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Medical molecular imaging with positron emission tomography (PET) is sensitive to patient motion since PET scans last several minutes. Despite advancements in PET, such as improved photon-pair time-of-flight (TOF) difference resolution, motion deformations limit image resolution and quantification. Previous research of head motion tracking has produced the data-driven centroid-of-distribution (COD) algorithm. COD generates a 3D center-of-mass (COM) over time via raw list-mode PET data, which can guide motion correction such as gating and event rebinning in non-TOF PET. Knowledge gaps: COD could potentially benefit from sinogram corrections used in image reconstruction, while rebinning has not extended to TOF PET. Methods: This study develops COD with event mass (incorporating random correction and line-of-response (LOR) normalization) and a simplistic TOF rebinner. In scans of phantoms and moving heads with F11 flouro-deoxy-glucose (FDG) tracer, COD alternatives are evaluated with a signal-to-noise ratio (SNR) via linear fit to image COM, while rebinning is evaluated with mean squared error (MSE). Results: COD SNR did not benefit from a corrected event mass. The prototype TOF rebinning reduced MSE, although there were discretization errors and event loss at extreme bins for LOR and TOF due to the simplistic design, which introduced image artifacts. In conclusion, corrected event mass in COD is not promising, while TOF rebinning appears viable if techniques from state-of-the-art LOR rebinning are incorporated.

Accurate attenuation correction is essential for quantitative positron emission tomography. Typically, this correction is based on a coincidence transmission measurement using an external source of positron emitter, which is positioned close to the detectors. This technique suffers from poor statistical quality and high dead time losses, especially with a high transmission source strength. We have proposed and tested the use of single photon transmission measurement with a rotating rod source, to measure the attenuation correction factors (ACFs). The singles projections are resampled into the coincidence geometry using the detector positions and the r,)d source location. A nonparalyzable dead time correction algorithm was developed for the block detectors used in the McMaster PET scanner. Transaxial resolution is approximately 6 mm, which is comparable to emission scanning performance. Axial resolution is about 25 mm, with only crude source collimation. ACFs are underestimated by approximately 10% due to increased crossplane scatter, compared to coincidence transmission scanning. Effective source collimation is necessary to obtain suitable axial resolution and improved accuracy. The response of the correction factors to object density is linear to within 15%, when comparing singles transmission measurement to current coincidence transmission measurement. The major advantage of using singles transmission measurement IS a dramatically increased count rate. A factor of seven increase in count rate over coincidence scanning is possible with a 2 mCi transmission rod source. There are no randoms counted in singles transmission scans, which makes the measured count rate nearly linearly proportional with source activity. Singles detector dead time is approximately 6% in the detectors opposite a 2 mCi rod source. Present hardware and software precludes the application of this technique in a clinical environment. We anticipate that real time acquisition of detector singles can reduce the transmission scanning time to under 2 minutes, and produce attenuation coefficient images with under 2% noise. This is a significant improvement compared to the current coincidence transmission technique. / Thesis / Master of Science (MS)

This study attempts to develop a method for absolute quantitation in Positron Emission Tomography. This includes the definition of the dimension and the position of a tumour in the brain as well as the evaluation of the amount of drug delivered to the tumour and to surrounding tissues in a pixel-by-pixel way, from the image. The defined objectives can be achieved using the calibrated FWHM values of the distribution of events in the tumour image, versus distance, to determine the dimension and the position of the tumour. The concentration activity in the tumour and the tumour-to-nontumour activity ratios can be obtained from the image, using a modified filter and the calibration of the tomograph. The colour scale of the image can be expressed in absolute units (μCi/ml) and the concentration activity can be evaluated in each pixel of the image or in each volume element of the body. / Thesis / Master of Science (MS)

L'imagerie médicale remonte à la fin du XIXe siècle avec la découverte des rayons X par Röntgen. Depuis, de nombreuses modalités d'imagerie ont été développées, et sont aujourd'hui utilisées dans une large gamme d'indications cliniques. L'imagerie TEP (Tomographie par Émission de Positron) est une modalité fonctionnelle, quantitative et ayant une haute sensibilité, ce qui en fait une modalité de choix, notamment en cancérologie. Hélas, sa diffusion est freinée en comparaison avec le scanner ou l'imagerie par résonance magnétique, en raison de son coût notamment. C'est dans ce contexte que s'insère cette thèse, qui a pour objectif de montrer la faisabilité d'un imageur TEP ambulatoire dédié au suivi thérapeutique en cancérologie. À partir de développements instrumentaux originaux (localisation des gammas par division de lumière dans des barreaux scintillateurs, lecture à l'aide de Silicon PhotoMultiplier, géométrie compacte), ces travaux s'efforcent de baisser les coûts tout en restant compétitif en terme de performances. Dans un premier temps, une étude extensive de la division de lumière à travers toute une série de paramètres (longueur des barreaux scintillateurs, revêtement optique, matériau scintillateur, traitement des données) a été menée. Une résolution spatiale inférieure à 5 mm pour un barreau de 75 mm de LYSO emballé dans du teflon a notamment été obtenue. À partir de cette configuration, une première image a été reconstruite, à partir de deux modules en coïncidence, offrant une résolution spatiale de 5 mm pour un tel imageur. Enfin, toute une série de simulations a été menée, à partir des données expérimentales et avec une géométrie originale. En particulier, les performances ont été mesurées à partir du protocole NEMA, un standard permettant de comparer les performances à travers la littérature. Une résolution spatiale intrinsèque de l'ordre de 4 mm a été obtenue, soit meilleure que le marché actuel. La sensibilité de l'ordre de 2.5 cps/kBq est revanche relativement basse par rapport à l'existant, mais s'explique par un champ de vue axial restreint. Enfin, le potentiel en terme de quantification a été adressé, et est comparable au marché actuel. / Medical imaging first began at the end of the XIXth century with the discover of X-rays by Röntgen. Then, numerous imaging modalities have been developed and are used now for a wide range of cases. Positron Emission Tomography (PET) has a high sensitivity, is functional and quantitative, thus being of high interest in cancer monitoring. Nevertheless, PET is not as much spread in hospitals as magnetic resonance imaging and scanner. In this context, this work aims to prove the faisability of PET dedicated for cancer monitoring. Thanks to instrumental developments such as light sharing in scintillating crystals, use of Silicon Photomultipliers, and an original geometry, cost is expected to be reduced while having same performances as commercial devices. An extensive study of light sharing within scintillating barrels has been made, through many parameters (crystal length, coating, data analysis...). An intrinsic spatial resolution of 4 mm has been measured over a 75 mm long crystal of LYSO, coated with teflon. From such a configuration, a first image has been reconstructed using two modules in coincidence. A spatial resolution of 5 mm has been measured in the image. Finally, Monte Carlo simulations has been made with experimental data as input, in order to measure the performances of the final PET device. Thanks to NEMA standard protocol, performances has been measured and compared to other systems. A spatial resolution of 4 mm has been reached, for a sensitivity of 2.5 cps/kBq. Quantification problem has been assessed, providing results similar to existing devices.

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.

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