Tools for improving high-dose-rate prostate cancer brachytherapy using three-dimensional ultrasound and magnetic resonance imaging

High-dose-rate brachytherapy (HDR-BT) is an interstitial technique for the treatment of intermediate and high-risk localized prostate cancer that involves placement of a radiation source directly inside the prostate using needles. Dose-escalated whole-gland treatments have led to improvements in survival, and tumour-targeted treatments may offer future improvements in therapeutic ratio. The efficacy of tumour-targeted HDR-BT depends on imaging tools to enable accurate dose delivery to prostate sub-volumes. This thesis is focused on implementing ultrasound tools to improve HDR-BT needle localization accuracy and efficiency, and evaluating dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) for tumour localization. First, we implemented a device enabling sagittally-reconstructed 3D (SR3D) ultrasound, which provides sub-millimeter resolution in the needle insertion direction. We acquired SR3D and routine clinical images in a cohort of 12 consecutive eligible HDR-BT patients, with a total of 194 needles. The SR3D technique provided needle insertion depth errors within 5 mm for 93\% of needles versus 76\% for the clinical imaging technique, leading to increased precision in dose delivered to the prostate. Second, we implemented an algorithm to automatically segment multiple HDR-BT needles in a SR3D image. The algorithm was applied to the SR3D images from the first patient cohort, demonstrating mean execution times of 11.0 s per patient and successfully segmenting 82\% of needles within 3 mm. Third, we augmented SR3D imaging with live-2D sagittal ultrasound for needle tip localization. This combined technique was applied to another cohort of 10 HDR-BT patients, reducing insertion depth errors compared to routine imaging from a range of [-8.1 mm, 7.7 mm] to [-6.2 mm, 5.9 mm]. Finally, we acquired DCE-MRI in 16 patients scheduled to undergo prostatectomy, using either high spatial resolution or high temporal resolution imaging, and compared the images to whole-mount histology. The high spatial resolution images demonstrated improved high-grade cancer classification compared to the high temporal resolution images, with areas under the receiver operating characteristic curve of 0.79 and 0.70, respectively. In conclusion, we have translated and evaluated specialized imaging tools for HDR-BT which are ready to be tested in a clinical trial investigating tumour-targeted treatment

Skeletal Muscle Fibrosis in the mdx/utrn plus /- Mouse Validates Its Suitability as a Murine Model of Duchenne Muscular Dystrophy

Various therapeutic approaches have been studied for the treatment of Duchenne muscular dystrophy (DMD), but none of these approaches have led to significant long-term effects in patients. One reason for this observed inefficacy may be the use of inappropriate animal models for the testing of therapeutic agents. The mdx mouse is the most widely used murine model of DMD, yet it does not model the fibrotic progression observed in patients. Other murine models of DMD are available that lack one or both alleles of utrophin, a functional analog of dystrophin. The aim of this study was to compare fibrosis and myofiber damage in the mdx, mdx/utrn+/- and double knockout (dko) mouse models. We used Masson\u27s trichrome stain and percentage of centrally-nucleated myofibers as indicators of fibrosis and myofiber regeneration, respectively, to assess disease progression in diaphragm and gastrocnemius muscles harvested from young and aged wild-type, mdx, mdx/utrn+/- and dko mice. Our results indicated that eight week-old gastrocnemius muscles of both mdx/utrn+/- and dko hind limb developed fibrosis whereas age-matched mdx gastrocnemius muscle did not (p = 0.002). The amount of collagen found in the mdx/utrn+/- diaphragm was significantly higher than that found in the corresponding diaphragm muscles of wild-type animals, but not of mdx animals (p = 0.0003). Aged mdx/utrn+/- mice developed fibrosis in both diaphragm and gastrocnemius muscles compared to wild-type controls (p = 0.003). Mdx diaphragm was fibrotic in aged mice as well (p = 0.0235), whereas the gastrocnemius muscle in these animals was not fibrotic. We did not measure a significant difference in collagen staining between wild-type and mdx gastrocnemius muscles. The results of this study support previous reports that the moderately-affected mdx/utrn+/- mouse is a better model of DMD, and we show here that this difference is apparent by 2 months of age

Skeletal Muscle Fibrosis in the mdx/utrn+/- Mouse Validates Its Suitability as a Murine Model of Duchenne Muscular Dystrophy

Various therapeutic approaches have been studied for the treatment of Duchenne muscular dystrophy (DMD), but none of these approaches have led to significant long-term effects in patients. One reason for this observed inefficacy may be the use of inappropriate animal models for the testing of therapeutic agents. The mdx mouse is the most widely used murine model of DMD, yet it does not model the fibrotic progression observed in patients. Other murine models of DMD are available that lack one or both alleles of utrophin, a functional analog of dystrophin. The aim of this study was to compare fibrosis and myofiber damage in the mdx, mdx/utrn+/- and double knockout (dko) mouse models.We used Masson’s trichrome stain and percentage of centrally-nucleated myofibers as indicators of fibrosis and myofiber regeneration, respectively, to assess disease progression in diaphragm and gastrocnemius muscles harvested from young and aged wild-type, mdx, mdx/utrn+/- and dko mice. Our results indicated that eight week-old gastrocnemius muscles of both mdx/utrn+/- and dko hind limb developed fibrosis whereas age-matched mdx gastrocnemius muscle did not (p = 0.002). The amount of collagen found in the mdx/utrn+/- diaphragm was significantly higher than that found in the corresponding diaphragm muscles of wild-type animals, but not of mdx animals (p = 0.0003). Aged mdx/utrn+/- mice developed fibrosis in both diaphragm and gastrocnemius muscles compared to wild-type controls (p = 0.003). Mdx diaphragm was fibrotic in aged mice as well (p = 0.0235), whereas the gastrocnemius muscle in these animals was not fibrotic. We did not measure a significant difference in collagen staining between wild-type and mdx gastrocnemius muscles. The results of this study support previous reports that the moderately-affected mdx/utrn+/- mouse is a better model of DMD, and we show here that this difference is apparent by 2 months of age

