Die vorliegende Arbeit untesucht die Darstellung tumoröser und entzündlicher muskuloskelettaler Läsionen mit der diffusionsgewichteten MRT-Bildgebung bei Kindern und Jugendlichen. Es sollten die Machbarkeit und die Zuverlässigkeit der Methode in der klinischen Routinebildgebung überprüft werden. Zusätzlich untersuchten wir den Einsatz von ADC-Werten zur Differenzierung von malignen und benignen Tumoren sowie bei inflammatorischen Knochen- und Weichteilbefunden. Wie die klassische MRT, ist die diffusionsgewichtete Bildgebung nicht-invasiv: da der Bildkontrast allein mittels magnetischer Feldgradienten erzielt wird, erfordert sie weder eine Injektion von Kontrastmitteln, noch den Einsatz von ionisierender Strahlung. Sie garantiert eine schnelle Aquisitionstechink um Artefakte zu begrenzen und die Untersuchungen kindergerechter zu gestalten. Die von uns erfassten Daten wurden in zwei unterschiedlichen Studien aufgeteilt. Die Erste Studie erfasst Ergebnisse bzgl. der Detektion und Dignitätsabschätzung kinderlicher muskuloskelettaler Tumoren mittels diffusionsgewichteten MRT Bilder. Das zweite Forschungsprojekt, befasst sich mit dem erstmaligen Einsatz der diffusionsgewichteten MRT zur Identifikation und Differenzierung von Knochenmarködem, Weichteilödem und Synovitis bei pädiatrischen Patienten. / This study investigates the presentation of tumorous and inflammatory musculoskeletal lesions by diffusion-weighted MRI imaging in children and adolescents. The feasibility and reliability of the method should be tested in clinical routine imaging. In addition, we investigated the use of ADC values ​​for the differentiation of malignant and benign tumors as well as for inflammatory bone and soft tissue findings. Like the classical MRI, diffusion-weighted imaging is non-invasive: since the image contrast is achieved solely by means of magnetic field gradients, it does not require either the injection of contrast agents or the use of ionizing radiations. This technique allows a quick aquisition to limit artefacts and to shape the investigations in a more child-friendly way. The data we collected were divided into two different studies. The first study records results concerning the detection and dignity-assessment of childhood musculoskeletal tumors using diffusion-weighted MRI images. The second research project deals with the initial use of diffusion-weighted MRI for the identification and differentiation of bone marrow edema, soft tissue edema and synovitis in Pediatric patients.

In dieser Studie wurden 280 Patienten, die im Zeitraum vom 01.01.2008 bis 30.06.2012 am Universitätsklinikum Würzburg aufgrund einer Raumforderung der Leber operiert wurden, analysiert. Davon konnten 150 Patienten mit insgesamt 385 Tumoren bewertet werden. Die zentrale Fragestellung der Arbeit beschäftigte sich damit, die Sensitivität der MR-DWI mit anderen präoperativen bildgebenden Untersuchungsmethoden zu bewerten. Bisherige Studien beschäftigten sich bereits mit dem Vergleich der MR-DWI mit anderen diagnostischen Verfahren. Jedoch wurden dabei nicht konkret die aus Sicht eines Chirurgen wichtigen Punkte detailliert beleuchtet. In dieser Arbeit wurden daher die Ergebnisse der Befunde der MR-DWI, CT und konventionellem MRT dem intraoperativen und histopathologisch gesichertem Endbefund gegenübergestellt und bezüglich der Parameter: Tumordignität, Tumoranzahl, Tumorgröße und Tumorlokalisation verglichen. Während die Sensitivität der MR-DWI zur Tumorlokalisation etwas unter der Sensitivität der CT und MRT lag, konnten für die Parameter Tumoranzahl und Tumordignität bessere Ergebnisse der MR-DWI als für die CT herausgestellt werden. Die Genauigkeit der DWI für diese beiden Punkte liegt nah bei der hohen Sensitivität der MRT. Jedoch müssen die sehr guten Ergebnisse der MRT in dieser Arbeit durch die geringe Anzahl der MRT Untersuchungen relativiert werden. Bezüglich der Tumoranzahl