A radioterapia moderna continua evoluindo e trazendo mudanças tecnológicas que envolvem novas modalidades de imagem, novos acessórios de imobilização e novos sistemas para a entrega da dose. Esses avanços possibilitam reduzir a dose recebida pelos tecidos sadios e, consequentemente, diminuem o risco de toxicidade e morbidade. Ao mesmo tempo, maiores doses podem ser prescritas para os volumes tumorais, o que aumenta a probabilidade de controle locorregional. Técnicas tradicionais de IMRT oferecem todas essas vantagens, porém, o tempo de cada sessão de tratamento costuma ser muito longo, principalmente para os casos de cabeça e pescoço. Atualmente, a técnica VMAT é uma realidade em vários centros de referência ao redor do mundo. Essa tecnologia melhorou a eficiência na entrega da dose em relação aos tratamentos convencionais de IMRT, diminuindo o tempo de cada aplicação, e apresenta mais graus de liberdade no processo de otimização do tratamento. A modulação dos feixes de radiação é obtida pela variação simultânea de parâmetros dinâmicos como a taxa de dose, velocidade de gantry e a velocidade das lâminas do sistema de colimação. A alta complexidade associada às novas tendências de tratamento, inevitavelmente, exige um maior rigor em relação aos testes de controle da qualidade que devem ser realizados. Os métodos de comissionamento reportados para a tecnologia RapidArc foram estendidos e adaptados para um acelerador Elekta Synergy através de arquivos que podem ser construídos utilizando o software iComCAT. São apresentados testes específicos para o controle da qualidade da máquina e o processo de validação dosimétrica empregado no sistema de planejamento Monaco. Os parâmetros específicos de lâmina, modelados através do algoritmo Monte Carlo, foram avaliados e os testes do TG 119 foram adaptados para os planejamentos de VMAT. No final é apresentado o programa que foi desenvolvido para o controle da qualidade específico da tecnologia VMAT em aceleradores Elekta. / Modern radiation therapy keeps evolving and the technological changes include new imaging modalities, new patient immobilization devices and new treatment delivery systems. These advances have made it possible to reduce the dose to normal tissue structures and consequently minimize the risk of toxicity and morbidity, while allowing for dose escalation to the tumor volumes, potencially leading to improved locoregional control. Traditional IMRT techniques offer all of these features but the treatment session time is usually long, mainly for the head and neck cases. Currently, the VMAT technique is a reality in reference centers around the world. This technology has improved delivery efficiency over IMRT, decreasing the treatment application time, as this modality introduces extra degrees of freedom in the optimization process. The modulation of the radiation beams is achieved by simultaneous variation of dynamic parameters such as dose rate, gantry speed and leaves speed. The high level of complexity associated to the new treatment trends, inevitably, requires more accuracy and more rigorous quality assurance programs. The commissioning methods reported for the Varian RapidArc system were extended to an Elekta Synergy linear accelerator, using custom files built in the iComCAT software. Specific tests for the machine quality assurance are presented and also the dosimetric validation process applied to the Monaco treatment planning system. The MLC parameters, modeled by the Monte Carlo algorithm, were analyzed and the TG 119 tests were adapted for VMATplanning. In the end, a specific program developed for the VMAT technology for Elekta accelerators is presented.

