Es wird erwartet, dass die Integration der Magnetresonanztomografie (MRT) in die Protonentherapie die Treffgenauigkeit bei der Strahlentherapie für Krebserkrankungen deutlich verbessern wird. Besonders für Tumoren in beweglichen Organen des Thorax oder des Abdomens könnte die MRT-integrierte Protonentherapie (MRiPT) eine Synchronisierung der Bestrahlung mit der Tumorposition ermöglichen, was zu einer verminderten Normalgewebsdosis und weniger Nebenwirkungen führen könnte. Bis heute ist solch eine Integration jedoch aufgrund fehlender Studien zu potenziellen gegenseitigen Störeinflüssen dieser beiden Systeme nicht vollzogen worden. Diese Arbeit widmete sich zwei solcher Störeinflüsse, und zwar der Ablenkung des Protonenstrahls im Magnetfeld des MRT- Scanners, und umgekehrt, dem Einfluss der elekromagnetischen Felder der Protonentherapieanlage und des Protonenstrahls selbst auf die MRT-Bilder. Obwohl vorangegangene Studien den derzeitigen Konsens aufgezeigt haben, dass die Trajektorie eines abgebremsten Protonenstrahls im homogenen Phantom in einem transversalen Magnetfeld vorhersagbar ist, zeigte sich im quantitativen Vergleich der publizierten Modelle, der im ersten Teil dieser Arbeit vorgestellt wurde, dass die Vorhersagen dieser Modelle nur für eine begrenzte Anzahl von Kombinationen aus Magnetfeldstärke und Protonenenergie übereinstimmen. Die Schwächen bestehender analytischer Modelle wurden deshalb analysiert und quantifiziert. Kritische Annahmen und die mangelnde Anwendbarkeit auf realistische, d.h. inhomogene Magnetfeldstärken und Patientengeometrien wurden als Hauptprobleme identifiziert. Um diese zu überwinden, wurde ein neues semianalytisches Modell namens RAMDIM entwickelt. Es wurde gezeigt, dass dieses auf realistischere Fälle anwendbar und genauer ist als existierende analytische Modelle und dabei schneller als Monte-Carlo-basierte Teilchenspursimulationen. Es wird erwartet, dass dieses Modell in der MRiPT Anwendung findet zur schnellen und genauen Ablenkungsberechnung, zur Betrahlungsplanoptimierung und bei der MRT-geführten Strahlnachführung. In einem zweiten Schritt wurde die magnetfeldinduzierte Protonenstrahlablenkung in einem gewebeähnlichen Material durch Filmdosimetrie erstmalig gemessen und mit Monte-Carlo-Simulationen verglichen. In einem transversalen Magnetfeld einer Flussdichte von 0,95 T wurde experimentell gezeigt, dass die laterale Versetzung des Bragg-Peaks für Protonenenergien zwischen 80 und 180 MeV in PMMA zwischen 1 und 10 mm liegt. Die Retraktion des Bragg-Peaks war ≤ 0,5 mm. Es wurde gezeigt, dass die gemessene Versetzung des Bragg-Peaks innerhalb von 0,8 mm mit Monte-Carlo-basierten Vorhersagen übereinstimmt. Diese Ergebnisse weisen darauf hin, dass die Protonenstrahlablenkung durch Monte-Carlo-Simulationen genau vorhersagbar ist und damit der Realisierbarkeit der MRiPT nicht im Wege steht. Im zweiten Teil dieser Arbeit wurde erstmalig ein MRT-Scanner in eine Protonenstrahlführung integriert. Hierfür wurde ein offener Niederfeld-MRT-Scanner am Ende einer statischen Forschungsstrahlführung einer Protonentherapieanlage platziert. Die durch das statische Magnetfeld des MRT-Scanners hervorgerufene Strahlablenkung wurde bei der Ausrichtung des MRT-Scanners berücksichtigt. Die sequenzabhängigen, veränderlichen Gradientenfelder hatten keinen messbaren Einfluss auf das transversale Strahlprofil hinter dem MRT-Scanner. Die Magnetfeldhomogenität des Scanners lag innerhalb der Herstellervorgaben und zeigte keinen relevanten Einfluss von Rotationen der Protonengantry im benachbarten Bestrahlungsraum. Eine magnetische Abschirmung war zum gleichzeitigen Betrieb des MRT-Scanners und der Protonentherapieanlage nicht notwendig. Dies beweist die Machbarkeit gleichzeitiger Bestrahlung und Bildgebung in einem ersten MRiPT Aufbau. Die MRT-Bildqualität des Aufbaus wurde darauffolgend anhand eines angepassten Standardprotokolls aus Spin-Echo- und Gradienten-Echo-Sequenzen quantifiziert und es wurde gezeigt, dass die Bildqualität sowohl ohne als auch mit gleichzeitiger Bestrahlung hinreichend ist. Alle bestimmten geometrischen Parameter stimmten mit den physikalischen Abmessungen des verwendeten Phantoms innerhalb eines Bildpixels überein. Wie es für Niederfeld-MRT-Scanner üblich ist, war das Signal-Rausch-Verhältnis (SNR) der MRT-Bilder gering, was im Vergleich zu den Standardkriterien zu einer geringen Bildhomogenität und zu einem hohen Geisterbildanteil im Bild führte. Außerdem wurde aufgrund von Unsicherheiten in der Hochfrequenzkalibrierung des MRT-Scanners eine starke Schwankung der vertikalen Phantomposition mit einem Interquartilabstand von bis zu 1,5 mm