Search

Viviane Sonaglio,1 Ana C de Carvalho,2 Silvia R C Toledo,3,4 Carolina Salinas-Souza,3,4 André L Carvalho,5 Antonio S Petrilli,3 Beatriz de Camargo,6 André L Vettore21Pediatrics Department, A C Camargo Hospital, São Paulo, Brazil; 2Biological Science Department, Federal University of São Paulo, Diadema, Brazil; 3Department of Pediatrics, Pediatric Oncology Institute, GRAACC/Federal University of São Paulo, São Paulo, Brazil; 4Department of Morphology and Genetics, Federal University of São Paulo, São Paulo, Brazil; 5Department of Head and Neck Surgery, PIO XII Foundation, Barretos Cancer Hospital, Barretos, São Paulo, Brazil; 6Research Program Pediatric Oncology Program, CPNq, Instituto Nacional do Cancer, Rio de Janeiro, BrazilAbstract: Osteosarcoma (OS) is the eighth most common form of childhood and adolescence cancer. Approximately 10%–20% of patients present metastatic disease at diagnosis and the 5-year overall survival remains around 70% for nonmetastatic patients and around 30% for metastatic patients. Metastatic disease at diagnosis and the necrosis grade induced by preoperative treatment are the only well-established prognostic factors for osteosarcoma. The DNA aberrant methylation is a frequent epigenetic alteration in humans and has been described as a molecular marker in different tumor types. This study evaluated the DNA aberrant methylation status of 18 genes in 34 OS samples without previous chemotherapy treatment and in four normal bone specimens and compared the methylation profile with clinicopathological characteristics of the patients. We were able to define a three-gene panel (AIM1, p14ARF, and ESR1) in which methylation was correlated with OS cases. The hypermethylation of p14ARF showed a significant association with the absence of metastases at diagnoses, while ESR1 hypermethylation was marginally associated with worse overall survival. This study demonstrated that aberrant promoter methylation is a common event in OS and provides evidence that p14ARF and ESR1 hypermethylation could be useful as a prognostic indicator for this disease.Keywords: DNA methylation, ESR1, hypermethylation, osteosarcoma, p14ARF

Abstract Background Childhood cancer differs from most common adult cancers, suggesting a distinct aetiology for some types of childhood cancer. Our objective in this study was to test the difference in incidence rates of 4 non-CNS embryonic tumours and their correlation with socioeconomic status (SES) in Brazil. Methods Data was obtained from 13 Brazilian population-based cancer registries (PBCRs) of neuroblastoma (NB), Wilms'tumour (WT), retinoblastoma (RB), and hepatoblastoma (HB). Incidence rates by tumour type, age, and gender were calculated per one million children. Correlations between social exclusion index (SEI) as an indicator of socioeconomic status (SES) and incidence rates was investigated using the Spearman's test. Results WT, RB, and HB presented with the highest age-adjusted incidence rates (AAIRs) in 1 to 4 year old of both genders, whereas NB presented the highest AAIR in ≤11 month-olds. However, differences in the incidence rates among PBCRs were observed. Higher incidence rates were found for WT and RB, whereas lower incidence rates were observed for NB. Higher SEI was correlated with higher incidences of NB (0.731; p = 0.0117), whereas no SEI correlation was observed between incidence rates for WT, RB, and HB. In two Brazilian cities, the incidence rates of NB and RB were directly correlated with SEI; NB had the highest incidence rates (14.2, 95% CI, 8.6-19.7), and RB the lowest (3.5, 95% CI, 0.7-6.3) in Curitiba (SEI, 0.730). In Natal (SEI, 0.595), we observed just the opposite; the highest incidence rate was for RB and the lowest was for NB (4.6, 95% CI, 0.1-9.1). Conclusion Regional variations of SES and the incidence of embryonal tumours were observed, particularly incidence rates for NB and RB. Further studies are necessary to investigate risk factors for embryonic tumours in Brazil.

The recent International Symposium on Molecular epidemiology in Embryonal Tumours and Paediatric Leukaemia was held on 4-6 March 2008 in Rio de Janeiro, Brazil. It proved a very productive meeting in which studies relating to genetics, therapeutical trials, identification of risk factors in acute leukaemia neuroblastoma and Wilms' tumours were presented. Over 120 participants gathered for three days of fruitful discussions, including representatives of paediatrics, haematology, laboratory, epidemiology and pathology. Debates were held about strategies of applications of important biomarkers for clinical trials. Highlights of each of the scientific presentations are summarized below. [ABSTRACT FROM AUTHOR]

