Low-field magnetic resonance imaging (MRI) has recently been integrated with radiation therapy systems to provide image guidance for daily cancer radiation treatments. The main benefit of the low-field strength is minimal electron return effects. The main disadvantage of low-field strength is increased image noise compared to diagnostic MRIs conducted at 1.5 T or higher. The increased image noise affects both the discernibility of soft tissues and the accuracy of further image processing tasks for both clinical and research applications, such as tumor tracking, feature analysis, image segmentation, and image registration. An innovative method, adaptive anatomical preservation optimal denoising (AAPOD), was developed for optimal image denoising, i. e., to maximally reduce noise while preserving the tissue boundaries. AAPOD employs a series of adaptive nonlocal mean (ANLM) denoising trials with increasing denoising filter strength (i. e., the block similarity filtering parameter in the ANLM algorithm), and then detects the tissue boundary losses on the differences of sequentially denoised images using a zero-crossing edge detection method. The optimal denoising filter strength per voxel is determined by identifying the denoising filter strength value at which boundary losses start to appear around the voxel. The final denoising result is generated by applying the ANLM denoising method with the optimal per-voxel denoising filter strengths. The experimental results demonstrated that AAPOD was capable of reducing noise adaptively and optimally while avoiding tissue boundary losses. AAPOD is useful for improving the quality of MRIs with low-contrast-to-noise ratios and could be applied to other medical imaging modalities, e.g., computed tomography. (C) 2017 Society of Photo-Optical Instrumentation Engineers (SPIE)

Les faisceaux de photons produits par les accélérateurs d'électrons linéaires médicaux sont plats, grâce à un cône égalisateur. Les technologies ont évolué et la présence d'un cône n'est plus indispensable. On parle alors de faisceaux FFF (flattening filter free). Les faisceaux FFF présentent des débits de dose plus élevés, des profils de dose hétérogènes, des spectres énergétiques différents et une diminution de la dose hors-champ. Cette thèse a eu pour but d'étudier les caractéristiques des faisceaux FFF, ainsi que l'impact de leur utilisation thérapeutique. Plusieurs thématiques ont été. Des expériences d'irradiation in vitro ont tout d'abord permis de s'assurer que les débits de dose FFF n'ont pas d'impact radiobiologique sur la réponse des cellules irradiées. Une large revue de la littérature a permis de corroborer ces résultats. Afin de maitriser les caractéristiques physiques des faisceaux FFF, des mesures ont été faites avec différents détecteurs. Les effets du spectre et du débit de dose sur la calibration en dose ont aussi été étudiés. Les faisceaux FFF ont été modélisés dans deux TPS. Les modèles ont été comparés entre les deux types de faisceaux et entre les deux TPS. La mise en place des traitements stéréotaxiques a aussi été l'occasion d'appréhender la dosimétrie des petits faisceaux. Nous avons étudié des cas VMAT de cancer de la prostate et des cas de stéréotaxies 3D de tumeurs pulmonaires. La comparaison donne un avantage aux faisceaux FFF. La maitrise de la physique et de la biologie des haut débits a permis de débuter les traitements FFF à l'IPC. Des études comparatives nous permettent aujourd'hui d'adapter leur utilisation au cas par cas. / In medical linear electron accelerators, photon beams profiles are homogenised using flattening filters. Technologies have evolved and the presence of this filter is no longer necessary. Flattening filter free (FFF) beams exhibit higher dose rates, heterogeneous dose profiles, modified energy spectra and lower out-of-field dose. This PhD aimed at studying the characteristics of unflattened beams, as well as their impact in clinical utilization. Several subjects were thoroughly investigated: radiobiology, dosimetry, quality controls, modelling and treatment planning. In vitro experiments ensured that the high dose-rate of FFF beams had not a radiobiological impact. A wide review of the literature was conducted to corroborate these results. In order to understand thoroughly the characteristics of FFF beams, measurements were conducted using several detectors. The effect of the spectra and dose rates of unflattened beams on dose calibration were also studied. FFF beams were modeled in two TPSs. The methods, results and model parameters have been compared between the available beam qualities as well as between both TPSs. Furthermore, the implementation of stereotactic treatments technique was the occasion to investigate small beam dosimetry. Prostate cancer cases treated with VMAT and pulmonary tumors treated with stereotactic 3D beams were also studied. The comparison of dose distributions and treatment metrics give advantage to FFF beams. Mastering physical and biological aspects of flattening filter free beams allowed the IPC to start FFF treatments. Comparative studies have since resulted in a deeper understanding on the pertinent use of these beams.