京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第13032号 / 論医博第2114号 / 新制||医||1016(附属図書館) / 32990 / 横浜市立大学大学院医科学専攻 / (主査)教授 増永 慎一郎, 教授 坂井 義治, 教授 小川 修 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

Radiotherapy has become an ever more successful treatment option for cancer.Advances in imaging protocols combined with precise therapy devices suchas linear accelerators contribute towards millimeter precision of treatmentdelivery with far fewer side effects. The ultimate goal of radiotherapy is tomaximize tumor control while minimizing adverse effects to healthy tissues,more importantly organs at risk surrounding the tumor. External beamradiotherapy is currently on the brink of breaking a new frontier: MagneticResonance Imaging (MRI) guided tumor tracking. Here, a combined linearaccelerator and MRI system can be used to treat and follow the tumor duringirradiation, called Real-time Adaptive Radiotherapy (ART). Tailoring of thebeam shape, by means of the Multi-leaf Collimator (MLC) on the fly has thepotential to complete a fully automated radiotherapy process. Recent advances in Reinforcement Learning (RL), a sub field of artificialintelligence has pushed the frontiers further in sequential decision making processesfurther in various fields. In a MLC tracking scenario, we hypothesizethat an RL agent trained on real-time tumor delineations and dose informationcould fulfill a specified dosimetric criteria on the fly over the moving target.To investigate the feasibility of RL for MLC tracking further: we designeda simulator, devised an appropriate RL framework and interfaced them to aDeep Q-Network (DQN) algorithm. Our results demonstrate the feasibility of employing RL for MLC trackingalong with numerous design choices that need to be considered while developingsuch a system. We believe to have taken the first step to bridge MLCtracking and RL by proposing a closed loop solution using dose information.

In treatment of cancer using high energetic radiation the problem arises how to irradiate the tumor without damaging the healthy tissue in the immediate vicinity. In order to do this, intensity modulated radiation therapy (IMRT) is used. In this thesis, the general goal is to modulate the homogeneous radiation field delivered by an external accelerator using a multileaf collimator in comparison with beam modifying devices. In order to generate intensity modulated fields in a static mode with multileaf collimators, the heuristic algorithm of Galvin, Chen and Smith is used. This method aims at finding a segmentation with a small number of segments, taking account of mechanical constraints such as leaves can move only in one direction, on one row, the right and left leaves cannot overlap (Interleaf Collision) and also every element between the leaf and the side of the collimator to which the leaf is connected is also covered (no holes in leaves). During the implementation of the algorithm, the initial intensity matrix with the desired radiation rates is inserted and using essential transformations, a positive combination of special matrices, segments, corresponding to fixed positions of multileaf collimator are obtained. All calculations end with the superposition of segments which leads to the creation of the 3-D matrix that will be used to irradiate the tumor. The algorithm is implemented in C++. The calculations are fast and the procedure is user friendly. The model is implemented for the case of protection the spinal cord while treating a tumor in the neck area. Furthermore, dose distributions obtained with this model and beam modifying devices in the neck area were compared. / Κατά τη θεραπεία του καρκίνου με χρήση υψηλής ενέργειας ακτινοβολίας, πρόβλημα αποτελεί ο περιορισμός της ακτινοβολίας στον όγκο στόχο και ο περιορισμός της συμμετοχής του υγιούς ιστού, της γειτονικής περιοχής, στο ελάχιστο. Προκειμένου να επιλυθεί το πρόβλημα αυτό χρησιμοποιείται ακτινοθεραπεία με πεδία ακτινοβολίας διαμορφωμένης έντασης (Ιntensity Μodulated Radiαtion Therapy – IMRT), με τη βοήθεια των κατευθυντήρων πολλαπλών φύλλων (Multileaf Collimators- MLC). Στόχος της συγκεκριμένης διπλωματικής εργασίας είναι η διαμόρφωση του ομοιογενούς πεδίου ακτινοβολίας, που διανέμεται μέσω του γραμμικού επιταχυντή χρησιμοποιώντας κατευθυντήρα πολλαπλών φύλλων και η σύγκριση των αποτελεσμάτων της προσομοίωσης με τις συσκευές διαμόρφωσης δέσμης (Beam Modifying Devices). Προκειμένου να παραχθούν