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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introducci&#243;n</span><p id="par0005" class="elsevierStylePara elsevierViewall">La leucemia mielobl&#225;stica aguda &#40;LMA&#41; constituye el 20&#37; de todas las leucemias agudas infantiles<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">1</span></a>&#46; Se diagnostican cerca de 60 casos al a&#241;o en nuestro pa&#237;s&#46; Los esquemas de tratamiento actualmente vigentes se basan en la administraci&#243;n de poliquimioterapia&#44; combinando altas dosis de citarabina con antrac&#237;clicos e inhibidores de topoisomerasa<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">2</span></a>&#46; Adem&#225;s&#44; los pacientes con mala respuesta al tratamiento de inducci&#243;n&#59; los considerados al inicio de alto riesgo&#44; bien por tratarse de una LMA secundaria o por sus caracter&#237;sticas citogen&#233;ticas&#44; y los pacientes clasificados de riesgo intermedio con donante familiar id&#233;ntico&#44; son subsidiarios de recibir en primera remisi&#243;n completa un trasplante alog&#233;nico de progenitores hematopoy&#233;ticos &#40;TPH&#41;<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">3&#44;4</span></a>&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">La supervivencia de los pacientes con LMA ha mejorado sustancialmente en los &#250;ltimos 40 a&#241;os&#44; fundamentalmente debido a la mejor&#237;a en el tratamiento de soporte&#46; Sin embargo se ha estancado en el 60&#37; en las &#250;ltimas d&#233;cadas&#46; Conocemos cada vez m&#225;s la heterogeneidad gen&#233;tica de la LMA y su importancia en el pron&#243;stico<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">5&#44;6</span></a>&#46; Existen alteraciones citogen&#233;ticas con pron&#243;stico favorable como las t&#40;8&#59;21&#41;&#40;q22&#59;q22&#41;&#44; inv&#40;16&#41;&#40;p13&#46;1q22&#41; o t&#40;16&#59;16&#41;&#40;p13&#46;1&#59;q22&#41;&#44; t&#40;15&#59;17&#41;&#40;q22&#59;q12&#41;&#44; cuya presencia se traduce en una supervivencia del 80&#37; solo con quimioterapia&#59; mientras que las alteraciones desfavorables como 5<span class="elsevierStyleHsp" style=""></span>q&#44; t&#40;6&#59;9&#41;&#40;p23&#59;q34&#41;&#44; monosom&#237;a 7 y los cariotipos complejos&#44; son refractarios a la quimioterapia e incluso con TPH alcanzan una supervivencia no superior al 40&#37;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">6&#8211;8</span></a>&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Hasta el momento el potencial de estas alteraciones gen&#233;ticas como dianas terap&#233;uticas no ha impactado de manera significativa en la supervivencia<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">9&#44;10</span></a>&#46; Recientemente&#44; y de manera complementaria a los fen&#243;menos gen&#233;ticos y epigen&#233;ticos&#44; se est&#225; desarrollando un enfoque inmunobiol&#243;gico en la LMA<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">11&#44;12</span></a>&#46; Los datos que sustentan este acercamiento inmunol&#243;gico residen en varias observaciones&#58; <span class="elsevierStyleItalic">a&#41;</span> el papel tan importante del TPH<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">3&#44;13</span></a>&#59; <span class="elsevierStyleItalic">b&#41;</span> el &#233;xito de la inmunoterapia adoptiva con linfocitos del donante postrasplante para revertir la enfermedad m&#237;nima residual y&#47;o quimerismo mixto hematopoy&#233;tico<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">14&#44;15</span></a>&#59; y <span class="elsevierStyleItalic">c&#41;</span> la experiencia cl&#237;nica y precl&#237;nica favorable con algunos anticuerpos como gemtuzumab &#40;anti-CD33&#41; y anticuerpos biespec&#237;ficos de linfocitos T &#40;CD33&#47;CD3&#44; AMG 330&#41;<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">16&#44;17</span></a>&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">En este sentido&#44; el grupo de Perugia liderado por el Dr&#46; Velardi ha puesto de relieve el efecto antileucemia del TPH de donante haploid&#233;ntico en pacientes adultos con LMA a trav&#233;s de los linfocitos natural killer &#40;NK&#41; del donante<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">18&#44;19</span></a>&#46; Posteriormente&#44; el grupo de St Jude confirm&#243; estos datos en LMA pedi&#225;trica y ha sido pionero en desarrollar un esquema de terapia celular con NK como tratamiento de consolidaci&#243;n en pacientes con LMA de riesgo bajo e intermedio<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">20</span></a>&#46; Conocemos c&#243;mo la actividad antileucemia de las c&#233;lulas NK est&#225; regulada por el reconocimiento a trav&#233;s de receptores inhibidores y activadores de sus ligandos en las c&#233;lulas bl&#225;sticas<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">21</span></a>&#46; Estos ligandos son las mol&#233;culas human leucocyte antigen class I &#40;HLA-I&#41;&#44; para los receptores inhibidores&#44; y major histocompatibility complex &#40;MHC&#41; class <span class="elsevierStyleSmallCaps">i</span>&#8211;related chain A&#47;B &#40;MICA&#47;B&#41;&#44; y UL16-binding proteins 1-4 &#40;ULBP 1-4&#41;&#44; para los receptores activadores<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">22</span></a>&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">En