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1.
Br J Haematol ; 2020 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-32510599

RESUMO

In the European LeukemiaNet favourable risk category, allogeneic haematopoietic stem cell transplantation (alloSCT) is not indicated in first complete remission for patients with acute myeloid leukaemia (AML) with NPM1 mutations (ELNfav NPM1 AML), although a proportion of these patients will relapse. Given the prognostic importance of measurable residual disease (MRD), CETLAM-12 considered a pre-emptive intervention in patients with molecular failure (MF). We analyzed 110 ELNfav NPM1 AML patients achieving complete remission (CR) after induction chemotherapy. Two-year cumulative incidence of relapse (CIR), overall survival (OS) and leukaemia-free survival (LFS) were 17%, 81·5% and 82%, respectively. Forty-six patients required additional therapy for MF (n = 33) or haematological relapse (HemR; n = 13), resulting in a molecular LFS (molLFS) and a cumulative incidence of MF at two years of 61% and 38% respectively. Two-year OS for these 46 patients was 66%, with a different outcome between patients with MF (86%) and HemR (42%) (P = 0·002). Quantitative NPM1 detection at different timepoints was predictive of molLFS; an MRD ratio (NPM1mut/ABL1 × 100) cut-off of 0·05 after first consolidation identified two cohorts with a two-year molLFS of 77% and 40% for patients below and above 0·05, respectively. In conclusion, MRD-based pre-emptive intervention resulted in a favourable outcome for ELNfav NPM1 AML patients.

2.
Br J Haematol ; 189(5): 920-925, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32020596

RESUMO

Acute myeloid leukaemia (AML) with t(6;9)(p23;q34) is a poor-risk entity, commonly associated with FLT3-ITD (internal tandem duplication). Allogeneic stem-cell tranplantation (allo-SCT) is recommended, although studies analysing the outcome of allo-SCT in this setting are lacking. We selected 195 patients with t(6;9) AML, who received a first allo-SCT between 2000 and 2016 from the EBMT (European Society for Blood and Marrow Transplantation) registry. Disease status at time of allo-SCT was the strongest independent prognostic factor, with a two-year leukaemia-free survival and relapse incidence of 57% and 19% in patients in CR1 (first complete remission), 34% and 33% in CR2 (second complete remission), and 24% and 49% in patients not in remission, respectively (P < 0·001). This study, which represents the largest one available in t(6;9) AML, supports the recommendation to submit these patients to allo-SCT in CR1.

5.
Sci Rep ; 8(1): 13883, 2018 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-30224768

RESUMO

Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) are chronic myeloid clonal neoplasms. To date, the only potentially curative therapy for these disorders remains allogeneic hematopoietic progenitor cell transplantation (HCT), although patient eligibility is limited due to high morbimortality associated with this procedure coupled with advanced age of most patients. Dopamine receptors (DRs) and serotonin receptors type 1 (HTR1s) were identified as cancer stem cell therapeutic targets in acute myeloid leukemia. Given their close pathophysiologic relationship, expression of HTR1s and DRs was interrogated in MDS and CMML. Both receptors were differentially expressed in patient samples compared to healthy donors. Treatment with HTR1B antagonists reduced cell viability. HTR1 antagonists showed a synergistic cytotoxic effect with currently approved hypomethylating agents in AML cells. Our results suggest that HTR1B constitutes a novel therapeutic target for MDS and CMML. Due to its druggability, the clinical development of new regimens based on this target is promising.


Assuntos
Leucemia Mielomonocítica Crônica/patologia , Síndromes Mielodisplásicas/patologia , Receptor 5-HT1B de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/uso terapêutico , Adulto , Linhagem Celular Tumoral , Feminino , Humanos , Leucemia Mielomonocítica Crônica/tratamento farmacológico , Leucemia Mielomonocítica Crônica/metabolismo , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/metabolismo , Receptor 5-HT1B de Serotonina/metabolismo
6.
PLoS One ; 13(6): e0199531, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29953464

