INTRODUÇÃO: Em pacientes com infarto do miocárdio (IM) e disfunção cardíaca, a evidência de viabilidade miocárdica é primordial, e o exame tomográfico por emissão de pósitrons com 18F-fluoro-desoxi-glicose (18FDG-PET) é o padrão-ouro para essa identificação. Existe preferência, na literatura, pela realização do clamp hiperínsulínico euglicêmico (CLAMP) antes da injeção de 18FDG para estimular todo o miocárdio a consumir glicose (GLI), garantindo assim a sua captação pelas áreas de miocárdio hibernado (MH). No entanto, essa técnica é trabalhosa, além do risco de hipoglicemia durante a realização. Desenvolvemos uma nova técnica na qual o paciente é submetido a uma dieta restrita em carboidratos (DIETA) por 24 horas antes do exame, sem a necessidade de CLAMP, com o objetivo de diminuir os níveis de insulina e aumentar ácidos graxos livres (AGL), estimulando o miocárdio normal a consumir AGL, e não GLI. A área de MH, porém, não consegue realizar o metabolismo oxidativo de AGL, mantendo o consumo de GLI. OBJETIVOS: comparar o PET após DIETA (PET-DIETA) com o PET após CLAMP (PET-CLAMP), para a pesquisa de viabilidade miocárdica. MÉTODOS: Trinta pacientes com IM prévio e hipocinesia na área infartada foram submetidos à cintilografia de perfusão miocárdica com 99mTc-sestamibi (MIBI), PET-CLAMP e PET-DIETA. A DIETA limitava-se a 15-20g de carboidratos por dia. Os exames foram submetidos à análise visual e classificados por escores (0 a 4). Foram consideras áreas de mismatch (MH) aquelas com hipoperfusão ao MIBI e captação presente no PET-CLAMP ou no PET-DIETA, em um modelo de 17 segmentos, além da análise por parede, território arterial e por paciente. A análise por segmentos foi realizada ainda dividindo-se os pacientes em diabéticos (DM) e não diabéticos (NDM). O PET-DIETA também foi submetido à análise automática (por percentual de captação) RESULTADOS: Durante o CLAMP, seis (20%) pacientes apresentaram hipoglicemia. Nenhum paciente apresentou hipoglicemia após a DIETA. Houve concordância na análise visual do PET-CLAMP e PET-DIETA para detecção de áreas de mismatch em 94,5% dos segmentos analisados, com um índice kappa de 0,78 (concordância substancial). Essa concordância se manteve na análise por parede (0,80), território arterial (k=0,79) e por paciente (0,79). Quando dividimos os pacientes em NDM (22) e DM (8), encontramos k=0,78 para o subgrupo NDM e 0,70 para o subgrupo DM. A análise automática para o PET-DIETA evidenciou, quando comparada com a análise visual do PET-CLAMP, uma concordância moderada, com índice kappa de 0,50 para análise por segmento, 0,54 por parede, 0,60 por território arterial e 0,48 por paciente. CONCLUSÕES: Concluímos assim que o exame de PET-DIETA apresenta uma excelente concordância para detecção de áreas de mismatch com o PET-CLAMP, ambos em conjunto com a análise do MIBI, possivelmente com mais segurança para o paciente. Essa concordância se mantém quando avaliamos os subgrupos de DM e NDM / BACKGROUND: In patients with myocardial infarction and left ventricular dysfunction, the evidence of myocardial viability has important clinical implications. Positron emission tomography (PET) using 18F-fluoro-desoxi-glucose (18FDG) is considered the gold standard for viability detection. The euglycemic hyperinsulinemic clamping (CLAMP) before 18FDG injection stimulates uptake of both glucose and 18FDG in the myocardium, including areas of hibernating myocardium (MH), and it is the most used protocol. However, this imaging protocol has an increased risk for hypoglycemia and is relatively time-consuming. We developed a new protocol using a 24 hours low-carbohydrate diet (DIET), aiming to reduce insulin levels and increase free fatty acids (FFA). This protocol stimulates the normal myocardium to use FFA, not glucose, but the area of hibernating myocardium (viable area) may not use oxidative metabolism with FFA, keeping glucose uptake and becoming a hot spot at PET images. The aim of this study was to compare both techniques by segments, regions, vascular territories and patients. METHODS: Thirty patients with previous myocardial infarction and left ventricular dysfunction were studied. All of them underwent into a SPECT perfusion scan with 99mTc-sestamibi and two 18FDG PET studies to asses myocardial viability, one with CLAMP (PET-CLAMP) and another using a 24 hours low-carbohydrate diet (PET-DIET). For the analysis, the myocardium was divided into 17 segments, 5 regions and 3 vascular territories. A visual and an automatic semi-quantitative analysis (only for PET-DIET) were carried out according to the following score indicating radiotracer uptake: 0 = normal to 4 = absent. Myocardial viability was