Made available in DSpace on 2014-06-12T23:04:27Z (GMT). No. of bitstreams: 2 arquivo8877_1.pdf: 1460374 bytes, checksum: c08f2c8b72d50467c3068b2ce9762c97 (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 2007 / A proteína cerbB-2 tem sido bastante estudada não só por sua importância como fator prognóstico dos carcinomas da mama, mas sobretudo por ser um indicador para terapias com esquemas quimioterápicos. Para eliminar a subjetividade da interpretação do método imunohistoquímico convencional, este estudo tem como objetivo quantificar, morfometricamente, a imunomarcação da proteína cerbB-2 expressa em tumores de mama. Fragmentos de tecido mamário normal (n=10) e com doença tumoral (carcinoma ductal invasivo, CDI, n=51; fibroadenoma, n=11) foram fixados em formalina, submetidos à rotina histológica para inclusão em parafina. Cortes histológicos (4mm), corados em hematoxilina e eosina foram examinados para confirmar o diagnóstico. Os cortes foram incubados com solução de anticorpos por uma por uma hora em temperatura ambiente. A marcação foi visualizada após incubação com diaminobenzidina (DAB) e peróxido de hidrogênio. A análise morfométrica foi realizada utilizando uma estação de análise digital de imagens através do software de análise OPTIMAS®. A partir dos resultados obtidos pode-se concluir que a superexpressão do cerbB-2 em casos de CDI é um fenômeno condizente com o estágio de proliferação das células neoplásicas e quando analisados os casos de fibroadenoma, este marcador não exibiu qualquer correlação ou padrão específico, ao contrário apresentaram resultados semelhantes ao tecido mamário normal. Não houve diferenças significativas entre os diferentes scores qualitativos e a análise morfométrica digital, o que no mínimo demonstra a necessidade de estudos mais acurados a fim de resolver esta dificuldade de interpretação

Diese Arbeit beschäftigt sich mit der prognostischen und prädiktiven Bedeutung der Serummessung des shed antigens des Onkoproteins HER-2/neu (s-HER-2/neu) für Mammakarzinompatientinnen in unterschiedlichen Erkrankungsstadien sowie unter verschiedenen Formen der Systemtherapie inklusive der Behandlung mit dem monoklonalen Antikörper Herceptin. Hierbei wurde der Stellenwert von s-HER-2/neu mit weiteren biochemischen Serummarkern (s-EGFR, s-uPA, CA 27.29) und etablierten Prognosefaktoren des Mammakarzinoms verglichen. Da HER-2/neu zu verschiedenen Zeitpunkten der Erkrankung mit verschiedenen Methoden an unterschiedlichen Materialien bestimmt werden kann, mußte schwerpunktmäßig auch die differentielle Wertigkeit von s-HER-2/neu im Vergleich zu Methoden der HER-2/neu-Bestimmung am Tumormaterial untersucht werden. Hierbei wurde insbesondere hinterfragt, ob die verschiedenen Methoden der HER-2/neu-Diagnostik stets zum gleichen Ergebnis führen, welche biologischen und technischen Ursachen möglichen Diskordanzen zugrunde liegen, und welche Konsequenzen diese Diskordanzen für die Therapiewahl (vor allem mit Herceptin beim metastasierten Mammakarzinom) mit sich bringen. Es wurden folgende Ergebnisse erzielt: - Grenzwerte: s-HER-2/neu: 50 ng/ml mit großer Wahrscheinlichkeit auch eine HER-2/neu-Überexpression am Tumorgewebe aufweisen. - Insgesamt 70% der Patientinnen mit HER-2/neu-negativen Tumoren hatten bei der späteren Fernmetastasierung einen erhöhten s-HER-2/neu-Spiegel. Diese Zunahme des Nachweises der HER-2/neu-Positivität zwischen Gewebenachweis am Primärtumor und dem Serumnachweis im Stadium IV ist nicht zufällig (p=0,001) und allenfalls teilweise durch den Einfluß der Tumormasse erklärbar. Klonale Veränderungen müssen in Erwägung gezogen werden. / This work focuses on the prognostic and predictive impact of the determination of the shed antigen of the oncoprotein HER-2/neu in serum (s-HER-2/neu) for breast cancer patients in different stages of the disease as well as under different forms of systemic therapy including treatment with the monocloncal antibody Herceptin. The biological meaning of s-HER-2/neu was compared to other serum markers (s-EGFR, s-uPA, CA 27.29) and established prognostic markers in breast cancer. As HER-2/neu can be measured at different times during the course of the disease using different methods and material, the differential meaning of s-HER-2/neu had to be investigated in relation to methods of HER-2/neu determination in tissue. Key questions were whether different methods of HER-2/neu testing lead to the same result, what biological and/or technical reason may lead to discordances, and if so, which are the consequences of these discordances for therapeutic decision making (before all Herceptin therapy in metastatic breast cancer). The results of the investigations are as follows: - Cut-offs of normal: s-HER-2/neu: 50 ng/ml are most probably HER-2/neu-positive in tissue. - Altogether, 70% of the patients with HER-2/neu negative tumors showed elevated s-HER-2/neu concentrations at later metastatic spread. This increase of the number of HER-2/neu positivity between tissue determination at the primary tumor and the serum results at stage IV disease cannot be explained by pure coincidence (p=0.001) and can only in part be explained by the influence of tumor burden . Clonal changes during the course of the disease must be considered.

