Image analysis for diagnostic support in biomedicine: neuromuscular diseases and pigmented lesions

Tesis descargada desde TESEOEsta tesis presenta dos sistemas implementados mediante técnicas de procesamiento de imagen, para ayuda al diagnóstico de enfermedades neuromusculares a partir de imágenes de microscopía de fluorescencia y análisis de lesiones pigmentadas a partir de imágenes dermoscópicas. El diagnóstico de enfermedades neuromusculares se basa en la evaluación visual de las biopsias musculares por parte del patólogo especialista, lo que conlleva una carga subjetiva. El primer sistema propuesto en esta tesis analiza objetivamente las biopsias musculares y las clasifica en distrofias, atrofias neurógenas o control (sin enfermedad) a través de imágenes de microscopía de fluorescencia. Su implementación reúne los elementos propios de un sistema de ayuda al diagnóstico asistido por ordenador: segmentación, extracción de características, selección de características y clasificación. El procedimiento comienza con una segmentación precisa de las fibras musculares usando morfología matemática y una transformada Watershed. A continuación, se lleva a cabo un paso de extracción de características, en el cual reside la principal contribución del sistema, ya que no solo se extraen aquellas que los patólogos tienen en cuenta para diagnosticar sino características que se escapan de la visión humana. Estas nuevas características se extraen suponiendo que la estructura de la biopsia se comporta como un grafo, en el que los nodos se corresponden con las fibras musculares, y dos nodos están conectados si dos fibras son adyacentes. Para estudiar la efectividad que estos dos conjuntos presentan en la categorización de las biopsias, se realiza una selección de características y una clasi- ficación empleando una red neuronal Fuzzy ARTMAP. El procedimiento concluye con una estimación de la severidad de las biopsias con patrón distrófico. Esta caracterización se realiza mediante un análisis de componentes principales. Para la validación del sistema se ha empleado una base de datos compuesta por 91 imágenes de biopsias musculares, de las cuales 71 se consideran imágenes de entrenamiento y 20 imágenes de prueba. Se consigue una elevada tasa de aciertos de clasificacion y se llega a la importante conclusión de que las nuevas características estructurales que no pueden ser detectadas por inspección visual mejoran la identificación de biopsias afectadas por atrofia neurógena. La segunda parte de la tesis presenta un sistema de clasificación de lesiones pigmentadas. Primero se propone un algoritmo de segmentación de imágenes en color para ais lar la lesión de la piel circundante. Su desarrollo se centra en conseguir un algoritmo relacionado con las diferencias color percibidas por el ojo humano. Consiguiendo así, no solo un método de segmentación de lesiones pigmentadas sino un algoritmo de segmentación de propósito general. El método de segmentación propuesto se basa en un gradiente para imágenes en color integrado en una técnica de level set para detección de bordes. La elección del gradiente se derivada a partir de un análisis de tres gradientes de color implementados en el espacio de color uniforme CIE L∗a∗b∗ y basados en las ecuaciones de diferencia de color desarrolladas por la comisión internacional de iluminación (CIELAB, CIE94 y CIEDE2000). El principal objetivo de este análisis es estudiar cómo estas ecuaciones afectan en la estimación de los gradientes en términos de correlación con la percepción visual del color. Una técnica de level-set se aplica sobre estos gradientes consiguiendo así un detector de borde que permite evaluar el rendimiento de dichos gradientes. La validación se lleva a cabo sobre una base de datos compuesta por imágenes sintéticas diseñada para tal fin. Se realizaron tanto medidas cuantitativas como cualitativas. Finalmente, se concluye que el detector de bordes basado en la ecuación de diferencias de color CIE94 presenta la mayor correlación con la percepción visual del color. A partir de entonces, la tesis intenta emular el método de análisis de patrones, la técnica de diagnóstico de lesiones pigmentadas de la piel más empleada por los dermatólogos. Este método trata de identificar patrones específicos, pudiendo ser tanto globales como locales. En esta tesis se presenta una amplia revisión de los métodos algorítmicos, publicados en la literatura, que detectan automáticamente dichos patrones a partir de imágenes dermoscópicas de lesiones pigmentadas. Tras esta revisón se advierte que numerosos trabajos se centran en la detección de patrones locales, pero solo unos pocos abordan la detección de patrones globales. El siguiente paso de esta tesis, por tanto, es la propuesta de diferentes métodos de clasi- ficación de patrones globales. El objetivo es identificar tres patrones: reticular, globular y empedrado (considerado un solo patrón) y homogéneo. Los métodos propuestos se basan en un análisis de textura mediante técnicas de modelado. En primer lugar una imagen demoscópica se modela mediante campos aleatorios de Markov, los