Search Results (100)

Background/Objectives: Gastrin-releasing peptide receptor (GRPR) is overexpressed in breast cancer and might be used as a theranostics target. The expression of GRPR strongly correlates with estrogen receptor (ER) expression. Visualization of GRPR-expressing breast tumors might help to select the optimal treatment. Developing GRPR-specific probes for SPECT would permit imaging-guided therapy in regions with restricted access to PET facilities. In this first-in-human study, we evaluated the safety, biodistribution, and dosimetry of the [^99mTc]Tc-DB8 GRPR-antagonistic peptide. We also addressed the important issue of finding the optimal injected peptide mass. Methods: Fifteen female patients with ER-positive primary breast cancer were enrolled and divided into three cohorts receiving [^99mTc]Tc-DB8 (corresponding to three distinct doses of 40, 80, or 120 µg DB8) comprising five patients each. Additionally, four patients with ER-negative primary tumors were injected with 80 µg [^99mTc]Tc-DB8. The injected activity was 360 ± 70 MBq. Planar scintigraphy was performed after 2, 4, 6, and 24 h, and SPECT/CT scans followed planar imaging 2, 4, and 6 h after injection. Results: No adverse events were associated with [^99mTc]Tc-DB8 injections. The effective dose was 0.009–0.014 mSv/MBq. Primary tumors and all known lymph node metastases were visualized irrespective of injected peptide mass. The highest uptake in the ER-positive tumors was 2 h after injection of [^99mTc]Tc-DB8 at a 80 µg DB8 dose (SUV_max 5.3 ± 1.2). Injection of [^99mTc]Tc-DB8 with 80 µg DB8 provided significantly (p < 0.01) higher uptake in primary ER-positive breast cancer lesions than injection with 40 µg DB8 (SUV_max 2.0 ± 0.3) or 120 µg (SUV_max 3.2 ± 1.4). Tumor-to-contralateral breast ratio after injection of 80 μg was also significantly (p < 0.01, ANOVA test) higher than ratios after injection of other peptide masses. The uptake in ER-negative lesions was significantly lower (SUV_max 2.0 ± 0.3) than in ER-positive tumors. Conclusions: Imaging using [^99mTc]Tc-DB8 is safe, tolerable, and associated with low absorbed doses. The tumor uptake is dependent on the injected peptide mass. The injection of an optimal mass (80 µg) provides the highest uptake in ER-positive tumors. At optimal dosing, the uptake was significantly higher in ER-positive than in ER-negative lesions. Full article

As data exchange demands increase also in widespread wearable technologies, transitioning to higher bandwidths and mmWave frequencies (30–300 GHz) is essential. This shift raises concerns about RF exposure. At such high frequencies, the most crucial human tissue for RF power absorption is the skin, since EMF penetration is superficial. It becomes thus very important to assess how the model used to represent the skin in numerical dosimetry studies affects the estimated level of absorbed power. The present study, for the first time, assesses the absorbed power density (APD) using FDTD simulations on two realistic human models in which: (i) the skin has a two-layer structure made of the stratum corneum and the viable epidermis and dermis layers, and (ii) the skin is modelled as a homogeneous dermis stratum. These results were compared with ones using flat phantom models, with and without the stratified skin. The exposure assessment study was performed with two sources (a wearable patch antenna and a plane wave) tuned to 28 GHz. For the wearable antenna, the results evidence that the exposure levels obtained when using the homogeneous version of the models are always lower than the levels in the stratified skin version with percentage differences from 16% to 30%. This trend is more noticeable with the female model. In the case of plane wave exposure, these differences were less pronounced and lower than 11%. Full article