este trabajo revisamos de manera retrospectiva nuestra experiencia en el manejo de la LMA pedi&#225;trica y describimos en 10 leucemias agudas &#40;5 mieloides y 5 linfoides&#41; la expresi&#243;n de los ligandos de los receptores de las c&#233;lulas NK en las c&#233;lulas bl&#225;sticas&#44; comparando dicha expresi&#243;n en ambos tipos de leucemia aguda&#44; con el objetivo de aportar nuevos datos que persigan incorporar la inmunoterapia adoptiva con c&#233;lulas NK en los protocolos convencionales de quimioterapia&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Pacientes y m&#233;todo</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Pacientes</span><p id="par0030" class="elsevierStylePara elsevierViewall">De manera retrospectiva&#44; se recogen los datos epidemiol&#243;gicos&#44; las caracter&#237;sticas morfol&#243;gicas seg&#250;n la clasificaci&#243;n French-American-British &#40;FAB&#41;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">23</span></a> o la clasificaci&#243;n inmunol&#243;gica propuesta por el grupo europeo &#40;EGIL&#41;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">24</span></a>&#44; las alteraciones citogen&#233;ticas&#44; el tratamiento y la evoluci&#243;n de los pacientes diagnosticados de LMA en el per&#237;odo comprendido entre 1996 y 2014&#44; en la unidad de Hemato-Oncolog&#237;a Infantil del Hospital Universitario La Paz de Madrid&#44; Espa&#241;a &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">tabla 1</a>&#41;&#46; Los pacientes fueron tratados consecutivamente seg&#250;n las sucesivas versiones del protocolo de la Sociedad Espa&#241;ola de Hemato-Oncolog&#237;a Pedi&#225;trica &#40;SHOP-96&#44; SHOP-2001&#44; SHOP-2007&#41;&#46; Quedaron excluidos del an&#225;lisis los pacientes con LMA y con s&#237;ndrome de Down&#46; Para los estudios biol&#243;gicos&#44; se obtuvo consentimiento informado de todos los responsables de los pacientes y se obtuvo aprobaci&#243;n para este estudio por parte del Comit&#233; de &#201;tica del Hospital La Paz&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Anticuerpos y citometr&#237;a de flujo</span><p id="par0035" class="elsevierStylePara elsevierViewall">En 10 muestras de aspirado de m&#233;dula &#243;sea obtenidas en el momento del diagn&#243;stico y correspondientes a 5 pacientes con LMA y 5 pacientes con leucemia linfobl&#225;stica aguda y mediante citometr&#237;a de flujo multiparam&#233;trica&#44; utilizando el cit&#243;metro Becton Dickinson FACS CANTO II&#44; se determin&#243; la intensidad media de fluorescencia &#40;IMF&#41; de HLA-I&#44; constituyen los ligandos de los receptores inhibidores KIR de las c&#233;lulas NK&#44; ligando para los receptores inhibidores de las c&#233;lulas NK&#44; y MICA-B&#44; ULBP-1&#44; ULBP-2&#44; ULBP-3 y ULBP-4&#44; ligandos del receptor activador NKG2D de las c&#233;lulas NK&#44; en las c&#233;lulas leuc&#233;micas seleccionadas previamente mediante tama&#241;o y complejidad&#46; Se utilizaron los siguientes anticuerpos&#58; HLA-I-PE &#40;clon G46-2&#46;6&#41; de Beckton Dickinson&#59; y MICA-PE &#40;clon 159227&#41;&#44; MICB-PE &#40;clon 236511&#41;&#44; ULBP-1-PE &#40;clon 170818&#41;&#44; ULBP-2&#47;5&#47;6-APC &#40;clon 165903&#41;&#44; ULBP3-PE &#40;clon 166510&#41;&#44; ULBP4-PE &#40;clon 709116&#41; de R&#38;D Sytems&#46; El nivel de expresi&#243;n se defini&#243; como la ratio de la intensidad media de fluorescencia de los valores obtenidos con los anticuerpos espec&#237;ficos divididos por los valores obtenidos mediante la autofluorescencia de las c&#233;lulas&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">An&#225;lisis estad&#237;stico</span><p id="par0040" class="elsevierStylePara elsevierViewall">Los datos se expresaron en media &#177; desviaci&#243;n est&#225;ndar&#44; salvo que se indicara otra unidad de medida&#46; Los c&#225;lculos estad&#237;sticos fueron realizados utilizando el paquete estad&#237;stico SPSS 12&#46;0 para Windows &#40;Statistical Package for the Social Sciences&#41;&#46; La supervivencia libre de eventos &#40;SLE&#41;&#44; definidos como reca&#237;da o muerte&#44; es la principal variable del estudio y se calcul&#243; con el m&#233;todo de Kaplan-Meier&#44; y la prueba log rank test&#44; con el intervalo de confianza del 95&#37;&#46; Tambi&#233;n se calcul&#243; la probabilidad de reca&#237;da y de muerte no relacionada con la enfermedad &#40;muerte t&#243;xica&#41; por este mismo m&#233;todo&#46; Se utiliz&#243; el test no param&#233;trico U de Mann-Whitney para buscar diferencias estad&#237;sticas entre las variables no param&#233;tricas&#46; Se consider&#243; una diferencia estad&#237;sticamente significativa cuando la p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;05&#46;</p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Resultados</span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Caracter&#237;sticas de los pacientes</span><p id="par0045" class="elsevierStylePara elsevierViewall">Entre 1996 y 2014&#44; un total de 67 pacientes &#40;33 ni&#241;os y 34 ni&#241;as&#41; con una media de edad de 7&#44;2 a&#241;os &#40;rango 0-18&#41; fueron diagnosticados de LMA y recibieron tratamiento en nuestra unidad seg&#250;n los protocolos SHOP-96 &#40;30&#37;&#41;&#44; SHOP-2001 &#40;25&#37;&#41;&#44; o SHOP-2007 &#40;45&#37;&#41;&#46; Las caracter&#237;sticas epidemiol&#243;gicas de los pacientes con LMA incluidas en las