Nuevo modelo pronóstico de supervivencia del cáncer de vejiga basado en los genes vinculados a la ferroptosis (FRGS)

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un nuevo tipo de muerte celular programada&#44; difiere de los procesos t&#237;picos de muerte celular&#46; Se activa por la acumulaci&#243;n de hidroper&#243;xidos lip&#237;dicos dependientes del hierro&#44; involucrando cambios citol&#243;gicos hasta llegar a la muerte celular&#46; Gracias a los avances de las investigaciones sobre la ferroptosis&#44; estudios actuales<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">3&#44;4</span></a> han revelado su compleja funci&#243;n biol&#243;gica en ciertas enfermedades humanas&#44; como la enfermedad degenerativa y la lesi&#243;n renal aguda&#46; Adem&#225;s&#44; se ha demostrado que la ferroptosis desempe&#241;a un papel importante en la supresi&#243;n del crecimiento y la progresi&#243;n tumoral<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">5</span></a>&#44; por lo que podr&#237;a constituir una terapia potencialmente beneficiosa para el c&#225;ncer&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Estudios anteriores<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">6-8</span></a> hab&#237;an indicado&#44; aunque de manera superficial&#44; una correlaci&#243;n entre la ferroptosis y el CV&#46; Recientemente&#44; Jasim y Gesquiere<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">9</span></a> informaron del desarrollo de nuevas nanopart&#237;culas polim&#233;ricas conjugadas &#40;CPNP&#41; con hierro encapsulado para terapia quimiodin&#225;mica &#40;CDT&#41;&#44; matando las c&#233;lulas tumorales a trav&#233;s de la ferroptosis&#44; con una excelente efectividad y bien dirigida hacia las c&#233;lulas tumorales&#44; espec&#237;ficamente para las c&#233;lulas tumorales de la vejiga&#46; Por lo tanto&#44; hemos realizado este estudio para explorar la funci&#243;n biol&#243;gica de los genes vinculados a la ferroptosis en el CV&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Materiales y m&#233;todos</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Expresi&#243;n de genes vinculados a la ferroptosis en el CV</span><p id="par0020" class="elsevierStylePara elsevierViewall">Descargamos el conjunto de datos del atlas del genoma del c&#225;ncer &#40;TCGA&#41; &#40;<a href="https://portal.gdc.cancer.gov/">https&#58;&#47;&#47;portal&#46;gdc&#46;cancer&#46;gov&#47;</a>&#41; en enero de 2020&#44; cuyo m&#233;todo de adquisici&#243;n y aplicaci&#243;n se ajustaba a las directrices y a las normas&#46; Se incluyeron 402 casos de c&#225;ncer de vejiga &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">tabla 1</a>&#41;&#44; y se obtuvieron los datos de recuentos brutos de secuenciaci&#243;n de ARN &#40;nivel<span class="elsevierStyleHsp" style=""></span>3&#41; y la informaci&#243;n cl&#237;nica correspondiente&#46; Se filtraron 25 genes vinculados a la ferroptosis derivados del an&#225;lisis sistem&#225;tico de Liu et al&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">10</span></a> sobre las aberraciones e implicaciones funcionales de la ferroptosis en el c&#225;ncer&#46; Exploramos la distribuci&#243;n de la expresi&#243;n del ARNm vinculado a la ferroptosis&#44; la relaci&#243;n entre la ferroptosis y el ARNm&#44; y el mapa de calor de la expresi&#243;n g&#233;nica de la ferroptosis en los tejidos del tumor vesical y en los tejidos normales&#46; Todos los m&#233;todos de an&#225;lisis mencionados y el paquete R fueron implementados por <span class="elsevierStyleItalic">The R Foundation for Statistical Computing</span> &#40;2020&#41; versi&#243;n 4&#46;0&#46;3 y los paquetes de software ggplot2 y pheatmap&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">An&#225;lisis de supervivencia</span><p id="par0025" class="elsevierStylePara elsevierViewall">Se utiliz&#243; el an&#225;lisis de supervivencia KM con la prueba log-rank para comparar la diferencia de supervivencia de 25 expresiones g&#233;nicas vinculadas a la ferroptosis en el CV del conjunto de datos TCGA&#46; Para las curvas de Kaplan-Meier se analiz&#243; la supervivencia global &#40;SG&#41; y la supervivencia espec&#237;fica de la enfermedad &#40;SEE&#41;&#44; donde se generaron los valores p y la relaci&#243;n de riesgo &#40;HR&#41; con un intervalo de confianza &#40;IC&#41; del 95&#37; mediante pruebas de log-rank y regresi&#243;n de riesgos proporcionales de Cox univariante&#46; El valor p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;05 se consider&#243; estad&#237;sticamente significativo&#46; Tras seleccionar los genes vinculados a la ferroptosis que afectaron significativamente la supervivencia en el CV&#44; estos se definieron como &#171;genes diana&#187;&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Significaci&#243;n pron&#243;stica de la expresi&#243;n g&#233;nica vinculada a la ferroptosis</span><p id="par0030" class="elsevierStylePara elsevierViewall">Realizamos an&#225;lisis de regresi&#243;n de Cox univariante y multivariante para identificar los t&#233;rminos adecuados para construir el nomograma de los &#171;genes diana&#187;&#46; Se utiliz&#243; el diagrama de bosque para mostrar el valor de p&#44; el HR y el IC del 95&#37; de cada variable a trav&#233;s del paquete R &#171;forest plot&#187;&#46; Se desarroll&#243; un nomograma basado en los resultados del an&#225;lisis multivariante de riesgos proporcionales de Cox para predecir la supervivencia global a 1&#44; 3 y 5<span class="elsevierStyleHsp" style=""></span>a&#241;os&#46; El nomograma proporcion&#243; una representaci&#243;n gr&#225;fica de los factores que pueden utilizarse para calcular la probabilidad de supervivencia de un