Made available in DSpace on 2014-06-11T19:33:25Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-11-28Bitstream added on 2014-06-13T19:44:11Z : No. of bitstreams: 1 paiva_ce_dr_botfm.pdf: 1567376 bytes, checksum: a85fd07082b19096a7181e31cd1b5247 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / O câncer de mama (CM) representa um importante problema de saúde pública no mundo, com aproximadamente 1.400.000 casos diagnosticados e 460.000 mortes por ano. É considerada uma doença heterogênea, com alterações em diversas vias de sinalização molecular. Tanto os marcadores prognósticos quanto os preditivos são de grande importância para a tomada de decisões terapêuticas. No caso do CM operado, os marcadores prognósticos ajudam a determinar se a paciente necessita de tratamento adicional e os marcadores preditivos auxiliam o clínico a decidir qual tratamento a ser utilizado. Desta forma, o melhor conhecimento dos marcadores prognósticos e preditivos conhecidos e a identificação de novos marcadores, poderão auxiliar o tratamento de pacientes com CM de forma mais adequada. Dois marcadores tumorais com possíveis implicações clínicas são o TGF-β1 e o seu receptor TGF-βRII. Em relação ao impacto preditor de resposta a quimioterapia, os referidos marcadores ainda não foram devidamente estudados. Quanto ao papel prognóstico, os estudos em literatura são contraditórios. Acredita-se que o TGF-β atue de forma diferente em função do tipo celular e do contexto biológico envolvido. Assim, é supressor tumoral nos estágios iniciais da carcinogenese e promotor tumoral nos estágios tardios. O momento da troca de papéis não está estabelecido, porém, sabe-se que, em um mesmo tumor, o TGF-β pode atuar tanto como supressor quanto como promotor tumoral simultaneamente. Em face da complexidade biológica do TGF-β, optou-se por estudar um grupo homogêneo de mulheres com CM em estádio TNM III, com longo período de seguimento clínico, submetidas à quimioterapia neoadjuvante (QtNeo) baseada em doxorrubicina e também à quimioterapia adjuvante. Desta forma, o objetivo deste... / Breast cancer (BC) represents an important public heatlh problem worldwide, with approximately 1.4 million new cases and 460,000 deaths per year. It is considered a heterogeneous disease with changes in several molecular signalling pathways. Both the predictive and prognostic markers are important for making therapeutic decisions. In the case of operated BC, prognostic markers help to determine if the patient needs additional treatment and predictive markers help the clinician to decide which treatment to use. Thus, a better knowledge of known predictive and prognostic markers and the identification of new markers, may improve the treatment of BC patients. Two tumor markers with potential clinical implications are TGF-β1 and its receptor TGF-βRII. Regarding the prediction of response to cancer chemotherapy, these markers have not been adequately studied. Considering its prognostic value, published studies are contradictory. It is believed that the TGF-β acts differently depending on the cell type and the biological context involved. Thus, it acts as a tumor suppressor in the early stages of carcinogenesis and as a tumor promoter in later stages. The moment of role switch is not established, however, it is known that in the same tumor, TGF-β can act as both tumor suppressor and promoter simultaneously. Given the biological complexity of TGF-β, we chose to study a homogeneous group of women with TNM stage III BCs comprising tumors with long follow-up period, submitted to doxorubicinbased neoadjuvant chemotherapy (NAC) and adjuvant chemotherapy as well. Thus, the aim of this study was to evaluate the protein expression of TGF-β1 and TGF-βRII in a sample of BCs and to correlate it with clinical and pathological response rates, occurrence of distant metastasis, and survival analysis. To this end... (Complete abstract click electronic access below)

abstract: Breast cancer is the second leading cause of disease related death in women, contributing over 40,000 fatalities annually. The severe impact of breast cancer can be attributed to a poor understanding of the mechanisms underlying cancer metastasis. A primary aspect of cancer metastasis includes the invasion and intravasation that results in cancer cells disseminating from the primary tumor and colonizing distant organs. However, the integrated study of invasion and intravasation has proven to be challenging due to the difficulties in establishing a combined tumor and vascular microenvironments. Compared to traditional in vitro assays, microfluidic models enable spatial organization of 3D cell-laden and/or acellular matrices