beobachtet. T2*-gewichtete Gradientenechosequenzen zeigten zudem aufgrund von Magnetfeldinho- mogenitäten relevante ortsabhängige Bildverzerrungen. Es wurde gezeigt, dass die meisten Bildqualitätsparameter mit und ohne gleichzeitige Betrahlung äquivalent sind. Es wurde jedoch ein signifikanter Betrahlungseinfluss in Form von einer vertikalen Bildverschiebung und einer Verminderung des SNR beobachtet, die durch eine Änderung im Magnetfeld des MRT-Scanners erklärt werden können, welche durch zu diesem Feld parallel ausgerichtete Komponenten im Fernfeld der Strahlführungsmagneten hervorgerufen wird. Während das verminderte SNR vermutlich irrelevant ist (Dif- ferenz im Median ≤ 1,5), ist die sequenzabhängige Bildverschiebung (Differenz im Median bis zu 0,7 mm) nicht immer vernachlässigbar. Diese Ergebisse zeigen, dass die MRT-Bilder durch gleichzeitige Bildgebung nicht schwerwiegend verfälscht werden, dass aber eine dedizierte Optimierung der Hochfrequenzkalibrierung und der MRT-Bildsequenzen notwendig ist. Im letzten Teil der Arbeit wurde gezeigt, dass ein stromabhängiger Einfluss des Protonenstrahls auf MRT-Bilder eines Wasserphantoms durch zwei verschiedene MRT-Sequenzen messbar gemacht und zur Reichweiteverifikation genutzt werden kann. Der Effekt war in verschiedenen Flüssigkeiten, jedoch nicht in viskosen und festen Materialen, nachweisbar und wurde auf Hitzekonvektion zurückgeführt. Es wird erwartet, dass diese Methode in der MRiPT für Konstanztests der Protonenreichweite bei der Maschinenqualitätssicherung nützlich sein wird. Zusammenfassend hat diese Arbeit die Genauigkeit der Vorhersage der Strahlablenkung quantifiziert und verbessert, sowie Potenzial und Realisierbarkeit einer gleichzeitigen MRT-Bildgebung und Protonenbestrahlung gezeigt. Die weitere Entwicklung eines ersten MRiPT-Prototyps ist demnach gerechtfertigt.:List of Figures v List of Tables vii 1 General Introduction 1 2 State of the Art: Proton Therapy and Magnetic Resonance Imaging 3 2.1 Proton Therapy 4 2.1.1 Physical Principle 4 2.1.2 Beam Delivery 7 2.1.3 Motion Management and the Role of Image Guidance 10 2.2 Magnetic Resonance Imaging 14 2.2.1 Physical Principle 14 2.2.2 Image Generation by Pulse Sequences 18 2.2.3 Image Quality 21 2.3 MR-Guided Radiotherapy 24 2.3.1 Offline MR Guidance 24 2.3.2 On-line MR Guidance 25 2.4 MR-Integrated Proton Therapy 28 2.4.1 Aims of this Thesis 32 3 Magnetic Field-Induced Beam Deflection and Bragg Peak Displacement 35 3.1 Analytical Description 36 3.1.1 Review of Analytical Models 36 3.1.2 New Model Formulation 41 3.1.3 Evaluation of Analytical and Numerical Models 44 3.1.4 Discussion 51 3.2 Monte Carlo Simulation and Experimental Verification 54 3.2.1 Verification Setup 54 3.2.2 Monte Carlo Simulation 56 3.2.3 Experimental Verification 60 3.2.4 Discussion 61 3.3 Summary 63 4 Integrated In-Beam MR System: Proof of Concept 65 4.1 Integration of a Low-Field MR Scanner and a Static Research Beamline 65 4.1.1 Proton Therapy System 66 4.1.2 MR Scanner 66 4.1.3 Potential Sources of Interference 67 4.1.4 Integration of Both Systems 68 4.2 Beam and Image Quality in the Integrated Setup 70 4.2.1 Beam Profile 70 4.2.2 MR Magnetic Field Homogeneity 72 4.2.3 MR Image Quality - Qualitative In Vivo and Ex Vivo Test 74 4.2.4 MR Image Quality - Quantitative Phantom Tests 77 4.3 Feasibility of MRI-based Range Verification 86 4.3.1 MR Sequences 86 4.3.2 Proton Beam Parameters 88 4.3.3 Target Material Dependence 91 4.3.4 Discussion 92 4.4 Summary 96 5 Discussion and Future Perspectives 99 6 Summary/Zusammenfassung 105 6.1 Summary 105 6.2 Zusammenfassung 108 Bibliography I Supplementary Information XXIX A Beam Deflection: Experimental Measurements XXIX A.1 Setup XXIX A.2 Film Handling and Evaluation XXX A.3 Uncertainty Estimation XXX B Beam Deflection: Monte Carlo Simulations XXXIII B.1 Magnetic Field Model XXXIII B.2 Uncertainty Estimation XXXIV C Integrated MRiPT Setup XXXVI C.1 Magnetic Field Map XXXVI C.2 Sequence Parameters XXXVI C.3 Image Quality Parameters XLII C.4 Range Verification Sequences XLII / The integration of magnetic resonance imaging (MRI) into proton therapy is expected to strongly increase the targeting accuracy in radiation therapy for cancerous diseases. Especially for tumours situated in mobile organs in the thorax and abdomen, MR-integrated proton therapy (MRiPT) could enable the synchronisation of irradiation to the tumour position, resulting in less dose to normal tissue and reduced side effects. However, such an integration has been hindered so far by a lack of scientific studies on the potential mutual interference between the two components. This thesis was dedicated to