paciente individual mediante los puntos asociados a cada factor de riesgo a trav&#233;s del paquete R &#171;rms&#187;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">11</span></a>&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Diagrama del estadio patol&#243;gico y an&#225;lisis de la metilaci&#243;n del ADN</span><p id="par0035" class="elsevierStylePara elsevierViewall">Investigamos la diferencia de expresi&#243;n en diferentes estadios patol&#243;gicos y el an&#225;lisis de metilaci&#243;n del ADN de los &#171;genes diana&#187; mediante la web UALCAN &#40;http&#58;<a href="http://ualcan.path.uab.edu/index.html">http&#58;&#47;&#47;ualcan&#46;path&#46;uab&#46;edu&#47;index&#46;html</a>&#41; y la base de datos <span class="elsevierStyleItalic">Gene Expression Profiling Interactive Analysis</span> &#40;GEPIA&#41; &#40;<a href="http://gepia.cancer-pku.cn/">http&#58;&#47;&#47;gepia&#46;cancer-pku&#46;cn&#47;</a>&#41; del proyecto TCGA&#46; Para realizar estos an&#225;lisis se utilizaron los m&#243;dulos &#171;Expresi&#243;n&#187; y &#171;Metilaci&#243;n&#187; de UALCAN&#44; con la configuraci&#243;n de &#171;Estadio individual del c&#225;ncer&#187;&#46; Mientras tanto&#44; se llev&#243; a cabo el <span class="elsevierStyleItalic">Expression analysis-Box Plots</span> de GEPIA para asegurar el diagrama del estadio patol&#243;gico&#44; y se establecieron el valor p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;05&#44; log2FC <span class="elsevierStyleItalic">&#40;fold change&#41;</span> &#60;<span class="elsevierStyleHsp" style=""></span>1 y <span class="elsevierStyleItalic">Match TCGA tumor</span>&#46; Los gr&#225;ficos de caja o viol&#237;n se aplican con datos de expresi&#243;n transformados a log2 &#40;transcripciones por mill&#243;n &#91;TPM&#93;<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>1&#41;&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">An&#225;lisis de la carga mutacional tumoral &#40;TMB&#41;</span><p id="par0040" class="elsevierStylePara elsevierViewall">Utilizamos el software R v4&#46;0&#46;3 y los paquetes R &#171;ggstatsplot&#187; para el an&#225;lisis estad&#237;stico con el fin de evaluar la relaci&#243;n entre la carga mutacional tumoral &#40;<span class="elsevierStyleItalic">tumor mutational burden</span> &#91;TMB&#93;&#41; y los &#171;genes diana&#187;&#46; La TMB se ha adquirido del art&#237;culo de Thorsson et al&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">12</span></a> de 2019&#46; Si no se indica lo contrario&#44; la prueba de suma de rangos detecta dos conjuntos de datos&#44; y un valor p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;05 se considera estad&#237;sticamente significativo&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">An&#225;lisis de enriquecimiento</span><p id="par0045" class="elsevierStylePara elsevierViewall">Navegamos por la plataforma STRING &#40;<a href="https://string-db.org/">https&#58;&#47;&#47;string-db&#46;org&#47;</a>&#41; estableciendo la b&#250;squeda de &#171;Target Genes&#187;&#44; organism &#40;&#171;Homo sapiens&#187;&#41; con los siguientes par&#225;metros principales&#58; puntuaci&#243;n de interacci&#243;n m&#237;nima requerida &#91;&#171;Low confidence &#40;0&#46;150&#41;&#187;&#93;&#44; el significado de los bordes de la red &#40;&#171;evidence&#187;&#41;&#44; el n&#250;mero m&#225;ximo de interacciones a mostrar &#40;&#171;no m&#225;s de 50 interacciones&#187;&#41; y las fuentes de interacci&#243;n activas &#40;&#171;Experiments&#187;&#41;&#46; Mientras tanto&#44; subimos las listas de genes a la <span class="elsevierStyleItalic">Database for annotation&#44; visualization&#44; and integrated discovery</span> &#40;DAVID&#41;&#44; las configuramos como &#40;&#171;OFFICIAL&#95;GENE&#95;SYMBOL&#187;&#41; y especie &#40;&#171;Homo sapiens&#187;&#41;&#44; y obtuvimos los datos del gr&#225;fico de anotaci&#243;n funcional&#46; Las v&#237;as enriquecidas se visualizaron finalmente con los paquetes R de &#171;tidyr&#187; y &#171;ggplot2&#187;&#46; Un valor p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;05 se consider&#243; estad&#237;sticamente significativo&#46; Adem&#225;s&#44; combinamos los datos anteriores en la <span class="elsevierStyleItalic">Kyoto encyclopedia of genes and genomes</span> &#40;KEGG&#41; para encontrar una posible v&#237;a<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">11&#44;13</span></a>&#46;</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Resultados</span><p id="par0050" class="elsevierStylePara elsevierViewall">Tras analizar m&#250;ltiples datos de TCGA&#44; encontramos que 23 genes vinculados a la ferroptosis ten&#237;an una fuerte correlaci&#243;n entre s&#237; en el CV&#44; y la mayor&#237;a eran de correlaci&#243;n positiva&#46; SAT1&#44; SLC1A5&#44; HSPA5&#44; SLC7A11 y CISD1 ten&#237;an cl&#250;steres m&#225;s grandes &#40;<a class="elsevierStyleCrossRef" href="#fig0010">fig&#46; 1</a>A&#41;&#46; En cuanto a la distribuci&#243;n de la expresi&#243;n&#44; ocho genes vinculados a la ferroptosis &#8212;CDKN1A&#44; HSPA5&#44; NFE2L2&#44; MT1G&#44; FANCD2&#44; CISD1&#44; TFRC&#44; NCOA4&#8212; ten&#237;an una expresi&#243;n y un mapa de calor con una diferencia significativa entre el CV y el tejido vesical normal adyacente &#40;<a class="elsevierStyleCrossRef" href="#fig0010">fig&#46; 1</a>B&#44; C&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Significaci&#243;n pron&#243;stica de la expresi&#243;n g&#233;nica vinculada a la ferroptosis</span><p id="par0055" class="elsevierStylePara elsevierViewall">Seg&#250;n los niveles de expresi&#243;n&#44; dividimos los casos de CV en dos grupos&#58; de baja expresi&#243;n y de alta expresi&#243;n&#46; Se realizaron curvas