<p>This thesis investigated the predictive and the prognostic powers of angiogenesis related markers in both operable and inoperable non-small cell lung cancer (NSCLC) patients.</p><p>In the first and second study, we investigated the serological fractions of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in 2 cohorts of patients with either operable or inoperable NSCLC. </p><p>Regarding operable NSCLC, we demonstrated significant correlations between VEGF and tumour volume and overall survival. Regarding bFGF, significant correlations with recurrent disease and survival were demonstrated. VEGF and bFGF correlated to each other and with platelet counts. In multivariate analysis, bFGF proved to be a significantly independent prognostic factor.</p><p>Regarding inoperable NSCLC, we demonstrated that patients with elevated bFGF levels before any treatment and during chemotherapy had a significantly poorer survival. During chemotherapy, each rise of one unit of bFGF (ng/L) corresponded to a 4 times increased risk of death. Regarding VEGF, elevated levels after radiotherapy corresponded with better survival. All prognostic information demonstrated in this study concerned patients with a, co-sampled, normal platelet count.</p><p>In the third study, three putative markers, HER-2, EGFR and COX-2, suitable for targeted therapies in resected NSCLC were investigated in a panel of 53 tumours and further investigated for a possible correlation with microvessel density. We demonstrated that HER-2 and COX-2 were mainly expressed in adenocarcinomas, whereas EGFR was only expressed in squamous cell carcinomas. COX-2 showed a trend towards a correlation with microvesssel density. The expression profile, HER-2+/EGFR-, was significantly correlated to poorer survival. </p><p>In the fourth study, a predictive model for recurrences consisting of p53, CD34 and CD105, and circulating serum fractions of VEGF and bFGF, was investigated. The two endothelial markers correlated with each other. CD105 expression correlated with p53 expression. No other significant correlations between markers could be demonstrated. A significant correlation between p53 overexpression and recurrent disease was demonstrated. The mutational status could not confirm the immunohistochemical correlation between p53 and recurrences. </p><p> In conclusion, the present thesis demonstrates that the angiogenic factors VEGF and bFGF analysed in sera have both predictive and prognostic information when measured in operable and inoperable NSCLC. Since HER-2 is overexpressed in NSCLC and linked with prognostic information, this marker might be a suitable target for therapy in NSCLC. Furthermore, in patients with operable NSCLC, p53 expression status was linked with recurrent disease and mean MVD. </p>

This thesis investigated the predictive and the prognostic powers of angiogenesis related markers in both operable and inoperable non-small cell lung cancer (NSCLC) patients. In the first and second study, we investigated the serological fractions of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in 2 cohorts of patients with either operable or inoperable NSCLC. Regarding operable NSCLC, we demonstrated significant correlations between VEGF and tumour volume and overall survival. Regarding bFGF, significant correlations with recurrent disease and survival were demonstrated. VEGF and bFGF correlated to each other and with platelet counts. In multivariate analysis, bFGF proved to be a significantly independent prognostic factor. Regarding inoperable NSCLC, we demonstrated that patients with elevated bFGF levels before any treatment and during chemotherapy had a significantly poorer survival. During chemotherapy, each rise of one unit of bFGF (ng/L) corresponded to a 4 times increased risk of death. Regarding VEGF, elevated levels after radiotherapy corresponded with better survival. All prognostic information demonstrated in this study concerned patients with a, co-sampled, normal platelet count. In the third study, three putative markers, HER-2, EGFR and COX-2, suitable for targeted therapies in resected NSCLC were investigated in a panel of 53 tumours and further investigated for a possible correlation with microvessel density. We demonstrated that HER-2 and COX-2 were mainly expressed in adenocarcinomas, whereas EGFR was only expressed in squamous cell carcinomas. COX-2 showed a trend towards a correlation with microvesssel density. The expression profile, HER-2+/EGFR-, was significantly correlated to poorer survival. In the fourth study, a predictive model for recurrences consisting of p53, CD34 and CD105, and circulating serum fractions of VEGF and bFGF, was investigated. The two endothelial markers correlated with each other. CD105 expression correlated with p53 expression. No other significant correlations between markers could be demonstrated. A significant correlation between p53 overexpression and recurrent disease was demonstrated. The mutational status could not confirm the immunohistochemical correlation between p53 and recurrences. In conclusion, the present thesis demonstrates that the angiogenic factors VEGF and bFGF analysed in sera have both predictive and prognostic information when measured in operable and inoperable NSCLC. Since HER-2 is overexpressed in NSCLC and linked with prognostic information, this marker might be a suitable target for therapy in NSCLC. Furthermore, in patients with operable NSCLC, p53 expression status was linked with recurrent disease and mean MVD.