two of these sources of interference, namely the deflection of the proton beam by the magnetic field of the MR scanner and, vice versa, alterations of the MR image induced by the electromagnetic fields of the proton therapy facility and by the beam itself. Although previous work has indicated that there is general consensus that the trajectory of a slowing down proton beam in a homogeneous phantom inside a transverse magnetic field is predictable, a quantitative comparison of the published methods, as presented in the first part of this thesis, has shown that predictions of different models only agree for certain proton beam energies and magnetic flux densities. Therefore, shortcomings of previously published analytical methods have been analysed and quantified. The inclusion of critical assumptions and the lack of applicability to realistic, i.e. non-uniform, magnetic flux densities and patient anatomies have been identified as main problems. To overcome these deficiencies, a new semi-analytical model called RAMDIM has been developed. It was shown that this model is both applicable to more realistic setups and less assumptive than existing analytical approaches, and faster than Monte Carlo based particle tracking simulations. This model is expected to be useful in MRiPT for fast and accurate deflection estimations, treatment plan optimisation, and MR-guided beam tracking. In a second step, the magnetic field-induced proton beam deflection has been measured for the first time in a tissue-mimicking medium by film dosimetry and has been compared against Monte Carlo simulations. In a transverse magnetic field of 0.95 T, it was experimentally shown that the lateral Bragg peak displacement ranges between 1 mm and 10 mm for proton energies between 80 and 180 MeV in PMMA. Range retraction was found to be ≤ 0.5 mm. The measured Bragg peak displacement was shown to agree within 0.8 mm with Monte Carlo simulations. These results indicate that proton beam deflection in a homogeneous medium is accurately predictable for intermediate proton beam energies and magnetic flux densities by Monte Carlo simulations and therefore not impeding the feasibility of MRiPT. In the second part of this thesis, an MR scanner has been integrated into a proton beam line for the first time. For this purpose, an open low-field MR scanner has been placed at the end of a fixed horizontal proton research beam line in a proton therapy facility. The beam deflection induced by the static magnetic field of the scanner was taken into account for alignment of the beam and the FOV of the scanner. The pulse sequence-dependent dynamic gradient fields did not measurably affect the transverse beam profile behind the MR scanner. The MR magnetic field homogeneity was within the vendor’s specifications and not relevantly influenced by the rotation of the proton gantry in the neighbouring treatment room. No magnetic field compensation system was required for simultaneous operation of the MR scanner and the proton therapy system. These results proof that simultaneous irradiation and imaging is feasible in an in-beam MR setup. The MR image quality of the in-beam MR scanner was then quantified by an adapted standard protocol comprising spin and gradient echo imaging and shown to be acceptable both with and without simultaneous proton beam irradiation. All geometrical parameters agreed with the mechanical dimensions of the used phantom within one pixel width. As common for low-field MR scanners, the signal-to-noise ratio (SNR) of the MR images was low, which resulted in a low image uniformity and a high ghosting ratio in comparison to the standardised test criteria. Furthermore, a strong fluctuation of the vertical phantom position due to uncertainties in the pre-scan frequency calibration was observed, with an interquartile range of up to 1.5 mm. T2*-weighted gradient echo images showed relevant nonuniform deformations due to magnetic field inhomogeneities. Most image quality parameters were shown to be equivalent with and without simultaneous proton beam irradiation. However, a significant influence of simultaneous irradiation was observed as a shift of the vertical phantom position and a decrease in the SNR, both of which can be explained by a change in the B0 field of the MR scanner induced by components of the fringe field of the beam line magnets directed parallel to B0 . While the decrease in SNR is not expected to be relevant (median differences were within 1.5 ), the sequence-dependent phantom shift (median differences of up to 0.7 mm) can become non-negligible. These results show that the MR images are not severely distorted by