de supervivencia de Kaplan-Meier para trazar la asociaci&#243;n en los resultados de supervivencia de los pacientes con CV&#44; utilizando principalmente los conjuntos de datos de TCGA&#46; Encontramos que los pacientes de CV con niveles de expresi&#243;n gradualmente ascendentes de HSPA5 y CISD1 tendr&#237;an una SG y diferentes&#46; La expresi&#243;n baja de CISD1 tiene una mejor SG &#40;<a class="elsevierStyleCrossRef" href="#fig0015">fig&#46; 2</a>A&#41; y una mejor supervivencia libre de enfermedad &#40;SLE&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0015">fig&#46; 2</a>C&#41; que la expresi&#243;n alta&#46; De forma similar&#44; se mostr&#243; un resultado peor de SG &#40;<a class="elsevierStyleCrossRef" href="#fig0015">fig&#46; 2</a>B&#41; y una SLE &#40;<a class="elsevierStyleCrossRef" href="#fig0015">fig&#46; 2</a>D&#41; en la expresi&#243;n alta de HSPA5&#46; Por lo tanto&#44; estos dos genes se consideraron &#171;genes diana&#187;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Construcci&#243;n del modelo predictivo</span><p id="par0060" class="elsevierStylePara elsevierViewall">Intentamos construir un modelo predictivo que combinara los &#171;genes diana&#187; con algunas covariables clinicopatol&#243;gicas principales&#46; Se realizaron an&#225;lisis univariantes y multivariantes para explorar el HR en el CV&#46; HSPA5 &#40;HR&#58; 1&#44;31&#59; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;014&#41; y CISD1 &#40;HR&#58; 1&#44;33&#59; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;0049&#41; tuvieron una influencia significativa en el an&#225;lisis univariante &#40;<a class="elsevierStyleCrossRef" href="#fig0020">fig&#46; 3</a>A&#41;&#44; y combinando con el an&#225;lisis multivariante&#44; CISD1 tambi&#233;n se mostr&#243; como factor pron&#243;stico &#40;HR&#58; 1&#44;56&#59; p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;05&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0020">fig&#46; 3</a>B&#41; de manera significativa&#46; Realizamos el nomograma y construimos un modelo para predecir las tasas de SG de 1 a 5<span class="elsevierStyleHsp" style=""></span>a&#241;os en el grupo de estudio utilizando el algoritmo de regresi&#243;n de Cox&#46; Los predictores inclu&#237;an la expresi&#243;n de CISD1&#44; la edad de los pacientes&#44; la pTNM&#44; el cumpliendo con los criterios de p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;05 en la evaluaci&#243;n del riesgo y las tasas de SG de 1 a 5<span class="elsevierStyleHsp" style=""></span>a&#241;os&#44; que fueron altamente predictivas en comparaci&#243;n con un modelo ideal en toda la cohorte &#40;&#237;ndice C&#58; 0&#44;697&#59; p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0020">fig&#46; 3</a>C-D&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Gr&#225;fico de estadios patol&#243;gicos y metilaci&#243;n del ADN</span><p id="par0065" class="elsevierStylePara elsevierViewall">Exploramos a fondo la correlaci&#243;n de los niveles de HSPA5 y CISD1 con los diferentes estadios patol&#243;gicos&#46; Como se muestra en las figuras&#44; HSPA5 presentaba diferencias significativas entre estadios &#40;<a class="elsevierStyleCrossRef" href="#fig0025">fig&#46; 4</a>A&#44;B&#41;&#44; y CISD1 tambi&#233;n se expresaba de forma diferente en el tejido normal y en el estadio 1&#47;2 del c&#225;ncer de vejiga &#40;<a class="elsevierStyleCrossRef" href="#fig0025">fig&#46; 4</a>C&#44;D&#41;&#46; Adem&#225;s&#44; se demostr&#243; que los estadios m&#225;s altos &#40;T3-4&#41; se asociaban a una mayor expresi&#243;n de HSPA5 &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;01 en la <a class="elsevierStyleCrossRef" href="#fig0025">fig&#46; 4</a>B&#41;&#46; As&#237; mismo&#44; se analiz&#243; la metilaci&#243;n del ADN mediante UALCAN&#44; y los resultados mostraron que HSPA5 y CISD1 ten&#237;an una tasa de metilaci&#243;n m&#225;s baja que el tejido normal &#40;<a class="elsevierStyleCrossRef" href="#fig0030">fig&#46; 5</a>&#41;&#46;</p><elsevierMultimedia ident="fig0025"></elsevierMultimedia><elsevierMultimedia ident="fig0030"></elsevierMultimedia></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">An&#225;lisis de enriquecimiento</span><p id="par0070" class="elsevierStylePara elsevierViewall">Con el objetivo de estudiar a fondo el mecanismo molecular y la importancia biol&#243;gica de los genes vinculados a la ferroptosis en el CV&#44; intentamos seleccionar los genes y v&#237;as relacionados con la expresi&#243;n de HPSA5 mediante an&#225;lisis de enriquecimiento&#46; Bas&#225;ndonos en la herramienta STRING&#44; varios genes como HSP90B1&#44; ATF6&#44; CANX&#44; CALR&#44; DNAJC10&#44; PDIA3&#44; ERN1&#44; DNAJB11&#44; PDIA4 y P4HB ten&#237;an una fuerte correlaci&#243;n con HSPA &#40;<a class="elsevierStyleCrossRef" href="#fig0035">fig&#46; 6</a>A&#41;&#46; Adem&#225;s&#44; los an&#225;lisis de enriquecimiento de GO mostraron que HSPA5 estaba implicado en la uni&#243;n y en la actividad de prote&#237;nas&#44; especialmente en la adhesi&#243;n de prote&#237;nas desplegadas&#44; la actividad de la disulfuro oxidorreductasa y la uni&#243;n de prote&#237;nas Hsp70 &#40;<a class="elsevierStyleCrossRef" href="#fig0035">fig&#46; 6</a>B&#41;&#46; Tambi&#233;n se aplic&#243; KEGG para encontrar posibles v&#237;as&#46; La replicaci&#243;n del ADN&#44; el ciclo celular&#44; la exportaci&#243;n de prote&#237;nas&#44; la v&#237;a de se&#241;alizaci&#243;n de P53&#44; etc&#46;&#44; tambi&#233;n fueron relevantes &#40;<a class="elsevierStyleCrossRef" href="#fig0035">fig&#46; 6</a>C&#41;&#46;</p><elsevierMultimedia ident="fig0035"></elsevierMultimedia></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">An&#225;lisis de carga