L’hypoxie est connue pour être responsable d’une propagation tumorale accrue. En conséquence, les tumeurs hypoxiques nécessitent un diagnostic rapide et précis. L’accès à toutes les localisations tumorales par l’imagerie nucléaire est devenu un intérêt majeur pour l’orientation thérapeutique. Dans la première partie de ce manuscrit, un nouveau traceur de l’hypoxie tumorale marqué au technétium 99m a été développé avec succès. De nouveaux traceurs organosilylés marqués au fluor 18 ont également été étudiés. Un second travail a porté sur le développement d’une nouvelle stratégie de fluoration nucléophile pour la préparation de traceurs TEP. Des essais synthèse du Fluorodésoxyglucose ont été réalisés. L’élaboration de cette stratégie a également conduit au développement d’une nouvelle méthodologie de synthèse de dérivés d’acides sulfoniques par déprotection de thiols au moyen d’hypochlorite de tert-butyle. / It has been recognized that hypoxia plays a major negative role in overall tumor progression. The identification and quantitative estimation of tumor hypoxia by means of nuclear imaging is an important factor in planning the therapeutic strategy for a better clinical outcome. In the present work, a new 99mTc tracer for imaging tumor hypoxia has been successfully developed. New organosilicon fluorinated derivatives were also studied. Every synthesized compounds incorporated a nitroimidazole moiety, which is selectively trapped in hypoxic cells. The second part of this work, led to the development of a new nucleophilic fluorination strategy for the preparation of PET tracers. The new strategy was attempted for the preparation of Fluorodeoxyglucose. In the course of this study, a novel oxidative deprotection method of thiols was developed. Herein was described, the synthesis of sulfonic acid derivatives by oxidative deprotection of thiols using tert-butyl hypochlorite.

Medical imaging is a technique that allows us to visualize non surgically the internal structure of the human body in order to diagnose or treat medical conditions. It permits also monitoring of physical processes or functions of different organs inside the body. The medical imaging encompasses wide range of techniques based on different physical prin- ciples, including techniques using ionizing radiation. The quality of the images depends significantly on the quality of the used imaging detectors. There are many types of the detectors, from old analog devices (e.g. films) to fully digital detectors such as flat panels, that are the most widely used today. The newer technology is being developed and the techniques such as photon counting explored. However, the state of the art technology is the single photon counting, where the experimental detectors such as Medipix are able to count and process each individual photon. This works studies the properties, features and applications of the newest detector from the Medipix family Timepix3 in different imaging modalities. Firstly, a design of a new hardware readout interface for Timepix3 is presented together with data acquisition software and new analysis and calibration algorithms. Then, different applications of Timepix3 detector were explored: very...

1 ABSTRACT The presented dissertation deals with prognostic factors influencing a favorable postoperative outcome in patients undergoing surgical treatment of epilepsy and the possibilities of improving the methods used in the localization of epileptogenic lesions. This work is based on the results of four published studies. The first study evaluated the factors influencing the long-term outcomes of epilepsy surgery in MRI-negative (nonlesional) extratemporal lobe epilepsy (nETLE). The aim of the study was to evaluate the benefit of non-invasive diagnostic tests and their relationship with a favorable surgical outcome in a group nETLE patients. Univariate analysis showed that localized interictal epileptiform discharges (IEDs) on the scalp EEG were associated with a favorable surgical outcome. Diagnostic difficulty in this group of patients is highlighted by the fact that, although 9 of 24 patients undergoing surgery had a favorable outcome, and only nine of 85 patients with nETLE achieved such a favorable outcome. The second work evaluated the benefit of SPECT (Single Photon Emission Tomography) statistical processing over traditional subtraction methods in patients with MRI-negative temporal lobe epilepsy (nTLE) and MRI-negative extratemporal epilepsy (nETLE). 49 consecutive patients who underwent...