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22642号 / 医博第4625号 / 新制||医||1044(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 武田 俊一, 教授 増永 慎一郎, 教授 鈴木 実 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Bakgrund: Varje år insjuknar 300 barn i cancer varav cirka 30% av dessa diagnostiseras med hjärntumör. Protonstrålning har sedan 2015 varit ett bra behandlingsalternativ för att minska seneffekterna av strålningen. I dagsläget görs all protonstrålning i Uppsala. Barn med cancer vill vara delaktiga i sin vård och behandling och ålderanpassad information är då viktigt. Syfte: Att beskriva barnsjuksköterskans erfarenhet av att förbereda barn med hjärntumör inför protonstrålning på annan ort. Metod: Sju stycken kvalitativa intervjuer genomfördes med sjuksköterskor. Insamlat material analyserades med kvalitativ innehållsanalys (Elo och Kyngäs 2008). Resultat: Resultatet presenterar tre kategorier: Att nå barnet beskriver vikten av att ha barnet i fokus och anpassa informationen utifrån individen. Att möta utmaningar belyser tidens betydelse för hur förberedelserna blir, att det upplevdes som svårare att förbereda barn när det utförs på annan ort. Att inge trygghet beskriver sjuksköterskans roll att vara en trygg punkt för familjen samt att se till hela familjen. Konklusion: Konklusionen av studien är att barnsjuksköterskorna är medvetna om vikten av att göra barn delaktiga i förberedelser för att främja hälsa samt att tidens påverkan spelar in när sjuksköterskan ska förbereda och nå fram till barnet. / Background: Every year, 300 children are diagnosed with cancer, of which about 30% are diagnosed with brain tumor. Proton radiation therapy has been a good treatment alternative since 2015 to reduce the late effects of radiation. At the moment, all proton radiation therapy in Sweden is carried out in Uppsala. Children with cancer want to participate in their care and treatment and age-appropriate information is therefore important. Purpose: To describe the pediatric nurse's experience in preparing children with brain tumors for proton radiation therapy in another location. Method: Seven qualitative interviews were conducted with nurses. Collected material was analyzed with qualitative content analysis (Elo & Kyngäs, 2008). Result: The result presents three categories: Reaching the child describes the importance of having the child in focus and adapting the information based on the individual. Facing challenges highlights the importance of time and how it affects the preparations, it was perceived as more difficult to prepare children getting treatment in another location. Providing security describes the nurse's role to be a safe point for the family and to look after the whole family. Conclusion: The conclusion of the study is that the pediatric nurses are aware of the importance of children’s’ participation in their preparation, to promote health and that time plays an influential role in the preparation and the nurse’s ability to connect with the children.

In-beam Positron Emission Tomography (PET) is a system for monitoring high precision radiation therapy which is in the most cases applied to the tumors near organs at risk. High quality and fast availability of in-beam PET images are, therefore, extremely important for successful verification of the dose delivery. Two main problems make an in-beam PET monitoring a challenging task. Firstly, in-beam PET measurements result in a very low counting statistics. Secondly, an integration of the PET scanner into the treatment facility requires significant reduction of the sensitive surface of the scanner and leads to a dual-head form resulting in imaging artifacts. The aim of this work is to bring the imaging process by means of in-beam PET to optimum quality and time scale. The following topics are under consideration: - analysis of image quality for in-beam PET; - image reconstruction; - solutions for building, testing, and integration of a PET monitoring system into the dedicated treatment facility.

