Development of a Fluoroscopic Radiostereometric Analysis System With an Application to Glenohumeral Joint Kinematics

Ideally, joint kinematics should be measured with high accuracy, void of skin motion artefact, in three dimensions, and under dynamic conditions. Radiostereometric analysis (RSA) has the potential to fulfill all of these requirements. The objectives of this thesis were (1) to implement and validate a fluoroscopy-based RSA system, (2) to determine the effect of varying the calibration frame, (3) to correct image distortion, (4) to investigate errors in coordinate system creation for glenohumeral (shoulder) joint kinematics, (5) to introduce a new coordinate system definition for the scapula with limited radiation exposure, and (6) to use RSA to examine glenohumeral joint motions in- vivo. An RSA system consisting of two portable C-arm fluoroscopy units and two personal computers was assembled. Calibration was performed using a custom-made calibration frame. Images were digitized and RSA reconstruction was performed using custom-written software. Images taken using fluoroscopy under ideal conditions can produce reconstructions that are as accurate as those taken with digital radiography, with standard errors of measurement of 43pm and 0.23° and 36pm and 0.12°, respectively. RSA is more accurate than optical tracking for rigid body motion. The fluoroscopes may be positioned at angles less than 135° without affecting the accuracy of reconstruction. A global polynomial approach to distortion correction is appropriate for use with RSA; however, the polynomial degree must be determined for each system with an independent accuracy measure. m An alternative scapular coordinate system was introduced to decrease the required radiation exposure for coordinate system creation by approximately half. The kinematic angles obtained using the alternative coordinate system were different from those obtained using the International Society of Biomechanics standard; however, the differences are not clinically significant. As a first clinical application, glenohumeral joint translation was examined. The preliminary data suggests that humeral head position does not differ in active and static joint positioning. Fluoroscopy allows subjects to be examined while in motion and should enable substantial improvements to the study of even subtle in-vivo kinematics. It is likely that the RSA system will lead to an increased understanding of the effects of disease progression, surgical techniques and rehabilitation protocols on joint motion

Advanced capabilities for planar X-ray systems

Mención Internacional en el título de doctorThe past decades have seen a rapid evolution towards the use of digital detectors in radiology and a more flexible robotized movement of the system components, X-ray tube and detector. This evolution opened the possibility for incorporating advanced capabilities in these planar X-ray systems, and for providing new valuable diagnostic information compared to the previous technology. Some of the current challenges for radiography are to obtain more quantitative images and to reduce the inherent superposition of tissues because of the 2D nature of the technique. Dual energy radiography, based on the acquisition of two images at different source voltages, enables a separate characterization of soft tissue and bone structures. Its benefits over conventional radiography have been proven in different applications, since it improves information content without adding significant extra acquisition time or radiation dose. In a different direction, a really disruptive advance would be to obtain 3D imaging with systems designed just for planar images. The incorporation of tomographic capabilities into these systems would have to deal with the acquisition of a limited number of projections, with non-standard geometrical configurations. This thesis presents original contributions in these two directions: dual energy radiography and 3D imaging with X-ray systems designed for planar imaging. The work is framed in a line of research of the Biomedical Imaging and Instrumentation Group from the Bioengineering and Aerospace Department of University Carlos III de Madrid working jointly with the University Hospital Gregorio Marañón, focused on the advance of radiology systems. This research line is carried out in collaboration with the group of Computer Architecture, Communications and Systems (ARCOS), from the same university, the Imaging Research Laboratory (IRL) of the University of Washington and the research center CREATIS, France. The research has a clear focus on technology transfer to the industry through the company Sedecal, a Spanish multinational among the 10 best world companies in the medical imaging field. The first contribution of this thesis is a complete novel protocol to incorporate dual energy capabilities that enable quantitative planar studies. The proposal is based on the use of a preliminary