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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">Actualmente el factor predictivo m&#225;s importante de la supervivencia de los pacientes con melanoma es la presencia de met&#225;stasis en el ganglio centinela &#40;GC&#41;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>&#46; Aunque no se ha demostrado que la resecci&#243;n ganglionar precoz de los ganglios afectados mejore la supervivencia global<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a>&#44; se acepta que el conocimiento del grado de afectaci&#243;n regional proporciona un pron&#243;stico m&#225;s preciso y&#44; por ello&#44; puede ayudar a establecer una actuaci&#243;n terap&#233;utica adecuada<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a>&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">El &#237;ndice de Breslow y la presencia de ulceraci&#243;n son los factores que sistem&#225;ticamente se han relacionado con una mayor probabilidad de afectaci&#243;n del GC<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#8211;7</span></a>&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">En los &#250;ltimos a&#241;os el &#237;ndice mit&#243;tico &#40;IM&#41; ha adquirido un protagonismo creciente&#44; tanto como factor pron&#243;stico como factor predictivo de la afectaci&#243;n metast&#225;sica del GC&#44; especialmente tras establecerse el m&#233;todo mejor para su evaluaci&#243;n<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#8211;11</span></a>&#46; A pesar de ello&#44; en la &#250;ltima versi&#243;n de la estadificaci&#243;n de la <span class="elsevierStyleItalic">American Joint Committee on Cancer</span> &#40;AJCC&#41; su papel pron&#243;stico actual queda formalmente establecido exclusivamente en el caso de los melanomas finos<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">En medicina&#44; en la toma de decisiones es importante buscar metodolog&#237;as que sean precisas y nos ayuden a resolver los problemas que surgen a la hora de clasificar&#44; estratificar o pronosticar a nuestros pacientes<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a>&#46; Una de estas herramientas&#44; cada vez m&#225;s utilizadas&#44; son los &#225;rboles de decisi&#243;n&#44; m&#225;s concretamente los &#225;rboles de clasificaci&#243;n y regresi&#243;n &#40;tambi&#233;n conocidos como CART&#44; del ingl&#233;s <span class="elsevierStyleItalic">Classification And Regression Trees</span>&#41;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a>&#46; Este modelo tiene como ventajas respecto a la regresi&#243;n log&#237;stica la simplicidad en su utilizaci&#243;n e interpretaci&#243;n&#44; y adem&#225;s el hecho de que tiene un car&#225;cter no param&#233;trico que no requiere ninguna hip&#243;tesis relativa a la distribuci&#243;n de los predictores y la respuesta ni a la respuesta entre estos y sus posibles interacciones&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">El objetivo principal de este estudio ha sido identificar los factores predictivos de la afectaci&#243;n metast&#225;sica del GC usando la metodolog&#237;a CART y la regresi&#243;n log&#237;stica&#46; Como objetivos secundarios se ha evaluado el papel de estos factores en la recurrencia y la supervivencia global de estos pacientes&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Material y m&#233;todo</span><p id="par0030" class="elsevierStylePara elsevierViewall">Se dise&#241;&#243; un estudio observacional retrospectivo&#46;</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Poblaci&#243;n de estudio</span><p id="par0035" class="elsevierStylePara elsevierViewall">Los participantes en el estudio fueron seleccionados de las bases de datos de pacientes con melanoma del Hospital Virgen de la Victoria &#40;HVV&#41; de M&#225;laga&#44; Espa&#241;a&#44; y del Instituto Valenciano de Oncolog&#237;a de Valencia &#40;IVO&#41;&#44; Espa&#241;a&#46; El uso de ambas bases de datos se realiza de acuerdo con la regulaci&#243;n &#233;tica vigente&#46; Las bases de datos han sido descritas previamente en detalle en otros trabajos<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14&#8211;16</span></a>&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Con motivo del estudio se seleccionaron todos los pacientes con un solo melanoma cut&#225;neo y un estadio cl&#237;nico <span class="elsevierStyleSmallCaps">i</span> o <span class="elsevierStyleSmallCaps">ii</span> a los que se les hab&#237;a realizado la biopsia selectiva del GC&#44; y que hab&#237;an sido incluidos de forma prospectiva en las bases de datos anteriormente mencionadas entre el 1 de enero de 2000 y el 31 de diciembre de 2012 para el IVO y entre el 1 de octubre de 2001 y el 31 de diciembre de 2012 para el HVV&#46; Los pacientes a los que se les realiz&#243; la t&#233;cnica&#44; pero en los que no se pudo identificar el GC&#44; fueron excluidos del estudio&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">El estudio fue aprobado por el comit&#233; &#233;tico de ambas instituciones&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">La variable dependiente del estudio fue el estado del GC&#44; que fue definido como positivo o negativo cuando hab&#237;a presencia o ausencia de c&#233;lulas de melanoma en el GC&#44; respectivamente&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Estado del ganglio centinela</span><p id="par0055" class="elsevierStylePara elsevierViewall">El estudio histol&#243;gico del GC es bastante similar en ambos centros y se describe de la siguiente forma&#58;</p><p id="par0060" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">HVV</span>&#46; El estudio comienza con la identificaci&#243;n macrosc&#243;pica del GC y&#44; si es necesario&#44; la limpieza de la grasa periganglionar&#46; Una vezidentificada la adenopat&#237;a se sumerge en formaldeh&#237;do al 10&#37; para la fijaci&#243;n y posterior inclusi&#243;n en un bloque de parafina&#46; Se realizan tandas cada 250<span class="elsevierStyleHsp" style=""></span>m&#956; de 3 secciones en serie&#44; la primera y la &#250;ltima secci&#243;n para la tinci&#243;n con hematoxilina-eosina y la segunda para la tinci&#243;n inmunohistoqu&#237;mica con HMB-45 hasta agotar el bloque&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">IVO</span>&#46; Primeramente se lleva a cabo una identificaci&#243;n macrosc&#243;pica del GC y&#44; si es necesario&#44; la limpieza de la grasa periganglionar&#46; Una vez identificada&#44; la muestra adenop&#225;tica se coloca en 10&#37; de formaldeh&#237;do para la fijaci&#243;n y posterior incrustaci&#243;n en un bloque de parafina&#46; Se obtienen secciones transversales en serie cada 250<span class="elsevierStyleHsp" style=""></span>m&#956; a partir de todo el ganglio linf&#225;tico incluido en parafina&#46; Tres secciones transversales se obtienen en cada secci&#243;n&#44; una de las cuales se ti&#241;e con hematoxilina-eosina&#44; y las otras est&#225;n reservadas para la tinci&#243;n inmunohistoqu&#237;mica con S-100 y HMB-45&#44; que se realiza solo despu&#233;s de verificar que no hay met&#225;stasis en las secciones de hematoxilina-eosina&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Variables independientes</span><p id="par0070" class="elsevierStylePara elsevierViewall">Como variables independientes se seleccionaron las siguientes caracter&#237;sticas cl&#237;nicas e histol&#243;gicas&#58;</p><p id="par0075" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Factores cl&#237;nicos</span>&#58; el sexo&#44; la edad &#40;&#8804;<span class="elsevierStyleHsp" style=""></span>65 vs &#62;<span class="elsevierStyleHsp" style=""></span>65 a&#241;os&#41; y la localizaci&#243;n anat&#243;mica&#46; Esta &#250;ltima variable fue dicotomizada como &#171;axial&#187; &#40;cabeza&#44; cuello&#44; tronco&#44; superficies volar o subungueal&#41; o en &#171;extremidad&#187;&#46; Usamos la clasificaci&#243;n de Kruper et al&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> para clasificar a los melanomas volares y subungueales como axiales debido a que presentan un peor pron&#243;stico que&#44; en parte&#44; pudiera deberse a alteraciones gen&#233;ticas que lo diferencien del resto<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a>&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Factores histol&#243;gicos</span>&#58; el espesor de Breslow &#40;categorizado de acuerdo con la AJCC en &#8804;<span class="elsevierStyleHsp" style=""></span>1&#44;00&#44; 1&#44;01-2&#44; 2&#44;01-4 y &#62;<span class="elsevierStyleHsp" style=""></span>4<span class="elsevierStyleHsp" style=""></span>mm&#41;&#44; la ulceraci&#243;n &#40;presente vs&#46; ausente&#41;&#44; la regresi&#243;n &#40;presente vs&#46; ausente&#41;&#44; el IM &#40;expresado como el n&#250;mero de mitosis por mil&#237;metros cuadrados &#91;0&#44;1-5&#44;<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>6&#93;&#41;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> y los linfocitos infiltrantes de tumor &#40;LIT&#41; &#40;ausente&#44; no intenso&#44; intenso&#41;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a>&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">An&#225;lisis estad&#237;stico</span><p id="par0085" class="elsevierStylePara elsevierViewall">La variable &#171;respuesta&#187; fue la positividad del GC&#46; Las variables fueron incluidas como variables binarias &#40;sexo&#44; edad&#44; ulceraci&#243;n&#44; localizaci&#243;n y regresi&#243;n&#41; o como variables categ&#243;ricas &#40;espesor de Breslow&#44; LIT e IM&#41;&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">En