mutacional tumoral &#40;TMB&#41;</span><p id="par0075" class="elsevierStylePara elsevierViewall">Para explorar m&#225;s a fondo el papel de HSPA5 y CISD1 en la tumorig&#233;nesis del CV realizamos un an&#225;lisis de correlaci&#243;n de Spearman de TMB con HSPA5 y CISD1&#46; Debemos destacar que encontramos una interacci&#243;n positiva entre HSPA5 y TMB &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;02&#59; <a class="elsevierStyleCrossRef" href="#sec0095">fig&#46; S1</a>&#41;&#46;</p></span></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Discusi&#243;n</span><p id="par0080" class="elsevierStylePara elsevierViewall">El c&#225;ncer de vejiga es un carcinoma urotelial maligno que supone una amenaza para la salud humana<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">14</span></a>&#46; La resecci&#243;n quir&#250;rgica&#44; la terapia de infusi&#243;n intravesical&#44; la quimioterapia&#44; la inmunoterapia&#44; etc&#46;&#44; eran tratamientos opcionales&#59; sin embargo&#44; la supervivencia del CV no era la esperada<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">15</span></a>&#46; Lo importante para prolongar el tiempo de supervivencia puede residir en encontrar un nuevo m&#233;todo subsidiario o nuevas terapias&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">La ferroptosis<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">16</span></a> tiene caracter&#237;sticas y mecanismos que difieren de aquellos de la apoptosis y la necroptosis&#44; y con frecuencia participa en la regulaci&#243;n de diversas enfermedades&#46; Adicionalmente&#44; se ha confirmado una funci&#243;n potencial de supresi&#243;n del crecimiento tumoral y de eliminaci&#243;n de las c&#233;lulas tumorales<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">17</span></a>&#46; Recientemente&#44; Zekun Liu inform&#243; de que los veinticuatro genes reguladores de la ferroptosis &#40;FRG&#41; desempe&#241;aban funciones esenciales en la regulaci&#243;n de la ferroptosis tumoral&#46; Con el objetivo de evaluar la correlaci&#243;n de los FRG con el CV en el presente estudio&#44; demostramos que algunos genes vinculados a la ferroptosis&#44; SAT1&#44; SLC1A5&#44; HSPA5&#44; SLC7A11 y CISD1&#44; ten&#237;an una fuerte relaci&#243;n entre s&#237; en el c&#225;ncer vesical&#46; Al investigar m&#225;s a fondo su expresi&#243;n y el mapa de calor&#44; encontramos que CDKN1A&#44; HSPA5&#44; NFE2L2&#44; MT1G&#44; FANCD2&#44; CISD1&#44; TFRC&#44; NCOA4 ten&#237;an una distribuci&#243;n de expresi&#243;n diferente en el c&#225;ncer vesical&#46; En particular&#44; los distintos niveles de HSPA5 y CISD1 afectan significativamente la SG y la SLE de los pacientes con c&#225;ncer de vejiga&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">En consonancia con el estudio anterior&#44; Zhu et al&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">18</span></a> demostraron que HSPA5 regula la muerte celular por ferroptosis a trav&#233;s de la v&#237;a HSPA5- GPX4 en las c&#233;lulas cancerosas&#46; En la investigaci&#243;n de Yuan et al&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">19</span></a>&#44; los autores demostraron que CISD1&#44; una prote&#237;na de la membrana mitocondrial externa que posee un dominio de uni&#243;n a hierro&#44; ten&#237;a un papel novedoso en la protecci&#243;n contra la lesi&#243;n mitocondrial en la ferroptosis y pod&#237;a regular negativamente la muerte celular por ferroptosis del c&#225;ncer&#46; El HSPA5 ten&#237;a un papel realmente importante en la regulaci&#243;n de la homeostasis mitocondrial&#44; tambi&#233;n involucrado en la ferroptosis&#46; Tras analizar los resultados&#44; hemos supuesto que HSPA5 y CISD1 ten&#237;an un papel importante en la inhibici&#243;n del crecimiento y de la progresi&#243;n tumoral&#46; En nuestro estudio descubrimos que CISD1 tambi&#233;n se mostraba como factor pron&#243;stico &#40;HR&#58; 1&#44;56&#59; p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;05&#41; de manera significativa&#44; y que ten&#237;a un nomograma perfecto para predecir la SG a un a&#241;o &#40;&#237;ndice C&#58; 0&#44;701&#59; p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">Al investigar exhaustivamente&#44; confirmamos que HSPA5 y CISD1 ten&#237;an una tasa de metilaci&#243;n del ADN inferior a la del tejido normal y que HSPA5 ten&#237;a una interacci&#243;n positiva con TMB &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;02&#41;&#46; Adem&#225;s&#44; seg&#250;n el an&#225;lisis de enriquecimiento y KEGG&#44; HSPA5 participaba en la replicaci&#243;n del ADN y en la v&#237;a de se&#241;alizaci&#243;n de P53&#44; y CISD1 mediaba la fosforilaci&#243;n oxidativa y la regulaci&#243;n positiva de la v&#237;a de se&#241;alizaci&#243;n intr&#237;nseca de la apoptosis&#46; De la misma manera que estudios anteriores<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">20-22</span></a> hab&#237;an informado que las v&#237;as de se&#241;alizaci&#243;n y los genes relacionados anteriormente afectaban a la carcinog&#233;nesis y la progresi&#243;n&#44; seg&#250;n nuestro estudio&#44; HSPA5 y CISD1 podr&#237;an contribuir a la supresi&#243;n de la tumorig&#233;nesis en el CV&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Hemos tenido que admitir ciertas limitaciones en este estudio&#46; Aunque se utilizaron varias bases de datos en el an&#225;lisis&#44; fueron necesarios m&#225;s ensayos cl&#237;nicos e investigaciones celulares para verificar las funciones de los genes vinculados a la ferroptosis&#46; Adem&#225;s&#44; descubrimos que el HSPA5 pod&#237;a estar involucrado en la v&#237;a de se&#241;alizaci&#243;n de p53 que afectaba al CV&#44; pero se opt&#243; por estudiar