Central nervous system relapse in diffuse large B cell lymphoma: Risk factors

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Distribution of the screening rates of hazardous drinking and harmful drinking and brief advice obtained from ODHIN project.<a class="elsevierStyleCrossRef" href="#bib0145">29</a>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Antoni Gual, José Zarco, Joan Colom Farran, Jürgen Rehm" "autores" => array:5 [ 0 => array:2 [ "nombre" => "Antoni" "apellidos" => "Gual" ] 1 => array:2 [ "nombre" => "José" "apellidos" => "Zarco" ] 2 => array:2 [ "nombre" => "Joan" "apellidos" => "Colom Farran" ] 3 => array:2 [ "nombre" => "Jürgen" "apellidos" => "Rehm" ] 4 => array:1 [ "colaborador" => "on behalf of the Group for the Study of Hypertension and Alcohol Use Disorder" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0025775315004625" "doi" => "10.1016/j.medcli.2015.07.014" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775315004625?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020616301838?idApp=UINPBA00004N" "url" => "/23870206/0000014600000002/v1_201605240650/S2387020616301838/v1_201605240650/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S2387020616301395" "issn" => "23870206" "doi" => "10.1016/j.medcle.2015.06.002" "estado" => "S300" "fechaPublicacion" => "2016-01-15" "aid" => "3368" "copyright" => "Elsevier España, S.L.U." 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Chillarón, Juan Pedro-Botet" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Mercè" "apellidos" => "Fernández-Miró" ] 1 => array:2 [ "nombre" => "Juan J." 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It is a heterogeneous group of diseases with similar cellular origin and aggressive clinical behavior. Its unknown etiopathogenesis involves immunodeficiency situations, contact with toxic agents and even viruses.<a class="elsevierStyleCrossRef" href="#bib0235">1</a>Lymph nodes are the most common manifestation, although nearly half of the cases may have extranodal involvement. Lymph node biopsy shows diffuse large cell infiltration, with a B-phenotype cell origin, and characteristically they express CD20 antigen in their membrane. Two distinct profiles of gene expression have been identified through microarray assays: germinal center DLBCL and activated B-cell DLBCL, with a different clinical behavior and prognosis.<a class="elsevierStyleCrossRef" href="#bib0235">1</a>The prognosis depends on factors derived from the patient, lymphoma and its extension, and treatment. The international prognostic index (IPI)<a class="elsevierStyleCrossRef" href="#bib0240">2</a> considers five factors with unfavorable prognostic influence: age (>60 years versus ≤60 years), condition of the patient (by the Eastern Cooperative Oncology Group scale, 2-4 versus 0-1), Ann Arbor stage (3-4 versus 1-2), number of extranodal sites (≥2 versus <2) and serum lactate dehydrogenase (LDH) levels. Thus, good prognosis is described as patients with an IPI value 0–2, while the prognosis worsens in patients with 3–5 IPI scores. There is a simplified IPI, the age-adjusted IPI (aaIPI), assigning only one score to poor general condition, high serum LDH levels and advanced Ann Arbor stage.The standard treatment in DLBCL patients is based on the R-CHOP or R-CHOP-like immunochemotherapy, where the monoclonal anti-CD20 antibody rituximab is combined with the standard CHOP pattern (which includes cyclophosphamide, doxorubicin, vincristine and prednisone), administered every 21 days for 6–8 cycles. With this treatment, complete response rates are above 75%, and long term event-free survival is around 63–74%, depending on the prognosis.<a class="elsevierStyleCrossRefs" href="#bib0245">3–5</a>Central nervous system relapse in diffuse large B-cell lymphomaNeuromeningeal relapse in lymphoma patients is a complication that occurs in about 5% of patients (with large variability depending on the subtype of lymphoma), usually in the course of progressive disease. NHLs can invade the central nervous system (CNS) as a meningeal or intraparenchymal infiltration. The site, although heterogeneous, usually lies in the skull base and around the spinal cord.<a class="elsevierStyleCrossRef" href="#bib0260">6</a> The mechanisms of neuromeningeal infiltration include hematogenous spread, direct spread from adjacent tumors and centripetal migration following perineural or perivascular spaces.<a class="elsevierStyleCrossRef" href="#bib0265">7</a> The prognosis after infiltration into the CNS is very negative, and patients suffering it have a deteriorating quality of life due to both infiltration itself and the toxicity associated with treatments against CNS (radiotherapy, intrathecal [IT] chemotherapy and high-dose systemic chemotherapy).Risk factors of neuromeningeal relapse in patients with lymphoma have been identified through the analysis of large series. The histological subtype is the main risk factor. Therefore, the high-grade histological subtypes, such as lymphoblastic or Burkitt lymphoma should systematically receive prophylaxis of neuromeningeal infiltration because of their well-known propensity to infiltrate the CNS. However, low-grade lymphomas have low risk of infiltration and CNS prophylaxis is not recommended. The most controversial group regarding neuromeningeal prophylaxis consists of other aggressive lymphomas, especially DLBCL, with CNS relapse rates of around 5%, in which there is no consensus on when to administer prophylaxis.<a class="elsevierStyleCrossRefs" href="#bib0260">6–8</a> Given the poor prognosis of CNS relapse, with a survival below 6 months,<a class="elsevierStyleCrossRefs" href="#bib0275">9–11</a> identifying patients at risk of relapse is essential to decide when and how to administer prophylaxis, especially in those with DLBCL. However, finding risk factors leads to difficulties, such as the retrospective nature of most studies, inclusion of various aggressive lymphomas other than DLBCL, the fact that CNS relapse is not a frequent event in DLBCL, and type heterogeneity and prophylaxis criteria,<a class="elsevierStyleCrossRef" href="#bib0270">8</a> which do not allow comparison among different studies. In addition, the impact of new diagnostic techniques, such as Multiparameter flow cytometry,<a class="elsevierStyleCrossRef" href="#bib0290">12</a> or new treatments developed in the past decade, especially rituximab, whose influence on the neuromeningeal relapse is still unclear.Regarding the influence of adding rituximab to standard treatment of DLBCL, several studies have shown a decreased CNS relapse rate<a class="elsevierStyleCrossRefs" href="#bib0280">10,11,13–16</a> compared to pre-rituximab era. This proves that the best lymphoma systemic control might protect against infiltration into the CNS. A modification in the pattern of neuromeningeal relapse has also been observed, with predominance of parenchymal relapses,<a class="elsevierStyleCrossRefs" href="#bib0280">10,11,13,14,17–19</a> the isolated on CNS,<a class="elsevierStyleCrossRefs" href="#bib0280">10,19,20</a> or late relapses. However, this tendency to a lower rate of relapses in the CNS has not been corroborated by other authors.<a class="elsevierStyleCrossRefs" href="#bib0275">9,18,20–23</a> A recent meta-analysis<a class="elsevierStyleCrossRef" href="#bib0350">24</a> showed significant decreased incidence of neuromeningeal relapse in patients receiving rituximab (4.7 compared to 5.7%, odds ratio 0.7, confidence interval 95% 0.54–0.91), and the recent British guidelines agree with this<a class="elsevierStyleCrossRef" href="#bib0355">25</a> (<a class="elsevierStyleCrossRefs" href="#tbl0005">Tables 1 and 2</a>).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Risk factors for central nervous system relapse in the pre-rituximab and rituximab erasIn pre-rituximab era, several retrospective studies<a class="elsevierStyleCrossRefs" href="#bib0360">26–29</a> described a higher rate of relapses in the CNS in patients with high serum LDH levels and/or presence of more than one extranodal site affected by the lymphoma. In the paper by Van Besien et al.,<a class="elsevierStyleCrossRef" href="#bib0360">26</a> with more than 600 patients with B-lymphoma, neuromeningeal relapse was observed in 24 (4.5%), although only 11 had high serum LDH levels and more than one extranodal site. These same factors were described in a large French study.<a class="elsevierStyleCrossRef" href="#bib0365">27</a> However after using the IPI in the multivariate analysis, only this index was associated with increased risk of CNS relapse. The IPI was also a risk factor for neuromeningeal relapse in a study by the Southwest Oncology Group,<a class="elsevierStyleCrossRef" href="#bib0385">31</a> along with more than one extranodal site. However, another large Nordic study<a class="elsevierStyleCrossRef" href="#bib0370">28</a> showed a model of risk of CNS relapse based on 5 independent factors including high serum LDH levels and infiltration in more than one extranodal site (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>).<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>In the era of immuno-chemotherapy a French study<a class="elsevierStyleCrossRef" href="#bib0275">9</a> in DLBCL patients aged over 60, randomized to CHOP or R-CHOP found that the only risk factor for CNS relapse was an aaIPI>1, present in all patients with CNS relapse, but also in over 60% of all study patients. After excluding the aaIPI from analysis, an increased serum LDH and a poor general condition (performance status [PS]>1) were independent predictors of CNS relapse. In a similar study,<a class="elsevierStyleCrossRef" href="#bib0280">10</a> also in DLBCL patients aged over 60, were randomized to chemotherapy with R-CHOP or CHOP administered every 14 days, with CNS prophylaxis with IT chemotherapy in high-risk patients. When analyzed only patients treated with R-CHOP, the independent risk factors associated with CNS relapse were: more than one extranodal site, high serum LDH and PS>1. This combination of risk factors was present in 4.8% of patients where the probability of relapse was 33.5% compared to only 2.8% in the remaining patients who received R-CHOP. Also, in a review of 2196 patients with aggressive B-cell lymphoma treated with clinical trials of the German High-Grade Non-Hodgkin Lymphoma Study Group<a class="elsevierStyleCrossRef" href="#bib0305">15</a> it was found that high serum LDH levels and the condition of more than one extranodal site were associated with CNS relapse (multivariate analysis). However, the combination of these risk factors failed in predicting neuromeningeal relapse in over 70% of cases. High serum LDH levels have also been described as a risk factor for neuromeningeal relapse in other studies of posrituximab era,<a class="elsevierStyleCrossRefs" href="#bib0295">13,21</a> as well as infiltration of more than one extranodal<a class="elsevierStyleCrossRef" href="#bib0295">13</a> site and an intermediate-high or high IPI.