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Journal of Nuclear Medicine Technology Mar 2022For CE credit, you can access the test for this article, as well as additional CE tests, online at https://www.snmmilearningcenter.org Complete the test online no...
For CE credit, you can access the test for this article, as well as additional CE tests, online at https://www.snmmilearningcenter.org Complete the test online no later than March 2025. Your online test will be scored immediately. You may make 3 attempts to pass the test and must answer 75% of the questions correctly to receive Continuing Education Hour (CEH) credit. Credit amounts can be found in the SNMMI Learning Center Activity. SNMMI members will have their CEH credit added to their VOICE transcript automatically; nonmembers will be able to print out a CE certificate upon successfully completing the test. The online test is free to SNMMI members; nonmembers must pay $15.00 by credit card when logging onto the website to take the test.α-emitting radionuclides provide an effective means of delivering large radiation doses to targeted treatment locations. RaCl is Food and Drug Administration-approved for treatment of metastatic castration-resistant prostate cancer, and Ac (Ac-lintuzumab) radiolabeled antibodies have been shown to be beneficial for patients with acute myeloid leukemia. In recent years, there has been increasing use of α-emitters in theranostic agents with both small- and large-molecule constructs. The proper precautionary means for their use and surveying documentation of these isotopes in a clinical setting are an essential accompaniment to these treatments. Patient treatment data collected over a 3-y period, as well as regulatory requirements and safety practices, are described. Commonly used radiation instruments were evaluated for their ability to identify potential radioactive material spills and contamination events during a clinical administration of Ac. These instruments were placed at 0.32 cm from a 1.0-cm Ac disk source for measurement purposes. Radiation background values, efficiencies, and minimal detectable activities were measured and calculated for each type of detector. The median external measured dose rate from RaCl patients ( = 611) was 2.5 μSv h on contact and 0.2 μSv h at 1 m immediately after administration. Similarly, Ac-lintuzumab ( = 19) patients had median external dose rates of 2.0 μSv h on contact and 0.3 μSv h at 1 m. For the measurement of Ac samples, a liquid scintillation counter was found to have the highest overall efficiency (97%), whereas a ZnS α-probe offered the lowest minimal detectable activity at 3 counts per minute. In this article, we report data from 630 patients who were undergoing treatment with the α-emitting isotopes Ra and Ac. Although α-emitters have the ability to deliver a higher internal radiation dose to the exposed tissues than can other unsealed radionuclides, they typically present minimal concerns about external dose rate. Additionally, α-radiation can be efficiently detected with appropriate radiation instrumentation, such as a liquid scintillation counter or ZnS probe, which should be prioritized when surveying for spills of α-emitters.
Topics: Humans; Male; Prostatic Neoplasms; Radioisotopes
PubMed: 34750237
DOI: 10.2967/jnmt.121.262294 -
Current Oncology Reports Nov 2023[Lu]Lu-PSMA-617 is a radiopharmaceutical that emits beta-minus radiation and targets prostate-specific membrane antigen (PSMA)-positive prostate cancer. Despite its... (Review)
Review
PURPOSE OF REVIEW
[Lu]Lu-PSMA-617 is a radiopharmaceutical that emits beta-minus radiation and targets prostate-specific membrane antigen (PSMA)-positive prostate cancer. Despite its clinical success, there are still patients not showing sufficient response rates. This review compiles latest studies aiming at therapy improvement in [Lu]Lu-PSMA-617-naïve and -resistant patients by alternative or combination treatments.
RECENT FINDINGS
A variety of agents to combine with [Lu]Lu-PSMA-617 are currently under investigation including alpha radiation-emitting pharmaceuticals, radiosensitizers, taxane chemotherapeutics, androgen receptor pathway inhibitors, immune checkpoint inhibitors, and external beam radiation. Actinium-225 (Ac)-labeled PSMA-targeting inhibitors are the most studied pharmaceuticals for combination therapy or as an alternative for treatment after progression under [Lu]Lu-PSMA-617 therapy. Alpha emitters seem to have a potential of achieving a response to PSMA-targeting radionuclide therapy in both initial non-responders or responders to [Lu]Lu-PSMA-617 later developing treatment resistance. Emerging evidence for immunostimulatory effects of radiopharmaceuticals and first prospective studies support the combination of [Lu]Lu-PSMA-617 and immune checkpoint inhibition for late-stage prostate cancer.
