Microbeam radiation therapy (MRT) is an experimental form of radiation treatment which causes less damage to normal tissue in comparison with customary broad-beam radiation treatment. In this method the synchrotron generated X-ray beam is passed through a multislit collimator and applied to the tumor in the form of an array of planar microbeams. MRT dosimetry is an extremely challenging task and no current detector can provide the required wide dynamic rang and high spatial resolution. In this thesis, fluorophosphate (FP) and fluoroaluminate (FA) glass plates doped with trivalent samarium (Sm3+) are characterized towards developing a potential X-ray detector suitable for MRT dosimetry. The detection is based on the difference in the photoluminescence signatures of Sm3+ ions and Sm2+ ions; the latter are formed under X-ray irradiation. This valency conversion is accompanied by the formation of defects including hole centers (HCs) and electron centers (ECs) in the glass structure which absorb light in the UV and visible regions (induced absorbance). Both FP and FA glasses show promising dynamic range for MRT and may be used as a linear sensor up to ~150 Gy and as a nonlinear sensor up to ∼2400 Gy, where saturation is reached. X-ray induced defects saturate at the same dose. The optimum doping concentration is in the 0.001˗ 0.2 at.% range. Doping with higher concentrations will decrease the conversion efficiency. The glass plates also show a very promising spatial resolution (as high as a few microns) for recording the dose profile of microbeams which is readout using a confocal fluorescence microscopy technique. These plates are restorable as well and the response is reproducible. The effects of previous X-ray exposure including samarium valency conversion as well as induced absorbance may be erased by annealing at temperatures exceeding the glass transition temperature Tg while annealing at TA < Tg enhances the response. This enhancement is explained by a thermally stimulated relaxation of host glass ionic matrix surrounding X-ray induced Sm2+ ions. Optical erasure is another practical means to erase the recorded data. Nearly complete Sm2+ to Sm3+ reconversion (erasure) is achieved by intense optical illumination at 405 nm. While, existing X-ray induced bands would be only partially erased. Electron spin resonance (ESR) and optical absorbance spectroscopy are used to investigate the nature of X-ray induced defects and their correlation with Sm valency conversion. A model based on competition between defect center formation and the Sm3+ ⇆ Sm2+ conversion successfully explains the different processes occurring in the glass matrix under X-ray irradiation.

Although the prostate specific antigen (PSA) test is widely used in clinical settings for prostate cancer (PCa) diagnosis and post-treatment follow-up monitoring, false positive PSA test results, which contribute to over-diagnosis of PCa, and false negative results, which miss some patients with aggressive PCa, remain problems of clinical importance. Our study demonstrates that radiation therapy, which is widely used for treatment of localized PCa, generates TNF-α in tumor cells and stromal fibroblasts, redox dependently. Interestingly, TNF-α rapidly and transiently triggers the RelA-mediated NF-κB canonical pathway, but its effect on RelB expression is more robust and long lasting, which leads to sustainable suppression of PSA expression. TNF-α further amplifies endogenous reactive oxygen species (ROS) partially through NADPH oxidase activation and mediates redox-dependent downstream signaling pathways. Addition of the NADPH oxidase inhibitor or ROS scavengers such as superoxide dismutase (SOD) mimetic can abrogate TNF-α-mediated suppression of PSA expression by inhibiting the RelB-AR axis. Treatment with TNF-α suppresses PSA expression and it confers minor yet statistically significant protection to LNCap cells against irradiation, indicating that radiation-induced TNF-α may not only interfere with the PSA-based PCa diagnosis and post-treatment monitoring but may also diminish the efficacy of radiotherapy. In addition, we uncover a role for RelB in suppressing PSA expression at the advanced stage of PCa, which could be a mechanism for the low PSA level in some patients bearing aggressive PCa. Experiments with both RelB overexpression and siRNA knockdown indicate that RelB negatively regulates androgen receptor (AR) and PSA levels in human prostate cancer, LNCap, cells. RelB directly interacts with AR to form a complex on the enhancer elements of the PSA promoter. Thus, the RelB-AR axis is an important contributor to PSA suppression at the advanced stage of PCa. Overall, this study is the first to reveal a redox-mediated association among radiation-generated TNF-α, activation of the RelB-mediated alternative NF-kappaB pathway and PSA suppression. This mechanistic information provides new insights with practical and clinical implications for PSA-based PCa diagnosis and post-treatment monitoring as well as redox intervention in radiation therapy.