<a class="elsevierStyleCrossRefs" href="#bib0305">15,19,21</a> In a recent meta-analysis<a class="elsevierStyleCrossRef" href="#bib0350">24</a> both high serum LDH and the presence of more than one extranodal sites were independent risk factors of neuromeningeal relapse (<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>). With these results a recent<a class="elsevierStyleCrossRef" href="#bib0390">32</a> review has recommended to consider as patients at high risk of CNS relapse, those with high serum LDH and more than one extranodal site.<elsevierMultimedia ident="tbl0020"></elsevierMultimedia>Extranodal involvement as a risk factor for central nervous system relapseRegarding the testicular infiltration, either as primary lymphoma site or as an extended lymph node lymphoma, evidence of an increased risk of CNS relapse is clear both in the pre and postrituximab studies.<a class="elsevierStyleCrossRefs" href="#bib0285">11,17,22,33–36</a> In what is probably the study with the highest number of patients (373 primary testicular lymphomas),<a class="elsevierStyleCrossRef" href="#bib0400">34</a> the neuromeningeal relapse rate was 15% (only 18% of patients received IT prophylaxis), similar to that of another study.<a class="elsevierStyleCrossRef" href="#bib0410">36</a> Breast infiltration also means an increased risk of CNS relapse.<a class="elsevierStyleCrossRefs" href="#bib0340">22,30,37–39</a> A retrospective study of several U.S. centers with 76 patients with primary breast lymphoma<a class="elsevierStyleCrossRef" href="#bib0425">39</a> revealed 16% of neuromeningeal relapse (CNS prophylaxis was administered to 9% of the total). This result is identical to that of another Korean study<a class="elsevierStyleCrossRef" href="#bib0420">38</a> (16% neuromeningeal relapse compared to 0 in a control group of stage 1–2 nodal lymphomas) and similar to another French study.<a class="elsevierStyleCrossRef" href="#bib0415">37</a>Recently, some studies have linked lymphoma kidney infiltration with increased risk of neuromeningeal relapse. In a large Canadian<a class="elsevierStyleCrossRef" href="#bib0430">40</a> retrospective study of 2656 patients diagnosed with DLBCL, 52 (2%) had lymphoma kidney infiltration, and 20 (36%) of these, infiltration into the CNS (16 as relapse). Tai et al.<a class="elsevierStyleCrossRef" href="#bib0340">22</a> observed that lymphoma kidney infiltration was the most significant risk factor for CNS relapse, even more significant than breast or testicular infiltration.The evidence in relation to other sites is less clear. Bone marrow infiltration does not appear associated with higher neuromeningeal relapse. Despite the results of some studies of era prior to rituximab,<a class="elsevierStyleCrossRef" href="#bib0400">34</a> a more recent study specifically investigating the infiltration of bone marrow in DLBCL, found that this was only associated with increased risk of CNS relapse if accompanied by high LDH levels.<a class="elsevierStyleCrossRef" href="#bib0435">41</a> However, in a recent meta-analysis,<a class="elsevierStyleCrossRef" href="#bib0350">24</a> both bone marrow and testicular infiltration were independent risk factors for neuromeningeal relapse. Another extranodal site that has been associated with an increased risk of CNS relapse is the epidural space, although the evidence comes from old studies.<a class="elsevierStyleCrossRef" href="#bib0395">33</a> In a large Japanese retrospective study<a class="elsevierStyleCrossRef" href="#bib0380">30</a>, bone or adrenal gland infiltration, in addition to breast condition, were independent risk factors for CNS relapse.One of the factors that has traditionally guided the administration of prophylaxis of CNS relapses is the craniofacial extranodal involvement (orbit, paranasal sinuses and oral cavity).<a class="elsevierStyleCrossRef" href="#bib0400">34</a> However, a recent study by the German High-Grade Non-Hodgkin Lymphoma Study Group<a class="elsevierStyleCrossRef" href="#bib0440">42</a> found no difference in the cumulative incidence of CNS disease between patients with and without craniofacial involvement (1.6% versus 3.4%, p=0.682) in patients treated with rituximab, while in the era prior to rituximab, neuromeningeal infiltration was more frequent (4.2% versus 2.8%, p=0.038). No differences were reported in the infiltration rate in the CNS based on the IT methotrexate prophylaxis (4.2% in those receiving prophylaxis versus 2.3% in those who did not, p=0.981). This led the authors to suggest that rituximab eliminates the risk of neuromeningeal relapse in patients with craniofacial extranodal infiltration, finding similar to another recent study.<a class="elsevierStyleCrossRef" href="#bib0445">43</a>Other risk factors for central nervous system relapseThere is controversy as to consider bulky disease as a risk factor for neuromeningeal relapse.<a class="elsevierStyleCrossRefs" href="#bib0305">15,23</a> Regarding the biology of lymphoma, there is no evidence to show the possible influence of the B-cell origin (germinal center or activated B-cell) on infiltration in the CNS. However, several studies have reported a high percentage of CNS infiltration in patients with DLBCL and MYC gene rearrangement.<a class="elsevierStyleCrossRefs" href="#bib0450">44–46</a> Based on these results, a recent review<a class="elsevierStyleCrossRef" href="#bib0385">31</a> has recommended to consider as high-risk neuromeningeal relapse, patients with DLBCL and MYC gene rearrangements.ConclusionsCNS infiltration in DLBCL patients is a relatively rare complication associated with poor prognosis. Knowing the risk factors of such infiltration is essential to determine which patients might benefit from receiving prophylaxis and, in turn, exclude those who have little risk of neuromeningeal relapse. The information available in the literature is mostly provided by retrospective and heterogeneous studies regarding the patient population included, systemic treatment and criteria for administering relapse prophylaxis in CNS. The evidence seems to support the hypothesis that after the introduction of the rituximab-based immuno-chemotherapy it has been observed a tendency to a lower CNS relapse rate. The coexistence of high serum LDH levels with more than one extranodal site appear to be risk factors associated with a higher neuromeningeal relapse rate in studies of both the pre and postrituximab era, although administering prophylaxis only in the presence of both factors is not enough to prevent relapses. Patients with breast or testicular infiltration are at high risk of relapse. Therefore, prophylaxis administration in these cases is required. In addition, prophylaxis should be considered in cases of DLBCL and renal or epidural infiltration, as well as in cases with MYC gene rearrangements, although more studies might be required to investigate these aspects.FundingThis paper has been funded in part with an unrestricted grant from Mundipharma Spain and with the grant RD12-0036-029 from RTIOCC, Instituto Carlos III.Conflict of interestsThe authors report no conflict of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:13 [ 0 => array:3 [ "identificador" => "xres644391" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec657461" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres644392" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec657460" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Central nervous system relapse in diffuse large B-cell lymphoma" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Risk factors for central nervous system relapse in the pre-rituximab and rituximab eras" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Extranodal involvement as a risk factor for central nervous system relapse" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Other risk factors for central nervous system relapse" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Conclusions" ] 10 => array:2 [ "identificador" => "sec0035" "titulo" => "Funding" ] 11 => array:2 [ "identificador" => "sec0040" "titulo" => "Conflict of interests" ] 12 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2014-11-04" "fechaAceptado" => "2014-12-11" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec657461" "palabras" => array:4 [ 0 => "Central nervous system" 1 => "Diffuse large B-cell lymphoma" 2 => "Relapse" 3 => "Prophylaxis" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec657460" "palabras" => array:4 [ 0 => "Sistema nervioso central" 1 => "Linfoma B difuso de célula grande" 2 => "Recaída" 3 => "Profilaxis" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Central nervous system (CNS) involvement by lymphoma is a complication associated, almost invariably, with a poor prognosis. The knowledge of the risk factors for CNS relapse is important to determine which patients could benefit from prophylaxis. Thus, patients with very aggressive lymphomas (such as lymphoblastic lymphoma or Burkitt's lymphoma) must systematically receive CNS prophylaxis due to a high CNS relapse rate (25–30%), while in patients with indolent lymphoma (such as follicular lymphoma or marginal lymphoma) prophylaxis is unnecessary. However, the question about CNS prophylaxis in patients with diffuse large B-cell lymphoma (DLBCL), the most common type of lymphoma, remains controversial. The information available is extensive, mainly based on retrospective and heterogeneous studies. There seems that immunochemotherapy based on rituximab reduces the CNS relapse rate. On the other hand, patients with increased serum lactate dehydrogenase plus more than one extranodal involvement seem to have a higher risk of CNS relapse, but a prophylaxis strategy based only on the presence of these 2 factors does not prevent all CNS relapses. Patients with involvement of testes or breast have high risk of CNS relapse and prophylaxis is mandatory. Finally, CNS prophylaxis could be considered in patients with DLBCL and renal or epidural space involvement, as well as in those cases with MYC rearrangements, although additional studies are necessary." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "La infiltración del sistema nervioso central (SNC) en pacientes con linfoma es una complicación que se asocia, casi invariablemente, a un pronóstico mortal. El conocimiento de los factores de riesgo de dicha infiltración es fundamental para determinar qué pacientes podrían beneficiarse de recibir una profilaxis. Mientras que los pacientes con linfoma muy agresivo (como linfoma linfoblástico y linfoma de Burkitt) deben recibir sistemáticamente profilaxis del SNC por su elevado riesgo de recaída neuromeníngea (25-30%), los pacientes con linfoma indolente (folicular o marginal, por ejemplo) no la reciben prácticamente nunca debido a su bajo riesgo de recaída en el SNC. Sin embargo, existe controversia sobre cuándo debe administrarse en pacientes con linfoma B difuso de célula grande (LBDCG), el subtipo más frecuente de linfoma. La información disponible en la bibliografía procede en su mayoría de estudios retrospectivos y heterogéneos. La evidencia parece apoyar la hipótesis de que la inmunoquimioterapia basada en rituximab reduce las recaídas en el SNC. La coexistencia de valores de lactato deshidrogenasa sérica elevados junto con más de una localización extraganglionar son factores de riesgo asociados con una mayor frecuencia de recaída neuromeníngea, aunque una estrategia basada solo en administrar profilaxis en presencia de ambos factores no previene todas las recaídas. Los pacientes con infiltración testicular y de mama tienen un elevado riesgo de recaída en el SNC y deben recibir profilaxis. Podría considerarse, asimismo, la profilaxis de la recaída neuromeníngea en casos de LBDCG con infiltración renal o del espacio epidural, o en aquellos que presenten reordenamientos del gen MYC, aunque hacen falta más estudios que investiguen estos aspectos." ] ] "NotaPie" => array:2 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Sancho J-M, Ribera J-M. Recaída en el sistema nervioso central en el linfoma B difuso de célula grande: factores de riesgo. Med Clin (Barc). 