Background: Among patients with nephroblastoma, those with bilateral disease are a unique population where maximising tumour control must be balanced with preserving renal parenchyma., Methods: The SIOP 2001 protocol recommended surgery after neoadjuvant cycle(s) of Dactinomycin and Vincristine (AV) with response-adapted intensification, if needed. Adjuvant treatment was given based on the lesion with the worst histology., Results: Three hundred and twenty seven patients with stage V disease were evaluable: 174 had bilateral Wilms tumour (BWT), 101 unilateral WT and contralateral nephroblastomatosis (NB) and 52 bilateral nephroblastomatosis. In these three groups, the estimated 5y-EFS was 76.1%, 84.6%, and 74.9%, respectively. AV chemotherapy alone was the successful chemotherapy for 58.7% of all the patients and 65.6% of the non-metastatic patients. Among the 174 patients with BWT, 149 (88.2%) had at least one nephron-sparing surgery. Twenty of 61 bilateral stage I patients were treated with four-week AV postoperatively achieving 94.4% 5y-EFS. At last follow-up, 87% of patients had normal renal function., Conclusions: This study demonstrates that AV without anthracyclines is sufficient to achieve NSS and good survival in the majority of patients. For patients with bilateral stage I WT and intermediate risk histology, only four weeks adjuvant AV seems to be sufficient., Clinical Trial Registration: NCT00047138., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: The COVID-19 pandemic had global catastrophic effects on the management of non-communicable diseases including paediatric cancers. Restrictions during the start of 2020 complicated timely referrals of patients to specialized centres. We aimed to evaluate the pandemic's impact on the number of new diagnoses, disease characteristics and management delay for paediatric renal tumour patients included in the SIOP-RTSG-UMBRELLA study, as compared with data from a historical SIOP-RTSG trial (2005-2009)., Methods: The number of intensive care admissions, population mobility rates and national lockdown periods/restrictions were used as proxies of the pandemic's severity and impact on societies. Clinical and tumour data were extracted from the SIOP-RTSG-UMBRELLA study and from historical SIOP-RTSG trials., Results: During the first lockdown in Europe, the number of newly diagnosed patients decreased following restrictions and population immobilisation. Additionally, there was a higher proportion of advanced disease (37% vs. 17% before and after COVID-9, p < 0.001) and larger median tumour volume (559 cm 3 vs. 328 and 434 cm 3 before and after, p < 0.0001). Also in Brazil, the proportion of advanced disease was higher during the national decrease in mobilisation and start of restrictions (50% and 24% vs. 11% and 18% before and after, p < 0.01). Tumour volume in Brazil was also higher during the first months of COVID-19 (599 cm 3 vs. 459 and 514 cm 3 ), although not significant (p = 0.17). We did not observe any delays in referral time nor in time to start treatment, even though COVID-19 restrictions may have caused children to reach care later., Conclusion: The COVID-19 pandemic briefly changed the tumour characteristics of children presenting with renal tumours. The longer-term impact on clinical outcomes will be kept under review., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: International comparisons of patient demographics, tumor characteristics, and survival can shed light on areas for health care system improvement. The International Society of Pediatric Oncology Wilms Tumor 2001 trial/study registered patients through national clinical study groups in Western Europe and Brazil. This retrospective post hoc analysis of the International Society of Pediatric Oncology Wilms Tumor 2001 database aims to make visible and suggest reasons for any variations in outcomes., Methods: All patients with unilateral Wilms tumor (WT), age > 6 months, treated with preoperative chemotherapy as per protocol, and registered between 2001 and 2011 were eligible. Countries were grouped to give comparable case numbers and geographical representation. Cox univariable and multivariable (MVA) statistics were applied, with the German collaborative group (Gesellschaft für Pädiatrische Onkologie und Hämatologie-Austria, Germany, and Switzerland) as reference for hazard ratios for event-free survival (EFS) and overall survival (OS)., Results: A total of 3,176 eligible patients were registered from 24 countries assigned into six groups. Age and histologic risk group distribution were similar across all groupings. The distribution of WT stage varied by country grouping, with 14.9% (range, 11.1%-18.2%) metastatic at diagnosis. Median follow-up was 78.9 months. For localized WT, 5-year EFS varied from 80% (Brazilian group) to 91% (French group; P < .0001), retaining significance only for Brazil in MVA ( P = .001). Five-year OS varied from 89% (Brazilian group) to 98% (French group; P < .0001). In MVA, only superior OS in France was significant ( P = .001). Five-year EFS/OS for stage IV did not vary significantly. High-risk histology and tumor volume at surgery were significantly associated with increased risk of death in MVA for metastatic disease., Conclusion: International benchmarking of survival rates from WT within a large trial/study database has demonstrated statistically significant differences. Clinical interpretation should take account of variation in tumor stage but also treatment factors., Competing Interests: Rhoikos FurtwänglerStock and Other Ownership Interests: Fresesnius Medical Care Daniel SaundersUncompensated Relationships: Children's Cancer and Leukaemia Group (UK)No other potential conflicts of interest were reported.

Pediatric cancer NMR-metabonomics might be a powerful tool to discover modified biochemical pathways in tumor development, improve cancer diagnosis, and, consequently, treatment. Wilms tumor (WT) is the most common kidney tumor in young children whose genetic and epigenetic abnormalities lead to cell metabolism alterations, but, so far, investigation of metabolic pathways in WT is scarce. We aimed to explore the high-resolution magic-angle spinning nuclear magnetic resonance (HR-MAS NMR) metabonomics of WT and normal kidney (NK) samples. For this study, 14 WT and 7 NK tissue samples were obtained from the same patients and analyzed. One-dimensional and two-dimensional HR-MAS NMR spectra were processed, and the one-dimensional NMR data were analyzed using chemometrics. Chemometrics enabled us to elucidate the most significant differences between the tumor and normal tissues and to discover intrinsic metabolite alterations in WT. The metabolic differences in WT tissues were revealed by a validated PLS-DA applied on HR-MAS T 2 -edited 1 H-NMR and were assigned to 16 metabolites, such as lipids, glucose, and branched-chain amino acids (BCAAs), among others. The WT compared to NK samples showed 13 metabolites with increased concentrations and 3 metabolites with decreased concentrations. The relative BCAA concentrations were decreased in the WT while lipids, lactate, and glutamine/glutamate showed increased levels. Sixteen tissue metabolites distinguish the analyzed WT samples and point to altered glycolysis, glutaminolysis, TCA cycle, and lipid and BCAA metabolism in WT. Significant variation in the concentrations of metabolites, such as glutamine/glutamate, lipids, lactate, and BCAAs, was observed in WT and opened up a perspective for their further study and clinical validation.

