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1.
J Clin Oncol ; 37(34): 3291-3299, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31609651

RESUMO

PURPOSE: Patients with relapsed or refractory primary mediastinal large B-cell lymphoma (rrPMBCL) have a poor prognosis, and their treatment represents an urgent and unmet need. Because PMBCL is associated with genetic aberrations at 9p24 and overexpression of programmed cell death-1 (PD-1) ligands (PD-L1), it is hypothesized to be susceptible to PD-1 blockade. METHODS: In the phase IB KEYNOTE-013 (ClinicalTrials.gov identifier: NCT01953692) and phase II KEYNOTE-170 (ClinicalTrials.gov identifier: NCT02576990) studies, adults with rrPMBCL received pembrolizumab for up to 2 years or until disease progression or unacceptable toxicity. The primary end points were safety and objective response rate in KEYNOTE-013 and objective response rate in KEYNOTE-170. Secondary end points included duration of response, progression-free survival, overall survival, and safety. Exploratory end points included association between biomarkers and pembrolizumab activity. RESULTS: The objective response rate was 48% (7 complete responses; 33%) among 21 patients in KEYNOTE-013 and 45% (7 complete responses; 13%) among 53 patients in KEYNOTE-170. After a median follow-up time of 29.1 months in KEYNOTE-013 and 12.5 months in KEYNOTE-170, the median duration of response was not reached in either study. No patient with complete response experienced progression, including 2 patients with complete response for at least 1 year off therapy. Treatment-related adverse events occurred in 24% of patients in KEYNOTE-013 and 23% of patients in KEYNOTE-170. There were no treatment-related deaths. Among 42 evaluable patients, the magnitude of the 9p24 gene abnormality was associated with PD-L1 expression, which was itself significantly associated with progression-free survival. CONCLUSION: Pembrolizumab is associated with high response rate, durable activity, and a manageable safety profile in patients with rrPMBCL.

2.
Psicothema ; 30(1): 14-20, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29363465

RESUMO

BACKGROUND: Behavioral activation (BA) and acceptance and commitment therapy (ACT) are considered particularly useful treatments when dealing with emotional problems of cancer survivors. The efficacy of these two treatments, applied on a group basis, were evaluated and compared. METHOD: An analysis was carried out of pre-post treatment changes in the emotional state and patterns of activation/avoidance of 52 cancer patients, with anxiety and/or depression, randomly assigned to three groups (BA/ACT/waiting list control). RESULTS: Both therapies were superior to no treatment in all the variables evaluated. Significant differences were found between the two treatments in favor of ACT in social impairment and avoidance/rumination. CONCLUSIONS: BA and ACT, applied on a group basis, are efficacious in the treatment of those emotional difficulties most prevalent in cancer survivors. Results suggest that activation and avoidance are the mechanisms responsible for the changes.


Assuntos
Terapia de Aceitação e Compromisso , Ansiedade/terapia , Terapia Comportamental/métodos , Depressão/terapia , Neoplasias/psicologia , Sobreviventes/psicologia , Atividades Cotidianas , Adulto , Ansiedade/etiologia , Transtornos de Ansiedade/etiologia , Transtornos de Ansiedade/terapia , Aprendizagem da Esquiva , Depressão/etiologia , Transtorno Depressivo/etiologia , Transtorno Depressivo/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Inquéritos e Questionários , Resultado do Tratamento
3.
Br J Haematol ; 178(5): 699-708, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28782811