diferentes versiones del protocolo SHOP fueron homog&#233;neas&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">En 60 pacientes &#40;88&#37;&#41; el diagn&#243;stico fue LMA de novo&#44; mientras que 7 pacientes &#40;12&#37;&#41; presentaron LMA secundaria o relacionada con s&#237;ndromes mielodispl&#225;sicos&#46; La clasificaci&#243;n morfol&#243;gica y las alteraciones citogen&#233;ticas se muestran en la <a class="elsevierStyleCrossRef" href="#tbl0005">tabla 1</a>&#46; Un 66&#37; de los pacientes presentaba alteraciones citogen&#233;ticas&#44; mientras que un 34&#37; presentaba una citogen&#233;tica normal&#46; Hasta un tercio de los pacientes &#40;29&#37;&#41; presentaba alteraciones citogen&#233;ticas consideradas de buen pron&#243;stico como son t&#40;8&#59;21&#41;&#44; inv<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">16</span></a> y la t&#40;15&#59;17&#41;&#44; un 20&#37; presentaba alteraciones citogen&#233;ticas sin factor pron&#243;stico conocido y un 16&#44;5&#37; de los pacientes presentaba alteraciones citogen&#233;ticas desfavorables&#44; reordenamiento del gen MLL y monosom&#237;a del 7&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Un total de 25 pacientes &#40;44&#37;&#41; se trat&#243; solo con quimioterapia&#46; Un total de 20 pacientes &#40;30&#37;&#41; recibieron un TPH aut&#243;logo &#40;el &#250;ltimo el 30 de abril del 2012&#41; y un total de 22 pacientes &#40;33&#37;&#41; recibieron un TPH alog&#233;nico &#40;7 de un donante familiar HLA id&#233;ntico&#44; 7 de un donante no familiar HLA id&#233;ntico&#44; 4 de sangre de cord&#243;n umbilical y 4 de un donante haploid&#233;ntico&#41;&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">En el momento de redactar este documento&#44; 24 pacientes hab&#237;an fallecido&#44; 13 de ellos por enfermedad y 11 por complicaciones relacionadas con el tratamiento &#40;infecciosas en 9 pacientes y hemorr&#225;gicas en 2 pacientes&#41;&#46; Con una mediana de seguimiento de 26 meses&#44; la SLE de los pacientes con LMA de nuestra serie fue del 61&#37; &#40;IC del 95&#37;&#44; 55-67&#37;&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">fig&#46; 1</a> a&#41; y la supervivencia global del 62&#37; &#40;IC del 95&#37;&#44; 56-68&#37;&#41;&#46; La probabilidad de reca&#237;da fue del 38&#37; &#40;IC del 95&#37;&#44;31-45&#37;&#41; y la probabilidad de muerte no relacionada con la LMA fue del 19&#37; &#40;IC del 95&#37;&#44; 14-23&#37;&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0010">fig&#46; 2</a> a y b&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">An&#225;lisis univariante de la supervivencia libre de eventos</span><p id="par0065" class="elsevierStylePara elsevierViewall">En el an&#225;lisis univariante para la SLE no encontramos diferencias entre el sexo&#44; edad o versi&#243;n de protocolo SHOP &#40;<a class="elsevierStyleCrossRef" href="#fig0005">fig&#46; 1</a> b&#41;&#46; Se observan diferencias significativas en la SLE entre LMA de novo vs&#46; secundarias &#40;68&#37;&#44; IC del 95&#37; 61-75 vs&#46; 35&#37;&#44; IC del 95&#37; 16-54&#41;&#44; LMA M3 vs&#46; distinta de M3 &#40;80&#37;&#44; IC del 95&#37; 68-92 vs&#46; 57&#37;&#44; IC del 95&#37; 50-64&#41; y presencia vs&#46; ausencia de alteraciones citogen&#233;ticas favorables &#40;77&#37;&#44; IC del 95&#37; 68-86 vs&#46; 53&#37;&#44; IC del 95&#37; 45-61&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">fig&#46; 1</a> c-e&#41;&#46; La probabilidad de reca&#237;da en los grupos con citogen&#233;tica favorable no es significativamente inferior &#40;29 vs&#46; 42&#37;&#44; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;07&#41;&#46; No se observan diferencias significativas entre la probabilidad de reca&#237;da o muerte t&#243;xica entre las diferentes versiones de protocolo de tratamiento SHOP &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">tabla 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">El papel del trasplante alog&#233;nico de progenitores hematopoy&#233;ticos en la leucemia mielobl&#225;stica aguda</span><p id="par0070" class="elsevierStylePara elsevierViewall">El n&#250;mero de TPH alog&#233;nicos ha aumentado significativamente en el protocolo SHOP-2007 con respecto a los previos &#40;SHOP-2007 53&#37; vs&#46; SHOP-2001 25&#37;&#44; y SHOP-1996 26&#37;&#41;&#46; Por el contrario&#44; el n&#250;mero de TPH aut&#243;logos han disminuido en el protocolo actual &#40;SHOP-2007 15&#37; vs&#46; SHOP-2001 58&#37; y SHOP-1996 46&#37;&#41;&#46; En cuanto al impacto del TPH en la SLE&#44; se observa una tendencia favorable pero no estad&#237;sticamente significativa &#40;76&#37;&#44; IC del 95&#37; 64-88&#37; vs&#46; 56&#37;&#44; IC del 95&#37; 48-64&#37;&#59; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;08&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">fig&#46; 1</a> f&#41;&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Expresi&#243;n de HLA-I y ligandos de NKG2D en blastos leuc&#233;micos en pacientes pedi&#225;tricos</span><p id="par0075" class="elsevierStylePara elsevierViewall">Mediante citometr&#237;a de flujo multiparam&#233;trica se determin&#243; la expresi&#243;n de los ligandos HLA-I y MICA&#47;B y ULBP-1&#44; ULPB-2&#44; ULPB-3 y ULBP-4 en 10 muestras de blastos leuc&#233;micos analizados seg&#250;n el tama&#241;o y la complejidad &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">tabla 3</a>&#41;&#46; Observamos