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BackgroundTo overcome knowledge gaps and optimize long-term follow-up (LTFU) care for childhood cancer survivors, the concept of the Survivorship Passport (SurPass) has been invented. Within the European PanCareSurPass project, the semiautomated and interoperable SurPass (version 2.0) will be optimized, implemented, and evaluated at 6 LTFU care centers representing 6 European countries and 3 distinct health system scenarios: (1) national electronic health information systems (EHISs) in Austria and Lithuania, (2) regional or local EHISs in Italy and Spain, and (3) cancer registries or hospital-based EHISs in Belgium and Germany. ObjectiveWe aimed to identify and describe barriers and facilitators for SurPass (version 2.0) implementation concerning semiautomation of data input, interoperability, data protection, privacy, and cybersecurity. MethodsIT specialists from the 6 LTFU care centers participated in a semistructured digital survey focusing on IT-related barriers and facilitators to SurPass (version 2.0) implementation. We used the fit-viability model to assess the compatibility and feasibility of integrating SurPass into existing EHISs. ResultsIn total, 13/20 (65%) invited IT specialists participated. The main barriers and facilitators in all 3 health system scenarios related to semiautomated data input and interoperability included unaligned EHIS infrastructure and the use of interoperability frameworks and international coding systems. The main barriers and facilitators related to data protection or privacy and cybersecurity included pseudonymization of personal health data and data retention. According to the fit-viability model, the first health system scenario provides the best fit for SurPass implementation, followed by the second and third scenarios. ConclusionsThis study provides essential insights into the information and IT-related influencing factors that need to be considered when implementing the SurPass (version 2.0) in clinical practice. We recommend the adoption of Health Level Seven Fast Healthcare Interoperability Resources and data security measures such as encryption, pseudonymization, and multifactor authentication to protect personal health data where applicable. In sum, this study offers practical insights into integrating digital health solutions into existing EHISs.

Leukemia is the most common childhood cancer and its etiology could be related to various environmental contaminants such as particulate matter (PM). The objective of our study is to evaluate the potential association between exposure to PM during pregnancy and the incidence of childhood leukemia. We established a population-based nationwide cohort using the Spanish Birth Registry Statistics database of the National Statistics Institute. We used spatiotemporal land use random forest models to estimate the concentrations of PM10 and PM2.5 for the entire pregnancy and by trimesters. We conducted logistic regression analyses adjusted for various covariates. In addition, we fitted generalized additive models (GAMs) to estimate the non-linear relationship between PM levels and leukemia incidence. The study included 3,112,123 children and 1066 cases of leukemia. The results for the continuous variable of PM10 exposure levels suggested an increased risk of childhood leukemia to be associated with higher exposure. The results for the categorized PM10 variable suggest an increased risk of childhood leukemia among pregnant women whose exposure levels were higher than the median (third and fourth quartiles). The results for PM2.5 were weaker. We found association between exposure to PM10 during pregnancy and an increased risk of childhood leukemia. Our findings indicate that public health interventions should aim to reduce air pollution to lower the incidence of childhood leukemia.

IntroductionVariation in stage at diagnosis of childhood cancers (CC) may explain differences in survival rates observed across geographical regions. The BENCHISTA project aims to understand these differences and to encourage the application of the Toronto Staging Guidelines (TG) by Population-Based Cancer Registries (PBCRs) to the most common solid paediatric cancers.MethodsPBCRs within and outside Europe were invited to participate and identify all cases of Neuroblastoma, Wilms Tumour, Medulloblastoma, Ewing Sarcoma, Rhabdomyosarcoma and Osteosarcoma diagnosed in a consecutive three-year period (2014-2017) and apply TG at diagnosis. Other non-stage prognostic factors, treatment, progression/recurrence, and cause of death information were collected as optional variables. A minimum of three-year follow-up was required. To standardise TG application by PBCRs, on-line workshops led by six tumour-specific clinical experts were held. To understand the role of data availability and quality, a survey focused on data collection/sharing processes and a quality assurance exercise were generated. To support data harmonization and query resolution a dedicated email and a question-and-answers bank were created.Results67 PBCRs from 28 countries participated and provided a maximally de-personalized, patient-level dataset. For 26 PBCRs, data format and ethical approval obtained by the two sponsoring institutions (UCL and INT) was sufficient for data sharing. 41 participating PBCRs required a Data Transfer Agreement (DTA) to comply with data protection regulations. Due to heterogeneity found in legal aspects, 18 months were spent on finalizing the DTA. The data collection survey was answered by 68 respondents from 63 PBCRs; 44% of them confirmed the ability to re-consult a clinician in cases where stage ascertainment was difficult/uncertain. Of the total participating PBCRs, 75% completed the staging quality assurance exercise, with a median correct answer proportion of 92% [range: 70% (rhabdomyosarcoma) to 100% (Wilms tumour)].ConclusionDifferences in interpretation and processes required to harmonize general data protection regulations across countries were encountered causing delays in data transfer. Despite challenges, the BENCHISTA Project has established a large collaboration between PBCRs and clinicians to collect detailed and standardised TG at a population-level enhancing the understanding of the reasons for variation in overall survival rates for CC, stimulate research and improve national/regional child health plans.

