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京都大学 / 新制・課程博士 / 博士(人間健康科学) / 甲第23826号 / 人健博第97号 / 新制||人健||7(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 精山 明敏, 教授 椎名 毅, 教授 平井 豊博 / 学位規則第4条第1項該当 / Doctor of Human Health Sciences / Kyoto University / DFAM

<p dir="ltr">Human brain tumors present significant challenges due to their heterogeneous nature, known as intra-tumoral heterogeneity (ITH), which evolves over space and time, leading to treatment resistance and poor patient outcomes. Current diagnostic methods rely on pre-surgical imaging and single biopsy samples, providing only a partial understanding of the tumor microenvironment (TME) and often resulting in incomplete targeting of tumor mutations, leaving residual disease vulnerable to recurrence. Our hypothesis proposes a novel approach: utilizing multimodal and multiparametric <i>in vivo</i> imaging to map the cellular and molecular characteristics of the TME. By correlating imaging signatures with underlying somatic and genomic aberrations, we aim to develop a predictive model guiding personalized targeted therapies to effectively address the heterogeneity of brain tumors.</p><p dir="ltr">To achieve this goal, we designed, tested, and validated a predictive model through a pilot study using clinical MRI scans and one stereotactic biopsy sample. Subsequently, we optimized a multimodal and multiparametric imaging protocol including MRI and PET scans, to acquire comprehensive morphological, functional, and molecular data from the TME. Additionally, we established a detailed pipeline for subject recruitment, data collection, and post-processing to ensure the robustness and reliability of our model.</p><p dir="ltr">This innovative approach has the potential to overcome the limitations of current diagnostic methods by providing a comprehensive understanding of the TME using minimally-invasive imaging techniques. By correlating imaging data with ground truth pathology and genomics, this model will enhance brain tumor diagnosis and facilitate the implementation of targeted therapies, ultimately improving treatment response and patient outcomes.</p>

Alzheimer’s disease (AD) is the leading cause of dementia and is alone responsible for 60-70% of all cases of dementia. Though sharing clinical symptoms with other types of dementia, the hallmarks of AD are the abundance of extracellular depositions of β-amyloid (Aβ) plaques, intracellular neurofibrillary tangles of hyper phosphorylated tau proteins and synaptic depletion. The onset of the physiological hallmarks may precede clinical symptoms with a decade or more, and once clinical symptoms occur it may be difficult to separate AD from other types of dementia based on clinical symptoms alone. Since the introduction of radiolabeled Aβ tracer substances for positron emission tomography (PET) imaging it is possible to image the Aβ depositions in-vivo, strengthening the confidence in the diagnosis. Because the accumulation of Aβ may occur years before the first clinical symptoms are shown and even reach a plateau, Aβ PET imaging may not be feasible for disease progress monitoring. However, a negative scan may be used to rule out AD as the underlying cause to the clinical symptoms. It may also be used as a predictor to evaluate the risk of developing AD in patients with mild cognitive impairment (MCI) as well as monitoring potential effects of anti-amyloid drugs.Though currently validated for dichotomous visual assessment only, there is evidence to suggest that quantification of Aβ PET images may reduce inter-reader variability and aid in the monitoring of treatment effects from anti-amyloid drugs.The aim of this thesis was to refine existing methods and develop new ones for processing, quantification and visualization of Aβ PET images to aid in the diagnosis and monitoring of potential treatment of AD in clinical routine. Specifically, the focus for this thesis has been to find a way to fully automatically quantify and visualize a patient’s Aβ PET image in such way that it is presented in a uniform way and show how it relates to what is considered normal. To achieve the aim of the thesis registration algorithms, providing the means to register a patient’s Aβ PET image to a common stereotactic space avoiding the bias of different uptake patterns for Aβ- and Aβ+ images, a suitable region atlas and a 3-dimensional stereotactic surface projections (3D SSP) method, capable of projecting cortical activity onto the surface of a 3D model of the brain without sampling white matter, were developed and evaluated.The material for development and testing comprised 724 individual amyloid PET brain images from six distinct cohorts, ranging from healthy volunteers to definite AD. The new methods could be implemented in a fully automated workflow and were found to be highly accurate, when tested by comparisons to Standards of Truth, such as defining regional uptake from PET images co-registered to magnetic resonance images, post-mortem histopathology and the visual consensus diagnosis of imaging experts.

