Joint EURADOS-EANM initiative for an advanced computational framework for the assessment of external dose rates from nuclear medicine patients.

BACKGROUND: In order to ensure adequate radiation protection of critical groups such as staff, caregivers and the general public coming into proximity of nuclear medicine (NM) patients, it is necessary to consider the impact of the radiation emitted by the patients during their stay at the hospital or after leaving the hospital. Current risk assessments are based on ambient dose rate measurements in a single position at a specified distance from the patient and carried out at several time points after administration of the radiopharmaceutical to estimate the whole-body retention. The limitations of such an approach are addressed in this study by developing and validating a more advanced computational dosimetry approach using Monte Carlo (MC) simulations in combination with flexible and realistic computational phantoms and time activity distribution curves from reference biokinetic models. RESULTS: Measurements of the ambient dose rate equivalent H*(10) at 1 m from the NM patient have been successfully compared against MC simulations with 5 different codes using the ICRP adult reference computational voxel phantoms, for typical clinical procedures with 99mTc-HDP/MDP, 18FDG and Na131I. All measurement data fall in the 95% confidence intervals, determined for the average simulated results. Moreover, the different MC codes (MCNP-X, PHITS, GATE, GEANT4, TRIPOLI-4®) have been compared for a more realistic scenario where the effective dose rate E of an exposed individual was determined in positions facing and aside the patient model at 30 cm, 50 cm and 100 cm. The variation between codes was lower than 8% for all the radiopharmaceuticals at 1 m, and varied from 5 to 16% for the face-to face and side-by-side configuration at 30 cm and 50 cm. A sensitivity study on the influence of patient model morphology demonstrated that the relative standard deviation of H*(10) at 1 m for the range of included patient models remained under 16% for time points up to 120 min post administration. CONCLUSIONS: The validated computational approach will be further used for the evaluation of effective dose rates per unit administered activity for a variety of close-contact configurations and a range of radiopharmaceuticals as part of risk assessment studies. Together with the choice of appropriate dose constraints this would facilitate the setting of release criteria and patient restrictions.

Extremity exposure of nuclear medicine workers: results from an EANM and EURADOS survey.

BACKGROUND: Extremity exposure during the handling of unsealed radioactive sources is a matter of concern for nuclear medicine workers. Next to 99mTc and 18F, other radiopharmaceuticals have seen an increase in their use over the last decade. However, limited information on their impact on extremity dose is available. This study aimed to gain insight into the status of extremity exposure and dose monitoring in Europe. METHODS: A survey was conducted at the end of 2020 among the European Association of Nuclear Medicine community. It contained 24 questions considering department characteristics, worker tasks, dosimeter use, typical worker extremity dose, department workload for selected radionuclides (99mTc, 18F, 68Ga, 177Lu, 90Y) and protective measures. RESULTS: A total of 106 replies were received, 92% of which were from Europe. About half of the respondents were from academic hospitals. Ninety-nine departments implement extremity dose monitoring for a total of 1335 workers. Most workers (95%) wear a ring dosimeter, generally on the non-dominant hand, and 44% on the index finger. Monthly doses were generally low (median values at different ring position: 0.4-1.8 mSv), although higher doses were reported (20.8-38.8 mSv). About 1/3 of workers performed the full task range (preparation, dispensing, and administration). Administration is associated with significantly lower extremity doses. Interestingly, no correlation between department workload and collective dose was found. The adoption of vial and syringe shielding, as well as distance tools, was common. The workers dispensing 99mTc without syringe shielding or PET nuclides without automated system received a significantly higher dose. Handling 68Ga, 177Lu and 90Y did not appear to have an impact on the reported doses. CONCLUSIONS: Protective measures play a significant role in lowering extremity doses, while department workload and more recently introduced radionuclides seem not to be major dose determinants.

Main challenges in radiation protection with emerging radionuclide therapies.

