La technique de radiothérapie VMAT (Volumetric Modulated Arc Therapy), diffusée en 2009, combine les avantages des techniques d'arc thérapie dynamique aux avantages des techniques de radiothérapie conformationnelle avec modulation d'intensité (RCMI) par faisceaux stationnaires. L'objectif de la thèse est de rendre optimales les conditions de mise en œuvre du VMAT autour d'un accélérateur linéaire d'électrons Synergy/Elekta afin de sécuriser la technique et de pouvoir bénéficier de l'apport clinique potentiellement attendu. Sur la base d'une analyse de l'influence des différents paramètres de la chaîne de traitement, nous proposons des éléments d'optimisation du traitement à la fois sur la planification dosimétrique et sur le contrôle de son exécution sur la machine. Nous montrons que si la qualité de l'optimisation de la technique dépend des caractéristiques intrinsèques de l'accélérateur, elle est également fortement influencée par le paramétrage du système de planification des traitements (TPS). Nous mettons en évidence des différences comparées des collimateurs Beam Modulateur (largeur de lames de 4 mm) et MLCi2 (largeur de lames de 10 mm) tant sur le plan de la distribution de dose obtenue que sur l'efficience. Nous montrons que, si pour deux principaux TPS commercialisés (Pinnacle/Philips et Monaco/Elekta) les distributions de dose aux volumes cibles sont peu modifiées, les différences de méthodes implémentées influencent la distribution de dose aux tissus sains. Nous proposons des programmes de contrôles de qualité au niveau de l'accélérateur, des plans dosimétriques de traitement et de l'exécution des traitements. Afin de garantir un niveau de confiance élevé sur la dose délivrée, nous proposons une méthode d'évaluation de la fluence délivrée en cours de traitement basée sur l'analyse des paramètres machines. Nous établissons que le processus de traitement VMAT optimisé fournit des performances de qualité supérieure que les techniques de RCMI par faisceaux stationnaires pour quatre localisations tumorales majeures étudiées. / VMAT (Volumetric Modulated Arc Therapy) technique has been introduced in 2009, it combines advantage of arctherapy techniques with advantage of IMRT (Intensity Modulated Radio Therapy) techniques delivered with stationary beams. The purpose of the thesis is to optimise implementation conditions of VMAT for a Synergy/Elekta linear accelerator in order to secure the technique and to be able to benefit from potentially expected clinical improvement. From analysis of influence of various work flow parameters, we propose treatment optimisation factors both on dosimetric planning and on delivering control on the accelerator. We show that if optimisation quality depends on intrinsic accelerator characteristics, it also depends very much on configuration of treatment planning system (TPS). We highlight compared differences between Beam Modulateur (leaf width of 4 mm) and MLCi2 (leaf width of 10 mm) on dose distribution and on efficiency. We show that if differences of dose distributions are small for two major TPS (Pinnacle/Philips and Monao/Elekta), the differences of implemented methods affect dose distribution of healthy tissues. We suggest quality control set for accelerators, for treatment plans and for treatment delivery. In order to provide a high safety level on delivered dose, we suggest an evaluation method of the real fluence provided during treatment delivery by analysing accelerator parameters. We establish that optimised process of VMAT treatment provides better performance than RCMI techniques delivered with stationary beams for the four major cancer cases that has been studied.