RESUMO

OBJECTIVES: We assess the epidemiology and risk factors for mortality of bloodstream infection (BSI) in patients with acute leukemia (AL). METHODS: Prospectively collected data of a cohort study from July 2004 to February 2016. Multivariate analyses were performed. RESULTS: 589 episodes of BSI were documented in 357 AL patients, 55% caused by gram-positive bacteria (coagulase-negative staphylococci 35.7%, Enterococcus spp 10.8%) and 43.5% by gram-negative bacteria (E. coli 21%, PA 12%). We identified 110 (18.7%) multidrug-resistant (MDR) microorganisms, especially MDR-Pseudomonas aeruginosa (7%) and extended-spectrum beta-lactamase producing Enterobacteriaceae (7%). The 30-day mortality was 14.8%. Age (OR 3.1; 95% CI 1.7-5.7); chronic lung disease (4.8; 1.1-21.8); fatal prognosis according to McCabe index (13.9; 6.4-30.3); shock (3.8; 1.9-7.7); pulmonary infection (3.6; 1.3-9.9); and MDR-PA infections with inappropriate treatment (12.8; 4.1-40.5) were related to mortality. MDR-PA BSI was associated to prior antipseudomonal cephalosporin use (9.31; 4.38-19.79); current use of betalactams (2.01; 1.01-4.3); shock (2.63; 1.03-6.7) and pulmonary source of infection (9.6; 3.4-27.21). CONCLUSIONS: MDR organisms were commonly isolated in BSI in AL. Inappropriate empiric antibiotic treatment for MDR-PA is the primary factor related to mortality that can be changed. New treatment strategies to improve the coverage of MDR-PA BSI should be considered in those patients with risk factors for this infection.


Assuntos
Bacteriemia/complicações , Bacteriemia/mortalidade , Leucemia/complicações , Leucemia/mortalidade , Adulto , Bacteriemia/microbiologia , Bacteriemia/terapia , Farmacorresistência Bacteriana Múltipla , Feminino , Humanos , Leucemia/microbiologia , Leucemia/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Fatores de Risco
8.
Leuk Lymphoma ; 59(10): 2394-2404, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29390924

RESUMO

In intermediate-risk cytogenetic acute myeloid leukemia (IRC-AML) patients, novel biomarkers to guide post-remission therapy are needed. We analyzed with high-density arrays 40 IRC-AML patients who received a non-allogeneic hematopoietic stem-cell transplantation-based post-remission therapy, and identified a signature that correlated with early relapse. Subsequently, we analyzed selected 187 genes in 49 additional IRC-AML patients by RT-PCR. BAALC, MN1, SPARC and HOPX overexpression correlated to refractoriness. BAALC or ALDH2 overexpression correlated to shorter overall survival (OS) (5-year OS: 33 ± 8.6% vs. 73.7 ± 10.1%, p = .006; 32 ± 9.3% vs. 66.4 ± 9.7%, p = .016), whereas GPR44 or TP53INP1 overexpression correlated to longer survival (5-year OS: 66.7 ± 10.3% vs. 35.4 ± 9.1%, p = .04; 58.3 ± 8.2% vs. 23.1 ± 11.7%, p = .029). A risk-score combining these four genes expression distinguished low-risk and high-risk patients (5-year OS: 79 ± 9% vs. 30 ± 8%, respectively; p = .001) in our cohort and in an independent set of patients from a public repository. Our 4-gene signature may add prognostic information and guide post-remission treatment in IRC-AML patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/genética , Recidiva Local de Neoplasia/diagnóstico , Transcriptoma/genética , Adolescente , Adulto , Idoso , Aberrações Cromossômicas , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Seleção de Pacientes , Prognóstico , Medição de Risco , Adulto Jovem
9.
Ann Hematol ; 97(5): 763-772, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29392425

RESUMO

Clinical outcomes of patients with acute myeloid leukemia (AML) showing the first primary refractory or early-relapsed disease remain very poor. The Programa Español de Tratamientos en Hematología (PETHEMA) group designed a phase I-II trial using FLAG-Ida (fludarabine, idarubicin, cytarabine, and G-CSF) plus high-dose intravenous plerixafor, a molecule inducing mobilization of blasts through the SDF-1α-CXCR4 axis blockade and potentially leading to chemosensitization of the leukemic cells. We aimed to establish a recommended phase 2 dose (RP2D) of plerixafor plus FLAG-Ida, as well as the efficacy and safety of this combination for early-relapsed (first complete remission (CR/CRi) < 12 months) or primary refractory AML. Between 2012 and 2015, 57 patients were enrolled, and 41 received the RP2D (median age 52 years [range, 18-64]). Among these patients, 20 (49%) achieved CR/CRi, and 3 (7%) died during induction. CR/CRi rate was 50% (13/26) among primary refractory and 47% (7/15) among early relapse. Overall, 25 patients (61%) were allografted. Median overall and disease-free survivals were 9.9 and 13 months, respectively. In summary, the combination of plerixafor plus FLAG-Ida resulted in a relatively high CR/CRi rate in adult patients with primary refractory or early relapsed AML, with an acceptable toxicity profile and induction mortality rate, bridging the majority of patients to allogeneic stem cell transplantation. ClinicalTrials.gov Identifier: NCT01435343.


