Publications by authors named "Teresa de Rojas"

24 Publications

  • Page 1 of 1

Intercontinental collaboration in clinical trials for children and adolescents with cancer-A systematic review by ACCELERATE.

Cancer Med 2021 Oct 23. Epub 2021 Oct 23.

Food & Drug Administration, Silver Spring, Maryland, USA.

Background: Since pediatric cancer drug development is a global enterprise, we sought to provide an overview of the landscape of intercontinental clinical trials in pediatric oncology opened over the last decade.

Methods: ClinicalTrials.gov was systematically searched to identify all clinical therapeutic trials which opened between 2010 and 2020 and recruited pediatric patients (<18 years) with cancer.

Results: Over the last 10 years, 295 (8.7%) of 3383 therapeutic pediatric cancer trials were international and 182 (5.4%) were intercontinental. Most intercontinental trials were phase-1 or 2, with 25% late-phase, 65% were sponsored by industry, and North America was involved in 92%. Industry-sponsored proportionally more phase-1 trials than academia (41% vs. 25%); conversely, academia sponsored more phase-2 and late-phase trials (39% and 31% vs. 36% and 21%, respectively) (p = 0.020). North America-Europe collaboration was predominantly industry sponsored as opposed to North America-Oceania and Europe-Oceania collaboration, more frequently academic (p < 0.0001). Most late-phase trials (18/20, 90%) focusing on pediatric malignancies were conducted by academic sponsors and 10 of these were conducted by Children's Oncology Group (COG)/National Cancer Institute in the United States and Oceania. There was no significant increase over time of intercontinental trials and a trend for a reduction in academic trials.

Conclusions: Despite the relative rarity of childhood malignancies, especially within molecular subtypes, only 5.4% of pediatric cancer trials were intercontinental. The number of intercontinental trials remains small, with no significant increase over the last decade. The ACCELERATE International Collaboration Working Group aims to identify existing hurdles and propose solutions to improve intercontinental collaboration in clinical research for the benefit of children and adolescents with cancer.
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http://dx.doi.org/10.1002/cam4.4356DOI Listing
October 2021

Second Paediatric Strategy Forum for anaplastic lymphoma kinase (ALK) inhibition in paediatric malignancies: ACCELERATE in collaboration with the European Medicines Agency with the participation of the Food and Drug Administration.

Eur J Cancer 2021 Nov 15;157:198-213. Epub 2021 Sep 15.

Hospital for Sick Children, Toronto, Canada.

The first (2017) and sixth (2021) multistakeholder Paediatric Strategy Forums focused on anaplastic lymphoma kinase (ALK) inhibition in paediatric malignancies. ALK is an important oncogene and target in several paediatric tumours (anaplastic large cell lymphoma [ALCL], inflammatory myofibroblastic tumour [IMT], neuroblastoma and hemispheric gliomas in infants and young children) with unmet therapeutic needs. ALK tyrosine kinase inhibitors have been demonstrated to be active both in ALK fusion-kinase positive ALCL and IMT. ALK alterations differ, with fusions occurring in ALCL, IMT and gliomas, and activating mutations and amplification in neuroblastoma. While there are many ALK inhibitors in development, the number of children diagnosed with ALK driven malignancies is very small. The objectives of this ALK Forum were to (i) Describe current knowledge of ALK biology in childhood cancers; (ii) Provide an overview of the development of ALK inhibitors for children; (iii) Identify the unmet needs taking into account planned or current ongoing trials; (iv) Conclude how second/third-generation inhibitors could be evaluated and prioritised; (v) Identify lessons learnt from the experience with ALK inhibitors to accelerate the paediatric development of other anti-cancer targeted agents in the new regulatory environments. There has been progress over the last four years, with more trials of ALK inhibitors opened in paediatrics and more regulatory submissions. In January 2021, the US Food and Drug Administration approved crizotinib for the treatment of paediatric and young adult patients with relapsed or refractory ALCL and there are paediatric investigation plans (PIPs) for brigatinib and for crizotinib in ALCL and IMT. In ALCL, the current goal is to investigate the inclusion of ALK inhibitors in front-line therapy with the aim of decreasing toxicity with higher/similar efficacy compared to present first-line therapies. For IMT, the focus is to develop a joint prospective trial with one product in children, adolescents and adults, taking advantage of the common biology across the age spectrum. As approximately 50% of IMTs are ALK-positive, molecular analysis is required to identify patients to be treated with an ALK inhibitor. For neuroblastoma, crizotinib has not shown robust anti-tumour activity. A focused and sequential development of ALK inhibitors with very good central nervous system (CNS) penetration in CNS tumours with ALK fusions should be undertaken. The Forum reinforced the strong need for global academic collaboration, very early involvement of regulators with studies seeking possible registration and early academia-multicompany engagement. Innovations in study design and conduct and the use of 'real-world data' supporting development in these rare sub-groups of patients for whom randomised clinical trials are not feasible are important initiatives. A focused and sequenced development strategy, where one product is evaluated first with other products being assessed sequentially, is applicable for ALK inhibitors and other medicinal products in children.
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http://dx.doi.org/10.1016/j.ejca.2021.08.022DOI Listing
November 2021