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.

IntroductionThe aim of this study was to describe incidence, incidence trends and survival patterns of lymphoid neoplasms (LNs) and its subtypes in Spain in the period 2002-2013 using data from the Spanish Network of Cancer Registries (REDECAN).Materials and MethodsData were extracted from 13 Spanish population-based cancer registries. LNs incident cases were codified using the International Classification of Diseases for Oncology, third edition (ICD-O-3) and grouped according to the WHO 2008 classification. Age-standardized incidence rates to the 2013 European standard population (ASIRe) were obtained. Poisson regression models were used to analyze trends in incidence rates and estimate the annual percentage change (APC) for each subtype. The number of cases in Spain for 2023 was estimated by applying the estimated age-specific rates for the year 2023 to the 2023 Spanish population. Observed survival (OS) was estimated by the Kaplan-Meier method and net survival (NS) by the Pohar-Perme method. Sex- and age-specific estimates of 5-year NS were calculated, as well as its changes according to two periods of diagnosis (2002-2007 and 2008-2013).ResultsLNs accounted for 69% (n=39,156) of all hematological malignancies (n=56,751) diagnosed during the period of study. Median age at diagnosis was 67 years (interquartile range (IQR) = 52-77). The overall ASIRe was 34.23 (95% confidence interval (CI): 33.89, 34.57) and showed a marked male predominance in almost all subtypes (global sex ratio = 1.45). During the study period, incidence trends of LNs remained stable (APC: 0.3; 95% CI: -0.1, 0.6), nevertheless some subtypes showed statistically significant variations, such as LNs NOS category (APC: -5.6; 95% CI: -6.8, -4.3). Around 17,926 new cases of LNs will be diagnosed in 2023 in Spain. Survival rates differed considerably across age-groups, while they were similar between men and women. Five- year NS was 62.81% (95% CI: 62.1, 63.52) for all LNs, and varied widely across LNs subtypes, ranging from 39.21% to 90.25%. NS for all LNs improved from the first period of diagnosis to the second one, being 61.57% (95% CI: 60.56, 62.61) in 2002-2007 and 64.17% (95% CI: 63.29, 65.07) in 2008-2013.ConclusionsThis study presents the first complete and extensive population-based analysis of LNs incidence and survival in Spain. These population-based data provide relevant information to better understand the epidemiology of LNs in Southern Europe and it features some useful points for public health authorities and clinicians. However, additional improvements regarding the registration of these hematological neoplasms can be implemented.

Anthracyclines are widely used in the treatment of many solid cancers, but their efficacy is limited by cardiotoxicity. As the number of pediatric cancer survivors continues to rise, there has been a concomitant increase in people living with anthracycline-induced cardiotoxicity. Accordingly, there is an ongoing need for new models to better understand the pathophysiological mechanisms of anthracycline-induced cardiac damage. Here we generated induced pluripotent stem cells (iPSCs) from two pediatric oncology patients with acute cardiotoxicity induced by anthracyclines and differentiated them to ventricular cardiomyocytes (hiPSC-CMs). Comparative analysis of these cells (CTX hiPSC-CMs) and control hiPSC-CMs revealed that the former were significantly more sensitive to cell injury and death from the anthracycline doxorubicin (DOX), as measured by viability analysis, cleaved caspase 3 expression, oxidative stress, genomic and mitochondrial damage and sarcomeric disorganization. The expression of several mRNAs involved in structural integrity and inflammatory response were also differentially affected by DOX. Functionally, optical mapping analysis revealed higher arrythmia complexity after DOX treatment in CTX iPSC-CMs. Finally, using a panel of previously identified microRNAs associated with cardioprotection, we identified lower levels of miR-22-3p, miR-30b-5p, miR-90b-3p and miR-4732-3p in CTX iPSC-CMs under basal conditions. Our study provides valuable phenotype information for cellular models of cardiotoxicity and highlights the significance of using patient-derived cardiomyocytes for studying the associated pathogenic mechanisms.

