This study will investigate the difference in radiation at different volumes between traditional electron beam therapy and a novel IMET. The difference in dose will be recorded between the novel IMET and the IMET with a slight shift in the target area. The percent difference between this new model treatment and the model treatment with a shift will be calculated. The main goal of this project is to determine if the target area is still sufficiently treated with this slight shift of the patient in different directions. The percent difference is crucial for the success of this project. It will determine if this method can be implemented in the future for use in radiation therapy treatments, depending on if the target area is still treated with a minimal percent difference. If successful, this project will mean that IMET can be further evaluated onto the next stage of testing before clinical use for patient care.

Voir pdf page 3

Cancer treatment by adoptive immune cell therapy (AIT) is a form of immunotherapy that relies on the in vitro activation and/or expansion of immune cells. In this approach, immune cells, particularly CD8+ T lymphocytes, can potentially be harvested from a tumor-bearing patient, then activated and/or expanded in vitro in the presence of cytokines and other growth factors, and then transferred back into the same patient to induce tumor regression. AIT allows the in vitro generation and activation of T-lymphocytes away from the immunosuppressive tumor microenvironment, thereby providing optimum conditions for potent anti-tumor activity. The overall objective of this study is to: a) develop multi-modality (optical- and radionuclide-based) molecular imaging approaches to study the overall kinetics of labeled adoptively transferred T- lymphocytes in vivo, b) to non-invasively image and assess in-vivo, targeting and retention of adoptively transferred labeled T-lymphocytes at the tumor site. T-lymphocytes obtained from draining lymph nodes of 4T1 (murine breast cancer cell) sensitized BALB/C mice were activated in vitro with Bryostatin/ Ionomycin for 18 hours, and were grown in either Interleukin-2 (IL-2) or combination of Interleukin-7 and Interleukin-15 (IL-7/IL-15) for 13 days, (cells grown in IL-2 called IL2 cells, and cells grown in IL7/15 called IL7/15 cells). In order to validate the methodology and to offer future clinical translation, both direct and indirect cell labeling methods were expanded and employed. The first method was based on direct in vitro cell labeling by lipophilic near-infrared (NIR) fluorescent probe, 1,1- dioctadecyltetramethyl indotricarbocyanine iodide, (DiR), followed by intravenous (i.v.) injection into BALB/C mice for multi-spectral fluorescence imaging (MSFI). The second method was based on indirect labeling of T- lymphocytes through transduction of a reporter gene (cell cytoplasm labeling Herpes Simplex Virus type 1- thymidine kinase (HSV-1 tk). The product of this reporter gene is an enzyme (HSV-1TK) which phosphorylates a radio labeled substrate 2-fluoro-2-deoxy-1 β- D- arabinofuranosyl-5-iodouracil ([124I]-FIAU) for Positron Emission tomography (PET) imaging. ATP based cell viability assay, flow cytometry and interferon-γ (IFN-γ) ELISA were used to investigate if there are any changes in cell viability, proliferation and function respectively, before and after direct and indirect labeling. The results showed that cell viability, proliferation, and function of labeled 4T1 specific T-lymphocytes were not affected by labeling for direct labeling methods at DiR concentration of 320µg/ml. For the indirect labeling method, the viability and proliferation results showed that cell viability decreases as multiplicity of infectious (MOI) increases. In particular, at MOI of 10 almost all cells die 3 days post transduction. At MOI of 5, cells viability was ≤ 30% and at MOI of 2 was ≤ 60%. Cell viability was 80% at MOI of 1. The results of optical imaging were as follows: when the recipient mice with established 4T1 tumors were injected with DiR labeled 4T1 specific T-lymphocytes, the 4T1 specific T-lymphocytes (IL2 cells) infused into tumor-bearing mice showed high tumor retention, which peaked 3 or 6 days post infusion depending on the tumor size and persisted at the tumor site for 3 weeks. In contrast, IL7/15 cells showed lower signal at the tumor site and this peaked on day 8. On the other case when 4T1 tumor cells were implanted 1-week post-infusion of labeled T-lymphocytes. IL2 T-lymphocytes moved out of lymphoid compartments to the site of subsequent 4T1 inoculation within two hours and peaked on day 3 and the signal persisted for 2 more weeks. In contrast with infusion of IL7/15 cells, the signal was barely detected and did not show a similar trafficking pattern as with IL2 cells. The results of the indirect labeling method, PET reporter gene (PRG) system (HSV-1tk / [124I ] FIAU ) showed that both IL2 and IL7/15 cells were successfully transduced as verified ex vivo by real time PCR and western blot. T Cells transduction efficiency was assessed from cell uptake study in comparison to stable transduced Jurkat cells which have transduction efficiency of 100 %. Both IL2 and IL7/15 cells showed lower transduction efficiency (≤ 30%) compared to Jurkat cells. Consequently, PET imaging did not show a detectable signal of transduced T cells in vivo. Biodistribution study was carried out on day 3 post [124I]-FIAU injections. Results were consistent with the optical imaging results, except for IL7/15 cells. Transduced and untransduced IL2 and IL7/15 cells were labeled with DiR and injected ( i.v.) into Balb / C mice and then imaged by both imaging modalities (MSFI and PET) at the same time. MSFI images of transduced IL2 cell showed detectable signal starting from 2 hours, peaked at 72 hours and persisted up to 2 weeks, while IL7/15 cells were detectable at the tumor site starting at 24 hours, peaked at 72 hours and persisted up to 2 weeks. By the end of this study animals were dissected and tissue activities were counted using gamma counting and expressed as % Injected dose/gram of tissue (%ID/gm). Transduced IL2 and IL7/15 cells showed higher %ID/gm than other organs at lungs, liver, spleen, tumor, lymph nodes and bone/bone marrow. IL7/15 cells compared to IL2 cells showed higher %ID/gm at same organs. Neither IL2 nor IL7/15 untransduced DiR labeled cells showed any activity at tumor site, and their activities at other organs was very low compared to transduced cells. To investigate whether labeled T-lymphocytes will localize at tumor metastases or not, and to study the difference in their migration patterns to the tumor site versus tumor metastases, 4T1 tumor cells were successfully transduced with HSV-1tk as confirmed by RT-PCR , western blot and cell uptake study. Transduced 4T1 cells were implanted in the right flank or in the mammary fat pad of the mouse. Serial PET imaging was carried out in the third and fourth week post tumor implantation to know when the tumor will metastasizes. PET imaging showed only signal at the tumor site and no metastasis were detected.

