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.

Die Strahlentherapie ist einer der drei Partner im interdisziplinären Feld der Onkologie. In Europa, Asien und den USA besteht zunehmend die Möglichkeit einer Therapie mit Strahlen aus geladenen Ionen anstelle von Photonen. Eine Anlage in Dresden befindet sich in der Kommissionierungsphase. Die Ionenstrahltherapie bietet den Vorteil einer sehr konformalen Behandlung des Tumorvolumens durch die endliche Reichweite der Strahlen und ein ausgeprägtes Dosismaximum kurz vor dem Ende des Strahlpfades. Da eine Therapie in der Regel über bis zu 30 Sitzungen an verschiedenen Tagen durchgeführt wird und der Strahlweg stark von dem durchdrungenen Gewebe beeinflusst wird, sind Verfahren für eine in vivo Verifikation der Strahlapplikation wünschenswert. Eine dieser Methoden ist die Partikeltherapie–Positronen-Emissions-Tomografie (PT-PET). Sie beruht auf der Messung der vom Therapiestrahl erzeugten β+-Aktivitätsverteilung. Da eine direkte Berechnung der Dosis aus der Aktivität in lebendem Gewebe nicht möglich ist, wird die gemessene Aktivitätsverteilung mit einer berechneten Vorhersage verglichen und anschließend entschieden, ob die nächste Therapiesitzung wie geplant erfolgen kann oder Anpassungen notwendig sind. Die vorliegende Arbeit beschäftigt sich mit drei Themen aus dem Bereich der Datenverarbeitung für die PT-PET. Im ersten Teil wird ein Algorithmus zur Bestimmung von Reichweitendifferenzen aus zwei β+- Aktivitätsverteilungen adaptiert und evaluiert. Dies geschieht zunächst anhand einer Simulationsstudie mit realen Patientendaten. Ein Ansatz für eine automatisierte Analyse der Daten lieferte keine zufriedenstellenden Ergebnisse. Daher wird ein Software-Prototyp für eine semiautomatische, assistierte Datenanalyse entwickelt. Die Evaluierung erfolgt durch Experimente mit Phantomen am 12C-Strahl. Die erzeugte Aktivitätsverteilung wird von physiologischen Prozessen im Organismus beeinflusst. Dies führt zu einer Entfernung von Emittern vom Ort ihrer Erzeugung und damit zu einer Verringerung der diagnostischen Wertigkeit der erfassten Verteilung. Zur Quantifizierung dieses als Washout bezeichneten Effektes existiert ein am Tierexperiment gewonnenes Modell. Dieses Modell wird im zweiten Teil der Arbeit auf reale Patientendaten angewendet. Es konnte gezeigt werden, dass das Modell grundsätzlich anwendbar ist und für die betrachtete Tumorlokalisation Schädelbasis ein Washout mit einer Halbwertszeit von (155,7±4,6) s existiert. Die Berechnung der Vorhersage der β+-Aktivitätsverteilung kann durch übliche Monte-Carlo-Verfahren erfolgen. Dabei werden die Wechselwirkungsquerschnitte zahlreicher Reaktionskanäle benötigt. Als alternatives Verfahren wurde die Verwendung gemessener Ausbeuten (Yields) radioaktiver Nuklide in verschiedenen Referenzmaterialien vorgeschlagen. Auf Basis einer vorhandenen Datenbank dieser Yields und einer existierenden Condensed-History-Monte-Carlo-Simulation wird ein Programm zur Berechnung von Aktivitätsverteilungen auf Yieldbasis entwickelt. Mit der Methode kann die β+-Aktivitätsverteilung in Phantomen und Patienten zufriedenstellend vorhergesagt werden. Die entwickelten Verfahren sollen einen Einsatz der PT-PET im klinischen Umfeld erleichtern und damit einen breiten Einsatz ermöglichen, um das volle Potential der Ionenstrahltherapie nutzbar zu machen.