τα διαμορφωμένης έντασης πεδία ακτινοβολίας, σε στατική μορφή, χρησιμοποιήθηκε ο αλγόριθμος των Galvin, Chen και Smith. H μέθοδος αποσκοπεί στην τμηματοποίηση του πίνακα με τα επιθυμητά ποσοστά ακτινοβολίας σε έναν μικρό αριθμό τμημάτων “segments”, λαμβάνοντας υπόψιν μηχανικούς περιορισμούς. (i) Τα φύλλα δύναται να κινηθούν μόνο κατά μήκος μιας διεύθυνσης, (ii) σε μια γραμμή, το αριστερό και το δεξί φύλλο δεν μπορούν να επικαλυφτούν (Interleaf Collision) και (iii) κάθε στοιχείο μεταξύ του φύλλου και της πλευράς του διαμορφωτή, με την οποία είναι συνδεδεμένο, είναι πάντα καλυμμένο (Νo holes in leaves). Κατά την υλοποίηση του αλγορίθμου, εισάγεται ο αρχικός πίνακας με τα επιθυμητά ποσοστά ακτινοβολίας και με τη χρήσης κατάλληλων μετασχηματισμών, προκύπτει ένας συνδυασμός από ειδικούς πίνακες (segments), οι οποίοι αντιστοιχούν σε θέσεις των κατευθυντήρων πολλαπλών φύλλων και θα χρησιμοποιηθούν για την ακτινοβόληση του όγκου. Ο αλγόριθμος υλοποιήθηκε σε C++. Οι υπολογισμοί είναι γρήγοροι και η διεργασία είναι φιλική προς το χρήστη. Το μοντέλο υλοποιήθηκε για την περίπτωση προστασίας της σπονδυλικής στήλης κατά τη θεραπεία όγκου στην περιοχή του λαιμού. Τέλος, οι κατανομές δόσεις που προέκυψαν με την προαναφερθέν μοντέλο συγκρίθηκαν με αυτές των συσκευών διαμόρφωσης δέσμης.

En proton thérapie, la technique de balayage, permet de traiter efficacement le patient vis à vis de l'irradiation de la tumeur et la protection des tissus sains. Ces bénéfices dosimétriques peuvent cependant être grandement dégradés par les mouvements intra-fraction. Par conséquent, l'étude de méthodes d'atténuation ou d'adaptation est nécessaire. C'est pour cela, que nous avons développé un logiciel ”open-source” de calcul et d'évaluation de dose en 4D, MSPT (Motion Simulator for Proton Therapy), pour la technique de balayage. Son but est de mettre en avant l'impact des mouvements intra-fraction en calculant la répartition de dose dans le patient. En outre, l'utilisation de MSPT nous a permis de mettre au point et de proposer une nouvelle méthode d'atténuation du mouvement basée sur l'ajustement du poids du faisceau quand celui-ci balaye la tumeur. En photon thérapie, un enjeu principal pour les traitements délivrés à l'aide de collimateurs multi-lames (MLC) consiste à trouver un ensemble de configurations du MLC permettant d'irradier correctement la tumeur. L'efficacité d'un tel ensemble se mesure par le total beam-on time et le total setup time. Dans notre étude, nous nous intéressons à la minimisation de ces critères, d'un point de vue algorithmique, pour de nouvelles technologies de MLC: le MLC rotatif et le MLC à double couche. De plus, nous proposons un algorithme d'approximation pour trouver un ensemble de configurations minimisant le total beam-on time pour le MLC rotatif / In proton therapy, the delivery method named spot scanning, can provide a particularly efficient treatment in terms of tumor coverage and healthy tissues protection. The dosimetric benefits of proton therapy may be greatly degraded due to intra-fraction motions. Hence, the study of mitigation or adaptive methods is necessary. For this purpose, we developed an open-source 4D dose computation and evaluation software, MSPT (Motion Simulator for Proton Therapy), for the spot-scanning delivery technique. It aims at highlighting the impact of intra-fraction motions during a treatment delivery by computing the dose distribution in the moving patient. In addition, the use of MSPT allowed us to develop and propose a new motion mitigation strategy based on the adjustment of the beam's weight when the proton beam is scanning across the tumor. In photon therapy, a main concern for deliveries using a multileaf collimator (MLC) relies on finding a series of MLC configurations to deliver properly the treatment. The efficiency of such series is measured by the total beam-on time and the total setup time. In our work, we study the minimization of these efficiency criteria from an algorithmic point of view, for new variants of MLCs: the rotating MLC and the dual-layer MLC. In addition, we propose an approximation algorithm to find a series of configurations that minimizes the total beam-on time for the rotating MLC