Topics: Male; Humans; Radioisotopes; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Radiopharmaceuticals; Pharmaceutical Preparations; Treatment Outcome
PubMed: 37861915
DOI: 10.1007/s11912-023-01458-6 -
Frontiers in Cell and Developmental... 2022Exposure to environmental ionizing radiation is prevalent, with greatest lifetime doses typically from high Linear Energy Transfer (high-LET) alpha particles the... (Review)
Review
Exposure to environmental ionizing radiation is prevalent, with greatest lifetime doses typically from high Linear Energy Transfer (high-LET) alpha particles the radioactive decay of radon gas in indoor air. Particle radiation is highly genotoxic, inducing DNA damage including oxidative base lesions and DNA double strand breaks. Due to the ionization density of high-LET radiation, the consequent damage is highly clustered wherein ≥2 distinct DNA lesions occur within 1-2 helical turns of one another. These multiply-damaged sites are difficult for eukaryotic cells to resolve either quickly or accurately, resulting in the persistence of DNA damage and/or the accumulation of mutations at a greater rate per absorbed dose, relative to lower LET radiation types. The proximity of the same and different types of DNA lesions to one another is challenging for DNA repair processes, with diverse pathways often confounding or interplaying with one another in complex ways. In this context, understanding the state of the higher order chromatin compaction and arrangements is essential, as it influences the density of damage produced by high-LET radiation and regulates the recruitment and activity of DNA repair factors. This review will summarize the latest research exploring the processes by which clustered DNA damage sites are induced, detected, and repaired in the context of chromatin.
PubMed: 35912116
DOI: 10.3389/fcell.2022.910440 -
Journal of Medical Imaging and... Dec 2019Despite ongoing efforts with new chemotherapeutics, small-molecule inhibitors and biologics, patients with distant metastases continue to have a grim prognosis.... (Review)
Review
Despite ongoing efforts with new chemotherapeutics, small-molecule inhibitors and biologics, patients with distant metastases continue to have a grim prognosis. Radiopharmaceutical therapy (RPT) with alpha-particle-emitting radionuclides has shown efficacy against widespread disease. Alpha-particle emitters are particularly effective because their short range and high energy deposit density lead to complex and largely irreparable DNA double-strand breaks. The high potency against tumors can also lead to high toxicity. Unlike most systemic treatment of cancer, the biodistribution of RPT agents may be imaged in humans using nuclear medicine imaging modalities. In this context, dosimetry provides a precision medicine approach to implementing RPT with alpha-emitters.
Topics: Alpha Particles; Humans; Neoplasms; Radiation Injuries; Radiometry; Radiopharmaceuticals; Radiotherapy; Radiotherapy Dosage
PubMed: 31537496
DOI: 10.1016/j.jmir.2019.07.007 -
Seminars in Nuclear Medicine Mar 2020Neuroendocrine tumors (NET) are a heterogeneous group of neoplasms, arising from cells of the endocrine system, with various clinical behaviors. Although these neoplasms... (Review)
Review
Neuroendocrine tumors (NET) are a heterogeneous group of neoplasms, arising from cells of the endocrine system, with various clinical behaviors. Although these neoplasms are considered rare, a significant increase in the incidence and detectability of NET has been noted in many epidemiological studies in recent years. Among the various therapeutic options, peptide receptor radionuclide therapy (PRRT), using somatostatine has been shown to be highly effective and a well-tolerated therapy, improving survival parameters. The current use of radionuclides for PRRT is β-emitters. Due to hypoxia cancer tissue could be resistant for β-emitters. Quite long penetration range had a significant impact on side effects. α-particles with higher energy and shorter penetration range in comparison to β-particles, have distinct advantages for use in targeted therapy. The clinical experience with somatostatine based targeted α therapy (TAT) in NET showed very promising results even in patienicts refractory to treatment with β-emitters. This article summarizes current developments in preclinical and clinical investigation on TAT in NET.
Topics: Alpha Particles; Animals; Clinical Trials as Topic; Humans; Molecular Targeted Therapy; Neuroendocrine Tumors; Treatment Outcome
PubMed: 32172802
DOI: 10.1053/j.semnuclmed.2019.11.003 -
Theranostics 2020This is the initial report of an α-based pre-targeted radioimmunotherapy (PRIT) using Ac and its theranostic pair, In. We call our novel tumor-targeting DOTA-hapten...
