Assuntos
2',5'-Oligoadenilato Sintetase/genética , Cromossomos Humanos Par 12/química , Íntrons , Leucemia Linfocítica Crônica de Células B/genética , Polimorfismo de Nucleotídeo Único , Alelos , Estudos de Casos e Controles , Mapeamento Cromossômico , Frequência do Gene , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Razão de Chances , RiscoAssuntos
Antineoplásicos/farmacologia , Monitoramento de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Seleção de Pacientes , Ensaios Clínicos Controlados Aleatórios como Assunto , Vidarabina/análogos & derivados , Bioensaio , Seguimentos , Humanos , Leucemia Linfocítica Crônica de Células B/sangue , Leucemia Linfocítica Crônica de Células B/mortalidade , Estudos Multicêntricos como Assunto , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/mortalidade , Valor Preditivo dos Testes , Prognóstico , Distribuição Aleatória , Taxa de Sobrevida , Vidarabina/farmacologiaAssuntos
Genes MHC Classe I/genética , Antígeno HLA-A2/genética , Leucemia Linfocítica Crônica de Células B/etiologia , Polimorfismo de Nucleotídeo Único/genética , Estudos de Casos e Controles , DNA de Neoplasias/genética , Feminino , Seguimentos , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase , Prognóstico , Fatores de RiscoAssuntos
Perfilação da Expressão Gênica , Leucemia de Células Pilosas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Aberrações Cromossômicas , Terapia Combinada , DNA de Neoplasias/genética , Feminino , Dosagem de Genes , Genes Neoplásicos , Genes Supressores de Tumor , Humanos , Leucemia de Células Pilosas/classificação , Leucemia de Células Pilosas/tratamento farmacológico , Leucemia de Células Pilosas/cirurgia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , EsplenectomiaAssuntos
Citidina Desaminase/genética , Variação Genética , Leucemia de Células Pilosas/genética , Linfoma de Zona Marginal Tipo Células B/genética , Neoplasias Esplênicas/genética , Western Blotting , Diferenciação Celular , Citidina Desaminase/metabolismo , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Região Variável de Imunoglobulina/genética , Imunofenotipagem , Leucemia de Células Pilosas/metabolismo , Leucemia de Células Pilosas/patologia , Linfoma de Zona Marginal Tipo Células B/metabolismo , Linfoma de Zona Marginal Tipo Células B/patologia , Mutação/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias Esplênicas/metabolismo , Neoplasias Esplênicas/patologiaRESUMO
In a series of 48 patients with splenic marginal zone lymphoma (SMZL) with circulating villous lymphocytes, we describe the clinical and laboratory features of nine cases that transformed to high-grade B-cell lymphoma. These patients had a significantly greater incidence of peripheral lymph node involvement at diagnosis when compared to SMZL patients who did not transform (P < 0.03). While transformation in the bone marrow is frequently refractory to therapy and associated with poor outcome in SMZL, lymph node transformation responds well to chemotherapy with durable progression-free and overall survival.
Assuntos
Transformação Celular Neoplásica/patologia , Linfonodos/patologia , Linfócitos/patologia , Linfoma de Zona Marginal Tipo Células B/patologia , Neoplasias Esplênicas/patologia , Idoso , Distribuição de Qui-Quadrado , Intervalo Livre de Doença , Feminino , Humanos , Linfoma de Zona Marginal Tipo Células B/tratamento farmacológico , Linfoma de Zona Marginal Tipo Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias Esplênicas/tratamento farmacológico , Neoplasias Esplênicas/mortalidade , Taxa de SobrevidaAssuntos
Cromossomos Humanos Par 8 , Predisposição Genética para Doença , Leucemia Linfocítica Crônica de Células B/etiologia , Polimorfismo de Nucleotídeo Único , Análise Mutacional de DNA , Feminino , Genótipo , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
A possible role for DNA mismatch repair defects and microsatellite instability (MSI) in the pathogenesis of a number of B-cell lymphoproliferative disorders has recently been debated. To gain further insight into the impact of MSI on B-CLL, we evaluated samples from a series of 982 patients using the mono-satellite markers BAT25 and BAT26, which are highly sensitive in demonstrating classical mismatch repair (MMR) deficiency. Only 1% of cases displayed MSI and this was not correlated with stage of disease or family history of B-CLL. A sub-polymorphic germline variant of BAT25 was identified in one familial case, which was also detected in the patient's affected brother. In conclusion, our study demonstrates that MSI does not have a prominent role in the pathogenesis of B-CLL.
