<p>On-board imaging is useful for guiding radiation to patients in the treatment position; however, current treatment-room imaging modalities are not sensitive to physiology - features that may differentiate tumor from nearby tissue or identify biological targets, e.g., hypoxia, high tumor burden, or increased proliferation. Single photon emission computed tomography (SPECT) is sensitive to physiology. We propose on-board SPECT for biological target localization.</p><p>Localization performance was studied in computer-simulated and scanner-acquired parallel-hole SPECT images. Numerical observers were forced to localize hot targets in limited search volumes that account for uncertainties common to radiation therapy delivery. Localization performance was studied for spherical targets of various diameters, activity ratios, and anatomical locations. Also investigated were the effects of detector response function compensation (DRC) and observer normalization on target localization. Localization performance was optimized as a function of iteration number and degree of post-reconstruction smoothing. Localization error patterns were analyzed for directional dependencies and were related to the detector trajectory. Localization performance and the effect of the detector trajectory were investigated in a hardware study using a whole-body phantom.</p><p>Typically targets of 6:1 activity were localized as accurately using 4-minute scans as those of 3:1 activity using 20-minute scans. This trend is consistent with the relationship between contrast and noise in the contrast-to-noise ratio (CNR) and implies that higher contrast targets are better candidates for on-board SPECT because of time constraints in the treatment room. Using 4-minute scans, mean localization errors were within 2 mm for superficial targets of 6:1 activity that were proximal to the detector trajectory and of at least 14 mm in diameter. Localization was significantly better (p < 0.05, Wilcoxon signed-rank test) with than without observer normalization and DRC at 5 of 6 superficial tumor sites. Observer normalization improved localization substantially for a target proximal to the much hotter heart. Localization error patterns were shown to be anisotropic and dependent on target position relative to the detector trajectory. Detector views of close approach and of minimal attenuation were predictive of directions with the smallest (magnitude) localization bias and precision. The detector trajectory had a substantial effect on localization performance. In scanner-acquired SPECT images, mean localization errors of a 22-mm-diameter superficial target were 0.8, 1.5, and 6.9 mm respectively using proximal 180°, 360°, and distal 180° detector trajectories, thus demonstrating the benefits of using a proximal 180° detector trajectory.</p><p>In conclusion, the potential performance characteristics of on-board SPECT were investigated using computer-simulation and real-detector studies. Mean localization errors < 2 mm were obtained for proximal, superficial targets with diameters >14 mm and of 6:1 activity relative to background using scan times of approximately 5 minutes. The observed direction-dependent localization errors are related to the detector trajectory and have important implications for radiation therapy. This works shows that parallel-hole SPECT could be useful for localizing certain biological targets.</p> / Dissertation

<p>Imaging respiratory induced tumor motion in the radiation therapy treatment room could eliminate the necessity for large motion encompassing margins that result in excessive irradiation of healthy tissues. Currently available image guidance technologies are ill-suited for this task. Two-dimensional fluoroscopic images are acquired with sufficient speed to image respiratory motion. However, volume information is not present, and soft tissue structures are often not visible because a large volume is projected onto a single plane. Currently available volumetric imaging modalities are not acquired with sufficient speed to capture full motion trajectory information. Four-dimensional cone-beam computed tomography (4D CBCT) using a gantry mounted 2D flat panel imaging device has been proposed but has been limited by high doses, long scan times and severe under-sampling artifacts. The focus of the work completed in this thesis was to find ways to improve 4D imaging using a gantry mounted 2D kV imaging system. Specifically, the goals were to investigate methods for minimizing imaging dose and scan time while achieving consistent, controllable, high quality 4D images.