This is the initial report of an α-based pre-targeted radioimmunotherapy (PRIT) using Ac and its theranostic pair, In. We call our novel tumor-targeting DOTA-hapten PRIT system "proteus-DOTA" or "Pr." Herein we report the first results of radiochemistry development, radiopharmacology, and stoichiometry of tumor antigen binding, including the role of specific activity, anti-tumor efficacy, and normal tissue toxicity with the Pr-PRIT approach (as α-DOTA-PRIT). A series of α-DOTA-PRIT therapy studies were performed in three solid human cancer xenograft models of colorectal cancer (GPA33), breast cancer (HER2), and neuroblastoma (GD2), including evaluation of chronic toxicity at ~20 weeks of select survivors. Preliminary biodistribution experiments in SW1222 tumor-bearing mice revealed that Ac could not be efficiently pretargeted with current DOTA-Bn hapten utilized for Lu or Y, leading to poor tumor uptake . Therefore, we synthesized Pr consisting of an empty DOTA-chelate for Ac, tethered via a short polyethylene glycol linker to a lutetium-complexed DOTA for picomolar anti-DOTA chelate single-chain variable fragment (scFv) binding. Pr was radiolabeled with Ac and its imaging surrogate, In. studies verified anti-DOTA scFv recognition of [Ac]Pr, and biodistribution and clearance studies were performed to evaluate hapten suitability and targeting efficiency. Intravenously (i.v.) administered Ac- or In-radiolabeled Pr in mice showed rapid renal clearance and minimal normal tissue retention. pretargeting studies show high tumor accumulation of Pr (16.71 ± 5.11 %IA/g or 13.19 ± 3.88 %IA/g at 24 h p.i. for [Ac]Pr and [In]Pr, respectively) and relatively low uptake in normal tissues (all average ≤ 1.4 %IA/g at 24 h p.i.). Maximum tolerated dose (MTD) was not reached for either [Ac]Pr alone or pretargeted [Ac]Pr at administered activities up to 296 kBq/mouse. Single-cycle treatment consisting of α-DOTA-PRIT with either huA33-C825 bispecific anti-tumor/anti-DOTA-hapten antibody (BsAb), anti-HER2-C825 BsAb, or hu3F8-C825 BsAb for targeting GPA33, HER2, or GD2, respectively, was highly effective. In the GPA33 model, no complete responses (CRs) were observed but prolonged overall survival of treated animals was 42 d for α-DOTA-PRIT vs. 25 d for [Ac]Pr only ( < 0.0001); for GD2, CRs (7/7, 100%) and histologic cures (4/7, 57%); and for HER2, CRs (7/19, 37%) and histologic cures (10/19, 56%) with no acute or chronic toxicity. [Ac]Pr and its imaging biomarker [In]Pr demonstrate optimal radiopharmacologic behavior for theranostic applications of α-DOTA-PRIT. For this initial evaluation of efficacy and toxicity, single-cycle treatment regimens were performed in all three systems. Histologic toxicity was not observed, so MTD was not observed. Prolonged overall survival, CRs, and histologic cures were observed in treated animals. In comparison to RIT with anti-tumor IgG antibodies, [Ac]Pr has a much improved safety profile. Ultimately, these data will be used to guide clinical development of toxicity and efficacy studies of [Ac]Pr, with the goal of delivering massive lethal doses of radiation to achieve a high probability of cure without toxicity.
Topics: Actinium; Alpha Particles; Animals; Cell Line, Tumor; Dose-Response Relationship, Radiation; Female; Half-Life; Heterocyclic Compounds, 1-Ring; Humans; Indium Radioisotopes; Mice; Nanoparticles; Neoplasms; Radioimmunotherapy; Radiopharmaceuticals; Radiotherapy Dosage; Theranostic Nanomedicine; Tissue Distribution; Toxicity Tests, Chronic; Xenograft Model Antitumor Assays
PubMed: 33052220
DOI: 10.7150/thno.48810 -
Journal of Nuclear Medicine : Official... Oct 2022The application of radiopharmaceutical therapy for the treatment of certain diseases is well established, and the field is expanding. New therapeutic...
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.