The recent development of radionuclide therapy and radioligand therapy has raised a call for achieving the highest quality standards, for either radiopharmacy or radiation protection. Novel radionuclides are now being used, either under the form of in-house production radiopharmaceuticals or available from companies. Over the last 20 years, they include radiolabeled microspheres for selective internal radiotherapy (SIRT), the introduction of the first commercially available alpha emitter radiopharmaceutical, 223Ra, and the radiosynoviorthesis which is highly variable across Europe. More important is the development of radioligand therapy, often called theranostics. In this concept, a diagnostic radiopharmaceutical can determine the chance of success of a therapeutic one. Typically, diagnostic radiopharmaceuticals for positron emission tomography, are labeled with 18F or 68Ga, such as the PSMA ligands or somatostatin analogs, and the therapeutic radiopharmaceutical is labeled with 177Lu. This has revolutionized the world of Nuclear Medicine, but also all concepts that shall be applied to properly apply quality assurance and radiation protection in the field. This article will follow the example of 131I as the main used radionuclide for therapy during the last 80 years. Proposals can be general, and in parallel expert's articles will give specific guidance on issues with particular radionuclides, i.e., alpha emitters and 177Lu. This article will also give insight in the radiation protection issues related to the use of microspheres radiolabeled with either 90Y or 166Ho.

Nanocarriers Based on Gold Nanoparticles for Epigallocatechin Gallate Delivery in Cancer Cells.

Gold nanoparticles (AuNPs) are inorganic and biocompatible nanovehicles capable of conjugating biomolecules to enhance their efficacy in cancer treatment. The high and reactive surface area provides good advantages for conjugating active compounds. Two approaches were developed in this work to improve the Epigallocatechin-3-gallate (EGCG) antioxidant efficacy. AuNPs were synthesized by reducing gold salt with chitosan. One other nanosystem was developed by functionalizing AuNPs with cysteamine using the Turkevitch method. The physico-chemical characterization of EGCG conjugated in the two nanosystems-based gold nanoparticles was achieved. The in vitro toxic effect induced by the nanoconjugates was evaluated in pancreatic cancer cells, showing that encapsulated EGCG keeps its antioxidant activity and decreasing the BxPC3 cell growth. A significant cell growth inhibition was observed in 50% with EGCG concentrations in the range of 2.2 and 3.7 µM in EGCG-ChAuNPs and EGCG-Cyst-AuNPs nanoconjugates, respectively. The EGCG alone had to be present at 23 µM to induce the same cytotoxicity response. Caspase-3 activity assay demonstrated that the conjugation of EGCG induces an enhancement of BxPC3 apoptosis compared with EGCG alone. In conclusion, AuNPs complexes can be used as delivery carriers to increase EGCG antioxidant activity in cancer tissues.

Review of extremity dosimetry in nuclear medicine.

The exposure of the fingers is one of the major radiation protection concerns in nuclear medicine (NM). The purpose of this paper is to provide an overview of the exposure, dosimetry and protection of the extremities in NM. A wide range of reported finger doses were found in the literature. Historically, the highest finger doses are found at the fingertip in the preparation and dispensing of18F for diagnostic procedures and90Y for therapeutic procedures. Doses can be significantly reduced by following recommendations on source shielding, increasing distance and training. Additionally, important trends contributing to a lower dose to the fingers are the use of automated procedures (especially for positron emission tomography (PET)) and the use of prefilled syringes. On the other hand, the workload of PET procedures has substantially increased during the last ten years. In many cases, the accuracy of dose assessment is limited by the location of the dosimeter at the base of the finger and the maximum dose at the fingertip is underestimated (typical dose ratios between 1.4 and 7). It should also be noted that not all dosimeters are sensitive to low-energy beta particles and there is a risk for underestimation of the finger dose when the detector or its filter is too thick. While substantial information has been published on the most common procedures (using99mTc,18F and90Y), less information is available for more recent applications, such as the use of68Ga for PET imaging. Also, there is a need for continuous awareness with respect to contamination of the fingers, as this factor can contribute substantially to the finger dose.

CytoRADx: A High-Throughput, Standardized Biodosimetry Diagnostic System Based on the Cytokinesis-Block Micronucleus Assay.

