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Murcia-Zaragoza, M. Bernabeu-Wittel" "autores" => array:2 [ 0 => array:2 [ "nombre" => "J." "apellidos" => "Murcia-Zaragoza" ] 1 => array:2 [ "nombre" => "M." 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Bernabeu-Wittel, J. Díez-Manglano, D. Nieto-Martín, N. Ramírez-Duque, M. Ollero-Baturone" "autores" => array:6 [ 0 => array:2 [ "nombre" => "M." "apellidos" => "Bernabeu-Wittel" ] 1 => array:2 [ "nombre" => "J." "apellidos" => "Díez-Manglano" ] 2 => array:2 [ "nombre" => "D." "apellidos" => "Nieto-Martín" ] 3 => array:2 [ "nombre" => "N." "apellidos" => "Ramírez-Duque" ] 4 => array:2 [ "nombre" => "M." "apellidos" => "Ollero-Baturone" ] 5 => array:1 [ "colaborador" => "on behalf of the PROFUND Project researchers" ] ] ] 1 => array:2 [ "autoresLista" => "Lucy Abella-Vázquez, Mariano Aguayo-Canela, Mónica Albert-Coll, Antonio Alemán, Jordi Aligué, José Barbé Gil-Ortega, Bosco Barón-Franco, Máximo Bernabeu-Wittel, Cristina de la Calle-Cabrera, Manuel Cassani-Garza, Manuela Castillo-Blasco, Felipe Díez, Jesús Díez-Manglano, Alberto Escalera-Zalvide, Luis Feliu-Mazaria, Manuel Francisco Fernández-Miera, Antonio Fernández-Moyano, Francesc Formiga, Jordy Forteza-Rey, Aurelio Fuertes-Martín, Javier Galindo-Ocaña, Pilar Giner, Montserrat Godoy, Sandra Gómez-Lesmes, Hernán Llorente-Cancho, Carolina Luque-Amado, José Manuel Machín-Lázaro, María Maiz-Jiménez, Francisco Martínez, Tomás Martínez, Francisco Martos, Beatriz Massa, Jesús Medina, Francisco Medrano-González, Manuel Montero Pérez-Barquero, Antonia Mora-Rufete, Clotilde Morales, Lourdes Moreno-Gaviño, Alberto Muela-Molinero, José Murcia-Zaragoza, M. Dolores Nieto-Martín, Ignacio Novo Valeiro, Manuel Ollero-Baturone, Blanca Pinilla, Nieves Ramírez-Duque, Carmen Ramos-Cantos, Manuel Rincón-Gómez, M. Luisa Rodríguez-Benedito, Virginia Rodríguez-Martínez, Manuel Romero-Jiménez, Sixto Ruiz, Alberto Ruiz-Cantero, Emilio Sacanella, María Sánchez-Ledesma, Antonio Sanjosé-Laporte, Carlos Sanromán, M. Ángeles Soria-López, Alicia Tejera-Concepción, Pedro Tenllado-Doblas, Guillermo Ternavasio, Eulalia Villegas-Bruguera" "autores" => array:62 [ 0 => array:1 [ "colaborador" => "PROFUND Project Researchers" ] 1 => array:2 [ "nombre" => "Lucy" "apellidos" => "Abella-Vázquez" ] 2 => array:2 [ "nombre" => "Mariano" "apellidos" => "Aguayo-Canela" ] 3 => array:2 [ "nombre" => "Mónica" "apellidos" => "Albert-Coll" ] 4 => array:2 [ "nombre" => "Antonio" "apellidos" => "Alemán" ] 5 => array:2 [ "nombre" => "Jordi" "apellidos" => "Aligué" ] 6 => array:2 [ "nombre" => "José" "apellidos" => "Barbé Gil-Ortega" ] 7 => array:2 [ "nombre" => "Bosco" "apellidos" => "Barón-Franco" ] 8 => array:2 [ "nombre" => "Máximo" "apellidos" => "Bernabeu-Wittel" ] 9 => array:2 [ "nombre" => "Cristina" "apellidos" => "de la Calle-Cabrera" ] 10 => array:2 [ "nombre" => "Manuel" "apellidos" => "Cassani-Garza" ] 11 => array:2 [ "nombre" => "Manuela" "apellidos" => "Castillo-Blasco" ] 12 => array:2 [ "nombre" => "Felipe" "apellidos" => "Díez" ] 13 => array:2 [ "nombre" => "Jesús" "apellidos" => "Díez-Manglano" ] 14 => array:2 [ "nombre" => "Alberto" "apellidos" => "Escalera-Zalvide" ] 15 => array:2 [ "nombre" => "Luis" "apellidos" => "Feliu-Mazaria" ] 16 => array:2 [ "nombre" => "Manuel" "apellidos" => "Francisco Fernández-Miera" ] 17 => array:2 [ "nombre" => "Antonio" "apellidos" => "Fernández-Moyano" ] 18 => array:2 [ "nombre" => "Francesc" "apellidos" => "Formiga" ] 19 => array:2 [ "nombre" => "Jordy" "apellidos" => "Forteza-Rey" ] 20 => array:2 [ "nombre" => "Aurelio" "apellidos" => "Fuertes-Martín" ] 21 => array:2 [ "nombre" => "Javier" "apellidos" => "Galindo-Ocaña" ] 22 => array:2 [ "nombre" => "Pilar" "apellidos" => "Giner" ] 23 => array:2 [ "nombre" => "Montserrat" "apellidos" => "Godoy" ] 24 => array:2 [ "nombre" => "Sandra" "apellidos" => "Gómez-Lesmes" ] 25 => array:2 [ "nombre" => "Hernán" "apellidos" => "Llorente-Cancho" ] 26 => array:2 [ "nombre" => "Carolina" "apellidos" => "Luque-Amado" ] 27 => array:2 [ "nombre" => "José" "apellidos" => "Manuel Machín-Lázaro" ] 28 => array:2 [ "nombre" => "María" "apellidos" => "Maiz-Jiménez" ] 29 => array:2 [ "nombre" => "Francisco" "apellidos" => "Martínez" ] 30 => array:2 [ "nombre" => "Tomás" "apellidos" => "Martínez" ] 31 => array:2 [ "nombre" => "Francisco" "apellidos" => "Martos" ] 32 => array:2 [ "nombre" => "Beatriz" "apellidos" => "Massa" ] 33 => array:2 [ "nombre" => "Jesús" "apellidos" => "Medina" ] 34 => array:2 [ "nombre" => "Francisco" "apellidos" => "Medrano-González" ] 35 => array:2 [ "nombre" => "Manuel" "apellidos" => "Montero Pérez-Barquero" ] 36 => array:2 [ "nombre" => "Antonia" "apellidos" => "Mora-Rufete" ] 37 => array:2 [ "nombre" => "Clotilde" "apellidos" => "Morales" ] 38 => array:2 [ "nombre" => "Lourdes" "apellidos" => "Moreno-Gaviño" ] 39 => array:2 [ "nombre" => "Alberto" "apellidos" => "Muela-Molinero" ] 40 => array:2 [ "nombre" => "José" "apellidos" => "Murcia-Zaragoza" ] 41 => array:2 [ "nombre" => "M." "apellidos" => "Dolores Nieto-Martín" ] 42 => array:2 [ "nombre" => "Ignacio" "apellidos" => "Novo Valeiro" ] 43 => array:2 [ "nombre" => "Manuel" "apellidos" => "Ollero-Baturone" ] 44 => array:2 [ "nombre" => "Blanca" "apellidos" => "Pinilla" ] 