A quantitative evaluation of single photon emission computed tomography (SPECT) and planar scintigraphic imaging may be valuable for both diagnostic and therapeutic purposes. For an accurate quantification it is usually necessary to correct for attenuation and scatter and in some cases also for septal penetration. For planar imaging a background correction for the contribution from over- and underlying tissues is needed. In this work a few correction methods have been evaluated and further developed. Much of the work relies on the Monte Carlo method as a tool for evaluation and optimisation. A method for quantifying the activity of I-125 labelled antibodies in a tumour inoculated in the flank of a mouse, based on planar scintigraphic imaging with a pin-hole collimator, has been developed and two different methods for background subtraction have been compared. The activity estimates of the tumours were compared with measurements in vitro. The major part of this work is attributed to SPECT. A method for attenuation and scatter correction of brain SPECT based on computed tomography (CT) images of the same patient has been developed, using an attenuation map calculated from the CT image volume. The attenuation map is utilised not only for attenuation correction, but also for scatter correction with transmission dependent convolution subtraction (TDCS). A registration method based on fiducial markers, placed on three chosen points during the SPECT examination, was evaluated. The scatter correction method, TDCS, was then optimised for regional cerebral blood flow (rCBF) SPECT with Tc-99m, and was also compared with a related method, convolution scatter subtraction (CSS). TDCS has been claimed to be an iterative technique. This requires however some modifications of the method, which have been demonstrated and evaluated for a simulation with a point source. When the Monte Carlo method is used for evaluation of corrections for septal penetration, it is important that interactions in the collimator are taken into account. A new version of the Monte Carlo program SIMIND with this capability has been evaluated by comparing measured and simulated images and energy spectra. This code was later used for the evaluation of a few different methods for correction of scatter and septal penetration of I-123 brain SPECT. The methods were CSS, TDCS and a method where correction for scatter and septal penetration are included in the iterative reconstruction. This study shows that quantitative accuracy in I-123 brain SPECT benefits from separate modelling of scatter and septal penetration.

Certes malalties neurològiques estan associades amb problemes en els sistemes de neurotransmissió. Una aproximació a l'estudi d'aquests sistemes és la tomografia d'emissió SPECT (Single Photon Emission Computed Tomography) com a tècnicano-invasiva que proporciona imatges funcionals representatives de l'activitat neuronal. Aquesta tècnica permet la visualització i l'anàlisi de diferents òrgans i teixits dins l'àmbit de la Medicina Nuclear.Malgrat que la inspecció visual de la imatge a vegades és suficient per establir el diagnòstic, la quantificació dels paràmetres de la imatge reconstruida poden millorar la fiabilitat i exactitud del diagnòstic precoç de la malaltia. En particular, la quantificació d'estudis de neurotransmissors de dopamina pot ajudar a detectar els estadis inicials de malalties com el Parkinson. Així mateix, la quantificació permet un seguiment més acurat de l'evolució de la malaltia i una evaluació dels efectes de la terapèutica aplicada.La quantificació es veu afectada pels efectes degradants de la imatge com són el soroll estadístic, la resposta del sistema col.limador/detector i l'efecte de dispersió i/o atenuació dels fotons en la seva interacció amb la matèria. Alguns d'aquests efectes poden ser corregits mitjançant l'ús d'algoritmes de reconstrucció iteratius.L'objectiu d'aquesta tesi és aconseguir una quantificació tant absoluta com relativa dels valors numèrics de la imatge reconstruida de manera que reprodueixin la distribució d'activitat real del pacient en el moment de l'adquisició de l'estudi de SPECT. Per aconseguir-ho s'han desenvolupat diferents codis i algoritmes per millorar els mètodes de reconstrucció existents i validar-ne els seus resultats.La validació i millora dels algoritmes s'ha basat en l'ús de tècniques de simulació Monte Carlo. S'han analitzat els diferents codis Monte Carlo disponibles en l'àmbit de la Medicina Nuclear i s'ha escollit SimSET. La interpretació dels resultats obtinguts i la comparació amb els resultats experimentals ens van dur a incorporar modificacions