Liposomal cytarabine for the treatment of leptomeningeal dissemination of central nervous system tumours in children and adolescents

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Hospital General de Alicante, Alicante, Spain" "etiqueta" => "h" "identificador" => "aff0040" ] 8 => array:3 [ "entidad" => "Servicio de Oncología Pediátrica, Hospital Universitario de Burgos, Burgos, Spain" "etiqueta" => "i" "identificador" => "aff0045" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Citarabina liposomal para el tratamiento de la diseminación leptomeníngea en tumores del sistema nervioso central en niños y adolescentes" ] ] "textoCompleto" => "IntroductionDefinition and aetiologyThe meninges are the most frequent site of metastatic spread in paediatric central nervous system (CNS) tumours. This dissemination can be present at initial diagnosis or persist as minimal residual disease despite initial treatment and recur as metastatic disease.<a class="elsevierStyleCrossRef" href="#bib0130">1</a> Another explanation for the phenomenon of persistent minimal residual disease and leptomeningeal metastatic recurrence is the presence of the blood–brain barrier (BBB), which blocks the delivery of drugs that are administered systemically.<a class="elsevierStyleCrossRef" href="#bib0135">2</a>DiagnosisDissemination is suspected based on clinical symptoms and confirmed by abnormal MRI findings or the presence of cancerous cells in cerebrospinal fluid (CSF). The most frequent symptoms are headache, cranial nerve palsy, back pain or radiculalgia. Other possible manifestations include impaired CSF flow or reabsorption with secondary hydrocephalus. Diagnostic MRI findings can have a linear, nodular or mixed enhancement pattern. The diffuse pattern shows contrast uptake or thickening along the margins of the meninges, which can reach nerve root exits in the spinal region.<a class="elsevierStyleCrossRef" href="#bib0140">3</a> Magnetic resonance abnormalities may be accompanied by the detection of malignant cells in CSF cytology, although in embryonal tumours it is possible to find evidence of dissemination in CSF cytology in the absence of abnormal MRI findings. The usefulness of flow cytometry of CSF samples from paediatric brain tumours has yet to be determined.Incidence of metastatic dissemination in different types of paediatric tumoursThe highest incidence corresponds to embryonal tumours.<a class="elsevierStyleCrossRef" href="#bib0145">4</a> In medulloblastoma, the most frequent type of malignant CSN tumour in the paediatric age group, the incidence of metastasis at the time of diagnosis ranges between 20% and 30%. Thirty percent of medulloblastomas do recur, usually with leptomeningeal dissemination. Metastatic disease becoming resistant to multimodal therapy is the usual cause of death in these patients, as opposed to local recurrence. The incidence of metastasis is particularly high in group 3, followed by group 4 and the Sonic Hedgehog medulloblastoma subgroups.<a class="elsevierStyleCrossRef" href="#bib0150">5</a> In other embryonal tumours, such as the supratentorial primitive neuroectodermal tumours (PNET), which include pineoblastoma, embryonal tumours with multilayered rosettes (ETMRT), and atypical teratoid-rhabdoid tumours (ATRTs), dissemination may be found at the time of diagnosis or in a subsequent recurrence.The incidence of dissemination is lower in gliomas.<a class="elsevierStyleCrossRefs" href="#bib0155">6,7</a> Recent studies on diffuse intrinsic pontine glioma revealed that up to 38% of patients had leptomeningeal spread at autopsy.<a class="elsevierStyleCrossRef" href="#bib0165">8</a> A study on ependymoma reported that 9–20% of patients had dissemination at diagnosis, with a higher incidence in recurrent cases.<a class="elsevierStyleCrossRef" href="#bib0170">9</a> Dissemination is rarely found in glioneural tumours, such as ganglioglioma or dysembryoplastic neuroectodermal tumour, but is a consistent finding in the rare cases of disseminated glioneural tumour.<a class="elsevierStyleCrossRef" href="#bib0175">10</a> The incidence of dissemination in malignant germ cell tumours (germinomas, secretory germ cell tumours and mixed germ cell tumours) ranges between 10% and 20% at the time of diagnosis.<a class="elsevierStyleCrossRef" href="#bib0180">11</a>The probability of developing CNS metastases from extracranial tumours is much lower in children and adolescents than in adults. The most frequent tumours with CNS metastases are sarcoma (Ewing sarcoma, osteosarcoma, synovial sarcoma), neuroblastoma, Wilms tumour and retinoblastoma.<a class="elsevierStyleCrossRef" href="#bib0185">12</a>Treatment optionsThe goal of treatment for leptomeningeal dissemination can be preventive, when dissemination is not detectable by the usually available methods at initiation, or therapeutic, when there is evidence of metastatic disease in MRI or cytology. The treatment used most commonly is craniospinal irradiation covering the entire neural axis. In combination with chemotherapy, this approach has achieved cure rates in excess of 60% in patients with metastatic medulloblastoma, at the expense of mid- to long-term sequelae that are primarily neurocognitive. This limits its use in children aged less than 5 years.Alternative treatment options are few and their mid- and long-term efficacy is poor. Most frequently, leptomeningeal dissemination is found after completion of multimodal frontline therapy, for instance in metastatic relapses of previously irradiated medulloblastoma. New therapies are needed to improve survival in refractory disease and reduce long-term sequelae in survivors. One possible strategy is the use of high doses of systemic chemotherapeutic agents such as methotrexate, or high doses of conventional chemotherapy followed by salvage therapy with hematopoietic stem cell transplantation, although this approach is not efficacious in previously irradiated relapsing medulloblastomas.<a class="elsevierStyleCrossRef" href="#bib0190">13</a> When radiotherapy is not an option because it has been used previously or due to the age of the patient, one possible option to increase the penetrance of chemotherapy in the CNS is the direct injection of drugs via the intrathecal route.<a class="elsevierStyleCrossRef" href="#bib0195">14</a> Few chemotherapeutic agents can be safely delivered intrathecally, and they have been studied more extensively in the context of leukaemias, although the use of other cytostatic agents (methotrexate, cytarabine, topotecan or etoposide) and new drugs (interferon alpha, interleukin 2 or anti-GD2 monoclonal antibodies) is currently being investigated. Intrathecal administration into the subarachnoid space via lumbar puncture has the advantage of bypassing the BBB. There are also drawbacks to repeated lumbar punctures with the corresponding anaesthesia and sedation: risk of inadequate injection technique, post-puncture headache, infection or haemorrhage. Placement of an Ommaya reservoir could alleviate some of these problems, allowing direct intraventricular delivery. Other drawbacks of intrathecal delivery are impaired CSF flow, CSF flow obstruction, and in patients with ventriculoperitoneal or ventriculoatrial shunts, inadequate drug exposure due to the shunt clearing the drug from the CSF space. Yet another drawback is their potential additive neurotoxic effect, of which there is evidence in drugs such as methotrexate.In this article, we review the current evidence on the pharmacology, safety and efficacy of intrathecal liposomal cytarabine for the treatment of CNS tumours with leptomeningeal dissemination.Pharmacology and pharmacokineticsCytarabine (Ara-C) is an antimetabolite, a pyrimidine nucleoside analogue of cytidine. It is converted intracellularly into the active metabolite arabinosylcytosine triphosphate (ara-CTP). It is a drug that acts specifically on the S phase of the cell cycle, inhibiting DNA synthesis (a competitive inhibitor of DNA polymerase).Cytarabine is eliminated through its conversion to the inactive metabolite uracil arabinoside (ara-U) and subsequent secretion in the urine. When cytarabine is administered systemically it is quickly metabolised to ara-U, but in the CSF, conversion of cytarabine to ara-U is negligible due to the low activity of cytidine deaminase, so that the clearance rate of cytarabine in the CSF is similar to the rate of CSF bulk flow: 0.24mL per minute.<a class="elsevierStyleCrossRefs" href="#bib0200">15,16</a> Still, there is probably interindividual variability in the cytidine deaminase concentration in the brain and CSF, which seems to increase with age.<a class="elsevierStyleCrossRef" href="#bib0205">16</a>The three anticancer drugs that are commonly administered via the intrathecal route are methotrexate, cytarabine and hydrocortisone. Both methotrexate and cytarabine act specifically on cells in the S phase of the cell cycle, and thus their efficacy increases with prolonged cytotoxic concentrations.<a class="elsevierStyleCrossRefs" href="#bib0200">15,16</a>The elimination half-life of free cytarabine following its intrathecal injection is 3.4h. Solid tumours have a lower proliferation rate than leukaemias and have higher cytotoxic thresholds that would require repeated intrathecal injections to maintain those concentrations in the CSF.<a class="elsevierStyleCrossRef" href="#bib0200">15</a>Liposomal cytarabine is a cytarabine formulation that is prepared by packing an aqueous solution of the drug in capsules or multivesicular spherical particles<a class="elsevierStyleCrossRefs" href="#bib0200">15–18</a> that consist of vesicles made of concentric membranes, formed by one or more phospholipid bilayers, that hold an aqueous solution and allow the slow release of cytarabine to the CSF. Five hours after intrathecal administration, a peak in the concentration of free cytarabine is observed in the ventricular and lumbar sac regions. The exposure to the active principle in these two regions is similar, regardless of the route of administration.The recommended dose of liposomal cytarabine for adults is 50mg delivered by intrathecal injection every two weeks, which results in an elimination half-life for free cytarabine in the CSF of 80h compared to the 3.4 half-life of non-liposomal cytarabine.<a class="elsevierStyleCrossRef" href="#bib0210">17</a>Unlike changes in the body surface area, which continues to increase through childhood and adolescence, the volume of CSF, as happens with head circumference, increases rapidly in the first years of life and reaches its final volume at age 3–4 years.<a class="elsevierStyleCrossRef" href="#bib0220">19</a> The doses of liposomal cytarabine tried out in children are based on this principle.<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> summarises the currently available pharmacological data on the use of liposomal cytarabine in the paediatric population.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Studies in children aged less than 3 years found levels similar to those found in older children, but lower than those found in adults.<a class="elsevierStyleCrossRefs" href="#bib0200">15,17,18</a> The concentrations of free cytarabine found in the intraventricular CSF following administration by lumbar puncture were comparable to those found following intraventricular administration, which demonstrates that cytarabine diffuses through the neural axis following lumbar injection. On the other hand, the concentrations of encapsulated cytarabine dropped faster following lumbar administration compared to cytarabine delivered intraventricularly. The authors concluded than in children aged less than 3 years, 25mg of intrathecal liposomal cytarabine can achieve the same drug exposure as doses of 35mg in children aged more than 3 years and doses of 50mg in adults, respectively.<a class="elsevierStyleCrossRef" href="#bib0200">15</a>The same group of researchers studied the pharmacokinetics of intrathecal liposomal cytarabine administered every two to four weeks in doses of 35mg to children aged 3–10 years (8 patients) or 50mg in children aged more than 10 years (7 patients).<a class="elsevierStyleCrossRef" href="#bib0205">16</a>These studies have demonstrated that liposomal preparations of cytarabine achieve prolonged cytotoxic concentrations following their intrathecal administration in children. The longer half-life observed in younger children could be due to lower concentrations of cytidine deaminase in the CSF of this subset of patients.Paediatric dosage and administrationRecommended doses and administration regimensIn Spain, liposomal cytarabine has been approved for treatment of lymphomatous meningitis in adults. As is the case of other drugs commonly used in paediatrics that have not been properly tested in the paediatric population, there is some published evidence from several early clinical trials, pharmacokinetic studies and retrospective studies analysing clinical experience. Based on this evidence, there seems to be a consensus regarding the dosages that could be recommended in the paediatric age group. At any rate, such off-label use should always be approved following established procedure in each hospital, including the decision of a multidisciplinary board responsible for weighing the benefits and risks in each individual case, and the informed consent of the parents or legal guardians for the off-label use of the drug, which should include information on its expected benefits, its potential toxicities, and alternative treatments.