<p>Positron emission tomography (PET) is a nuclear medicine diagnostic imaging exam of metabolic processes in the body. Radiotracers, which consist of positron emitting radioisotopes and a molecular probe, are introduced into the body, emitted radiation is detected, and tomographic images are reconstructed. The primary clinical PET application is in oncology using a glucose analogue radiotracer, which is avidly taken up by some cancers.</p><p>It is well known that PET performance and image quality degrade as body size increases, and epidemiological studies over the past two decades show that the adult US population's body size has increased dramatically and continues to increase. Larger patients have more attenuating material that increases the number of emitted photons that are scattered or absorbed within the body. Thus, for a fixed amount of injected radioactivity and acquisition duration, the number of measured true coincidence events will decrease, and the background fractions will increase. Another size-related factor, independent of attenuation, is the volume throughout which the measured coincidence counts are distributed: for a fixed acquisition duration, as the body size increases, the counts are distributed over a larger area. This is true for both a fixed amount of radioactivity, where the concentration decreases as size increases, and a fixed concentration, where the amount radioactivity increases with size.</p><p>Time-of-flight (TOF) PET is a recently commercialized technology that allows the localization, with a certain degree of error, of a positron annihilation using timing differences in the detection of coincidence photons. Both heuristic and analytical evaluations predict that TOF PET will have improved performance and image quality compared to non-TOF PET, and this improvement increases as body size increases. The goal of this dissertation is to parameterize the image quality improvement of TOF PET compared to non-TOF PET as a function of body size. Currently, no standard for comparison exists.</p><p>Previous evaluations of TOF PET's improvement have been made with either computer-simulated data or acquired data using a few discrete phantom sizes. A phantom that represents a range of attenuating dimensions, that can have a varying radioactivity distribution, and that can have radioactive inserts positioned throughout its volume would facilitate characterizing PET system performance and image quality as a function of body size. A fillable, tapered phantom, was designed, simulated, and constructed. The phantom has an oval cross-section ranging from 38.5 &times; 49.5 cm to 6.8 &times; 17.8 cm, a length of 51.1 cm, a mass of 6 kg (empty), a mass of 42 kg (water filled), and 1.25-cm acrylic walls.</p><p>For this dissertation research, PET image quality was measured using multiple, small spheres with diameters near the spatial resolution of clinical whole-body PET systems. Measurements made on a small sphere, which typically include a small number of image voxels, are susceptible to fluctuations over the few voxels, so using multiple spheres improves the statistical power of the measurements that, in turn, reduces the influence of these fluctuations. These spheres were arranged in an array and mounted throughout the tapered phantom's volume to objectively measure image quality as a function of body size. Image quality is measured by placing regions of interest on images and calculating contrast recovery, background variability, and signal to noise ratio.</p><p>Image quality as a function of body size was parameterized for TOF compared to non-TOF PET using 46 1.0-cm spheres positioned in six different body sizes in a fillable, tapered phantom. When the TOF and non-TOF PET images were reconstructed for matched contrast, the square of the ratio of the images' signal-to-noise ratios for TOF to non-TOF PET was plotted as a function, <italic>f</italic>(<italic>D</italic>), of the radioactivity distribution size, <italic>D</italic>, in cm. A linear regression was fit to the data: <italic>f</italic>(<italic>D</italic>) = 0.108<italic>D</italic> - 1.36. This was compared to the ratio of <italic>D</italic> and the localization error, <italic>&sigma;_d</italic>, based on the system timing resolution, which is approximately 650 ps for the TOF PET system used for this research. With the image quality metrics used in this work, the ratio of TOF to non-TOF PET fits well to a linear relationship and is parallel to <italic>D/&sigma;_d</italic>. For <italic>D</italic> < 20 cm, there is no image quality improvement, but for radioactivity distributions <italic>D</italic> > 20 cm, TOF PET improves image quality over non-TOF PET. PET imaging's clinical use has increased over the past decade, and TOF PET's image quality improvement for large patients makes TOF an important new technology because the occurrence of obesity in the US adult population continues to increase.</p> / Dissertation