en el codi original. D'aquesta manera vam obtenir i validar SimSET com a generador d'estudis de SPECT a partir de pacients i objectes virtuals.La millora dels algoritmes es va basar en la incorporació de models analítics de la resposta del sistema col.limador/detector. La modelització del sistema es va implementar per diferents configuracions i energies de la font amb la utilització del codi Monte Carlo PENELOPE. Així mateix es va dissenyar un nou algoritme iteratiu que incorporés l'efecte 3D del sistema i es va tenir en compte la valoració de la imatge en tot el seu volum.Finalment, es va proposar una correcció de l'scattering utilitzant el simulador SimSET modificat per tal d'accelerar el procés de reconstrucció. Els valors reconstruits de la imatge ens han permès recuperar més d'un 95\% dels valors originals, permetent per tant la quantificació absoluta de les imatges de SPECT. / Many forms of brain diseases are associated with problems in the neurotransmission systems. One approach to the assessment of such systems is the use of Single Photon Emission Computed Tomography (SPECT) brain imaging. Neurotransmission SPECT has become an important tool in neuroimaging and is today regarded as a useful method in both clinical and basic research. SPECT is able to non-invasively visualize and analyze different organs and tissues functions or properties in Nuclear Medicine.Although visual inspection is often sufficient to assess neurotransmission imaging, quantification might improve the diagnostic accuracy of SPECT studies of the dopaminergic system. In particular, quantification of neurotransmission SPECT studies in Parkinson Disease could help us to diagnose this illness in the early pre-clinical stages. One of the main research topics in SPECT is to achieve early diagnosis, indeed preclinical diagnosis in neurodegenerative illnesses. In this field detailed analysis of shapes and values of the region of interest (ROIs) of the image is important, thus quantification is needed. Moreover, quantification allows a follow-up of the progression of disease and to assess the effects of potential neuroprotective treatment strategies. Therefore, the aim of this thesis is to achieve quantification of both the absolute activity values and the relative values of the reconstructed SPECT images.Quantification is affected by the degradation of the image introduced by statistical noise, attenuation, collimator/detector response and scattering effects. Some of these degradations may be corrected by using iterative reconstruction algorithms, which thus enable a more reliable quantification. The importance of correcting degradations in reconstruction algorithms to improve quantification accuracy of brain SPECT studies has been proved.Monte Carlo simulations are the --gold standard' for testing reconstruction algorithms in Nuclear Medicine. We analyzed the available Monte Carlo codes and we chose SimSET as a virtual phantom simulator. A new stopping criteria in SimSET was established in order to reduce the simulation time. The modified SimSET version was validated as a virtual phantom simulator which reproduces realistic projection data sets in SPECT studies.Iterative algorithms permit modelling of the projection process, allowing for correction of spatially variant collimator response and the photon crosstalk effect between transaxial slices. Thus, our work was focused on the modelling of the collimator/detector response for the parallel and fan beam configurations using the Monte Carlo code PENELOPE. Moreover, a full 3D reconstruction with OS-EM algorithms was developed.Finally, scattering has recognized to be one of the most significant degradation effects in SPECT quantification. Nowadays this subject is an intensive field of research in SPECT techniques. Monte Carlo techniques appear to be the most reliable way to include this correction. The use of the modified SimSET simulator accelerates the forward projection process although the computational burden is already a challenge for this technique.Full 3D reconstruction simultaneously applied with Monte Carlo-based scattering correction and the 3D evaluation procedure is a major upgrade technique in order to obtain valuable, absolute quantitative estimates of the reconstructed images. Once all the degrading effects were corrected, the obtained values were 95\% of the theoretical values. Thus, the absolute quantification was achieved.