Non-coding RNAs are involved with maintenance and regulation of physiological mechanisms and are involved in pathological processes, such as cancer. Among the small ncRNAs, miRNAs are the most explored in tumorigenesis, metastasis development, and resistance to chemotherapy. These small molecules of ~ 22 nucleotides are modulated during early renal development, involved in the regulation of gene expression and Wilms' tumor progression. Wilms' tumors are embryonic tumors with few mutations and complex epigenetic dysregulation. In recent years, the small ncRNAs have been explored as potentially related both in physiological development and in the tumorigenesis of several types of cancer. Besides, genes regulated by miRNAs are related to biological pathways as PI3K, Wnt, TGF-β, and Hippo signaling pathways, among others, which may be involved with the underlying mechanisms of resistance to chemotherapy, and in this way, it has emerged as potential targets for cancer therapies, including for Wilms' tumors., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: Wilms tumour (WT) patients with a localised completely necrotic nephroblastoma after preoperative chemotherapy are a favourable outcome group. Since the introduction of the SIOP 2001 protocol, the SIOP- Renal Tumour Study Group (SIOP-RTSG) has omitted radiotherapy for such patients with low-risk, local stage III in an attempt to reduce treatment burden. However, for metastatic patients with local stage III, completely necrotic WT, the recommendations led to ambiguous use. The purpose of this descriptive study is to demonstrate the outcomes of patients with metastatic, completely necrotic and local stage III WT in relation to the application of radiotherapy or not., Methods and Materials: all metastatic patients with local stage III, completely necrotic WT after 6 weeks of preoperative chemotherapy who were registered in the SIOP 2001 study were included in this analysis. The pattern of recurrence according to the usage of radiation treatment and 5 year event-free survival (EFS) and overall survival (OS) was analysed., Results: seven hundred and three metastatic WT patients were registered in the SIOP 2001 database. Of them, 47 patients had a completely necrotic, local stage III WT: 45 lung metastases (11 combined localisations), 1 liver/peritoneal, and 1 tumour thrombus in the renal vein and the inferior vena cava with bilateral pulmonary arterial embolism. Abdominal radiotherapy was administered in 29 patients (62%; 29 flank/abdominal irradiation and 9 combined with lung irradiation). Eighteen patients did not receive radiotherapy. Median follow-up was 6.6 years (range 1-151 months). Two of the 47 patients (4%) developed disease recurrence in the lung (one combined with abdominal relapse) and eventually died of the disease. Both patients had received abdominal radiotherapy, one of them combined with lung irradiation. Five-year EFS and OS were 95% and 95%, respectively., Conclusions: the outcome of patients with stage IV, local stage III, completely necrotic Wilms tumours is excellent. Our results suggest that abdominal irradiation in this patient category may not be of added value in first-line treatment, consistent with the current recommendation in the SIOP-RTSG 2016 UMBRELLA protocol.

Biological invasion is one of the main threats to native biodiversity. For a species to become invasive, it must be voluntarily or involuntarily introduced by humans into a nonnative habitat. Mammals were among first taxa to be introduced worldwide for game, meat, and labor, yet the number of species introduced in the Neotropics remains unknown. In this data set, we make available occurrence and abundance data on mammal species that (1) transposed a geographical barrier and (2) were voluntarily or involuntarily introduced by humans into the Neotropics. Our data set is composed of 73,738 historical and current georeferenced records on alien mammal species of which around 96% correspond to occurrence data on 77 species belonging to eight orders and 26 families. Data cover 26 continental countries in the Neotropics, ranging from Mexico and its frontier regions (southern Florida and coastal-central Florida in the southeast United States) to Argentina, Paraguay, Chile, and Uruguay, and the 13 countries of Caribbean islands. Our data set also includes neotropical species (e.g., Callithrix sp., Myocastor coypus, Nasua nasua) considered alien in particular areas of Neotropics. The most numerous species in terms of records are from Bos sp. (n = 37,782), Sus scrofa (n = 6,730), and Canis familiaris (n = 10,084); 17 species were represented by only one record (e.g., Syncerus caffer, Cervus timorensis, Cervus unicolor, Canis latrans). Primates have the highest number of species in the data set (n = 20 species), partly because of uncertainties regarding taxonomic identification of the genera Callithrix, which includes the species Callithrix aurita, Callithrix flaviceps, Callithrix geoffroyi, Callithrix jacchus, Callithrix kuhlii, Callithrix penicillata, and their hybrids. This unique data set will be a valuable source of information on invasion risk assessments, biodiversity redistribution and conservation-related research. There are no copyright restrictions. Please cite this data paper when using the data in publications. We also request that researchers and teachers inform us on how they are using the data., (© 2020 The Authors. Ecology © 2020 The Ecological Society of America.)