2016;146:74–80." ] 1 => array:3 [ "etiqueta" => "◊" "nota" => "The names of the components of the Working Group on Diagnosis, Prevention and Treatment of CNS infiltration in patients with DLBCL are listed in <a class="elsevierStyleCrossRef" href="#sec0045">Annex</a>." "identificador" => "fn0005" ] ] "apendice" => array:1 [ 0 => array:1 [ "seccion" => array:1 [ 0 => array:3 [ "apendice" => "Working Group on Diagnosis, Prevention and Treatment of CNS infiltration in patients with DLBCL: Francisco-Javier Peñalver, Juan-Manuel Sancho, Alberto Orfao, Adolfo de la Fuente, Maite Olave, Alejandro Martín García-Sancho, Carlos Panizo, Elena Pérez-Ceballos, Antonio Salar." "etiqueta" => "Annex" "identificador" => "sec0045" ] ] ] ] "multimedia" => array:4 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "aaIPI: age-adjusted international prognostic index; CHOEP: cyclophosphamide, adriamycin, vincristine, etoposide, and prednisone; CHOP: cyclophosphamide, adriamycin, vincristine and prednisone; IPI: International Prognostic Index; IT: intrathecal; DLBCL: diffuse large B-cell lymphoma; BM: bone marrow; R: rituximab; CNS: central nervous system." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Authors and reference (year) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Number of patients and type of lymphoma \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Incidence of CNS relapse \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Type of CNS relapse \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Use and type of CNS prophylaxis \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Criteria for CNS prophylaxis \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Boehme et al.<a class="elsevierStyleCrossRef" href="#bib0280">10</a> (2009) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1217 B-cell lymphomas (944 DLBCL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">58 CNS relapses: 6.9% (CHOP) and 4.1% (R-CHOP) (2-year cumulative incidence) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Parenchymal or intraspinal in 38/58 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IT methotrexate on days 1 and 5 in the first 2 cycles of chemotherapy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Infiltration in bone marrow, testicles, head and neck (paranasal sinuses, orbit, oral cavity, tongue and salivary glands) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Shimazu et al.<a class="elsevierStyleCrossRef" href="#bib0295">13</a> (2009) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">435 DLBCL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">42 CNS relapses: 13.3% (CHOP) and 8.4% (R-CHOP) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Parenchymal in 32/42, meningeal in 10/32 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IT methotrexate (only 18 patients) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Infiltration in paranasal sinuses, testicles or vertebrae \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Villa et al.<a class="elsevierStyleCrossRef" href="#bib0285">11</a> (2010) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">435 DLBCL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">31 CNS relapses: 9.7% (CHOP) and 6.4% (R-CHOP); p=0.085 (probability of CNS relapse within 3 years) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Parenchymal (65% in R-CHOP versus 25% in CHOP) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Alternate IT methotrexate with IT cytarabine (6 doses) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Before 2002, if BM or peripheral blood, epidural space, testicle or paranasal sinus infiltration After 2002 if paranasal sinus infiltration \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Mitrovic et al.<a class="elsevierStyleCrossRef" href="#bib0300">14</a> (2012) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1197 DLBCL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">38 CNS relapses: 3.7% (similar to CHOP) and 2.1% (similar to R-CHOP). Cumulative incidence of CNS relapse within 5 years 3.6% versus 2.2% (p=0.049) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Parenchymal in the field of R-CHOP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Schmitz et al.<a class="elsevierStyleCrossRef" href="#bib0305">15</a> (2012) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2210 aggressive B-cell lymphomas (1809 DLBCL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">56 CNS relapses: 1–13.2% (chemotherapy without R) and 0–9.7% (R-chemotherapy). aaIPI 0–1: 1–2.6% (chemotherapy) versus 0–0.5% (R-chemotherapy). aaIPI >2: 4.6–13.2% (chemotherapy) versus 4.2–9.7% (R-chemotherapy) (CHOP±etoposide) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IT methotrexate on days 1 and 15 in the first 2 cycles \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">In the high-CHOEP and mega-CHOEP studies: patients with head and neck infiltration (including paranasal sinuses, orbit, oral cavity, tongue and salivary glands), BM or testicles \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Tomita et al.<a class="elsevierStyleCrossRef" href="#bib0380">30</a> (2012) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1221 DLBCL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">82 CNS episodes: 6.7% (R-CHOP) (5-year cumulative probability 8.4%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Zhang et al.<a class="elsevierStyleCrossRef" href="#bib0350">24</a> (2014) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4911 DLBCL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5.7% (chemotherapy) and 4.7% (R-chemotherapy) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1062192.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Studies showing the decreasing central nervous system relapses in diffuse large B-cell lymphoma upon introduction of rituximab." ] ] 1 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "CHOP: cyclophosphamide, adriamycin, vincristine and prednisone; IT: intrathecal; DLBCL: diffuse large B-cell lymphoma; BM: bone marrow; R: rituximab; CNS: central nervous system." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Authors and reference (year) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Number of cases and type of lymphoma \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Incidence of CNS relapse \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Type of CNS relapse \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Use and type of CNS prophylaxis \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Criteria for CNS prophylaxis \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Feugier et al.<a class="elsevierStyleCrossRef" href="#bib0275">9</a> (2004) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">399 DLBCL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">20 CNS relapses: 4.6% (CHOP) and 5.4% (R-CHOP) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Yamamoto et al.<a class="elsevierStyleCrossRef" href="#bib0335">21</a> (2010) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">375 DLBCL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">13 CNS relapses: 2.9% (CHOP) and 3.9% (R-CHOP) (p=0.71) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Chihara et al.<a class="elsevierStyleCrossRef" href="#bib0345">23</a> (2011) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">386 DLBCL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">24 CNS relapses: 7.3% (CHOP) and 5.3% (R-CHOP); p=0.42 (5-year cumulative incidence) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Meningeal at 15/24 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IT Methotrexate or cytarabine×4 doses \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Testicle (after 1999) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Tai et al.<a class="elsevierStyleCrossRef" href="#bib0340">22</a> (2011) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">499 DLBCL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">30 CNS relapses: 5.1% (CHOP) and 6% (R-CHOP) (2-year cumulative incidence) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IT prophylaxis in 82 patients according to physician judgment and patient preference \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">>1 extranodal site, orbital sinus, postnasal space, breast, testicles, BM \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Cao et al.<a class="elsevierStyleCrossRef" href="#bib0320">18</a> (2012) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">315 DLBCL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10 CNS relapses: 3.03% (CHOP) and 3.33% (R-CHOP) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Parenchymal in 9/10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Deng et al.<a class="elsevierStyleCrossRef" href="#bib0330">20</a> (2013) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">599 DLBCL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">32 CNS relapses: 6.5% (CHOP) and 4.3% (R-CHOP) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1062191.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Studies not proving the decreasing central nervous system relapses in diffuse large B-cell lymphoma upon introduction of rituximab." ] ] 2 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "cytaBOM: cytarabine, bleomycin, vincristine and methotrexate; IPI: International Prognostic Index; IT: intrathecal; LDH: lactate dehydrogenase; m-BACOD: methotrexate, bleomycin, cyclophosphamide, and etoposide; proMACE: prednisone, methotrexate, doxorubicin, cyclophosphamide and etoposide; CNS: central nervous system." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Authors and reference (year) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Number of cases \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">CNS relapse \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Risk factors (multivariate analysis) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Remark \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Van Besien et al.