Primary myelofibrosis: risk stratification by IPSS identifies patients with poor clinical outcome

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Lima, Irene Lorand-Metze, Marcia Torresan Delamain, Gislaine Borba Oliveira, Daiane de Almeida, Carmino Antonio de Souza, Jose Vassallo, Katia Borgia Barbosa Pagnano" "autores" => array:9 [ 0 => array:3 [ "nombre" => "Bruno Deltreggia" "apellidos" => "Benites" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "I" "identificador" => "aff1" ] ] ] 1 => array:3 [ "nombre" => "Carolina Silva Costa" "apellidos" => "Lima" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "I" "identificador" => "aff1" ] ] ] 2 => array:3 [ "nombre" => "Irene" "apellidos" => "Lorand-Metze" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "I" "identificador" => "aff1" ] ] ] 3 => array:3 [ "nombre" => "Marcia Torresan" "apellidos" => "Delamain" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "I" "identificador" => "aff1" ] ] ] 4 => array:3 [ "nombre" => "Gislaine Borba" "apellidos" => "Oliveira" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "I" "identificador" => "aff1" ] ] ] 5 => array:3 [ "nombre" => "Daiane" "apellidos" => "de Almeida" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "I" "identificador" => "aff1" ] ] ] 6 => array:3 [ "nombre" => "Carmino Antonio" "apellidos" => "de Souza" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "I" "identificador" => "aff1" ] ] ] 7 => array:3 [ "nombre" => "Jose" "apellidos" => "Vassallo" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "II" "identificador" => "aff2" ] ] ] 8 => array:4 [ "nombre" => "Katia Borgia Barbosa" "apellidos" => "Pagnano" "email" => array:1 [ 0 => "kborgia@unicamp.br" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "I" "identificador" => "aff1" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor1" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Universidade Estadual de Campinas, Centro de Hematologia e Hemoterapia, Hemocentro, Campinas/São Paulo, Brazil" "etiqueta" => "I" "identificador" => "aff1" ] 1 => array:3 [ "entidad" => "Universidade Estadual de Campinas, Laboratory of Investigative and Molecular Pathology, CIPED, Campinas/SP, Brazil" "etiqueta" => "II" "identificador" => "aff2" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor1" "etiqueta" => "*" "correspondencia" => "Tel.: 55 19 3521-8740" ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig2" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "cln-68-03-339-g002.jpeg" "Alto" => 544 "Ancho" => 739 "Tamanyo" => 26466 ] ] "descripcion" => array:1 [ "en" => "Overall survival of patients according to the IPSS." ] ] ] "textoCompleto" => "INTRODUCTIONPrimary myelofibrosis (PMF) is a clonal hematopoietic stem cell disorder characterized by bone marrow fibrosis, extra-medullary hematopoiesis with splenomegaly and leukoerythroblastosis in the peripheral blood (<a class="elsevierStyleCrossRef" href="#bib1">1</a>,<a class="elsevierStyleCrossRef" href="#bib2">2</a>). The clinical manifestations of PMF include severe anemia, marked hepatosplenomegaly and constitutional symptoms. Ineffective erythropoiesis and extra-medullary hematopoiesis are the main causes of anemia and organomegaly, respectively. Approximately 20% of patients diagnosed with PMF may present progression to acute leukemia, but most patients die of other conditions, such as cardiovascular events, or as a consequence of cytopenias, such as infections or bleeding (<a class="elsevierStyleCrossRef" href="#bib3">3</a>).The diagnostic criteria for this disease have been revised since the discovery in 2005 of the acquired mutation V617F in the JAK2 gene, which is found in 50-60% of patients with PMF (<a class="elsevierStyleCrossRef" href="#bib4">4</a>). The JAKs, which include JAK1, JAK2, JAK3 and TYK, are a family of cytoplasmic tyrosine kinases that are essential for cytokine signaling and gene transcription. The JAK2V617F mutation results in the constitutive activation of JAK2 tyrosine kinase and its downstream targets, which leads to increased signaling of associated cytokine receptors and the subsequent proliferation of hematopoietic cells harboring these receptors (<a class="elsevierStyleCrossRef" href="#bib5">5</a>). The clinical significance of the mutation is evident in that homozygosis for JAK2 V617F results in a more symptomatic illness relative to heterozygous patients. However, the prognostic significance of the mutation is controversial, including its implication in poor clinical outcomes and the risk of progression to leukemia (<a class="elsevierStyleCrossRef" href="#bib6">6</a>).Until recently, the most widely used prognostic classification of PMF was the Lille score, which categorizes patients into three risk groups based on the hemoglobin level and leukocyte count at diagnosis (<a class="elsevierStyleCrossRef" href="#bib7">7</a>). However, the Lille score fails to clearly discriminate between intermediate- and high-risk prognostic categories.Recognition of these limitations led to a multicenter study aimed at building a new International Prognostic Scoring System (IPSS) for PMF, in which seven European and American centers contributed data from more than 1,000 PMF patients. In the multivariate analysis, the initial features independently associated with a poor prognosis were an age older than 65 years, the presence of constitutional symptoms, hemoglobin <10 g/dL, WBC count >25×109/L and the presence of blasts in the peripheral blood. These prognostic factors formed the basis for four risk groups with clear-cut, non-overlapping survival curves: no factors (low risk), one factor (intermediate risk-1), two factors (intermediate risk-2) or three or more factors (high risk) (<a class="elsevierStyleCrossRef" href="#bib8">8</a>).The IPSS demonstrated a higher discriminatory power than previous scoring systems and showed a high degree of replicability and predictive accuracy. The IPSS is based on prognostic factors recorded at the diagnosis of PMF that are not necessarily stable over the course of the disease. To address this shortcoming, a dynamic prognostic model (DIPSS) was subsequently developed, and it utilizes the same prognostic variables used in IPSS but can be applied at any time during the course of the disease (<a class="elsevierStyleCrossRef" href="#bib9">9</a>). The DIPSS assigns two, rather than one, adverse points for hemoglobin <10 g/dL, and the risk categorization is accordingly modified: low (0 adverse points), intermediate-1 (1 or 2 points), intermediate-2 (3 or 4 points) and high (5 or 6 points).As many patients are elderly at diagnosis or present several comorbidities, most PMF patients are managed with supportive care only. Thus, a high degree of prognostic certainty is desired to permit the recommendation of more aggressive or high-risk therapeutic procedures, and the patient's classification by prognostic score enables better therapeutic planning, especially for patients who are younger and eligible for bone marrow transplantation. Furthermore, the development of methods to assess and validate measures for clinical outcome becomes crucial