calibration with a very simple and low-cost phantom formed by two parts that represent soft tissue and bone equivalent materials. This calibration is performed automatically with no strict placement requirements. Compared to current Dual-energy X-ray Absorptiometry (DXA) systems, 1) it provides real mass-thickness values directly, enabling quantitative planar studies instead of relative comparisons, and 2) it is based on an automatic preliminary calibration without the need of interaction of an experienced technician. The second contribution is a novel protocol for the incorporation of tomographic capabilities into X-ray systems originally intended for planar imaging. For this purpose, we faced three main challenges. First, the geometrical trajectory of equipment follows non-standard circular orbits, thus posing severe difficulties for reconstruction. To handle this, the proposed protocol comprises a new geometrical calibration procedure that estimates all the system parameters per-projection. Second, the reconstruction of a limited number of projections from a reduced angular span leads to severe artifacts when using conventional reconstruction methods. To deal with these limited-view data, the protocol includes a novel advanced reconstruction method that incorporates the surface information of the sample, which can be extracted with a 3D light surface scanner. These data are introduced as an imposed constraint following the Split Bregman formulation. The restriction of the search space by exploiting the surface-based support becomes crucial for a complete recovery of the external contour of the sample and surroundings when the angular span is extremely reduced. The modular, efficient and flexible design followed for its implementation allows for the reconstruction of limited-view data with non-standard trajectories. Third, the optimization of the acquisition protocols has not yet explored with these systems. This thesis includes a study of the optimum acquisition protocols that allowed us to identify the possibilities and limitations of these planar systems. Using the surface-constrained method, it is possible to reduce the total number of projections up to 33% and the angular span down to 60 degrees. The contributions of this thesis open the way to provide depth and quantitative information very valuable for the improvement of radiological diagnosis. This could impact considerably the clinical practice, where conventional radiology is still the imaging modality most used, accounting for 80-90% of the total medical imaging exams. These advances open the possibility of new clinical applications in scenarios where 1) the reduction of the radiation dose is key, such as lung cancer screening or Pediatrics, according to the ALARA criteria (As Low As Reasonably Achievable), 2) a CT system is not usable due to movement limitations, such as during surgery or in an ICU and 3) where costs issues complicate the availability of CT systems, such as rural areas or underdeveloped countries. The results of this thesis has a clear application in the industry, since it is part of a proof of concept of the new generation of planar X-ray systems that will be commercialized worldwide by the company SEDECAL (Madrid, Spain).Los últimos años están viendo un rápido avance de los sistemas de radiología hacia el uso de detectores digitales y a una mayor flexibilidad de movimientos de los principales componentes del sistema, el tubo de rayos X y el detector. Esta evolución abre la posibilidad de incorporar capacidades avanzadas en sistemas de imagen plana por rayos X proporcionando nueva información valiosa para el diagnóstico. Dos retos en radiografía son obtener imágenes cuantitativas y reducir la superposición de tejidos debida a la naturaleza proyectiva de la técnica. La radiografía de energía dual, basada en la adquisición de dos imágenes a diferente kilovoltaje, permite obtener imágenes de tejido blando y hueso por separado. Los beneficios de esta técnica que aumenta la cantidad de información sin añadir un tiempo de adquisición o de dosis de radiación extra significativos frente al uso de radiografía convencional, han sido demostrados en diferentes aplicaciones. En otra dirección, un avance realmente disruptivo sería la obtención de imagen 3D con sistemas diseñados únicamente para imagen plana. La incorporación de capacidades tomográficas en estos sistemas tendría que lidiar con la adquisición de un número limitado de proyecciones siguiendo trayectorias no estándar. Esta tesis presenta contribuciones originales en esas dos direcciones: radiografía de energía dual e imagen 3D con sistemas de rayos X diseñados para imagen plana. El trabajo se encuadra en una línea de investigación del grupo de Imagen Biomédica e Instrumentación del Departamento de Bioingeniería e Ingeniería Aerospacial de la Universidad Carlos III de Madrid junto con el Hospital Universitario Gregorio Marañon, centrada en el avance de sistemas de