Rare use of patient-reported outcomes in childhood cancer clinical trials - a systematic review of clinical trial registries.

Eur J Cancer 2021 Jul 2;152:90-99. Epub 2021 Jun 2.

Pediatric OncoGenomics Unit, Children's University Hospital Niño Jesús, Madrid, Spain. Electronic address:

Background: Patient-reported outcomes (PROs) are the gold standard to assess the patients' subjective health status. While both the Food and Drug Administration and European Medicines Agency recommend the use of PROs as end-points in paediatric clinical trials to support claims for medical product labelling, it is not known how often PROs are actually used. The aim of this study was to assess the usage of PRO instruments in childhood cancer clinical trials investigating anti-cancer medication.

Methods: In June 2020 ClinicalTrials and EudraCT were systematically searched for all trials including children and adolescents (≤21 years) with cancer registered between 2007 and 2020. The use of PRO measures and trials characteristics were analysed. To investigate which trial characteristics are associated with the use of PROs, a binary logistic regression was calculated.

Results: Of 4789 identified trials, 711 were included. The most frequent reason for exclusion was age limitation (age >21 years). Of all included trials, only 8.2% used PROs as end-points; .6% as the primary end-point. The most commonly used questionnaire was the PedsQL™ (32.8%), followed by the Patient-Reported Outcomes Measurement Information System scales (12.1%). No association was observed between the use of PROs and trial region, number of centres, trial phase, time period or intervention type (all p > .05). The use of PROs did not substantially increase over time. Only 20.3% of the closed studies had published their results.

Conclusion: Despite recommendations of regulatory agencies, PRO assessment is extremely rare in paediatric oncology clinical trials. More efforts should be undertaken to facilitate implementation of PRO in paediatric trials to guarantee patient-centred research and treatments.
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http://dx.doi.org/10.1016/j.ejca.2021.04.023DOI Listing
July 2021

Therapeutic implications of improved molecular diagnostics for rare CNS embryonal tumor entities: results of an international, retrospective study.

Neuro Oncol 2021 09;23(9):1597-1611

Department of Neurooncology, Russian Scientific Center of Radiology, Moscow, Russia.

Background: Only few data are available on treatment-associated behavior of distinct rare CNS embryonal tumor entities previously treated as "CNS-primitive neuroectodermal tumors" (CNS-PNET). Respective data on specific entities, including CNS neuroblastoma, FOXR2 activated (CNS NB-FOXR2), and embryonal tumors with multilayered rosettes (ETMR) are needed for development of differentiated treatment strategies.

Methods: Within this retrospective, international study, tumor samples of clinically well-annotated patients with the original diagnosis of CNS-PNET were analyzed using DNA methylation arrays (n = 307). Additional cases (n = 66) with DNA methylation pattern of CNS NB-FOXR2 were included irrespective of initial histological diagnosis. Pooled clinical data (n = 292) were descriptively analyzed.

