@phdthesis{Schmitt2013,
  author    = {Schmitt, Peter},
  title     = {MR imaging of tumors: Approaches for functional and fast morphological characterization},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-135967},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2013},
  abstract  = {The subject of this work was to develop, implement, optimize and apply methods for quantitative MR imaging of tumors. In the context of functional and physiological characterization, this implied transferring techniques established in tumor model research to human subjects and assessing their feasibility for use in patients. In the context of the morphologic assessment and parameter imaging of tumors, novel concepts and techniques were developed, which facilitated the simultaneous quantification of multiple MR parameters, the generation of "synthetic" MR images with various contrasts, and the fast single-shot acquisition of purely T2-weighted images.},
  subject      = {Kernspintomografie},
  language  = {en}
}
@phdthesis{Nube2013,
  author    = {Nube, Jacqueline Sui Lin},
  title     = {Comparative Analysis of Vaccinia Virus-Encoded Markers Reflecting Actual Viral Titres in Oncolytic Virotherapy},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-85689},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2013},
  abstract  = {Using viruses to treat cancer is a novel approach to an age-old disease. Oncolytic viruses are native or recombinant viruses that have the innate or enhanced capability to infect tumour cells, replicate within the tumour microenvironment and subsequently lyse those cells. One representative, the vaccinia virus (VACV), belongs to the orthopoxvirus genus of the Poxviridae family. GLV-1h68, a recombinant and attenuated vaccinia virus devel- oped by the Genelux Corporation, is a member of this family currently being tested in various phase I/II clinical trials under the name GL-ONC1. It has been shown to specif- ically replicate in tumour cells while sparing healthy tissue and to metabolise prodrug at or transport immunological payloads to the site of affliction. Since imaging modalities offer little insight into viral replication deep within the body, and because oncolytic virotherapy is dependent on replication within the target tissue, the need for a monitoring system is evident. Pharmacokinetic analysis of this oncolytic agent was to give insight into the dynamics present in tumours during treatment. This, in turn, would give clinicians the opportunity to monitor the efficacy as early as possible after the onset of treatment, to observe treatment progression and possibly to gauge prognosis, without resorting to invasive procedures, e.g. biopsies. A criteria for viable biomarkers was that it had to be directly dependent on viral replica- tion. Ideally, a marker for treatment efficacy would be specific to the treatment modality, not necessarily the treatment type. Such a marker would be highly detectable (high sen- sitivity), specific for the treatment (high specificity), and present in an easily obtained specimen (blood). Taking this into consideration, the biomarkers were chosen for their potential to be indicators of viral replication. Thus, the biomarkers analysed in this thesis are: the native proteins expressed by the viral genes A27L and B5R, the virally encoded recombinant proteins β-galactosidase, β-glucuronidase, green fluorescent protein (GFP), carboxypeptidase G2 (CPG2) and carcinoembryonic antigen (CEA). Each marker is under the control of one of five different promoters present. All recombinant viruses used in this thesis express A27L, B5R, GFP and β-glucuronidase and all are derived from the parental virus GLV-1h68. In addition to these markers, GLV-1h68 expresses β-galactosidase; GLV-1h181 expresses CPG2. [...]},
  subject      = {Onkolyse},
  language  = {en}
}
@phdthesis{Huang2013,
  author    = {Huang, Ting},
  title     = {Vaccinia Virus-mediated Therapy of Solid Tumor Xenografts: Intra-tumoral Delivery of Therapeutic Antibodies},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-91327},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2013},
  abstract  = {Over the past 30 years, much effort and financial support have been invested in the fight against cancer, yet cancer still represents the leading cause of death in the world. Conventional therapies for treatment of cancer are predominantly directed against tumor cells. Recently however, new treatments options have paid more attention to exploiting the advantage of targeting the tumor stroma instead. Vaccinia virus (VACV) has played an important role in human medicine since the 18th century as a vaccination against smallpox. In our laboratory, the recombinant, replication-competent vaccinia virus, GLV-1h68, was shown to enter, colonize and destroy cancer cells both in cell culture, and in vivo, in xenograft models (Zhang, Yu et al. 2007). In addition, combined therapy of GLV-1h68 and anti-VEGF immunotherapy significantly enhanced antitumor therapy in vivo (Frentzen, Yu et al. 2009). In this study, we constructed several new recombinant VACVs carrying genes encoding different antibodies against fibroblast activation protein (FAP) in stroma (GLV-1h282), nanobody against the extracellular domain of epidermal growth factor receptor (EGFR, GLV-1h442) or antibodies targeting both vascular endothelial growth factor (VEGF) and EGFR (GLV-1h444) or targeting both VEGF and FAP (GLV-1h446). The expression of the recombinant proteins was first verified using protein analytical methods, SDS-gel electrophoresis, Western blot analysis, immunoprecipitation (IP) assays and ELISA