Assuntos
Citarabina/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Compostos Heterocíclicos/administração & dosagem , Idarubicina/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Vidarabina/análogos & derivados , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Feminino , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Recidiva , Indução de Remissão/métodos , Taxa de Sobrevida/tendências , Vidarabina/administração & dosagem , Adulto Jovem
11.
Leuk Lymphoma ; 59(10): 2383-2393, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29345176

RESUMO

Vascular endothelial growth factor C (VEGFC) stimulates leukemia cell proliferation and survival, and promotes angiogenesis. We studied VEGFC expression in bone marrow samples from 353 adult acute myeloid leukemia (AML) patients and its relationship with several clinical, cytogenetic, and molecular variables. We also studied the expression of 84 genes involved in VEGF signaling in 24 patients. We found that VEGFC expression was higher in AML patients with myelodysplasia-related changes (AML-MRC) than in patients with non-AML-MRC. We also found an association between VEGFC expression and the patient cytogenetic risk group, with those with a worse prognosis having higher VEGFC expression levels. No correlation was observed between VEGFC expression and survival or complete remission. VEGFC expression strongly correlated with expression of the VEGF receptors FLT1, KDR, and NRP1. Thus, in this series, VEGFC expression was increased in AML-MRC and in subgroups with a poorer prognosis, but has no impact on survival.


Assuntos
Biomarcadores Tumorais/metabolismo , Leucemia Mieloide Aguda/patologia , Síndromes Mielodisplásicas/patologia , Fator C de Crescimento do Endotélio Vascular/metabolismo , Adolescente , Adulto , Idoso , Medula Óssea/patologia , Aberrações Cromossômicas , Feminino , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/mortalidade , Neuropilina-1/metabolismo , Prognóstico , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Adulto Jovem
12.
J Transl Med ; 14: 261, 2016 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-27604463

RESUMO

BACKGROUND: Treatment for acute myeloid leukemia (AML) has not significantly changed in the last decades and new therapeutic approaches are needed to achieve prolonged survival rates. Leukemia stem cells (LSC) are responsible for the initiation and maintenance of AML due to their stem-cell properties. Differentiation therapies aim to abrogate the self-renewal capacity and diminish blast lifespan. METHODS: An in silico screening was designed to search for FDA-approved small molecules that potentially induce differentiation of AML cells. Bromocriptine was identified and validated in an in vitro screening. Bromocriptine is an approved drug originally indicated for Parkinson's disease, acromegaly, hyperprolactinemia and galactorrhoea, and recently repositioned for diabetes mellitus. RESULTS: Treatment with bromocriptine reduced cell viability of AML cells by activation of the apoptosis program and induction of myeloid differentiation. Moreover, the LSC-enriched primitive AML cell fraction was more sensitive to the presence of bromocriptine. In fact, bromocriptine decreased the clonogenic capacity of AML cells. Interestingly, a negligible effect is observed in healthy blood cells and hematopoietic stem/progenitor cells. CONCLUSIONS: Our results support the use of bromocriptine as an anti-AML drug in a repositioning setting and the further clinical validation of this preclinical study.


Assuntos
Bromocriptina/uso terapêutico , Reposicionamento de Medicamentos , Leucemia Mieloide Aguda/tratamento farmacológico , Adulto , Bromocriptina/farmacologia , Antígeno CD11b/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
13.
Oncotarget ; 7(29): 46002-46013, 2016 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-27329591

RESUMO

PiwiRNAs, small non-coding RNAs processed by Piwi proteins, are involved in maintaining genome stability in germline cells. Recently, piwiRNA expression has been identified in some tumors. We have examined the potential reactivation of the Piwi/piwiRNA pathway in classical Hodgkin lymphoma (cHL). We found that Piwi proteins and three selected piwiRNAs, including piR-651, were expressed in cHL patients and cell lines, indicating that the Piwi/piwiRNA pathway is active in cHL. Interestingly, low levels of piR-651 were associated with lack of complete response to first-line treatment, as well as shorter disease-free and overall survival in a cohort of 94 cHL patients. At diagnosis, piR-651 was underexpressed in cHL serum samples compared to healthy controls, while after complete remission, piR-651 levels increased to levels similar to healthy controls. This is the first evidence that piwiRNAs are active in tumor and serum samples and impact prognosis in cHL.