c&#243;mo en los blastos mieloides la intensidad media de fluorescencia es significativamente menor en HLA- I &#40;11<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3 vs&#46; 60<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>10&#44; p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;05&#41; y en ULBP-4 &#40;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2 vs&#46; 20<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7&#44; p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;05&#41; que en los blastos linfoides&#46; Las diferencias en MICA&#47;B&#44; ULBP-1&#44; ULBP-2 y ULBP-3 no fueron significativas &#40;<a class="elsevierStyleCrossRefs" href="#fig0015">figs&#46; 3 y 4</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Discusi&#243;n</span><p id="par0080" class="elsevierStylePara elsevierViewall">Los resultados de nuestra serie retrospectiva son similares a la experiencia descrita en pacientes pedi&#225;tricos con LMA tanto a nivel nacional como internacional&#46; El registro espa&#241;ol de tumores infantiles &#40;RETI&#41; comunica en su &#250;ltimo informe que comprende el per&#237;odo 1980-2013&#44; una supervivencia global a 5 a&#241;os del 54&#37; en los a&#241;os 1995-1999&#44; el 59&#37; en 2000-2004 y el 62&#37; durante 2005-2007&#46; El grupo europeo NOPHO describe recientemente en su protocolo NOPHO-AML2004&#44; una SLE a 5 a&#241;os del 55&#37;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">25</span></a>&#59; el grupo del hospital de St Jude de Memphis&#44; EE&#46; UU&#46;&#44; en su protocolo AML-02 incluye 230 pacientes durante el per&#237;odo 2000-2008 y describe una SLE a 5 a&#241;os del 63&#37;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">26</span></a>&#46; Seg&#250;n nuestros datos la supervivencia libre de enfermedad en la LMA infantil no se ha modificado sustancialmente en las 3 &#250;ltimas versiones del protocolo SHOP y se mantiene estancada desde hace m&#225;s de 2 d&#233;cadas&#44; a&#250;n en valores sub&#243;ptimos&#46; Adem&#225;s&#44; en consonancia con lo conocido&#44; las LMA secundarias &#40;relacionadas con el tratamiento o s&#237;ndromes mielodispl&#225;sicos&#41; presentan una supervivencia muy inferior a las LMA de novo<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">27</span></a>&#46; Por otro lado&#44; la heterogeneidad de la LMA se ejemplifica en el caso de la LMA promieloc&#237;tica &#40;FAB M3&#41; que presenta una SLE muy superior al resto de las LMA &#40;80&#37; vs&#46; 57&#37;&#44; p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;05&#41;&#44; poniendo de manifiesto el impacto favorable del &#225;cido transretinoico sobre la supervivencia&#44; y la necesidad de hallar una diana molecular para el resto de las LMA<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">28</span></a>&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">En nuestra serie tambi&#233;n resultan determinantes las alteraciones citogen&#233;ticas en el pron&#243;stico&#46; As&#237;&#44; la presencia en un tercio de nuestros pacientes de alteraciones consideradas favorables como t&#40;8&#59;21&#41;&#44; inv<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">16</span></a>&#44; t&#40;15&#59;17&#41; se tradujo en mayor supervivencia&#44; posiblemente debido a una menor probabilidad de reca&#237;da&#44; pese a no alcanzar significaci&#243;n estad&#237;stica debido al peque&#241;o tama&#241;o muestral&#46; El TPH alog&#233;nico ha ido aumentando como estrategia terap&#233;utica en los &#250;ltimos protocolos y disminuyendo el TPH aut&#243;geno&#46; Las mejoras en los estudios citogen&#233;ticos&#44; identificando alteraciones de alto riesgo pudieron influir en este hallazgo&#46; El TPH alog&#233;nico muestra una tendencia favorable sobre la SLE&#44; tal y como describen otras series<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">3&#44;29</span></a>&#46; Un mayor tama&#241;o muestral nos podr&#237;a haber permitido detectar diferencias significativas en nuestros pacientes&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Las causas de muerte en los pacientes de nuestra serie fueron la reca&#237;da y las relacionadas con el tratamiento&#58; infecciones y hemorragias&#46; En los sucesivos protocolos&#44; la mortalidad de causa t&#243;xica tiende a disminuir&#44; mientras que la reca&#237;da sigue siendo un evento importante que no se ha modificado<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">30</span></a>&#46; El reducido tama&#241;o muestral de nuestro estudio no nos permite identificar factores pron&#243;sticos para la probabilidad de reca&#237;da&#46; Consideramos que un 38&#37; de reca&#237;das es todav&#237;a una cifra muy elevada&#46; Incluso en el grupo de pacientes con citogen&#233;tica favorable la probabilidad de reca&#237;da se aproxima al 30&#37;&#46; Por ello consideramos que todos los pacientes son subsidiarios de nuevos procedimientos terap&#233;uticos&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">En adici&#243;n a este estudio retrospectivo&#44; nuestro trabajo aporta los resultados preliminares sobre la expresi&#243;n de los ligandos de los receptores inhibidores y activadores en los blastos leuc&#233;micos mieloides y linfoides con la intenci&#243;n de explicar la mayor susceptibilidad de la LMA a la citotoxicidad de los linfocitos NK descrita por otros grupos