parámetros estimados de este modelo se consideran características. A su vez, se supone que la distribución de estas características a lo largo de la lesión sigue diferentes modelos: un modelo gaussiano, un modelo de mezcla de gaussianas o un modelo de bolsa de características. La clasificación se lleva a cabo mediante una recuperación de imágenes basada en diferentes métricas de distancia. Para validar los métodos se emplea un conjunto significativo de imágenes dermatológicas, concluyendo que el modelo basado en mezcla de gaussianas proporciona la mejor tasa de clasificación. Además, se incluye una evaluación adicional en la que se clasifican melanomas con patrón multicomponente obteniendo resultados prometedores. Finalmente, se presenta una discusión sobre los hallazgos y conclusiones más relevantes extraídas de esta tesis, así como las líneas futuras que se derivan de este trabajo.Premio Extraordinario de Doctorado U

Development of Fast, Distributed Computational Schemes for Full Body Bio-Models and Their Application to Novel Action Potential Block in Nerves Using Ultra-Short, High Intensity Electric Pulses

An extremely robust and novel scheme for computing three-dimensional, time-dependent potential distributions in full body bio-models is proposed, which, to the best of our knowledge, is the first of its kind. This simulation scheme has been developed to employ distributed computation resources, to achieve a parallelized numerical implementation for enhanced speed and memory capability. The other features of the numerical bio-model included in this dissertation research, are the ability to incorporate multiple electrodes of varying shapes and arbitrary locations. The parallel numerical tool also allows for user defined, current or potential stimuli as the excitation input. Using the available computation resources at the university, a strong capability for extremely large bio-models was developed. So far a maximum simulation comprised of 6.7 million nodes has been achieved for a full rat bio-model with a 1 mm spatial resolution at an average of 30 seconds per iteration. The ability to compute the resulting potential distribution in a full animal body allows for realistic and accurate studies of bio-responses to electrical stimuli. For example, the voltages computed from the full-body models at various sites and tissue locations could be used to examine the potential for using nanosecond, high-intensity, pulsed electric fields for blocking neural action or action potential (AP) propagation. This would be a novel, localized, and reversible method of controlling neural function without tissue damage. It could potentially be used in electrically managed pain relief, non-lethal incapacitation, and neural/muscular therapy. The above concept has quantitatively been evaluated in this dissertation. Specifically, the effects of high-intensity (kilo-Volt), ultra-short (∼100 nanosecond) electrical pulses have been evaluated, and compared with available experimental data. Good agreement with available data is demonstrated. It is also shown that nerve membrane electroporation, brought about by the high-intensity, external pulsing, could indeed be instrumental in halting AP propagation. Simulations based on a modified distributed cable model to represent nerve segments have been used to demonstrate a numerical proof-of-concept

Characterising pattern asymmetry in pigmented skin lesions

Abstract. In clinical diagnosis of pigmented skin lesions asymmetric pigmentation is often indicative of melanoma. This paper describes a method and measures for characterizing lesion symmetry. The estimate of mirror symmetry is computed first for a number of axes at different degrees of rotation with respect to the lesion centre. The statistics of these estimates are the used to assess the overall symmetry. The method is applied to three different lesion representations showing the overall pigmentation, the pigmentation pattern, and the pattern of dermal melanin. The best measure is a 100% sensitive and 96% specific indicator of melanoma on a test set of 33 lesions, with a separate training set consisting of 66 lesions

Exploring 3D Shapes through Real Functions

This thesis lays in the context of research on representation, modelling and coding knowledge related to digital shapes, where by shape it is meant any individual object having a visual appareance which exists in some two-, three- or higher dimensional space. Digital shapes are digital representations of either physically existing or virtual objects that can be processed by computer applications. While the technological advances in terms of hardware and software have made available plenty of tools for using and interacting with the geometry of shapes, to manipulate and retrieve huge amount of data it is necessary to define methods able to effectively code them. In this thesis a conceptual model is proposed which represents a given 3D object through the coding of its salient features and defines an abstraction of the object, discarding irrelevant details. The approach is based on the shape descriptors