el an&#225;lisis de regresi&#243;n log&#237;stica primero se analiz&#243; la asociaci&#243;n de la positividad del GC con las variables a estudio usando el test de la chi cuadrado&#44; o un an&#225;lisis de regresi&#243;n log&#237;stica univariante&#46; Basado en el m&#233;todo de Wald se calcularon los cocientes de riesgo con sus intervalos de confianza &#40;IC 95&#37;&#41; de todas las variables&#46; Se realiz&#243; una regresi&#243;n log&#237;stica m&#250;ltiple para identificar los predictores independientes de la positividad del GC y se analizaron las posibles interacciones entre las variables&#46; Se comprob&#243; la bondad de ajuste mediante el test de Hosmer-Lemeshow&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">En el desarrollo del &#225;rbol de clasificaci&#243;n se utiliz&#243; la metodolog&#237;a denominada CART<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> que permite construir &#225;rboles de decisi&#243;n mediante una serie de reglas sobre las decisiones tomadas para asignar un valor de salida a una determinada entrada&#44; mediante divisiones binarias sucesivas&#46; Esto es&#44; se divide cada nodo madre en 2 nodos hijos homog&#233;neos mediante la aplicaci&#243;n de respuestas s&#237;&#47;no en cada nodo de decisi&#243;n&#46; Las etapas para la generaci&#243;n del modelo son&#58; a&#41; construcci&#243;n del &#225;rbol&#59; b&#41; parada del proceso de crecimiento del &#225;rbol &#40;se construye un &#225;rbol m&#225;ximo que sobreajusta la informaci&#243;n contenida en la base de datos&#41;&#59; c&#41; podado del &#225;rbol haci&#233;ndolo m&#225;s sencillo y dejando solo los nodos m&#225;s importantes&#59; y por &#250;ltimo d&#41; selecci&#243;n del &#225;rbol &#243;ptimo con capacidad de generalizaci&#243;n<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a>&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Se utiliz&#243; el software SSPS 20&#46;0 &#40;SPSS&#44; Illinois&#44; Inc&#59; EE&#46; UU&#46;&#41;&#44; m&#233;todo de crecimiento por medio de CART&#44; con an&#225;lisis de sensibilidad basado en el m&#233;todo de Gini<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> y sistema de validaci&#243;n cruzada&#46; En el &#225;rbol final cada grupo ten&#237;a al menos 20 casos &#40;10 casos en an&#225;lisis de subgrupos&#41;&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Para la elaboraci&#243;n de las curvas COR y el c&#225;lculo del &#225;rea bajo la curva de ambos se utiliz&#243; el paquete estad&#237;stico MedCalcStatistical Software versi&#243;n 14&#46;8&#46;1&#46; La comparaci&#243;n de ambas curvas se realiz&#243; siguiendo el m&#233;todo de DeLong<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a>&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Para el estudio de supervivencia libre de enfermedad &#40;SLE&#41; y supervivencia espec&#237;fica por melanoma &#40;SEM&#41; se elaboraron las curvas mediante el m&#233;todo de Kaplan-Meier&#44; y para la comparaci&#243;n univariada entre los grupos definidos se utiliz&#243; la prueba de los rangos logar&#237;tmicos&#46; El an&#225;lisis multivariante se realiz&#243; usando el modelo de los riesgos proporcionales de Cox&#46; Se consider&#243; una p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;05 como significativa&#46; Para la realizaci&#243;n de las pruebas estad&#237;sticas se us&#243; el software SSPS 20&#46;0 &#40;SPSS&#44; Illinois&#44; Inc&#59; EE&#46; UU&#46;&#41;&#46;</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Resultados</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Participantes</span><p id="par0115" class="elsevierStylePara elsevierViewall">De acuerdo con los criterios de selecci&#243;n un total de 855 pacientes cumpl&#237;an los criterios histol&#243;gicos&#44; a los que se les proporcion&#243; un consentimiento informado y se les someti&#243; a la biopsia selectiva del GC&#46; Se identific&#243; el GC en 818 casos &#40;95&#44;6&#37;&#41;&#46; De esos 818 pacientes incluidos en el an&#225;lisis 434 &#40;53&#44;1&#37;&#41; fueron mujeres y 384 hombres &#40;46&#44;9&#37;&#41;&#46; La mediana de edad fue de 53 a&#241;os &#40;rango intercuart&#237;lico 43-66&#41;&#46; En la <a class="elsevierStyleCrossRef" href="#tbl0005">tabla 1</a> se resumen las caracter&#237;sticas cl&#237;nicas e histol&#243;gicas de la poblaci&#243;n de estudio estratificada por el estado del GC&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0120" class="elsevierStylePara elsevierViewall">La afectaci&#243;n del GC se asocia con un incremento en el espesor de Breslow&#44; la presencia de ulceraci&#243;n&#44; la ausencia de regresi&#243;n&#44; un mayor IM y la ausencia de infiltrado inflamatorio&#46; Por otro lado&#44; no se relacion&#243; con el sexo&#44; la edad ni la localizaci&#243;n&#46; Entre las variables gr&#225;ficamente se comprueba que existe una asociaci&#243;n entre el IM y un mayor espesor y la presencia de ulceraci&#243;n &#40;<a class="elsevierStyleCrossRef" href="#fig0005">fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Estado del ganglio centinela</span><p id="par0125" class="elsevierStylePara elsevierViewall">El an&#225;lisis univariante mostr&#243; que las siguientes variables se relacionaron con la afectaci&#243;n del GC&#58; el espesor tumoral&#44; la ulceraci&#243;n&#44; la ausencia de regresi&#243;n&#44; un mayor IM y la ausencia de LIT &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">tabla 2</a>&#41;&#46; Despu&#233;s de incluir estas variables en un an&#225;lisis de regresi&#243;n log&#237;stica m&#250;ltiple solo la ulceraci&#243;n&#44; el espesor tumoral y un IM elevado &#40;&#8805;<span class="elsevierStyleHsp" style=""></span>6 mitosis&#47;mm<span class="elsevierStyleSup">2</span>&#41; se relacionaron con la afectaci&#243;n metast&#225;sica del GC de forma independiente&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">&#193;rbol de clasificaci&#243;n y regresi&#243;n</span><p id="par0130" class="elsevierStylePara elsevierViewall">Tras la inclusi&#243;n de las 8 variables de estudio el &#225;rbol utiliz&#243; 6 de ellas&#46; El espesor de Breslow fue el factor m&#225;s importante dicotomizando la muestra en 2<span class="elsevierStyleHsp" style=""></span>mm&#46; Para los melanomas de espesor mayor de 2<span class="elsevierStyleHsp" style=""></span>mm en orden de importancia las variables utilizadas fueron el infiltrado inflamatorio &#40;ausencia vs&#46; resto&#41;&#44; la edad y la localizaci&#243;n&#46; Para los melanomas menores de 2<span class="elsevierStyleHsp" style=""></span>mm las variables utilizadas en orden de importancia fueron el &#237;ndice mit&#243;tico &#40;&#62;<span class="elsevierStyleHsp" style=""></span>6 mitosis&#47;mm<span class="elsevierStyleSup">2</span> vs&#46; &#8804;<span class="elsevierStyleHsp" style=""></span>6 mitosis&#47;mm<span class="elsevierStyleSup">2</span>&#41;&#44; la ulceraci&#243;n y el espesor &#40;<a class="elsevierStyleCrossRef" href="#fig0010">fig&#46; 2</a>&#41;&#46; De esta forma el grupo de mayor riesgo de afectaci&#243;n del GC fueron los melanomas de m&#225;s de 2<span class="elsevierStyleHsp" style=""></span>mm con ausencia de LIT&#44; en pacientes menores de 65 a&#241;os y de localizaci&#243;n en las extremidades &#40;58&#37; positividad en GC&#59; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>60&#41;&#44; mientras que el grupo de menor riesgo de afectaci&#243;n del GC fueron aquellos con &#8804;<span class="elsevierStyleHsp" style=""></span>6 mit&#47;mm<span class="elsevierStyleSup">2</span>&#44; no ulcerados y <span class="elsevierStyleHsp" style=""></span>&#8804;1<span class="elsevierStyleHsp" style=""></span>mm de grosor &#40;3&#44;3&#37; positividad en GC&#59; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>181&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0135" class="elsevierStylePara elsevierViewall">Las curvas COR para ambos modelos no mostraron diferencias entre ellos &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;7&#41;&#44; con un &#225;rea bajo la curva de 0&#44;77 &#40;IC 95&#37;&#58; 0&#44;73-0&#44;81&#41; para el modelo CART y de 0&#44;78 &#40;0&#44;74-0&#44;82&#41; para la regresi&#243;n log&#237;stica &#40;<a class="elsevierStyleCrossRef" href="#fig0015">fig&#46; 3</a>&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Supervivencia libre de enfermedad y supervivencia espec&#237;fica por melanoma</span><p id="par0140" class="elsevierStylePara elsevierViewall">Tras una mediana de seguimiento de 58 meses &#40;intervalo&#58; 1-157&#41;&#44; 104 pacientes fallecieron de melanoma en el seguimiento y 172 sufrieron alguna reca&#237;da &#40;no censurados en el an&#225;lisis de los riesgos proporcionales de Cox&#41;&#46; El factor pron&#243;stico m&#225;s importante tanto para la SLE como para la SEM fue la afectaci&#243;n metast&#225;sica del GC&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">La SEM para los pacientes con GC negativo fue de 93&#44;1&#37;&#44; mientras que para los pacientes con GC positivo fue de 68&#44;1&#37;&#46; El modelo de riesgos proporcionales de Cox se ajust&#243; para las variables significativas en el an&#225;lisis univariante&#46; La afectaci&#243;n del GC fue el factor pron&#243;stico m&#225;s importante tanto para la SLE &#40;cociente de riesgo&#58; 2&#44;3&#59; IC 95&#37;&#58; 1&#44;5-3&#44;6&#41; como para la SEM &#40;cociente de riesgo&#58; 3&#44;5&#59; IC 95&#37;&#58; 1&#44;9-6&#44;3&#41;&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">El resto de las variables significativas para la SLE se detallan en la <a class="elsevierStyleCrossRef" href="#tbl0015">tabla 