defined as the presence of normal or mildly reduced FDG uptake in an area with reduced perfusion (99mTc-sestamibi uptake). We also performed subgroup analyses in diabetes (DM) and non-diabetic patients (NDM). RESULTS: While using CLAMP protocol, six (20%) patients had hypoglycemia. None of the patients had hypoglycemia after using DIET. High agreement rates were observed with visual analysis in comparing mismatch areas (kappa=0,78 substancial concordance). Similar rates were find in regions (0,80), vascular territories (0,79) and patient (0,79) analysis. In subgroup analysis, DM (8) presented with kappa=0,70 and NDM (22) with kappa=0,78. Upon analysis, the automatic method for PET-DIET showed moderate agreement when compared with PET-CLAMP visual analysis by segments (Kappa=0,50), regions (0,54), vascular territories (0,60) and patient (0,48). CONCLUSIONS: This has led to the suggestion that PET-DIET study proved an excellent agreement in detects mismatch areas assessed by PET-CLAMP, with probably more safety. The same results occurs in the in diabetes and non-diabetic patients subgroups

Background Novel theranostic options for high-risk non-muscle invasive bladder cancer are urgently needed. This requires a thorough evaluation of experimental approaches in animal models best possibly reflecting human disease before entering clinical studies. Although several bladder cancer xenograft models were used in the literature, the establishment of an orthotopic bladder cancer model in mice remains challenging. Methods Luciferase-transduced UM-UC-3LUCK1 bladder cancer cells were instilled transurethrally via 24G permanent venous catheters into athymic NMRI and BALB/c nude mice as well as into SCID-beige mice. Besides the mouse strain, the pretreatment of the bladder wall (trypsin or poly-L-lysine), tumor cell count (0.5 × 106–5.0 × 106) and tumor cell dwell time in the murine bladder (30 min – 2 h) were varied. Tumors were morphologically and functionally visualized using bioluminescence imaging (BLI), magnetic resonance imaging (MRI), and positron emission tomography (PET). Results Immunodeficiency of the mouse strains was the most important factor influencing cancer cell engraftment, whereas modifying cell count and instillation time allowed fine-tuning of the BLI signal start and duration – both representing the possible treatment period for the evaluation of new therapeutics. Best orthotopic tumor growth was achieved by transurethral instillation of 1.0 × 106 UM-UC-3LUCK1 bladder cancer cells into SCID-beige mice for 2 h after bladder pretreatment with poly-L-lysine. A pilot PET experiment using 68Ga-cetuximab as transurethrally administered radiotracer revealed functional expression of epidermal growth factor receptor as representative molecular characteristic of engrafted cancer cells in the bladder. Conclusions With the optimized protocol in SCID-beige mice an applicable and reliable model of high-risk non-muscle invasive bladder cancer for the development of novel theranostic approaches was established.

Das S100A4-Protein ist für die Manifestierung eines metastatischen Phänotyps bei vielen Tumorarten von enormer Bedeutung. Die Aufklärung der zugrunde liegenden Mechanismen und der Interaktionspartner von S100A4 stellt daher einen vielsprechenden Forschungsansatz dar, um neue Erkenntnisse über das Verhalten von Tumorzellen während des Metastasierungsprozesses zu erhalten. Darauf aufbauend können neue Ansatzpunkte für die Therapie metastasierender Krebserkrankungen gewonnen werden. In dieser Hinsicht ist das bisher einer Behandlung kaum zugängliche maligne Melanom als besonders aggressiver und frühzeitig metastasierender Tumor ein ideales Modell zur Aufklärung der zellulären und molekularen Prozesse, über die S100A4 seine Metastasen-fördernden Wirkungen ausübt. Das Ziel der vorliegenden Arbeit war die biochemische und radiopharmakologische Charakterisierung der S100A4-RAGE-Interaktion sowie die Untersuchung der Beteiligung von S100A4 an Prozessen der Metastasierungskaskade in vitro und in vivo. Dies erforderte die Herstellung von rekombinantem S100A4-Protein und die Generierung von stabil mit S100A4-transfizierten Melanomzellen, die damit eine heraufregulierte S100A4-Proteinbiosynthese aufweisen. Die Gewinnung von rekombinantem S100A4 in biologisch funktioneller Form unter Verwendung eines prokaryotischen Expressionssystems erfolgte mit einem Reinheitsgrad von ca. 92%. Das rekombinante S100A4-Protein wurde mit dem Aktivester N-Succinimidyl-4-[18F]fluorbenzoat radioaktiv markiert und charakterisiert. Es wurde die Interaktion zwischen S100A4 bzw. 18F-markiertem S100A4 und der löslichen RAGE-Isoform sRAGE mit einer