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.

Objective: CSL360 is a chimeric IgG1 mAb recognizing CD123+/CD131- LSCs responsible for acute myeloid leukemia (AML). The in vitro targeting properties of 111In-labeled CSL360 modified with nuclear localization sequence (NLS) were evaluated in AML cells. Methods: 111In-NLS-CSL360 was constructed and its binding affinity, cellular uptake and nuclear importation were analyzed on CD123+ cells. Cytotoxicity was evaluated by clonogenic assays on AML cells (CD123+/CD131-). Results: 111In-NLS-CSL360 exhibited preserved binding to CD123. High cellular and nuclear uptake was observed at 266 nM after 24 hour of incubation. Nuclear uptake of 111In-NLS-CSL360 (266 nM) was 2.0-fold higher than 111In-CSL360 (266 nM) after 24 hour of incubation. Clonogenic survival (CS) of AML cells was reduced to 27.5 ± 4.1%. The nuclear uptake and cytotoxicity were reduced when pre-exposed to unlabeled CSL360, indicating 111In-NLS-CSL360 was CD123-specific. Conclusion: 111In-NLS-CSL360 could be a promising radioimmunotherapeutic agent specific for LSCs.

Objective: CSL360 is a chimeric IgG1 mAb recognizing CD123+/CD131- LSCs responsible for acute myeloid leukemia (AML). The in vitro targeting properties of 111In-labeled CSL360 modified with nuclear localization sequence (NLS) were evaluated in AML cells. Methods: 111In-NLS-CSL360 was constructed and its binding affinity, cellular uptake and nuclear importation were analyzed on CD123+ cells. Cytotoxicity was evaluated by clonogenic assays on AML cells (CD123+/CD131-). Results: 111In-NLS-CSL360 exhibited preserved binding to CD123. High cellular and nuclear uptake was observed at 266 nM after 24 hour of incubation. Nuclear uptake of 111In-NLS-CSL360 (266 nM) was 2.0-fold higher than 111In-CSL360 (266 nM) after 24 hour of incubation. Clonogenic survival (CS) of AML cells was reduced to 27.5 ± 4.1%. The nuclear uptake and cytotoxicity were reduced when pre-exposed to unlabeled CSL360, indicating 111In-NLS-CSL360 was CD123-specific. Conclusion: 111In-NLS-CSL360 could be a promising radioimmunotherapeutic agent specific for LSCs.

L’imagerie préclinique est devenue une ressource incontournable pour l’évaluation de paramètres physiopathologiques, pour le suivi du développement tumoral ainsi que pour le développement de thérapies anticancéreuses. Les évolutions technologiques apparues ces dernières années ont conduit au développement de nouvelles modalités d’imagerie ayant un fort potentiel de translation vers la clinique. Ce manuscrit présente diverses approches par imagerie échographique, photoacoustique et de fluorescence dans le proche infrarouge pour le suivi de la pathologie cancéreuse. Dans un premier temps, nous nous sommes intéressés à la caractérisation de l’hypoxie et son suivi au cours du temps dans différents modèles de cancers humains. Différentes stratégies d’imagerie multimodale ont ensuite été mises en oeuvre pour évaluer l’efficacité d’une nouvelle prodrogue thérapeutique permettant la libération d’une molécule active dans le proche environnement tumoral sur des modèles humains de tumeurs pancréatiques, mammaires, pulmonaires. Enfin, dans un contexte de recherche translationnelle, nous avons exploré le potentiel de l’imagerie photoacoustique et de la fluorescence infrarouge pour la mise en évidence de l’invasion ganglionnaire tumorale en mettant en oeuvre des modèles de ganglions sentinelles minimalement envahis. Au cours de ce travail, nous avons montré l’intérêt du suivi de l’hypoxie tumorale en onco-pharmacologie et mis en évidence le fort potentiel de l’imagerie PA pour les approches translationnelles en oncologie. La principale limitation correspond à la profondeur relativement faible des régions explorables, mais ce point suscite actuellement de nombreux développements technologiques. Les études de faisabilité réalisées ainsi que la validation de protocoles de preuves de concept permettront l’exploitation en routine de ces nouvelles modalités d’imagerie. / Preclinical imaging has become an unavoidable step for pathophysiological parameters assessments, for the follow up of tumor growth and for the anticancer therapies development. Technological improvements have emerged in recent years, allowing the emergence of new imaging modalities with a high potential for translation into clinical practice. This manuscript presents several approaches by ultrasound imaging, photoacoustics and near infrared fluorescence in order to monitor the cancer pathology. Initially, we focused on the characterization of hypoxia and its longitudinal assessment in various preclinical models of human cancers. Various multimodal imaging strategies were implemented to assess the efficacy of a new therapeutic prodrug allowing the release of an active molecule in the tumor microenvironment on human models of pancreatic, breast and lung tumors. Finally, in a context of translational research, we explored the potential of photoacoustic and near infrared fluorescence imaging to highlight the lymph node invasion by cancer cells implementing minimally invaded sentinel lymph node models. In this work, we have shown the interest in monitoring the tumor hypoxia in onco-pharmacology and highlighted the high potential of photoacoustic imaging for oncology translational approaches. The main limitation is the relatively shallow depth of regions that we can explore, but this point is currently subject to many technological developments. Feasibility studies performed and validation of proof of concept protocols will enable routine exploitation of these new imaging modalities.