3</a> y fueron&#58; el espesor de Breslow&#44; la edad&#44; la localizaci&#243;n y el IM &#40;<a class="elsevierStyleCrossRef" href="#fig0020">fig&#46; 4</a>&#41;&#46; Igualmente&#44; para la SEM &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">tabla 4</a>&#41; el IM fue una variable pron&#243;stica independiente junto con la edad&#44; la localizaci&#243;n y el espesor tumoral &#40;<a class="elsevierStyleCrossRef" href="#fig0025">fig&#46; 5</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><elsevierMultimedia ident="fig0020"></elsevierMultimedia><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><elsevierMultimedia ident="fig0025"></elsevierMultimedia></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Discusi&#243;n</span><p id="par0155" class="elsevierStylePara elsevierViewall">En este trabajo hemos mostrado en una serie de 818 de pacientes con melanoma que el IM&#44; junto con el espesor tumoral y la ulceraci&#243;n&#44; tienen un papel significativo en la predicci&#243;n de la afectaci&#243;n metast&#225;sica del GC&#46; Adem&#225;s&#44; el IM tiene un valor pron&#243;stico independiente para la supervivencia de los pacientes con melanoma&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">El &#237;ndice mit&#243;tico no es un factor que se haya observado uniformemente como predictivo de la afectaci&#243;n metast&#225;sica del GC&#44; a diferencia de lo que ocurre con la ulceraci&#243;n y&#44; sobre todo&#44; con el espesor tumoral<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a>&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">En nuestro estudio el IM se ha mostrado como predictivo con respecto al basal en el grupo<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>6 mitosis&#47;mm<span class="elsevierStyleSup">2</span> en la regresi&#243;n log&#237;stica&#46; Por otro lado&#44; en el an&#225;lisis CART las mitosis se muestran como el factor m&#225;s importante despu&#233;s del espesor tumoral&#44; pero solo en los tumores con un espesor menor de 2<span class="elsevierStyleHsp" style=""></span>mm&#44; el cual se dicotomiza entre los melanomas<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>6 mitosis&#47;mm<span class="elsevierStyleSup">2</span> y el resto&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">Con las mismas variables se pueden construir distintas aproximaciones para una clasificaci&#243;n&#46; Sin embargo&#44; entre la regresi&#243;n log&#237;stica y el m&#233;todo CART&#44; el segundo ofrece una ventaja en la interpretaci&#243;n de los resultados debido a que es mucho m&#225;s intuitivo&#44; dado que permite identificar variables predictivas que influyen de forma diferente en grupos espec&#237;ficos de pacientes<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a>&#46; Los modelos no tienen que ser excluyentes entre s&#237; ya que&#44; ante un mismo problema&#44; deben barajarse distintas metodolog&#237;as que pueden colaborar en la b&#250;squeda de un resultado &#243;ptimo<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a>&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">El espesor de Breslow est&#225; considerado como el factor predictivo de la afectaci&#243;n metast&#225;sica del GC m&#225;s importante<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a>&#46; En nuestra muestra el punto de corte diferencial se encuentra en los 2<span class="elsevierStyleHsp" style=""></span>mm en el m&#233;todo CART&#46; Parece que este espesor diferencia de forma m&#225;xima el riesgo de met&#225;stasis ganglionar<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a>&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">La ulceraci&#243;n es otro factor predictivo importante en los diferentes estudios<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a>&#46; En el nuestro tambi&#233;n se ha confirmado esta independencia como factor predictivo de la afectaci&#243;n metast&#225;sica&#46; Sin embargo&#44; en el m&#233;todo CART solo tiene relevancia para los melanomas menores de 2<span class="elsevierStyleHsp" style=""></span>mm y un IM menor de 6 mitosis&#47;mm<span class="elsevierStyleSup">2</span>&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">Con el modelo CART lo que se sugiere es que para melanomas con un espesor mayor de 2<span class="elsevierStyleHsp" style=""></span>mm ni el n&#250;mero de mitosis ni la ulceraci&#243;n pueden discriminar grupos de mayor riesgo de afectaci&#243;n metast&#225;sica en el GC&#46; Sin embargo&#44; la ausencia de infiltrado inflamatorio confiere una mayor probabilidad de afectaci&#243;n metast&#225;sica del GC&#46; Taylor et al&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> fueron los primeros en describir una relaci&#243;n significativa entre la ausencia de LIT y la presencia de met&#225;stasis regionales&#46; Al igual que en nuestro estudio&#44; tampoco encontraron diferencias en la supervivencia con respecto al infiltrado inflamatorio&#46; Estos autores encuentran adem&#225;s que los pacientes con ausencia de LIT presentaron mayor frecuencia de recurrencias en los ganglios linf&#225;ticos regionales&#44; pero tienen una proporci&#243;n similar de recurrencias a distancia que aquellos casos con presencia de infiltrado inflamatorio&#44; lo que podr&#237;a explicar&#44; al menos en parte&#44; este fen&#243;meno&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">Otras variables que aparecen en los nodos finales en el m&#233;todo CART y que pueden discriminar subgrupos son&#58; la edad y la localizaci&#243;n&#44; variables que no alcanzan la significaci&#243;n estad&#237;stica en la regresi&#243;n log&#237;stica&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">La localizaci&#243;n axial produce una menor afectaci&#243;n relativa del GC que los melanomas en extremidades en tumores gruesos y en melanomas menores de 2<span class="elsevierStyleHsp" style=""></span>mm con presencia de ulceraci&#243;n&#46; Sin embargo&#44; se relacionan con una peor SLE y supervivencia global en algunos trabajos&#46; Este hecho&#44; corroborado por otros autores&#44; no deja de ser intrigante<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a>&#46; Se ha achacado a un aumento de la vascularizaci&#243;n en tumores de localizaci&#243;n axial&#44; sobre todo en la regi&#243;n de la cabeza y el cuello&#44; por tanto con una mayor probabilidad de met&#225;stasis hemat&#243;genas o&#44; en el sentido opuesto&#44; existe una menor proporci&#243;n de GC afectados por la complejidad del sistema linf&#225;tico a este nivel&#44; lo que dificulta su localizaci&#243;n<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a>&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">En este mismo sentido&#44; para los melanomas gruesos localizados en las extremidades&#44; la edad por debajo de 65 a&#241;os se asocia con una mayor afectaci&#243;n metast&#225;sica del GC y parad&#243;jicamente presenta una mejor supervivencia&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">En el grupo de melanomas finos &#8804;<span class="elsevierStyleHsp" style=""></span>1<span class="elsevierStyleHsp" style=""></span>mm la frecuencia de afectaci&#243;n del GC es del 5&#44;6&#37;&#44; que baja al 3&#44;3&#37; en caso de ausencia de ulceraci&#243;n y un n&#250;mero de mitosis<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>6 mitosis&#47;mm<span class="elsevierStyleSup">2</span>&#46; Existe una amplia literatura para identificar subgrupos de pacientes con mayor riesgo de afectaci&#243;n del GC y un peor pron&#243;stico en los melanomas finos revisados por Venna et al&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a>&#46; La ulceraci&#243;n se identifica como un factor predictivo importante en los trabajos m&#225;s recientes<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">28&#44;29</span></a>&#46; Por el contrario&#44; los factores predictivos que con m&#225;s frecuencia se relacionan con la afectaci&#243;n del GC son el grosor tumoral&#44; el IM&#44; el nivel de Clark y la ausencia de LIT&#46; En menor medida se han descrito asociaciones con la edad&#44; el g&#233;nero&#44; la fase de crecimiento vertical o la invasi&#243;n linfovascular<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a>&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">Por otro lado&#44; el IM se ha mostrado como un factor pron&#243;stico importante&#44; tras la afectaci&#243;n del GC y el espesor de Breslow tanto para la SLE como la SEM&#46; Esto est&#225; en consonancia con los hallazgos de Azzola et al&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> y revalidado recientemente por su grupo&#44; con un mayor n&#250;mero de casos donde el IM como factor pron&#243;stico se muestra claramente superior a la ulceraci&#243;n<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a>&#46;</p><p id="par0215" class="elsevierStylePara elsevierViewall">En conclusi&#243;n&#44; el IM se asocia con una mayor afectaci&#243;n metast&#225;sica del GC en melanomas de menos de 2<span class="elsevierStyleHsp" style=""></span>mm&#44; aunque su papel m&#225;s relevante se encuentra en el efecto sobre la supervivencia de estos pacientes&#46; Despu&#233;s de la afectaci&#243;n regional linf&#225;tica y el espesor de Breslow es el factor pron&#243;stico m&#225;s importante&#44; incluso por encima de la ulceraci&#243;n&#46; Por otro lado&#44; el infiltrado inflamatorio del melanoma se ha demostrado predictor de la afectaci&#243;n metast&#225;sica del GC para melanomas de m&#225;s de 2<span class="elsevierStyleHsp" style=""></span>mm&#44; aunque no tiene relevancia en el