45 => array:2 [ "nombre" => "Nieves" "apellidos" => "Ramírez-Duque" ] 46 => array:2 [ "nombre" => "Carmen" "apellidos" => "Ramos-Cantos" ] 47 => array:2 [ "nombre" => "Manuel" "apellidos" => "Rincón-Gómez" ] 48 => array:2 [ "nombre" => "M." "apellidos" => "Luisa Rodríguez-Benedito" ] 49 => array:2 [ "nombre" => "Virginia" "apellidos" => "Rodríguez-Martínez" ] 50 => array:2 [ "nombre" => "Manuel" "apellidos" => "Romero-Jiménez" ] 51 => array:2 [ "nombre" => "Sixto" "apellidos" => "Ruiz" ] 52 => array:2 [ "nombre" => "Alberto" "apellidos" => "Ruiz-Cantero" ] 53 => array:2 [ "nombre" => "Emilio" "apellidos" => "Sacanella" ] 54 => array:2 [ "nombre" => "María" "apellidos" => "Sánchez-Ledesma" ] 55 => array:2 [ "nombre" => "Antonio" "apellidos" => "Sanjosé-Laporte" ] 56 => array:2 [ "nombre" => "Carlos" "apellidos" => "Sanromán" ] 57 => array:2 [ "nombre" => "M." "apellidos" => "Ángeles Soria-López" ] 58 => array:2 [ "nombre" => "Alicia" "apellidos" => "Tejera-Concepción" ] 59 => array:2 [ "nombre" => "Pedro" "apellidos" => "Tenllado-Doblas" ] 60 => array:2 [ "nombre" => "Guillermo" "apellidos" => "Ternavasio" ] 61 => array:2 [ "nombre" => "Eulalia" "apellidos" => "Villegas-Bruguera" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0014256519301110" "doi" => "10.1016/j.rce.2019.04.005" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0014256519301110?idApp=WRCEE" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2254887419301675?idApp=WRCEE" "url" => "/22548874/0000021900000008/v1_201910300730/S2254887419301675/v1_201910300730/en/main.assets" ] "en" => array:20 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Brief Original</span>" "titulo" => "Comprehensive clinical, molecular and histopathological analysis of bone marrow in chronic myeloproliferative neoplasia" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "440" "paginaFinal" => "444" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "L. Medina Vega, L. Hernández Nieto, E. Salido Ruíz, H. Álvarez-Argüelles Cabrera, J.M. Raya Sánchez" "autores" => array:5 [ 0 => array:4 [ "nombre" => "L." "apellidos" => "Medina Vega" "email" => array:1 [ 0 => "lilianmedinatfe@hotmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "L." "apellidos" => "Hernández Nieto" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "E." "apellidos" => "Salido Ruíz" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 3 => array:3 [ "nombre" => "H." "apellidos" => "Álvarez-Argüelles Cabrera" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 4 => array:3 [ "nombre" => "J.M." "apellidos" => "Raya Sánchez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Servicio de Bioquímica Clínica, Hospital Universitario de Canarias, La Laguna, Santa Cruz de Tenerife, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Hematología y Hemoterapia, Hospital Universitario de Canarias, La Laguna, Santa Cruz de Tenerife, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Servicio de Anatomía Patológica, Hospital Universitario de Canarias, La Laguna, Santa Cruz de Tenerife, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Análisis integrado clínico, molecular e histopatológico de la médula ósea en las neoplasias mieloproliferativas crónicas" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Background</span><p id="par0005" class="elsevierStylePara elsevierViewall">New mutations that explain the clonality of the disease and the histopathology findings from the bone marrow biopsy (BMB) have gained significant relevance, as demonstrated in the current classifications, and both have been included in the criteria necessary for establishing the diagnosis. The Janus kinase 2 (JAK2)-V617F gene mutation is present in approximately 95% of patients with polycythemia vera (PV) and 50% of patients with essential thrombocythemia (ET) and myelofibrosis.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">1</span></a> Somatic mutations of the recently identified calreticulin (CALR) gene occur exclusively in patients with ET and myelofibrosis who do not present JAK2 or myeloproliferative leukemia (MPL) gene mutations and have never been observed in patients with PV.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">2</span></a> Numerous other mutations have been identified and contribute to the disease's development, progression and prognosis and include those of <span class="elsevierStyleItalic">MPL</span>, exon 12 of <span class="elsevierStyleItalic">JAK2</span>, <span class="elsevierStyleItalic">LNK</span>, <span class="elsevierStyleItalic">TET</span>, <span class="elsevierStyleItalic">MPL</span>, <span class="elsevierStyleItalic">CBL</span> and <span class="elsevierStyleItalic">EZH2</span>.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Bone marrow biopsy (BMB) has diagnostic importance in the 3 Philadelphia-negative myeloproliferative neoplasias (Ph− MPN), given the essential nature of assessing the biopsy.</p><p id="par0015" class="elsevierStylePara elsevierViewall">Given the marked clinical, evolutionary and therapeutic differences among the neoplasias, a correct differential diagnosis is essential for proper management. The potential impact of bone marrow morphology and the presence of mutations on the clinical management of patients with Ph− MPN has been increasingly studied.