</p><p>First, we introduced four-dimensional digital tomosynthesis (4D DTS) and characterized its potential for 3D motion analysis using a motion phantom. The motion phantom was programmed to exhibit motion profiles with various known amplitudes in all three dimensions and scanned using a 2D kV imaging system mounted on a linear accelerator. Two arcs of projection data centered about the anterior-posterior and lateral axes were used to reconstruct phase resolved DTS coronal and sagittal images. Respiratory signals were obtained by analyzing projection data, and these signals were used to derive phases for each of the projection images. Projection images were sorted according to phase, and DTS phase images were reconstructed for each phase bin. 4D DTS target location accuracies for peak inhalation and peak exhalation in all three dimensions were limited only by the 0.5 mm pixel resolution for all DTS scan angles. The average localization errors for all phases of an assymetric motion profile with a 2 cm peak-to-peak amplitude were 0.68, 0.67 and 1.85 mm for 60 <super> o <super/> 4D DTS, 360<super> o <super/> CBCT and 4DCT, respectively. Motion artifacts for 4D DTS were found to be substantially less than those seen in 4DCT, which is the current clinical standard in 4D imaging. </p><p>We then developed a comprehensive framework for relating patient respiratory parameters with acquisition and reconstruction parameters for slow gantry rotation 4D DTS and 4D CBCT imaging. This framework was validated and optimized with phantom and lung patient studies. The framework facilitates calculation of optimal frame rates and gantry rotation speeds based on patient specific respiratory parameters and required temporal resolution (task dependent). We also conducted lung patient studies to investigate required scan angles for 4D DTS and achievable dose and scan times for 4D DTS and 4D CBCT using the optimized framework. This explicit and comprehensive framework of relationships allowed us to demonstrate that under-sampling artifacts can be controlled, and 4D CBCT images can be acquired using lower doses than previously reported. We reconstructed 4D CBCT images of three patients with accumulated doses of 4.8 to 5.7 cGy. These doses are three times less than the doses used for the only previously reported 4D CBCT investigation that did not report images characterized by severe under-sampling artifacts. </p><p>We found that scan times for 200<super> o <super/> 4D CBCT imaging using acquisition sequences optimized for reduction of imaging dose and under-sampling artifacts were necessarily between 4 and 7 minutes (depending on patient respiration). The results from lung patient studies concluded that scan times could be reduced using 4D DTS. Patient 4D DTS studies demonstrated that tumor visibility for the lung patients we studied could be achieved using 30<super> o <super/> scan angles for coronal views. Scan times for those cases were between 41 and 50 seconds. Additional dose reductions were also demonstrated. Image doses were between 1.56 and 2.13 cGy. These doses are well below doses for standard CBCT scans. The techniques developed and reported in this thesis demonstrate how respiratory motion can be imaged in the radiotherapy treatment room using clinically feasible imaging doses and scan times.</p> / Dissertation

Stereotactic radiosurgery with several static conformal beams shaped by a micro multileaf collimator (muMLC) is used for treating small irregularly shaped brain lesions. Specific requirements for this technique are a precise localization and positioning of the target (1mm) and a precise (1mm) and numerically accurate (+/-5%) dose delivery. In this work, a pencil beam algorithm based treatment planning software BrainScan 5.2 (Brainlab, Germany) is validated against measurements (diode, radiographic films) and Monte Carlo simulations (BEAMnrc and XVMC codes). The latter is required because of difficulties in obtaining precise and accurate dose measurements for small fields. A dedicated muMLC component module for the BEAMnrc code was developed as part of this project. Results show that Monte Carlo calculations agree with measured dose distributions to within 2% and/or 1 mm except for field sizes smaller than 1.2 cm where agreement is within 5% due to uncertainties in measured output factors. Comparison with the pencil beam algorithm calculations were performed for square and irregularly shaped fields at different incidence angles on rectangular and humanoid homogeneous phantoms. Results show that the pencil beam algorithm is suitable for radiosurgery although some differences were found in the comparison of interleaf leakage and beam profile penumbras.