pron&#243;stico de estos pacientes&#46;</p><p id="par0220" class="elsevierStylePara elsevierViewall">Las implicaciones pr&#225;cticas de este estudio son que con la metodolog&#237;a CART es posible una predicci&#243;n m&#225;s pr&#225;ctica e intuitiva de la afectaci&#243;n metast&#225;sica del GC con vistas al manejo cl&#237;nico de estos pacientes o su inclusi&#243;n en ensayos cl&#237;nicos&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Responsabilidades &#233;ticas</span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Protecci&#243;n de personas y animales</span><p id="par0230" class="elsevierStylePara elsevierViewall">Los autores declaran que para esta investigaci&#243;n no se han realizado experimentos en seres humanos ni en animales&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Confidencialidad de los datos</span><p id="par0235" class="elsevierStylePara elsevierViewall">Los autores declaran que han seguido los protocolos de su centro de trabajo sobre la publicaci&#243;n de datos de pacientes&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Derecho a la privacidad y consentimiento informado</span><p id="par0240" class="elsevierStylePara elsevierViewall">Los autores declaran que en este art&#237;culo no aparecen datos de pacientes&#46;</p></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Conflicto de intereses</span><p id="par0225" class="elsevierStylePara elsevierViewall">Los autores declaran que no tienen ning&#250;n conflicto de intereses&#46;</p></span></span>"
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              "titulo" => "Estado del ganglio centinela"
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            2 => array:2 [
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              "titulo" => "Variables independientes"
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              "titulo" => "Supervivencia libre de enfermedad y supervivencia espec&#237;fica por melanoma"
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              "titulo" => "Confidencialidad de los datos"
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            2 => "Pron&#243;stico"
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            4 => "Linfocitos que infiltran los tumores"
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            1 => "Sentinel lymph node biopsy"
            2 => "Prognosis"
            3 => "Mitotic index"
            4 => "Tumor infiltrating lymphocytes"
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    "resumen" => array:2 [
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objetivo</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">El objetivo principal de este estudio es identificar factores predictivos de la afectaci&#243;n metast&#225;sica del ganglio centinela &#40;GC&#41;&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Pacientes y m&#233;todo</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Se trata de un estudio de cohortes retrospectivo realizado en 2 centros hospitalarios de tercer nivel&#46; Se incluyeron un total de 818 pacientes&#46; La medida de resultado principal fue la afectaci&#243;n del GC&#46; La valoraci&#243;n de predictores independientes de esta afectaci&#243;n se realiz&#243; mediante una regresi&#243;n log&#237;stica m&#250;ltiple y un &#225;rbol de clasificaci&#243;n y regresi&#243;n &#40;CART&#41;&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Resultados</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">El an&#225;lisis de regresi&#243;n log&#237;stica m&#250;ltiple mostr&#243; que la ulceraci&#243;n&#44; el grosor tumoral y un alto &#237;ndice mit&#243;tico &#40;IM&#41; &#40;&#8805;<span class="elsevierStyleHsp" style=""></span>6 mitosis&#47;mm<span class="elsevierStyleSup">2</span>&#41; se relacionaron con la afectaci&#243;n metast&#225;sica del GC de forma independiente&#46; El CART mostr&#243; que el grosor de Breslow fue el factor m&#225;s importante como predictor de la afectaci&#243;n linf&#225;tica&#46; Para los melanomas gruesos &#40;&#62;<span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>mm&#41; las variables predictoras fueron la ausencia de infiltrado inflamatorio&#44; la edad y la localizaci&#243;n&#46; Para los melanomas menores de 2<span class="elsevierStyleHsp" style=""></span>mm las variables predictoras fueron el IM &#40;&#62;<span class="elsevierStyleHsp" style=""></span>6 mitosis&#47;mm<span class="elsevierStyleSup">2</span>&#41;&#44; la ulceraci&#243;n y el grosor&#46; El grosor tumoral&#44; la edad&#44; la localizaci&#243;n y el IM fueron predictores de la supervivencia de estos pacientes&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusi&#243;n</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Un alto IM se asocia con una mayor afectaci&#243;n metast&#225;sica del GC y una peor supervivencia&#46; Con la metodolog&#237;a CART es posible una mejor predicci&#243;n de la afectaci&#243;n metast&#225;sica regional con vistas al mejor manejo cl&#237;nico de estos pacientes o su inclusi&#243;n en ensayos cl&#237;nicos&#46;</p></span>"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Objective</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">The main aim of this study was to identify predictors of sentinel lymph node &#40;SN&#41; metastasis in cutaneous melanoma&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Patients and methods</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">This was a retrospective cohort study of 818 patients in 2 tertiary-level hospitals&#46; The primary outcome variable was SN involvement&#46; Independent predictors were identified using multiple logistic regression and a classification and regression tree &#40;CART&#41; analysis&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Results</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Ulceration&#44; tumor thickness&#44; and a high mitotic rate &#40;&#8805;6 mitoses&#47;mm<span class="elsevierStyleSup">2</span>&#41; were independently associated with SN metastasis in the multiple regression analysis&#46; The most important predictor in the CART analysis was Breslow thickness&#46; Absence of an inflammatory infiltrate&#44; patient age&#44; and tumor location were predictive of SN metastasis in patients with tumors thicker than 2<span class="elsevierStyleHsp" style=""></span>mm&#46; In the case of thinner melanomas&#44; the predictors were mitotic rate &#40;&#62;<span class="elsevierStyleHsp" style=""></span>6 mitoses&#47;mm<span class="elsevierStyleSup">2</span>&#41;&#44; presence of ulceration&#44; and tumor thickness&#46; Patient age&#44; mitotic rate&#44; and tumor thickness and location were predictive of survival&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusions</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">A high mitotic rate predicts a higher risk of SN involvement and worse survival&#46; CART analysis improves the prediction of regional metastasis&#44; resulting in better clinical management of melanoma patients&#46; It may also help select suitable candidates for inclusion in clinical trials&#46;</p></span>"
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Extremidades&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Grosor tumoral de Breslow &#40;mm&#41;</span></td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>1&#44;01-2&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t  " colspan="5" align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">&#205;ndice mit&#243;tico &#40;mitosis&#47;mm</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleItalic">&#41;</span></td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t">0&#44;01&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#8230;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>1&#44;01-2 <a class="elsevierStyleCrossRef" href="#tblfn0005">&#42;</a> ulceraci&#243;n&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>2&#44;01-4 <a class="elsevierStyleCrossRef" href="#tblfn0005">&#42;</a> ulceraci&#243;n&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>4 <a class="elsevierStyleCrossRef" href="#tblfn0005">&#42;</a> ulceraci&#243;n&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#44;07 &#40;0&#44;01-0&#44;5&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Riesgo proporcional &#40;IC 95&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Axial&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Extremidades&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Grosor tumoral de Breslow &#40;mm&#41;</span></td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>1&#44;01-2&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Axial&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Extremidades&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Grosor tumoral de Breslow &#40;mm&#41;</span></td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>1&#44;01-2&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;027&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#8230;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>2&#44;01-4&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t  " align="" valign="\n
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Original
Factores predictivos del estado del ganglio centinela en el melanoma cutáneo: análisis mediante un árbol de clasificación y regresión
Predictors of Sentinel Lymph Node Status in Cutaneous Melanoma: A Classification and Regression Tree Analysis
A. Tejera-Vaquerizoa,
Autor para correspondencia
antoniotejera@aedv.es
antoniotejera@globalderm.es

Autor para correspondencia.