In a large-scale catastrophe, such as a nuclear detonation in a major city, it will be crucial to accurately diagnose large numbers of people to direct scarce medical resources to those in greatest need. Currently no FDA-cleared tests are available to diagnose radiation exposures, which can lead to complex, life-threatening injuries. To address this gap, we have achieved substantial advancements in radiation biodosimetry through refinement and adaptation of the cytokinesis-block micronucleus (CBMN) assay as a high throughput, quantitative diagnostic test. The classical CBMN approach, which quantifies micronuclei (MN) resulting from DNA damage, suffers from considerable time and expert labor requirements, in addition to a lack of universal methodology across laboratories. We have developed the CytoRADx™ System to address these drawbacks by implementing a standardized reagent kit, optimized assay protocol, fully automated microscopy and image analysis, and integrated dose prediction. These enhancements allow the CytoRADx System to obtain high-throughput, standardized results without specialized labor or laboratory-specific calibration curves. The CytoRADx System has been optimized for use with both humans and non-human primates (NHP) to quantify radiation dose-dependent formation of micronuclei in lymphocytes, observed using whole blood samples. Cell nuclei and resulting MN are fluorescently stained and preserved on durable microscope slides using materials provided in the kit. Up to 1,000 slides per day are subsequently scanned using the commercially based RADxScan™ Imager with customized software, which automatically quantifies the cellular features and calculates the radiation dose. Using less than 1 mL of blood, irradiated ex vivo, our system has demonstrated accurate and precise measurement of exposures from 0 to 8 Gy (90% of results within 1 Gy of delivered dose). These results were obtained from 636 human samples (24 distinct donors) and 445 NHP samples (30 distinct subjects). The system demonstrated comparable results during in vivo studies, including an investigation of 43 NHPs receiving single-dose total-body irradiation. System performance is repeatable across laboratories, operators, and instruments. Results are also statistically similar across diverse populations, considering various demographics, common medications, medical conditions, and acute injuries associated with radiological disasters. Dose calculations are stable over time as well, providing reproducible results for at least 28 days postirradiation, and for blood specimens collected and stored at room temperature for at least 72 h. The CytoRADx System provides significant advancements in the field of biodosimetry that will enable accurate diagnoses across diverse populations in large-scale emergency scenarios. In addition, our technological enhancements to the well-established CBMN assay provide a pathway for future diagnostic applications, such as toxicology and oncology.

Open-label placebo for chronic low back pain: a 5-year follow-up.

ABSTRACT: Long-term follow-up of patients treated with open-label placebo (OLP) are nonexistent. In this article, we report a 5-year follow-up of a 3-week OLP randomized controlled trial (RCT) in patients with chronic low back pain. We recontacted the participants of original RCT and reassessed their pain, disability, and use of pain medication. We obtained follow-up data from 55 participants (82% of those who took OLP during the parent RCT), with a mean elapsed time between the end of the 3 weeks placebo trial and the follow-up interview of 55 months (SD = 7.85). We found significant reductions in both pain and disability between the baseline assessment immediately before the 3 weeks trial with placebo pills and the original trial endpoint (P < 0.00001 for the 2 primary outcomes of pain and disability). At the 5-year follow-up, we found no significant differences in either outcome between original trial endpoint and follow-up. Improvements persisted after 5 years and were accompanied by substantial reductions compared with baseline in the use of pain medication (from 87% to 38%), comprising analgesics (from 80% to 31%), antidepressants (from 24% to 11%), and benzodiazepines (from 15% to 5%). By contrast, the use of alternative approaches to pain management increased (from 18% to 29%). Although the reduction in pain and medication is comparable with the improvements that occurred in the original study, a major limitation of this long-term follow-up is the absence of controls for spontaneous improvement and new cointerventions. Nonetheless, our data suggest that reductions in pain and disability after OLP may be long lasting.

Cytogenetically-based biodosimetry after high doses of radiation.

