La synthèse d'une membrane composite formée d'une couche fine de surface de structure très réticulée et permsélective aux gaz déposée sur un substrat poreux a été étudiée comme solution pour accroître la perméabilité aux gaz tout en conservant une sélectivité importante. Une couche mince de polymère-plasma SiOCH a été retenue comme membrane de séparation gazeuse car elle possède une structure dont l'ultramicroporisté peut être contrôlée en ajustant les paramètres du procédé plasma comme la puissance, le flux de monomère et la pression de travail. Néanmoins, dans la membrane SiOCH, la taille moyenne des pores et leur distribution sont difficiles à appréhender par des techniques de caractérisation classiques, notamment proche de la surface car elle est très fine. Ce mémoire de thèse concerne le contrôle de la structure poreuse dans une couche mince de polymère-plasma SiOCH déposée sur un substrat polymère en utilisant un précurseur organosilicié. La spectroscopie d'annihilation de positron couplée à un faisceau de positron lent a été utilisée pour identifier la microstructure de couches minces SiOCH avec la profondeur. Ceci a nécessité tout d'abord l'acquisition d'une bonne connaissance de la caractérisation de l'annihilation de positron de matériaux polymères et céramiques. Des couches minces de SiOCH conformes ou superhydrophobes (SHP) ont été obtenues à deux fréquences différentes, respectivement à 13,56 MHz ou 40 kHz. Pour une couche conforme, le type de substrat, la structure chimique du précurseur et la puissance RF sont les paramètres majeurs qui influencent la structure des pores. Quand les films de SiOCH sont composées de deux couches (couche uniforme de surface et couche de transition) déposées sur un substrat poreux, l'analyse PAS met en évidence une couche de transition large et l'ensemble possède une perméabilité aux gaz élevée grâce à la porosité de surface du support. Lors de la préparation des couches minces SHP, quand la pression totale dépasse 0,6 mbar, la nucléation en phase gaz apparaît ce qui augmente la rugosité de la surface. Ceci induit des angles de contact à l'eau supérieurs à 160° et une hystérésis d'angles de contact avancée-reculée de seulement 2°. La préservation des chaînes carbonées et la microstructure sont les facteurs déterminant pour accroître l'hydrophobicité des couches minces de SiOCH. / In gas separation, the fabrication of composite membranes consisting of a permselective thin top layer with high cross-linking structures and a porous substrate has been regarded as a solution for improving gas permeability and simultaneously retaining high selectivity. A plasma-polymerized SiOCH film has been known as an appropriate gas separation membrane because it possesses a dense structure, the crosslinking degree of which could be controlled by adjusting plasma parameters such as plasma power, monomer flow rate, and system pressure. However, the pore size and distribution in SiOCH films, especially in the region of depth profile, are difficult to measure by conventional techniques because of they are very thin.This thesis is concerned with the control of pore structure in a plasma-polymerized SiOCH film on a polymeric substrate by using an organosilicon source. The positron annihilation spectroscopy (PAS) coupled to the slow positron beam technique was used to identify the microstructure of SiOCH films as a function of depth. This step required to have a good understanding of the positron annihilation characteristics of different materials such as organic, inorganic, and hybrid materials. Depending on plasma frequency adjustments, SiOCH films with a flat and a superhydrophobic (SHP) surface were fabricated at 13.56 MHz and 40 kHz, respectively. For a flat SiOCH film, substrate type, chemical structure of precursor, and RF power were the major variables that influenced the pore structure. When SiOCH films composed of two layers (bulk and transitions layers) were deposited on porous substrates, they displayed a long transition layer based on the PAS analysis and possessed a high gas permeability due to the surface porosity of the substrate. When the precursor used possessed a cyclic ring structure, an opportunity of a break-up of the cyclic ring would increase with increasing RF power and then induce formation of new big pores. For the preparation of SHP films, when the total pressure was higher than 0.6 mbar, the gas nucleation reaction was enhanced to induce roughness on SiOCH films, and it would show a high WCA of over 160o and a low WCAH of only 2 degrees. Both the hydrocarbon preservation and microstructure were the main factors in improving the surface superhydrophobicity of SiOCH films.