radiología. Esta línea de investigación se desarollada en colaboración con el grupo Computer Architecture, Communications and Systems (ARCOS), de la misma universidad, el grupo Imaging Research Laboratory (IRL) de la Universidad de Washington y el centro de investigación CREATIS, de Francia. Se trata de una línea de investigación con un claro enfoque de transferencia tecnológica a la industria a través de la compañía SEDECAL, una multinacional española de entre las 10 líderes del mundo en el campo de la radiología. La primera contribución de esta tesis es un protocolo completo para incorporar capacidades de energía dual que permitan estudios cuantitativos de imagen plana. La propuesta se basa en una calibración previa con un maniquí simple y de bajo coste formado por dos materiales equivalentes de tejido blando y hueso respectivamente. Comparado con los sistemas actuales DXA (Dual-energy X-ray Absorptiometry), 1) proporciona valores reales de tejido atravesado, 2) se basa en una calibración automática que no requiere la interacción de un técnico con gran experiencia. La segunda contribución es un protocolo nuevo para la incorporación de capacidades tomográficas en sistemas de rayos X originariamente diseñados para imagen plana. Para ello, nos enfrentamos a tres principales dificultades. En primer lugar, las trayectorias que pueden seguir la fuente y el detector en estos sistemas no constituyen órbitas circulares estándares, lo que plantea retos importantes en la caracterización geométrica. Para solventarlo, el protocolo propuesto incluye una calibración geométrica que estima todos los parámetros geométricos del sistema para cada proyección. En segundo lugar, la reconstrucción de un número limitado de proyecciones adquiridas en un rango angular reducido da lugar a artefactos graves cuando se reconstruye con algoritmos convencionales. Para lidiar con estos datos de ángulo limitado, el protocolo incluye un nuevo método avanzado de reconstrucción que incorpora la información de superficie de la muestra, que se puede se obtener con un escáner 3D. Esta información se impone como una restricción siguiendo la formulación de Split Bregman, para compensar la falta de datos. La restricción del espacio de búsqueda a través de la explotación del soporte basado en superficie, es crucial para una recuperación completa del contorno externo de la muestra cuando el rango angular es extremadamente pequeño. El diseño modular, eficiente y flexible de la implementación propuesta permite reconstruir datos de ángulo limitado obtenidos con posiciones de fuente y detector no estándar. En tercer lugar, hasta la fecha, no se ha explorado la optimización del protocolo de adquisición con estos sistemas. Esta tesis incluye un estudio de los protocolos óptimos de adquisición que permitió identificar las posibilidades y limitaciones de estos sistemas de imagen plana. Gracias al método de reconstrucción basado en superficie, es posible reducir el número total de proyecciones hasta el 33% y el rango angular hasta 60 grados. Las contribuciones de esta tesis abren la posibilidad de proporcionar información de profundidad y cuantitativa muy valiosa para la mejora del diagnóstico radiológico. Esto podría impactar considerablemente en la práctica clínica, donde la radiología convencional es todavía la modalidad de imagen más utilizada, abarcando el 80- 90% del total de los exámenes de imagen médica. Estos avances abren la posibilidad de nuevas aplicaciones clínicas en escenarios donde 1) la reducción de la dosis de radiación es clave, como en screening de cáncer de pulmón, de acuerdo con el criterio ALARA (As Low As Reasonably Achievable), 2) no se puede usar un sistema TAC por limitaciones de movimiento como en cirugía o UCI, o 3) el coste limita la disponibilidad de sistemas TAC, como en zonas rurales o en países subdesarrollados. Los resultados de esta tesis presentan una clara aplicación industrial, ya que son parte de un prototipo de la nueva generación de sistemas planos de rayos X que serán distribuidos mundialmente por la compañía SEDECAL.This thesis has been developed as part of several research projects with public funding: - DPI2016-79075-R. ”Nuevos escenarios de tomografía por rayos X”, IP: Mónica Abella García, Ministerio de Economía y Competitividad, 01/01/2017-31/12/2019, 147.620 e. - ”Nuevos escenarios de tomografía por rayos X (NEXT) DPI2016-79075-R. Ministerio de Economía”, Industria y Competitividad. (Universidad Carlos III de Madrid). 30/12/2016-29/12/2019. 147.620 e. (…) - FP7-IMI-2012 (GA-115337), ”PreDict-TB: Model-based preclinical development of anti-tuberculosis drug combinations”. FP7-IMI - Seventh Framework Programme (EC-EFPIA). Unión Europea. (Universidad Carlos III de Madrid). 01/05/2012-31/10/2017. (…) - TEC2013-47270-R, ”Avances en Imagen Radiológica (AIR)”, Ministerio de Economía y Competitividad”, 01/01/2014-31/12/2016. IP: Mónica Abella Garcia and Manuel Desco Menéndez. 