In the environment, plastic waste degrades into small particles known as microplastics and nanoplastics (MNPLs), depending on their size. Given the potential harmful effects associated with MNPL exposure, it is crucial to develop environmentally representative particles for hazard assessment. These so-called true-to-life MNPLs are generated through in-house degradation of real-world plastic products. In this study, we produced titanium-doped nanoplastics (NPLs) from opaque polyethylene terephthalate (PET) milk bottles, which contain titanium dioxide as a filler. The resulting PET(Ti)-NPLs were thoroughly characterized using scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDS), mass spectrometry (MS), dynamic light scattering (DLS), ζ-potential measurements, transmission electron microscopy (TEM), and Fourier-transform infrared (FTIR) spectroscopy. Human-derived THP-1 monocytes were employed to investigate particle uptake kinetics, dosimetry, and genotoxicity. A combination of flow cytometry and inductively coupled plasma mass spectrometry (ICP-MS) enabled the quantification of internalized particles, while the comet assay assessed DNA damage. The results revealed dose- and time-dependent effects of PET(Ti)-NPLs on THP-1 cells, particularly in terms of internalization. Titanium doping facilitated detection and influenced genotoxic outcomes. This study demonstrates the relevance of using environmentally representative nanoplastic models for evaluating human health risks and underscores the importance of further mechanistic research. Full article

The results of radiotherapy in patients with primary malignant brain tumors are extremely dissatisfactory: the overall survival after a diagnosis of glioblastoma is typically less than three years. The development of spatially fractionated radiotherapy techniques could help to improve this bleak prognosis. In order to develop technical equipment and organ-specific therapy plans, dosimetry studies as well as radiobiology studies are conducted. Although perfect spheres are considered optimal phantoms by physicists, this does not reflect the wide variety of head sizes and shapes in our patient community. Depth from surface and X-ray dose absorption by tissue between dose entry point and target, two key parameters in medical physics planning, are largely determined by the shape and thickness of the skull bone. We have, therefore, designed and produced a biomimetic tool to correlate measured technical dose and biological response in human cancer cells: a brain phantom, produced from tissue-equivalent materials. In a first pilot study, utilizing our phantom to correlate technical dose measurements and metabolic response to radiation in human cancer cell lines, we demonstrate why an anthropomorphic phantom is preferable over a simple spheroid phantom. Full article

In South Korea, issues have been raised regarding exposure to humidifier disinfectant products containing certain chemicals postulated to induce lung diseases in consumers. Several rodent studies utilizing whole-body inhalation, which comprises freely moving animals breathing through the nares, and intranasal instillation involving restraint, were conducted by various Korean Governmental Agencies on these products to investigate whether there is a causal relationship between these products and the development of lung diseases. In particular, the humidifier disinfectant product Kathon, containing chloromethylisothiazolinone and methylisothiazolinone (CMIT and MIT), when directly introduced into inhalation chambers at varying concentrations for up to 13 weeks, produced no significant histopathological alterations and no marked changes in pulmonary function parameters. Further, there was no evidence of cytotoxicity; total and differential cell counts did not differ from control. In addition, the levels of cytokine markers of inflammation were not markedly altered. In contrast to published papers utilizing intratracheal and intranasal instillation, where the animal is anesthetized and chemical bypasses the defense mechanisms in the respiratory tract, then reaches the pulmonary region, ignoring recommended dose levels was found to initiate fibrotic responses in mice and rats. However, the usefulness of experimental results to extrapolate to humans obtained following intratracheal and intranasal instillation studies is of limited value because the data generated did not use a realistic design and appropriate dosimetry. Therefore, these findings have significant drawbacks in their use to characterize an inhalation risk for pulmonary fibrosis in humans and cannot be used for the extrapolation of such risk to humans. It is thus evident that the inhalation data generated by the Korean Regulatory Agencies are more realistic and show that exposure to CMIT and MIT does not initiate pulmonary fibrosis. Although inhalation studies still do not fully replicate real-world human exposure scenarios and have limitations for direct extrapolation to humans, they are nevertheless more appropriate than intratracheal or intranasal instillation models. Full article