defined with respect to real functions, which provide a very useful shape abstraction method for the analysis and structuring of the information contained in the discrete shape model. A distinctive feature of these shape descriptors is their capability of combining topological and geometrical information properties of the shape, giving an abstraction of the main shape features. To fully develop this conceptual model, both theoretical and computational aspects have been considered, related to the definition and the extension of the different shape descriptors to the computational domain. Main emphasis is devoted to the application of these shape descriptors in computational settings; to this aim we display a number of application domains that span from shape retrieval, to shape classification and to best view selection.Questa tesi si colloca nell\u27ambito di ricerca riguardante la rappresentazione, la modellazione e la codifica della conoscenza connessa a forme digitali, dove per forma si intende l\u27aspetto visuale di ogni oggetto che esiste in due, tre o pi? dimensioni. Le forme digitali sono rappresentazioni di oggetti sia reali che virtuali, che possono essere manipolate da un calcolatore. Lo sviluppo tecnologico degli ultimi anni in materia di hardware e software ha messo a disposizione una grande quantit? di strumenti per acquisire, rappresentare e processare la geometria degli oggetti; tuttavia per gestire questa grande mole di dati ? necessario sviluppare metodi in grado di fornirne una codifica efficiente. In questa tesi si propone un modello concettuale che descrive un oggetto 3D attraverso la codifica delle caratteristiche salienti e ne definisce una bozza ad alto livello, tralasciando dettagli irrilevanti. Alla base di questo approccio ? l\u27utilizzo di descrittori basati su funzioni reali in quanto forniscono un\u27astrazione della forma molto utile per analizzare e strutturare l\u27informazione contenuta nel modello discreto della forma. Una peculiarit? di tali descrittori di forma ? la capacit? di combinare propriet? topologiche e geometriche consentendo di astrarne le principali caratteristiche. Per sviluppare questo modello concettuale, ? stato necessario considerare gli aspetti sia teorici che computazionali relativi alla definizione e all\u27estensione in ambito discreto di vari descrittori di forma. Particolare attenzione ? stata rivolta all\u27applicazione dei descrittori studiati in ambito computazionale; a questo scopo sono stati considerati numerosi contesti applicativi, che variano dal riconoscimento alla classificazione di forme, all\u27individuazione della posizione pi? significativa di un oggetto

Positron Emission Tomography for the dose monitoring of intra-fractionally moving Targets in ion beam therapy

Ion beam therapy (IBT) is a promising treatment option in radiotherapy. The characteristic physical and biological properties of light ion beams allow for the delivery of highly tumour conformal dose distributions. Related to the sparing of surrounding healthy tissue and nearby organs at risk, it is feasible to escalate the dose in the tumour volume to reach higher tumour control and survival rates. Remarkable clinical outcome was achieved with IBT for radio-resistant, deep-seated, static and well fixated tumour entities. Presumably, more patients could benefit from the advantages of IBT if it would be available for more frequent tumour sites. Those located in the thorax and upper abdominal region are commonly subjected to intra-fractional, respiration related motion. Different motion compensated dose delivery techniques have been developed for active field shaping with scanned pencil beams and are at least available under experimental conditions at the GSI Helmholtzzentrum für Schwerionenforschung (GSI) in Darmstadt, Germany. High standards for quality assurance are required in IBT to ensure a safe and precise dose application. Both underdosage in the tumour and overdosage in the normal tissue might endanger the treatment success. Since minor unexpected anatomical changes e.g. related to patient mispositioning, tumour shrinkage or tissue swelling could already lead to remarkable deviations between planned and delivered dose distribution, a valuable dose monitoring system is desired for IBT. So far, positron emission tomography (PET) is the only in vivo, in situ and non-invasive qualitative dose monitoring method applied under clinical conditions. It makes use of the tissue autoactivation by nuclear fragmentation reactions occurring along the beam path. Among others, +-emitting nuclides are generated and decay according to their half-life under the emission of a positron. The subsequent positron-electron annihilation creates two 511 keV photons which are emitted in opposite direction and can be detected as coincidence event by a dedicated PET scanner. The induced three-dimensional (3D) +- activity distribution in the patient can be reconstructed from the measured coincidences. Conclusions about the delivered dose distribution can be drawn indirectly from a comparison between two +-activity