@phdthesis{Alkonyi2014,
  author    = {Alkonyi, Balint},
  title     = {Differential imaging characteristics and dissemination potential of pilomyxoid astrocytomas versus pilocytic astrocytomas},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-116062},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2014},
  abstract  = {Background and Aims: PMA is a recently described rare tumor entity occuring most often in young children. Due the worse outcome of PMA-patients as compared to children with pilocytic astrocytoma (PA), it has received a grade II assignment in the latest WHO classification. Nevertheless, increasing evidence suggests that the two tumor types are indeed pathologically and genetically related. The radiological differentiation of PMAs from PAs is challenging and the limited available data could not yet provide unequivocal distinguishing imaging features. Furthermore, it is not completely clarified whether PMA cases are associated with a higher rate of CSF dissemination compared to similarly young patients with PA. The aim of our study was firstly to compare MR/CT imaging features of these tumors, and secondly, to evaluate the occurrence of CSF dissemination. Material and Methods: The study population included 15 children with PMA and 32 children with PA. A third group consisted of eight children with PAs with focal pilomyxoid features. All cases had been registered in the German multicenter SIOP/HIT-LGG trials. The initial MRIs (and CT scans, if available) at establishing the diagnosis were retrospectively analyzed according to standardized criteria and the findings compared between PMAs and PAs. Furthermore, we compared the occurrence of imaging evidences of CSF tumor dissemination between children with PMA and PA, respectively. Results: The imaging appearance of PMAs and PAs was very similar. However, PAs tended to show more frequently cystic components (p=0.03). As opposed to PAs, PMAs did not have large tumor cysts. We did not find differences with respect to tumor size and tumor margin. Gadolinium enhancement of PMAs was significantly more frequently homogeneous (p=0.006). PMAs appeared to show more often intratumoral hemorrhages (p=0.047). Furthermore, suprasellar PMAs tended to have a more homogeneus texture on T2-weighted MR images (p=0.026). Within the subgroup < 6 years of age the PMA histology tended to have a larger effect on the occurrence of CSF dissemination than the age (p=0.05 vs.0.12). Conclusions: Although the radiological appearance of PMAs and PAs is similar, some imaging features, like enhancement pattern or presence of cysts or hemorrhage may help differentiating these low-grade gliomas. Our results corroborate previous scarce data suggesting higher rate of CSF dissemination in PMAs, even in the youngest patient population. Thus, in young children with a chiasmatic-hypothalamic tumor suggestive of a PMA, an intensive search for CSF dissemination along the entire neuraxis should be performed.},
  subject      = {Astrozytom},
  language  = {en}
}
@phdthesis{Paul2014,
  author    = {Paul, Alfred},
  title     = {Palliativmedizinische Tagesklinik - Sektoren{\"u}bergreifende palliativmedizinische Versorgung im Rahmen eines Modellprojektes},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-117612},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2014},
