@phdthesis{MeirgebRother2015,
  author    = {Meir [geb. Rother], Juliane},
  title     = {Influence of oncolytic vaccinia viruses on metastases of human and murine tumors},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-118530},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2015},
  abstract  = {Cancer is one of the leading causes of death. 90\% of all deaths are caused by the effects of metastases. It is of major importance to successfully treat the primary tumor and metastases. Tumors and metastases often differ in their properties and therefore, treatment is not always successful. In contrast, those therapeutic agents can even promote formation and growth of metastases. Hence, it is indispensable to find treatment options for metastatic disease. One promising candidate represents the oncolytic virus therapy with vaccinia viruses. The aim of this work was to analyze two cell lines regarding their metastatic abilities and to investigate whether oncolytic vaccinia viruses are useful therapy options. The cell lines used were the human cervical cancer cell line C33A implanted into immune-compromised mice and the murine melanoma cell line B16F10, implanted into immune-competent mice. The initial point of the investigations was the observation of enlarged lumbar und renal lymph nodes in C33A tumor-bearing mice 35 days post implantation of C33A cells subcutaneously into immune-compromised nude mice. Subsequently, the presence of human cells in enlarged lymph nodes was demonstrated by RT-PCR. To facilitate the monitoring of cancer cell spreading, the gene encoding for RFP was inserted into the genome of C33A cells. In cell culture experiments, it was possible to demonstrate that this insertion did not negatively affect the susceptibility of the cells to virus infection, replication and virus-mediated cell lysis. The analysis of the metastatic process in a xenografted mouse model revealed the continuous progression of lumbar (LN) and renal (RN) lymph node metastasis after C33A-RFP tumor cell implantation. The lymph node volume and the amount of RFP-positive LNs and RNs was increasing from week to week in accordance with the gain of the primary tumor volume. Moreover, the metastatic spread of cancer cells in lymph vessels between lumbar and renal lymph nodes was visualized. Additionally, the haematogenous way of cancer cell migration was demonstrated by RFP positive cancer cells in blood vessels. The haematogenous route of spreading was confirmed by detecting micrometastases in lungs of tumor bearing mice. The next step was to investigate whether the recombinant oncolytic vaccinia virus GLV-1h68 is a suitable candidate to cure the primary tumor and metastases. Therefore, GLV-1h68 was systemically injected into C33A-RFP tumor bearing mice 21 days after tumor cell implantation. It was demonstrated that the volume of the primary tumor was drastically reduced, and the volume and the amount of RFP positive lumbar and renal lymph nodes were significantly decreasing compared to the untreated control group. Subsequently, this process was analyzed further by investigating the colonization pattern in the C33A-RFP model. It was shown that first the primary tumor was colonized with highest detectable virus levels, followed by LN and RN lymph nodes. Histological analyses revealed the proliferative status of tumor cells in the tumor and lymph nodes, the amount of different immune cell populations and the vascular permeability in primary tumors and lymph nodes having an influence on the colonization pattern of the virus. Whereby, the vascular permeability seems to have a crucial impact on the preferential colonization of tumors compared to lymph node metastases in this tumor model. C33A turned out to be a useful model to study the formation and therapy of metastases. However, a metastatic model in which the influence of the immune system on tumors and especially on tumor therapy can be analyzed would be preferable. Therefore, the aim of the second part was to establish a syngeneic metastatic mouse model. Accordingly, the murine