were organs that showed high absorbed doses of 177Lu-DOTA-TATE.

Small-scale (sub-organ and cellular level) alpha-particle dosimetry methods using an iQID digital autoradiography imaging system.

Targeted radiopharmaceutical therapy with alpha-particle emitters (αRPT) is advantageous in cancer treatment because the short range and high local energy deposition of alpha particles enable precise radiation delivery and efficient tumor cell killing. However, these properties create sub-organ dose deposition effects that are not easily characterized by direct gamma-ray imaging (PET or SPECT). We present a computational procedure to determine the spatial distribution of absorbed dose from alpha-emitting radionuclides in tissues using digital autoradiography activity images from an ionizing-radiation quantum imaging detector (iQID). Data from 211At-radioimmunotherapy studies for allogeneic hematopoietic cell transplantation in a canine model were used to develop these methods. Nine healthy canines were treated with 16.9-30.9 MBq 211At/mg monoclonal antibodies (mAb). Lymph node biopsies from early (2-5 h) and late (19-20 h) time points (16 total) were obtained, with 10-20 consecutive 12-µm cryosections extracted from each and imaged with an iQID device. iQID spatial activity images were registered within a 3D volume for dose-point-kernel convolution, producing dose-rate maps. The accumulated absorbed doses for high- and low-rate regions were 9 ± 4 Gy and 1.2 ± 0.8 Gy from separate dose-rate curves, respectively. We further assess uptake uniformity, co-registration with histological pathology, and requisite slice numbers to improve microscale characterization of absorbed dose inhomogeneities in αRPT.

Free-moving Quantitative Gamma-ray Imaging.

The ability to map and estimate the activity of radiological source distributions in unknown three-dimensional environments has applications in the prevention and response to radiological accidents or threats as well as the enforcement and verification of international nuclear non-proliferation agreements. Such a capability requires well-characterized detector response functions, accurate time-dependent detector position and orientation data, a digitized representation of the surrounding 3D environment, and appropriate image reconstruction and uncertainty quantification methods. We have previously demonstrated 3D mapping of gamma-ray emitters with free-moving detector systems on a relative intensity scale using a technique called Scene Data Fusion (SDF). Here we characterize the detector response of a multi-element gamma-ray imaging system using experimentally benchmarked Monte Carlo simulations and perform 3D mapping on an absolute intensity scale. We present experimental reconstruction results from hand-carried and airborne measurements with point-like and distributed sources in known configurations, demonstrating quantitative SDF in complex 3D environments.

Collimatorless Scintigraphy for Imaging Extremely Low Activity Targeted Alpha Therapy (TAT) with Weighted Robust Least Squares (WRLS).

A technology for imaging extremely low photon flux is an unmet need, especially in targeted alpha therapy (TAT) imaging, which requires significantly improved sensitivity to detect as many photons as possible while retaining a reasonable spatial resolution. In scintigraphy using gamma cameras, the radionuclide collimator rejects a large number of photons that are both primary photons and scattered photons, unsuitable for photon-starved imaging scenarios like imaging TAT. In this paper we develop a min-min weighted robust least squares (WRLS) algorithm to solve a general reconstruction problem with uncertainties and validate it with the extreme scenario: collimatorless scintigraphy. Ra-223, a therapeutic alpha emitting radionuclide whose decay chain includes x-ray and gamma-ray photons, is selected for an exploratory study. Full Monte Carlo simulations are performed using Geant4 to obtain realistic projection data with collimatorless scintigraphy geometry. The results show that our proposed min-min WRLS algorithm could successfully reconstruct point sources and extended sources in the collimatorless scintigraphy with a resolution close to its system resolution and figures of merit (FOM) better than the collimator-based scintigraphy for extremely low activity TAT. This approach could be expanded as a 3D algorithm, which could lead to 3D collimatorless SPECT.

Advances in Nuclear Radiation Sensing: Enabling 3-D Gamma-Ray Vision.