Assuntos
Biomarcadores Tumorais/genética , Doença de Hodgkin/patologia , RNA não Traduzido/genética , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Perfilação da Expressão Gênica , Doença de Hodgkin/genética , Doença de Hodgkin/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Transcriptoma
14.
Cancer Cell Int ; 15: 122, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26696777

RESUMO

BACKGROUND: The resulting clinical impact of the combined use of G-CSF with chemotherapy as a chemosensitizing strategy for treatment of acute myeloid leukemia (AML) patients is still controversial. In this study, the effect of ex vivo treatment with G-CSF on AML primary blasts was studied. METHODS: Peripheral blood mononuclear cells from AML patients were treated with G-CSF at increasing doses, alone or in co-culture with HS-5 stromal cells. Cell viability and surface phenotype was determined by flow cytometry 72 h after treatment. For clonogenicity assays, AML primary samples were treated for 18 h with G-CSF at increasing concentrations and cultured in methyl-cellulose for 14 days. Colonies were counted based on cellularity and morphology criteria. RESULTS: The presence of G-CSF reduced the overall viability of AML cells co-cultured with bone marrow stroma; whereas, in absence of stroma, a negligible effect was observed. Moreover, clonogenic capacity of AML cells was significantly reduced upon treatment with G-CSF. Interestingly, reduction in the AML clonogenic capacity correlated with the sensitivity to chemotherapy observed in vivo. CONCLUSIONS: These ex vivo results would provide a biological basis to data available from studies showing a clinical benefit with the use of G-CSF as a priming agent in patients with a chemosensitive AML and would support implementation of further studies exploring new strategies of chemotherapy priming in AML.

15.
Oncotarget ; 6(31): 31613-27, 2015 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-26436590

RESUMO

Long non-coding RNAs (lncRNAs) are deregulated in several tumors, although their role in acute myeloid leukemia (AML) is mostly unknown.We have examined the expression of the lncRNA HOX antisense intergenic RNA myeloid 1 (HOTAIRM1) in 241 AML patients. We have correlated HOTAIRM1 expression with a miRNA expression profile. We have also analyzed the prognostic value of HOTAIRM1 expression in 215 intermediate-risk AML (IR-AML) patients.The lowest expression level was observed in acute promyelocytic leukemia (P < 0.001) and the highest in t(6;9) AML (P = 0.005). In 215 IR-AML patients, high HOTAIRM1 expression was independently associated with shorter overall survival (OR:2.04;P = 0.001), shorter leukemia-free survival (OR:2.56; P < 0.001) and a higher cumulative incidence of relapse (OR:1.67; P = 0.046). Moreover, HOTAIRM1 maintained its independent prognostic value within the favorable molecular subgroup (OR: 3.43; P = 0.009). Interestingly, HOTAIRM1 was overexpressed in NPM1-mutated AML (P < 0.001) and within this group retained its prognostic value (OR: 2.21; P = 0.01). Moreover, HOTAIRM1 expression was associated with a specific 33-microRNA signature that included miR-196b (P < 0.001). miR-196b is located in the HOX genomic region and has previously been reported to have an independent prognostic value in AML. miR-196b and HOTAIRM1 in combination as a prognostic factor can classify patients as high-, intermediate-, or low-risk (5-year OS: 24% vs 42% vs 70%; P = 0.004).Determination of HOTAIRM1 level at diagnosis provided relevant prognostic information in IR-AML and allowed refinement of risk stratification based on common molecular markers. The prognostic information provided by HOTAIRM1 was strengthened when combined with miR-196b expression. Furthermore, HOTAIRM1 correlated with a 33-miRNA signature.


