Newborn Screening for the Detection of the TP53 R337H Variant and Surveillance for Early Diagnosis of Pediatric Adrenocortical Tumors: Lessons Learned and Way Forward.

The incidence of pediatric adrenocortical tumors (ACT) is high in southern Brazil due to the founder TP53 R337H variant. Neonatal screening/surveillance (NSS) for this variant resulted in early ACT detection and improved outcomes. The medical records of children with ACT who did not participate in newborn screening (non-NSS) were reviewed (2012-2018). We compared known prognostic factors between the NSS and non-NSS cohorts and estimated surveillance and treatment costs. Of the 16 non-NSS children with ACT carrying the R337H variant, the disease stages I, II, III, and IV were observed in five, five, one, and five children, respectively. The tumor weight ranged from 22 to 608 g. The 11 NSS children with ACT all had disease stage I and were alive. The median tumor weight, age of diagnosis, and interval between symptoms and diagnosis were 21 g, 1.9 years, and two weeks, respectively, for the NSS cohort and 210 g, 5.2 years, and 15 weeks, respectively, for the non-NSS cohort. The estimated surveillance/screening cost per year of life saved is US$623/patient. NSS is critical for improving the outcome of pediatric ACT in this region. Hence, we strongly advocate for the inclusion of R337H in the state-mandated universal screening and surveillance.

Influence of different asparaginase formulations in the prognosis of children with acute lymphocytic leukaemia in Brazil: a multicentre, retrospective controlled study.

Our group recently showed that the (ASNase) formulation available in Brazil from 2017 to 2018 when used at the same dose and frequency as the formulation provided previously did not reach the activity considered therapeutic. Based on these, our goal was to assess the impact of these facts on the prognosis of children with ALL at different oncology centers. A multicentre retrospective observational study followed by a prospective follow-up. Patients aged >1 and <18 years in first-line treatment followed up at 10 referral centres, between 2014 and 2018 who received the formulation Leuginase® were identified (Group B). For each patient, the centre registered 2 patients who received ASNase in the presentation of Aginasa® exclusively (Group A). Data collection was registered using (Redcap® ). A total of 419 patients were included; 282 in Group A and 137 in B. Group A had a 3-year OS and EFS of 91·8% and 84·8% respectively, while Group B had a 3-year OS of 83·8% (P = 0·003) and EFS of 76·1% (P = 0·008). There was an impact on 3-year OS and EFS of children who received a formulation. This result highlights the importance of evaluating ASNase and monitoring its activity.

Penetrance of the TP53 R337H Mutation and Pediatric Adrenocortical Carcinoma Incidence Associated with Environmental Influences in a 12-Year Observational Cohort in Southern Brazil.

The TP53 R337H mutation is associated with increased incidence of pediatric adrenocortical tumor (ACT). The different environmental conditions where R337H carriers live have not been systematically analyzed. Here, the R337H frequencies, ACT incidences, and R337H penetrance for ACT were calculated using the 2006 cohort with 4165 R337H carriers living in Paraná state (PR) subregions. The effectiveness of a second surveillance for R337H probands selected from 42,438 tested newborns in PR (2016 cohort) was tested to detect early stage I tumor among educated families without periodical exams. Estimation of R337H frequencies and ACT incidence in Santa Catarina state (SC) used data from 50,115 tested newborns without surveillance, ACT cases from a SC hospital, and a public cancer registry. R337H carrier frequencies in the population were 0.245% (SC) and 0.306% (PR), and 87% and 95% in ACTs, respectively. The ACT incidence was calculated as ~6.4/million children younger than 10 years per year in PR (95% CI: 5.28; 7.65) and 4.15/million in SC (CI 95%: 2.95; 5.67). The ACT penetrance in PR for probands followed from birth to 12 years was 3.9%. R337H carriers living in an agricultural subregion (C1) had a lower risk of developing pediatric ACT than those living in industrial and large urban subregion (relative risk = 2.4). One small ACT (21g) without recurrence (1/112) was detected by the parents in the 2016 cohort. ACT incidence follows R337H frequency in each population, but remarkably environmental factors modify these rates.

Spatial trends in congenital malformations and stream water chemistry in Southern Brazil.

