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1.
Artigo em Inglês | MEDLINE | ID: mdl-34894176

RESUMO

BACKGROUND: Flow cytometry (FCM) aids the diagnosis and prognostic stratification of patients with suspected or confirmed myelodysplastic syndrome (MDS). Over the past few years, significant progress has been made in the FCM field concerning technical issues (including software and hardware) and pre-analytical procedures. METHODS: Recommendations are made based on the data and expert discussions generated from 13 yearly meetings of the European LeukemiaNet international MDS Flow working group. RESULTS: We report here on the experiences and recommendations concerning (1) the optimal methods of sample processing and handling, (2) antibody panels and fluorochromes, and (3) current hardware technologies. CONCLUSIONS: These recommendations will support and facilitate the appropriate application of FCM assays in the diagnostic workup of MDS patients. Further standardization and harmonization will be required to integrate FCM in MDS diagnostic evaluations in daily practice.

2.
Artigo em Inglês | MEDLINE | ID: mdl-34897979

RESUMO

This article discusses the rationale for inclusion of flow cytometry (FCM) in the diagnostic investigation and evaluation of cytopenias of uncertain origin and suspected myelodysplastic syndromes (MDS) by the European LeukemiaNet international MDS Flow Working Group (ELN iMDS Flow WG). The WHO 2016 classification recognizes that FCM contributes to the diagnosis of MDS and may be useful for prognostication, prediction, and evaluation of response to therapy and follow-up of MDS patients.

3.
Blood Adv ; 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34644385

RESUMO

Lymphoma represents a heterogeneous hematological malignancy (HM), which is characterized by severe immunosuppression. Patients diagnosed of coronavirus disease (COVID-19) during the course of HM have been described to have poor outcome, with only few reports specifically addressing lymphoma patients. Here, we investigated the clinical behaviour and clinical parameters of a large multicenter cohort of adult patients with different lymphoma subtypes, with the aim of identifying predictors of death. The study included 856 patients, of whom 619 were enrolled prospectively in a 1-year frame and were followed-up for a median of 66 days (range 1-395). Patients were managed as outpatient (not admitted cohort, n=388), or required hospitalization (n=468), and median age was 63 years (range 19-94). Overall, the 30- and 100-days mortality was 13% (95%CI 11-15%) and 23% (95%CI 20-27%), respectively. Anti-lymphoma treatment, including anti-CD20 containing regimens, did not impact on survival. Patients with Hodgkin's lymphoma had the more favourable survival, but this was partly related to significantly younger age. The time interval between lymphoma diagnosis and COVID-19 was inversely related to mortality. Multivariable analysis recognized 4 easy-to-use factors (age, gender, lymphocyte, and platelet count) that were associated with risk of death, both in the admitted and in the not-admitted cohort (HR 3.79 and 8.85 for the intermediate and high-risk group, respectively). Overall, our study shows that patients should not be deprived of the best available treatment for their underlying disease, and indicates which patients are at higher risk of death. This study was registered with ClinicalTrials.gov, NCT04352556.

5.
J Clin Oncol ; 39(11): 1223-1233, 2021 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-33539200

RESUMO

PURPOSE: Recurrently mutated genes and chromosomal abnormalities have been identified in myelodysplastic syndromes (MDS). We aim to integrate these genomic features into disease classification and prognostication. METHODS: We retrospectively enrolled 2,043 patients. Using Bayesian networks and Dirichlet processes, we combined mutations in 47 genes with cytogenetic abnormalities to identify genetic associations and subgroups. Random-effects Cox proportional hazards multistate modeling was used for developing prognostic models. An independent validation on 318 cases was performed. RESULTS: We identify eight MDS groups (clusters) according to specific genomic features. In five groups, dominant genomic features include splicing gene mutations (SF3B1, SRSF2, and U2AF1) that occur early in disease history, determine specific phenotypes, and drive disease evolution. These groups display different prognosis (groups with SF3B1 mutations being associated with better survival). Specific co-mutation patterns account for clinical heterogeneity within SF3B1- and SRSF2-related MDS. MDS with complex karyotype and/or TP53 gene abnormalities and MDS with acute leukemia-like mutations show poorest prognosis. MDS with 5q deletion are clustered into two distinct groups according to the number of mutated genes and/or presence of TP53 mutations. By integrating 63 clinical and genomic variables, we define a novel prognostic model that generates personally tailored predictions of survival. The predicted and observed outcomes correlate well in internal cross-validation and in an independent external cohort. This model substantially improves predictive accuracy of currently available prognostic tools. We have created a Web portal that allows outcome predictions to be generated for user-defined constellations of genomic and clinical features. CONCLUSION: Genomic landscape in MDS reveals distinct subgroups associated with specific clinical features and discrete patterns of evolution, providing a proof of concept for next-generation disease classification and prognosis.