</p><p id="par0020" class="elsevierStylePara elsevierViewall">The aim of our study was to analyze the potential correlation between the molecular changes in the <span class="elsevierStyleItalic">JAK2</span>, <span class="elsevierStyleItalic">MPL</span> and <span class="elsevierStyleItalic">CALR</span> genes, the bone marrow's morphological pattern and the patients’ clinical-hematologic profile.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Materials and methods</span><p id="par0025" class="elsevierStylePara elsevierViewall">We conducted a retrospective study with 140 patients diagnosed with PV (44), ET (78) or myelofibrosis (18) by the Department of Hematology and Hemotherapy according to the diagnostic criteria proposed by the World Health Organization in 2016.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">4</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The clinical data collected at the onset of the disease were the presence of splenomegaly and hepatomegaly. The need for antiplatelet and cytoreductive therapy was recorded.</p><p id="par0035" class="elsevierStylePara elsevierViewall">We collected blood count and biochemical data at the time the disease was diagnosed.</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Analysis of the <span class="elsevierStyleItalic">JAK2-V617F</span>, <span class="elsevierStyleItalic">JAK2</span> exon 12, <span class="elsevierStyleItalic">MPL</span> exon 10 and <span class="elsevierStyleItalic">CALR</span> mutations</span><p id="par0040" class="elsevierStylePara elsevierViewall">The mutation analysis was performed with DNA purified of granulocytes. For exon 14 of <span class="elsevierStyleItalic">JAK2</span>, we employed the Invitrogen® primer (Thermo Fisher Scientific, Waltham, MA, US). We analyzed the allele burden of the <span class="elsevierStyleItalic">JAK2-V617F</span> mutation in a PyroMark System® pyrosequencer (Qiagen, Hiden, Germany) according to the manufacturer's specifications.</p><p id="par0045" class="elsevierStylePara elsevierViewall">For exon 12 of <span class="elsevierStyleItalic">JAK2</span>, we employed the IDT® primer (Integrated DNA Technologies, Coralville, IA, US). We performed the analysis by sequencing in an ABI® analyzer (Applied Biosystems, CA, US).</p><p id="par0050" class="elsevierStylePara elsevierViewall">The primers employed to analyze the mutation in exon 10 of <span class="elsevierStyleItalic">MPL</span> were from IDT®, both of which were designed to be cut by the HpyCH4V enzyme.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Bone marrow biopsy</span><p id="par0055" class="elsevierStylePara elsevierViewall">We evaluated the BMB for the following histopathologic variables for the 3 diseases: overall cellularity, red series, granulocytic series, megakaryocyte series, megakaryocyte size, megakaryocyte accumulation, megakaryocyte nucleus, presence of naked megakaryocyte nuclei, intrasinusoidal megakaryocytes, paratrabecular megakaryocytes, abnormal localization of immature precursors, emperipolesis, lymphoid nodules, microvasculature, ectasia–hyperplasia, iron levels, fibrosis and osteosclerosis. We examined the presence of collagen fibrosis, CD34 precursors and intrasinusoidal hematopoiesis exclusively in myelofibrosis. The biopsies were evaluated without knowing the patient's personal or clinical data, except for their age. The assessment of the bone marrow fibrosis intensity was conducted according to the ranking system of the European Expert Consensus.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">2</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Statistical analysis</span><p id="par0060" class="elsevierStylePara elsevierViewall">We analyzed the association between the quantitative variables and the 3 groups of diseases with the Kruskal–Wallis test. When the results of this test were significant, we applied the non-parametric matched-pair Mann–Whitney <span class="elsevierStyleItalic">U</span> test. To determine the association of the qualitative variables, we employed the chi-squared test or Fisher's exact test, as appropriate. To calculate the correlation between the quantitative variables, we employed the Pearson correlation coefficient and Spearman's test. We employed logistical and linear multivariate regression models. All statistical tests were considered bilateral, and significant values were those with <span class="elsevierStyleItalic">p</span>-values <.05. For the statistical analysis, we employed SPSS® v17.0 (Chicago, IL).</p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Results</span><p id="par0065" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows a summary of the most common histopathological findings for each condition.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Mutation study</span><p id="par0070" class="elsevierStylePara elsevierViewall">The overall mutation frequency was as follows: For PV, the frequency was 4.7% for exon 12 of <span class="elsevierStyleItalic">JAK2</span>, 88.3% for exon 14 of <span class="elsevierStyleItalic">JAK2</span> and 7% for no mutations. For ET, the frequency was 43.4% for <span class="elsevierStyleItalic">JAK2-V617F</span>, 26.4% for the <span class="elsevierStyleItalic">CALR</span> mutation and 30.2% for no mutations. For myelofibrosis, the frequency was 31.2% for <span class="elsevierStyleItalic">JAK2-V617F</span> and 31.2% for <span class="elsevierStyleItalic">CALR.