internacionales<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">31</span></a>&#46; En consonancia con esta evidencia&#44; la intensidad media de fluorescencia de HLA-I&#44; ligando de los receptores inhibidores KIR&#44; es significativamente menor en los blastos mieloides que en los linfoides&#44; lo que sugiere una mayor sensibilidad a la citotoxicidad NK a trav&#233;s de sus receptores inhibidores&#46; Con respecto a la expresi&#243;n de los ligandos MICA&#47;B y ULBP&#44; solo encontramos diferencias significativas en la expresi&#243;n de ULBP-4&#44; lo que podr&#237;a poner de manifiesto la menor importancia de la v&#237;a activadora con respecto a la inhibidora&#44; tal y c&#243;mo reflejan otros autores<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">32</span></a>&#46; En esta misma l&#237;nea se ha descrito c&#243;mo la disminuci&#243;n de la expresi&#243;n de los ligandos para los receptores activadores en los pacientes con LMA supone un mecanismo de escape al control del sistema inmunitario<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">33</span></a>&#46; Recientemente&#44; se est&#225; explorando la terapia celular con linfocitos NK haploid&#233;nticos como tratamiento de consolidaci&#243;n en pacientes pedi&#225;tricos con LMA de riesgo bajo e intermedio que no tienen indicaci&#243;n de TPH<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">20&#44;34</span></a>&#46; Los resultados son muy prometedores&#44; con un 0&#37; de toxicidad y un 100&#37; de supervivencia libre de reca&#237;da tras una mediana de seguimiento superior a 3 a&#241;os<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">34</span></a>&#46; La biotecnolog&#237;a nos permite actualmente aislar c&#233;lulas NK a partir de af&#233;resis de donantes sanos&#46; Adem&#225;s&#44; actualmente en nuestro pa&#237;s se est&#225;n investigando 2 nuevos productos celulares&#44; las c&#233;lulas NK estimuladas con IL-15 a partir de af&#233;resis de donante haploid&#233;ntico &#40;NK-IL-15&#41; y las c&#233;lulas NK activadas y expandidas &#40;NKAE&#41; a partir de sangre perif&#233;rica del paciente &#40;NKAE aut&#243;logas&#41; o de donante haploid&#233;ntico &#40;NKAE haploid&#233;nticas&#41;&#46; Hasta el momento no se han comunicado toxicidades importantes &#40;&#62; 2 seg&#250;n NCI 3&#46;0&#41; en pacientes con enfermedad avanzada<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">35</span></a>&#44; por lo que ser&#237;a factible incorporar esta estrategia de terapia celular en un estudio prospectivo multic&#233;ntrico nacional&#44; especialmente para los pacientes en remisi&#243;n que no son candidatos a un TPH alog&#233;nico&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Como conclusi&#243;n&#44; actualmente la SLE en la LMA contin&#250;a estando en valores sub&#243;ptimos y la reca&#237;da constituye un problema importante&#46; Es necesario investigar en procedimientos diagn&#243;sticos&#44; terap&#233;uticos y de seguimiento que mejoren la supervivencia actual&#46; En este sentido&#44; la terapia celular con c&#233;lulas NK podr&#237;a constituir un procedimiento a desarrollar dado el componente inmunol&#243;gico tan importante de la LMA&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Conflicto de intereses</span><p id="par0105" class="elsevierStylePara elsevierViewall">Los autores declaran no tener ning&#250;n conflicto de intereses&#46;</p></span></span>"
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              "titulo" => "An&#225;lisis univariante de la supervivencia libre de eventos"
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              "titulo" => "El papel del trasplante alog&#233;nico de progenitores hematopoy&#233;ticos en la leucemia mielobl&#225;stica aguda"
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              "titulo" => "Expresi&#243;n de HLA-I y ligandos de NKG2D en blastos leuc&#233;micos en pacientes pedi&#225;tricos"
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    "fechaRecibido" => "2015-04-21"
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            0 => "Leucemia mielobl&#225;stica aguda"
            1 => "C&#233;lulas <span class="elsevierStyleItalic">natural killer</span>"
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            3 => "Major histocompatibility complex &#40;MHC&#41; class-I related chain A&#47;B &#40;MICA&#47;B&#41;"
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            0 => "Acute myeloid leukaemia"
            1 => "Natural killer cells"
            2 => "Human leucocyte antigen class I &#40;HLA-I&#41;"
            3 => "Major histocompatibility complex &#40;MHC&#41; class-I related chain A&#47;B &#40;MICA&#47;B&#41;"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introducci&#243;n</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">La leucemia mielobl&#225;stica aguda &#40;LMA&#41; constituye la segunda hemopat&#237;a maligna en la poblaci&#243;n pedi&#225;trica y una de las principales causas de mortalidad por c&#225;ncer infantil&#46; La supervivencia se sit&#250;a alrededor del 60&#37; sin haber mejorado en las &#250;ltimas d&#233;cadas&#44; por lo que son necesarios nuevos enfoques terap&#233;uticos&#46; El efecto antileuc&#233;mico ejercido por los linfocitos y las c&#233;lulas natural killer &#40;NK&#41; del sistema inmunol&#243;gico est&#225; bien establecido en el trasplante de c&#233;lulas madre hematopoy&#233;ticas