The objective of this work is to develop an on-line planning and delivery technique for palliative radiotherapy of spinal metastases using a linear accelerator capable of cone-beam CT (CBCT) imaging. This technique integrates all preparation and delivery steps into a single session equivalent to an initial treatment session. The key technical challenges pertaining to the development and implementation of this novel treatment technique are related to CBCT image performance, efficient system integration, development of on-line planning tools and design of novel quality assurance (QA) phantoms and processes. Hardware and software image corrections were first implemented to make CBCT images suitable for target definition and planning. These corrections reduced CBCT non-uniformity and improved CBCT-number accuracy. The on-line treatment technique workflow and the integration of all the subsystems involved in the process were assessed on a customized spine phantom constructed for the study. The challenges related to the routine QA of the highly integrated on-line treatment technique were addressed with the construction and validation of an integral test phantom. This phantom, which contains point detectors (diodes) allows for real-time QA of the entire image guidance, planning and treatment process in terms of dose delivery accuracy. The integral test phantom was also effective for the QA of high-dose, high-precision spinal radiosurgery. Simulation of the on-line treatment technique on patient data showed that the planning step was the one of the most time consuming tasks due predominantly to manual target definition. A semi-automatic method for detection and identification of vertebrae on CBCT images was developed and validated to streamline vertebra segmentation and improve the on-line treatment efficiency. With a single patient setup at the treatment unit, patient motion during the on-line process represents the main source of geometric uncertainty for dose delivery. Spine intra-fraction motion was assessed on CBCT for a group of 49 patients treated with a palliative intent. The use of surface marker tracking as a surrogate for spine motion was also evaluated. Finally, the complete on-line planning and delivery technique was implemented in a research ethics board (REB) approved clinical study at the Princess Margaret Hospital and 7 patients have been successfully treated at the time of this report with this novel treatment approach.

Radiation therapy is administered to more than 50% of patients diagnosed with cancer. Mechanisms of interaction between radiation and tumour cells are relatively well understood on a molecular level, but much remains uncertain regarding how radiation interacts with the tumour as a whole. Recent studies have suggested that tumour response to radiation may in fact be regulated by endothelial cell response, consequently stressing the role of tumour blood vessels in radiation treatment response. As a result, various treatment regimens have been proposed to strategically combine radiation with vascular targeting agents. A great deal of effort has been aimed towards developing efficient vascular targeting agents. Nonetheless, no optimal method has yet been devised to strategically deliver such agents. Recent evidence suggesting that these drugs may “normalize” tumour blood vessels and enhance radiosensitivity, is supporting experiments where anti-angiogenic drugs are combined with cytotoxic therapies such as radiotherapy. In contrast, ultrasound-stimulated microbubbles have recently been demonstrated to enhance radiation therapy by biophysically interacting with endothelial cells. When combined with single radiation doses, these microbubbles are believed to cause localized vascular destruction followed by tumour cell death. Finally, a new form of ‘pro-angiogenics’ has also been demonstrated to induce a therapeutic tumour response. The overall aim of this thesis is to study the role of tumour blood vessels in treatment responses to single-dose radiation therapy and to investigate radiation-based vascular targeting strategies. Using pharmacological and biophysical agents, blood vessels were altered to determine how they influence tumour cell death, clonogenicity, and tumour growth, and to study how these may be optimally combined with radiation. Three-dimensional high-frequency power Doppler ultrasound was used throughout these studies to investigate vascular response to therapy.