simultaneous irradiation, but a dedicated optimisation of the pre-scan RF calibration and the MR sequences is required for MRiPT. Lastly, a current-dependent influence of the proton beam on the MR image was shown to be measurable in water in two different MR sequences, which allowed for range verification measurements. The effect was observed in different liquids but not in highly viscose and solid materials, and most probably induced by heat convection. This method is expected to be useful in MRiPT for consistency tests of the proton range during machine-specific quality assurance. In conclusion, this work has improved and quantified the accuracy of beam deflection predictions and shown the feasibility and potential of in-beam MR imaging, justifying further research towards a first MRiPT prototype.:List of Figures v List of Tables vii 1 General Introduction 1 2 State of the Art: Proton Therapy and Magnetic Resonance Imaging 3 2.1 Proton Therapy 4 2.1.1 Physical Principle 4 2.1.2 Beam Delivery 7 2.1.3 Motion Management and the Role of Image Guidance 10 2.2 Magnetic Resonance Imaging 14 2.2.1 Physical Principle 14 2.2.2 Image Generation by Pulse Sequences 18 2.2.3 Image Quality 21 2.3 MR-Guided Radiotherapy 24 2.3.1 Offline MR Guidance 24 2.3.2 On-line MR Guidance 25 2.4 MR-Integrated Proton Therapy 28 2.4.1 Aims of this Thesis 32 3 Magnetic Field-Induced Beam Deflection and Bragg Peak Displacement 35 3.1 Analytical Description 36 3.1.1 Review of Analytical Models 36 3.1.2 New Model Formulation 41 3.1.3 Evaluation of Analytical and Numerical Models 44 3.1.4 Discussion 51 3.2 Monte Carlo Simulation and Experimental Verification 54 3.2.1 Verification Setup 54 3.2.2 Monte Carlo Simulation 56 3.2.3 Experimental Verification 60 3.2.4 Discussion 61 3.3 Summary 63 4 Integrated In-Beam MR System: Proof of Concept 65 4.1 Integration of a Low-Field MR Scanner and a Static Research Beamline 65 4.1.1 Proton Therapy System 66 4.1.2 MR Scanner 66 4.1.3 Potential Sources of Interference 67 4.1.4 Integration of Both Systems 68 4.2 Beam and Image Quality in the Integrated Setup 70 4.2.1 Beam Profile 70 4.2.2 MR Magnetic Field Homogeneity 72 4.2.3 MR Image Quality - Qualitative In Vivo and Ex Vivo Test 74 4.2.4 MR Image Quality - Quantitative Phantom Tests 77 4.3 Feasibility of MRI-based Range Verification 86 4.3.1 MR Sequences 86 4.3.2 Proton Beam Parameters 88 4.3.3 Target Material Dependence 91 4.3.4 Discussion 92 4.4 Summary 96 5 Discussion and Future Perspectives 99 6 Summary/Zusammenfassung 105 6.1 Summary 105 6.2 Zusammenfassung 108 Bibliography I Supplementary Information XXIX A Beam Deflection: Experimental Measurements XXIX A.1 Setup XXIX A.2 Film Handling and Evaluation XXX A.3 Uncertainty Estimation XXX B Beam Deflection: Monte Carlo Simulations XXXIII B.1 Magnetic Field Model XXXIII B.2 Uncertainty Estimation XXXIV C Integrated MRiPT Setup XXXVI C.1 Magnetic Field Map XXXVI C.2 Sequence Parameters XXXVI C.3 Image Quality Parameters XLII C.4 Range Verification Sequences XLII

There are approximately 1.8 million diagnoses of colorectal cancer, 1 million diagnoses of stomach cancer, and 0.6 million diagnoses of esophageal cancer each year globally. An automatic computer-assisted diagnostic (CAD) tool to rapidly detect colorectal and esophagogastric cancer tissue in optical images would be hugely valuable to a surgeon during an intervention. Based on a colon dataset with 12 patients and an esophagogastric dataset of 10 patients, several state-of-the-art machine learning methods have been trained to detect cancer tissue using hyperspectral imaging (HSI), including Support Vector Machines (SVM) with radial basis function kernels, Multi-Layer Perceptrons (MLP) and 3D Convolutional Neural Networks (3DCNN). A leave-one-patient-out cross-validation (LOPOCV) with and without combining these sets was performed. The ROC-AUC score of the 3DCNN was slightly higher than the MLP and SVM with a difference of 0.04 AUC. The best performance was achieved with the 3DCNN for colon cancer and esophagogastric cancer detection with a high ROC-AUC of 0.93. The 3DCNN also achieved the best DICE scores of 0.49 and 0.41 on the colon and esophagogastric datasets, respectively. These scores were significantly improved using a patient-specific decision threshold to 0.58 and 0.51, respectively. This indicates that, in practical use, an HSI-based CAD system using an interactive decision threshold is likely to be valuable. Experiments were also performed to measure the benefits of combining the colorectal and esophagogastric datasets (22 patients), and this yielded significantly better results with the MLP and SVM models.