Les maladies cardio-vasculaires demeurent une cause majeure de mortalité et morbidité dans les sociétés développées. La recherche de déterminants prédictifs d’évènements vasculaires représente toujours un enjeu d’actualité face aux coûts croissants des dépenses reliées aux soins médicaux et à l’élargissement des populations concernées, notamment face à l’occidentalisation des pays émergeants comme l’Inde, le Brésil et la Chine. La cardiologie nucléaire occupe depuis trente ans, une place essentielle dans l’arsenal des méthodes diagnostiques et pronostiques des cardiopathies. De plus, de nouvelles percées permettront de dépister d’une façon plus précoce et précise, la maladie athérosclérotique cardiaque et périphérique chez les populations atteintes ainsi qu’en prévention primaire. Nous présenterons dans cette thèse, deux approches nouvelles de la cardiologie nucléaire. La dysfonction endothéliale est considérée comme le signal pathologique le plus précoce de l’athérosclérose. Les facteurs de risques cardiovasculaires traditionnels atteignent la fonction endothéliale et peuvent initier le processus d’athérosclérose même en l’absence de lésion endothéliale physique. La quantification de la fonction endothéliale coronarienne comporte donc un intérêt certain comme biomarqueur précoce de la maladie coronarienne. La pléthysmographie isotopique, méthodologie développée lors de ce cycle d’étude, permet de quantifier la fonction endothéliale périphérique, cette dernière étant corrélée à la fonction endothéliale coronarienne. Cette méthodologie est démontrée dans le premier manuscrit (Harel et. al., Physiol Meas., 2007). L’utilisation d’un radiomarquage des érythrocytes permet la mesure du flot artériel au niveau du membre supérieur pendant la réalisation d’une hyperémie réactive locale. Cette nouvelle procédure a été validée en comparaison à la pléthysmographie par jauge de contrainte sur une cohorte de 26 patients. Elle a démontré une excellente reproductibilité (coefficient de corrélation intra-classe = 0.89). De plus, la mesure du flot artérielle pendant la réaction hyperémique corrélait avec les mesure réalisées par la méthode de référence (r=0.87). Le deuxième manuscrit expose les bases de la spectroscopie infrarouge comme méthodologie de mesure du flot artériel et quantification de la réaction hyperémique (Harel et. al., Physiol Meas., 2008). Cette étude utilisa un protocole de triples mesures simultanées à l’aide de la pléthysmographie par jauge de contrainte, radio-isotopique et par spectroscopie infrarouge. La technique par spectroscopie fut démontrée précise et reproductible quant à la mesure des flots artériels au niveau de l’avant-bras. Cette nouvelle procédure a présenté des avantages indéniables quant à la diminution d’artéfact et à sa facilité d’utilisation. Le second volet de ma thèse porte sur l’analyse du synchronisme de contraction cardiaque. En effet, plus de 30% des patients recevant une thérapie de resynchronisation ne démontre pas d’amélioration clinique. De plus, ce taux de non-réponse est encore plus élevé lors de l’utilisation de critères morphologiques de réponse à la resynchronisation (réduction du volume télésystolique). Il existe donc un besoin urgent de développer une méthodologie de mesure fiable et précise de la dynamique cardiaque. Le troisième manuscrit expose les bases d’une nouvelle technique radio-isotopique permettant la quantification de la fraction d’éjection du ventricule gauche (Harel et. al. J Nucl Cardiol., 2007). L’étude portant sur 202 patients a démontré une excellente corrélation (r=0.84) avec la méthode de référence (ventriculographie planaire). La comparaison avec le logiciel QBS (Cedar-Sinai) démontrait un écart type du biais inférieur (7.44% vs 9.36%). De plus, le biais dans la mesure ne démontrait pas de corrélation avec la magnitude du paramètre pour notre méthodologie, contrairement au logiciel alterne. Le quatrième manuscrit portait sur la quantification de l’asynchronisme intra-ventriculaire gauche (Harel et. al. J Nucl Cardiol, 2008). Un nouveau paramètre tridimensionnel (CHI: contraction homogeneity index) (médiane 73.8% ; IQ 58.7% - 84.9%) permis d’intégrer les composantes d’amplitude et du synchronisme de la contraction ventriculaire. La validation de ce paramètre fut effectuée par comparaison avec la déviation standard de l’histogramme de phase (SDΦ) (médiane 28.2º ; IQ 17.5º - 46.8º) obtenu par la ventriculographie planaire lors d’une étude portant