, P. Martín-Cuevasa, E. Gallegob, E. Herrera-Acostaa, V. Travesc, E. Herrera-Ceballosa, E. Nagored
a Servicio de Dermatología, Instituto de Biomedicina de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria/Universidad de Málaga, Málaga, España
b Servicio de Anatomía Patológica, Instituto de Biomedicina de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria/Universidad de Málaga, Málaga, España
c Departamento de Anatomía Patológica, Instituto Valenciano de Oncología, Valencia, España
d Servicio de Dermatología, Instituto Valenciano de Oncología, Valencia. España
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ha adquirido un protagonismo creciente&#44; tanto como factor pron&#243;stico como factor predictivo de la afectaci&#243;n metast&#225;sica del GC&#44; especialmente tras establecerse el m&#233;todo mejor para su evaluaci&#243;n<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#8211;11</span></a>&#46; A pesar de ello&#44; en la &#250;ltima versi&#243;n de la estadificaci&#243;n de la <span class="elsevierStyleItalic">American Joint Committee on Cancer</span> &#40;AJCC&#41; su papel pron&#243;stico actual queda formalmente establecido exclusivamente en el caso de los melanomas finos<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">En medicina&#44; en la toma de decisiones es importante buscar metodolog&#237;as que sean precisas y nos ayuden a resolver los problemas que surgen a la hora de clasificar&#44; estratificar o pronosticar a nuestros pacientes<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a>&#46; Una de estas herramientas&#44; cada vez m&#225;s utilizadas&#44; son los &#225;rboles de decisi&#243;n&#44; m&#225;s concretamente los &#225;rboles de clasificaci&#243;n y regresi&#243;n &#40;tambi&#233;n conocidos como CART&#44; del ingl&#233;s <span class="elsevierStyleItalic">Classification And Regression Trees</span>&#41;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a>&#46; Este modelo tiene como ventajas respecto a la regresi&#243;n log&#237;stica la simplicidad en su utilizaci&#243;n e interpretaci&#243;n&#44; y adem&#225;s el hecho de que tiene un car&#225;cter no param&#233;trico que no requiere ninguna hip&#243;tesis relativa a la distribuci&#243;n de los predictores y la respuesta ni a la respuesta entre estos y sus posibles interacciones&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">El objetivo principal de este estudio ha sido identificar los factores predictivos de la afectaci&#243;n metast&#225;sica del GC usando la metodolog&#237;a CART y la regresi&#243;n log&#237;stica&#46; Como objetivos secundarios se ha evaluado el papel de estos factores en la recurrencia y la supervivencia global de estos pacientes&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Material y m&#233;todo</span><p id="par0030" class="elsevierStylePara elsevierViewall">Se dise&#241;&#243; un estudio observacional retrospectivo&#46;</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Poblaci&#243;n de estudio</span><p id="par0035" class="elsevierStylePara elsevierViewall">Los participantes en el estudio fueron seleccionados de las bases de datos de pacientes con melanoma del Hospital Virgen de la Victoria &#40;HVV&#41; de M&#225;laga&#44; Espa&#241;a&#44; y del Instituto Valenciano de Oncolog&#237;a de Valencia &#40;IVO&#41;&#44; Espa&#241;a&#46; El uso de ambas bases de datos se realiza de acuerdo con la regulaci&#243;n &#233;tica vigente&#46; 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&#233;tico de ambas instituciones&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">La variable dependiente del estudio fue el estado del GC&#44; que fue definido como positivo o negativo cuando hab&#237;a presencia o ausencia de c&#233;lulas de melanoma en el GC&#44; respectivamente&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Estado del ganglio centinela</span><p id="par0055" class="elsevierStylePara elsevierViewall">El estudio histol&#243;gico del GC es bastante similar en ambos centros y se describe de la siguiente forma&#58;</p><p id="par0060" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">HVV</span>&#46; El estudio comienza con la identificaci&#243;n macrosc&#243;pica del GC y&#44; si es necesario&#44; la limpieza de la grasa periganglionar&#46; Una vezidentificada la adenopat&#237;a se sumerge en formaldeh&#237;do al 10&#37; para la fijaci&#243;n y posterior inclusi&#243;n en un bloque de parafina&#46; Se realizan tandas cada 250<span class="elsevierStyleHsp" style=""></span>m&#956; de 3 secciones en serie&#44; la primera y la &#250;ltima secci&#243;n para la tinci&#243;n con hematoxilina-eosina y la segunda para la tinci&#243;n inmunohistoqu&#237;mica con HMB-45 hasta agotar el bloque&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">IVO</span>&#46; Primeramente se lleva a cabo una identificaci&#243;n macrosc&#243;pica del GC y&#44; si es necesario&#44; la limpieza de la grasa periganglionar&#46; Una vez identificada&#44; la muestra adenop&#225;tica se coloca en 10&#37; de formaldeh&#237;do para la fijaci&#243;n y posterior incrustaci&#243;n en un bloque de parafina&#46; Se obtienen secciones transversales en serie cada 250<span class="elsevierStyleHsp" style=""></span>m&#956; a partir de todo el ganglio linf&#225;tico incluido en parafina&#46; Tres secciones transversales se obtienen en cada secci&#243;n&#44; una de las cuales se ti&#241;e con hematoxilina-eosina&#44; 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o en &#171;extremidad&#187;&#46; Usamos la clasificaci&#243;n de Kruper et al&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> para clasificar a los melanomas volares y subungueales como axiales debido a que presentan un peor pron&#243;stico que&#44; en parte&#44; pudiera deberse a alteraciones gen&#233;ticas que lo diferencien del resto<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a>&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Factores histol&#243;gicos</span>&#58; el espesor de Breslow &#40;categorizado de acuerdo con la AJCC en &#8804;<span class="elsevierStyleHsp" style=""></span>1&#44;00&#44; 1&#44;01-2&#44; 2&#44;01-4 y &#62;<span class="elsevierStyleHsp" style=""></span>4<span class="elsevierStyleHsp" style=""></span>mm&#41;&#44; la ulceraci&#243;n &#40;presente vs&#46; ausente&#41;&#44; la regresi&#243;n &#40;presente vs&#46; ausente&#41;&#44; el IM &#40;expresado como el n&#250;mero de mitosis por mil&#237;metros cuadrados &#91;0&#44;1-5&#44;<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>6&#93;&#41;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> y los linfocitos infiltrantes de tumor &#40;LIT&#41; &#40;ausente&#44; no intenso&#44; intenso&#41;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a>&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">An&#225;lisis estad&#237;stico</span><p id="par0085" class="elsevierStylePara elsevierViewall">La variable &#171;respuesta&#187; fue la positividad del GC&#46; Las variables fueron incluidas como variables binarias &#40;sexo&#44; edad&#44; ulceraci&#243;n&#44; localizaci&#243;n y regresi&#243;n&#41; o como variables categ&#243;ricas &#40;espesor de Breslow&#44; LIT e IM&#41;&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">En el an&#225;lisis de regresi&#243;n log&#237;stica primero se analiz&#243; la asociaci&#243;n de la positividad del GC con las variables a estudio usando el test de la chi cuadrado&#44; o un an&#225;lisis de regresi&#243;n log&#237;stica univariante&#46; Basado en el m&#233;todo de Wald se calcularon los cocientes de riesgo con sus intervalos de confianza &#40;IC 95&#37;&#41; de todas las variables&#46; Se realiz&#243; una regresi&#243;n log&#237;stica m&#250;ltiple para identificar los predictores independientes de la positividad del GC y se analizaron las posibles interacciones entre las variables&#46; Se comprob&#243; la bondad de ajuste mediante el test de Hosmer-Lemeshow&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">En el desarrollo del &#225;rbol de clasificaci&#243;n se utiliz&#243; la metodolog&#237;a denominada CART<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> que permite construir &#225;rboles de decisi&#243;n mediante una serie de reglas sobre las decisiones tomadas para asignar un valor de salida a una determinada entrada&#44; mediante divisiones binarias sucesivas&#46; Esto es&#44; se divide cada nodo madre en 2 nodos hijos homog&#233;neos mediante la aplicaci&#243;n de respuestas s&#237;&#47;no en cada nodo de decisi&#243;n&#46; Las etapas para la generaci&#243;n del modelo son&#58; a&#41; construcci&#243;n del &#225;rbol&#59; b&#41; parada del proceso de crecimiento del &#225;rbol &#40;se construye un &#225;rbol m&#225;ximo que sobreajusta la informaci&#243;n contenida en la base de datos&#41;&#59; c&#41; podado del &#225;rbol haci&#233;ndolo m&#225;s sencillo y dejando solo los nodos m&#225;s importantes&#59; y por &#250;ltimo d&#41; selecci&#243;n del &#225;rbol &#243;ptimo con capacidad de generalizaci&#243;n<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a>&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Se utiliz&#243; el software SSPS 20&#46;0 &#40;SPSS&#44; Illinois&#44; Inc&#59; EE&#46; UU&#46;&#41;&#44; m&#233;todo de crecimiento por medio de CART&#44; con an&#225;lisis de sensibilidad basado en el m&#233;todo de Gini<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> y sistema de validaci&#243;n cruzada&#46; En el &#225;rbol final cada grupo ten&#237;a al menos 20 casos &#40;10 casos en an&#225;lisis de subgrupos&#41;&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Para la elaboraci&#243;n de las curvas COR y el c&#225;lculo del &#225;rea bajo la curva de ambos se utiliz&#243; el paquete estad&#237;stico MedCalcStatistical Software versi&#243;n 