The incidence of variable congenital malformation (CM) among 399 municipalities in the state of Paraná, southern Brazil, suggests the etiological role of environmental factors. This study examined a) environmental concentrations of chlorine anions (Cl-) associated with organochlorines (OCs) and b) associations between these chemicals and agricultural output with CMs using a geographical information system. In one of the three years during the sampling period (2008, 2009 or 2010) Cl-, dichlorodiphenyltrichloroethane (p,p'-DDT), dichlorodiphenyldichloroethylene (p,p'-DDE), dichlorodiphenyldichloroethane (p,p'-DDD), and endosulfan levels were measured in 465 (465/736, 63%) catchment basins. Agricultural outputs for crops during 2006-2010 were also evaluated (t/km2). Further, CM kernel density for the 399 municipalities in Paraná during 2007-2014 was investigated. Cl- levels increased significantly in one of the three years (2008, 2009 or 2010) in western catchment basins, compared to 1996 (p < 0.0001). The municipalities were divided according to the obtained Cl- levels, where sub-region C2 (central-southern) < 1.8 mg/L ≤ sub-regions C1 (northern-western) and C3 (eastern-southern). We identified 8756 cases of CMs among 1,221,287 newborns (NB) in all sub-regions. C1 had higher DDT-DDE-DDD (p,p'-DDT + p,p'-DDE + p,p'-DDD) concentrations, agricultural output, and CM kernel density. C2 and C3 had minor agricultural outputs (per square kilometer) and CM densities. A 2.96 mg/L increase in Cl- between sub-regions C1 and C2 was co-localized with a 45% increase in CM density (spatial relative risk = 1.45, CI 95%: 1.36-1.55). C1 had the highest log likelihood ratios (p = 0.001) identified via SaTScan clustering analyses. Organochlorines and other toxic chlorinated chemicals may contribute to CMs in humans, and these chemicals are ultimately transformed and release Cl- in rivers. Higher Cl- levels were correlated significantly with higher agricultural productivity, DDT-DDE-DDD levels, and CMs in some parts of the northern and western sub-regions (C1).

The frequency of ßS-globin haplotypes in the state of Paraná, Brazil, and clinical manifestations of sickle cell anemia / Frequência dos haplótipos da globina ßS no estado do Paraná, Brasil, e manifestações clínicas em pacientes com anemia falciforme

ABSTRACT Introduction: Haplotypes in the β S-globin cluster are named according to their geographical origin as Central African Republic (CAR), Benin (BEN), Senegal (SEN), Cameroon (CAM) and Arab-Indian. They are considered to have influence on the diversity of clinical manifestations in sickle cell anemia (HbSS). Objective: To identify β S haplotypes and genotypes, their frequencies and their probable association with clinical presentation in patients with sickle cell anemia in the state of Paraná. Method: Longitudinal and descriptive study for the definition of haplotypes, and associative study for analysis of their influence on clinical severity. By polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), polymorphic regions of 100 HbSS patients were identified. The association of haplotypes with clinical manifestations was analyzed in a subset of 52 pediatric patients. Results: In the state of Paraná, haplotype frequencies were: CAR: 76% BEN: 17.5% SEN: 0.5%, CAM: 0.5% and Atypical (Atp): 5.5%. Genotype frequencies were: CAR/CAR: 62%; CAR/BEN: 20%; CAR/Atp: 6%; CAR/ SEN: 1%; CAR/CAM: 1%; BEN/BEN: 6%; BEN/Atp: 3%, Atp/Atp: 1%. The average percentage of fetal hemoglobin (HbF) in CAR/CAR and CAR/BEN patients was higher than in other studies. Clinical manifestations were not influenced by β S haplotypes. Dactylitis and splenic sequestration occurred more frequently in children below 3 years of age. Conclusion: In this study, no association was found between haplotypes and clinical manifestations, probably given the almost absolute predominance of CAR and BEN haplotypes. However, this fact alerts to the possible influence of other polymorphisms and miscegenation in the Brazilian population.

RESUMO Introdução: A variabilidade nas manifestações clínicas da anemia falciforme (HbSS) pode ser influenciada pelos haplótipos no grupamento da globina β S, nomeados de acordo com a origem geográfica: República Centro-Africana (CAR), Benin (BEN), Senegal (SEN) Camarões (CAM) e árabe-indiano. Objetivo: Identificar haplótipos e genótipos da globina β S, suas frequências e as possíveis associações com manifestações clínicas em pacientes com anemia falciforme no estado do Paraná. Método: Estudo longitudinal e descritivo na distribuição dos haplótipos e associativo na análise da influência destes sobre as manifestações clínicas. Identificaram-se as regiões polimórficas da globina β S de 100 pacientes HbSS pela técnica da polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). A associação dos haplótipos com as manifestações clínicas foi analisada em um subgrupo de 52 pacientes pediátricos. Resultados: As frequências dos haplótipos foram CAR: 76%; BEN: 17,5%; SEN: 0,5%; CAM: 0,5% e Atípico (Atp): 5,5%. Os genótipos foram CAR/CAR: 62%; CAR/BEN: 20%; CAR/Atp: 6%; CAR/SEN: 1%; CAR/CAM: 1%; BEN/BEN: 6%; BEN/Atp: 3% e Atp/Atp: 1%. A porcentagem média de hemoglobina fetal (HbF) dos pacientes CAR/CAR e CAR/BEN foi maior que em outros estudos. Os haplótipos da globina β S não tiveram influência nas manifestações clínicas. A dactilite e o sequestro esplênico ocorreram com mais frequência nas crianças abaixo de 3 anos de idade. Conclusão: Na população estudada, não foi possível identificar associação dos haplótipos com as manifestações clínicas. Esse fato pode ser decorrente do predomínio quase absoluto dos haplótipos CAR e BEN, de diferentes polimorfismos e da miscigenação da população brasileira.