Topics: Humans; Radiometry; Radiopharmaceuticals
PubMed: 36192334
DOI: 10.2967/jnumed.121.262305 -
Frontiers in Medicine 2022Targeted alpha therapy is an oncological treatment, where cytotoxic doses of alpha radiation are locally delivered to tumor cells, while the surrounding healthy tissue... (Review)
Review
Targeted alpha therapy is an oncological treatment, where cytotoxic doses of alpha radiation are locally delivered to tumor cells, while the surrounding healthy tissue is minimally affected. This therapeutic strategy relies on radiopharmaceuticals made of medically relevant radionuclides chelated by ligands, and conjugated to targeting vectors, which promote the drug accumulation in tumor sites. This review discusses the state-of-the-art in the development of radiopharmaceuticals for targeted alpha therapy, breaking down their key structural components, such as radioisotope, targeting vector, and delivery formulation, and analyzing their pros and cons. Moreover, we discuss current drawbacks that are holding back targeted alpha therapy in the clinic, and identify ongoing strategies in field to overcome those issues, including radioisotope encapsulation in nanoformulations to prevent the release of the daughters. Lastly, we critically discuss potential opportunities the field holds, which may contribute to targeted alpha therapy becoming a gold standard treatment in oncology in the future.
PubMed: 36619636
DOI: 10.3389/fmed.2022.1020188 -
Frontiers in Medicine 2022[Ra]RaCl and [Ra]RaCl are bone seekers, emitting high LET, and short range (< 100 μm) alpha-particles. Both radionuclides show similar decay properties; the total alpha... (Review)
Review
[Ra]RaCl and [Ra]RaCl are bone seekers, emitting high LET, and short range (< 100 μm) alpha-particles. Both radionuclides show similar decay properties; the total alpha energies are comparable (Ra: ≈28 MeV, Ra: ≈26 MeV). [Ra]RaCl has been used from the mid-1940s until 1990 for treating different bone and joint diseases with activities of up to approximately 50 MBq [Ra]RaCl. In 2013 [Ra]RaCl obtained marketing authorization by the FDA and by the European Union for the treatment of metastatic prostate cancer with an activity to administer of 0.055 MBq per kg body weight for six cycles. For intravenous injections in humans a model calculation using the biokinetic model of ICRP67 shows a ratio of organ absorbed dose coefficients (Ra:Ra) between 0.37 (liver) and 0.97 except for the kidneys (2.27) and blood (1.57). For the red marrow as primary organ-at-risk, the ratio is 0.57. The differences are mainly caused be the differing half-lives of the decay products of both radium isotopes. Both radionuclides show comparable DNA damage patterns in peripheral blood mononuclear cells after internal irradiation. Data on the long-term radiation-associated side effects are only available for treatment with [Ra]RaCl. Two epidemiological studies followed two patient groups treated with [Ra]RaCl for more than 25 years. One of them was the "Spiess study", a cohort of 899 juvenile patients who received several injections of [Ra]RaCl with a mean specific activity of 0.66 MBq/kg. Another patient group of ankylosing spondylitis patients was treated with 10 repeated intravenous injections of [Ra]RaCl, 1 MBq each, 1 week apart. In total 1,471 of these patients were followed-up in the "Wick study". In both studies, an increased cancer mortality by leukemia and solid cancers was observed. Similar considerations on long-term effects likely apply to [Ra]RaCl as well since the biokinetics are similar and the absorbed doses in the same range. However, this increased risk will most likely not be observed due to the much shorter life expectancy of prostate cancer patients treated with [Ra]RaCl.
PubMed: 36687439
DOI: 10.3389/fmed.2022.1057373 -
Scientific Reports May 2023In search for critical elements, polymetallic nodules at the deep abyssal seafloor are targeted for mining operations. Nodules efficiently scavenge and retain several...
In search for critical elements, polymetallic nodules at the deep abyssal seafloor are targeted for mining operations. Nodules efficiently scavenge and retain several naturally occurring uranium-series radioisotopes, which predominantly emit alpha radiation during decay. Here, we present new data on the activity concentrations of thorium-230, radium-226, and protactinium-231, as well as on the release of radon-222 in and from nodules from the NE Pacific Ocean. In line with abundantly published data from historic studies, we demonstrate that the activity concentrations for several alpha emitters are often higher than 5 Bq g at the surface of the nodules. These observed values can exceed current exemption levels by up to a factor of 1000, and even entire nodules commonly exceed these limits. Exemption levels are in place for naturally occurring radioactive materials (NORM) such as ores and slags, to protect the public and to ensure occupational health and radiation safety. In this context, we discuss three ways of radiation exposure from nodules, including the inhalation or ingestion of nodule fines, the inhalation of radon gas in enclosed spaces and the potential concentration of some radioisotopes during nodule processing. Seen in this light, inappropriate handling of polymetallic nodules poses serious health risks.
Topics: Alpha Particles; Mining; Radioisotopes; Pacific Ocean; Uranium; Radiation Monitoring
PubMed: 37198245
DOI: 10.1038/s41598-023-33971-w