Assuntos
Genômica/métodos , Síndromes Mielodisplásicas/classificação , Feminino , Humanos , Masculino , Síndromes Mielodisplásicas/genética , Prognóstico , Estudos Retrospectivos
7.
Eur J Haematol ; 99(1): 27-35, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28332730

RESUMO

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) diagnostic guidelines recommend single-tube five- to six-color or two-tube four-color assays. PNH clones are detectable in only a fraction of patients at risk, and screening for new PNH cases can be complex and expensive. In this multicenter study, we have validated a simplified, one-tube two-color FLAER-based assay suitable for PNH screening. METHODS: Six laboratories received samples containing spiked PNH leukocyte clones to be analyzed in parallel with a common six-color cocktail (FLAER/CD24/CD45/CD64/CD15/CD14) and a simplified two-color mixture (FLAER/CD15), a shared calibration procedure, and a common analysis protocol. Replicate precision and sensitivity tests were performed on PNH patients, from undiluted to 1:10 000. Specificity tests were performed on normal donors to identify the possible sources of artifacts. RESULTS: The performance comparison between six-color and two-color assays showed an excellent agreement for granulocyte PNH clones. Dilution experiments showed an accurate detectability down to 0.01% sensitivity level for granulocyte PNH clones and to 1% for monocytes. Specificity experiments disclosed that basophils and platelets can contaminate the monocyte gate and generate false PNH events. CONCLUSIONS: A simplified two-color (FLAER/CD15) PNH screening test has been validated in a highly standardized multicenter study and proved feasible and effective in ongoing regional programs. Precision, sensitivity, and specificity of the simplified test for granulocytes were comparable to the more complex and expensive six-color assay and applicable for screening also in peripheral laboratories. The diagnostic confirmation of PNH should be always performed by a reference center using the established technique on all cell lineages.


Assuntos
Hemoglobinúria Paroxística/diagnóstico , Biomarcadores , Citometria de Fluxo/economia , Citometria de Fluxo/métodos , Citometria de Fluxo/normas , Hemoglobinúria Paroxística/sangue , Humanos , Contagem de Leucócitos , Leucócitos/metabolismo , Programas de Rastreamento , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
8.
Mediterr J Hematol Infect Dis ; 9(1): e2017017, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28293405

RESUMO

The pathological hallmark of myelodysplastic syndromes (MDS) is marrow dysplasia, which represents the basis of the WHO classification of these disorders. This classification provides clinicians with a useful tool for defining the different subtypes of MDS and individual prognosis. The WHO proposal has raised some concern regarding minimal diagnostic criteria particularly in patients with normal karyotype without robust morphological markers of dysplasia (such as ring sideroblasts or excess of blasts). Therefore, there is clearly need to refine the accuracy to detect marrow dysplasia. Flow cytometry (FCM) immunophenotyping has been proposed as a tool to improve the evaluation of marrow dysplasia. The rationale for the application of FCM in the diagnostic work up of MDS is that immunophenotyping is an accurate method for quantitative and qualitative evaluation of hematopoietic cells and that MDS have been found to have abnormal expression of several cellular antigens. To become applicable in clinical practice, FCM analysis should be based on parameters with sufficient specificity and sensitivity, data should be reproducible between different operators, and the results should be easily understood by clinicians. In this review, we discuss the most relevant progresses in detection of marrow dysplasia by FCM in MDS.

