The backprojection-then-filtering algorithm was applied to proton CT data to reconstruct a map of proton stopping power relative to water (RSP) in air, water and bone. Backprojections were performed along three commonly used path estimates for the proton: straight line path, cubic spline path, and most likely path. The proton CT data was obtained through simulations using the GEANT4 simulation toolkit. Two elliptical phantoms were inspected, and an accuracy of 0.2% and 0.8% was obtained for the RSP in water and bone respectively in the region of interest, while the RSP of air was significantly underestimated.

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Yes / Despite considerable progress with our understanding of glioblastoma multiforme (GBM) and the precise delivery of radiotherapy, the prognosis for GBM patients is still unfavorable with tumor recurrence due to radioresistance being a major concern. We recently developed a cross-linked iron oxide nanoparticle conjugated to azademethylcolchicine (CLIO-ICT) to target and eradicate a subpopulation of quiescent cells, glioblastoma initiating cells (GICs), which could be a reason for radioresistance and tumor relapse. The purpose of our study was to investigate if CLIO-ICT has an additive therapeutic effect to enhance the response of GBMs to ionizing radiation. Methods: NSG™ mice bearing human GBMs and C57BL/6J mice bearing murine GBMs received CLIO-ICT, radiation, or combination treatment. The mice underwent pre- and post-treatment magnetic resonance imaging (MRI) scans, bioluminescence imaging (BLI), and histological analysis. Tumor nanoparticle enhancement, tumor flux, microvessel density, GIC, and apoptosis markers were compared between different groups using a one-way ANOVA and two-tailed Mann-Whitney test. Additional NSG™ mice underwent survival analyses with Kaplan–Meier curves and a log rank (Mantel–Cox) test. Results: At 2 weeks post-treatment, BLI and MRI scans revealed significant reduction in tumor size for CLIO-ICT plus radiation treated tumors compared to monotherapy or vehicle-treated tumors. Combining CLIO-ICT with radiation therapy significantly decreased microvessel density, decreased GICs, increased caspase-3 expression, and prolonged the survival of GBM-bearing mice. CLIO-ICT delivery to GBM could be monitored with MRI. and was not significantly different before and after radiation. There was no significant caspase-3 expression in normal brain at therapeutic doses of CLIO-ICT administered. Conclusion: Our data shows additive anti-tumor effects of CLIO-ICT nanoparticles in combination with radiotherapy. The combination therapy proposed here could potentially be a clinically translatable strategy for treating GBMs.

Image-guided radiation therapy (IGRT) provides accurate and precise tumour targeting. To ensure adequate coverage in IGRT, a planning target volume (PTV) margin is added around the target to account for treatment uncertainties. Treatment plans are designed to deliver a high percentage of the prescription dose to the PTV; thus, portions of healthy tissue are also subjected to high radiation dose. IGRT employs dedicated devices that enable visual assessment of some treatment uncertainties, such as variations in patient set-up. Safe and effective IGRT delivery requires adherence to disease site-specific protocols that describe process details such as imaging technique, alignment method, and corrective action levels. Protocol design is challenging since its effect on treatment accuracy is currently unknown. This thesis aims to understand the interplay between lung IGRT protocol parameters by developing a framework that quantifies geometrical accuracy. Deformable image registration was used to account for changes in target shape and size throughout treatment. Sufficient accuracy was considered when at least 99% of the target surface fell within the PTV. This analysis revealed that the clinical 10 mm PTV margin can be safely reduced by at least 2 mm in each direction. Evaluation of IGRT accuracy was extended to spinal cord alignment. Simulations were carried out with various matching strategies to correct for set-up error, including rotational off-sets. Inappropriate combinations of matching strategies and safety margins resulted in sub-optimal geometrical coverage. Various lung IGRT protocol options were recommended to optimize accuracy and workflow efficiency. For example, an 8 mm PTV margin can be used with spinal cord alignment, a 4 mm cord margin, and up to 5° of rotational error. A more aggressive protocol involved a 6 mm PTV margin with direct target alignment, a 5 mm cord margin, and a 4° rotational tolerance. / Thesis / Master of Science (MSc)

