A nephron-based model of the kidneys for macro-to-micro α-particle dosimetry
Department of Radiology, Johns Hopkins University, Baltimore MD, USA.Physics in Medicine and Biology (Impact Factor: 2.76). 06/2012; 57(13):4403-24. DOI: 10.1088/0031-9155/57/13/4403
Targeted α-particle therapy is a promising treatment modality for cancer. Due to the short path-length of α-particles, the potential efficacy and toxicity of these agents is best evaluated by microscale dosimetry calculations instead of whole-organ, absorbed fraction-based dosimetry. Yet time-integrated activity (TIA), the necessary input for dosimetry, can still only be quantified reliably at the organ or macroscopic level. We describe a nephron- and cellular-based kidney dosimetry model for α-particle radiopharmaceutical therapy, more suited to the short range and high linear energy transfer of α-particle emitters, which takes as input kidney or cortex TIA and through a macro to micro model-based methodology assigns TIA to micro-level kidney substructures. We apply a geometrical model to provide nephron-level S-values for a range of isotopes allowing for pre-clinical and clinical applications according to the medical internal radiation dosimetry (MIRD) schema. We assume that the relationship between whole-organ TIA and TIA apportioned to microscale substructures as measured in an appropriate pre-clinical mammalian model also applies to the human. In both, the pre-clinical and the human model, microscale substructures are described as a collection of simple geometrical shapes akin to those used in the Cristy-Eckerman phantoms for normal organs. Anatomical parameters are taken from the literature for a human model, while murine parameters are measured ex vivo. The murine histological slides also provide the data for volume of occupancy of the different compartments of the nephron in the kidney: glomerulus versus proximal tubule versus distal tubule. Monte Carlo simulations are run with activity placed in the different nephron compartments for several α-particle emitters currently under investigation in radiopharmaceutical therapy. The S-values were calculated for the α-emitters and their descendants between the different nephron compartments for both the human and murine models. The renal cortex and medulla S-values were also calculated and the results compared to traditional absorbed fraction calculations. The nephron model enables a more optimal implementation of treatment and is a critical step in understanding toxicity for human translation of targeted α-particle therapy. The S-values established here will enable a MIRD-type application of α-particle dosimetry for α-emitters, i.e. measuring the TIA in the kidney (or renal cortex) will provide meaningful and accurate nephron-level dosimetry.
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ABSTRACT: Through its programmatic efforts and its publications, the International Atomic Energy Agency (IAEA) has helped define the role and responsibilities of the nuclear medicine physicist in the practice of nuclear medicine. This paper describes the initiatives that the IAEA has undertaken to support medical physics in nuclear medicine. In 1984, the IAEA provided guidance on how to ensure that the equipment used for detecting, imaging, and quantifying radioactivity is functioning properly (Technical Document [TECDOC]-137, "Quality Control of Nuclear Medicine Instruments"). An updated version of IAEA-TECDOC-137 was issued in 1991 as IAEA-TECDOC-602, and this included new chapters on scanner-computer systems and single-photon emission computed tomography systems. Nuclear medicine physics was introduced as a part of a project on radiation imaging and radioactivity measurements in the 2002-2003 IAEA biennium program in Dosimetry and Medical Radiation Physics. Ten years later, IAEA activities in this field have expanded to cover quality assurance (QA) and quality control (QC) of nuclear medicine equipment, education and clinical training, professional recognition of the role of medical physicists in nuclear medicine physics, and finally, the coordination of research and development activities in internal dosimetry. As a result of these activities, the IAEA has received numerous requests to support the development and implementation of QA or QC programs for radioactivity measurements in nuclear medicine in many Member States. During the last 5 years, support was provided to 20 Member States through the IAEA's technical cooperation programme. The IAEA has also supported education and clinical training of medical physicists. This type of support has been essential for the development and expansion of the Medical Physics profession, especially in low- and middle-income countries. The need for basic as well as specialized clinical training in medical physics was identified as a priority for healthcare providers in many countries. The IAEA's response to meet the increasing needs for training has been 2-folds. Through its regular program, a priority is given to the development of standardized syllabi and education and clinical training guides. Through its technical cooperation programme, support is given for setting up national medical physics education and clinical training programs in countries. In addition, fellowships are granted for professionals working in the field for specialized training, and workshops are organized at the national and regional level in specialized topics of nuclear medicine physics. So as to support on-the-job training, the IAEA has also setup a gamma camera laboratory in Seibersdorf, Austria. The laboratory is also equipped with QC tools and equipments, and radioisotopes are procured when training events are held. About 2-3 specialized courses are held every year for medical physicists at the IAEA gamma camera laboratory. In the area of research and development, the IAEA supports, through its coordinated research projects, new initiatives in quantitative nuclear medicine and internal dosimetry. The future of nuclear medicine is driven by advances in instrumentation, by the ever increasing availability of computing power and data storage, and by the development of new radiopharmaceuticals for molecular imaging and therapy. Future developments in nuclear medicine are partially driven by, and will influence, nuclear medicine physics and medical physics. To summarize, the IAEA has established a number of programs to support nuclear medicine physics and will continue to do so through its coordinated research activities, education and training in clinical medical physics, and through programs and meetings to promote standardization and harmonization of QA or QC procedures for imaging and treatment of patients.Seminars in nuclear medicine 05/2013; 43(3):181-7. DOI:10.1053/j.semnuclmed.2012.11.008 · 3.34 Impact Factor
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ABSTRACT: Radiopharmaceutical therapy (RPT) involves the use of radionuclides that are either conjugated to tumor-targeting agents (e.g., nanoscale constructs, antibodies, peptides, and small molecules) or concentrated in tissue through natural physiological mechanisms that occur predominantly in neoplastic or otherwise targeted cells (e.g., Graves disease). The ability to collect pharmacokinetic data by imaging and use this to perform dosimetry calculations for treatment planning distinguishes RPT from other systemic treatment modalities such as chemotherapy, wherein imaging is not generally used. Treatment planning has not been widely adopted, in part, because early attempts to relate dosimetry to outcome were not successful. This was partially because a dosimetry methodology appropriate to risk evaluation rather than efficacy and toxicity was being applied to RPT. The weakest links in both diagnostic and therapeutic dosimetry are the accuracy of the input and the reliability of the radiobiological models used to convert dosimetric data to the relevant biologic end points. Dosimetry for RPT places a greater demand on both of these weak links. To date, most dosimetric studies have been retrospective, with a focus on tumor dose-response correlations rather than prospective treatment planning. In this regard, transarterial radioembolization also known as intra-arterial radiation therapy, which uses radiolabeled ((90)Y) microspheres of glass or resin to treat lesions in the liver holds much promise for more widespread dosimetric treatment planning. The recent interest in RPT with alpha-particle emitters has highlighted the need to adopt a dosimetry methodology that specifically accounts for the unique aspects of alpha particles. The short range of alpha-particle emitters means that in cases in which the distribution of activity is localized to specific functional components or cell types of an organ, the absorbed dose will be equally localized and dosimetric calculations on the scale of organs or even voxels (~5mm) are no longer sufficient. This limitation may be overcome by using preclinical models to implement macromodeling to micromodeling. In contrast to chemotherapy, RPT offers the possibility of evaluating radiopharmaceutical distributions, calculating tumor and normal tissue absorbed doses, and devising a treatment plan that is optimal for a specific patient or specific group of patients.Seminars in nuclear medicine 05/2014; 44(3):172-178. DOI:10.1053/j.semnuclmed.2014.03.007 · 3.34 Impact Factor