9.
Haematologica ; 102(2): 308-319, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27758818

RESUMO

Current recommendations for diagnosing myelodysplastic syndromes endorse flow cytometry as an informative tool. Most flow cytometry protocols focus on the analysis of progenitor cells and the evaluation of the maturing myelomonocytic lineage. However, one of the most frequently observed features of myelodysplastic syndromes is anemia, which may be associated with dyserythropoiesis. Therefore, analysis of changes in flow cytometry features of nucleated erythroid cells may complement current flow cytometry tools. The multicenter study within the IMDSFlow Working Group, reported herein, focused on defining flow cytometry parameters that enable discrimination of dyserythropoiesis associated with myelodysplastic syndromes from non-clonal cytopenias. Data from a learning cohort were compared between myelodysplasia and controls, and results were validated in a separate cohort. The learning cohort comprised 245 myelodysplasia cases, 290 pathological, and 142 normal controls; the validation cohort comprised 129 myelodysplasia cases, 153 pathological, and 49 normal controls. Multivariate logistic regression analysis performed in the learning cohort revealed that analysis of expression of CD36 and CD71 (expressed as coefficient of variation), in combination with CD71 fluorescence intensity and the percentage of CD117+ erythroid progenitors provided the best discrimination between myelodysplastic syndromes and non-clonal cytopenias (specificity 90%; 95% confidence interval: 84-94%). The high specificity of this marker set was confirmed in the validation cohort (92%; 95% confidence interval: 86-97%). This erythroid flow cytometry marker combination may improve the evaluation of cytopenic cases with suspected myelodysplasia, particularly when combined with flow cytometry assessment of the myelomonocytic lineage.


Assuntos
Células Eritroides/metabolismo , Células Eritroides/patologia , Síndromes Mielodisplásicas/metabolismo , Síndromes Mielodisplásicas/patologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Células da Medula Óssea/metabolismo , Estudos de Casos e Controles , Feminino , Citometria de Fluxo , Humanos , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Adulto Jovem
10.
J Clin Oncol ; 34(30): 3627-3637, 2016 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-27601546

RESUMO

PURPOSE: The genetic basis of myelodysplastic syndromes (MDS) is heterogeneous, and various combinations of somatic mutations are associated with different clinical phenotypes and outcomes. Whether the genetic basis of MDS influences the outcome of allogeneic hematopoietic stem-cell transplantation (HSCT) is unclear. PATIENTS AND METHODS: We studied 401 patients with MDS or acute myeloid leukemia (AML) evolving from MDS (MDS/AML). We used massively parallel sequencing to examine tumor samples collected before HSCT for somatic mutations in 34 recurrently mutated genes in myeloid neoplasms. We then analyzed the impact of mutations on the outcome of HSCT. RESULTS: Overall, 87% of patients carried one or more oncogenic mutations. Somatic mutations of ASXL1, RUNX1, and TP53 were independent predictors of relapse and overall survival after HSCT in both patients with MDS and patients with MDS/AML (P values ranging from .003 to .035). In patients with MDS/AML, gene ontology (ie, secondary-type AML carrying mutations in genes of RNA splicing machinery, TP53-mutated AML, or de novo AML) was an independent predictor of posttransplantation outcome (P = .013). The impact of ASXL1, RUNX1, and TP53 mutations on posttransplantation survival was independent of the revised International Prognostic Scoring System (IPSS-R). Combining somatic mutations and IPSS-R risk improved the ability to stratify patients by capturing more prognostic information at an individual level. Accounting for various combinations of IPSS-R risk and somatic mutations, the 5-year probability of survival after HSCT ranged from 0% to 73%. CONCLUSION: Somatic mutation in ASXL1, RUNX1, or TP53 is independently associated with unfavorable outcomes and shorter survival after allogeneic HSCT for patients with MDS and MDS/AML. Accounting for these genetic lesions may improve the prognostication precision in clinical practice and in designing clinical trials.

