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            "colaborador" => "on behalf of the Sociedad Espa&#241;ola de Hematolog&#237;a and Oncolog&#237;a Pedi&#225;trica &#40;SEHOP&#41; and the New Drug Development Group in Pediatric Oncology"
          ]
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        "afiliaciones" => array:13 [
          0 => array:3 [
            "entidad" => "Unidad de Investigaci&#243;n Cl&#237;nica CNIO-HNJ&#44; Servicio de Hematolog&#237;a&#44; Oncolog&#237;a y Trasplante de Progenitores Hematopoy&#233;ticos&#44; Hospital Infantil Universitario Ni&#241;o Jes&#250;s&#44; Madrid&#44; Spain"
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    "titulosAlternativos" => array:1 [
      "es" => array:1 [
        "titulo" => "Ensayos cl&#237;nicos precoces en oncolog&#237;a pedi&#225;trica en Espa&#241;a&#58; una perspectiva nacional"
      ]
    ]
    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">In Spain&#44; a new case of cancer is diagnosed in 1 out of 6&#44;500 children aged less than 15 years every year&#46; This amounts to 1&#44;100 new cases in children aged 0 to 14 years&#44; while there are 450 in adolescents aged 15&#8211;19 years&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">There have been enormous medical and therapeutic advances in paediatric cancer&#46; In Europe&#44; the mortality associated with childhood cancer decreased by 60&#37; between the 1950s and the 1990s&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">2</span></a> These figures have continued to improve since&#44; although there has been a plateau in some diseases&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">1</span></a> In Europe&#44; the overall 5-year survival for all types of cancer diagnosed between 2000 and 2007 was 77&#46;9&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">3</span></a> This success is due in large part to the development of multicentric clinical trials conducted by collaborative research groups&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">4</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">However&#44; cancer continues to be the leading cause of death by disease from the first year of life and through adolescence<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">1</span></a>&#58; in 2014&#44; cancer caused 29&#37; of deaths in children aged 1&#8211;14 years&#44; and 20&#37; of deaths in adolescents aged 15&#8211;19 years&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">5</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">More specifically&#44; the prognosis of certain diseases continues to be bleak&#44; for instance in metastatic medulloblastoma&#44; sarcoma or neuroblastoma&#44; high-grade glioma or in patients with other types of cancer that recurs or is refractory to first-line treatment&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Thus&#44; there is a pressing need for new drugs&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">These novel anticancer drugs are needed to improve survival and reduce the sequelae that result from multimodal treatment combining surgery&#44; radiotherapy&#44; chemotherapy and haematopoietic stem cell transplantation&#46; Recently&#44; the identification of particular molecular changes in specific tumours has led to the development of targeted therapies against them&#44; which has come to be known as &#8220;precision medicine&#46;&#8221;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">6</span></a> This has opened the door to strategies adapted to the presence of molecular changes or immunotherapy at the time of diagnosis or relapse&#44; which are exclusive to oncology patients&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">There is evidence of the usefulness of new targeted therapies in some paediatric solid tumours&#58; ALK inhibitors for anaplastic large-cell lymphoma&#44;<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">7&#44;8</span></a> Sonic-hedgehog signalling pathway inhibitors for medulloblastoma<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">9</span></a> or BRAF inhibitors for high-grade glioma in patients with BRAF-V600E mutations&#46;<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">10&#44;11</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">In leukaemia&#44; the best 2 examples correspond to chronic myelogenous leukaemia and acute lymphoblastic leukaemia&#44; in which the discovery of the Philadelphia chromosome &#40;t&#40;9&#59;22&#41;&#40;q34&#59;q11&#41;&#41; allowed the identification of the BCR-ABL fusion protein&#44; which plays an essential role in their pathogenesis&#46; This finding has allowed the development of drugs such as imatinib&#44; dasatinib or nilotinib that can kill leukaemia cells through the inhibition of ABL kinase activity&#44; improving the prognosis of these patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">12&#44;13</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Thus&#44; continued investment in research and development of novel anticancer agents for paediatric cancer is of vital importance&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">Motivated by the dearth of paediatric data for already authorised medicines&#44; new legislation was introduced in Europe in 2007 regarding the regulation of medicines in paediatrics that refers to the &#8220;paediatric investigation plan&#8221; that pharmaceutical companies need to submit to the European Medicines Agency at the time of applying for authorisation of a new drug&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">14</span></a> Thus&#44; whenever a pharmaceutical company gets a new drug authorised &#40;usually for the adult population&#41;&#44; it must be accompanied by a plan for paediatric development &#40;as long as the drug is potentially useful in children&#41;&#46; When paediatric investigation plans are completed satisfactorily&#44; the medicine is eligible for a 6-month supplementary protection certificate&#44; or in case of a so-called orphan medicinal product&#44; for an extension of 2 years to the 10 years of market exclusivity for the already authorised indication&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">The aims of this measure are<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">15</span></a>&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">-</span><p id="par0060" class="elsevierStylePara elsevierViewall">To increase availability of new medicines authorised for use in children through generation of accurate safety and efficacy data and high-quality ethical paediatric clinical research</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">-</span><p id="par0065" class="elsevierStylePara elsevierViewall">To produce better information on existing paediatric medicines&#46;</p></li></ul></p><p id="par0070" class="elsevierStylePara elsevierViewall">Despite the introduction of these initiatives in Europe in the past 15 years&#44; the development of novel drugs for the treatment of paediatric cancer is still insufficient&#58; 14 out of the 28 anticancer agents approved for adults have been waived for paediatric development&#44; while 26 of them were relevant to childhood cancers&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">16</span></a> Thus&#44; it is necessary for representatives of academic institutions&#44; regulatory bodies&#44; the pharmaceutical industry&#44; parent organisations&#44; patient rights advocacy groups and other charities to continue working and collaborating closely to facilitate children access to these new drugs&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">16</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">Generally speaking&#44; the use of certain drugs in patients with refractory or relapsed cancer is not based on a solid foundation of scientific evidence&#44; and most are not indicated for the paediatric age group&#46; The off-label use of drugs that are only authorised in adults carries significant risks and does not help improve the scientific evidence on their use&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">17</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Traditionally&#44; the development of a new drug involves different phases &#40;I through III&#41; to evaluate its toxicity and safety &#40;I&#41;&#44; efficacy &#40;II&#41; and improvements in survival &#40;III&#41; in specific