<a class="elsevierStyleCrossRef" href="#bib0360">26</a> (1998) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">605<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4.5% (24 patients)<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">High LDH; >1 extranodal site \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No CNS prophylaxis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Haioun et al.<a class="elsevierStyleCrossRef" href="#bib0365">27</a> (2000) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">974<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.6% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">High IPI; high LDH; >1 extranodal site<a class="elsevierStyleCrossRef" href="#tblfn0015">c</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CNS prophylaxis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hollender et al.<a class="elsevierStyleCrossRef" href="#bib0370">28</a> (2002) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2514 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5.2%<a class="elsevierStyleCrossRef" href="#tblfn0020">d</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">High LDH; >1 extranodal site; albumin<35g/l; age>60 years; retroperitoneal condition \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Boehme et al.<a class="elsevierStyleCrossRef" href="#bib0375">29</a> (2007) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1693<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2.2% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">High LDH; >1 extranodal site; no etoposide administration \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CNS prophylaxis (IT) by 4.2% according to medical criteria \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Bernstein et al.<a class="elsevierStyleCrossRef" href="#bib0385">31</a> (2009) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">899<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2.8% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IPI; >1 extranodal site \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CNS prophylaxis only if systemic chemotherapy with m-BACOD or proMACE-cytaBOM \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1062193.png" ] ] ] "notaPie" => array:4 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "Aggressive histology." ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "Only 11 of the 24 patients had high lactate dehydrogenase and more than one extranodal site." ] 2 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "c" "nota" => "After removing the international prognostic index." ] 3 => array:3 [ "identificador" => "tblfn0020" "etiqueta" => "d" "nota" => "Central nervous system relapse in the high-grade subgroup (not including lymphoblastic lymphoma and Burkitt lymphoma)." ] ] ] "descripcion" => array:1 [ "en" => "Risk factors for central nervous system relapse in lymphomas in the era prior to rituximab." ] ] 3 => array:8 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at4" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "aaIPI: age-adjusted international prognostic index; CHOEP: cyclophosphamide, adriamycin, vincristine, etoposide, and prednisone; CHOP: cyclophosphamide, adriamycin, vincristine and prednisone; ECOG: Eastern Cooperative Oncology Group; IPI: International Prognostic Index; IT: intrathecal; DLBCL: diffuse large B-cell lymphoma; LDH: lactate dehydrogenase; BM: bone marrow; PS: performance status; R: rituximab; CR: complete response; CNS: central nervous system." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Authors and reference (year) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Number of patients and type of lymphoma \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">CNS relapse \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Risk factors of CNS relapse \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Remark \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Feugier et al.<a class="elsevierStyleCrossRef" href="#bib0275">9</a> (2004) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">399 DLBCL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5.4% (in those treated with R-CHOP) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">aaIPI>1 (LDH and PS after excluding aaIPI) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No CNS prophylaxis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Boehme et al.<a class="elsevierStyleCrossRef" href="#bib0280">10</a> (2009) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1217 B-cell lymphomas (944 DLBCL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4.1% (in those treated with R-CHOP) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Global Series: >1 extranodal site; B signs; LDH (not significant) (multivariate analysis). Patients treated with R-CHOP: >1 extranodal site; LDH; ECOG>1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CNS prophylaxis is administered with IT methotrexate in the first 2 cycles of chemotherapy in patients with head and neck or testicular extranodal infiltration \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Shimazu et al.<a class="elsevierStyleCrossRef" href="#bib0295">13</a> (2009) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">435 DLBCL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">8.4% (in those treated with R-CHOP) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">age>60 years; LDH; >1 extranodal site; BM; No R (multivariate analysis) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Prophylaxis with IT methotrexate in a very small group (18 patients) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Villa et al.<a class="elsevierStyleCrossRef" href="#bib0285">11</a> (2010) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">435 DLBCL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6.4% (in those treated with R-CHOP) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Testicle; kidney; stage 4; no R \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Alternate IT Methotrexate with IT cytarabine (6 doses) if paranasal sinuses involved \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Yamamoto et al.<a class="elsevierStyleCrossRef" href="#bib0335">21</a> (2010) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">375 DLBCL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3.9% (in those treated with R-CHOP) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">None in the multivariate analysis (in univariate analysis: LDH, high IPI, BM, systemic relapse) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No CNS prophylaxis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Chihara et al.<a class="elsevierStyleCrossRef" href="#bib0345">23</a> (2011) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">386 DLBCL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5.3% (in those treated with R-CHOP) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Bulky disease; B-cells <1000mm–3; extranodal infiltration (multivariate analysis of competing risks) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Prophylaxis with methotrexate or cytarabine only if testicular infiltration \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Tai et al.<a class="elsevierStyleCrossRef" href="#bib0340">22</a> (2011) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">499 DLBCL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6% (in those treated with R-CHOP) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ECOG>1; no RC; testicle; kidney; breast (multivariate analysis) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IT prophylaxis according to medical criteria \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Schmitz et al.<a class="elsevierStyleCrossRef" href="#bib0305">15</a> (2012) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2210 aggressive B-cell lymphomas (1809 DLBCL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.6% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Global Series: >1 extranodal site; LDH. In patients treated with R-chemotherapy: stage 3–4; LDH \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CNS prophylaxis with IT methotrexate on days 1 and 15 of the first 2 cycles in High-CHOEP and Mega-CHOEP studies in high-risk patients \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Tomita et al.<a class="elsevierStyleCrossRef" href="#bib0380">30</a> (2012) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1221 DLBCL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6.7% (in those treated with R-CHOP) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">age<60 years; adrenal gland; bone; breast \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No CNS prophylaxis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Guirguis et al.<a class="elsevierStyleCrossRef" href="#bib0315">17</a> (2012) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">217 DLBCL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3.7% (in those treated with R-CHOP) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Testicle \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CNS prophylaxis in high-risk cases (with IT methotrexate and intravenous) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Kumar et al.<a class="elsevierStyleCrossRef" href="#bib0325">19</a> (2012) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">989 DLBCL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2% (in those treated with R-CHOP) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Intermediate-high and high IPI \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CNS prophylaxis does not reduce relapse \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Zhang et al.<a class="elsevierStyleCrossRef" href="#bib0350">24</a> (2014) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4911 DLBCL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4.7% (in those treated with R-chemotherapy) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Stage 3/4; IPI>1; PS>1; high LDH; >1 extranodal site; BM; testicle \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Meta-analysis \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1062194.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0025" "etiqueta" => "a" "nota" => "Some studies include other histologies of aggressive B-cell lymphoma." ] ] ] "descripcion" => array:1 [ "en" => "Risk factors of central nervous system relapse in diffuse large B cell lymphoma<a class="elsevierStyleCrossRef" href="#tblfn0025">a</a> upon introduction of rituximab." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:46 [ 0 => array:3 [ "identificador" => "bib0235" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Linfomas y otras enfermedades ganglionares" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "A. 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Central nervous system relapse in diffuse large B cell lymphoma: Risk factors

Recaída en el sistema nervioso central en el linfoma B difuso de célula grande: factores de riesgo

Juan-Manuel Sancho

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jsancho@iconcologia.net

Corresponding author.