11.
Blood ; 126(2): 233-41, 2015 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-25957392

RESUMO

Refractory anemia with ring sideroblasts (RARS) is a myelodysplastic syndrome (MDS) characterized by isolated erythroid dysplasia and 15% or more bone marrow ring sideroblasts. Ring sideroblasts are found also in other MDS subtypes, such as refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS). A high prevalence of somatic mutations of SF3B1 was reported in these conditions. To identify mutation patterns that affect disease phenotype and clinical outcome, we performed a comprehensive mutation analysis in 293 patients with myeloid neoplasm and 1% or more ring sideroblasts. SF3B1 mutations were detected in 129 of 159 cases (81%) of RARS or RCMD-RS. Among other patients with ring sideroblasts, lower prevalence of SF3B1 mutations and higher prevalence of mutations in other splicing factor genes were observed (P < .001). In multivariable analyses, patients with SF3B1 mutations showed significantly better overall survival (hazard ratio [HR], .37; P = .003) and lower cumulative incidence of disease progression (HR = 0.31; P = .018) compared with SF3B1-unmutated cases. The independent prognostic value of SF3B1 mutation was retained in MDS without excess blasts, as well as in sideroblastic categories (RARS and RCMD-RS). Among SF3B1-mutated patients, coexisting mutations in DNA methylation genes were associated with multilineage dysplasia (P = .015) but had no effect on clinical outcome. TP53 mutations were frequently detected in patients without SF3B1 mutation, and were associated with poor outcome. Thus, SF3B1 mutation identifies a distinct MDS subtype that is unlikely to develop detrimental subclonal mutations and is characterized by indolent clinical course and favorable outcome.


Assuntos
Anemia Sideroblástica/genética , Mutação , Síndromes Mielodisplásicas/classificação , Síndromes Mielodisplásicas/genética , Fosfoproteínas/genética , Ribonucleoproteína Nuclear Pequena U2/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia Sideroblástica/diagnóstico , Anemia Sideroblástica/epidemiologia , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/epidemiologia , Prognóstico , Fatores de Processamento de RNA , Adulto Jovem
12.
Blood ; 124(9): 1513-21, 2014 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-24970933

RESUMO

Our knowledge of the genetic basis of myelodysplastic syndromes (MDS) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) has considerably improved. To define genotype/phenotype relationships of clinical relevance, we studied 308 patients with MDS, MDS/MPN, or acute myeloid leukemia evolving from MDS. Unsupervised statistical analysis, including the World Health Organization classification criteria and somatic mutations, showed that MDS associated with SF3B1-mutation (51 of 245 patients, 20.8%) is a distinct nosologic entity irrespective of current morphologic classification criteria. Conversely, MDS with ring sideroblasts with nonmutated SF3B1 segregated in different clusters with other MDS subtypes. Mutations of genes involved in DNA methylation, splicing factors other than SF3B1, and genes of the RAS pathway and cohesin complex were independently associated with multilineage dysplasia and identified a distinct subset (51 of 245 patients, 20.8%). No recurrent mutation pattern correlated with unilineage dysplasia without ring sideroblasts. Irrespective of driver somatic mutations, a threshold of 5% bone marrow blasts retained a significant discriminant value for identifying cases with clonal evolution. Comutation of TET2 and SRSF2 was highly predictive of a myeloid neoplasm characterized by myelodysplasia and monocytosis, including but not limited to, chronic myelomonocytic leukemia. These results serve as a proof of concept that a molecular classification of myeloid neoplasms is feasible.


Assuntos
Leucemia Mieloide Aguda/genética , Mutação , Síndromes Mielodisplásicas/genética , Doenças Mieloproliferativas-Mielodisplásicas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas de Ciclo Celular/genética , Proteínas Cromossômicas não Histona/genética , Estudos de Coortes , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Metilação de DNA/genética , Feminino , Genes ras , Estudos de Associação Genética , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patologia , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/classificação , Síndromes Mielodisplásicas/patologia , Doenças Mieloproliferativas-Mielodisplásicas/classificação , Doenças Mieloproliferativas-Mielodisplásicas/patologia , Células Mieloides/patologia , Fosfoproteínas/genética , Prognóstico , Fatores de Processamento de RNA , Ribonucleoproteína Nuclear Pequena U2/genética
13.
Blood ; 123(15): 2333-42, 2014 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-24558201