ergibt sich bei der MR-DWI die höchste Sensitivität, gefolgt von MRT und CT. Zusammenfassend kann gesagt werden, dass die MR-DWI wie auch die CT und MRT ein sehr sensitives Verfahren zur Detektion von Leberläsionen darstellt. Dabei müssen gewisse Vor- und Nachteile gegenüber den anderen Methoden abgewogen werden. Eine als ungünstig zu wertende Strahlenexposition besteht nicht, ebenso kein zusätzlicher zeitlicher Aufwand. In nahezu allen hier untersuchten Bereichen zeigte die MR-DWI vorrangig bessere Resultate als die CT. Im Vergleich mit der MRT konnten geringfügig niedrigere oder ähnlich gute Werte ermittelt werden. In Bezug auf die Tumoranzahl war die MR-DWI das sensitivste Verfahren. Um die hier erbrachten Ergebnisse zu sichern, sollten zukünftige Studien die Homogenität der Patienten sowie die Anzahl der CT, MRT und MR-DWI Untersuchungen erhöhen. Weiterhin könnten die Geräteeinstellungen bei der MRDWI an bestimmte Fragestellungen angepasst und so genauere Ergebnisse erzielt werden. Bruegel et al konnte für unterschiedliche Leberläsionen bereits die charakteristischen ADC-Werte ermitteln. In einer weiteren Studie von Kilickesmez wurden ebenfalls maligne und benigne Leberläsionen über die entsprechenden ADC-Werte voneinander abgegrenzt. Daraus ergab sich die Empfehlung, zur Diagnostik von Leberläsionen die konventionelle MRT mit der MRDWI zu ergänzen. Ein weiterer Ansatzpunkt ist die Reduktion von Störfaktoren für die MR-DWI und damit die Verbesserung der Bildbeurteilung. In einer Arbeit von Yu-Chun wurde beispielsweise die optimale Temperatur für die MR-DWI Schnittbildgebung am Tiermodell angewandt und so auf molekularer Ebene die Artefaktbildung reduziert. Eine Verbesserung konnte auch durch Ergänzung der MR-DWI mit anderen Verfahren nachgewiesen werden. MR-DWI in Verbindung mit Kontrastmittel ergab eine erhöhte Sensitivität für kleine HCC bis 2cm als Kontrastmittel-MRT ohne DWI. Es ist zu erwarten, dass die MR-DWI in Zukunft durch exaktere Einstellungen der b- Werte und ADC-Messungen in Abhängigkeit der zu untersuchenden Organregion, durch Reduktion störender Faktoren oder durch Kombination mit anderen bildgebenden Verfahren zur Optimierung der präoperativen Diagnostik bei Lebertumoren beiträgt. / Objective: This study was realized to compare the sensitivity of difusion weighted MRI (DWI) with sensitivity of MRI and CT to find liver tumors. There were 4 parameters determined which are most important for surgeons in pre-surgical preparation: number of tumors, dignity, size and localisation in liver. The comparison was based on these 4 parameters. Materials an methods: In a period of 4 years and 6 months (2008-2012) were analysed 150 patients with 385 tumors. All preoperative findings in DWI, MRI and CT have been compared with intraoperative ultrasound and histopathological results. Results: Referring to the number of tumors DWI was more sensitive (55,68%) than CT (47,41) or MRI (27,78%). Also, in finding hepatocellular carcinoma the DWI had better sensitivity (93,74%) than CT (80%) or MRI (47,67%). In the parameter of size the DWI had correlation in 67,65%, better than CT (61,05%) and worse than MRI (71,42%). A correct correlation of dignity was found in DWI in 71,59%, in MRI 77,78% and in CT 60,91%. The sensitivity in the parameter localisation of DWI was 76,92% in comparison with CT 81,73% and MRI 85,19%. We suspect that the DWI is more sensitive to movements of patients while examination is being proceed. Conclusion: DWI is a very sensitive method for finding liver tumors. In the parameter number of tumors and finding of HCC is more sensitive than CT or MRI. In dignity and size its sensitivity is compareable with CT or MRI and only in localisation the results are a little bit worse. To improve the method for the future it’s neccessary to investigate how to switch off the sensibility for movement and also optimize some frame factors.