Results: DNA methylation profiling of "CNS-PNET" classified 58 (19%) cases as ETMR, 57 (19%) as high-grade glioma (HGG), 36 (12%) as CNS NB-FOXR2, and 89(29%) cases were classified into 18 other entities. Sixty-seven (22%) cases did not show DNA methylation patterns similar to established CNS tumor reference classes. Best treatment results were achieved for CNS NB-FOXR2 patients (5-year PFS: 63% ± 7%, OS: 85% ± 5%, n = 63), with 35/42 progression-free survivors after upfront craniospinal irradiation (CSI) and chemotherapy. The worst outcome was seen for ETMR and HGG patients with 5-year PFS of 18% ± 6% and 22% ± 7%, and 5-year OS of 24% ± 6% and 25% ± 7%, respectively.

Conclusion: The historically reported poor outcome of CNS-PNET patients becomes highly variable when tumors are molecularly classified based on DNA methylation profiling. Patients with CNS NB-FOXR2 responded well to current treatments and a standard-risk CSI-based regimen may be prospectively evaluated. The poor outcome of ETMR across applied treatment strategies substantiates the necessity for evaluation of novel treatments.
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http://dx.doi.org/10.1093/neuonc/noab136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408859PMC
September 2021

Impact of COVID-19 in paediatric early-phase cancer clinical trials in Europe: A report from the Innovative Therapies for Children with Cancer (ITCC) consortium.

Eur J Cancer 2020 12 9;141:82-91. Epub 2020 Oct 9.

Center for Child Health Research, Tampere University and Department of Pediatrics, Tampere University Hospital, Tampere, Finland, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.

Introduction: Data regarding real-world impact on cancer clinical research during COVID-19 are scarce. We analysed the impact of the COVID-19 pandemic on the conduct of paediatric cancer phase I-II trials in Europe through the experience of the Innovative Therapies for Children with Cancer (ITCC).

Methods: A survey was sent to all ITCC-accredited early-phase clinical trial hospitals including questions about impact on staff activities, recruitment, patient care, supply of investigational products and legal aspects, between 1st March and 30th April 2020.

Results: Thirty-one of 53 hospitals from 12 countries participated. Challenges reported included staff constraints (30% drop), reduction in planned monitoring activity (67% drop of site initiation visits and 64% of monitoring visits) and patient recruitment (61% drop compared with that in 2019). The percentage of phase I, phase II trials and molecular platforms closing to recruitment in at least one site was 48.5%, 61.3% and 64.3%, respectively. In addition, 26% of sites had restrictions on performing trial assessments because of local contingency plans. Almost half of the units suffered impact upon pending contracts. Most hospitals (65%) are planning on improving organisational and structural changes.

Conclusion: The study reveals a profound disruption of paediatric cancer early-phase clinical research due to the COVID-19 pandemic across Europe. Reported difficulties affected both patient care and monitoring activity. Efforts should be made to reallocate resources to avoid lost opportunities for patients and to allow the continued advancement of oncology research. Identified adaptations to clinical trial procedures may be integrated to increase preparedness of clinical research to futures crises.
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http://dx.doi.org/10.1016/j.ejca.2020.09.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546235PMC
December 2020

Comment on: Developing a risk assessment score for patients with cancer during the coronavirus disease 2019 pandemic.

Eur J Cancer 2020 11 6;140:158-160. Epub 2020 Sep 6.

Pediatric OncoGenomics Unit, Pediatric Hematology-Oncology, Children's University Hospital Niño Jesús, Av. Menendez Pelayo 65, 28009, Madrid, Spain. Electronic address:

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http://dx.doi.org/10.1016/j.ejca.2020.08.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7474888PMC
November 2020

Pediatric Oncology Clinical Trials and Collaborative Research in Africa: Current Landscape and Future Perspectives.

JCO Glob Oncol 2020 08;6:1264-1275

Pediatric Haematology and Oncology Center, University Mohamed V. Rabat, Rabat, Morocco.

Purpose: Adequate clinical services have yet to be established in the majority of African countries, where childhood cancer survival rates vary from 8.1% to 30.3%. The aim of this review is to describe the landscape of pediatric oncology trials in Africa, identify challenges, and offer future opportunities for research collaborations.

Methods: The study includes data from the International Pediatric Oncology Society (SIOP) global mapping survey, meta-research identifying trials in Africa in ClinicalTrials.gov, and a literature overview of publications on the subject of pediatric oncology clinical research supported by expert opinions on the current situation and challenges.