to better mimic human physiology. Thus, microfluidics can be leveraged to model complex steps of metastasis. The fundamental aim of this thesis was to develop a three-dimensional microfluidic model to study the mechanism through which breast cancer cells invade the surrounding stroma and intravasate into outerlying blood vessels, with a primary focus on evaluating cancer cell motility and vascular function in response to biochemical cues. A novel concentric three-layer microfluidic device was developed, which allowed for simultaneous observation of tumor formation, vascular network maturation, and cancer cell invasion/intravasation. Initially, MDA-MB-231 disseminated from the primary tumor and invaded the acellular collagen present in the adjacent second layer. The presence of an endothelial network in the third layer of the device drastically increased cancer cell invasion. Furthermore, by day 6 of culture, cancer cells could be visually observed intravasating into the vascular network. Additionally, the effect of tumor cells on the formation of the surrounding microvascular network within the vascular layer was evaluated. Results indicated that the presence of the tumor significantly reduced vessel diameter and increased permeability, which correlates with prior in vivo data. The novel three-layer platform mimicked the in vivo spatial organization of the tumor and its surrounding vasculature, which enabled investigations of cell-cell interactions during cancer invasion and intravasation. This approach will provide insight into the cascade of events leading up to intravasation, which could provide a basis for developing more effective therapeutics. / Dissertation/Thesis / Masters Thesis Biomedical Engineering 2017

Made available in DSpace on 2014-06-11T19:23:08Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-03-04Bitstream added on 2014-06-13T20:10:27Z : No. of bitstreams: 1 ribeiro_ghfp_me_botfm.pdf: 202757 bytes, checksum: a228e2c941a14ad9806caa5f27608410 (MD5) / Empresa Privada / Fundação Pio Xii - Barretos / A mastectomia radical modificada ainda se constitui em um dos principais procedimentos cirúrgicos em mastologia. A principal complicação relacionada a cirurgia constitui o seroma axilar. O bisturi Harmônico, apesar de pouco difundido, foi descrito como um mecanismo para diminuir a formação do seroma axilar, associado a diminuição do tempo de utilização do dreno. Estudo prospectivo randomizado utilizando-se o bisturi harmônico ou o elétrico de pacientes submetidas a mastectomia radical no Hospital de Câncer de Barretos, no ano de 2008, sendo que a randomização ocorreu em função do índice de massa corpórea. As variáveis relacionadas às pacientes, às cirurgias e suas principais complicações pós operatórias (seroma, necrose de retalhos, hematomas e infecção) foram tabuladas e submetidas a análise estatística. Das 95 pacientes submetidas a mastectomia, em 49 foi utilizado o bisturi harmônico. A comparação entre os bisturis na realização da mastectomia radical mostrou diferença estatística na ocorrência da necrose de retalhos das cirurgias. Outras complicações (seroma, hematoma e infecção) não tiveram significância estatística. A utilização do bisturi harmônico em mastectomias radicais proporciona menor risco de necrose de retalhos. O tipo do bisturi utilizado não influencia na formação de seroma. O índice de massa corpórea, volume de drenagem ao sétimo dia pós-operatório e redução percentual da drenagem do 2° ao 7° dia pós-operatório são fatores independentes na formação de seroma. A utilização do bisturi harmônico proporciona diminuição significativa da necrose de retalho em relação ao bisturi elétrico. / This randomized prospective study has the purpose of comparing the post-operative complication rates on the electric scalpel and the harmonic scalpel. The study was accomplished in the Hospital de Câncer de Barretos from January to November, 2008. The breast cancer patients with radical mastectomy proposal were randomized into two groups according to their body mass index (bmi): electric scalpel (46) and harmonic scalpel (49). The variables related to the patients, to the surgeries and its their post-operative main complications (seroma, flap necrosis, haematomas and infections), were tabulated and submitted to statistical analysis. The comparison between the scalpels on the radical mastectomy has show statistic difference on the occurrence of the flap necrosis on the surgeries. Other complications (seroma, haematoma and infection) have not had statistic significance). The usage of the harmonic scalpel in radical mastectomies provides smaller risk of flap necrosis in comparison with the electric scalpel.