High‐risk neuroblastoma (NB) patients with 11q deletion frequently undergo late but consecutive relapse cycles with fatal outcome. To date, no actionable targets to improve current multimodal treatment have been identified. We analyzed immune microenvironment and genetic profiles of high‐risk NB correlating with 11q immune status. We show in two independent cohorts that 11q‐deleted NB exhibits various immune inhibitory mechanisms, including increased CD4+ resting T cells and M2 macrophages, higher expression of programmed death‐ligand 1, interleukin‐10, transforming growth factor‐beta‐1, and indoleamine 2,3‐dioxygenase 1 (P

Resumen: Introducción: La enfermedad oncohematológica continúa siendo la primera causa de mortalidad no traumática en la infancia y una importante causa de morbilidad. El paciente menor de 18 meses presenta particularidades clínicas, diagnósticas y terapéuticas que es interesante conocer por todo pediatra, con el fin de lograr una mayor supervivencia y una menor comorbilidad a lo largo de su vida. Material y métodos: Estudio descriptivo retrospectivo de variables clínicas, diagnósticas y terapéuticas en pacientes menores de 18 meses diagnosticados de enfermedad oncohematológica que reciben quimioterapia en una unidad de oncología pediátrica entre enero 2007 y agosto 2019. Resultados: Setenta y dos pacientes fueron diagnosticados de 76 neoplasias que precisaron quimioterapia. La neoplasia de mayor incidencia fue la leucemia (21 pacientes), seguida del neuroblastoma (15 pacientes) y los tumores del sistema nervioso central (12 pacientes). La presentación con «síntomas amenazantes para la vida» tuvo lugar en el 20,8% de los afectados, especialmente en tumores de estirpe neural (13/15). El 18% de pacientes no presentaron síntomas al inicio. El 51% de los diagnósticos totales tuvieron lugar en «estadios avanzados». Concretamente en el caso de los tumores sólidos, el 23,6% de los inicios presentaron metástasis. Se aislaron importantes porcentajes de alteraciones genéticas implicadas en la etiopatogenia de las diferentes neoplasias. Conclusiones: El cáncer en la primera etapa de la vida supone un reto diagnóstico y terapéutico por su diversidad fenotípica, su carga genética y sus dificultades terapéuticas. El conocimiento de sus particularidades es fundamental para un abordaje precoz y eficaz. Abstract: Introduction: Oncological-haematological disease continues to be the first cause of non-traumatic mortality in childhood, as well as a significant cause of morbidity. The patient less than 18-months-old has special clinical, diagnostic, and therapeutic features that all paediatricians are interested in determining, with the aim of achieving greater survival and a lower morbidity throughout the lives of their patients. Material and methods: A retrospective, descriptive study was carried out using the clinical, diagnostic, and therapeutic variables in patients less than 18-months-old diagnosed with an oncological-haematological that received chemotherapy in a Paediatric Oncology Unit between January 2007 and August 2019. Results: A total of 72 patients were diagnosed with 76 cancers that required chemotherapy. The most common cancer was leukaemia (21 patients), followed by neuroblastoma (15 patients), and tumours of the central nervous system (12 patients). The presentation of “life-threatening symptoms” was seen in 20.8% of cases, particularly in tumours of neural origin (13/15). Although 18% of patients showed no symptoms on diagnosis, just over half (51%) of the diagnoses took place in the “advanced stages”. Particularly in the case of solid tumours in which 23.6% were diagnosed with metastases. A significant percentage of genetic alterations implicated in the aetiopathogenesis of the different cancers were found. Conclusions: Cancer in the first stages of life is a diagnostic and therapeutic challenge due to its phenotypical diversity, its genetic load, and its therapeutic difficulties. Knowledge of its particular features is essential for its early and effective approach.

