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1.
Haematologica ; 104(4): 778-788, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-29954928

RESUMO

Constitutive activation of the chemokine receptor CXCR4 has been associated with tumor progression, invasion, and chemotherapy resistance in different cancer subtypes. Although the CXCR4 pathway has recently been suggested as an adverse prognostic marker in diffuse large B-cell lymphoma, its biological relevance in this disease remains underexplored. In a homogeneous set of 52 biopsies from patients, an antibody-based cytokine array showed that tissue levels of CXCL12 correlated with high microvessel density and bone marrow involvement at diagnosis, supporting a role for the CXCL12-CXCR4 axis in disease progression. We then identified the tetra-amine IQS-01.01RS as a potent inverse agonist of the receptor, preventing CXCL12-mediated chemotaxis and triggering apoptosis in a panel of 18 cell lines and primary cultures, with superior mobilizing properties in vivo than those of the standard agent. IQS-01.01RS activity was associated with downregulation of p-AKT, p-ERK1/2 and destabilization of MYC, allowing a synergistic interaction with the bromodomain and extra-terminal domain inhibitor, CPI203. In a xenotransplant model of diffuse large B-cell lymphoma, the combination of IQS-01.01RS and CPI203 decreased tumor burden through MYC and p-AKT downregulation, and enhanced the induction of apoptosis. Thus, our results point out an emerging role of CXCL12-CXCR4 in the pathogenesis of diffuse large B-cell lymphoma and support the simultaneous targeting of CXCR4 and bromodomain proteins as a promising, rationale-based strategy for the treatment of this disease.

2.
Leuk Res ; 38(4): 509-15, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24480549

RESUMO

The analysis of immunoglobulin heavy chain variable (IGHV) region may disclose the influence of antigens in Burkitt's lymphomas (BL). IGHV sequences from 38 patients and 35 cell lines were analyzed. IGHV3 subset genes were the most used and IGHV4-34 gene was overrepresented. IGHV genes were mutated in 98.6% of the cases, 36% acquired potential glycosylation sites, and in 52% somatic-hypermutation-process was ongoing. Binding motifs for superantigens like Staphylococcal protein A and carbohydrate I/i were preserved in 89% of the cases. IGHV analysis of BL cells supports a germinal center origin and points toward a role for superantigens in lymphomagenesis.


Assuntos
Linfoma de Burkitt/genética , Transformação Celular Neoplásica , Análise Mutacional de DNA , Centro Germinativo/patologia , Cadeias Pesadas de Imunoglobulinas/genética , Região Variável de Imunoglobulina/genética , Superantígenos/fisiologia , Adolescente , Adulto , Idoso , Linfoma de Burkitt/patologia , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/imunologia , Criança , Pré-Escolar , Feminino , Centro Germinativo/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade
3.
Haematologica ; 98(10): 1554-62, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23716551

RESUMO

MYC alterations influence the survival of patients with diffuse large B-cell lymphoma. Most studies have focused on MYC translocations but there is little information regarding the impact of numerical alterations and protein expression. We analyzed the genetic alterations and protein expression of MYC, BCL2, BCL6, and MALT1 in 219 cases of diffuse large B-cell lymphoma. MYC rearrangement occurred as the sole abnormality (MYC single-hit) in 3% of cases, MYC and concurrent BCL2 and/or BCL6 rearrangements (MYC double/triple-hit) in 4%, MYC amplifications in 2% and MYC gains in 19%. MYC single-hit, MYC double/triple-hit and MYC amplifications, but not MYC gains or other gene rearrangements, were associated with unfavorable progression-free survival and overall survival. MYC protein expression, evaluated using computerized image analysis, captured the unfavorable prognosis of MYC translocations/amplifications and identified an additional subset of patients without gene alterations but with similar poor prognosis. Patients with tumors expressing both MYC/BCL2 had the worst prognosis, whereas those with double-negative tumors had the best outcome. High MYC expression was associated with shorter overall survival irrespectively of the International Prognostic Index and BCL2 expression. In conclusion, MYC protein expression identifies a subset of diffuse large B-cell lymphoma with very poor prognosis independently of gene alterations and other prognostic parameters.