Resumo: O carcinoma mucinoso da mama é um tipo histológico raro e de prognóstico favorável, sendo classificado em puro e misto. A proposta deste trabalho foi estudar os aspectos anatomoclínicos do carcinoma mucinoso da mama, identificando os fatores prognósticos nos tipos puros e mistos. Foi conduzido estudo clínico, descritivo e transversal, tendo como base de dados os prontuários e respectivos laudos de carcinoma mucinoso de mama, arquivados no Instituto Brasileiro de Controle do Câncer (IBCC) no período 1990-2005. Por meio de protocolo foram avaliados: idade, menopausa, paridade, antecedentes, estadiamento, tempo de seguimento, tipo de cirurgia, adjuvância, tamanho do tumor, linfonodos, assim como o intervalo livre de doença (ILD) e a sobrevida global. Na análise estatística foram empregados teste t-student, teste do Qui-Quadrado ou Exato de Fisher e o teste de Wilcoxon. Resultados: Dos 71 casos analisados, 44 foram classificados como carcinomas mucinosos puros (CMP) e 27, como mistos (CMM). O tempo médio de seguimento foi 59,25 meses (1-155meses). O CMP associou-se a maior faixa etária quando comparado ao CMM (69,2±13 vs 58,7±17anos) (p<0,05). Quanto ao estadiamento clínico, 31,8% das pacientes com CMP estavam no estádio IIA, enquanto 51,8% daquelas com CMM encontravam-se no estádio IIB. Na avaliação da axila evidenciou-se metástase em 27,8% dos CMP e em 76% dos CMM (p=0,0001)). Não houve diferença quanto à sobrevida e ao ILD entre o CMP e o CMM. No CMP observou-se correlação negativa entre a celularidade e o ILD. No CMM, a correlação entre o percentual de mucina e o ILD foi positiva. Conclusões: O carcinoma mucinoso do tipo puro associou-se a maior faixa etária e menor comprometimento...(Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Mucinous breast cancer is a rare histologic type with a favorable prognosis. It is classified into pure (PMC) and mixed (MMC). The purpose of this study is to assess the clinicopathological characteristics of this tumor and identify prognostic features in pure and mixed subtypes. It was conducted a descriptive, transverse, clinical study in the Brazilian Institute of Control of the Cancer's (IBCC) database between 1990-2005. The protocol included: age at diagnosis, age of menarche and menopause, number of pregnancies, family history of breast cancer, clinical stage, follow up, surgery, adjuvant therapy, tumor size, nodal status, disease free survival and overall survival. In the statistical analysis, were used t-student test, chi-square test or Fisher's exact test and Wilcoxon test. Out of 71 cases analysed; 44 were classified as pure mucoid carcinoma and 27, as mixed mucoid carcinoma. The mean follow up was 59,25months (range 1-155months) Pure mucinous carcinoma was more prevalent in older patients than the mixed subtype (69,2±13 vs 58,7±17years)(p<0,05). About clinical stage, 31,8% of the PMCs were in IIA stage and 51,8% of the MMCs were in IIB stage. Axillary nodal metastases were present in 27,8% of the PMCs and 76% of the MMCs (p= 0,0001). There was no difference in relapse-free and overall survival between pure and mixed tumors. In the PMCs was found a negative correlation between cellularity and relapse-free; and in the MMCs the correlation between mucoid component and relapse-free was positive. Conclusions: The PMC presented in older patients and axillary nodal disease was less frequent than in MMC, showing a better prognosis. / Orientador: Eliana Aguiar Petri Nahás / Coorientador: Heloísa M. De Luca Vespoli / Banca: José Costa de Andrade / Banca: Mariângela Esther Alencar Marques / Mestre

Thesis (DTech(Biomedical Technology))--Cape Technikon, Cape Town, 2000 / The diagnosis of breast cancer is not possible using currently available serological detection of cancer markers as these lack adequate sensitivity or specificity. This study investigates the prevalence and significance of anti-p53 antibody and c-erbB-2 protein in the post-surgical sera of South African breast cancer patients and correlates these features with the clinicopathological characteristics of breast cancer. Further, this study investigates the possibilityofimproving prognostic sensitivityby combining the two subject markers to monitor each patient. Further, this study will provide the opportunity to investigate lNhether only certain types of breast cancer can elicit an immunological response and at what stage and grade of tumour antibodies are present in the postoperative serum. The study also establishes a foundation for determining in South Africa lNhether there is a genetic influence in the response to p53 mutation and INhther this response is higher in the indigenous African women compared to other South African women. The purpose of the study is to determine if the resulting findings can be used to enhance our ability to diagnose breast cancer and to identify node-negative breast cancer patients at high risk for early disease recurrence and or death, for 1Nh0m adjuvant therapy is unequivocally justified. The study accrued 92 South African breast cancer patients who were essentially women of colour 62 [67%] indigenous African women and 20 [22%] Caucasian of Indian descent, 6 [6%J of mixed [ColouredJ background and only 4 [4%J Caucasian of White descent. A predominantly indigenous African populationwas chosen becausethey are the group most likely to benefitfrom an easily repeatable, affordable serological cancer marker.