Introduction: Oncological-haematological disease continues to be the first cause of non-traumatic mortality in childhood, as well as a significant cause of morbidity. The patient less than 18-months-old has special clinical, diagnostic, and therapeutic features that all paediatricians are interested in determining, with the aim of achieving greater survival and a lower morbidity throughout the lives of their patients. Material and methods: A retrospective, descriptive study was carried out using the clinical, diagnostic, and therapeutic variables in patients less than 18-months-old diagnosed with an oncological-haematological that received chemotherapy in a Paediatric Oncology Unit between January 2007 and August 2019. Results: A total of 72 patients were diagnosed with 76 cancers that required chemotherapy. The most common cancer was leukaemia (21 patients), followed by neuroblastoma (15 patients), and tumours of the central nervous system (12 patients). The presentation of “life-threatening symptoms” was seen in 20.8% of cases, particularly in tumours of neural origin (13/15). Although 18% of patients showed no symptoms on diagnosis, just over half (51%) of the diagnoses took place in the “advanced stages”. Particularly in the case of solid tumours in which 23.6% were diagnosed with metastases. A significant percentage of genetic alterations implicated in the aetiopathogenesis of the different cancers were found. Conclusions: Cancer in the first stages of life is a diagnostic and therapeutic challenge due to its phenotypical diversity, its genetic load, and its therapeutic difficulties. Knowledge of its particular features is essential for its early and effective approach. Resumen: Introducción: La enfermedad oncohematológica continúa siendo la primera causa de mortalidad no traumática en la infancia y una importante causa de morbilidad. El paciente menor de 18 meses presenta particularidades clínicas, diagnósticas y terapéuticas que es interesante conocer por todo pediatra, con el fin de lograr una mayor supervivencia y una menor comorbilidad a lo largo de su vida. Material y métodos: Estudio descriptivo retrospectivo de variables clínicas, diagnósticas y terapéuticas en pacientes menores de 18 meses diagnosticados de enfermedad oncohematológica que reciben quimioterapia en una Unidad de Oncología Pediátrica entre enero 2007 y agosto 2019. Resultados: 72 pacientes fueron diagnosticados de 76 neoplasias que precisaron quimioterapia. La neoplasia de mayor incidencia fue la leucemia (21 pacientes), seguida del neuroblastoma (15 pacientes) y los tumores sistema nervioso central (12 pacientes). La presentación con “síntomas amenazantes para la vida” tuvo lugar en el 20,8% de los afectados, especialmente en tumores de estirpe neural (13/15). 18% de pacientes no presentaron síntomas al debut. El 51% de los diagnósticos totales tuvieron lugar en “estadios avanzados”. Concretamente en el caso de los tumores sólidos, el 23,6% de los debuts presentaron metástasis. Se aislaron importantes porcentajes de alteraciones genéticas implicadas en la etiopatogenia de las diferentes neoplasias. Conclusiones: El cáncer en la primera etapa de la vida supone un reto diagnóstico y terapéutico por su diversidad fenotípica, su carga genética y sus dificultades terapéuticas. El conocimiento de sus particularidades es fundamental para un abordaje precoz y eficaz.

Abstract PRIMAGE is one of the largest and more ambitious research projects dealing with medical imaging, artificial intelligence and cancer treatment in children. It is a 4-year European Commission-financed project that has 16 European partners in the consortium, including the European Society for Paediatric Oncology, two imaging biobanks, and three prominent European paediatric oncology units. The project is constructed as an observational in silico study involving high-quality anonymised datasets (imaging, clinical, molecular, and genetics) for the training and validation of machine learning and multiscale algorithms. The open cloud-based platform will offer precise clinical assistance for phenotyping (diagnosis), treatment allocation (prediction), and patient endpoints (prognosis), based on the use of imaging biomarkers, tumour growth simulation, advanced visualisation of confidence scores, and machine-learning approaches. The decision support prototype will be constructed and validated on two paediatric cancers: neuroblastoma and diffuse intrinsic pontine glioma. External validation will be performed on data recruited from independent collaborative centres. Final results will be available for the scientific community at the end of the project, and ready for translation to other malignant solid tumours.