Proton therapy, a relatively young modality in radiation therapy, has proven useful in cases where a sharp dose gradient or low secondary irradiation is required. In Canada proton therapy it was performed at the TRIUMF Proton Therapy Facility in the treatment of large or difficultly positioned ocular melanomas. This rare primary malignant cancer of the eye has a poor prognosis if untreated. Patient vision sparing is critical for quality of life and is strongly affected by the accuracy of the chosen treatment. Reduction in irradiation of critical structures is a proven strength of proton therapy due to the high dose-gradient and finite range in tissue. But, with the advantage of steep dose gradients, comes the requirement of precision target positioning and planning. Monte Carlo particle transport software is a valuable tool for understanding treat- ment doses in cases where measurement is time consuming or difficult. Accurate simulation of primary proton dose to water aids in the evaluation of beam charac- teristics and allows for study into improving dose application for patient treatment. In this work, a full Monte Carlo model of the TRIUMF proton therapy facility was developed. Measurements were taken in water to validate simulated results within 2% over the treatment depth for a wide range of beam modulations. The second advantage of proton therapy lies in its reduced dose bath to healthy tissue. This is especially important in pediatric cases where extraneous dose comes with a high risk of secondary carcinogenesis. Whereas multi-angle photon treatments necessarily irradiate large volumes of healthy tissue to produce a flat target dose, proton treatments may irradiate a target with a single beam. With this advantage comes a trade-off - protons produce a large number of neutrons as they are prepared for patient treatment. These neutrons are the largest contributor to secondary dose in proton therapy and must be well modeled and shielded to ensure patient safety. The second part of this work involves the measurement of secondary neutron doses in the TRIUMF treatment room. Measurements were validated within 20% of simulated values with uncertainties dominated by calibration of the detector. Neutron doses to an anatomic human model showed that calibrated secondary doses were in line with similar treatment facilities reporting globally. Simulations indicated that the source of neutrons was primarily in the unshieldable region of the beamline opening. Thus the total treatment time was the determining factor in secondary dose to the patient. With primary proton dose well modeled, it became possible to study the pre- cision of treatment and possible avenues for improvement. The beam modulation wheels and optimization scheme was developed in the late 90‘s when computational and manufacturing technologies were less developed. Updated optimization methods indicated that moving to a smooth scheme of energy modulation, as opposed to a stepped modulation wheel, could improve distal dose sharpness. This was contrary to the long-held belief that there was an optimal number of steps for modulation. The third portion of this work explored the use of 3D printers to enable the fabri- cation of smoothly transitioning modulator wheels. Materials and printer methods were studied, indicating a strong candidate in the PolyJet TM method for beam mod- ulation. Both stepped and newly-optimized smooth modulator wheels were printed and validated. Total turnaround time for modulator production was under 24 hours - proving the feasibility of patient-specific beam modulation. The last portion of this work explored the use of positron emitting isotopes for dose validation. Protons traversing tissue or plastic generate β + emitting isotopes via nuclear interactions. The resulting back-to-back annihilation photons can be re- constructed into the isotope distribution produced by the beam. This can potentially provide information about beam position in the target and hence position of a phan- tom or patient. An anatomic 3D printed eye phantom was designed and irradiated to test the feasibility of this method. While a strong isotope signal was reconstructed, the test did not yield a viable technique due to the low resolution of the phantom scan. The phantom position was poorly reconstructed using the transmission scan. Despite this, it could be possible to improve this method by using other methods for phantom position registration. / Graduate

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Purpose: Meningiomas are common intracranial tumors, often well controlled with surgical resection alone. While the efficacy of radiation therapy in improving local control and progression-free survival is well documented, prognostic data substantiate factors that are predictive of poor local control following definitive radiation therapy. PCNA is a DNA polymerase expressed at the highest levels in the S-phase, the most resistant portion of the cell cycle to ionizing radiation in vitro. We investigated the possible correlation between the levels of PCNA expression and the clinical outcome of patients treated with definitive radiation therapy. Methods and Materials: Archival tissue was collected from 33 cases of meningioma treated at our institution for definitive radiation therapy between 1970 and 1990. Age-matched normal meningeal tissue and asymptomatic meningiomas removed at autopsy served as tissue controls. A standard ABC immumoperoxidase technique employing antibodies to PCNA, PC-10 (Dako, California) was used to stain specimen slides for PCNA. PCNA index was defined as the number of positive nuclei per 10 high-power fields at 400x magnification. Two independent observers scored the slides without prior knowledge of the cases at hand. Results: Patients with high PCNA index were less likely to be controlled by therapeutic radiation (p < 0.001, Kaplan- Meier). All patients with a PCNA index greater that 25 failed radiation therapy. Using multivariate analyses, malignant (but not atypical), histology and PCNA index were significant predictors of progression following radiation therapy (p < 0.05, log rank). Conclusion: PCNA index may be a useful adjunct to more standard histopathologic criteria in the determination of meningioma local control and progression-free survival following therapeutic irradiation. Data on a more expanded population evaluated on a prospective basis will be needed before such criteria are routinely employed in the clinical setting.