, Josep-Maria Ribera, on behalf of the Working Group on Diagnosis, Prevention and Treatment of CNS infiltration in patients with DLBCL ◊

Servicio de Hematología Clínica, Institut Català d’Oncologia-Hospital Germans Trias i Pujol, Institut de Recerca contra la Leucemia Josep Carreras, Universitat Autònoma de Barcelona, Badalona, Barcelona, Spain

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Diffuse large B-cell lymphoma &#40;DLBCL&#41; is the most common subtype of non-Hodgkin lymphoma &#40;NHL&#41; in the Western world&#44; where it represents more than a third of all lymphomas&#46; It is a heterogeneous group of diseases with similar cellular origin and aggressive clinical behavior&#46; Its unknown etiopathogenesis involves immunodeficiency situations&#44; contact with toxic agents and even viruses&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Lymph nodes are the most common manifestation&#44; although nearly half of the cases may have extranodal involvement&#46; Lymph node biopsy shows diffuse large cell infiltration&#44; with a B-phenotype cell origin&#44; and characteristically they express CD20 antigen in their membrane&#46; Two distinct profiles of gene expression have been identified through microarray assays&#58; germinal center DLBCL and activated B-cell DLBCL&#44; with a different clinical behavior and prognosis&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">1</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">The prognosis depends on factors derived from the patient&#44; lymphoma and its extension&#44; and treatment&#46; The international prognostic index &#40;IPI&#41;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">2</span></a> considers five factors with unfavorable prognostic influence&#58; age &#40;&#62;60 years versus &#8804;60 years&#41;&#44; condition of the patient &#40;by the Eastern Cooperative Oncology Group scale&#44; 2-4 versus 0-1&#41;&#44; Ann Arbor stage &#40;3-4 versus 1-2&#41;&#44; number of extranodal sites &#40;&#8805;2 versus &#60;2&#41; and serum lactate dehydrogenase &#40;LDH&#41; levels&#46; Thus&#44; good prognosis is described as patients with an IPI value 0&#8211;2&#44; while the prognosis worsens in patients with 3&#8211;5 IPI scores&#46; There is a simplified IPI&#44; the age-adjusted IPI &#40;aaIPI&#41;&#44; assigning only one score to poor general condition&#44; high serum LDH levels and advanced Ann Arbor stage&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">The standard treatment in DLBCL patients is based on the R-CHOP or R-CHOP-like immunochemotherapy&#44; where the monoclonal anti-CD20 antibody rituximab is combined with the standard CHOP pattern &#40;which includes cyclophosphamide&#44; doxorubicin&#44; vincristine and prednisone&#41;&#44; administered every 21 days for 6&#8211;8 cycles&#46; With this treatment&#44; complete response rates are above 75&#37;&#44; and long term event-free survival is around 63&#8211;74&#37;&#44; depending on the prognosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">3&#8211;5</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Central nervous system relapse in diffuse large B-cell lymphoma</span><p id="par0025" class="elsevierStylePara elsevierViewall">Neuromeningeal relapse in lymphoma patients is a complication that occurs in about 5&#37; of patients &#40;with large variability depending on the subtype of lymphoma&#41;&#44; usually in the course of progressive disease&#46; NHLs can invade the central nervous system &#40;CNS&#41; as a meningeal or intraparenchymal infiltration&#46; The site&#44; although heterogeneous&#44; usually lies in the skull base and around the spinal cord&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">6</span></a> The mechanisms of neuromeningeal infiltration include hematogenous spread&#44; direct spread from adjacent tumors and centripetal migration following perineural or perivascular spaces&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">7</span></a> The prognosis after infiltration into the CNS is very negative&#44; and patients suffering it have a deteriorating quality of life due to both infiltration itself and the toxicity associated with treatments against CNS &#40;radiotherapy&#44; intrathecal &#91;IT&#93; chemotherapy and high-dose systemic chemotherapy&#41;&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Risk factors of neuromeningeal relapse in patients with lymphoma have been identified through the analysis of large series&#46; The histological subtype is the main risk factor&#46; Therefore&#44; the high-grade histological subtypes&#44; such as lymphoblastic or Burkitt lymphoma should systematically receive prophylaxis of neuromeningeal infiltration because of their well-known propensity to infiltrate the CNS&#46; However&#44; low-grade lymphomas have low risk of infiltration and CNS prophylaxis is not recommended&#46; The most controversial group regarding neuromeningeal prophylaxis consists of other aggressive lymphomas&#44; especially DLBCL&#44; with CNS relapse rates of around 5&#37;&#44; in which there is no consensus on when to administer prophylaxis&#46;<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">6&#8211;8</span></a> Given the poor prognosis of CNS relapse&#44; with a survival below 6 months&#44;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">9&#8211;11</span></a> identifying patients at risk of relapse is essential to decide when and how to administer prophylaxis&#44; especially in those with DLBCL&#46; However&#44; finding risk factors leads to difficulties&#44; such as the retrospective nature of most studies&#44; inclusion of various aggressive lymphomas other than DLBCL&#44; the fact that CNS relapse is not a frequent event in DLBCL&#44; and type heterogeneity and prophylaxis criteria&#44;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">8</span></a> which do not allow comparison among different studies&#46; In addition&#44; the impact of new diagnostic techniques&#44; such as Multiparameter flow cytometry&#44;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">12</span></a> or new treatments developed in the past decade&#44; especially rituximab&#44; whose influence on the neuromeningeal relapse is still unclear&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Regarding the influence of adding rituximab to standard treatment of DLBCL&#44; several studies have shown a decreased CNS relapse rate<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">10&#44;11&#44;13&#8211;16</span></a> compared to pre-rituximab era&#46; This proves that the best lymphoma systemic control might protect against infiltration into the CNS&#46; A modification in the pattern of neuromeningeal relapse has also been observed&#44; with predominance of parenchymal relapses&#44;<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">10&#44;11&#44;13&#44;14&#44;17&#8211;19</span></a> the isolated on CNS&#44;<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">10&#44;19&#44;20</span></a> or late relapses&#46; However&#44; this tendency to a lower rate of relapses in the CNS has not been corroborated by other authors&#46;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">9&#44;18&#44;20&#8211;23</span></a> A recent meta-analysis<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">24</span></a> showed significant decreased incidence of neuromeningeal relapse in patients receiving rituximab &#40;4&#46;7 compared to 5&#46;7&#37;&#44; odds ratio 0&#46;7&#44; confidence interval 95&#37; 0&#46;54&#8211;0&#46;91&#41;&#44; and the recent British guidelines agree with this<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">25</span></a> &#40;<a class="elsevierStyleCrossRefs" href="#tbl0005">Tables 1 and 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Risk factors for central nervous system relapse in the pre-rituximab and rituximab eras</span><p id="par0040" class="elsevierStylePara elsevierViewall">In pre-rituximab era&#44; several retrospective studies<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">26&#8211;29</span></a> described a higher rate of relapses in the CNS in patients with high serum LDH levels and&#47;or presence of more than one extranodal site affected by the lymphoma&#46; In the paper by Van Besien et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">26</span></a> with more than 600 patients with B-lymphoma&#44; neuromeningeal relapse was observed in 24 &#40;4&#46;5&#37;&#41;&#44; although only 11 had high serum LDH levels and more than one extranodal site&#46; These same factors were described in a large French study&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">27</span></a> However after using the IPI in the multivariate analysis&#44; only this index was associated with increased risk of CNS relapse&#46; The IPI was also a risk factor for neuromeningeal relapse in a study by the Southwest Oncology Group&#44;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">31</span></a> along with more than one extranodal site&#46; However&#44; another large Nordic study<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">28</span></a> showed a model of risk of CNS relapse based on 5 independent factors including high serum LDH levels and infiltration in more than one extranodal site &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall">In the era of immuno-chemotherapy a French study<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">9</span></a> in DLBCL patients aged over 60&#44; randomized to CHOP or R-CHOP found that the only risk factor for CNS relapse was an aaIPI<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>1&#44; present in all patients with CNS relapse&#44; but also in over 60&#37; of all study patients&#46; After excluding the aaIPI from analysis&#44; an increased serum LDH and a poor general condition &#40;performance status &#91;PS&#93;<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>1&#41; were independent predictors of CNS relapse&#46; In a similar study&#44;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">10</span></a> also in DLBCL patients aged over 60&#44; were randomized to chemotherapy with R-CHOP or CHOP administered every 14 days&#44; with CNS prophylaxis with IT chemotherapy in high-risk patients&#46; When analyzed only patients treated with R-CHOP&#44; the independent risk factors associated with CNS relapse were&#58; more than one extranodal site&#44; high serum LDH and PS<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>1&#46; This combination of risk factors was present in 4&#46;8&#37; of patients where the probability of relapse was 33&#46;5&#37; compared to only 2&#46;8&#37; in the remaining patients who received R-CHOP&#46; Also&#44; in a review of 2196 patients with aggressive B-cell lymphoma treated with clinical trials of the German High-Grade Non-Hodgkin Lymphoma Study Group<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">15</span></a> it was found that high serum LDH levels and the condition of more than one extranodal site were associated with CNS relapse &#40;multivariate analysis&#41;&#46; However&#44; the combination of these risk factors failed in predicting neuromeningeal relapse in over 70&#37; of cases&#46; High serum LDH levels have also been described as a risk factor for neuromeningeal relapse in other studies of posrituximab era&#44;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">13&#44;21</span></a> as well as infiltration of more than one extranodal<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">13</span></a> site and an intermediate-high or high IPI&#46;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">15&#44;19&#44;21</span></a> In a recent meta-analysis<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">24</span></a> both high serum LDH and the presence of more than one extranodal sites were independent risk factors of neuromeningeal relapse &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46; With these results a recent<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">32</span></a> review has recommended to consider as patients at high risk of CNS relapse&#44; those with high serum LDH and more than one extranodal site&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Extranodal involvement as a risk factor for central nervous system relapse</span><p id="par0050" class="elsevierStylePara elsevierViewall">Regarding the testicular infiltration&#44; either as primary lymphoma site or as an extended lymph node lymphoma&#44; evidence