las v&#237;as claras de tumorig&#233;nesis&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">En conclusi&#243;n&#44; nuestro estudio confirm&#243; que los genes vinculados a la ferroptosis ten&#237;an una fuerte correlaci&#243;n con el CV&#59; en particular&#44; HSPA5 y CISD1 pueden desempe&#241;ar un papel en la inducci&#243;n de la ferroptosis para suprimir la tumorig&#233;nesis de la vejiga y CISD1 puede ser un nuevo biomarcador pron&#243;stico&#44; as&#237; como una diana eficaz para el diagn&#243;stico y el tratamiento en el CV&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Consideraciones &#233;ticas</span><p id="par0110" class="elsevierStylePara elsevierViewall">Este art&#237;culo no contiene ning&#250;n estudio con participantes humanos o animales realizado por el autor&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Contribuciones de los autores</span><p id="par0115" class="elsevierStylePara elsevierViewall">Metodolog&#237;a&#44; redacci&#243;n del borrador original&#44; Yue Yang&#59; programas inform&#225;ticos&#44; Hanchao Zhang&#59; an&#225;lisis formal&#44; Lin Chen&#59; conservaci&#243;n de datos&#44; Haifeng Hu&#59; redacci&#243;n-revisi&#243;n y edici&#243;n&#44; Jin Yang&#46;</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Conflicto de intereses</span><p id="par0135" class="elsevierStylePara elsevierViewall">Los autores declaran no tener ning&#250;n conflicto de intereses&#46;</p></span></span>"
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    "fechaAceptado" => "2021-12-11"
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            1 => "Ferroptosis"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introducci&#243;n</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">El c&#225;ncer de vejiga &#40;CV&#41; es un carcinoma urotelial maligno con altas tasas de mortalidad&#46; La ferroptosis es un nuevo tipo de muerte celular programada&#44; cuyo funcionamiento impide el crecimiento y la progresi&#243;n tumoral&#46; Sin embargo&#44; existen pocos estudios centrados en la ferroptosis y el CV&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Materiales y m&#233;todos</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Exploramos las posibles funciones oncog&#233;nicas de los genes vinculados a la ferroptosis en el CV bas&#225;ndonos en m&#250;ltiples conjuntos de datos p&#250;blicos&#46; Posteriormente utilizamos la regresi&#243;n de Cox univariante y multivariante para construir un nuevo modelo de supervivencia basado en los genes vinculados a la ferroptosis para predecir la supervivencia en el CV&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Resultados</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Encontramos que 23 genes vinculados a la ferroptosis estaban fuertemente correlacionados entre s&#237; en el CV&#46; Ocho genes vinculados a la ferroptosis &#8212;CDKN1A&#44; HSPA5&#44; NFE2L2&#44; MT1G&#44; FANCD2&#44; CISD1&#44; TFRC&#44; NCOA4&#8212; ten&#237;an una expresi&#243;n y un mapa de calor significativamente diferentes&#46; HSPA5 y CISD1 mostraron una diferencia estad&#237;sticamente significativa en t&#233;rminos de supervivencia global &#40;SG&#41; y supervivencia libre de enfermedad &#40;SLE&#41;&#46; Adem&#225;s&#44; CISD1 ten&#237;a un nomograma excelente para predecir la SG a 1-3-5<span class="elsevierStyleHsp" style=""></span>a&#241;os &#40;&#237;ndice<span class="elsevierStyleHsp" style=""></span>C&#58; 0&#44;701&#59; p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;&#46; Adicionalmente&#44; HSPA5 y CISD1 ten&#237;an una tasa de metilaci&#243;n del ADN inferior a la del tejido normal y HSPA5 ten&#237;a un v&#237;nculo positivo con la carga mutacional tumoral &#40;<span class="elsevierStyleItalic">tumor mutational burden</span> &#91;TMB&#93;&#41; &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;02&#41;&#46; Adem&#225;s&#44; se observ&#243; participaci&#243;n del HSPA5 en la replicaci&#243;n del ADN y en la v&#237;a de se&#241;alizaci&#243;n de P53&#44; y mediaci&#243;n del CISD1 en la fosforilaci&#243;n oxidativa y la regulaci&#243;n positiva de la v&#237;a intr&#237;nseca de la apoptosis&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusi&#243;n</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Los genes vinculados a la ferroptosis mostraron una fuerte correlaci&#243;n con el CV&#59; en particular&#44; puede ser relevante el papel de HSPA5 y CISD1 en la inducci&#243;n de la ferroptosis para suprimir la tumorig&#233;nesis vesical y el gen CISD1 puede ser un nuevo biomarcador pron&#243;stico&#44; as&#237; como una diana eficaz para el diagn&#243;stico y el tratamiento del CV&#46;</p></span>"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Background</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Bladder cancer &#40;BLCA&#41; is a malignant urothelial carcinoma with a high mortality rate&#46; Ferroptosis is a new type of programmed cell death and functions in suppressing tumor growth and progression&#46; However&#44; few studies focus on ferroptosis and BLCA&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Materials and methods</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">We explored the potential oncogenic roles of ferroptosis-related genes in BLCA based on multiple public datasets&#46; We then used univariate and multivariate cox regression to build a new survival model based on ferroptosis-related genes to predict the survival of BLCA&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Results</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">We found that 23 ferroptosis-related genes had a strong correlation with each other in BLCA&#46; Eight ferroptosis-related