RESUMO

The diagnostic criteria for follicular lymphoma (FL) transformation vary among the largest series, which commonly exclude histologically-documented transformation (HT) mandatorily. The aims of this retrospective observational multicentre study by the Spanish Grupo Español de Linfoma y Transplante Autólogo de Médula Ósea, which recruited 1734 patients (800 males/934 females; median age 59 years), diagnosed with FL grades 1-3A, were, (i) the cumulative incidence of HT (CI-HT); (ii) risk factors associated with HT; and (iii) the role of treatment and response on survival following transformation (SFT). With a median follow-up of 6·2 years, 106 patients developed HT. Ten-year CI-HT was 8%. Considering these 106 patients who developed HT, median time to transformation was 2·5 years. High-risk FL International Prognostic Index [Hazard ratio (HR) 2·6, 95% confidence interval (CI): 1·5-4·5] and non-response to first-line therapy (HR 2·9, 95% CI: 1·3-6·8) were associated with HT. Seventy out of the 106 patients died (5-year SFT, 26%). Response to HT first-line therapy (HR 5·3, 95% CI: 2·4-12·0), autologous stem cell transplantation (HR 3·9, 95% CI: 1·5-10·1), and revised International Prognostic Index (HR 2·2, 95% CI: 1·1-4·2) were significantly associated with SFT. Response to treatment and HT were the variables most significantly associated with survival in the rituximab era. Better therapies are needed to improve response. Inclusion of HT in clinical trials with new agents is mandatory.


Assuntos
Antineoplásicos/uso terapêutico , Transformação Celular Neoplásica/patologia , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/patologia , Rituximab/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transformação Celular Neoplásica/efeitos dos fármacos , Progressão da Doença , Feminino , Humanos , Linfoma Folicular/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Medição de Risco/métodos , Espanha/epidemiologia , Análise de Sobrevida , Adulto Jovem
4.
Case Rep Hematol ; 2016: 3947510, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27867670

RESUMO

We report a patient who developed up to three different lymphomas with the same clonal IGH rearrangement. She was first diagnosed of splenic zone marginal lymphoma and relapsed for the first time with Hodgkin lymphoma histology and later with diffuse large B-cell lymphoma histology. Subsequent biopsies and analysis of clonally rearranged IGH genes helped to elucidate the clonal relationship between the three histologies and to confirm a common origin from the three tissue histologies. An integrated diagnosis should always be performed in order to achieve the most accurate diagnosis and be able to choose the best therapeutic options for our patients.

6.
Ann Hematol ; 89(5): 453-8, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-19943049

RESUMO

We have analyzed brain and acute leukemia, cytoplasmic (BAALC) gene expression and other genetic markers (ERG, EVI1, MN1, PRAME, WT1, FLT3, and NPM1 mutations) in 127 intermediate-risk acute myeloid leukemia (AML) patients: 98 cytogenetically normal and 29 with intermediate-risk cytogenetic alterations. High versus low BAALC expressers showed a higher refractoriness to induction treatment (31% vs 10%; p = .005), lower complete remission rate after salvage therapy (82% vs 97%; p = .010), and lower 3-year overall (23% vs 58%, p < .001) and relapse-free survival (26% vs 52%, p = .006). Similar results were found when cytogenetic subgroups were analyzed separately. Multivariate models confirmed the unfavorable prognosis of this marker. In conclusion, BAALC is a relevant prognostic marker in intermediate-risk AML.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/biossíntese , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Proteínas de Neoplasias/biossíntese , Adolescente , Adulto , Idoso , Biomarcadores Tumorais/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Valor Preditivo dos Testes , Fatores de Risco , Taxa de Sobrevida/tendências , Resultado do Tratamento , Adulto Jovem
7.
Leuk Res ; 33(12): 1706-9, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19457552

RESUMO

The PI3/AKT pathway is up-regulated in acute myeloid leukemia (AML), but its prognostic relevance in cytogenetically normal AML (CN-AML) is unclear. We evaluated RNA levels of AKT and two downstream substrates (FOXO3a-p27) in 110 de novo CN-AML, included in the Spanish PETHEMA therapeutic protocols. Patients with high FOXO3a gene expression displayed shorter OS (p=0.015) and RFS (p=0.048) than low FOXO3a expressers. Features selected in the multivariate analysis as having an independent prognostic value for a shorter survival were WBC>50x10(9)/L, age >65 years and high FOXO3a expression. We concluded that FOXO3a assessment could contribute to improve the molecular-based risk stratification in CN-AML.


