Purpose Ra-223, an α-particle emitting bone-seeking radionuclide, has recently been used in clinical trials for osseous metasteses of prostate cancer. We investigated the relationship between absorbed fraction-based red marrow dosimetry and cell level-dosimetry using a model that accounts for the expected localization of this agent relative to marrow cavity architecture. We show that cell level-based dosimetry is essential to understanding potential marrow toxicity. Methods The GEANT4 software package was used to create simple spheres representing marrow cavities. Ra-223 was positioned on the trabecular bone surface or in the endosteal layer and simulated for decay, along with the descendants. The interior of the sphere was divided into cell-size voxels and the energy was collected in each voxel and interpreted as dose cell histograms. The average absorbed dose values and absorbed fractions were also calculated in order to compare those results with previously published values. Results The absorbed dose was predominantly deposited near the trabecular surface. The dose cell histograms results were used to plot the percentage of cells that received a potentially toxic absorbed dose (2 or 4 Gy) as a function of the average absorbed dose over the marrow cavity. The results show (1) a heterogeneous distribution of cellular absorbed dose, strongly dependent on the position of the cell within the marrow cavity; and (2) that increasing the average marrow cavity absorbed dose, or equivalently, increasing the administered activity resulted in only a small increase in potential marrow toxicity (i.e., the number of cells receiving more than 4 or 2 Gy), for a range of average marrow cavity absorbed doses from 1 Gy to 20 Gy. Conclusion The results from the trabecular model differ markedly from a standard absorbed fraction method while presenting comparable average dose values. These suggest that increasing the amount of radioactivity may not substantially increase the risk of toxicity, a result unavailable to the absorbed fraction method of dose calculation.

Hybrid phantoms represent a third generation of computational models of human anatomy needed for dose assessment in both external and internal radiation exposures. Recently, we presented the first whole-body hybrid phantom of the ICRP reference newborn with a skeleton constructed from both non-uniform rational B-spline and polygon-mesh surfaces (Lee et al 2007 Phys. Med. Biol. 52 3309-33). The skeleton in that model included regions of cartilage and fibrous connective tissue, with the remainder given as a homogenous mixture of cortical and trabecular bone, active marrow and miscellaneous skeletal tissues. In the present study, we present a comprehensive skeletal tissue model of the ICRP reference newborn to permit a heterogeneous representation of the skeleton in that hybrid phantom set-both male and female-that explicitly includes a delineation of cortical bone so that marrow shielding effects are correctly modeled for low-energy photons incident upon the newborn skeleton. Data sources for the tissue model were threefold. First, skeletal site-dependent volumes of homogeneous bone were obtained from whole-cadaver CT image analyses. Second, selected newborn bone specimens were acquired at autopsy and subjected to micro-CT image analysis to derive model parameters of the marrow cavity and bone trabecular 3D microarchitecture. Third, data given in ICRP Publications 70 and 89 were selected to match reference values on total skeletal tissue mass. Active marrow distributions were found to be in reasonable agreement with those given previously by the ICRP. However, significant differences were seen in total skeletal and site-specific masses of trabecular and cortical bone between the current and ICRP newborn skeletal tissue models. The latter utilizes an age-independent ratio of 80%/20% cortical and trabecular bone for the reference newborn. In the current study, a ratio closer to 40%/60% is used based upon newborn CT and micro-CT skeletal image analyses. These changes in mineral bone composition may have significant dosimetric implications when considering localized marrow dosimetry for radionuclides that target mineral bone in the newborn child.