Made available in DSpace on 2014-06-11T19:29:52Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-02-18Bitstream added on 2014-06-13T19:59:57Z : No. of bitstreams: 1 kamiya_cp_me_botfm.pdf: 892360 bytes, checksum: b3e0867e3c536c34f6c7298680175be9 (MD5) / Avon / A ultra-sonografia mamária tem sido um método padrão complementar à mamografia há mais de dez anos. Permite o detalhamento da morfologia capaz de diferenciar lesões benignas de malignas. A angiogênese tumoral é crítica para o crescimento autônomo e desenvolvimento do câncer de mama. A alteração hemodinâmica que acompanha tal angiogênese fornece base para o estudo das lesões no Doppler US O estudo Doppler US permite a análise de parâmetros objetivos do fluxo como sinais de fluxo, velocidade máxima sistólica (Vmax), índice de resistência (RI) e índice de pulsatilidade (PI). Avaliar o papel do Power Doppler estudando tais variáveis de fluxo. O estudo foi realizado no Setor de Diagnóstico e Imagem do Centro de Avaliação em Mastologia (CAM) do Departamento de Ginecologia, Obstetrícia e Mastologia da Faculdade de Medicina de Botucatu – UNESP, de dezembro de 2004 a dezembro de 2007. Este estudo é retrospectivo, analítico e observacional. Resultados: Foram estudadas 613 lesões mamárias, avaliadas por Power Doppler e citologia aspirativa ou biópsia percutânea. Pelo estudo, 462 lesões não apresentaram vascularização: 340 benignas (26,41%) e 122 malignas (73,59%). Observou-se vascularização em 151 lesões: 98 malignas (64,90%) e 53 benignas (35,10%). As benignas apresentaram média de 1,79 vasos por lesão; Vmax de 15,86cm/s; IP de 0,99 e IR de 0,61. Já as malignas com fluxo Doppler, observou-se média de 5,6 vasos por lesão; Vmax de 21,0cm/s; IP de 1,45 e IR de 0,74. Pela curva ROC, para predizer malignidade, observou-se sensibilidade e especificidade respectivos de 64,3% e 73,6% para 1,5 vasos por lesão; 61,3% e 56,6% para Vmax de 16,50 cm/s ; 72,8% e 66,7% para IP de 1,08 e 70,6% e 68,0% para IR de 0,66. O estudo Power Doppler das lesões mamárias consegue determinar limites que auxiliam na diferenciação entre lesões benignas e malignas. / has been a standard complementary procedure to mammography for more than 10 years. It gives morphological details which enable differentiation between benign and malignant lesions. Tumor angiogenesis is critical for the autonomous growth and spread of breast cancers. The altered hemodynamics that accompany tumor angiogenesis provide a basis for discriminating between malignant and benign breast masses at color Doppler US. The Doppler Sonographic study of vascularity includes assessment of parameters like number of flow signals, peak flow velocity (Vmax), resistivity index (RI), and pulsatility index (PI). Objective: The aim is to evaluate the role of Power Doppler at breast lesions, studying flow variables. Methods: The study was conducted in Setor de Diagnóstico e Imagem of Centro de Avaliação em Mastologia (CAM), Department of Gynecology, Obstetrics and Mastology - Faculty of Medicine of Botucatu - UNESP in the period of December 2004 to December 2007. This study is retrospective, observational and analytical. Results: We studied 613 breast lesions, evaluated by Power Doppler and percutaneous biopsy or aspiration cytology. By PD study, 462 lesions showed no vascularity: 340 benign (26.41%) and 122 malignant (73.59%). Vascularization was observed in 151 lesions: 98 malignant lesions (64.90%) and 53 benign lesions (35.10%). Benign lesions has an average of 1.79 vessels per lesion; Vmax of 15.86 cm / s; PI of 0.99 and RI of 0.61. Already the malignant lesions with Doppler flow, it was observed an avaerage of 5.6 vessels per lesion; Vmax of 21.0 cm / s; PI of 1.45 and RI of 0.74. For the ROC curve, to predict malignancy, was observed a sensitivity and specificity of 64,3% and 73,6% for the presence of 1.5 vessels per lesion; 61,3% and 56,6% for Vmax of 16.50 cm / s, 72,8% and 66,7% for PI of 1.08 and 70,6% and 68,0% for RI of 0.66. Has been a standard complementary procedure to mammography for more than 10 years.