Made available in DSpace on 2015-04-20T12:31:16Z (GMT). No. of bitstreams: 1 lesemky.pdf: 1202883 bytes, checksum: f8220049d5a1bd344120a49c3ed2500a (MD5) Previous issue date: 2012-12-12 / Cytokeratin 19 (CK 19) is a molecular marker that express cell replication and differentiation, and HER-2 oncogene (Human Epidermal Growth factor receptor-Type 2) is the second member of the human epidermal growth factor receptor (EGFR) family. Its overexpression can mean aggressiveness and poor prognostic in various kinds of tumors, as breast, lung and prostate. In last few decades the diagnostic of morphological changes of the thyroid gland was increased. When being diagnosed with ultrasound, the thyroid nodule prevalence reaches 20% to 30% in the general population. The aim of this prospective study is verify the presence of these markers in thyroid glands in operated non-coastal Amazon inhabitants, and its relationship with pathologic findings. We selected 34 samples of formalin-fixed, paraffin-embedded thyroid tumor tissues, from patients treated at Hospital Adriano Jorge, Manaus, Amazonas. The patients consisted of six men and 28 women, aged between 25 and 76 years, average 47 years. The tissues corresponded to nine multinodular goiter (MNG), seven colloid goiters (CG), five nodular hyperplasia (NH) four adenomatous goiters (AG), three papillary thyroid microcarcinoma (PTMC) and five papillary thyroid carcinomas (PTC). Immunohistochemistry (IHC) staining with CK 19 and HER-2 were performed using the labeled streptavidin biotin peroxidase complex system (LSAB2, DAKO, USA) on all tissues using monoclonal antibodies BA17 mab mouse (Dako M0772, USA) and SP3 rabbit mab (Spring M3034, USA) and inferential statistical analysis applying (Fisher exact test with 5% significance level). HER-2 IHC was not found in all samples. We found a strong positive reactivity for IHC CK19 in all 3 patients with PTMC, in four with PTC, one with MNG, and one with CG. We found focal positivity for CK 19 in one PTC, two MNG, 4 CG and one AG. Statistical significance was found only between CK 19 and histopathology. The results suggest thats HER-2 oncogene has no predictive or prognostic value in thyroid tissues and CK 19 marker showed affinity for PTC, although it is also found in benign tissues with less intensity. / A citoqueratina 19 (CK 19) é um marcador molecular que expressa diferenciação e replicação celular e o oncogene HER-2 (Human Epidermal Growth factor receptor-Type 2), membro da família Fator de Crescimento Epidérmico Humano (EGFR), uma proteína que quando sobre-expressa pode significar maior ploriferação celular e agressividade em vários tipos de tumores, dentre eles mama, pulmão e próstata. Nas últimas décadas vêm aumentando o diagnóstico de alterações morfológicas da glândula tireoide, sendo que quando diagnosticado à ultrassonografia a prevalência do nódulo tireoideano chega a 20% a 30% na população geral. Objetivamos neste estudo prospectivo verificar a presença destes marcadores em glândulas tireoideas operadas em pacientes habitantes em região amazônica não litorânea, e sua relação com as alterações morfológicas encontradas. Foram selecionadas 34 amostras de tecido tireoidiano preservados em formol e armazenados em parafina, de pacientes operados na Fundação Hospital Adriano Jorge, de Manaus, Amazonas. Os pacientes corresponderam a seis homens e 28 mulheres, com idade entre 25 e 76 anos e média de 47 anos. Os tecidos corresponderam a nove bócios multinodulares (BMN), sete bócios coloides (BC), cinco hiperplasias nodulares (HN) quatro bócios adenomatosos (BA), três microcarcinomas papilíferos (MCP) e cinco carcinomas papilíferos da tireóide (CPT). Exames de imuno-histoquímica em busca dos marcadores CK19 e HER-2 foram realizados em todos os tecidos usando anticorpos monoclonais BA17 (mab rato, Dako M0772, EUA) e SP3 (policlonal em coelho, Spring M3034, EUA) e o método esteptavidina-biotina-peroxidade (Kit LSAB, Dako, EUA) e análise estatística inferencial aplicando o teste Exato de Fisher com nível de significância de 5%. Não foi encontrada positividade para o marcador HER-2 em tecidos tireoidianos malignos ou benignos. Foram encontrados positividade média a forte intensidade para CK19 em todos os três pacientes com MCP, quatro CPT, um BMN e um BC. Foram encontrados positividade focal em um CPT, dois BMN, quatro BC e um BA. A análise estatística demonstrou significância estatística somente entre as variáveis CK 19 e tipo histopatológico. Os resultados da amostra analisada demonstraram que a pesquisa no oncogene HER-2 não apresentou presença deste marcador em nenhum dos tecidos tireoidianos, e o marcador CK 19 foi presente em maior intensidade nos casos de Carcinoma que nos tecidos benignos onde foi encontrado.

