京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22724号 / 医博第4642号 / 新制||医||1045(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 戸井 雅和, 教授 小川 修, 教授 黒田 知宏 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22735号 / 医博第4653号 / 新制||医||1046(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 羽賀 博典, 教授 伊達 洋至, 教授 万代 昌紀 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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Magnetic nanoparticles offer a plethora of application possibilities in various fields of human endeavors. The fundamental understanding of their physical properties, related to the constituent magnetic phase, surface termination, and possible coating, synthesis method, size, shape, or even clustering, is crucial for their effective use and optimization for the intended applications. This thesis aims to contextualize original results, concerning especially the structure and magnetic properties, obtained during fundamental research on nanoparticles of selected iron-containing systems and employ these findings in testing the nanoparticles in chosen applications. Iron presents an ideal constituting element due to its low cost, high abundance in the Earth's crust, exploitability, and low toxicity. The selected systems involved in this thesis comprise iron-containing oxides (ferrites, and various polymorphs of iron(III) oxide, including ε-Fe2O3 and doped counterparts), and sulfides (greigite, chalcopyrite), all of which exhibit specific properties such as magnetic or structural transitions. Among the studied applications, the largest attention is devoted to the use of magnetic nanoparticles as contrast agents in magnetic resonance imaging, and the analysis of their efficacy in contrast enhancement -...

Objectives: MRI is of great clinical utility for the guidance of special diagnostic and therapeutic interventions. The majority of such procedures are performed iteratively (\"in-and-out\") in standard, closed-bore MRI systems with control imaging inside the bore and needle adjustments outside the bore. The fundamental limitations of such an approach have led to the development of various assistance techniques, from simple guidance tools to advanced navigation systems. The purpose of this work was to thoroughly assess the targeting accuracy, workflow and usability of a clinical add-on navigation solution on 240 simulated biopsies by different medical operators. Methods: Navigation relied on a virtual 3D MRI scene with real-time overlay of the optically tracked biopsy needle. Smart reference markers on a freely adjustable arm ensured proper registration. Twenty-four operators – attending (AR) and resident radiologists (RR) as well as medical students (MS) – performed well-controlled biopsies of 10 embedded model targets (mean diameter: 8.5 mm, insertion depths: 17-76 mm). Targeting accuracy, procedure times and 13 Likert scores on system performance were determined (strong agreement: 5.0). Results: Differences in diagnostic success rates (AR: 93%, RR: 88%, MS: 81%) were not significant. In contrast, between-group differences in biopsy times (AR: 4:15, RR: 4:40, MS: 5:06 min: sec) differed significantly (p<0.01). Mean overall rating was 4.2. The average operator would use the system again (4.8) and stated that the outcome justifies the extra effort (4.4). Lowest agreement was reported for the robustness against external perturbations (2.8). Conclusions: The described combination of optical tracking technology with an automatic MRI registration appears to be sufficiently accurate for instrument guidance in a standard (closed-bore) MRI environment. High targeting accuracy and usability was demonstrated on a relatively large number of procedures and operators. Between groups with different expertise there were significant differences in experimental procedure times but not in the number of successful biopsies.

1 ABSTRACT The presented dissertation deals with prognostic factors influencing a favorable postoperative outcome in patients undergoing surgical treatment of epilepsy and the possibilities of improving the methods used in the localization of epileptogenic lesions. This work is based on the results of four published studies. The first study evaluated the factors influencing the long-term outcomes of epilepsy surgery in MRI-negative (nonlesional) extratemporal lobe epilepsy (nETLE). The aim of the study was to evaluate the benefit of non-invasive diagnostic tests and their relationship with a favorable surgical outcome in a group nETLE patients. Univariate analysis showed that localized interictal epileptiform discharges (IEDs) on the scalp EEG were associated with a favorable surgical outcome. Diagnostic difficulty in this group of patients is highlighted by the fact that, although 9 of 24 patients undergoing surgery had a favorable outcome, and only nine of 85 patients with nETLE achieved such a favorable outcome. The second work evaluated the benefit of SPECT (Single Photon Emission Tomography) statistical processing over traditional subtraction methods in patients with MRI-negative temporal lobe epilepsy (nTLE) and MRI-negative extratemporal epilepsy (nETLE). 49 consecutive patients who underwent...