Les gliomes sont des tumeurs du système nerveux central. Leur plus haut degré de malignité est le glioblastome (GBM), le plus fréquent des cancers du cerveau. Les patients atteints de GBM sont d’abord opérés (si possible) puis traités par la radiothérapie avec témozolomide concomitant et adjuvant. Ce traitement n’est cependant pas curatif, en partie en raison d’une radiorésistance primaire élevée des cellules de GBM. La voie de signalisation JAK/STAT3 (Janus Kinase/Signal Transducer and Activator of Transcription 3) semble contribuer à la gravité des GBM. STAT3 est une protéine intracellulaire de transduction du signal. Elle est activée par phosphorylation de ses résidus tyrosine 705 (pSTAT3-Y705) et sérine 727 (pSTAT3-S727). L’activation de la tyrosine 705 se produit en aval du signal induit par la liaison de la cytokine interleukine 6 (IL-6) à son complexe récepteur transmembranaire gp130-IL-6Rα. Les mécanismes d’activation de la sérine 727 sont moins bien caractérisés. Le rôle de l’activation de STAT3 dans la radiorésistance des GBM a été ici étudié. Une évaluation du niveau basal de pSTAT3-Y705, pSTAT3-S727 et de la radiorésistance intrinsèque a été faite sur un panel de 15 lignées de GBM humain. L’activation de STAT3 dans les lignées cellulaires de gliomes a été évaluée par western blot et la radiorésistance par la survie cellulaire à l’irradiation. En plus de la description de l’état basal d’activation de STAT3 dans les lignées cellulaires de gliomes, cette étude a mis en évidence pour la première fois, une corrélation de pSTAT3-S727 avec la radiorésistance intrinsèque des GBM. Une stratégie de blocage pharmacologique de STAT3 nous a permis d’identifier le Gö6976 comme inhibant la phosphorylation Y705 de STAT3 dans les cellules de GBM. Celui-ci s’est avéré inhiber aussi la phosphorylation S727 mais seulement dans les lignées de GBM pSTAT3-Y705 négatives. Le traitement par le Gö6976 ralentit la croissance des cellules de GBM, indépendamment du statut d’activation de STAT3. De façon intéressante, le Gö6976 a montré un pouvoir radiosensibilisant très significatif sur les lignées pSTAT3-Y705 négatives, ce qui est concordant avec la baisse du niveau de pSTAT3-S727. La pertinence de ces résultats est confortée par un marquage immunohistochimique sur des échantillons cliniques de GBM, montrant la présence à des degrés variables de pSTAT3-S727 dans toutes les cellules cancéreuses de tous les patients. En parallèle, une étude in vitro des fonctions de pSTAT3-S727 utilisant des dominants positif et négatif est en cours. En somme, nous avons démontré que pSTAT3-S727 participe à la radiorésistance intrinsèque et que pSTAT3-Y705 est un marqueur prédictif négatif de la réponse des cellules de GBM au Gö6976 à la fois comme inhibiteur de pSTAT3-S727 et radiosensibilisant. L’ensemble de nos résultats conforte l’intérêt d’une inhibition spécifique de pSTAT3-S727 pour radiosensibiliser les GBM et ainsi améliorer le traitement des patients. / Gliomas are tumors of the central nervous system. The highest degree in glioma malignancy is Glioblastoma (GBM) that is the most frequent of the brain cancers. GBM patients are treated by surgery at first (if it is possible), followed by radiotherapy and concomitant and adjuvant temozolomide. However, this treatment is not curative in part because GBM cells display an outstanding primary radioresistance. The JAK/STAT3 (Janus Kinase/Signal Transducer and Activator of Transcription 3) signaling pathway seems to be involved in the GBM aggressiveness. STAT3 is an intracellular signal transducer protein. It is activated by phosphorylation on its tyrosine 705 (pSTAT3-Y705) and serine 727 (pSTAT3-S727) residues. The tyrosine 705 activation is produced downstream the signal induced by the binding of interleukine-6 (IL-6) cytokine to its gp130-IL-6Rα transmembrane receptor complex. The mechanisms of the serine 727 phosphorylation are less characterized. The role of STAT3 activation in the radioresistance of GBM was studied here. Basal levels of pSTAT3-Y705, pSTAT3-S727 and intrinsic radioresistance were evaluateded in a panel of 15 GBM cel lines. Activation of STAT3 in the glioma cell lines was assessed by western blotting and radioresistance through cell surviving fraction to irradiation. In addition to the description of the basal activation of STAT3 in the glioma cell lines, this study evidenced, for the first time, a correlation between pSTAT3-S727 and GBM intrinsic radioresistance. Using a pharmacological inhibition strategy, we identified Gö6976 as a chemical blocking Y705 phosphorylation of STAT3 in GBM cells. Gö6976 also inhibited pSTAT3-S727 but only in the pSTAT3-Y705-negative cell lines. Treating GBM cell with Gö6976 slowed their growth regardless of STAT3 activation status. Interestingly, Gö6976 showed a highly significant radiosensitizing effect on pSTAT3-Y705-negative cell lines that was consistent with the down-modulation of pSTAT3-S727. The relevance of these results is strengthened by immunohistochemical assay performed of GBM clinical samples that showed a variable level of pSTAT3-S727 positive staining in all tumor cells of all the patients. Furthermore, we are currently running on an in vitro study of the pSTAT3-S727 biological function by the mean of STAT3 dominant positive and dominant negative proteins. In summary, we showed that pSTAT3-S727 is involved in the intrinsic radioresistance and that pSTAT3-Y705 is a negative predicting marker of GBM cell response to Gö6976 as both a pSTAT3-S727 inhibitor and a radiosensitizer. Altogether, our results strengthen the clinical relevance of a specific inhibition of pSTAT3-S727 to radiosensitize GBM and then improve the patient treatment.