Interações iniciais entre pais, mães e bebês de 0 a 3 anos: Revisão de literatura / Early interactions between fathers, mothers and babies from 0 to 3 years old: Review of the literature / Interacciones iniciales entre padres, madres y bebés de 0 a 3 años: Revisión de literatura

Resumo O estudo das interações iniciais dos bebês com seus cuidadores pode ser feito a partir da análise da responsividade parental. Com o objetivo de revisar os aspectos metodológicos e as tendências de análise das interações iniciais em estudos produzidos no Brasil, foram selecionados e analisados 110 artigos em bases eletrônicas de dados (Lilacs, SciELO, IndexPsi-Periódicos e Periódicos Capes). Os resultados apontaram para a predominância de estudos observacionais envolvendo as interações diádicas mãe-bebê. A coleta dos dados mais frequente foi por meio de combinação de instrumentos diretos e indiretos, e a análise se distribuiu de forma equivalente entre métodos qualitativos e quantitativos. Encontraram-se 55% de estudos sobre processos de desenvolvimento típico das interações e 45% de estudos com populações com risco biológico e social, abrindo questões para estudos futuros. Finalmente, sucedeu-se a análise dos fenômenos observados, levantando a discussão sobre os métodos de pesquisa na ciência psicológica.

Abstract The study of early interactions between babies and their caretakers can be performed from the analysis of parental responsiveness. Aiming to review the methodological aspects and trends in the analyses of early interactions from studies performed in Brazil, 110 articles were chosen from electronic databases (Lilacs, SciELO, IndexPsi-Periódicos and Periódicos Capes) and then they were fully analyzed. The results revealed a predominance of observational studies involving dyadic mother-baby interactions. The most frequently form of data collection combined direct and indirect methods; and the analysis was equivalently distributed between qualitative and quantitative methods. Of the studies found, 55% of the studies focused on the developmental processes that are typical of interactions, and 45% of the studies focused on processes among populations at biological and social risk, which brought up relevant questions for future studies. Finally, the analysis of interactions raises discussion of the research methods in the psychological science.

Resumen El estudio de las interacciones iniciales de los bebés con sus cuidadores puede hacerse desde el análisis de la responsividad parental. Para revisar los aspectos metodológicos y tendencias de análisis de las interacciones iniciales en los estudios producidos en Brasil, se seleccionaron y analizaron 110 artículos en bases de datos electrónicas (Lilacs, SciELO, IndexPsi-Periódicos y Periódicos Capes). Los resultados señalaron el predominio de los estudios observacionales que implican interacciones diádicas madre-niño. La recolección de datos más frecuente fue a través de una combinación de instrumentos directos e indirectos, y el análisis se distribuyó de forma equivalente entre métodos cualitativos y cuantitativos. Se han encontrado 55% de estudios sobre los procesos de desarrollo típico de las interacciones y 45% de estudios con poblaciones con riesgo biológico y social, abriendo preguntas para futuros estudios. Por último, se hizo el análisis de los fenómenos observados, levantando la discusión sobre los métodos de investigación en la ciencia psicológica.

Erythrocyte oxidative stress markers in children with sickle cell disease / Marcadores de estresse oxidativo em eritrócitos de crianças com doença falciforme

Abstract Objective To determine eight parameters of oxidative stress markers in erythrocytes from children with sickle cell disease and compare with the same parameters in erythrocytes from healthy children, since oxidative stress plays an important role in the pathophysiology of sickle cell disease and because this disease is a serious public health problem in many countries. Methods Blood samples were obtained from 45 children with sickle cell disease (21 males and 24 females with a mean age of 9 years; range: 3–13 years) and 280 blood samples were obtained from children without hemoglobinopathies (137 males and 143 females with a mean age of 10 years; range: 8–11 years), as a control group. All blood samples were analyzed for methemoglobin, reduced glutathione, thiobarbituric acid reactive substances, percentage of hemolysis, reactive oxygen species, and activity of the enzymes glucose 6-phosphate dehydrogenase, superoxide dismutase, and catalase. Data were analyzed using Student's t-test and were expressed as the mean ± standard deviation. A p-value of <0.05 was considered significant. Results Significant differences were observed between children with sickle cell disease and the control group for the parameters methemoglobin, thiobarbituric acid reactive substances, hemolysis, glucose 6-phosphate dehydrogenase activity, and reactive oxygen species, with higher levels in the patients than in the controls. Conclusions Oxidative stress parameters in children's erythrocytes were determined using simple laboratory methods with small volumes of blood; these biomarkers can be useful to evaluate disease progression and outcomes in patients.