Results: The SIOP global mapping survey received responses from 47 of 54 African countries, of which 23 have active clinical research programs. A preliminary search of ClinicalTrials.gov showed that only 105 (12.1%) of 868 African oncology studies included children and adolescents. Of these, 53 (50.5%) were interventional trials according to the registry's classification. The small number of African trials for children and adolescents included palliative care and leukemia trials. In African oncology journals and international pediatric oncology journals, < 1% of the pediatric oncology publications come from Africa. Services and research were strengthened by international collaboration. National studies focused on clinical needs, local challenges, or interventional priorities. Both the literature review and the expert opinions highlight the need to expand clinical research in Africa, despite ongoing regional instability and lack of resources.

Conclusion: While a low number of pediatric clinical treatment trials are open to African children and adolescents, clinical research of high quality is being done in Africa. Several initiatives are stimulating the development of the research capacity across the continent, which should increase the publication output.
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http://dx.doi.org/10.1200/GO.20.00159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456323PMC
August 2020

COVID-19 infection in children and adolescents with cancer in Madrid.

Pediatr Blood Cancer 2020 07 8;67(7):e28397. Epub 2020 May 8.

Pediatric Oncology-Hematology Department, Hospital Quirón, Madrid, Spain.

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http://dx.doi.org/10.1002/pbc.28397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235530PMC
July 2020

Comment on: "Early advice on managing children with cancer during the COVID-19 pandemic and a call for sharing experiences".

Pediatr Blood Cancer 2020 07 4;67(7):e28377. Epub 2020 May 4.

Pediatric OncoGenomics Unit, Pediatric Oncology, Haematology and Stem Cell Transplantation Department, Children's University Hospital Niño Jesús, Madrid, Spain.

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http://dx.doi.org/10.1002/pbc.28377DOI Listing
July 2020

Access to Clinical Trials for Adolescents and Young Adults With Cancer: A Meta-Research Analysis.

JNCI Cancer Spectr 2019 Dec 1;3(4):pkz057. Epub 2019 Aug 1.

Medical Department, Brussels, Belgium.

Background: The 18-year-old age limit for inclusion in clinical trials constitutes a hurdle for adolescents and young adults (AYAs) with cancer. We analyzed the impact of this age barrier on the access of AYAs to cancer trials and novel therapies.

Methods: ClinicalTrials.gov was searched to identify all the trials including patients with 10 malignancies relevant for AYAs (January 2007 to July 2018). The trials were categorized as pediatric (patients <18 y), adult (≥18 y), and transitional (including adult and pediatric patients). Transitional trials with a lower limit between 12 and 18 years and an upper limit younger than 40 years were considered AYA-specific.

Results: Of 2764 identified trials, 2176 were included: 79% adult, 19% transitional, 2% pediatric. Five trials were AYA-specific. The proportion of academic trials was higher for transitional (69%; 288 of 421) than for adult trials (48%; 832 of 1718) ( < .0001). The total number of new trials increased over the years (156 in 2007; 228 in 2017); however, the number of transitional trials remained stable. The availability of trials increased with age, with a major increase at age 18 years: at age 17 years, 20% (442 of 2176) of trials were potentially accessible vs 95% (2075 of 2176) at 18 years. For trials investigating targeted therapies, this increase was 460% (197 trials available at age 17 years; 901 at 18 years) and for immunotherapies, 1200% (55 at age 17 years; 658 at 18 years).

Conclusions: AYAs have limited access to cancer trials and innovative therapies, with no improvement over the last decade. The 18-years-old age limit continues to be a major hurdle. Our findings are consistent with the internationally supported idea that age inclusion criteria in oncological trials should be changed.
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http://dx.doi.org/10.1093/jncics/pkz057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050014PMC
December 2019

Clinical research in cancer palliative care: a metaresearch analysis.

BMJ Support Palliat Care 2020 Jun 24;10(2):249-258. Epub 2020 Mar 24.

Medical Department, EORTC Headquarters, Brussels, Belgium.

Objective: This metaresearch of the clinicaltrials.gov database aims to evaluate how clinical research on palliative care is conducted within the setting of advanced cancer.