sur 235 patients. Ces quatre manuscrits, déjà publiés dans la littérature scientifique spécialisée, résument une fraction des travaux de recherche que nous avons effectués durant les trois dernières années. Ces travaux s’inscrivent dans deux axes majeurs de développement de la cardiologie du 21ième siècle. / Cardiovascular diseases remain a major cause of mortality and morbidity in developed countries. The search for predictive determinants of vascular events represents a relevant and timely goal, considering the increasing costs of medical care and the progress in developing countries such as India, Brazil and China. Nuclear cardiology has, for 30 years, played an essential role in the diagnosis and prognosis of various cardiac and vascular diseases. Moreover, new developments will allow earlier and more specific detection of cardiac and peripheral atherosclerosis disease in affected individuals and in primary prevention. In this thesis, we will focus on advances in two major themes of nuclear cardiology. Endothelial dysfunction is regarded as the earliest pathological markers of atherosclerosis. Traditional cardiovascular risks factors impair endothelial function and can initiate the atherosclerosis process, even in the absence of overt endothelial disruption. Quantification of coronary endothelial function is, therefore, of considerable interest as an early biomarker for coronary disease. The radionuclide plethysmography methodology developed during the course of my doctoral studies allows the quantification of peripheral endothelial function, which has been correlated with coronary endothelial function. This methodology is detailed in the first manuscript (Harel et. al., Physiol Meas., 2007). The use of red blood cell radio-labeling permits arterial flow to be measured in the upper limb during local reactive hyperemia. This new procedure was validated against strain gauge plethysmography in a cohort of 26 patients with excellent reproducibility (intraclass coefficient of correlation = 0.89). Moreover, the arterial measurements of flow during the hyperemic reaction correlated well with the reference method (r=0.87). The second manuscript exposes the basis of infrared spectroscopy as a method for measuring arterial flow and quantifying the hyperemic reaction (Harel et. al., Physiol Meas., 2008). The study protocol consisted of simultaneous measurements by strain gauge, radionuclide and infrared spectroscopy plethysmography. The spectroscopy technique was shown to be precise and reproducible for forearm measurement of arterial blood flow. This novel procedure came major advantages in reducing artifacts and in its ease of use. The second axis of my thesis relates to the analysis of cardiac contraction synchrony. Indeed, more than 30% of patients receiving resynchronization therapy do not show clinical improvement. Moreover, this non-response rate is even higher if we consider morphological criteria of resynchronization (end-systolic volume reduction). There is therefore, an urgent need to improve a methodology to reliably and precisely measure cardiac dynamics so as to identify and monitor potential responders. The third manuscript exposes the basis of a new radionuclide technique to quantify left ventricle ejection fraction (Harel et. al. J Nucl Cardiol., 2007). The study of 202 patients showed an excellent correlation (r=0.84) with the reference method (planar ventriculography). The comparison with QBS software (Cedar-Sinai), showed a lower standard deviation of bias (7.44% vs 9.36%). Moreover, unlike the alternative software, the bias did not correlate with the magnitude of the ejection fraction. The fourth manuscript relates to the quantification of the left intra-ventricular synchronism (Harel et. al. J Nucl Cardiol, 2008). A new three-dimensional parameter (CHI: contraction homogeneity index) (median 73.8%; IQ 58.7% - 84.9%) was defined to allow the integration of amplitude and synchrony components of ventricular contraction. Validation of this parameter was undertaken out by comparing the standard deviation of the histogram of phase (SDΦ) (median 28.2º; IQ 17.5º- 46.8º) obtained by planar ventriculography in a study of 235 patients. These four manuscripts, already published in the specialized scientific literature, summarize a fraction of the research tasks that we have carried out during the three last years, representing two major axes of nuclear cardiology advancement in the 21st century.