pero tambi&#233;n como estrategia de inmunoterapia adoptiva tras la quimioterapia de consolidaci&#243;n&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Pacientes y m&#233;todos</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">De manera retrospectiva&#44; se analizan las caracter&#237;sticas cl&#237;nicas de los pacientes diagnosticados de LMA en nuestro centro durante el per&#237;odo 1996-2014&#46; Adem&#225;s en 10 leucemias agudas&#44; 5 linfoides y 5 mieloides&#44; se analizaron la intensidad media de fluorescencia de HLA-I&#44; MICA-B&#44; ULBP1-4&#44; ligandos para los receptores de las c&#233;lulas NK&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Resultados</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Un total de 67 pacientes formaron parte de este an&#225;lisis&#46; La supervivencia libre de eventos con una mediana de seguimiento de 25 meses fue del 62&#37; &#40;IC del 95&#37;&#44; 55-67&#41;&#46; Las LMA con menor supervivencia fueron las secundarias&#44; las no M3 y las carentes de marcadores citogen&#233;ticos favorables&#46; La probabilidad de reca&#237;da fue del 38&#37; &#40;IC del 95&#37;&#44; 31-45&#41;&#46; La expresi&#243;n de HLA-I y ULBP-4 fue significativamente menor en los blastos mieloides que en los linfoides&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusiones</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Nuestros resultados cl&#237;nicos son similares a los descritos en la literatura&#46; No se ha modificado significativamente la supervivencia en las &#250;ltimas d&#233;cadas y la probabilidad de reca&#237;da sigue siendo elevada&#46; Los blastos mieloides podr&#237;an ser m&#225;s susceptibles a las c&#233;lulas NK al expresar menos HLA-I&#44; por lo que estrategias de terapia celular podr&#237;an ser eficaces tal y como reportan otros grupos&#46;</p></span>"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introduction</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Acute myeloid leukaemia &#40;AML&#41; is the second haematological malignancy in the paediatric population&#44; and one of the leading causes of childhood cancer mortality&#46; Survival is currently around 60&#37;&#44; with no improvement in last decades&#44; suggesting that new therapeutic approaches are needed&#46; The anti-leukaemia effect mediated by the lymphocytes and natural killer &#40;NK&#41; cells of the immune system has been established in haematopoietic stem cell transplantation&#44; and also as adoptive immunotherapy after consolidation chemotherapy schemes&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Patients and methods</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">A retrospective study was conducted on the clinical characteristics of patients diagnosed and treated for AML in our centre during 1996-2014&#46; The mean fluorescence intensities of HLA-I&#44; MICA&#47;B and ULBP1-4&#44; ligands for NK cell receptors&#44; were also analysed in ten new diagnosed leukaemia cases&#44; five myeloid and five lymphoid&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Results</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">A total of 67 patients were used in this analysis&#46; With a median follow up of 25 months&#44; the event-free survival was 62&#37; &#40;95&#37; CI&#58; 55-67&#41;&#46; Secondary AML&#44; non-M3 phenotype&#44; and the absence of favourable cytogenetic markers had a lower survival&#46; The probability of relapse was 38&#37; &#40;95&#37; CI&#58; 31-45&#41;&#46; The expression of HLA-I and ULBP-4 was significantly lower in myeloid than in lymphoid blast cells&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusions</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Our clinical results are similar to those described in the literature&#46; Survival did not significantly change in recent decades&#44; and the likelihood of relapse remains high&#46; Myeloid blasts might be more susceptible to the cytotoxicity of NK cells through their lower expression of HLA-I&#46; NK therapy strategies in minimal disease situation could be effective&#44; as reported by other groups&#46;</p></span>"
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="bottom">&#62; 10 a&#241;os&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="bottom">27 &#40;41&#44;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="bottom">Sin datos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="bottom">2 pacientes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="bottom"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="bottom"><span class="elsevierStyleItalic">Sexo &#40;&#37;&#41;</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="bottom"><span class="elsevierStyleHsp" style=""></span>Var&#243;n&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="bottom">33 &#40;49&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="bottom"><span class="elsevierStyleHsp" style=""></span>Mujer&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="bottom">34 &#40;51&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="bottom"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="bottom"><span class="elsevierStyleItalic">LMA &#40;&#37;&#41;</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="bottom"><span class="elsevierStyleHsp" style=""></span>De novo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="bottom">60 &#40;88&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="bottom"><span class="elsevierStyleHsp" style=""></span>Secundaria&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="bottom">7 &#40;12&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="bottom"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="bottom"><span class="elsevierStyleItalic">Clasificaci&#243;n morfol&#243;gica &#40;&#37;&#41;</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="bottom"><span class="elsevierStyleHsp" style=""></span>M0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="bottom">3 &#40;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="bottom"><span class="elsevierStyleHsp" style=""></span>M1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="bottom">6 &#40;10&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="bottom"><span class="elsevierStyleHsp" style=""></span>M2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="bottom">10 &#40;17&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="bottom"><span class="elsevierStyleHsp" style=""></span>M3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="bottom">10 &#40;17&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="bottom"><span class="elsevierStyleHsp" style=""></span>M4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="bottom">9 &#40;15&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="bottom"><span class="elsevierStyleHsp" style=""></span>M5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="bottom">5 &#40;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="bottom"><span class="elsevierStyleHsp" style=""></span>M6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="bottom">1 &#40;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="bottom"><span class="elsevierStyleHsp" style=""></span>M7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="bottom">12 &#40;20&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="bottom"><span class="elsevierStyleHsp" style=""></span>EGIL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="bottom">4 &#40;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="bottom"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="char" valign="bottom"><span class="elsevierStyleItalic">Anormalidades gen&#233;ticas &#40;&#37;&#41;</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="bottom"><span class="elsevierStyleHsp" style=""></span>Normal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="bottom">23 &#40;34&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="bottom"><span class="elsevierStyleHsp" style=""></span>t&#40;8&#59;21&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="bottom">6 &#40;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="bottom"><span class="elsevierStyleHsp" style=""></span>inv 16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="bottom">5 &#40;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="bottom"><span class="elsevierStyleHsp" style=""></span>t&#40;15&#59;17&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="bottom">8 &#40;12&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="bottom"><span class="elsevierStyleHsp" style=""></span>MLL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="bottom">10 &#40;15&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="bottom"><span class="elsevierStyleHsp" style=""></span>Monosom&#237;a 7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="bottom">1 &#40;1&#44;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="bottom"><span class="elsevierStyleHsp" style=""></span>Otras&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="bottom">14 &#40;20&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="bottom"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="char" valign="bottom"><span class="elsevierStyleItalic">Fecha diagn&#243;stico &#40;&#37;&#41;</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="bottom"><span class="elsevierStyleHsp" style=""></span>1996-2001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="bottom">25 &#40;38&#44;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="bottom"><span class="elsevierStyleHsp" style=""></span>2002-2008&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="bottom">17 &#40;26&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="bottom"><span class="elsevierStyleHsp" style=""></span>2009-2014&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="bottom">23 &#40;35&#44;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="bottom"><span class="elsevierStyleHsp" style=""></span>Sin datos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="bottom">2 pacientes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="bottom"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="char" valign="bottom"><span class="elsevierStyleItalic">Protocolo SHOP &#40;&#37;&#41;</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="bottom"><span class="elsevierStyleHsp" style=""></span>1996&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="bottom">18 &#40;30&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="bottom"><span class="elsevierStyleHsp" style=""></span>2001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="bottom">15 &#40;25&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="bottom"><span class="elsevierStyleHsp" style=""></span>2007&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="bottom">27 &#40;45&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="bottom"><span