</span> For the patients in whom the <span class="elsevierStyleItalic">MPL</span> mutation was investigated, none of those with ET or myelofibrosis without the <span class="elsevierStyleItalic">JAK2</span> and <span class="elsevierStyleItalic">CALR</span> mutations had the <span class="elsevierStyleItalic">MPL</span> mutation.</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090"><span class="elsevierStyleItalic">JAK2-V617F</span> mutation</span><p id="par0075" class="elsevierStylePara elsevierViewall">For PV, the patients without the mutation (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>5) presented higher lactate dehydrogenase values (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>.025) than those with the mutation (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>38). Hepatomegaly was more common in the homozygotic patients (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>.029). For the ET group, the patients with the <span class="elsevierStyleItalic">JAK2-V617F</span> mutation (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>24) had more neutrophils than those without the mutation (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>33; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>.007). For myelofibrosis, we found that the patients with the <span class="elsevierStyleItalic">JAK2-V617F</span> mutation (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>6) had more neutrophils (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>.017) than those without the mutation (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>10). In the BMB, the patients with the mutation had higher overall cellularity (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>.016) and constant emperipolesis (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>.016). Moreover, 2 of the 5 patients without the <span class="elsevierStyleItalic">JAK2-V617F</span> mutation presented a mutation in exon 12 of <span class="elsevierStyleItalic">JAK2</span>.</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095"><span class="elsevierStyleItalic">CALR</span> mutation</span><p id="par0080" class="elsevierStylePara elsevierViewall">Fourteen patients with ET presented a <span class="elsevierStyleItalic">CALR</span> mutation. These patients had more platelets than those without the mutation (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>15; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>.028), as well as a greater use of cytoreductive agents (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>.018).</p><p id="par0085" class="elsevierStylePara elsevierViewall">In the patients with myelofibrosis, we found that hepatomegaly appeared in 4/5 (80%) of those with the <span class="elsevierStyleItalic">CALR</span> mutation but did not appear in those without the mutation (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>.028). Lactate dehydrogenase levels were higher in the patients with the <span class="elsevierStyleItalic">CALR</span> mutation (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>.025). The patients with the <span class="elsevierStyleItalic">CALR</span> mutation showed differences in megakaryocyte nuclei morphology, which was shared between hypolobulated and hyperlobulated megakaryocytes, while the patients without the mutation presented normal megakaryocyte nuclei in terms of lobulation (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>.018). All patients who carried the mutation presented naked nuclei in the BMB, while only one of the patients without the mutation presented these nuclei (33.3%; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>.035).</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100"><span class="elsevierStyleItalic">JAK2 V617F</span> vs. <span class="elsevierStyleItalic">CALR</span></span><p id="par0090" class="elsevierStylePara elsevierViewall">The main differences in terms of the presence of the mutation in the patients with ET and myelofibrosis are shown in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a></p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Discussion</span><p id="par0095" class="elsevierStylePara elsevierViewall">The patients with the <span class="elsevierStyleItalic">JAK</span><span class="elsevierStyleItalic">V617F</span> mutation presented higher leukocyte and neutrophil levels than those who did not present the mutation, a result of the recognized myeloproliferative capacity induced by the <span class="elsevierStyleItalic">JAK2</span> mutation.<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">5–7</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Some 93.3% of the patients with ET and the <span class="elsevierStyleItalic">CALR</span> mutation took cytoreductive agents, while 56.3% of those without the mutation took cytoreductive agents. This finding could be explained by the higher mean platelet count in the patients with the <span class="elsevierStyleItalic">CALR</span> mutation and, therefore, the greater need for cytoreduction.