ECLIM-SEHOP: how to develop a platform to conduct academic trials for childhood cancer.

INTRODUCTION: ECLIM-SEHOP platform was created in 2017. Its main objective is to establish the infrastructure to allow Spanish participation into international academic collaborative clinical trials, observational studies, and registries in pediatric oncology. The aim of this manuscript is to describe the activity conducted by ECLIM-SEHOP since its creation. METHODS: The platform's database was queried to provide an overview of the studies integrally and partially supported by the organization. Data on trial recruitment and set-up/conduct metrics since its creation until November 2023 were extracted. RESULTS: ECLIM-SEHOP has supported 47 studies: 29 clinical trials and 18 observational studies/registries that have recruited a total of 5250 patients. Integral support has been given to 25 studies: 16 trials recruiting 584 patients and nine observational studies/registries recruiting 278 patients. The trials include front-line studies for leukemia, lymphoma, brain and solid extracranial tumors, and other key transversal topics such as off-label use of targeted therapies and survivorship. The mean time from regulatory authority submission to first patient recruited was 12.2 months and from first international site open to first Spanish site open was 31.3 months. DISCUSSION: ECLIM-SEHOP platform has remarkably improved the availability and accessibility of international academic clinical trials and has facilitated the centralization of resources in childhood cancer treatment. Despite the progressive improvement on clinical trial set-up metrics, timings should still be improved. The program has contributed to leveling survival rates in Spain with those of other European countries that presented major differences in the past.

Evaluation of circulating tumor DNA by electropherogram analysis and methylome profiling in high-risk neuroblastomas.

Background: Liquid biopsy has emerged as a promising, non-invasive diagnostic approach in oncology because the analysis of circulating tumor DNA (ctDNA) reflects the precise status of the disease at diagnosis, progression, and response to treatment. DNA methylation profiling is also a potential solution for sensitive and specific detection of many cancers. The combination of both approaches, DNA methylation analysis from ctDNA, provides an extremely useful and minimally invasive tool with high relevance in patients with childhood cancer. Neuroblastoma is an extracranial solid tumor most common in children and responsible for up to 15% of cancer-related deaths. This high death rate has prompted the scientific community to search for new therapeutic targets. DNA methylation also offers a new source for identifying these molecules. However, the limited blood sample size which can be obtained from children with cancer and the fact that ctDNA content may occasionally be diluted by non-tumor cell-free DNA (cfDNA) complicate optimal quantities of material for high-throughput sequencing studies. Methods: In this article, we present an improved method for ctDNA methylome studies of blood-derived plasma from high-risk neuroblastoma patients. We assessed the electropherogram profiles of ctDNA-containing samples suitable for methylome studies, using 10 ng of plasma-derived ctDNA from 126 samples of 86 high-risk neuroblastoma patients, and evaluated several bioinformatic approaches to analyze DNA methylation sequencing data. Results: We demonstrated that enzymatic methyl-sequencing (EM-seq) outperformed bisulfite conversion-based method, based on the lower proportion of PCR duplicates and the higher percentage of unique mapping reads, mean coverage, and genome coverage. The analysis of the electropherogram profiles revealed the presence of nucleosomal multimers, and occasionally high molecular weight DNA. We established that 10% content of the mono-nucleosomal peak is sufficient ctDNA for successful detection of copy number variations and methylation profiles. Quantification of mono-nucleosomal peak also showed that samples at diagnosis contained a higher amount of ctDNA than relapse samples. Conclusions: Our results refine the use of electropherogram profiles to optimize sample selection for subsequent high-throughput analysis and support the use of liquid biopsy followed by enzymatic conversion of unmethylated cysteines to assess the methylomes of neuroblastoma patients.

Personalized Medicine in Infant Population with Cancer: Pharmacogenetic Pilot Study of Polymorphisms Related to Toxicity and Response to Chemotherapy.