melanoma cell line B16F10 was analyzed in immunocompetent mice. First, the highly attenuated GLV 1h68 virus was compared to its parental strain LIVP 1.1.1 concerning infection, replication and cell lysis efficacy in cell culture. LIVP 1.1.1 was more efficient than GLV-1h68 and was subsequently used for following mouse studies. Comparative studies were performed, comparing two different implantation sites of the tumor cells, subcutaneously and footpad, and two different mouse strains, FoxN1 nude and C57BL/6 mice. Implantation into the footpad led to a higher metastatic burden in lymph nodes compared to the subcutaneous implantation site. Finally, the model of choice was the implantation of B16F10 into the footpad of immune-competent C57BL/6 mice. Furthermore, it was inevitable to deliver the virus as efficient as possible to the tumor and metastases. Comparison of two different injection routes, intravenously and intratumorally, revealed, that the optimal injection route was intratumorally. In summary, the murine B16F10 model is a promising model to study the effects of the immune system on vaccinia virus mediated therapy of primary tumors and metastases.},
  subject      = {Krebs <Medizin>},
  language  = {en}
}
@phdthesis{Kierstein2015,
  author    = {Kierstein, Katharina},
  title     = {Postoperative Morbidit{\"a}t und {\"U}berleben nach laserchirurgischer pulmonaler Metastasenresektion},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-137888},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2015},
  abstract  = {Hintergrund und Zielsetzung: Eine zunehmende Anzahl von Studien belegt, dass Patienten mit pulmonaler Metastasierung extrathorakaler Tumore von einer chirurgischen Sanierung profitieren. Dabei werden bevorzugt nicht anatomische, Gewebe sparende Resektionen der suspekten Herde durchgef{\"u}hrt. Ziel dieser Arbeit war es, die Eigenschaften der laserchirurgischen Technik bei atypischen Keilresektionen zu analysieren sowie Langzeitergebnisse und Vor- oder Nachteile bez{\"u}glich {\"U}berleben und Morbidit{\"a}t gegen{\"u}ber konventionellen Techniken zu untersuchen. Methoden Im Zeitraum von Juni 2006 bis Dezember 2010 wurden an der Universit{\"a}tsklinik W{\"u}rzburg mit Hilfe eines Martin® Nd:YAG MY40 1.3 Lasers 115 atypische Keilresektionen bei 82 Patienten mit pulmonalen Metastasen durchgef{\"u}hrt. Insgesamt wurden 507 suspekte Rundherde entfernt, im Durchschnitt 4 Herde pro Patient. Retrospektiv wurden die Morbidit{\"a}t und die Komplikationsraten in diesem Kollektiv untersucht sowie die {\"U}berlebenszeitanalyse anhand der Kaplan-Meier-Methode durchgef{\"u}hrt. Der Beobachtungszeitraum betrug 3 bis 7 Jahre. Ergebnisse Eine komplette Resektion (Resektionsgrad R0) wurde in 86,7\% der F{\"a}lle pathologisch best{\"a}tigt, bei 9,9\% der Patienten zeigte sich ein maligner Lymphknotenbefall. Die 1-, 3- und 5-Jahres {\"U}berlebensraten im Gesamtkollektiv betrugen 78,9\%, 62,7\% und 46,3\%, wobei das {\"U}berleben nach kompletter Resektion deutlich besser war als nach R1- oder R2- Resektion (54,3\% vs 16,7\% nach 5 Jahren). Prognostisch g{\"u}nstig zeigte sich das Vorhandensein einer singul{\"a}ren Metastase im Vergleich zu einem multiplen Befall. Es gab keinen {\"U}berlebensvorteil bei Patienten mit 2-3 oder 4-10 Metastasen (31\% vs 37\% nach 5 Jahren). Die Komplikationsrate war mit 14,6\% {\"a}hnlich wie bei konventionellen Techniken ohne schwerwiegende Vorf{\"a}lle. Postoperativ sch{\"a}tzten nachsorgende Fach{\"a}rzte die Lebensqualit{\"a}t und Lungenfunktion der Patienten zum Großteil als gut bis sehr gut ein. Zusammenfassung Die Laserchirurgie zeigt sich als schonende und komplikationsarme, dabei pr{\"a}zise und effektive Technik bei der Entfernung von Lungenmetastasen. Das 5-Jahres-{\"U}berleben in W{\"u}rzburg war im Vergleich zu historischen Kollektiven von Patienten nach atypischer Keilresektion in konventioneller Staplertechnik signifikant h{\"o}her. Vor allem Patienten mit multiplem oder rezidivierendem Befall profitieren von der Lasertechnik.},
  subject      = {Laserchirurgie},
  language  = {de}
}