in the era of targeted therapies, in which the therapeutic potential of JAK inhibitor molecules has emerged (<a class="elsevierStyleCrossRefs" href="#bib10">10-12</a>).Thus, the aim of our study was to analyze the clinical and laboratory data of consecutive PMF cases diagnosed in a single center, focusing on the Lille and IPSS prognostic scores and comparing their applicability to predict a poor outcome.PATIENTS AND METHODSSeventy-four consecutive patients with primary myelofibrosis diagnosed between January 1992 and August 2011 were included in this study for retrospective analysis. The local ethics committee approved this study. All cases were reclassified according to the WHO classification. In all cases, the presence of increased reticulin and/or collagen bone marrow content without any apparent cause (such as chronic myeloid leukemia, PV, myelodysplasia, lymphoproliferative disorders, scleroderma and primary pulmonary hypertension) was required in addition to the presence of features typical of this disease, including palpable splenomegaly, leukoerythroblastosis or histological demonstration of myeloid metaplasia.The variables selected for their prognostic significance were assessed at diagnosis and included the following: peripheral blood counts (hemoglobin, total leukocytes, platelets and circulating blasts), splenomegaly, constitutional symptoms (weight loss greater than 10% of the baseline value in the year preceding the PMF diagnosis and/or unexplained persistent fever or excessive sweating) and myelofibrosis grade on a bone marrow biopsy based on the Baumeister scale and karyotype obtained from the marrow aspirate. JAK-2 mutation status was analyzed at diagnosis or during the follow-up. The Lille and IPSS prognostic scores were also calculated (<a class="elsevierStyleCrossRef" href="#tbl1">Table 1</a>.<elsevierMultimedia ident="tbl1"></elsevierMultimedia>Statistical analysisOverall survival (OS) was calculated from the diagnosis until the last follow-up or death, and transformation-free survival (TFS) was calculated from diagnosis until the progression to acute myeloid leukemia, last evaluation or death. Survival curves were calculated using the log-rank test (software Winstat 3.11 Statistics for Windows, version 3.1, Kalmia Co. Inc). Correlations between thrombosis and the JAK2 mutation and between the myelofibrosis grade in the bone marrow and IPSS were evaluated using the chi-square test.RESULTSPatient features at presentationThe main clinical and laboratory data of the 74 patients in this study are summarized in <a class="elsevierStyleCrossRef" href="#tbl2">Table 2</a>. The median age at diagnosis was 71.5 years. The hemoglobin level was <10 g/dL in 13 patients, the WBC was >25×109/l in eight patients and splenomegaly was found in 31 patients (42%). Cytogenetic analysis was performed in 34 patients (46%), and one case showed a partial deletion of chromosomes 13 and 15. The myelofibrosis grade based on the Baumeister scale was available in 54 patients: 13 (24%) were classified as grade 2, 27 (50%) as grade 3, and 14 (26%) as grade 4.<elsevierMultimedia ident="tbl2"></elsevierMultimedia>TreatmentSixty-six patients (89%) received hydroxyurea (HU), which was discontinued in six cases: three patients switched to anagrelide because of toxicity (lower limb ulcers), and three patients switched to thalidomide and prednisone because of therapeutic failure. Three patients were treated only with supportive care (transfusion). Three patients received no specific treatment during the course of this study because they presented as clinically stable and had blood counts similar to the normal range.A splenectomy was performed in two patients, and three others received splenic radiotherapy to control the symptoms. Only one patient was eligible for allogeneic bone marrow transplantation, and he achieved complete remission, which was maintained by the end of this study (15 months of disease-free survival).Thrombotic events were observed in 13 (18%) patients (arterial occlusion in seven and venous thrombosis in six); only one event occurred during thalidomide treatment. There was no other relationship between these events and the therapy applied or any other clinical or laboratory variable.V617F JAK2 mutation analysisA V617F JAK2 mutation was detected in 32 cases (47%). Patients with the mutation presented a shorter overall survival (39% vs. 77%), although this difference was not significant (p = 0.448) (<a class="elsevierStyleCrossRef" href="#fig1">Figure 1</a>.<elsevierMultimedia ident="fig1"></elsevierMultimedia>Risk stratification and clinical endpointsAccording to the Lille score, most patients presented a low risk (73.5%) (<a class="elsevierStyleCrossRef" href="#tbl2">Table 2</a>. The IPSS classification is described in <a class="elsevierStyleCrossRef" href="#tbl3">Table 3</a>.<elsevierMultimedia ident="tbl3"></elsevierMultimedia>During the analysis period, 15 deaths were recorded: nine due to infectious complications, three after a blast crisis (occurring a median of 45 months after the diagnosis), and three others by causes not related to the disease.According to the Lille classification, no significant difference was observed in overall survival (<a class="elsevierStyleCrossRef" href="#fig1">Figure 1</a>. However, in the IPSS data, patients classified in the high-risk groups (high and int-2 scores) showed a significantly lower overall survival than patients in the low-risk groups (int-1 and low) (p = 0.02) (<a class="elsevierStyleCrossRef" href="#fig2">Figure 2</a>.<elsevierMultimedia ident="fig2"></elsevierMultimedia>There was no significant difference in overall survival when patients were stratified according to myelofibrosis grade (p = 0.81). We did not find a correlation between myelofibrosis grade and IPSS score (p = 0.59).DISCUSSIONMyelofibrosis is a myeloproliferative stem cell disorder that is curable exclusively by allogeneic hematopoietic stem cell transplantation. It also has substantial patient morbidity and mortality, which results in an important need for improved therapies. Recent advances in the understanding of the pathogenetic mechanisms underlying this disease have led to many clinical trials evaluating novel therapies, such as ruxolitinib, which is the first JAK2 inhibitor approved by the FDA for the treatment of patients with intermediate- or high-risk myelofibrosis (13-15). Clinical trials of these compounds have demonstrated improvement in constitutional symptoms and splenomegaly in patients with both mutated and wild-type JAK2 PMF (<a class="elsevierStyleCrossRef" href="#bib15">16</a>,<a class="elsevierStyleCrossRef" href="#bib16">17</a>).However, the development and validation of useful tools to determine the prognosis and estimate survival is necessary for better management of these patients. Although the association was not significant, our findings suggest that positivity for the JAK2 (V617F) mutation in our group of patients may be associated with poorer survival. Published data regarding the role of the JAK2 (V617F) mutation in the prediction of the survival of PMF patients reveal