Equispaced beam arrangements are typically used for IMRT plans. This beam arrangement provides adequate dose coverage to the target while sparing dose to other structures. However, an equispaced beam arrangement may not provide the best dose coverage to the target while sparing dose to the other structures. Beam angle optimization attempts to optimize the beam directions to produce a better IMRT plan; this is achieved by increasing dose to the target while minimizing dose to the remaining structures. Most methods of beam angle optimization attempt to optimize the beam angles and the beam intensity profiles to find an optimal set of beam angles. This thesis attempts to optimize the beam angles without determining the beam intensity profiles. An MCNP simulation is run to score the beam directions; the simulation is run as an adjoint problem to reduce simulation time, with the target as the source and the detectors scoring the dose for the gantry angles of the beam. Then, an optimization algorithm is run to select a set of beam angles for an optimized IMRT plan. The optimized IMRT plan is compared to an equispaced IMRT plan on a commercial treatment planning system to determine if this method of beam angle optimization is better than using an equispaced beam arrangement. The results of this thesis indicate that the coupling of an MCNP simulation for scoring with an optimization algorithm to select beam angles will produce a better IMRT plan than an equispaced IMRT plan. Three different geometries were used and for all geometries, the optimized IMRT plan had a higher average dose to the target while maintaining or increasing dose sparing to the critical structure and normal tissue.

In medical and health physics, we are interested in the effects of ionizing radiation on biological systems, in particular, human biology. The main process by which ionizing radiations causes damage to biological systems, is through the creation of radicals close to DNA strands. The radicals are very reactive and those created within close proximity to DNA will react with the DNA causing damage, in particular single strand or double strand breaks. This damage to the DNA can cause mutations that can kill the cell, either mitotically or apoptotically, or possibly lead to a cancerous formation. Therefore it is important to study how these radicals interact with DNA strands for a correlation between the resultant products of radical reactions and DNA strand breaks. For this study, we look at the most important radical, the OH radical and it's addition to DNA bases. We will study, through quantum chemistry, the thermodynamics of OH radical addition to the four bases, Adenine, Guanine, Cytosine and Thymine. The Jaguar program developed by Schrodinger was used for DFT calculations of the Gibbs free energy of the addition. In addition, calculations for the partial charge, HOMO's and Fukui indices were calculated and compared to experiment.

Purpose: At the Wellington Blood and Cancer Centre (WBCC), Volumetric Modulated Arc Therapy (VMAT) is used to treat a variety of head and neck (H&N) cancers. Presently, the complexity of plans is limited to ensure the accuracy of patient treatment within the range of the departmental experience. The complexity limitation is applied through use of a monitor unit (MU) constraint during plan optimisation. Plans of higher complexity can be obtained by loosening the MU constraint, and setting more stringent optimisation objectives on organs at risk (OAR) and target volumes (PTV). This could potentially yield higher quality treatment plans but may also degrade the accuracy of the TPS calculation or the plan delivery at the treatment machine. The aim of this study is to investigate the level of plan complexity that results in accurate treatment plan calculation and delivery, and quantify the corresponding gain in plan quality. Methods: Five previously treated H&N patients were selected for the study. Each patient’s clinical plan was used as the lowest complexity level and labelled C1. Subsequently, an approximate pareto-optimal plan (C3) was created that focused equally on sparing spinal cord, brain stem and parotid gland while maintaining, or improving on, the previously obtained target coverage. Next, a C2 plan was created such that the plan quality was in between C1 and C3. Plan quality of each complexity level was assessed in terms of OAR sparing and PTV coverage. The average leaf pair opening (LPO), critical leaf pair opening (%LPO<1cm) and mean leaf travel were used as plan complexity metrics. The calculation and delivery accuracy of each complexity level using Varian TrueBeam LINAC/Eclipse TPS was verified using time resolved point dose measurements (TRPD), EBT film measurements (Ashland Inc.) and ArcCheck measurements (Sun Nuclear Corp.). A comprehensive uncertainty analysis was carried out including a quantification of the measurement and delivery reproducibility. Results: Increasing plan complexity from C1 to C3 reduced the Spinal Cord D1cc, Brain Stem D1 and Parotid Gland Dmean up to 14.7 Gy, 7.1 Gy and 7.8 Gy, respectively. In addition, C3 plans improved the target coverage compared to C1 plans, with the PTV66 and PTV54 D98 increasing up to 1.0 Gy and 0.6 Gy, respectively. The verification measurements showed that the plan calculation and delivery for all complexity levels was well within clinical acceptance levels (Table 1). TRPD showed that VMAT dose delivery itself was repeatable within 0.1% (1 S.D.) over 10 consecutive deliveries for both C1 and C3 complexity levels. Discussion & Conclusions: This study has shown that increasing the plan complexity can provide significant dosimetric advantages for the treatment of H&N cancer. Verification measurement results indicated that this did not noticeably degrade the calculation and delivery accuracy of VMAT using a Varian TrueBeam LINAC and our Eclipse TPS beam model. H&N VMAT at the WBCC can now be developed further with greater confidence in the dosimetric accuracy of higher complexity plans.