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.

Modern image guided radiation therapy involves the use of an isocentrically mounted imaging system to take radiographs of a patient's position before the start of each treatment. Image guidance helps to minimize errors associated with a patients setup, but the radiation dose received by patients from imaging must be managed to ensure no additional risks. The Varian On-Board Imager (OBI) (Varian Medical Systems, Inc., Palo Alto, CA) does not have an automatic exposure control system and therefore requires exposure factors to be manually selected. Without patient specific exposure factors, images may become saturated and require multiple unnecessary exposures. A software based automatic exposure control system has been developed to predict optimal, patient specific exposure factors. The OBI system was modelled in terms of the x-ray tube output and detector response in order to calculate the level of detector saturation for any exposure situation. Digitally reconstructed radiographs are produced via ray-tracing through the patients' volumetric datasets that are acquired for treatment planning. The ray-trace determines the attenuation of the patient and subsequent x-ray spectra incident on the imaging detector. The resulting spectra are used in the detector response model to determine the exposure levels required to minimize detector saturation. Images calculated for various phantoms showed good agreement with the images that were acquired on the OBI. Overall, regions of detector saturation were accurately predicted and the detector response for non-saturated regions in images of an anthropomorphic phantom were calculated to generally be within 5 to 10 % of the measured values. Calculations were performed on patient data and found similar results as the phantom images, with the calculated images being able to determine detector saturation with close agreement to images that were acquired during treatment. Overall, it was shown that the system model and calculation method could potentially be used to predict patients' exposure factors before their treatment begins, thus preventing the need for multiple exposures. / Graduate / 0760 / 0574 / 0756

Hensikt: Hensikten med studien er å få innsikt i kreftpasienters behov for og opplevelse av informasjon i forbindelse med strålebehandling og hvordan de bruker informasjon i sin nye livssituasjon. Metode: Det ble gjort en kvalitativ intervjuundersøkelse med ti kreftpasienter som skulle gjennomgå strålebehandling. Intervjuene ble gjennomført i forkant av strålebehandlingen, med unntak av to tilfeller der samtalen ble gjennomført henholdsvis etter at strålebehandlingen begynte og etter at CT undersøkelsen var tatt. Dataanalysen ble utført med Grounded theory metode. Resultater: Kjernekategorien som sprang ut av data var det er det lille som teller. Kategoriene som kom frem var informasjonssynergi, følelse av usikkerhet og mestring. Seks underkategorier inngikk i de tre kategoriene. Følelser og uvitenhet inngikk i følelse av usikkerhet. Informasjonsønsker og informasjonsmåter inngikk i kategorien informasjonssynergi. Forståelse og trygghet inngikk i kategorien mestring. Konklusjon: Kjernekategorien det er det lille som teller sammenfatter viktigheten av å gi hver enkelt pasient svar på akkurat det han eller hun lurer på. Informasjonssynergi, følelse av usikkerhet og mestring er grunnsøyler for at pasientene er optimalt rustet til å gjennomgå strålebehandling. Dette vil stille større krav til helsevesenet med hensyn til å kommunisere med pasienter på forskjellige måter, både med dialog og visuelt i form av film og skriftlig informasjon. / Aim: This study aimed to increase understanding the information needs of cancer patients before and during radiation therapy. We also explored how cancer patients adapt such information to their new life situations. Method: Among 10 participants in our qualitative interview survey, eight individuals were interviewed before radiation therapy commenced, one was interviewed during treatment and one was interviewed following CT examination. We used grounded theory to analyse our data.Results: Our study identified one core category: small things matter. Other categories included information synergy (desire for information and manner of delivery), vulnerability (emotions and lack of knowledge), and coping skills (comprehension and security). Conclusions: This study identified the importance of answering patients´ questions. Providing accurate information, minimizing vulnerability, and enhancing coping skills all play an important role in optimizing patient preparation for radiation therapy. However, the process of developing a variety of communication methods (e.g., improved patient dialogue, printed information, and video presentations) will increase demands on the healthcare system. / <p>ISBN 978-91-86739-13-3</p>