Jean Thibaud est né à Lyon en 1901. Ingénieur électricien, il se dirige vers la recherche fondamentale en soutenant une thèse sous la direction de Maurice de Broglie en 1924, alors directeur du laboratoire de physique des rayons X. Thibaud travaille en particulier, sur les tout premiers dispositifs accélérateurs de particules, linéaires et circulaires, entre 1931 et 1933. Il précise en 1933, grâce à une technique expérimentale qu'il met au point (la méthode de la trochoïde), les caractéristiques physiques du positron ; la première antiparticule, découverte par C.D Anderson en 1932. De conserve avec Frédéric Joliot, il parvient en usant de la technique de la trochoïde, à observer pour la première fois, l'annihilation du positron. En 1935-1936, Jean Thibaud créer l'Institut de Physique atomique de Lyon, rue Raulin tout en occupant une chaire de physique expérimentale à la Faculté des Sciences de Lyon. Ce laboratoire constitue le premier laboratoire de province dédié à l'étude de l'atome. Treize chercheurs, techniciens et assistants composent ce laboratoire en 1937. Le 1944. Thibaud profitera de la dotation de 20 millions de francs qui lui sera faite après la guerre, pour acquérir un générateur de Cockcroft-Walton. Cet instrument sera installé, avec le concours de l'armée, au fort de la Vitriolerie à Lyon. En contrepartie, Thibaud acceptera de mettre son expertise et celle de ses collaborateurs au profit de la formation en physique atomique d'officiers et de techniciens de l'armée de terre, de 1951 à 1960. Parallèlement Thibaud travaille sur les plans de son nouveau laboratoire, projeté sur le domaine de la Doua, à Villeurbanne. Il ne verra pas sortir de terre ce nouveau laboratoire — inauguré en 1963 — qui constitue l'actuel Institut de Physique Nucléaire de Lyon. Jean Thibaud apparaît pourtant comme une figure méconnue du XXe siècle scientifique. Mise à part le Prix Thibaud, décerné par l'Académie des Sciences, Belles- Lettres et Arts de Lyon tous les deux ans, aucune instance ou artefact universitaire n'en garde la mémoire. Aucune rue ou amphithéâtre n'en porte le nom, pas même à Lyon, sa ville natale. Pour comprendre la marginalisation de Jean Thibaud dans la mémoire savante et dans la mémoire locale, nous articulons les différents registres d'activités de Jean Thibaud autour de trois bifurcations qui nous semblent avoir marqué son existence. Sa non participation au congrès Solvay 1933 marque la première bifurcation. Les directions d'institutions scientifiques durant le régime de Vichy et l'Occupation constituent la seconde bifurcation. La dernière est associée à une affaire de plagiat devant l'Académie des sciences, en janvier 1951 / Jean Thibaud was born in Lyon in 1901. An electrical engineer, he goes to basic research in a thesis under the direction of Maurice de Broglie in 1924, then he becomes the director of the X-ray physics laboratory. Thibaud worked in particular on the first particle accelerator devices, linear and circular, between 1931 and 1933. He states in 1933, thanks to an experimental technique he developed (the method of the trochoid), the physical characteristics of the positron ; the first antiparticle, discovered by C.D Anderson in 1932. Independently with Frédéric Joliot, he succeeds in making use of the technique of trochoïde to observe for the first time, the annihilation of the positron. In 1935-1936, Jean Thibaud created the Atomic Physics Institute in Lyon, rue Raulin, while occupying a chair of experimental physics at the Faculty of Sciences of Lyon. This laboratory is the first province laboratory dedicated to the study of the atom. Thirteen researchers, technicians and assistants built up this laboratory in 1937. The laboratory will be partially destroyed during the Allied bombing of 26 May 1944. Thibaud benefited from the allocation of 20 million francs to be made after the war, to acquire Cockcroft-Walton generator. This instrument will be installed, with the assistance of the army, at the top of the Vitriolerie in Lyon. In return, Thibaud agreed to put his expertise and