distributions: the measured one and an expected one generated by a Monte-Carlo simulation. This workflow has been proven to be valuable for the dose monitoring in IBT when it was applied for about 440 patients, mainly suffering from deep-seated head and neck tumours that have been treated with 12C ions at GSI. In the presence of intra-fractional target motion, the conventional 3D PET data processing will result in an inaccurate representation of the +-activity distribution in the patient. Fourdimensional, time-resolved (4D) reconstruction algorithms adapted to the special geometry of in-beam PET scanners allow to compensate for the motion related blurring artefacts. Within this thesis, a 4D maximum likelihood expectation maximization (MLEM) reconstruction algorithm has been implemented for the double-head scanner Bastei installed at GSI. The proper functionality of the algorithm and its superior performance in terms of suppressing motion related blurring artefacts compared to an already applied co-registration approach has been demonstrated by a comparative simulation study and by dedicated measurements with moving radioactive sources and irradiated targets. Dedicated phantoms mainly made up of polymethyl methacrylate (PMMA) and a motion table for regular one-dimensional (1D) motion patterns have been designed and manufactured for the experiments. Furthermore, the general applicability of the 4D MLEM algorithm for more complex motion patterns has been demonstrated by the successful reduction of motion artefacts from a measurement with rotating (two-dimensional moving) radioactive sources. For 1D cos2 and cos4 motion, it has been clearly illustrated by systematic point source measurements that the motion influence can be better compensated with the same number of motion phases if amplitudesorted instead of time-sorted phases are utilized. In any case, with an appropriate parameter selection to obtain a mean residual motion per phase of about half of the size of a PET crystal size, acceptable results have been achieved. Additionally, it has been validated that the 4D MLEM algorithm allows to reliably access the relevant parameters (particle range and lateral field position and gradients) for a dose verification in intra-fractionally moving targets even from the intrinsically low counting statistics of IBT-PET data. To evaluate the measured +-activity distribution, it should be compared to a simulated one that is expected from the moving target irradiation. Thus, a 4D version of the simulation software is required. It has to emulate the generation of +-emitters under consideration of the intra-fractional motion, their decay at motion state dependent coordinates and to create listmode data streams from the simulated coincidences. Such a revised and extended version that has been compiled for the special geometry of the Bastei PET scanner is presented within this thesis. The therapy control system provides information about the exact progress of the motion compensated dose delivery. This information and the intra-fractional target motion needs to be taken into account for simulating realistic +-activity distributions. A dedicated preclinical phantom simulation study has been performed to demonstrate the correct functionality of the 4D simulation program and the necessity of the additional, motionrelated input parameters. Different to the data evaluation for static targets, additional effort is required to avoid a potential misleading interpretation of the 4D measured and simulated +-activity distributions in the presence of deficient motion mitigation or data processing. It is presented that in the presence of treatment errors the results from the simulation might be in accordance to the measurement although the planned and delivered dose distribution are different. In contrast to that, deviations may occur between both distributions which are not related to anatomical changes but to deficient 4D data processing. Recommendations are given in this thesis to optimize the 4D IBT-PET workflow and to prevent the observer from a mis-interpretation of the dose monitoring data. In summary, the thesis contributes on a large scale to a potential future application of the IBT-PET monitoring for intra-fractionally moving target volumes by providing the required reconstruction and simulation algorithms. Systematic examinations with more realistic, multi-directional and irregular motion patterns are required for further improvements. For a final rating of the expectable benefit from a 4D IBT-PET dose monitoring, future investigations should include real treatment plans, breathing curves and 4D patient CT images

Applications of Medical Physics

Applications of Medical Physics” is a Special Issue of Applied Sciences that has collected original research manuscripts describing cutting-edge physics developments in medicine and their translational applications. Reviews providing updates on the latest progresses in this field are also included. The collection includes a total of 20 contributions by authors from 9 different countries, which cover several areas of medical physics, spanning from radiation therapy, nuclear medicine, radiology, dosimetry, radiation protection, and radiobiology