Nicotinic acetylcholine receptor (α7-nAChR) plays a crucial role in cognitive functions like memory and attention. Positron emission tomography (PET) imaging of α7-nAChR is gaining attraction for understanding and monitoring central nervous system disorders, such as Alzheimer’s disease, Parkinson’s disease, and schizophrenia. We developed [¹¹C]KIn83, a novel α7-nAChR radioligand, and evaluated its biological properties. This study focused on two objectives: (1) to validate its Good Manufacturing Practice (GMP)-compliant production, and (2) to assess the dosimetry of [¹¹C]KIn83 using non-human primate (NHP) whole-body PET data. Radiolabeling and drug product delivery of [¹¹C]KIn83 were conducted using an automated synthesis module within a controlled GMP environment. The quality control tests performed adhered to the European Pharmacopoeia guidelines. The production of [¹¹C]KIn83 was validated according to GMP standards, encompassing automated synthesis and quality control measures. For the dosimetry assessment, two female cynomolgus monkeys underwent whole-body PET scans. The radioactivity values injected for [¹¹C]KIn83 were 150 MBq and 155 MBq, respectively, with an estimated radiation dose of 0.0047 mSv/MBq. Our findings pave the way for future clinical studies that investigate the potential of [¹¹C]KIn83 to measure α7-nAChR, aiding our understanding and possibly supporting diagnoses of different cognitive disorders. Full article

Pyrethroid insecticides have been extensively utilized in agriculture and residential areas in the United States. This study evaluated the exposure risk by age using available biomonitoring data. We analyzed pyrethroid metabolite concentrations in urine using the National Health and Nutrition Examination Survey (NHANES) data. Reverse dosimetry was conducted with a high-throughput model and a physiologically based kinetic (PBK) model integrated with a Bayesian inference framework. We further derived Benchmark Dose (BMD) values and systemic points of departure in rats using Bayesian BMD and PBK models. Margins of exposure (MOE) were calculated to assess neurotoxic risk based on estimated daily oral intake and dose metrics in plasma and brain. Results from both models indicated that young children have higher pyrethroid exposure compared to other age groups. All estimated risk values were within acceptable levels of acute neurotoxic effect. Additionally, MOEs calculated from oral doses were lower than those derived from internal doses, highlighting that traditional external exposure assessments tend to overestimate risk compared to advanced internal dose-based techniques. In conclusion, combining high-throughput and PBK approaches enhances the understanding of human health risks associated with pyrethroid exposures, demonstrating their potential for future applications in exposure tracking and health risk assessment. Full article

Objectives: Annexin-A1 is a 37 kDa phospholipid-binding protein which is concentrated in a truncated 34 kDa form (AnnA1) in caveolae on the tumor vascular endothelial cell surface with expression in many tumor types. PRISM developed the monoclonal mouse antibody mAnnA1 against AnnA1 for evaluation of AnnA1 as a potential target for imaging and therapy in oncology. mAnnA1 was humanized to make hAnnA1 for translation to clinical studies. Both PRISM-produced mAnnA1 and cGMP contractor-produced hAnnA1 were investigated using noninvasive PET/CT imaging, and dosimetry was evaluated to enable clinical translation of this strategy and to investigate in vivo behavior of hAnnA1. Methods: Antibodies mAnnA1 and hAnnA1 (PRISM “hAnnA1-P” or contractor generated “hAnnA1-C”) were conjugated with the chelator deferoxamine and evaluated for immunoreactivity with ELISA. Conjugated antibodies were radiolabeled with zirconium-89. Naïve mice, rats, and non-human primates (NHP) were injected with [⁸⁹Zr]mAnnA1 or [⁸⁹Zr]hAnnA1 and imaged with PET/CT up to 10 days post injection. After imaging, mice and rats were euthanized and organs were collected, weighed, and radioactivity was quantified using a gamma counter. Dosimetry in mice and NHPs were calculated using OLINDA. Results: [⁸⁹Zr]mAnnA1 showed similar biodistribution to other antibodies with slow clearance through the liver. Transition to [⁸⁹Zr]hAnnA1-C during the dosimetry studies revealed substantial uptake in the spleen (130 ± 48% ID/g at day 5 post injection in female BALB/c), which was not observed with [⁸⁹Zr]mAnnA1 (5.6 ± 1.7% ID/g at day 7 PI). Further studies in multiple strains of mice showed variable elevated splenic uptake of [⁸⁹Zr]hAnnA1-C across mouse strains, with the highest uptake observed in female BALB/c mice (118.4 ± 23.1% ID/g) and the lowest uptake observed in male CD1 mice (34.7 ± 10.2% ID/g). Additionally, splenic uptake of hAnnA1-C was observed in Fischer rats (2.8 ± 0.6% ID/organ) and NHPs (1.6 ± 0.6% ID/organ), although at lower levels than what was observed in BALB/c mice (8.8 ± 1.8% ID/organ). Dosimetry results showed similar values between estimates based on mouse and NHP data, with the largest difference seen in the spleen (5.2 vs. 2.6 mSv/MBq in females respectively). Sequencing of hAnnA1-C revealed a frameshift mutation in the antibody sequence introduced during cGMP manufacture. Restoration of the antibody sequence by PRISM returned the antibody distribution into alignment with mAnnA1. Conclusions: An aberration introduced during cGMP production of hAnnA1-C resulted in increased splenic uptake and alteration of the biodistribution in mice. PET imaging enabled quantitative detection of the immunogenic behavior of hAnnA1, which led to detection of the sequence error. Restoration of the sequence resulted in an antibody which was non-immunogenic to mice. Full article