genes&#44; CDKN1A&#44; HSPA5&#44; NFE2L2&#44; MT1G&#44; FANCD2&#44; CISD1&#44; TFRC&#44; NCOA4&#44; had a significantly different expression and heat-map&#46; HSPA5 and CISD1 have a statistically significant difference in OS and DFS&#46; Besides&#44; CISD1 had an ideal nomogram to predict the 1-3-5-year OS &#40;C-index&#58; 0&#46;701&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#46; Furthermore&#44; HSPA5 and CISD1 had a lower DNA methylation rate than normal tissue and HSPA5 had a positive connection with tumor mutational burden &#40;TMB&#41; &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;02&#41;&#46; In addition&#44; HSPA5 participated in the DNA replication and P53 signaling pathway&#44; and CISD1 mediated the oxidative phosphorylation and positive regulation of the intrinsic apoptotic signaling pathway&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusion</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Ferroptosis-related genes had a strong correlation with BLCA&#44; notably&#44; HSPA5 and CISD1 may play a role in inducing ferroptosis to suppress bladder tumorigenesis and CISD1 can be a novel prognostic biomarker as well as an effective target for diagnosis and treatment in BLCA&#46;</p></span>"
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          "es" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">An&#225;lisis de correlaci&#243;n&#46; A&#41;<span class="elsevierStyleHsp" style=""></span>Correlaci&#243;n de 23 genes vinculados a la ferroptosis en el CV&#46; El c&#237;rculo representa el ARNm relacionado con la ferroptosis&#44; y las l&#237;neas representan la relaci&#243;n entre genes&#46; El rojo representa la correlaci&#243;n positiva y el azul&#44; la negativa&#46; La l&#237;nea m&#225;s gruesa representa una mayor correlaci&#243;n entre los dos genes&#46; B&#41;<span class="elsevierStyleHsp" style=""></span>Expresi&#243;n del ARNm vinculado a la ferroptosis en los tejidos de CV y normales&#46; El eje horizontal representa diferentes ARNm&#44; el eje vertical representa la distribuci&#243;n de la expresi&#243;n del ARNm&#44; los diferentes colores representan diferentes grupos&#44; y la esquina superior izquierda representa el m&#233;todo de prueba del valor p de significaci&#243;n&#46; Los asteriscos representan los niveles de significaci&#243;n&#46; C&#41;<span class="elsevierStyleHsp" style=""></span>Mapa de calor de la expresi&#243;n g&#233;nica vinculada a la ferroptosis&#44; donde los diferentes colores representan la tendencia de expresi&#243;n en las diferentes muestras &#40;&#42;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;05&#59; &#42;&#42;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;01&#59; &#42;&#42;&#42;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;&#46;</p>"
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          "es" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">An&#225;lisis de supervivencia de Kaplan-Meier&#58; supervivencia global &#40;SG&#41; de CISD1 &#40;A&#41; y HSPA5 &#40;B&#41;&#59; supervivencia libre de enfermedad &#40;SLE&#41; de CISD1 &#40;D&#41; y HSPA5 &#40;E&#41;&#46;</p>"
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          "es" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Modelo predictivo&#58; an&#225;lisis univariante &#40;A&#41; y multivariante &#40;B&#41; de HSPA5 y CISD1&#46; C&#41;<span class="elsevierStyleHsp" style=""></span>Nomograma de CISD1 para predecir la supervivencia global a 1-3-5<span class="elsevierStyleHsp" style=""></span>a&#241;os de los pacientes con CV&#46; D&#41;<span class="elsevierStyleHsp" style=""></span>Curva de calibraci&#243;n del modelo de nomograma de supervivencia global en el grupo&#46; La l&#237;nea diagonal discontinua representa el nomograma ideal&#46;</p>"
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          "es" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Gr&#225;fico de los estadios patol&#243;gicos&#46; A&#41;<span class="elsevierStyleHsp" style=""></span>Expresi&#243;n de HSPA5 basada en el estadio individual del c&#225;ncer por UALCAN&#46; B&#41;<span class="elsevierStyleHsp" style=""></span>Gr&#225;fico de estadios patol&#243;gicos de HSPA5 por GEPIA&#46; C&#41;<span class="elsevierStyleHsp" style=""></span>Expresi&#243;n de CISD1 basada en el estadio individual del c&#225;ncer por UALCAN&#46; D&#41;<span class="elsevierStyleHsp" style=""></span>Gr&#225;fico de los estadios patol&#243;gicos de CISD1 seg&#250;n GEPIA&#46;</p>"
        ]
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      4 => array:7 [
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          "es" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Nivel de metilaci&#243;n del promotor en CV&#46; A&#41;<span class="elsevierStyleHsp" style=""></span>CISD1&#46; B&#41;<span class="elsevierStyleHsp" style=""></span>HSPA5&#46;</p>"
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      5 => array:7 [
        "identificador" => "fig0035"
        "etiqueta" => "Figura 6"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
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          "es" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">An&#225;lisis de enriquecimiento&#58; A&#41;<span class="elsevierStyleHsp" style=""></span>Primero obtuvimos las prote&#237;nas de uni&#243;n a HSPA5 determinadas experimentalmente utilizando la herramienta STRING&#46; B&#41;<span class="elsevierStyleHsp" style=""></span>Funci&#243;n molecular &#40;oncolog&#237;a gen&#233;tica&#41; de HSPA5&#46; C&#41;<span class="elsevierStyleHsp" style=""></span>Sobre la base de los genes de uni&#243;n a HSPA5 y de los genes interactuados se realiz&#243; un an&#225;lisis de v&#237;as KEGG&#46;</p>"