Deformable registration of X-ray and MRI for post-implant dosimetry in low-dose-rate prostate brachytherapy

Purpose Dosimetric assessment following permanent prostate brachytherapy (PPB) commonly involves seed localization using CT and prostate delineation using coregistered MRI. However, pelvic CT leads to additional imaging dose and requires significant resources to acquire and process both CT and MRI. In this study, we propose an automatic postimplant dosimetry approach that retains MRI for soft‐tissue contouring, but eliminates the need for CT and reduces imaging dose while overcoming the inconsistent appearance of seeds on MRI with three projection x rays acquired using a mobile C‐arm. Methods Implanted seeds are reconstructed using x rays by solving a combinatorial optimization problem and deformably registered to MRI. Candidate seeds are located in MR images using local hypointensity identification. X ray‐based seeds are registered to these candidate seeds in three steps: (a) rigid registration using a stochastic evolutionary optimizer, (b) affine registration using an iterative closest point optimizer, and (c) deformable registration using a local feature point search and nonrigid coherent point drift. The algorithm was evaluated using 20 PPB patients with x rays acquired immediately postimplant and T2‐weighted MR images acquired the next day at 1.5 T with mean 0.8 × 0.8 × 3.0 mmurn:x-wiley:00942405:media:mp13667:mp13667-math-0001 voxel dimensions. Target registration error (TRE) was computed based on the distance from algorithm results to manually identified seed locations using coregistered CT acquired the same day as the MRI. Dosimetric accuracy was determined by comparing prostate D90 determined using the algorithm and the ground truth CT‐based seed locations. Results The mean ± standard deviation TREs across 20 patients including 1774 seeds were 2.23 ± 0.52 mm (rigid), 1.99 ± 0.49 mm (rigid + affine), and 1.76 ± 0.43 mm (rigid + affine + deformable). The corresponding mean ± standard deviation D90 errors were 5.8 ± 4.8%, 3.4 ± 3.4%, and 2.3 ± 1.9%, respectively. The mean computation time of the registration algorithm was 6.1 s. Conclusion The registration algorithm accuracy and computation time are sufficient for clinical PPB postimplant dosimetry

Muscle pathology in 8 week-old diaphragm muscle of wild-type, mdx, mdx/utrn+/- and dko mice.

<p>Extent of total collagen staining (blue) in 8 week-old wild-type (A), mdx (B), mdx/utrn+/- (C) and dko (D) diaphragms was used as a marker of fibrosis. Proportion of centrally nucleated fibers in the same tissues (E, F, G, and H) were measured to assess extent of regeneration. Quantification of total collagen staining (I) and proportion of centrally-nucleated myofibers (J) is represented as the mean +SD. * represents p<0.05, ** represents p<0.01, and *** represents p<0.001 (scale bar = 100μm)</p

Comparison of histopathology of 12 week-old mdx/utrn+/- diaphragm, quadriceps, soleus, tibialis anterior and gastrocnemius muscles.

<p>Extent of collagen staining (A,C,E,G,I) and muscle regeneration (B,D,F,H,J) in 12 week-old mdx/utrn+/- mice. Quantification of total collagen staining (K) and centrally-nucleated myofibers (CNF, L) is represented as the mean ±SD. * represents p<0.05, ** represents p<0.01, and *** represents p<0.001 (scale bar = 100μm). TA = tibialis anterior, GM = gastrocnemius.</p

Muscle pathology in 10 month-old GM muscle of wild-type, mdx and mdx/utrn+/- mice.

<p>Extent of total collagen staining (blue) in 10 month-old wild-type (A), mdx (B) and mdx/utrn+/- (C) GM muscle was used as a marker of fibrosis. Proportion of centrally nucleated fibers in the same tissues (D, E, and F) were measured to assess extent of regeneration. Quantification of total collagen staining (G) and proportion of centrally-nucleated myofibers (H) is represented as the mean +SD. * represents p<0.05 and ** represents p<0.01 (scale bar = 100μm).</p

Muscle pathology in 10 month-old diaphragm muscle of wild-type, mdx and mdx/utrn+/- mice.

<p>Extent of total collagen staining (blue) in 10 month-old wild-type (A), mdx (B) and mdx/utrn+/- (C) diaphragms was used as a marker of fibrosis. Proportion of centrally nucleated fibers in the same tissues (D, E, and F) were measured to assess extent of regeneration. Quantification of total collagen staining (G) and proportion of centrally-nucleated myofibers (H) is represented as the mean +SD. * represents p<0.05 and *** represents p<0.001 (scale bar = 100μm).</p

Muscle pathology in 8 week-old GM muscle of wild-type, mdx, mdx/utrn+/- and dko mice.

<p>Extent of total collagen staining (blue) in 8 week-old wild-type (A), mdx (B), mdx/utrn+/- (C) and dko (D) GM muscles was used as a marker of fibrosis. Proportion of centrally nucleated fibers in the same tissues (E, F, G, and H) were measured to assess extent of regeneration. Quantification of total collagen staining (I) and proportion of centrally-nucleated myofibers (J) is represented as the mean +SD. * represents p<0.05, ** represents p<0.01, and *** represents p<0.001 (scale bar = 100μm).</p