RESUMO

Approximately one-third of patients with myelodysplastic syndrome (MDS) receiving allogeneic hematopoietic stem cell transplantation (HSCT) are cured by this treatment. Treatment failure may be due to transplant complications or relapse. To identify predictive factors for transplantation outcome, we studied 519 patients with MDS or oligoblastic acute myeloid leukemia (AML, <30% marrow blasts) who received an allogeneic HSCT and were reported to the Gruppo Italiano Trapianto di Midollo Osseo registry between 2000 and 2011. Univariate and multivariate survival analyses were performed using Cox proportional hazards regression. High-risk category, as defined by the revised International Prognostic Scoring System (IPSS-R), and monosomal karyotype were independently associated with relapse and lower overall survival after transplantation. On the other hand, older recipient age and high hematopoietic cell transplantation-comorbidity index (HCT-CI) were independent predictors of nonrelapse mortality. Accounting for various combinations of patient's age, IPSS-R category, monosomal karyotype, and HCT-CI, the 5-year probability of survival after allogeneic HSCT ranged from 0% to 94%. This study indicates that IPSS-R risk category and monosomal karyotype are important factors predicting transplantation failure both in MDS and oligoblastic AML. In addition, it reinforces the concept that allogeneic HSCT offers optimal eradication of myelodysplastic hematopoiesis when the procedure is performed before MDS patients progress to advanced disease stages.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Síndromes Mielodisplásicas/cirurgia , Adolescente , Adulto , Idoso , Aloenxertos , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/mortalidade , Prognóstico , Modelos de Riscos Proporcionais , Recidiva , Fatores de Risco , Resultado do Tratamento , Adulto Jovem
15.
Blood ; 122(25): 4021-34, 2013 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-24136165

RESUMO

Myelodysplasia is a diagnostic feature of myelodysplastic syndromes (MDSs) but is also found in other myeloid neoplasms. Its molecular basis has been recently elucidated by means of massive parallel sequencing studies. About 90% of MDS patients carry ≥1 oncogenic mutations, and two thirds of them are found in individuals with a normal karyotype. Driver mutant genes include those of RNA splicing (SF3B1, SRSF2, U2AF1, and ZRSR2), DNA methylation (TET2, DNMT3A, and IDH1/2), chromatin modification (ASXL1 and EZH2), transcription regulation (RUNX1), DNA repair (TP53), signal transduction (CBL, NRAS, and KRAS), and cohesin complex (STAG2). Only 4 to 6 genes are consistently mutated in ≥10% MDS patients, whereas a long tail of ∼50 genes are mutated less frequently. At presentation, most patients typically have 2 or 3 driver oncogenic mutations and hundreds of background mutations. MDS driver genes are also frequently mutated in other myeloid neoplasms. Reliable genotype/phenotype relationships include the association of the SF3B1 mutation with refractory anemia with ring sideroblasts, TET2/SRSF2 comutation with chronic myelomonocytic leukemia, and activating CSF3R mutation with chronic neutrophilic leukemia. Although both founding and subclonal driver mutations have been shown to have prognostic significance, prospective clinical trials that include the molecular characterization of the patient's genome are now needed.


Assuntos
Genoma Humano , Leucemia Mielogênica Crônica BCR-ABL Positiva , Mutação , Síndromes Mielodisplásicas , Proteínas de Neoplasias , Animais , Cromatina/genética , Cromatina/metabolismo , Cromatina/patologia , Ensaios Clínicos como Assunto , Análise Mutacional de DNA , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Splicing de RNA/genética , Transdução de Sinais/genética , Transcrição Genética/genética
16.
Blood ; 122(22): 3616-27; quiz 3699, 2013 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-24030381

RESUMO

Myelodysplastic syndromes (MDS) are a heterogeneous group of chronic hematological malignancies characterized by dysplasia, ineffective hematopoiesis and a variable risk of progression to acute myeloid leukemia. Sequencing of MDS genomes has identified mutations in genes implicated in RNA splicing, DNA modification, chromatin regulation, and cell signaling. We sequenced 111 genes across 738 patients with MDS or closely related neoplasms (including chronic myelomonocytic leukemia and MDS-myeloproliferative neoplasms) to explore the role of acquired mutations in MDS biology and clinical phenotype. Seventy-eight percent of patients had 1 or more oncogenic mutations. We identify complex patterns of pairwise association between genes, indicative of epistatic interactions involving components of the spliceosome machinery and epigenetic modifiers. Coupled with inferences on subclonal mutations, these data suggest a hypothesis of genetic "predestination," in which early driver mutations, typically affecting genes involved in RNA splicing, dictate future trajectories of disease evolution with distinct clinical phenotypes. Driver mutations had equivalent prognostic significance, whether clonal or subclonal, and leukemia-free survival deteriorated steadily as numbers of driver mutations increased. Thus, analysis of oncogenic mutations in large, well-characterized cohorts of patients illustrates the interconnections between the cancer genome and disease biology, with considerable potential for clinical application.