This research studied Ho166/PLLA microspheres, a promising treatment for tumours in the liver. The Ho166 is generated through a neutron capture reaction during irradiation in a nuclear reactor. Previous work has found that neutron-irradiation in-core causes damage to microspheres and causes additional degradation to progress once suspended in media. The cause of this damage was not well understood and is the focus of this research. This research studied factors present in-core such as heat, gamma radiation, and impacts of lead shielding, for their impact on microsphere quality. Additionally, this research looked at the potential of reactive oxygen species causing damage once microspheres are suspended in liquid. Thresholds for damage were identified to correlate with the glass transition temperature of poly- l-lactic acid. Exposure to gamma radiation induces heating, as well as structural changes to the polymer which shifts the temperature where the glass transition occurs. Damage formed from gamma radiation, independent of other variables, was seen at extreme accumulated doses. Notably, exposure to gamma radiation and heat did not cause a progression of damage over time. Samples exposed only to these factors remained stable in solution for extended periods. A theory was proposed that reactive oxygen species formed by the interaction of ionizing radiation with the suspending media may be causing the progression of damage over time. This factor would only be present for microspheres having undergone neutron capture reactions, forming radioactive holmium. Testing confirmed a potential impact of radiation interactions with the suspending media contributing to damage progression. Several thicknesses of lead shielding surrounding the sample chamber were tested in-core. There were significant impacts on temperature, neutron flux, and microsphere quality. / Thesis / Master of Science (MSc) / This research studied Ho166/PLLA microspheres, a promising treatment for tumours in the liver. The preparation of this treatment includes microspheres being neutron irradiated in the core of a nuclear reactor. Irradiation in-core leads to damage of microspheres. This research studied factors present in-core such as heat, gamma radiation, and thickness of lead shielding, for their impact on microsphere quality. Additionally, this research looked at the potential of reactive oxygen species causing damage once microspheres are suspended in liquid. Thresholds for damage were identified for temperature and gamma radiation exposure. Radiation interactions in liquid suggest possible damaging effects over time. Finally changing the thickness of lead shielding in core had significant impact on temperature, neutron flux, and microsphere quality.

Radiation therapy has been successful in treating lung cancer patients, but its efficacy is limited by the inability to account for the respiratory motion during treatment planning and radiation dose delivery. Physics-based lung deformation models facilitate the motion computation of both tumor and local lung tissue during radiation therapy. In this dissertation, a novel method is discussed to accurately register 3D lungs across the respiratory phases from 4D-CT datasets, which facilitates the estimation of the volumetric lung deformation models. This method uses multi-level and multi-resolution optical flow registration coupled with thin plate splines (TPS), to address registration issue of inconsistent intensity across respiratory phases. It achieves higher accuracy as compared to multi-resolution optical flow registration and other commonly used registration methods. Results of validation show that the lung registration is computed with 3 mm Target Registration Error (TRE) and approximately 3 mm Inverse Consistency Error (ICE). This registration method is further implemented in GPU based real time dose delivery simulation to assist radiation therapy planning.

A well-established method for treating lung cancer is curative-intent radiation therapy (RT). The most significant challenge for RT is to accurately target the lesion volume while avoiding the irradiation of surrounding healthy tissue. Currently at the Juravinski Cancer Centre (JCC), treatment plans for lung cancer patients are completed using fluorodeoxyglucose positron emission tomography (FDG-PET) and four-dimensional computed tomography (4DCT) images. There is no clear protocol, however, to compensate for respiratory motion in PET images and it is not known how lesion volumes generated from PET reflect the true volume. This project evaluated methods to optimize the use of PET images in the radiation treatment planning workflow and quantify the effects of respiratory motion. First, a 4D XCAT digital phantom was used to quantify respiratory motion and its effects on lesion displacement. A CTN physical phantom and 3D-printed irregularly shaped lesion were imaged to determine the accuracy of the PET EDGE automated segmentation algorithm (ASA). Lastly, rigid and deformable image registration techniques were used to propagate the diagnostic PET scan of the irregular lesion to the 4D planning CT. PET EDGE was used to generate target volumes which were then compared to internal target volumes (ITVs) generated from manual contouring of the 4DCT image alone. We found that lesion displacement due to respiratory motion can be adequately modeled using a moving platform set to oscillate 1 cm and 2 cm for normal and deep breathing, respectively. Optimal target delineation was found when diagnostic PET was propagated to the planning CT using rigid image registration for lesions that experienced 1 cm of oscillatory motion during imaging. In contrast, PET EDGE would overestimate volumes in static cases and underestimate volumes in instances of 2 cm dynamic motion meant to simulate deep breathing. / Thesis / Master of Science (MSc)

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