Assuntos
Fatores de Transcrição Forkhead/genética , Regulação Neoplásica da Expressão Gênica , Leucemia Mieloide Aguda/genética , Adolescente , Adulto , Idoso , Feminino , Proteína Forkhead Box O3 , Humanos , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinases/metabolismo , Prognóstico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Análise de Sobrevida , Adulto Jovem
8.
Blood ; 114(1): 148-52, 2009 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-19398719

RESUMO

We have evaluated 9 new molecular markers (ERG, EVI1, MLL-PTD, MN1, PRAME, RHAMM, and WT1 gene-expression levels plus FLT3 and NPM1 mutations) in 121 de novo cytogenetically normal acute myeloblastic leukemias. In the multivariate analysis, high ERG or EVI1 and low PRAME expressions were associated with a shorter relapse-free survival (RFS) and overall survival (OS). A 0 to 3 score was given by assigning a value of 0 to favorable parameters (low ERG, low EVI1, and high PRAME) and 1 to adverse parameters. This model distinguished 4 subsets of patients with different OS (2-year OS of 79%, 65%, 46%, and 27%; P = .001) and RFS (2-year RFS of 92%, 65%, 49%, and 43%; P = .005). Furthermore, this score identified patients with different OS (P = .001) and RFS (P = .013), even within the FLT3/NPM1 intermediate-risk/high-risk subgroups. Here we propose a new molecular score for cytogenetically normal acute myeloblastic leukemias, which could improve patient risk-stratification.


Assuntos
Biomarcadores Tumorais/genética , Leucemia Mieloide Aguda/genética , Modelos Genéticos , Adulto , Idoso , Antígenos de Neoplasias/genética , Análise Citogenética , Proteínas de Ligação a DNA/genética , Intervalo Livre de Doença , Feminino , Expressão Gênica , Marcadores Genéticos , Humanos , Leucemia Mieloide Aguda/mortalidade , Proteína do Locus do Complexo MDS1 e EVI1 , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Proto-Oncogenes/genética , Fatores de Risco , Espanha/epidemiologia , Taxa de Sobrevida , Transativadores/genética , Fatores de Transcrição/genética , Regulador Transcricional ERG
9.
Leuk Lymphoma ; 48(11): 2172-8, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17990179

RESUMO

Mantle cell lymphoma constitutes one of the lymphomas with poorest prognosis at relapse with limited effective salvage regimens due to advanced age. We present results of a new salvage regimen, rituximab, gemcitabine and oxaliplatin (GEMOX-R), in 14 patients with relapsing (n = 9) or refractory (n = 5) mantle cell lymphoma. The median number of cycles was 5.5 for a total of 72 cycles evaluated in the current study. The median age was 69.5 years with high-risk features. Patients received a mean number of prior treatment lines of 1.79. Sixty-four percent achieved CR (total response rate of 85%). With a median follow-up of 11 months, OS and PFS were 58% and 45% at 12 months. The major toxicity was thrombopenia grade III-IV (35%). Factors related with overall survival were ECOG performance status and a-IPI at GEMOX-R. We conclude that GEMOX-R displays an outstanding efficacy with an excellent toxicity profile in a pretreated elderly population.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina/análogos & derivados , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/patologia , Compostos Organoplatínicos/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Murinos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Linfoma de Célula do Manto/mortalidade , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/efeitos adversos , Oxaliplatina , Recidiva , Rituximab , Terapia de Salvação , Análise de Sobrevida , Transplante Autólogo , Falha de Tratamento , Resultado do Tratamento
10.
Biol Blood Marrow Transplant ; 12(2): 172-83, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16443515