A Neuroimagem Funcional evoluiu muito nos últimos anos com o aparecimento de técnicas como Positron Emission Tomography ou PET (Tomógrafo por Emissão de Pósitrons) e Functional Magnetic Ressonance Image ou fMRI (Imagem de RessonÂncia Magnética Funcional) [Belliveau et al., 1991]. Elas permitem a observação de atividade no cérebro com uma resolução de alguns milímetros, e devido a natureza do sinal medido, com uma resolução temporal da ordem de 5 segundos [Kim et al., 1997]. Magnetoencefalografia e Eletroencefalografia (M/EEG), por outro lado, possuem uma resoluçao temporal da ordem de milissegundos, já que o sinal é produzido pela movimentação do íons através das membranas celulares [Nunez and Srinivasan, 2006]. Porém a sua resoluçeo espacial é muito baixa jé que tipicamente são problemas mal postos, com muito mais variáveis do que dados. Um equipamento de M/EEG de alta resolução possui da ordem de O(200) canais, que permitem medidas do campo magnético (para o MEG) ou do potencial elétrico (para o EEG) em O(200) posições em torno da cabeça. Para uma escala com resolução de ordem l existem (L /l )3 variáveis, onde L = aprox. 15cm. Neste trabalho procuramos estudar métodos para aumentar a resolução espacial das técnicas de EEG, pois o mapeamento funcional do cérebro humano esta intimamente relacionado à localização da atividade no espaço bem como no tempo [Friston, 2009] (muitas relativo ao momento de um estímulo externo). Todo o trabalho de localização de fontes para EEG pode ser facilmente estendido para MEG. Métodos Bayesianos são o cenário natural para lidar com problemas mal postos [Wipf and Nagarajan, 2009]. Existem, essencialmente, duas direções nas quais os algoritmos Bayesianos podem ser melhoradas, através da construção de uma melhor verossimilhança ou uma distribuição a Priori. Embora reconheçamos que avanços importantes podem ser feitos no direção anterior, aqui nos concentramos na segunda. Neste trabalho nós introduzimos um método multiescala para construir uma melhor distribuição a Priori. Uma idéia similar foi estudada dentro do contexto mais simples de fMRI [Amaral et al., 2004]. Muitos novos problemas aparecem ao lidar com o caráter vetorial do EEG. O mais importante, é a construção de um conjunto de superfícies renormalizadas que aproximam a região cortical onde a fonte de atividade esta localizada e o problema relacionado de de nir as variáveis relevantes para representar o cérebro em uma escala com menor resolução. A validação do novo algoritmo é sempre um problema essencial. Nós apresentamos resultados que sugerem, em dados simulados, que nosso método pode ser uma alternativa válida para os atuais algoritmos, julgando ambos pela taxa de erros na localização de fontes bem como pelo tempo que eles levam para convergir. / Functional Neuroimaging has evolved in the last few decades with the introduction of techniques such as Positron Emission Tomography or PET and Functional Magnetic Ressonance Image or fMRI [Belliveau et al., 1991]. These allow observing brain activity with a resolution of a few millimeters and, due to the nature of the signal, a time resolution of the order of 5 seconds [Kim et al., 1997]. M/EEG, on the other hand, have a millisecond time resolution, since the signal is produced by the transport of ions through cell membranes [Nunez and Srinivasan, 2006]. However their space resolution is much lower since these are typically ill posed problems with many more unknowns than data points. A high resolution M/EEG has of the order of O(200) data channels, which allow measuring the magnetic or electric field at O(200) positions around the head. For a resolution scale of order l there are O(L l )3 variables, where L = 15cm. In this work we aim at studying methods to increase the spatial resolution of EEG techniques, since functional mapping of the human brain is intimately related to the localization of the activity in space as well as in time [Friston, 2009] (often relative to the time of external stimuli). Any advance in the inverse problem of source localization for EEG can rather easily be extended to deal with MEG. Bayesian methods are the natural setting to deal with ill posed problems [Wipf and Nagarajan, 2009]. There are essentially two directions in which Bayesian algorithms can be improved, by building a better likelihood or a prior distribution. While we recognize that important advances can be done in the former direction we here concentrate in the latter. In this work we introduce a multiscale method to build an improved prior distribution. A similar idea has been studied within an easier context of fMRI [Amaral et al., 2004]. Several new problems appear in dealing with the vectorial character of EEG. The most important, is the construction of a set of renormalized lattices that approximate the cortex region where the source activity is located and the related problem of de ning the relevant variables in coarser scale representation of the cortex. Validation of a new algorithm is always an essential problem. We present results which suggest on simulated data, that our method might be a valid alternative to current algorithms, judged both by the rate of errors in source localization as well as by the time it takes to converge.