Focused ultrasound (FUS) is a less-invasive medical technique with the potential to improve the treatment outcome of many diseases by utilizing acoustic transducers to generate and concentrate the multiple intersecting ultrasonic waves on a targeted site in the body. The bio-effects induced by FUS are mostly classified into thermal and mechanical effects (mainly focus on cavitation effect). Cavitation is capable of disrupting tumor vasculature and cell membranes. Numerous studies reported that cavitation-induced sonoporation could provoke multiple anti-proliferative effects on cancer cells, including cell-cycle arrest, cell apoptosis, and clonogenicity suppression. Therefore, the combination of FUS-induced cavitation and other treatment modalities like radiation therapy is of great interest, but research in this field is inadequate. A special high-throughput FUS system was used for cancer cell treatment with a customized 1.467 MHz single focused transducer. Characterization of acoustic behavior of gas-filled cavities was performed via a fiber-optic hydrophone (FOH) system and chemical terephthalic acid method helped to define the acoustic parameters, which could lead to occurrence of cavitation at the bottom of 96-well cell culture plates where cancer cells were located. Cavitation occurs at and above the acoustic intensity of 344 W/ cm2 for the 1.467 MHz transducer. The short- and long-term effects of FUS-induced cavitation and adjuvant effects to radiation therapy, standard hyperthermia and testosterone treatment (only for prostate cancer) were investigated comprehensively at the cellular and molecular levels in human prostate cancer (PC-3 and LNCap), glioblastoma (T98G) and head and neck (FaDu) cells in vitro. The long-term additive effects of short FUS shots (with or without cavitation) to radiation therapy (RT) or hyperthermia (HT) were displayed by significantly reduced clonogenic survival in PC-3, T98G and FaDu cells compared to single treatments. The combination treatment of short FUS with cavitation (FUS-Cav) and RT led to a comparable radio-sensitization effect to HT at 45 °C for 30 min and showed a significant reduction in treatment duration, especially for PC-3 cells. The short-term additive effects of short FUS shots to RT or HT are manifested in reducing the potential of cells to invade and decreased metabolic activity. The induction of sonoporation by FUS-Cav was supposed to be the mechanism of cancer cell sensitization to other therapies at the cellular level. The dramatic decline of 5α-reductase type III (SRD5A3) level induced by combination treatment with FUS-Cav and HT is presumed as the underlying mechanism of additive effects of FUS-Cav to HT at the molecular level. Besides, testosterone solutions with normal physiological levels were discovered to inhibit the long-term metabolic activity of androgen-dependent prostate cancer cells LNCap in vitro, while short FUS shots displayed a long-term additive effect to the testosterone treatment. The presented multilevel study demonstrates that short FUS shots using FUS-induced cavitation carry the potential to sensitize cancer cells to other cancer treatment modalities precisely and less-invasively, providing a promising adjuvant therapy to cancer treatments in the future.:1 Abbreviations 2 Summary 3 Introduction 4 Medical and technical background 4.1 The biological basis of prostate cancer treatment 4.1.1 Androgen receptor: an essential signaling pathway for progression of prostate cancer 4.1.2 5α-reductase: a promising therapeutic target for prostate cancer therapy 4.1.3 Testosterone: duality effects in prostate cancer development 4.2 Advantages and disadvantages of current clinical treatments of prostate cancer 4.3 Basics of focused ultrasound (FUS) 4.3.1 Medical application of FUS-induced thermal