Resumo Objetivo Determinar parâmetros de estresse oxidativo em eritrócitos de crianças com doença falciforme e compará-los com os mesmos parâmetros em eritrócitos de crianças saudáveis, pois o estresse oxidativo desempenha um importante papel na fisiopatologia da doença falciforme, considerada um sério problema de saúde pública em muitos países. Métodos Foram obtidas amostras de sangue de 45 crianças com doença falciforme (21 meninos e 24 meninas com média de 9 anos, variação de 3 a 13) e 280 amostras de sangue de crianças sem hemoglobinopatias (137 meninos e 143 meninas com média de 10 anos, variação de 8 a 11), como grupo controle. Em todas as amostras foram determinados meta-hemoglobina, glutationa reduzida, substâncias reativas ao ácido tiobarbitúrico, porcentagem de hemólise, espécies reativas de oxigênio e atividade das enzimas glucose6-fosfato desidrogenase, superóxido dismutase e catalase. Os dados foram analisados com o teste t de Student e foram expressos como média ± desvio padrão. Um valor de p < 0,05 foi considerado significativo. Resultados Foram observadas diferenças significativas entre as crianças com doença falciforme e o grupo controle para os parâmetros meta-hemoglobina, substâncias reativas ao ácido tiobarbitúrico, porcentagem de hemólise, espécies reativas de oxigênio e atividade da enzima glucose6-fosfato desidrogenase, com níveis aumentados nos pacientes. Conclusões Foi possível determinar parâmetros de estresse oxidativo em eritrócitos de crianças, com técnicas laboratoriais simples e pequenos volumes de sangue. Esses biomarcadores podem ser úteis na avaliação da progressão e dos resultados de tratamentos da doença.

Erythrocyte oxidative stress markers in children with sickle cell disease.

OBJECTIVE: To determine eight parameters of oxidative stress markers in erythrocytes from children with sickle cell disease and compare with the same parameters in erythrocytes from healthy children, since oxidative stress plays an important role in the pathophysiology of sickle cell disease and because this disease is a serious public health problem in many countries. METHODS: Blood samples were obtained from 45 children with sickle cell disease (21 males and 24 females with a mean age of 9 years; range: 3-13 years) and 280 blood samples were obtained from children without hemoglobinopathies (137 males and 143 females with a mean age of 10 years; range: 8-11 years), as a control group. All blood samples were analyzed for methemoglobin, reduced glutathione, thiobarbituric acid reactive substances, percentage of hemolysis, reactive oxygen species, and activity of the enzymes glucose 6-phosphate dehydrogenase, superoxide dismutase, and catalase. Data were analyzed using Student's t-test and were expressed as the mean±standard deviation. A p-value of <0.05 was considered significant. RESULTS: Significant differences were observed between children with sickle cell disease and the control group for the parameters methemoglobin, thiobarbituric acid reactive substances, hemolysis, glucose 6-phosphate dehydrogenase activity, and reactive oxygen species, with higher levels in the patients than in the controls. CONCLUSIONS: Oxidative stress parameters in children's erythrocytes were determined using simple laboratory methods with small volumes of blood; these biomarkers can be useful to evaluate disease progression and outcomes in patients.

Lowered Cisplatin Dose and No Bleomycin in the Treatment of Pediatric Germ Cell Tumors: Results of the GCT-99 Protocol From the Brazilian Germ Cell Pediatric Oncology Cooperative Group.