Innovations and new advancements in intraoperative real-time imaging have gained significant importance in the field of gastric cancer surgery in the recent past. Currently, the most promising procedures include indocyanine green fluorescence imaging (ICG-FI) and hyperspectral imaging or multispectral imaging (HSI, MSI). ICG-FI is utilized in a broad range of clinical applications, e.g., assessment of perfusion or lymphatic drainage, and additional implementations are currently investigated. HSI is still in the experimental phase and its value and clinical relevance require further evaluation, but initial studies have shown a successful application in perfusion assessment, and prospects concerning non-invasive tissue and tumor classification are promising. The application of machine learning and artificial intelligence technologies might enable an automatic evaluation of the acquired image data in the future. Both methods facilitate the accurate visualization of tissue characteristics that are initially indistinguishable for the human eye. By aiding surgeons in optimizing the surgical procedure, image-guided surgery can contribute to the oncologic safety and reduction of complications in gastric cancer surgery and recent advances hold promise for the application of HSI in intraoperative tissue diagnostics.

No description available.

Les travaux de cette Thèse porte sur des éléments de guidage d'une thérapie focale du cancer de la prostate par Ultrasons Focalisés Haute Intensité (HIFU). Actuellement l'IRM est la seule technique d'imagerie qui permet de localiser la tumeur dans la prostate. Par contre, la tumeur n'est pas visible dans l'échographie qui est l'imagerie utilisée pour la planification et le guidage de la thérapie. L'objectif de la Thèse est de proposer des techniques de recalage de l'IRM T2 vers l'échographie. Deux approches ont été explorées : 1) Une approche basée région et plus particulièrement une méthode de descripteurs de la texture en échographie basée sur des moments invariants en rotation et en échelle. Ces descripteurs sont sensibles à la distribution du speckle quelle que soit son échelle ou son orientation. Certains de ces descripteurs permettent de caractériser les régions présentant une même distribution de speckle, mais nous avons également constaté que certains autres de ces descripteurs étaient sensibles aux contours de ces régions. Cette caractéristique nous semble très utile pour les méthodes de segmentation intégrant à la fois l'information de contours et l'information de régions (contours actifs, graph cut, etc.). 2) Une approche basée surface. Nous avons adapté une méthode de Définition Optimale de la Surface (OSD) à la segmentation de la prostate en IRM T2. Et plus particulièrement une segmentation concurrente de la prostate, de la vessie et du rectum par OSD multi-objets. Les surfaces de la prostate extraites du volume échographique et du volume IRM T2 nous ont permis d'envisager une première tentative de recalage surface/surface par la méthode des démons. / The work of this Thesis is focused on image guided focal therapy of prostate cancer by High Intensity Focused Ultrasound (HIFU). Currently MRI is the only imaging technique that can locate the tumor in prostate. In contrast, the tumor is not visible in the ultrasound image which is used to guide the HIFU planning and therapy. The aim of the Thesis is to provide registration techniques of T2 MRI to ultrasound. Two approaches were explored: 1) Region-based registration. More particularly, we studied an ultrasound texture descriptors based on moments invariant to rotation and scaling. These descriptors are sensitive to speckle distribution regardless of the scale or the orientation. As we expected, some of these descriptors can be used to characterize regions sharing a similar speckle spatial distribution. But, we also found that some other descriptors were sensitive to the contours of these regions. This property seems very useful to adapt the classical boundary-based or mixed region/boundary-based segmentation methods (active contours, graph cut, etc.) to process US images. 2) Surface-based registration approach.. We adapted the Optimal Definition Surface (OSD) method to the segmentation of the prostate in T2 MRI, Furthermore, we proposed the multiple-objects OSD which is a concurrent segmentation of the prostate, bladder and rectum. Finally we used the prostate surface extracted from the ultrasound volume and from T2 MRI in a surface-to-surface elastic registration scheme. This registration allowed us to merge the preoperative MR information in the peroperative US volume.

