O linfoma difuso de grandes células B (LDGCB) é o subtipo de linfoma mais comum em países em desenvolvimento. Entretanto, apesar de sua prevalência e importância, ainda existem poucas publicações com dados epidemiológicos para a população brasileira. Conhecer os fatores de prognóstico é imperativo para identificar os pacientes que responderão melhor ao tratamento, além de permitir sua individualização terapêutica. Alguns estudos demonstraram que pacientes com o mesmo Índice Internacional de Prognóstico (IPI) podem apresentar diferentes sobrevidas, justificando a necessidade de identificar novos marcadores biológicos de prognóstico. O objetivo deste estudo foi avaliar o impacto prognóstico da expressão dos genes BCL2, MDR1 e OCT1, de suas respectivas proteínas e da translocação t(14;18), nos desfechos de resposta completa (RC), sobrevida global (SG), sobrevida livre de doença (SLD) e sobrevida livre de progressão (SLP) em pacientes com LDGCB. Foram avaliados de forma retrospectiva 98 pacientes com LDGCB de novo tratados com R-CHOP. A expressão gênica foi avaliada por PCR em Tempo Real com RNA extraído de amostras parafinadas. A expressão proteica foi avaliada pelo método de imuno-histoquímica. A mediana de idade foi de 54,5 anos e 49 pacientes (50%) eram do sexo masculino. Sessenta e quatro pacientes (85,3%) obtiveram RC, com uma mediana de acompanhamento de 2,66 anos. A expressão mediana de BCL2, MDR1 e OCT1 foi 6,27; 0 e 24,49, respectivamente. Não encontramos impacto prognóstico da expressão do gene BCL2 na RC (p=0,277), SG (p=0,068) e SLD (p=0,860). Porém, a expressão de BCL2 >= à mediana associou-se à menor SLP (p=0,040). Encontramos associação entre expressão do gene OCT1 >= à mediana e pior prognóstico para SG (p=0,010) e SLP (p=0,016). Porém, não observamos impacto prognóstico da expressão de OCT1 para RC (p=0,464) e SLD (p=0,717). Não houve associação entre expressão do gene MDR1 e das proteínas BCL-2, Pg-p e OCT-1 com o prognóstico dos pacientes em relação à RC, SG, SLD e SLP. O número de sítios extralinfonodais (p=0,004 e p=0,005), estádio clínico (p < 0,001 para ambas), IPI (p < 0,001 para ambas) e nível de DHL (p=0,010 e p=0,008) apresentaram impacto prognóstico na SG e SLP, respectivamente. Quando os pacientes foram estratificados pelo estádio, IPI e idade, o grupo com expressão de OCT1 >= à mediana e IPI intermediário-alto ou alto risco apresentou pior SG (p=0,048) e o grupo com idade >= 60 anos e expressão de OCT1 >= à mediana apresentou pior prognóstico para SG e SLP (p=0,025 para ambas). Em conclusão, a expressão de MDR1 não apresentou impacto no prognóstico de portadores de LDGCB, porém, a expressão do gene BCL2 >= à mediana foi associada a menor SLP. Além disso, a hiperexpressão de OCT1 apresentou valor preditivo de prognóstico para a SG e SLP em pacientes com LDGCB tratados com R-CHOP / The diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype in developing countries. However, despite its prevalence and importance, there are still few publications showing the epidemiological data of the Brazilian population. Knowing the prognostic factors is imperative to identify patients supposed to better respond to treatment, as well as to allow their therapeutic individualization. Some studies have shown that patients with the same International Prognostic Index (IPI) may present different survival rates, thus justifying the need to identify new prognosis biomarkers. The aim of this study was to assess the prognostic impact of the genes BCL2, MDR1 and OCT1 and their respective proteins and t (14; 18) translocation on the complete response (CR), overall survival (OS), disease-free survival (DFS) and progression-free survival (PFS) of patients with DLBCL. We retrospectively assessed 98 patients with de novo DLBCL treated with R-CHOP. The gene expression was assessed through real-time PCR using RNA extracted from paraffin samples. The protein expression was assessed through the immunohistochemistry method. The median age was 54.5 years; 49 patients (50%) were men. Sixty-four patients (85.3%) had CR and median follow-up 2.66 years. The median expression of BCL2, MDR1 and OCT1 was 6.27; 0 and 24.49, respectively. We did not find the prognostic impact of the BCL2 gene expression on CR (p = 0.277), OS (p = 0.068) and on DFS (p = 0.860). However, the expression of BCL2 >= the median was associated with the lower PFS (p = 0.040). We found association between OCT1 gene expression >= the median and worse prognosis for OS (p = 0.010) and PFS (p = 0.016). However, we did not find the prognostic impact of OCT1 expression on CR (p = 0.464) and DFS (p = 0.717). There was no association between the MDR1 gene expression and the BCL-2, Pg-p and OCT-1 proteins, and the patients\' prognosis regarding CR, OS, DFS and PFS. The number of extranodal sites (p = 0.004 and p = 0.005), the clinical status (p <0.001 for both), the IPI (p < 0.001 for both) and DHL levels (p = 0.010 and p = 0.008) presented PFS, respectively. When the patients were stratified by stage, IPI and age, the group with OCT1 expression at the median and intermediate-to-high or high-risk IPI had worse OS results (p = 0.048) and the patients in the age group >= 60 years and expression of OCT1 >= the median presented worse prognosis for OS and PFS (p = 0.025 for both). Therefore, the MDR1 expression had no impact on the prognosis of DLBCL carriers. However, the expression of the BCL2 gene >= the median was associated with lower PFS. In addition, the OCT1 hyperexpression presented a predictive prognosis value for OS and PFS in patients with DLBCL treated with R-CHOP