moderaten Bindungsaffinität im µM-Bereich nachgewiesen. Des Weiteren erfolgte erstmals die Analyse der radiopharmakologischen Eigenschaften von 18F-S100A4 mittels Untersuchungen zur zellulären Assoziation sowie zur metabolischen Stabilität, Bioverteilung und zu In-vivo-Interaktionen mittels Kleintier-Positronen-Emissions-Tomographie in der Ratte. Die In-vitro-Experimente wurden an Endothelzellen (HAEC) und an stabil mit RAGE-transfizierten A375-, A375-mock bzw. nicht transfizierten A375-Melanomzellen durchgeführt. Die A375-hRAGE-Zellen zeigten eine deutlich heraufregulierte RAGE-Proteinbiosynthese während die Endothelzellen eine vergleichsweise geringe intrazelluläre RAGE-Proteinkonzentration aufwiesen. Bei den Melanomzellen kann aufgrund der höheren Assoziation von 18F-S100A4 an A375-hRAGE-Zellen auf eine selektive Bindung von 18F S100A4 an RAGE-Rezeptoren auf der Zelloberfläche geschlossen werden. Die Assoziation von 18F S100A4 an Endothelzellen war bei 37°C in Gegenwart von nicht markiertem rekombinantem S100A4 signifikant vermindert, dementsprechend findet eine spezifische Interaktion von 18F-S100A4 mit Zelloberflächenrezeptoren der Endothelzellen statt. Dieses Ergebnis und die insgesamt höhere Bindung von 18F S100A4 an Endothelzellen im Vergleich zur Assoziation an Melanomzellen lassen neben RAGE noch andere Rezeptoren wie z. B. internalisierende Scavenger-Rezeptoren vermuten. Die In-vivo-Stabilitätsuntersuchungen verdeutlichen einen proteolytischen Abbau von 18F S100A4, allerdings belegen das Vorhandensein von 67% intaktem 18F-S100A4-Protein nach einer Stunde, die Stabilität von 18F-S100A4 in vivo. Die Bioverteilungs- bzw. PET-Untersuchungen zeigen eine schnelle, innerhalb weniger Minuten stattfindende hohe Akkumulation in den Nieren und verdeutlichen somit die renale Ausscheidung von 18F S100A4. Die maßgeblichen Anreicherungen in Milz, Leber, Blut, Lunge und Nebennieren lassen Interaktionen mit Oberflächenrezeptoren dieser Gewebe erkennen. Die temporäre Retention von 18F-S100A4 in der Lunge, dem Hauptsyntheseorgan von RAGE, und die verminderte 18F-S100A4-Akkumulation in Gegenwart des spezifischen RAGE-Liganden glykLDL ist ein Hinweis dafür, dass S100A4 in vivo in der Lunge an RAGE bindet. Die Aktivitätsanreicherungen in Milz, Leber und Nebenniere deuten aufgrund der geringeren RAGE-Synthese in diesen Organen auf die Interaktion von 18F-S100A4 mit anderen Zelloberflächenrezeptoren z. B. aus der Familie der Scavenger-Rezeptoren hin. Die Beteiligung von S100A4 an Metastasierungsprozessen des malignen Melanoms wurde an stabil mit S100A4-transfizierten A375-Melanomzellen, die eine Heraufregulierung der humanen bzw. murinen S100A4-Proteinbiosynthese im Vergleich zu A375-mock- (Vektor-Kontrolle) und nicht-transfizierten A375-Zellen zeigen, untersucht. Die A375-hS100A4-Zellen sezernierten zudem eine signifikant höhere S100A4-Proteinkonzentration in das umgebende Zellkulturmedium im Vergleich zu den Kontrollen. In dieser Hinsicht konnte bei den A375-hS100A4-Zellen, vermutlich aufgrund der höheren extrazellulären S100A4-Konzentration, eine gesteigerte Proliferations-, Motilitäts-, Migrations- und Invasionsrate gegenüber den A375-mock- und A375-Zellen nachgewiesen werden. In diesem Zusammenhang stehen ebenso die gesteigerte RAGE-Proteinbiosynthese und die signifikant höhere Aktivität des Transkriptionsfaktors NF-κB bei A375-Zellen nach 24-stündiger Inkubation mit Kulturmedium der A375-hS100A4-Zellen. Demnach wirkt vermutlich das extrazelluläre S100A4-Protein als autokriner bzw. parakriner Regulator von RAGE und NF κB. Die subkutane Injektion der A375- und stabil transfizierten A375-Melanomzellen in Nacktmäuse führte zur Entwicklung subkutaner Tumore an der Injektionsstelle. Bereits zwei Wochen nach der Injektion etablierten die A375-hS100A4-Zellen die signifikant größeren Tumore im Vergleich zu den A375-mS100A4-, A375-mock und A375-Zellen. Nach Injektion der Zellen in die Schwanzvene der Nacktmäuse konnte keine Entwicklung von Metastasen im Tierkörper festgestellt werden. IN DER VORLIEGENDEN ARBEIT WURDE NACHGEWIESEN: • RAGE ist ein Rezeptor für das S100A4-Protein. Allerdings gibt es eindeutige Hinweise für weitere S100A4-Zielproteine an der Zelloberfläche. • Die bedeutende Rolle von extrazellulärem S100A4 bei wichtigen zellulären Metastasierungsprozessen sowie bei der Aktivierung von Signalproteinen wie NF-κB und RAGE beim malignen Melanom. Die weitere Aufklärung der S100A4-spezifischen Signalkaskaden und Rezeptoren bei metastasierenden Tumorerkrankungen sowie die Charakterisierung von S100A4 als klinischen Parameter bei Patienten mit malignem Melanom stellen hoch interessante Aspekte in der Krebsforschung dar.