        ]
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Caracter&#237;stica&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Grupo 1&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Grupo 2&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">157&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  " align="left" valign="\n
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                  \t\t\t\t">149&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="left" valign="\n
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                  \t\t\t\t">149&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">1&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Edad&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Media &#40;DE&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">60&#44;1 &#40;11&#44;2&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">61&#44;1 &#40;11&#44;9&#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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Mediana &#91;min&#44; max&#93;&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">60 &#91;19&#44;90&#93;&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">61 &#91;19&#44;90&#93;&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="left" valign="\n
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                  \t\t\t\t">0&#44;222&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Sexo&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="left" valign="\n
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                  \t\t\t\t">Mujer&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
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">134&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="" valign="\n
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                  \t\t\t\t</td><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">Var&#243;n&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="left" valign="\n
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                  \t\t\t\t">234&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="left" valign="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Indio americano&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
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                  \t\t\t\t">2&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">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Asi&#225;tico&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&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">10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Negro&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">34&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">47&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Blanco&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">260&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">428&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;82&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Estadio pT&#95;&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">T1&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">34&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">T2&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">44&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="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\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
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MX&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">20&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;687&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Estadio pTNM&#95;&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">IVA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">290&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">290&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
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">IVB&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">13&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">13&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
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">IVC&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">I&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">25&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">II&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">81&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">III&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">90&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="left" 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></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Grado&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">G1&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">27&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">62&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">G2&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">190&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">300&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
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">G3&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">76&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">119&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
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">G4&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="left" 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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">GX&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No disponible&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;722&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Estadio tumor&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Met&#225;stasis&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">18&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">19&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