Orientador: Luis Otavio Sarian / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-13T16:46:52Z (GMT). No. of bitstreams: 1 Peres_RaquelMaryRodrigues_M.pdf: 3735744 bytes, checksum: 4434d6d60dd1d2987e70272804df20f0 (MD5) Previous issue date: 2009 / Resumo: Introdução: Há evidências indicando que a transição de carcinoma ductal in situ (CDIS) para carcinoma ductal invasivo (CDI) é regulada por um número restrito de genes. Ainda permanece obscuro se a expressão do receptor erbB-2 e dos receptores hormonais predizem o potencial invasivo dos CDIS. Objetivos: Avaliar a expressão dos receptores de estrógeno e progesterona (RE/RP) e da proteína erbB-2 em áreas específicas em tumores que apresentem componentes de CDIS e CDI concomitantemente, indicando uma possível transição. Materiais e Métodos: Foram selecionados 85 casos de carcinomas da mama apresentando regiões contíguas de CDIS e CDI e obtidas amostras histológicas separadas, uma da região CDIS e outra da região CDI, do bloco de parafina original do diagnóstico, para montagem de um TMA (tissue microarray). A expressão das proteínas erbB-2, RE e RP foram verificadas através da técnica convencional de imuno-histoquímica. Os dados clínicos das pacientes foram coletados por consulta ao prontuário. Resultados: Aproximadamente 35% das áreas invasivas foram classificadas como 2+ ou 3+ para o erbB-2, em contraste a 47% no componente invasivo correspondente. A expressão de erbB-2 não se mostrou diferente nos componentes in situ e invasivo (p=0,12). A expressão de RP não foi estatisticamente diferente comparando-se regiões in situ e invasivas do tumor (p=0,06). Em contraste, houve uma discreta mudança na expressão de RE (p=0,04). O coeficiente de concordância intraclasse (ICC) revelou forte concordância nas comparações entre as amostras de erbB-2 (ICC=0,61), RP (ICC=0,61) e RE (ICC=0,70), nos componentes in situ e invasivo. Conclusão: Os achados sugerem que a expressão de erbB-2, RE e RP não diferem entre os componentes in situ e invasivo do carcinoma da mama, especialmente nas regiões de transição de um componente a outro. Espera-se que as alterações moleculares ocorridas antes da mudança morfológica do tecido persistam na forma invasiva do tumor. A concomitância da atuação de fatores epigenéticos pode explicar porque alguns tumores in situ evoluem para invasivos, enquanto outros tumores in situ com características moleculares semelhantes não apresentam a mesma evolução, suportando a hipótese de uma base multifatorial para a progressão da doença. / Abstract: Introduction: There is evidence indicating that the transition from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) is regulated by a restrict number of genes. It remains unknown whether erbB-2 and hormone receptor status predict the invasive potential of DCIS. Objectives: To evaluate estrogen/progesterone receptor (ER/PR) and protein erbB-2 status in the specific areas of breast tumors which share both components of DCIS and IDC, concomitantly, indicating a possible transition. Materials and methods: 85 cases of breast malignancies harboring contiguous regions of DCIS and IDC were selected. Separate histological samples, one from the DCIS and other from the neighboring IDC, from the original paraffin block used on diagnosis, were sampled using tissue microarrays (TMA). The erbB-2 and ER/PR status was assessed using conventional immunohistochemistry techniques. Clinicopathological data from the patients and from the disease were retrieved out of the patients' medical records. Results: Approximatelly 35% of the invasive areas were erbB-2 2+ or 3+, compared to 47% of their in situ counterparts. The expression of erbB-2 did not differ in the in situ and in the invasive components of the breast tumors (p=0.12). The PR status was not statistically different comparing the in situ and invasive regions of the tumors (p=0.06). By