that of his employees to the benefit of the training in atomic physics of officers and technicians in the Army from 1951 to 1960. Meanwhile Thibaud was working on the plans of his new laboratory planned to be built on the field of La Doua, in Villeurbanne. He will not see the new laboratory spring up - it was inaugurated in 1963- which is the current Institute of Nuclear Physics of Lyon. Jean Thibaud yet appears as a little-known figure of the twentieth century science. Apart from the Thibaud Prize, awarded by the Academy of Sciences, Arts and Belles-Lettres de Lyon every two years, no proceeding or university artifact keeps his memory. No street or amphitheater bears his name, not even in Lyon, his hometown. To understand the marginalization of Jean Thibaud in scholarly memory and in local memory, we can articulate the different registers of Jean Thibaud’s activities around three bifurcations that his existence seems to have taken. His non-participation in the 1933 Solvay conference marks the first bifurcation. The directions of scientific institutions during the Vichy period and the Occupation constitute the second bifurcation. The latter is associated with a plagiarism case at the Academy of Sciences in January 1951

Ein fundamentaler Baustein des Standardmodels, des heute am weitesten akzeptierten Models der Elementarteilchenphysik, ist die Selbstkopplung der elektroschwachen Eichbosonen gamma, Z und W. Waehrend andere Vorhersagen des Standardmodels mit hoher Praezision getestet wurden, ist ueber die Staerke der Selbstkopplung der Bosonen wenig bekannt. Erste indirekte Hinweise ueber solche Kopplungen wurden aus praezisen Messungen der Fermionpaarproduktion auf dem Z-Pol gewonnen. Diese Messungen sind sensitiv auf Strahlungskorrekturen. In dieser Analyse werden zum ersten Mal alle verfuegbaren elektroschwachen Praezisionsdaten, die unter anderen bei LEP 1, am SLAC und am TEVATRON gewonnen wurden, benutzt, um in einer globalen Anpassung die Kopplungsstaerken der elektroschwachen Eichbosonen zu ermitteln. Praezise direkte Messungen der Kopplungsstaerke wurden durch die Erhoehung der Schwerpunktsenergie am LEP-Beschleuniger im Jahre 1996 moeglich, die die Paarproduktion von W-Bosonen, e+e- -> W+W-, erlaubte. Zusaetzlich zu diesem Kanal wurde auch noch die Kopplungsabhaengigkeit des Wirkungsquerschnitts der einfach-resonanten W-Produktion, e+e- -> W e nu, und der Photonproduktion, e+e- -> nu nu gamma, benutzt, um die Selbstkopplung der Bosonen zu bestimmen. Zur Analyse wurden Daten, die einer Gesamtluminositaet von 77 pb^-1 entsprechen und bei Schwerpunktsenergien von 161, 172 und 183 GeV in den Jahren 1996 und 1997 mit dem L3 Detektor aufgezeichnet wurden, benutzt. Die Vorhersagen des Standardmodels sind in guter Uebereinstimmung mit allen Messungen. Insbesondere mit der Messung von g_1^Z konnte zum ersten Mal die Existenz des ZWW Vertex experimentell nachgewiesen werden. Zusaetzlich fordert das Standardmodel die Erhaltung der C- und P-Paritaet am ZWW Vertex. Diese Vorhersage wurde durch die Messung getestet und es wurde gute Uebereinstimmung mit der Standardmodelvorhersage gefunden. Die Messung der Kopplungsstaerken in drei unterschiedlichen Kanaelen entspricht der Messung in unterschiedliche Regionen von Impulsuebertraegen. Die Messungen zeigen keine Abhaengigkeit, so dass sowohl das magnetische Dipolmoment als auch das elektrische Quadrupolmoment des W-Bosons aus den Kopplungen hervorgehen. Diese statischen Eigenschaften des W-Bosons geben Informationen ueber dessen Groesse und geometrische Struktur. So folgt aus der Messung das der Radius der W-Bosons kleiner als 10^-18 m ist. Zusaetzlich zu diesen Informationen ueber das W-Boson, konnte der Parameterbereich einer Erweiterung der Standardmodels durch ein sequentielles Z'-Boson eingeschraenkt werden. Ein Model von Klein das die Vereinigung von Kraeften und Materie beschreibt wurde mit 10 Standardabweichungen ausgeschlossen. Zusammenfassung als PostScript-Datei / The couplings between the bosons of the electroweak interaction, gamma, Z and W, is one