<div> <p> Essential tremor (ET) is one of the most common movement disorders, characterized by kinetic tremor in the upper extremities with additional cranial tremor often present in the neck or jaw. While it is well established that ET is primarily a cerebellar disorder, recent investigations have shown more widespread pathological effects throughout the brain. Furthermore, the neurodegenerative nature of ET is still disputed and requires additional investigation. Additionally, the link between ET and Parkinson’s disease (PD) is of special interest, as it can be challenging to clinically differentiate these diseases.</p> <p> While post-mortem studies have helped to further the pathological understanding of these diseases, non-invasive in-vivo techniques allow for more accurate diagnosis in the clinic. With a more accurate diagnosis comes a more targeted treatment, and hopefully an improved remediation of the disease. My thesis seeks to further investigate the neurodegenerative hypothesis of ET as well as explore magnetic resonance imaging (MRI) biomarkers for potential differences in ET and PD. </p> <p>These aims will be accomplished in three steps. First, gray matter volume loss in the cerebellum was investigated using voxel-based morphometry and the Spatially Unbiased Infra-Tentorial Template (SUIT) atlas on a lobule level. High resolution 3D T1-weighted MRI images were acquired on 47 ET cases and 36 controls. The cerebellum was segmented into 34 lobules using the SUIT atlas. Percent gray matter was calculated as the ratio of lobule gray matter volume divided by total lobule volume. No significant differences were identified between ET cases and controls in any of the 34 lobules. However, nine lobules had significantly decreased percent gray matter in ET cases with head or jaw tremor (n = 27) compared to controls. Also, 11 lobules had significantly decreased percent gray matter in ET cases with voice tremor (n = 22) compared to controls. This result confirms, with increased regional accuracy, gray matter volume loss in the cerebellum of ET cases.</p> <p>Second, gray matter volume loss beyond the cerebellum, in the cerebrum, was investigated using voxel-based morphometry. High resolution 3D T1-weighted MRI images were acquired on 47 ET cases and 36 controls for processing in SPM12. The processing steps of SPM12 were updated to include a higher resolution atlas and set of tissue probability maps to optimize the segmentation and normalization of each subject image. After segmentation, normalization, and smoothing, a voxel-wise statistical analysis was performed to identify clusters of gray matter volume in ET cases compared to controls. ET cases showed decreased gray matter volume in the bilateral superior temporal region and the anterior and posterior cingulate cortex. These results, in combination with previous work provide support of wide-spread neurodegeneration in ET using optimized methodology.</p> <p>Third, we applied T2* mapping to determine relative iron concentrations in the substantia nigra (SN) and globus pallidus (GP) in ET and PD cases. Three separate studies were independently investigated to validate the reproducibility and detectability of group differences using T2* mapping. The first study (ET study) acquired T2* maps on 21 ET cases and 12 matched controls, the second study (PD study 1) acquired T2* maps on 10 PD cases and 7 controls, and the third study (PD study 2) acquired T2* maps on 21 PD cases and 17 controls. Regions of interest (ROIs) were manually placed in the SN and GP for each subject and group differences were calculated independently for each study using a linear regression model with age and sex as covariates. A significant decrease in T2* was found in PD study 1 and PD study 2 in the right SN in PD cases compared to their respective controls, indicating increased iron deposition. No significant difference was found in the ET group compared to their respective controls in the SN. No significant differences were found in any of the three studies in the GP. These results provide evidence for a difference in brain iron regulation in the pathology of ET and PD.</p> <p>Together, these thesis aims provide additional evidence in support of the neurodegenerative hypothesis of ET using updated methodology and present a quantitative imaging difference between groups of ET and PD cases. </p> </div> <br>