L’efficacité de la stimulation cérébrale profonde subthalamique dans certains cas de maladie de Parkinson est maintenant bien établie. Toutefois, des progrès restent possibles, à la fois en terme de contrôle du geste chirurgical et en terme de définition de la cible chirurgicale. Dans la première partie de ce travail, nous nous sommes intéressés à l’optimisation du contrôle de l’implantation des électrodes de stimulation cérébrale profonde. Nous avons tout d’abord analysé rétrospectivement les résultats obtenus en réalisant une imagerie tridimensionnelle per-opératoire pour le contrôle de positionnement des électrodes. Nous nous sommes ensuite intéressés à la possibilité d’utiliser un repère de visée radiologique per-opératoire. Nous avons revu pour cela une série de patients ayant subi une réimplantation d’électrodes, pour lesquels l’électrode déjà en place était utilisée comme point de repère à la fois pour définir la cible de la réimplantation et pour contrôler radiologiquement l’implantation de la nouvelle électrode. Dans la seconde partie, nous avons travaillé à l’optimisation de la cible subthalamique. Nous avons tout d’abord évalué la pertinence du repérage du faisceau mamillo-thalamique sur des coupes IRM axiales comme marqueur de la coordonnée y du bord antérieur du noyau subthalamique. Ensuite, nous avons tâché de proposer une normalisation tridimensionnelle de l’espace stéréotaxique à partir de données recueillies dans une série de volontaires sains. Enfin, pour une série de patients opérés avec un bon résultat, nous avons cherché à corréler la position des contacts actifs en stimulation chronique avec des points de repères profonds visibles en IRM. Nous avons pu proposer ainsi une cible normalisée dont les coordonnées sont : x = 0,44xbord latéral du V3 + 10,71mm; y = 0,69xfaisceau mamillothalamique + 1,62 mm ou 0,34 distance CACP + 2,52 mm; z = 0,72 hauteur du thalamus – 16 mm. Cette cible sera évaluée dans une future étude prospective. / The clinical efficacy of subthalamic deep brain stimulation is now well established. Nevertheless, progress is possible, regarding especially (1) the accuracy of electrodes implantation and (2) the definition of the surgical target. In the first part of this work, we worked on the optimization of DBS electrodes implantation. First, we analyzed retrospectively the results obtained by using intra-operative 3D imaging for the control of microelectrodes and definite leads placement. Thereafter, we considered the possibility to use a radiological landmark for intraoperative controls. To this end, we studied the cases of patients who underwent reimplantation of DBS electrodes. The initial electrode (still implanted) was used as a landmark: (1) for the deifntion of the reimplantation target and (2) for the radiological control of the new lead positioning. In the second part, we worked on the optimization of the surgical target. First, we assessed the interest of the mamillothalamic tract as a landmark of the anteroposterior coordinate of the anterior border of the STN in MR axial images. Thereafter, we tried to identify MR landmarks for tridimensionnal normalization of the stereotactic space. Finally, we tried to correlate the coordinates of active contacts with MR-defined landmarks in a series of patients that had been operated with good clinical results. Based on our results, we can propose the following coordinates for a new normalized subthalamic target : x = 0.44xlat edge 3rd ventricle + 10.71mm; y = 0.69xmamillo-thalamic tract + 1.62 mm or 0.34 ACPC length + 2.52 mm; z = 0.72xthalamus height – 16 mm. We will assess this target in a future prospective study.