Methods: Clinicaltrials.gov was searched to identify registered studies recruiting patients with cancer, and investigating issues relevant to palliative care. The European Organisation for Research and Treatment of Cancer QLQ-C15-PAL (Quality of Life in palliative cancer care patients) questionnaire was taken into account to define the research domains of interest. Studies investigating cancer-directed therapy, management of cancer treatment-related adverse events and diagnostic tests were excluded. Publication status was crosschecked using PubMed.

Results: Of 3950 identified studies, 514 were included. The most frequent reason for exclusion was cancer-directed therapy (2491). In 2007-2012, 161 studies were registered versus 245 in 2013-2018. Included studies were interventional (84%) or observational (16%). Most studies were monocentric (60%), sponsored by academia (79%), and conducted in North America (57%) or Europe (25%). Seventy-nine per cent of studies evaluated a heterogeneous population (>1 tumour type). Interventional studies most frequently investigated systemic drugs (34%), behavioural interventions (29%) and procedures for pain (24%). Pain, quality of life and physical function were the most frequently studied research domains (188, 95 and 52 studies, respectively). The most applied primary outcome measures were efficacy/symptom control (61%), quality of life (14%) and feasibility (12%). Only 16% of the closed studies had published results in PubMed.

Conclusions: Our study describes the heterogeneous landscape of studies conducted to address the issues of patients with advanced cancer in palliative care. Albeit the observed increase in the number of studies over the last decade, the generalisation of the results brought by the existing trials is limited due to methodological issues and lack of reporting. A greater effort is needed to improve clinical research that supports evidence-based palliative cancer care.
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http://dx.doi.org/10.1136/bmjspcare-2019-002086DOI Listing
June 2020

Clinical research tools in pediatric oncology: challenges and opportunities.

Cancer Metastasis Rev 2020 03;39(1):149-160

Paediatric Oncology & Haematology Department, Vall d'Hebron University Hospital, Passeig de la Vall d'Hebron 119, 129, 08035, Barcelona, Spain.

Survival for childhood cancers has improved significantly over the last decades. However, patient outcomes have plateaued over the last decade for difficult-to-treat diseases. With high cure rates, decreasing long-term toxicities and sequelae remains crucial. Since many advances in childhood cancer research come from the adult oncology world, one of the key areas is improving the adaptation of tools that are essential for clinical trial conduct that were developed for adults into pediatrics. These include tools to evaluate toxicity, quality of life, radiological response, statistical methodology, or indicators of cancer care quality. In this review, we present ongoing international efforts to validate and adapt these tools for children and adolescents and discuss remaining challenges. These efforts will hopefully accelerate and improve the quality of pediatric oncology research in the upcoming years.
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http://dx.doi.org/10.1007/s10555-020-09856-zDOI Listing
March 2020

EORTC SPECTA-AYA: A unique molecular profiling platform for adolescents and young adults with cancer in Europe.

Int J Cancer 2020 08 14;147(4):1180-1184. Epub 2019 Sep 14.

Division of Cancer Sciences, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom.

For most adolescent and young adult (AYA) cancers, age-specific molecular features are poorly understood. EORTC-SPECTA, an academic translational research infrastructure for biomaterial collection, will explicitly recruit AYA patients and will therefore collect empirical data to bridge the molecular gap between pediatric and adult oncology. The initial pilot study, activated in February 2019 across Europe, will recruit 100 AYA patients (aged 12-29 years) with newly diagnosed or relapsed high-grade gliomas and high-grade bone and soft tissue sarcomas. The primary objective of the pilot is to determine feasibility and recruitment rates. Formalin-fixed tumor tissue and whole blood from study participants will be prospectively collected with clinical data and stored centrally at the Integrated BioBank of Luxembourg. Whole exome sequencing of matched tumor and blood, and tumor RNA sequencing and DNA methylation profiling will be performed at the German Cancer Research Center, Heidelberg, Germany. Virtual central pathology review of scanned diagnostic slides will be undertaken by an international expert panel, and diagnostic material returned to the participating centers. A multidisciplinary molecular tumor board will release a clinically validated report to referring clinicians within 4-6 weeks after biopsy. SPECTA-AYA constitutes a major opportunity to gain knowledge about the tumor biology of this unique age group. It incorporates notable innovative aspects: AYA specificity, pan-European academic collaboration, centralized biobanking, comprehensive molecular profiling and virtual central pathology review, among others. SPECTA-AYA will help untangle the tumor particularities of AYAs with cancer and aims to improve their access to novel drugs and personalized medicine.
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http://dx.doi.org/10.1002/ijc.32651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383917PMC
August 2020