Positron emission tomography (PET) is a molecular imaging technique that provides a direct and accurate evaluation of tissue function in vivo. PET of the glucose analogue 18F-fluoro-deoxy-glucose, is increasingly in use to aid in gross target volume delineation in radiotherapy treatment planning (RTP) where it shows reduced inter-observer variability. The aim of this thesis was to develop and investigate a new technique for delineating PET-GTV with sufficient accuracy for RTP. A new technique, volume and contrast adjusted thresholding (VCAT), has been developed to automatically determine the optimum threshold value that measures the true volume on PET images. The accuracy was investigated in spherical and irregular lesions in phantoms using both iterative and filtered back-projection reconstructions and different image noise levels. The accuracy of delineation for the irregular lesions was assessed by comparison with CT using the Dice Similarity Coefficient and Euclidean Distance Transformation. A preliminarily investigation of implementing the newly developed technique in patients was carried out. VCAT proved to determine volumes and delineate tumour boundaries on PET/CT well within the acceptable errors for radiotherapy treatment planning irrespective of lesion contrast, image noise level and reconstruction technique.

<p>Abstract</p><p>The goal of modern radiotherapy is to precisely deliver a prescribed radiation dose to delineated target volumes that contain a significant amount of tumor cells while sparing the surrounding healthy tissues/organs. Precise delineation of treatment and avoidance volumes is the key for the precision radiation therapy. In recent years, considerable clinical and research efforts have been devoted to integrate MRI into radiotherapy workflow motivated by the superior soft tissue contrast and functional imaging possibility. Dynamic contrast-enhanced MRI (DCE-MRI) is a noninvasive technique that measures properties of tissue microvasculature. Its sensitivity to radiation-induced vascular pharmacokinetic (PK) changes has been preliminary demonstrated. In spite of its great potential, two major challenges have limited DCE-MRI’s clinical application in radiotherapy assessment: the technical limitations of accurate DCE-MRI imaging implementation and the need of novel DCE-MRI data analysis methods for richer functional heterogeneity information. </p><p>This study aims at improving current DCE-MRI techniques and developing new DCE-MRI analysis methods for particular radiotherapy assessment. Thus, the study is naturally divided into two parts. The first part focuses on DCE-MRI temporal resolution as one of the key DCE-MRI technical factors, and some improvements regarding DCE-MRI temporal resolution are proposed; the second part explores the potential value of image heterogeneity analysis and multiple PK model combination for therapeutic response assessment, and several novel DCE-MRI data analysis methods are developed.</p><p>I. Improvement of DCE-MRI temporal resolution. First, the feasibility of improving DCE-MRI temporal resolution via image undersampling was studied. Specifically, a novel MR image iterative reconstruction algorithm was studied for DCE-MRI reconstruction. This algorithm was built on the recently developed compress sensing (CS) theory. By utilizing a limited k-space acquisition with shorter imaging time, images can be reconstructed in an iterative fashion under the regularization of a newly proposed total generalized variation (TGV) penalty term. In the retrospective study of brain radiosurgery patient DCE-MRI scans under IRB-approval, the clinically obtained image data was selected as reference data, and the simulated accelerated k-space acquisition was generated via undersampling the reference image full k-space with designed sampling grids. Two undersampling strategies were proposed: 1) a radial multi-ray grid with a special angular distribution was adopted to sample each slice of the full k-space; 2) a Cartesian random sampling grid series with spatiotemporal constraints from adjacent frames was adopted to sample the dynamic k-space series at a slice location. Two sets of PK parameters’ maps were generated from the undersampled data and from the fully-sampled data, respectively. Multiple quantitative measurements and statistical studies were performed to evaluate the accuracy of PK maps generated from the undersampled data in reference to the PK maps generated from the fully-sampled data. Results showed that at a simulated acceleration factor of four, PK maps could be faithfully calculated from the DCE images that were reconstructed using undersampled data, and no statistically significant differences were found between the regional PK mean values from undersampled and fully-sampled data sets. DCE-MRI acceleration using the investigated image reconstruction method has been suggested as feasible and promising. </p><p>Second, for high temporal resolution DCE-MRI, a new PK model fitting method was developed to solve PK parameters for better calculation accuracy and efficiency. This method is based on a derivative-based deformation of the commonly used Tofts PK model, which is presented as an integrative expression. This method also includes an advanced Kolmogorov-Zurbenko (KZ) filter to remove the potential noise