Trabalhos anteriores sobre a síntese de imagens de difusão por ressonância magnética se limitaram a estudos sobre estruturas microscópicas, menores que as dimensões típicas de um voxel (e.g., [BF08] [BF13] [LFS + 10] e [BA94]). Isto decorre em parte devido às metodologias utilizadas, que têm como ponto em comum serem simulações de tipo Monte Carlo, nas quais os elementos mínimos da simulação são as partículas de água. Portanto o custo computacional destas simulações é proporcional ao número de partículas a simular, e isto limita os volumes que podem ser simulados a tamanhos microscópicos. Propomos uma metodologia alternativa, que utiliza a imagem T 2 de uma amostra para sintetizar imagens de difusão por ressonância magnética. Os elementos mínimos desta nova metodologia são os pontos da imagem T 2 , e portanto seu custo computacional é proporcional à resolução da imagem T 2 utilizada, o que permite a síntese a partir de amostras de qualquer tamanho físico. Estas sínteses são realizadas por meio da integração numérica da equação do artigo seminal de Stejskal e Tanner [ST65] que relaciona a atenuação do sinal de ressonância magnética devida à difusão com os parâmetros da sequência de pulsos PGSE. Usamos os parâmetros típicos dessa sequência (b, gamma, tau\', g 0, g, delta e Delta), que podem ser configurados explicitamente em máquinas de ressonância magnética, para calcular valores do coeficiente de difusão aparente D em direções arbitrárias. Desenvolvemos software, disponibilizado [Bor] por licença GPL [Fou07], para realizar estas simulações, e para especificar uma máscara de direções, útil para modelar a difusão de uma amostra. Estas ferramentas permitem o estudo sistemático das variações dos parâmetros na síntese de imagens de difusão por ressonância magnética. Apresentamos um estudo de um fantoma de capilares imersos em água, exemplificando como utilizar as ferramentas para investigar a influência destes parâmetros na difusão da água da amostra. / Previous work on the synthesis of diffusion-weighted magnetic resonance imaging are limited to microscopic structures, smaller than the typical dimensions of a single voxel (e.g., [BF08] [BF13] [LFS + 10] and [BA94]). This is consequence, in part, of the methodologies used, that have in common the adoption of Monte Carlo simulation strategies, in which the minimal elements of simulation are the water particles. Therefore the computational cost of these simulations is proportional to the number of particles to simulate, and this limits the volume to be simulated to microscopic sizes. We propose a novel methodology, that uses the T 2 image from a sample to synthesize diffusion-weighted magnetic resonance images. The mininal elements of this novel methodology are the points of the T 2 image, and therefore its computational cost is proportional to the resolution of the T 2 image to be used, which allows the synthesis from samples of any physical size. These syntheses are made through numerical integration of the equation from the seminal article by Stejskal and Tanner [ST65] that relates the attenuation of the magnetic resonance signal due to diffusion to the parameters of the PGSE pulse sequence. We use the typical parameters of this sequence (b, gamma, tau\', g 0, g, delta and Delta), that can be explicitly configured in magnetic resonance machines, to calculate apparent diffusion coefficients D in arbitrary directions. We developed software, available [Bor] through GPL license [Fou07], to run these simulations, and to specify a mask of directions useful to model diffusion. These tools allow the systematic study of parameter variation in the synthesis of diffusion-weighted magnetic resonance images. We present a case study of a phantom made of capillary tubes immersed in water, to exemplify the use of these tools and how to investigate the influence of parameter variation on diffusion in the sample.