Positron emission tomography for the dose monitoring of intra-fractionally moving targets in ion beam therapy

Ion beam therapy (IBT) is a promising treatment option in radiotherapy. The characteristic physical and biological properties of light ion beams allow for the delivery of highly tumour conformal dose distributions. Related to the sparing of surrounding healthy tissue and nearby organs at risk, it is feasible to escalate the dose in the tumour volume to reach higher tumour control and survival rates. Remarkable clinical outcome was achieved with IBT for radio-resistant, deep-seated, static and well fixated tumour entities. Presumably, more patients could benefit from the advantages of IBT if it would be available for more frequent tumour sites. Those located in the thorax and upper abdominal region are commonly subjected to intra-fractional, respiration related motion. Different motion compensated dose delivery techniques have been developed for active field shaping with scanned pencil beams and are at least available under experimental conditions at the GSI Helmholtzzentrum für Schwerionenforschung (GSI) in Darmstadt, Germany. High standards for quality assurance are required in IBT to ensure a safe and precise dose application. Both underdosage in the tumour and overdosage in the normal tissue might endanger the treatment success. Since minor unexpected anatomical changes e.g. related to patient mispositioning, tumour shrinkage or tissue swelling could already lead to remarkable deviations between planned and delivered dose distribution, a valuable dose monitoring system is desired for IBT. So far, positron emission tomography (PET) is the only in vivo, in situ and non-invasive qualitative dose monitoring method applied under clinical conditions. It makes use of the tissue autoactivation by nuclear fragmentation reactions occurring along the beam path. Among others, β+-emitting nuclides are generated and decay according to their half-life under the emission of a positron. The subsequent positron-electron annihilation creates two 511 keV photons which are emitted in opposite direction and can be detected as coincidence event by a dedicated PET scanner. The induced three-dimensional (3D) β+-activity distribution in the patient can be reconstructed from the measured coincidences. Conclusions about the delivered dose distribution can be drawn indirectly from a comparison between two β+-activity distributions: the measured one and an expected one generated by a Monte-Carlo simulation. This workflow has been proven to be valuable for the dose monitoring in IBT when it was applied for about 440 patients, mainly suffering from deep-seated head and neck tumours that have been treated with 12C ions at GSI. In the presence of intra-fractional target motion, the conventional 3D PET data processing will result in an inaccurate representation of the β+-activity distribution in the patient. Four-dimensional, time-resolved (4D) reconstruction algorithms adapted to the special geometry of in-beam PET scanners allow to compensate for the motion related blurring artefacts. Within this thesis, a 4D maximum likelihood expectation maximization (MLEM) reconstruction algorithm has been implemented for the double-head scanner Bastei installed at GSI. The proper functionality of the algorithm and its superior performance in terms of suppressing motion related blurring artefacts compared to an already applied co-registration approach has been demonstrated by a comparative simulation study and by dedicated measurements with moving radioactive sources and irradiated targets. Dedicated phantoms mainly made up of polymethyl methacrylate (PMMA) and a motion table for regular one-dimensional (1D) motion patterns have been designed and manufactured for the experiments. Furthermore, the general applicability of the 4D MLEM algorithm for more complex motion patterns has been demonstrated by the successful reduction of motion artefacts from a measurement with rotating (two-dimensional moving) radioactive sources. For 1D cos^2 and cos^4 motion, it has been clearly illustrated by systematic point source measurements that the motion influence can be better compensated with the same number of motion phases if amplitude-sorted instead of time-sorted phases are utilized. In any case, with an appropriate parameter selection to obtain a mean residual motion per phase of about half of the size of a PET crystal size, acceptable results have been achieved. Additionally, it has been validated that the 4D MLEM algorithm allows to reliably access the relevant parameters (particle range and lateral field position and gradients) for a dose verification in intra-fractionally moving targets even from the intrinsically low counting statistics of IBT-PET data. To evaluate the measured β+-activity distribution, it should be compared to a simulated one that is expected from the moving target irradiation. Thus, a 4D version of the simulation software