</p><p id="par0105" class="elsevierStylePara elsevierViewall">In ET, the patients with the <span class="elsevierStyleItalic">CALR</span> mutation had an earlier disease onset (47.1 years) than those with the <span class="elsevierStyleItalic">JAK2</span> mutation (57.1 years).<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">8</span></a> Those patients with the <span class="elsevierStyleItalic">JAK2</span> mutation also presented significantly higher leukocyte and neutrophil counts,<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">9,10</span></a> when compared with those with the <span class="elsevierStyleItalic">CALR</span> mutation.</p><p id="par0110" class="elsevierStylePara elsevierViewall">Significant differences in the BMB only occurred in the cases of myelofibrosis. The patients with the <span class="elsevierStyleItalic">CALR</span> mutation were more often associated with abnormal megakaryocyte morphology, a diagnosis of prefibrotic myelofibrosis and a lower degree of medullar cellularity and higher megakaryocyte readings.<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">11,12</span></a> In the patients with the <span class="elsevierStyleItalic">CALR</span> mutation, we observed the presence of naked megakaryocyte nuclei, compared with only a third of the patients without the mutation, a significant difference. Additionally, these same patients showed a greater degree of heterogeneity in the morphology of the megakaryocyte nuclei than the patients without the mutation.</p><p id="par0115" class="elsevierStylePara elsevierViewall">Similarly, the differences observed between the patients with the <span class="elsevierStyleItalic">JAK2</span> mutation and those with the <span class="elsevierStyleItalic">CALR</span> mutation were interesting; the cases with MPN associated with the JAK2-V617F mutation had a more heterogeneous histology than those with the <span class="elsevierStyleItalic">CALR</span> mutation.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">11</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">All patients with myelofibrosis and the <span class="elsevierStyleItalic">JAK2</span> mutation presented highly increased overall cellularity, while the patients with the <span class="elsevierStyleItalic">CALR</span> mutation showed predominantly normal overall cellularity. Likewise, hyperlobulated nuclei in the megakaryocytes appeared in 80% of the patients with the <span class="elsevierStyleItalic">CALR</span> mutation, while these nuclei did not appear in the patients with the <span class="elsevierStyleItalic">JAK2</span> mutation.</p><p id="par0125" class="elsevierStylePara elsevierViewall">In terms of study limitations, it is worth noting the scarce information on the patients’ clinical course and prognosis, which could provide greater understanding of the progression of the disease in terms of the mutational state. The small number of patients when breaking down by disease could explain the lack of <span class="elsevierStyleItalic">MPL</span> mutations, which constituted 5–10% of cases.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">3</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">In conclusion, the mutational state for <span class="elsevierStyleItalic">JAK2</span> and <span class="elsevierStyleItalic">CALR</span> defines subtypes of patients with ET with substantially different clinical courses and prognoses. In myelofibrosis, the <span class="elsevierStyleItalic">JAK2</span> mutation affects the degree of bone marrow cellularity, while the <span class="elsevierStyleItalic">CALR</span> mutation causes morphological changes focused mainly on abnormalities in megakaryocyte nucleus lobulation and on the systematic presence of naked nuclei.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:3 [ "identificador" => "xres1260007" "titulo" => "Abstract" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Patients and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1167029" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1260006" "titulo" => "Resumen" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "abst0020" "titulo" => "Objetivos" ] 1 => array:2 [ "identificador" => "abst0025" "titulo" => "Pacientes y métodos" ] 2 => array:2 [ "identificador" => "abst0030" "titulo" => "Resultados" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1167028" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Background" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Materials and methods" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Analysis of the JAK2-V617F, JAK2 exon 12, MPL exon 10 and CALR mutations" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Bone marrow biopsy" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Statistical analysis" ] ] ] 6 => array:3 [ "identificador" => "sec0030" "titulo" => "Results" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0035" "titulo" => "Mutation study" ] 1 => array:2 [ "identificador" => "sec0040" "titulo" => "JAK2-V617F mutation" ] 2 => array:2 [ "identificador" => "sec0045" "titulo" => "CALR mutation" ] 3 => array:2 [ "identificador" => "sec0050" "titulo" => "JAK2 V617F vs. CALR" ] ] ] 7 => array:2 [ "identificador" => "sec0055" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "xack432209" "titulo" => "Acknowledgements" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2018-08-08" "fechaAceptado" => "2018-11-26" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1167029" "palabras" => array:7 [ 0 => "Myeloproliferative neoplasia" 1 => "<span class="elsevierStyleItalic">JAK2</span>" 2 => "<span class="elsevierStyleItalic">CALR</span>" 3 => "Bone marrow biopsy" 4 => "Polycythemia vera" 5 => "Essential thrombocythemia" 6 => "Myelofibrosis" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1167028" "palabras" => array:7 [ 0 => "Neoplasias mieloproliferativas" 1 => "<span class="elsevierStyleItalic">JAK2</span>" 2 => "<span class="elsevierStyleItalic">CALR</span>" 3 => "Biopsia de médula ósea" 4 => "Policitemia vera" 5 => "Trombocitemia esencial" 6 => "Mielofibrosis primaria" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objectives</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">To analyze the possible correlation between molecular changes in the <span class="elsevierStyleItalic">JAK2</span>, <span class="elsevierStyleItalic">MPL</span> and <span class="elsevierStyleItalic">CALR</span> genes, the morphological pattern of bone marrow and the clinical-hematologic profile of patients.</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Patients and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">We conducted a retrospective study that included 140 patients diagnosed with Philadelphia-negative myeloproliferative neoplasia (Ph-MPN) in a single center.</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">In essential thrombocythemia (ET), the patients with the <span class="elsevierStyleItalic">JAK2 V617F</span> mutation presented more leucocytes and neutrophils than patients who presented the <span class="elsevierStyleItalic">CALR</span> mutation, who had more platelets and a greater need for cytoreductive therapy. These findings support the fact that the mutational state in ET appears to define subtypes of patients with substantially different clinical courses and prognoses. In myelofibrosis, the mutational state appears to influence the histopathological changes found in the bone marrow biopsy, which did not occur in polycythemia vera or ET.</p></span>" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Patients and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "<span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Objetivos</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Análisis de las posibles correlaciones entre las alteraciones moleculares en los genes <span class="elsevierStyleItalic">JAK2</span>, <span class="elsevierStyleItalic">MPL</span> y <span class="elsevierStyleItalic">CALR</span>, el patrón morfológico de la médula ósea y el perfil clínico-hematológico de los pacientes.</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Pacientes y métodos</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Se trata de un estudio retrospectivo que incluye 140 pacientes con diagnóstico de neoplasias mieloproliferativas Filadelfia negativas (NMP Fi−) de un único centro.</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Resultados</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">En la TE, los pacientes con la mutación el <span class="elsevierStyleItalic">JAK2 V617F</span>, presentaron un mayor número de leucocitos y neutrófilos que aquellos que presentaron la mutación en <span class="elsevierStyleItalic">CALR</span>. Los <span class="elsevierStyleItalic">CALR</span> mutados obtuvieron un mayor número de plaquetas y mayor necesidad de tratamiento citorreductor. Estos hallazgos apoyan el hecho de que el estado mutacional en la TE parece definir subtipos de pacientes con un curso clínico y pronóstico substancialmente diferentes. En la MF el estado mutacional parece influir en los cambios histopatológicos encontrados en la BMO, lo que no ocurrió en PV y TE.</p></span>" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "abst0020" "titulo" => "Objetivos" ] 1 => array:2 [ "identificador" => "abst0025" "titulo" => "Pacientes y métodos" ] 2 => array:2 [ "identificador" => "abst0030" "titulo" => "Resultados" ] ] ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Medina Vega L, Hernández Nieto L, Salido Ruíz E, Álvarez-Argüelles Cabrera H, Raya Sánchez JM. Análisis integrado clínico, molecular e histopatológico de la médula ósea en las neoplasias mieloproliferativas crónicas. Rev Clin Esp. 2019;219:440–444.</p>" ] ] "multimedia" => array:2 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>: ALIP, abnormal localization of immature precursors; BMP, bone marrow biopsy; ECT, essential thrombocythemia; MF, primary myelofibrosis; PV, polycythemia vera.