The enormous advances in sensing and data processing technologies in combination with recent developments in nuclear radiation detection and imaging enable unprecedented and "smarter" ways to detect, map, and visualize nuclear radiation. The recently developed concept of three-dimensional (3-D) Scene-data fusion allows us now to "see" nuclear radiation in three dimensions, in real time, and specific to radionuclides. It is based on a multi-sensor instrument that is able to map a local scene and to fuse the scene data with nuclear radiation data in 3-D while the instrument is freely moving through the scene. This new concept is agnostic of the deployment platform and the specific radiation detection or imaging modality. We have demonstrated this 3-D Scene-data fusion concept in a range of configurations in locations, such as the Fukushima Prefecture in Japan or Chernobyl in Ukraine on unmanned and manned aerial and ground-based platforms. It provides new means in the detection, mapping, and visualization of radiological and nuclear materials relevant for the safe and secure operation of nuclear and radiological facilities or in the response to accidental or intentional releases of radioactive materials where a timely, accurate, and effective assessment is critical. In addition, the ability to visualize nuclear radiation in 3-D and in real time provides new means in the communication with public and facilitates to overcome one of the major public concerns of not being able to "see" nuclear radiation.

Erratum: Invasive house geckos (hemidactylus spp.): their current, potential and future distribution.

[This corrects the article DOI: 10.1093/cz/zox052.][This corrects the article DOI: 10.1093/cz/zox052.].

Invasive house geckos (hemidactylus spp.): their current, potential and future distribution.

In this study, we identified the current distribution of five globally distributed invasive Hemidactylus species and predicted their potential and future distribution using species distribution models based on climate and elevation data. These species included H. brookii, H. frenatus, H. garnotii, H. mabouia, and H. turcicus. We show that many regions with tropical and Mediterranean climates are suitable for most of these species. However, their current and potential distributions suggest that climate is not the only limiting factor. We hypothesize that climatic conditions may affect competition and other interactions resulting in a segregated distribution of the studied Hemidactylus species. As an effect of global climate change it is likely that H. brookii will expand its range to areas that are currently colonized by H. mabouia and/or H. frenatus, while H. turcicus is likely to expand its range to areas that are not yet invaded by any Hemidactylus species. The role of species interactions in the range expansion of these five Hemidactylus species still remains poorly understood, but could be of major importance in understanding and managing these invasive species.

Unbiased and biased estimators in coded aperture imaging for far field standoff detection at low count rates.

In general, the reconstructed image in coded aperture imaging is affected by the source configuration. Fenimore's balanced convolution method in conjunction with the uniformly redundant array can remove the interference due to the source configuration. As an extension of Fenimore's balanced convolution method, we present general conditions for designing an unbiased mean estimator for a far-field coded aperture imaging system with a random binary mask. As part of the general conditions, we propose decoding arrays whose elements are variable with respect to source directions. We also show that the unbiased mean estimator from Fenimore's balanced convolution method is a special case of the general conditions. We also present a practical example of designing restoring arrays for a coded aperture system with a random mask.

Treatment planning for molecular targeted radionuclide therapy.

Molecular targeted radionuclide therapy promises to expand the usefulness of radiation to successfully treat widespread cancer. The unique properties of radioactive tags make it possible to plan treatments by predicting the radiation absorbed dose to both tumors and normal organs, using a pre-treatment test dose of radiopharmaceutical. This requires a combination of quantitative, high-resolution, radiation-detection hardware and computerized dose-estimation software, and would ideally include biological dose-response data in order to translate radiation absorbed dose into biological effects. Data derived from conventional (external beam) radiation therapy suggests that accurate assessment of the radiation absorbed dose in dose-limiting normal organs could substantially improve the observed clinical response for current agents used in a myeloablative regimen, enabling higher levels of tumor control at lower tumor-to-normal tissue therapeutic indices. Treatment planning based on current radiation detection and simulations technology is sufficient to impact on clinical response. The incorporation of new imaging methods, combined with patient-specific radiation transport simulations, promises to provide unprecedented levels of resolution and quantitative accuracy, which are likely to increase the impact of treatment planning in targeted radionuclide therapy.