effect in data and solve the PK parameter as a linear problem in matrix format. In the computer simulation study, PK parameters representing typical intracranial values were selected as references to simulated DCE-MRI data for different temporal resolution and different data noise level. Results showed that at both high temporal resolutions (<1s) and clinically feasible temporal resolution (~5s), this new method was able to calculate PK parameters more accurate than the current calculation methods at clinically relevant noise levels; at high temporal resolutions, the calculation efficiency of this new method was superior to current methods in an order of 102. In a retrospective of clinical brain DCE-MRI scans, the PK maps derived from the proposed method were comparable with the results from current methods. Based on these results, it can be concluded that this new method can be used for accurate and efficient PK model fitting for high temporal resolution DCE-MRI. </p><p>II. Development of DCE-MRI analysis methods for therapeutic response assessment. This part aims at methodology developments in two approaches. The first one is to develop model-free analysis method for DCE-MRI functional heterogeneity evaluation. This approach is inspired by the rationale that radiotherapy-induced functional change could be heterogeneous across the treatment area. The first effort was spent on a translational investigation of classic fractal dimension theory for DCE-MRI therapeutic response assessment. In a small-animal anti-angiogenesis drug therapy experiment, the randomly assigned treatment/control groups received multiple fraction treatments with one pre-treatment and multiple post-treatment high spatiotemporal DCE-MRI scans. In the post-treatment scan two weeks after the start, the investigated Rényi dimensions of the classic PK rate constant map demonstrated significant differences between the treatment and the control groups; when Rényi dimensions were adopted for treatment/control group classification, the achieved accuracy was higher than the accuracy from using conventional PK parameter statistics. Following this pilot work, two novel texture analysis methods were proposed. First, a new technique called Gray Level Local Power Matrix (GLLPM) was developed. It intends to solve the lack of temporal information and poor calculation efficiency of the commonly used Gray Level Co-Occurrence Matrix (GLCOM) techniques. In the same small animal experiment, the dynamic curves of Haralick texture features derived from the GLLPM had an overall better performance than the corresponding curves derived from current GLCOM techniques in treatment/control separation and classification. The second developed method is dynamic Fractal Signature Dissimilarity (FSD) analysis. Inspired by the classic fractal dimension theory, this method measures the dynamics of tumor heterogeneity during the contrast agent uptake in a quantitative fashion on DCE images. In the small animal experiment mentioned before, the selected parameters from dynamic FSD analysis showed significant differences between treatment/control groups as early as after 1 treatment fraction; in contrast, metrics from conventional PK analysis showed significant differences only after 3 treatment fractions. When using dynamic FSD parameters, the treatment/control group classification after 1st treatment fraction was improved than using conventional PK statistics. These results suggest the promising application of this novel method for capturing early therapeutic response. </p><p> The second approach of developing novel DCE-MRI methods is to combine PK information from multiple PK models. Currently, the classic Tofts model or its alternative version has been widely adopted for DCE-MRI analysis as a gold-standard approach for therapeutic response assessment. Previously, a shutter-speed (SS) model was proposed to incorporate transcytolemmal water exchange effect into contrast agent concentration quantification. In spite of richer biological assumption, its application in therapeutic response assessment is limited. It might be intriguing to combine the information from the SS model and from the classic Tofts model to explore potential new biological information for treatment assessment. The feasibility of this idea was investigated in the same small animal experiment. The SS model was compared against the Tofts model for therapeutic response assessment using PK parameter regional mean value comparison. Based on the modeled transcytolemmal water exchange rate, a biological subvolume was proposed and was automatically identified using histogram analysis. Within the biological subvolume, the PK rate constant derived from the SS model were proved to be superior to the one from Tofts model in treatment/control separation and classification. Furthermore, novel biomarkers were designed to integrate PK rate constants from these two models. When being evaluated in the biological subvolume, this biomarker was able to reflect significant treatment/control difference in both post-treatment evaluation. These results confirm the potential value of SS model as well as its combination with Tofts model for therapeutic response assessment. </p><p>In summary, this study addressed two problems of DCE-MRI application in radiotherapy assessment. In the first part, a method of accelerating DCE-MRI acquisition for better temporal resolution was investigated, and a novel PK model fitting algorithm was proposed for high temporal resolution DCE-MRI. In the second part, two model-free texture analysis methods and a multiple-model analysis method were developed for DCE-MRI therapeutic response assessment. The presented works could benefit the future DCE-MRI routine clinical application in radiotherapy assessment.</p> / Dissertation