Assuntos
Regulação Neoplásica da Expressão Gênica , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/genética , Proteínas Proto-Oncogênicas c-myc/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Imunoterapia , Linfoma Difuso de Grandes Células B/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteínas Proto-Oncogênicas c-myc/biossíntese , Taxa de Sobrevida/tendências , Resultado do Tratamento , Adulto Jovem
4.
Blood ; 120(11): 2290-6, 2012 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-22740447

RESUMO

Biologic factors that predict the survival of patients with a diffuse large B-cell lymphoma, such as cell of origin and stromal signatures, have been discovered by gene expression profiling. We attempted to simulate these gene expression profiling findings and create a new biologic prognostic model based on immunohistochemistry. We studied 199 patients (125 in the training set, 74 in the validation set) with de novo diffuse large B-cell lymphoma treated with rituximab and CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or CHOP-like therapies, and immunohistochemical stains were performed on paraffin-embedded tissue microarrays. In the model, 1 point was awarded for each adverse prognostic factor: nongerminal center B cell-like subtype, SPARC (secreted protein, acidic, and rich in cysteine) < 5%, and microvascular density quartile 4. The model using these 3 biologic markers was highly predictive of overall survival and event-free survival in multivariate analysis after adjusting for the International Prognostic Index in both the training and validation sets. This new model delineates 2 groups of patients, 1 with a low biologic score (0-1) and good survival and the other with a high score (2-3) and poor survival. This new biologic prognostic model could be used with the International Prognostic Index to stratify patients for novel or risk-adapted therapies.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Sistemas Especialistas , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Modelos Biológicos , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos/uso terapêutico , Inteligência Artificial , Estudos de Coortes , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Prednisona/uso terapêutico , Prognóstico , Rituximab , Análise de Sobrevida , Análise Serial de Tecidos , Vincristina/uso terapêutico , Adulto Jovem
5.
Haematologica ; 96(7): 996-1001, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21546504

RESUMO

BACKGROUND: Diffuse large B-cell lymphoma is a clinically and molecularly heterogeneous disease. Gene expression profiling studies have shown that the tumor microenvironment affects survival and that the angiogenesis-related signature is prognostically unfavorable. The contribution of histopathological microvessel density to survival in diffuse large B-cell lymphomas treated with immunochemotherapy remains unknown. The purpose of this study is to assess the prognostic impact of histopathological microvessel density in two independent series of patients with diffuse large B-cell lymphoma treated with immunochemotherapy. DESIGN AND METHODS: One hundred and forty-seven patients from the Leukemia Lymphoma Molecular Profiling Project (training series) and 118 patients from the Catalan Lymphoma-Study group-GELCAB (validation cohort) were included in the study. Microvessels were immunostained with CD31 and quantified with a computerized image analysis system. The stromal scores previously defined in 110 Leukemia Lymphoma Molecular Profiling Project cases were used to analyze correlations with microvessel density data. RESULTS: Microvessel density significantly correlated with the stromal score (r=0.3209; P<0.001). Patients with high microvessel density showed significantly poorer overall survival than those with low microvessel density both in the training series (4-year OS 54% vs. 78%; P=0.004) and in the validation cohort (57% vs. 81%; P=0.006). In multivariate analysis, in both groups high microvessel density was a statistically significant unfavorable prognostic factor independent of international prognostic index [training series: international prognostic index (relative risk 2.7; P=0.003); microvessel density (relative risk 1.96; P=0.002); validation cohort: international prognostic index (relative risk 4.74; P<0.001); microvessel density (relative risk 2.4; P=0.016)]. CONCLUSIONS: These findings highlight the impact of angiogenesis in the outcome of patients with diffuse large B-cell lymphoma and the interest of evaluating antiangiogenic drugs in clinical trials.