populations&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">18</span></a> Phase IV trials are postmarketing studies that seek to identify toxicities that were not observed previously and assess long-term efficacy&#46; When it comes to oncology&#44; the subset of patients that participate in early-phase trials &#40;I and II&#41; mostly consists of those who have relapsed after at least one course of treatment&#44; or with refractory cancer&#46; This is a long and costly process&#8212;usually more than 10 years from target identification in a laboratory to marketing with costs of up to 2000 million dollars per product&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">19</span></a> Fewer than 5&#37; of medicines evaluated in phase I clinical trials gain market authorisation&#44;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">20</span></a> and only 1 out of 10<span class="elsevierStyleHsp" style=""></span>000 compounds ever reach the market&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">21</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Along these lines&#44; the Innovative Therapies For Children With Cancer consortium &#40;ITCC&#59; <a href="http://www.itcc-consortium.org/">http&#58;&#47;&#47;www&#46;itcc-consortium&#46;org</a>&#41; is an international organisation whose principal aim is to evaluate novel therapies for the treatment of cancer in children and adolescents&#46; The ITCC provides the necessary accreditation to develop and implement clinical trials in childhood cancer&#44; facilitates contact with academic or pharmaceutical industry sponsors&#44; and opens new clinical research centres<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">22</span></a> with the purpose of expediting access to these medicines for children&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">The aim of this study is to describe the activity in early-phase clinical trials in paediatric cancer in Spain in the past 10 years&#44; to evaluate the hurdles that we are facing&#44; their potential solutions&#44; and future challenges&#46; This study will provide a reference for this field for future comparison&#44; following the example of the BEST project of Farma Industry&#44; an association that seeks to promote excellence in clinical research of medicines in Spain and to assess performance&#44; efficacy and quality in the field &#40;<a href="http://www.farmaindustry.es/">www&#46;farmaIndustry&#46;es</a>&#41;&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Patients and methods</span><p id="par0095" class="elsevierStylePara elsevierViewall">The Sociedad Espa&#241;ola de Hematolog&#237;a y Oncolog&#237;a Pedi&#225;trica &#40;Spanish Society of Paediatric Haematology and Oncology &#91;SEHOP&#93;&#59; <a href="http://www.sehop.org/">www&#46;sehop&#46;org</a>&#41; represents all paediatric oncology units in Spain&#46; We contacted all the SEHOP members to identify phase I and II trials for solid tumours and blood cancers initiated between 2005 and 2015&#46; We chose this period because in Spain&#44; early-phase trials in the paediatric population started to be conducted in 2005&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">For each of the trials&#44; we collected data regarding the type of trial &#40;phase I or II&#41;&#44; sponsor &#40;academia or pharmaceutical industry&#41;&#44; number of participating centres&#44; enrolment period&#44; type&#40;s&#41; of tumour&#40;s&#41; under study&#44; drug under investigation&#44; mechanism of action and number of patients enrolled in the trial&#46; We updated these data on December 1&#44; 2015&#46; We checked whether trials were still recruiting patients in June 15&#44; 2016&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">When further information was needed&#44; we resorted to the clinical trials registry of the United States National Institutes of Health &#40;<a href="http://www.clinicaltrials.gov/">www&#46;clinicaltrials&#46;gov</a>&#41;&#44; the European Union Clinical Trials Register &#40;<a href="http://www.clinicaltrialsregister.eu/">www&#46;clinicaltrialsregister&#46;eu</a>&#41; and the Spanish Register of Clinical Trials of the Agencia Espa&#241;ola del Medicamento y Productos Sanitarios &#40;Spanish Agency of Medicines and Medical Devices &#91;AEMPS&#93;&#59; <a href="https://reec.aemps.es/">https&#58;&#47;&#47;reec&#46;aemps&#46;es</a>&#41;&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Results</span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Centres with units devoted to early-phase clinical trials&#58; The role of the ITCC consortium</span><p id="par0110" class="elsevierStylePara elsevierViewall">Since 2010&#44; 4 Spanish hospitals have joined the ITCC consortium&#58; the Hospital Universitari La Fe in Valencia&#59; the Hospital Universitari Vall d&#8217;Hebron in Barcelona&#44; the Hospital Ni&#241;o Jes&#250;s in Madrid and the Hospital Sant Joan de D&#233;u in Barcelona&#46; Other centres that are members of the SEHOP have also partaken in some of the studies described here&#44; most of them phase II trials&#58; La Paz&#44; Gregorio Mara&#241;&#243;n and Doce de Octubre hospitals &#40;Madrid&#41;&#44; Hospital Santa Creu i Sant Pau &#40;Barcelona&#41;&#44; Hospital Virgen del Roc&#237;o &#40;Seville&#41;&#44; Hospital Virgen de la Arrixaca &#40;Murcia&#41;&#44; Hospital de Cruces &#40;Bilbao&#41;&#44; Hospital Son Espases &#40;Palma de Mallorca&#41;&#44; Hospital Cl&#237;nico &#40;Valencia&#41;&#44; Hospital Universitario de Canarias &#40;Tenerife&#41;&#44; Hospital Miguel Servet &#40;Zaragoza&#41;&#44; Hospital Central de Asturias &#40;Oviedo&#41;&#44; Hospital Regional Universitario &#40;Malaga&#41; and Hospital General Universitario &#40;Alicante&#41;&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Paediatric oncology clinical trial portfolio</span><p id="par0115" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRefs" href="#tbl0005">Tables 1 and 2</a> list the early-phase clinical trials in patients with solid tumours and blood cancer&#44; respectively&#44; initiated between 2005 and 2015 in Spain&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0120" class="elsevierStylePara elsevierViewall">A total of 30 trials have been launched&#58; 21 &#40;70&#37;&#41; in patients with solid tumours and 9 &#40;30&#37;&#41; in patients with blood cancers&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">Of the trials for solid tumours&#44; 3 &#40;14&#37;&#41; are separate phase I trials&#44; 6 &#40;29&#37;&#41; are parallel phase <span class="elsevierStyleSmallCaps">I</span>&#47;II trials&#44; and 12 &#40;57&#37;&#41; are separate phase <span class="elsevierStyleSmallCaps">II</span> trials&#46; Six &#40;28&#37;&#41; are assessing tyrosine kinase inhibitors &#40;TKIs&#41;&#44; 6 &#40;28&#37;&#41; cytotoxic agents&#44; 3 &#40;14&#37;&#41; a combination of cytotoxic agents with a monoclonal antibody &#40;mAb&#41;&#44; 2 &#40;9&#37;&#41; a combination of 2 immunotherapy drugs for neuroblastoma&#44; 1 &#40;5&#37;&#41; a mAb for melanoma&#44; 1 &#40;5&#37;&#41; the combination of a TKI with a cytotoxic agent for osteosarcoma&#44; 1 &#40;5&#37;&#41; an oncolytic virus &#40;Celyvir<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">23&#44;24</span></a>&#41; and 1 &#40;5&#37;&#41; a combination of interleukin-15-stimulated natural killer cells and haploidentical hematopoietic stem cell transplantation&#46; Two trials &#40;10&#37;&#41; focused on tumours with specific molecular changes&#44; 14 &#40;66&#37;&#41; on specific types of tumours and 5 &#40;24&#37;&#41; were for solid tumours of any type&#46; Half of the trials were sponsored by pharmaceutical companies and the other half by academic institutions&#59; 15 &#40;72&#37;&#41; focused exclusively on the paediatric population &#40;age &#60;18 years&#41;&#44; 4 &#40;19&#37;&#41; included young adults up to age 21 years and 2 &#40;9&#37;&#41; included paediatric as well as adult patients&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Of the blood cancer trials&#44; 2 &#40;22&#46;2&#37;&#41; were phase I trials&#44; 3 &#40;33&#46;3&#37;&#41; were phase I&#47;II trials&#44; and 4 &#40;44&#46;5&#37;&#41; phase II trials&#59; 2 &#40;22&#46;2&#37;&#41; studied a TKI&#44; 2 &#40;22&#46;2&#37;&#41; a mAb&#44; 2 &#40;22&#46;2&#37;&#41; cell therapy with and without chemotherapy&#44; 1 &#40;11&#46;1&#37;&#41; a combination of a mAb with cytotoxic agents&#44; 1 &#40;11&#46;1&#37;&#41; a