Radiotherapy practice for paediatric brain tumours across Europe and quality assurance initiatives: Current situation, international survey and future perspectives.

Eur J Cancer 2019 06 28;114:36-46. Epub 2019 Apr 28.

Dept. of Radiation Oncology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, the Netherlands; Princess Maxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS, Utrecht, the Netherlands.

Aim: The aim of the study is to analyse radiotherapy quality assurance (RTQA) processes in the treatment of paediatric central nervous system (CNS) tumours across Europe.

Methods: The RTQA aspects of major past and current European trials for paediatric CNS tumours were reviewed based on study protocols and publications. A survey among radiation oncologists and paediatric oncologists about the practices of RTQA in paediatric CNS tumours across European countries was also performed.

Results: Several (inter)national initiatives to implement RTQA are being developed across Europe, with an apparent paradigm shift from retrospective to prospective RTQA. Experts from 21 of 29 contacted countries responded to the survey. National consensus guidelines for paediatric CNS tumours are available in 10 of 21 countries. Twenty-one of 33 experts believe that the level of involvement of paediatric radiation oncologists in the meetings and activities of the national paediatric oncology societies is adequate. Central storage of radiotherapy data is available in France, Germany and Denmark. RTQA programmes for paediatric brain tumours are available in 7 countries. Twelve of 21 experts believe that there is a well-established national referral network for the radiation treatment of paediatric patients in their respective countries.

Conclusion: As a result of the review and survey, the following measures are proposed: (1) developing international RT guidelines for paediatric CNS tumours, (2) improving the collaboration between paediatric oncologists and paediatric radiation oncologists, (3) building a central storage system for RT data, (4) implementing international prospective RTQA platforms and (5) promoting European referral networks to reduce inequality.
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http://dx.doi.org/10.1016/j.ejca.2019.03.018DOI Listing
June 2019

Re: Everything is awesome: Don't forget the lego.

J Paediatr Child Health 2019 04;55(4):485-486

Medical Oncology Department, Cancer Institute of the "Hospices Civils" of Lyon, Lyon, France.

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http://dx.doi.org/10.1111/jpc.14403DOI Listing
April 2019

Infantile hemangiopericytoma leading to hypovolemic shock in a neonate.

Pediatr Blood Cancer 2018 05 4;65(5):e26950. Epub 2018 Jan 4.

Neonatology Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain.

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http://dx.doi.org/10.1002/pbc.26950DOI Listing
May 2018

Mitochondrial Disease in Children: The Nephrologist's Perspective.

JIMD Rep 2018 17;42:61-70. Epub 2017 Dec 17.

Department of Paediatric Neurology, Children's University Hospital Niño Jesús, Madrid, Spain.

Mitochondrial diseases (MD) are a heterogeneous group of clinical syndromes characterized by the involvement of different organ systems. They constitute the most prevalent hereditary metabolic disease group.

Objective: To review the importance of the kidney in MD from the nephrologist's perspective within the setting of a pediatric tertiary reference center.

Study Design: Retrospective study of children (<18 years) with MD followed between 2000 and 2016 at a tertiary Spanish center.

Results: 52 patients were included. The mean age at the time of the study was 10 years (SD ± 5.1). The mean follow-up time was 6.1 years (SD ± 4.7). The median age at diagnosis was 2.5 years (0.3-13.5).The median number of affected systems was two (range 1-6). The nervous system was the most affected system, with 51 patients (~98%) presenting with neurological involvement. 20 patients (~40%) presented with endocrinological manifestations, 18 (~35%) with vision problems, 16 (~30%) with gastrointestinal symptoms, 5 (~10%) patients developed hearing impairment, and 6 (~10%) cardiac disease.We detected renal involvement in 13 patients (25%). Eight patients had tubular disease, most frequently hypercalciuria with hypouricemia and five patients had glomerular involvement, with proteinuria and/or decreased glomerular filtration rate as the most frequent symptoms. Only 21 patients (~40%) had been seen by a pediatric nephrologist.