contradictory results. Campbell et al. showed that patients positive for the mutation had a shorter overall survival, even after correction for confounding factors (p = 0.01) (<a class="elsevierStyleCrossRef" href="#bib17">18</a>). However, a recent study showed that a positive qualitative test for the V617F mutation does not predict survival but that patients with a lower V617F allele burden presented a worse survival, which most likely indicates the presence of an overriding V617F-negative clone that confers a more aggressive disease phenotype (<a class="elsevierStyleCrossRef" href="#bib18">19</a>,<a class="elsevierStyleCrossRef" href="#bib19">20</a>).Although important for the differential diagnosis of PMF with ET, the myelofibrosis grade based on the Baumeister scale was not correlated with survival or the IPSS score. Most of our patients presented with grade 3 or 4 (76%).Our study also demonstrated that the IPSS is an appropriate method for identifying patients with a worse overall survival, which agrees with data from other studies (<a class="elsevierStyleCrossRef" href="#bib8">8</a>,<a class="elsevierStyleCrossRef" href="#bib9">9</a>,<a class="elsevierStyleCrossRef" href="#bib20">21</a>). Patients classified as high-risk (high and intermediate-2 scores) showed a significantly lower overall survival than low-risk patients (intermediate-1 and low scores). In addition to demonstrating the efficacy of the IPSS for prognosis evaluation in myelofibrosis, our results also demonstrate the limitations of the Lille score in determining risk for patients with a more severe disease. The Lille score model was initially designed using 195 patients with PMF. As described in other studies, the Lille score is capable of identifying a well-defined group of patients with a good prognosis but fails to clearly identify patients with a very poor prognosis and those with an intermediate prognosis. This issue may be partially explained by the reliance of the score on the hemoglobin level because leukopenia and leukocytosis greater than 30×109/L are infrequent at the time of the PMF diagnosis (<a class="elsevierStyleCrossRef" href="#bib8">8</a>,<a class="elsevierStyleCrossRef" href="#bib21">22</a>). In fact, in our population, only two patients presented leukocytosis greater than 30×109/L, and six presented with leukocytosis <4×109/L at diagnosis.These findings corroborate the evidence indicating that the IPSS must be evaluated for all patients recently diagnosed as having PMF. In addition to predicting survival, it is a helpful tool to evaluate therapeutic options; it is easy to calculate and requires the evaluation of only simple clinical and laboratory data. Other clinical trials should be encouraged to better evaluate the influence of the IPSS score in predicting the response to the new drugs available for the treatment of PMF.In summary, this study confirmed the importance of the IPSS for risk factor stratification. Adjunctive treatment with hydroxyurea is able to control low-risk patients in the cellular phase of the disease. However, patients with intermediate- and high-risk disease are candidates for other therapeutic approaches, such as bone marrow transplantation or experimental drug therapies.AUTHOR CONTRIBUTIONSBenites BD contributed to the study conception and design, data collection, analysis and interpretation. Pagnano KB and Lorand-Metze I contributed to the study conception and design, data analysis and interpretation. Lima CS contributed to data collection, analysis and interpretation. Delamain MC, Oliveira GB, Souza CA and Vassallo J contributed to data analysis and interpretation. Almeida D contributed to the JAK2 mutation analysis. All authors helped in the collection or assembly of data, analysis and interpretation of data and critical revision of the article for important intellectual content." "textoCompletoSecciones" => array:1 [ "secciones" => array:7 [ 0 => array:2 [ "identificador" => "xpalclavsec1582896" "titulo" => "KEYWORDS" ] 1 => array:2 [ "identificador" => "cesec10" "titulo" => "INTRODUCTION" ] 2 => array:3 [ "identificador" => "cesec20" "titulo" => "PATIENTS AND METHODS" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "cesec30" "titulo" => "Statistical analysis" ] ] ] 3 => array:3 [ "identificador" => "cesec40" "titulo" => "RESULTS" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "cesec50" "titulo" => "Patient features at presentation" ] 1 => array:2 [ "identificador" => "cesec60" "titulo" => "Treatment" ] 2 => array:2 [ "identificador" => "cesec70" "titulo" => "V617F JAK2 mutation analysis" ] 3 => array:2 [ "identificador" => "cesec80" "titulo" => "Risk stratification and clinical endpoints" ] ] ] 4 => array:2 [ "identificador" => "cesec90" "titulo" => "DISCUSSION" ] 5 => array:2 [ "identificador" => "cesec100" "titulo" => "AUTHOR CONTRIBUTIONS" ] 6 => array:1 [ "titulo" => "REFERENCES" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2012-10-11" "fechaAceptado" => "2012-11-15" "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "KEYWORDS" "identificador" => "xpalclavsec1582896" "palabras" => array:3 [ 0 => "Primary Myelofibrosis" 1 => "IPSS" 2 => "Prognosis" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:2 [ "resumen" => "OBJECTIVESTo evaluate whether risk scores used to classify patients with primary myelofibrosis and JAK-2 V617F mutation status can predict clinical outcome. METHODSA review of clinical and laboratory data from 74 patients with primary myelofibrosis diagnosed between 1992 and 2011. The IPSS and Lille scores were calculated for risk stratification and correlated with overall survival. RESULTSA V617F JAK2 mutation was detected in 32 cases (47%), with no significant correlation with overall survival. The patients were classified according to the scores: Lille - low, 53 (73.%); intermediate, 13 (18%); and high, 5 (7%); and IPSS – low, 15 (26%); intermediate-1, 23 (32%); intermediate-2, 19 (26%); and high, 15 (31%). Those patients presenting a higher risk according to the IPSS (high and intermediate-2) had a significantly shorter overall survival relative to the low risk groups (intermediate-1 and low) (p = 0.02). CONCLUSIONSThese results emphasize the importance of the IPSS prognostic score for risk assessment in predicting the clinical outcome of primary myelofibrosis patients." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "ceabs10" "titulo" => "OBJECTIVES" ] 1 => array:2 [ "identificador" => "ceabs20" "titulo" => "METHODS" ] 2 => array:2 [ "identificador" => "ceabs30" "titulo" => "RESULTS" ] 3 => array:2 [ "identificador" => "ceabs40" "titulo" => "CONCLUSIONS" ] ] ] ] "NotaPie" => array:1 [ 0 => array:1 [ "nota" => "No potential conflict of interest was reported." ] ] "multimedia" => array:5 [ 0 => array:7 [ "identificador" => "fig1" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "cln-68-03-339-g001.jpeg" "Alto" => 535 "Ancho" => 744 "Tamanyo" => 19107 ] ] "descripcion" => array:1 [ "en" => "Overall survival of patients according to V617F JAK2 mutation status." ] ] 1 => array:7 [ "identificador" => "fig2" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "cln-68-03-339-g002.jpeg" "Alto" => 544 "Ancho" => 739 "Tamanyo" => 26466 ] ] "descripcion" => array:1 [ "en" => "Overall survival of patients according to the IPSS." ] ] 2 => array:7 [ "identificador" => "tbl1" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Risk model \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Risk factors \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Point per factor \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Risk stratification \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lille \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hb <10 g/dL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Low: 0 points \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">WBC <4 or >30×109/l \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Intermediate: 1 points \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">High: 2 points \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IPSS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Age >65 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Low: 0 points \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hb <10 g/dL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Intermediate-1: 1 points \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">WBC >25×109/l \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Intermediate-2: 2 points \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Circulating blasts ≥1% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">High: 3 or more points \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Constitutional symptoms \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] ] "descripcion" => array:1 [ "en" => "Risk models for myelofibrosis applied in the current study." ] ] 3 => array:7 [ "identificador" => "tbl2" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Demographics/Characteristics \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">N \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Age (median and range) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">71.5 (31-92) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Presence of V617V JAK2 mutation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">32 (47%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Splenomegaly at diagnosis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">31 (42%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hb (g/dL) (median and range) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12.2 (5.4-16.9) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Leucocytes/mm3 (median and range) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11.4 (0.9-47.3) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">>30,000/mm3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><4000/mm3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Platelets (median and range) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">456 (76-1.545) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] ] "descripcion" => array:1 [ "en" => "Clinical data of the primary myelofibrosis patients (n = 74)." ] ] 4 => array:7 [ "identificador" => "tbl3" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">IPSS \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">N \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Low \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15 (26%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Intermediate-1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">23 (32%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Intermediate-2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">19 (26%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">High \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15 (31%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lille \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Low \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">53 (73.5%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Intermediate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13 (18%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">High \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 (7%) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] ] "descripcion" => array:1 [ "en" => "Risk stratification according to the Lille and IPSS scores." ] ] ] "bibliografia" => array:2 [ "titulo" => "REFERENCES" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "cebibsec10" "bibliografiaReferencia" => array:22 [ 0 => array:3 [ "identificador" => "bib1" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Advances in the understanding and management of primary myelofibrosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => """ F Cervantes \n \t\t\t\t\t\t\t\t """ 1 => """ A Pereira \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/CCO.0b013e32834bb83f" "Revista" => array:7 [ "tituloSerie" => "Curr Opin Oncol" "fecha" => "2011" "volumen" => "23" "numero" => "6" "paginaInicial" => "665" "paginaFinal" => "671" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21892083" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib2" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ JW Vardiman \n \t\t\t\t\t\t\t\t """ 1 => """ J Thiele \n \t\t\t\t\t\t\t\t """ 2 => """ DA Arber \n \t\t\t\t\t\t\t\t """ 3 => """ RD Brunning \n \t\t\t\t\t\t\t\t """ 4 => """ MJ Borowitz \n \t\t\t\t\t\t\t\t """ 5 => """ A Porwit \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1182/blood-2009-03-209262" "Revista" => array:7 [ "tituloSerie" => "Blood" "fecha" => "2009" "volumen" => "114" "numero" => "5" "paginaInicial" => "937" "paginaFinal" => "951" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19357394" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib3" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Myelofibrosis with myeloid metaplasia" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => """ A Tefferi \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJM200004273421706" "Revista" => array:7 [ "tituloSerie" => "N Engl J Med" "fecha" => "2000" "volumen" => "342" "numero" => "17" "paginaInicial" => "1255" "paginaFinal" => "1265" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10781623" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib4" "etiqueta" => "4" 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array:1 [ 0 => """ A Tefferi \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/leu.2010.69" "Revista" => array:7 [ "tituloSerie" => "Leukemia" "fecha" => "2010" "volumen" => "24" "numero" => "6" "paginaInicial" => "1128" "paginaFinal" => "1138" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20428194" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib6" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "JAK2 V617F mutational status predicts progression to large splenomegaly and leukemic transformation in primary myelofibrosis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ G Barosi \n \t\t\t\t\t\t\t\t """ 1 => """ G Bergamaschi \n \t\t\t\t\t\t\t\t """ 2 => """ M Marchetti \n \t\t\t\t\t\t\t\t """ 3 => """ AM Vannucchi \n \t\t\t\t\t\t\t\t """ 4 => """ P Guglielmelli \n \t\t\t\t\t\t\t\t """ 5 => """ E Antonioli \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1182/blood-2007-07-099184" "Revista" => array:7 [ "tituloSerie" => "Blood" "fecha" => "2007" "volumen" => "110" "numero" => "12" "paginaInicial" => "4030" "paginaFinal" => "4036" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17712047" "web" => "Medline" ] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib7" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Prognostic factors in agnogenic myeloid metaplasia: a report on 195 cases with a new scoring system" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ B Dupriez \n \t\t\t\t\t\t\t\t """ 1 => """ P Morel \n \t\t\t\t\t\t\t\t """ 2 => """ JL Demory \n \t\t\t\t\t\t\t\t """ 3 => """ JL Lai \n \t\t\t\t\t\t\t\t """ 4 => """ M Simon \n \t\t\t\t\t\t\t\t """ 5 => """ I Plantier \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] 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CLINICAL SCIENCE