160.204 e (…) - RTC-2014-3028-1, ”Nuevos Escenarios Clínicos con Radiología Avanzada (NECRA)”, Ministerio de Economía y Competitividad, 01/06/2014-31/12/2016 IP: Mónica Abella García. 2014-2016. 219.458,96 e - IDI-20130301, ”Nuevo sistema integral de radiografía (INNPROVE: INNovative image PROcessing in medicine and VEterinary)”, IP: Mónica Abella García and Manuel Desco Menéndez. Ministerio de Economía y Competitividad. Subcontratación CDTI, 14/01/2013-31/03/2015. Total: 1.860.629e (UC3M: 325.000e). (Art. 83) - IPT-2012-0401-300000 INNPACTO 2012, ”Tecnologías para Procedimientos Intraoperatorios Seguros y Precisos. XIORT. MINECO. (Universidad Carlos III de Madrid). 01/01/2013-31/12/2015.Programa Oficial de Doctorado en Ingeniería MatemáticaPresidente: Doménec Ros Puig.- Secretario: Cyril Riddell.- Vocal: Yannick Boursie

Application of a novel CCD technology to medical imaging

This thesis describes an evaluation of a novel low light level charge couple device (L3CCD) technology. Two L3CCDs have been fully evaluated in terms of their signal and noise properties. The primary aim of this work is to identify the device characteristics that affect the overall performance. Conclusions have been made to this end and a prediction of the optimal performance in terms of the device sensitivity is made. Comparisons with other detectors suitable for use in medical imaging have shown that the L3CCD surpasses other detectors in specific performance characteristics and is comparable in others. The competitive performance of the L3CCD confirms that it may afford benefits in those areas in which the L3CCD has superior performance compared to other detectors. Two diagnostic imaging techniques which were identified as applications of L3CCD technology have been investigated. Linear systems analysis has been used to predict the performance of two L3CCD based imaging systems for use in fluoroscopic imaging. Comparison of the predicted performance of the two system with systems in clinical use show that an L3CCD coupled to an x-ray phosphor via a tapered fibre optic is a competitive alternative to present fluoroscopic imaging systems. Experimental validation of the model has confirmed this conclusion. An L3 detector has been designed, built and evaluated for diffraction enhanced breast imaging. To demonstrate the use of the L3 detector for diffraction enhanced breast imaging it has been used to acquire diffraction images of human breast tissue with cancerous inclusions. Measurements of scatter contrast confirm improvements in scatter contrast compared to transmission contrast. The successful demonstration of the L3CCDs ability to collect diagnostic information has shown that the L3CCD is suitable for diffraction enhanced breast imaging

Image enhancement in digital X-ray angiography

Anyone who does not look back to the beginning throughout a course of action, does not look forward to the end. Hence it necessarily follows that an intention which looks ahead, depends on a recollection which looks back. | Aurelius Augustinus, De civitate Dei, VII.7 (417 A.D.) Chapter 1 Introduction and Summary D espite the development of imaging techniques based on alternative physical phenomena, such as nuclear magnetic resonance, emission of single photons ( -radiation) by radio-pharmaceuticals and photon pairs by electron-positron annihilations, re ection of ultrasonic waves, and the Doppler eect, X-ray based im- age acquisition is still daily practice in medicine. Perhaps this can be attributed to the fact that, contrary to many other phenomena, X-rays lend themselves naturally for registration by means of materials and methods widely available at the time of their discovery | a fact that gave X-ray based medical imaging an at least 50-year head start over possible alternatives. Immediately after the preliminary communica- tion on the discovery of the \new light" by R¨ ontgen [317], late December 1895, the possible applications of X-rays were investigated intensively. In 1896 alone, almost one 1,000 articles about the new phenomenon appeared in print (Glasser [119] lists all of them). Although most of the basics of the diagnostic as well as the therapeutic uses of X-rays had been worked out by the end of that year [289], research on im- proved acquisition and reduction of potential risks for humans continued steadily in the century to follow. The development of improved X-ray tubes, rapid lm changers, image intensiers, the introduction of television cameras into uoroscopy, and com- puters in digital radiography and computerized tomography, formed a succession of achievements which increased the diagnostic potential of X-ray based imaging. One of the areas in medical imaging where X-rays have always played an im- portant role is angiography,y which concerns the visualization of blood vessels in the human body. As already suggested, research on the possibility of visualization of the human vasculature was initiated shortly after the discovery of X-rays. A photograph of a rst \angiogram" | obtained by injection of a mixture of chalk, red mercury, and petroleum into an amputated hand, followed by almost an hour of exposure to X-rays | was published as early as January 1896, by Hascheck & Lindenthal [139]. Although studies on cadavers led to greatly improved knowledge of the anatomy of the human vascular system, angiography in living man for the purpose of diagnosis and intervention became feasible only after substantial progress in the development yA term originating from the Greek words o (aggeion), meaning \vessel" or \bucket", and -' (graphein), meaning \to write" or \to record". 