Introduction The goal of this work is to advance the production and use of 52Mn (t½ = 5.6 d, β+: 242 keV, 29.6%) as a radioisotope for in vivo preclinical nuclear imaging. More specifically, the aims of this study were: (1) to measure the excitation function for the natCr(p,n)52Mn reaction at low energies to verify past results [1–4]; (2) to measure binding constants of Mn(II) to aid the design of a method for isolation of Mn from an irradiated Cr target via ion-exchange chromatography, building upon previously published methods [1,2,5–7]; and (3) to perform phantom imaging by positron emission tomography/magnetic resonance (PET/MR) imaging with 52Mn and non-radioactive Mn(II), since Mn has potential dual-modality benefits that are beginning to be investigated [8]. Material and Methods Thin foils of Cr metal are not available commercially, so we fabricated these in a manner similar to that reported by Tanaka and Furukawa [9]. natCr was electroplated onto Cu discs in an industrial-scale electroplating bath, and then the Cu backing was digested by nitric acid (HNO3). The remaining thin Cr discs (~1 cm diameter) were weighed to determine their thickness (~ 75–85 μm) and arranged into stacked foil targets, along with ~25 μm thick Cu monitor foils. These targets were bombarded with ~15 MeV protons for 1–2 min at ~1–2 μA from a CS-15 cyclotron (The Cyclotron Corporation, Berkeley, CA, USA). The beamline was perpendicular to the foils, which were held in a machined 6061-T6 aluminum alloy target holder. The target holder was mounted in a solid target station with front cooling by a jet of He gas and rear cooling by circulating chilled water (T ≈ 2–5 °C). Following bombardment, these targets were disassembled and the radioisotope products in each foil were counted using a high-purity Ge (HPGe) detector. Cross-sections were calculated for the natCr(p,n)52Mn reaction. Binding constants of Mn(II) were measured by incubating 54Mn(II) (t½ = 312 d) dichloride with anion- or cation-exchange resin (AG 1-X8 (Cl− form) or AG 50W-X8 (H+ form), respectively; both: 200–400 mesh; Bio-Rad, Hercules, CA) in hydrochloric acid (HCl) ranging from 10 mM-8 M (anion-exchange) and from 1 mM-1 M (cation-exchange) or in sulfuric acid (H2SO4) ranging from 10 mM-8 M on cation-exchange resin only. The amount of unbound 54Mn(II) was measured using a gamma counter, and binding constants (KD) were calculated for the various concentrations on both types of ion-exchange resin. We have used the unseparated product for preliminary PET and PET/MR imaging. natCr metal was bombarded and then digested in HCl, resulting in a solution of Cr(III)Cl3 and 52Mn(II)Cl2. This solution was diluted and imaged in a glass scintillation vial using a microPET (Siemens, Munich, Germany) small animal PET scanner. The signal was corrected for abundant cascade gamma-radiation from 52Mn that could cause random false coincidence events to be detected, and then the image was reconstructed by filtered back-projection. Additionally, we have used the digested target to spike non-radioactive Mn(II)Cl2 solutions for simultaneous PET/MR phantom imaging using a Biograph mMR (Siemens) clinical scanner. The phantom consisted of a 4×4 matrix of 15 mL conical tubes containing 10 mL each of 0, 0.5, 1.0, and 2.0 mM concentrations of non-radioactive Mn(II)Cl2 with 0, 7, 14, and 27 μCi (at start of PET acquisition) of 52Mn(II)Cl2 from the digested target added. The concentrations were based on previous MR studies that measured spin-lattice relaxation time (T1) versus concentration of Mn(II), and the activities were based on calculations for predicted count rate in the scanner. The PET/MR imaging consisted of a series of two-dimensional inversion-recovery turbo spin echo (2D-IR-TSE) MR sequences (TE = 12 ms; TR = 3,000 ms) with a wide range of inversion times (TI) from 23–2,930 ms with real-component acquisition, as well as a 30 min. list-mode PET acquisition that was reconstructed as one static frame by 3-D ordered subset expectation maximization (3D-OSEM). Attenuation correction was performed based on a two-point Dixon (2PD) MR sequence. The DICOM image files were loaded, co-registered, and windowed using the Inveon Research Workplace software (Siemens).