PURPOSE: We describe the results of a risk-adapted, response-based therapeutic approach from the Brazilian GCT-99 study on germ cell tumors. PATIENTS AND METHODS: From May 1999 to October 2009, 579 participants were enrolled in the Brazilian GCT-99 study. Treatment, defined as specific chemotherapy regimen and number of cycles, was allocated by means of risk-group assignment at diagnosis with consideration for stage and primary tumor site. Patients at low risk received no chemotherapy. Patients at intermediate risk (IR) with a good response (GR) received four cycles of platinum and etoposide (PE), for total doses of platinum 420 mg/m(2) and etoposide 2,040 mg/m(2). Patients at IR with a partial response (PR) received three cycles of PE plus three cycles of ifosfamide, vinblastine, and bleomycin. Patients at high risk (HR) with a GR received four cycles of PE and ifosfamide (PEI) at total doses of platinum 420 mg/m(2), etoposide 1,200 mg/m(2), and ifosfamide 30 g/m(2). Patients at HR with a PR received six cycles of PEI. RESULTS: The risk-group distribution was 213 LR, 138 IR, and 129 HR for 480 evaluable patients. Overall survival (OS) and event-free survival (EFS) rates at 10 years were, respectively, 90% and 88.6% in the IR-GR group (n = 126) and 74.1% and 74.1% in the IR-PR group (n = 12). Ten-year rates for the HR-GR group (n = 86) were an OS of 66.8% and an EFS of 62.5%. The HR-PR group (n = 43) had an OS of 74.8% and an EFS of 73.4%. In univariable and multivariable analysis, increased serum lactate dehydrogenase level and histology for a metastatic immature teratoma were prognostic of a worsened outcome. CONCLUSION: Reduction of therapy to two drugs did not compromise survival outcomes for patients in the IR-GR group, and escalation of therapy with PEI did not significantly improve OS and EFS in patients at HR.

Hemophagocytic Lymphohistiocytosis After Initiation of Chemotherapy for Bilateral Adrenal Neuroblastoma.

Hemophagocytic lymphohistiocytosis (HLH) is a rare and aggressive syndrome characterized by overactivation of the immune system. Although secondary HLH has been frequently associated with malignancies, this entity is rarely triggered by solid tumors, such as neuroblastomas. Herein, we describe a 14-month-old girl with a late diagnosis of bilateral adrenal neuroblastoma who developed HLH 6 days after the initiation of chemotherapy. On the basis of the large tumoral mass and the time of onset of her symptoms suggestive of HLH, we hypothesize that tumor cell destruction induced by chemotherapy drugs was the trigger to the development of hematophagocytic lymphohistiocytosis syndrome.

Medidas antropométricas para o acompanhamento do estado nutricional de crianças e adolescentes com câncer, o que utilizar na prática clínica? / Anthropometric measures to monitor the nutritional status of children with cancer, which should be used in the practical clinic? / Medidas antropométricas para el acompañamiento del estado nutricional de niños y adolescentes con cáncer, ¿que utilizar en la práctica clínica?

Introdução: A avaliação do estado nutricional de crianças e adolescentes com câncer é fundamental para a elaboração do plano de cuidados nutricionais adequado, entretanto as alterações da própria doença e do tratamento podem dificultar essa avaliação. Objetivo: Descrever quais são os métodos antropométricos mais utilizados na avaliação do estado nutricional de crianças e adolescentes com câncer. Método: Realizou-se revisão sistemática da literatura de publicações referentes à avaliação nutricional de crianças e adolescentes com câncer, dos últimos dez anos nas bases de dados MEDLINE, PubMed, Web of Science e LILACS . Resultados: Foram incluídos nove artigos, nos quais foram destacados a amostra, o objetivo e os métodos de avaliação nutricional utilizados. A avaliação de dados isolados da antropometria como peso e estatura de crianças e adolescentes com câncer não é suficiente, uma vez que essa população apresenta alteração da composição corporal. Conclusão: Na prática clínica, a utilização da circunferência do braço, circunferência muscular do braço e dobra cutânea tricipital é indicada para avaliação e acompanhamento da evolução do estado nutricional.

Introduction: The evaluation of nutritional status of children and adolescents with cancer is fundamental to the elaboration of adequate planning for nutritional monitoring, however alterations caused by the disease and/or the treatment may hamper this evaluation. Objective: Describing anthropometric methods mostly used at the evaluation of nutritional status of children and adolescents with cancer. Method: Systematic review of the literature of publications produced within the last ten years referring to nutritional evaluation of children and teenagers with cancer took place based on data from MEDLINE, PubMed, Web of Science and LILACS . Results: Nine articles were studied from which samples were highlighted, objectives and methods for nutritional evaluation were also used. The evaluation of isolated anthropometric data such as weight and height of children and teenagers with cancer is not sufficient once this specific population presents alteration on body composition. Conclusion: The utilization of arm muscle circumference, arm muscle area and triceps skinfold thickness measurements are proposed in order to evaluate and monitor nutritional status in practical clinics.