An increasing number of cancer patients is treated with proton beams or other light ion beams which allow to deliver dose precisely to the tumor. However, the depth dose distribution of these particles, which enables this precision, is sensitive to deviations from the treatment plan, as e.g. anatomical changes. Thus, to assure the quality of the treatment, a non-invasive in-vivo dose verification is highly desired. This monitoring of particle therapy relies on the detection of secondary radiation which is produced by interactions between the beam particles and the nuclei of the patient’s tissue. Up to now, the only clinically applied method for in-vivo dosimetry is Positron Emission Tomography which makes use of the beta+-activity produced during the irradiation (PT-PET). Since from a PT-PET measurement the applied dose cannot be directly deduced, the simulated distribution of beta+-emitting nuclei is used as a basis for the analysis of the measured PT-PET data. Therefore, the reliable modeling of the production rates and the spatial distribution of the beta+-emitters is required. PT-PET applied during instead of after the treatment is referred to as in-beam PET. A challenge concerning in-beam PET is the design of the PET camera, because a standard full-ring scanner is not feasible. For instance, a double-head PET camera is applicable, but low count rates and the limited solid angle coverage can compromise the image quality. For this reason, a detector system which provides a time resolution allowing the incorporation of time-of-flight information (TOF) into the iterative reconstruction algorithm is desired to improve the quality of the reconstructed images. Secondly, Prompt Gamma Imaging (PGI), a technique based on the detection of prompt gamma-rays, is currently pursued. Concerning the emissions of prompt gamma-rays during particle irradiation, experimental data is not sufficiently available, making simulations necessary. Compton cameras are based on the detection of incoherently scattered photons and are investigated with respect to PGI. Monte Carlo simulations serve for the optimization of the camera design and the evaluation of criteria for the selection of measured events. Thus, for in-beam PET and PGI dedicated detection systems and, moreover, profound knowledge about the corresponding radiation fields are required. Using various simulation codes, this thesis contributes to the modelling of the beta+-emitters and photons produced during particle irradiation, as well as to the evaluation and optimization of hardware for both techniques. Concerning the modeling of the production of the relevant beta+-emitters, the abilities of the Monte Carlo simulation code PHITS and of the deterministic, one-dimensional code HIBRAC were assessed. The Monte Carlo tool GEANT4 was applied for an additional comparison. For irradiations with protons, helium, lithium, and carbon, the depth-dependent yields of the simulated beta+-emitters were compared to experimental data. In general, PHITS underestimated the yields of the considered beta+-emitters in contrast to GEANT4 which provided acceptable values. HIBRAC was substantially extended to enable the modeling of the depth-dependent yields of specific nuclides. For proton beams and carbon ion beams HIBRAC can compete with GEANT4 for this application. Since HIBRAC is fast, compact, and easy to modify, it could be a basis for the simulations of the beta+-emitters in clinical application. PHITS was also applied to the modeling of prompt gamma-rays during proton irradiation following an experimental setup. From this study, it can be concluded that PHITS could be an alternative to GEANT4 in this context. Another aim was the optimization of Compton camera prototypes. GEANT4 simulations were carried out with the focus on detection probabilities and the rate of valid events. Based on the results, the feasibility of a Compton camera setup consisting of a CZT detector and an LSO or BGO detector was confirmed. Several recommendations concerning the design and arrangement of the Compton camera prototype were derived. Furthermore, several promising event selection strategies were evaluated. The GEANT4 simulations were validated by comparing simulated to measured energy depositions in the detector layers. This comparison also led to the reconsideration of the efficiency of the prototype. A further study evaluated if electron-positron pairs resulting from pair productions could be detected with the existing prototype in addition to Compton events. Regarding the efficiency and the achievable angular resolution, the successful application of the considered prototype as pair production camera to the monitoring of particle therapy is questionable. Finally, the application of a PET camera consisting of Resistive Plate Chambers (RPCs) providing a good time resolution to in-beam PET was discussed. A scintillator-based PET camera based on a commercially available scanner was used as reference. This evaluation included simulations of the detector response, the image reconstructions using various procedures, and the analysis of image quality. Realistic activity distributions based on real treatment plans for carbon ion therapy were used. The low efficiency of the RPC-based PET camera led to images of poor quality. Neither visually nor with the semi-automatic tool YaPET a reliable detectability of range deviations was possible. The incorporation of TOF into the iterative reconstruction algorithm was especially advantageous for the considered RPC-based PET camera in terms of convergence and artifacts. The application of the real-time capable back projection method Direct TOF for the RPCbased PET camera resulted in an image quality comparable to the one achieved with the iterative algorihms. In total, this study does not indicate the further investigation of RPC-based PET cameras with similar efficiency for in-beam PET application. To sum up, simulation studies were performed aimed at the progress of in-vivo dosimetry. Regarding the modeling of the beta+-emitter production and prompt gamma-ray emissions, different simulation codes were evaluated. HIBRAC could be a basis for clinical PT-PET simulations, however, a detailed validation of the underlying cross section models is required. Several recommendations for the optimization of a Compton Camera prototype resulted from systematic variations of the setup. Nevertheless, the definite evaluation of the feasibility of a Compton camera for PGI can only be performed by further experiments. For PT-PET, the efficiency of the detector system is the crucial factor. Due to the obtained results for the considered RPC-based PET camera, the focus should be kept to scintillator-based PET cameras for this purpose.

