Christopher J. Watchman

A bone marrow toxicity model for 223Ra alpha-emitter radiopharmaceutical therapy

Ra-223, an α-particle emitting bone-seeking radionuclide, has recently been used in clinical trials for osseous metastases 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. 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. The absorbed dose was predominantly deposited near the trabecular surface. The dose cell histogram 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 to 20 Gy. 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.

Spatial Distribution of Blood Vessels and CD34+ Hematopoietic Stem and Progenitor Cells Within the Marrow Cavities of Human Cancellous Bone

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+/CD31−) and vascular endothelium (CD34+/CD31+). Distances from hematopoietic CD34+ cells and blood vessels to the nearest bone trabecula surface were measured digitally and then binned in 50-μm increments, with the results then normalized per unit area of marrow tissue. The distances separating hematopoietic CD34+ cells from vessels were also tallied. Results: Hematopoietic CD34+ cells were found to exist along a linear spatial gradient with a maximal areal concentration localized within the first 50 μm 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+ 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 β- or α-particle emitter localized on the bone surfaces.

Spatial gradients of blood vessels and hematopoietic stem and progenitor cells within the marrow cavities of the human skeleton

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. The distance of each BVF, or CD34(+) or CD117(+) HSPC to the nearest trabecular surface was measured and binned in 50-microm increments. The relative concentration of HSPCs and BVFs within cancellous marrow was observed to diminish with increasing distance in the marrow space. On average, 50% of the CD34(+) HSPC population, 60% of the CD117(+) HSPC population, and 72% of the BVFs were found within 100 microm of the bone surfaces. HSPCs were also found to exist in close proximity to BVFs, which supports the notion of a shared HSPC and vessel spatial niche.

Effectiveness of image-guided radiotherapy for laryngeal sparing in head and neck cancer

We would like to compare the effectiveness of image-guided (IGRT) and intensity-modulated (IMRT) radiotherapy to spare the larynx in head and neck cancer patients. A retrospective review of 48 patients undergoing radiation for non-laryngeal and non-hypopharyngeal head and neck cancers. Mean laryngeal and hypopharyngeal dose was compared between 11 patients treated with IMRT and 37 patients treated with IGRT. Mean laryngeal dose was, respectively, 41.2 Gy and 22.8 Gy for the IMRT and IGRT technique (p<0.001). The radiation dose to the middle and inferior pharyngeal muscles was also significantly reduced with the IGRT technique. Mean pharyngeal dose was, respectively, 52 Gy and 26 Gy for the IMRT and IGRT technique (p=0.0001). Laryngeal sparing IGRT technique for head and neck cancer minimizes radiotherapy dose to the larynx and pharynx without sacrificing target coverage, even in the presence of neck lymph nodes.

Surface area overestimation within three-dimensional digital images and its consequence for skeletal dosimetry.

The most recent methods for trabecular bone dosimetry are based on Monte Carlo transport simulations within three-dimensional (3D) images of real human bone samples. Nuclear magnetic resonance and micro-computed tomography have been commonly used as imaging tools for studying trabecular microstructure. In order to evaluate the accuracy of these techniques for radiation dosimetry, a previous study was conducted that showed an overestimate in the absorbed fraction of energy for low-energy electrons emitted within the marrow space and irradiating the bone trabeculae. This problem was found to be related to an overestimate of the surface area of the true bone-marrow interface within the 3D digital images, and was identified as the surface-area effect. The goal of the present study is to better understand how this surface-area effect occurs in the case of single spheres representing individual marrow cavities within trabecular bone. First, a theoretical study was conducted which showed that voxelization of the spherical marrow cavity results in a 50% overestimation of the spherical surface area. Moreover, this overestimation cannot be reduced through a reduction in the voxel size (e.g., improved image resolution). Second, a series of single-sphere marrow cavity models was created with electron sources simulated within the sphere (marrow source) and outside the sphere (bone trabeculae source). The series of single-sphere models was then voxelized to represent 3D digital images of varying resolution. Transport calculations were made for both marrow and bone electron sources within these simulated images. The study showed that for low-energy electrons (<100 keV), the 50% overestimate of the bone-marrow interface surface area can lead to a 50% overestimate of the cross-absorbed fraction. It is concluded that while improved resolution will not reduce the surface area effects found within 3D image-based transport models, a tenfold improvement in current image resolution would compensate the associated errors in cross-region absorbed fractions for low-energy electron sources. Alternatively, other methods of defining the bone-marrow interface, such as with a polygonal isosurface, would provide improvements in dosimetry without the need for drastic reductions in image voxel size.