class="elsevierStyleHsp" style=""></span>Sin datos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="bottom">7 pacientes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="bottom"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="char" valign="bottom"><span class="elsevierStyleItalic">TPH &#40;&#37;&#41;</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="bottom"><span class="elsevierStyleHsp" style=""></span>Aut&#243;geno&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="bottom">20 &#40;30&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="bottom"><span class="elsevierStyleHsp" style=""></span>Alog&#233;nico&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="bottom">22 &#40;33&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="bottom"><span class="elsevierStyleHsp" style=""></span>No TPH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="bottom">25 &#40;44&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="bottom"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="char" valign="bottom"><span class="elsevierStyleItalic">Reca&#237;das &#40;&#37;&#41;</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="bottom"><span class="elsevierStyleHsp" style=""></span>S&#237;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="bottom">18 &#40;30&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="bottom"><span class="elsevierStyleHsp" style=""></span>No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="bottom">43 &#40;70&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="bottom"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="char" valign="bottom"><span class="elsevierStyleItalic">Muertes &#40;&#37;&#41;</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="bottom"><span class="elsevierStyleHsp" style=""></span>S&#237;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="bottom">24 &#40;35&#44;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="bottom"><span class="elsevierStyleHsp" style=""></span>No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="bottom">43 &#40;64&#44;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="bottom"><span class="elsevierStyleHsp" style=""></span>SLE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="bottom">61 &#177; 6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="bottom"><span class="elsevierStyleHsp" style=""></span>SG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="bottom">62 &#177; 6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab1023010.png"
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        "descripcion" => array:1 [
          "es" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Caracter&#237;sticas de los pacientes pedi&#225;tricos diagnosticados de LMA durante el per&#237;odo 1996-2014 en nuestra unidad</p>"
        ]
      ]
      5 => array:7 [
        "identificador" => "tbl0010"
        "etiqueta" => "Tabla 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">ns&#58; no significativa&#46;</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" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">SHOP 1996&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">SHOP 2001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">SHOP 2007&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">p&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Reca&#237;da&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">22&#37; &#40;IC del 95&#37;&#44; 11-33&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">32&#37; &#40;IC del 95&#37;&#44; 19-45&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">45&#37; &#40;IC del 95&#37;&#44; 33-57&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#44;6 &#40;ns&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Muerte t&#243;xica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">33&#37; &#40;IC del 95&#37;&#44; 23-43&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">14&#37; &#40;IC del 95&#37;&#44; 6-22&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">8&#37; &#40;IC del 95&#37;&#44; 6-14&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#44;2 &#40;ns&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab1023012.png"
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        ]
        "descripcion" => array:1 [
          "es" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Probabilidad de reca&#237;a y muerte t&#243;xica en las diferentes versiones del protocolo SHOP en nuestra serie</p>"
        ]
      ]
      6 => array:7 [
        "identificador" => "tbl0015"
        "etiqueta" => "Tabla 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">Se muestran la media &#177; desviaci&#243;n est&#225;ndar&#46; En cursiva y negrita se expresan las diferencias estad&#237;sticamente significativas&#46;</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" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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          "es" => "<p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">Ratio de la intensidad media de fluorescencia &#40;IMF&#41; de los blastos mieloides y linfoides&#46; El experimento es el resultado del an&#225;lisis de 10 leucemias agudas&#44; 5 mielobl&#225;sticas y 5 linfobl&#225;sticas</p>"
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                      "doi" => "10.1586/era.12.1"
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