2 1 Introduction and Summary of relatively safe contrast media and methods of administration, as well as advance- ments in radiological equipment. Of special interest in the context of this thesis is the improvement brought by photographic subtraction, a technique known since the early 1900s and since then used successfully in e.g. astronomy, but rst introduced in X-ray angiography in 1934, by Ziedses des Plantes [425, 426]. This technique al- lowed for a considerable enhancement of vessel visibility by cancellation of unwanted background structures. In the 1960s, the time consuming lm subtraction process was replaced by analog video subtraction techniques [156, 275] which, with the in- troduction of digital computers, gave rise to the development of digital subtraction angiography [194] | a technique still considered by many the \gold standard" for de- tection and quantication of vascular anomalies. Today, research on improved X-ray based imaging techniques for angiography continues, witness the recent developments in three-dimensional rotational angiography [88, 185, 186, 341,373]. The subject of this thesis is enhancement of digital X-ray angiography images. In contrast with the previously mentioned developments, the emphasis is not on the further improvement of image acquisition techniques, but rather on the development and evaluation of digital image processing techniques for retrospective enhancement of images acquired with existing techniques. In the context of this thesis, the term \enhancement" must be regarded in a rather broad sense. It does not only refer to improvement of image quality by reduction of disturbing artifacts and noise, but also to minimization of possible image quality degradation and loss of quantitative information, inevitably introduced by required image processing operations. These two aspects of image enhancement will be claried further in a brief summary of each of the chapters of this thesis. The rst three chapters deal with the problem of patient motion artifacts in digital subtraction angiography (DSA). In DSA imaging, a sequence of 2D digital X-ray projection images is acquired, at a rate of e.g. two per second, following the injection of contrast material into one of the arteries or veins feeding the part of the vasculature to be diagnosed. Acquisition usually starts about one or two seconds prior to arrival of the contrast bolus in the vessels of interest, so that the rst few images included in the sequence do not show opacied vessels. In a subsequent post-processing step, one of these \pre-bolus" images is then subtracted automatically from each of the contrast images so as to mask out background structures such as bone and soft- tissue shadows. However, it is clear that in the resulting digital subtraction images, the unwanted background structures will have been removed completely only when the patient lied perfectly still during acquisition of the original images. Since most patients show at least some physical reaction to the passage of a contrast medium, this proviso is generally not met. As a result, DSA images frequently show patient-motion induced artifacts (see e.g. the bottom-left image in Fig. 1.1), which may in uence the subsequent analysis and diagnosis carried out by radiologists. Since the introduction of DSA, in the early 1980s, many solutions to the problem of patient motion artifacts have been put forward. Chapter 2 presents an overview of the possible types of motion artifacts reported in the literature and the techniques that have been proposed to avoid them. The main purpose of that chapter is to review and discuss the techniques proposed over the past two decades to correct for 1 Introduction and Summary 3 Figure 1.1. Example of creation and reduction of patient motion artifacts in cerebral DSA imaging. Top left: a \pre-bolus" or mask image acquired just prior to the arrival of the contrast medium. Top right: one of the contrast or live images showing opacied vessels. Bottom left: DSA image obtained after subtraction of the mask from the contrast image, followed by contrast enhancement. Due to patient motion, the background structures in the mask and contrast image were not perfectly aligned, as a result of which the DSA image does not only show blood vessels, but also additional undesired structures (in this example primarily in the bottom-left part of the image). Bottom right: DSA image resulting from subtraction of the mask and contast image after application of the automatic registration algorithm described in Chapter 3. 