of the fundamental building blocks of the Standard Model, which was not yet tested with high precision. Indirect hints for the existence of boson self-coupling have been obtained by analysing Z pole data with respect to radiative corrections. This analysis uses for the first time all available electroweak precision data obtained at LEP 1, SLC, TEVATRON and at low energy experiments. The coupling strength between the electroweak gauge bosons is obtained by a global fit to all these data. A precise direct measurement of triple gauge boson couplings became possible in 1996 at LEP 2, where W bosons could be produced in pairs, e+e- -> W+W-. In addition single-resonant W production, e+e- -> W e nu, and single photon production, e+e- -> nu nu gamma, are evaluated with respect to boson self-couplings. In total a luminosity of 77 pb^-1 was collected with the L3 detector at 161, 172 and 183 GeV centre-of-mass energy in the years 1996 and 1997. The Standard Model expectations show good agreement with this measurement. The measurement is the first proof of the existence of a ZWW vertex. The LEP 2 data were further used to limit violation of parity and C-parity at the ZWW vertex. The results of the measurement for the three different channels, corresponding to three different regions of momentum transfer showed no dependence. Thus the magnetic dipole moment and electric quadrupole moment are derived. These two static properties of the W give information on the size and the geometrical form of the W, such that the W radius could be limited to 10^-18 m. In addition the coupling constants were used to limit the phase space of the extension of the Standard Model with a sequential Z' boson in terms of mixing angle and Z' mass. The unified matter theory by Klein is ruled out with more than ten standard deviations. abstract in PostScript

<p>The major advantage of position sensitive radiation detector systems lies in their ability to non invasively map the regional distribution of the emitted radiation in real-time. Three of such detector systems were studied in this thesis, gamma-cameras, positron cameras and CMOS image sensors. A number of physical factors associated to these detectors degrade the qualitative and quantitative properties of the obtained images. These blurring factors could be divided into two groups. The first group consists of the general degrading factors inherent to the physical interaction processes of radiation with matter, such as scatter and attenuation processes which are common to all three detectors The second group consists of specific factors inherent to the particular radiation detection properties of the used detector which have to be separately studied for each detector system. Therefore, the aim of this thesis was devoted to the development of computational methods to enable quantitative molecular imaging in PET, SPET and in vivo patient dosimetry with CMOS image sensors.</p><p>The first task was to develop a novel quantitative dual isotope method for simultaneous assessments of regional lung ventilation and perfusion using a SPET technique. This method included correction routines for photon scattering, non uniform attenuation at two different photon energies (140 and 392 keV) and organ outline. This quantitative method was validated both with phantom experiments and physiological studies on healthy subjects.</p><p>The second task was to develop and clinically apply a quantitative method for tumour to background activity uptake measurements using planar mammo-scintigraphy, with partial volume compensation.</p><p>The third stage was to produce several computational models to assess the spatial resolution limitations in PET from the positron range, the annihilation photon non-collineairy and the photon depth of interaction.</p><p>Finally, a quantitative image processing method for a CMOS image sensor for applications in ion beam therapy dosimetry was developed.