Abstract
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Introduction: Radiopharmaceutical therapy (or RPT) is one of the more rapidly expanding fields of cancer treatment. Its growth can be attributed to both the development of new targeting strategies for agent localization (e.g., prostate-specific membrane antigen, PSMA), as well as the shift in focus from high-energy beta-particle emitters (e.g., 90Y) to more therapeutically advantageous lower-energy beta emitters (e.g., 177Lu) and a variety of alpha-particle emitters (e.g., 223Ra, 212Bi, and 225Ac). In most forms of external beam radiotherapy, the treatment objective is to deliver a prescribed absorbed (or equieffective) dose to a targeted tumor site, while minimizing energy deposition to critical organs and tissues within or adjacent to the treatment field. In contrast, radiopharmaceutical therapy is typically administered for widely disseminated disease, and thus the objective of dosimetry-based treatment-planning is generally not driven by achievement of a desired tumor dose but is structured to ensure doses to normal organs approach but stay below thresholds for organ toxicity. The goal of this present study was thus to develop a 3D histology-based model of the renal cortical labyrinth to support radiation dosimetry of alpha-particles (50–80 μm range) as needed for the development and clinical use of dose-response models of renal toxicity in RPT.
Methods: Digital images of 31 serially sectioned microtome tissue specimens of human kidney were obtained using a Zeiss Axiophot microscope using a 20X Plan Aprochromat objective lens and a Jenoptik ProgRes color CCD camera. Within each digital image, a region of interest was selected and vertically aligned thus defining a cuboidal volume (1296 x 1152 x 975 mm3) of the renal cortical labyrinth. Image segmentation, facilitated by 3D Slicer and Rhinoceros v7, was performed in which seven renal corpuscles (glomeruli and Bowman's capsules) were identified and modeled in a polygon mesh format. Next, centerlines of proximal convoluted tubules (PCT) and distal convoluted tubules (DCT) – as distinguished via wall histological features – were traced for those tubules closest to each of the seven renal corpuscles. Final tubular models were created using standardized lumen diameters and wall thicknesses of 65 and 16 microns, respectively for the PCT, and 50 and 9.4 microns, respectively for the DCT. Random segments of these tubular structures were then generated to create a “tubular library” of models which were then used to space fill regions intermediate to each renal corpuscle and their neighboring PCTs and DCTs.
Results: Measurements for PCT and DCT lumen diameters were performed in 3D Slicer software using the embedded ruler function. Mean PCT and DCT lumen diameters were measured to be 65.1 ± 4.52 μm (n=52) and 50.0 ± 4.36 μm (n=52), respectively. Mean PCT and DCT wall thicknesses were measured to be 16.01 ± 2.61 μm (n=34) and 9.35 ± 1.54 μm (n=34), respectively. Mean glomerulus radius was measured to be 106 ± 11.11 μm (n=7), while the mean glomerulus volume was measured to be 7.43 x 106 ± 2.13 x 106 μm3 (n=7). Glomerulus to glomerulus (center to center) distance was measured to be 579 ± 184 μm (n=21).
Conclusions: This study has established a realistic, histology-based 3D model of the renal cortical labyrinth to support microscale radiation dosimetry at a cellular level. Current efforts are devoted toward simulating the radiation transport of both alpha particles, as well as electron/beta particles, for various source-target combinations under the MIRD schema. Additional work will explore similar cuboidal renal cortical models for both different regions of the same human kidney, as well as various microscale models across histology sections from different human subjects, thus allowing for quantification of both intra-kidney and inter-patient variability in cellular-level renal cortex dosimetry. Funding - DoD W81XWH2110984, NCI R43 CA224643, NCI R01 CA157542
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