Assuntos
Reparo de Erro de Pareamento de DNA , Reparo do DNA/genética , Leucemia Linfocítica Crônica de Células B/genética , Instabilidade de Microssatélites , Idoso , Biomarcadores Tumorais/genética , Saúde da Família , Feminino , Marcadores Genéticos , Humanos , Leucemia Linfocítica Crônica de Células B/etiologia , Masculino , Repetições de Microssatélites , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Previous studies of patients with chronic lymphocytic leukaemia reported high response rates to fludarabine combined with cyclophosphamide. We aimed to establish whether this treatment combination provided greater survival benefit than did chlorambucil or fludarabine. METHODS: 777 patients with chronic lymphocytic leukaemia requiring treatment were randomly assigned to fludarabine (n=194) or fludarabine plus cyclophosphamide (196) for six courses, or chlorambucil (387) for 12 courses. The primary endpoint was overall survival, with secondary endpoints of response rates, progression-free survival, toxic effects, and quality of life. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number NCT 58585610. FINDINGS: There was no significant difference in overall survival between patients given fludarabine plus cyclophosphamide, fludarabine, or chlorambucil. Complete and overall response rates were better with fludarabine plus cyclophosphamide than with fludarabine (complete response rate 38%vs 15%, respectively; overall response rate 94%vs 80%, respectively; p<0.0001 for both comparisons), which were in turn better than with chlorambucil (complete response rate 7%, overall response rate 72%; p=0.006 and 0.04, respectively). Progression-free survival at 5 years was significantly better with fludarabine plus cyclophosphamide (36%) than with fludarabine (10%) or chlorambucil (10%; p<0.00005). Fludarabine plus cyclophosphamide was the best combination for all ages, including patients older than 70 years, and in prognostic groups defined by immunoglobulin heavy chain gene (V(H)) mutation status and cytogenetics, which were tested in 533 and 579 cases, respectively. Patients had more neutropenia and days in hospital with fludarabine plus cyclophosphamide, or fludarabine, than with chlorambucil. There was less haemolytic anaemia with fludarabine plus cyclophosphamide (5%) than with fludarabine (11%) or chlorambucil (12%). Quality of life was better for responders, but preliminary analyses showed no significant difference between treatments. A meta-analysis of these data and those of two published phase III trials showed a consistent benefit for the fludarabine plus cyclophosphamide regimen in terms of progression-free survival. INTERPRETATION: Fludarabine plus cyclophosphamide should now become the standard treatment for chronic lymphocytic leukaemia and the basis for new protocols that incorporate monoclonal antibodies.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Idoso , Clorambucila/administração & dosagem , Clorambucila/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Vidarabina/administração & dosagem , Vidarabina/efeitos adversos , Vidarabina/análogos & derivadosAssuntos
Fatores de Troca do Nucleotídeo Guanina/genética , Leucemia Linfocítica Crônica de Células B/etiologia , Proteínas Proto-Oncogênicas/genética , Transativadores/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte , Saúde da Família , Feminino , Mutação em Linhagem Germinativa , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Masculino , Pessoa de Meia-IdadeRESUMO
Mantle cell lymphoma (MCL), characterised by t(11;14)(q13;q32), has a poor prognosis. Many cases have additional cytogenetic abnormalities, and often have a complex karyotype. Fluorescence in situ hybridisation (FISH) was used to study 60 cases with leukaemic presentation of MCL, to determine the frequency, clinical correlations and prognostic impact of a panel of molecular cytogenetic abnormalities: 17p13 (TP53 locus), 13q14, 12 p11.1-q11 (centromere), 6q21 and 11q23. CD38 expression, of prognostic value in chronic lymphocytic leukaemia (CLL), was also studied, and correlations with clinical and cytogenetic abnormalities sought. Eighty per cent of cases had at least one abnormality in addition to t(11;14). Deletions at 17p13 (TP53) and 13q14 were most frequent and involved the majority of the leukaemic clone. Cases with TP53 deletion were more likely to have splenomegaly and marked leucocytosis (>30 x 10(9)/l), and less likely to have lymphadenopathy than those without deletion. Deletions at 11q23 and 6q21 were associated with extranodal disease. 13q14 and 11q23 deletions showed a trend towards worse prognosis by univariate analysis. In multivariate analysis, deletions at 13q14 and 6q21 were independent predictors of poor outcome. Deletion at 17p13 did not show prognostic impact in this series. CD38, positive in two-thirds of cases, was associated with male gender and nodal disease but not with any cytogenetic abnormality, or with survival.
Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 14/genética , Leucemia/genética , Linfoma de Célula do Manto/genética , ADP-Ribosil Ciclase 1/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Deleção Cromossômica , Métodos Epidemiológicos , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Prognóstico , Translocação GenéticaRESUMO
AIMS: To augment the limited literature on bone marrow (BM) appearances in T-cell large granular lymphocyte (LGL) leukaemia and to identify a histological signature to aid in diagnosis of this condition. METHODS AND RESULTS: A descriptive analysis of the histology of the BM in T-cell LGL leukaemia was performed (n = 38). Antibodies against CD3, CD4, CD5, CD8, CD16, CD56, CD57 and CD20 or CD79a were employed. Antibodies against CD68 (macrophages) and CD34 (sinusoids) were also included. BM was normocellular or hypercellular in the majority of cases, with interstitial lymphoid infiltration in 97%. Lymphoid nodules were present in 55% and intrasinusoidal permeation in 58%. Apoptotic figures and haemosiderin deposition were common. All cases showed trilinear haematopoiesis with normal or increased megakaryopoiesis and erythropoiesis, but normal/reduced myelopoiesis. Reticulin was increased (Grade II-III). Immunohistochemistry revealed interstitial infiltration in all cases and helped to identify lymphoid nodules in two-thirds of cases. Preferential localization of CD8+ T lymphocytes to the interstitium and CD4+ T lymphocytes to the periphery of CD20+ B-cell nodules was seen in almost 90% of cases. CONCLUSIONS: Nodules with non-clonal B-cell centres surrounded by CD4+ cells, with interstitial CD8+ cells, are a characteristic finding in T-cell LGL leukaemia and may represent a histological signature for this condition.