Abstract Background Understanding pediatric cancer biology is a huge challenge in continuous development that is currently being implemented into the clinical practice thanks to the new high throughput technologies integrated by personalized medicine. We present the results of the Precision Medicine program for children and adolescents with solid tumors in relapse/progression carried out in University La Fe Hospital (Valencia) from 2014. This is the first Spanish experience in precision medicine published in pediatric oncology. Methods Study enrollment was offered to all patients having a refractory or relapsed solid tumor and an available biopsy treated in La Fe Hospital (Valencia, Spain) or in other Spanish pediatric oncologic center. Eighty four patients were finally studied. The commercial Human Comprehensive Cancer GeneReadDNAseq Targeted genes Panel (Qiagen©) was sequenced in fresh/frozen samples. Variants considered pathogenic or likely pathogenic were classified using the algorithm published by Parsons et al. based on perceived clinical utility. Results Thirteen of 84 patients (15%) received therapeutic recommendations due to an actionable variant detected and three patients received prognosis information based on sequencing results. Conclusions Precision medicine projects based on targetable gene panel approximations can obtain translatable information to pediatric patients with reasonable efforts. This approach lowers economic expenses and reduces time of response with respect to whole exome sequencing. Since the translation to the clinical practice is the main objective of these projects, limiting the number of relatively well-known biological markers will allow us to transfer similar amount of information with less economic and human effort.

Abstract Background Vitronectin is a multifunctional glycoprotein known in several human tumors for its adhesive role in processes such as cell growth, angiogenesis and metastasis. In this study, we examined vitronectin expression in neuroblastoma to investigate whether this molecule takes part in cell-cell or cell-extracellular matrix interactions that may confer mechanical properties to promote tumor aggressiveness. Methods We used immunohistochemistry and image analysis tools to characterize vitronectin expression and to test its prognostic value in 91 neuroblastoma patients. To better understand the effect of vitronectin, we studied its in vitro expression using commercial neuroblastoma cell lines and in vivo using intra-adrenal gland xenograft models by immunohistochemistry. Results Digital image analysis allowed us to associate vitronectin staining intensity and location discriminating between territorial vitronectin and interterritorial vitronectin expression patterns. High territorial vitronectin expression (strong staining associated with pericellular and intracellular location) was present in tumors from patients with metastatic undifferentiating neuroblastoma, that were MYCN amplified, 11q deleted or with segmental chromosomal profiles, in the high-risk stratification group and with high genetic instability. In vitro studies confirmed that vitronectin is expressed in tumor cells as small cytoplasmic dot drops. In vivo experiments revealed tumor cells with high and dense cytoplasmic vitronectin expression. Conclusions These findings highlight the relevance of vitronectin in neuroblastoma tumor biology and suggest its potential as a future therapeutic target in neuroblastoma.

Abstract Background Neuroblastic tumours (NBTs) are paediatric solid tumours derived from embryonic neural crest cells which harbour their own cancer stem cells (CSC). There is evidence indicating that CSC may be responsible for tumour progression, chemotherapy resistance and recurrence in NBTs. Oct4 is a transcription factor which plays a key role in mammal embryonic development and stem cell fate regulation. The aim of the study is to elucidate the clinical significance of Oct4 in NBTs. Methods We studied Oct4 expression in 563 primary NBTs using digital image quantification. Chi-square test was applied to analyse the correlation between histopathology and the Oct4+ cell percentage. Survival analysis was carried out with Kaplan-Meier curves and log-rank test. Additionally, a multivariate Cox regression analysis with the stepwise backwards (Wald) method was undertaken to calculate the impact of Oct4 expression level on survival. Results We found that tumours with a high proportion of cells expressing Oct4 correlated statistically with undifferentiated and poorly differentiated neuroblastoma / nodular ganglioneuroblastoma, and that Oct4 expression was not present in ganglioneuroma (p

Objective: Pheochromocytomas (PHEOs) and paragangliomas (PGLs) arise from adrenal extra-adrenal paraganglia. They often secrete catecholamine and approximately 1/3 are hereditary. Almost 50% of metastatic PGLs are caused by mutations in the succinate dehydrogenase gene, particularly in subunits B and D (SDHB/D). These tumors remain a diagnostic and therapeutic challenge due to a limited number of effective treatment options. To our best knowledge, we present the first report that uses induction therapy to elicit a significant response in both primary and metastatic lesions, followed by complete surgical resection of a primary SDHB-related PGL. Case description: A 45-year-old female presented with an 8.5 cm unresectable primary SDHB-related PGL with multiple bone metastases. She had an initial blood pressure of 210/130 mmHg and a heart rate of 150 bpm. Initially, she was treated with cisplatin, vinblastine, and dacarbazine (CVD) chemotherapy and lanreotide (120 mg/sc/28d), which resulted in tumor shrinkage. The patient later progressed, and monotherapy with a shortened interval of lanreotide (120 mg/sc/14d) was initiated. Following 2.5 months at this interval, the patient nearly achieved complete control of her clinical symptoms, and experienced a 30% reduction in 18F-flurodeoxyglucose uptake in her primary and metastatic lesions. Following the surgical resection of her primary PGL, all prior antihypertensive medications were stopped. Conclusions: CVD, together with a 14-day regimen of high dose lanreotide, may be an effective treatment option for SDHB-related metastatic PGLs. Therefore, further evaluation of somatostatin analogues, preferably lanreotide, in the treatment of metastatic SDHB-related PGLs is warranted. We believe that ours is the first report detailing the successful use of lanreotide treatment prior to a surgical rescue after systemic treatment. Keywords: Paraganglioma, Lanreotide, SDHB, Metastatic