Introducción: La evaluación del estado nutricional de niños y adolescentes con cáncer es fundamental para la elaboración de un plan de cuidados nutricionales adecuados, sin embargo las alteraciones de la propia enfermedad y del tratamiento pueden dificultar esta evaluación. Objetivo: Describir cuales son los métodos antropométricos más utilizados en la evaluación del estado nutricional de niños y adolescentes con cáncer. Método: Se realizó revisión sistemática de la literatura y de publicaciones referentes a la evaluación nutricional de niños y adolescentes con cáncer, de los últimos diez años en las bases de datos MEDLINE, PubMed, Web of Science y LILACS . Resultados: Se incluyeron nueve artículos, en los cuales fueron destacados la muestra, objetivo y métodos de evaluación nutricional utilizados. La evaluación de datos aislados de la antropometría como peso y estatura de niños y adolescentes con cáncer no es suficiente, una vez que esta población presenta alteración de la composición corporal. Conclusión: En la práctica clínica, la utilización de la circunferencia del brazo, circunferencia muscular y dobla cutánea tricípite es indicada para evaluación y acompañamiento de la evolución del estado nutricional.

Evolução do estado nutricional na doença de Gaucher tipo I em tratamento com reposição enzimática - relato de dois casos / The evolution of nutritional status in type I Gaucher’s disease treated with enzyme replacement - two case histories

A doença de Gaucher é um erro do metabolismo enzimático que leva ao acúmulo de glicocerebrosídeo nas células, o que caracteriza os sinais e sintomas da doença. No momento do diagnóstico, além de outros sinais e sintomas, é observado retardo no crescimento em crianças e adolescentes. O tratamento é realizado por meio de reposição enzimática, que pode ocasionar ganho de peso no paciente pela diminuição do metabolismo energético. Descrição: dois irmãos com diagnóstico de doença de Gaucher tipo I foram avaliados antes de iniciarem a reposição enzimática e depois a cada 2 meses de tratamento, por um período de 6 meses. A composição corporal foi avaliada por impedância bioelétrica, que avaliou a quantidade de massa livre de gordura e massa de gordura; o consumo energético e a relação de macronutrientes foram avaliados por registro alimentar de 3 dias. Discussão: os dois pacientes apresentavam baixa estatura para idade ao diagnóstico e tiveram aumento de massa de gordura durante o tratamento, sendo que um paciente também apresentou aumento da massa livre de gordura. O consumo energético e a relação de macronutrientes mantiveram-se semelhantes durante todo o período de acompanhamento para ambos os pacientes...

Gaucher’s disease is flaw in enzyme metabolism that leads to the accumulation of glycocerebrosides in cells that characterizes the signs and symptoms of the condition. At the time of diagnosis, retarded growth, among other signs and symptoms, is observed in children and adolescents. The disease is treated by enzyme replacement, which may lead to weight gain in the patient, owing to the reduction in energy metabolism. Description: two brothers diagnosed with type I Gaucher’s disease were evaluated prior to commencing enzyme replacement therapy and subsequently after every two months of treatment, for a period of six months. Body composition was assessed using bioelectrical impedance, which measures the quantity of fat-free and fat mass; energy consumption and macronutrients were evaluated using a three-day food diary. Discussion: the two patients were of low height for age on diagnosis and had experienced an increase in fat mass during treatment, with one patient also presenting with an increase in fat free mass. Energy consumption and macronutrients remained fairly constant during the follow-up period in both patients...

Correlation between FLT3-ITD status and clinical, cellular and molecular profiles in promyelocytic acute leukemias.

Internal tandem duplications (ITD) of FLT3 gene occur in about a third of acute promyelocytic leukemias (APL). We investigated the patterns of blood count, surface antigen, expression, chromosome aberrations, PML-RARa isoform, gene expression profile (GEP) and survival in 34 APL patients according to FLT3-ITD status. 97% had a t(15;17) and all of them carried PML-RARa gene fusion, 8 (23.5%) had a FLT3-ITD mutation. Presence of ITD was associated with higher Hb and WBC levels, bcr3 isoform, CD34 expression, CD2 or CD2/CD34 expression. In a multivariate analysis, Hb>9.6g/dL and WBC≥20 × 10(9)/L were important factors for predicting ITD presence. GEP showed that FLT3-ITD carriers clustered separately, even when as few as 5 genes were considered. This study provides further evidence that FLT3-ITDs carriers constitute a biologically distinct group of APL patients.