Conclusions: Renal disease was a common occurrence in patients with mitochondrial disease, present in our study in 25% of patients. A regular screening of renal function parameters and the involvement of a nephrologist as part of the multidisciplinary approach to mitochondrial disease appears warranted.
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http://dx.doi.org/10.1007/8904_2017_78DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6226400PMC
December 2017

Management and outcome of children and adolescents with non-medulloblastoma CNS embryonal tumors in Spain: room for improvement in standards of care.

J Neurooncol 2018 Mar 16;137(1):205-213. Epub 2017 Dec 16.

Pediatric Oncology Department, Hospital Niño Jesús, Av. Menéndez Pelayo, 65, 28009, Madrid, Spain.

Non-medulloblastoma CNS embryonal tumors (former PNET/Pineoblastomas) are aggressive malignancies with poor outcome that have been historically treated with medulloblastoma protocols. The purpose of this study is to present a tumor-specific, real-world data cohort of patients with CNS-PNET/PB to analyze quality indicators that can be implemented to improve the outcome of these patients. Patients 0-21 years with CNS-PNET treated in eight large institutions were included. Baseline characteristics, treatment and outcome [progression-free and overall survival (PFS and OS respectively)] were analyzed. From 2005 to 2014, 43 patients fulfilled entry criteria. Median age at diagnosis was 3.6 years (range 0.0-14.7). Histology was pineoblastoma (9%), ependymoblastoma (5%), ETANTR (7%) and PNET (77%). Median duration of the main symptom was 2 weeks (range 0-12). At diagnosis, 28% presented with metastatic disease. Seventeen different protocols were used on frontline treatment; 44% had gross total resection, 42% craniospinal radiotherapy, 86% chemotherapy, and 33% autologous hematopoietic stem cell transplantation (aHSCT). Median follow-up for survivors was 3.5 years (range 1.7-9.3). 3-year PFS was 31.9% (95% CI 17-47%) and OS 35.1% (95% CI 20-50%). Age, extent of resection and radiotherapy were prognostic of PFS and OS in univariate analysis (p < 0.05). Our series shows a dismal outcome for CNS-PNET, especially when compared to patients included in clinical trials. Establishing a common national strategy, implementing referral circuits and collaboration networks, and incorporating new molecular knowledge into routine clinical practice are accessible measures that can improve the outcome of these patients.
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http://dx.doi.org/10.1007/s11060-017-2713-4DOI Listing
March 2018

Tumor predisposition syndromes: The challenge of de novo mutations.

Pediatr Blood Cancer 2018 03 14;65(3). Epub 2017 Nov 14.

Pediatric Oncology and Hematology Department, Hospital Infantil Universitario Niño Jesús, Madrid, Spain.

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http://dx.doi.org/10.1002/pbc.26882DOI Listing
March 2018

Medulloblastoma in children and adolescents: a systematic review of contemporary phase I and II clinical trials and biology update.

Cancer Med 2017 Nov 4;6(11):2606-2624. Epub 2017 Oct 4.

CNIO-HNJ Clinical Research Unit, Pediatric Oncology, Hematology and Stem Cell Transplant Department, Hospital Infantil Universitario Niño Jesús, Avenida Menéndez Pelayo, 65, 28009, Madrid, Spain.

