Existing cancer treatments, while perhaps proving effective in being destructive of tumours, can also cause significant damage to surrounding healthy tissue. This can cause severe side effects which one would wish to avoid. In order to improve the localisation of the inflicted damage in the tumours, as well as increase the actual damage itself when using X-rays as therapy, the potential effect of attaching a high Z atom into the DNA of the cancer cells as markers or antenna for the X-rays is investigated. The larger size and higher absorption cross section of the iodine makes it favourable for this purpose, as it becomes more sensitive to the X-rays. This has been studied for a single stranded DNA molecule which is three bases long, loaded with iodine, using quantum mechanical/molecular dynamical simulations in SIESTA. The purpose was to study in what way the presence of the iodine affected and possibly increased the fragmentation of the molecule due to ionisation of the 2p orbital and the following Auger cascade, as well as use the results to better interpret mass over charge spectra from experiments. If the molecule fragments more, it becomes more difficult for the cell to repair it and thus perform effective DNA replication. It has been found that by matching the X-rays to above the 2p orbital of the iodine, the parent molecule fragments into much more and smaller remains, than when matching the X-rays to below this edge, meaning an increased damage when using the high Z atom. In addition to this, the results in this thesis provide a complement to existing experimental data, contributing with detailed information about specific fragmentation pathways of the molecule, facilitating the interpretation of mass over charge spectra from experiments.

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.

This work establishes a framework for Monte Carlo simulations of complex, modulated electron fields produced by Varian's TrueBeam medical linear accelerator for investigations into modulated electron radiation therapy (MERT) and combined modulated photon and electron radiation therapy (MPERT). Both MERT and MPERT have shown potential for reduced low dose to normal tissue without compromising target coverage in the external beam radiation therapy of some breast, chest wall, head and neck, and scalp cancers. This reduction in low dose could translate into the reduction of immediate radiation side effects as well as long term morbidities and incidence of secondary cancers. Monte Carlo dose calculations are widely accepted as the gold standard for complex radiation therapy dose modelling, and are used almost exclusively for modelling the complex electron fields involved in MERT and MPERT. The introduction of Varian's newest linear accelerator, the TrueBeam, necessitated the development of new Monte Carlo models in order to further research into the potential role of MERT and MPERT in radiation therapy. This was complicated by the fact that the field independent internal schematics of TrueBeam were kept proprietary, unlike in previous generations of Varian accelerators. Two approaches are presented for performing Monte Carlo simulations of complex electron fields produced by TrueBeam. In the first approach, the dosimetric characteristics of electron fields produced by the TrueBeam were first compared with those produced by an older Varian accelerator, the Clinac 21EX. Differences in depth and profile characteristics of fields produced by the TrueBeam and those produced by the Clianc 21EX were found to be within 3%/3 mm. Given this information, complete accelerator models of the Clinac 21EX, based on its known internal geometry, were then successfully modified in order to simulate 12 and 20 MeV electron fields produced by the TrueBeam to within 2%/2 mm of measured depth and profile curves and to within 3.7% of measured relative output. While the 6 MeV TrueBeam model agreed with measured depth and profile data to within 3%/3 mm, the modified Clinac 21EX model was unable to reproduce trends in relative output as a function of field size with acceptable accuracy. The second approach to modelling TrueBeam electron fields used phase-space source files provided by Varian that were scored below the field-independent portions of the accelerator head geometry. These phase-spaces were first validated for use in MERT and MPERT applications, in which simulations using the phase-space source files were shown to model depth dose curves that agreed with measurement within 2%/2 mm and profile curves that agreed with measurement within 3%/3 mm. Simulated changes in output as a function of field size fell within 2.7%, for the most part. In order to inform the positioning of jaws in MLC-shaped electron field delivery, the change in output as a function of jaw position for fixed MLC-apertures was investigated using the phase-space source files. In order to achieve maximum output and minimize treatment time, a jaw setting between 5 and 10 cm beyond the MLC- field setting is recommended at 6 MeV, while 5 cm or closer is recommended for 12 and 20 MeV with the caveat that output is most sensitive to jaw position when the jaws are very close to the MLC-field periphery. Additionally, output was found to be highly sensitive to jaw model. A change in divergence of the jaw faces from a point on the source plane to a 3x3 mm^2 square in the source plane changed the shape of the output curve dramatically. Finally, electron backscatter from the jaws into the monitor ionization chamber of the TrueBeam was measured and simulated to enable accurate absolute dose calculations. Two approaches were presented for measuring backscatter into the monitor ionization chamber without specialized electronics by turning o the dose and pulse forming network servos. Next, a technique was applied for simulating backscatter factors for the TrueBeam phase-space source models without the exact specifications of the monitor ionization chamber. By using measured backscatter factors, the forward dose component in a virtual chamber was determined and then used to calculate backscatter factors for arbitrary fields to within 0.21%. Backscatter from the jaws was found to contribute up to 2.6% of the overall monitor chamber signal. The measurement techniques employed were not sensitive enough to quantify backscatter from the MLC, however, Monte Carlo simulations predicted this contribution to be 0.3%, at most, verifying that this component can be neglected. / Graduate / 0756 / lloyd.samantha@gmail.com