Improvements in the use of traditional breast cancer therapies have improved the overall survival of women with early stage disease. Remarkable advances in research have created a unique opportunity for developing active vaccination strategies that engage the bodys own immune system in the fight against breast cancer. Human Epidermal Growth Factor Receptor 2 (HER-2/neu) is a breast tumor antigen (Ag) commonly overexpressed in 30% of breast cancer cases. HER-2/neu-targeted DNA-based and fiber-modified dendritic cell (DC)-based vaccines are both analyzed as potent elements in eliciting HER-2/neu specific antitumor immune responses. A HER-2/neu-expressing DNA plasmid (pcDNA/neu) coadministered with the appropriate adjuvant vector was the first study looking at improving vaccine efficacy and enhancing immune responses. Various protection and prevention studies, using FVB/N (wild-type) and FVB/neuN [transgenic (Tg)] mice and Tg1-1 tumor cells, derived from a spontaneous tumor from Tg mice, are used to help narrow down the large panel of adjuvant vectors. Results showed the adjuvant vector pcDNA/TNF-α, when coadministered with pcDNA/neu, induced more efficient protective tumor-specific immunity and significantly delayed breast cancer development in Tg mice.<p>Another study utilized an<i>in vivo</i> murine tumor model expressing the rat neu Ag to compare the immunization efficacy between DC transduced with replication-deficient fiber-modified adenovirus (AdV) containing neu (AdV(RGD)neu), to form DC(RGD)neu, and non-modified DCneu. DC(RGD)neu displayed an upregulation of immunologically important molecules and inflammatory cytokine expression through FACS Analysis, and more importantly increased expression of neu, when compared to DCneu. DC(RGD)neu stimulated a higher percentage of HER-2/neu-specific CD8+ T cells, a stronger neu-specific CTL response, and induced a much stronger Th1- and Th2-type immune response than DCneu. Furthermore, vaccination with DC(RGD)neu induced enhanced protective tumor-specific immunity compared to DCneu in wild-type and Tg mice.<p>Overall the construction of recombinant vectors containing two transgenes (HER-2/neu and TNF-α), can not overcome the induction of HER-2/neu-directed immune tolerance. The fiber-modified (RGD) DCneu vaccine induced enhanced anti-HER-2/neu immunity compared to non-modified DCneu in the prevention of breast cancers.