RESUMO

We report the results of reduced-intensity conditioning allogeneic stem cell transplantation (allo-RIC) in patients with advanced Hodgkin lymphoma (HL). Forty patients with relapsed or refractory HL were homogeneously treated with an RIC protocol (fludarabine 150 mg/m(2) intravenously plus melphalan 140 mg/m(2) intravenously) and cyclosporin A and methotrexate as graft-versus-host disease (GVHD) prophylaxis. Twenty-one patients (53%) had received >2 lines of chemotherapy, 23 patients (58%) had received radiotherapy, and 29 patients (73%) had experienced treatment failure with a previous autologous stem cell transplantation. Twenty patients (50%) were allografted in resistant relapse, and 38 patients received hematopoietic cells from an HLA-identical sibling. Five patients (12%) died from early transplant-related mortality (before day +100 after allo-RIC). One-year transplant-related mortality was 25%. Acute GVHD developed in 18 patients (45%). Chronic GVHD developed in 17 (45%) of the 31 evaluable patients. The response rate 3 months after the allo-RIC was 67% (21 [52%] complete remissions and 6 [15%] partial remissions). Eleven patients received donor lymphocyte infusions (DLIs) for disease relapse. The response rate after DLI was 54% (3 complete remissions and 3 partial remissions). Overall survival (OS) and progression-free survival (PFS) were 48% +/- 10% and 32% +/- 10% at 2 years, respectively. Refractoriness to chemotherapy was the only adverse prognostic factor for both OS (63% +/- 12% versus 35% +/- 13%; P = .05) and PFS (55% +/- 16% versus 10% +/- 9%; P = .006). For patients with failure of a prior autologous hematopoietic stem cell transplantation, results were especially good for those who experienced late relapses (>/=12 months: 2-year OS and PFS were 75% +/- 16% and 70% +/- 18%, respectively). These data suggest that allo-RIC is feasible in heavily pretreated HL patients and has an acceptable early transplant-related mortality. Results are better in patients allografted in sensitive disease. Both responses observed after the development of GVHD and DLI may suggest a graft-versus-HL effect. Allo-RIC has to be considered an effective therapeutic approach for patients who have had treatment failure with a previous autologous hematopoietic stem cell transplantation.


Assuntos
Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/mortalidade , Doença de Hodgkin/mortalidade , Transplante de Células-Tronco , Condicionamento Pré-Transplante , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/prevenção & controle , Doença de Hodgkin/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Recidiva , Espanha , Transplante de Células-Tronco/mortalidade , Taxa de Sobrevida , Condicionamento Pré-Transplante/métodos , Condicionamento Pré-Transplante/mortalidade , Transplante Homólogo
11.
Br J Haematol ; 130(3): 394-403, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16042689

RESUMO

The graft-versus-host disease (GVHD) characteristics of 150 consecutive patients undergoing reduced intensity conditioning allogeneic (allo-RIC) transplants and 88 patients undergoing myeloablative conditioning regimen were analysed. All patients received the same GVHD prophylaxis and peripheral blood stem cells from a human leucocyte antigen identical sibling. The cumulative incidence of acute GVHD (aGVHD) was 67% and 44% in the myeloablative and allo-RIC regimen groups, respectively (P < 0.001), and was 39% vs. 29%, respectively (P = 0.043), for grades 2-4 aGVHD. Only conditioning type (myeloablative versus allo-RIC) significantly influenced the incidence of aGVHD in multivariate analysis: Hazard ratio (HR) = 2.16 [95% confidence interval (CI): 1.52-3.07], P < 0.0001. The cumulative incidence of chronic GVHD (cGVHD) was 63% and 71% among myeloablative and allo-RIC patients respectively (P = 0.084). This trend was because of the higher incidence of limited cGVHD, but not extensive cGVHD among allo-RIC recipients [HR = 3.3 (95% CI: 1.42-8.08), P = 0.0017]. Moreover, among patients who developed cGVHD, the cumulative incidence of limited cGVHD was significantly lower in the myeloablative group than in the allo-RIC group (7% vs. 25%, P = 0.007). Duration of immunosuppression was shorter among allo-RIC patients (35.5% vs. 68.8% required systemic immunosuppression 36 months after transplant, P = 0.028). Although prospective controlled trials are required to further evaluate the effect of the conditioning regimen on GVHD, our results suggest that RIC modifies the incidence and characteristics of both acute and cGVHD after allogeneic transplantation, and decreases the immunosuppression requirements in long-term follow up when compared with myeloablative conditioning.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco de Sangue Periférico , Condicionamento Pré-Transplante/métodos , Doença Aguda , Adulto , Doença Crônica , Ciclosporina/uso terapêutico , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Imunossupressores/uso terapêutico , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Agonistas Mieloablativos/administração & dosagem , Pré-Medicação , Estudos Retrospectivos , Estatísticas não Paramétricas , Transplante Homólogo , Resultado do Tratamento
12.
Transfusion ; 42(9): 1159-72, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12430673