The diploma thesis on the topic "Activation of Collimating System of Linear Accelerator through Photon Radiation and its Impact on the Doses Received by the Staff" is divided into two parts, a theoretical and a practical part. The introductory theoretical part is devoted to the basic information about ionizing radiation. What are the types of ionizing radiation, its characteristics, properties and sources of ionizing radiation. Furthermore, there are mentioned direct and indirect interactions of ionizing radiation, a brief description of charged particle accelerators, collimator systems and radioisotope irradiation devices. Another part deals with radiation protection, basic legislation, methods and principles of radiation protection, personal dosimetry and medical supervision of radiation workers. Literary sources, available internet links and valid legal regulations were used for the work. In the practical part, a number of measurements were carried out to measure and to analyse the doses of secondary radiation of the linear accelerator collimator system for different photon beam energies, depending on time, distance from source, position of radiologic assistant around the table when working with the patient, as well as sizes of irradiated field. The aim of the work was to find out how large the doses of secondary radiation are, although measurable, but their values are not sufficient to be detected by personal dosimeters of radiological assistants. Confirm the hypothesis that the doses from the secondary radiation of the linear accelerator collimator system are so low that the dose power does not exceed 0.031 mGy/hr. The results obtained from various measurements are processed into transparent tables and graphically displayed. Based on the results of the measurements, the hypotheses were confirmed.

The diploma thesis on "Radiation exposure of persons working at risk of ionising radiation at the Pilsen University Hospital" is divided into two parts. The first analyses personal effective doses of the employees of the Pilsen University Hospital in 20092013, and the second focuses on measurements of secondary radiation created after the activation of collimator systems of linear accelerators. The introduction of the theoretical part discusses the history of radiology, followed by a summary of information on the sources of ionising radiation, its characteristics, properties, methods of interaction with the environment and biological effects on organisms. The chapter on radiation protection focuses on basic legislative regulations relevant to the topic. In the Czech Republic, radiation protection of people working with sources of ionising radiation is mostly based on Act No. 18/1997 Coll., on peaceful uses of nuclear energy, and Regulation of the State Office for Nuclear Safety No. 307/2002 Coll., on radiation protection. The thesis also lists dose limits and basic information about personal dosimetry, and the theoretical section is concluded with information on the methods of protecting personnel and on provided healthcare. The thesis uses as its sources primary literature, internet links, current legislation and data from the database of the State Office for Nuclear Safety on records from personal dosimeters in the analysed period. The thesis had two objectives. The first was to compare levels of exposure at the Pilsen University Hospital. The analysis involved 579 persons in total; after arranging the data into tables and dividing employees into groups by the type of tasks they perform and their job, it was possible to compare median value indicators, confirming the hypothesis that persons carrying out intervention tasks are exposed to more ionising radiation. In order to compare the development of doses over time, a double-selection t-test was performed on data from 2009 and 2013, confirming the effectiveness of anti-radiation measures adopted at the University Hospital and a reduction in the exposure of employees in this period. The second objective was to confirm or deny the hypothesis that secondary radiation created by collimator systems, while measurable, is not sufficiently large to be detected by personal dosimeters. In order to achieve this objective, measurements were carried out at the Oncology and Radiology Clinic of the Pilsen University Hospital. The first measurements tried to determine the relationship between dose and time at various levels of energy, the second compared the relationship between dose and distance from the collimator plane and the third monitored the number of exposures until the collimator plates are saturated and dose is no longer increased. All results were arranged in tables and projected in charts. The results of the research confirmed the hypothesis that secondary radiation created during the use of high-energy equipment is just below the detection limits of personal dosimeters. For this reason, it is recommended to frequently rotate personnel working with the equipment.