is required. It has to emulate the generation of β+-emitters under consideration of the intra-fractional motion, their decay at motion state dependent coordinates and to create listmode data streams from the simulated coincidences. Such a revised and extended version that has been compiled for the special geometry of the Bastei PET scanner is presented within this thesis. The therapy control system provides information about the exact progress of the motion compensated dose delivery. This information and the intra-fractional target motion needs to be taken into account for simulating realistic β+-activity distributions. A dedicated preclinical phantom simulation study has been performed to demonstrate the correct functionality of the 4D simulation program and the necessity of the additional, motion-related input parameters. Different to the data evaluation for static targets, additional effort is required to avoid a potential misleading interpretation of the 4D measured and simulated β+-activity distribu- tions in the presence of deficient motion mitigation or data processing. It is presented that in the presence of treatment errors the results from the simulation might be in accordance to the measurement although the planned and delivered dose distribution are different. In contrast to that, deviations may occur between both distributions which are not related to anatomical changes but to deficient 4D data processing. Recommendations are given in this thesis to optimize the 4D IBT-PET workflow and to prevent the observer from a mis-interpretation of the dose monitoring data. In summary, the thesis contributes on a large scale to a potential future application of the IBT-PET monitoring for intra-fractionally moving target volumes by providing the required reconstruction and simulation algorithms. Systematic examinations with more realistic, multi-directional and irregular motion patterns are required for further improvements. For a final rating of the expectable benefit from a 4D IBT-PET dose monitoring, future investigations should include real treatment plans, breathing curves and 4D patient CT images.:1 Motivation 1.1 Potential and obstacles of ion beam therapy 1.2 Objectives of the thesis 2 Ion beam therapy and moving targets 2.1 Physical and biological properties of ion beams 2.1.1 Dose deposition 2.1.2 Biological effectivity 2.2 Technical aspects of ion beam delivery 2.2.1 Active and passive beam delivery technique 2.2.2 Beam monitoring for pencil beam scanning 2.2.3 Considerations in treatment planning related to patient CT image 2.3 Organ motion in ion beam therapy 2.3.1 Types of organ motion 2.3.2 Detection of intra-fractional motion 2.3.3 Motion compensated ion beam therapy 2.4 Dose monitoring by means of positron emission tomography 2.4.1 Principle of PET imaging in ion beam therapy 2.4.2 In-beam PET at GSI 3 Reconstruction of in-beam PET data taken from moving targets 3.1 Reconstruction algorithm 3.1.1 3D MLEM reconstruction applied at GSI 3.1.2 4D in-beam PET reconstruction methods 3.1.3 Comparison of gated co-registration and 4D MLEM 3.2 Experiments with moving radioactive sources 3.2.1 Rotation of radioactive sources 3.2.2 One-dimensional point source motion 3.3 In-beam PET measurements with moving targets 3.3.1 Verification of lateral field position and gradients 3.3.2 Verification of particle range 3.4 Summary and discussion 4 Simulation of phase-sorted in-beam PET data for moving targets 4.1 Upgrading the IBT-PET simulation from 3D to 4D 4.1.1 General and motion-related simulation demands 4.1.2 Input parameters for the 4D simulation program 4.1.3 Workflow of the 4D simulation program 4.2 Verification of the 4D simulation code by means of a preclinical phantom study 4.2.1 Experiment design 4.2.2 4D in-beam PET data simulation 4.2.3 Comparison with 3D simulation 4.3 Summary and discussion 5 Interpretation of 4D IBT-PET data with respect to deficient motion mitigation or data processing 5.1 Detectability of failed motion mitigation 5.1.1 Failure in gated beam delivery 5.1.2 Failure in lateral target tracking 5.2 Deficient correlation between motion and PET data 5.3 Recommendations for the 4D IBT-PET workflow 6 Summary and outlook 7 Appendix A Transformation matrices A.1 Composition of transformation matrices A.2 Storage of transformation matrices A.3 Transformation matrices for rotation B Noise reduction in analogue signals by FFT-based filtering C Motion tables and corresponding motion patterns C.1 Rotational motion C.2 Motion table with stepping motor for precise 1D motion patterns C.3 Motion table enabling relative target movement D Synchronisation of PET, motion and beam monitoring data E Sorting PET data by time or amplitude and calculating corresponding mean offsets BibliographyDie Ionenstrahltherapie (englisch: ion beam therapy, IBT) ist eine vielversprechende Behandlungsoption im Bereich der Strahlentherapie. Die charakteristischen physikalischen und biologischen Eigenschaften der Ionenstrahlen werden genutzt, um tumorkonformale Dosisverteilungen zu erzeugen. Die verbesserte Schonung des an den Tumor angrenzenden