Bakgrund: Uträkning av vänsterkammarens (VK) volymer (Enddiastolisk volym, EDV; Endsystolisk volym, ESV; Slagvolym, SV) och ejektionsfraktion (EF) går att göra med elektrokardiografi (EKG)-styrd gating vid positronemissionstomografi (PET) med spårämnet 15O-vatten. Metoden behöver utredas noggrannare och optimeras för att kunna introduceras i klinisk rutinverksamhet. Syfte: Syftet med denna studie var att undersöka bildanalys av PET-rekonstruktioner med olika spatial och temporal upplösning i samband med 15O-vatten-PET utförd med EKG-gating, samt jämföra analysutfallen av VK-volymer och EF mot CMR och sinsemellan, för att utreda möjligheten att optimera metoden. Metod: Totalt 25 patienter som genomgått en 15O-vatten-PET, varav n=11 hade undersökts med CMR samma dag, inkluderades. Olika gating-rekonstruktioner med varierande upplösning utfördes retrospektivt och analyserades automatiskt samt manuellt. Analysutfallen för VK-volymer och EF för PET och CM jämfördes statistiskt. Resultat: I studien fanns en stark till mycket stark korrelation mellan PET och CMR för EDV, stark korrelation för ESV, medel till stark korrelation för SV och svag till medel korrelation för EF. Rekonstruktion med 12 gating-bins och 256x256 matrisstorlek hade starkast korrelation för SV och EF. Samtliga PET-rekonstruktioner korrelerade starkt-till mycket starkt med varandra för VK-volymer och EF. Bland-Altman-analyser visade på en god repeterbarhet, framförallt vid manuell analys, för beräkning av EF med 15O-vatten-PET. Slutsats: VK-volymer och EF kan beräknas med 15O-vatten-PET med en repeterbarhet liknande den för andra, mer använda modaliteter. Att använda en högre upplösning än vad som tidigare testats gav högre värden för EF, och starkare korrelation i jämförelse mot CMR. / Background: Calculation of left ventricle (LV)-volumes (End Diastolic Volume, EDV; End Systolic Volume, ESV; Stroke Volume, SV) and ejection fraction (EF) is possible with electrocardiography (ECG)-gated Positron Emission Tomography (PET) using 15O-water, but the method needs to be further investigated and optimized before clinical routine implementation. Purpose: The purpose of this study was to investigate how altered image resolution affects the analysis and values of LV-volumes and ejection fraction on 15O-water-PET and compare the results against Cardiac Magnetic Resonance imaging (CMR) to enable optimization of the PET-method.  Method: In total, 25 patients who previously underwent a 15O-water-PET, where n=11 also performed CMR on the same day were included in the study. Different gating-reconstructions with varying resolution were performed retrospectively and underwent analysis, both automatically and manually.  Results: Correlation analysis found a strong to very strong correlation comparing PET against CMR for EDV, a strong correlation for ESV, a moderate to strong correlation for SV and a weak to moderate correlation for EF. The reconstruction containing 12 gating-bins and a 256x256 matrix size showed the strongest correlation for SV and EF. All PET-reconstructions correlated strong to very strong against each other for all LV-volumes and EF. Bland-Altman-plots showed good repeatability, especially for manual analysis, when calculating EF on 15O-water-PET.  Conclusion: LV-volumes and EF can be calculated on 15O-water-PET, with repeatability close to that of other modalities. Using an increased resolution than previously tested resulted in higher EF and stronger correlation in comparison with CMR.

Le projet CaLIPSO (Calorimètre Liquide Ionisation Position Scintillation Organométallique) a pour ambition de mettre au point un détecteur de γ 511 keV très efficace et très rapide pour la tomographie par émission de positons. Pour cela nous utilisons comme milieu de détection un nouveau liquide, le TMBi (TriMéthylBismuth). Dans le TMBi, l’interaction de photons γ produit des photons optiques et des paires électrons-ions. Le but de cette thèse est de mesurer les paramètres d’ionisation du TMBi et de construire, un détecteur de charge instrumentant efficacement ce liquide, et son électronique associée. Afin de pouvoir détecter les électrons libres créés par l’ionisation du liquide, celui-ci doit être ultrapur, c’est-à-dire débarrassé de tout composé électronégatif qui pourraient capturer les électrons et diminuer le signal. Ceci a été travaillé à l’aide de tamis moléculaires. Les signaux à détecter sont très faibles (fA, fC). Ainsi, l’environnement de l’expérience et le détecteur ont été développés pour des mesures très bas bruit (niveaux de bruit mesurés inférieurs à 10 fA et 200 électrons). Nous avons travaillé à mesurer le rendement d’ionisation (ou Gfi) qui quantifie le rendement de production de charge dans le liquide, la mobilité des électrons dans le TMBi et la résolution en énergie du détecteur. Ce sont les principaux paramètres permettant de valider l’utilisation de TMBi pour l’imagerie TEP. Les futurs développements comprennent la mise en œuvre d’un détecteur densément pixellisé et l’optimisation de la résolution en énergie. / The CALIPSO project (Calorimètre Liquide Ionisation Position Scintillation Organométallique) aims to develop a very efficient and very fast 511 keV γ detector for positron emission tomography. For this we use an organometallic liquid for the detection medium, the TMBi (TriMéthylBismuth). In TMBi, the interaction of a γ photon produces optical photons and electron-ion pairs.The aim of this thesis is to measure the ionization parameters of the liquid TMBi and build an efficient charge detector and its associated electronics.In order to detect the free electrons created by the ionization in the liquid, this liquid must be highly pure (which means free of any electronegative compound which could capture electrons and reduce the signal). This has been worked on using molecular sieves.The signals to be detected are very weak (fA, fC). Thus, the test setup and detector were developed for very low noise measurements (measured noise levels below 10 fA and 200 electrons).We measured the ionization yield (or Gfi) which quantifies the charge production yield in the liquid, the electrons mobility in the TMBi and the energy resolution of the detector. These are the main parameters to validate the use of TMBi for PET imaging.Future developments include the implementation of a pixelated detector and optimization of the detector energy resolution.