INTRODUÇÃO: O linfoma difuso de grandes células B, sem outras especificaçoes (LDGCB, SOE) é uma neoplasia agressiva caracterizada pela heterogeneidade morfológica, imunofenotípica e molecular, porém o atual tratamento padrão utilizando imunoquimioterapia (R-CHOP) não considera tal diversidade. Há percentual significativo de pacientes que são refratários à terapia de primeira linha e alguns que apresentam recidiva precoce ou tardia, os quais representam as vítimas desta doença. O estudo imuno-histoquímico (IHQ), que é um método simples e universalmente disponível, vem sendo utilizado para reconhecer a diversidade biológica do LDGCB, SOE, identificando biomarcadores e subgrupos distintos da doença, que poderiam predizer a resposta terapêutica ao tratamento padrão e apontar possíveis candidatos a novas estratégias terapêuticas. OBJETIVOS: Este estudo avalia o valor prognóstico de cinco algoritmos para classificação do LDGCB segundo a célula de origem (COO) e da expressão de três biomarcadores (BCL2, CD30 e MYC) tendo como endpoint a sobrevida global. MÉTODOS: Foi realizado estudo retrospectivo com setenta e nove pacientes com LDGCB,SOE de novo tratados com imunoquimioterapia padrão, estadiados e acompanhados protocolarmente. Os casos foram classificados como subgrupo célula B centrogerminativa símile (GCB) ou como subgrupo célula B não-centrogerminativa símile (NGCB), de acordo com três algoritmos IHQ (Hans, Choi, e Visco-Young) pareados com estudo do perfil de expressão gênica (PEG) e dois algoritmos IHQ não-PEG pareados (Muris e Nyman). Foi estimado o valor prognóstico destes algoritmos e também avaliado a concordância entre eles. O valor prognóstico da expressão do BCL2, CD30 e MYC utilizando IHQ também foi analisado. RESULTADOS: Os algoritmos IHQ PEG pareados revelaram maior concordância entre si, porém nenhum deles revelou força prognóstica. A expressão do CD30 mostrou tendência a melhor prognóstico, porém a expressão de BCL2 e MYC avaliados isoladamente não revelaram impacto prognóstico. Contudo, a coexpressão do BCL2 e MYC, denominado como fenótipo linfoma duplo-expressor (LDE), revelou-se importante marcador prognóstico desfavorável. Foram identificados três subgrupos de risco baseado no fenótipo LDE e o Índice Prognóstico Internacional (IPI). CONCLUSÃO: Em pacientes com LDGCB, SOE de novo tratados com esquema terapêutico padrão, a pesquisa da expressão do fenótipo LDE é mais relevante do ponto vista prognóstico que a classificação em subgrupo GCB ou NGCB. Além disso, a expressão do CD30 pode ser relevante tanto para identificar subgrupo com tendência a melhor prognóstico como para identificar possíveis candidatos a nova terapia alvo / BACKGROUND: Diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS) is an aggressive neoplasm characterized by morphological, phenotypic and molecular heterogeneity, but the current standard therapy using immunochemotherapy (R-CHOP) does not consider such diversity. There is a significant percentage of patients who are refractory to first-line therapy and those with early or late recurrence, whose represent the victims of this disease. Immunohistochemistry (IHC), a simple and universally available method, has been used to recognize the biological diversity of DLBCL, NOS, to identify biomarkers and distinct subgroups of the disease, which would predict the therapeutic response to standard treatment and point possible candidates for novel therapeutic strategies. OBJECTIVES: The current study was conducted to evaluate the prognostic value from five algorithms for classification of DLBCL based on cell of origin (COO) and the expression of three biomarkers (BCL2, CD30 and MYC) with overall survival (OS) as an endpoint. METHODS: We retrospectively evaluated seventy nine patients with de novo DLBCL, NOS treated with R-CHOP-like immunochemotherapy. The cases were assigned as germinal center B-cell like (GCB) or non-GCB subgroup (NGCB) according to five different IHC algorithms, including three algorithms based on gene expressing profile study (GEP), proposed by Hans, Choi, and Visco-Young, and two non-GEP based algoritms proposed by Muris, and Nyman. We evaluated their prognostic relevance and the concordance between these algorithms. The prognostic power of BCL2, CD30 and MYC expression were also assessed by IHC. RESULTS: None of the profiles assessed by IHC algorithms was able to predict overall survival (OS). The