CONTEXTO E OBJETIVO: O manejo do carcinoma hepatocelular (HCC) é desafiador devido a agressividade tumoral e cirrose associada. Faltam opções locais efetivas após falha à quimioembolização transarterial (TACE). Nosso objetivo foi testar através de estudo prospectivo fase II, a eficácia e segurança da Radioterapia Estereotáctica Corpórea (SBRT) em pacientes com HCC e resposta parcial ou contraindicação à TACE. MÉTODO: Pacientes com até 5 lesões de HCC restritas ao fígado realizaram SBRT na dose de 30 a 50 Gy em 5 frações. O desfecho primário foi sobrevida livre de progressão das lesões tratadas. Os desfechos secundários foram sobrevida livre de progressão hepática, sobrevida livre de progressão a distância, sobrevida global e toxicidade. Este estudo está registrado em clinicaltrials.gov sob o número NCT02221778. RESULTADO: De novembro de 2014 a junho de 2018, 19 pacientes receberam SBRT na dose mediana de 40 Gy (range 30 - 50 Gy). Todos tinham escore de Child Pugh A. A idade mediana foi de 67 anos (range 42-84 anos). A doença de base foi hepatite C em 42%, hepatite B em 26% e álcool em 26%. TACE prévia foi realizada em 84% dos pacientes, com mediana de duas TACEs (range 0-5). O número mediano de lesões foi dois (range 1-4), com tamanho mediano de 4 cm (1,5-10 cm). 32% dos pacientes tinham trombose tumoral; a AFP mediana pré-tratamento foi de 142,5 ng/ml (range 4,2 - 5 494 ng/ml). A sobrevida livre de progressão local em 1 ano foi de 80% (IC95%, 50% a 93%). A sobrevida livre de progressão hepática, sobrevida livre de progressão a distância e sobrevida global em 1 ano foram, respectivamente, de 52%, 82% e 84%. Não houve toxicidades clínicas grau 3 ou 4. Toxicidades laboratoriais até grau 3 ocorreram em 3 pacientes (16%). Resposta radiológica completa foi atingida em 53% dos pacientes, 42% tiveram resposta parcial. O tempo mediano para melhor resposta foi de 3,4 meses (range 2,4-12,6 meses). CONCLUSÃO: A SBRT é uma opção eficaz, segura e não invasiva em pacientes com HCC e resposta parcial ou contraindicação à quimioembolização / BACKGROUND AND PURPOUSE: Management of hepatocellular carcinoma (HCC) is challenging due to tumor aggressiveness and associated cirrhosis. There is paucity of effective local options after failure of transarterial chemoembolization (TACE). Our objective was to test in the setting of a phase II prospective study, the efficacy and safety of Stereotactic Body Radiation Therapy (SBRT) in patients with partial response or unsuitable for TACE. METHODS: Patients with HCC and up to five liver-only lesions received SBRT 30 to 50 Gy in 5 fractions. Primary endpoint was local progression-free survival. Secondary endpoints were liver progression-free survival, distant progression-free survival, overall survival and toxicity. This study is registered at clinicaltrials.gov NCT02221778. RESULTS: From Nov 2014 through Jun 2018, 19 patients received SBRT with a median dose of 40Gy (range 30 - 50 Gy). All patients were Child Pugh A. Median age was 67 years old (range 42-84y). Underlying liver disease was hepatitis C in 42% of patients, hepatitis B in 26% and alcohol-related in 26%. 84% received previous TACE, with a median of two TACEs (range 0-5). Patients had a median of two lesions (range 1-4), with median size of 4 cm (1.5-10 cm). 32% had tumor vascular thrombosis; median pretreatment AFP was 142.5 ng/ml (range 4.2 - 5,494 ng/ml). 1y local progression-free survival was 80% (95% CI, 50% to 93%). 1y liver progression-free survival, distant progression-free survival and overall survival were, respectively, 52%, 82% and 84%. No patient had clinical grade 3 or 4 toxicities. Laboratory toxicities up to grade 3 occurred in three patients (16%). Complete radiological response was seen in 53% of patients, 42% had partial response. Median time for best response was 3.4 months (range 2.4-12.6 months). CONCLUSION: SBRT is an effective, safe and noninvasive option in HCC patients with partial response or unsuitable for TACE

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Abstract Minimally invasive surgery (MIS) techniques have seen rapid growth as methods for improved operational procedures. The main technology of MIS is based on image guided surgery (IGS) devices, namely surgical navigators, surgical robotics and image scanners. With their widespread use in various fields of surgery, methods and tools that may be used routinely in the hospital setting for “real world” assessment of the accuracy of these devices are lacking. In this thesis the concept of accuracy testing was developed to meet the needs of quality assurance of navigators and robots in a hospital environment. Thus, accuracy was defined as the difference between actual and measured distances from an origin, also including determination of directional accuracy within a specific volume. Two precision engineered accuracy assessment phantoms with assessment protocols were developed as advanced materials and methods for the community. The phantoms were designed to include a common region of surgical interest (ROSI) that was determined to roughly mimic the size of the human head. These tools and methods were utilized in accuracy assessment of two commercial navigators, both enabling the two most widely used tracking modalities, namely the optical tracking system (OTS) and the electromagnetic tracking system (EMTS). Also a study of the accuracy and repeatability of a prototype surgical interactive robot (SIRO) was done. Finally, the phantoms were utilized in spatial accuracy assessment of a commercial surgical 3D CT scanner, the O-Arm. The experimental results indicate that the proposed definitions, tools and methods fulfill the requirements of quality assurance of IGS devices in the hospital setting. The OTS and EMTS tracking modalities were nearly identical in overall accuracy but had unique error trends. Also, the accuracy of the prototype robot SIRO was in the range recommended in the IGS community. Finally, the image quality of the O-Arm could be analyzed using the developed phantoms. Based on the accuracy assessment results, suggestions were made when setting up each IGS device for surgical procedures and for new applications in minimally invasive surgery. / Tiivistelmä Mini-invasiivisen eli täsmäkirurgian tekniikoita ja teknologioita on alettu hyödyntää viime aikoina yhä