Bruno Deltreggia BenitesI, Carolina Silva Costa LimaI, Irene Lorand-MetzeI, Marcia Torresan DelamainI, Gislaine Borba OliveiraI, Daiane de AlmeidaI, Carmino Antonio de SouzaI, Jose VassalloII, Katia Borgia Barbosa PagnanoI,

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Tel.: 55 19 3521-8740

I Universidade Estadual de Campinas, Centro de Hematologia e Hemoterapia, Hemocentro, Campinas/São Paulo, Brazil

II Universidade Estadual de Campinas, Laboratory of Investigative and Molecular Pathology, CIPED, Campinas/SP, Brazil

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="cesec10" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle60">INTRODUCTION</span><p id="para10" class="elsevierStylePara elsevierViewall">Primary myelofibrosis &#40;PMF&#41; is a clonal hematopoietic stem cell disorder characterized by bone marrow fibrosis&#44; extra-medullary hematopoiesis with splenomegaly and leukoerythroblastosis in the peripheral blood &#40;<a class="elsevierStyleCrossRef" href="#bib1">1</a>&#44;<a class="elsevierStyleCrossRef" href="#bib2">2</a>&#41;&#46; The clinical manifestations of PMF include severe anemia&#44; marked hepatosplenomegaly and constitutional symptoms&#46; Ineffective erythropoiesis and extra-medullary hematopoiesis are the main causes of anemia and organomegaly&#44; respectively&#46; Approximately 20&#37; of patients diagnosed with PMF may present progression to acute leukemia&#44; but most patients die of other conditions&#44; such as cardiovascular events&#44; or as a consequence of cytopenias&#44; such as infections or bleeding &#40;<a class="elsevierStyleCrossRef" href="#bib3">3</a>&#41;&#46;</p><p id="para20" class="elsevierStylePara elsevierViewall">The diagnostic criteria for this disease have been revised since the discovery in 2005 of the acquired mutation V617F in the JAK2 gene&#44; which is found in 50-60&#37; of patients with PMF &#40;<a class="elsevierStyleCrossRef" href="#bib4">4</a>&#41;&#46; The JAKs&#44; which include JAK1&#44; JAK2&#44; JAK3 and TYK&#44; are a family of cytoplasmic tyrosine kinases that are essential for cytokine signaling and gene transcription&#46; The JAK2V617F mutation results in the constitutive activation of JAK2 tyrosine kinase and its downstream targets&#44; which leads to increased signaling of associated cytokine receptors and the subsequent proliferation of hematopoietic cells harboring these receptors &#40;<a class="elsevierStyleCrossRef" href="#bib5">5</a>&#41;&#46; The clinical significance of the mutation is evident in that homozygosis for JAK2 V617F results in a more symptomatic illness relative to heterozygous patients&#46; However&#44; the prognostic significance of the mutation is controversial&#44; including its implication in poor clinical outcomes and the risk of progression to leukemia &#40;<a class="elsevierStyleCrossRef" href="#bib6">6</a>&#41;&#46;</p><p id="para30" class="elsevierStylePara elsevierViewall">Until recently&#44; the most widely used prognostic classification of PMF was the Lille score&#44; which categorizes patients into three risk groups based on the hemoglobin level and leukocyte count at diagnosis &#40;<a class="elsevierStyleCrossRef" href="#bib7">7</a>&#41;&#46; However&#44; the Lille score fails to clearly discriminate between intermediate- and high-risk prognostic categories&#46;</p><p id="para40" class="elsevierStylePara elsevierViewall">Recognition of these limitations led to a multicenter study aimed at building a new International Prognostic Scoring System &#40;IPSS&#41; for PMF&#44; in which seven European and American centers contributed data from more than 1&#44;000 PMF patients&#46; In the multivariate analysis&#44; the initial features independently associated with a poor prognosis were an age older than 65 years&#44; the presence of constitutional symptoms&#44; hemoglobin &#60;10 g&#47;dL&#44; WBC count &#62;25&#215;10<span class="elsevierStyleSup">9</span>&#47;L and the presence of blasts in the peripheral blood&#46; These prognostic factors formed the basis for four risk groups with clear-cut&#44; non-overlapping survival curves&#58; no factors &#40;low risk&#41;&#44; one factor &#40;intermediate risk-1&#41;&#44; two factors &#40;intermediate risk-2&#41; or three or more factors &#40;high risk&#41; &#40;<a class="elsevierStyleCrossRef" href="#bib8">8</a>&#41;&#46;</p><p id="para50" class="elsevierStylePara elsevierViewall">The IPSS demonstrated a higher discriminatory power than previous scoring systems and showed a high degree of replicability and predictive accuracy&#46; The IPSS is based on prognostic factors recorded at the diagnosis of PMF that are not necessarily stable over the course of the disease&#46; To address this shortcoming&#44; a dynamic prognostic model &#40;DIPSS&#41; was subsequently developed&#44; and it utilizes the same prognostic variables used in IPSS but can be applied at any time during the course of the disease &#40;<a class="elsevierStyleCrossRef" href="#bib9">9</a>&#41;&#46; The DIPSS assigns two&#44; rather than one&#44; adverse points for hemoglobin &#60;10 g&#47;dL&#44; and the risk categorization is accordingly modified&#58; low &#40;0 adverse points&#41;&#44; intermediate-1 &#40;1 or 2 points&#41;&#44; intermediate-2 &#40;3 or 4 points&#41; and high &#40;5 or 6 points&#41;&#46;</p><p id="para60" class="elsevierStylePara elsevierViewall">As many patients are elderly at diagnosis or present several comorbidities&#44; most PMF patients are managed with supportive care only&#46; Thus&#44; a high degree of prognostic certainty is desired to permit the recommendation of more aggressive or high-risk therapeutic procedures&#44; and the patient&#39;s classification by prognostic score enables better therapeutic planning&#44; especially for patients who are younger and eligible for bone marrow transplantation&#46; Furthermore&#44; the development of methods to assess and validate measures for clinical outcome becomes crucial in the era of targeted therapies&#44; in which the therapeutic potential of JAK inhibitor molecules has emerged &#40;<a class="elsevierStyleCrossRefs" href="#bib10">10-12</a>&#41;&#46;</p><p