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      Bcl-2 protein frequency in patients with high-risk diffuse large B-cell lymphoma Translated title: Frequência da proteína Bcl-2 em pacientes com linfoma difuso de grandes células B de alto risco

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          ABSTRACT

          CONTEXT AND OBJECTIVE:

          Gene expression and immunohistochemical profiling of diffuse large B-cell lymphoma (DLBCL) have revealed important prognostic subgroups: germinal center B-cell-like (GCB-like) DLBCL and activated B cell-like (ABC-like) DLBCL. Although few reports on high-risk DLBCL are available, the prognosis for the GCB-like subgroup has been shown to be better than that of the ABC-like subgroup. The role of Bcl-2 as a predictor of survival in DLBCL cases is unclear and its expression varies between the two subgroups of DLBCL. In this study, we analyzed the frequency and prognostic impact of Bcl-2 protein expression in high-risk DLBCL cases.

          DESIGN AND SETTING:

          Retrospective cohort study among DLBCL patients treated at Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo (HC-FMUSP).

          METHODS:

          The prognostic impact of the expression of the proteins CD10, Bcl-6, MUM1 (multiple myeloma oncogene-1) and Bcl-2 on high-risk DLBCL cases was evaluated by means of immunohistochemistry. Seventy-three patients aged 18-60 years were evaluated for all these markers.

          RESULTS:

          Twenty-four cases (32.9%) were GCB-like and 49 (67.1%) were ABC-like, with no difference regarding complete remission, disease-free survival or overall survival rates. Twenty-seven patients (37%) showed Bcl-2 expression, which was the only independent factor predicting a worse prognosis for overall survival according to multivariate analysis.

          CONCLUSION:

          Bcl-2 protein was expressed in 37% of the high-risk DLBCL patients, without any difference between the ABC-like DLBCL and GCB-like DLBCL cases.

          RESUMO

          CONTEXTO E OBJETIVO:

          A expressão gênica e imunoistoquímica do linfoma difuso de grandes células B (LDGCB) vem permitindo a identificação de importantes subgrupos prognósticos: LDGCB do centro germinativo (CG) e LDGCB de células B ativadas (CBA). Entretanto, existem poucos dados disponíveis com LDGCB de alto risco, sendo o prognóstico dos LDGCB do CG melhor que os LDGCB de CBA. A participação do Bcl-2 como preditor de sobrevida nos LDGCB não é clara e sua expressão é variável entre os dois subgrupos de LDGCB. Neste estudo é avaliada a frequência e o prognóstico da expressão da proteína Bcl-2 em LDGCB de alto risco.

          TIPO DE ESTUDO E LOCAL:

          Estudo de coorte retrospectivo realizado entre portadores de LDGCB tratados no Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo.

          MఙTODOS:

          Foi avaliado o impacto prognóstico da expressão das proteínas CD10, Bcl-6, MUM1 (multiple myeloma oncogene-1) e Bcl-2 por imunoistoquímica em LDGCB de alto risco. Foram avaliados, para todos os marcadores, 73 pacientes com idade de 18 a 60 anos.

          RESULTADOS:

          Vinte e quatro (32,9%) pacientes foram classificados como LDGCB do CG e 49 (67,1%) como LDGCB de CBA, sem diferença nas taxas de remissão completa, sobrevida livre de doença e sobrevida global. Vinte e sete (37%) apresentaram expressão de Bcl-2, o qual foi o único fator preditivo independente de pior prognóstico de sobrevida global à análise multivariada.

          CONCLUSÃO:

          A expressão da proteína Bcl-2 ocorreu em 37% dos portadores de LDGCB de alto risco, sem diferença entre os subgrupos de LDGCB do CG ou de CBA.

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          Most cited references39

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          Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling.

          Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin's lymphoma, is clinically heterogeneous: 40% of patients respond well to current therapy and have prolonged survival, whereas the remainder succumb to the disease. We proposed that this variability in natural history reflects unrecognized molecular heterogeneity in the tumours. Using DNA microarrays, we have conducted a systematic characterization of gene expression in B-cell malignancies. Here we show that there is diversity in gene expression among the tumours of DLBCL patients, apparently reflecting the variation in tumour proliferation rate, host response and differentiation state of the tumour. We identified two molecularly distinct forms of DLBCL which had gene expression patterns indicative of different stages of B-cell differentiation. One type expressed genes characteristic of germinal centre B cells ('germinal centre B-like DLBCL'); the second type expressed genes normally induced during in vitro activation of peripheral blood B cells ('activated B-like DLBCL'). Patients with germinal centre B-like DLBCL had a significantly better overall survival than those with activated B-like DLBCL. The molecular classification of tumours on the basis of gene expression can thus identify previously undetected and clinically significant subtypes of cancer.
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            Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray.