BACKGROUND: Pharmacogenetics is a personalized medicine tool that aims to optimize treatments by adapting them to each individual's genetics, maximizing their efficacy while minimizing their toxicity. Infants with cancer are especially vulnerable, and their co-morbidities have vital repercussions. The study of their pharmacogenetics is new in this clinical field. METHODS: A unicentric, ambispective study of a cohort of infants receiving chemotherapy (from January 2007 to August 2019). The genotypes of 64 patients under 18 months of age were correlated with severe drug toxicities and survival. A pharmacogenetics panel was configured based on PharmGKB, drug labels, and international experts' consortiums. RESULTS: Associations between SNPs and hematological toxicity were found. Most meaningful were: MTHFR rs1801131 GT increasing the anemia risk (OR 1.73); rs1517114 GC, XPC rs2228001 GT, increasing neutropenia risk (OR 1.50 and 4.63); ABCB1 rs1045642 AG, TNFRSF11B rs2073618 GG, CYP2B6 rs4802101 TC and SOD2 rs4880 GG increasing thrombocytopenia risk (OR 1.70, 1.77, 1.70, 1.73, respectively). Regarding survival, MTHFR rs1801133 GG, TNFRSF11B rs2073618 GG, XPC rs2228001 GT, CYP3A4 rs2740574 CT, CDA rs3215400 del.del, and SLC01B1 rs4149015 GA were associated with lower overall survival probabilities (HR 3.12, 1.84, 1.68, 2.92, 1.90, and 3.96, respectively). Lastly, for event-free survival, SLC19A1 rs1051266 TT and CDA rs3215400 del.del increased the relapse probability (HR 1.61 and 2.19, respectively). CONCLUSIONS: This pharmacogenetic study is a pioneer in dealing with infants under 18 months of age. Further studies are needed to confirm the utility of the findings in this work to be used as predictive genetic biomarkers of toxicity and therapeutic efficacy in the infant population. If confirmed, their use in therapeutic decisions could improve the quality of life and prognosis of these patients.

Atención al adolescente con cáncer. ¿Qué ha cambiado en nuestro país en una década? / Adolescent cancer care: What has changed in Spain in the past decade?

Introducción y objetivo: En el año 2012 el Grupo de trabajo de adolescentes con cáncer publicó los resultados de una encuesta sobre la asistencia a adolescentes en España como punto de partida para futuras actuaciones. Nuestro objetivo fue evaluar si las líneas de trabajo han supuesto cambios asistenciales en la última década. Material y métodos: Encuesta que consta de las mismas preguntas analizadas y publicadas en el año 2012. La encuesta se divide en: epidemiología, atención psicosocial, infraestructuras, tratamiento y seguimiento de los adolescentes con cáncer. Se envió a todos los hospitales con unidades de hematología y oncología pediátrica. Se realizó un análisis estadístico descriptivo de los resultados. Resultados: El porcentaje de pacientes hasta los 18 años tratados en unidades pediátricas ha aumentado del 35,9% al 77,5%. Las hemopatías malignas tratadas en unidades pediátricas se incrementan del 31% al 52% y los tumores sólidos del 49% al 85%. En 2012 30 (39) unidades referían que los casos nuevos de adolescentes representaban un 10%. Actualmente 14 (40) mantienen este porcentaje. Hace una década no existían unidades específicas para adolescentes con cáncer en España. Actualmente, 7 (40) centros disponen de unidades. La atención psicológica para adolescentes apenas ha variado. El seguimiento de supervivientes se realiza por especialistas pediátricos en el 82,5% de los centros. Conclusiones: El trabajo para centralizar los cuidados de adolescentes con cáncer en unidades específicas multidisciplinarias, o en su defecto pediátricas, se ve reflejado en los cambios en la atención sanitaria en nuestro país en la última década. Aún queda un largo recorrido en pilares fundamentales en el abordaje de esta población. (AU)