id="para70" class="elsevierStylePara elsevierViewall">Thus&#44; the aim of our study was to analyze the clinical and laboratory data of consecutive PMF cases diagnosed in a single center&#44; focusing on the Lille and IPSS prognostic scores and comparing their applicability to predict a poor outcome&#46;</p></span><span id="cesec20" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle70">PATIENTS AND METHODS</span><p id="para80" class="elsevierStylePara elsevierViewall">Seventy-four consecutive patients with primary myelofibrosis diagnosed between January 1992 and August 2011 were included in this study for retrospective analysis&#46; The local ethics committee approved this study&#46; All cases were reclassified according to the WHO classification&#46; In all cases&#44; the presence of increased reticulin and&#47;or collagen bone marrow content without any apparent cause &#40;such as chronic myeloid leukemia&#44; PV&#44; myelodysplasia&#44; lymphoproliferative disorders&#44; scleroderma and primary pulmonary hypertension&#41; was required in addition to the presence of features typical of this disease&#44; including palpable splenomegaly&#44; leukoerythroblastosis or histological demonstration of myeloid metaplasia&#46;</p><p id="para90" class="elsevierStylePara elsevierViewall">The variables selected for their prognostic significance were assessed at diagnosis and included the following&#58; peripheral blood counts &#40;hemoglobin&#44; total leukocytes&#44; platelets and circulating blasts&#41;&#44; splenomegaly&#44; constitutional symptoms &#40;weight loss greater than 10&#37; of the baseline value in the year preceding the PMF diagnosis and&#47;or unexplained persistent fever or excessive sweating&#41; and myelofibrosis grade on a bone marrow biopsy based on the Baumeister scale and karyotype obtained from the marrow aspirate&#46; JAK-2 mutation status was analyzed at diagnosis or during the follow-up&#46; The Lille and IPSS prognostic scores were also calculated &#40;<a class="elsevierStyleCrossRef" href="#tbl1">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl1"></elsevierMultimedia><span id="cesec30" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle80">Statistical analysis</span><p id="para100" class="elsevierStylePara elsevierViewall">Overall survival &#40;OS&#41; was calculated from the diagnosis until the last follow-up or death&#44; and transformation-free survival &#40;TFS&#41; was calculated from diagnosis until the progression to acute myeloid leukemia&#44; last evaluation or death&#46; Survival curves were calculated using the log-rank test &#40;software Winstat 3&#46;11 Statistics for Windows&#44; version 3&#46;1&#44; Kalmia Co&#46; Inc&#41;&#46; Correlations between thrombosis and the JAK2 mutation and between the myelofibrosis grade in the bone marrow and IPSS were evaluated using the chi-square test&#46;</p></span></span><span id="cesec40" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle90">RESULTS</span><span id="cesec50" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle100">Patient features at presentation</span><p id="para110" class="elsevierStylePara elsevierViewall">The main clinical and laboratory data of the 74 patients in this study are summarized in <a class="elsevierStyleCrossRef" href="#tbl2">Table 2</a>&#46; The median age at diagnosis was 71&#46;5 years&#46; The hemoglobin level was &#60;10 g&#47;dL in 13 patients&#44; the WBC was &#62;25&#215;10<span class="elsevierStyleSup">9</span>&#47;l in eight patients and splenomegaly was found in 31 patients &#40;42&#37;&#41;&#46; Cytogenetic analysis was performed in 34 patients &#40;46&#37;&#41;&#44; and one case showed a partial deletion of chromosomes 13 and 15&#46; The myelofibrosis grade based on the Baumeister scale was available in 54 patients&#58; 13 &#40;24&#37;&#41; were classified as grade 2&#44; 27 &#40;50&#37;&#41; as grade 3&#44; and 14 &#40;26&#37;&#41; as grade 4&#46;</p><elsevierMultimedia ident="tbl2"></elsevierMultimedia></span><span id="cesec60" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle110">Treatment</span><p id="para120" class="elsevierStylePara elsevierViewall">Sixty-six patients &#40;89&#37;&#41; received hydroxyurea &#40;HU&#41;&#44; which was discontinued in six cases&#58; three patients switched to anagrelide because of toxicity &#40;lower limb ulcers&#41;&#44; and three patients switched to thalidomide and prednisone because of therapeutic failure&#46; Three patients were treated only with supportive care &#40;transfusion&#41;&#46; Three patients received no specific treatment during the course of this study because they presented as clinically stable and had blood counts similar to the normal range&#46;</p><p id="para130" class="elsevierStylePara elsevierViewall">A splenectomy was performed in two patients&#44; and three others received splenic radiotherapy to control the symptoms&#46; Only one patient was eligible for allogeneic bone marrow transplantation&#44; and he achieved complete remission&#44; which was maintained by the end of this study &#40;15 months of disease-free survival&#41;&#46;</p><p id="para140" class="elsevierStylePara elsevierViewall">Thrombotic events were observed in 13 &#40;18&#37;&#41; patients &#40;arterial occlusion in seven and venous thrombosis in six&#41;&#59; only one event occurred during thalidomide treatment&#46; There was no other relationship between these events and the therapy applied or any other clinical or laboratory variable&#46;</p></span><span id="cesec70" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle120">V617F JAK2 mutation analysis</span><p id="para150" class="elsevierStylePara elsevierViewall">A V617F JAK2 mutation was detected in 32 cases &#40;47&#37;&#41;&#46; Patients with the mutation presented a shorter overall survival &#40;39&#37; <span class="elsevierStyleItalic">vs</span>&#46; 77&#37;&#41;&#44; although this difference was not significant &#40;<span class="elsevierStyleItalic">p</span>&#8202;&#61;&#8202;0&#46;448&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig1">Figure 1</a>&#46;</p><elsevierMultimedia ident="fig1"></elsevierMultimedia></span><span id="cesec80" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle130">Risk stratification and clinical endpoints</span><p id="para160" class="elsevierStylePara elsevierViewall">According to the Lille score&#44; most patients presented a low risk &#40;73&#46;5&#37;&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl2">Table 2</a>&#46; The IPSS classification is described in <a class="elsevierStyleCrossRef" href="#tbl3">Table 3</a>&#46;</p><elsevierMultimedia ident="tbl3"></elsevierMultimedia><p id="para170" class="elsevierStylePara elsevierViewall">During the analysis period&#44; 15 deaths were recorded&#58; nine due to infectious complications&#44; three after a blast crisis &#40;occurring a median of 45 months after the diagnosis&#41;&#44; and three others by causes not related to the disease&#46;</p><p id="para180" class="elsevierStylePara elsevierViewall">According to the Lille classification&#44; no significant difference was observed in overall