RESUMO

BACKGROUND: Effects of mobilization regimen on the composition of leukapheresis products (LPs) and on hematopoietic reconstitution after autologous peripheral blood progenitor cell transplantation (PBPCT) are not well known. STUDY DESIGN AND METHODS: The effects of three different mobilization regimens--stem cell factor (SCF) plus granulocyte colony stimulating factor (G-CSF) plus cyclophosphamide (CCP), G-CSF alone, and G-CSF plus CCP--on the composition of LPs from patients with nonhematologic PBPC malignancies compared to LPs from G-CSF-mobilized healthy donors and normal marrow (BM) samples were analyzed. The impact of LP composition on both short- and long-term engraftment after autologous PBPCT was also evaluated. RESULTS: The most effective regimen for mobilization of CD34+ hematopoietic progenitor cells (HPCs) into peripheral blood was SCF, G-CSF, and CCP, providing the highest numbers of all CD34+ HPCs subsets analyzed. Patients mobilized with SCF plus G-CSF plus CCP showed the highest numbers of neutrophils and monocytes, whereas the highest numbers of lymphocytes and NK cells were observed in LPs from G-CSF-mobilized patients. The overall number of CD34+ HPCs was the strongest factor for predicting recovery of platelets, whereas the number of myelomonocytic-committed CD34+ precursors was the most powerful independent prognostic factor for WBC and neutrophil recovery. The overall number of CD4+ T cells returned showed an independent prognostic value for predicting the occurrence of infections, during the first year after transplant. CONCLUSIONS: The use of different mobilization regimens modifies the overall number of CD34+ HPCs obtained during leukapheresis procedures, and also affects both the absolute and the relative composition of the LPs in different CD34+ and CD34- cell subsets.


Assuntos
Ciclofosfamida/farmacologia , Fator Estimulador de Colônias de Granulócitos/farmacologia , Mobilização de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/efeitos dos fármacos , Leucaférese , Contagem de Leucócitos , Leucócitos/efeitos dos fármacos , Neoplasias/sangue , Transplante de Células-Tronco de Sangue Periférico/métodos , Fator de Células-Tronco/farmacologia , Adulto , Antígenos CD34/análise , Plaquetas/efeitos dos fármacos , Células da Medula Óssea/efeitos dos fármacos , Neoplasias da Mama/sangue , Neoplasias da Mama/terapia , Diferenciação Celular , Terapia Combinada , Ciclofosfamida/administração & dosagem , Sinergismo Farmacológico , Feminino , Citometria de Fluxo , Germinoma/sangue , Germinoma/terapia , Sobrevivência de Enxerto , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Humanos , Leucócitos/classificação , Linfócitos/efeitos dos fármacos , Masculino , Mieloma Múltiplo/sangue , Mieloma Múltiplo/terapia , Neoplasias/terapia , Prognóstico , Fator de Células-Tronco/administração & dosagem
13.
Br J Haematol ; 119(1): 135-43, 2002 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12358918