Proton therapy (PT) is expected to greatly benefit from the integration with magnetic resonance imaging (MRI). This holds true especially for moving tumors, as the combination allows tumor motion tracking and subsequently a gated treatment or real-time treatment adaptation. At the time of starting the research work as described in this thesis, only one research-grade prototype 0.22 T MRiPT (MR integrated proton therapy) system existed at a static horizontal proton research beamline. The technical feasibility of imaging at that beamline has been presented previously (Schellhammer, 2019). However, a detailed magnetometric study of magnetic field interactions between the MRI scanner and all components of the proton therapy facility was missing so far. Furthermore, to bring the concept of MRiPT towards clinical application, active proton beam delivery seems essential (Oborn et al., 2017). Therefore, the aim of this thesis is to exploratively investigate the feasibility of integrating an MRI scanner with an actively scanned proton beam, focussing on the magnetic field interactions between the MRI and PT systems and their effects on MR image quality. In the first part of this thesis, a study is described which shows the effects of (1) different positions and rotation of the gantry in the nearby treatment room, (2) the operation of the static proton beamline in the research room, and (3) the operation of the treatment room beamline on the B0 field of the in-beam MRI scanner. While the operation of the gantry was found to have negligible effect on the resonance frequency and magnetic field homogeneity of the in-beam MRI scanner, the operation of the two beamlines was found to result in a beam energy-dependent change in resonance frequency on the order of 0.5 μT (20 Hz). This measured change in resonance frequency results in an apparent shift of the MR images. This effect was observed in a previous image quality study during simultaneous imaging and static irradiation performed with the same setup (Gantz et al., 2021; Schellhammer, 2019). It is therefore mandatory to monitor all beamline activities and synchronize the MR image acquisition with the operation of both beamlines in order to guarantee artefact-free MR images and the correct spatial representation of objects in the MR images. Furthermore, a daily drift of the static magnetic field of the MRI scanner was observed and could be correlated to ambient temperature changes, indicating limitations in the heating and the thermal insulation of the permanent magnet material of the MRI scanner. However, this drift can be accounted for by an optimization of the MR frequency calibration prior to each image acquisition. The second part of this thesis presents the combination of the in-beam MRI scanner with an actively scanned proton beam at a Pencil Beam Scanning (PBS) beamline. The investigation focusses on the influences of the magnetic fringe fields of the PT system onto the MR image quality. First, the suitability of the beam-stopper is shown. Moreover, the maximum radiation field of the beamline for operation with the MRI scanner at the beamline is theoretically presented and confirmed by radiochromic film measurements. In order to prevent a direct irradiation of the MRI scanner, it is shown that a reduction of the field size in vertical direction to 20 cm is required, while the full 40 cm field size is applicable in horizontal direction. Furthermore, a beam energy-dependent trapezoidal distortion of the rectangular radiation field induced by the B0 field of the MRI scanner is, for the first time, experimentally quantified at the isocenter of the MRI scanner and confirms previously published computer simulation studies (Oborn et al., 2015). Additionally, a previously unknown proton beam spot rotation is observed for spot positions in the outer corners of the radiation field, with rotations relative to the main axis of up to 22°, which requires future studies to understand the observed effect. Second, the feasibility of simultaneous imaging and dynamic PBS irradiation is investigated, by (1) a magnetometry study and (2) MR image quality experiments during simultaneous PBS irradiation. These measurements reveal that the operation of the horizontal scanning magnet results in a severe loss of image quality in the form of ghosting artefacts along the phase-encoding direction, whereas vertical beam scanning and proton beam energy variation is found to cause no visual degradation of image quality. The origin of the observed ghosting artefacts is unravelled by phase-offsets in the k-space information of the acquired images. A theoretical description of these artefacts is presented, which is capable to explain the experimentally observed image artefacts due to the B0 field perturbations found in the magnetometry study. In order to eliminate the observed artefacts, two concepts for artefact-free imaging during PBS dose delivery are suggested, which include magnetic decoupling of the MRI scanner and PT system, and an online image correction strategy that accounts for the changes in the B0 field caused by the operation of the horizontal scanning magnet. Future studies are crucial to evaluate the feasibility and effectiveness of these approaches. The third part of the thesis tests the hypothesis that a proton beam-induced signal change in MR images, which is indicative of effective proton dose delivery in fluid-filled phantom material, is caused by heat-induced convection (Schellhammer, 2019). It is clearly shown that the inhibition of water flow could fully suppress the beam-induced MRI signal loss that was observed in previous experiments. Furthermore, the introduction of an external flow condition using similar flow velocities as expected during proton irradiation produces similar MRI signal losses. The combination of both results suggests that the observed MRI signal loss is most likely caused by convection and is hence most likely not transferable to solid materials and tissues. However, the method holds potential for the coordinate system co-localization of the MRI scanner and PT system, as well