Mammalian carnivores are considered a key group in maintaining ecological health and can indicate potential ecological integrity in landscapes where they occur. Carnivores also hold high conservation value and their habitat requirements can guide management and conservation plans. The order Carnivora has 84 species from 8 families in the Neotropical region: Canidae; Felidae; Mephitidae; Mustelidae; Otariidae; Phocidae; Procyonidae; and Ursidae. Herein, we include published and unpublished data on native terrestrial Neotropical carnivores (Canidae; Felidae; Mephitidae; Mustelidae; Procyonidae; and Ursidae). NEOTROPICAL CARNIVORES is a publicly available data set that includes 99,605 data entries from 35,511 unique georeferenced coordinates. Detection/non-detection and quantitative data were obtained from 1818 to 2018 by researchers, governmental agencies, non-governmental organizations, and private consultants. Data were collected using several methods including camera trapping, museum collections, roadkill, line transect, and opportunistic records. Literature (peer-reviewed and grey literature) from Portuguese, Spanish and English were incorporated in this compilation. Most of the data set consists of detection data entries (n = 79,343; 79.7%) but also includes non-detection data (n = 20,262; 20.3%). Of those, 43.3% also include count data (n = 43,151). The information available in NEOTROPICAL CARNIVORES will contribute to macroecological, ecological, and conservation questions in multiple spatio-temporal perspectives. As carnivores play key roles in trophic interactions, a better understanding of their distribution and habitat requirements are essential to establish conservation management plans and safeguard the future ecological health of Neotropical ecosystems. Our data paper, combined with other large-scale data sets, has great potential to clarify species distribution and related ecological processes within the Neotropics. There are no copyright restrictions and no restriction for using data from this data paper, as long as the data paper is cited as the source of the information used. We also request that users inform us of how they intend to use the data., (© 2020 The Authors. Ecology © 2020 The Ecological Society of America.)

Background: The increasing incidence of thyroid cancer has been described worldwide. Overdiagnosis, improved imaging, and increased environmental risk factors have contributed to the rising incidence. The objective of this study was to analyze the population incidence rate and trends during the period of 2000-2013 in children, adolescents and young adults (AYAs) in Brazil., Methods: Data were extracted from 11 population-based cancer registries (PBCRs) encompassing the five geographic regions of Brazil. Incidence rates per million in children (0-14) and AYAs (15-39) according to world population were analyzed according to sex, age, and type of carcinoma. Incidence trends were evaluated using joinpoint regression., Results: During 2000 to 2013, we identified 11,081 children and AYAs (0-39 years) with thyroid carcinoma in 11 PBCRs, with an age-adjusted incidence rate (AAIR) of 42 cases per million. Females had a higher AAIR of 66 cases per million versus 14 cases per million in males. Age-specific incidence rate (ASR) increased with age. Geographic variation was also observed; the Midwest and Southeast regions had the highest ASR in all age groups. The lowest ASR in all age groups was seen in the North region. Papillary subtype was the most common. Overall, the incidence rates in children and AYAs significantly increased from 0.2 in 2000 to 2.8 in 2013 and from 47.1 to 115.3, respectively, with an annual average percent change of 18.8 [8.1; 30.6] for children and 7.9 [CI 5.6; 10.3] for AYAs., Conclusions: Rates of thyroid cancer, particularly the papillary subtype, are steadily increasing in children and AYAs, especially among females. There are variations among geographic areas. This increased incidence is unlikely to be explained by screening, as children less than 14 years of age do not typically undergo medical surveillance. Environmental risk factors must be investigated., Competing Interests: The authors have declare no competing interests.

Objective: To identify delays in the health care system experienced by children and adolescents and young adults (AYA; aged 0-29 years) with osteosarcoma and Ewing sarcoma using information from the Brazilian hospital-based cancer registries., Methods: Patient data were extracted from 161 Brazilian hospital-based cancer registries between 2007 and 2011. Hospital, diagnosis, and treatment delays were analyzed in patients without a previous histopathological diagnosis. Referral, hospital, and health care delays were calculated for patients with a previous histopathological diagnosis. The time interval was measured in days., Results: There was no difference between genders in overall delays. All delays increased at older ages. Patients without a previous histopathological diagnosis had the longest hospital delay when compared to patients with a previous histopathological diagnosis before first contact with the cancer center. Patients with Ewing sarcoma had longer referral and health care delays than those with osteosarcoma who had a previous histopathological diagnosis before first contact with the cancer center. The North and Northeast regions had the longest diagnosis delay, while the Northeast and Southeast regions had the longest treatment delay., Conclusion: Health care delay among patients with a previous diagnosis was longer, and was probably associated with the time taken for to referral to cancer centers. Patients without a previous histopathological diagnosis had longer hospital delays, which could be associated with possible difficulties regarding demand and high-cost procedures. Despite limitations, this study helps provide initial knowledge about the healthcare pathway delays for patients with bone cancer inside several Brazilian hospitals., (Copyright © 2018 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.)

To identify underlying mechanisms involved with metastasis formation in Wilms tumors (WTs), we performed comprehensive DNA methylation and gene expression analyses of matched normal kidney (NK), WT blastemal component, and metastatic tissues (MT) from patients treated under SIOP 2001 protocol. A linear Bayesian framework model identified 497 differentially methylated positions (DMPs) between groups that discriminated NK from WT, but MT samples were divided in two groups. Accordingly, methylation variance grouped NK and three MT samples tightly together and all WT with four MT samples that showed high variability. WT were hypomethylated compared to NK, and MT had a hypermethylated pattern compared to both groups. The methylation patterns were in agreement with methylases and demethylases expression. Methylation data pointed to the existence of two groups of metastases. While hierarchical clustering analysis based on the expression of all 2569 differentially expressed genes (DEGs) discriminated WT and MT from all NK samples, the hierarchical clustering based on the expression of 44 genes with a differentially methylated region (DMR) located in their promoter region revealed two groups: one containing all NKs and three MTs and one containing all WT and four MTs. Methylation changes might be controlling expression of genes associated with WT progression. The 44 genes are candidates to be further explored as a signature for metastasis formation in WT.