<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> presents the recommended doses per administration. It must be noted that the dose in children aged less than 3 years must be individualised, starting with a low dose, such as 1mg/kg, that can be increased to a maximum of 25mg in subsequent administrations.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Corticosteroid prophylaxisSeveral studies have shown that the use of corticosteroids decreases the incidence and severity of arachnoiditis associated with the use of liposomal cytarabine, with the best outcomes obtained with concomitant intrathecal administration of corticosteroids. Therefore, concomitant intrathecal administration of dexamethasone (see <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>) is recommended with each dose. In some patients, dexamethasone may be substituted with intrathecal hydrocortisone, which is better tolerated.<a class="elsevierStyleCrossRef" href="#bib0225">20</a> In addition, oral administration of dexamethasone is recommended three to five days after the administration of liposomal cytarabine, and the dose and regimen can be adjusted for each individual patient.Mode of administrationLiposomal Cytarabine is administered by lumbar puncture or placement of an Ommaya reservoir. The procedure must be performed under deep sedation and analgesia, with one clinician performing sedation and a different clinician administering the drug. After collecting CSF, liposomal cytarabine must be infused slowly over one to five minutes, followed by the intrathecal administration of dexamethasone over one minute. If the drug is administered via lumbar puncture, the patient must remain in the supine position for at least an hour. The drugs must be administered by a clinician with demonstrated experience in lumbar puncture and the delivery of intrathecal chemotherapy.Schedule. According to the summary of product characteristics, the first five doses must be administered every other week, followed by five more doses given every four weeks. No data are available on the safety of the continued use of liposomal cytarabine after 10 doses, and clinicians should weigh the risks and benefits of continuing treatment on a case-by-case basis.Analysing CSF cytology is recommended at the time each dose is administered to monitor the cytologic response (in case the CSF had tested positive at baseline), as is performance of craniospinal MRI every eight to twelve weeks to assess the response of leptomeningeal dissemination.ToxicityThe adverse reactions found most frequently in studies in adults are headache, arachnoiditis, pyrexia, weakness, nausea, vomiting, confusion, diarrhoea, thrombocytopaenia and fatigue. The main severe toxicities (in less than 10% of patients) are myelopathys, seizures, extreme somnolence, hemiplegia, visual changes, hearing loss and cranial nerve palsy. Other reported adverse effects include signs and symptoms of peripheral neuropathy such as pain, paraesthesias and even faecal and urinary incontinence.There are few data on the toxicity of cytarabine in children (see <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>). In general, toxicity seems to be slightly lesser than the toxicity reported in adults. In the reviewed studies, forty-seven percent of children did not develop adverse reactions. The most common adverse reactions (in more than 5%) were headache, arachnoiditis, neurologic impairment, cauda equina syndrome, seizures, papilloedema and inflammation at the lumbar puncture site.<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>Efficacy on central nervous system tumoursLiposomal cytarabine is one of the drugs that has been studied most extensively in the past decade for the treatment or prophylaxis of leptomeningeal dissemination via intrathecal administration. At the time of this writing, there are no randomised studies comparing the efficacy of liposomal cytarabine to that of other drugs in the paediatric population.As is often the case in paediatric diseases, data from studies in adults are used to assess its potential use in this age group. There is evidence of a cytologic response in adults with leptomeningeal dissemination and different histological types, such as lung cancer, melanoma, PNET and medulloblastoma, among others.<a class="elsevierStyleCrossRef" href="#bib0230">21</a>Studies in adults comparing it with intrathecal methotrexate seem to show a better response to liposomal cytarabine, although this trend was not statistically significant. However, significant differences have been found in the median time to neurologic progression (30 days for methotrexate versus 58 days for liposomal cytarabine).<a class="elsevierStyleCrossRef" href="#bib0235">22</a>All the evidence on its use in brain tumours in the paediatric age group comes from single-arm studies, many of which do not differentiate between de novo and relapsed patients, or between its therapeutic and prophylaxis use, making it difficult to draw solid conclusions.Approximately 100 cases of children and adolescents with CNS tumours treated with liposomal cytarabine have been described in the literature (see <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>), often in combination with other treatment modalities, most of which were cases of relapsing embryonal cell tumours. Cytologic responses have been described in the treatment of leptomeningeal dissemination with an acceptable toxicity profile, but the data did not suffice to clearly prove that this cytologic efficacy correlates with an improvement in survival.<elsevierMultimedia ident="tbl0020"></elsevierMultimedia>A nationwide, multicentre study conducted in Spain included 20 cases of CNS tumours with leptomeningeal dissemination: four ependymomas, 10 medulloblastomas, three supratentorial PNETs and three other cases, which included both de novo and relapse cases.<a class="elsevierStyleCrossRef" href="#bib0240">23</a> Approximately, half of the patients received concomitant chemotherapy without radiotherapy. Eleven out of nineteen patients (59%) responded to treatment, with five achieving complete remission and six partial remission. The response was neurologic in eleven out of nineteen and cytologic in seven out of ten of the evaluable cases, with a median progression-free survival of 180 days and development of adverse effects in 11 out of 20 cases.Another case series presented a retrospective study of patients aged less than 30 years with CNS embryonal tumours: five de novo cases (3 ATRT, 2 of supratentorial PNET) and twelve recurrent cases (all medulloblastoma).<a class="elsevierStyleCrossRef" href="#bib0245">24</a> None of the patients with negative CSF cytology at diagnosis developed malignant CSF cytology during treatment. Six patients with malignant cytology treated with at least two doses (mean, 3 doses) cleared their CSF. The survival in this study was four out of five in de novo patients and one out of twelve in relapsed patients (median, 26.8 months). Yet another published series reported favourable outcomes of its use with concomitant antiangiogenic therapy in patients with medulloblastoma. When it comes to ATRT, a study with a small sample of patients has reported promising results.<a class="elsevierStyleCrossRef" href="#bib0250">25</a> A phase II clinical trial is needed to assess the efficacy of liposomal cytarabine in embryonal CNS tumours.The data currently available is insufficient to provide recommendations supported by high quality evidence. Nevertheless, patients with CNS tumours with leptomeningeal dissemination have a very poor prognosis, and in many cases there are no potentially curative therapeutic alternatives for them. Therefore, the use of liposomal cytarabine could be considered in various situations:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">–1st or subsequent recurrences of supratentorial PNET or medulloblastoma with leptomeningeal dissemination.</li><li class="elsevierStyleListItem" id="lsti0010">–1st or subsequent recurrences of ependymoma with leptomeningeal dissemination.</li><li class="elsevierStyleListItem" id="lsti0015">–In patients with ATRT at the time of diagnosis and until initiation of radiotherapy.</li><li class="elsevierStyleListItem" id="lsti0020">–In patients with leptomeningeal dissemination of any other type of CNS tumour, excluding gliomas, until initiation of radiotherapy, or in patients that are ineligible for radiotherapy (for example, children aged less than 3 years).</li></ul>ConclusionsPaediatric embryonal CNS tumours with leptomeningeal dissemination continue to pose significant challenges to the paediatric oncologist due to a dearth of therapeutic options both in relapse patients and for cases that carry a poor prognosis from the time of diagnosis. Treatment with intrathecal liposomal cytarabine is an alternative to consider in selected cases. The toxicity profile is acceptable when cytarabine is combined with prophylactic treatment with intrathecal and oral dexamethasone and pharmacotherapy is performed in facilities with experience in the treatment of CNS tumours. Although the potential long-term applications of liposomal cytarabine remain to be determined by large-scope studies, the current literature reports favourable cytologic and clinical outcomes in a proportion of patients with high-risk tumours that have experienced multiple relapses.Conflict of interestsAll authors of this article have participated in an advisory board on the use of liposomal cytarabine in paediatric patients." "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres746750" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec749919" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres746751" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec749920" "titulo" => "Palabras clave" ] 4 => array:3 [ "identificador" => "sec0005" "titulo" => "Introduction" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0010" "titulo" => "Definition and aetiology" ] 1 => array:2 [ "identificador" => "sec0015" "titulo" => "Diagnosis" ] 2 => array:2 [ "identificador" => "sec0020" "titulo" => "Incidence of metastatic dissemination in different types of paediatric tumours" ] 3 => array:2 [ "identificador" => "sec0025" "titulo" => "Treatment options" ] ] ] 5 => array:2 [ "identificador" => "sec0030" "titulo" => "Pharmacology and pharmacokinetics" ] 6 => array:3 [ "identificador" => "sec0035" "titulo" => "Paediatric dosage and administration" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0040" "titulo" => "Recommended doses and administration regimens" ] 1 => array:2 [ "identificador" => "sec0045" "titulo" => "Corticosteroid prophylaxis" ] 2 => array:2 [ "identificador" => "sec0050" "titulo" => "Mode of administration" ] ] ] 7 => array:2 [ "identificador" => "sec0055" "titulo" => "Toxicity" ] 8 => array:2 [ "identificador" => "sec0060" "titulo" => "Efficacy on central nervous system tumours" ] 9 => array:2 [ "identificador" => "sec0065" "titulo" => "Conclusions" ] 10 => array:2 [ "identificador" => "sec0070" "titulo" => "Conflict of interests" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2016-01-05" "fechaAceptado" => "2016-02-17" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec749919" "palabras" => array:6 [ 0 => "Liposomal cytarabine" 1 => "Leptomeningeal dissemination" 2 => "Central nervous system tumours" 3 => "Medulloblastoma" 4 => "Ependymoma" 5 => "Intrathecal" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec749920" "palabras" => array:6 [ 0 => "Citarabina liposomal" 1 => "Diseminación leptomeníngea" 2 => "Tumores del sistema nervioso central" 3 => "Meduloblastoma" 4 => "Ependimoma" 5 => "Intratecal" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Leptomeningeal dissemination in paediatric central nervous system (CNS) tumours is associated with a poor outcome, and new therapeutic strategies are desperately needed. One of the main difficulties in the treatment of CNS tumours is blood brain barrier penetration. Intrathecal therapy has shown to be effective in several paediatric tumours. The aim of this article is to review the data available on the use of liposomal cytarabine for paediatric patients with leptomeningeal dissemination of CNS tumours, including the pharmacology, administration, safety and efficacy data." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "Los tumores pediátricos del sistema nervioso central (SNC) con diseminación leptomeníngea tienen mal pronóstico y es preciso encontrar nuevas alternativas terapéuticas. Una de las principales dificultades en el tratamiento de los tumores del SNC es la penetración de la barrera hematoencefálica, por lo que el tratamiento intratecal ha demostrado su eficacia en múltiples tumores pediátricos. En este artículo se revisa la experiencia disponible sobre la utilización de citarabina liposomal para pacientes pediátricos con tumores del SNC con diseminación leptomeníngea: farmacología, forma de administración, datos de seguridad y estudios de eficacia." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Moreno L, García Ariza MA, Cruz O, Calvo C, Fuster JL, Salinas JA, et al. Citarabina liposomal para el tratamiento de la diseminación leptomeníngea en tumores del sistema nervioso central en niños y adolescentes. An Pediatr (Barc). 