Objective: Degeneration of dopaminergic neurons in the substantia nigra projecting to the striatum is responsible for the motor symptoms in Parkinson’s disease (PD). Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a well-established procedure to alleviate these symptoms in advanced PD. Yet the mechanism of action, especially the effects of STN-DBS on the availability of striatal dopamine transporter (DAT) as a marker of nigrostriatal nerve cell function, remains largely unknown. The aim of our study was therefore to evaluate whether 1) DAT availability changes within one year of STN-DBS and whether 2) the clinical outcome is predictable by DAT availability before surgical procedure (pre-op). Methods: Twenty-seven PD patients (age: 62.7 ± 8.9 years (y); duration of illness: 13.0 ± 4.9y; PD subtypes: akinetic-rigid n=11, equivalence n=13, tremor-dominant n=3) underwent [123I]FP-CIT single-photon emission computed tomography (SPECT) pre-op and one year after STN-DBS (post-op). DAT availability (specific-to-unspecific binding ratio, SBR) was assessed by volume of interest (VOI) analysis of the caudate nucleus and the putamen ipsilateral and contralateral to the clinically more affected side. Results: 1) Unified Parkinson’s Disease Rating Scale (UPDRS) III (pre-op on: on medication; pre-op off: off medication; post-op on/on: on medication/on stimulation; post-op on/off: on medication/off stimulation) improved significantly (pre-op on: 25.6 ± 12.3, pre-op off: 42.3 ± 15.2, post-op on/off: 41.4 ± 13.2; post-op on/on: 16.1 ± 9.4; pre-op on vs. post-op on/on: p = 0.006) while L-dopa equivalent daily dose (LEDD) was reduced (pre-op 957 ± 440 mg, post-op 313 ± 189 mg; p < 0.001). SBR did not differ significantly before and one year after DBS, regardless of PD subtypes. 2) Pre-op DAT availability was not related to the change in UPDRS III but the change in DAT availability was significantly correlated with the change in UPDRS III (contralateral head of the caudate VOI: p=0.014, contralateral putamen VOI: p=0.018). Conclusion Overall, DAT availability did not change significantly after one-year of STN-DBS. However, on an individual base, the improvement in UPDRS III was associated with an increase of DAT availability while DAT availability before STN-DBS surgery did not predict the clinical outcome. Whether a subtype-specific pattern of pre-op DAT availability can become a reliable predictor for successful STN-DBS has to be evaluated in larger study cohorts.:Introduction 2 1.1 Parkinson’s Disease Pathophysiology 2 1.2 Parkinson’s Disease Clinical Manifestation 4 1.2.1 Parkinson’s Disease Diagnosis 5 1.2.1.1 Unified Parkinson’s Disease Rating Scale 5 1.2.1.2 Imaging 6 1.2.2 Parkinson’s Disease Subtypes 6 1.3 Parkinson’s Disease Therapy 7 1.3.1 Pharmacologic Therapy 7 1.3.2 Surgical Therapy – Deep Brain Stimulation 9 1.3.2.1 Patient Selection 9 1.3.2.2 Operative Technique 9 1.3.2.3 Efficacy 10 1.3.2.4 Complications 11 1.3.2.5 Mechanism of action 11 2 Publication 15 3 Summary of Work 23 3.1 Background 23 3.2 DAT availability changes after STN-DBS 24 3.3 Pre-op DAT availability predicts the clinical outcome 25 3.4 DBS has a neuroprotective effect 25 3.5 Limitations and future direction 26 3.6 Conclusion 26 4 References 27 5 Attachments 35 5.1 Index of Abbreviations 35 5.2 List of figures 36 5.3 Academic Contribution 37 5.4 Declaration of the independent writing of this thesis 39 5.5 Declaration of Submission 40 5.6 Curriculum Vitae 41 5.7 Acknowledgements 43

Le suivi longitudinal en oncologie consiste à évaluer régulièrement l'évolution tumorale afin de définir un protocole de traitement adapté à chaque patient. Il est alors nécessaire d'identifier des biomarqueurs pertinents, qui permettent de quantifier précocement l'évolution tumorale. Les examens d'imagerie permettent d’assurer un suivi non invasif et de proposer des biomarqueurs complémentaires de ceux préexistants. Cette recherche de nouveaux biomarqueurs nécessite de s’appuyer sur des études cliniques et d’effectuer une étude comparative des examens réalisés à différents temps, dans différentes modalités, et ce tant au niveau global que local. Dans cette thèse, nous nous sommes attachés à développer une approche intégrée de traitement d’images pour analyser la pertinence d'indices pour le suivi