Orientadores: Gustavo Antonio de Souza, Maria Salete Costa Gurgel / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-08T02:38:19Z (GMT). No. of bitstreams: 1 Oliveira_MarianaMaiaFreirede_M.pdf: 2870270 bytes, checksum: 3cc12d99aeebd1b7364b222041edf8b1 (MD5) Previous issue date: 2007 / Resumo: A fisioterapia no pós-operatório de câncer de mama visa a prevenir as complicações e promover a independência funcional. Porém, não há dados na literatura sobre a influência da fisioterapia realizada durante a radioterapia, bem como qual a melhor abordagem. Objetivo: Avaliar a eficácia da realização da fisioterapia durante a radioterapia na prevenção das seguintes complicações físicas loco-regionais: limitação da amplitude de movimento do ombro, aumento da circunferência e incapacidade funcional do membro superior e aderência cicatricial em mulheres em tratamento por câncer de mama. Sujeitos e Métodos: Ensaio clínico controlado randomizado, realizado no Serviço de Fisioterapia do Centro de Atenção Integral à Saúde da Mulher da Universidade Estadual de Campinas, com 66 mulheres em tratamento radioterápico após cirurgia para câncer de mama e fisioterapia pós-operatória. As mulheres foram alocadas no Grupo 1 (32 mulheres) que realizou fisioterapia durante a radioterapia e no Grupo 2 (34 mulheres), controle, sendo avaliadas no início e no final da radioterapia e 6 meses após seu término. A amplitude de movimento do ombro foi avaliada através da goniometria, a circunferência do braço, pela cirtometria e a aderência cicatricial, pela palpação e fricção cicatricial. A capacidade funcional foi graduada através de escore de dificuldade para movimentar o ombro. Para cálculos estatísticos foram utilizados MANOVA com estatísitca de Wilks ou Friedman e os testes de associação qui-quadrado ou exato de Fisher, assumindo nível de significância a = 5%. Resultados: A idade média foi de 52,3 ± 10,6 anos no Grupo 1 e de 48,7 ± 10,8 anos no Grupo 2. Os valores médios de amplitude de movimento do ombro para abdução e flexão observados nas três avaliações revelaram melhores resultados para Grupo1 em relação ao Grupo 2 (p= 0,0244 e 0,0044, respectivamente). Os valores médios da circunferência do braço obtidos nas avaliações não se alteraram em ambos os grupos. Há evidências de que a fisioterapia realizada durante a radioterapia possa favorecer a melhora da capacidade funcional. Na avaliação final, a freqüência de aderência cicatricial no Grupo1 foi duas vezes menor que a observada no Grupo 2 (24% e 48%, p= 0,0477). Conclusão: A fisioterapia realizada durante a radioterapia para tratamento de câncer de mama previne a limitação na amplitude de movimento do ombro e minimiza a incidência de aderência cicatricial. Os resultados sugerem também favorecer a melhora da capacidade funcional. No período estudado, não foi encontrada associação entre a realização da fisioterapia e alteração na circunferência do braço / Abstract: Physiotherapy following surgery for breast cancer is recommended for the prevention of complications and to stimulate functional independence. However, there are no data in the literature on the influence of physiotherapy carried out during radiotherapy (RT), nor on its optimal management. Objective: To evaluate the influence of physiotherapy carried out during radiotherapy on the following physical, locoregional complications: limitations in amplitude of movement and functional capacity, increased arm circumference, and the presence of scar tissue. Subjects and Methods: A randomized, controlled clinical trial was carried out in the Physiotherapy Department of the Center for Women¿s Integrated Healthcare, Universidade Estadual de Campinas, in 66 women undergoing radiotherapy following surgery for breast cancer, and postoperative physiotherapy. Women were randomized to Group 1 (G1) in which physiotherapy was provided, and Group 2 (G2), the control group. Evaluations were carried out at the beginning and at the conclusion of RT, and 6 months after its conclusion. Amplitude of shoulder movement was evaluated by goniometry; arm circumference was measured, and the presence of scar tissue was evaluated by digital palpation of the region. Functional capacity was graded according to a score evaluating difficulty of the patient in moving the shoulder. Statistical analysis was carried out using multivariate analysis of variance (MANOVA) with the Wilks or Friedman tests, and the chi-square or Fisher¿s exact tests of association. Significance level was established as a = 5%. Results: Thirty-two women were randomized to G1 and 34 to G2. Mean age was 52.3 ± 10.6 years in G1 and 48.7 ± 10.8 years in G2. The mean values of amplitude of shoulder movement with respect to abduction and flexion found at the three evaluation times indicated better results for G1 compared to G2 (p=0.0244 and 0.0044, respectively). During the period of this study, no association was found between physiotherapy and changes in arm circumference. There are evidences that the physiotherapy carried out during radiotherapy could encourage an improvement in functional capacity. At the final evaluation, the presence of scar tissue in G1 was half that found in patients in G2 (24% and 48%, p=0.0477). Conclusion: Physiotherapy carried out during radiotherapy for breast cancer prevents limitations in the amplitude of shoulder movement, minimizes the presence of scar tissue and appears to result in an improvement in functional capacity. During the period studied, no association was found between carrying out physiotherapy and changes in arm circumference / Mestrado / Ciencias Biomedicas / Mestre em Tocoginecologia