Trabalhos anteriores sobre a síntese de imagens de difusão por ressonância magnética se limitaram a estudos sobre estruturas microscópicas, menores que as dimensões típicas de um voxel (e.g., [BF08] [BF13] [LFS + 10] e [BA94]). Isto decorre em parte devido às metodologias utilizadas, que têm como ponto em comum serem simulações de tipo Monte Carlo, nas quais os elementos mínimos da simulação são as partículas de água. Portanto o custo computacional destas simulações é proporcional ao número de partículas a simular, e isto limita os volumes que podem ser simulados a tamanhos microscópicos. Propomos uma metodologia alternativa, que utiliza a imagem T 2 de uma amostra para sintetizar imagens de difusão por ressonância magnética. Os elementos mínimos desta nova metodologia são os pontos da imagem T 2 , e portanto seu custo computacional é proporcional à resolução da imagem T 2 utilizada, o que permite a síntese a partir de amostras de qualquer tamanho físico. Estas sínteses são realizadas por meio da integração numérica da equação do artigo seminal de Stejskal e Tanner [ST65] que relaciona a atenuação do sinal de ressonância magnética devida à difusão com os parâmetros da sequência de pulsos PGSE. Usamos os parâmetros típicos dessa sequência (b, gamma, tau\', g 0, g, delta e Delta), que podem ser configurados explicitamente em máquinas de ressonância magnética, para calcular valores do coeficiente de difusão aparente D em direções arbitrárias. Desenvolvemos software, disponibilizado [Bor] por licença GPL [Fou07], para realizar estas simulações, e para especificar uma máscara de direções, útil para modelar a difusão de uma amostra. Estas ferramentas permitem o estudo sistemático das variações dos parâmetros na síntese de imagens de difusão por ressonância magnética. Apresentamos um estudo de um fantoma de capilares imersos em água, exemplificando como utilizar as ferramentas para investigar a influência destes parâmetros na difusão da água da amostra. / Previous work on the synthesis of diffusion-weighted magnetic resonance imaging are limited to microscopic structures, smaller than the typical dimensions of a single voxel (e.g., [BF08] [BF13] [LFS + 10] and [BA94]). This is consequence, in part, of the methodologies used, that have in common the adoption of Monte Carlo simulation strategies, in which the minimal elements of simulation are the water particles. Therefore the computational cost of these simulations is proportional to the number of particles to simulate, and this limits the volume to be simulated to microscopic sizes. We propose a novel methodology, that uses the T 2 image from a sample to synthesize diffusion-weighted magnetic resonance images. The mininal elements of this novel methodology are the points of the T 2 image, and therefore its computational cost is proportional to the resolution of the T 2 image to be used, which allows the synthesis from samples of any physical size. These syntheses are made through numerical integration of the equation from the seminal article by Stejskal and Tanner [ST65] that relates the attenuation of the magnetic resonance signal due to diffusion to the parameters of the PGSE pulse sequence. We use the typical parameters of this sequence (b, gamma, tau\', g 0, g, delta and Delta), that can be explicitly configured in magnetic resonance machines, to calculate apparent diffusion coefficients D in arbitrary directions. We developed software, available [Bor] through GPL license [Fou07], to run these simulations, and to specify a mask of directions useful to model diffusion. These tools allow the systematic study of parameter variation in the synthesis of diffusion-weighted magnetic resonance images. We present a case study of a phantom made of capillary tubes immersed in water, to exemplify the use of these tools and how to investigate the influence of parameter variation on diffusion in the sample.