X-ray scatter in cone-beam computed tomography (CBCT) is known to reduce image quality by introducing image artifacts, reducing contrast, and limiting computed tomography (CT) number accuracy. The extent of the effect of x-ray scatter on CBCT image quality is determined by the shape and magnitude of the scatter distribution in the projections. A method to allay the effects of scatter is imperative to enable application of CBCT to solve a wider domain of clinical problems. The work contained herein proposes such a method. A characterization of the scatter distribution through the use of a validated Monte Carlo (MC) model is carried out. The effects of imaging parameters and compensators on the scatter distribution are investigated. The spectral frequency components of the scatter distribution in CBCT projection sets are analyzed using Fourier analysis and found to reside predominately in the low frequency domain. The exact frequency extents of the scatter distribution are explored for different imaging configurations and patient geometries. Based on the Fourier analysis it is hypothesized the scatter distribution can be represented by a finite sum of sine and cosine functions. The fitting of MC scatter distribution estimates enables the reduction of the MC computation time by diminishing the number of photon tracks required by over three orders of magnitude. The fitting method is incorporated into a novel scatter correction method using an algorithm that simultaneously combines multiple MC scatter simulations. Running concurrent MC simulations while simultaneously fitting the results allows for the physical accuracy and flexibility of MC methods to be maintained while enhancing the overall efficiency. CBCT projection set scatter estimates, using the algorithm, are computed on the order of 1-2 minutes instead of hours or days. Resulting scatter corrected reconstructions show a reduction in artifacts and improvement in tissue contrast and voxel value accuracy.

X-ray scatter in cone-beam computed tomography (CBCT) is known to reduce image quality by introducing image artifacts, reducing contrast, and limiting computed tomography (CT) number accuracy. The extent of the effect of x-ray scatter on CBCT image quality is determined by the shape and magnitude of the scatter distribution in the projections. A method to allay the effects of scatter is imperative to enable application of CBCT to solve a wider domain of clinical problems. The work contained herein proposes such a method. A characterization of the scatter distribution through the use of a validated Monte Carlo (MC) model is carried out. The effects of imaging parameters and compensators on the scatter distribution are investigated. The spectral frequency components of the scatter distribution in CBCT projection sets are analyzed using Fourier analysis and found to reside predominately in the low frequency domain. The exact frequency extents of the scatter distribution are explored for different imaging configurations and patient geometries. Based on the Fourier analysis it is hypothesized the scatter distribution can be represented by a finite sum of sine and cosine functions. The fitting of MC scatter distribution estimates enables the reduction of the MC computation time by diminishing the number of photon tracks required by over three orders of magnitude. The fitting method is incorporated into a novel scatter correction method using an algorithm that simultaneously combines multiple MC scatter simulations. Running concurrent MC simulations while simultaneously fitting the results allows for the physical accuracy and flexibility of MC methods to be maintained while enhancing the overall efficiency. CBCT projection set scatter estimates, using the algorithm, are computed on the order of 1-2 minutes instead of hours or days. Resulting scatter corrected reconstructions show a reduction in artifacts and improvement in tissue contrast and voxel value accuracy.

The objective of this work is to develop an on-line planning and delivery technique for palliative radiotherapy of spinal metastases using a linear accelerator capable of cone-beam CT (CBCT) imaging. This technique integrates all preparation and delivery steps into a single session equivalent to an initial treatment session. The key technical challenges pertaining to the development and implementation of this novel treatment technique are related to CBCT image performance, efficient system integration, development of on-line planning tools and design of novel quality assurance (QA) phantoms and processes. Hardware and software image corrections were first implemented to make CBCT images suitable for target definition and planning. These corrections reduced CBCT non-uniformity and improved CBCT-number accuracy. The on-line treatment technique workflow and the integration of all the subsystems involved in the process were assessed on a customized spine phantom constructed for the study. The challenges related to the routine QA of the highly integrated on-line treatment technique were addressed with the construction and validation of an integral test phantom. This phantom, which contains point detectors (diodes) allows for real-time QA of the entire image guidance, planning and treatment process in terms of dose delivery accuracy. The integral test phantom was also effective for the QA of high-dose, high-precision spinal radiosurgery. Simulation of the on-line treatment technique on patient data showed that the planning step was the one of the most time consuming tasks due predominantly to manual target definition. A semi-automatic method for detection and identification of vertebrae on CBCT images was developed and validated to streamline vertebra segmentation and improve the on-line treatment efficiency. With a single patient setup at the treatment unit, patient motion during the on-line process represents the main source of geometric uncertainty for dose delivery. Spine intra-fraction motion was assessed on CBCT for a group of 49 patients treated with a palliative intent. The use of surface marker tracking as a surrogate for spine motion was also evaluated. Finally, the complete on-line planning and delivery technique was implemented in a research ethics board (REB) approved clinical study at the Princess Margaret Hospital and 7 patients have been successfully treated at the time of this report with this novel treatment approach.

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