</p><p>From the obtained phantom and physiological results it was concluded that the methodologies developed for the simultaneous measurement of the lung ventilation and perfusion and for the quantification of the tumour malignancy grade in breast carcinoma were both accurate. Further, the obtained models for the influence that the positron range in various human tissues, and the photon emission non-collinearity and depth of interaction have on PET image spatial resolution, could be used both to optimise future PET camera designs and spatial resolution recovery algorithms. Finally, it was shown that the proton fluence rate in a proton therapy beam could be monitored and visualised by using a simple and inexpensive CMOS image sensor.</p>

The major advantage of position sensitive radiation detector systems lies in their ability to non invasively map the regional distribution of the emitted radiation in real-time. Three of such detector systems were studied in this thesis, gamma-cameras, positron cameras and CMOS image sensors. A number of physical factors associated to these detectors degrade the qualitative and quantitative properties of the obtained images. These blurring factors could be divided into two groups. The first group consists of the general degrading factors inherent to the physical interaction processes of radiation with matter, such as scatter and attenuation processes which are common to all three detectors The second group consists of specific factors inherent to the particular radiation detection properties of the used detector which have to be separately studied for each detector system. Therefore, the aim of this thesis was devoted to the development of computational methods to enable quantitative molecular imaging in PET, SPET and in vivo patient dosimetry with CMOS image sensors. The first task was to develop a novel quantitative dual isotope method for simultaneous assessments of regional lung ventilation and perfusion using a SPET technique. This method included correction routines for photon scattering, non uniform attenuation at two different photon energies (140 and 392 keV) and organ outline. This quantitative method was validated both with phantom experiments and physiological studies on healthy subjects. The second task was to develop and clinically apply a quantitative method for tumour to background activity uptake measurements using planar mammo-scintigraphy, with partial volume compensation. The third stage was to produce several computational models to assess the spatial resolution limitations in PET from the positron range, the annihilation photon non-collineairy and the photon depth of interaction. Finally, a quantitative image processing method for a CMOS image sensor for applications in ion beam therapy dosimetry was developed. From the obtained phantom and physiological results it was concluded that the methodologies developed for the simultaneous measurement of the lung ventilation and perfusion and for the quantification of the tumour malignancy grade in breast carcinoma were both accurate. Further, the obtained models for the influence that the positron range in various human tissues, and the photon emission non-collinearity and depth of interaction have on PET image spatial resolution, could be used both to optimise future PET camera designs and spatial resolution recovery algorithms. Finally, it was shown that the proton fluence rate in a proton therapy beam could be monitored and visualised by using a simple and inexpensive CMOS image sensor.

Abstract: Sunitinib (Sutent®) is a multitargeted, small molecule receptor tyrosine kinase inhibitor used as an anti-cancer drug. It has increased the overall survival rate of metastatic renal cell carcinoma patients as well as the survival time of patients with pancreatic neuroendocrine tumors. Although the clinical use of sunitinib is a significant leap forward in the therapy of those cancers, its induction of cardiac toxicity in a substantial fraction of patients remains a critical problem. Sunitinib may cause hypertension, arrhythmias, drop of the left ventricular ejection fraction and congestive heart failure, fatal in some cases. These side effects