enemmän. Tavoitteena on ollut parantaa kirurgisten operaatioiden tarkkuutta ja turvallisuutta. Täsmäkirurgiassa käytetyt teknologiat pohjautuvat kuvaohjattuihin kirurgisiin paikannuslaitteisiin. Kuvaohjattuihin laitteisiin kuuluvat navigaattorit, kirurgiset robotit ja kuvantalaitteet. Näiden laitteistojen kehittyminen on mahdollistanut tekniikoiden hyödyntämisen monialaisessa kirurgiassa. Paikannuslaitteistojen ja robottien yleistyminen on kuitenkin nostanut sairaaloissa esiin yleisen ongelman paikannustarkkuuden määrittämisessä käytännön olosuhteissa. Tässä väitöskirjassa esitetään kirurgisten yksiköiden käyttöön menetelmä sekä kaksi uutta fantomia ja protokollaa käytössä olevien paikannuslaitteistojen tarkkuuden määrittämiseen. Fantomit suunniteltiin sisältämään ennalta määritetty kirurginen kohdealue, mikä rajattiin käsittämään ihmisen kallon tilavuus. Fantomeita ja protokollaa hyödynnettiin kahden kaupallisen paikannuslaitteen tarkkuuden määrityksessä. Navigaattorit käyttivät optiseen ja elektromagneettiseen paikannukseen perustuvaa tekniikkaa. Lisäksi työssä kehitetyillä menetelmillä tutkittiin prototyyppivaiheessa olevan kirurgisen robotin paikannus- ja toistotarkkuutta sekä tietokonetomografialaitteen O-kaaren kuvan tarkkuuden määritystä. Kokeellisten tulosten perusteella työssä kehitetyt fantomit ja protokollat ovat luotettavia ja tarkkoja menetelmiä kirurgisten paikannuslaitteistojen tarkkuuden määrittämiseen sairaalaoloissa. Kirurgisten navigaattoreiden tarkkuuden määritystulokset osoittivat optisen ja elektromagneettisen paikannustekniikan olevan lähes yhtä tarkkoja. Prototyyppirobotin tarkkuus oli tulosten perusteella kirjallisuudessa esitettyjen suosituksien mukainen. Lisäksi O-kaaren kuvanlaatua voitiin tutkia kehitetyillä fantomeilla. Tarkkuudenmääritystulosten perusteella työssä ehdotetaan menetelmiä laitteistojen optimaalisesta käytöstä leikkaussalissa sekä laajennetaan niiden käyttömahdollisuuksia. Tuloksia voidaan hyödyntää myös paikannuslaitteistojen kehittämistyössä.

Diffuse optical tomography (DOT) is one of the promising imaging modalities that pro- vides functional information of the soft biological tissues in-vivo, such as breast and brain tissues. The near infrared (NIR) light (600-1000 nm) is the interrogating radiation, which is typically delivered and collected using fiber bundles placed on the boundary of the tissue. The internal optical property distribution is estimated via model-based image reconstruction algorithm using these limited boundary measurements. Image reconstruction problem in DOT is known to be non-linear, ill-posed, and some times under-determined due to the multiple scattering of NIR light in the tissue. Solving this inverse problem requires regularization to obtain meaningful results, with Tikhonov-type regularization being the most popular one. The choice of the regularization parameter dictates the reconstructed optical image quality and is typically chosen empirically or based on prior experience. An automated method for optimal selection of regularization parameter that is based on regularized minimal residual method (MRM) is proposed and is compared with the traditional generalized cross-validation method. The results obtained using numerical and gelatin phantom data indicate that the MRM-based method is capable of providing the optimal regularization parameter. A new approach that can easily incorporate any generic penalty function into the diffuse optical tomographic image reconstruction is introduced to show the utility of non-quadratic penalty functions. The penalty functions that were used include, quadratic (`2), absolute (`1), Cauchy, and Geman-McClure. The regularization parameter in each of these cases were obtained automatically using the generalized cross-validation (GCV) method. The reconstruction results were systematically compared with each other via utilization of quantitative metrics, such as relative error and Pearson correlation. The reconstruction results indicate that while quadratic penalty may be able to provide better separation between two closely spaced targets, it's contrast recovery capability is limited and the sparseness promoting penalties, such as `1, Cauchy, Geman-McClure have better utility in reconstructing high-contrast and complex-shaped targets with Geman-McClure penalty being the most optimal one. Effective usage of image guidance by incorporating the refractive index (RI) variation in computational modeling of light propagation in tissue is investigated to assess its impact on optical-property estimation. With the aid of realistic patient breast three-dimensional models, the variation in RI for different regions of tissue under investigation is shown to influence the estimation of optical properties in image-guided diffuse optical tomography (IG-DOT) using numerical simulations. It is also shown that by assuming identical RI for all regions of tissue would lead to erroneous estimation of optical properties. The a priori knowledge of the RI for the segmented regions of tissue in IG-DOT, which is difficult to obtain for the in vivo cases, leads to more accurate estimates of optical properties. Even inclusion of approximated RI values, obtained from the literature, for the regions of tissue resulted in better estimates of optical properties, with values comparable to that of having the correct knowledge of RI for different regions of tissue. Image reconstruction in IG-DOT procedure involves reduction of the number of optical parameters to be reconstructed equal to the number of distinct regions identified in the structural information provided by the traditional imaging modality. This makes the image reconstruction problem to be well-determined compared to traditional under- determined case. Still, the methods that are deployed in this case are same as the one used for traditional diffuse optical image reconstruction, which involves regularization term as well as computation of the Jacobian. A gradient-free Nelder-Mead simplex method was proposed here to perform the image reconstruction procedure and shown to be providing solutions that are closely matching with ones obtained using established methods. The proposed method also has the distinctive advantage of being more efficient due to being regularization free, involving only repeated forward calculations.