Lung metastasis is the major cause of death in osteosarcoma patients. However, molecular mechanisms underlying this metastasis remain poorly understood. To identify key molecules related with pulmonary metastasis of pediatric osteosarcomas, we analyzed high‐throughput miRNA expression in a cohort of 11 primary tumors and 15 lung metastases. Results were further validated with an independent cohort of 10 primary tumors and 6 metastases. In parallel, we performed immunohistochemical analysis of activated signaling pathways in 36 primary osteosarcomas. Only phospho‐AKT associated with lower overall survival in primary tumors, supporting its role in osteosarcoma progression. CTNNB1 expression also associated with lower overall survival but was not strong enough to be considered an independent variable. Interestingly, miR‐200c was overexpressed in lung metastases, implicating an inhibitory feed‐back loop to PI3K‐AKT. Moreover, transfection of miR200c‐mimic in U2‐OS cells reduced phospho‐AKT levels but increased cellular migration and proliferation. Notably, miR‐200c expression strongly correlated with miR‐141 and with the osteogenic inhibitor miR‐375, all implicated in epithelial to mesenchymal transition. These findings contrast epithelial tumors where reduced miR‐200c expression promotes metastasis. Indeed, we noted that osteosarcoma cells in the lung also expressed the epithelial marker CDH1, revealing a change in their mesenchymal phenotype. We propose that miR‐200c upregulation occurs late in osteosarcoma progression to provide cells with an epithelial phenotype that facilitates their integration in the metastatic lung niche. Thus, our findings identify phospho‐AKT in the primary tumor and miR‐200c later during tumor progression as prognostic molecules and potential therapeutic targets to prevent progression and metastasis of pediatric osteosarcomas.

Metastatic pheochromocytoma and paraganglioma (mPHEO/PGL) are frequently associated with succinate dehydrogenase B ( SDHB ) mutations. Cyclophosphamide-dacarbazine-vincristine (CVD) regimen is recommended as standard chemotherapy for advanced mPHEO/PGL. There is limited evidence to support the role of metronomic schemes (MS) of chemotherapy in mPHEO/PGL treatment. We report 2 patients with SDHB -related mPGL who received a regimen consisting of MS temozolomide (TMZ) and high-dose lanreotide after progression on both CVD chemotherapy and high-dose lanreotide. Molecular profiling of the tumor tissue from both patients revealed hypermethylation of the O6-methylguanine-DNA-methyltransferase ( MGMT ) promoter. In one patient, progression-free survival was 13 months and the second patient remained under treatment after 27 months of stabilization of metabolic response of his disease. Treatment was well tolerated, and adverse effects were virtually absent. A modification in the scheme of TMZ from standard schemes to MS is safe and feasible and can be considered in patients with progressive mPHEO/PGL refractory to dacarbazine in standard doses.

Whole-body 123I-Metaiodobenzylguanidine (mIBG) scintigraphy is used as the primary image modality in neuroblastoma detection. It is the most sensitive and specific method for staging and response evaluation. Validated semi-quantitative scoring methods with low interobserver variability and high reproducibility have shown to be indispensable for the evaluation of response to therapy. However, low resolution, noise and acquisition difficulties, specially in children, make low definition scans. These facts increase observer dependent interpretations that limit assessment and complicate to put a scoring method successfully into practice. It is essential to have an objective and reliable measure of response to test the activity of therapies. In this paper we propose the use of a quantitative observer-independent measurement of the strength of uptake to be used as an additional tool for assisting the International Society of Paediatric Oncology Europe Neuroblastoma Group (SIOPEN) semi-quantitative scoring method. This is the scoring method recommended by the SIOPEN Nuclear Medicine and Physics Committee, in collaborative work with the Children’s Oncology Group, as the standard one for acquiring and reporting diagnostic paediatric mIBG scans across Europe. Our proposed method is based on the ratio between the amount of specific uptake at tumours and the amount of non-specific uptake at SIOPEN anatomical sectors which has shown to be constant in all the scans of the patients.