Therapeutic response assessment is a key component in adaptive image-guided radiotherapy. Conventional anatomic measures of response offer little information about the spatial distribution of tumor change. Recently developed voxel-wise response assessment methods operating on functional and biological imaging are better capable of evaluating the heterogeneity of response within the tumor, and thus may yield greater sensitivity than conventional approaches. However, voxel-wise analyses are limited by local registration uncertainties inherent to longitudinal imaging of tumors with changing morphology. A multi-resolution local histogram (LH) moment-based measure of voxel similarity was developed for the purpose of assessing the strength of correspondence between voxels of serial tumor images. This measure was first benchmarked through a series of experiments designed to establish robustness to image intensity variation and sensitivity to alterations in tissue structure through application of simulated deformations. The LH similarity method was subsequently developed as a means of mapping the spatial extent of structural change in tumors through the incorporation of an estimate of image complexity. The change maps were applied to a voxel-wise analysis of diffusion-weighted magnetic resonance imaging of patients with glioblastoma, acquired pre- and post-chemoradiotherapy. The sensitivity of the voxel-wise analysis in differentiating responding/stable patients from non-responding/progressing patients was improved by stratifying the analysis voxels according to regions of interest (ROI) based on the LH similarity-based estimate of tumor change. Meaningful correspondence relationships between evaluated voxels are essential for accurate image-based quantification of tumor structure and function with voxel-wise analysis techniques. The LH similarity methods developed here can robustly evaluate the quality of spatial and temporal voxel correspondence relationships and provide an automated tool for ROI selection and voxel change stratification. It is readily extendable to the analysis of the wide array of anatomic, functional and biological imaging currently used to characterize tumors, guide therapy and assess response.

Therapeutic response assessment is a key component in adaptive image-guided radiotherapy. Conventional anatomic measures of response offer little information about the spatial distribution of tumor change. Recently developed voxel-wise response assessment methods operating on functional and biological imaging are better capable of evaluating the heterogeneity of response within the tumor, and thus may yield greater sensitivity than conventional approaches. However, voxel-wise analyses are limited by local registration uncertainties inherent to longitudinal imaging of tumors with changing morphology. A multi-resolution local histogram (LH) moment-based measure of voxel similarity was developed for the purpose of assessing the strength of correspondence between voxels of serial tumor images. This measure was first benchmarked through a series of experiments designed to establish robustness to image intensity variation and sensitivity to alterations in tissue structure through application of simulated deformations. The LH similarity method was subsequently developed as a means of mapping the spatial extent of structural change in tumors through the incorporation of an estimate of image complexity. The change maps were applied to a voxel-wise analysis of diffusion-weighted magnetic resonance imaging of patients with glioblastoma, acquired pre- and post-chemoradiotherapy. The sensitivity of the voxel-wise analysis in differentiating responding/stable patients from non-responding/progressing patients was improved by stratifying the analysis voxels according to regions of interest (ROI) based on the LH similarity-based estimate of tumor change. Meaningful correspondence relationships between evaluated voxels are essential for accurate image-based quantification of tumor structure and function with voxel-wise analysis techniques. The LH similarity methods developed here can robustly evaluate the quality of spatial and temporal voxel correspondence relationships and provide an automated tool for ROI selection and voxel change stratification. It is readily extendable to the analysis of the wide array of anatomic, functional and biological imaging currently used to characterize tumors, guide therapy and assess response.