A radiocirugia estereotáxica é uma técnica que fornece altas doses de radiação utilizando campos pequenos para conformação da dose no volume alvo do tratamento. Devido à complexidade desta técnica torna-se necessária a verificação da distribuição de dose no volume de tratamento. Neste trabalho, as distribuições tridimensionais (3D) de doses de casos clínicos de neoplasias cranianas foram estudadas utilizando-se um objeto simulador de cabeça. A reconstrução das distribuições de doses nos volumes alvo e nas regiões adjacentes a estes foram avaliadas com o código de simulação PENELOPE, o dosímetro MAGIC-f gel e com o sistema de planejamento iPlan. Filmes radiocrômicos também foram empregados para a determinação das distribuições de dose em planos do tratamento. As respostas obtidas com as ferramentas dosimétricas utilizadas foram analisadas através de distribuições de índices gama, comparando-se os mapas centrais das distribuições de dose obtidas com as quatro ferramentas dosimétricas utilizadas. Usando-se critérios de tolerância de 3% e 3mm, a análise realizada na região da prescrição de dose (isodoses de 95%) mostrou-se equivalente para todas as ferramentas dosimétricas utilizadas; resultado diferente foi observado para isodoses menores, com uma equivalência máxima de 76,5%. As distribuições volumétricas, obtidas através do PENELOPE, MAGIC-f gel e o iPlan, foram comparadas, ainda, através dos histogramas dose-volume, para cada caso estudado, mostrando que 95% da dose absorvida relativa encontra-se dentro do volume alvo para todos os planos estudados. A probabilidade de controle tumoral, TCP, foi avaliada para os casos de radiocirurgia estudados, a partir das distribuições volumétricas de dose, resultando em uma probabilidade de controle tumoral máxima de 72%, para todos os casos, conforme o modelo matemático de TCP utilizado. Das comparações realizadas pode-se inferir que o dosímetro MAGIC-f gel e o código de simulação PENELOPE-Monte Carlo podem ser utilizados para determinar as distribuições de dose em 3D para a técnica de radiocirurgia estereotáxica. Essas ferramentas dosimétricas podem, dessa forma, auxiliar no comissionamento de unidades de terapia e em verificações 3D de doses do tratamento dos pacientes, permitindo avaliações dentro e ao redor do volume alvo e podendo se tornar ferramentais de rotina nos serviços de radioterapia. / Stereotactic radiosurgery is a technique which delivers high radiation doses using small fields to conform the absorbed dose into the target volume. Due to the complexity of this technique it is necessary to verify the dose distribution in the treatment volume. Thus, in this study the three-dimensional (3D) dose distributions of selected clinical cases of cranial tumors were obtained using a head phantom. The the dose distributions of target volumes and adjacent regions were evaluated with PENELOPE Monte Carlo simulation code, MAGIC-f dosimeter and iPlan® treatment planning system. Radiochromic films were also used to determine the dose distribution on selected plans of the treatment. The obtained results for the proposed dosimetric tools were analyzed by the gamma index distributions, comparing the maps of the central dose distributions obtained with the four dosimetric tools. Using the dose criteria of 3% in 3 mm, the gamma index test showed equivalence in the region of dose prescription (95% isodose) and a different result was observed for lower isodoses, with maximum accordance of 76.5%. The volumetric dose distributions obtained with PENELOPE, MAGIC-f and iPlan were also compared using the dose-volume histograms for each studied case, showing that 95% of the absorbed dose yield within the target volume. The tumor control probability, TCP, was evaluated for the studied radiosurgery cases, from the dose distributions-volumetric, resulting in a maximum probability of tumor control of 72% for all cases, for the used mathematical model of TCP. From the results it can be inferred that the MAGIC-f gel dosimeter and the PENELOPE Monte Carlo simulation code can be used to determine 3D dose distributions for stereotactic radiosurgery. These dosimetric tools can assist the commissioning of treatment units and 3D dose verifications of patients treatments, allowing assessments in and around the target volume and may become routine in radiotherapy services.