Objective: Approximately 6% of all cancers arise in adolescents and young adults. Currently, the ward type best placed to treat this patient group remains controversial. The aim of this study was to evaluate exactly where adolescents and young adults with cancer are treated in Brazil., Methods: Data were extracted from 271 Brazilian hospital-based cancer registries (2007-2011), including all five national regions (North, Northeast, Midwest, South, and Southeast). Variables included gender, age, ethnicity, National Code of Health Establishment, hospital unit state, and region. Tumors were classified according to the World Health Organization classification for adolescents and young adults with cancer. Odds ratios with 95% confidence intervals were computed by unconditional logistic regression., Results: Most patients were managed on medical oncology wards, followed by pediatric oncology and then by non-specialist wards. Of patients aged 15-19 years, 49% were managed on pediatric wards; most of the older patients (96%; aged 20-24) were managed on adult wards. Patients were more likely to be seen in medical oncology wards as their age increased (OR=2.03 [1.98-2.09]), or if they were based in the South (OR=1.50 [1.29-1.73]). Conversely, bone tumors were less likely to be treated (decreased OR) on medical oncology wards, regardless of age, gender, and region., Conclusion: An elevated risk of treatment on medical oncology wards was observed for older patients and those treated in the South. Bone tumors were generally treated in pediatric oncology wards, while skin cancers were treated in medical oncology wards, regardless of age, gender, and region., (Published by Elsevier Editora Ltda.)

Background: Wilms tumor (WT) is a curable pediatric renal malignancy, but there is a need for new molecular biomarkers to improve relapse risk-directed therapy. Somatic alterations occur at relatively low frequencies whereas epigenetic changes at 11p15 are the most common aberration. We analyzed long interspersed element-1 (LINE-1) methylation levels in the blastemal component of WT and normal kidney samples to explore their prognostic significance., Results: WT samples presented a hypomethylated pattern at all five CpG sites compared to matched normal kidney samples; therefore, the averaged methylation levels of the five CpG sites were used for further analyses. WT presented a hypomethylation profile (median 65.0%, 47.4-73.2%) compared to normal kidney samples (median 71.8%, 51.5-77.5%; p  < 0.0001). No significant associations were found between LINE-1 methylation levels and clinical-pathological characteristics. We observed that LINE-1 methylation levels were lower in tumor samples from patients with relapse (median methylation 60.5%) compared to patients without relapse (median methylation 66.5%; p  = 0.0005), and a receiving operating characteristic curve analysis was applied to verify the ability of LINE-1 methylation levels to discriminate WT samples from these patients. Using a cut-off value of 62.71% for LINE-1 methylation levels, the area under the curve was 0.808, with a sensitivity of 76.5% and a specificity of 83.3%. Having identified differences in LINE-1 methylation between WT samples from patients with and without relapse in this cohort, we evaluated other prognostic factors using a logistic regression model. This analysis showed that in risk stratification, LINE-1 methylation level was an independent variable for relapse risk: the lower the methylation levels, the higher the risk of relapse. The logistic regression model indicated a relapse risk increase of 30% per decreased unit of methylation (odds ratio 1.30; 95% confidence interval 1.07-1.57)., Conclusion: Our results reinforce previous data showing a global hypomethylation profile in WT. LINE-1 methylation levels can be suggested as a marker of relapse after chemotherapy treatment in addition to risk classification, helping to guide new treatment approaches., Competing Interests: The protocol was approved by the Research Ethics Committee of INCA, number 131/13, and informed consent was signed by the children’s guardians.Consent for publication was obtained from all patients.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Objective: The population-based cancer registries (PBCR) and the Information System on Live Births in Brazil (Sistema de Informações sobre Nascidos Vivos [SINASC]) have information that enables the test for risk factors associated with leukemia at an early age. The aim of this study was to identify maternal and birth characteristics associated with early-age acute leukemia (EAL) in Brazil., Methods: A case-cohort study was performed using secondary dataset information of PBCR and SINASC. The risk association variables were grouped into (i) characteristics of the child at birth and (ii) characteristics of maternal exposure during pregnancy. The case-control ratio was 1:4. Linkage was performed using R software; odds ratio (OR) and 95% confidence interval (CI) were calculated by logistic regression models., Results: EAL was associated with maternal occupational exposure to chemicals (agricultural, chemical, and petrochemical industry; adjOR: 2.18, 95% CI: 1.16-4.10) and with birth defects (adjOR: 3.62, 95% CI: 1.19-11.00)., Conclusions: The results of this study, with the identification of EAL risk factors in population-based case-cohort study, strengthen the knowledge and improve databases, contributing to investigations on risk factors associated with childhood leukemia worldwide., (Copyright © 2017 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.)

Objective: To analyze the relationship between the development of childhood solid tumors and 1) birth weight and 2) fetal growth, using two Brazilian population-based data sets., Methods: A case-cohort study was performed using two population-based data sets, and linkage between the Live Birth Information System (Sistema de Informação sobre Nascidos Vivos, SINASC) and 14 population-based cancer registries (PBCRs) was established. Four controls per case were chosen randomly from the SINASC data set. Tumors were classified as central nervous system (CNS), non-CNS embryonal, and other tumors ("miscellaneous"). Adjustments were made for potential confounders (maternal age, mode of delivery, maternal education, birth order, gestational age, sex, and geographic region). Odds ratios (ORs) with 95% confidence intervals (CIs) were computed using unconditional logistic regression analysis., Results: In a trend analysis, for every 500 g of additional birth weight, the crude OR was 1.12 (CI: 1.00-1.24) and the adjusted OR was 1.02 (CI: 0.90-1.16) for all tumors. For every 1 000 g of additional birth weight, the crude OR was 1.25 (CI: 1.00-1.55) and the adjusted OR was 1.04 (CI: 0.82-1.34) for all tumors. Among children diagnosed after reaching the age of 3 years, in the miscellaneous tumor category, the OR was significantly increased for every additional 500 g and 1 000 g of birth weight., Conclusions: The study data suggested that increased birth weight was associated with childhood solid tumor development, especially among children more than 3 years old with "miscellaneous" tumors.