Normalgewebes und eventuell naheliegender Risikoorgane ermöglicht eine Dosissteigerung im Zielgebiet und somit potentiell höhere Tumorkontroll- und Überlebensraten. Für tiefliegende, gegenüber konventioneller Strahlung resistente, statische und gut fixierte Tumore wurden bereits beachtliche klinische Resultate erzielt. Wahrscheinlich könnten noch mehr Patienten von den Vorteilen der IBT profitieren, wenn diese auch für häufiger auftretende und intrafraktionell bewegliche Tumore uneingeschränkt nutzbar wäre. Verschiedene bewegungskompensierte Bestrahlungsmethoden wurden entwickelt und stehen zumindest unter experimentellen Bedingungen für weitere Untersuchungen am GSI Helmholtzzentrum für Schwerionenforschung (GSI) in Darmstadt zur Verfügung. Um eine sichere und präzise Dosisapplikation in der IBT zu ermöglichen, werden hohe Anforderungen an die Qualitätssicherung gesetzt. Sowohl auftretende Überdosierungen im Normalgewebe als auch Unterdosierungen im Tumor können den Therapieerfolg gefährden. Da bereits kleine, unerwartete anatomische Veränderungen, zum Beispiel durch Fehlpositionierung des Patienten, Schrumpfung des Tumors oder Schwellungen, zu erheblichen Abweichungen zwischen geplanter und applizierter Dosisverteilung führen können, gibt es Bestrebungen, die applizierte Dosis zumindest qualitativ zu verifizieren. Die Positronen-Emissions-Tomografie (PET) ist derzeit die einzige, bereits klinisch erprobte Methode für ein in vivo, in situ und nicht-invasives qualitatives Dosismonitoring. Diese Methode ist im Stande, die Autoaktivierung des bestrahlten Gewebes zu erfassen, welche aufgrund von Kernfragmentierungsprozessen entlang des Strahlweges erzeugt wird. Unter anderem werden in diesen Reaktionen instabile Nuklide erzeugt, die entsprechend ihrer Halbwertszeit unter Emission eines Positrons zerfallen. Bei der anschließenden Positron-Elektron-Annihilation werden zwei 511keV Photonen in entgegengesetzter Richtung emittiert und können mittels eines geeigneten PET-Scanners als Koinzidenzereignis detektiert werden. Die im Patienten induzierte dreidimensionale (3D) β+-Aktivitätsverteilung kann aus den gemessenen Koinzidenzen rekonstruiert werden. Ein Vergleich der gemessenen mit einer erwarteten, mittels Monte-Carlo Simulation erzeugten β+-Aktivitätsverteilung erlaubt es, Schlussfolgerungen über die tatsächlich im Patienten deponierte 3D Dosisverteilung zu ziehen. Diese Art der Datenauswertung wurde erfolgreich für die qualitative Dosisverifikation von über 440 Patienten eingesetzt, deren Tumore (vorwiegend im Kopf- und Halsbereich) an der GSI mit 12C-Ionen bestrahlt wurden. Bei der konventionellen 3D IBT-PET-Datenverarbeitung wird eine mögliche intrafraktionelle Bewegung des Zielgebietes nicht berücksichtigt und fehlerhaft rekonstruierte β+-Aktivitätsverteilungen sind die Folge. Daher werden vierdimensionale, zeitaufgelöste (4D) Rekonstruktionsalgorithmen benötigt, die für die spezielle Geometrie eines in-beam PET-Scanner adaptiert wurden und eine Kompensation der bewegungsinduzierten Artefakte ermöglichen. Im Rahmen der vorliegenden Arbeit wurde für den an der GSI installierten Doppelkopf-PET-Scanner Bastei ein 4D Maximum-Likelihood-Expectation-Maximization (MLEM) Algorithmus implementiert. Die Funktionsfähigkeit des Algorithmus sowie dessen verbesserte Reduktion von Bewegungsartefakten im Vergleich zu einem bereits vorhandenen Koregistrierungsansatz wurde anhand verschiedener Messungen mit bewegten radioaktiven Quellen und bestrahlten Phantomen sowie einer vergleichenden Simulationsstudie dargelegt. Für die Experimente wurden entsprechende Phantomgeometrien (zumeist aus Polymethylmethacrylat (PMMA)) sowie ein Bewegungstisch für reguläre eindimensionale (1D) Bewegungsmuster entworfen und gefertigt. Zudem wurde durch die erfolgreiche, quasi-statische und nahezu artefaktfreie Rekonstruktion einer rotierenden und sich damit zweidimensional bewegenden Aktivitätsverteilung die prinzipielle Anwendbarkeit des 4D MLEM Algorithmus für komplexere Bewegungsmuster gezeigt. Systematische Punktquellenmessungen mit 1D cos^2- und cos^4-förmigen Bewegungsmustern haben deutlich gemacht, dass der Bewegungseinfluss mit der gleichen Anzahl an Bewegungsphasen besser kompensiert werden kann, wenn die Bewegungsphasen entsprechend der Bewegungsamplitude anstelle der -phase unterteilt sind. In jedem Fall können aber zufriedenstellende Rekonstruktionsergebnisse erzielt werden, wenn durch geeignete Parameterwahl eine mittlere Restbewegung pro Bewegungsphase von maximal etwa der halben Größe eines Detektorkristalls eingestellt wird. Durch weitere Experimente konnte gezeigt werden, dass nach der Rekonstruktion mit dem 4D MLEM Algorithmus die relevanten Parameter für die qualitative Dosisverifikation (Teilchenreichweite, laterale Feldposition und -gradienten) zuverlässig erfasst werden können. Dies ist auch dann der Fall, wenn nur eine verminderte Anzahl an Koinzidenzereignissen, so wie sie unter klinischen Bedingungen zu erwarten ist, für die Auswertung verwendet wird. Um die gemessene β+-Aktivitätsverteilung besser zu beurteilen, sollte sie mit einer