A Monte Carlo model has been developed using MCNP5 to simulate the Nucletron Ir-192 HDR source in order to investigate the influence of tissue heterogeneities on dose calculations compared to the dose in homogeneous water media, as it is typically calculated by brachytherapy Treatment Planning Systems (TPS). Validity of the simulation was verified in water medium in comparison with peer reviewed results using the dosimetric parameters recommended by AAPM, Task Group-43. The dose-rates in simulated prostate, bladder and rectum were compared to those obtained in the homogeneous water phantom. Based on the resulting dose differences, it is inferred that TPS algorithms for brachytherapy dose calculations overestimate the dose to tissues like prostate and bladder by up to 49%. A clinically relevant dose underestimation of 5.5% to the rectum was also found. We recommend that further investigation using actual patient CT data as input to the Monte Carlo simulation be performed. / by Ramsâes Herrera. / Thesis (M.S.)--Florida Atlantic University, 2012. / Includes bibliography. / Mode of access: World Wide Web. / System requirements: Adobe Reader.

External beam radiation therapy for prostate cancer can result in urinary, sexual, and rectal side effects, often impairing quality of life. A polyethylene glycol-based product, SpaceOAR hydrogel (SOH), implanted into the connective tissue between prostate gland and rectum can significantly reduce the dose received by the rectum and hence risk of rectal toxicity. The optimal way to manage the hydrogel and rectal structures for plan optimization is therefore of interest. A retrospective planning study was completed with 13 patients to examine optimal planning and treatment methods. Computerized tomography (CT) scans were taken pre- and post-SOH implant. Six hypofractionated (60 Gy in 20 fractions) treatment plans were produced per patient using either a structure of rectum plus the hydrogel, termed composite rectum wall (CRW), or rectal wall (RW) as the inverse optimization structure and intensity modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) as the treatment technique. Dose-volume histogram metrics were compared between plans to determine which optimization structure and treatment technique offered the maximum rectal dose sparing. RW structures offered a statistically significant decrease in rectal dose over CRW structures, whereas the treatment technique (IMRT vs VMAT) did not significantly affect the rectal dose. However, there was improvement seen in bladder and penile bulb dose when VMAT was used as a treatment technique over IMRT. Overall, treatment plans using the RW optimization structure offered the lowest rectal dose while VMAT treatment technique offered the lowest bladder and penile bulb dose. These treatment techniques and optimization structures have now been implemented at BC Cancer - Victoria based on this retrospective study. SOH implant has been shown not to be equally effective in all patients. Determining a priori patients in which the implant will offer most benefit allows for effective management of SOH resources. Several factors have been shown to be correlated to reduction in rectal dose including distance between rectum and planning treatment volume (PTV), volume of rectum in the PTV and change in rectum volume pre- to post-SOH. Several of these factors along with other pre-SOH CT metrics were found via multiple linear regression models to predict reduction of rectal dose using data from 21 patients who received SOH implant. Two high rectal dose metrics were modeled, change in the relative volume receiving 55 Gy and change in the partial high dose integral, integrating over the dose-volume histogram (DVH) from 55 Gy to 60 Gy. Models were also produced to predict pre-SOH RV55Gy. These models offered R-squared between 0.57 and 0.87 with statistical significance in each model. Applying a 3.5% lower limit on pre-SOH RV55Gy removed one third of patients as implant candidates. This may offer a clinically useful tool in deciding which patients should receive SOH implant given limited resources. Predictive models, nomograms and a workflow diagram were produced for clinical management of SOH implant. / Graduate