Dosimetry is an important tool for triage and treatment planning following any radiation exposure accident, and biological dosimetry, which estimates exposure dose using a biological parameter, is a practical means of determining the specific dose an individual receives. The cytokinesis-blocked micronucleus assay (CBMN) is an established biodosimetric tool to measure chromosomal damage in mitogen-stimulated human lymphocytes. The CBMN method is especially valuable for biodosimetry in triage situations thanks to simplicity in scoring and adaptability to high-throughput automated sample processing systems. While this technique produces dose-response data which fit very well to a linear-quadratic model for exposures to low linear energy transfer (LET) radiation and for doses up for 5 Gy, limitations to the accuracy of this method arise at larger doses. Accuracy at higher doses is limited by the number of cells reaching mitosis. Whereas it would be expected that the yield of micronuclei increases with the dose, in many experiments it has been shown to actually decrease when normalized over the total number of cells. This variation from a monotonically increasing dose response poses a limitation for retrospective dose reconstruction. In this study we modified the standard CBMN assay to increase its accuracy following exposures to higher doses of photons or a mixed neutron-photon beam. The assay is modified either through inhibitions of the G2/M and spindle checkpoints with the addition of caffeine and/or ZM447439 (an Aurora kinase inhibitor), respectively to the blood cultures at select times during the assay. Our results showed that caffeine addition improved assay performance for photon up to 10 Gy. This was achieved by extending the assay time from the typical 70 h to just 74 h. Compared to micronuclei yields without inhibitors, addition of caffeine and ZM447439 resulted in improved accuracy in the detection of micronuclei yields up to 10 Gy from photons and 4 Gy of mixed neutrons-photons. When the dose-effect curves were fitted to take into account the turnover phenomenon observed at higher doses, best fitting was achieved when the combination of both inhibitors was used. These techniques permit reliable dose reconstruction after high doses of radiation with a method that can be adapted to high-throughput automated sample processing systems.

Hyperpolarized MRI Visualizes Warburg Effects and Predicts Treatment Response to mTOR Inhibitors in Patient-Derived ccRCC Xenograft Models.

The ever-changing tumor microenvironment constantly challenges individual cancer cells to balance supply and demand, presenting tumor vulnerabilities and therapeutic opportunities. Everolimus and temsirolimus are inhibitors of mTOR (mTORi) approved for treating metastatic renal cell carcinoma (mRCC). However, treatment outcome varies greatly among patients. Accordingly, administration of mTORi in mRCC is diminishing, which could potentially result in missing timely delivery of effective treatment for select patients. Here, we implemented a clinically applicable, integrated platform encompassing a single dose of [1-13C] pyruvate to visualize the in vivo effect of mTORi on the conversion of pyruvate to lactate using hyperpolarized MRI. A striking difference that predicts treatment benefit was demonstrated using two preclinical models derived from patients with clear cell RCC (ccRCC) who exhibited primary resistance to VEGFRi and quickly succumbed to their diseases within 6 months after the diagnosis of metastasis without receiving mTORi. Our findings suggest that hyperpolarized MRI could be further developed to personalize kidney cancer treatment. SIGNIFICANCE: These findings demonstrate hyperpolarized [1-13C]pyruvate MRI as a tool for accurately assessing the clinical success of mTOR inhibition in patients with ccRCC.

High-Throughput Indirect Quantitation of 13C Enriched Metabolites Using 1H NMR.

Nuclear magnetic resonance (NMR) spectroscopy is widely used in metabolomics to perform quantitative profiling of low-molecular weight compounds from biological specimens. The measurement of endogenous metabolites using NMR has proven to be a powerful tool to identify new metabolic biomarkers in physiological and pathological conditions, and to study and evaluate treatment efficiency. In this study we present a rapid approach to indirectly quantify 13C enriched molecules using one-dimensional (1D) 1H NMR. We demonstrate this approach using isotopically labeled [1,6-13C]glucose and in four different cell lines. We confirm the applicability of this approach for treatment follow-up, utilizing a renal cancer cell line with rapamycin as a tool compound to study changes in metabolic profiles. Finally, we validate the applicability of this method to study metabolic biomarkers from ex vivo tumor extracts, after infusion, using isotopically enriched glucose. Given the high throughput and increased sensitivity of direct-detect 1H NMR, this analytical approach provides an avenue for simple and rapid metabolic analysis of biological samples including blood, urine, and biopsies.