tumoral. Cette stratégie se décompose en trois étapes: le recalage des données acquises à différents temps et provenant de modalités différentes, la segmentation des lésions tumorales sur les examens de chaque modalité, et le calcul d'indices globaux et locaux traduisant l'évolution spatio-temporelle de la tumeur.L'aspect le plus innovant réside dans l'étape de recalage pour laquelle, au vu des difficultés rencontrées avec les approches classiques, nous avons proposé une nouvelle approche consistant en l'utilisation de plusieurs méthodes de recalage et la sélection de la meilleure pour chaque jeu de données, grâce à un critère quantitatif défini en fonction des applications considérées. L'apport de cette approche a été démontré dans le cadre de deux études cliniques : 1) le suivi de patients atteints de gliomes de haut grade traités par un médicament antiangiogénique nécessitant la mise en correspondance de données de tomographie d’émission monophotonique (TEMP) obtenues après injection de Sestamibi marqué au Technétium-99m avec des images de résonnance magnétique (IRM) pondérées en T1 et acquises après l'injection d'un produit de contraste; 2) le suivi de patients atteints de lésions hépatiques et traités par différents médicaments anticancéreux, nécessitant le recalage de données de perfusion en tomodensitométrie (TDM).La stratégie complète d'analyse a été appliquée à la première étude. Les zones tumorales ont été segmentées sur les IRM en utilisant une méthode classique de Level Set 2D et sur les données TEMP à l'aide de cinq méthodes de seuillage qui diffèrent par les options de choix du seuil. Malgré une forte corrélation en terme de volumes globaux, les indices locaux ont permis de montrer qu'une partie des volumes tumoraux détectés sur les examens TEMP précoces (réalisés 15 minutes après injection) et tardifs (réalisés 3 heures après injection) pouvaient être localisés en-dehors des volumes détectés sur les IRM après injection de Gadolinium. La corrélation élevée constatée entre, d’une part, les variations d'intensité au sein des volumes tumoraux au cours du traitement sur les examens TEMP tardifs et, d’autre part, l'indice de survie globale, suggère que cette variation relative d'intensité pourrait être prédictive de la durée de survie globale des patients, ce qui n’est pas le cas des indices utilisant les données IRM sur notre série limitée de patients. Ainsi ces résultats montrent que l’imagerie TEMP, avec un examen réalisé 3 heures après l’injection de Sestamibi marqué au Technétium-99m, peut être complémentaire de l’IRM, pour évaluer l'évolution tumorale des glioblastomes.Les perspectives de ce travail de thèse sont d'appliquer la stratégie d'analyse à d'autres études cliniques. Néanmoins chaque étape doit être adaptée aux spécificités de l'application concernée, notamment aux modalités d'imagerie impliquées et à la zone anatomique considérée. La principale difficulté à résoudre réside dans l'automatisation et la robustesse des différentes étapes de traitement d’images envisagées. / Longitudinal follow-up in oncology consists in assessing tumor progression in order to define a treatment strategy for each patient. It is thus necessary to identify relevant biomarkers that allow an early evaluation of the tumor’s response to the treatment. Biomedical imaging exams help to ensure a non-invasive monitoring of patients and to propose complementary biomarkers to existing ones. This search for new biomarkers requires relying on clinical studies to compare globally and locally exams acquired at different times and in different modalities.In this PhD dissertation, we focused on developing an integrated image processing framework to analyze the relevance of indices for evaluating the tumor evolution. The strategy includes three steps: registration data acquired at different times and in different modalities, the segmentation of tumor lesions on exams in each modality, and the computation of global and local indices reflecting the spatiotemporal evolution of the tumor.The most innovative aspect lies in the registration step: due to the difficulties faced with conventional methods, we proposed a new approach consisting in using several registration methods and selecting the best one for each dataset, thanks to a quantitative criterion based on the