Flight line personnel are constantly exposed to noise and jet fuel while working on flight lines. Studies suggest that jet fuel in combination with noise affects hearing loss more than noise exposure alone. This study examined the combined effects of jet fuel and noise exposure on the hearing of flight line personnel stationed at Japan Air Self-Defense Force Air Bases (Hamamatsu, Matsushima, Hyakuri, Yokota, and Iruma) and US Air Force Air Bases (Kadena and Misawa) in Japan. Samples were collected from all participants, 97 flightline-exposed and 71 control volunteers, to measure their individual noise levels with a personal sound level meter and volatile organic chemicals (VOCs) with a chemical sampling pump during a single shift. Blood samples were collected post shift. Urine samples (entire void) were collected prior to the shift (morning first void) and post shift. VOCs were measured in air, blood, and urine. An audiometric test battery, consisting of immittance measurements, audiograms, distortion product otoacoustic emissions, and the auditory brain response, was conducted after the shift to examine the hearing of participants. Total VOCs in personal air samples were in the ppb range for each group. Tinnitus and temporary hearing loss were reported in audiological histories but were also present in some controls. Noise levels on the flight line were greater than the action level for requiring hearing protection and exceeded exposure limits, but all exposed subjects reported wearing hearing protection. Audiometric tests identified significant differences and trends between flight line and control personnel, indicating the potential for hearing disorders. In spite of very low levels of VOC exposure and wearing hearing protection for noise, there is still the potential for hearing issues in flight line personnel. Full article

Photobiomodulation (PBM) therapy, a therapeutic approach utilizing low-level light, has garnered significant attention for its potential to modulate various biological processes. This study aimed at optimizing and investigating the effects of PBM on angiogenesis and mitochondrial metabolic activity. In vitro experiments using human umbilical vein endothelial cells (HUVECs) and vascular smooth muscle cells (VSMCs) were performed to assess PBM’s impacts on cell migration, proliferation, endogenous protoporphyrin IX production, mitochondrial membrane potential, Rhodamine 123 fluorescence lifetime, mitochondrial morphology, and oxygen consumption. Our findings demonstrated that the PBM approach significantly stimulates HUVECs and VSMCs, highlighting the importance of precise light dosimetry for optimal outcomes. Interestingly, our results indicate that in our conditions, the optimal radiometric and spectral parameters are similar for HUVECs and VSMCs for the different endpoints mentioned above. In conclusion, our study strongly suggests that PBM holds promise as a therapeutic intervention for conditions characterized by impaired angiogenesis, such as wound healing, ischemia, and cardiovascular disease. Further research is necessary to fully elucidate the underlying mechanisms and optimize the radiometric and spectral parameters for clinical applications. Full article