hypomethylating agent and 1 &#40;11&#46;1&#37;&#41; a proteasome inhibitor&#46; Two trials &#40;22&#46;2&#37;&#41; focused on diseases with specific molecular changes and 7 &#40;77&#46;8&#37;&#41; on specific blood cancers&#46; Most are sponsored by the pharmaceutical industry &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>6&#46;66&#37;&#41;&#46; They are all exclusively focused on the paediatric population under 18 years&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> shows the considerable increase in the options available for the groups of diseases for which clinical trials have been available in the past 5 years in Spain&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Enrolment in paediatric cancer clinical trials</span><p id="par0140" class="elsevierStylePara elsevierViewall">A total of 212 patients were enrolled during this period&#58; 179 &#40;84&#37;&#41; in solid tumour clinical trials and 33 &#40;16&#37;&#41; in blood cancer clinical trials&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Completed clinical trials</span><p id="par0145" class="elsevierStylePara elsevierViewall">The findings of completed trials and of ongoing trials whose intermediate results have been made available demonstrate the positive contribution of Spanish researchers&#44; the introduction of targeted molecular therapies in the paediatric population and the benefits that patients may derive from these new drugs &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">8&#44;10&#44;23&#44;25&#8211;31</span></a></p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Discussion</span><p id="par0150" class="elsevierStylePara elsevierViewall">This article describes the activity in the development of new treatments for paediatric cancer in Spain&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">Children with cancers that are high-risk or carry a poor prognosis continue to have difficulty accessing new drugs&#46; The number of trials opening in Spain has increased in the past 5 years&#44; probably as a result of hospitals joining the ITCC&#44; changes in legislation applying to paediatrics and institutional efforts to establish units devoted to these trials staffed by physicians&#44; research nurses&#44; project managers and data managers&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">Between 2010 and 2014&#44; 4 centres have joined the ITCC&#44; a consortium established in 2003 that comprises 9 European basic research laboratories and 47 paediatric oncology centres with the necessary resources to carry out phase I and II clinical trials in paediatric oncology&#46; One of the aims of the consortium is to develop novel therapies for paediatric malignancies in collaboration with pharmaceutical companies&#44; regulatory bodies and patient and parent associations&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">22</span></a> Since 2007 the number of drugs in early phase trials being run by the ITCC has grown from one in 2007 to 12 in 2013&#44; with half of these trials being conducted to comply with the regulatory requirements of a paediatric investigation plan&#59; this has significantly improved access of European children to novel therapies&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">15</span></a> For Spain&#44; being actively involved in the ITCC allows us to participate in international collaborative trials&#44; which facilitates access to promising therapies to our patients&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Most of the early-phase clinical trials in paediatric oncology and haematology that have opened in Spain have been sponsored by the pharmaceutical industry &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>16&#59; 53&#37;&#41;&#46; Only one third of the total focus on blood cancers&#46; This is possibly due to the fact that the overall cure rate with first-line treatment is high for leukaemias and lymphomas&#44; and that a significant percentage of patients that relapse achieve full remission for the second time and eventually a cure with conventional chemotherapy or haematopoietic stem cell transplantation&#46; Thus&#44; the target paediatric population for new drugs for blood cancers is smaller&#46; Recruitment is further complicated by the stringent inclusion and exclusion criteria&#44; the challenges involved in transferring patients from their original hospitals to the centres where these new therapies are available&#44; and the natural history of the disease&#44; which sometimes does not allow delays in treatment initiation&#46; These factors also apply to solid tumour patients&#44; and in specific nervous system diseases or sarcomas&#44; there are even fewer clinical trials&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">For all the above reasons&#44; paediatric cancer as a whole constitutes a &#8220;small&#8221; market with few incentives for the pharmaceutical industry&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">32</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">We believe that these groups of &#8220;orphan&#8221; patients should benefit from academic clinical trials&#46; From our paediatric haematology and oncology society&#44;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">33</span></a> and in collaboration with other scientific societies&#44; such as the Grupo Espa&#241;ol de Investigaci&#243;n en Sarcomas &#40;Spanish Sarcoma Research Group &#91;GEIS&#93;&#41;&#44; we aim to develop and participate in collaborative academic clinical trials to promote therapeutic advances and the optimisation of existing therapies for rare diseases like childhood cancer&#44; which are not usually the target of pharmaceutical companies&#46; Our duty as researchers is to improve on study design to add adaptability and flexibility&#44; and to develop trials on the basis of solid scientific evidence so that they target populations that are more likely to show a favourable response&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">34</span></a> In this regard&#44; the Sociedad Espa&#241;ola de Oncolog&#237;a M&#233;dica &#40;Spanish Society of Medical Oncology&#41; took an important initiative in addressing a manifesto to policymakers requesting support for independent academic clinical research&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">35</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">An added difficulty is the lack of funding for clinical development in academic settings&#46; This poses barriers to participation in international academic clinical trials&#44; as the costs of opening the trial at the local and national levels must be assumed nearly in full by participating countries&#46; Few not-for-profit organisations fund paediatric cancer research programmes or have specific agendas to support clinical trials&#46; The recent Royal Decree 1090&#47;2015 regulating drug clinical benefits non-commercial clinical research studies through exemption of fees or reduced fees and by simplifying the costly and complex bureaucracy involved in opening such trials&#46; Lack of funding does not only ail this side of the Atlantic&#46; In the United States&#44; 60&#37; of the funding for biomedical research comes from the biopharmaceutical industry&#44;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">36</span></a> followed by the National Institutes of Health&#44; which contributes another 25&#37;&#46; However&#44; funding from the pharmaceutical industry is nearly nonexistent in paediatric cancer&#44; so that research in the field depends on the National Institutes of Health&#44; private institutions and charities&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">32</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">On the bright side&#44; the favourable outcomes observed in samples selected based on molecular findings and treated with targeted therapies such as ALK or BRAF inhibitors<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">8&#44;10&#44;11</span></a> or with the use of anti-GD2 mAb in high-risk neuroblastoma<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">26</span></a> are encouraging&#44; so we must remain optimistic&#46; Such evidence ought to stimulate investment in basic and clinical research and help patients be referred more easily to centres that can offer new therapies that may be beneficial&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">The experience of 2 or the largest early-phase