Positron emission tomography (PET) is a well-established functional imaging method used in nuclear medicine. It allows for retrieving information about biochemical and physiological processes in vivo. The currently possible spatial resolution of PET is about 5 mm for brain acquisitions and about 8 mm for whole-body acquisitions, while recent improvements in image reconstruction point to a resolution of 2 mm in the near future. Typical acquisition times range from minutes to hours due to the low signal-to-noise ratio of the measuring principle, as well as due to the monitoring of the metabolism of the patient over a certain time. Therefore, patient motion increasingly limits the possible spatial resolution of PET. In addition, patient immobilisations are only of limited benefit in this context. Thus, patient motion leads to a relevant resolution degradation and incorrect quantification of metabolic parameters. The present work describes the utilisation of a novel motion compensation method for clinical brain PET acquisitions. By using an external motion tracking system, information about the head motion of a patient is continuously acquired during a PET acquisition. Based on the motion information, a newly developed event-based motion compensation algorithm performs spatial transformations of all registered coincidence events, thus utilising the raw data of a PET system - the so-called `list-mode´ data. For routine acquisition of this raw data, methods have been developed which allow for the first time to acquire list-mode data from an ECAT Exact HR+ PET scanner within an acceptable time frame. Furthermore, methods for acquiring the patient motion in clinical routine and methods for an automatic analysis of the registered motion have been developed. For the clinical integration of the aforementioned motion compensation approach, the development of additional methods (e.g. graphical user interfaces) was also part of this work. After development, optimisation and integration of the event-based motion compensation in clinical use, analyses with example data sets have been performed. Noticeable changes could be demonstrated by analysis of the qualitative and quantitative effects after the motion compensation. From a qualitative point of view, image artefacts have been eliminated, while quantitatively, the results of a tracer kinetics analysis of a FDOPA acquisition showed relevant changes in the R0k3 rates of an irreversible reference tissue two compartment model. Thus, it could be shown that an integration of a motion compensation method which is based on the utilisation of the raw data of a PET scanner, as well as the use of an external motion tracking system, is not only reasonable and possible for clinical use, but also shows relevant qualitative and quantitative improvement in PET imaging. / Die Positronen-Emissions-Tomographie (PET) ist ein in der Nuklearmedizin etabliertes funktionelles Schnittbildverfahren, das es erlaubt Informationen über biochemische und physiologische Prozesse in vivo zu erhalten. Die derzeit erreichbare räumliche Auflösung des Verfahrens beträgt etwa 5 mm für Hirnaufnahmen und etwa 8 mm für Ganzkörperaufnahmen, wobei erste verbesserte Bildrekonstruktionsverfahren eine Machbarkeit von 2 mm Auflösung in Zukunft möglich erscheinen lassen. Durch das geringe Signal/Rausch-Verhältnis des Messverfahrens, aber auch durch die Tatsache, dass der Stoffwechsel des Patienten über einen längeren Zeitraum betrachtet wird, betragen typische PET-Aufnahmezeiten mehrere Minuten bis Stunden. Dies hat zur Folge, dass Patientenbewegungen zunehmend die erreichbare räumliche Auflösung dieses Schnittbildverfahrens limitieren. Eine Immobilisierung des Patienten zur Reduzierung dieser Effekte ist hierbei nur bedingt hilfreich. Es kommt daher zu einer relevanten Auflösungsverschlechterung sowie zu einer Verfälschung der quantifizierten Stoffwechselparameter. Die vorliegende Arbeit beschreibt die Nutzbarmachung eines neuartigen Bewegungskorrekturverfahrens für klinische PET-Hirnaufnahmen. Mittels eines externen Bewegungsverfolgungssystems wird während einer PET-Untersuchung kontinuierlich die Kopfbewegung des Patienten registriert. Anhand dieser Bewegungsdaten führt ein neu entwickelter event-basierter Bewegungskorrekturalgorithmus eine räumliche Korrektur aller registrierten Koinzidenzereignisse aus und nutzt somit die als "List-Mode" bekannten Rohdaten eines PET Systems. Für die Akquisition dieser Daten wurden eigens Methoden entwickelt, die es erstmals erlauben, diese Rohdaten von einem ECAT Exact HR+ PET Scanner innerhalb eines akzeptablen Zeitraumes zu erhalten. Des Weiteren wurden Methoden für die klinische Akquisition der Bewegungsdaten sowie für die automatische Auswertung dieser Daten entwickelt. Ebenfalls Teil der Arbeit waren die Entwicklung von Methoden zur Integration in die klinische Routine (z.B. graphische Nutzeroberflächen). Nach der Entwicklung, Optimierung und Integration der event-basierten Bewegungskorrektur für die klinische Nutzung wurden Analysen anhand von Beispieldatensätzen vorgenommen. Es zeigten sich bei der Auswertung sowohl der qualitativen als auch der quantitativen Effekte deutliche Änderungen. In qualitativer Hinsicht wurden Bildartefakte eliminiert; bei der quantitativen Auswertung einer FDOPA Messung zeigte sich eine revelante Änderung der R0k3 Einstromraten eines irreversiblen Zweikompartment-Modells mit Referenzgewebe. Es konnte somit gezeigt werden, dass eine Integration einer Bewegungskorrektur unter Zuhilfenahme der Rohdaten eines PET Systems sowie unter Nutzung eines externen Verfolgungssystems nicht nur sinnvoll und in der klinischen Routine machbar ist, sondern auch zu maßgeblichen qualitativen und quantitativen Verbesserungen in der PET-Bildgebung beitragen kann.