4 1 Introduction and Summary patient motion artifacts retrospectively, by means of digital image processing. The chapter addresses fundamental problems, such as whether it is possible to construct a 2D geometrical transformation that exactly describes the projective eects of an originally 3D transformation, as well as practical problems, such as how to retrieve the correspondence between mask and contrast images by using only the grey-level information contained in the images, and how to align the images according to that correspondence in a computationally ecient manner. The review in Chapter 2 reveals that there exists quite some literature on the topic of (semi-)automatic image alignment, or image registration, for the purpose of motion artifact reduction in DSA images. However, to the best of our knowledge, research in this area has never led to algorithms which are suciently fast and robust to be acceptable for routine use in clinical practice. By drawing upon the suggestions put forward in Chapter 2, a new approach to automatic registration of digital X-ray angiography images is presented in Chapter 3. Apart from describing the functionality of the components of the algorithm, special attention is paid to their computationally optimal implementation. The results of preliminary experiments described in that chapter indicate that the algorithm is eective, very fast, and outperforms alterna- tive approaches, in terms of both image quality and required computation time. It is concluded that the algorithm is most eective in cerebral and peripheral DSA imag- ing. An example of the image quality enhancement obtained after application of the algorithm in the case of a cerebral DSA image is provided in Fig 1.1. Chapter 4 reports on a clinical evaluation of the automatic registration technique. The evaluation involved 104 cerebral DSA images, which were corrected for patient motion artifacts by the automatic technique, as well as by pixel shifting | a manual correction technique currently used in clinical practice. The quality of the DSA images resulting from the two techniques was assessed by four observers, who compared the images both mutually and to the corresponding original images. The results of the evaluation presented in Chapter 4 indicate that the dierence in performance between the two correction techniques is statistically signicant. From the results of the mutual comparisons it is concluded that, on average, the automatic registration technique performs either comparably, better than, or even much better than manual pixel shifting in 95% of all cases. In the other 5% of the cases, the remaining artifacts are located near the borders of the image, which are generally diagnostically non-relevant. In addition, the results show that the automatic technique implies a considerable reduction of post-processing time compared to manual pixel shifting (on average, one second versus 12 seconds per DSA image). The last two chapters deal with somewhat dierent topics. Chapter 5 is concerned with visualization and quantication of vascular anomalies in three-dimensional rota- tional angiography (3DRA). Similar to DSA imaging, 3DRA involves the acquisition of a sequence of 2D digital X-ray projection images, following a single injection of contrast material. Contrary to DSA, however, this sequence is acquired during a 180 rotation of the C-arch on which the X-ray source and detector are mounted antipo- dally, with the object of interest positioned in its iso-center. The rotation is completed in about eight seconds and the resulting image sequence typically contains 100 images, which form the input to a ltered back-projection algorithm for 3D reconstruction. In contrast with most other 3D medical imaging techniques, 3DRA is capable of provid- 1 Introduction and Summary 5 Figure 1.2. Visualizations of a clinical 3DRA dataset, illustrating the qualitative improvement obtained after noise reduction ltering. Left: volume rendering of the original, raw image. Right: volume rendering of the image after application of edge-enhancing anisotropic diusion ltering (see Chapter 5 for a description of this technique). The visualizations were obtained by using the exact same settings for the parameters of the volume rendering algorithm. ing high-resolution isotropic datasets. However, due to the relatively high noise level and the presence of other unwanted background variations caused by surrounding tissue, the use of noise reduction techniques is inevitable in order to obtain smooth visualizations of these datasets (see Fig. 1.2). Chapter 5 presents an inquiry into the eects of several linear and nonlinear noise reduction techniques on the visualization and subsequent quantication of vascular anomalies in 3DRA images. The evalua- tion is