clinical trial units in paediatric oncology in Europe&#44; the Royal Marsden &#40;London&#44; United Kingdom&#41;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">37</span></a> and Gustave Roussy &#40;Villejuif&#44; France&#41;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">38</span></a> proves that implementing these therapies in the context of everyday paediatric oncology practice is possible and safe for patients&#44; while allowing a significant percentage of paediatric cancer patients to benefit from these treatments&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">Clinical trials are a necessary and indispensable means to evaluate new treatments that can provide robust and solid data on their safety and efficacy&#44; which is as beneficial to the scientific community as it is to patients&#46; The evaluation of new anticancer drugs in children and adolescents must comply with current legislation&#44; avoiding off-label use<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">17&#44;39</span></a> and in the context of clinical trials approved by ethics committees and conducted in adherence to good clinical practice principles&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Conflict of interests</span><p id="par0200" class="elsevierStylePara elsevierViewall">The authors have no conflict of interests to declare&#46;</p></span></span>"
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              "titulo" => "Centres with units devoted to early-phase clinical trials&#58; The role of the ITCC consortium"
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              "titulo" => "Paediatric oncology clinical trial portfolio"
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              "titulo" => "Enrolment in paediatric cancer clinical trials"
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            0 => "Paediatric haematology and oncology"
            1 => "Early phase clinical trials"
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            0 => "Oncolog&#237;a y hematolog&#237;a pedi&#225;trica"
            1 => "Ensayos cl&#237;nicos precoces"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Cancer is the leading cause of death between the first year of life and adolescence&#44; and some types of diseases are still a major challenge in terms of cure&#46; There is&#44; therefore&#44; a major need for new drugs&#46; Recent findings in cancer biology open the door to the development of targeted therapies against individual molecular changes&#44; as well as immunotherapy&#46; Promising results in adult anti-cancer drug development have not yet been translated into paediatric clinical practice&#46; A report is presented on the activity in early paediatric oncology trials &#40;phase I&#8211;II&#41; in Spain&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Material and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">All members of the Spanish Society of Paediatric Haematology Oncology &#40;SEHOP&#41; were contacted in order to identify early clinical trials in paediatric cancer opened between 2005 and 2015&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">A total of 30 trials had been opened in this period&#58; 21 &#40;70&#37;&#41; in solid tumours&#44; and 9 &#40;30&#37;&#41; in malignant haemopathies&#46; A total of 212 patients have been enrolled&#46; The majority was industry sponsored &#40;53&#37;&#41;&#46; Since 2010&#44; four centres have joined the international consortium of Innovative Therapies for Children with Cancer &#40;ITCC&#41;&#44; which has as its aim to develop novel therapies for paediatric tumours&#46; A significant number of new studies have opened since 2010&#44; improving the treatment opportunities for our children&#46; Results of recently closed trials show the contribution of Spanish investigators&#44; the introduction of molecularly targeted agents&#44; and their benefits&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The activity in clinical trials has increased in the years analysed&#46; The SEHOP is committed to develop and participate in collaborative academic trials&#44; in order to help in the advancement and optimisation of existing therapies in paediatric cancer&#46;</p></span>"
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        "titulo" => "Resumen"
        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introducci&#243;n</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">El c&#225;ncer es la primera causa de muerte por enfermedad entre el primer a&#241;o de vida y la adolescencia&#46; Algunos tipos de enfermedad siguen constituyendo un reto en t&#233;rminos de curaci&#243;n&#46; Existe por tanto una necesidad imperiosa de nuevos f&#225;rmacos&#46; Algunos descubrimientos recientes en la biolog&#237;a del c&#225;ncer abren la puerta al desarrollo de terapias dirigidas contra alteraciones moleculares concretas e inmunoterapia&#46; Esto se ha traducido en resultados prometedores sobre todo en oncolog&#237;a de adultos&#44; y en menor medida todav&#237;a en ni&#241;os&#46; Presentamos la actividad en ensayos cl&#237;nicos precoces &#40;fase <span class="elsevierStyleSmallCaps">i</span>-<span class="elsevierStyleSmallCaps">ii</span>&#41; en oncolog&#237;a pedi&#225;trica en Espa&#241;a&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Material y m&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">A trav&#233;s de la Sociedad Espa&#241;ola de Oncolog&#237;a y Hematolog&#237;a Pedi&#225;trica &#40;SEHOP&#41; contactamos a sus miembros para identificar los ensayos fase <span class="elsevierStyleSmallCaps">i</span>-<span class="elsevierStyleSmallCaps">ii</span> en c&#225;ncer pedi&#225;trico abiertos entre 2005 y 2015&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">En este periodo se abrieron 30 ensayos&#58; 21 &#40;70&#37;&#41; en tumores s&#243;lidos y 9 &#40;30&#37;&#41; en hemopat&#237;as malignas y se incluy&#243; a 212 pacientes&#46; La mayor&#237;a est&#225;n promovidos por la industria farmac&#233;utica &#40;53&#37;&#41;&#46; Desde 2010&#44; 4 centros se han integrado en el consorcio internacional ITCC cuyo objetivo es desarrollar nuevas terapias en c&#225;ncer infantil&#46; Esto ha permitido ampliar el abanico de posibilidades terap&#233;uticas&#46; Los resultados de ensayos cl&#237;nicos terminados muestran la contribuci&#243;n de los investigadores espa&#241;oles&#44; la introducci&#243;n de terapias dirigidas y sus beneficios&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">La actividad en ensayos cl&#237;nicos precoces ha aumentado en estos a&#241;os&#46; La SEHOP est&#225; comprometida a desarrollar y participar en ensayos cl&#237;nicos acad&#233;micos colaborativos&#44; que favorezcan el avance en las terapias frente al c&#225;ncer infantil&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Bautista F&#44; Gallego S&#44; Ca&#241;ete A&#44; Mora J&#44; D&#237;az de Heredia C&#44; Cruz O&#44; et al&#46; Ensayos cl&#237;nicos precoces en oncolog&#237;a pedi&#225;trica en Espa&#241;a&#58; una perspectiva nacional&#46; An Pediatr &#40;Barc&#41;&#46; 2017&#59;87&#58;155&#8211;163&#46;</p>"
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          "leyenda" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Clinical trials that are no longer recruiting patients as of June 15&#44; 2016 are presented in boldface&#46;</p><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">CTLA-4&#44; cytotoxic T-lymphocyte antigen 4&#59; GIST&#44; gastrointestinal stromal tumour&#59; HSCT&#44; haematopoietic stem cell transplantation&#59; IL&#44; interleukin&#59; mAb&#44; monoclonal antibody&#59; RMS&#44; rhabdomyosarcoma&#59; TKI&#44; tyrosine kinase inhibitor&#59; VEGF&#44; vascular endothelial growth factor&#59; VEGFR&#44; vascular endothelial growth factor receptor&#46;</p><p id="spar0060" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Source</span>&#58; <span class="elsevierStyleInterRef" id="intr0005" href="http://www.clinicaltrials.gov/www.clinicaltrialsregister.eu">www&#46;clinicaltrials&#46;gov&#47;www&#46;clinicaltrialsregister&#46;eu</span>&#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">Drug under study&#47;name of clinical trial&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">Mechanism of action&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">Trial