Les masses kystiques latérales du cou (MKLC) bénignes et malignes sont difficiles à différencier cliniquement. L’utilité des modalités d’imagerie et de prélèvement doit être clarifiée. Une revue rétrospective de cas entre 2010 et 2016. Les données d’imagerie ont été récoltées et plusieurs variables propres à la masse furent analysées. Les rapports de cytoponction à l’aiguille fine (CAAF), de la biopsie au trocart (BT) et des examens extemporanés (EE) ont été analysés. La sensibilité, la spécificité, la valeur prédictive positive (VPP) et la valeur prédictive négative (VPN) pour prédire la malignité ont été calculées pour toutes les variables comparées entre les masses kystiques bénignes et malignes. Aucune variable d’imagerie n’a pu différencier les masses kystiques bénignes de malignes. La sensibilité de la CAAF est plus basse que celle de la BT (59% vs 83%; p=0.036) et de l’EE (59% vs 93%; p=0.01). L’EE a une meilleure VPN que la CAAF (92% vs 40%; p<0.001) et que la BT (92% vs 50%; p=0.062). La VPP et la spécificité étaient similaires dans tous les groupes. Les cliniciens ne peuvent pas se fier uniquement à l’imagerie pour différencier les masses bénignes des masses malignes. Vu sa VPP adéquate (92%), la CAAF devrait être utilisée initialement pour tous les patients avec une MKLC. Si la CAAF s’avère négative, la BT devrait être utilisée vu sa meilleure sensibilité. Un examen extemporané devrait toujours suivre une BT négative vu la faible VPN de la BT. Un résultat positif à l’une des trois modalités de prélèvement indique la présence de malignité. / Benign and malignant lateral cystic neck masses (LCNM) are difficult to distinguish clinically. The usefulness of imaging and sampling modalities in clarifying the diagnosis remains unclear. Retrospective review of cases between 2010 and 2016. Imaging data was reviewed and the variables pertaining to the mass were assessed including the following: size, nodal level, fat stranding, extracapsular spread, calcifications, vascularity, necrosis and standardized uptake value. Sampling reports of fine-needle aspiration (FNA), core-needle biopsy (CNB) and frozen section (FS) were also assessed. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for predicting malignancy were calculated for all variables and compared between benign and malignant cystic neck masses. Ultrasound was used in 47.2% and CT-Scan in 90.5% of patients. No variables on imaging could definitely differentiate benign from malignant LCNM. FNA had a lower sensitivity then CNB (59% vs 83%; p=0.036) and FS (59% vs 93%; p=0.01). FS had a better NPV when compared to FNA (92% vs 40%; p<0.001) and CNB (92% vs 50%; p=0.062). Specificities and PPV were similar among all groups. Clinicians cannot rely on imaging to differentiate benign from malignant LCNM. Given its adequate PPV (92%), FNA should be used initially on lateral cystic neck masses. Because of its high sensitivity, CNB should be considered if FNA is not diagnostic of malignancy. FS should always follow a CNB not indicative of malignancy, because of the low NPV. Any result diagnostic of malignancy on either FNA, CNB or FS strongly indicates presence of malignancy.

Indiana University-Purdue University Indianapolis (IUPUI) / Drug addiction is a behavioral disorder characterized by impulsive behavior and continued intake of drug in the face of adverse consequences. Millions of people suffer the financial and social consequences of addiction, and yet many of the current therapies for addiction treatment have limited efficacy. Therefore, there is a critical need to characterize the neurobiological substrates of addiction in order to formulate better treatment options. In the first chapter, the striatal dopamine system is interrogated with [11C]raclopride PET to assess differences between chronic cannabis users and healthy controls. The results of this chapter indicate that chronic cannabis use is not associated with a reduction in striatal D2/D3 receptor availability, unlike many other drugs of abuse. Additionally, recent cannabis consumption in chronic users was negatively correlated with D2/D3 receptor availability. Chapter 2 describes a retrospective analysis in which striatal D2/D3 receptor availability is compared between three groups of alcohol-drinking and tobacco-smoking subjects: nontreatment-seeking alcoholic smokers, social-drinking smokers, and social-drinking non-smokers. Results showed that smokers had reduced D2/D3 receptor availability throughout the striatum, independent of drinking status. The results of the first two chapters suggest that some combustion product of marijuana and tobacco smoke may have an effect on striatal dopamine concentration. Furthermore, they serve to highlight the effectiveness of using baseline PET imaging to characterize dopamine dysfunction in addictions. The final chapter explores the use of [18F]fallypride PET in a proof-of-concept study to determine whether changes in cortical dopamine can be detected during a response inhibition task. We were able to detect several cortical regions of significant dopamine changes in response to the task, and the amount of change in three regions was significantly associated with task performance. Overall, the results of Chapter 3 validate the use of [18F]fallypride PET to detect cortical dopamine changes during a impulse control task. In summary, the results reported in the current document demonstrate the effectiveness of PET imaging as a tool for probing resting and activated dopamine systems in addiction. Future studies will expand on these results, and incorporate additional methods to further elucidate the neurobiology of addiction.