2016;85:274." ] ] "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:1 [ "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">Study \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">Sample size/diagnosis \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">Dosage \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">Pharmacology \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">Conclusion \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">Phase I trial: Bomgaars et al. (2004) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">19 patients with CNS involvement due to leukaemia, lymphoma or solid tumours (ages 3–21 years) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Dose escalation: 25mg followed by 35 and 50mg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Peak at 1–2h from administration Half-life, 50–57h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Dose recommended for children aged more than 3 years: 35mg Administration via lumbar puncture or reservoir achieves prolonged exposures of >7 days \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">Peyrl et al. (2009) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4 children aged less than 3 years (11–35 months) with malignant CNS tumours \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">25mg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Peak at the time of administration. Half-life, 59.3–56.7h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Prolonged exposure of up to 14 days achieved. In children aged less than 3 years, a 25mg dose achieved comparable drug exposure as 35mg in older children \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">Peyrl et al. (2014) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">15 patients (8 aged 3–10 years and 7 aged >10 years) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">35mg for ≤10 years 50mg for >10 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Half-life, 31.5–40.9h in young children and 43.7–36.4h in children >10 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Cytotoxic levels detected during week 1 in most patients \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1233460.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Studies on the pharmacology and pharmacokinetics of liposomal cytarabine in the paediatric population." ] ] 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" => "DXM, dexamethasone." "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">Age range \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">Dose of liposomal cytarabine \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">Corticosteroid 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">More than 18 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">50mg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4mg of intrathecal DXM 4mg oral/IV DXM every 12h for 2–3 day \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">10–18 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">50mg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4mg of intrathecal DXM 4mg oral/IV DXM every 12h for 2–3 days \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">3–10 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">35mg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2mg of intrathecal DXM 0.15mg/kg/dose (maximum 4mg/dose) oral/IV DXM every 12h for 2–3 days \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"><3 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Determined on case-by-case basis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1mg of intrathecal DXM 0.15mg/kg/dose (maximum 4mg/dose) oral/IV DXM every 12h for 2–3 days \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1233462.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Dosage and schedule of liposomal cytarabine treatment in paediatric patients." ] ] 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:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="table-head ; entry_with_role_rowhead " align="left" valign="top" scope="col">Type \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Navajas et al. (2012) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Benesch et al. (2007) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Benesch et al. (2009) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Lassaletta et al. (2009) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Peyrl et al. (2009) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Sommer et al. (2008) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Total \t\t\t\t\t\t\n \t\t\t\t</th></tr><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">N=11 \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">N=5 \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">N=19 \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">N=9 \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">N=6 \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">N=3 \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">N=53 \t\t\t\t\t\t\n \t\t\t\t</th></tr><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \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 \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">R ALL, R AML, CNS \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 \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">SNC, NHL, Rhabd \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 \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 \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \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">Headache \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10 (18.8%) \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">Neurologic impairment \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5 (9.4%) \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">Arachnoiditis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">9 (16.9%) \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">Cauda equina syndrome \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4 (7.5%) \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">Irritability \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 (3.7%) \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">Nausea or vomiting \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2(3.7%) \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">Fever \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 (3.7%) \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">Acute encephalopathy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 (1.8%) \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">Seizures \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 (5.6%) \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">Papilloedema \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 (5.6%) \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">Radiculopathy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 (1.8%) \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">Post-puncture inflammation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 (3.7%) \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">Post-puncture infection \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 (1.8%) \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">None \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">25 (47.1%) \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">Grade IV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 (4.2%) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1233459.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Toxicities associated most frequently with the use of liposomal cytarabine in paediatric patients." ] ] 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:2 [ "leyenda" => "CNS, central nervous system; FR, full remission; LC, liposomal cytarabine; n.d., not documented; RTX, radiotherapy." "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">Study \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">Sample size/diagnosis \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">Age \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">Intrathecal treatment \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">Other treatment \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">Status \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">Follow up \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">Partap et al. (2010) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">17 CNS (embryonal) 5 de novo 12 recurrences \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6 doses (1–16) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Chemotherapy+RTX \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5/17 alive 4/5 1/12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">48 months \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">Benesch et al. (2009) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">19 CNS 14 CNS (embryonal) 5 other CNS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><23 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4 doses (1–10) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Chemotherapy+RTX \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">13/19 alive 3 in FR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12 months \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">Lassaletta et al. (2009) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9 CNS 5 CNS (embryonal) 4 other CNS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4 doses (1–7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Chemotherapy 2 RTX \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5/9 alive \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">20 months \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">Peyrl et al. (2012) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">16 CNS (embryonal) 5 recurrent no Depocyt \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0–12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10 doses (1–18) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Metronomic \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10/16 alive 7/11 alive on Depocyt \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">33 months (10–58) \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">Bomgaars et al. (2004) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7 CNS 6 CNS (embryonal) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3–21 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 doses (2–10) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Chemotherapy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7/7 deceased \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" 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">Mastronuzzi et al. (2013) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 CNS (embryonal) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6–17 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Not specified \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Chemotherapy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2/3 alive and diseased \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10 months \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">Slavc et al. (2014) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">8 CNS (ATRT) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0–17 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5 doses (LC in only 5 patients) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Chemotherapy+RTX \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">8/8 alive \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">16–197 months \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">Navajas et al. (2012) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">20 CNS 15 CNS (embryonal) 5 Other CNS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">8 months–18 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5 doses (1–9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Chemotherapy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10/18 alive (2 n.d.) 6/13 alive (2 n.d.) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">>180 days \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">Peyrl et al. (2014) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">16 CNS 9 CNS (embryonal) 7 other \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3–18 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6 doses (3–18) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Chemotherapy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">8/16 alive 6/9 alive \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6–69 months \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">Nygaard et al. (2011) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 (medulloblastoma) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">14 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">13 doses \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Metronomic \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Alive \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">34 months \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="7" align="left" valign="top"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Total \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">116 CNS/94 embryonal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">60/114 alive \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1233461.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Data on the efficacy of liposomal cytarabine in paediatric patients with CNS tumours." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:25 [ 0 => array:3 [ "identificador" => "bib0130" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A perspective on cancer cell metastasis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "C.L. 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Liposomal cytarabine for the treatment of leptomeningeal dissemination of central nervous system tumours in children and adolescents