Background: In childhood acute lymphoblastic leukemia (ALL), the cure rate has now reached 80% in the western world. Even so, 15¬–20% will die from the disease or treatment-related causes, among them children who did not present any known unfavorable features at diagnosis. Treatment of childhood ALL is risk-adapted, meaning that certain factors that are related to the child or the leukemic blasts stratifies to more or less intensive treatment. In this thesis, characteristics of the bone marrow (BM) stroma, reflecting the interaction between the leukemic cells and their microenvironment, were evaluated. The aims were to investigate these factors in relation to other known data in order to further understand the biology of leukemia, and to suggest additional risk factors that would further improve decision making for the treatment of individual children diagnosed with ALL. Methods: We retrospectively investigated microvessel density (MVD), blast-congested vessel fraction (BCVF), and degree of fibrosis – reticulin fiber density (RFD) – in sections from diagnostic BM biopsies from children diagnosed in Umeå, Uppsala, and Stockholm. RFD was also studied in BM sections from treatment day 29. Results: RFD had prognostic impact in patients with high-hyperdiploid (HeH) leukemia. Moreover, rapid reduction of RFD during induction treatment was associated with a favorable prognosis compared to slow reduction, in B-cell precursor (BCP) ALL patients. There was also a correlation between RFD at diagnosis and minimal residual disease (MRD) measured by flow cytometry on treatment day 29 in BCP patients. BCP patients with high RFD and high MVD had an unfavorable outcome compared to all other BCP patients. In addition, MVD and RFD were both associated with immunophenotype, and MVD with cytogenetic aberrations. There was a correlation between MVD and WBC count in BCP high-risk patients. There was also a strong correlation between BCVF and WBC count in all BCP patients, but not between BCVF and MVD or RFD. There was a negative correlation between MVD and in vitro cellular resistance to several drugs in BCP patients. A drug-resistance score combining the drugs most strongly correlated to MVD – cytarabine, doxorubicin, and dexametasone (ADD score) – identified the prognostic potential of ADD score in HeH patients with no unfavorable features. Conclusions: Taken together, these studies indicate that stroma factors in leukemia are related to both phenotypic and genotypic features of acute leukemia. Stroma factors also seem to influence the response to induction treatment, in vitro drug resistance, and outcome in certain subgroups of childhood ALL patients. The results emphasize the importance of BM stroma in leukemia and the need for greater use of BM biopsy at diagnosis.

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Made available in DSpace on 2014-08-20T14:37:57Z (GMT). No. of bitstreams: 1 dissertacao_matheus_folgearin_silveira.pdf: 274999 bytes, checksum: 17765fa39ad1a46f221283537ac0adae (MD5) Previous issue date: 2009-05-20 / Soft tissue sarcomas are mesenchymal origin neoplasms collectively classified according to histological characteristics and biological behaviour similiarities. Various neoplasms are included in this major group, as fibrosarcoma, hemangiosarcoma, peripheral nerve sheath tumor, myxosarcoma, liposarcoma, leiomyosarcoma, rhabdomiosarcoma, malignant fibrous histiocytoma, synovial cell sarcoma and undifferentiated sarcoma. The microvessel density measure has been applied to investigate tumor angiogenesis in many neoplasms. The objectives of this study were to evaluate de microvessel density in canine and feline soft tissue sarcomas and compare the general vessel measurement area and intense vascular areas hot spot. Those data were compared to usually applied prognostic factors like mitotic index, necroses presence and amount and cellular differentiation. Soft tissue sarcomas were collected in Laboratório Regional de Diagnóstico da Universidade Federal de Pelotas from 1978 to 2008 among canine and feline necropsies and biopsies. In a total of 1668 neoplasms cases during this period, 100 were soft tissue sarcomas, 87 canine and 13 feline. Sex prevalence was not observed in the analyzed species. The major prevalence in canine were hemangiosarcomas (n=34) and fibrosarcomas (n=20), being the mongrel dogs (n=35) most. The large breeds presented major frequence (n=22), followed by medium size (n=16) and small sized breeds (n=9). . In feline population, there were not accentuated prevalence, exciding hemangiosarcomas (n=4) and fibrosarcomas (n=4). In those 100 cases, 39 paraffin blocks were obtained, being 36 canine and 3 feline, mostly mongrel specimens, with 9,21(±2,99) medium age. The general vascular and hot spot areas were significantly correlated (r2=0,98; p<0,01). The mitotic index between areas were in those areas (r2=0,95, p<0,01). Hemangiosarcomas presented major vascular media in the techniques, followed by muscular sarcomas and fibrosarcomas (p<0,05). The microvessel density in soft tissue sarcomas do not present correlation to other prognostic factor usually applied. Hot spot areas can be utilized to determine the vascular degree and mitotic index in soft tissue sarcomas. / Os sarcomas de tecidos moles são neoplasmas de origem mesenquimal classificados coletivamente devido a características histológicas e comportamento biológico similares. Vários neoplasmas estão incluídos neste grande grupo, como fibrossarcoma, hemangiossarcoma, tumor de bainha de nervo periférico, mixossarcoma, lipossarcoma, leiomiossarcoma, rabdomiossarcoma, histiocitoma fibroso maligno, sarcoma sinovial e sarcoma indiferenciado. A mensuração da densidade vascular tem sido utilizada para investigar a angiogênese tumoral em diferentes neoplasmas. Este estudo teve como objetivo a determinação da microdensidade vascular de sarcomas de tecidos moles caninos e felinos através da comparação entre a mensuração geral vascular e áreas de intensa proliferação hot spot. Estes dados foram comparados a fatores prognósticos usualmente empregados, como índice mitótico, presença e quantidade de necrose e diferenciação celular. Os sarcomas de tecidos moles foram resgatados dos arquivos do Laboratório Regional de Diagnóstico da Universidade Federal de Pelotas entre 1978 a 2008 dentre necropsias e biópsias caninas e felinas. Num total de 1668 neoplasmas deste período, 100 eram sarcomas de tecidos moles, sendo 87 caninos e 13 felinos. Não se observou prevalência de sexo nas espécies analisadas. Em caninos, a maior prevalência foi de hemangiossarcomas (n=34) e fibrossarcomas (n=20), sendo os sem raça definida (n=35) os mais acometidos. Os animais de porte grande apresentaram maior freqüência (n=22), seguidos pelos de porte médio (n=16) e de porte pequeno (n=9). Em felinos não houve uma prevalência acentuada, destacando-se os hemangiossarcomas (n=4) e fibrossarcomas (n=4). Destes 100, obtiveram-se blocos de 39 casos, sendo 36 caninos e 3 felinos, em sua maioria sem raça definida nas duas espécies, com idade média observada foi de 9,21(±2,99 anos). A mensuração vascular geral e de áreas hot spot apresentaram correlação significativa (r2=0,98; p<0,01). O índice mitótico nas duas áreas observadas foram significativas (r2=0,95, p<0,01). Os hemangiossarcomas apresentaram maior média vascular nas duas técnicas, seguidos pelos sarcomas musculares e fibrossarcomas (p<0,05). Houve diferença entre os hemangiossarcomas e os fibrossarcomas, e os sarcomas musculares não diferiram desses (p<0,05). A microdensidade vascular em sarcomas de tecidos moles não apresentou correlação com outros fatores empregados usualmente. A visualização de campos hot spot pode ser utilizada para determinar o grau vascular e índice mitótico.