Improvements in the use of traditional breast cancer therapies have improved the overall survival of women with early stage disease. Remarkable advances in research have created a unique opportunity for developing active vaccination strategies that engage the bodys own immune system in the fight against breast cancer. Human Epidermal Growth Factor Receptor 2 (HER-2/neu) is a breast tumor antigen (Ag) commonly overexpressed in 30% of breast cancer cases. HER-2/neu-targeted DNA-based and fiber-modified dendritic cell (DC)-based vaccines are both analyzed as potent elements in eliciting HER-2/neu specific antitumor immune responses. A HER-2/neu-expressing DNA plasmid (pcDNA/neu) coadministered with the appropriate adjuvant vector was the first study looking at improving vaccine efficacy and enhancing immune responses. Various protection and prevention studies, using FVB/N (wild-type) and FVB/neuN [transgenic (Tg)] mice and Tg1-1 tumor cells, derived from a spontaneous tumor from Tg mice, are used to help narrow down the large panel of adjuvant vectors. Results showed the adjuvant vector pcDNA/TNF-α, when coadministered with pcDNA/neu, induced more efficient protective tumor-specific immunity and significantly delayed breast cancer development in Tg mice.<p>Another study utilized an<i>in vivo</i> murine tumor model expressing the rat neu Ag to compare the immunization efficacy between DC transduced with replication-deficient fiber-modified adenovirus (AdV) containing neu (AdV(RGD)neu), to form DC(RGD)neu, and non-modified DCneu. DC(RGD)neu displayed an upregulation of immunologically important molecules and inflammatory cytokine expression through FACS Analysis, and more importantly increased expression of neu, when compared to DCneu. DC(RGD)neu stimulated a higher percentage of HER-2/neu-specific CD8+ T cells, a stronger neu-specific CTL response, and induced a much stronger Th1- and Th2-type immune response than DCneu. Furthermore, vaccination with DC(RGD)neu induced enhanced protective tumor-specific immunity compared to DCneu in wild-type and Tg mice.<p>Overall the construction of recombinant vectors containing two transgenes (HER-2/neu and TNF-α), can not overcome the induction of HER-2/neu-directed immune tolerance. The fiber-modified (RGD) DCneu vaccine induced enhanced anti-HER-2/neu immunity compared to non-modified DCneu in the prevention of breast cancers.

Universiẗat, Diss., 2006--Frankfurt (Main).

No description available.

No description available.

O objetivo do estudo foi avaliar a importância da expressão das proteínas topoisomerase II alfa (topo II) e HER-2 como fatores preditvos da resposta à quimioterapia neoadjuvante e prognóstico em pacientes com câncer de mama nos estádio clínico II e III. Pacientes e métodos: 99 pacientes receberam quimioterapia neoadjuvante com docetaxel (75mg /m²) e epirrubicina (50 mg/m²) em infusão endovenosa no dia 1 a cada 3 semanas após terem sido submetidas a biópsia incisional. Foi complementado tratamento sistêmico com quimioterapia adjuvante com CMF ou FEC de acordo com o estado axilar avaliada após a cirurgia definitiva e/ou hormonioterapia de acordo com a avaliacãodos receptores hormonais. Avaliamos a taxa de resposta ao tratamento neoadjuvante e a influência da topo II alfa e do HER-2 na taxa de resposta à quimioterapia neoadjuvante bem comona sobrevida livre de doença e sobrevida global. Também foram avaliadas a expressão dos receptores hormonais. Resultados: a taxa de resposta clínica objetiva foi de 80,8 % com 9,1 % de resposta patológica completa. A expressão da topo II alfa nao apresentou significância nas taxas de resposta ou na sobrevida das pacietnes e nao houve correlação entre a expressão desta proteína e de HER-2. A superexpressão da proteína HER-2 foi associada com uma redução significante nas taxas de sobrevida livre de doença e sobrevida global (p= 0,04 e p= 0,004, respectivamente). Conclusão: a expressão da topo II alfa não demonstrou, em nosso estudo, ser fator preditivo ou prognóstico nas pácientes submetidas a quimioterapia neoadjuvante com docetaxel e epirrubicina. / The objective of this study is to evaluate the importance of the expression of the proteins topoisomerase II alpha (topo II) and HER-2 as predictive factors to response to neoadjuvant chemotherapy and the prognosis of patients diagnosed with clinical stage II and stage III breast cancer. Patients and methods: 99 patients have received neoadjuvant chemotherapy with docetaxel (75mg /m²) and epirrubicine (50 mg/m²) through intravenous infusion on D1 q3 weeks, after submitted to pathologic specimen harvest. Systemic treatment was then complemented with CMF or FEC according to the status of axilla involvement after surgical staging and/or hormone therapy according tohormone receptor status. We evaluated the response rate to neoadjuvant treatment and the influence of topo II alpha and HER-2 expression on the response rate and disease free survival and overall survival. The expression of hormone receptors was also evaluated. Results: Objective clinical response was 78,8%, with 8,2% of complete pathological response.Topo II alpha expression did not correlate to response to chemotherapy or survival and there was no correlation between topo II alpha expression and HER-2 expression. Superexpression of HER-2 protein was associated to a significant reduction in disease free survival and overall survival (p=0,04 and p=0,004, respectively). Conclusion: topo II alpha expression did not demonstrate, in our study, to be a predictive nor prognostic factor to the patientssubmitted to neoadjuvant with docetaxel and epirrubicin.