Les travaux de thèse ont porté sur le développement de deux plateformes de radiomarquage polyvalentes pour faciliter l’incorporation du fluor-18, un isotope de choix pour l’imagerie TEP (Tomographie par Emission de Positons). La première plateforme comporte une structure sultone conduisant à un [18F]fluorosulfonate par ouverture du cycle avec le [18F]fluorure. Celle-ci a été valorisée par le couplage avec des ligands 2-nitroimidazoliques pour former un agent d’imagerie TEP spécifique de l’hypoxie. Une série de dérivés caractérisés par des propriétés d’hydrophilie différentes a été synthétisée afin de comparer leur efficacité en imagerie. Parmi ces dérivés, le [18F]FLUSONIM a révélé dans différents modèles précliniques tumoraux (rhabdomyosarcome, tumeurs cérébrales et mélanome) des ratios tumeur sur bruit de fond inégalés jusqu’à présent, et ce à des temps très précoces post-injection. La deuxième plateforme est de nature boratrane. Celle-ci est capable de réagir avec le [18F]fluorure en milieu physiologique pour former un [18F]monofluoroborate zwitterionique facile à séparer du précurseur boratrane. / This work focused on the development of versatile platforms for fluorine-18 labelling. The first platform contained a sultone moiety which was converted to [18F]fluorosulfonate by ring opening with [18F]fluoride. The sultone was coupled to 2-nitroimidazolyl ligands to obtain radiotracers for hypoxia PET imaging. A series of compounds were synthesized in order to compare their performance in PET imaging. Among them, [18F]FLUSONIM displayed high tumor/background ratios after a short delay post-injection on different animal models (rabdomyosarcoma, glioblastoma and melanoma). The second platform was based on a boratrane structure, that was able to captur [18F]fluoride in aqueous medium to form zwiterionic [18F]monofluoroborate.

京都大学 / 0048 / 新制・課程博士 / 博士(薬学) / 甲第18218号 / 薬博第808号 / 新制||薬||238(附属図書館) / 31076 / 京都大学大学院薬学研究科医療薬科学専攻 / (主査)教授 佐治 英郎, 教授 橋田 充, 教授 髙倉 喜信 / 学位規則第4条第1項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DFAM

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Positron emission tomography (PET) is a nuclear medicine imaging techniquethat uses radiotracers to visualize processes like metabolism and perfusion. Theradiotracer emits positrons, which collide with shell electrons of the atomsthat make up the surrounding tissue. Such a collision produces two gammarayphotons, emitted roughly 180 degrees apart [1]. PET captures thesephotons using a cylindrical arrangement of detectors. When two photons aredetected simultaneously by different detectors, it registers as a line of response(LOR). These LORs are then pre-processed into a sinogram. A mathematicalreconstruction method is used to computationally recover the 3D distribution ofthe radiotracer (activity map) from the sinogram. However, genuine LORs can becorrupted by false LORs that come from scattering, random events, and spuriousevents. Mitigating these in reconstruction algorithms is essential for improvingPET imaging accuracy and reliability.This paper explores the theoretical foundation of the Time of Flight (TOF) SingleScatter Simulation (SSS) model by Watson (2007) [2]. It also includes a Pythonimplementation of the MATLAB code associated with [2]. The model modelsCompton scattering to accurately estimate scattered photons in PET.Incorporating TOF data into the SSS model improves estimation accuracy, albeitat the cost of increased computational time. To expedite computations, thealgorithm was simplified by restricting operations to a subset of rings anddetectors and by pre-processing images through cropping and downscaling.Interpolation fills in missing data, ensuring complete estimation.The outcome of this project is a Python implementation that exhibited a strongcorrelation with the estimates obtained using the MATLAB implementation. Anotable issue arose during the comparison between the main components ofthe SSS algorithm in Python and MATLAB. The Euclidean norm between theresults from these two implementations was significant, indicating that they wereon different scales. Nevertheless, both implementations accurately predictedthe scatter in the same locations and relative magnitudes, despite the scalediscrepancy. Investigation into the discrepancy’s cause is ongoing, but theproject demonstrates the feasibility of implementing the TOF SSS algorithm inPython.