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "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-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Histological variable \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">PV \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">ET \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">MF \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>44 \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>78 \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>18 \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-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Overall cellularity \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="left" 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="left" 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="left" 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-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Erythroid cellularity \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="left" 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="left" 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="left" 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-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">White cellularity \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="left" 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="left" 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="left" 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-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Megakaryocyte/quantity \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="left" 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="left" 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="left" 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-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Megakaryocyte/size \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Small to large \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Small to large \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Small to giant \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Megakaryocyte/nuclei \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Normal \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Normal or hyperlobulated \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Variable \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Megakaryocyte/accumulations \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Loose over dense \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Loose \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dense over loose \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Megakaryocyte/naked nuclei \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Uncommon \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Uncommon \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Common \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Megakaryocyte/intrasinusoidals \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Uncommon \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Very uncommon \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Common \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Megakaryocyte/dystopia \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Uncommon \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Very uncommon \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Common \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Megakaryocyte/emperipolesis \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="left" 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="left" 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="left" 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-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Vasculature/ectasia \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="left" 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="left" 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="left" 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-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Vasculature/quantity \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="left" 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="left" 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="left" 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-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ALIP \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="left" 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="left" 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="left" 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-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lymphoid nodules \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="left" 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="left" 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="left" 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-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Medullary iron \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="left" 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="left" 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="left" 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-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Reticulin fibrosis MF-2 to MF-3 \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Uncommon \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Very common \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Common \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Osteosclerosis \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="left" 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="left" 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="left" 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> """ ] "imagenFichero" => array:1 [ 0 => "xTab2155276.