Assuntos
Biomarcadores Tumorais/genética , Análise Citogenética , Perfilação da Expressão Gênica , Proteínas de Homeodomínio/genética , Leucemia Mieloide Aguda/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Adolescente , Adulto , Idoso , Distribuição de Qui-Quadrado , Progressão da Doença , Intervalo Livre de Doença , Feminino , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Mutação , Proteínas Nucleares/genética , Razão de Chances , Fenótipo , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
16.
Oncotarget ; 5(12): 4337-46, 2014 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-24952669

RESUMO

Acute myeloid leukemia (AML) is a neoplasia characterized by the rapid expansion of immature myeloid blasts in the bone marrow, and marked by poor prognosis and frequent relapse. As such, new therapeutic approaches are required for remission induction and prevention of relapse. Due to the higher chemotherapy sensitivity and limited life span of more differentiated AML blasts, differentiation-based therapies are a promising therapeutic approach. Based on public available gene expression profiles, a myeloid-specific differentiation-associated gene expression pattern was defined as the therapeutic target. A XIAP inhibitor (Dequalinium chloride, DQA) was identified in an in silico screening searching for small molecules that induce similar gene expression regulation. Treatment with DQA, similarly to Embelin (another XIAP inhibitor), induced cytotoxicity and differentiation in AML. XIAP inhibition differentially impaired cell viability of the most primitive AML blasts and reduced clonogenic capacity of AML cells, sparing healthy mature blood and hematopoietic stem cells. Taken together, these results suggest that XIAP constitutes a potential target for AML treatment and support the evaluation of XIAP inhibitors in clinical trials.


Assuntos
Células-Tronco Hematopoéticas/metabolismo , Leucemia Mieloide Aguda/metabolismo , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/antagonistas & inibidores , Adulto , Morte Celular , Diferenciação Celular , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo
17.
Ann Hematol ; 93(10): 1695-703, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24824767

RESUMO

Acute myeloid leukemia (AML) with myelodysplasia-related changes is characterized by the presence of multilineage dysplasia (MLD), frequently related to high-risk cytogenetics and poor outcome. However, the presence of MLD does not modify the favorable prognostic impact of NPM1 mutation. The prognosis of patients with AML presenting marked dysplasia lacking high-risk cytogenetics and NPM1 mutation is uncertain. We evaluated the prognostic impact of MLD in 177 patients with intermediate-risk cytogenetics AML (IR-AML) and wild-type NPM1. Patients were categorized as MLD-WHO (WHO myelodysplasia criteria; n = 43, 24 %), MLD-NRW (significant MLD non-reaching WHO criteria; n = 16, 9 %), absent MLD (n = 80, 45 %), or non-evaluable MLD (n = 38, 22 %). No differences concerning the main characteristics were observed between patients with or without MLD. Outcome of patients with MLD-WHO and MLD-NRW was similar, and significantly worse than patients lacking MLD. The presence of MLD (66 vs. 80 %, p = 0.03; HR, 95 % CI = 2.3, 1.08-4.08) and higher leukocyte count at diagnosis was the only variable associated with lower probability of complete remission after frontline therapy. Concerning survival, age and leukocytes showed an independent prognostic value, whereas MLD showed a trend to a negative impact (p = 0.087, HR, 95 % CI = 1.426, 0.95-2.142). Moreover, after excluding patients receiving an allogeneic stem cell transplantation in first CR, MLD was associated with a shorter survival (HR, 95 % CI = 1.599, 1.026-2.492; p = 0.038). In conclusion, MLD identifies a subgroup of patients with poorer outcome among patients with IR-AML and wild-type NPM1.


Assuntos
Medula Óssea/patologia , Linhagem da Célula , Leucemia Mieloide Aguda/patologia , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Adolescente , Adulto , Idoso , Núcleo Celular/ultraestrutura , Citoplasma/ultraestrutura , Análise Mutacional de DNA , Feminino , Hematopoese , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Leucemia Mielomonocítica Aguda/tratamento farmacológico , Leucemia Mielomonocítica Aguda/genética , Leucemia Mielomonocítica Aguda/mortalidade , Leucemia Mielomonocítica Aguda/patologia , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/patologia , Prognóstico , Modelos de Riscos Proporcionais , Indução de Remissão , Risco , Adulto Jovem
18.
PLoS One ; 8(5): e64716, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23705004