positive expression of CD30 showed a trend toward a better outcome. Neither the positive expression of BCL2 nor the positive expression of MYC were associated with outcome. However, the double-expressor lymphoma phenotype (DEL), represented by the concurrent expression of MYC and BCL2, exhibited a negative prognostic impact. Three different risk subgroups were identified based on the DEL phenotype and the International Prognostic Index (IPI) score. CONCLUSIONS: These data suggest that the DEL, rather than the cell of origin classification based on IHC, is a better predictor of OS in patients with DLBCL treated with R-CHOP-like immunochemotherapy. Besides, the CD30 expression may be a useful prognostic marker and a possible therapeutic target

En France, les hémopathies lymphoïdes, se situant au sixième rang des cancers les plus fréquents, sontun problème majeur de santé publique. Ce travail a pour objectif d’étudier l’impact de la prise en charge thérapeutiquesur la survie et sur la qualité de vie (QdV) des patients atteints de ce type d’hémopathies. Le premierobjectif de ce travail est un état des lieux de l’épidémiologie des hémopathies lymphoïdes avec l’étudede l’évolution de l’incidence et de la survie nette en Côte d’Or entre 1980 et 2009. L’incidence, en nette augmentationdepuis 1980, semble se stabiliser depuis les années 2000 pour certaines entités, notamment pourles lymphomes folliculaires (LF) et les lymphomes B diffus à grandes cellules (LBDGC). Nous observons globalementune amélioration de la survie nette avec, toutefois, un pronostic à court et à long terme qui restedéfavorable pour certaines entités. Les LF et les LBDGC sont les premiers lymphomes à bénéficier de l’introductiondes anticorps monoclonaux dans leur prise en charge thérapeutique. Notre deuxième étude a pourobjectif demesurer l’impact du rituximab sur la survie globale des patients atteints d’un LF ou d’un LBDGC enCôte d’Or en utilisant une méthodologie basée sur le score de propension. Nos résultats confirment le bénéficesignificatif du rituximab sur la survie globale en population générale, sans critère de sélection. En vue de cesrésultats, nous avons étudié la QdV de ces patients pendant et à la suite de la prise en charge thérapeutique. LaQdV évolue différemment au cours du suivi en fonction du type de lymphome. / In France, hematologic malignancies, which are the sixthmost common cancers, are amajor public healthproblem. This work aimed to study the impact of the therapeutic management on survival and healt-relatedquality of life (HRQoL) in patients with these hematologic malignancies. The first objective of this work is topresent an overview of the epidemiology of lymphoid malignancies with a study of changes in the incidenceand net survival in the Côte d’Or department between 1980 and 2009. The incidence, which has increased since1980, seems to have stabilized since the 2000s for some entities, including follicular lymphoma (FL) and diffuselarge B-cell lymphoma (DLBCL). Overall, we observed an improvement in net survival, with, however, a lessfavorable prognosis in the short and long-term for some entities. FL and DLBCL were the first lymphomas tobenefit from the introduction of monoclonal antibodies in their therapeutic management. Our second studyaimed to assess the impact of rituximab on overall survival in patients with FL or DLBCL in the Côte d’Or departmentusing a methodology based on the propensity score. Our results confirmed the significant benefit ofrituximab on overall survival in an unselected population of patients. In view of these results, we studied theHRQoL of these patients during and after treatment. HRQoL evolved differently during follow-up dependingon the type of lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. It is a molecular and prognostic heterogeneous disease. Three main genetic subtypes are called germinal center-like DLBCL (GC-like DLBCL), non-germinal center-like DLBCL (nonGC-like DLBCL) and primary mediastinal B-cell lymphoma (PMBL). These subtypes can be reliably distinguished only with usage of gene expression profiling (GEP). The GEP method can be applied only when fresh frozen tissue is available. The method is technically difficult and expensive. Thus, it is not used routinely. Since the DLBCL subtypes differ in prognosis, it is extremely important to be able to distinguish them. The presented thesis is focused on distinguishing of PMBL diagnosis in the group of DLBCL. Easily stored formalin-fixed, paraffin-embedded tissue (FFPE) and gene expression analysis using real-time quantitative polymerase chain reaction (RTqPCR) are used. In the first step, PMBL and DLBCL cases were distinguished with an internationally accepted clinical-pathological method. The agreement between clinical-pathological diagnosis and GEP is only 76%. In the presented text a genetic algorithm for PMBL/DLBCL distinguishing is suggested. It uses three carefully chosen genes and their expression is measured with RTqPCR. Both, the...