phase&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">Disease&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">Sponsor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Number of participating centres&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">Reference&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">CLDK378X2103&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ALK-TKI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">I&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Solid tumours with ALK mutations&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Industry&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="left" valign="top">NCT01742286&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">Afatinib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Multi-TKI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">I&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Brain tumours and rhabdomyosarcomas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Industry&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="left" valign="top">NCT02372006&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">BRIM-P&#58; vemurafenib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">BRAF-TKI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">I&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Melanoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Industry&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="left" valign="top">NCT01519323&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">Lenvatinib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">VEGFR-TKI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">I&#47;II&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Solid tumours&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Industry&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="left" valign="top">EudraCT&#58; 2013-005534-38&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">Dabrafenib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">BRAF-TKI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">I&#47;II&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Solid tumours with <span class="elsevierStyleItalic">BRAF-V600E</span> mutation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Industry&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="left" valign="top">NCT01677741&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">Abraxane<br>&#40;nab-placitaxel&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Cytotoxic agent&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">I&#47;II&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Solid tumours&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Industry&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="left" valign="top">NCT01962103&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"><span class="elsevierStyleBold">CELYVIR</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">Oncolytic virus</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">I&#47;II</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">Solid tumours</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">Academia</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top"><span class="elsevierStyleBold">1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">NCT01844661</span>&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"><span class="elsevierStyleBold">Haplo TPH</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">&#43;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">IL-15 NK</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">Haplo TPH</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">&#43;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">IL-15 NK</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">I&#47;II</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">Solid tumours</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">Academia</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top"><span class="elsevierStyleBold">1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">NCT01337544</span>&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">LTI ch14&#46;18&#47;CHO-IL2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Immunotherapy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">I&#47;II&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Neuroblastoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Academia&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="left" valign="top">NCT01701479&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">Dinutuximab-IL2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Immunotherapy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">II&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Neuroblastoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Academia&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="left" valign="top">NCT02169609&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">BEACON&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Cytotoxic agent<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>antiVEGF mAb&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">II&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Neuroblastoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Academia&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="left" valign="top">NCT02308527&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"><span class="elsevierStyleBold">Irinotecan&#47;cisplatin</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">Cytotoxic agent</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">II</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">Brain tumours</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">Academia</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top"><span class="elsevierStyleBold">1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">NCT01574092</span>&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"><span class="elsevierStyleBold">HERBY</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">Cytotoxic agent</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">&#43;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">radiotherapy</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">&#43;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">antiVEGF mAb</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">II</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">High-grade gliomas</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">Industry</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top"><span class="elsevierStyleBold">10</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">EudraCT&#58;</span><br><span class="elsevierStyleBold">2010-022189-28</span>&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"><span class="elsevierStyleBold">TEMIRI &#40;temozolomide</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">&#43;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">irinotecan&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">Cytotoxic agent</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">II</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">Medulloblastomas and high-grade gliomas</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">Academia</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top"><span class="elsevierStyleBold">3</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">EudraCT&#58;</span><br><span class="elsevierStyleBold">2006-005476-40</span>&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"><span class="elsevierStyleBold">TOTEM &#40;topotecan</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">&#43;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">temozolomide&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Cytotoxic agents&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">II</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">Solid tumours</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">Academia</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top"><span class="elsevierStyleBold">3</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">NCT00918320</span>&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">Ipilimumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Anti-CTLA-4 