Background: Several maternal and birth characteristics have been reported to be associated with an increased risk of many childhood cancers. Our goal was to evaluate the risk of childhood embryonal solid tumors in relation to pre- and perinatal characteristics., Methods: A case-cohort study was performed using two population-based datasets, which were linked through R software. Tumors were classified as central nervous system (CNS) or non-CNS-embryonal (retinoblastoma, neuroblastoma, renal tumors, germ cell tumors, hepatoblastoma and soft tissue sarcoma). Children aged <6 years were selected. Adjustments were made for potential confounders. Odds ratios (OR) with 95% confidence intervals (CI) were computed by unconditional logistic regression analysis using SPSS., Results: Males, high maternal education level, and birth anomalies were independent risk factors. Among children diagnosed older than 24 months of age, cesarean section (CS) was a significant risk factor. Five-minute Apgar ≤8 was an independent risk factor for renal tumors. A decreasing risk with increasing birth order was observed for all tumor types except for retinoblastoma. Among children with neuroblastoma, the risk decreased with increasing birth order (OR = 0.82 (95% CI 0.67-1.01)). Children delivered by CS had a marginally significantly increased OR for all tumors except retinoblastoma. High maternal education level showed a significant increase in the odds for all tumors together, CNS tumors, and neuroblastoma., Conclusion: This evidence suggests that male gender, high maternal education level, and birth anomalies are risk factors for childhood tumors irrespective of the age at diagnosis. Cesarean section, birth order, and 5-minute Apgar score were risk factors for some tumor subtypes., Competing Interests: The authors have declared that no competing interests exist.

Wilms tumour (WT) is an embryonal kidney neoplasia for which very few driver genes have been identified. Here we identify DROSHA mutations in 12% of WT samples (26/222) using whole-exome sequencing and targeted sequencing of 10 microRNA (miRNA)-processing genes. A recurrent mutation (E1147K) affecting a metal-binding residue of the RNase IIIb domain is detected in 81% of the DROSHA-mutated tumours. In addition, we identify non-recurrent mutations in other genes of this pathway (DGCR8, DICER1, XPO5 and TARBP2). By assessing the miRNA expression pattern of the DROSHA-E1147K-mutated tumours and cell lines expressing this mutation, we determine that this variant leads to a predominant downregulation of a subset of miRNAs. We confirm that the downregulation occurs exclusively in mature miRNAs and not in primary miRNA transcripts, suggesting that the DROSHA E1147K mutation affects processing of primary miRNAs. Our data underscore the pivotal role of the miRNA biogenesis pathway in WT tumorigenesis, particularly the major miRNA-processing gene DROSHA.

Purpose: The risk of developing childhood leukemia has been associated with gene polymorphisms that decrease the activity of detoxifying metabolic enzymes and enzymes involved in systemic oxidative stress. We investigated the NQO1 and PON1 polymorphisms for associations with susceptibility to childhood leukemia., Methods: Samples from 1,027 Brazilian children (519 acute lymphoblastic leukemia, ALL; 107 acute myeloid leukemia, AML; 401 controls) were analyzed. TaqMAN real-time assays were used to determine the NQO1 rs1800566 (C609T), PON1 rs662 (Q192R), and PON1 rs854560 (L55M) frequencies. Logistic regression was used to evaluate the association of polymorphisms with cases and controls, with age and somatic fusion genes (MLL-r and ETV6-RUNX1) as covariables., Results: Children with at least one NQO1 variant allele were at lower risk for developing infant AML (odds ratio (OR) 0.26, 95 % confidence interval (CI) 0.10-0.68); no association was detected for ALL. PON1 rs854560 (L55M) was associated with an increased risk of developing childhood leukemia (LM + MM, OR 1.93, 95 % CI 1.32-2.81). The PON1 rs662 R192R genotype had a statistically significant decreased frequency in ALL (OR 0.64, 95 % CI 0.43-0.93). Infant ALL cases were more likely to harbor homozygous PON1 rs854560 alleles than controls (OR 1.72, 95 % CI 1.03-2.89); at least one M allele was associated with an increased risk of ALL in children older than 1 year (OR 1.99, 95 % CI 1.17-3.3)., Conclusions: The NQO1 rs1800566 (C609T), PON1 rs854560 (L55M), and PON1 rs662 (Q192R) polymorphisms modified risk depending on leukemia subtype (decreased in AML, increased and decreased in ALL, respectively), age strata, and variant genotype combinations.