Durch Weiterentwicklungen der MR-Technologie hat die diffusionsgewichtete MRT in der Bildgebung des Abdomens zunehmend an Bedeutung gewonnen. Einige wenige Studien zeigten bereits vielversprechende Ergebnisse für den Einsatz der DWI in der Diagnostik und Verlaufsbeurteilung des Morbus Crohn. Ziel dieser Arbeit war es, zu untersuchen, ob die DWI zur Detektion entzündlicher Darmwandläsionen und extraluminaler Komplikationen bei pädiatrischen Patienten mit Morbus Crohn ebenso geeignet ist wie die kontrastmittelverstärkte MRT. Hierzu wurden retrospektiv die klinischen und MR-tomographischen Daten von 48 Kindern, Jugendlichen und jungen Erwachsenen mit Morbus Crohn sowie von 42 Kontrollpatienten ausgewertet, bei denen im Zeitraum zwischen Juli 2008 und Mai 2013 eine MRT-Untersuchung durchgeführt wurde. Aktuelle Befunde einer Ileokoloskopie waren als Referenz bei 60% der Morbus Crohn Patienten und bei etwa einem Drittel der Patienten der Kontrollgruppe vorhanden. Das Bestehen eines Morbus Crohn konnte bei 47 der insgesamt 48 Patienten anhand der diffusionsgewichteten Sequenzen und in 46 Fällen mittels der kontrastverstärkten T1w-Aufnahmen korrekt nachgewiesen werden. Extramurale Komplikationen wie Abszesse oder Fisteln konnten sowohl mittels DWI als auch durch die KM-MRT detektiert werden. Da die DWI weder eine intravenöse Kontrastmittelapplikation noch Atemanhaltetechniken erfordert, ist sie gerade bei pädiatrischen Patienten ein geeignetes Bildgebungsverfahren. Wegen der relativ geringen Ortsauflösung der diffusionsgewichteten Sequenzen sollte jedoch zusätzlich eine Standardsequenz, wie die T2-gewichtete HASTE-Sequenz, akquiriert werden. Nach den Ergebnissen dieser Studie ist die diffusionsgewichtete MRT zur Beurteilung der entzündlichen Veränderungen des Morbus Crohn sehr gut geeignet und besitzt das Potenzial, nicht nur ergänzend, sondern als Alternative zur KM-MRT zum Einsatz zu kommen. / The purpose of this retrospective study was to evaluate the detectability of inflammatory bowel lesions and of extramural complications with diffusion-weighted MRI (DWI), compared to contrast-enhanced MRI (CE-MRI), in pediatric patients with Crohn disease. The study included 48 children and young adults with Crohn disease and 42 matched controls who underwent routine MRI with DWI and contrast-enhanced T1-weighted sequences during a 5-year-period. Colonoscopy as reference standard was available in about two-thirds of the children with Crohn disease and in about one-third of controls. Overall diagnostic accuracy for identifying pediatric patients with inflammatory bowel lesions among patients and controls in our study was 99% (89/90) for DWI and 98% (88/90) for CE-MRI. In conclusion, the results suggest that free-breathing DWI has potential as an alternative to standard CE-MRI protocols in pediatric patients with known or suspected Crohn disease, without a substantial loss of diagnostic information and without the need for intravenous administration of contrast medium.