  abstract  = {Im Rahmen eines Modellprojektes wurden Palliativpatienten im Klinikum Aschaffen¬burg in einer Palliativmedizinischen Tagesklinik (PTK) behandelt. In den ersten eineinhalb Behandlungsjahren wurden bei 82 Patienten insgesamt 526 teilstation{\"a}re, multiprofessionelle Behandlungen durchgef{\"u}hrt. Das Lebensalter der Patienten lag im Median bei 68 Lebensjahren. 77 der 82 Pati-enten (94\%) litten an weit fortge¬schrittenen metastasierten malignen Grunderkrankungen, zwei Patienten an einer dekompensierten Leberzirrhose, ein Patient an einem chronischen Immundefizienz-Syndrom und zwei Patienten hatten schwere Organinsuffizienzen von Herz und Lunge mit irreversiblen Folge¬sch{\"a}den. Die Patienten waren {\"u}ber einen Behandlungszeitraum von im Median 21 Tagen an die Tagesklinik angebunden (25\%-Quantil 7, 75\%-Quantil 56 Tage). Im Median wurden 3 Behandlungseinheiten realisiert (25\%-Quantil 2, 75\%-Quantil 7 Behand¬lungen). Die Behandlungsdauer lag im Median bei 199 Minuten (25\%-Quantil 120, 75\%-Quantil 290 Minuten). F{\"u}hrende klinische Symptome waren Kachexie in Verbindung mit k{\"o}rperlicher Schw{\"a}che, gefolgt von Schmerzen, Fatigue, gastrointestinalen Problemen, neuropsychiatrischen Symptomen wie Unruhe, Angst und Depression sowie Atemnot. Bei den Patienten lagen im Median 9 palliativ-medizinisch zu behandelnde Symptome vor (25\%-Quantil 7, 75\%-Quantil 10 Symptome). Bei 45 der 82 Patienten (55\%) hatte die Erkrankung zu einer maßgeblichen psychosozialen Belastung oder zu einer {\"U}berlastung der betreuenden Angeh{\"o}rigen gef{\"u}hrt. Im Rahmen der tagesklinischen Palliativbehandlung lagen die teilstation{\"a}ren Therapieschwerpunkte am h{\"a}ufigsten im Bereich der Patientenedukation, gefolgt von Schmerztherapie, speziellen {\"a}rztlichen und pflegerischen Maßnahmen, Physiotherapie und/oder Lymphdrainage, Infusions- und/oder Transfusionstherapie sowie operativen und invasiven Maßnahmen. Bei 39 der 82 Patienten (48\%) waren psychosozial stabilisierende Maßnahmen wie Psychoonkologie, Kunst- und Musiktherapie sowie Seelsorge wesentliche Behandlungselemente. Dar{\"u}ber hinaus wurden h{\"a}ufig Beratungsleistungen auch im Hinblick auf Entscheidungsfindungsprozesse - die Gestaltung des Lebensendes betreffend - von Patienten und Angeh{\"o}rigen in Anspruch genommen. Bei 54 der 82 Patienten mit onkologischer Grunderkrankung (66\%) erfolgte die teilstation{\"a}re palliativmedizinische Behandlung im Sinne der Fr{\"u}hintegration palliativmedizinischer Maßnahmen. Diese Behandlung fand als ein besonders niedrigschwelliges palliativmedizinisches Therapieangebot eine leichtere Akzeptanz durch die Betroffenen. Es resultierte eine fr{\"u}hzeitige Integration palliativen Denkens und Handelns in eine zum Beispiel noch andauernde tumorspezifische, oft vom Patienten noch als kurativ empfundene Therapie. An Hand von Kasuistiken konnte gezeigt werden, wie durch die teilstation{\"a}re Nutzung palliativmedizinischer Behandlungsm{\"o}glichkeiten und der Infrastruktur eines Krankenhauses eine station{\"a}re Krankenhausbehandlung von Palliativpatienten verz{\"o}gert, verk{\"u}rzt oder vermieden werden konnte. Dar{\"u}ber hinaus wurden die ambulanten Versorgungsstrukturen gest{\"u}tzt und Patienten in sozialer Isolation psychosozial stabilisiert. Dies wurde im Rahmen der Evaluation von den {\"u}berweisenden {\"A}rzten sowie von den Patienten und Angeh{\"o}rigen eindrucksvoll best{\"a}tigt. Insbesondere beurteilten die Haus- und Fach{\"a}rzte die Unterst{\"u}tzung ihrer {\"a}rztlichen Arbeit durch die Palliativmedizinische Tagesklinik mit der Bestnote und beschrieben sie als „sinnvollen, erg{\"a}nzenden Baustein zu AAPV, SAPV und station{\"a}rer palliativmedizinischer Versorgung". Die Aussagen der Haus{\"a}rzte, Patienten und Angeh{\"o}rigen belegen, dass die Palliativmedizinische Tagesklinik ein wichtiger, erg{\"a}nzender Baustein eines palliativmedizinischen Versorgungsnetzes und keine Konkurrenz zu bereits etablierten spezialisierten Behandlungsstrukturen ist. Sektoren{\"u}bergreifend, in Erg{\"a}nzung und nicht in Konkurrenz zu AAPV und SAPV, schließt die Tagesklinik somit eine Versorgungsl{\"u}cke f{\"u}r Palliativpatienten im ambulanten Bereich und verst{\"a}rkt dar{\"u}ber hinaus bei Patienten und deren Angeh{\"o}rigen die Empfindung von Verl{\"a}sslichkeit, Sicherheit und Vertrauen in „End of Life Care".},