Background: The majority of the currently used treatment protocols for osteosarcoma are based on a combination of doxorubicin, cisplatin, methotrexate (MTX) and/or ifosfamide, of which MTX seems to be one of the most active drugs. However, in the literature, this has not been unambiguously proven., Objectives: To compare the effectiveness of treatment including MTX with treatment without MTX for children and young adults (up to 21 years) with primary high-grade osteosarcoma., Search Strategy: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library, issue 4, 2010), MEDLINE (1966 to January 2011) and EMBASE (1980 to January 2011). In addition, we searched reference lists of relevant articles, conference proceedings and ongoing trials databases., Selection Criteria: Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing the effectiveness of treatment including MTX with treatment without MTX in the treatment of paediatric high-grade osteosarcoma., Data Collection and Analysis: Two reviewers independently performed the study selection. One reviewer performed the data extraction and quality assessment, which was checked by another reviewer., Main Results: We could not identify any studies in which the only difference between the treatment groups was the use of MTX.We did identify a RCT comparing MTX with cisplatin (n=30 children). The risk of bias in this study was difficult to assess due to a lack of reporting. Survival could not be evaluated, but no evidence of a significant difference in response rate between the treatment groups was identified (RR=0.44; 95% CI 0.17 to 1.13; P=0.09). A significant difference in the occurrence of toxicities in favour of MTX was identified, but with regard to quality of life treatment with cisplatin seemed to give better results.For other combinations of treatment including and not including MTX no studies were identified., Authors' Conclusions: Since no RCTs or CCTs in which only the use of MTX differed between the treatment groups were identified, no definitive conclusions can be made about the effects on antitumour efficacy, toxicities and quality of life of the addition of MTX to treatment of children and young adults with primary high-grade osteosarcoma. The same is true for combinations of treatment including and not including MTX other than treatment with MTX versus treatment with cisplatin. Only 1 RCT comparing MTX with cisplatin treatment was available and therefore, no definitive conclusions can be made about the effectiveness of these agents in children and young adults with primary high-grade osteosarcoma. Furthermore, this study was performed in a different treatment era. Nowadays single agent treatment of osteosarcoma is considered inadequate. Based on the currently available evidence, we are not able to give recommendations for the use of MTX in clinical practice. More high quality research is needed.

Background: Childhood cancer differs from most common adult cancers, suggesting a distinct aetiology for some types of childhood cancer. Our objective in this study was to test the difference in incidence rates of 4 non-CNS embryonic tumours and their correlation with socioeconomic status (SES) in Brazil., Methods: Data was obtained from 13 Brazilian population-based cancer registries (PBCRs) of neuroblastoma (NB), Wilms'tumour (WT), retinoblastoma (RB), and hepatoblastoma (HB). Incidence rates by tumour type, age, and gender were calculated per one million children. Correlations between social exclusion index (SEI) as an indicator of socioeconomic status (SES) and incidence rates was investigated using the Spearman's test., Results: WT, RB, and HB presented with the highest age-adjusted incidence rates (AAIRs) in 1 to 4 year old of both genders, whereas NB presented the highest AAIR in ≤11 month-olds. However, differences in the incidence rates among PBCRs were observed. Higher incidence rates were found for WT and RB, whereas lower incidence rates were observed for NB. Higher SEI was correlated with higher incidences of NB (0.731; p = 0.0117), whereas no SEI correlation was observed between incidence rates for WT, RB, and HB. In two Brazilian cities, the incidence rates of NB and RB were directly correlated with SEI; NB had the highest incidence rates (14.2, 95% CI, 8.6-19.7), and RB the lowest (3.5, 95% CI, 0.7-6.3) in Curitiba (SEI, 0.730). In Natal (SEI, 0.595), we observed just the opposite; the highest incidence rate was for RB and the lowest was for NB (4.6, 95% CI, 0.1-9.1)., Conclusion: Regional variations of SES and the incidence of embryonal tumours were observed, particularly incidence rates for NB and RB. Further studies are necessary to investigate risk factors for embryonic tumours in Brazil.

Hepatoblastoma comprises only 1% of all cancers in childhood. Because of its low frequency, a small number of prognostic factors are described in hepatoblastoma and most of them are related to resectability. Microarray studies showed a large number of underexpressed genes in hepatoblastoma. Because aberrant DNA methylation has been recognized as an alternative mechanism for tumor suppressor gene inactivation, this could be involved with gene downregulation in these tumors. Despite the rarity of hepatoblastoma, this study evaluated the methylation pattern of 25 genes in 20 paraffin-embedded tumor specimens and five non-neoplastic liver samples (normal control) by quantitative methylation-specific PCR (QMSP). The examination of the methylation profile of hepatoblastoma samples and normal liver specimens revealed a high tumor-specific DNA hypermethylation in the promoter regions of five genes (APC, CDH1, MT1G, RASSF1A, and SOCS1). Furthermore, MT1G hypermethylation showed a significant correlation with poor prognosis of patients with hepatoblastoma. This study represents the first quantitative evaluation of promoter hypermethylation in hepatoblastoma and demonstrated that aberrant methylation is a frequent event in this malignancy. Furthermore, our data provide evidence that MT1G hypermethylation may be useful as prognostic indicator for this disease and suggest that patients with hepatoblastoma may benefit from demethylating drug treatments.