Orientador: Pedro Duarte Novaes / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba / Made available in DSpace on 2018-08-22T06:39:35Z (GMT). No. of bitstreams: 1 Silva_KarlaRovarisda_M.pdf: 5383756 bytes, checksum: f46eb2dfd48068a21c19841f2e4d3581 (MD5) Previous issue date: 2013 / Resumo: Os efeitos adversos da radioterapia sobre os tecidos orais vêm sendo estudados com intuito de, cada vez mais, entender como esta age sobre o organismo, bem como para o desenvolvimento de métodos ou substâncias que visem à minimização dessas sequelas. Dentre os tecidos que estão na área de exposição, está o ligamento periodontal, que se afetado, pode ocasionar a perna dentária que impreterivelmente interfere na qualidade de vida do indivíduo. Este trabalho teve como objetivo avaliar o efeito da radiação ionizante sobre o ligamento periodontal do dente incisivo de rato albinus wistar, por meio da microscopia de polarização e do teste de força. A amostra constituiu-se de 30 ratos albinus wistar machos divididos em dois grupos, o grupo controle (15) e o grupo irradiado (15). O grupo irradiado foi submetido à sessão única de radioterapia com dose de 15Gy e após 14 dias todos os animais foram sacrificados. Um animal de cada grupo foi perdido durante a execução do trabalho. Desta forma, sete animais de cada grupo foram submetidos ao teste de resistência do ligamento periodontal e os sete restantes tiveram a organização do colágeno avaliada através da microscopia de polarização. Os resultados mostraram que ambos os testes apresentaram diferença estatisticamente significante entre os grupos (p<0,001). Através dos coeficientes de correlação de Pearson encontrou-se também uma forte correlação entre os resultados dos testes (resistência/polarização) de cada grupo (controle/irradiado) (R = 0,683; p < 0,001). Portanto, concluiu-se que a radioterapia pode levar à diminuição da resistência à força de intrusão e provocou a desorganização do colágeno no ligamento periodontal / Abstract: The adverse effects of radiotherapy on oral tissues have been studied in order to increasingly understand how it works on the body, as well as for the development of methods and substances aimed at minimizing these sequelae. Among the tissues that are in the exposition area, is the periodontal ligament which, when affected, can lead to tooth loss, that unfailingly interferes with quality of life. This study had as purpose to evaluate the effect of ionizing radiation over the periodontal ligament of the incisive tooth of the albinus wistar rat, trough the polarizing microscope and the strength test. The sample was composed of 30 albinus wistar male rats, separated into two groups, the control group (15) and the irradiated one (15). The irradiated group was subjected to an only session of radiotherapy, with a 15Gy dose, and after 14 days all the animals were sacrificed. One animal in each group was lost during the study's execution. Hence, seven animals of each group were subjected to the periodontal's ligament resistance test, and the seven remaining had their collagen organization evaluated trough the polarizing microscopy. The results showed that both tests exhibited statistically significance difference between the groups (p<0,001). Using the Pearson correlation coefficients a strong correlation was also found between the tests results (resistance/polarizing) of each group (control/irradiated) (R = 0,683; p<0,0001). Thereby, the conclusion was that radiotherapy can lead to a diminished resistance to the intrusion strength and to a disorganization of the periodontal's ligament collagen / Mestrado / Radiologia Odontologica / Mestra em Radiologia Odontológica

Orientadores: Eduardo Tavares Costa, Paulo José Cecílio / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Engenharia Elétrica e de Computação / Made available in DSpace on 2018-08-24T11:03:55Z (GMT). No. of bitstreams: 1 Biazotto_Bruna_M.pdf: 4075478 bytes, checksum: 077630eb4f66ca28ec46de7251c31e3f (MD5) Previous issue date: 2013 / Resumo: A experiência clínica em tratamentos radioterápicos de neoplasia de próstata baseia-se no cálculo de doses em meios homogêneos. Entretanto, o feixe de radiação atravessa tecidos de densidades eletrônicas diferentes como os ossos, que alteram a distribuição de dose. Com o advento da tomografia computadorizada e de algoritmos mais avançados que modelam o feixe de radiação, as heterogeneidades entre os tecidos podem ser incorporadas nos planejamentos de tratamentos radioterápicos. Todavia, não há consenso se as alterações na dose por correções de