Introduction and objective: In 2012, the Adolescents with Cancer working group published the results of a survey on care delivery for the adolescent population in Spain as a starting point for future intervention. The aim of this nationwide survey was to outline the current situation and assess whether the implemented strategies have resulted in changes in care delivery. Material and methods: Survey consisting of the same items analysed and published in 2012. The questionnaire was structured into sections devoted to epidemiology, psychosocial care, infrastructure, treatment and follow-up of adolescents with cancer. It was submitted to all hospitals in Spain with a paediatric haematology and oncology unit. We conducted a descriptive analysis of the results. Results: The percentage of patients aged up to 18 years managed in paediatric units has increased from 35.9% to 77.5% in the past decade. The proportion of malignant blood tumours treated in paediatric units increased from 31% to 52%, and the proportion of solid tumours from 49% to 85%. In 2012, 30 units (out of 39) reported that new cases in adolescents amounted to up to 10% of the total. At present, only 14 (out of 40) continue to report this percentage. A decade ago, there were no specific adolescent cancer units in Spain. Now, 7 centres (out of 40) have specific multidisciplinary units. There has been little change in psychological support services for adolescents. The follow-up of survivors is carried out by paediatric specialists in 82.5% of the hospitals. Conclusions: The efforts made to centralise the care of adolescents with cancer in specific multidisciplinary adolescent units or, failing that, paediatric units, is reflected in the changes in care delivery in Spain in the past decade. Much remains to be done in key components of the management of adolescents with cancer. (AU)

Adolescent cancer care: What has changed in Spain in the past decade?

INTRODUCTION AND OBJECTIVES: In 2012, the Adolescents with Cancer Working Group published the results of a survey on care delivery for the adolescent population in Spain as a starting point for future intervention. The aim of this nationwide survey was to outline the current situation and assess whether the implemented strategies have resulted in changes in care delivery. MATERIAL AND METHODS: Survey consisting of the same items analysed and published in 2012. The questionnaire was structured into sections devoted to epidemiology, psychosocial care, infrastructure, treatment and follow-up of adolescents with cancer. It was submitted to all hospitals in Spain with a paediatric haematology and oncology unit. We conducted a descriptive analysis of the results. RESULTS: The percentage of patients aged up to 18 years managed in paediatric units has increased from 35.9% to 77.5% in the past decade. The proportion of malignant blood tumours treated in paediatric units increased from 31% to 52%, and the proportion of solid tumours from 49% to 85%. In 2012, 30 units (out of 39) reported that new cases in adolescents amounted to up to 10% of the total. At present, only 14 (out of 40) continue to report this percentage. A decade ago, there were no specific adolescent cancer units in Spain. Now, 7 centres (out of 40) have specific multidisciplinary units. There has been little change in psychological support services for adolescents. The follow-up of survivors is carried out by paediatric specialists in 82.5% of the hospitals. CONCLUSIONS: The efforts made to centralise the care of adolescents with cancer in specific multidisciplinary adolescent units or, failing that, paediatric units, is reflected in the changes in care delivery in Spain in the past decade. Much remains to be done in key components of the management of adolescents with cancer.

Results of a survey on the treatment of adolescents and young adult (AYA) sarcoma patients in Spain at present time.

INTRODUCTION: We aimed to analyse health care services for adolescents and young adults (AYA) with sarcomas in Spain. METHODS: A survey was sent to all Spanish cancer centres, including questions about demographic, facilities, and treatment strategies for AYAs with sarcomas in the last 2 years. RESULTS: Thirty-five units participated in the survey, 17 paediatric and 15 adult units. There were three specialized AYA units. First line regimen varied depending on whether the treating unit was paediatric or not, for osteosarcomas, rhabdomyosarcomas, and non-rhabdomyosarcomas. By contrast, 91.4% of Ewing sarcomas were treated according to EE2012. In the relapse setting, differences between units were higher in all tumours. Additionally, 48% of the units reported not having trials for this population. CONCLUSION: There are major differences in the treatment of AYAs with sarcomas between adult and paediatric units. Enormous efforts are needed to homogenize treatments and increase the access to innovation.

Germline variant in Ctcf links mental retardation to Wilms tumor predisposition.

CTCF germline mutations have been related to MRD21. We report the first bilateral Wilms tumor suffered by a MRD21 patient carrying an unreported CTCF missense variant in a zinc finger domain of CTCF protein. We found that germline heterozygous variant I446K became homozygous in the tumor due to a loss of heterozygosity rearrangement affecting the whole q arm on chromosome 16. Our findings propose CTCF I446K variant as a link between MRD21 and Wilms tumor predisposition.

Germline Predisposition to Pediatric Cancer, from Next Generation Sequencing to Medical Care.