Voxel effects within digital images of trabecular bone and their consequences on chord-length distribution measurements

Chord-length distributions through the trabecular regions of the skeleton have been investigated since the early 1960s. These distributions have become important features for bone marrow dosimetry; as such, current models rely on the accuracy of their measurements. Recent techniques utilize nuclear magnetic resonance (NMR) microscopy to acquire 3D images of trabecular bone that are then used to measure 3D chord-length distributions by Monte Carlo methods. Previous studies have shown that two voxel effects largely affect the acquisition of these distributions within digital images. One is particularly pertinent as it dramatically changes the shape of the distribution and reduces its mean. An attempt was made to reduce this undesirable effect and good results were obtained for a single-sphere model using minimum acceptable chord (MAC) methods (Jokisch et al 2001 Med. Phys. 28 1493-504). The goal of the present work is to extend the study of these methods to more general models in order to better quantify their consequences. First, a mathematical model of a trabecular bone sample was used to test the usefulness of the MAC methods. The results showed that these methods were not efficient for this simulated bone model. These methods were further tested on a single voxelized sphere over a large range of voxel sizes. The results showed that the MAC methods are voxel-size dependent and overestimate the mean chord length for typical resolutions used with NMR microscopy. The study further suggests that bone and marrow chord-length distributions currently utilized in skeletal dosimetry models are most likely affected by voxel effects that yield values of mean chord length lower than their true values.

An image-based skeletal tissue model for the ICRP reference newborn

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.

Feasibility of tomotherapy for Graves’ ophthalmopathy

PurposeTo compare the dosimetry of tomotherapy and the conventional half-beam technique (HBT) or non-split beam technique (NSBT) for target coverage and radiation dose to the lacrimal glands and lens.Patients and MethodsA retrospective review of 7 patients with Graves’ ophthalmopathy who had radiotherapy because of disease progression on high steroid dose is reported: 3 patients were treated with tomotherapy and 4 patients with HBT.ResultsCompared to HBT, tomotherapy may provide better target coverage and significant reduction of radiation dose to the lacrimal glands and a higher dose to the lens. The NSBT improved target coverage but resulted in significantly higher doses to the lens and lacrimal glands.ConclusionTomotherapy may provide better coverage of the target volume and may be more effective in reducing severe exophthalmos compared to the conventional radiotherapy technique.ZusammenfassungZielVergleich zwischen Dosimetrie der Tomotherapie und der konventionellen Half-beam-Technik (HBT) oder Non-split-beam-Technik (NSBT) für die Erfassung des Zielvolumens und der Strahlendosis an Tränendrüsen und Linse.Patienten und MethodenEine retrospektive Analyse von 7 Patienten mit Graves’ Ophthalmopathie, die wegen Progression der Erkrankung zur Notwendigkeit hochdosierter Steroidgabe eine Strahlentherapie erhielten. 3 Patienten wurden mit Tomotherapie und 4 Patienten mit HBT behandelt.ErgebnisseIm Vergleich zu HBT konnte die Tomotherapie bessere Erfassung des Zielvolumens und signifikante Reduktion der Strahlendosis an den Tranendrüsen sowie eine höhere Strahlendosis an der Linse erreichen. NSBT verbesserte die Erfassung des Zielvolumens, resultierte aber in signifikant höherer Strahlendosis an Linse und Tränendrüsen.SchlussfolgerungTomotherapie kann – verglichen mit konventioneller Strahlentherapietechnik – zu besserer Erfassung des Zielvolumens und wirksamerer Verminderung des schweren Exophthalmus führen.