14&#46;8&#46;1&#46; La comparaci&#243;n de ambas curvas se realiz&#243; siguiendo el m&#233;todo de DeLong<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a>&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Para el estudio de supervivencia libre de enfermedad &#40;SLE&#41; y supervivencia espec&#237;fica por melanoma &#40;SEM&#41; se elaboraron las curvas mediante el m&#233;todo de Kaplan-Meier&#44; y para la comparaci&#243;n univariada entre los grupos definidos se utiliz&#243; la prueba de los rangos logar&#237;tmicos&#46; El an&#225;lisis multivariante se realiz&#243; usando el modelo de los riesgos proporcionales de Cox&#46; Se consider&#243; una p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;05 como significativa&#46; Para la realizaci&#243;n de las pruebas estad&#237;sticas se us&#243; el software SSPS 20&#46;0 &#40;SPSS&#44; Illinois&#44; Inc&#59; EE&#46; UU&#46;&#41;&#46;</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Resultados</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Participantes</span><p id="par0115" class="elsevierStylePara elsevierViewall">De acuerdo con los criterios de selecci&#243;n un total de 855 pacientes cumpl&#237;an los criterios histol&#243;gicos&#44; a los que se les proporcion&#243; un consentimiento informado y se les someti&#243; a la biopsia selectiva del GC&#46; Se identific&#243; el GC en 818 casos &#40;95&#44;6&#37;&#41;&#46; De esos 818 pacientes incluidos en el an&#225;lisis 434 &#40;53&#44;1&#37;&#41; fueron mujeres y 384 hombres &#40;46&#44;9&#37;&#41;&#46; La mediana de edad fue de 53 a&#241;os &#40;rango intercuart&#237;lico 43-66&#41;&#46; En la <a class="elsevierStyleCrossRef" href="#tbl0005">tabla 1</a> se resumen las caracter&#237;sticas cl&#237;nicas e histol&#243;gicas de la poblaci&#243;n de estudio estratificada por el estado del GC&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0120" class="elsevierStylePara elsevierViewall">La afectaci&#243;n del GC se asocia con un incremento en el espesor de Breslow&#44; la presencia de ulceraci&#243;n&#44; la ausencia de regresi&#243;n&#44; un mayor IM y la ausencia de infiltrado inflamatorio&#46; Por otro lado&#44; no se relacion&#243; con el sexo&#44; la edad ni la localizaci&#243;n&#46; Entre las variables gr&#225;ficamente se comprueba que existe una asociaci&#243;n entre el IM y un mayor espesor y la presencia de ulceraci&#243;n &#40;<a class="elsevierStyleCrossRef" href="#fig0005">fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Estado del ganglio centinela</span><p id="par0125" class="elsevierStylePara elsevierViewall">El an&#225;lisis univariante mostr&#243; que las siguientes variables se relacionaron con la afectaci&#243;n del GC&#58; el espesor tumoral&#44; la ulceraci&#243;n&#44; la ausencia de regresi&#243;n&#44; un mayor IM y la ausencia de LIT &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">tabla 2</a>&#41;&#46; Despu&#233;s de incluir estas variables en un an&#225;lisis de regresi&#243;n log&#237;stica m&#250;ltiple solo la ulceraci&#243;n&#44; el espesor tumoral y un IM elevado &#40;&#8805;<span class="elsevierStyleHsp" style=""></span>6 mitosis&#47;mm<span class="elsevierStyleSup">2</span>&#41; se relacionaron con la afectaci&#243;n metast&#225;sica del GC de forma independiente&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">&#193;rbol de clasificaci&#243;n y regresi&#243;n</span><p id="par0130" class="elsevierStylePara elsevierViewall">Tras la inclusi&#243;n de las 8 variables de estudio el &#225;rbol utiliz&#243; 6 de ellas&#46; El espesor de Breslow fue el factor m&#225;s importante dicotomizando la muestra en 2<span class="elsevierStyleHsp" style=""></span>mm&#46; Para los melanomas de espesor mayor de 2<span class="elsevierStyleHsp" style=""></span>mm en orden de importancia las variables utilizadas fueron el infiltrado inflamatorio &#40;ausencia vs&#46; resto&#41;&#44; la edad y la localizaci&#243;n&#46; Para los melanomas menores de 2<span class="elsevierStyleHsp" style=""></span>mm las variables utilizadas en orden de importancia fueron el &#237;ndice mit&#243;tico &#40;&#62;<span class="elsevierStyleHsp" style=""></span>6 mitosis&#47;mm<span class="elsevierStyleSup">2</span> vs&#46; &#8804;<span class="elsevierStyleHsp" style=""></span>6 mitosis&#47;mm<span class="elsevierStyleSup">2</span>&#41;&#44; la ulceraci&#243;n y el espesor &#40;<a class="elsevierStyleCrossRef" href="#fig0010">fig&#46; 2</a>&#41;&#46; De esta forma el grupo de mayor riesgo de afectaci&#243;n del GC fueron los melanomas de m&#225;s de 2<span class="elsevierStyleHsp" style=""></span>mm con ausencia de LIT&#44; en pacientes menores de 65 a&#241;os y de localizaci&#243;n en las extremidades &#40;58&#37; positividad en GC&#59; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>60&#41;&#44; mientras que el grupo de menor riesgo de afectaci&#243;n del GC fueron aquellos con &#8804;<span class="elsevierStyleHsp" style=""></span>6 mit&#47;mm<span class="elsevierStyleSup">2</span>&#44; no ulcerados y <span class="elsevierStyleHsp" style=""></span>&#8804;1<span class="elsevierStyleHsp" style=""></span>mm de grosor &#40;3&#44;3&#37; positividad en GC&#59; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>181&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0135" class="elsevierStylePara elsevierViewall">Las curvas COR para ambos modelos no mostraron diferencias entre ellos &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;7&#41;&#44; con un &#225;rea bajo la curva de 0&#44;77 &#40;IC 95&#37;&#58; 0&#44;73-0&#44;81&#41; para el modelo CART y de 0&#44;78 &#40;0&#44;74-0&#44;82&#41; para la regresi&#243;n log&#237;stica &#40;<a class="elsevierStyleCrossRef" href="#fig0015">fig&#46; 3</a>&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Supervivencia libre de enfermedad y supervivencia espec&#237;fica por melanoma</span><p id="par0140" class="elsevierStylePara elsevierViewall">Tras una mediana de seguimiento de 58 meses &#40;intervalo&#58; 1-157&#41;&#44; 104 pacientes fallecieron de melanoma en el seguimiento y 172 sufrieron alguna reca&#237;da &#40;no censurados en el an&#225;lisis de los riesgos proporcionales de Cox&#41;&#46; El factor pron&#243;stico m&#225;s importante tanto para la SLE como para la SEM fue la afectaci&#243;n metast&#225;sica del GC&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">La SEM para los pacientes con GC negativo fue de 93&#44;1&#37;&#44; mientras que para los pacientes con GC positivo fue de 68&#44;1&#37;&#46; El modelo de riesgos proporcionales de Cox se ajust&#243; para las variables significativas en el an&#225;lisis univariante&#46; La afectaci&#243;n del GC fue el factor pron&#243;stico m&#225;s importante tanto para la SLE &#40;cociente de riesgo&#58; 2&#44;3&#59; IC 95&#37;&#58; 1&#44;5-3&#44;6&#41; como para la SEM &#40;cociente de riesgo&#58; 3&#44;5&#59; IC 95&#37;&#58; 1&#44;9-6&#44;3&#41;&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">El resto de las variables significativas para la SLE se detallan en la <a class="elsevierStyleCrossRef" href="#tbl0015">tabla 3</a> y fueron&#58; el espesor de Breslow&#44; la edad&#44; la localizaci&#243;n y el IM &#40;<a class="elsevierStyleCrossRef" href="#fig0020">fig&#46; 4</a>&#41;&#46; Igualmente&#44; para la SEM &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">tabla 4</a>&#41; el IM fue una variable pron&#243;stica independiente junto con la edad&#44; la localizaci&#243;n y el espesor tumoral &#40;<a class="elsevierStyleCrossRef" href="#fig0025">fig&#46; 5</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><elsevierMultimedia ident="fig0020"></elsevierMultimedia><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><elsevierMultimedia ident="fig0025"></elsevierMultimedia></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Discusi&#243;n</span><p id="par0155" class="elsevierStylePara elsevierViewall">En este trabajo hemos mostrado en una serie de 818 de pacientes con melanoma que el IM&#44; junto con el espesor tumoral y la ulceraci&#243;n&#44; tienen un papel significativo en la predicci&#243;n de la afectaci&#243;n metast&#225;sica del GC&#46; Adem&#225;s&#44; el IM tiene un valor pron&#243;stico independiente para la supervivencia de los pacientes con melanoma&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">El &#237;ndice mit&#243;tico no es un factor que se haya observado uniformemente como predictivo de la afectaci&#243;n metast&#225;sica del GC&#44; a diferencia de lo que ocurre con la ulceraci&#243;n y&#44; sobre todo&#44; con el espesor tumoral<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a>&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">En nuestro estudio el IM se ha mostrado como predictivo con respecto al basal en el grupo<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>6 mitosis&#47;mm<span class="elsevierStyleSup">2</span> en la regresi&#243;n log&#237;stica&#46; Por otro lado&#44; en el an&#225;lisis CART las mitosis se muestran como el factor m&#225;s importante despu&#233;s del espesor tumoral&#44; pero solo en los tumores con un espesor menor de 2<span class="elsevierStyleHsp" style=""></span>mm&#44; el cual se dicotomiza entre los melanomas<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>6 mitosis&#47;mm<span class="elsevierStyleSup">2</span> y el resto&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">Con las mismas variables se pueden construir distintas aproximaciones para una clasificaci&#243;n&#46; Sin embargo&#44; entre la regresi&#243;n log&#237;stica y el m&#233;todo CART&#44; el segundo ofrece una ventaja en la interpretaci&#243;n de los resultados debido a que es mucho m&#225;s intuitivo&#44; dado que permite identificar variables predictivas que influyen de forma diferente en grupos espec&#237;ficos