are a frequent reason for interruption of its use. The mechanism(s) underlying sunitinib cardiotoxicity are not fully understood. Similar to other receptor tyrosine kinase inhibitors, it binds to a large number of cellular kinases, thus it can affect multiple cellular processes. In vivo, the pattern of toxicity is complex and unpredictable, with symptomatic heart failure sometimes observed early during treatment. The pattern of events preceding the onset of symptomatic cardiac dysfunction during treatment is not established. This represents a significant problem for the clinical diagnosis of cardiovascular complications before they become symptomatic. The identification and early detection of those events would be highly-beneficial for the clinical management of anti-cancer therapy with sunitinib. Positron Emission Tomography (PET) is recognized for its ability to probe metabolic and functional aspects of myocardial function. Under the working concept that heart failure can occur early during sunitinib treatment, and may be sustained by early myocardial metabolic and structural alterations, we performed a study with the objective of assessing the use of PET for the early detection of sunitinib-induced ardiotoxicity. For this, we established a model of cardiotoxicity in C57BL/6 male mice given 80mg/Kg/day of sunitinib or water, orally for 4 weeks. General and cardiac toxicity were monitored by biochemical, microscopical (H&E, immunofluorescence and electron microscopy) as well as gene expression analyses and blood pressure measurements. PET scans were performed weekly using [superscript 11]C-acetate and [superscript 18]F-FDG to evaluated the myocardial blood flow (MBF), myocardial oxidative metabolism through the quantification of oxygen consumption (MVO[subscript 2]), glucose uptake (K[subscript i]), myocardial metabolic rate of glucose (MMRG) and the left ventricular ejection fractions (LVEF). We found that sunitibib was cardiotoxic as revealed by histopathology, immunostaining and electron microscopy. Signs of inflammation and tissue remodeling were found by gene expression analyses and collagen staining. No hypertension or renal damage were detected on the study. FDG-PET revealed an early decrease of the LVEF, indicative of cardiac dysfunction, which developed into grade-2 heart failure by the end of the study. However, no signs of alterations in cardiac metabolism were uncovered by FDG- or [superscript 11]C-acetate-PET. Our results hint that the onset of sunitinib-induced contractile dysfunction may occur in the absence of hypertension or overt metabolic damage and call for further studies with longer treatments to clearly mark the onset of metabolic cardiotoxicity. // Résumé: Le sunitinib est un inhibiteur de tyrosine kinase qui est utilisée comme agent anticancéreux. Bien que l'utilisation clinique du sunitinib représente une percée significative pour le traitement de certains cancers, ce médicament s’avère cardiotoxique chez plusieurs patients, une situation qui est problématique. Le sunitinib peut provoquer une hypertension, des arythmies, une chute de la fraction d'éjection ventriculaire gauche et une insuffisance cardiaque congestive qui peut être fatale. Le mécanisme responsable de la cardiotoxicité de sunitinib n’est pas encore bien compris. Comme plusieurs autres inhibiteurs des récepteurs de la tyrosine kinase, il se lie à un grand nombre de kinases et peut affecter de nombreux processus cellulaires. In vivo, les mécanismes responsables de la toxicité sont complexes et imprévisibles et une insuffisance cardiaque est parfois observée tôt pendant le traitement. La séquence des évènements menant à l'apparition d’une dysfonction cardiaque pendant le traitement n’est pas connue. Cela pose un problème important pour le diagnostic de complications cardiovasculaires avant qu'elles ne deviennent symptomatiques. Une identification précoce de ces événements néfastes serait très bénéfique pour le suivi du traitement au sunitinib. La tomographie d'émission par positrons (TEP) est une méthode reconnue