A radioterapia moderna continua evoluindo e trazendo mudanças tecnológicas que envolvem novas modalidades de imagem, novos acessórios de imobilização e novos sistemas para a entrega da dose. Esses avanços possibilitam reduzir a dose recebida pelos tecidos sadios e, consequentemente, diminuem o risco de toxicidade e morbidade. Ao mesmo tempo, maiores doses podem ser prescritas para os volumes tumorais, o que aumenta a probabilidade de controle locorregional. Técnicas tradicionais de IMRT oferecem todas essas vantagens, porém, o tempo de cada sessão de tratamento costuma ser muito longo, principalmente para os casos de cabeça e pescoço. Atualmente, a técnica VMAT é uma realidade em vários centros de referência ao redor do mundo. Essa tecnologia melhorou a eficiência na entrega da dose em relação aos tratamentos convencionais de IMRT, diminuindo o tempo de cada aplicação, e apresenta mais graus de liberdade no processo de otimização do tratamento. A modulação dos feixes de radiação é obtida pela variação simultânea de parâmetros dinâmicos como a taxa de dose, velocidade de gantry e a velocidade das lâminas do sistema de colimação. A alta complexidade associada às novas tendências de tratamento, inevitavelmente, exige um maior rigor em relação aos testes de controle da qualidade que devem ser realizados. Os métodos de comissionamento reportados para a tecnologia RapidArc foram estendidos e adaptados para um acelerador Elekta Synergy através de arquivos que podem ser construídos utilizando o software iComCAT. São apresentados testes específicos para o controle da qualidade da máquina e o processo de validação dosimétrica empregado no sistema de planejamento Monaco. Os parâmetros específicos de lâmina, modelados através do algoritmo Monte Carlo, foram avaliados e os testes do TG 119 foram adaptados para os planejamentos de VMAT. No final é apresentado o programa que foi desenvolvido para o controle da qualidade específico da tecnologia VMAT em aceleradores Elekta. / Modern radiation therapy keeps evolving and the technological changes include new imaging modalities, new patient immobilization devices and new treatment delivery systems. These advances have made it possible to reduce the dose to normal tissue structures and consequently minimize the risk of toxicity and morbidity, while allowing for dose escalation to the tumor volumes, potencially leading to improved locoregional control. Traditional IMRT techniques offer all of these features but the treatment session time is usually long, mainly for the head and neck cases. Currently, the VMAT technique is a reality in reference centers around the world. This technology has improved delivery efficiency over IMRT, decreasing the treatment application time, as this modality introduces extra degrees of freedom in the optimization process. The modulation of the radiation beams is achieved by simultaneous variation of dynamic parameters such as dose rate, gantry speed and leaves speed. The high level of complexity associated to the new treatment trends, inevitably, requires more accuracy and more rigorous quality assurance programs. The commissioning methods reported for the Varian RapidArc system were extended to an Elekta Synergy linear accelerator, using custom files built in the iComCAT software. Specific tests for the machine quality assurance are presented and also the dosimetric validation process applied to the Monaco treatment planning system. The MLC parameters, modeled by the Monte Carlo algorithm, were analyzed and the TG 119 tests were adapted for VMATplanning. In the end, a specific program developed for the VMAT technology for Elekta accelerators is presented.

京都大学 / 0048 / 新制・課程博士 / 博士(人間健康科学) / 甲第22390号 / 人健博第76号 / 新制||人健||5(附属図書館) / 京都大学大学院医学研究科人間健康科学系専攻 / (主査)教授 椎名 毅, 教授 精山 明敏, 教授 富樫 かおり / 学位規則第4条第1項該当 / Doctor of Human Health Sciences / Kyoto University / DFAM

RCSN-3 cells are a cloned cell line derived from the substantia nigra of an adult rat. The cell line grows in monolayer and does not require differentiation to express catecholaminergic traits, such as (i) tyrosine hydroxylase; (ii) dopamine release; (iii) dopamine transport; (iv) norepinephrine transport; (v) monoamine oxidase (MAO)-A expression, but not MAO-B; (vi) formation of neuromelanin; (vii) vesicular monoamine transporter-2 (VMAT-2) expression. In addition, this cell line expresses serotonin transporters, divalent metal transporter, DMT1, dopamine receptor 1 mRNA under proliferating conditions, and dopamine receptor 5 mRNA after incubation with dopamine or dicoumarol. Expression of dopamine receptors D2, D3 and D4 mRNA were not detected in proliferating cells or when the cells were treated with dopamine, CuSO4, dicoumarol or dopamine-copper complex. Angiotensin II receptor mRNA was also found to be expressed, but it underwent down regulation in the presence of aminochrome. Total quinone reductase activity corresponded 94% to DT-diaphorase. The cells also express antioxidant enzymes such as superoxide dismutase, catalase and glutathione peroxidase. This cell line is a suitable in vitro model for studies of dopamine metabolism, since under proliferating conditions the cells express all the pertinent markers.