This report evaluates the spatial profile of blood vessel fragments (BVFs) and CD34 ؉ and CD117 ؉ hematopoietic stem and progenitor cells (HSPCs) in human cancellous bone. Bone specimens were sectioned, immunostained (anti-CD34 and anti-CD117), and digitally imaged. Immunoreactive cells and vessels were then optically and morphometrically identified and labeled on the corresponding digital image. IntroductionQuantifying the spatial profile of blood vessels and primitive cell populations most susceptible to myelosuppression or hematologic toxicity is of major interest in basic cancer research, bone marrow transplantation, and molecular radiotherapy. [1][2][3] Although several groups have investigated the spatial location of hematopoietic stem and progenitor cells (HSPCs) in murine models, 4-7 evidence for corresponding HSPC spatial profiles within human bone marrow has only recently been established. 8 In their study, Watchman et al used novel methods for the digital quantification of the CD34 ϩ hematopoietic stem cells and blood vessel fragments (BVFs) in human iliac crest. 8 The present study uses similar techniques of immunohistochemistry and digital image processing to directly measure the concentration of BVFs and CD34 ϩ HSPCs as a function of distance from the most proximal trabecular surface in human bone marrow. The study further advances the findings of Watchman et al, however, through (1) immunohistochemical stratification of the additional population of CD117 ϩ hematopoietic stem and progenitor cells, (2) consideration of a possible bone-site dependence of the BVF and HSPC spatial gradient, (3) use of larger field-of-view marrow specimens through autopsy harvest, and (4) explicit consideration of active versus total bone marrow area. MethodsPostmortem bone samples were collected during the autopsy of 9 recently deceased patients determined to be absent of marrow disease under a Health Insurance Portability and Accountability Act-compliant and University of Florida institutional review board-approved protocol that followed the Declaration of Helsinki provisions. Sections of bone were collected from the right iliac crest, L 1 vertebrae, and 1 left rib, within 24 hours of death. Excised bone samples were placed in stock formaldehyde, rough sectioned, decalcified, and acid neutralized following the manufacturer's instructions (Formical-4 and Cal-Arrest; Decal Chemical Corp). The paraffin tissue blocks were faced and 4 sequential sections were collected from each specimen at a thickness of 5 m. ImmunohistochemistrySerial sections collected from decalcified, paraffin-embedded blocks were manually immunostained using mouse anti-CD34 (dilution 1:25, QBEND10; DAKO Cytomation) and rabbit anti-CD117 (dilution 1:300, c-Kit; DAKO Cytomation). Antigen retrieval was achieved using heat-induced epitope retrieval and treatment of slides with 10 mM Citra buffer (pH 6.0), after which slides were stained by the ABC-Elite method (Vector Labs) following the manufacturer's instructions. Positive signal was detected with dia...

Current bone marrow dosimetry methods inherently assume that the target cells of interest for the assessment of leukemia risk (stochastic effects) or marrow toxicity (deterministic effects) are uniformly localized throughout the marrow cavities of cancellous bone. Previous studies on mouse femur, however, have demonstrated a spatial gradient for the hematopoietic stem and progenitor cells, with higher concentrations near the bone surfaces. The objective of the present study was to directly measure the spatial concentration of these cells, as well as marrow vasculature structures, within images of human disease-free bone marrow. Methods: Core-biopsy samples of normal bone marrow from the iliac crest were obtained from clinical cases at Shands Hospital at the University of Florida Department of Pathology. The specimens were sectioned and immunohistochemically stained for CD34 (red) and CD31 (brown) antigens. These 2 stains were used simultaneously to differentiate between hematopoietic stem and progenitor cells (CD34 1 /CD31 2 ) and vascular endothelium (CD34 1 /CD31 1 ). Distances from hematopoietic CD34 1 cells and blood vessels to the nearest bone trabecula surface were measured digitally and then binned in 50-mm increments, with the results then normalized per unit area of marrow tissue. The distances separating hematopoietic CD34 1 cells from vessels were also tallied. Results: Hematopoietic CD34 1 cells were found to exist along a linear spatial gradient with a maximal areal concentration localized within the first 50 mm of the bone surfaces. An exponential spatial concentration gradient was found in the concentration of blood vessel fragments within the images. Distances between hematopoietic CD34 1 cells and blood vessels exhibited a lognormal distribution indicating a shared spatial niche. Conclusion: Study results confirm that the spatial gradient of hematopoietic stem and progenitor cells previously measured in mouse femur is also present within human cancellous bone. The dosimetric implication of these results may be significant for those scenarios in which the absorbed dose itself is nonuniformly delivered across the marrow tissues, as would be the case for a low-energy b-or a-particle emitter localized on the bone surfaces.

In 1995, the International Commission on Radiological Protection (ICRP) issued ICRP Publication 70 which provided an extensive update to the physiological and anatomical reference data for the skeleton of adults and children originally issued in ICRP Publication 23. Although ICRP Publication 70 has been a valuable document in the development of reference voxel computational phantoms, additional guidance is needed for dose assessment in the skeletal tissues beyond that given in ICRP Publication 30. In this study, a computed tomography (CT) and micro-CT-based model of the skeletal tissues is presented, which considers (1) a 50-microm depth in marrow for the osteoprogenitor cells, (2) electron escape from trabecular spongiosa to the surrounding cortical bone, (3) cortical bone to trabecular spongiosa cross-fire for electrons and (4) variations in specific absorbed fraction with changes in bone marrow cellularity for electrons. A representative data set is given for electron dosimetry in the craniofacial bones of the adult male.