Objectifs : Etablir des corrélations dose-volume effet entre les paramètres dosimétriques proposés par le GEC-ESTRO et la probabilité de survenue d’événements tels que le contrôle tumoral ou une toxicité radio-induite.Matériel et méthodes : Les données cliniques et dosimétriques de cohortes de patientes traitées à Gustave Roussy et dans différents centres ont été confrontées. Dans un premier temps les paramètres dosimétriques de la curiethérapie 3D ont été comparés à ceux de la curiethérapie classique. Dans un second temps, la topographie des zones les plus exposées des organes à risque, ainsi que l’impact des mouvements de la vessie, du rectum, et du colon sigmoïde sur l’évaluation de la dose délivrée, ont été étudiés. Enfin, des analyses dose-volume effets ont été réalisées.Résultats : Les valeurs des paramètres dosimétriques volumétriques (D2cm3) de la vessie et du rectum se sont révélées faiblement corrélées et significativement supérieures aux doses évaluées aux points de l’ICRU ou à un point vésical alternatif. Les zones les plus exposées de la vessie et du rectum sont apparues situées au-dessus des points de l’ICRU. Les mouvements des organes autour de l’implant pendant la délivrance du traitement sont apparus marginaux pour la vessie et sigmoïde, en dehors de variations individuelles. En revanche, la dose délivrée au rectum étaient en moyenne plus élevée que le dose planifiée. Les analyses dose-volume effets ont montré des corrélations significatives entre D0.1cm3 et D2cm3 et la probabilité de survenue d’une morbidité tardive urinaire ou rectale. De la même manière, des corrélations significatives ont été établies entre la D90 des CTV à haut risque et à risque intermédiaire et la probabilité d’obtention du contrôle local. Divers caractéristiques tumorales (largeur au diagnostic, volume du CTV-HR, stade FIGO), impactent ces relations, de même que l’étalement total du traitement.Conclusion : Des corrélations dose-volume effets ont été établies entre les paramètres dosimétriques modernes et la probabilité d’obtenir le contrôle local ou d’entraîner une morbidité tardive. En ce qui concerne le contrôle tumoral, les objectifs de prescription doivent être personnalisés en fonction de critères carcinologiques. Pour les organes à risque, de contraintes de dose basées sur l’expérience de la curiethérapie 3D peuvent être établies, mais doivent être affinées dans de futures études en fonction de cofacteurs tels que les comorbidités. Les points gardent un intérêt en recherche clinique, pour l’étude de la morbidité vésicale ou vaginale.Ce travail a l'objet de 6 publications dans des revues internationales à comité de lecture. La septième est présentée sous forme de manuscrit. / Objectives: To establish dose-volume effects correlations between volumetric dosimetric parameters proposed by the GEC-ESTRO and the probability of occurrence of events such as tumor control or radiation-induced toxicity.Methods: Clinical and dosimetric data of patients treated at Gustave Roussy and in different centers have been reviewed. At first step, dosimetric parameters of image-guided brachytherapy were compared with those of conventional brachytherapy. Secondly, the topography of the most exposed areas of the organs at risk, and the impact of the movements of the bladder, rectum, and sigmoid colon on the assessment of the delivered dose, were studied. Finally, analyzes dose-volume effects were performed.Results: The values of volumetric dosimetric parameters (D2cm3) of the bladder and rectum appeared weakly correlated and significantly higher than the doses evaluated at ICRU points of bladder and rectum , an even in an alternative bladder point. The most exposed areas of the bladder and rectum appeared located above the points of the ICRU. The movements of the organs around the implant during the delivery of the treatment appeared marginal for the bladder and sigmoid, apart from individual variations. However, the mean delivered dose to the rectum was higher than the planned dose. Dose-volume effects correlations showed significant correlations between D0.1cm3 and D2cm3 and the probability of occurrence of urinary or rectal late morbidity. Similarly, significant correlations have been established between the D90 of the high risk, intermediate risk-CTV and the probability of achieving local control. Various tumor characteristics (width, HR-CTV volume, FIGO stage) impact these relationships, as well as the treatment time.Conclusion: Dose-volume effects correlations have been established between modern dosimetric parameters and the probability of achieving local control or cause late morbidity. Regarding tumor control, prescription aims must be customized according to oncologic criteria. For organs at risk, new dose constraints based on 3D brachytherapy experience can be established but should be refined in future studies based on cofactors such as comorbidities. The points retain an interest in clinical research for the study of bladder or vaginal morbidity.