simulierten, für die bewegungskompensierte Bestrahlung erwarteten Verteilung verglichen werden und es bedarf deshalb einer 4D Version der Simulationssoftware. Diese muss die Erzeugung sowie den Zerfall der Positronenemitter unter Berücksichtigung der intrafraktionellen Bewegung simulieren und aus den gültigen Koinzidenzereignissen Listmode-Datensätze erstellen. Eine derart überarbeitet Version des Simulationsprogramms wurde für den Bastei PET-Scanner erstellt und wird in dieser Arbeit vorgestellt. Informationen über den exakten Verlauf der bewegungskompensierten Bestrahlung werden durch das Therapiekontrollsystem geliefert. Diese Informationen sowie die intrafraktionelle Bewegung werden in die Simulation realistischer β+-Aktivitätsverteilungen bzw. der zugehörigen Listmode-Datensätze einbezogen. Anhand einer präklinischen Phantom-Simulationsstudie wurde die korrekte Funktionsweise des Simulationsprogramms sowie die Notwendigkeit der zusätzlichen Parameter gezeigt. Im Gegensatz zur Datenauswertung für statische Zielvolumina bedarf es bei intrafraktioneller Bewegung gegebenenfalls zusätzlichen Aufwand, um eine Fehlinterpretation aus dem Vergleich der gemessenen und simulierten β+-Aktivitätsverteilung zu vermeiden. In der vorliegenden Arbeit wird beispielhaft gezeigt, dass sich bei fehlerhafter Bewegungskompensation die gemessene und simulierte β+-Aktivitätsverteilung einander ähneln können, obwohl die applizierte Dosisverteilung deutlich von der geplanten abweicht. Im Gegensatz dazu können auch Abweichungen zwischen Messung und Simulation auftreten, die nicht auf anatomische Veränderungen, sondern auf eine ungenaue 4D Datenverarbeitung zurückzuführen sind. Es werden Vorschläge unterbreitet, um den Prozess der 4D IBT-PET Datenauswertung zu optimieren und somit Fehlinterpretationen zu vermeiden. Die vorliegende Dissertationsschrift enthält durch die Bereitstellung der benötigten 4D Rekonstruktions- und Simulationsprogramme grundlegende Arbeiten für eine mögliche zukünftige Anwendung der 4D IBT-PET als qualitatives Dosismonitoring bei intrafraktionell bewegten Zielvolumina. Für weitere Verbesserungen des Verfahrens sind zusätzliche systematische Betrachtungen mit realistischeren, mehrdimensionalen und unregelmäßigen Bewegungsmustern notwendig. Zukünftige Untersuchungen sollten außerdem echte Bestrahlungspläne, Atemkurven sowie 4D Patienten-CT-Daten einschließen, um den erwartbaren Nutzen eines 4D IBT-PET Dosismonitorings besser abschätzen zu können.:1 Motivation 1.1 Potential and obstacles of ion beam therapy 1.2 Objectives of the thesis 2 Ion beam therapy and moving targets 2.1 Physical and biological properties of ion beams 2.1.1 Dose deposition 2.1.2 Biological effectivity 2.2 Technical aspects of ion beam delivery 2.2.1 Active and passive beam delivery technique 2.2.2 Beam monitoring for pencil beam scanning 2.2.3 Considerations in treatment planning related to patient CT image 2.3 Organ motion in ion beam therapy 2.3.1 Types of organ motion 2.3.2 Detection of intra-fractional motion 2.3.3 Motion compensated ion beam therapy 2.4 Dose monitoring by means of positron emission tomography 2.4.1 Principle of PET imaging in ion beam therapy 2.4.2 In-beam PET at GSI 3 Reconstruction of in-beam PET data taken from moving targets 3.1 Reconstruction algorithm 3.1.1 3D MLEM reconstruction applied at GSI 3.1.2 4D in-beam PET reconstruction methods 3.1.3 Comparison of gated co-registration and 4D MLEM 3.2 Experiments with moving radioactive sources 3.2.1 Rotation of radioactive sources 3.2.2 One-dimensional point source motion 3.3 In-beam PET measurements with moving targets 3.3.1 Verification of lateral field position and gradients 3.3.2 Verification of particle range 3.4 Summary and discussion 4 Simulation of phase-sorted in-beam PET data for moving targets 4.1 Upgrading the IBT-PET simulation from 3D to 4D 4.1.1 General and motion-related simulation demands 4.1.2 Input parameters for the 4D simulation program 4.1.3 Workflow of the 4D simulation program 4.2 Verification of the 4D simulation code by means of a preclinical phantom study 4.2.1 Experiment design 4.2.2 4D in-beam PET data simulation 4.2.3 Comparison with 3D simulation 4.3 Summary and discussion 5 Interpretation of 4D IBT-PET data with respect to deficient motion mitigation or data processing 5.1 Detectability of failed motion mitigation 5.1.1 Failure in gated beam delivery 5.1.2 Failure in lateral target tracking 5.2 Deficient correlation between motion and PET data 5.3 Recommendations for the 4D IBT-PET workflow 6 Summary and outlook 7 Appendix A Transformation matrices A.1 Composition of transformation matrices A.2 Storage of transformation matrices A.3 Transformation matrices for rotation B Noise reduction in analogue signals by FFT-based filtering C Motion tables and corresponding motion patterns C.1 Rotational motion C.2 Motion table with stepping motor for precise 1D motion patterns C.3 Motion table enabling relative target movement D Synchronisation of PET, motion and beam monitoring data E Sorting PET data by time or amplitude and calculating corresponding mean offsets Bibliograph