contrast, there was a slight imbalance in ER status (p=0.04). The intraclass correlation coefficient (ICC) disclosed good agreement in sample-by-sample comparisons of erbB-2 (ICC = 0.61), PR (ICC= 0.61) and ER (ICC=0.70) expression in the in situ and invasive components. Conclusion: Our findings suggest that the expression of erbB-2 and ER/PR does not differ accross the in situ and invasive components of breast malignancies, especially in the transition region from one component to the other. It is expected that the molecular alterations which take place before the morphologic tissue changes persist in the invasive forms of breast tumors. The ocurrance of concomitant epigenetic factors may explain why some in situ tumors develop to an invasive phenotype, while other in situ tumors with similar molecular characteristics do not have the same evolution, supporting the hypothesis for a multifactorial basis for disease progression. / Mestrado / Ciencias Biomedicas / Mestre em Tocoginecologia

Orientadores: Gustavo Antonio de Souza, Luis Otavio Sarian / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-11T03:29:01Z (GMT). No. of bitstreams: 1 Kestelman_FabiolaProcaci_M.pdf: 577232 bytes, checksum: acf1199f373751447b51be36a9c1cb18 (MD5) Previous issue date: 2008 / Resumo: Objetivo: Determinar o valor preditivo positivo das categorias 4A, 4B e 4C da 4ª edição do BI-RADS e determinar a variação interobservador desta classificação em lesões submetidas à biópsia cirúrgica. Métodos: Este estudo retrospectivo foi conduzido no Instituto Nacional de Câncer (INCA), Rio de Janeiro, Brasil. Os casos para análise foram selecionados no banco de dados do setor de radiologia, entre mulheres submetidas à marcação pré-cirúrgica para biópsia cirúrgica entre janeiro de 1999 e dezembro de 2002, que foram previamente classificadas como BIRADS 4. As mamografias foram revisadas por três radiologistas especializados em radiologia mamária. Os avaliadores classificaram as lesõs considerando a probabilidade de malignidade, dentro da categoria 4, em 4A, 4B e 4C. Para a análise estatética, foi realizado um consenso a partir dos resultados dos três radiologistas. A variação interobservador foi calculada utilizando o índice de kappa ponderado. Resultados: De 775 lesõs, o resultado consensual mostrou 235 (30,3%) mamografias classificadas como 4A, 338 (43,6%) como 4B e o restante 161 (20,8%) como 4C. Os radiologistas não obtiveram consenso em 41 (5,3%) lesões. A concordância geral entre os avaliadores foi moderada (?=0,44), variando entre ?=0,38 considerando os radiologistas dois e tr? e ?=0,54 considerando os radiologistas um e dois. A concordância variou de mínima (categoria 4B, k= 0,09) a pobre, considerando as categorias 4A e 4C. A proporção de lesões nos grupos 4A, 4B e 4C foi similar e o VPP foi progressivo (23,0%, 47,6% e 72,7%, respectivamente). Conclusão: O VPP das categorias 4A, 4B and 4C foi progressivo e a concord?cia entre os observadores foi moderada / Abstract: Purpose: To determine the predictive positive value of BI-RADS 4th edition categories 4A, 4B and 4C and determine the inter-observer variability for lesion on which biopsies had been performed. Methods: This cross-sectional study was conducted at the National Institute of Cancer (INCA), Rio de Janeiro, Brazil. Cases for analysis were selected from the medical records among women who were submitted to breast needle localization and diagnostic surgical biopsy, from January 1999 to December 2002, and which had been previously categorized as BIRADS 4. The mammograms were reviewed by three senior breast imaging radiologists. Readers provided a BI-RADS final assessment category to indicate the probability of malignancy in category 4. For statistical calculations, a ¿consensus¿ variable was created using the outputs from the three assessors. Interobserver variability for each subcategory was determined using the weighted kappa statistic. Results: Of 775 lesions, ¿consensual¿ assessment rendered 235 (30.3%) mammograms classified as 4A, 338 (43.6%) as 4B and the remainder 161 (20.8%) as 4C. Radiologists did not reach a consensus in 41 (5.3%) exams. Overall agreement between raters was moderate (?