<p>Yttrium-90 (⁹⁰Y) is one of the most commonly used radionuclides in targeted radionuclide therapy (TRT). In treatment planning, reliable prediction of the 90Y distribution <i>in vivo</i> is essential to performing both safe and effective therapy. However, the distribution of surrogate agents used in treatment planning may not exactly predict the distribution of ⁹⁰Y. Thus it would be useful to image the ⁹⁰Y distribution after therapeutic administration to provide the ground truth for the ⁹⁰Y distribution. This would facilitate evaluating and potentially improving pre-therapy methods for individualizing and optimizing the therapy. Single photon emission computed tomography (SPECT) is a powerful imaging technique for estimating 3D distribution of radionuclides <i> in vivo.</i> However, as an essentially pure &beta;-particle emitter, ⁹⁰Y does not emit gamma photons considered appropriate for SPECT imaging. One possible solution is to image bremsstrahlung photons generated by the interaction of the 13-particles with atomic nuclei in the body. The continuous and broad energy distribution of bremsstrahlung photons, however, imposes substantial challenges on quantitative SPECT imaging. The overall goal of this work was to develop and evaluate new quantitative bremsstrahlung SPECT methods for improving the reliability (accuracy and precision) of the ⁹⁰Y activity estimates for the dosimetry application. </p><p> Reconstruction method, acquisition energy window, and collimator are three crucial factors that determine the reliability of quantitative SPECT imaging. </p><p> In this work, we first developed an improved quantitative reconstruction method. The improvement resulted from more accurate modeling of the image formation process in a statistical iterative reconstruction method. Improvements in the model included enhancements to the Monte Carlo (MC) bremsstrahlung simulation used to generate various components of the model and better modeling of the energy dependence of various image degrading effects through the use of multiple energy ranges. The evaluation, using both a physical phantom experiment and an XCAT phantom simulation, demonstrated more accurate modeling of the image formation process and more accurate organ activity estimates than previous methods. </p><p> We then developed new methods for optimizing the acquisition energy window and parallel-hole collimator, respectively, for quantitative imaging. These methods account for the effects of energy window or collimator on both the bias and the variance of the activity estimates, and are applicable to radionuclides with any type of emission energy spectra. We applied these methods to optimizing the energy window and collimator for quantitative ⁹⁰Y bremsstrahlung SPECT in microsphere brachytherapy. </p><p> In addition to improving the reliability of quantitative imaging, we also did some work on improving the visual image quality for ⁹⁰Y bremsstrahlung SPECT imaging. We optimized the energy window for a detection task based on the performance of an observer that accounts for the degradation of the image quality due to model-mismatch. This is important as detection of post-administration extra-hepatic 90Y could be useful in predicting and preparing for complications such as radiation-induced gastro-intestinal ulcerations. </p>

GEANT4 is a Monte Carlo code developed in an object-oriented environment. It provides three models of electromagnetic physics, namely Standard, Low-energy, and Penelope. In this work, we examined the accuracy of the photon and electron interactions, and developed a user code for external beam radiotherapy simulations. The code has the capabilities to collect phase space data, perform variance reduction schemes, and calculate dose distributions in a phantom. For all three models, the dose distributions of monoenergetic and clinical photon beams in water are in good agreement with the EGSnrc simulations. For electron beams, the results depend on the maximum electron step size. Significant step size artifacts are also found in the transport of electrons through a thin aluminum slab. Our studies of interface perturbation effects and Fano cavity response illustrated potential problems with the condensed history algorithm. Overall, GEANT4 can be used in applications where electron transport is not critical.

This thesis addresses the problem of registration, merging and viewing medical images from multiple modalities for stereotactic surgery planning. A technique is presented, using volumetric rendering of tomographic data, to create anatomical perspective projections that can be easily merged with vascular projections. / The geometry of the digital subtraction angiogram (DSA) projection is reproduced by the rendering process to enable registration between the DSA radiograph and the volumetric projection. The viewing parameters are calculated from the location of fiducial markers in the image. Each angiogram is overlayed onto a translucent volumetric projection of computed tomography (CT) or magnetric resonance (MR) data, rendered to give a matched view. / Until recently, rendered medical volumes have been used qualitatively in the diagnostic and surgical planning process. Since the volumetric projections are matched to the DSA images, the complete set of stereotactic surgery planning tools can be used to identify points and measure distances in the rendered images. / A point spread function of the rendering process is derived to establish a theoretical limit on the accuracy of the technique and is verified by experimentation.