pour l’évaluation du métabolisme et de la fonctionnalité du myocarde. Selon notre hypothèse de travail, une insuffisance cardiaque peut survenir rapidement pendant le traitement au sunitinib, elle est l’expression d’altérations structurelles et métaboliques au niveau du myocarde; ces modifications se produisent tôt pendant le traitement. Nous avons effectué une étude pour évaluer la faisabilité d’utiliser l’imagerie TEP pour la détection précoce de la cardiotoxicité induite par le sunitinib. La première étape a été de développer un modèle de cardiotoxicité chez des souris. L’induction de la cardiotoxicité s’est faite par administration orale pour une période de quatre semaines, soit de sunitinib 80mg/Kg/jour ou d'eau pour les souris contrôles. Le suivi inclut la mesure de la pression sanguine, l’évaluation des altérations biochimiques, l’expression de certains gènes et un examen histologique du myocarde. Un suivi par imagerie TEP a été effectué chaque semaine avec du [indice supérieur 11]C-acétate et du [indice supérieur 18]F-FDG afin d'évaluer le flux sanguin myocardique (MBF), le métabolisme oxydatif du myocarde incluant la consommation d'oxygène (MVO2), l'absorption du glucose (K[indice inférieur i]), le taux métabolique oxydatif du glucose (MMRG) ainsi que la fraction d'éjection ventriculaire gauche (FEVG). Les résultats que nous avons obtenus par histopathologie, immunocoloration et microscopie électronique montrent que notre modèle est capable d’induire une cardiotoxicité. Nous avons également observé des évidences d'inflammation et de remodelage tissulaire à partir de l’étude de l'expression de certains gènes et de l’analyse de l’accumulation de collagène. Nous n’avons pas observé d’hypertension ni de lésions rénales. La TEP avec [indice supérieur 18]FDG a montré une diminution rapide de la FEVG, une indication d’une dysfonction cardiaque qui a été classée comme insuffisance cardiaque de grade 2 à la fin de l'étude. Cependant, aucun signe de modifications du métabolisme cardiaque n’a été mis en évidence par TEP/[indice supérieur 18]FDG- ou TEP/[indice supérieur 11]C-acétate. Nos résultats laissent penser que l'apparition de la dysfonction contractile induite par sunitinib peut se produire en l'absence d'hypertension ou de dommages métaboliques manifestes. De nouvelles études avec des traitements plus longs permettraient peut être de mieux définir le début de la cardiotoxicité métabolique.

Purpose: The five point Deauville (D) scale is widely used to assess interim PET metabolic response to chemotherapy in Hodgkin lymphoma (HL) patients. An International Validation Study reported good concordance among reviewers in ABVD treated advanced stage HL patients for the binary discrimination between score D1,2,3 and score D4,5. Inter-reader reliability of the whole scale is not well characterised. Methods: Five international expert readers scored 100 interim PET/CT scans from paediatric HL patients. Scans were acquired in 51 European hospitals after two courses of OEPA chemotherapy (according to the EuroNet-PHL-C1 study). Images were interpreted in direct comparison with staging PET/CTs. Results: The probability that two random readers concord on the five point D score of a random case is only 42% (global kappa = 0.24). Aggregating to a three point scale D1,2 vs. D3 vs. D4,5 improves concordance to 60% (kappa = 0.34). Concordance if one of two readers assigns a given score is 70% for score D1,2 only 36% for score D3 and 64% for D4,5. Concordance for the binary decisions D1,2 vs. D3,4,5 is 67% and 86% for D1,2,3 vs D4,5 (kappa = 0.36 resp. 0.56). If one reader assigns D1,2,3 concordance probability is 92%, but only 64% if D4,5 is called. Discrepancies occur mainly in mediastinum, neck and skeleton. Conclusion: Inter-reader reliability of the five point D-scale is poor in this interobserver analysis of paediatric patients who underwent OEPA. Inter-reader variability is maximal in cases assigned to D2 or D3. The binary distinction D1,2,3 versus D4,5 is the most reliable criterion for clinical decision making.