Knowledge about genetic predisposition to pediatric cancer is constantly expanding. The categorization and clinical management of the best-known syndromes has been refined over the years. Meanwhile, new genes for pediatric cancer susceptibility are discovered every year. Our current work shares the results of genetically studying the germline of 170 pediatric patients diagnosed with cancer. Patients were prospectively recruited and studied using a custom panel, OncoNano V2. The well-categorized predisposing syndromes incidence was 9.4%. Likely pathogenic variants for predisposition to the patient's tumor were identified in an additional 5.9% of cases. Additionally, a high number of pathogenic variants associated with recessive diseases was detected, which required family genetic counseling as well. The clinical utility of the Jongmans MC tool was evaluated, showing a high sensitivity for detecting the best-known predisposing syndromes. Our study confirms that the Jongmans MC tool is appropriate for a rapid assessment of patients; however, the updated version of Ripperger T criteria would be more accurate. Meaningfully, based on our findings, up to 9.4% of patients would present genetic alterations predisposing to cancer. Notably, up to 20% of all patients carry germline pathogenic or likely pathogenic variants in genes related to cancer and, thereby, they also require expert genetic counseling. The most important consideration is that the detection rate of genetic causality outside Jongmans MC et al. criteria was very low.

Casuística de tumor miofibroblástico inflamatorio en centro terciario / Casuistics of inflammatory myofibroblastic tumor in a tertiary center

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Retinoblastoma and mosaic 13q deletion: a case report.

BACKGROUND: Patients with 13q-syndrome are at risk of retinoblastoma when the RB1 gene, located in the chromosomal band 13q14.2, is deleted. This syndrome is frequently associated with congenital malformations and developmental delay, although these signs could be mild. Mosaic 13q-deletion patients have been previously reported in the literature; their phenotype is variable, and they may not be recognized. CASE PRESENTATION: Retinoblastoma diagnosed in a child with 13q-mosaicism confirmed in blood, oral mucosa, healthy retina and retinoblastoma. A second RB1 hit is present exclusively in the retinoblastoma sample (RB1 c.958C>T p.Arg320Ter). Other detected molecular events in retinoblastoma are 6p12.3pter gain and 6q25.3qter loss. Clinical examination is unremarkable except for clinodactyly of the right fifth finger. DISCUSSION AND CONCLUSIONS: We describe a case of mosaic 13q deletion syndrome affected by retinoblastoma. Molecular data obtained from the tumor analysis are similar to previous data available about this malignancy. High clinical suspicion is essential for an adequate diagnosis of mosaic cases.

Next-Generation Sequencing Identifies Potential Actionable Targets in Paediatric Sarcomas.

Background: Bone and soft-tissue sarcomas represent 13% of all paediatric malignancies. International contributions to introduce next-generation sequencing (NGS) approaches into clinical application are currently developing. We present the results from the Precision Medicine program for children with sarcomas at a reference centre. Results: Samples of 70 paediatric sarcomas were processed for histopathological analysis, reverse transcriptase polymerase chain reaction (RT-PCR) and next-generation sequencing (NGS) with a consensus gene panel. Pathogenic alterations were reported and, if existing, targeted recommendations were translated to the clinic. Seventy paediatric patients with sarcomas from 10 centres were studied. Median age was 11.5 years (range 1-18). Twenty-two (31%) had at least one pathogenic alteration by NGS. Thirty pathogenic mutations in 18 different genes were detected amongst the 22 patients. The most frequent alterations were found in TP53, followed by FGFR4 and CTNNB1. Combining all biological studies, 18 actionable variants were detected and six patients received targeted treatment observing a disease control rate of 78%. Extrapolating the results to the whole cohort, 23% of the patients would obtain clinical benefit from this approach. Conclusions: Paediatric sarcomas have a different genomic landscape when compared to adult cohorts. Incorporating NGS targets into paediatric sarcomas' therapy is feasible and allows personalized treatments with clinical benefit in the relapse setting.

Publisher Correction: Clinical Features of Neuroblastoma With 11q Deletion: An Increase in Relapse Probabilities In Localized And 4S Stages.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Metabolomic profiling in neuroblastoma.