specific features of the application. The contribution of this approach was proven in two clinical studies: 1) monitoring of patients with high-grade gliomas treated with an antiangiogenic drug, where Single Photon Emission Tomography data (SPECT) obtained after injection of Technetium-99m Sestamibi have to be matched with T1-weighted Magnetic Resonance Images (MRI) acquired after the injection of a contrast agent; 2) monitoring of patients with liver damage treated with various anticancer drugs, requiring the alignment of Computed Tomography (CT) data.The complete image processing framework was applied to the first study. Tumor areas were segmented on MR images using a conventional 2D Level Set method, as well as on the TEMP data using five thresholding methods that differ in the choice of the threshold options. Despite a strong correlation in terms of overall volumes, local indices have shown that some of the detected tumor volumes on early SPECT exams (performed 15 minutes after injection) and late SPECT exams (performed 3 hours after injection) could be located out of the tumor volumes detected on MRI. The high correlation found between the intensity variations in tumor volume during treatment on late SPECT exams and the index of Overall Survival (OS) suggests that this relative change of intensity could be predictive of the patient overall survival, which is not the case with the indices derived from the MRI data on our limited series of patients. Thus, these results show that SPECT imaging, with an exam performed 3 hours after injection of Technetium-99m Sestamibi, can be complementary to MRI in the assessment of tumor progression in glioblastomas.The main perspective for this PhD work would consist in applying the analysis strategy to other clinical studies. However, each step must be adapted to suit the specific nature of the targeted application, including the imaging modalities involved and the considered anatomical area. The expected sticking points are the automation and the robustness of the different steps of the processing chain.

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京都大学 / 新制・課程博士 / 博士(人間健康科学) / 甲第23825号 / 人健博第96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 椎名 毅, 教授 精山 明敏, 教授 中本 裕士 / 学位規則第4条第1項該当 / Doctor of Human Health Sciences / Kyoto University / DFAM

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京都大学 / 新制・課程博士 / 博士(医学) / 甲第24965号 / 医博第5019号 / 新制||医||1069(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 川口 義弥, 教授 波多野 悦朗, 教授 中本 裕士 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Bakgrund: Lungemboli är en av de vanligaste dödsorsakerna för gravida kvinnor och symtomen är ofta diffusa. Korrekt tillämpad bilddiagnostik är centralt vid lungemboliutredning för att undvika över- och underdiagnostisering, vilka båda kan leda till allvarliga konsekvenser. De vanligaste modaliteterna för att utreda lungemboli är datortomografisk lungangiografi (DTLA) och lungscintigrafi med planar eller tomografisk bildtagning, så kallad single photon emission tomography (SPECT). Idag saknas konsensus om vilken metod som är bäst lämpad för gravida kvinnor. Syfte: Syftet med denna litteraturstudie är att jämföra de diagnostiska metoderna DTLA, planar lungscintigrafi och SPECT, vid diagnostik av lungemboli hos gravida kvinnor.  Metod: Denna studie är en systematisk litteraturstudie. Urvalet bestod av 20 vetenskapliga artiklar som valdes ut via databaserna PubMed och CINAHL för att kunna besvara syftet. Willmans protokoll för kvantitativa studier har använts vid granskning av de artiklar som samlades in till denna litteraturstudie.   Resultat: Lungscintigrafisk undersökning gav lägre stråldos till den gravida kvinnan jämfört med DTLA i samtliga av de granskade artiklarna. DTLA var den metod som gav lägre stråldos till fostret i första och andra trimestern, medan lungscintigrafi gav lägre stråldos i tredje trimestern. Det diagnostiska utfallet från DTLA, planar scintigrafi och SPECT var likvärdigt. Slutsats: Vid jämförelse av de diagnostiska metoderna var lungscintigrafi med SPECT den metod som gav lägst stråldos till gravida kvinnor och var därför att föredra framför DTLA. Fler studier behövs inom området för att kunna avgöra vilken bilddiagnostisk metod som bör användas då det finns fler aspekter att undersöka.