Anemia falciforme: caracterização dos pacientes atendidos em um ambulatório de referência / Sickle cell anemia: characterization of the patients attended in a specialist outpatient center / Anemia falciforme: caracterización de los pacientes atendidos en un ambulatorio de referencia

Pesquisa de abordagem quantitativa que objetivou descrever perfil clínico, social e demográfico de pacientes com anemia falciforme atendidos em ambulatório de referência para Hematologia Pediátrica, em Curitiba/Paraná. Buscaram-se, de 1 a 19 de outubro de 2012, todos os prontuários de hemoglobinopatas do ambulatório e foram identificados 58 que atendiam aos critérios de inclusão. Dados de anamneses e exames clínicos, desde o primeiro atendimento até a data da coleta, foram organizados em categorias. Com predomínio (76%) de crianças (1 a 12 anos), procedentes de 14 regionais de saúde do estado (70,5%), diagnosticadas no primeiro ano de vida (80%), acompanhados há três anos ou mais (86,2%), com sinais clínicos de palidez cutânea (94,8%) e febre (93,1%), e como complicação principal a crise álgica (70,7%). Os resultados podem subsidiar o planejamento e ajustes no cuidado ao paciente com anemia falciforme e seus familiares neste serviço ambulatorial e também em outros semelhantes.

This qualitative research aimed to describe the clinical, social and demographic profile of patients with sickle cell anemia attended in a specialist outpatient center for Pediatric Hematology in Curitiba, Paraná. Between the 1st and 19th of October 2012, all the medical records of persons with hemoglobinopathies in the outpatient center were sought; 58 persons were identified who met the inclusion criteria. Data from case histories and clinical tests, from the first attendance up to the date of collection, were organized in categories. There was a predominance (76%) of children (1 to 12 years old), originating from 14 health regions in the state (70.5%), diagnosed in the first year of life (80%), monitored for three years or more (86.2%), with clinical signs of skin paleness (94.8%) and fever (93.1%), with pain crisis as the main complication (70.7%). The results may support planning and operations in the care of the patient with sickle cell anemia and her family members in this outpatient service and also in other similar services.

Investigación de abordaje cuantitativo cuya finalidad fue describir perfil clínico, social y demográfico de pacientes con anemia falciforme atendidos en ambulatorio de referencia para Hematología Pediátrica, en Curitiba/Paraná. Fueron investigados, de 1 a 19 de octubre de 2012, todos los prontuarios de hemoglobinopatas del ambulatorio e identificados 58 que atendían a los criterios de inclusión. Fueron organizados en categorías los datos de anamnesis y exámenes clínicos desde el primer atendimiento hasta la fecha en que fueron obtenidos. Con predominio (76%) de niños (1 a 12 años), procedentes de 14 regionales de salud del estado (70,5%), diagnosticados en el primer año de vida (80%), acompañados por tres años o más (86,2%), con señales clínicos de palidez cutánea (94,8%) y fiebre (93,1%), y como complicación principal la crisis de dolor intenso (70,7%). Los resultados pueden subsidiar el planeamiento y ajustes en el cuidado al paciente con anemia falciforme y sus familiares en este servicio ambulatorial, así como en otros semejantes.

Cytomorphometric and cytomorphologic analysis of oral mucosa in children with sickle cell anemia.

BACKGROUND: Sickle cell anemia (SCA) is an autosomal recessive genetic disorder, characterized by chronic hemolytic anemia, episodic painful crises, and pathologic involvement of many organs, consequence of vaso occlusive phenomenon and vasculopathy. Several forms of the chronic anemia, consequence of hemolysis, can be associated with oral epithelial cells changes. Exfoliative cytology can be used to detect real changes in the oral mucosa in SCA. AIMS: To evaluate morphometric and morphological changes in oral epithelial cells by exfoliative cytology in children with SCA. MATERIALS AND METHODS: Oral smears were collected from clinically normal-appearing mucosa by liquid-based exfoliative cytology in 20 SCA children (SCA group) and 20 healthy children (C group), matched for age and gender. The slides were prepared and stained by the Papanicolaou technique. Cell morphology and cellularity were analyzed and compared by Chi-square test (P < 0.05). Images of 50 cells per slide were captured and the nuclear area (NA) and cytoplasmic area (CA) were analyzed using an image analysis system. The nucleus-to-cytoplasmic area ratio (NA/CA) was calculated. To compare the means of groups SCA and C, the Student's t-test (P < 0.05) was applied to NA and CA; test non-parametric Mann Whitney U (P < 0.05) was used to compare NA/CA. RESULTS: MEAN VALUES FOR SCA AND C GROUPS WERE: NA (69.38 and 59.63 µm²; P = 0.01); CA (2321.85 and 2185.60 µm²; P = 0.24); NA/CA (0.03 and 0.02; P = 0.13), respectively. A significant increase in NA for SCA group (P = 0.01) was seen. No morphological differences were found between the groups. There was a predominance of nucleated cells of the superficial layer in the smears of both groups. Class I smears were predominant in both groups. CONCLUSIONS: This study revealed that SCA was able to induce significant changes on nuclear area of the oral epithelial cells.