The aim of stereotactic radiosurgery is to deliver a high and uniform radiation dose to the target volume and a minimized dose to the surrounding healthy tissue. Various linac-based radiosurgical techniques are used clinically: multiple non-coplanar converging arcs, dynamic arc rotation, and conical rotation. The techniques differ in their beam distribution over the patient's head. / A study of the beam distribution characteristics for the clinical linac-based radiosurgical techniques is presented. Two spiral linac-based radiosurgical techniques are developed: the uniform dose-rate spiral irradiation and the dose-rate-weighted spiral irradiation. Both exhibit the same spiraling beam entry trace over the patient's head; however, they differ in their beam distribution along the spiral. The dose-rate-weighted spiral irradiation provides a uniform beam distribution over the 2pi solid angle available in radiosurgery. / The currently existing techniques and the spiral techniques are then compared using the cumulative dose-volume histogram (CDVH) tools available with the McGill Treatment Planning System (MPS). The dose-rate-weighted spiral technique leads to lower dose inhomogeneities within the target volume and better dose conformity within the target. Moreover, it also encompasses smaller volumes of tissue at all isodose levels with larger differences at low isodose levels. A conclusion is reached that the dose-rate-weighted spiral irradiation technique offers interesting advantages over the currently used clinical linac-based techniques.

Algorithms for optimization and verification of radiation treatments have been developed. The first one, an active set algorithm for inverse treatment planning employs a conjugate gradient routine for subspace minimization in order to achieve a higher rate of convergence than the widely used constrained steepest descent method at the expense of a negligeable amount of overhead calculations and storage. The active set algorithm is found to be superior to the constrained steepest descent in terms of both its convergence properties and the residual value of the cost functions at termination. The active set approach can significantly accelerate the process of inverse treatment planning by decreasing the number of time consuming dose calculations. / The second algorithm employs a continuous penalty function method to solve approximately a large-scale constrained minimization problem which reflects the goal of sparing healthy tissues as much as possible while delivering the necessary tumorcidal dose. The performance of the continuous penalty function method is optimized by a numerical investigation of a few integration schemes and a pair of weighting functions which influence the performance of the method. Clinical examples are presented that illustrate possible applications of the techniques in the context of multi-objective optimization. / An image correlation based algorithm for automatic registration of pairs of portal images has also been developed. Accounting for both in-plane translations and rotations, the algorithm uses fast-Fourier-transforms and a sequential approach to speed up the registration without degrading the accuracy of the match. The technique has also been applied to the automatic registration of portal images to digitally reconstructed radiographs (DRRs) which have been modified to resemble megavoltage images. The results indicate the feasibility of this approach as a tool for treatment setup verification.

To increase the effectiveness of conventional radiotherapy in the treatment of cancer, different drugs can be administered. The aim of this project is to investigate biodegradable polyanhydride carrier matrices (PCPP-SA; 20:80) as a localized slow release delivery system for halogenated pyrimidines, in our case Bromodeoxyuridine (BrdU). Our in vitro experiments show that RIF-1 cells which have incorporated BrdU into their DNA over 4 doublings show significant increase in the initial slope (alpha-value) of their radiation cell survival curves, indicating an increase in radiosensitivity. To investigate the radiosensitization potential of BrdU in vivo, biodegradable BrdU/polymer combinations (20% w/w) were prepared and implanted directly into RIF-1 tumors, grown subcutaneously on the backs of C3H/Km mice. Clonogenic/excision assays were done with these tumors exposed to BrdU/polymer implants for several cell cycles before irradiation in situ to determine the extent of radiosensitization on the basis of cell survival. Tumor growth delay (TGD) measurements were also used as an index of tumor control following different treatments (single dose or fractionated doses) with and without the drug/polymer implants. All results indicate that BrdU, combined with radiation, increases TGD, while having no effect on non-irradiated tumors. The extent of substitution of thymidine by BrdU in DNA were also determined. This project was supported by the National Cancer Institute of Canada.