assays. The proteins were detected after infection of the cells with the different VACVs and the recombinant proteins purified by affinity adsorption. The purified antibodies were shown to specifically bind to their respective antigens. Secondly, the infection and replication capability of all the virus strains was analyzed in cell culture using several human tumor cell lines (A549, FaDu or DU145), revealing that all the new recombinant VACVs were able to infect cancer cells with comparable efficiency to the parental viruses from which they were derived. Thirdly, the antitumor efficacy of the new recombinant VACVs was evaluated in vivo using several human cancer xenograft models in mice. In A549 and DU145 xenografts, the new recombinant VACVs exhibited an enhanced therapeutic efficacy compared to GLV-1h68 with no change in toxicity in mice. In the FaDu xenograft, treatment with GLV-1h282 (anti-FAP) significantly slowed down the speed of tumor growth compared to GLV-1h68. Additionally, treatment with the recombinant VACVs expressed the various antibodies achieved comparable or superior therapeutic effects compared to treatment with a combination of GLV-1h68 and the commercial therapeutic antibodies, Avastin, Erbitux or both. Next, the virus distribution in tumors and organs of treated mice was evaluated. For most of the viruses, the virus titer in tumors was not signficantly diffferent than GLV-1h68. However, for animals treated with GLV-1h282, the virus titer in tumors was significantly higher than with GLV-1h68. This may be the reason for enhanced antitumor efficacy of GLV-1h282 in vivo. Lastly, the underlying mechanisms of therapeutic antibody-enhanced antitumor effects were investigated by immunohistochemistry. Blood vessels density and cell proliferation in tumors were suppressed after treatment with the antibody-encoded VACVs. The results indicated that the suppression of angiogenesis or cell proliferation in tumors may cause the observed therapeutic effect. In conclusion, the results of the studies presented here support the hypothesis that the treatment of solid tumors with a combination of oncolytic virotherapy and immunotherapy has an additive effect over each treatment alone. Moreover, expression of the immunotherapeutic antibody by the oncolytic VACV locally in the tumor enhances the antitumor effect over systemic treatment with the same antibody. Combined, these results indicate that therapy with oncolytic VACVs expressing-therapeutic antibodies may be a promising approach for the treatment of cancer.},
  subject      = {Vaccinia-Virus},
  language  = {en}
}
@phdthesis{Roesch2013,
  author    = {Roesch, Johannes},
  title     = {Der Einfluss von Rotations- und Translationsbewegungen bei kranieller stereotaktischer Radiotherapie},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-106137},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2013},
  abstract  = {Hintergrund: Kranielle Stereotaxie ist ein wichtiges Therapieinstrument zur Behandlung kranieller neoplastischer L{\"a}sionen. Mittels bildgef{\"u}hrter Radiotherapie konnten in den vergangenen Jahren Genauigkeit und Komfort der Patientenlagerung essentiell verbessert werden. Folgende Arbeit untersucht die Bedeutung der bildgef{\"u}hrten Patientenlagerung (Image Guidance) in Bezug auf geometrische Unsicherheiten und deren Einfluss auf die dosimetrische Verteilung. Material und Methoden: In W{\"u}rzburg wurden zwischen 2006 und 2010, 98 kranielle L{\"a}sionen in 71 Patienten radiochirurgisch behandelt. Mittels Cone-Beam CT wurden die Patientenverlagerungen bezogen auf alle 6 Freiheitsgrade vor Behandlungsbeginn (n=98) sowie nach der Therapie (n=64) aufgezeichnet. Aus den Daten f{\"u}r die einzelnen Raumachsen wurde der absolute Versatz (3D-Vektor) sowie maximale Rotation um die resultierende Drehachse berechnet. Die Prae- sowie Posttherapeutische Verlagerungen wurden im Planungssystem simuliert. F{\"u}r Szenarien mit unterschiedlichen Sicherheits{\"a}umen (0 mm,1 mm, 2 mm) wurde der Ausgleich der Translationen sowie der Rotationen in Bezug auf Dosis-Konformit{\"a}t und Zielabdeckung getrennt untersucht. Ergebnisse: Der mittlere Prae-IG Versatz betrug 3.96 mm ± 1.89 mm mit einer mittleren maximalen Rotation im Raum von 2,02°±0,84°. Der mittlere Lagerungsfehler nach Therapieende betrug 0,88mm±0,61mm mit einer mittleren maximalen Rotation von 0,65°±0,64°. Die Verlagerung w{\"a}hrend der Bestrahlung korrelierte signifikant mit der Behandlungszeit (0,7mm±0,5mm f{\"u}r t<23min; 1,2mm±0,7mm f{\"u}r t>23min). Die Simulation der Behandlung ohne IG-Ausgleich zeigte einen Einbruch der Zielabdeckung (Coverage Index) von 96,0\%±5,7\% auf 72,1\%±19,0\% und der Konformit{\"a}t (Paddick Conformity Index) von 73,3\%±11,1\% auf 43,4\%±17,8\%. Pro 1mm Abweichung nahmen Zielabdeckung sowie Konformit{\"a}t um 6\% bzw. 10\% ab. Alleiniger Ausgleich der Translationen ohne Rotationen f{\"u}hrte zu nicht signifikanten Einbussen. Bewegungen w{\"a}hrend der Bestrahlung f{\"u}hrten zu einem Abfall des CI auf 94,3\%±6,8\% bzw. des PCI auf 70,4\%±10,8\%. Ein 1mm Sicherheitssaum gen{\"u}gte um diese Bewegungen zu kompensieren Schlussfolgerungen: Bildgef{\"u}hrte Radiotherapie ist ein wichtiges Instrument zur Verbesserung der Therapiepr{\"a}zision. Unter offensichtlichen Voraussetzungen kann auf den pr{\"a}therapeutischen Ausgleich der rotatorischen Komponente bei kranieller Stereotaxie verzichtet werden. Bewegungen w{\"a}hrend der Behandlung reduzieren die gew{\"u}nschte Zielabdeckung sofern dem nicht durch geeignete Sicherheitss{\"a}ume Rechnung getragen wird.},
  subject      = {Radiochirurgie},
  language  = {de}
}