Background/Objectives: To evaluate an end-to-end pipeline for normo-fractionated prostate-only and whole-pelvic cancer treatments that requires minimal human input and generates a machine-deliverable plan as an output. Methods: In collaboration with TheraPanacea, a treatment planning pipeline was developed that takes as its input a planning CT with organs-at-risk (OARs) and planning target volume (PTV) contours, the targeted linac machine, and the prescription dose. The primary components are (i) dose prediction by a single deep learning model for both localizations and (ii) a direct aperture VMAT plan optimization that seeks to mimic the predicted dose. The deep learning model was trained on 238 cases, and a held-out set of 86 cases was used for model validation. An end-to-end clinical evaluation study was performed on another 40 cases (20 prostate-only, 20 whole-pelvic). First, a quantitative evaluation was performed based on dose–volume histogram (DVH) points and plan parameter metrics. Then, the plan deliverability was assessed via portal dosimetry using the global gamma index. Additionally, the reference clinical manual plans were compared with the automated plans in terms of monitor unit (MU) numbers and modulation complexity scores (MCSv). Results: The automated plans provided adequate treatment plans (or minor deviations) with respect to the dose constraints, and the quality of the plans was similar to the manual plans for both localizations. Moreover, the automated plans showed successful deliverability and passed the portal dose verification. Despite higher median total MUs, no statistically significant correlation was observed between any of the gamma criteria tested and the number of MUs or MCSv. Conclusions: This study shows the feasibility of a deep learning-based fully automated treatment planning pipeline that generates high-quality plans that are competitive with manually made plans and are clinically approved in terms of dosimetry and machine deliverability. Full article

In this work an innovative approach was developed to address a significant challenge in the field of radiation dosimetry: the accurate measurement of spatial dose distributions using Fricke gel dosimeters. Hydrogels are widely used in radiation dosimetry due to their ability to simulate the tissue-equivalent properties of human tissue, making them ideal for measuring and mapping radiation dose distributions. Among the various gel dosimeters, Fricke gels exploit the radiation-induced oxidation of ferrous ions to ferric ions and are particularly notable due to their sensitivity. The concentration of ferric ions can be measured using various techniques, including magnetic resonance imaging (MRI) or spectrophotometry. While Fricke gels offer several advantages, a significant hurdle to their widespread application is the diffusion of ferric ions within the gel matrix. This phenomenon leads to a blurring of the dose distribution over time, compromising the accuracy of dose measurements. To mitigate the issue of ferric ion diffusion, researchers have explored various strategies such as the incorporation of additives or modification of the gel composition to either reduce the mobility of ferric ions or stabilize the gel matrix. The computational method proposed leverages the power of artificial intelligence, particularly deep learning, to mitigate the effects of ferric ion diffusion that can compromise measurement precision. By employing Physics Informed Neural Networks (PINNs), the method introduces a novel way to apply physical laws directly within the learning process, optimizing the network to adhere to the principles governing ion diffusion. This is particularly advantageous for solving the partial differential equations that describe the diffusion process in 2D and 3D. By inputting the spatial distribution of ferric ions at a given time, along with boundary conditions and the diffusion coefficient, the model can backtrack to accurately reconstruct the original ion distribution. This capability is crucial for enhancing the fidelity of 3D spatial dose measurements, ensuring that the data reflect the true dose distribution without the artifacts introduced by ion migration. Here, multidimensional models able to handle 2D and 3D data were developed and tested against dose distributions numerically evolved in time from 20 to 100 h. The results in terms of various metrics show a significant agreement in both 2D and 3D dose distributions. In particular, the mean square error of the prediction spans the range $1\times {10}^{-6}$–$1\times {10}^{-4}$, while the gamma analysis results in a 90–100% passing rate with 3%/2 mm, depending on the elapsed time, the type of distribution modeled and the dimensionality. This method could expand the applicability of Fricke gel dosimeters to a wider range of measurement tasks, from simple planar dose assessments to intricate volumetric analyses. The proposed technique holds great promise for overcoming the limitations imposed by ion diffusion in Fricke gel dosimeters. Full article