focussed on frequently occurring anomalies such as a narrowing (or stenosis) of the internal carotid artery or a circumscribed dilation (or aneurysm) of intracra- nial arteries. Experiments on anthropomorphic vascular phantoms indicate that, of the techniques considered, edge-enhancing anisotropic diusion ltering is most suit- able, although the practical use of this technique may currently be limited due to its memory and computation-time requirements. Finally, Chapter 6 addresses the problem of interpolation of sampled data, which occurs e.g. when applying geometrical transformations to digital medical images for the purpose of registration or visualization. In most practical situations, interpola- tion of a sampled image followed by resampling of the resulting continuous image on a geometrically transformed grid, inevitably implies loss of grey-level information, and hence image degradation, the amount of which is dependent on image content, but also on the employed interpolation scheme (see Fig. 1.3). It follows that the choice for a particular interpolation scheme is important, since it in uences the re- sults of registrations and visualizations, and the outcome of subsequent quantitative analyses which rely on grey-level information contained in transformed images. Al- though many interpolation techniques have been developed over the past decades, 6 1 Introduction and Summary Figure 1.3. Illustration of the fact that the loss of information due to interpola- tion and resampling operations is dependent on the employed interpolation scheme. Left: slice of a 3DRA image after rotation over 5:0, by using linear interpolation. Middle: the same slice, after rotation by using cubic spline interpolation. Right: the dierence between the two rotated images. Although it is not possible with such a comparison to come to conclusions as to which of the two methods yields the smallest loss of grey-level information, this example clearly illustrates the point that dierent interpolation methods usually yield dierent results. thorough quantitative evaluations and comparisons of these techniques for medical image transformation problems are still lacking. Chapter 6 presents such a compar- ative evaluation. The study is limited to convolution-based interpolation techniques, as these are most frequently used for registration and visualization of medical image data. Because of the ubiquitousness of interpolation in medical image processing and analysis, the study is not restricted to XRA and 3DRA images, but also includes datasets from many other modalities. It is concluded that for all modalities, spline interpolation constitutes the best trade-o between accuracy and computational cost, and therefore is to be preferred over all other methods. In summary, this thesis is concerned with the improvement of image quality and the reduction of image quality degradation and loss of quantitative information. The subsequent chapters describe techniques for reduction of patient motion artifacts in DSA images, noise reduction techniques for improved visualization and quantication of vascular anomalies in 3DRA images, and interpolation techniques for the purpose of accurate geometrical transformation of medical image data. The results and con- clusions of the evaluations described in this thesis provide general guidelines for the applicability and practical use of these techniques

Investigation of 18F-Fluoro-L-Thymidine to monitor treatment response in murine models of pancreatic cancer: development of tools and validation

I characterised performance of the Positron Emission Tomography (PET) and the Computed Tomography (CT) modules of the 2-ring Albira PET/SPECT/CT, a small-animal imaging platform. The evaluation of PET was done in concordance with the National Electrical Manufacturer’s Association (NEMA) NU4-2008 standard. The performance of the Albira CT was assessed using microCT phantom. As a way of verification of the results of the phantom studies, example images from the tri-modal PET/SPECT/CT experiment were analysed. Additionally, gamma counter was evaluated as a tool for measuring biodistribution of the radiolabelled probes ex vivo. 18F-Fluoro-L-Thymidine (18F-FLT) was used in the investigation of the treatment response in the mouse models of pancreatic ductal adenocarcinoma (PDAC). Results from the two studies using mTOR and TGFβ inhibitors are reported. The mTOR inhibitor, rapamycin used 18F-FLT in the PET imaging to study, which aimed to compare the effects of the treatment on proliferation in two mouse models recapitulating the features of human PDAC, namely the KC Pten and KPC. TGFβ inhibitor study characterised the acute impact the administered TGFβ antibody has on proliferation in KPC mice in addition and as opposed to gemcitabine monotherapy, which is currently considered a golden standard in the treatment of pancreatic cancer. This study utilized gamma counting, autoradiography and Ki67 immunohistochemistry (IHC)