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Doctoral Thesis
DOI
https://doi.org/10.11606/T.5.2015.tde-18062015-115931
Document
Author
Full name
Renata de Oliveira Costa
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2015
Supervisor
Committee
Pereira, Juliana (President)
Chamone, Dalton de Alencar Fischer
Menezes, Yara de
Nicolau, José Eduardo
Siqueira, Sheila Aparecida Coelho
Title in Portuguese
Estudo das variáveis de prognóstico clínico, da PET e PET/CT com 18FDG tomografia por emissão de pósitron/tomografia computadorizada ínterim, e do conceito de célula de origem por imuno-histoquímica em pacientes com linfoma difuso de grandes células B tratados com quimioimunoterapia
Keywords in Portuguese
Fluordesoxiglucose F18
Imuno-histoquímica
Linfoma não Hodgkin/quimioterapia
Prognóstico
Quimioterapia
Terapêutica
Tomografia por emissão de pósitrons
Abstract in Portuguese
O linfoma difuso de grandes células B (LDGCB) é o linfoma não-Hodgkin mais comum em nossa instituição (49,5%) e a classificação da Organização Mundial da Saúde reconhece vários subtipos de LDGCB com base na morfologia, imuno-histoquímica (IHQ) e perfil molecular. Metade dos pacientes permanecem incuráveis com terapia padrão baseada no anticorpo monoclonal anti-CD20 (rituximabe) e quimioterapia baseada em antraciclina. Portanto, é necessário identificar pacientes de alto risco e melhorar o seu prognóstico. Na era pré-rituximabe, a melhor maneira de identificar esse grupo de alto risco baseava-se no Índice de Prognóstico Internacional (IPI). Mais recentemente, grande interesse em subtipos moleculares e a caracterização da assinatura gênica das células malignas têm sido publicados. Pacientes com perfil de expressão gênica do centro germinativo (CG) parecem ter melhor prognóstico do que aqueles com assinatura de células B ativadas. Algoritmos IHC correspondentes foram propostos e o de Hans é o mais usado. No entanto, estes indicadores prognósticos têm sido questionados na era rituximabe. Além da classificação molecular, imagem funcional das células tumorais com 18F-fluodesoxiglucose (18F-FDG), a tomografia por emissão de pósitrons (PET/CT) tem sido recomendada ao diagnóstico e final do tratamento para aumentar a acurácia do estadiamento e avaliação de resposta. Embora alguns estudos tenham demonstrado que PET ínterim pode prognosticar a eficácia do tratamento, não há consenso e a utilização da PETi permanece controversa. O objetivo deste estudo foi investigar o impacto de fatores prognósticos clínicos, da PETi após dois ciclos de quimioterapia, e a célula de origem (CO) usando o algoritmo de Hans, como ferramentas prognósticas em pacientes tratados com R-CHOP 21. Foram analisados prospectivamente 147 pacientes. Dados clínicos estavam disponíveis em 146 casos. PETi foi realizada em 111 pacientes e 114 pacientes foram classificados em CG e NCG pelo algoritmo IHC de Hans. Com mediana de seguimento de 42,8 meses, a sobrevida global (SG), sobrevida livre de progressão (SLP) e resposta global (RG) para todos os pacientes foram 73,8%, 84,3% e 87,7%, respectivamente. IPI, R-IPI e NCCN IPI foram todos preditivos de SG. O IPI NCCN foi capaz de melhor discriminar um grupo de alto risco quando comparado ao de outros índices prognósticos clínicos. Embora PETi- tenha identificado um grupo com melhor SG (89,3% SG para PETi- versus 77,5% para a PETi+)(p = 0,04), a SLP entre os dois grupos não foi prognóstica (p=0,45), com SLP em 30 meses de 87,7%/81,2% para PETi- e PET+, respectivamente. O algoritmo de Hans não foi preditivo de SG, SLP ou RG. Associado à PETi-, ser do CG identificou um grupo de muito bom prognóstico, com SG e SLP de 100% em 48 meses. A análise univariada e multivariada revelou que, além da PETi-, o IPI, R-IPI e IPI do NCCN, juntamente com algumas variáveis que compõem este índice, foram preditivos para o SG, SLP e resposta completa. Este estudo mostrou que os fatores prognósticos clínicos são relevantes na era R-CHOP e a PETI, junto com a CO, foram capazes de identificar um subgrupo de muito bom prognóstico. Nossos resultados necessitam de confirmação
Title in English
Study of clinical prognostic factors, interim PET and PET/CT with 18-FDG positron emission tomography/computed tomography, and immunohistochemistry cell of origin in patients
Keywords in English
Drug therapy
Fluordesoxiglucose F18
Immunohistochemistry
Lymphoma non-Hodgkin/drug therapy
Positron-emission tomography
Prognosis
Therapeutics
Abstract in English
Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma in our institution (49.5%) and the World Health Organization classification recognizes several subtypes of DLBCL based on morphology, immunohistochemistry (IHC) and molecular analysis. A half of patients remain incurable with standard strategy with anti-CD20 monoclonal antibody (rituximab) and anthracycline-based chemotherapy. Therefore, it is necessary to identify high risk patients and improve their prognosis. In the pre-rituximab era, the best way to identify this high risk group was based on International Prognostic Index (IPI). More recently, lot of interest on molecular subtypes and aspects that characterize the gene signature of the malignant cells have been published. Patients with gene expression profile from germinal center (GC) seem to show better prognosis than those with Bcells activated signature. Correspondents algorithms based on IHC were proposed and Hans algorithm is the most commonly used. However these prognostic indicators have also been questioned in the rituximab era. In addition to the molecular classification, functional imaging of the tumor cells with 18F-fludeoxyglucose (18F-FDG) positron emission tomography PET/CT has been recommended at diagnosis and at the end of treatment to improve accuracy of staging and response evaluation. Although some studies have shown that interim PET may be a prognostic indicator of effectiveness of treatment, there is no agreement and the use of interim PET as a prognostic factor remains controversial. The objective of this study was to investigate the impact of clinical prognostic factors, interim imaging with 18F-FDG PET/CT after 2 cycles of treatment and cell of origin (CO) using Hans' algorithm as prognostic tools in patients treated with R-CHOP 21. 147 DLBCL patients were analyzed prospectively and clinical data was available in 146 cases. 18 F-FDG interim PET/CT was performed in 111 patients and DLBCL was classified as GC and NGC subtype by IHC using Hans's algorithm in 114 patients. With a median follow-up of 42.8 months, overall survival (OS), progression free survival (PFS) and overall response (OR) for all patients were 73.8%, 84.3% and 87.7% respectively. IPI, R-IPI and NCCN IPI were all predictive of OS. NCCN IPI was able to better discriminate a high risk group comparable with other clinical prognostic indexes. Although negative iPET identified a group with better OS (89.3% OS for PETi- versus 77.5% for PETi+)(p=0.04), PFS between the two groups was not prognostic (p=0.45) with a 30 months PFS of 87.7% and 81.2%, for PETi- and PET+, respectively. Hans algorithm was not predictive for OS, PFS or OR. Instead it was, together with PETi- and CG origin, able to predict a very good prognostic group, with both 100% OS/PFS in 48 months. The univariate and multivariate analysis revealed that besides negative interim PET, IPI, R-IPI and NCCN IPI along with some variables that compose this indexes, were predictive for OS, PFS and complete response. This study showed that clinical prognostic factors are relevant in R-CHOP era and PETi, along with CO, were able to identify a very good prognostic subgroup. Our results should be confirmed in others studies
 
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Publishing Date
2015-06-19
 
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