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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. Resumen: Introduccion 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. 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 envío a todos los hospitales con Unidades de hematología y Oncología Pediátrica.Análisis estadístico descriptivo de los resultados. Resultados: El porcentaje de pacientes hasta 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%. 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.

Resumen: 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. Abstract: 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.

BackgroundLiquid 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.MethodsIn 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.ResultsWe 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.ConclusionsOur 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.

Abstract 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.

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 cellfree 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 mononucleosomal 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. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer is still the leading cause of disease-related death in pediatric populations and an important source of morbidity. These can be due to the neoplasm itself but also to the treatment administered; infants are patients of special vulnerability. The aim of this work was to identify genetic variants that correlate with significant impacts on treatments' safety and efficacy. 64 oncologic infant patients (under 18 months of age) were genotyped, calling for SNPs (single nucleotide polymorphisms) in genes related to the efficacy and/or toxicity of the chemotherapeutic drugs employed. The relationship of these genetic variants with 37 clinical parameters during 578 chemotherapy cycles was analyzed. Associations were found between 46 SNPs (in genes involved in drug transport and metabolism, gene repair, tumor suppression, and other biological functions) and survival and hematological toxicity. Following studies that confirm these findings, personalized medicine could be offered to improve response and tolerance to chemotherapeutic schemes. 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. [ABSTRACT FROM AUTHOR]

Rhabdomyosarcoma (RMS) is the most frequent soft tissue sarcoma (STS) in children and adolescents. In Spain the annual incidence is 4.4 cases per million children < 14 years. It is an uncommon neoplasm in adults, but 40% of RMS are diagnosed in patients over 20 years of age, representing 1% of all STS in this age group. RMS can appear anywhere in the body, with some sites more frequently affected including head and neck, genitourinary system and limbs. Assessment of a patient with suspicion of RMS includes imaging studies (MRI, CT, PET-CT) and biopsy. All patients with RMS should receive chemotherapy, either at diagnosis in advanced or metastatic stages, or after initial resection in early local stages. Local control includes surgery and/or radiotherapy depending on site, stage, histology and response to chemotherapy. This guide provides recommendations for diagnosis, staging and treatment of this neoplasm. [ABSTRACT FROM AUTHOR]

Simple Summary: The idea that motivated the design of the project is to offer a genetic germline analysis to all pediatric patients diagnosed in our pediatric oncology unit. The main objective is to determine the incidence of predisposing genetic variants when studying a cohort of pediatric cancer patients using an NGS gene panel. The custom panel employed is designed to detect variants in a large number of genes involved in pediatric cancer in order to be able to identify new genotype–phenotype relationships. The data obtained are valuable for estimating the incidence of predisposing genetic alterations, due to the large number of pediatric patients included in the study. Furthermore, the novel results collected in the main document, which suggest the involvement of new genes in the predisposition to different oncological diseases, are worthwhile. 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]