Die Positronen-Emissions-Tomographie (PET) bei der Schwerionentherapie ist eine wichtige Methode zur Qualitätskontrolle in der Tumortherapie mit Kohlenstoffionen. Die vorliegende Arbeit beschreibt die Verbesserungen des PET-Verfahrens, wodurch sich in der Folge präzisere Aussagen zur Dosisapplikation treffen lassen. Aufbauend auf den Grundlagen (Kap. 2) werden die Neuentwicklungen in den drei darauf folgenden Abschnitten (Modellierung des Abbildungsprozesses bei der PET, Streukorrektur für PET bei der Schwerionentherapie, Verarbeitung der rekonstruierten PET-Daten) beschrieben. Die PET-Methode bei der Schwerionentherapie basiert auf dem Vergleich zwischen den gemessenen und vorausberechneten Aktivitätsverteilungen. Die verwendeten Modelle in der Simulation (Erzeugung der Positronenemitter, deren Ausbreitung, der Transport und der Nachweis der Annihilationsquanten) sollten so präzise wie möglich sein, damit ein aussagekräftiger Vergleich möglich wird. Die Genauigkeit der Beschreibung der physikalischen Prozesse wurde verbessert und zeiteffiziente Algorithmen angewendet, die zu einer erheblichen Verkürzung der Rechenzeit führen. Die erwarteten bzw. die gemessenen räumlichen Radioaktivitätsverteilungen werden mit einem iterativen Verfahren rekonstruiert [Lau99]. Die gemessenen Daten müssen hinsichtlich der im Messobjekt auftretenden Comptonstreuung der Annihilationsphotonen korrigiert werden. Es wird ein geeignetes Verfahren zur Streukorrektur für die Therapieüberwachung vorgeschlagen und dessen Realisierung beschrieben. Zur Einschätzung der Güte der Behandlung wird die gemessene und die simulierte Aktivitätsverteilung verglichen. Dazu wurde im Rahmen der vorliegenden Arbeit eine Software entwickelt, das die rekonstruierten PET-Daten visualisiert und die anatomischen Informationen des Röntgentomogramms mit einbezieht. Nur durch dieses Auswerteverfahren war es möglich, Fehler im physikalischen Strahlmodell aufzudecken und somit die Bestrahlungsplanung zu verbessern.

La prévalence de l’arthrose féline augmente fortement avec l’âge atteignant plus de 80% des chats de plus de 11 ans. L'arthrose induit une douleur chronique s’exprimant par des changements de comportements et une diminution de la mobilité. Il n'existe aucun outil validé pour évaluer la douleur chronique associée à l’arthrose chez le chat. Conséquemment, aucun traitement ciblant cette douleur n’a pu être validé. Notre hypothèse de recherche est que la douleur arthrosique chez le chat induit des handicaps fonctionnels, des changements neurophysiologiques et un état d'hypersensibilité qu'il faut évaluer pour quantifier de manière fiable cette douleur et ses répercussions sur la qualité de vie de l'animal. Nos objectifs étaient 1) de développer des outils adaptés aux chats mesurant les handicaps fonctionnels grâce à des outils cinématiques, cinétiques et de suivi de l'activité motrice ; 2) de caractériser les changements fonctionnels et neurophysiologiques secondaires à la douleur arthrosique et de tester avec ces outils un traitement analgésique à base d'anti-inflammatoire non stéroïdien ; 3) de développer une technique adaptée aux chats pouvant caractériser la présence du phénomène de sensibilisation centrale à l'aide d'une évaluation de la sommation temporelle mécanique ; 4) de tester la possibilité de mesurer le métabolisme glucidique cérébral par tomographie d’émission par positrons comme marqueur des changements supraspinaux secondaires à la chronicisation de la douleur. Grâce au développement d’outils de mesure de douleur chronique objectifs, sensibles et répétables nous avons caractérisé la douleur chez les chats arthrosiques. Ils présentent des signes de boiterie quantifiée par une diminution de l’amplitude de l’articulation ou par une diminution de la force verticale d’appui au sol et une diminution de l’activité motrice quotidienne. Ces deux derniers outils ont permis de démontrer qu’un anti-inflammatoire non stéroïdien (le méloxicam) administré pendant quatre semaines réduit la douleur arthrosique. De plus, grâce au développement de tests sensoriels quantitatifs et à l'utilisation d'imagerie cérébrale fonctionnelle, nous avons démontré pour la première fois que la douleur arthrosique conduisait à des modifications du système nerveux central chez le chat. Particulièrement, les chats arthrosiques développent le phénomène de sensibilisation centrale mis en évidence par un seuil de retrait aux filament de von Frey diminué (mesure réflexe) mais aussi par une facilitation de la sommation temporelle mécanique (mesure tenant compte de la composante cognitive et émotionnelle de la douleur). L'augmentation du métabolisme cérébral dans le cortex somatosensoriel secondaire, le thalamus et la substance grise périaqueducale, souligne aussi l'importance des changements liés à la chronicisation de la douleur. Un traitement analgésique adapté à l’arthrose permettra d’améliorer la qualité de vie des chats atteints, offrira une option thérapeutique valide aux praticiens vétérinaires, et profitera aux propriétaires qui retrouveront un chat actif et sociable. La découverte de l'implication du phénomène de sensibilisation central combiné à l'investigation des changements cérébraux secondaires à la douleur chronique associée à l'arthrose par imagerie fonctionnelle ouvre de nouvelles avenues de recherche chez le chat (développement et/ou validation de traitements adaptés à l'état d'hypersensibilité) et les humains (potentiel modèle naturel de douleur chronique associée à l'arthrose). / Feline osteoarthritis prevalence increases with age, up to 80% in cats aged 11 years old and more. Osteoarthritis is associated with chronic pain expressing as altered behaviour and a decrease in mobility. Currently, there is no validated technique to evaluate osteoarthritis-associated chronic pain in cats. This situation leads to an absence of approved medication for the treatment of OA-associated chronic pain in cats. Our hypothesis states that osteoarthritis-associated pain in cats is expressed as physical disabilities, neurophysiologic changes, hypersensibility, which need to be assessed to quantify adequately this pain and