Neuroblastoma (NB) is a common malignancy in children but rarely occurs during adolescence or adulthood. This subgroup is characterized by an indolent disease course, almost uniformly fatal, yet little is known about the biologic characteristics. The aim of this study was to identify differential features regarding DNA copy number alterations, α-thalassemia/mental retardation syndrome X-linked (ATRX) protein expression, and the presence of tumor-associated inflammatory cells. Thirty-one NB patients older than 10 years who were included in the Spanish NB Registry were considered for the current study; seven young and middle-aged adult patients (range 18-60 years) formed part of the cohort. We performed single nucleotide polymorphism arrays, immunohistochemistry for immune markers (CD4, CD8, CD20, CD11b, CD11c, and CD68), and ATRX protein expression. Assorted genetic profiles were found with a predominant presence of a segmental chromosome aberration (SCA) profile. Preadolescent and adolescent NB tumors showed a higher number of SCA, including 17q gain and 11q deletion. There was also a marked infiltration of immune cells, mainly high and heterogeneous, in young and middle-aged adult tumors. ATRX negative expression was present in the tumors. The characteristics of preadolescent, adolescent, young adult, and middle-aged adult NB tumors are different, not only from childhood NB tumors but also from each other. Similar examinations of a larger number of such tumor tissues from cooperative groups should lead to a better older age–dependent tumor pattern and to innovative, individual risk-adapted therapeutic approaches for these patients.

Actualmente la intervención e investigación en psicooncología pediátrica se dirige hacia la evaluación de las consecuencias de la enfermedad y los efectos secundarios de los tratamientos, y a los factores predictivos tanto de desajustes como de aspectos adaptativos a la enfermedad del paciente y de su familia. Las tasas de curación alcanzadas en la actualidad, nos permiten contar con un número considerable de supervivientes de cáncer infantil, susceptibles de ser evaluados y poder determinar así las secuelas a largo plazo de la enfermedad y sus procedimientos terapéuticos. Además de incrementar considerablemente la supervivencia, también se ha mejorado la calidad de vida de los niños, mediante el tratamiento de soporte que amortigua notablemente los efectos secundarios de los tratamientos y su toxicidad, permitiendo de este modo, junto con la intervención temprana de los equipos multidisciplinares, que el niño mantenga continuidad con sus actividades habituales, aún estando en el periodo de tratamiento. Durante la última década, diversos estudios ponen de manifiesto la ausencia de diferencias significativas entre niños enfermos oncológicos, en relación a la población de niños sanos, en cuanto al funcionamiento psicosocial se refiere. No obstante, los pacientes afectos de tumores cerebrales y leucemias u otros tumores que han recibido quimioterapia intratecal y/o irradiación cráneo-espinal, constituyen un grupo de riesgo que requiere de una evaluación y un tratamiento específico.

Opsoclonus-ataxia, also called “dancing eye syndrome,” is a serious neurologic condition that is often a paraneoplastic manifestation of occult neuroblastoma in early childhood. Although survival is high with anti-tumoral treatment and immunosuppressive therapy, outcome generally includes significant developmental and behavioral sequelae. We report a case diagnosed at nine month of age, treated in our Unit and refered for a multidisciplinary neuropsychological rehabilitation when she was 4 year old.

Among the last years the survivor’s number of childhood cancer has increased considerably, this has allowed to know the consequences resulting from the disease and its treatments. Several studies have prooved how the involvement of white and gray matter radiotherapy and chemotherapy, and tumor location, lead to various cognitive and behavioral sequelae in these children. The aim of this paper seeks to highlight the instruments and procedures used in the neuropsychological examination of children. Because deficits in children may not appear until several years, that increases the need for extensive neuropsychological studies and monitoring that reveal these consequences in short, medium and long term.