In external beam radiotherapy quality assurance is carried out on the individual components of the treatment chain. The patient simulating device, planning system and linear accelerators are tested regularly according to set protocols developed by national and international organizations. Even though these individual systems are tested errors can be made in the transfer between systems. The best quality assurance for the system is at the end of the treatment planning chain. In-vivo dosimetry measures the dose to the target volume through indirect measures at the end of the treatment planning chain and is therefore the most likely method for picking up errors which might occur earlier in the chain. Metal Oxide Semiconductor Field Effect Transistors (MOSFETs) have been shown to have a similar error in estimating entrance dose for in-vivo dosimetry to diodes, but no studies have been done clinically with entrance dose in-vivo dosimetry with MOSFETs. The time savings for using MOSFETs makes them preferable to TLD's. Due to their small size and versatility in other applications they are useful as more than dedicated in-vivo dosimetry systems using diodes. Clinical implementation of external beam in-vivo dosimetry would add another use to the MOSFETs without purchasing more specialized equipment. My studies have shown that MOSFETs can be used clinically for external beam in-vivo dosimetry using entrance dose measurements. After the MOSFET measurement system was implemented using a custom built aluminium build up cap clinical measurements were performed. A total of 23 patients and 54 fields were studied. The mean for all clinical measurements was 1.3 %, with a standard deviation of 2.6 %. Results were normally distributed around a mean with skewness and kurtosis as -0.39 and 0.34 respectively. For breasts the mean was 1.8 %, with a standard deviation of 2.7 %. For prostates and hips the mean was 1.3 % with a standard deviation of 2.9 %. These results are similar to studies conducted with diodes and TLD's. From these results one can conclude that MOSFETs can be used for entrance dose in-vivo dosimetry and are no worse than diodes or TLD's in terms of their measurement accuracy. / Thesis (M.Sc.)--School of Chemistry and Physics, 2006.

The presence of hypoxia in tumors has been related to poor prognosis and low overall survival. In particular, cyclic hypoxia has been related to higher metastatic potential. Hence, it is important to study the mechanisms involved in the response of tumors when these experience cyclic hypoxia. In this work A-07-GFP human melanoma xenografts with dorsal window chambers were used as a model to study the effects of exposure to cyclic hypoxia on tumor growth and on the morphology and function of the tumor vascular networks. First-pass imaging of a fluorescent tracer was used to study the function of tumor vasculature, and tumor vascular morphology was assessed by producing vascular masks from high-resolution images. Vascular morphology was described by quantification of vascular length density, vascular area fraction, interstitial distance and vessel diameter. The function of the tumor vasculature was assessed by quantification of the blood supply times (BSTs). It was found that exposure to cyclic hypoxia resulted in higher vascular densities, a trend towards higher BST values and decreased growth rate in the tumors. The results could be associated with enhanced angiogenesis in the tumors that received the cyclic hypoxia treatment due to overexpression of pro-angiogenic genes regulated by HIF-1&#945;.

Monte Carlo (MC) methods are widely accepted as the most accurate technique for calculating dose distributions in radiation therapy physics. Simulating the particle transport through the treatment head of a linear accelerator utilizing a MC based code is both a widespread and practical approach to determining detailed clinical beam characteristics such as the energy, angular and spatial distribution of particles which are needed to properly quantify dose. One particular and versatile MC code, the Monte Carlo N-Particle (MCNP) radiation transport code, developed by Los Alamos National Laboratory, has been commonly used to model ionizing radiations for medical physics applications. In this thesis, a Varian 2100C linear accelerator (linac) is modeled and the electron and photon transport through the primary components of the treatment head are simulated using MCNP Version 5_1.3. The 6 MV photon spectra was characterized in a standard 10 x 10 cm2 field and subsequent dose calculations were made in a Virtual Water (VW) phantom. Energy fluence, percent depth dose and beam profile measurements were taken in a modeled VW phantom and the calculated data was compared to measured reference data. In addition, a human phantom was modeled for future dose calculations using the modeled linac. The linac model created can incorporate different beam energies for determining the dose distribution of multiple beam treatments in phantoms for standard 6 MV plans. The adaptability of this MCNP model allows for any number of geometries and sources encountered in medical physics to be computed and applied with relative ease. Future studies can involve adding complex multi-leaf collimator beam shaping and calculating the dose in human phantom models, which would serve as a basis for studies involving MCNP modeling for dose optimization in medical physics applications.