  subject      = {Palliativmedizin},
  language  = {de}
}
@phdthesis{Varagnolo2014,
  author    = {Varagnolo, Linda},
  title     = {PRC2 inhibition counteracts the culture-associated loss of engraftment potential of human cord blood-derived hematopoietic stem/progenitor cells},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-108073},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2014},
  abstract  = {Cord blood hematopoietic stem cells (CB-HSCs) are an outstanding source for the treatment of a variety of malignant and non-malignant disorders. However, the low amount of cells collected per donor is often insufficient for treatment of adult patients. In order to make sufficient numbers of CB-HSCs available for adults, expansion is required. Different approaches were described for HSC expansion, however these approaches are impeded by the loss of engrafting potential during ex vivo culture. Little is known about the underlying molecular mechanisms. Epigenetic mechanisms play essential roles in controlling stem cell potential and fate decisions and epigenetic strategies are considered for HSC expansion. Therefore, this study aimed to characterize global and local epigenotypes during the expansion of human CB-CD34+, a well established CB progenitor cell type, to better understand the molecular mechanisms leading to the culture-associated loss of engrafting potential. Human CB-CD34+ cells were cultured using 2 different cytokine cocktails: the STF cocktail containing SCF, TPO, FGF-1 and the STFIA cocktail, which combines STF with Angiopoietin-like 5 (Angptl5) and Insulin-like growth factor-binding protein 2 (IGFBP2). The latter expands CB-HSCs ex vivo. Subsequently, the NOD-scid gamma (NSG) mouse model was used to study the engraftment potential of expanded cells. Engraftment potential achieved by fresh CB-CD34+ cells was maintained when CB-CD34+ cells were expanded under STFIA but not under STF conditions. To explore global chromatin changes in freshly isolated and expanded CB-CD34+ cells, levels of the activating H3K4me3 and the repressive H3K27me3 histone marks were determined by chromatin flow cytometry and Western blot analyses. For analysis of genome-wide chromatin changes following ex vivo expansion, transcriptome profiling by microarray and chromatin immunoprecipitation combined with deep sequencing (ChIP-seq) were performed. Additionally, local chromatin transitions were monitored by ChIP analyses on promoter regions of developmental and self-renewal factors. On a global level, freshly isolated CD34+ and CD34- cells differed in H3K4me3 and H3K27me3 levels. After 7 days of expansion, CD34+ and CD34- cells adopted similar levels of active and repressive marks. Expanding the cells without IGFBP2 and Angptl5 led to a higher global H3K27me3 level. ChIP-seq analyses revealed a cytokine cocktail-dependent redistribution of H3K27me3 profiles. Chemical inhibition of the H3K27 methyltransferase EZH2 counteracted the culture-associated loss of NSG engraftment potential. Collectively, the data presented in this study revealed that by adding epigeneticly active compounds in the culture media we observed changes on a chromatin level which counteracted the loss of engraftment potential. H3K27me3 rather than H3K4me3 may be critical to establish a specific engraftment supporting transcriptional program. Furthermore, I identified a critical function for the Polycomb repressive complex 2-component EZH2 in the loss of engraftment potential during the in vitro expansion of HPSCs. Taken together this thesis provides a better molecular understanding of chromatin changes upon expansion of CB-HSPCs and opens up new perspectives for epigenetic ex vivo expansion strategies.},
  subject      = {Epigenetik},
  language  = {en}
}