Citarabina liposomal para el tratamiento de la diseminación leptomeníngea en tumores del sistema nervioso central en niños y adolescentes

Lucas Morenoa,b,

Corresponding author

lmorenom@ext.cnio.es
lucas.moreno@salud.madrid.org

Corresponding author.

, Miguel Angel García Arizac, Ofelia Cruzd, Carlota Calvoe, José Luis Fusterf, José Antonio Salinasg, Cristina Moscardoh, Raquel Portugali, José Manuel Merinoi, Luis Maderoa,b

a Servicio de Onco-Hematología Pediátrica, Hospital Infantil Universitario Niño Jesús, Madrid, Spain

b Instituto de Investigación La Princesa, Madrid, Spain

c Servicio de Oncología Pediátrica, Hospital de Cruces, Bilbao, Vizcaya, Spain

d Servicio de Hemato-Oncología, Hospital Sant Joan de Déu, Barcelona, Spain

e Servicio de Oncología Pediátrica, Hospital Miguel Servet, Zaragoza, Spain

f Servicio de Oncología Pediátrica, Hospital Virgen de la Arrixaca, Murcia, Spain

g Servicio de Oncología Pediátrica, Hospital Son Espases, Palma de Mallorca, Islas Baleares, Spain

h Servicio de Oncología Pediátrica, Hospital General de Alicante, Alicante, Spain

i Servicio de Oncología Pediátrica, Hospital Universitario de Burgos, Burgos, Spain