            Diffuse large B-cell lymphoma (DLBCL) can be divided into prognostically important subgroups with germinal center B-cell-like (GCB), activated B-cell-like (ABC), and type 3 gene expression profiles using a cDNA microarray. Tissue microarray (TMA) blocks were created from 152 cases of DLBCL, 142 of which had been successfully evaluated by cDNA microarray (75 GCB, 41 ABC, and 26 type 3). Sections were stained with antibodies to CD10, bcl-6, MUM1, FOXP1, cyclin D2, and bcl-2. Expression of bcl-6 (P <.001) or CD10 (P =.019) was associated with better overall survival (OS), whereas expression of MUM1 (P =.009) or cyclin D2 (P <.001) was associated with worse OS. Cases were subclassified using CD10, bcl-6, and MUM1 expression, and 64 cases (42%) were considered GCB and 88 cases (58%) non-GCB. The 5-year OS for the GCB group was 76% compared with only 34% for the non-GCB group (P <.001), which is similar to that reported using the cDNA microarray. Bcl-2 and cyclin D2 were adverse predictors in the non-GCB group. In multivariate analysis, a high International Prognostic Index score (3-5) and the non-GCB phenotype were independent adverse predictors (P <.0001). In summary, immunostains can be used to determine the GCB and non-GCB subtypes of DLBCL and predict survival similar to the cDNA microarray.
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              Revised response criteria for malignant lymphoma.

              Standardized response criteria are needed to interpret and compare clinical trials and for approval of new therapeutic agents by regulatory agencies. The International Working Group response criteria (Cheson et al, J Clin Oncol 17:1244, 1999) were widely adopted, but required reassessment because of identified limitations and the increased use of [18F]fluorodeoxyglucose-positron emission tomography (PET), immunohistochemistry (IHC), and flow cytometry. The International Harmonization Project was convened to provide updated recommendations. New guidelines are presented incorporating PET, IHC, and flow cytometry for definitions of response in non-Hodgkin's and Hodgkin's lymphoma. Standardized definitions of end points are provided. We hope that these guidelines will be adopted widely by study groups, pharmaceutical and biotechnology companies, and regulatory agencies to facilitate the development of new and more effective therapies to improve the outcome of patients with lymphoma.
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                Author and article information

                Journal
                Sao Paulo Med J
                Sao Paulo Med J
                Sao Paulo Med J
                São Paulo Medical Journal
                Associação Paulista de Medicina - APM
                1516-3180
                1806-9460
                07 January 2010
                2010
                : 128
                : 1
                : 14-17
                Affiliations
                [I ] originalMD, PhD. Substitute professor, Department of Hematology, Universidade Federal de Juiz de Fora (UFJF), Juiz de Fora, Minas Gerais, Brazil.
                [II ] originalMD, PhD. Attending physician, Department of Pathological Anatomy, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil.
                [III ] originalMD, PhD. Associate professor, Department of Hematology, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil.
                [IV ] originalMD, PhD. Associate professsor, Department of Statistics, Universidade Federal de Juiz de Fora (UFJF), Juiz de Fora, Minas Gerais, Brazil.
                [V ] originalMD. Attending physician, Department of Hematology, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil.
                [VI ] originalMD, PhD. Titular professor, Department of Hematology, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil.
                Author notes
                [Address for correspondence: ] Abrahão Elias Hallack Neto Av. Dr. Enéas de Carvalho Aguiar, 155 — 1 o andar — sala 61 Cerqueira César — São Paulo (SP) — Brasil CEP 05403-000 Tel. (+55 11) 3061-5544 Fax. (+55 32) 3215-1523 Cel. (+55 32) 9112-6692 E-mail: abrahallack@ 123456uol.com.br

                Conflict of interest: Not declared

                Article
                10.1590/S1516-31802010000100004
                10936133
                20512275
                325d3191-17e7-4730-afcf-34dc69741c0b

                This is an open access article distributed under the terms of the Creative Commons license.

                History
                : 06 February 2009
                : 13 January 2010
                : 13 January 2010
                Page count
                Figures: 0, Tables: 3, Equations: 0, References: 21, Pages: 4
                Categories
                Original Article

                lymphoma,oncogene proteins,prognosis,biological markers,germinal center,linfoma,proteínas oncogênicas,prognóstico,marcadores biológicos,centro germinativo

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