No description available.

Cette thèse a été réalisée dans le cadre de la dosimétrie des faisceaux de haute énergie délivrés au patient pendant un traitement de radiothérapie externe. L'objectif de ce travail est de vérifier que la distribution de dose 3D absorbée dans le patient est conforme au calcul réalisé sur le système de planification de traitement (TPS) à partir de l'imageur portal (en anglais : Electronic Portal Imaging Device, EPID). L'acquisition est réalisée en mode continu avec le détecteur aS-1200 au silicium amorphe embarqué sur la machine TrueBeam STx (VARIAN Medical system, Palo Alto, USA). Les faisceaux ont une énergie de 10 MeV et un débit de 600 UM.min-1. La distance source-détecteur (DSD) est de 150 cm. Après correction des pixels défectueux, une étape d'étalonnage permet de convertir leur signal en dose absorbée dans l'eau via une fonction de réponse. Des kernels de correction sont également utilisés pour prendre en compte la différence de matériaux entre l'EPID et l'eau et pour corriger la pénombre sur les profils de dose. Un premier modèle de calcul a permis ensuite de rétroprojeter la dose portale en milieu homogène en prenant en compte plusieurs phénomènes : les photons diffusés provenant du fantôme et rajoutant un excès de signal sur les images, l'atténuation des faisceaux, la diffusion dans le fantôme, l'effet de build-up et l'effet de durcissement du faisceau avec la profondeur. La dose reconstruite est comparée à celle calculée par le TPS avec une analyse gamma globale (3% du maximum de dose et 3 mm de DTA). L'algorithme a été testé sur un fantôme cylindrique homogène et sur un fantôme de pelvis à partir de champs modulés en intensité (RCMI) et à partir de champs d'arcthérapie volumique modulés, VMAT selon l'acronyme anglais Volumetric Modulated Arc Therapy. Le modèle a ensuite été affiné pour prendre en compte les hétérogénéités traversées dans le milieu au moyen des distances équivalentes eau dans une nouvelle approche de dosimétrie plus connue sous le terme de " in aqua vivo " (1). Il a été testé sur un fantôme thorax et, in vivo sur 10 patients traités pour une tumeur de la prostate à partir de champs VMAT. Pour finir, le modèle in aqua a été testé sur le fantôme thorax avant et après y avoir appliqué certaines modifications afin d'évaluer la possibilité de détection de sources d'erreurs pouvant influencer la bonne délivrance de la dose au patient.[...] / This thesis aims at the dosimetry of high energy photon beams delivered to the patient during an external radiation therapy treatment. The objective of this work is to use EPID the Electronic Portal Imaging Device (EPID) in order to verify that the 3D absorbed dose distribution in the patient is consistent with the calculation performed on the Treatment Planning System (TPS). The acquisition is carried out in continuous mode with the aS-1200 amorphous silicon detector embedded on the TrueBeam STx machine (VARIAN Medical system, Palo Alto, USA) for 10MV photons with a 600 UM.min-1 dose rate. The source-detector distance (SDD) is 150 cm. After correction of the defective pixels, a calibration step is performed to convert the signal into an absorbed dose in water via a response function. Correction kernels are also used to take into account the difference in materials between EPID and water and to correct penumbra. A first model of backprojection was performed to reconstruct the absorbed dose distribution in a homogeneous medium by taking into account several phenomena: the scattered photons coming from the phantom to the EPID, the attenuation of the beams, the diffusion into the phantom, the build-up, and the effect of beam hardening with depth. The reconstructed dose is compared to the one calculated by the TPS with global gamma analysis (3% as the maximum dose difference criteria and 3mm as the distance to agreement criteria). The algorithm was tested on a homogeneous cylindrical phantom and a pelvis phantom for Intensity-Modulated Radiation Therapy (IMRT) and (Volumetric Arc Therapy (VMAT) technics. The model was then refined to take into account the heterogeneities in the medium by using radiological distances in a new dosimetrical approach better known as "in aqua vivo" (1). It has been tested on a thorax phantom and, in vivo on 10 patients treated for a prostate tumor from VMAT fields. Finally, the in aqua model was tested on the thorax phantom before and after making some modifications to evaluate the possibility of detecting errors that could affect the correct delivery of the dose to the patient. [...]