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Definition and aetiology</span><p id="par0005" class="elsevierStylePara elsevierViewall">The meninges are the most frequent site of metastatic spread in paediatric central nervous system &#40;CNS&#41; tumours&#46; This dissemination can be present at initial diagnosis or persist as minimal residual disease despite initial treatment and recur as metastatic disease&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">1</span></a> Another explanation for the phenomenon of persistent minimal residual disease and leptomeningeal metastatic recurrence is the presence of the blood&#8211;brain barrier &#40;BBB&#41;&#44; which blocks the delivery of drugs that are administered systemically&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">2</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Diagnosis</span><p id="par0010" class="elsevierStylePara elsevierViewall">Dissemination is suspected based on clinical symptoms and confirmed by abnormal MRI findings or the presence of cancerous cells in cerebrospinal fluid &#40;CSF&#41;&#46; The most frequent symptoms are headache&#44; cranial nerve palsy&#44; back pain or radiculalgia&#46; Other possible manifestations include impaired CSF flow or reabsorption with secondary hydrocephalus&#46; Diagnostic MRI findings can have a linear&#44; nodular or mixed enhancement pattern&#46; The diffuse pattern shows contrast uptake or thickening along the margins of the meninges&#44; which can reach nerve root exits in the spinal region&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">3</span></a> Magnetic resonance abnormalities may be accompanied by the detection of malignant cells in CSF cytology&#44; although in embryonal tumours it is possible to find evidence of dissemination in CSF cytology in the absence of abnormal MRI findings&#46; The usefulness of flow cytometry of CSF samples from paediatric brain tumours has yet to be determined&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Incidence of metastatic dissemination in different types of paediatric tumours</span><p id="par0015" class="elsevierStylePara elsevierViewall">The highest incidence corresponds to embryonal tumours&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">4</span></a> In medulloblastoma&#44; the most frequent type of malignant CSN tumour in the paediatric age group&#44; the incidence of metastasis at the time of diagnosis ranges between 20&#37; and 30&#37;&#46; Thirty percent of medulloblastomas do recur&#44; usually with leptomeningeal dissemination&#46; Metastatic disease becoming resistant to multimodal therapy is the usual cause of death in these patients&#44; as opposed to local recurrence&#46; The incidence of metastasis is particularly high in group 3&#44; followed by group 4 and the Sonic Hedgehog medulloblastoma subgroups&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">5</span></a> In other embryonal tumours&#44; such as the supratentorial primitive neuroectodermal tumours &#40;PNET&#41;&#44; which include pineoblastoma&#44; embryonal tumours with multilayered rosettes &#40;ETMRT&#41;&#44; and atypical teratoid-rhabdoid tumours &#40;ATRTs&#41;&#44; dissemination may be found at the time of diagnosis or in a subsequent recurrence&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">The incidence of dissemination is lower in gliomas&#46;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">6&#44;7</span></a> Recent studies on diffuse intrinsic pontine glioma revealed that up to 38&#37; of patients had leptomeningeal spread at autopsy&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">8</span></a> A study on ependymoma reported that 9&#8211;20&#37; of patients had dissemination at diagnosis&#44; with a higher incidence in recurrent cases&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">9</span></a> Dissemination is rarely found in glioneural tumours&#44; such as ganglioglioma or dysembryoplastic neuroectodermal tumour&#44; but is a consistent finding in the rare cases of disseminated glioneural tumour&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">10</span></a> The incidence of dissemination in malignant germ cell tumours &#40;germinomas&#44; secretory germ cell tumours and mixed germ cell tumours&#41; ranges between 10&#37; and 20&#37; at the time of diagnosis&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">11</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">The probability of developing CNS metastases from extracranial tumours is much lower in children and adolescents than in adults&#46; The most frequent tumours with CNS metastases are sarcoma &#40;Ewing sarcoma&#44; osteosarcoma&#44; synovial sarcoma&#41;&#44; neuroblastoma&#44; Wilms tumour and retinoblastoma&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">12</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Treatment options</span><p id="par0030" class="elsevierStylePara elsevierViewall">The goal of treatment for leptomeningeal dissemination can be preventive&#44; when dissemination is not detectable by the usually available methods at initiation&#44; or therapeutic&#44; when there is evidence of metastatic disease in MRI or cytology&#46; The treatment used most commonly is craniospinal irradiation covering the entire neural axis&#46; In combination with chemotherapy&#44; this approach has achieved cure rates in excess of 60&#37; in patients with metastatic medulloblastoma&#44; at the expense of mid- to long-term sequelae that are primarily neurocognitive&#46; This limits its use in children aged less than 5 years&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Alternative treatment options are few and their mid- and long-term efficacy is poor&#46; Most frequently&#44; leptomeningeal dissemination is found after completion of multimodal frontline therapy&#44; for instance in metastatic relapses of previously irradiated medulloblastoma&#46; New therapies are needed to improve survival in refractory disease and reduce long-term sequelae in survivors&#46; One possible strategy is the use of high doses of systemic chemotherapeutic agents such as methotrexate&#44; or high doses of conventional chemotherapy followed by salvage therapy with hematopoietic stem cell transplantation&#44; although this approach is not efficacious in previously irradiated relapsing medulloblastomas&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">13</span></a> When radiotherapy is not an option because it has been used previously or due to the age of the patient&#44; one possible option to increase the penetrance of chemotherapy in the CNS is the direct injection of drugs via the intrathecal route&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">14</span></a> Few chemotherapeutic agents can be safely delivered intrathecally&#44; and they have been studied more extensively in the context of leukaemias&#44; although the use of other cytostatic agents &#40;methotrexate&#44; cytarabine&#44; topotecan or etoposide&#41; and new drugs &#40;interferon alpha&#44; interleukin 2 or anti-GD2 monoclonal antibodies&#41; is currently being investigated&#46; Intrathecal administration into the subarachnoid space via lumbar puncture has the advantage of bypassing the BBB&#46; There are also drawbacks to repeated lumbar punctures with the corresponding anaesthesia and sedation&#58; risk of inadequate injection technique&#44; post-puncture headache&#44; infection or haemorrhage&#46; Placement of an Ommaya reservoir could alleviate some of these problems&#44; allowing direct intraventricular delivery&#46; Other drawbacks of intrathecal delivery are impaired CSF flow&#44; CSF flow obstruction&#44; and in patients with ventriculoperitoneal or ventriculoatrial shunts&#44; inadequate drug exposure due to the shunt clearing the drug from the CSF space&#46; Yet another drawback is their potential additive neurotoxic effect&#44; of which there is evidence in drugs such as methotrexate&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">In this article&#44; we review the current evidence on the pharmacology&#44; safety and efficacy of intrathecal liposomal cytarabine for the treatment of CNS tumours with leptomeningeal dissemination&#46;</p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Pharmacology and pharmacokinetics</span><p id="par0045" class="elsevierStylePara elsevierViewall">Cytarabine &#40;Ara-C&#41; is an antimetabolite&#44; a pyrimidine nucleoside analogue of cytidine&#46; It is converted intracellularly into the active metabolite arabinosylcytosine triphosphate &#40;ara-CTP&#41;&#46; It is a drug that acts specifically on the S phase of the cell cycle&#44; inhibiting DNA synthesis &#40;a competitive inhibitor of DNA polymerase&#41;&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">Cytarabine is eliminated through its conversion to the inactive metabolite uracil arabinoside &#40;ara-U&#41; and subsequent secretion in the urine&#46; When cytarabine is administered systemically it is quickly metabolised to ara-U&#44; but in the CSF&#44; conversion of cytarabine to ara-U is negligible due to the low activity of cytidine deaminase&#44; so that the clearance rate of cytarabine in the CSF is similar to the rate of CSF bulk flow&#58; 0&#46;24<span class="elsevierStyleHsp" style=""></span>mL per minute&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">15&#44;16</span></a> Still&#44; there is probably interindividual variability in the cytidine deaminase concentration in the brain and CSF&#44; which seems to increase with age&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">16</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">The three anticancer drugs that are commonly administered via the intrathecal route are methotrexate&#44; cytarabine and hydrocortisone&#46; Both methotrexate and cytarabine act specifically on cells in the S phase of the cell cycle&#44; and thus their efficacy increases with prolonged cytotoxic concentrations&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">15&#44;16</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">The elimination half-life of free cytarabine following its intrathecal injection is 3&#46;4<span class="elsevierStyleHsp" style=""></span>h&#46; Solid tumours have a lower proliferation rate than leukaemias and have higher cytotoxic thresholds that would require repeated intrathecal injections to maintain those concentrations in the CSF&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">15</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Liposomal cytarabine is a cytarabine formulation that is prepared by packing an aqueous solution of the drug in capsules or multivesicular spherical particles<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">15&#8211;18</span></a> that consist of vesicles made of concentric membranes&#44; formed by one or more phospholipid bilayers&#44; that hold an aqueous solution and allow the slow release of cytarabine to the CSF&#46; Five hours after intrathecal administration&#44; a peak in the concentration of free cytarabine is observed in the ventricular and lumbar sac regions&#46; The exposure to the active principle in these two regions is similar&#44; regardless of the route of administration&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">The recommended dose of liposomal cytarabine for adults is 50<span class="elsevierStyleHsp" style=""></span>mg delivered by intrathecal injection every two weeks&#44; which results in an elimination half-life for free cytarabine in the CSF of 80<span class="elsevierStyleHsp" style=""></span>h compared to the 3&#46;4 half-life of non-liposomal cytarabine&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">17</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">Unlike changes in the body surface area&#44; which continues to increase through childhood and adolescence&#44; the volume of CSF&#44; as happens with head circumference&#44; increases rapidly in the first years of life and reaches its final volume at age 3&#8211;4 years&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">19</span></a> The doses of liposomal cytarabine tried out in children are based on this principle&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> summarises the currently available pharmacological data on the use of liposomal cytarabine in the paediatric population&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0085" class="elsevierStylePara elsevierViewall">Studies in children aged less than 3 years found levels similar to those found in older children&#44; but lower than those found in adults&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">15&#44;17&#44;18</span></a> The concentrations of free cytarabine found in the intraventricular CSF following administration by lumbar puncture were comparable to those found following intraventricular administration&#44; which demonstrates that cytarabine diffuses through the neural axis following lumbar injection&#46; On the other hand&#44; the concentrations of encapsulated cytarabine dropped faster following lumbar administration compared to cytarabine delivered intraventricularly&#46; The authors concluded than in children aged less than 3 years&#44; 25<span class="elsevierStyleHsp" style=""></span>mg of intrathecal liposomal cytarabine can achieve the same drug exposure as doses of 35<span class="elsevierStyleHsp" style=""></span>mg in children aged more than 3 years and doses of 50<span class="elsevierStyleHsp" style=""></span>mg in adults&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">15</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">The same group of researchers studied the pharmacokinetics of intrathecal liposomal cytarabine administered every two to four weeks in doses of 35<span class="elsevierStyleHsp" style=""></span>mg to children aged 3&#8211;10 years &#40;8 patients&#41; or 50<span class="elsevierStyleHsp" style=""></span>mg in children aged more than 10 years &#40;7 patients&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">16</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">These studies have demonstrated that liposomal preparations of cytarabine achieve prolonged cytotoxic concentrations following their intrathecal administration in children&#46; The longer half-life observed in younger children could be due to lower concentrations of cytidine deaminase in the CSF of this subset of patients&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Paediatric dosage and administration</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Recommended doses and administration regimens</span><p id="par0100" class="elsevierStylePara elsevierViewall">In Spain&#44; liposomal cytarabine has been approved for treatment of lymphomatous meningitis in adults&#46; As is the case of other drugs commonly used in paediatrics that have not been properly tested in the paediatric population&#44; there is some published evidence from several early clinical trials&#44; pharmacokinetic studies and retrospective studies analysing clinical experience&#46; Based on this evidence&#44; there seems to be a consensus regarding the dosages that could be recommended in the paediatric age group&#46; At any rate&#44; such off-label use should always be approved following established