Background: The majority of the currently used treatment protocols for osteosarcoma are based on a combination of doxorubicin, cisplatin, methotrexate (MTX) and/or ifosfamide, of which MTX seems to be one of the most active drugs. However, in the literature, this has not been unambiguously proven., Objectives: To compare the effectiveness of treatment including MTX with treatment without MTX for children and young adults (up to 21 years) with primary high-grade osteosarcoma., Search Strategy: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library, issue 3, 2008), MEDLINE (1966 to July 2008) and EMBASE (1980 to July 2008). In addition, we searched reference lists of relevant articles, conference proceedings and ongoing trials databases., Selection Criteria: Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing the effectiveness of treatment including MTX with treatment without MTX in the treatment of paediatric high-grade osteosarcoma., Data Collection and Analysis: Two reviewers independently performed the study selection. One reviewer performed the data extraction and quality assessment, which was checked by another reviewer., Main Results: We could not identify any studies in which the only difference between the treatment groups was the use of MTX.We did identify a RCT comparing MTX with cisplatin (n=30 children). The risk of bias in this study was difficult to assess due to a lack of reporting. Survival could not be evaluated, but no evidence of a significant difference in response rate between the treatment groups was identified (RR=0.44; 95% CI 0.17 to 1.13; P=0.09). A significant difference in the occurrence of toxicities in favour of MTX was identified, but with regard to quality of life treatment with cisplatin seemed to give better results.For other combinations of treatment including and not including MTX no studies were identified., Authors' Conclusions: Since no RCTs or CCTs in which only the use of MTX differed between the treatment groups were identified, no definitive conclusions can be made about the effects on antitumour efficacy, toxicities and quality of life of the addition of MTX to treatment of children and young adults with primary high-grade osteosarcoma. The same is true for combinations of treatment including and not including MTX other than treatment with MTX versus treatment with cisplatin. Only 1 RCT comparing MTX with cisplatin treatment was available and therefore, no definitive conclusions can be made about the effectiveness of these agents in children and young adults with primary high-grade osteosarcoma. Furthermore, this study was performed in a different treatment era. Nowadays single agent treatment of osteosarcoma is considered inadequate. Based on the currently available evidence, we are not able to give recommendations for the use of MTX in clinical practice. More high quality research is needed.

Introduction: There are few publications reporting health-related quality of life (HRQL) in developing nations. Most instruments measuring HRQL have been developed in English-speaking countries. These instruments need to be culturally adapted for use in non-English-speaking countries. The HUI2 and HUI3 are generic, preference-based systems for describing health status and HRQL. Developed in Canada, the systems have been translated into more than a dozen languages and used worldwide in hundreds of studies of clinical and general populations., Methods: The Brazilian-Portuguese translation of the HUI systems was supervised by senior HUInc staff having experience with both the HUI systems and translations. The process included two independent forward translations of the multi-attribute health status classification systems and related questionnaires, consensus between translators on a forward translation, back-translation by two independent translators of the forward translation, and review of the back-translations by original developers of the HUI. The final questionnaires were tested by surveying a sample of convenience of 50 patients recruited at the Centro de Tratamento e Pesquisa-Hospital do Cancer in São Paulo, Brazil., Results: Fifty patients were enrolled in the study. No assessor, patient or nurse or physician, reported problems answering the HUI questionnaires. No significant differences were found in mean overall HUI2 or HUI3 utility scores among types of assessors. Variability in scores are similar to those from other studies in Latin America and Canada., Conclusion: Test results provide preliminary evidence that the Brazilian-Portuguese translation is acceptable, understandable, reliable and valid for assessing health-status and HRQL among survivors of cancer in childhood in Brazil.

Objectives: To identify the main symptoms of retinoblastoma and to determine the mean time between symptom onset and diagnosis (lag time)., Patients and Methods: We carried out a retrospective analysis of the patients diagnosed with retinoblastoma between January 1991 and June 2000, at the Pediatric Department of the Hospital do Cancer, Sao Paulo, Brazil. Statistical analyses performed were: Student's t test, ANOVA, Tukey-HSD test (honest significant differences), Levene's test, multiple regression, ROC curve, logistic regression, Kaplan-Meier, and log rank., Results: 327 medical records (171 males) were reviewed. The mean age was 25 months. Localized disease was identified in 269 patients. The most frequent symptoms were leukocoria (79%), strabismus (10.7%) and tumor mass (3.4%). Mean lag time was 5.8 months. Patients older than 2 years old had longer lag time in comparison to infants (7.2 vs 4.7 months; p = 0.001). Lag time was longer among patients with strabismus (8.8 months) in comparison to patients with tumor mass (2.3 months) and leukocoria (5.6 months); p = 0.014. Patients with metastatic disease had longer lag time (10.6 months; p < 0.001). Lag time was influenced by advanced disease (OR = 3.25/CI = 1.61:6.55), metastatic disease (OR=3.52/ CI = 1.21:10.21) and strabismus (OR = 2.84/IC = 1.36:5.92). Five-year overall survival rates were higher among patients with localized disease (94.6% ) and among patients with lag time less than 6 months (91%), in comparison to patients with longer lag time (78%; p < 0.001)., Conclusion: Most frequent symptoms of retinoblastoma were leukocoria, strabismus and tumor mass. Mean lag time was 5.8 months. Strabismus and advanced disease were associated to longer lag time. Patients with advanced disease and lag time longer than 6 months had worse prognosis.

Wilms' tumor is one of the most common solid tumors in children and is an interesting model for understanding the pathogenesis of embryonal tumors. Cytokeratins are intracellular fibrous proteins present in tissue of epithelial origin. The immunoexpression of the pan-cytokeratin AE1AE3 was studied in paraffin-embedded tissue sections from 24 Wilms' tumors (12 with nephrogenic rests) and also tissue samples from 15 corresponding normal kidneys, to evaluate epithelial differentiation in the genesis of Wilms' tumor. We observed that the intensity of the expression of AE1AE3 in the epithelial component of Wilms' tumors directly correlated with the degree of maturity of the epithelial structures correspondent to the collecting ducts.