La Thérapie par MicroFaisceaux (MRT) et la Thérapie Stéréotaxique par Rayonnement Synchrotron (SSRT) sont des techniques innovantes de radiothérapie expérimentale développées actuellement à l'ESRF. L'utilisation de modèles tumoraux différents pour chaque technique limite leur comparaison. <br />En MRT, sur rats porteurs de tumeur 9L, la médiane de survie des rats contrôle est doublée (de 20 jours à 40 jours) lors d'irradiation avec un espacement de 200 µm entre les microfaisceaux voire triplée (67 jours) à 100 µm d'espacement (mais provoquant alors d'importantes lésions du tissu sain). L'influence importante du collimateur multifentes, a également été démontrée. La combinaison de diverses drogues avec la technique de MRT a été testée. Des résultats prometteurs (médiane de survie de 40 jours et 30% de survivants à long terme) sont obtenus en injectant du gadolinium en intracérébral avant une irradiation MRT en faisceaux croisés à 460 Gy. De plus, l'irradiation MRT de tumeurs à stade plus précoce permet de quadrupler la médiane de survie (79 jours) et d'obtenir 30% de survivants à long terme. La mise en place d'un ciblage de la tumeur par imagerie avant l'irradiation et l'utilisation d'un collimateur adapté permettront d'améliorer encore ces résultats. Les différences entre les deux modèles tumoraux utilisés en MRT (modèle 9L) et en SSRT (modèle F98) étant importantes des expériences comparatives MRT/SSRT ont été réalisées sur ces deux modèles. Les résultats obtenus montrent une efficacité proche des 2 techniques sur le modèle F98 et une meilleure efficacité de la MRT sur le modèle 9L. Ces résultats pourront permettre d'orienter le type tumoral adapté à chaque technique.

Gold nanoparticles (GNPs) have recently attracted considerable interest for use in radiation therapy due to their unique physical and biological properties. Of interest, GNPs (and other high-atomic-number materials) have been used to enhance radiation dose in tumors by taking advantage of increased photoelectric absorption. This physical phenomenon is well-understood on a macroscopic scale. However, biological outcomes often depend on the intratumoral and even intracellular distribution of GNPs, among other factors. Therefore, there exists a need to precisely visualize and accurately quantify GNP distributions. By virtue of the photoelectric effect, x-ray fluorescence (XRF) photons (characteristic x-rays) from gold can be induced and detected, not only allowing the distribution of GNPs within biological samples to be determined but also providing a unique molecular imaging option in conjunction with bioconjugated GNPs. This work proposes the use of this imaging modality, known as XRF imaging, to develop experimental imaging techniques for detecting and quantifying sparse distributions of GNPs in preclinical settings, such as within small-animal-sized objects, tissue samples, and superficial tumors. By imaging realistic GNP distributions, computational methods can then be used to understand radiation dose enhancement on an intratumoral scale and perhaps even down to the nanoscopic, subcellular realm, elucidating observed biological outcomes (e.g., radiosensitization of tumors) from the bottom-up. Ultimately, this work will result in experimental and computational tools for developing a better understanding of GNP-mediated dose enhancement and associated radiosensitization within the scope of GNP-aided radiation therapy.