La proportion de survivants à un cancer dans la population des pays développés augmente rapidement. Dans plus de la moitié des cas, la radiothérapie a été une composante de leur traitement. Les rayons ionisants alors administrés peuvent induire de graves conséquences à long terme, en particulier les cancers radio-induits et les maladies cardiovasculaires. Ces évènements sont dus non seulement aux fortes doses administrées au volume cible, mais également aux doses plus faibles, de quelques milligray à quelques gray, non souhaitées, mais inévitablement administrées dans le reste du corps du patient par la dose hors champ. L’évolution des techniques de planification du traitement et de l’informatique en médecine permettent aujourd’hui d’obtenir, systématiquement, l’évaluation précise des doses les plus fortes administrées au patient. Les doses faibles à intermédiaires administrées en dehors du faisceau de traitement, ne sont pour leur part, ni habituellement prises en compte, ni correctement évaluées par les systèmes actuels de planification du traitement. L’objectif de ce travail était de proposer des méthodes pour estimer le rayonnement hors champ des faisceaux de photons des accélérateurs de radiothérapie externe. L’utilisation d’une bibliothèque graphique nous a permis de réaliser une représentation géométrique 3D partielle des appareils de traitement et des sources photoniques responsables de la dose reçue par le patient. Nous avons déterminé l’intensité de ces sources en utilisant des mesures réalisées dans des champs simples. Le modèle ainsi calibré permettait de simuler la variation de l’intensité des sources en fonction de la taille du champ. Cette approche a permis de décrire avec succès la variation de la dose mesurée par TLD en fonction de la distance et de la taille du champ en dehors de champs carrés. Les écarts entres les doses calculées et celles mesurées étaient inférieurs à 10 %. Une application dans des conditions cliniques a été menée, l’écart était alors en moyenne de 25 %. / The number of cancer survivors in developed counties increases rapidly. Fifty percent of patients treated for cancer will receive radiation therapy as part of their treatment. Ionizing radiation may induce severe long term effects, including secondary cancers and cardio-vascular diseases. Long term effects are not only due to high doses delivered in target volumes, but also to lower doses, ranging from several milligrays to several grays, undesired, but inevitably delivered in the rest of the patient’s body outside the treatment beams. Improvements in treatment planning technics and the use of computers in medicine made it possible to systematically estimate, prior to treatment, the highest doses delivered to the patient’s body. However, lower doses delivered outside the treatment beams are neither taken into account nor evaluated by present treatment planning systems. The aim of our work was to establish methods to estimate radiation doses outside photon beams from accelerators used in external radiation therapy. A graphics library was used to render a partial 3D representation of the accelerator and the photon sources associated. The intensity of these sources was determined using measurements performed in simple geometry fields. The calibrated model was hence used to estimate the source intensity variation with respect to field size. Using this method, we were able to estimate the variations of the TLD measured doses with respect to distance and field size with a 10% average discrepancy between calculations and measurements for points outside the field. Also, when testing the model in a clinical setup, the average discrepancy increased to 25%.

SPECT (Single Photon Emission Computed Tomography) is the modality of choice for myocardial perfusion imaging due to the high sensitivity and specificity, and the lower cost of equipment and radiotracers compared to PET. Dynamic SPECT imaging provides new possibilities for myocardial perfusion imaging by encoding more information in the reconstructed images in the form of time-activity functions. The recent introduction of small solid-state SPECT cameras using multiple pinhole collimators, such as the GE Discovery NM 530c, offers the ability to obtain accurate myocardial perfusion information with markedly decreased acquisition times and offers the possibility to obtain quantitative dynamic perfusion information. This research targets two aspects of dynamic SPECT imaging with the intent of contributing to the improvement of projection and reconstruction methods. First, we propose an adaptation of distance-driven projection to SPECT imaging systems using single-pinhole collimator detectors. The proposed distance-driven projection approach accounts for the finite size of the pinhole, the possibly coarse discretization of the detector and object spaces, and the tilt of the detector surface. We evaluate the projection method in terms of resolution and signal to noise ratio (SNR). We also propose two maximum a posteriori (MAP) iterative image reconstruction methods employing kernel density estimators. The proposed reconstruction methods cluster time-activity functions (or intensity values) by their spatial proximity and similarity, each of which is determined by spatial and range scaling parameters respectively. The results of our experiments support our belief that the proposed reconstruction methods are especially effective when performing reconstructions from low-count measurements. / Thesis / Doctor of Philosophy (PhD)