Assuntos
Mutação , Síndromes Mielodisplásicas/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Progressão da Doença , Epistasia Genética , Feminino , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mielomonocítica Crônica/genética , Masculino , Pessoa de Meia-Idade , Doenças Mieloproliferativas-Mielodisplásicas/genética , Oncogenes , Prognóstico , Splicing de RNA/genética , Spliceossomos/genética
17.
J Clin Oncol ; 31(28): 3557-64, 2013 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-24002510

RESUMO

PURPOSE: The diagnosis of patients with myelodysplastic syndromes (MDS) is largely dependent on morphologic examination of bone marrow aspirates. Several criteria that form the basis of the classifications and scoring systems most commonly used in clinical practice are affected by operator-dependent variation. To identify standardized molecular markers that would allow prediction of prognosis, we have used gene expression profiling (GEP) data on CD34+ cells from patients with MDS to determine the relationship between gene expression levels and prognosis. PATIENTS AND METHODS: GEP data on CD34+ cells from 125 patients with MDS with a minimum 12-month follow-up since date of bone marrow sample collection were included in this study. Supervised principal components and lasso penalized Cox proportional hazards regression (Coxnet) were used for the analysis. RESULTS: We identified several genes, the expression of which was significantly associated with survival of patients with MDS, including LEF1, CDH1, WT1, and MN1. The Coxnet predictor, based on expression data on 20 genes, outperformed other predictors, including one that additionally used clinical information. Our Coxnet gene signature based on CD34+ cells significantly identified a separation of patients with good or bad prognosis in an independent GEP data set based on unsorted bone marrow mononuclear cells, demonstrating that our signature is robust and may be applicable to bone marrow cells without the need to isolate CD34+ cells. CONCLUSION: We present a new, valuable GEP-based signature for assessing prognosis in MDS. GEP-based signatures correlating with clinical outcome may significantly contribute to a refined risk classification of MDS.


Assuntos
Biomarcadores Tumorais/genética , Perfilação da Expressão Gênica , Células-Tronco Hematopoéticas/metabolismo , Síndromes Mielodisplásicas/diagnóstico , Células-Tronco Neoplásicas/metabolismo , Idoso , Antígenos CD34/metabolismo , Feminino , Seguimentos , Células-Tronco Hematopoéticas/patologia , Humanos , Masculino , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/terapia , Células-Tronco Neoplásicas/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Análise de Componente Principal , Prognóstico , Taxa de Sobrevida
18.
Blood ; 122(17): 2943-64, 2013 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-23980065

RESUMO

Within the myelodysplastic syndrome (MDS) work package of the European LeukemiaNet, an Expert Panel was selected according to the framework elements of the National Institutes of Health Consensus Development Program. A systematic review of the literature was performed that included indexed original papers, indexed reviews and educational papers, and abstracts of conference proceedings. Guidelines were developed on the basis of a list of patient- and therapy-oriented questions, and recommendations were formulated and ranked according to the supporting level of evidence. MDSs should be classified according to the 2008 World Health Organization criteria. An accurate risk assessment requires the evaluation of not only disease-related factors but also of those related to extrahematologic comorbidity. The assessment of individual risk enables the identification of fit patients with a poor prognosis who are candidates for up-front intensive treatments, primarily allogeneic stem cell transplantation. A high proportion of MDS patients are not eligible for potentially curative treatment because of advanced age and/or clinically relevant comorbidities and poor performance status. In these patients, the therapeutic intervention is aimed at preventing cytopenia-related morbidity and preserving quality of life. A number of new agents are being developed for which the available evidence is not sufficient to recommend routine use. The inclusion of patients into prospective clinical trials is strongly recommended.