of an increased risk of CNS relapse is clear both in the pre and postrituximab studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">11&#44;17&#44;22&#44;33&#8211;36</span></a> In what is probably the study with the highest number of patients &#40;373 primary testicular lymphomas&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">34</span></a> the neuromeningeal relapse rate was 15&#37; &#40;only 18&#37; of patients received IT prophylaxis&#41;&#44; similar to that of another study&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">36</span></a> Breast infiltration also means an increased risk of CNS relapse&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">22&#44;30&#44;37&#8211;39</span></a> A retrospective study of several U&#46;S&#46; centers with 76 patients with primary breast lymphoma<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">39</span></a> revealed 16&#37; of neuromeningeal relapse &#40;CNS prophylaxis was administered to 9&#37; of the total&#41;&#46; This result is identical to that of another Korean study<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">38</span></a> &#40;16&#37; neuromeningeal relapse compared to 0 in a control group of stage 1&#8211;2 nodal lymphomas&#41; and similar to another French study&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">37</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Recently&#44; some studies have linked lymphoma kidney infiltration with increased risk of neuromeningeal relapse&#46; In a large Canadian<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">40</span></a> retrospective study of 2656 patients diagnosed with DLBCL&#44; 52 &#40;2&#37;&#41; had lymphoma kidney infiltration&#44; and 20 &#40;36&#37;&#41; of these&#44; infiltration into the CNS &#40;16 as relapse&#41;&#46; Tai et al&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">22</span></a> observed that lymphoma kidney infiltration was the most significant risk factor for CNS relapse&#44; even more significant than breast or testicular infiltration&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">The evidence in relation to other sites is less clear&#46; Bone marrow infiltration does not appear associated with higher neuromeningeal relapse&#46; Despite the results of some studies of era prior to rituximab&#44;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">34</span></a> a more recent study specifically investigating the infiltration of bone marrow in DLBCL&#44; found that this was only associated with increased risk of CNS relapse if accompanied by high LDH levels&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">41</span></a> However&#44; in a recent meta-analysis&#44;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">24</span></a> both bone marrow and testicular infiltration were independent risk factors for neuromeningeal relapse&#46; Another extranodal site that has been associated with an increased risk of CNS relapse is the epidural space&#44; although the evidence comes from old studies&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">33</span></a> In a large Japanese retrospective study<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">30</span></a>&#44; bone or adrenal gland infiltration&#44; in addition to breast condition&#44; were independent risk factors for CNS relapse&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">One of the factors that has traditionally guided the administration of prophylaxis of CNS relapses is the craniofacial extranodal involvement &#40;orbit&#44; paranasal sinuses and oral cavity&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">34</span></a> However&#44; a recent study by the German High-Grade Non-Hodgkin Lymphoma Study Group<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">42</span></a> found no difference in the cumulative incidence of CNS disease between patients with and without craniofacial involvement &#40;1&#46;6&#37; versus 3&#46;4&#37;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;682&#41; in patients treated with rituximab&#44; while in the era prior to rituximab&#44; neuromeningeal infiltration was more frequent &#40;4&#46;2&#37; versus 2&#46;8&#37;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;038&#41;&#46; No differences were reported in the infiltration rate in the CNS based on the IT methotrexate prophylaxis &#40;4&#46;2&#37; in those receiving prophylaxis versus 2&#46;3&#37; in those who did not&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;981&#41;&#46; This led the authors to suggest that rituximab eliminates the risk of neuromeningeal relapse in patients with craniofacial extranodal infiltration&#44; finding similar to another recent study&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">43</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Other risk factors for central nervous system relapse</span><p id="par0070" class="elsevierStylePara elsevierViewall">There is controversy as to consider bulky disease as a risk factor for neuromeningeal relapse&#46;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">15&#44;23</span></a> Regarding the biology of lymphoma&#44; there is no evidence to show the possible influence of the B-cell origin &#40;germinal center or activated B-cell&#41; on infiltration in the CNS&#46; However&#44; several studies have reported a high percentage of CNS infiltration in patients with DLBCL and MYC gene rearrangement&#46;<a class="elsevierStyleCrossRefs" href="#bib0450"><span class="elsevierStyleSup">44&#8211;46</span></a> Based on these results&#44; a recent review<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">31</span></a> has recommended to consider as high-risk neuromeningeal relapse&#44; patients with DLBCL and MYC gene rearrangements&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusions</span><p id="par0075" class="elsevierStylePara elsevierViewall">CNS infiltration in DLBCL patients is a relatively rare complication associated with poor prognosis&#46; Knowing the risk factors of such infiltration is essential to determine which patients might benefit from receiving prophylaxis and&#44; in turn&#44; exclude those who have little risk of neuromeningeal relapse&#46; The information available in the literature is mostly provided by retrospective and heterogeneous studies regarding the patient population included&#44; systemic treatment and criteria for administering relapse prophylaxis in CNS&#46; The evidence seems to support the hypothesis that after the introduction of the rituximab-based immuno-chemotherapy it has been observed a tendency to a lower CNS relapse rate&#46; The coexistence of high serum LDH levels with more than one extranodal site appear to be risk factors associated with a higher neuromeningeal relapse rate in studies of both the pre and postrituximab era&#44; although administering prophylaxis only in the presence of both factors is not enough to prevent relapses&#46; Patients with breast or testicular infiltration are at high risk of relapse&#46; Therefore&#44; prophylaxis administration in these cases is required&#46; In addition&#44; prophylaxis should be considered in cases of DLBCL and renal or epidural infiltration&#44; as well as in cases with MYC gene rearrangements&#44; although more studies might be required to investigate these aspects&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Funding</span><p id="par0080" class="elsevierStylePara elsevierViewall">This paper has been funded in part with an unrestricted grant from Mundipharma Spain and with the grant <span class="elsevierStyleGrantNumber" refid="gs1">RD12-0036-029</span> from <span class="elsevierStyleGrantSponsor" id="gs1">RTIOCC&#44; Instituto Carlos III</span>&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conflict of interests</span><p id="par0085" class="elsevierStylePara elsevierViewall">The authors report no conflict of interest&#46;</p></span></span>"
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          "titulo" => "Introduction"
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        5 => array:2 [
          "identificador" => "sec0010"
          "titulo" => "Central nervous system relapse in diffuse large B-cell lymphoma"
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          "identificador" => "sec0015"
          "titulo" => "Risk factors for central nervous system relapse in the pre-rituximab and rituximab eras"
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          "titulo" => "Extranodal involvement as a risk factor for central nervous system relapse"
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          "identificador" => "sec0025"
          "titulo" => "Other risk factors for central nervous system relapse"
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          "identificador" => "sec0030"
          "titulo" => "Conclusions"
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    "fechaRecibido" => "2014-11-04"
    "fechaAceptado" => "2014-12-11"
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            0 => "Central nervous system"
            1 => "Diffuse large B-cell lymphoma"
            2 => "Relapse"
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            0 => "Sistema nervioso central"
            1 => "Linfoma B difuso de c&#233;lula grande"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Central nervous system &#40;CNS&#41; involvement by lymphoma is a complication associated&#44; almost invariably&#44; with a poor prognosis&#46; The knowledge of the risk factors for CNS relapse is important to determine which patients could benefit from prophylaxis&#46; Thus&#44; patients with very aggressive lymphomas &#40;such as lymphoblastic lymphoma or Burkitt&#39;s lymphoma&#41; must systematically receive CNS prophylaxis due to a high CNS relapse rate &#40;25&#8211;30&#37;&#41;&#44; while in patients with indolent lymphoma &#40;such as follicular lymphoma or marginal lymphoma&#41; prophylaxis is unnecessary&#46; However&#44; the question about CNS prophylaxis in patients with diffuse large B-cell lymphoma &#40;DLBCL&#41;&#44; the most common type of lymphoma&#44; remains controversial&#46; The information available is extensive&#44; mainly based on retrospective and heterogeneous studies&#46; There seems that immunochemotherapy based on rituximab reduces the CNS relapse rate&#46; On the other hand&#44; patients with increased serum lactate dehydrogenase plus more than one extranodal involvement seem to have a higher risk of CNS relapse&#44; but a prophylaxis strategy based only on the presence of these 2 factors does not prevent all CNS relapses&#46; Patients with involvement of testes or breast have high risk of CNS relapse and prophylaxis is mandatory&#46; Finally&#44; CNS prophylaxis could be considered in patients with DLBCL and renal or epidural space involvement&#44; as well as in those cases with <span class="elsevierStyleItalic">MYC</span> rearrangements&#44; although additional studies are necessary&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La infiltraci&#243;n del sistema nervioso central &#40;SNC&#41; en pacientes con linfoma es una complicaci&#243;n que se asocia&#44; casi invariablemente&#44; a un pron&#243;stico mortal&#46; El conocimiento de los factores de riesgo de dicha infiltraci&#243;n es fundamental para determinar qu&#233; pacientes podr&#237;an beneficiarse de recibir una profilaxis&#46; Mientras que los pacientes con linfoma muy agresivo &#40;como linfoma linfobl&#225;stico y linfoma de Burkitt&#41; deben recibir sistem&#225;ticamente profilaxis del SNC por su elevado riesgo de reca&#237;da neuromen&#237;ngea &#40;25-30&#37;&#41;&#44; los pacientes con linfoma indolente &#40;folicular o marginal&#44; por ejemplo&#41; no la reciben pr&#225;cticamente nunca debido a su bajo riesgo de reca&#237;da en el SNC&#46; Sin embargo&#44; existe controversia sobre cu&#225;ndo debe administrarse en pacientes con linfoma B difuso de c&#233;lula grande &#40;LBDCG&#41;&#44; el subtipo m&#225;s frecuente de linfoma&#46; La informaci&#243;n disponible en la bibliograf&#237;a procede en su mayor&#237;a de estudios retrospectivos y heterog&#233;neos&#46; La evidencia parece apoyar la hip&#243;tesis de que la inmunoquimioterapia basada en rituximab reduce las reca&#237;das en el SNC&#46; La coexistencia de valores de lactato deshidrogenasa s&#233;rica elevados junto con m&#225;s de una localizaci&#243;n extraganglionar son factores de riesgo asociados con una mayor frecuencia de reca&#237;da neuromen&#237;ngea&#44; aunque una estrategia basada solo en administrar profilaxis en presencia de ambos factores no previene todas las reca&#237;das&#46; Los pacientes con infiltraci&#243;n testicular y de mama tienen un elevado riesgo de reca&#237;da en el SNC y deben recibir profilaxis&#46; Podr&#237;a considerarse&#44; asimismo&#44; la profilaxis de la reca&#237;da neuromen&#237;ngea en casos de LBDCG con infiltraci&#243;n renal o del espacio epidural&#44; o en aquellos que presenten reordenamientos del gen <span class="elsevierStyleItalic">MYC</span>&#44; aunque hacen falta m&#225;s estudios que investiguen estos aspectos&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0030">Please cite this article as&#58; Sancho J-M&#44; Ribera J-M&#46; Reca&#237;da en el sistema nervioso central en el linfoma B difuso de c&#233;lula grande&#58; factores de riesgo&#46; Med Clin &#40;Barc&#41;&#46; 2016&#59;146&#58;74&#8211;80&#46;</p>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0035">The names of the components of the Working Group on Diagnosis&#44; Prevention and Treatment of CNS infiltration in patients with DLBCL are listed in <a class="elsevierStyleCrossRef" href="#sec0045">Annex</a>&#46;</p>"