The purpose of this thesis was to evaluate and compare the peripheral dose associated with VMAT lung SABR treatments for 10X, 6X, and 10X-FFF beams. Flattening Filter Free (FFF) radiotherapy photon beams exhibit high dose rates as compared to standard flattened photon beams. The high dose rates available with FFF beams make them ideal for high dose treatments, such as Volumetric Modulated Arc Therapy (VMAT)-delivery lung Stereotactic Ablative Radiotherapy (SABR), where treatment delivery is longer than that of standard treatments. They are also known to show reductions in treatment head scatter, multi-leaf collimator (MLC) transmission and treatment head leakage radiation, compared to flattened beams. The use of FFF beams for VMAT lung SABR has been shown to significantly reduce treatment delivery time, while maintaining plan quality and accuracy. Another potential advantage of the use of FFF beams for VMAT lung SABR is the reduction in peripheral (out-of-field) dose, due mainly to the reduction in head scatter and treatment head leakage. The peripheral doses delivered by VMAT Lung SABR treatments using 10X-FFF, 10X and 6X were investigated for the Varian TrueBeam medical linear accelerator. There were three components to this investigation; (1) Ion chamber measurement of peripheral dose for static open, static MLC and dynamic MLC fields, (2) Validation of Monte Carlo, Acuros XB and AAA algorithms for peripheral dose prediction, and (3) Evaluation of peripheral doses for VMAT lung SABR treatments using the validated Monte Carlo model. Measurements of out-of field doses for static open, static MLC and dynamic MLC fields showed that 10X-FFF delivered peripheral doses in the range of 30% to 50%, 3% to 40% and 5% to 20% lower than the peripheral doses for flattened beams. Dose calculation algorithm validation showed that AAA and Acuros XB significantly under predicted the dose in the peripheral region. Monte Carlo was found to be the most accurate dose calculation algorithm for peripheral dose prediction. The VMAT lung SABR dose distributions were calculated for both static gantry delivery and arc delivery using the validated Monte Carlo model. For static gantry Monte Carlo simulation, 10X-FFF was found to show a reduction in peripheral dose in the range of 7% to 21% and 7% to 17% when compared to 6X and 10X. For arc delivery Monte Carlo simulation, 10X-FFF was found to deliver a statistically significant reduction in mean peripheral dose compared to 6X in four of the six cases, and was not found to deliver a statistically significant reduction in mean peripheral dose compared to 10X in any of the six cases. For this type of VMAT lung SABR treatment, 10X-FFF offers a reduction in peripheral dose over 6X. In terms of the benefits of using 10X-FFF for this type of treatment, the reduction in peripheral dose is added to the already-established reduction in treatment times. / Graduate / 0756 / 0574

No description available.