Two innovative radiotherapy (RT) approaches are under development at the ID17 Biomedical Beamline of the European Synchrotron Radiation Facility (ESRF): microbeam radiation therapy (MRT) and minibeam radiation therapy (MBRT). The two main distinct characteristics with respect to conventional RT are the use of submillimetric field sizes and spatial fractionation of the dose. This PhD work deals with different features related to small-field dosimetry involved in these techniques. Monte Carlo (MC) calculations and several experimental methods are used with this aim in mind. The core of this PhD Thesis consisted of the development and benchmarking of an MC-based computation engine for a treatment planning system devoted to MRT within the framework of the preparation of forthcoming MRT clinical trials. Additional achievements were the definition of safe MRT irradiation protocols, the assessment of scatter factors in MRT, the further improvement of the MRT therapeutic index by injecting a contrast agent into the tumour and the definition of a dosimetry protocol for preclinical trials in MBRT.

This thesis investigates the exact minimisation of treatment delivery time for Intensity Modulated Radiation Therapy (IMRT) for the treatment of cancer using Multileaf Collimators (MLC). Although patients are required to remain stationary during the delivery of IMRT, inevitably some patient movement will occur, particularly if treatment times are longer than necessary. Therefore minimising the treatment delivery time of IMRT may result in less patient movement, less inaccuracy in the dosage received and a potentially improved outcome for the patient. When IMRT is delivered using multileaf collimators in 'step and shoot' mode, it consists of a sequence of multileaf collimator configurations, or shape matrices; for each, time is needed to set up the configuration, and in addition the patient is exposed to radiation for a specified time, or beam-on time. The 'step and shoot leaf sequencing' problems for minimising treatment time considered in this thesis are the constant set-up time Total Treatment Time (TTT) problem and the Beam-on Time Constrained Minimum Cardinality (BTCMC) problem. The TTT problem minimises a weighted sum of total beam-on time and total number of shape matrices used, whereas the BTCMC problem lexicographically minimises the total beam-on time then the number of shape matrices used in a solution. The vast majority of approaches to these strongly NP-hard problems are heuristics; of the few exact approaches, the formulations either have excessive computation times or their solution methods do not easily incorporate multileaf collimator mechanical constraints (which are present in most currently used MLC systems). In this thesis, new exact mixed integer and integer programming formulations for solving the TTT and BTCMC problems are developed. The models and solution methods considered can be applied to the unconstrained and constrained versions of the problems, where 'constrained' refers to the modelling of additional MLC mechanical constraints. Within the context of integer programming formulations, new and existing methods for improving the computational efficiency of the models presented are investigated. Numerical results for all variations considered are provided. This thesis demonstrates that significant computational improvement can be achieved for the exact mixed integer and integer programming models investigated, via solution approaches based on an idea of systematically 'stepping-up' through the number of shape matrices used in a formulation, via additional constraints (particularly symmetry breaking constraints) and via the application of improved bounds on variables. This thesis also makes a contribution to the wider field of integer programming through the examination of an interesting substructure of an exact integer programming model. In summary, this thesis presents a thorough analysis of possible integer programming models for the strongly NP-hard 'step and shoot' leaf sequencing problems and investigates and applies methods for improving the computational efficiency of such formulations. In this way, this thesis contributes to the field of leaf sequencing for the application of Intensity Modulated Radiation Therapy using Multileaf Collimators.