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            "apendice" => "<p id="par0090" class="elsevierStylePara elsevierViewall">Working Group on Diagnosis&#44; Prevention and Treatment of CNS infiltration in patients with DLBCL&#58; Francisco-Javier Pe&#241;alver&#44; Juan-Manuel Sancho&#44; Alberto Orfao&#44; Adolfo de la Fuente&#44; Maite Olave&#44; Alejandro Mart&#237;n Garc&#237;a-Sancho&#44; Carlos Panizo&#44; Elena P&#233;rez-Ceballos&#44; Antonio Salar&#46;</p>"
            "etiqueta" => "Annex"
            "identificador" => "sec0045"
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          "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">aaIPI&#58; age-adjusted international prognostic index&#59; CHOEP&#58; cyclophosphamide&#44; adriamycin&#44; vincristine&#44; etoposide&#44; and prednisone&#59; CHOP&#58; cyclophosphamide&#44; adriamycin&#44; vincristine and prednisone&#59; IPI&#58; International Prognostic Index&#59; IT&#58; intrathecal&#59; DLBCL&#58; diffuse large B-cell lymphoma&#59; BM&#58; bone marrow&#59; R&#58; rituximab&#59; CNS&#58; central nervous system&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Authors and reference &#40;year&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Number of patients and type of lymphoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Incidence of CNS relapse&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Type of CNS relapse&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Use and type of CNS prophylaxis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Criteria for CNS prophylaxis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Boehme et al&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">10</span></a> &#40;2009&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1217 B-cell lymphomas &#40;944 DLBCL&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">58 CNS relapses&#58; 6&#46;9&#37; &#40;CHOP&#41; and 4&#46;1&#37; &#40;R-CHOP&#41; &#40;2-year cumulative incidence&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Parenchymal or intraspinal in 38&#47;58&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">IT methotrexate on days 1 and 5 in the first 2 cycles of chemotherapy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Infiltration in bone marrow&#44; testicles&#44; head and neck &#40;paranasal sinuses&#44; orbit&#44; oral cavity&#44; tongue and salivary glands&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Shimazu et al&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">13</span></a> &#40;2009&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">435 DLBCL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">42 CNS relapses&#58; 13&#46;3&#37; &#40;CHOP&#41; and 8&#46;4&#37; &#40;R-CHOP&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Parenchymal in 32&#47;42&#44; meningeal in 10&#47;32&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">IT methotrexate &#40;only 18 patients&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Infiltration in paranasal sinuses&#44; testicles or vertebrae&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Villa et al&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">11</span></a> &#40;2010&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">435 DLBCL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">31 CNS relapses&#58; 9&#46;7&#37; &#40;CHOP&#41; and 6&#46;4&#37; &#40;R-CHOP&#41;&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;085 &#40;probability of CNS relapse within 3 years&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Parenchymal &#40;65&#37; in R-CHOP versus 25&#37; in CHOP&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Alternate IT methotrexate with IT cytarabine &#40;6 doses&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Before 2002&#44; if BM or peripheral blood&#44; epidural space&#44; testicle or paranasal sinus infiltration After 2002 if paranasal sinus infiltration&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Mitrovic et al&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">14</span></a> &#40;2012&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1197 DLBCL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">38 CNS relapses&#58; 3&#46;7&#37; &#40;similar to CHOP&#41; and 2&#46;1&#37; &#40;similar to R-CHOP&#41;&#46; Cumulative incidence of CNS relapse within 5 years 3&#46;6&#37; versus 2&#46;2&#37; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;049&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Parenchymal in the field of R-CHOP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Schmitz et al&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">15</span></a> &#40;2012&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2210 aggressive B-cell lymphomas &#40;1809 DLBCL&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">56 CNS relapses&#58; 1&#8211;13&#46;2&#37; &#40;chemotherapy without R&#41; and 0&#8211;9&#46;7&#37; &#40;R-chemotherapy&#41;&#46; aaIPI 0&#8211;1&#58; 1&#8211;2&#46;6&#37; &#40;chemotherapy&#41; versus 0&#8211;0&#46;5&#37; &#40;R-chemotherapy&#41;&#46; aaIPI &#62;2&#58; 4&#46;6&#8211;13&#46;2&#37; &#40;chemotherapy&#41; versus 4&#46;2&#8211;9&#46;7&#37; &#40;R-chemotherapy&#41; &#40;CHOP<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>etoposide&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">IT methotrexate on days 1 and 15 in the first 2 cycles&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">In the high-CHOEP and mega-CHOEP studies&#58; patients with head and neck infiltration &#40;including paranasal sinuses&#44; orbit&#44; oral cavity&#44; tongue and salivary glands&#41;&#44; BM or testicles&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Tomita et al&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">30</span></a> &#40;2012&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1221 DLBCL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">82 CNS episodes&#58; 6&#46;7&#37; &#40;R-CHOP&#41; &#40;5-year cumulative probability 8&#46;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Zhang et al&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">24</span></a> &#40;2014&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4911 DLBCL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#46;7&#37; &#40;chemotherapy&#41; and 4&#46;7&#37; &#40;R-chemotherapy&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "leyenda" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">CHOP&#58; cyclophosphamide&#44; adriamycin&#44; vincristine and prednisone&#59; IT&#58; intrathecal&#59; DLBCL&#58; diffuse large B-cell lymphoma&#59; BM&#58; bone marrow&#59; R&#58; rituximab&#59; CNS&#58; central nervous system&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Authors and reference &#40;year&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Number of cases and type of lymphoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Incidence of CNS relapse&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Type of CNS relapse&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Use and type of CNS prophylaxis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Criteria for CNS prophylaxis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Feugier et al&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">9</span></a> &#40;2004&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">399 DLBCL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">20 CNS relapses&#58; 4&#46;6&#37; &#40;CHOP&#41; and 5&#46;4&#37; &#40;R-CHOP&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Yamamoto et al&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">21</span></a> &#40;2010&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">375 DLBCL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">13 CNS relapses&#58; 2&#46;9&#37; &#40;CHOP&#41; and 3&#46;9&#37; &#40;R-CHOP&#41; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;71&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Chihara et al&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">23</span></a> &#40;2011&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">386 DLBCL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">24 CNS relapses&#58; 7&#46;3&#37; &#40;CHOP&#41; and 5&#46;3&#37; &#40;R-CHOP&#41;&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;42 &#40;5-year cumulative incidence&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Meningeal at 15&#47;24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">IT Methotrexate or cytarabine<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>4 doses&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Testicle &#40;after 1999&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Tai et al&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">22</span></a> &#40;2011&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">499 DLBCL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">30 CNS relapses&#58; 5&#46;1&#37; &#40;CHOP&#41; and 6&#37; &#40;R-CHOP&#41; &#40;2-year cumulative incidence&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">IT prophylaxis in 82 patients according to physician judgment and patient preference&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#62;1 extranodal site&#44; orbital sinus&#44; postnasal space&#44; breast&#44; testicles&#44; BM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Cao et al&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">18</span></a> &#40;2012&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">315 DLBCL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10 CNS relapses&#58; 3&#46;03&#37; &#40;CHOP&#41; and 3&#46;33&#37; &#40;R-CHOP&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Parenchymal in 9&#47;10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Deng et al&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">20</span></a> &#40;2013&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">599 DLBCL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">32 CNS relapses&#58; 6&#46;5&#37; &#40;CHOP&#41; and 4&#46;3&#37; &#40;R-CHOP&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab1062191.png"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Studies not proving the decreasing central nervous system relapses in diffuse large B-cell lymphoma upon introduction of rituximab&#46;</p>"
        ]
      ]
      2 => array:8 [