Made available in DSpace on 2016-08-10T10:38:33Z (GMT). No. of bitstreams: 1 FLAVIA ALEIXO FERREIRA.pdf: 856261 bytes, checksum: 437e20f50936aac2d69cf7dcc15d95ed (MD5) Previous issue date: 2011-07-01 / Breast cancer is the second most frequent type of cancer worldwide and more common among women, accounting for 22% of new cases each year. These tumors appear as heterogeneous evolution and response to different treatment available whose prognostic and predictive factors guiding the therapeutic approach being used. The detection of oncogenic protein c-erbB-2 by immunohistochemistry is a prognostic factor for diagnostic, and in most cases, is associated with a worse prognosis. This study aimed to raise clinicopathological data of patients with breast cancer, as well as evaluating the expression c-erbB-2 in tumor tissue paraffin samples of these patients. Medical records of 286 female patients with breast carcinoma treated at Hospital Araújo Jorge (Association of Cancer Combat of Goiás), between 1979 and 2002 were collected and tabulated together with data from immunohistochemical detection of c-erbB protein -2. In our series the positive immunodetection of c-erbB-2 in tumor cells showed no association with conventional parameters clinicopathologics. The immunodetection of the protein c-erbB-2 did not significantly affect the survival of patients analyzed in our series, consistent with data obtained by other studies. We conclude that molecular methods should become more sensitive. / O câncer de mama é o segundo tipo mais frequente de câncer no mundo e o mais comum entre as mulheres, corresponde por 22% dos casos novos a cada ano. Esses tumores apresentam-se heterogêneos quanto a evolução e resposta às diferentes opções terapêuticas disponíveis, cujos fatores prognósticos e preditivos norteiam a conduta terapêutica a ser utilizada. A detecção da proteína oncogênica c-erbB-2 por imuno- histoquímica é um fator prognóstico auxiliar para avaliação diagnóstica e, na maioria dos casos, associa-se a um pior prognóstico. O presente estudo teve como objetivo levantar os dados clínicopatológicos de pacientes com câncer de mama, bem como avaliar a expresssão de c-erbB-2 nas amostras de tecido tumoral parafinadas dessas pacientes. Prontuários de 286 pacientes do sexo feminino com carcinoma de mama atendidas no Hospital Araújo Jorge (Associação de Combate ao Câncer em Goiás), entre 1979 e 2002, foram coletados e tabulados juntamente com os dados de imuno- histoquímica para detecção da proteína c-erbB-2. Em nossa casuística a imunodetecção positiva de c-erbB-2 nas células tumorais não demonstrou associação com os parâmetros clinicopatológicos convencionais. A imunodetecção da proteína c-erbB-2 não influenciou significativamente a sobrevida das pacientes analisadas em nossa série, condizendo com dados obtidos por outros estudos. Assim concluímos que os métodos moleculares devem se tornar mais sensíveis