<p>While radiation therapy is a standard treatment modality for managing primary and metastatic brain tumors, it causes irreversible and progressive long-term side effects that decrease the quality of life for pediatric brain tumor survivors. These side effects, known as radiation-induced brain injury (RIBI) and which occur at least 6 months post-treatment, create challenges in education, employment, and social relationships throughout the patients’ lifetime. With the prognosis for pediatric cancer patients constantly improving, long-term side effects such as RIBI pose a major clinical problem for post-treatment care. To create and evaluate treatments for this clinical injury, it is critical to understand how this condition forms and develops. However, this cannot be done in patients due to the invasive nature of cranial biopsies. The current scientific understanding behind the pathophysiology of these late-delayed forms of RIBI is therefore built upon studies of pre-clinical animal models. Such experimental models, typically of healthy rodents, are not currently capable of accurately replicating the radiological and histological changes seen in human patients. This inconsistency limits the efficacy of preclinical discoveries when translated to clinical trials. To address this issue, we chose to establish a mini-pig model for RIBI using a standard clinical approach of radiation delivery and follow-up imaging. Our hypothesis is that cranial irradiation of the mini-pig brain will elucidate the clinical magnetic resonance imaging (MRI) signatures of RIBI, which will then correspond to characteristic changes in diffusion properties, metabolite profiles, immune constituents, and glial and neuronal cell subpopulations as evidenced by advanced MRI techniques and histopathology. As such, results from Aim 1 have highlighted not only incongruencies between rodent models and clinical findings, but also various inconsistencies in current assessment techniques of late-delayed RIBI in patients. Additionally, results from Aim 2 have established the feasibility of a mini-pig model of RIBI based on the current clinical standard of diagnosis. Finally, results from Aim 3 describe characteristic changes in diffusion properties and histological appearances as well as novel changes in metabolite concentrations within our mini-pig model late-delayed RIBI. In conclusion, this intermediate animal model of RIBI can replicate the clinical condition and may ultimately provide valuable insight into the pathophysiology of RIBI. </p>

No description available.

Electron beam therapy planning and custom electron bolus design were identified as areas in which improvements in equipment and techniques could lead to significant improvements in treatment delivery and patient outcomes. The electron pencil beam algorithms used in conventional Treatment Planning Systems do not accurately model the dose distribution in irregularly shaped objects, near oblique surfaces or in inhomogeneous media. For this reason, at Christchurch Oncology Centre the TPS is not relied on for planning electron beam treatments. This project is an initial study of ways to improve the design of custom electron bolus, the planning of electron beam therapy, and other radiation therapy simulation tasks, by developing a system for the accurate assessment of dose distributions under irregular contours in clinically relevant situations. A shaped water phantom system and a diode array have been developed and tested. The design and construction of this water phantom dosimetry system are described, and its capabilities and limitations discussed. An EGS/BEAM Monte Carlo simulation system has been installed, and models of the Christchurch Oncology Centre linacs in 6MeV and 9MeV electron beam modes have been built and commissioned. A test was run comparing the EGS/BEAM Monte Carlo system and the CMS Xio conventional treatment planning system with the experimental measurement technique using the water phantom and the diode array. This test was successful as a proof of the concept of the experimental technique. At the conclusion of this project, the main limitation of the diode array system was the lack of data processing software. The array produces a large volume of raw data, but not enough processed data was produced during this project to match the spatial resolution of the computer models. An automated data processing system will be needed for clinical use of the array. It has been confirmed that Monte Carlo and pencil-beam algorithms predict significantly different dose distributions for an irregularly shaped object irradiated with megavoltage electron beams. The results from the diode array were consistent with the theoretical models. This project was an initial investigation. At the time of writing, the diode array and the water phantom systems were still at an early stage of development. The work reported here was performed to build, test and commission the equipment. Additional work will be needed to produce an instrument for clinical use. Research into electron beam therapy could be continued, or the equipment used to expand research into new areas.