as for verification of the proton beam range during machine quality control. In conclusion, this thesis greatly improves the understanding of the origin and magnitude of perturbations of the static magnetic field of the MRI scanner due to the presence of static and dynamic fringe fields of the beamline and scanning magnets of the PT system. The work shows that these interactions result in a severe loss of image quality during simultaneous MR imaging and active proton beam delivery. Combining the knowledge obtained from magnetometry, imaging and theoretical considerations, solid evidence is provided to understand why this loss of image quality is observed for one scanning direction only. Furthermore, this work shows that the current method used for online MRI-based proton beam visualization is caused by buoyancy-driven convection. These results stimulate further research targeting both non-clinical research solutions and the development of a first prototype MRiPT system for clinical use.:List of Figures vii List of Tables ix List of Abbreviations xi 1 Introduction 1 2 Theoretical background 5 2.1 Proton therapy 5 2.1.1 Physical principle 5 2.1.2 Beam delivery 8 2.2 Magnetic resonance imaging 10 2.2.1 Physical principle of MRI 10 2.2.2 Spatial encoding 12 2.2.3 Basic pulse sequences 13 2.3 Magnetometry for MRI systems 14 3 Magnetometry of the in-beam MRI scanner at the static research beamline 17 3.1 Material and methods 18 3.1.1 Measurement setup 18 3.1.2 Magnetic field camera 19 3.1.3 Magnetic field drift 20 3.1.4 Influence of gantry position and rotation 21 3.1.5 Effect of FBL and GTR beamline magnets 21 3.2 Results 22 3.2.1 Frequency drift and reference measurements 22 3.2.2 Influence of gantry position and rotation 24 3.2.3 Influence of FBL and GTR beamline operation 25 3.3 Discussion 25 4 Combination of the MRI scanner with a horizontal dedicated PBS Beamline 29 4.1 Installation of the MRI scanner at the PBS beamline 29 4.2 Position verification of the beam-stopper 31 4.3 Determination of maximum radiation field size inside the MRI scanner 36 4.4 Discussion 40 5 Magnetic interference and image artefacts during simultaneous imaging and irradiation 41 5.1 Material and methods 41 5.1.1 Magnetometry of external influences on the magnetic field of the MRI scanner 42 5.1.2 Image quality experiments 44 5.1.3 Theory and computer simulation 45 5.2 Results 47 5.2.1 Magnetometry results 47 5.2.2 Image quality experiments 50 5.2.3 Computer simulation 51 5.3 Discussion 52 6 Proton beam visualization by online MR imaging: Unravelling the convection hypothesis 59 6.1 Material and methods 60 6.1.1 Experimental setup 60 6.1.2 MRI sequence design 62 6.1.3 Baseline experiments: Validation of beam energy and current dependency 63 6.1.4 Flow restriction and inhibition 65 6.1.5 External flow measurements 66 6.2 Results 68 6.2.1 Baseline experiments 68 6.2.2 Vertical flow restriction and flow inhibition 71 6.2.3 MRI signal loss by external flow 73 6.3 Discussion 74 7 General discussion and future perspectives 77 7.1 General discussion 77 7.1.1 Magnetometry of the in-beam MRI system 77 7.1.2 Simultaneous MR imaging and active PBS beam delivery 79 7.1.3 MRI-based proton beam visualization 80 7.2 Future perspectives for MRiPT 82 7.2.1 Short-term perspectives 82 7.2.2 Long-term perspectives 83 7.3 Conclusion 87 8 Summary 89 9 Zusammenfassung 93 Bibliography 97 Appendix 109 A Results of film measurements at MR isocenter 109 B Angio TOF MRI pulse sequence parameters 110

This thesis describes the bene ts and disadvantages of using synthetic Magnetic Resonance Imaging (MRI) instead of conventional MRI. The thesis is based on a clinical study performed at Orebro University Hospital were 11 patients diagnosed with Multiple Sclerosis (MS) went through a brain examination with both methods. The examination time was measured and compared between the two methods, and the quality of the images was analysed by two radiologists. The study shows that the examination time can be reduced using the synthetic method instead of the conventional. The image quality is however not as good with the synthetic method which opens a discussion whether the time reduction is worth the loss of image quality. However, the conclusions are that the method can be useful for patients diagnosed with MS who are examined yearly and especially useful as a complement to the conventional sequence to gain as much information as possible that can be compared between the patients yearly exams. To completely replace other conventional examination types, the method has to be further evaluated and equipped with functions that are present in the conventional sequences, such as correction for motion artefacts. / Denna rapport beskriver de fördelar och nackdelar som finns med att använda syntetisk magnetresonanstomografi (MRI) istället för konventionell MRI. Rapporten är baserad på en klinisk studie som har genomförts vid Universitetssjukhuset i Örebro där 11 patienter diagnostiserade med Multipel Skleros (MS) genomförde en undersökning av hjärnan med båda metoderna. Undersökningstiden mättes och jämfördes metoderna emellan, och bildkvaliteten analyserades av två radiologer. Den kliniska studien visar att undersökningstiden kan förkortas när den syntetiska metoden används i jämförelse med den konventionella. Bildkvaliteten för de konventionella bilderna anses vara av högre kvalitet i denna studie vilket öppnar en diskussion gällande huruvida det är värt att förlora en viss bildkvalitet mot förkortat undersökningstid. Slutsatsen är att metoden är användbar för patienter diagnostiserade med MS som undersöks årligen, och speciellt användbar som ett komplement till de konventionella sekvenserna för att generera så mycket information som möjligt. Denna information är sedan användbar vid jämförelse av bilderna från patienternas återkommande undersökningar. För att helt ersätta de konventionella sekvenserna krävs vidare utvärderings av den syntetiska metoden samt att den kompletteras med er funktioner, exempelvis för att korrigera för rörelseartefakter.

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