Assuntos
Anticorpos Monoclonais Murinos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Microvasos/patologia , Microambiente Tumoral , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos/administração & dosagem , Feminino , Perfilação da Expressão Gênica , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Prognóstico , Reprodutibilidade dos Testes , Rituximab , Análise de Sobrevida , Resultado do Tratamento , Adulto Jovem
6.
Blood ; 117(18): 4836-43, 2011 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-21441466

RESUMO

Diffuse large B-cell lymphomas (DLBCLs) can be divided into germinal-center B cell-like (GCB) and activated-B cell-like (ABC) subtypes by gene-expression profiling (GEP), with the latter showing a poorer outcome. Although this classification can be mimicked by different immunostaining algorithms, their reliability is the object of controversy. We constructed tissue microarrays with samples of 157 DLBCL patients homogeneously treated with immunochemotherapy to apply the following algorithms: Colomo (MUM1/IRF4, CD10, and BCL6 antigens), Hans (CD10, BCL6, and MUM1/IRF4), Muris (CD10 and MUM1/IRF4 plus BCL2), Choi (GCET1, MUM1/IRF4, CD10, FOXP1, and BCL6), and Tally (CD10, GCET1, MUM1/IRF4, FOXP1, and LMO2). GEP information was available in 62 cases. The proportion of misclassified cases by immunohistochemistry compared with GEP was higher when defining the GCB subset: 41%, 48%, 30%, 60%, and 40% for Colomo, Hans, Muris, Choi, and Tally, respectively. Whereas the GEP groups showed significantly different 5-year progression-free survival (76% vs 31% for GCB and activated DLBCL) and overall survival (80% vs 45%), none of the immunostaining algorithms was able to retain the prognostic impact of the groups (GCB vs non-GCB). In conclusion, stratification based on immunostaining algorithms should be used with caution in guiding therapy, even in clinical trials.


Assuntos
Algoritmos , Perfilação da Expressão Gênica , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos/uso terapêutico , Antineoplásicos/uso terapêutico , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Imunofenotipagem , Imunoterapia , Estimativa de Kaplan-Meier , Linfoma Difuso de Grandes Células B/imunologia , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Rituximab , Adulto Jovem
7.
Pediatr Blood Cancer ; 47(7): 964-7, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16200567

RESUMO

Opsoclonus-myoclonus-ataxia (OMA) secondary to Epstein-Barr virus (EBV) infection has only been described in three pediatric patients. Previous reports suggested that evidence for a recent EBV infection in the absence of an occult neoplasm would predict a favorable prognosis for OMA as well as no tumor development. We present the case of a 20-month-old child with OMA associated with a microbiologically documented acute EBV infection and an occult thoracic ganglioneuroblastoma diagnosed 5 months later.


Assuntos
Infecções por Vírus Epstein-Barr/complicações , Ganglioneuroblastoma/complicações , Síndrome de Opsoclonia-Mioclonia/etiologia , Neoplasias Torácicas/complicações , Feminino , Humanos , Lactente
8.
Pediatr Blood Cancer ; 43(7): 785-7, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15390353

RESUMO

Primary congenital cervical neuroblastomas are very rare. A history of upper aerodigestive compromise with Horner syndrome can be of value for the early diagnosis of this lesion. Congenital neuroblastomas usually have a favorable outcome. Like all the other clinically relevant groups of neuroblastomas, management should take into consideration the biological findings of each tumor, which predicts outcome than other clinical findings.


Assuntos
Neoplasias de Cabeça e Pescoço/congênito , Neuroblastoma/congênito , Obstrução das Vias Respiratórias/etiologia , Análise Citogenética , Intervalo Livre de Doença , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/cirurgia , Histocitoquímica , Humanos , Recém-Nascido , Imagem por Ressonância Magnética , Masculino , Neuroblastoma/diagnóstico , Neuroblastoma/cirurgia
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