RESUMO

Currently, no information is available regarding the influence of the different CD34+ cell subsets infused on the haematopoietic recovery, following non-myeloablative allogeneic peripheral blood stem cell transplantation (allo-PBSCT). We have explored, in a group of 13 patients receiving non-myeloablative allo-PBSCT from human leucocyte antigen-identical sibling donors, the influence of the total dose of CD34+ haematopoietic progenitor cells (HPC) infused, compared with that of the different CD34+ HPC and CD34- leucocyte subsets in the leukapheresis samples, on both engraftment and clinical outcome. The overall numbers of total CD34+ HPC (P = 0.002) and myelomonocytic-committed CD34+ HPC infused (P = 0.0002) were strongly associated with neutrophil recovery (> 1 x 109 neutrophils/l), the latter being the only independent parameter influencing neutrophil recovery. Regarding long-term engraftment, only the number of immature CD34+ HPC infused/kg correlated with the duration of hospitalization in the first 2 years after discharge (r = -0.75, P = 0.005). Both the overall amount of CD34+ HPC and the number of myelomonocytic CD34+ HPC infused showed a significant influence on the risk of graft-versus-host disease (GVHD). Thus, the overall probability of GVHD was 100%vs 25% for patients receiving >/= 5 x 106 CD34+ HPC or >/= 3.5 x 106 of myelomonocytic-committed CD34+ HPC vs lower doses (P = 0.013). None of the other CD34+ and CD34- cell subsets analysed correlated with development of GVHD. In summary, our results suggest that in non-myeloablative allo-PBSCT, high numbers of CD34+ HPC, especially the myelomonocytic-committed CD34+ progenitors, lead to rapid neutrophil engraftment. However, they also strongly impair clinical outcome by increasing the incidence of GVHD.


Assuntos
Antígenos CD34/classificação , Células-Tronco Hematopoéticas/classificação , Linfoma/terapia , Transplante de Células-Tronco de Sangue Periférico/métodos , Adulto , Antígenos CD34/administração & dosagem , Feminino , Citometria de Fluxo , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/imunologia , Humanos , Leucócitos/classificação , Linfoma/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Prospectivos , Fatores de Risco , Quimeras de Transplante , Transplante Homólogo
14.
Br J Haematol ; 118(4): 1034-40, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12199782

RESUMO

In order to gain further insights into the role of the p16 gene in cell cycle regulation and the prognostic implications of its inactivation, we investigated the methylation status of the p16 gene in 98 untreated patients using a polymerase chain reaction assay based on the inability of some restriction enzymes to digest methylated sequences. Forty-one patients showed a p16 methylated gene (42%). The percentage of S-phase plasma cells (PC) in these patients was almost three times higher than in those with an unmethylated p16 gene (4.16% +/- 3.37%vs 1.5% +/- 1.41%, P < 0.001). The presence of p16 methylation also correlated with both elevated beta2-microglobulin serum levels and high C-reactive protein values. Patients with a p16 methylated gene had shorter overall and progression-free survival than those patients without p16 methylation. However, this feature did not retain independent prognostic influence on multivariate analysis, probably due to its association with the S-phase PC, which had more potent statistical significance in the Cox model. These findings showed methylation of the p16 gene was a frequent event inMM patients at diagnosis, and was associated with an increased proliferative rate of plasma cells and a poor prognosis, indicating an important role for p16 gene in the cell cycle regulation of multiple myeloma tumour cells, and thus in the clinical outcome of the disease.


Assuntos
Metilação de DNA , Genes p16 , Mieloma Múltiplo/genética , Plasmócitos/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Divisão Celular/genética , Feminino , Citometria de Fluxo , Humanos , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Análise Multivariada , Reação em Cadeia da Polimerase/métodos , Prognóstico
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