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Primario&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9&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
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Recurrente&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">22&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">39&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;421&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tabaquismo&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No fumador&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">59&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">111&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Fumador&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">240&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">381&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;395&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Radioterapia&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">21&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">62&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">S&#237;&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">93&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">121&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;006&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Terapia neoadyuvante previa&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">S&#237;&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">302&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">492&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;656&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tipo de terapia&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Quimioterapia&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">130&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">159&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Quimioterapia&#58; Inmunoterapia&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Quimioterapia&#58; Terapia molecular dirigida&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Quimioterapia&#58; Terapia molecular dirigida&#58; Vacuna&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="left" 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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inmunoterapia&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="left" 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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Quimioterapia&#58; Otros&#44; especificar en las notas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" 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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;999&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "es" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Caracter&#237;sticas de los pacientes incluidos en el TCGA</p>"
        ]
      ]
      7 => array:5 [
        "identificador" => "fig0005"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => false
        "mostrarDisplay" => true
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "mmc1.jpeg"
            "Alto" => 2535
            "Ancho" => 2508
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          ]
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    "bibliografia" => array:2 [
      "titulo" => "Bibliograf&#237;a"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0015"
          "bibliografiaReferencia" => array:22 [
            0 => array:3 [
              "identificador" => "bib0115"
              "etiqueta" => "1"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The global burden of urinary bladder cancer&#58; An update"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "A&#46; Richters"
                            1 => "K&#46; Aben"
                            2 => "L&#46; Kiemeney"
                          ]
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                    0 => array:2 [
                      "doi" => "10.1007/s00345-019-02984-4"
                      "Revista" => array:6 [
                        "tituloSerie" => "World J Urol&#46;"
                        "fecha" => "2020"
                        "volumen" => "38"
                        "paginaInicial" => "1895"
                        "paginaFinal" => "1904"
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                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31676912"
                            "web" => "Medline"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Bladder cancer&#58; A review"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "A&#46;T&#46; Lenis"
                            1 => "P&#46;M&#46; Lec"
                            2 => "K&#46; Chamie"
                            3 => "M&#46;D&#46; Mshs"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1001/jama.2020.17598"
                      "Revista" => array:6 [
                        "tituloSerie" => "JAMA&#46;"
                        "fecha" => "2020"
                        "volumen" => "324"
                        "paginaInicial" => "1980"
                        "paginaFinal" => "1991"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/33201207"
                            "web" => "Medline"
                          ]
                        ]
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