Feasibility of tomotherapy for Graves' ophthalmopathy: Dosimetry comparison with conventional radiotherapy.

PurposeTo compare the dosimetry of tomotherapy and the conventional half-beam technique (HBT) or non-split beam technique (NSBT) for target coverage and radiation dose to the lacrimal glands and lens.Patients and MethodsA retrospective review of 7 patients with Graves’ ophthalmopathy who had radiotherapy because of disease progression on high steroid dose is reported: 3 patients were treated with tomotherapy and 4 patients with HBT.ResultsCompared to HBT, tomotherapy may provide better target coverage and significant reduction of radiation dose to the lacrimal glands and a higher dose to the lens. The NSBT improved target coverage but resulted in significantly higher doses to the lens and lacrimal glands.ConclusionTomotherapy may provide better coverage of the target volume and may be more effective in reducing severe exophthalmos compared to the conventional radiotherapy technique.ZusammenfassungZielVergleich zwischen Dosimetrie der Tomotherapie und der konventionellen Half-beam-Technik (HBT) oder Non-split-beam-Technik (NSBT) für die Erfassung des Zielvolumens und der Strahlendosis an Tränendrüsen und Linse.Patienten und MethodenEine retrospektive Analyse von 7 Patienten mit Graves’ Ophthalmopathie, die wegen Progression der Erkrankung zur Notwendigkeit hochdosierter Steroidgabe eine Strahlentherapie erhielten. 3 Patienten wurden mit Tomotherapie und 4 Patienten mit HBT behandelt.ErgebnisseIm Vergleich zu HBT konnte die Tomotherapie bessere Erfassung des Zielvolumens und signifikante Reduktion der Strahlendosis an den Tranendrüsen sowie eine höhere Strahlendosis an der Linse erreichen. NSBT verbesserte die Erfassung des Zielvolumens, resultierte aber in signifikant höherer Strahlendosis an Linse und Tränendrüsen.SchlussfolgerungTomotherapie kann – verglichen mit konventioneller Strahlentherapietechnik – zu besserer Erfassung des Zielvolumens und wirksamerer Verminderung des schweren Exophthalmus führen.

Chord‐based versus voxel‐based methods of electron transport in the skeletal tissues

Anatomic models needed for internal dose assessment have traditionally been developed using mathematical surface equations to define organ boundaries, shapes, and their positions within the body. Many researchers, however, are now advocating the use of tomographic models created from segmented patient computed tomography (CT) or magnetic resonance (MR) scans. In the skeleton, however, the tissue structures of the bone trabeculae, marrow cavities, and endosteal layer are exceedingly small and of complex shape, and thus do not lend themselves easily to either stylistic representations or in-vivo CT imaging. Historically, the problem of modeling the skeletal tissues has been addressed through the development of chord-based methods of radiation particle transport, as given by studies at the University of Leeds (Leeds, U.K.) using a 44-year male subject. We have proposed an alternative approach to skeletal dosimetry in which excised sections of marrow-intact cadaver spongiosa are imaged directly via microCT scanning. The cadaver selected for initial investigation of this technique was a 66-year male subject of nominal body mass index (22.7 kg m(-2)). The objectives of the present study were to compare chord-based versus voxel-based methods of skeletal dosimetry using data from the UF 66-year male subject. Good agreement between chord-based and voxel-based transport was noted for marrow irradiation by either bone surface or bone volume sources up to 500-1000 keV (depending upon the skeletal site). In contrast, chord-based models of electron transport yielded consistently lower values of the self-absorbed fraction to marrow tissues than seen under voxel-based transport at energies above 100 keV, a feature directly attributed to the inability of chord-based models to account for nonlinear electron trajectories. Significant differences were also noted in the dosimetry of the endosteal layer (for all source tissues), with chord-based transport predicting a higher fraction of energy deposition than given by voxel-based transport (average factor of about 1.6). The study supports future use of voxel-based skeletal models which (1) permit nonlinear electron trajectories across the skeletal tissues, (2) do not rely on mathematical algorithms for treating the endosteal tissue layer, and (3) do not implicitly assume independence of marrow and bone trajectories as is the case for chord-based skeletal models.