Open-label placebo treatment in chronic low back pain: a randomized controlled trial.

This randomized controlled trial was performed to investigate whether placebo effects in chronic low back pain could be harnessed ethically by adding open-label placebo (OLP) treatment to treatment as usual (TAU) for 3 weeks. Pain severity was assessed on three 0- to 10-point Numeric Rating Scales, scoring maximum pain, minimum pain, and usual pain, and a composite, primary outcome, total pain score. Our other primary outcome was back-related dysfunction, assessed on the Roland-Morris Disability Questionnaire. In an exploratory follow-up, participants on TAU received placebo pills for 3 additional weeks. We randomized 97 adults reporting persistent low back pain for more than 3 months' duration and diagnosed by a board-certified pain specialist. Eighty-three adults completed the trial. Compared to TAU, OLP elicited greater pain reduction on each of the three 0- to 10-point Numeric Rating Scales and on the 0- to 10-point composite pain scale (P < 0.001), with moderate to large effect sizes. Pain reduction on the composite Numeric Rating Scales was 1.5 (95% confidence interval: 1.0-2.0) in the OLP group and 0.2 (-0.3 to 0.8) in the TAU group. Open-label placebo treatment also reduced disability compared to TAU (P < 0.001), with a large effect size. Improvement in disability scores was 2.9 (1.7-4.0) in the OLP group and 0.0 (-1.1 to 1.2) in the TAU group. After being switched to OLP, the TAU group showed significant reductions in both pain (1.5, 0.8-2.3) and disability (3.4, 2.2-4.5). Our findings suggest that OLP pills presented in a positive context may be helpful in chronic low back pain.

The role of molecular imaging in modern drug development.

Drug development represents a highly complex, inefficient and costly process. Over the past decade, the widespread use of nuclear imaging, owing to its functional and molecular nature, has proven to be a determinant in improving the efficiency in selecting the candidate drugs that should either be abandoned or moved forward into clinical trials. This helps not only with the development of safer and effective drugs but also with the shortening of time-to-market. The modern concept and future trends concerning molecular imaging will assumedly be hybrid or multimodality imaging, including combinations between high sensitivity and functional (molecular) modalities with high spatial resolution and morphological techniques.

Preclinical imaging: an essential ally in modern biosciences.

Translational research is changing the practice of modern medicine and the way in which health problems are approached and solved. The use of small-animal models in basic and preclinical sciences is a major keystone for these kinds of research and development strategies, representing a bridge between discoveries at the molecular level and clinical implementation in diagnostics and/or therapeutics. The development of high-resolution in vivo imaging technologies provides a unique opportunity for studying disease in real time, in a quantitative way, at the molecular level, along with the ability to repeatedly and non-invasively monitor disease progression or response to treatment. The greatest advantages of preclinical imaging techniques include the reduction of biological variability and the opportunity to acquire, in continuity, an impressive amount of unique information (without interfering with the biological process under study) in distinct forms, repeated or modulated as needed, along with the substantial reduction in the number of animals required for a particular study, fully complying with 3R (Replacement, Reduction and Refinement) policies. The most suitable modalities for small-animal in vivo imaging applications are based on nuclear medicine techniques (essentially, positron emission tomography [PET] and single photon emission computed tomography [SPECT]), optical imaging (OI), computed tomography (CT), magnetic resonance imaging (MRI), magnetic resonance spectroscopy imaging (MRSI), and ultrasound. Each modality has intrinsic advantages and limitations. More recently, aiming to overcome the inherent limitations of each imaging modality, multimodality devices designed to provide complementary information upon the pathophysiological process under study have gained popularity. The combination of high-resolution modalities, like micro-CT or micro-MRI, with highly sensitive techniques providing functional information, such as micro-PET or micro-SPECT, will continue to broaden the horizons of research in such key areas as infection, oncology, cardiology, and neurology, contributing not only to the understanding of the underlying mechanisms of disease, but also providing efficient and unique tools for evaluating new chemical entities and candidate drugs. The added value of small-animal imaging techniques has driven their increasing use by pharmaceutical companies, contract research organizations, and research institutions.