de pacientes<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a>&#46; Los modelos no tienen que ser excluyentes entre s&#237; ya que&#44; ante un mismo problema&#44; deben barajarse distintas metodolog&#237;as que pueden colaborar en la b&#250;squeda de un resultado &#243;ptimo<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a>&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">El espesor de Breslow est&#225; considerado como el factor predictivo de la afectaci&#243;n metast&#225;sica del GC m&#225;s importante<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a>&#46; En nuestra muestra el punto de corte diferencial se encuentra en los 2<span class="elsevierStyleHsp" style=""></span>mm en el m&#233;todo CART&#46; Parece que este espesor diferencia de forma m&#225;xima el riesgo de met&#225;stasis ganglionar<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a>&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">La ulceraci&#243;n es otro factor predictivo importante en los diferentes estudios<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a>&#46; En el nuestro tambi&#233;n se ha confirmado esta independencia como factor predictivo de la afectaci&#243;n metast&#225;sica&#46; Sin embargo&#44; en el m&#233;todo CART solo tiene relevancia para los melanomas menores de 2<span class="elsevierStyleHsp" style=""></span>mm y un IM menor de 6 mitosis&#47;mm<span class="elsevierStyleSup">2</span>&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">Con el modelo CART lo que se sugiere es que para melanomas con un espesor mayor de 2<span class="elsevierStyleHsp" style=""></span>mm ni el n&#250;mero de mitosis ni la ulceraci&#243;n pueden discriminar grupos de mayor riesgo de afectaci&#243;n metast&#225;sica en el GC&#46; Sin embargo&#44; la ausencia de infiltrado inflamatorio confiere una mayor probabilidad de afectaci&#243;n metast&#225;sica del GC&#46; Taylor et al&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> fueron los primeros en describir una relaci&#243;n significativa entre la ausencia de LIT y la presencia de met&#225;stasis regionales&#46; Al igual que en nuestro estudio&#44; tampoco encontraron diferencias en la supervivencia con respecto al infiltrado inflamatorio&#46; Estos autores encuentran adem&#225;s que los pacientes con ausencia de LIT presentaron mayor frecuencia de recurrencias en los ganglios linf&#225;ticos regionales&#44; pero tienen una proporci&#243;n similar de recurrencias a distancia que aquellos casos con presencia de infiltrado inflamatorio&#44; lo que podr&#237;a explicar&#44; al menos en parte&#44; este fen&#243;meno&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">Otras variables que aparecen en los nodos finales en el m&#233;todo CART y que pueden discriminar subgrupos son&#58; la edad y la localizaci&#243;n&#44; variables que no alcanzan la significaci&#243;n estad&#237;stica en la regresi&#243;n log&#237;stica&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">La localizaci&#243;n axial produce una menor afectaci&#243;n relativa del GC que los melanomas en extremidades en tumores gruesos y en melanomas menores de 2<span class="elsevierStyleHsp" style=""></span>mm con presencia de ulceraci&#243;n&#46; Sin embargo&#44; se relacionan con una peor SLE y supervivencia global en algunos trabajos&#46; Este hecho&#44; corroborado por otros autores&#44; no deja de ser intrigante<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a>&#46; Se ha achacado a un aumento de la vascularizaci&#243;n en tumores de localizaci&#243;n axial&#44; sobre todo en la regi&#243;n de la cabeza y el cuello&#44; por tanto con una mayor probabilidad de met&#225;stasis hemat&#243;genas o&#44; en el sentido opuesto&#44; existe una menor proporci&#243;n de GC afectados por la complejidad del sistema linf&#225;tico a este nivel&#44; lo que dificulta su localizaci&#243;n<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a>&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">En este mismo sentido&#44; para los melanomas gruesos localizados en las extremidades&#44; la edad por debajo de 65 a&#241;os se asocia con una mayor afectaci&#243;n metast&#225;sica del GC y parad&#243;jicamente presenta una mejor supervivencia&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">En el grupo de melanomas finos &#8804;<span class="elsevierStyleHsp" style=""></span>1<span class="elsevierStyleHsp" style=""></span>mm la frecuencia de afectaci&#243;n del GC es del 5&#44;6&#37;&#44; que baja al 3&#44;3&#37; en caso de ausencia de ulceraci&#243;n y un n&#250;mero de mitosis<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>6 mitosis&#47;mm<span class="elsevierStyleSup">2</span>&#46; Existe una amplia literatura para identificar subgrupos de pacientes con mayor riesgo de afectaci&#243;n del GC y un peor pron&#243;stico en los melanomas finos revisados por Venna et al&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a>&#46; La ulceraci&#243;n se identifica como un factor predictivo importante en los trabajos m&#225;s recientes<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">28&#44;29</span></a>&#46; Por el contrario&#44; los factores predictivos que con m&#225;s frecuencia se relacionan con la afectaci&#243;n del GC son el grosor tumoral&#44; el IM&#44; el nivel de Clark y la ausencia de LIT&#46; En menor medida se han descrito asociaciones con la edad&#44; el g&#233;nero&#44; la fase de crecimiento vertical o la invasi&#243;n linfovascular<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a>&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">Por otro lado&#44; el IM se ha mostrado como un factor pron&#243;stico importante&#44; tras la afectaci&#243;n del GC y el espesor de Breslow tanto para la SLE como la SEM&#46; Esto est&#225; en consonancia con los hallazgos de Azzola et al&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> y revalidado recientemente por su grupo&#44; con un mayor n&#250;mero de casos donde el IM como factor pron&#243;stico se muestra claramente superior a la ulceraci&#243;n<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a>&#46;</p><p id="par0215" class="elsevierStylePara elsevierViewall">En conclusi&#243;n&#44; el IM se asocia con una mayor afectaci&#243;n metast&#225;sica del GC en melanomas de menos de 2<span class="elsevierStyleHsp" style=""></span>mm&#44; aunque su papel m&#225;s relevante se encuentra en el efecto sobre la supervivencia de estos pacientes&#46; Despu&#233;s de la afectaci&#243;n regional linf&#225;tica y el espesor de Breslow es el factor pron&#243;stico m&#225;s importante&#44; incluso por encima de la ulceraci&#243;n&#46; Por otro lado&#44; el infiltrado inflamatorio del melanoma se ha demostrado predictor de la afectaci&#243;n metast&#225;sica del GC para melanomas de m&#225;s de 2<span class="elsevierStyleHsp" style=""></span>mm&#44; aunque no tiene relevancia en el pron&#243;stico de estos pacientes&#46;</p><p id="par0220" class="elsevierStylePara elsevierViewall">Las implicaciones pr&#225;cticas de este estudio son que con la metodolog&#237;a CART es posible una predicci&#243;n m&#225;s pr&#225;ctica e intuitiva de la afectaci&#243;n metast&#225;sica del GC con vistas al manejo cl&#237;nico de estos pacientes o su inclusi&#243;n en ensayos cl&#237;nicos&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Responsabilidades &#233;ticas</span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Protecci&#243;n de personas y animales</span><p id="par0230" class="elsevierStylePara elsevierViewall">Los autores declaran que para esta investigaci&#243;n no se han realizado experimentos en seres humanos ni en animales&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Confidencialidad de los datos</span><p id="par0235" class="elsevierStylePara elsevierViewall">Los autores declaran que han seguido los protocolos de su centro de trabajo sobre la publicaci&#243;n de datos de pacientes&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Derecho a la privacidad y consentimiento informado</span><p id="par0240" class="elsevierStylePara elsevierViewall">Los autores declaran que en este art&#237;culo no aparecen datos de pacientes&#46;</p></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Conflicto de intereses</span><p id="par0225" class="elsevierStylePara elsevierViewall">Los autores declaran que no tienen ning&#250;n conflicto de intereses&#46;</p></span></span>"
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              "titulo" => "Estado del ganglio centinela"
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              "titulo" => "Supervivencia libre de enfermedad y supervivencia espec&#237;fica por melanoma"
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    "fechaRecibido" => "2014-07-10"
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            4 => "Linfocitos que infiltran los tumores"
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    "resumen" => array:2 [