La planification de traitement en radiothérapie nécessite un calcul précis de la dose délivrée au patient. La méthode la plus fiable pour y parvenir est la simulation du transport des particules par technique Monte Carlo. Cette thèse constitue la première étude concernant la validation de la plateforme de simulation Monte Carlo GATE (GEANT4 Application for Tomographic Emission), basée sur les librairies de GEANT4 (GEometry ANd Tracking), pour le calcul de la dose absorbée déposée par des faisceaux d’électrons. L’objectif de cette thèse est de montrer que GATE/GEANT4 est capable d’atteindre le niveau d’exigences requis pour le calcul de la dose absorbée lors d’une planification de traitement, dans des situations où les algorithmes analytiques, actuellement utilisés dans les services de radiothérapie, n’atteignent pas un niveau de précision satisfaisant. L’enjeu est de prouver que GATE/GEANT4 est adapté pour la planification de traitement utilisant des électrons et capable de rivaliser avec d’autres codes Monte Carlo reconnus. Cet enjeu a été démontré par la simulation avec GATE/GEANT4 de faisceaux et des sources d’électrons réalistes utilisées en radiothérapie externe ou en radiothérapie moléculaire et la production de distributions de dose absorbée en accord avec les mesures expérimentales et avec d’autres codes Monte Carlo de référence pour la physique médicale. Par ailleurs, des recommandations quant à l’utilisation des paramètres de simulation à fixer, assurant un calcul de la distribution de dose absorbée satisfaisant les spécifications en radiothérapie, sont proposées. / Radiation therapy treatment planning requires accurate determination of absorbed dose in the patient. Monte Carlo simulation is the most accurate method for solving the transport problem of particles in matter. This thesis is the first study dealing with the validation of the Monte Carlo simulation plateform GATE (GEANT4 Application for Tomographic Emission), based on GEANT4 (GEometry And Tracking) libraries, for the computation of absorbed dose deposited by electron beams. This thesis aims at demonstrating that GATE/GEANT4 calculations are able to reach treatment planning requirements in situations where analatycal algorithms are not satisfactory. The goal is to prove that GATE/GEANT4 is useful for treatment planning using electrons and competes with well validated Monte Carlo codes. This is demonstrated by the simulations with GATE/GEANT4 of realistic electron beams and electron sources used for external radiation therapy or targeted radiation therapy. The computed absorbed dose distributions are in agreement with experimental measurements and/or calculations from other Monte Carlo codes. Furthermore, guidelines are proposed to fix the physics parameters of the GATE/GEANT4 simulations in order to ensure the accuracy of absorbed dose calculations according to radiation therapy requirements.

Cirurgia conservadora de mama seguida de radioterapia é considerada como tratamento padrão para câncer de mama. A radioterapia intraoperatória (IORT) pode ser vantajosa, pois diminui o tempo de tratamento, geralmente de 4 a 6 semanas, para uma única fração, aplicada durante o procedimento cirúrgico. As distribuições de doses para tratamento por IORT não são bem conhecidas, pois o volume a ser irradiado é definido no momento da aplicação e não existe uma rotina de otimização do plano. Dessa forma as distribuições de dose não foram foco de estudos até o momento, de forma que torna-se interessante conhece-las. O objetivo do presente trabalho é simular e comparar as distribuições de doses para IORT com diferentes feixes e geometrias mamárias e compará-las com as distribuições obtidas para radioterapia 3D (3DR). Através do pacote de simulação Monte Carlo PENELOPE foram obtidas as distribuições de doses em técnicas radioterápicas 3DR e IORT por feixe de elétrons, gerados pelo acelerador NOVAC7, e por raios-X de baixa energia, gerado pelo acelerador Intrabeam. A validação dos feixes estudados, realizada através de comparação com dados da literatura, mostrou, para o feixe de 3DR, o perfil de dose esperado para os feixes com os filtros simulados. As maiores diferenças ocorreram nas regiões de horns, que aparecem subestimados na simulação. Para os feixes de IORT, as maiores diferenças entre simulação e literatura, de 7,79 e 8,6 pontos percentuais, respectivamente para NOVAC7 e Intrabeam, ocorrem em baixas profundidades. A simulação do tratamento para três diferentes volumes mamários gerou distribuições de doses que puderam ser usadas para comparação qualitativa entre as técnicas de tratamento. Para 3DR, as distribuições de doses mostram que parte considerável da dose é depositada no tórax. Embora as maiores doses sejam entregues dentro do volume da mama, ocorrem regiões frias dentro desse volume. As distribuições de dose obtidas para o Intrabeam mostraram que parte da dose pode ser entregue no tórax, dependendo do volume mamário e da posição do aplicador. O tratamento com NOVAC7 apresentou distribuições mais homogêneas dentro do volume alvo, em relação às outras técnicas. De forma geral, os resultados indicam que os tratamentos podem ser largamente influenciados pelo tamanho e posicionamento do campo para 3DR e posicionamento do aplicador para ambas as técnicas de IORT. O tratamento através do Intrabeam é comparável à 3DR. Segundo os parâmetros de avaliação do plano, IORT por feixe de elétrons proporcionaria o melhor tratamento, independentemente do volume mamário. / Conservative breast surgery followed by radiation therapy is considered the standart treatment for breast cancer. Intraoperative radiation therapy (IORT) has the advantage of decreasing the treatment duration, from the usual 4 to 6 weeks, to a single fraction, delivered during the surgical procedure. The dose distribution for treatment given through IORT are not well known, as the volume to be irradiated is defined at the moment of treatment deliver and there is not a plan optimization routine. Therefore the dose distributions were not, to the moment, the goal of any study, what makes interesting to know them. The goal of the present work is to simulate and compare the IORT dose distribution for different beams and breast geometries, and to compare to the 3D radiation therapy (3DR) dose distribution. The dose distributions for 3DR and for electron beam IORT, generated by the NOVAC7 dedicated accelerator, and for low energy x-ray IORT, generated by Intrabeam dedicated accelerator, were obtained using the Monte Carlo simulation package PENELOPE. The beams validation, performed through comparison with literature data, showed, for the 3DR beam, the dose profile expected for the simulated filters. The greatest differences occurred at the horns region, that appear sub estimated in the simulation. For IORT beams the greatest difference between simulation and literature, of 7.79 and 8.6 percentage points, respectively for the NOVAC7 and Intrabeam, occurred at low depths. The treatment simulation, with three different breast volumes, generated dose distributions that were used for a qualitative comparison of the techniques. 3DR dose distribution showed that a considerable fraction of the dose was delivered to the thorax. Although the highest doses were delivered inside the breast volume, cold regions occurred inside this volume also. Intrabeam dose distributions showed that part of the dose may be delivered to the thorax, given the breast volume and applicator position. The treatment through NOVAC7 presented more homogeneous dose distribution in relation to the other techniques. In general the results indicated that the treatment may be greatly affected by field size and position in 3DR and by the applicator position for both of the IORT techniques. Treatment through low energy x-ray IORT is comparable to 3DR treatment. According to the plan evaluation parameters electron beam IORT could give the best treatment for all the breast volumes evaluated.