Survival rates for patients with medulloblastoma have improved in the last decades but for those who relapse outcome is dismal and new approaches are needed. Emerging drugs have been tested in the last two decades within the context of phase I/II trials. In parallel, advances in genetic profiling have permitted to identify key molecular alterations for which new strategies are being developed. We performed a systematic review focused on the design and outcome of early-phase trials evaluating new agents in patients with relapsed medulloblastoma. PubMed, clinicaltrials.gov, and references from selected studies were screened to identify phase I/II studies with reported results between 2000 and 2015 including patients with medulloblastoma aged <18 years. A total of 718 studies were reviewed and 78 satisfied eligibility criteria. Of those, 69% were phase I; 31% phase II. Half evaluated conventional chemotherapeutics and 35% targeted agents. Overall, 662 patients with medulloblastoma/primitive neuroectodermal tumors were included. The study designs and the response assessments were heterogeneous, limiting the comparisons among trials and the correct identification of active drugs. Median (range) objective response rate (ORR) for patients with medulloblastoma in phase I/II studies was 0% (0-100) and 6.5% (0-50), respectively. Temozolomide containing regimens had a median ORR of 16.5% (0-100). Smoothened inhibitors trials had a median ORR of 8% (3-8). Novel drugs have shown limited activity against relapsed medulloblastoma. Temozolomide might serve as backbone for new combinations. Novel and more homogenous trial designs might facilitate the development of new drugs.
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http://dx.doi.org/10.1002/cam4.1171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5673921PMC
November 2017

Cystinuria in a patient with 19q12q13.1 deletion.

CEN Case Rep 2016 May 19;5(1):67-69. Epub 2015 Sep 19.

Department of Genetics, Hospital Universitario de Getafe, Madrid, Spain.

Cystinuria is a genetic cause of kidney stones with a prevalence of 1 in 7000 births. So far, two genes have been described responsible for this disorder (SLC3A1 and SLC7A9). We report a patient with an SLC7A9 gene mutation located in 19q13.1 on one allele and with a 19q12q13 region deletion on the other allele. The characteristic clinical features of the 19q13.1 microdeletion syndrome include facial dysmorphism, signs of ectodermal dysplasia, growth retardation, neurologic features and genitourinary anomalies. Cystinuria has not yet been described as part of this syndrome, although one of its responsible genes (SLC7A9) is in the same genomic location. The index case is a 6-year-old male presented with distinctive facial features, cutis aplasia of the scalp, rudimentary teeth, microcephaly, intrauterine and postnatal growth retardation, psychomotor developmental delay, speech delay, epilepsy, inguinal hernias and cystinuria. An array-CGH analysis was performed, finding a large deletion of the 19q12q13.11 cytobands, which affects 19 genes. Two of them are involved in the 19q13.11 deletion syndrome and another affected gene is SLC7A9, responsible for type B cystinuria. Sanger sequencing was performed as well, detecting a heterozygous mutation of the SLC7A9 gene, located in 19q13.1. As far as we know, this is the first described case of cystinuria in a patient with SLC7A9 gene mutation located in 19q13.1 on one allele and with 19q12q13 region deletion on the other allele. Although this patient can be classified as a type B heterozygote and, therefore, his renal prognosis is not severe, the occasional nephrolithiasis found in such patients justifies a close follow-up with regular testing of urinary cystine excretion. We suggest that the recessive behavior of this case, explains the clinical features regarding cystinuria. We propose that in the face of patients affected of a phenotype matchable with 19q13.11 syndrome and cystinuria, a mutational or sequencing study of the SLC7A9 gene should be performed to allow an early onset of diagnosis and treatment.
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http://dx.doi.org/10.1007/s13730-015-0193-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5413741PMC
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J Clin Oncol 2016 06 25;34(18):2196-7. Epub 2016 Apr 25.

Hospital Infantil Universitario Niño Jesús, Madrid, Spain

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http://dx.doi.org/10.1200/JCO.2016.67.7104DOI Listing
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Autologous Cord Blood Cells Infusion as Salvage Therapy for Engraftment Failure After Haploidentical Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemia.

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Pediatric Oncology, Hematology and Stem Cell Transplant Department, Hospital Infantil Universitario Niño Jesús, Madrid, Spain.

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http://dx.doi.org/10.1002/pbc.25974DOI Listing
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IgA-Mediated Autoimmune Hemolytic Anemia: A Clinical Conundrum.

Pediatr Blood Cancer 2016 Apr 17;63(4):754. Epub 2015 Nov 17.

Pediatric Oncology Hematology and Stem Cell Transplant Department, Hospital Infantil Universitario Niño Jesús, Madrid, Spain.

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http://dx.doi.org/10.1002/pbc.25849DOI Listing
April 2016
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