A radiocirugia estereotáxica é uma técnica que fornece altas doses de radiação utilizando campos pequenos para conformação da dose no volume alvo do tratamento. Devido à complexidade desta técnica torna-se necessária a verificação da distribuição de dose no volume de tratamento. Neste trabalho, as distribuições tridimensionais (3D) de doses de casos clínicos de neoplasias cranianas foram estudadas utilizando-se um objeto simulador de cabeça. A reconstrução das distribuições de doses nos volumes alvo e nas regiões adjacentes a estes foram avaliadas com o código de simulação PENELOPE, o dosímetro MAGIC-f gel e com o sistema de planejamento iPlan. Filmes radiocrômicos também foram empregados para a determinação das distribuições de dose em planos do tratamento. As respostas obtidas com as ferramentas dosimétricas utilizadas foram analisadas através de distribuições de índices gama, comparando-se os mapas centrais das distribuições de dose obtidas com as quatro ferramentas dosimétricas utilizadas. Usando-se critérios de tolerância de 3% e 3mm, a análise realizada na região da prescrição de dose (isodoses de 95%) mostrou-se equivalente para todas as ferramentas dosimétricas utilizadas; resultado diferente foi observado para isodoses menores, com uma equivalência máxima de 76,5%. As distribuições volumétricas, obtidas através do PENELOPE, MAGIC-f gel e o iPlan, foram comparadas, ainda, através dos histogramas dose-volume, para cada caso estudado, mostrando que 95% da dose absorvida relativa encontra-se dentro do volume alvo para todos os planos estudados. A probabilidade de controle tumoral, TCP, foi avaliada para os casos de radiocirurgia estudados, a partir das distribuições volumétricas de dose, resultando em uma probabilidade de controle tumoral máxima de 72%, para todos os casos, conforme o modelo matemático de TCP utilizado. Das comparações realizadas pode-se inferir que o dosímetro MAGIC-f gel e o código de simulação PENELOPE-Monte Carlo podem ser utilizados para determinar as distribuições de dose em 3D para a técnica de radiocirurgia estereotáxica. Essas ferramentas dosimétricas podem, dessa forma, auxiliar no comissionamento de unidades de terapia e em verificações 3D de doses do tratamento dos pacientes, permitindo avaliações dentro e ao redor do volume alvo e podendo se tornar ferramentais de rotina nos serviços de radioterapia. / Stereotactic radiosurgery is a technique which delivers high radiation doses using small fields to conform the absorbed dose into the target volume. Due to the complexity of this technique it is necessary to verify the dose distribution in the treatment volume. Thus, in this study the three-dimensional (3D) dose distributions of selected clinical cases of cranial tumors were obtained using a head phantom. The the dose distributions of target volumes and adjacent regions were evaluated with PENELOPE Monte Carlo simulation code, MAGIC-f dosimeter and iPlan® treatment planning system. Radiochromic films were also used to determine the dose distribution on selected plans of the treatment. The obtained results for the proposed dosimetric tools were analyzed by the gamma index distributions, comparing the maps of the central dose distributions obtained with the four dosimetric tools. Using the dose criteria of 3% in 3 mm, the gamma index test showed equivalence in the region of dose prescription (95% isodose) and a different result was observed for lower isodoses, with maximum accordance of 76.5%. The volumetric dose distributions obtained with PENELOPE, MAGIC-f and iPlan were also compared using the dose-volume histograms for each studied case, showing that 95% of the absorbed dose yield within the target volume. The tumor control probability, TCP, was evaluated for the studied radiosurgery cases, from the dose distributions-volumetric, resulting in a maximum probability of tumor control of 72% for all cases, for the used mathematical model of TCP. From the results it can be inferred that the MAGIC-f gel dosimeter and the PENELOPE Monte Carlo simulation code can be used to determine 3D dose distributions for stereotactic radiosurgery. These dosimetric tools can assist the commissioning of treatment units and 3D dose verifications of patients treatments, allowing assessments in and around the target volume and may become routine in radiotherapy services.