procedure in each hospital&#44; including the decision of a multidisciplinary board responsible for weighing the benefits and risks in each individual case&#44; and the informed consent of the parents or legal guardians for the off-label use of the drug&#44; which should include information on its expected benefits&#44; its potential toxicities&#44; and alternative treatments&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> presents the recommended doses per administration&#46; It must be noted that the dose in children aged less than 3 years must be individualised&#44; starting with a low dose&#44; such as 1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#44; that can be increased to a maximum of 25<span class="elsevierStyleHsp" style=""></span>mg in subsequent administrations&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Corticosteroid prophylaxis</span><p id="par0110" class="elsevierStylePara elsevierViewall">Several studies have shown that the use of corticosteroids decreases the incidence and severity of arachnoiditis associated with the use of liposomal cytarabine&#44; with the best outcomes obtained with concomitant intrathecal administration of corticosteroids&#46; Therefore&#44; concomitant intrathecal administration of dexamethasone &#40;see <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41; is recommended with each dose&#46; In some patients&#44; dexamethasone may be substituted with intrathecal hydrocortisone&#44; which is better tolerated&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">20</span></a> In addition&#44; oral administration of dexamethasone is recommended three to five days after the administration of liposomal cytarabine&#44; and the dose and regimen can be adjusted for each individual patient&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Mode of administration</span><p id="par0115" class="elsevierStylePara elsevierViewall">Liposomal Cytarabine is administered by lumbar puncture or placement of an Ommaya reservoir&#46; The procedure must be performed under deep sedation and analgesia&#44; with one clinician performing sedation and a different clinician administering the drug&#46; After collecting CSF&#44; liposomal cytarabine must be infused slowly over one to five minutes&#44; followed by the intrathecal administration of dexamethasone over one minute&#46; If the drug is administered via lumbar puncture&#44; the patient must remain in the supine position for at least an hour&#46; The drugs must be administered by a clinician with demonstrated experience in lumbar puncture and the delivery of intrathecal chemotherapy&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Schedule&#46; According to the summary of product characteristics&#44; the first five doses must be administered every other week&#44; followed by five more doses given every four weeks&#46; No data are available on the safety of the continued use of liposomal cytarabine after 10 doses&#44; and clinicians should weigh the risks and benefits of continuing treatment on a case-by-case basis&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">Analysing CSF cytology is recommended at the time each dose is administered to monitor the cytologic response &#40;in case the CSF had tested positive at baseline&#41;&#44; as is performance of craniospinal MRI every eight to twelve weeks to assess the response of leptomeningeal dissemination&#46;</p></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Toxicity</span><p id="par0130" class="elsevierStylePara elsevierViewall">The adverse reactions found most frequently in studies in adults are headache&#44; arachnoiditis&#44; pyrexia&#44; weakness&#44; nausea&#44; vomiting&#44; confusion&#44; diarrhoea&#44; thrombocytopaenia and fatigue&#46; The main severe toxicities &#40;in less than 10&#37; of patients&#41; are myelopathys&#44; seizures&#44; extreme somnolence&#44; hemiplegia&#44; visual changes&#44; hearing loss and cranial nerve palsy&#46; Other reported adverse effects include signs and symptoms of peripheral neuropathy such as pain&#44; paraesthesias and even faecal and urinary incontinence&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">There are few data on the toxicity of cytarabine in children &#40;see <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; In general&#44; toxicity seems to be slightly lesser than the toxicity reported in adults&#46; In the reviewed studies&#44; forty-seven percent of children did not develop adverse reactions&#46; The most common adverse reactions &#40;in more than 5&#37;&#41; were headache&#44; arachnoiditis&#44; neurologic impairment&#44; cauda equina syndrome&#44; seizures&#44; papilloedema and inflammation at the lumbar puncture site&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Efficacy on central nervous system tumours</span><p id="par0140" class="elsevierStylePara elsevierViewall">Liposomal cytarabine is one of the drugs that has been studied most extensively in the past decade for the treatment or prophylaxis of leptomeningeal dissemination via intrathecal administration&#46; At the time of this writing&#44; there are no randomised studies comparing the efficacy of liposomal cytarabine to that of other drugs in the paediatric population&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">As is often the case in paediatric diseases&#44; data from studies in adults are used to assess its potential use in this age group&#46; There is evidence of a cytologic response in adults with leptomeningeal dissemination and different histological types&#44; such as lung cancer&#44; melanoma&#44; PNET and medulloblastoma&#44; among others&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">21</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">Studies in adults comparing it with intrathecal methotrexate seem to show a better response to liposomal cytarabine&#44; although this trend was not statistically significant&#46; However&#44; significant differences have been found in the median time to neurologic progression &#40;30 days for methotrexate versus 58 days for liposomal cytarabine&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">22</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">All the evidence on its use in brain tumours in the paediatric age group comes from single-arm studies&#44; many of which do not differentiate between de novo and relapsed patients&#44; or between its therapeutic and prophylaxis use&#44; making it difficult to draw solid conclusions&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">Approximately 100 cases of children and adolescents with CNS tumours treated with liposomal cytarabine have been described in the literature &#40;see <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#44; often in combination with other treatment modalities&#44; most of which were cases of relapsing embryonal cell tumours&#46; Cytologic responses have been described in the treatment of leptomeningeal dissemination with an acceptable toxicity profile&#44; but the data did not suffice to clearly prove that this cytologic efficacy correlates with an improvement in survival&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0165" class="elsevierStylePara elsevierViewall">A nationwide&#44; multicentre study conducted in Spain included 20 cases of CNS tumours with leptomeningeal dissemination&#58; four ependymomas&#44; 10 medulloblastomas&#44; three supratentorial PNETs and three other cases&#44; which included both de novo and relapse cases&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">23</span></a> Approximately&#44; half of the patients received concomitant chemotherapy without radiotherapy&#46; Eleven out of nineteen patients &#40;59&#37;&#41; responded to treatment&#44; with five achieving complete remission and six partial remission&#46; The response was neurologic in eleven out of nineteen and cytologic in seven out of ten of the evaluable cases&#44; with a median progression-free survival of 180 days and development of adverse effects in 11 out of 20 cases&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">Another case series presented a retrospective study of patients aged less than 30 years with CNS embryonal tumours&#58; five de novo cases &#40;3 ATRT&#44; 2 of supratentorial PNET&#41; and twelve recurrent cases &#40;all medulloblastoma&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">24</span></a> None of the patients with negative CSF cytology at diagnosis developed malignant CSF cytology during treatment&#46; Six patients with malignant cytology treated with at least two doses &#40;mean&#44; 3 doses&#41; cleared their CSF&#46; The survival in this study was four out of five in de novo patients and one out of twelve in relapsed patients &#40;median&#44; 26&#46;8 months&#41;&#46; Yet another published series reported favourable outcomes of its use with concomitant antiangiogenic therapy in patients with medulloblastoma&#46; When it comes to ATRT&#44; a study with a small sample of patients has reported promising results&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">25</span></a> A phase II clinical trial is needed to assess the efficacy of liposomal cytarabine in embryonal CNS tumours&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">The data currently available is insufficient to provide recommendations supported by high quality evidence&#46; Nevertheless&#44; patients with CNS tumours with leptomeningeal dissemination have a very poor prognosis&#44; and in many cases there are no potentially curative therapeutic alternatives for them&#46; Therefore&#44; the use of liposomal cytarabine could be considered in various situations&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">&#8211;</span><p id="par0180" class="elsevierStylePara elsevierViewall">1st or subsequent recurrences of supratentorial PNET or medulloblastoma with leptomeningeal dissemination&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">&#8211;</span><p id="par0185" class="elsevierStylePara elsevierViewall">1st or subsequent recurrences of ependymoma with leptomeningeal dissemination&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">&#8211;</span><p id="par0190" class="elsevierStylePara elsevierViewall">In patients with ATRT at the time of diagnosis and until initiation of radiotherapy&#46;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">&#8211;</span><p id="par0195" class="elsevierStylePara elsevierViewall">In patients with leptomeningeal dissemination of any other type of CNS tumour&#44; excluding gliomas&#44; until initiation of radiotherapy&#44; or in patients that are ineligible for radiotherapy &#40;for example&#44; children aged less than 3 years&#41;&#46;</p></li></ul></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Conclusions</span><p id="par0200" class="elsevierStylePara elsevierViewall">Paediatric embryonal CNS tumours with leptomeningeal dissemination continue to pose significant challenges to the paediatric oncologist due to a dearth of therapeutic options both in relapse patients and for cases that carry a poor prognosis from the time of diagnosis&#46; Treatment with intrathecal liposomal cytarabine is an alternative to consider in selected cases&#46; The toxicity profile is acceptable when cytarabine is combined with prophylactic treatment with intrathecal and oral dexamethasone and pharmacotherapy is performed in facilities with experience in the treatment of CNS tumours&#46; Although the potential long-term applications of liposomal cytarabine remain to be determined by large-scope studies&#44; the current literature reports favourable cytologic and clinical outcomes in a proportion of patients with high-risk tumours that have experienced multiple relapses&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Conflict of interests</span><p id="par0205" class="elsevierStylePara elsevierViewall">All authors of this article have participated in an advisory board on the use of liposomal cytarabine in paediatric patients&#46;</p></span></span>"
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          "titulo" => "Introduction"
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              "titulo" => "Incidence of metastatic dissemination in different types of paediatric tumours"
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    "fechaRecibido" => "2016-01-05"
    "fechaAceptado" => "2016-02-17"
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            0 => "Liposomal cytarabine"
            1 => "Leptomeningeal dissemination"
            2 => "Central nervous system tumours"
            3 => "Medulloblastoma"
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            1 => "Diseminaci&#243;n leptomen&#237;ngea"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Leptomeningeal dissemination in paediatric central nervous system &#40;CNS&#41; tumours is associated with a poor outcome&#44; and new therapeutic strategies are desperately needed&#46; One of the main difficulties in the treatment of CNS tumours is blood brain barrier penetration&#46; Intrathecal therapy has shown to be effective in several paediatric tumours&#46; The aim of this article is to review the data available on the use of liposomal cytarabine for paediatric patients with leptomeningeal dissemination of CNS tumours&#44; including the pharmacology&#44; administration&#44; safety and efficacy data&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Los tumores pedi&#225;tricos del sistema nervioso central &#40;SNC&#41; con diseminaci&#243;n leptomen&#237;ngea tienen mal pron&#243;stico y es preciso encontrar nuevas alternativas terap&#233;uticas&#46; Una de las principales dificultades en el tratamiento de los tumores del SNC es la penetraci&#243;n de la barrera hematoencef&#225;lica&#44; por lo que el tratamiento intratecal ha demostrado su eficacia en m&#250;ltiples tumores pedi&#225;tricos&#46; En este art&#237;culo se revisa la experiencia disponible sobre la utilizaci&#243;n de citarabina liposomal para pacientes pedi&#225;tricos con tumores del SNC con diseminaci&#243;n leptomen&#237;ngea&#58; farmacolog&#237;a&#44; forma de administraci&#243;n&#44; datos de seguridad y estudios de eficacia&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Moreno L&#44; Garc&#237;a Ariza MA&#44; Cruz O&#44; Calvo C&#44; Fuster JL&#44; Salinas JA&#44; et al&#46; Citarabina liposomal para el tratamiento de la diseminaci&#243;n leptomen&#237;ngea en tumores del sistema nervioso central en ni&#241;os y adolescentes&#46; An Pediatr &#40;Barc&#41;&#46; 2016&#59;85&#58;274&#46;</p>"