mAb&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">II&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Melanoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Industry&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="left" valign="top">NCT01696045&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">Sunitinib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Multi-TKI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">II&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">GIST&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Industry&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="left" valign="top">NCT01396148&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"><span class="elsevierStyleBold">GEIS-21</span><br><span class="elsevierStyleBold">&#40;gemcitabine</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">&#43;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">docetaxel&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Cytotoxic agents&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">II</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">Ewing sarcoma</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">Academia</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top"><span class="elsevierStyleBold">8</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">NCT01696669</span>&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">rEECur&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Cytotoxic agents&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">II&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ewing sarcoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Academia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">17&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">EudraCT&#58;<br>2014-000259-99&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"><span class="elsevierStyleBold">GEIS 29 &#40;gemcitabine</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">&#43;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">rapamycin&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">Cytotoxic agent</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">&#43;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">mTOR inhibitor mTOR</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">II</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">Osteosarcoma</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">Academia</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top"><span class="elsevierStyleBold">15</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">NCT02429973</span>&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"><span class="elsevierStyleBold">BERNIE</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">Cytotoxic agents</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">&#43;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">antiVEGF mAb</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">II</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">RMS and non-RMS soft tissue sarcomas</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">Industry</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top"><span class="elsevierStyleBold">4</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">NCT00643565</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Ongoing paediatric phase I&#47;II clinical trials for solid tumours in Spanish centres between 2005 and 2015&#46;</p>"
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          "leyenda" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Clinical trials that are no longer recruiting patients as of June 15&#44; 2016 are presented in boldface&#46;</p><p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">mAb&#44; monoclonal antibody&#59; NK&#44; natural killer&#59; TKI&#44; tyrosine kinase inhibitor&#46;</p><p id="spar0080" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Source</span>&#58; <span class="elsevierStyleInterRef" id="intr0010" href="http://www.clinicaltrials.gov/www.clinicaltrialsregister.eu">www&#46;clinicaltrials&#46;gov&#47;www&#46;clinicaltrialsregister&#46;eu</span></p>"
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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" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Drug under study&#47;name of clinical trial&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">Mechanism of action&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">Trial phase&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">Disease&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">Sponsor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Number of participating centres&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">Reference&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">LANK-2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NK cell therapy<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>cytotoxic agents&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">I&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Acute lymphoblastic and myeloid leukaemia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Academia&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="left" valign="top">NCT02074657&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">HNJ-NKAES-2012&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NK cell therapy<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>cytotoxic agents&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">I&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">T-cell acute lymphoblastic leukaemia and T-cell lymphoblastic lymphoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Academia&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="left" valign="top">NCT01944982&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">Dacogen&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hypomethylating agent&#43; cytotoxic agent&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">I&#47;II&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Acute myeloid leukaemia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Industry&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="left" valign="top">NCT01853228&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">Brentuximab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">mAb anti-CD30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">I&#47;II&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Anaplastic large-cell lymphoma and Hodgkin lymphoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Industry&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="left" valign="top">NCT01492088&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">Carfilzomib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Proteasome inhibitor<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>cytotoxic agent&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">I&#47;II&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Acute lymphoblastic leukaemia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Industry&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="left" valign="top">NCT02303821&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"><span class="elsevierStyleBold">Nilotinib</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">TKI</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">II</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">Ph&#43; chronic myelogenous leukaemia</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">Industry</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top"><span class="elsevierStyleBold">3</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">NCT01844765</span>&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"><span class="elsevierStyleBold">Dasatinib</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">TKI</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">II&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">Ph&#43; chronic myelogenous leukaemia</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">Industry</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top"><span class="elsevierStyleBold">6</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">NCT00777036</span>&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"><span class="elsevierStyleBold">Moxetumomab</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">Anti-CD22 mAb</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">II</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">Acute lymphoblastic leukaemia and lymphoblastic lymphoma</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">Industry</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top"><span class="elsevierStyleBold">2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">NCT02227108</span>&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">Inter-B-NHL-RITUX 2010&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rituximab &#40;mAb anti-CD20&#41;<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>cytotoxic agents&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">II&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Primary mediastinal B-cell lymphoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Academia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NCT01516580&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "leyenda" => "<p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">ALL&#44; acute lymphoblastic leukaemia&#59; AML&#44; acute myeloid leukaemia&#59; CML&#44; chronic myelogenous leukaemia&#46;</p>"