Las secuelas psicológicas más frecuentes de los pacientes pediátricos que han sobrevivido a la enfermedad, se refieren a cuadros depresivos, resultado de un bajo sentido de la competencia personal y de las dificultades de relación social, así como distintos tipos de trastornos de ansiedad como hipocondriasis, fobia social o estrés post-traumático. Estos déficits, se cronifican o consolidan al llegar a la edad adulta, teniendo serias implicaciones en la integración social y laboral de los supervivientes, siendo también consecuencia de las disfunciones físicas secundarias a la toxicidad producida por los tratamientos, o a la propia enfermedad. Por ello se plantea la necesidad de realizar estudios longitudinales que nos permitan detectar y tratar precozmente tales alteraciones psicopatológicas y funcionales, a fin de contribuir a su “Curación Global” y a su integración socio-laboral de manera satisfactoria. En este sentido, en este trabajo pretendemos justificar la necesidad de la creación de una consulta de seguimiento para supervivientes de cancer infantil, en la Unidad de Oncología Pediátrica del H.I. La Fe, con el objetivo de conocer las consecuencias de los tratamientos en nuestra población y desarrollar las vías clínicas oportunas para resolverlos.

Los avances en la medicina de las últimas décadas han permitido el aumento del número de supervivientes en oncología. La mayor supervivencia ha hecho que sean visibles secuelas, de distinto grado, a corto y largo plazo por la enfermedad y/o tratamientos. Recientes estudios de imagen muestran daño cerebral (afectación de sustancia blanca y gris) tanto por quimio como por radioterapia. La patología, tratamientos, edad, sexo… modulan el daño cerebral y sus secuelas. Junto con los déficit neuropsicológicos, ampliamente descritos, son frecuentes los problemas motores, actividades de la vida diaria, que condicionan su posterior adaptación escolar, laboral y social. Proponemos la atención y seguimiento interdisciplinar de especialistas en daño cerebral para algunos casos con secuelas más acusadas. La interacción de distintas disciplinas (neuropsicología, neuropediatría, terapia fa miliar, fisioterapia, terapia ocupacional, logopedia…) en estos equipos puede mejorar la calidad de vida de los pacientes y sus familias.

Objective. The aim of this paper is to understand the neuropsychological long-term effects of childhood cancer and its treatments. We include a proposal for cognitive rehabilitation. Method. Method consists of a systematic review of scientific literature results on chemo- and radiotherapy effects on CNS plus cognitive and behavioural functions detected through neuroimage studies as calcifications and white matter changes. We also present a neuropsychological assessment protocol exemplified with a common diagnosis showing generalized impairment. Moreover, we propose a rehabilitation program based on Attention Process Training (APT) by Mateer & Sohlberg. Results. Cranial radiotherapy and methotrexate produce generalized impairment reflected in neuropsychological deficits: IQ, attention, memory, motor and academic skills. Conclussions. Treatment development implies a reduction in sequelae. Nevertheless, cognitive and behavioral problems are frequent in CNS tumors and leukemias. Periodic neuropsychologic assessment and recent white matter models help us to understand these long-term effects. Hence, this evaluation is basic to diagnose more accurately those deficits avoiding false attributions and inadequate expectations. We emphasize the need of a follow up unit working in on interdisciplinary manner to promote a better quality of life in children with cancer.

BACKGROUND:Neuroblastma cell lines contain a side-population of cells which express stemness markers. These stem-like cells may represent the potential underlying mechanism for resistance to conventional therapy and recurrence of neuroblastoma in patients. METHODOLOGY/PRINCIPAL FINDINGS:To develop novel strategies for targeting the side-population of neurobastomas, we analyzed the effects of 13-cis-retinoic acid (RA) combined with the proteasome inhibitor MG132. The short-term action of the treatment was compared with effects after a 5-day recovery period during which both chemicals were withdrawn. RA induced growth arrest and differentiation of SH-SY5Y and SK-N-BE(2) neuroblastoma cell lines. Inhibition of the proteasome caused apoptosis in both cell lines, thus, revealing the critical role of this pathway in the regulated degradation of proteins involved in neuroblastoma proliferation and survival. The combination of RA with MG132 induced apoptosis in a dose-dependent manner, in addition to promoting G2/M arrest in treated cultures. Interestingly, expression of stem cell markers such as Nestin, Sox2, and Oct4 were reduced after the recovery period of combined treatment as compared with untreated cells or treated cells with either compound alone. Consistent with this, neurosphere formation was significantly impaired by the combined treatment of RA and MG132. CONCLUSIONS:Given that stem-like cells are associated with resistant to conventional therapy and are thought to be responsible for relapse, our results suggest that dual therapy of RA and proteasome inhibitor might be beneficial for targeting the side-population of cells associated residual disease in high-risk neuroblastoma.