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                  \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">Study&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">Sample size&#47;diagnosis&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">Dosage&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">Pharmacology&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">Conclusion&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">Phase I trial&#58; Bomgaars et al&#46; &#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">19 patients with CNS involvement due to leukaemia&#44; lymphoma or solid tumours &#40;ages 3&#8211;21 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">Dose escalation&#58; 25<span class="elsevierStyleHsp" style=""></span>mg followed by 35 and 50<span class="elsevierStyleHsp" style=""></span>mg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Peak at 1&#8211;2<span class="elsevierStyleHsp" style=""></span>h from administration<br>Half-life&#44; 50&#8211;57<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Dose recommended for children aged more than 3 years&#58; 35<span class="elsevierStyleHsp" style=""></span>mg<br>Administration via lumbar puncture or reservoir achieves prolonged exposures of &#62;7 days&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">Peyrl et al&#46; &#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">4 children aged less than 3 years &#40;11&#8211;35 months&#41; with malignant CNS tumours&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">25<span class="elsevierStyleHsp" style=""></span>mg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Peak at the time of administration&#46;<br>Half-life&#44; 59&#46;3&#8211;56&#46;7<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Prolonged exposure of up to 14 days achieved&#46;<br>In children aged less than 3 years&#44; a 25<span class="elsevierStyleHsp" style=""></span>mg dose achieved comparable drug exposure as 35<span class="elsevierStyleHsp" style=""></span>mg in older children&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">Peyrl et al&#46; &#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">15 patients &#40;8 aged 3&#8211;10 years and 7 aged &#62;10 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">35<span class="elsevierStyleHsp" style=""></span>mg for &#8804;10 years<br>50<span class="elsevierStyleHsp" style=""></span>mg for &#62;10 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Half-life&#44; 31&#46;5&#8211;40&#46;9<span class="elsevierStyleHsp" style=""></span>h in young children and 43&#46;7&#8211;36&#46;4<span class="elsevierStyleHsp" style=""></span>h in children &#62;10 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Cytotoxic levels detected during week 1 in most patients&nbsp;\t\t\t\t\t\t\n
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                  \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">Age range&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">Dose of liposomal cytarabine&nbsp;\t\t\t\t\t\t\n
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                  \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">More than 18 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">50<span class="elsevierStyleHsp" style=""></span>mg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4<span class="elsevierStyleHsp" style=""></span>mg of intrathecal DXM<br>4<span class="elsevierStyleHsp" style=""></span>mg oral&#47;IV DXM every 12<span class="elsevierStyleHsp" style=""></span>h for 2&#8211;3 day&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">10&#8211;18 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">50<span class="elsevierStyleHsp" style=""></span>mg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4<span class="elsevierStyleHsp" style=""></span>mg of intrathecal DXM<br>4<span class="elsevierStyleHsp" style=""></span>mg oral&#47;IV DXM every 12<span class="elsevierStyleHsp" style=""></span>h for 2&#8211;3 days&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">3&#8211;10 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">35<span class="elsevierStyleHsp" style=""></span>mg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2<span class="elsevierStyleHsp" style=""></span>mg of intrathecal DXM<br>0&#46;15<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;dose &#40;maximum 4<span class="elsevierStyleHsp" style=""></span>mg&#47;dose&#41; oral&#47;IV DXM every 12<span class="elsevierStyleHsp" style=""></span>h for 2&#8211;3 days&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">&#60;3 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Determined on case-by-case basis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1<span class="elsevierStyleHsp" style=""></span>mg of intrathecal DXM<br>0&#46;15<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;dose &#40;maximum 4<span class="elsevierStyleHsp" style=""></span>mg&#47;dose&#41; oral&#47;IV DXM every 12<span class="elsevierStyleHsp" style=""></span>h for 2&#8211;3 days&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="table-head ; entry_with_role_rowhead " align="left" valign="top" scope="col">Type&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">Navajas et al&#46; &#40;2012&#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">Benesch et al&#46; &#40;2007&#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">Benesch et al&#46; &#40;2009&#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">Lassaletta et al&#46; &#40;2009&#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">Peyrl et al&#46; &#40;2009&#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">Sommer et al&#46; &#40;2008&#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">Total&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col">&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"><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>11&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"><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5&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"><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>19&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"><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>9&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"><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>6&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"><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&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"><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>53&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">CNS&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">R ALL&#44; R AML&#44; CNS&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&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">SNC&#44; NHL&#44; Rhabd&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&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&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \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">Headache&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">10 &#40;18&#46;8&#37;&#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">Neurologic impairment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5 &#40;9&#46;4&#37;&#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">Arachnoiditis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">9 &#40;16&#46;9&#37;&#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">Cauda equina syndrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4 &#40;7&#46;5&#37;&#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">Irritability&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2 &#40;3&#46;7&#37;&#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">Nausea or vomiting&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&#40;3&#46;7&#37;&#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">Fever&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2 &#40;3&#46;7&#37;&#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">Acute encephalopathy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;8&#37;&#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">Seizures&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3 &#40;5&#46;6&#37;&#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">Papilloedema&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3 &#40;5&#46;6&#37;&#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">Radiculopathy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;8&#37;&#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">Post-puncture inflammation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2 &#40;3&#46;7&#37;&#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">Post-puncture infection&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#46;8&#37;&#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">None&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">25 &#40;47&#46;1&#37;&#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">Grade IV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2 &#40;4&#46;2&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "leyenda" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">CNS&#44; central nervous system&#59; FR&#44; full remission&#59; LC&#44; liposomal cytarabine&#59; n&#46;d&#46;&#44; not documented&#59; RTX&#44; radiotherapy&#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">Study&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">Sample size&#47;diagnosis&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">Age&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">Intrathecal treatment&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">Other treatment&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">Status&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">Follow up&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">Partap et al&#46; &#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">17 CNS &#40;embryonal&#41;<br>5 de novo<br>12 recurrences&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6 doses &#40;1&#8211;16&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Chemotherapy<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>RTX&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#47;17 alive<br>4&#47;5<br>1&#47;12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">48 months&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">Benesch et al&#46; &#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">19 CNS<br>14 CNS &#40;embryonal&#41;<br>5 other CNS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;23&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4 doses &#40;1&#8211;10&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Chemotherapy<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>RTX&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">13&#47;19 alive<br>3 in FR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12 months&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">Lassaletta et al&#46; &#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">9 CNS<br>5 CNS &#40;embryonal&#41;<br>4 other CNS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4 doses &#40;1&#8211;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Chemotherapy<br>2 RTX&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#47;9 alive&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">20 months&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">Peyrl et al&#46; &#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">16 CNS &#40;embryonal&#41;<br>5 recurrent<br>no Depocyt&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#8211;12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10 doses &#40;1&#8211;18&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Metronomic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&#47;16 alive<br>7&#47;11 alive on Depocyt&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">33 months<br>&#40;10&#8211;58&#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">Bomgaars et al&#46; &#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">7 CNS<br>6 CNS &#40;embryonal&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#8211;21&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3 doses &#40;2&#8211;10&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Chemotherapy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7&#47;7 deceased&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&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">Mastronuzzi et al&#46; &#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">3 CNS &#40;embryonal&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6&#8211;17&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Not specified&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Chemotherapy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#47;3 alive and diseased&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10 months&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">Slavc et al&#46; &#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">8 CNS &#40;ATRT&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#8211;17&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5 doses &#40;LC in only 5 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">Chemotherapy<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>RTX&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">8&#47;8 alive&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">16&#8211;197 months&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">Navajas et al&#46; &#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">20 CNS<br>15 CNS &#40;embryonal&#41;<br>5 Other CNS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">8 months&#8211;18 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5 doses &#40;1&#8211;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Chemotherapy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&#47;18 alive &#40;2 n&#46;d&#46;&#41;<br>6&#47;13 alive &#40;2 n&#46;d&#46;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#62;180 days&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">Peyrl et al&#46; &#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">16 CNS<br>9 CNS &#40;embryonal&#41;<br>7 other&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#8211;18 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6 doses &#40;3&#8211;18&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Chemotherapy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">8&#47;16 alive<br>6&#47;9 alive&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6&#8211;69 months&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">Nygaard et al&#46; &#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">1 &#40;medulloblastoma&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">13 doses&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Metronomic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Alive&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">34 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Total&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">116 CNS&#47;94 embryonal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">60&#47;114 alive&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Data on the efficacy of liposomal cytarabine in paediatric patients with CNS tumours&#46;</p>"
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      "titulo" => "References"
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        0 => array:2 [
          "identificador" => "bibs0005"
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            0 => array:3 [
              "identificador" => "bib0130"
              "etiqueta" => "1"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A perspective on cancer cell metastasis"
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Article information