Mammographic breast density (MBD) is a strong risk factor for developing breast cancer. MBD is typically estimated by manually selecting the area occupied by the dense tissue on a mammogram. There is interest in measuring the volume of dense tissue, or volumetric breast density (VBD), as it could potentially be a stronger risk factor. This dissertation presents and validates an algorithm to measure the VBD from digital mammograms. The algorithm is based on an empirical calibration of the mammography system, supplemented by physical modeling of x-ray imaging that includes the effects of beam polychromaticity, scattered radation, anti-scatter grid and detector glare. It also includes a method to estimate the compressed breast thickness as a function of the compression force, and a method to estimate the thickness of the breast outside of the compressed region. The algorithm was tested on 26 simulated mammograms obtained from computed tomography images, themselves deformed to mimic the effects of compression. This allowed the determination of the baseline accuracy of the algorithm. The algorithm was also used on 55 087 clinical digital mammograms, which allowed for the determination of the general characteristics of VBD and breast volume, as well as their variation as a function of age and time. The algorithm was also validated against a set of 80 magnetic resonance images, and compared against the area method on 2688 images. A preliminary study comparing association of breast cancer risk with VBD and MBD was also performed, indicating that VBD is a stronger risk factor. The algorithm was found to be accurate, generating quantitative density measurements rapidly and automatically. It can be extended to any digital mammography system, provided that the compression thickness of the breast can be determined accurately.

Raman microscopy (RM) is a vibrational spectroscopic technique capable of obtaining sensitive measurements of molecular composition, structure, and dynamics from a very small sample volume (~1 µm). In this work, a RM system was developed for future applications in cellular radiobiology, the study of the effects of ionizing radiation on cells and tissues, with particular emphasis on the capability to investigate the internal molecular composition of single cells (10-50 µm in diameter). The performance of the RM system was evaluated by imaging 5 µm diameter polystyrene microbeads dispersed on a silicon substrate. This analysis has shown that RM of single cells is optimized for this system when using a 100x microscope objective and a 50 µm confocal collection aperture. Quantitative measurements of the spatial, confocal, and spectral resolution of the RM system have been obtained using metal nanostructures deposited on a flat silicon substrate. Furthermore, a spectral investigation of several substrate materials was successful in identifying low-fluorescence quartz as a suitable substrate for RM analysis of single cells. Protocols have been developed for culturing and preparing two human tumor cell lines, A549 (lung) and DU145 (prostate), for RM analysis, and a spectroscopic study of these two cell lines was performed. Spectra obtained from within cell nuclei yielded detectable Raman signatures from all four types of biomolecules found in a human cell: proteins, lipids, carbohydrates, and nucleic acids. Furthermore, Raman profiles and 2D maps of protein and DNA distributions within single cells have been obtained with micron-scale spatial resolution. It was also found that the intensity of Raman scattering is highly dependent on the concentration of dense nuclear material at the point of Raman collection. RM shows promise for studying the interactions of ionizing radiation with single cells, and this work has been successful in providing a foundation for the development of future radiobiological RM experiments.