<p>The purpose of this thesis is to explore the angular response to dose of the MatriXX Evolution, manufactured by IBA Dosimetry, a 2-dimensional ion chamber array used for patient specific quality assurance of advanced radiotherapy techniques such as IMRT and VMAT. Investigations were made to characterize the angular response of the MatriXX and describe any differences from the Philips Pinnacle³ Treatment Planning System (TPS) used at the Juravinski Cancer Centre.</p> <p>A comparison was made between the gantry angle dependent correction factors supplied by the manufacturer and those derived by measurement. Gantry angle dependent correction factors were derived, with the MatriXX under 5cm polystyrene build-up and without any build-up, for the 5 x 5 cm², 10 x 10 cm² and 20 x 20 cm² field sizes.</p> <p>For gantry angles ranging from 320^o to 40^o the maximum difference between the derived gantry angle dependent correction factors and those provided by the manufacturer is 1.5%, at a gantry angle of 320^o, a 5 x 5 cm² field and without build-up. The differences for the 10 x 10 cm² and 20 x 20 cm² fields within this gantry angle range are less than 1%. Between gantry angles of 50^o and 130^o the largest difference is 4.9% at 100^o, for the 5 x 5 cm²field without build-up. The other field sizes show similar differences; 4.7% at gantry angle of 120^o for 10 x 10 cm² with build-up and 4.0% at a gantry angle of 80^o without build-up. Between gantry angles of 140^o to 220^o the greatest discrepancy is for the 5 x 5 cm² field with build-up, a difference of 3.0%. The 10 x 10 cm² has a maximum difference of 2.4% at gantry angles of 180^o and 200^o, both when the MatriXX has build-up. The maximum discrepancy for gantry angle dependent correction factors for the 20 x 20 cm² fields is at a gantry angle of 140^o, when the MatriXX has build-up. Between the gantry angles of 230^o to 310^o the largest discrepancy occurs between the derived gantry angle dependent correction factors and those supplied by the manufacturer. For the 5 x 5 cm², 10 x 10 cm² and 20 x 20 cm² fields respectively the largest differences are 5.9%, 4.5% and 4.9%. All three occur when there is no build-up.</p> / Master of Science (MSc)

Classical midgut carcinoids belong to neuroendocrine tumors of the gastroenteropancreatic tract (GEP-NETs) and are associated with serotonin overproduction. The term midgut is derived from the tumors’ embryological site of origin: enterochromaffin cells in the lower jejunum, ileum, caecum and the ascending colon. Despite their rather benign nature, these tumors can metastasize to mesentery and liver, putting patients at risk for the so-called carcinoid syndrome. This syndrome is characterized by flushes, diarrhoea and valvular heart disease due to the excessive serotonin secretion by tumor cells. Treatment of metastatic disease is currently ineffective and T cell immunotherapy has been suggested as a novel approach. We propose a number of midgut carcinoid-associated proteins as potential antigens for immunotherapy. Chromogranin A (CGA), tryptophan hydroxylase 1 (TPH-1), vesicular monoamine transporter 1 (VMAT-1), caudal type homeobox transcription factor 2 (CDX-2), islet autoantigen 2 (IA-2) and survivin represent interesting candidates based on their fairly restricted neuroendocrine tissue expression. In pursuit of potential antigens we identified a novel splicing variant of VMAT-1, lacking the second last exon. The variant, denoted VMAT1Δ15, encodes a differently translated C-terminal compared to the native form, is localized in the endoplasmic reticulum (ER) instead of large dense core vesicles and is unable to accumulate serotonin. We identify several immunogenic HLA-A*0201-binding peptide epitopes derived from our proposed antigens by analyzing CD8+ T cell responses in blood from midgut carcinoid patients. We demonstrate immune recognition of midgut carcinoid tumors in patients and in vitro generation of activated CD8+ T cells recognizing these peptide epitopes in blood from healthy controls. Patients also exhibit increased frequencies of circulating regulatory T cells (Tregs) with suppressive quality and patient lymphocytes display a decreased proliferative capacity compared to healthy controls. Midgut carcinoid tumors are frequently infiltrated by T cells, however always in the presence of Foxp3-expressing Tregs. Midgut carcinoid-associated antigens recognized by CD8+ T cells are of great interest for cellular therapies such as modified DC vaccines or adoptive T cell transfer. However, the systemic and local suppression of Th1 immunity must be considered and likely corrected in order to obtain clinically effective immunotherapies.