Assuntos
Antineoplásicos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/terapia , Adulto , Ensaios Clínicos como Assunto , Comorbidade , Europa (Continente) , Medicina Baseada em Evidências , Cardiopatias/diagnóstico , Cardiopatias/epidemiologia , Cardiopatias/patologia , Humanos , Síndromes Mielodisplásicas/epidemiologia , Síndromes Mielodisplásicas/patologia , Prognóstico , Medição de Risco , Inquéritos e Questionários , Transplante Homólogo
19.
Br J Haematol ; 161(5): 726-37, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23573868

RESUMO

In myelodysplastic syndromes with ring sideroblasts (MDS-RS), the iron deposited in the mitochondria of RS is present in the form of mitochondrial ferritin (FTMT), but it is unknown whether FTMT overexpression is the cause or the result of mitochondrial iron deposition. Lentivirus FTMT-transduced CD34(+) bone marrow cells from seven healthy donors and CD34(+) cells from 24 patients with MDS-RS were cultured according to a procedure that allowed the expansion of high numbers of erythroid progenitors. These cells were used to investigate the possible influence of experimentally-induced FTMT overexpression on normal erythropoiesis and the functional effects of FTMT in sideroblastic erythropoiesis. In MDS-RS progenitors, FTMT overexpression was associated with reduced cytosolic ferritin levels, increased surface transferrin receptor expression and reduced cell proliferation; FTMT effects were independent of SF3B1 mutation status. Similarly, FTMT overexpressing normal erythroid progenitors were characterized by reduced cytosolic ferritin content and increased CD71 expression, and also by higher apoptotic rate in comparison with the FTMT- controls. Significantly lower levels of STAT5 phosphorylation following erythropoietin stimulation were found in both sideroblastic and normal FTMT(+) erythroid cells compared to the FTMT- cells. In conclusion, experimental overexpression of FTMT may modify mitochondrial iron availability and lead to ineffective erythropoiesis.


Assuntos
Anemia Sideroblástica/metabolismo , Células Precursoras Eritroides/metabolismo , Ferritinas/metabolismo , Proteínas Mitocondriais/metabolismo , Anemia Sideroblástica/patologia , Antígenos CD34/metabolismo , Apoptose/fisiologia , Células da Medula Óssea/metabolismo , Células Cultivadas , Eritropoese/fisiologia , Feminino , Ferritinas/genética , Vetores Genéticos/genética , Humanos , Lentivirus/genética , Masculino , Mitocôndrias/metabolismo , Proteínas Mitocondriais/genética , Transdução Genética
20.
Blood ; 121(15): 3005-15, 2013 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-23372164

RESUMO

The natural course of chronic myelomonocytic leukemia (CMML) is highly variable but a widely accepted prognostic scoring system for patients with CMML is not available. The main aim of this study was to develop a new CMML-specific prognostic scoring system (CPSS) in a large series of 558 patients with CMML (training cohort, Spanish Group of Myelodysplastic Syndromes) and to validate it in an independent series of 274 patients (validation cohort, Heinrich Heine University Hospital, Düsseldorf, Germany, and San Matteo Hospital, Pavia, Italy). The most relevant variables for overall survival (OS) and evolution to acute myeloblastic leukemia (AML) were FAB and WHO CMML subtypes, CMML-specific cytogenetic risk classification, and red blood cell (RBC) transfusion dependency. CPSS was able to segregate patients into 4 clearly different risk groups for OS (P < .001) and risk of AML evolution (P < .001) and its predictive capability was confirmed in the validation cohort. An alternative CPSS with hemoglobin instead of RBC transfusion dependency offered almost identical prognostic capability. This study confirms the prognostic impact of FAB and WHO subtypes, recognizes the importance of RBC transfusion dependency and cytogenetics, and offers a simple and powerful CPSS for accurately assessing prognosis and planning therapy in patients with CMML.


Assuntos
Leucemia Mielomonocítica Crônica/diagnóstico , Avaliação de Resultados em Cuidados de Saúde/métodos , Medição de Risco/métodos , Doença Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Transfusão de Eritrócitos/estatística & dados numéricos , Feminino , Hemoglobinas/análise , Humanos , Leucemia Mieloide/sangue , Leucemia Mieloide/diagnóstico , Leucemia Mieloide/genética , Leucemia Mielomonocítica Crônica/sangue , Leucemia Mielomonocítica Crônica/genética , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Prognóstico , Modelos de Riscos Proporcionais , Reprodutibilidade dos Testes , Medição de Risco/estatística & dados numéricos , Fatores de Risco , Análise de Sobrevida , Adulto Jovem
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