The goal of this study was to quantify the impact of dose uncertainty on radio-biological treatment plan evaluation. A formalism was developed for assessing the impact of dose uncertainty on survival fraction (SF). To distinguish between spatial and probabilistic dose variations, we define equivalent stochastic dose (ESD) as the voxel dose that gives an expected survival fraction for the randomly deposited dose. In the case where the probabilistic voxel dose follows a Gaussian distribution, we de-rive an analytic expression for SF(ESD). We show the analytic expression can account for multi-voxel dose distributions that incorporate both probabilistic and spatial dose heterogeneities. In addition, we incorporate dose uncertainty in the calculation of tu¬mour control probability (TCP) using the ESD formalism. We verify the derivation and implementation of the derived expression using the Monte Carlo method for cases of 60 Gy and 70 Gy at 2 Gy per fraction. The results show that the derived formalism is an effective method for evaluating the radiobiological impact of dose uncertainties on treatment plan evaluation.

A technique for the in vivo dose verification of intensity modulated radiation therapy (IMRT) has been developed. An electronic portal image, calibrated in terms of absolute dose, is acquired for each radiation field following transmission through the patient at the time of treatment. For an IMRT field, the portal image signal is back-projected through a model of the patient in order to calculate the dose at the isocentric plane perpendicular to the beam central axis. The IMRT in vivo dose verification technique was adapted for volumetric modu- lated arc therapy (VMAT) treatments when a single dosimetric image is acquired over an arc. The patient dose along axis of gantry rotation can be directly related to the signal along the vertical axis of EPIs in integrated mode. In this novel VMAT in vivo dosimetry technique, the portal image signal is back-projected through a rotationally averaged model of the patient to calculate a 1D in vivo dose along the axis of gantry rotation. A research ethics board clinical study was approved and transmission portal images were acquired at regular intervals from human subjects. Portal image-derived isocenter point doses were in good agreement with treatment planning system (TPS) calculations for IMRT (mean difference δ=0.0%, standard deviation of the differences σ=4.3%) and VMAT (δ=1.1%, σ=1.7%). The one-dimensional (VMAT) and two-dimensional (IMRT) reconstructed doses were further analyzed by calculating mean dose differences and γ−evaluation pass-rates, which were also shown to be in good agreement with TPS calculations. The portal image-based in vivo dosimetry techniques were shown to be clinically feasible, with reconstruction times on the order of minutes for the first fraction and less than one minute for each fraction thereafter. / Graduate / 0760 / 0574 / 0760

Monitoring treatment efficacy is a large area of cancer research as it can increase the effectiveness of therapy regimens. Diffusion weighted Magnetic Resonance imaging (DWI), allows assessment of tissue microstructure without exogenous contrast agents. In this thesis, two different DWI techniques were used to acquire data from acute myeloid leukemia cells undergoing apoptosis, and data was fitted to an analytical model of re- stricted diffusion. Results indicated a decrease in average restriction size from 6.4 to 2.7μm, and an increase in the restricted diffusion coefficient from 0.17 to 0.82μm^2/ms in untreated versus treated cells. The free diffusion coefficient was constant indicating changes in restrictions, rather than any intrinsic changes in the intra-cellular or extra- cellular fluid. This combination of techniques has the potential for use in preclinical and clinical settings as it demonstrates that apoptotic changes may be measured consistently.

Monitoring treatment efficacy is a large area of cancer research as it can increase the effectiveness of therapy regimens. Diffusion weighted Magnetic Resonance imaging (DWI), allows assessment of tissue microstructure without exogenous contrast agents. In this thesis, two different DWI techniques were used to acquire data from acute myeloid leukemia cells undergoing apoptosis, and data was fitted to an analytical model of re- stricted diffusion. Results indicated a decrease in average restriction size from 6.4 to 2.7μm, and an increase in the restricted diffusion coefficient from 0.17 to 0.82μm^2/ms in untreated versus treated cells. The free diffusion coefficient was constant indicating changes in restrictions, rather than any intrinsic changes in the intra-cellular or extra- cellular fluid. This combination of techniques has the potential for use in preclinical and clinical settings as it demonstrates that apoptotic changes may be measured consistently.