Malignant melanoma (MM) is the deadliest skin cancer with an ever-increasing incidence. New treatments have improved the prognosis for patients with advanced MM. Still, most patients do not respond, and the side effects can be severe, underlining the need for better therapies. The overall aim of this thesis was to evaluate new means to improve the treatment for patients with advanced MM. Immunostimulatory gene therapy (AdCD40L) was evaluated in a clinical study and BRAF-inhibitory treatment in rare cases of BRAF-mutated MM. Due to its immunogenicity, MM is an attractive target for immunostimulatory gene therapy. AdCD40L is an adenovirus carrying the human gene for CD40 ligand, which in different ways can stimulate the immune system to combat cancer. We conducted a Phase I/IIa study with AdCD40L in patients with metastatic MM having received established treatments. In cohort 1 (n=6), four weekly, intratumoural AdCD40L injections were given. In cohort 2 (n=9), low dose cyclophosphamide was added to increase the immune response. Since irradiation may act synergistically with immunotherapy, patients in cohort 3 (n=9) also received a single fraction of radiotherapy (8 Gy). This fraction was given towards the lesion selected for injections. The primary objectives were to assess the feasibility and safety of AdCD40L-treatment and secondarily its anti-tumour effects. Patients were thoroughly assessed for toxicity. The anti-tumour response was evaluated by imaging techniques (FDG-PET/CT, DW-MRI scans), tumour biopsies and blood tests. Plasma protein markers were measured with a multiplex platform. Another objective was to evaluate the potential of DW-MRI and FDG-PET/CT for prediction of AdCD40L treatment response, in terms of overall survival (OS). AdCD40L was well tolerated with mild transient reactions. Local and distant responses in PET/CT scans along with a significantly better 6-month survival in the cohorts that received cyclophosphamide conditioning were observed. Effector lymphocyte responses were elicited. All patients had an increased T effector/T regulatory-cell ratio and death receptors were significantly up-regulated post therapy. Inflammatory cytokines and other plasma proteins were altered in favourable ways by the AdCD40L treatment. The analyses support that the functional DWI parameters may be better early predictors of OS than the established metabolic and morphologic criteria of FDG-PET/CT and CT/MRI, respectively. In conclusion, the stimulation of the CD40 pathway to initiate anti-tumour immunity is a promising treatment alternative for MM patients. However, further studies with developed treatment schemes are warranted. In the first report ever on treatment of a pregnant patient with a BRAF-inhibitor, the therapy was initiated in the second trimester. The treatment with vemurafenib enabled prolonged gestation, hence reducing the risk of immaturity-related complications. Further, we report the first case worldwide of a patient with metastatic conjunctival melanoma who benefitted from treatment with vemurafenib. Additional studies are needed to assess the efficacy of BRAF -inhibitors in the different subtypes of ocular melanoma.

This master thesis focuses on dMRI (diffusion magnetic resonance imaging) and its dependance on diffusion in human brain tissue. It is described how to retrieve an image from gained data and its properties, advantages and disadvantages. It mentions problem in detecting kissing fibres due to its similarity with crossing fibres. Design of mathematical models of axons is decribed and suggested measurement to detect difference in signals for kissing and crossing fibres. It describes new simulator of diffusion-weighted MRI (dMRI) data which is able to generate it based on random walk algorithm with geometrical constraints not only for crossing fiber geometry, but also as o novelty for bending and kissing fiber geometries. This study contains results of simulations and disscusion about their usefulness with suggestions for simulator improvement. Simulated dMRI data shows significant difference in certain gradients. Data reconstruction shows, that these reults cannot be reconstructed into the same geometry as it was simulated for.

L'IRMd est un moyen non invasif permettant d'étudier in vivo la structure des fibres nerveuses du cerveau. Dans cette thèse, nous modélisons des données IRMd à l'aide de tenseurs d'ordre 4 (T4). Les problèmes de comparaison de groupes ou d'individu avec un groupe normal sont abordés, et résolus à l'aide d'analyses statistiques sur les T4s. Les approches utilisent des réductions non linéaires de dimension, et bénéficient des métriques non euclidiennes pour les T4s. Les statistiques sont calculées dans l'espace réduit, et permettent de quantifier la dissimilarité entre le groupe (ou l'individu) d'intérêt et le groupe de référence. Les approches proposées sont appliquées à la neuromyélite optique et aux patients atteints de locked in syndrome. Les conclusions tirées sont cohérentes avec les connaissances médicales actuelles. / DW-MRI is a non-invasive way to study in vivo the structure of nerve fibers in the brain. In this thesis, fourth order tensors (T4) were used to model DW-MRI data. In addition, the problems of group comparison or individual against a normal group were discussed and solved using statistical analysis on T4s. The approaches use nonlinear dimensional reductions, assisted by non-Euclidean metrics for T4s. The statistics are calculated in the reduced space and allow us to quantify the dissimilarity between the group (or the individual) of interest and the reference group. The proposed approaches are applied to neuromyelitis optica and patients with locked in syndrome. The derived conclusions are consistent with the current medical knowledge.