Submitted by Pedro Silva Filho (pfsilva@ipen.br) on 2017-11-17T17:35:26Z No. of bitstreams: 0 / Made available in DSpace on 2017-11-17T17:35:26Z (GMT). No. of bitstreams: 0 / A utilização da técnica de teleterapia para tratamento de câncer tem sido usada por anos com bons resultados clínicos. Em meados da década de 90, a remoção do filtro aplainador, item que compõe o cabeçote de um acelerador linear de uso clínico, tem sido objeto de estudos por demonstrar bons resultados no tratamento de alguns tipos de câncer. Técnicas utilizadas como Radioterapia de Intensidade Modulada (IMRT) e Radioterapia Estereotáxica (SRT), mostram-se mais eficazes quando não se utiliza o filtro aplainador. A empresa Varian Oncology lançou em 2012 um acelerador linear de uso clínico capaz de operar com o filtro aplainador (FF) e sem o filtro aplainador (FFF), o TrueBeam. Os objetivos desse trabalho são avaliar a homogeneidade de dois importantes parâmetros utilizados para o cálculo de dose nos pacientes submetidos ao tratamento com esse modelo de acelerador linear, a porcentagem de dose profunda (PDP) e índice de qualidade do feixe (TPR20/10). Os dados fornecidos para a análise foram cedidos pelo Hospital Israelita Albert Einstein (HIAE), Real Hospital Português (RHP) e 3 instituições norte-americanas. Através de uma análise estatística dos dados das instituições citadas pode-se observar melhor o comportamento desses parâmetro que demonstraram-se muito homogêneos e com erros menores que 1% na maioria dos casos, confirmando desse modo que os aceleradores lineares do modelo TrueBeam mantém na maioria das vezes uma boa concordância dos parâmetros analisados. / Dissertação (Mestrado em Tecnologia Nuclear) / IPEN/D / Instituto de Pesquisas Energéticas e Nucleares - IPEN-CNEN/SP