its impact on quality of life. Our objectives were 1) to develop a cat adapted method to assess physical disabilities using kinematics, kinetics and motor activity evaluations; 2) to describe functional and neurophysiologic changes related to osteoarthritis-associated pain, and to test a non steroidal anti-inflammatory based analgesic treatment; 3) to develop a cat adapted method to detect central sensitisation using mechanical temporal summation; 4) to test the feasibility of measuring carbohydrate brain metabolism using positron emission tomography as a marker of supraspinal changes-associated with pain chronicity. Using objective chronic pain evaluation tools determined as sensitive and repeatable, we characterized feline osteoarthritis-associated pain. Cats afflicted with osteoarthritis presented lameness characterised by decreased joint amplitude, or decreased peak ground reaction vertical force, and decreased motor activity. Using the two latter tools, we demonstrated the efficacy of a non steroidal anti-inflammatory (meloxicam) to alleviate osteoarthritis-associated pain after four weeks of administration. Moreover, using quantitative sensory testing and brain functional imaging, we demonstrated for the first time, that osteoarthritis-associated pain in cats led to central nervous system changes. Specially, cats afflicted with osteoarthritis developed central sensitisation as indicated by a decreased von Frey withdrawal threshold (a reflex evaluation), and also by a facilitated mechanical temporal summation (an approach allowing to take into account affective and cognitive dimensions of pain). The increase of brain metabolism in the secondary somatosensory cortex, thalamus and periaqueductal grey matter also highlighted the importance of pain chronicity related changes. Using an analgesic treatment built to alleviate osteoarthritis-associated pain will improve cats quality of life, will help veterinarians, and will benefit owners who will retrieve an active and social cat. Demonstrating both the importance of central sensitisation and assessment of brain changes related to osteoarthritis-associated chronic pain using brain functional imaging opens new research opportunities in cats (development and/or validation of hypersensitivity related treatments), and humans (potential natural model of osteoarthritis-associated pain).

La modélisation pharmacocinétique en tomographie par émission par positrons (TEP) permet d’estimer les paramètres physiologiques liés à l’accumulation dynamique d’un radiotraceur. Les paramètres estimés sont biaisés par le bruit dans les images TEP dynamiques durant l’ajustement des courbes d’activité des tissus, plus communément appelées TAC de l’anglais Time Activity Curve. La qualité des images TEP dynamiques est limitée par la statistique de comptage et influencée par les paramètres de reconstruction choisis en termes de résolution spatiale et temporelle. Il n’existe pas de recommandations claires pour les paramètres de reconstruction à utiliser pour les images dynamiques TEP. L’objectif de ce projet de maitrise est d’évaluer le biais dans l’estimation des paramètres pharmacocinétiques afin de trouver les paramètres de reconstruction TEP les plus optimaux en termes de résolution spatiale et de niveau de bruit. Plus précisément, ce projet cherche à déterminer quel modèle d’AIF offre les meilleurs ajustements, mais aussi quel modèle de poids permet la meilleure estimation des paramètres pharmacocinétiques pour le modèle à deux compartiments. Ce faisant, il serait possible de mieux planifier la reconstruction d’images TEP dynamique et potentiellement améliorer leur résolution spatiale. Afin de tester les biais dans les paramètres pharmacocinétiques sous différents niveaux de bruit, un objet de référence numérique (DRO) avec les informations trouvées dans la littérature sera construit. Ensuite, des simulations numériques seront effectuées avec ce DRO afin de trouver les paramètres de reconstruction et le niveau de bruit le plus optimal. Un biais réduit des paramètres pharmacocinétiques et une meilleure résolution spatiale des images TEP dynamique permettrait de détecter des cancers ou tumeurs à des stades moins avancés de la maladie, permettant potentiellement un traitement plus efficace et avec moins de séquelles et d’effets secondaires pour les patients. En outre, cela permettrait aussi de visualiser l’hétérogénéité des tumeurs. / Pharmacokinetic models in positron emission tomography (PET) allow for the estimation of physiological parameters linked to the dynamic accumulation of a radiotracer. Estimated parameters are biased by noise in dynamic PET images during the fitting of Time Activity Curves (TAC). Image quality in dynamic PET is limited by counting statistics and influenced by the chosen reconstruction parameters in terms of spatial and temporal resolution. Clear recommendations and guidelines for the reconstruction parameters that should be used do not exist at the moment for dynamic PET. The goal of this masters project is to evaluate the bias in the pharmacokinetic parameters estimation to find the optimal PET reconstruction parameters in terms of spatial resolution and noise levels. More precisely, this project aims to determine which AIF model produces the best fits, but also which weight noise model allows for the best parameters estimation with the two compartment model. It would then be possible to plan the PET image reconstruction more finely and potentially improve spatial resolution. To test the pharmacokinetic parameters’ biases under different noise levels, a Digital Reference Object (DRO) with information and specifications found from the litterature will be built. Then, numerical simulations will be done with that DRO to find the optimal noise level and value for the pharmacokinetic parameter. A reduced bias in these parameters and an improved spatial resolution would allow the detection of tumors or lesions at earlier stages, which could potentially allow for a more potent treatment with less short and long term side effects. It would also allow the visualization and quantification of lesion heterogeneity.