survival &#40;<a class="elsevierStyleCrossRef" href="#fig1">Figure 1</a>&#46; However&#44; in the IPSS data&#44; patients classified in the high-risk groups &#40;high and int-2 scores&#41; showed a significantly lower overall survival than patients in the low-risk groups &#40;int-1 and low&#41; &#40;<span class="elsevierStyleItalic">p</span>&#8202;&#61;&#8202;0&#46;02&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig2">Figure 2</a>&#46;</p><elsevierMultimedia ident="fig2"></elsevierMultimedia><p id="para190" class="elsevierStylePara elsevierViewall">There was no significant difference in overall survival when patients were stratified according to myelofibrosis grade &#40;<span class="elsevierStyleItalic">p</span>&#8202;&#61;&#8202;0&#46;81&#41;&#46; We did not find a correlation between myelofibrosis grade and IPSS score &#40;<span class="elsevierStyleItalic">p</span>&#8202;&#61;&#8202;0&#46;59&#41;&#46;</p></span></span><span id="cesec90" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle140">DISCUSSION</span><p id="para200" class="elsevierStylePara elsevierViewall">Myelofibrosis is a myeloproliferative stem cell disorder that is curable exclusively by allogeneic hematopoietic stem cell transplantation&#46; It also has substantial patient morbidity and mortality&#44; which results in an important need for improved therapies&#46; Recent advances in the understanding of the pathogenetic mechanisms underlying this disease have led to many clinical trials evaluating novel therapies&#44; such as ruxolitinib&#44; which is the first JAK2 inhibitor approved by the FDA for the treatment of patients with intermediate- or high-risk myelofibrosis &#40;13-15&#41;&#46; Clinical trials of these compounds have demonstrated improvement in constitutional symptoms and splenomegaly in patients with both mutated and wild-type JAK2 PMF &#40;<a class="elsevierStyleCrossRef" href="#bib15">16</a>&#44;<a class="elsevierStyleCrossRef" href="#bib16">17</a>&#41;&#46;</p><p id="para210" class="elsevierStylePara elsevierViewall">However&#44; the development and validation of useful tools to determine the prognosis and estimate survival is necessary for better management of these patients&#46; Although the association was not significant&#44; our findings suggest that positivity for the JAK2 &#40;V617F&#41; mutation in our group of patients may be associated with poorer survival&#46; Published data regarding the role of the <span class="elsevierStyleItalic">JAK2</span> &#40;V617F&#41; mutation in the prediction of the survival of PMF patients reveal contradictory results&#46; Campbell et al&#46; showed that patients positive for the mutation had a shorter overall survival&#44; even after correction for confounding factors &#40;<span class="elsevierStyleItalic">p</span>&#8202;&#61;&#8202;0&#46;01&#41; &#40;<a class="elsevierStyleCrossRef" href="#bib17">18</a>&#41;&#46; However&#44; a recent study showed that a positive qualitative test for the V617F mutation does not predict survival but that patients with a lower V617F allele burden presented a worse survival&#44; which most likely indicates the presence of an overriding V617F-negative clone that confers a more aggressive disease phenotype &#40;<a class="elsevierStyleCrossRef" href="#bib18">19</a>&#44;<a class="elsevierStyleCrossRef" href="#bib19">20</a>&#41;&#46;</p><p id="para220" class="elsevierStylePara elsevierViewall">Although important for the differential diagnosis of PMF with ET&#44; the myelofibrosis grade based on the Baumeister scale was not correlated with survival or the IPSS score&#46; Most of our patients presented with grade 3 or 4 &#40;76&#37;&#41;&#46;</p><p id="para230" class="elsevierStylePara elsevierViewall">Our study also demonstrated that the IPSS is an appropriate method for identifying patients with a worse overall survival&#44; which agrees with data from other studies &#40;<a class="elsevierStyleCrossRef" href="#bib8">8</a>&#44;<a class="elsevierStyleCrossRef" href="#bib9">9</a>&#44;<a class="elsevierStyleCrossRef" href="#bib20">21</a>&#41;&#46; Patients classified as high-risk &#40;high and intermediate-2 scores&#41; showed a significantly lower overall survival than low-risk patients &#40;intermediate-1 and low scores&#41;&#46; In addition to demonstrating the efficacy of the IPSS for prognosis evaluation in myelofibrosis&#44; our results also demonstrate the limitations of the Lille score in determining risk for patients with a more severe disease&#46; The Lille score model was initially designed using 195 patients with PMF&#46; As described in other studies&#44; the Lille score is capable of identifying a well-defined group of patients with a good prognosis but fails to clearly identify patients with a very poor prognosis and those with an intermediate prognosis&#46; This issue may be partially explained by the reliance of the score on the hemoglobin level because leukopenia and leukocytosis greater than 30&#215;10<span class="elsevierStyleSup">9</span>&#47;L are infrequent at the time of the PMF diagnosis &#40;<a class="elsevierStyleCrossRef" href="#bib8">8</a>&#44;<a class="elsevierStyleCrossRef" href="#bib21">22</a>&#41;&#46; In fact&#44; in our population&#44; only two patients presented leukocytosis greater than 30&#215;10<span class="elsevierStyleSup">9</span>&#47;L&#44; and six presented with leukocytosis &#60;4&#215;10<span class="elsevierStyleSup">9</span>&#47;L at diagnosis&#46;</p><p id="para240" class="elsevierStylePara elsevierViewall">These findings corroborate the evidence indicating that the IPSS must be evaluated for all patients recently diagnosed as having PMF&#46; In addition to predicting survival&#44; it is a helpful tool to evaluate therapeutic options&#59; it is easy to calculate and requires the evaluation of only simple clinical and laboratory data&#46; Other clinical trials should be encouraged to better evaluate the influence of the IPSS score in predicting the response to the new drugs available for the treatment of PMF&#46;</p><p id="para250" class="elsevierStylePara elsevierViewall">In summary&#44; this study confirmed the importance of the IPSS for risk factor stratification&#46; Adjunctive treatment with hydroxyurea is able to control low-risk patients in the cellular phase of the disease&#46; However&#44; patients with intermediate- and high-risk disease are candidates for other therapeutic approaches&#44; such as bone marrow transplantation or experimental drug therapies&#46;</p></span><span id="cesec100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle150">AUTHOR CONTRIBUTIONS</span><p id="para260" class="elsevierStylePara elsevierViewall">Benites BD contributed to the study conception and design&#44; data collection&#44; analysis and interpretation&#46; Pagnano KB and Lorand-Metze I contributed to the study conception and design&#44; data analysis and interpretation&#46; Lima CS contributed to data collection&#44; analysis and interpretation&#46; Delamain MC&#44; Oliveira GB&#44; Souza CA and Vassallo J contributed to data analysis and interpretation&#46; Almeida D contributed to the JAK2 mutation analysis&#46; All authors helped in the collection or assembly of data&#44; analysis and interpretation of data and critical revision of the article for important intellectual content&#46;</p></span></span>"