There is always a need and drive to improve modern cancer care. Dynamic positron emission tomography (PET) offers the advantage of in vivo functional imaging, combined with the ability to follow the physiological processes over time. In addition, by applying tracer kinetic modeling to the dynamic PET data, thus estimating pharmacokinetic parameters associated to e.g. glucose metabolism, cell proliferation etc., more information about the tissue's underlying biology and physiology can be determined. This supplementary information can potentially be a considerable aid when it comes to the segmentation, diagnosis, staging, treatment planning, early treatment response monitoring and follow-up of cancerous tumors. We have found it feasible to use kinetic parameters for semi-automatic tumor segmentation, and found parametric images to have higher contrast compared to static PET uptake images. There are however many possible sources of errors and uncertainties in kinetic parameters obtained through compartment modeling of dynamic PET data. The variation in the number of detected photons caused by the random nature of radioactive decay, is of course always a major source. Other sources may include: the choice of an appropriate model that is suitable for the radiotracer in question, camera detectors and electronics, image acquisition protocol, image reconstruction algorithm with corrections (attenuation, random and scattered coincidences, detector uniformity, decay) and so on. We have found the early frame sampling scheme in dynamic PET to affect the bias and uncertainty in calculated kinetic parameters, and that scatter corrections are necessary for most but not all parameter estimates. Furthermore, analytical image reconstruction algorithms seem more suited for compartment modeling applications compared to iterative algorithms. This thesis and included papers show potential applications and tools for quantitative pharmacokinetic parameters in oncology, and help understand errors and uncertainties associated with them. The aim is to contribute to the long-term goal of enabling the use of dynamic PET and pharmacokinetic parameters for improvements of today's cancer care. / Det finns alltid ett behov och en strävan att förbättra dagens cancervård. Dynamisk positronemissionstomografi (PET) medför fördelen av in vivo funktionell avbilning, kombinerad med möjligheten att följa fysiologiska processer över tiden. Genom att därtill tillämpa kinetisk modellering på det dynamiska PET-datat, och därigenom skatta farmakokinetiska parametrar associerade till glukosmetabolism, cellproliferation etc., kan ytterligare information om vävnadens underliggande biologi och fysiologi bestämmas. Denna kompletterande information kan potentiellt vara till stor nytta för segmentering, diagnos, stadieindelning, behandlingsplanering, monitorering av tidig behandlingsrespons samt uppföljning av cancertumörer. Vi fann det möjligt att använda kinetiska parametrar för semi-automatisk tumörsegmentering, och fann även att parametriska bilder hade högre kontrast jämfört med upptagsbilder från statisk PET. Det finns dock många möjliga källor till osäkerheter och fel i kinetiska parametrar som beräknats genom compartment-modellering av dynamisk PET. En av de största källorna är det radioaktiva sönderfallets slumpmässiga natur som orsakar variationer i antalet detekterade fotoner. Andra källor inkluderar valet av compartment-modell som är lämplig för den aktuella radiotracern, PET-kamerans detektorer och elektronik, bildtagningsprotokoll, bildrekonstruktionsalgoritm med tillhörande korrektioner (attenuering, slumpmässig och spridd strålning, detektorernas likformighet, sönderfall) och så vidare. Vi fann att tidssamplingsschemat för tidiga bilder i dynamisk PET påverkar både fel och osäkerhet i beräknade kinetiska parametrar, och att bildkorrektioner för spridd strålning är nödvändigt för de flesta men inte alla parametrar. Utöver detta verkar analytiska bildrekonstruktionsalgoritmer vara bättre lämpade för tillämpningar som innefattar compartment-modellering i jämförelse med iterativa algoritmer. Denna avhandling med inkluderade artiklar visar möjliga tillämpningar och verktyg för kvantitativa kinetiska parametrar inom onkologiområdet. Den bidrar också till förståelsen av fel och osäkerheter associerade till dem. Syftet är att bidra till det långsiktiga målet att möjliggöra användandet av dynamisk PET och farmakokinetiska parametrar för att förbättra dagens cancervård.

Positron emission tomography (PET) is a non-invasive imaging technique which utilizes positron-emitting radiopharmaceuticals (PERs) to characterize biological processes in tissues of interest. A PET scanner is usually composed of multiple scintillation crystal detectors placed in a ring so as to capture coincident photons from a position annihilation. These detectors require a crystal lookup table (CLUT) to map the detector response to the crystal of interaction. These CLUTs must be accurate, lest events get mapped to the wrong crystal of interaction degrading the final image quality. This work describes an automated algorithm, for CLUT generation, focused around Gaussian Mixture Models (GMM) with Thin Plate Splines (TPS). The algorithm was tested with flood image data collected from 16 detectors. The method maintained at least 99.8% accuracy across all tests. This method is considerably faster than manual techniques and can be adapted to different detector configurations. / February 2016

published_or_final_version / abstract / Physics / Doctoral / Doctor of Philosophy