=0.44), ranging from ?=0.38 between raters two and three to ?=0.54 between radiologists one and two. Agreement between raters ranged from slight (category 4B, k=0.09) to fair, considering categories 4A and 4C. In BI-RADS 4B and 4C groups, the proportion of each abnormality in the whole group was similar to that in 4A, but the PPV were higher. Conclusions: The PPV for subcategories 4A, 4B and 4C was progressive and the agreement between readers was moderate. Key words: Breast cancer, mammography, BI-RADS / Mestrado / Tocoginecologia / Mestre em Tocoginecologia

Mes travaux de thèse ont permis d’identifier nectine-4 comme un nouveau biomarqueur, facteur de pronostic et cible thérapeutique dans 63% des cancers du sein triple-négatif (TNBC). Les TNBCs (20% des cancers du sein) sont de mauvais pronostics car, en dehors de la chimiothérapie, il n’existe pas de traitement dit « ciblé ». Ces travaux vont permettre à court terme d’adapter la stratégie thérapeutique et d’améliorer la prise en charge des patientes TNBC en fonction de leur profil d’expression de nectine-4. En effet, nous proposons une thérapie ciblée fondée sur la stratégie Antibody Drug Conjugate « ADC » anti-nectine-4 dans les TNBC équivalent au trastuzumab-emtansine dans le cancer du sein HER2+. Nous avons produit, sélectionné et validé cet outil thérapeutique innovant. Nous avons couplé cet anticorps à la monomethyl auristatin-E (MMAE) et testé son efficacité in vitro et in vivo en utilisant des modèles précliniques de souris PDX (Patient Derived Xenograft) greffées en conditions orthotopiques avec des tumeurs primaires TNBC. Nos résultats obtenus sur les tumeurs primitives et métastatiques sont très prometteurs, puisqu’il est possible de réduire voire de faire disparaitre la masse tumorale très rapidement après un seul traitement à la fois au niveau des tumeurs primitives, des métastases positives pour nectine-4. Cet anticorps anti-nectine-4 a fait l’objet d’un brevet international, a été humanisé et est en cours de développement clinique au sein d’une industrie pharmaceutique. Il est actuellement testé pour sa toxicité et son efficacité chez le singe cynomolgus. / Nectin-4 has been identified as a breast and ovarian biomarker at CRCM. Nectin-4 is a celladhesion molecule belonging to the immunoglobulin superfamily and is involved in ectodermaldevelopment in human. Nectin-4 has been recently identified as the epithelial receptor for themeasles virus. Together, this work has been rewarded by Inserm in 2012 (Prix del’Innovation). During my thesis, I have characterized nectin-4 as new prognosis biomarker andtherapeutic target in 63% of triple-negatif breast cancer (TNBC) . TNBCs represent 20% ofbreast cancer and are associated with poor prognosis as there is no exisiting targeted therapy.These results open the possibility for Antibody Drug Conjugate (ADC)-based targetedtreatment of primary and advanced TNBCs similar to trastuzumab-emtansine for HER2-positive breast cancers. We selected and validated a monoclonal antibody against nectin-4ectodomain and developed an ADC conjugated to monomethyl auristatin-E (MMAE). Weassessed the therapeutic efficiency of this ADC in vitro and in vivo in localised and metastaticTNBC Patient derived Xenografts (PDXs). In vivo, this ADC induced rapid, complete anddurable responses on nectin-4-positive xenograft TNBC samples including primary tumours,metastatic lesions, and local relapses. This antibody has been humanized, patented and iscurrently under clinical development by a pharmaceutical company testing toxicity and efficacyin cynomolgus monkeys.