In the last decade, geopolitical instability across the globe has increased the risk of a large-scale radiological event, when radiation biomarkers would be needed for an effective triage of an irradiated population. Ionizing radiation elicits a complex response in the proteome, genome, and metabolome and hence can be leveraged as rapid and sensitive indicators of irradiation-induced damage. We analyzed the plasma of total-body irradiated (TBI) leukemia patients (n = 24) and nonhuman primates (NHPs; n = 10) before and 24 h after irradiation, and we performed a global metabolomic study aiming to provide plasma metabolites as candidate radiation biomarkers for biological dosimetry. Peripheral blood samples were collected according to the appropriate ethical approvals, and metabolites were extracted and analyzed by liquid chromatography mass spectrometry. We identified an array of metabolites significantly altered by irradiation, including bilirubin, cholesterol, and 18-hydroxycorticosterone, which were detected in leukemia patients and NHPs. Pathway analysis showed overlapping perturbations in steroidogenesis, porphyrin metabolism, and steroid hormone biosynthesis and metabolism. Additionally, we observed dysregulation in bile acid biosynthesis and tyrosine metabolism in the TBI patient cohort. This investigation is, to our best knowledge, among the first to provide valuable insights into a comparison between human and NHP irradiation models. The findings from this study could be leveraged for translational biological dosimetry. Full article

The calculation of effective doses is crucial in many medical and radiation fields in order to ensure safety and compliance with regulatory limits. Traditionally, Monte Carlo codes using detailed human body computational phantoms have been used for such calculations. Monte Carlo dose calculations can be time-consuming and require expertise in different processes when building the computational phantom and dose calculations. This study employs various machine learning (ML) algorithms to predict the organ doses and effective dose conversion coefficients (DCCs) from different anthropomorphic phantoms. A comprehensive data set comprising neutron energy bins, organ labels, masses, and densities is compiled from Monte Carlo studies, and it is used to train and evaluate the supervised ML models. This study includes a broad range of phantoms, including those from the International Commission on Radiation Protection (ICRP-110, ICRP-116 phantom), the Visible-Human Project (VIP-man phantom), and the Medical Internal Radiation Dose Committee (MIRD-Phantom), with row data prepared using numerical data and organ categorical labeled data. Extreme gradient boosting (XGB), gradient boosting (GB), and the random forest-based Extra Trees regressor are employed to assess the performance of the ML models against published ICRP neutron DCC values using the mean square error, mean absolute error, and R² metrics. The results demonstrate that the ML predictions significantly vary in lower energy ranges and vary less in higher neutron energy ranges while showing good agreement with ICRP values at mid-range energies. Moreover, the categorical data models align closely with the reference doses, suggesting the potential of ML in predicting effective doses for custom phantoms based on regional populations, such as the Saudi voxel-based model. This study paves the way for efficient dose prediction using ML, particularly in scenarios requiring rapid results without extensive computational resources or expertise. The findings also indicate potential improvements in data representation and the inclusion of larger data sets to refine model accuracy and prevent overfitting. Thus, ML methods can serve as valuable techniques for the continued development of personalized dosimetry. Full article

Background: Cancer-associated fibroblasts have become a new target for therapy. Fibroblasts present within malignancies express the fibroblast activation protein (FAP). Inhibitors to FAP (FAPI) are small molecules recently developed as a theranostic agents for imaging and radiotherapy. All currently used FAPI rely on a linker–chelator complex attached to the ‘inhibitor’. We describe a new automated method of the direct attachment of the radioisotope to the inhibitor, resulting in a >50% MW reduction with the hope of an improved tumor-to-background ratio and tumor uptake. Methods: [¹⁸F]FluroFAPI was developed from a Sn precursor. This allowed for subsequent automated radioflourination. We obtained the biodistribution of [¹⁸F]FluroFAPI in rats, performed estimated human radiation dosimetry, and performed a 100× expected single dose toxicology analysis for eventual first-in-human experiments. Results: The synthesis of the Sn precursor for FluorFAPI and the automated synthesis of [¹⁸F]FluroFAPI was demonstrated. [¹⁸F]FluroFAPI had favorable estimated human radiation dosimetry, and demonstrated no adverse effects when injected at a dose of 100× that planned for [¹⁸F]FluroFAPI. Conclusions: With the successful development of an automated synthesis of [¹⁸F]FluroFAPI, first-in-human testing can be planned with the hope of an improved tumor-to-background performance compared to other FAPI agents. Full article