BACKGROUND AND OBJECTIVES: Previous studies on several cancer types show that metabolomics provides a potentially useful noninvasive screening approach for outcome prediction and accurate response to treatment assessment. Neuroblastoma (NB) accounts for at least 15% of cancer-related deaths in children. Although current risk-based treatment approaches in NB have resulted in improved outcome, survival for high-risk patients remains poor. This study aims to evaluate the use of metabolomics for improving patients' risk-group stratification and outcome prediction in NB. DESIGN AND METHODS: Plasma samples from 110 patients with NB were collected at diagnosis prior to starting therapy and at the end of treatment if available. Metabolomic analysis of samples was carried out by ultra-performance liquid chromatography-time of flight mass spectrometry (UPLC-MS). RESULTS: The metabolomic analysis was able to identify different plasma metabolic profiles in high-risk and low-risk NB patients at diagnosis. The metabolic model correctly classified 16 high-risk and 15 low-risk samples in an external validation set providing 84.2% sensitivity (60.4-96.6, 95% CI) and 93.7% specificity (69.8-99.8, 95% CI). Metabolomic profiling could also discriminate high-risk patients with active disease from those in remission. Notably, a plasma metabolomic signature at diagnosis identified a subset of high-risk NB patients who progressed during treatment. CONCLUSIONS: To the best of our knowledge, this is the largest NB study investigating the prognostic power of plasma metabolomics. Our results support the potential of metabolomic profiling for improving NB risk-group stratification and outcome prediction. Additional validating studies with a large cohort are needed.

Clinical Features of Neuroblastoma With 11q Deletion: An Increase in Relapse Probabilities In Localized And 4S Stages.

Neuroblastoma (NB) is a heterogeneous tumor with an extremely diverse prognosis according to clinical and genetic factors, such as the presence of an 11q deletion (11q-del). A multicentric study using data from a national neuroblastic tumor database was conducted. This study compared the most important features of NB patients: presence of 11q-del, presence of MYCN amplification (MNA) and remaining cases. A total of 357 patients were followed throughout an 8-year period. 11q-del was found in sixty cases (17%). 11q-del tumors were diagnosed at an older age (median 3.29 years). Overall survival (OS) was lower in 11q-del patients (60% at 5 years), compared to all other cases (76% at 5 years) p = 0.014. Event free survival (EFS) was 35% after 5 years, which is a low number when compared with the remaining cases: 75% after 5 years (p < 0.001). Localized tumors with 11q-del have a higher risk of relapse (HR = 3.312) such as 4 s 11q-del patients (HR 7.581). 11q-del in NB is a dismal prognostic factor. Its presence predicts a bad outcome and increases relapse probability, specially in localized stages and 4 s stages. The presence of 11q aberration should be taken into consideration when stratifying neuroblastoma risk groups.

¿Cómo tratamos el hemangioendotelioma kaposiforme? / How do we treat Kaposiform Haemangioendothelioma?

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[Early clinical trials in paediatric oncology in Spain: a nationwide perspective]. / Ensayos clínicos precoces en oncología pediátrica en España: una perspectiva nacional.

INTRODUCTION: Cancer is the leading cause of death between the first year of life and adolescence, and some types of diseases are still a major challenge in terms of cure. There is, therefore, a major need for new drugs. Recent findings in cancer biology open the door to the development of targeted therapies against individual molecular changes, as well as immunotherapy. Promising results in adult anti-cancer drug development have not yet been translated into paediatric clinical practice. A report is presented on the activity in early paediatric oncology trials (phase I-II) in Spain. MATERIAL AND METHODS: All members of the Spanish Society of Paediatric Haematology Oncology (SEHOP) were contacted in order to identify early clinical trials in paediatric cancer opened between 2005 and 2015. RESULTS: A total of 30 trials had been opened in this period: 21 (70%) in solid tumours, and 9 (30%) in malignant haemopathies. A total of 212 patients have been enrolled. The majority was industry sponsored (53%). Since 2010, four centres have joined the international consortium of Innovative Therapies for Children with Cancer (ITCC), which has as its aim to develop novel therapies for paediatric tumours. A significant number of new studies have opened since 2010, improving the treatment opportunities for our children. Results of recently closed trials show the contribution of Spanish investigators, the introduction of molecularly targeted agents, and their benefits. CONCLUSIONS: The activity in clinical trials has increased in the years analysed. The SEHOP is committed to develop and participate in collaborative academic trials, in order to help in the advancement and optimisation of existing therapies in paediatric cancer.