Assuntos
Células da Medula Óssea/patologia , Medula Óssea/patologia , Leucemia de Células T/patologia , Linfócitos T/patologia , Adulto , Idoso , Antígenos CD/metabolismo , Apoptose , Biomarcadores Tumorais/metabolismo , Medula Óssea/metabolismo , Células da Medula Óssea/metabolismo , Feminino , Hematopoese/fisiologia , Hemossiderina/metabolismo , Humanos , Imuno-Histoquímica , Leucemia de Células T/metabolismo , Tecido Linfoide/metabolismo , Tecido Linfoide/patologia , Masculino , Pessoa de Meia-Idade , Linfócitos T/metabolismoRESUMO
B-prolymphocytic leukemia (B-PLL) is a rare disease with poor prognosis. To further characterize the biological features of this disease, we analyzed immunoglobulin heavy chain (IgVH) mutations, ZAP-70 and CD38 in 19 cases with de novo B-PLL. Immunoglobulin heavy chain genes analysis showed an unmutated pattern (>98% homology to germ line) in 9/17 cases (53%), with 100% homology in eight. In the remaining, it ranged from 90 to 97.4%, with three cases slightly mutated (98-95%) and five heavily mutated (<95%). All B-PLL utilized members of VH3 (11/17) and VH4 (6/17) families, with V3-23, V4-59 and V4-34 gene accounting for more than half of them, regardless of mutational status. ZAP-70, assessed by flow cytometry, ranged from 1 to 91% cells, being > or =20% in 57% of cases. CD38 ranged from 1 to 99% (median 21%). There was no correlation between IgVH status and ZAP-70 or CD38 expression, but male gender and del(17p) were more common in the unmutated group. Neither IgVH mutations, CD38 expression nor del(17p) influenced patients' outcome. Unexpectedly, ZAP-70+ B-PLL patients survived longer (40 months) than ZAP-70- B-PLL (8 months). B-PLL appears biologically heterogeneous regarding IgVH mutations, ZAP-70 and CD38 expression, showing a pattern distinct from that of other lymphoproliferative disorders.
Assuntos
ADP-Ribosil Ciclase 1/genética , Cadeias Pesadas de Imunoglobulinas/genética , Região Variável de Imunoglobulina/genética , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Prolinfocítica/genética , Glicoproteínas de Membrana/genética , Proteína-Tirosina Quinase ZAP-70/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Aberrações Cromossômicas , Análise Mutacional de DNA , Feminino , Citometria de Fluxo , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , PrognósticoAssuntos
Proteínas de Ciclo Celular/genética , Proteínas de Ligação a DNA/genética , Deleção de Genes , Genes p53/genética , Leucemia Linfocítica Crônica de Células B/genética , Proteínas Serina-Treonina Quinases/genética , Proteína Supressora de Tumor p53/fisiologia , Proteínas Supressoras de Tumor/genética , Proteínas Mutadas de Ataxia Telangiectasia , Aberrações Cromossômicas , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Proteína Supressora de Tumor p53/genéticaAssuntos
Linfócitos B/patologia , Leucemia Linfocítica Crônica de Células B/genética , Linfocitose/diagnóstico , Linfocitose/genética , Adolescente , Adulto , Distribuição por Idade , Idoso , Causalidade , Células Clonais , Predisposição Genética para Doença , Testes Genéticos , Humanos , Leucemia Linfocítica Crônica de Células B/epidemiologia , Linfocitose/epidemiologia , Pessoa de Meia-Idade , Prevalência , Medição de Risco , Fatores de RiscoRESUMO
We describe a case of natural killer (NK) cell leukemia with acute presentation, systemic symptoms and hepatosplenomegaly. The uniform and aberrant phenotype of NK cells with infiltration of bone marrow and spleen was in keeping with a malignant diagnosis. Aggressive presentation was demonstrated by marked constitutional symptoms and significant tumor burden (liver, spleen, blood, bone marrow). The subsequent clinical course has been indolent, but this may have been influenced by treatment. Treatment consisted sequentially of splenectomy, intravenous pentostatin and the combination of cyclosporine A and recombinant human erythropoietin and has resulted in survival of over 48 months. We discuss the difficulties in the diagnosis of this condition, explore possible causes of cytopenia(s), and highlight the role of immunosuppression in controlling disease manifestations in large granular lymphocyte proliferative disorders.