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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" title="table-head  " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Clinical trials</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">2010&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">2015&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " rowspan="4" align="left" valign="top">Brain tumours</td><td class="td" title="table-entry  " align="left" valign="top">High-grade glioma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleGlyphlozf"></span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleGlyphlozf"></span>&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">Low-grade glioma&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"><span class="elsevierStyleGlyphlozf"></span>&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">Medulloblastoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleGlyphlozf"></span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleGlyphlozf"></span>&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">Other brain tumours&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"><span class="elsevierStyleGlyphlozf"></span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="4" align="left" valign="top">Leukaemia&#44; lymphoma</td><td class="td" title="table-entry  " align="left" valign="top">ALL&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"><span class="elsevierStyleGlyphlozf"></span>&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">AML&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"><span class="elsevierStyleGlyphlozf"></span>&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">CML&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleGlyphlozf"></span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleGlyphlozf"></span>&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">Lymphoma&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"><span class="elsevierStyleGlyphlozf"></span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="7" align="left" valign="top">Solid tumours</td><td class="td" title="table-entry  " align="left" valign="top">Osteosarcoma&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"><span class="elsevierStyleGlyphlozf"></span>&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">Ewing sarcoma&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"><span class="elsevierStyleGlyphlozf"></span>&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">Rhabdomyosarcoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleGlyphlozf"></span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleGlyphlozf"></span>&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">Other sarcomas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleGlyphlozf"></span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleGlyphlozf"></span>&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">Neuroblastoma&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"><span class="elsevierStyleGlyphlozf"></span>&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">Melanoma&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"><span class="elsevierStyleGlyphlozf"></span>&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">Other solid tumours&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"><span class="elsevierStyleGlyphlozf"></span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">Clinical trials conducted between 2010 and 2015 by specific disease groups&#46;</p>"
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          "leyenda" => "<p id="spar0100" class="elsevierStyleSimplePara elsevierViewall">AE&#44; adverse event&#59; AUC&#44; area under the curve&#59; DIC&#44; disseminated intravascular coagulation&#59; DLI&#44; donor lymphocyte infusion&#59; DLT&#44; dose-limiting toxicity&#59; EFS&#44; event-free survival&#59; GMP&#44; good manufacturing practice&#59; HR&#44; high risk&#59; IMT&#44; inflammatory myofibroblastic tumour&#59; RP2D&#44; recommended phase II dose&#59; LCH&#44; Langerhans cell histiocytosis&#59; IL&#44; interleukin&#59; LCAL&#44; large-cell anaplastic lymphoma&#59; MT&#44; myofibroblastic tumour&#59; NK&#44; natural killer&#59; OS&#44; overall survival&#59; PFS&#44; progression-free survival&#59; SR&#44; standard risk&#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">Clinical trial <span class="elsevierStyleSup">&#91;Ref&#93;</span>&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">Results&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">Ceritinib<br>&#40;LDK 378&#41;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">8</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">22 patients aged less than 18 years with relapsing&#47;refractory tumours with ALK mutations&#47;changes&#46; Patients were treated with increasing doses of ceritinib<br>RP2D&#58; 510<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span>&#46; Pharmacokynetics comparable to those in adults<br>2 DLTs at doses of 560<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span>&#47;day&#46; Frequent AEs&#58; diarrhoea&#44; vomiting&#44; nausea&#44; elevated ALT<br>6 objective responses&#58; 2 of 2 patients with LCAL and 4 of 7 patients with MT&#47;IMT&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">Dabrafenib<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">10</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">27 patients aged less than 18 years with relapsing&#47;refractory tumours with BRAF mutations&#47;changes&#46; Patients were treated with increasing doses of dabrafenib<br>RP2D&#58; 4&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day for patients &#62;12 years and 5&#46;25<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day for patients &#60;12 years<br>1 TLD at 4&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day&#46; Frequent AEs&#58; hypotension&#44; skin rash&#44; DIC&#44; fever and arthralgia<br>23 objective responses&#58; 6 of 8 patients with high-grade glioma&#44; 14 of 15 with low-grade glioma&#44; 2 LCH&#44; 1 other type of solid tumour&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">Abraxane &#40;nab-paclitaxel&#41;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">25</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">64 patients aged less than 18 years with relapsing&#47;refractory solid tumours except brain tumours<br>Patients were treated with increasing doses of nab-paclitaxel<br>RP2D&#58; 240<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span><br>2 TLD at doses of 120<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span> and 270<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span> &#40;dizziness and neutropaenia&#44; respectively&#41;<br>5 partial responses&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">Celyvir<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">23</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">14 patients aged less than 18 years with refractory or relapsed neuroblastoma<br>Weekly infusion of autologous pluripotent mesenchymal stem cells carrying an oncolytic virus &#40;range&#44; 4&#8211;70&#41;<br>Total cells &#40;min&#44; 70<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">6</span>&#44; max 2&#46;640<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">6</span>&#41; and viral particles &#40;min&#44; 1&#46;80<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">12</span>&#59; max&#44; 