RESUMO

BACKGROUND: In recent years, microRNA (miRNA) pathways have emerged as a crucial system for the regulation of tumorogenesis. miR-SNPs are a novel class of single nucleotide polymorphisms that can affect miRNA pathways. DESIGN AND METHODS: We analyzed eight miR-SNPs by allelic discrimination in 141 patients with Hodgkin lymphoma and correlated the results with treatment-related toxicity, response, disease-free survival (DFS) and overall survival (OS). RESULTS: The KRT81 (rs3660) GG genotype was associated with an increased risk of neurological toxicity (P = 0.016), while patients with XPO5 (rs11077) AA or CC genotypes had a higher rate of bleomycin-associated pulmonary toxicity (P = 0.048). Both miR-SNPs emerged as independent factors in the multivariate analysis. The XPO5 AA and CC genotypes were also associated with a lower response rate (P = 0.036). XPO5 (P = 0.039) and TRBP (rs784567) (P = 0.022) genotypes emerged as prognostic markers for DFS, and XPO5 was also associated with OS (P = 0.033). In the multivariate analysis, only XPO5 emerged as an independent prognostic factor for DFS (HR: 2.622; 95%CI 1.039-6.620; P = 0.041). Given the influence of XPO5 and TRBP as individual markers, we then investigated the combined effect of these miR-SNPs. Patients with both the XPO5 AA/CC and TRBP TT/TC genotypes had the shortest DFS (P = 0.008) and OS (P = 0.008). CONCLUSION: miR-SNPs can add useful prognostic information on treatment-related toxicity and clinical outcome in Hodgkin lymphoma and can be used to identify patients likely to be chemoresistant or to relapse.


Assuntos
Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/genética , MicroRNAs/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Frequência do Gene/genética , Doença de Hodgkin/patologia , Humanos , Carioferinas/genética , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Coativadores de Receptor Nuclear/genética , Resultado do Tratamento , Adulto Jovem
19.
Blood ; 121(14): 2734-8, 2013 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-23377436

RESUMO

Risk associated to FLT3 internal tandem duplication (FLT3-ITD) in patients with acute myeloid leukemia (AML) may depend on mutational burden and its interaction with other mutations. We analyzed the effect of FLT3-ITD/FLT3 wild-type (FLT3wt) ratio depending on NPM1 mutation (NPM1mut) in 303 patients with intermediate-risk cytogenetics AML treated with intensive chemotherapy. Among NPM1mut patients, FLT3wt and low ratio (<0.5) subgroups showed similar overall survival, relapse risk, and leukemia-free survival, whereas high ratio (≥0.5) patients had a worse outcome. In NPM1wt AML, FLT3-ITD subgroups showed a comparable outcome, with higher risk of relapse and shortened overall survival than FLT3wt patients. Allogeneic stem cell transplantation in CR1 was associated with a reduced relapse risk in all molecular subgroups with the exception of NPM1mut AML with absent or low ratio FLT3-ITD. In conclusion, effect of FLT3 burden is modulated by NPM1 mutation, especially in patients with a low ratio.


Assuntos
Antineoplásicos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Proteínas Nucleares/genética , Tirosina Quinase 3 Semelhante a fms/genética , Adulto , Alelos , Intervalo Livre de Doença , Feminino , Duplicação Gênica , Humanos , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Indução de Remissão , Fatores de Risco , Prevenção Secundária , Sequências de Repetição em Tandem , Resultado do Tratamento
20.
Acta Haematol ; 129(2): 65-71, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23154527

RESUMO

Significant progress in the understanding of the genetic basis of acute myeloid leukemia (AML) has been made during the last 30 years. The aim of the present study was to assess whether the detection of recurrent gene rearrangements by fluorescent in situ hybridization (FISH) studies and NPM1 and FLT3 gene mutations by molecular studies added clinically relevant information to the karyotype in 113 AML patients. Thus, FISH and molecular studies were found to add new information in 22 and 55% of the patients, respectively, particularly in cases with normal karyotype (NK) or when a cytogenetic analysis failed. Patients with NK changed their genetic risk group to favorable in 27 and 29% of cases using FISH and molecular biology studies, respectively. Our results demonstrate that molecular biology and FISH studies provide relevant information in AML and should be routinely performed.


Assuntos
Leucemia Mieloide Aguda/genética , Proteínas Nucleares/genética , Tirosina Quinase 3 Semelhante a fms/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Citogenética , Feminino , Rearranjo Gênico , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico
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