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        "resumen" => "<span id="ceabs10" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle10">OBJECTIVES</span><p id="spara60" class="elsevierStyleSimplePara elsevierViewall">To evaluate whether risk scores used to classify patients with primary myelofibrosis and JAK-2 V617F mutation status can predict clinical outcome&#46;</p></span> <span id="ceabs20" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle20">METHODS</span><p id="spara70" class="elsevierStyleSimplePara elsevierViewall">A review of clinical and laboratory data from 74 patients with primary myelofibrosis diagnosed between 1992 and 2011&#46; The IPSS and Lille scores were calculated for risk stratification and correlated with overall survival&#46;</p></span> <span id="ceabs30" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle30">RESULTS</span><p id="spara80" class="elsevierStyleSimplePara elsevierViewall">A V617F JAK2 mutation was detected in 32 cases &#40;47&#37;&#41;&#44; with no significant correlation with overall survival&#46; The patients were classified according to the scores&#58; Lille - low&#44; 53 &#40;73&#46;&#37;&#41;&#59; intermediate&#44; 13 &#40;18&#37;&#41;&#59; and high&#44; 5 &#40;7&#37;&#41;&#59; and IPSS &#8211; low&#44; 15 &#40;26&#37;&#41;&#59; intermediate-1&#44; 23 &#40;32&#37;&#41;&#59; intermediate-2&#44; 19 &#40;26&#37;&#41;&#59; and high&#44; 15 &#40;31&#37;&#41;&#46; Those patients presenting a higher risk according to the IPSS &#40;high and intermediate-2&#41; had a significantly shorter overall survival relative to the low risk groups &#40;intermediate-1 and low&#41; &#40;<span class="elsevierStyleItalic">p</span>&#8202;&#61;&#8202;0&#46;02&#41;&#46;</p></span> <span id="ceabs40" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle40">CONCLUSIONS</span><p id="spara90" class="elsevierStyleSimplePara elsevierViewall">These results emphasize the importance of the IPSS prognostic score for risk assessment in predicting the clinical outcome of primary myelofibrosis patients&#46;</p></span>"
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hb &#60;10 g&#47;dL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Low&#58; 0 points&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">WBC &#60;4 or &#62;30&#215;10<span class="elsevierStyleSup">9</span>&#47;l&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Intermediate&#58; 1 points&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">High&#58; 2 points&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">IPSS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Age &#62;65 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Low&#58; 0 points&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hb &#60;10 g&#47;dL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Intermediate-1&#58; 1 points&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">WBC &#62;25&#215;10<span class="elsevierStyleSup">9</span>&#47;l&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Intermediate-2&#58; 2 points&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Circulating blasts &#8805;1&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">High&#58; 3 or more points&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Constitutional symptoms&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara30" class="elsevierStyleSimplePara elsevierViewall">Risk models for myelofibrosis applied in the current study&#46;</p>"
        ]
      ]
      3 => array:7 [
        "identificador" => "tbl2"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Demographics&#47;Characteristics&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">N&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Age &#40;median and range&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">71&#46;5 &#40;31-92&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Presence of V617V JAK2 mutation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">32 &#40;47&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Splenomegaly at diagnosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">31 &#40;42&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hb &#40;g&#47;dL&#41; &#40;median and range&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12&#46;2 &#40;5&#46;4-16&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Leucocytes&#47;mm<span class="elsevierStyleSup">3</span> &#40;median and range&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11&#46;4 &#40;0&#46;9-47&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#62;30&#44;000&#47;mm<span class="elsevierStyleSup">3</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;4000&#47;mm<span class="elsevierStyleSup">3</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Platelets &#40;median and range&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">456 &#40;76-1&#46;545&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara40" class="elsevierStyleSimplePara elsevierViewall">Clinical data of the primary myelofibrosis patients &#40;n&#8202;&#61;&#8202;74&#41;&#46;</p>"
        ]
      ]
      4 => array:7 [
        "identificador" => "tbl3"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">IPSS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">N&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15 &#40;26&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Intermediate-1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">23 &#40;32&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Intermediate-2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">19 &#40;26&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">High&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15 &#40;31&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Lille&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">53 &#40;73&#46;5&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Intermediate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">13 &#40;18&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">High&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5 &#40;7&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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Article information

ISSN: 18075932
Original language: English

DOI:10.6061/clinics/2013(03)OA09

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Year/Month	Html	Pdf	Total

2024 November	8	3	11
2024 October	25	24	49
2024 September	19	15	34
2024 August	24	12	36
2024 July	14	15	29
2024 June	13	20	33
2024 May	20	9	29
2024 April	17	20	37
2024 March	15	11	26
2024 February	15	12	27
2024 January	15	13	28
2023 December	11	12	23
2023 November	20	20	40
2023 October	13	23	36
2023 September	18	21	39
2023 August	9	4	13
2023 July	15	28	43
2023 June	26	17	43
2023 May	12	1	13
2023 April	5	7	12
2023 March	4	0	4
2023 February	4	3	7
2023 January	1	5	6
2022 December	20	12	32

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