        "identificador" => "tbl0015"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at3"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">cytaBOM&#58; cytarabine&#44; bleomycin&#44; vincristine and methotrexate&#59; IPI&#58; International Prognostic Index&#59; IT&#58; intrathecal&#59; LDH&#58; lactate dehydrogenase&#59; m-BACOD&#58; methotrexate&#44; bleomycin&#44; cyclophosphamide&#44; and etoposide&#59; proMACE&#58; prednisone&#44; methotrexate&#44; doxorubicin&#44; cyclophosphamide and etoposide&#59; CNS&#58; central nervous system&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Authors and reference &#40;year&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Number of cases&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">CNS relapse&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Risk factors &#40;multivariate analysis&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Remark&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Van Besien et al&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">26</span></a> &#40;1998&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">605<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4&#46;5&#37; &#40;24 patients&#41;<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">High LDH&#59; &#62;1 extranodal site&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No CNS prophylaxis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Haioun et al&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">27</span></a> &#40;2000&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">974<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;6&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">High IPI&#59; high LDH&#59; &#62;1 extranodal site<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CNS prophylaxis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hollender et al&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">28</span></a> &#40;2002&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2514&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5&#46;2&#37;<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">High LDH&#59; &#62;1 extranodal site&#59; albumin<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>35<span class="elsevierStyleHsp" style=""></span>g&#47;l&#59; age<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>60 years&#59; retroperitoneal condition&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Boehme et al&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">29</span></a> &#40;2007&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1693<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&#46;2&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">High LDH&#59; &#62;1 extranodal site&#59; no etoposide administration&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CNS prophylaxis &#40;IT&#41; by 4&#46;2&#37; according to medical criteria&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Bernstein et al&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">31</span></a> &#40;2009&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">899<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&#46;8&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">IPI&#59; &#62;1 extranodal site&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CNS prophylaxis only if systemic chemotherapy with m-BACOD or proMACE-cytaBOM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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          "notaPie" => array:4 [
            0 => array:3 [
              "identificador" => "tblfn0005"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Aggressive histology&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0010"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Only 11 of the 24 patients had high lactate dehydrogenase and more than one extranodal site&#46;</p>"
            ]
            2 => array:3 [
              "identificador" => "tblfn0015"
              "etiqueta" => "c"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0015">After removing the international prognostic index&#46;</p>"
            ]
            3 => array:3 [
              "identificador" => "tblfn0020"
              "etiqueta" => "d"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0020">Central nervous system relapse in the high-grade subgroup &#40;not including lymphoblastic lymphoma and Burkitt lymphoma&#41;&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Risk factors for central nervous system relapse in lymphomas in the era prior to rituximab&#46;</p>"
        ]
      ]
      3 => array:8 [
        "identificador" => "tbl0020"
        "etiqueta" => "Table 4"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at4"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">aaIPI&#58; age-adjusted international prognostic index&#59; CHOEP&#58; cyclophosphamide&#44; adriamycin&#44; vincristine&#44; etoposide&#44; and prednisone&#59; CHOP&#58; cyclophosphamide&#44; adriamycin&#44; vincristine and prednisone&#59; ECOG&#58; Eastern Cooperative Oncology Group&#59; IPI&#58; International Prognostic Index&#59; IT&#58; intrathecal&#59; DLBCL&#58; diffuse large B-cell lymphoma&#59; LDH&#58; lactate dehydrogenase&#59; BM&#58; bone marrow&#59; PS&#58; performance status&#59; R&#58; rituximab&#59; CR&#58; complete response&#59; CNS&#58; central nervous system&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Authors and reference &#40;year&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Number of patients and type of lymphoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">CNS relapse&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Risk factors of CNS relapse&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Remark&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Feugier et al&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">9</span></a> &#40;2004&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">399 DLBCL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#46;4&#37; &#40;in those treated with R-CHOP&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">aaIPI<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>1 &#40;LDH and PS after excluding aaIPI&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No CNS prophylaxis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Boehme et al&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">10</span></a> &#40;2009&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1217 B-cell lymphomas &#40;944 DLBCL&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&#46;1&#37; &#40;in those treated with R-CHOP&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Global Series&#58; &#62;1 extranodal site&#59; B signs&#59; LDH &#40;not significant&#41; &#40;multivariate analysis&#41;&#46; Patients treated with R-CHOP&#58; &#62;1 extranodal site&#59; LDH&#59; ECOG<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CNS prophylaxis is administered with IT methotrexate in the first 2 cycles of chemotherapy in patients with head and neck or testicular extranodal infiltration&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Shimazu et al&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">13</span></a> &#40;2009&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">435 DLBCL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">8&#46;4&#37; &#40;in those treated with R-CHOP&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">age<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>60 years&#59; LDH&#59; &#62;1 extranodal site&#59; BM&#59; No R &#40;multivariate analysis&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Prophylaxis with IT methotrexate in a very small group &#40;18 patients&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Villa et al&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">11</span></a> &#40;2010&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">435 DLBCL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6&#46;4&#37; &#40;in those treated with R-CHOP&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Testicle&#59; kidney&#59; stage 4&#59; no R&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Alternate IT Methotrexate with IT cytarabine &#40;6 doses&#41; if paranasal sinuses involved&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Yamamoto et al&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">21</span></a> &#40;2010&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">375 DLBCL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#46;9&#37; &#40;in those treated with R-CHOP&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">None in the multivariate analysis &#40;in univariate analysis&#58; LDH&#44; high IPI&#44; BM&#44; systemic relapse&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No CNS prophylaxis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Chihara et al&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">23</span></a> &#40;2011&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">386 DLBCL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#46;3&#37; &#40;in those treated with R-CHOP&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bulky disease&#59; B-cells<span class="elsevierStyleHsp" style=""></span> &#60;<span class="elsevierStyleHsp" style=""></span>1000<span class="elsevierStyleHsp" style=""></span>mm<span class="elsevierStyleSup">&#8211;3</span>&#59; extranodal infiltration &#40;multivariate analysis of competing risks&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Prophylaxis with methotrexate or cytarabine only if testicular infiltration&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Tai et al&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">22</span></a> &#40;2011&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">499 DLBCL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6&#37; &#40;in those treated with R-CHOP&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ECOG<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>1&#59; no RC&#59; testicle&#59; kidney&#59; breast &#40;multivariate analysis&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">IT prophylaxis according to medical criteria&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Schmitz et al&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">15</span></a> &#40;2012&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2210 aggressive B-cell lymphomas &#40;1809 DLBCL&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;6&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Global Series&#58; &#62;1 extranodal site&#59; LDH&#46; In patients treated with R-chemotherapy&#58; stage 3&#8211;4&#59; LDH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CNS prophylaxis with IT methotrexate on days 1 and 15 of the first 2 cycles in High-CHOEP and Mega-CHOEP studies in high-risk patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Tomita et al&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">30</span></a> &#40;2012&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1221 DLBCL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6&#46;7&#37; &#40;in those treated with R-CHOP&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">age<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>60 years&#59; adrenal gland&#59; bone&#59; breast&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No CNS prophylaxis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Guirguis et al&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">17</span></a> &#40;2012&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">217 DLBCL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#46;7&#37; &#40;in those treated with R-CHOP&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Testicle&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CNS prophylaxis in high-risk cases &#40;with IT methotrexate and intravenous&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Kumar et al&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">19</span></a> &#40;2012&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">989 DLBCL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#37; &#40;in those treated with R-CHOP&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Intermediate-high and high IPI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CNS prophylaxis does not reduce relapse&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Zhang et al&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">24</span></a> &#40;2014&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4911 DLBCL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&#46;7&#37; &#40;in those treated with R-chemotherapy&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Stage 3&#47;4&#59; IPI<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>1&#59; PS<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>1&#59; high LDH&#59; <span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>1 extranodal site&#59; BM&#59; testicle&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Meta-analysis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Risk factors of central nervous system relapse in diffuse large B cell lymphoma<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">a</span></a> upon introduction of rituximab&#46;</p>"
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