effects 4.3.1.1 High-intensity focused ultrasound (HIFU) induced thermal ablation 4.3.1.2 Hyperthermia: an alternative heating strategy to sensitize cancer cells for radiation therapy and chemotherapy 4.3.1.3 FUS-induced hyperthermia triggered drug delivery with thermo-sensitive drug carriers 4.3.2 Medical application of FUS-induced mechanical/cavitation effects 4.3.2.1 Cell sonoporation for drug delivery 4.3.2.2 Sonoporation induced anti-proliferative effects for cancer cells 4.3.2.3 Histotripsy 4.3.2.4 Anti-vascular and anti-metastatic effects 4.3.3 The state of art of cavitation detection in medical application 4.3.3.1 Sonoluminescence and sonochemistry 4.3.3.2 Passive cavitation detection 4.3.3.3 Active cavitation detection 4.3.3.4 High-speed sequential photography of cavitation dynamics 4.3.3.5 Laser scattering technique 4.3.3.6 Synchrotron X-ray imaging technique 4.3.3.7 MRI techniques 5 Aims of the thesis 6 Materials and methods 6.1 Materials 6.1.1 Devices 6.1.2 Chemicals and reagents 6.1.3 Consumables 6.1.4 Human cancer cell lines 6.2 Methods 6.2.1 Composition of the FUS system for in vitro treatment of cells 6.2.2 Physical characterization of the in vitro FUS system 6.2.2.1 Setup of fiber-optic hydrophone system to characterize the FUS apparatus 6.2.2.2 Data analysis in MATLAB 6.2.3 Cavitation measurement with FOH system 6.2.4 Chemical cavitation measurement with terephthalic acid (TA) 6.2.5 Culture of human cancer cell lines 6.2.6 FUS treatment of cancer cells 6.2.7 Water bath hyperthermia treatment 6.2.8 Radiation therapy in vitro 6.2.9 The protocol of FUS\FUS-Cav combined with RT or HT 6.2.10 Evaluation of cell ability to reproduce with clonogenic assay 6.2.11 Measurement of cellular metabolic activity with WST-1 assay 6.2.12 Evaluation of cell invasion ability with Transwell® assay 6.2.13 Detection of sonoporation by cell staining with propidium iodide (PI) 6.2.14 Detection of SRD5A as a therapeutic target for prostate cancer with immunofluorescence microscopy 6.2.15 Quantification for the reduction of SRD5A proteins with flow cytometry 6.2.16 Testosterone treatment 6.2.17 FUS/FUS-Cav combined with testosterone treatment 7 Results 7.1 Physical characterization of the in vitro FUS system 7.2 Cavitation occurs at a certain level of acoustic intensity 7.2.1 Characteristics of ultrasonic spectrograms 7.2.2 Cavitation dose depends on the acoustic intensity 7.3 FUS/FUS-Cav supports RT to reduce the long-term clonogenic survival of cancer cells 7.4 FUS/FUS-Cav increases the effects of HT by reducing the long-term clonogenic survival of cancer cells 7.5 FUS/FUS-Cav enhances the suppressive effects of RT in short-term cell potential to invade and metabolic activity of prostate cancer cells 7.6 FUS/FUS-Cav supports HT to diminish the short-term cell potential to invade and metabolic activity of prostate cancer cells 7.7 FUS-Cav treatment immediately induces sonoporation effects in PC-3 and FaDu cells 7.8 FUS/FUS-Cav enhances the effects of HT by inhibiting the SRD5A protein level in prostate cancer cell lines 7.9 FUS-Cav enhances the effects of the testosterone treatment by reducing the long-term cell metabolic activity of androgen-dependent prostate cancer cell line 8 Discussion 8.1 Cavitation measurement in a defined 96-well plate by PCD technique and sonochemistry method 8.2 Short-term and long-term additive effects of FUS-Cav to RT or HT 8.3 Inhibitory effects of FUS-cav in the potential of prostate cancer cells to invade 8.4 The reduction of the long-term metabolic activity of androgen-dependent prostate cancer cells by the combination treatment of FUS-Cav and testosterone 9 Conclusion 10 References 11 Appendix 11.1 Erklärung über die eigenständige Abfassung der Arbeit 11.2 List of figures 11.3 List of tables 11.4 Curriculum vitae 11.5 Acknowledgments