Le présent travail de thèse décrit le développement d'un protocole d'irradiation stéréotaxique combinée à une radiothérapie conformationnelle avec modulation d'intensité. Ce projet a été initiée dans le service de radiothérapie-oncologie du Centre Hospitalier Lyon Sud. La première partie de ce travail fait état d'une revue de littérature sur les techniques d'irradiation du cancer de la prostate. Trois grands thèmes de recherche ont été identifiés et developpés : un premier thèse de recherche portant sur la définition optimale des volumes à irradier lors d'une irradiation stéréotaxique de la prostate et la fiabilité d'uin repérage de l'oragane par des marqueurs intra-prostatiques. La deuxième thématique de recherche était dédiée à la planification du traitement stéréotaxique de la prostate avec pour principal objectif une protection optimale de la paroi rectale avec deux approches différentes : a) une augmentation focalisée de la dose d'irradiation uniquement sur la tumeur macroscopiquement visible, ou b) l'utilisation d'un gel injecté entre la paroi du rectum et la prostate. Le nombre optimal de faisceaux à utiliser ainsi que l'énergie la mieux adaptée ont été évalués dans le cadre de la première approche avec uin boost intégré.. La trosième thématique portait sur les contrôles qualité à réaliser dans le cadre de la mise en route de cette technique d'irradiation. Trois détecteur dédiés aux contrôles de la distribution de dose sous l'accélarateur ont été évalués. L'ensemble de ces travaux serviront de supports à la réalisation d'une étude de phase II intégrant une irradiation stéréotaxique des cancers de la prostate avec injection de gel d'acide hyaluronique entre le rectum et la prostate / The current work decribes the implementation of a protocol for stereotactic body radiotherapy (SBRT) combined with an intensity-modulated radiation therapy technique (IMRT). the project was initiated in the Department of Radiation-Oncology from Lyon Sud Hospital. The first part summarizes the state of the art of prostate cancer with a literature review on irradiation techniques. Three research themes were described and developped : The first theme discusses the optimal definition of the volumes to be irradiated during a prostate SBRT and the accuracy of the target localization using intraprostatic markers. The second theme of research describes the treatment planning for prostate SBRT having as main purpose an optimal protection of the rectal-wall with two different approaches: a) an augmentation of the dose with simultaneous integrated boost only into visible macroscopic tumor, or b) the use of a gel injected between the rectal-wall and the prostate. The optimal number of fields, as well as the most favorable energy, was evaluated in the context of the first approach with a simultaneous integrated boost. The third theme discusses the quality assurance (QA) that needs to be performed for an IMRT-SBRT technique. Three detectors that ara dedicated to the QA of dose distribution under accelerator were evaluated. The results of all these studies will be used for the implementation of a phase II study for prostate SBRT with an injection of hyaluronic acid between the rectum and the prostate.

The skeletal system is the most common site of metastatic cancer spread. Bone metastases are often associated with severe morbidity, pain and functional impairment. Timely diagnosis and proper treatment may decrease morbidity, improve quality of life and in some cases even improve survival. External beam radiotherapy may effectively give pain relief in patients with painful bone metastases. In bone metastases from castration-resistant prostate cancer or urothelial bladder cancer, treatment with zoledronic acid or denosumab may reduce skeletal-related events. In contrast to castration-resistant prostate cancer, in patients with bone metastases from bladder cancer such treatment may even improve survival. On the other hand, the efficacy of these agents is questionable in patients with bone involvement from metastatic renal cell carcinoma or germ cell tumors. When bisphosphonates or denosumab are considered in such cases, the potential benefits of treatment should be critically weighed against the risk of side effects. In germ cell tumors, bone metastases may be cured by cisplatin-based chemotherapy, however, there are only limited data on the specific management of residual disease. Oligometastases may be treated by stereotactic radiotherapy or – especially in patients with renal cell carcinoma – by surgical resection and endoprosthetic replacement. Limited data are available on the management of bone involvement in germ cell tumors. Decisions on the resection or local radiotherapy of residual disease should be individualized considering the overall response and the feasibility and risks of resection.