heterogeneidade são significativas. Por tais razões, pretendeu-se no presente trabalho avaliar a necessidade das correções de heterogeneidade em planejamentos de tratamentos radioterápicos de câncer de próstata. Para isso, analisaram-se as médias das diferenças percentuais nas doses em volume alvo e órgãos de risco obtidas em cálculos com e sem correções de heterogeneidade utilizando imagens tomográficas reais de pacientes que trataram dessa neoplasia. Essa avaliação foi realizada para dois métodos de tratamentos diferentes. O primeiro é o conformacional tridimensional (25 casos), algoritmos de cálculo Convolution, Superposition e Fast Superposition do sistema de planejamento XiO/Elekta, feixes de 6 e 10 MV e 4 campos em box. O segundo por intensidade modulada (14 casos), algoritmo de cálculo Pencil Beam Convolution do sistema de planejamento Eclipse/Varian com dois métodos de correção Batho Modificado e Razão Tecido-Ar Equivalente, feixe de 6 MV e geometria de 5 campos oblíquos. As diferenças percentuais médias resultantes nos volumes estudados foram menores que a incerteza aceita atualmente no cálculo de dose de 3% para as duas modalidades de tratamento. Apesar disso, a variabilidade na anatomia dos pacientes, geometria de campos e energia dos feixes apontam para a necessidade de tais correções e a utilização de métodos ainda mais exatos para a diminuição dessa incerteza no futuro / Abstract: Clinical experience in radiotherapy treatments for prostate cancer is based on the calculation of doses in homogeneous media. However, the radiation beam traverses different electron densities in tissues such as bone, altering the dose distribution. With the advent of computed tomography and more advanced algorithms that model the radiation beam, the heterogeneity between tissues can be incorporated in the planning of radiotherapy treatments. However, there is no consensus whether changes in dose for inhomogeneity corrections are significant. For these reasons, this study intended to evaluate the need for inhomogeneity corrections in treatment planning for radiotherapy of prostate cancer. We have analyzed the average percentage differences in doses in the target volume and organs at risk obtained by calculations with and without heterogeneity corrections using actual CT images of patients treated for this cancer. This evaluation was performed for two different methods of treatments. The first is the three-dimensional conformational (25 cases), calculation algorithms Convolution, Superposition and Fast Superposition from the computerized planning system XiO/Elekta, beams of 6 and 10 MV and 4 fields in box. The second by intensity modulated (14 cases), calculation algorithm Pencil Beam Convolution from the computerized planning system Eclipse/Varian with two correction methods Modified Batho and Equivalent Tissue-Air Ratio, 6 MV beam and geometry of 5 oblique fields. The resulting average percentage differences in volumes studied were smaller than the currently accepted uncertainty in the dose calculation of 3% for both treatment modalities. Nevertheless, variability in anatomy of patients, geometry and field energy beams brings the need for these corrections and the use of more accurate methods to reduce this uncertainty in the future / Mestrado / Engenharia Biomedica / Mestra em Engenharia Elétrica

Orientador: Alessandro Ferrari Jacinto / Resumo: Introdução: A população idosa cresce no Brasil e com a transição demográfica ocorrem muitas alterações, algumas no âmbito da saúde, como o aumento do aparecimento de Doenças Crônicas Não Transmissíveis (DCNT) como, por exemplo, as neoplasias. Estas têm sido cada vez mais responsáveis pelos óbitos e frequente causa de preocupação e estudos. A radioterapia é uma possibilidade de tratamento para as neoplasias e em geral, sua população atendida é principalmente composta por idosos. É comum observarmos durante o adoecimento por câncer, bem como durante os períodos de tratamento, a presença de alterações na capacidade funcional e sofrimento psíquico, neste estudo tratado como transtorno mental comum (TMC). Objetivos: O presente trabalho teve como objetivo principal avaliar uma população de idosos em radioterapia quanto ao sofrimento psíquico e à capacidade funcional. E como objetivos secundários observar e descrever a população estudada bem como rastrear alterações cognitivas nesta população. Métodos: Foi realizado um estudo observacional, analítico e transversal com uma população de indivíduos com 60 anos ou mais que estavam em tratamento no Serviço de Radioterapia do Hospital das Clínicas da Faculdade de Medicina de Botucatu - UNESP .O período de inserção de sujeitos na pesquisa foi de 1 de abril de 2017 a 31 de agosto de 2017.Os instrumentos utilizados foram o “Self-Reporting Questionnaire” (SRQ-20) para rastreamento de transtornos mentais não psicóticos, e o Questionário de Ati... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Introduction: Old age does not grow in Brazil and with a series of classes that undergo many changes, such as in the health field, such as the increase in the appearance of Noncommunicable Chronic Diseases, such as neoplasia. This was the reason why they are costed and their frequencies cause the studies. Radiotherapy is a possible treatment for neoplasms and the population served is mainly composed of elderly people. It is common to observe during cancer sickness as well as during the treatment periods the presence of alertness in the Functioning and Psychological Suffering, in this study named as Common Mental Disorder. Objectives: The present study aimed to evaluate a population of elderly people in radiotherapy treatment with regard to psychic suffering and functional capacity. And as secondary objectives to observe and describe the studied population as well as to track cognitive alterations in this population. Methods: An observation and cross-sectional analytical study was carried out. Data collecting was carried out through Self – Reporting Questionnaire (SRQ-20) for tracking mental disorder non- psychotic, Functional Activities Questionnaire (FAQ) for evaluating functional capacity of subjects. Subjects were 60 years or older and were under radiotherapy treatment during the research period from April to August, 2017. Results: The sample consisted of 82 elderly patients in radiotherapy treatment, the most present neoplasia in the participants of the study was breast n... (Complete abstract click electronic access below) / Mestre

L’hypoxie est une caractéristique majeure des glioblastomes (GB). Elle est la cause principale de la résistance aux traitements observée dans ces tumeurs. Les conséquences de la baisse en oxygène au niveau tumoral, sont médiées par les facteurs de transcription Hypoxia Inducible Factors (HIF). Ces facteurs sont des protéines hétérodimériques HIF-α/HIF-1β responsables de la transcription de nombreux gènes cibles. Certaines de ces cibles participent à la progression tumorale et à la mise en place d’un phénotype agressif. L’une des cibles de l’isoforme HIF-2α, est la βIII-tubuline (βIII-t). Cette protéine, qui compose les microtubules, est décrite comme surexprimée dans les gliomes de haut grade, comme les GB. Ces travaux de thèse s’intéressent au rôle de la βIII-t dans la progression tumorale ainsi qu’au développement de stratégies permettant d’inhiber l’expression de HIF-2α. Les résultats obtenus montrent que la βIII-t a une importance centrale dans le développement tumoral. En effet, les tumeurs issues de l’implantation de cellules humaines de GB invalidées pour la βIII-t, se développent significativement moins vite comparées aux tumeurs contrôles. In vitro, nous avons montré que cette protéine est impliquée dans la prolifération, la migration et l’invasion cellulaires. En revanche, nous n’avons pas pu confirmer que la βIII-t est impliquée dans la résistance aux traitements (chimio- ou radiothérapeutiques). Les deux composés testés comme inhibiteurs de HIF-2α (SR2933 et PT2385) ont montré des résultats prometteurs sur la βIII-t, gène cible spécifique de HIF-2α. Cependant, malgré les stratégies développées, nous n’avons pas pu évaluer l’efficacité directe de ces deux composés sur l’hétérodimérisation de HIF-2α avec HIF-1β. / Hypoxia is a major feature of glioblastoma (GB). It is the main cause of the resistance to treatments observed in these tumors. The consequences of the decrease in oxygen at the tumor level, is mediated by the Hypoxia Inducible Factors (HIF). These transcription factors are heterodimeric proteins HIF-α/HIF-1β responsible for the transcription of many target genes. Some of these targets are responsible for setting up an aggressive phenotype and in tumor progression. One of the targets of the HIF-2α isoform is βIII-tubulin (βIII-t). This protein, which is a constituent of microtubules, is described as overexpressed in high grade gliomas, such as GB. In the present thesis, we examined the role of βIII-t in tumor progression and we developed strategies to inhibit the expression of HIF-2α. Our results show that βIII-t is of central importance in tumor development. Indeed, tumors resulting from the implantation of GB human cells invalidated for βIII-t, developed significantly less rapidly compared to control tumors. In vitro, we have shown that this protein is involved in cell proliferation, migration and invasion. However, we could not confirm that βIII-t is involved in resistance to treatments (chemotherapeutic or radiotherapeutic).The two compounds tested as inhibitors of HIF-2α (SR2933 and PT2385) showed promising results on βIII-t, a specific target gene of HIF-2α. However, despite the different tested strategies, we could not evaluate the direct inhibitory action of these two compounds on the heterodimerization of HIF-2α with HIF-1β.

Magister Scientiae - MSc / Despite recent advances in radiotherapy, some tumours have shown to be resistant to treatment and patients still experience long term side effects. Gold nanoparticles (AuNPs) have been identified as effective radiosensitizers when employed concurrently with kilovoltage X-rays, which could selectively increase the dose delivered to a patient's tumour. The clinical application of proton radiation has gained renewed attention due to the lower integral body dose of protons compared to traditional X-ray based therapy. While extensive research has been formed on the behaviour of AuNPs in photon beams, limited information is available on the combination of AuNPs and proton radiation. Several questions remain regarding the interaction of protons with the AuNPs and possible dose enhancement effects at different depths along the Spread Out Bragg Peak (SOBP).