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objetivo</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">El objetivo principal de este estudio es identificar factores predictivos de la afectaci&#243;n metast&#225;sica del ganglio centinela &#40;GC&#41;&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Pacientes y m&#233;todo</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Se trata de un estudio de cohortes retrospectivo realizado en 2 centros hospitalarios de tercer nivel&#46; Se incluyeron un total de 818 pacientes&#46; La medida de resultado principal fue la afectaci&#243;n del GC&#46; La valoraci&#243;n de predictores independientes de esta afectaci&#243;n se realiz&#243; mediante una regresi&#243;n log&#237;stica m&#250;ltiple y un &#225;rbol de clasificaci&#243;n y regresi&#243;n &#40;CART&#41;&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Resultados</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">El an&#225;lisis de regresi&#243;n log&#237;stica m&#250;ltiple mostr&#243; que la ulceraci&#243;n&#44; el grosor tumoral y un alto &#237;ndice mit&#243;tico &#40;IM&#41; &#40;&#8805;<span class="elsevierStyleHsp" style=""></span>6 mitosis&#47;mm<span class="elsevierStyleSup">2</span>&#41; se relacionaron con la afectaci&#243;n metast&#225;sica del GC de forma independiente&#46; El CART mostr&#243; que el grosor de Breslow fue el factor m&#225;s importante como predictor de la afectaci&#243;n linf&#225;tica&#46; Para los melanomas gruesos &#40;&#62;<span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>mm&#41; las variables predictoras fueron la ausencia de infiltrado inflamatorio&#44; la edad y la localizaci&#243;n&#46; Para los melanomas menores de 2<span class="elsevierStyleHsp" style=""></span>mm las variables predictoras fueron el IM &#40;&#62;<span class="elsevierStyleHsp" style=""></span>6 mitosis&#47;mm<span class="elsevierStyleSup">2</span>&#41;&#44; la ulceraci&#243;n y el grosor&#46; El grosor tumoral&#44; la edad&#44; la localizaci&#243;n y el IM fueron predictores de la supervivencia de estos pacientes&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusi&#243;n</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Un alto IM se asocia con una mayor afectaci&#243;n metast&#225;sica del GC y una peor supervivencia&#46; Con la metodolog&#237;a CART es posible una mejor predicci&#243;n de la afectaci&#243;n metast&#225;sica regional con vistas al mejor manejo cl&#237;nico de estos pacientes o su inclusi&#243;n en ensayos cl&#237;nicos&#46;</p></span>"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Objective</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">The main aim of this study was to identify predictors of sentinel lymph node &#40;SN&#41; metastasis in cutaneous melanoma&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Patients and methods</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">This was a retrospective cohort study of 818 patients in 2 tertiary-level hospitals&#46; The primary outcome variable was SN involvement&#46; Independent predictors were identified using multiple logistic regression and a classification and regression tree &#40;CART&#41; analysis&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Results</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Ulceration&#44; tumor thickness&#44; and a high mitotic rate &#40;&#8805;6 mitoses&#47;mm<span class="elsevierStyleSup">2</span>&#41; were independently associated with SN metastasis in the multiple regression analysis&#46; The most important predictor in the CART analysis was Breslow thickness&#46; Absence of an inflammatory infiltrate&#44; patient age&#44; and tumor location were predictive of SN metastasis in patients with tumors thicker than 2<span class="elsevierStyleHsp" style=""></span>mm&#46; In the case of thinner melanomas&#44; the predictors were mitotic rate &#40;&#62;<span class="elsevierStyleHsp" style=""></span>6 mitoses&#47;mm<span class="elsevierStyleSup">2</span>&#41;&#44; presence of ulceration&#44; and tumor thickness&#46; Patient age&#44; mitotic rate&#44; and tumor thickness and location were predictive of survival&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusions</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">A high mitotic rate predicts a higher risk of SN involvement and worse survival&#46; CART analysis improves the prediction of regional metastasis&#44; resulting in better clinical management of melanoma patients&#46; It may also help select suitable candidates for inclusion in clinical trials&#46;</p></span>"
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Extremidades&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Ausente&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Ausente&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">&#205;ndice mit&#243;tico &#40;mitosis&#47;mm</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleItalic">&#41;</span></td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Presente&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Ausente&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Regresi&#243;n</span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Presente&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;01&nbsp;\t\t\t\t\t\t\n
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                  \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">2&#44;1 &#40;1&#44;1-3&#44;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8230;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8230;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Ausente&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \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">1&nbsp;\t\t\t\t\t\t\n
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                  \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">&#8230;&nbsp;\t\t\t\t\t\t\n
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                  \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">&#8230;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">&#205;ndice mit&#243;tico &#40;mitosis&#47;mm</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleItalic">&#41;</span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>0&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \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"><span class="elsevierStyleHsp" style=""></span>1-5&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">2&#44;8 &#40;1&#44;2-6&#44;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8230;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>6&nbsp;\t\t\t\t\t\t\n
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                  \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">&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#44;5 &#40;3&#44;2-17&#44;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;046&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#44;6 &#40;1&#44;1-6&#44;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Infiltrado inflamatorio</span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Intenso&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \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"><span class="elsevierStyleHsp" style=""></span>No Intenso&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#46;S&#46;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Ausente&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">3&#44;2 &#40;1&#44;1-9&#44;2&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>1&#44;01-2 <a class="elsevierStyleCrossRef" href="#tblfn0005">&#42;</a> ulceraci&#243;n&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#44;06&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#44;16 &#40;0&#44;02-1&#44;05&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>2&#44;01-4 <a class="elsevierStyleCrossRef" href="#tblfn0005">&#42;</a> ulceraci&#243;n&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#44;03&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#44;15 &#40;0&#44;02-0&#44;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>4 <a class="elsevierStyleCrossRef" href="#tblfn0005">&#42;</a> ulceraci&#243;n&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#44;005&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#44;07 &#40;0&#44;01-0&#44;5&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Riesgo proporcional &#40;IC 95&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Edad &#40;a&#241;os&#41;</span></td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t">&#8230;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>65&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">1&#44;5 &#40;1&#44;1-2&#44;2&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#44;032&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">1&#44;5 &#40;1&#44;1-2&#44;2&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#44;8 &#40;0&#44;6-1&#44;1&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Hombre&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#46;S&#46;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8230;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8230;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Localizaci&#243;n</span></td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Axial&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#44;5 &#40;1&#44;2-1&#44;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#44;4 &#40;1&#44;2-1&#44;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Extremidades&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Intenso&nbsp;\t\t\t\t\t\t\n
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                  """
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        "descripcion" => array:1 [
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            0 => array:1 [
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Riesgo proporcional &#40;IC 95&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Grosor tumoral de Breslow &#40;mm&#41;</span></td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Ausente&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Presente&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">&#205;ndice mit&#243;tico &#40;mitosis&#47;mm</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleItalic">&#41;</span></td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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Información del artículo
ISSN: 00017310
Idioma original: Español
DOI:10.1016/j.ad.2014.10.012
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