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Characteristic findings in the bone marrow biopsy for each disease.</p>" ] ] 1 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>: ALIP, abnormal localization of immature precursors; BMP, bone marrow biopsy; ECT, essential thrombocythemia; MF, primary myelofibrosis; PV, polycythemia vera.</p>" "tablatextoimagen" => array:2 [ 0 => array:2 [ "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" style="border-bottom: 2px solid black">ET \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">JAK</span><span class="elsevierStyleSup"><span class="elsevierStyleItalic">mut</span></span>(<span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>24) \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">CALR</span><span class="elsevierStyleSup"><span class="elsevierStyleItalic">mut</span></span>(<span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>14) \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span>-value \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-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Age, 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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">57.1 \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">47.1 \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">.047 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Leukocytes (10<span class="elsevierStyleSup">9</span>/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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9.5 \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">6.2 \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">.017 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Neutrophils (10<span class="elsevierStyleSup">9</span>/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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6.20 \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">4.23 \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">.009 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2155277.png" ] ] 1 => array:2 [ "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" style="border-bottom: 2px solid black">MF \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">JAK</span><span class="elsevierStyleSup"><span class="elsevierStyleItalic">mut</span></span>(<span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>6) \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">CALR</span><span class="elsevierStyleSup"><span class="elsevierStyleItalic">mut</span></span>(<span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>5) \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span>-value \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-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Overall cellularity in BMB \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Greatly increased \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Normal \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">.025 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Megakaryocyte nuclei in BMB \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hyperlobulated 80% \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Normal 50%Hypolobulated 50% \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">.019 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2155275.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Main characteristics of patients with essential thrombocythemia and primary myelofibrosis according to the molecular profile.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:12 [ 0 => array:3 [ "identificador" => "bib0065" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "R.L. 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Le Beau" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1182/blood-2016-03-643544" "Revista" => array:6 [ "tituloSerie" => "Blood" "fecha" => "2016" "volumen" => "127" "paginaInicial" => "2391" "paginaFinal" => "2405" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27069254" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0085" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F mutation status: a prospective study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "P.J. Campbell" 1 => "L.M. Scott" 2 => "G. Buck" 3 => "K. Wheatley" 4 => "C.L. East" 5 => "J.T. 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The authors would also like to thank Dr. Eduardo Salido Ruíz for his supervision and focus and Dr. Hugo Álvarez Argüelles for his invaluable collaboration, which has been essential to this study.</p>" "vista" => "all" ] ] ] "idiomaDefecto" => "en" "url" => "/22548874/0000021900000008/v1_201910300730/S2254887419300918/v1_201910300730/en/main.assets" "Apartado" => array:4 [ "identificador" => "1903" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Brief Original" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/22548874/0000021900000008/v1_201910300730/S2254887419300918/v1_201910300730/en/main.pdf?idApp=WRCEE&text.app=https://revclinesp.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2254887419300918?idApp=WRCEE" ]