5&#46;280<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">13</span>&#41;<br>No serious adverse events<br>4 objective responses&#58; 1 stable disease&#44; 2 partial remissions and 1 full remission&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">Haplo<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>IL-15 NK cell<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">31</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6 patients aged less than 18 years with refractory sarcoma and relapsed adrenal gland carcinoma<br>DLI of haploidentical NK cells obtained by immunomagnetic separation in GMP conditions and stimulated with IL-15 overnight&#46;<br>Total infused cells 11<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">6</span>&#47;kg &#40;3&#8211;27<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">6</span>&#47;kg&#41;<br>No serious adverse events associated with NK cell infusion<br>4 objective responses&#58; 1 stable disease&#44; 2 partial remissions and 1 highly favourable partial remission&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">LTI ch14&#46;18&#47;CHO-IL2<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">26</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">97 patients aged less than 21 years with high-risk neuroblastoma<br>Pharmacokinetics of ch14&#46;18&#47;CHO in cycle 1&#58; <span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">max</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>12&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;4<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;mL&#44; <span class="elsevierStyleItalic">t</span><span class="elsevierStyleSup">&#189;</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>8&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;1 d&#44; AUC<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>145&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>5&#46;8<span class="elsevierStyleHsp" style=""></span>&#956;g<span class="elsevierStyleHsp" style=""></span>d&#47;mL<br>1-year and 4-year PFS&#58; 54&#46;4&#37;<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>06&#46;9&#37; and 32&#46;3&#37;<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>06&#46;9&#37; versus 19&#37;<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>02&#37; and 8&#37;<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>03&#37; of historical controls<br>1-year and 4-year OS&#58; 94&#46;2&#37;<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>03&#46;2&#37; and 60&#46;9&#37;<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>09&#46;0&#37; versus 56&#37;<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>03&#37; and 14&#37;<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>04&#37; of historical controls&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">GEIS-21<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">27</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">43 patients with Ewing sarcoma aged less than 40 years in first-line treatment<br>22 SR patients and 21 HR patients<br>Chemotherapy with mP6&#44; surgery and radiation in SR patients and window evaluation of gemcitabine&#47;docetaxel in HR patients<br>4-year EFS and OS in SR patients were 67&#37; and 74&#37;&#44; respectively<br>4-year EFS and OS in HR patients were 67&#37; and 42&#37;&#44; respectively<br>EFS and OS were significantly higher in the under-18 years group&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">TEMIRI<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">28</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">66 patients aged less than 18 years with relapsing&#47;refractory medulloblastoma<br>Patients were treated with temozolomide on days 1&#8211;5 and irinotecan on days 1&#8211;5 and 8&#8211;12 every 21 days<br>The most frequent toxicities were haematologic and gastrointestinal &#40;diarrhoea&#41;<br>The objective response rate was 33&#37;&#44; and 68&#37; showed clinical improvement&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">TOTEM<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">29</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">38 patients aged less than 18 years with relapsing&#47;refractory neuroblastoma<br>L patients were treated with temozolomide on days 1&#8211;5 and topotecan on days 1&#8211;5 and 8&#8211;12 every 28 days<br>The most frequent toxicity was haematologic<br>1-year PFS and OS were 42&#37; and 58&#37;&#44; respectively&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">BERNIE<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">30</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">154 patients aged less than 18 years with metastatic rhabdomyosarcoma<br>80 were randomly allocated to the chemotherapy-only arm&#44; and 74 to the chemotherapy<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>bevacizumab arm<br>The toxicity profile was similar in both groups<br>EFS was similar in both groups &#40;12&#46;5&#37; vs 18&#46;9&#37;&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#61;</span><span class="elsevierStyleHsp" style=""></span>&#46;71&#41;<br>OS was similar in both groups &#40;42&#46;2&#37; vs 32&#46;3&#37;&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#61;</span><span class="elsevierStyleHsp" style=""></span>&#46;32&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">Summary of some of the completed trials&#46;</p>"
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      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:39 [
            0 => array:3 [
              "identificador" => "bib0200"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Incidencia y supervivencia del c&#225;ncer infantil"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "R&#46; Peris"
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                        ]
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                    ]
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                  "host" => array:1 [
                    0 => array:1 [
                      "LibroEditado" => array:5 [
                        "titulo" => "Hematolog&#237;a y oncolog&#237;a pedi&#225;tricas"
                        "paginaInicial" => "263"
                        "paginaFinal" => "270"
                        "edicion" => "3&#46;&#170; ed&#46;"
                        "serieFecha" => "2015"
                      ]
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                  ]
                ]
              ]
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            1 => array:3 [
              "identificador" => "bib0205"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Childhood cancer mortality in Europe&#44; 1955&#8211;1995"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "F&#46; Levi"
                            1 => "C&#46; la Vecchia"
                            2 => "E&#46; Negri"
                            3 => "F&#46; Lucchini"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur J Cancer"
                        "fecha" => "2001"
                        "volumen" => "37"
                        "paginaInicial" => "785"
                        "paginaFinal" => "809"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11311655"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
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            2 => array:3 [
              "identificador" => "bib0210"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Childhood cancer survival in Europe 1999&#8211;2007&#58; results of EUROCARE-5 &#8211; a population-based study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "G&#46; Gatta"
                            1 => "L&#46; Botta"
                            2 => "S&#46; Rossi"
                            3 => "T&#46; Aareleid"
                            4 => "M&#46; Bielska-Lasota"
                            5 => "J&#46; Clavel"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S1470-2045(13)70548-5"
                      "Revista" => array:6 [
                        "tituloSerie" => "Lancet Oncol"
                        "fecha" => "2014"
                        "volumen" => "15"
                        "paginaInicial" => "35"
                        "paginaFinal" => "47"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24314616"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
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