L’hypothèse prédominante de cette thèse est que les traitements utilisés pour le cancer du sein de stade précoce (chimiothérapie avec des anthracyclines et/ou avec l’anticorps monoclonal trastuzumab) peuvent amener à des toxicités cardiaques à long terme, et qu’une évaluation de ce risque cardiaque ainsi qu’un suivi à long terme sont importants. Pour évaluer la toxicité cardiaque secondaire à ces deux agents chez les patientes avec un cancer du sein de stade précoce, nous avons réalisé deux séries d’études cliniques, la première pour évaluer la toxicité cardiaque à long terme induite par les anthracyclines, et la deuxième pour explorer la toxicité cardiaque induite par le trastuzumab. 1) Le premier chapitre de cette thèse explore la toxicité cardiaque à long terme induite par la chimiothérapie administrée aux patientes avec cancer du sein de stade précoce et ganglions positifs. La population de notre étude a été recrutée au sein de la population d’une étude de phase III randomisée menée entre 1988 et 1996 en Belgique et comparant trois schémas de traitement de chimiothérapie adjuvante, soit deux différents protocoles de chimiothérapies à base d’anthracyclines (basse dose ou haute dose d’epirubicine) ainsi qu’un schéma de chimiothérapie sans anthracyclines (CMF classique). Nous avons identifié 82 patientes (30%) traitées avec chimiothérapie adjuvante dans cette étude qui n’avaient pas de signe de récidive en 2010 (survivantes à long terme). Une évaluation cardiaque approfondie de ces patientes a été effectuée, incluant une échographie cardiaque, une résonance magnétique nucléaire, des marqueurs cardiaques sériques (pro-BNP et troponine), ainsi qu’un test de marche de 6 minutes. Cette étude nous a permis de démontrer que la toxicité cardiaque à long terme liée aux anthracyclines reste faible, et que la résonance magnétique est potentiellement plus précise que l’échographie cardiaque pour mesurer la fonction du ventricule gauche. Ceci devra cependant être confirmé dans d’autres études. Au cours de notre démarche, nous avons été confrontés à la difficulté de motiver les patientes plusieurs années après le traitement pour étudier les potentiels effets à long terme de ce dernier. 2) Le deuxième chapitre de cette thèse explore la toxicité cardiaque induite par l’anticorps monoclonal trastuzumab (anti-HER2). En un premier temps, nous avons examiné la toxicité cardiaque immédiate et à long terme au sein de la population de l’étude HERA, un large essai clinique randomisé de phase III du Breast International Group évaluant le bénéfice du trastuzumab en traitement adjuvant du cancer du sein HER2-positif. Après un suivi moyen de 8 ans des 5,102 participantes de l’étude, nous avons pu démontrer que la toxicité cardiaque demeure faible à long terme, avec très peu de nouveaux évènements cardiaques diagnostiqués dans la phase de suivi. Nous avons aussi pu démontrer que la toxicité cardiaque du trastuzumab apparait surtout pendant la phase de traitement, et qu’une fois le trastuzumab arrêté, la majorité des patientes récupèrent de l’épisode de toxicité cardiaque avec normalisation de la fraction d’éjection ventriculaire gauche. En un deuxième temps, en effectuant une analyse combinée de la toxicité cardiaque dans trois essais cliniques randomisés, nous avons démontré que l’usage concomitant du trastuzumab avec une chimiothérapie néo-adjuvante à base d’anthracyclines augmente le risque d’une toxicité cardiaque chez les patientes ayant un cancer du sein de stade précoce. Conséquemment, ces schémas de traitements ne sont pas recommandés de routine.En conclusion, une bonne évaluation cardiologique et oncologique doit avoir lieu avant de démarrer une chimiothérapie à base d’anthracyclines chez les patientes ayant un cancer du sein de stade précoce. Actuellement, la recommandation est d’évaluer les facteurs de risque cardiaque avant le traitement, et de suivre la fraction d’éjection du ventricule gauche avant, pendant et environs 6 mois après la fin du traitement. L’usage de marqueurs cardiaques et/ou de tests d’imagerie modernes pour un diagnostic de toxicité cardiaque tardive reste un domaine d’investigation intéressant. Pour les patientes avec un cancer du sein HER2-positif de stade précoce, le risque de toxicité cardiaque induite par le trastuzumab demeure faible. Cependant, les facteurs de risque doivent être évalués pour chaque patiente avant le traitement. L‘usage concomitant de trastuzumab et anthracyclines n’est pas recommandé vu le risque augmenté de toxicité cardiaque. En cas de facteurs de risque cardiaque, un dialogue étroit entre l’oncologue et le cardiologue est recommandé avant de débuter un traitement adjuvant. / Doctorat en Sciences médicales (Médecine) / info:eu-repo/semantics/nonPublished