ISSN: 23412879
Original language: English

DOI:10.1016/j.anpede.2016.02.002

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Year/Month	Html	Pdf	Total

2024 November	8	8	16
2024 October	52	46	98
2024 September	45	47	92
2024 August	68	74	142
2024 July	48	36	84
2024 June	57	28	85
2024 May	59	35	94
2024 April	55	39	94
2024 March	40	27	67
2024 February	42	28	70
2024 January	44	29	73
2023 December	30	19	49
2023 November	27	21	48
2023 October	37	29	66
2023 September	33	24	57
2023 August	32	22	54
2023 July	35	22	57
2023 June	45	21	66
2023 May	42	15	57
2023 April	38	15	53
2023 March	71	21	92
2023 February	59	17	76
2023 January	35	17	52
2022 December	80	20	100
2022 November	76	36	112
2022 October	68	42	110
2022 September	19	29	48
2022 August	41	53	94
2022 July	26	28	54
2022 June	18	33	51
2022 May	33	43	76
2022 April	34	42	76
2022 March	38	46	84
2022 February	26	25	51
2022 January	40	40	80
2021 December	30	36	66
2021 November	31	44	75
2021 October	61	83	144
2021 September	28	35	63
2021 August	35	49	84
2021 July	29	38	67
2021 June	49	37	86
2021 May	46	42	88
2021 April	65	68	133
2021 March	44	37	81
2021 February	30	17	47
2021 January	45	19	64
2020 December	43	24	67
2020 November	18	22	40
2020 October	21	19	40
2020 September	36	26	62
2020 August	23	23	46
2020 July	28	19	47
2020 June	17	11	28
2020 May	28	22	50
2020 April	24	20	44
2020 March	17	25	42
2020 February	23	12	35
2020 January	11	14	25
2019 December	38	16	54
2019 November	16	11	27
2019 October	24	15	39
2019 September	32	10	42
2019 August	51	21	72
2019 July	31	20	51
2019 June	29	18	47
2019 May	40	17	57
2019 April	59	39	98
2019 March	31	15	46
2019 February	38	17	55
2019 January	45	20	65
2018 December	43	30	73
2018 November	108	40	148
2018 October	160	53	213
2018 September	85	26	111
2018 August	4	0	4
2018 July	2	0	2
2018 June	4	0	4
2018 May	5	0	5
2018 April	40	0	40
2018 March	36	0	36
2018 February	15	0	15
2018 January	29	0	29
2017 December	18	0	18
2017 November	33	0	33
2017 October	12	0	12
2017 September	19	0	19
2017 August	17	0	17
2017 July	23	3	26
2017 June	33	8	41
2017 May	27	7	34
2017 April	23	20	43
2017 March	15	31	46
2017 February	7	10	17
2017 January	10	10	20
2016 December	27	23	50
2016 November	40	21	61
2016 October	9	19	28

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