3 Abstract The doctor thesis is composed of two major studies, both of them focused on the mantle cell lymphoma (MCL). The first part deals with the verification of the prognostic influence of Mantle Cell Lymphoma International Prognostic Index (MIPI) and of the proliferative activity in 235 patients with MCL diagnosed in 1996-2008 in the Czech Republic. This population study was performed in the collaboration with the Czech Lymphoma Study Group. The clinical data of patients were completed in April 2012. The diagnosis of MCL was confirmed by our central histopathologic examination of pretherapeutic histological samples. The median overall survival (OS) was 47 months, median progression free survival (PFS) was 22 months. We demonstrated the influence of proliferative activity, MIPI and of the therapy type (intensive/non-intensive) on OS and PFS in univariate and multivariate analysis. Using univariate analysis we showed the prognostic influence of aggressive/other cytomorphological variants of MCL, nodal/extranodal localization of primary sample and also of the variants of MIPI - s-MIPI, MIPIb and a completely new variant of MIPI - combined MIPI. The prognostic influence of growth pattern and of the results of immunohistochemical reaction with CD23, CD5 and cyclin D1 antibodies were not confirmed. The other...

3 Abstract The doctor thesis is composed of two major studies, both of them focused on the mantle cell lymphoma (MCL). The first part deals with the verification of the prognostic influence of Mantle Cell Lymphoma International Prognostic Index (MIPI) and of the proliferative activity in 235 patients with MCL diagnosed in 1996-2008 in the Czech Republic. This population study was performed in the collaboration with the Czech Lymphoma Study Group. The clinical data of patients were completed in April 2012. The diagnosis of MCL was confirmed by our central histopathologic examination of pretherapeutic histological samples. The median overall survival (OS) was 47 months, median progression free survival (PFS) was 22 months. We demonstrated the influence of proliferative activity, MIPI and of the therapy type (intensive/non-intensive) on OS and PFS in univariate and multivariate analysis. Using univariate analysis we showed the prognostic influence of aggressive/other cytomorphological variants of MCL, nodal/extranodal localization of primary sample and also of the variants of MIPI - s-MIPI, MIPIb and a completely new variant of MIPI - combined MIPI. The prognostic influence of growth pattern and of the results of immunohistochemical reaction with CD23, CD5 and cyclin D1 antibodies were not confirmed. The other...