Impact of neonatal screening and surveillance for the TP53 R337H mutation on early detection of childhood adrenocortical tumors.

PURPOSE: The incidence of pediatric adrenocortical tumors (ACTs) is remarkably high in southern Brazil, where more than 90% of patients carry the germline TP53 mutation R337H. We assessed the impact of early detection of this mutation and of surveillance of carriers. PATIENTS AND METHODS: Free newborn screening was offered at all hospitals in the state of Paraná. Parents of positive newborns were tested, and relatives in the carrier line were offered screening. Positive newborns and their relatives age < 15 years were offered surveillance (periodic clinical, laboratory, and ultrasound evaluations). ACTs detected by imaging were surgically resected. RESULTS: Of 180,000 newborns offered screening, 171,649 were screened, and 461 (0.27%) were carriers. As of April 2012, ACTs had been diagnosed in 11 of these carriers but in only two neonatally screened noncarriers (P < .001); six patient cases were identified among 228 carrier relatives age < 15 years (total, 19 ACTs). Surveillance participants included 347 (49.6%) of 699 carriers. Tumors were smaller in surveillance participants (P < .001) and more advanced in nonparticipants (four with stage III disease; two deaths). Neonatally screened carriers also had neuroblastoma (n = 1), glioblastoma multiforme (n = 1), choroid plexus carcinoma (n = 2), and Burkitt lymphoma (n = 1). Cancer histories and pedigrees were obtained for 353 families that included 1,704 identified carriers. ACTs were the most frequent cancer among carrier children (n = 48). CONCLUSION: These findings establish the prevalence of the TP53 R337H mutation in Paraná state and the penetrance of ACTs among carriers. Importantly, screening and surveillance of heterozygous carriers are effective in detecting ACTs when readily curable.

Enzyme replacement therapy with galsulfase in 34 children younger than five years of age with MPS VI.

BACKGROUND: Mucopolysaccharidosis type VI (MPS VI) is a progressive, chronic and multisystem lysosomal storage disease with a wide disease spectrum. Clinical and biochemical improvements have been reported for MPS VI patients on enzyme replacement therapy (ERT) with rhASB (recombinant human arylsulfatase B; galsulfase, Naglazyme®, BioMarin Pharmaceutical Inc.), making early diagnosis and intervention imperative for optimal patient outcomes. Few studies have included children younger than five years of age. This report describes 34 MPS VI patients that started treatment with galsulfase before five years of age. METHODS: Data from patients who initiated treatment at <5 years of age were collected from patients' medical records. Baseline and follow-up assessments of common symptoms that led to diagnosis and that were used to evaluate disease progression and treatment efficacy were evaluated. RESULTS: A significant negative correlation was seen with treatment with ERT and urinary GAG levels. Of those with baseline and follow-up growth data, 47% remained on their pre-treatment growth curve or moved to a higher percentile after treatment. Of the 9 patients with baseline and follow-up sleep studies, 5 remained unaffected and 1 patient initially with mild sleep apnea showed improvement. Data regarding cardiac, ophthalmic, central nervous system, hearing, surgical interventions and development are also reported. No patient discontinued treatment due to an adverse event and all that were treatment-emergent resolved. CONCLUSIONS: The prescribed dosage of 1mg/kg IV weekly with galsulfase ERT is shown to be safe and effective in slowing and/or improving certain aspects of the disease, although patients should be closely monitored for complications associated with the natural history of the disease, especially cardiac valve involvement and spinal cord compression. A long-term follow-up investigation of this group of children will provide further information on the benefits of early treatment as well as disease progression and treatment efficacy and safety in this young patient population.

SNP array profiling of childhood adrenocortical tumors reveals distinct pathways of tumorigenesis and highlights candidate driver genes.

CONTEXT: Childhood adrenocortical tumors (ACT) are rare malignancies, except in southern Brazil, where a higher incidence rate is associated to a high frequency of the founder R337H TP53 mutation. To date, copy number alterations in these tumors have only been analyzed by low-resolution comparative genomic hybridization. OBJECTIVE: We analyzed an international series of 25 childhood ACT using high-resolution single nucleotide polymorphism arrays to: 1) detect focal copy number alterations highlighting candidate driver genes; and 2) compare genetic alterations between Brazilian patients carrying the R337H TP53 mutation and non-Brazilian patients. RESULTS: We identified 16 significantly recurrent chromosomal alterations (q-value < 0.05), the most frequent being -4q34, +9q33-q34, +19p, loss of heterozygosity (LOH) of chromosome 17 and 11p15. Focal amplifications and homozygous deletions comprising well-known oncogenes (MYC, MDM2, PDGFRA, KIT, MCL1, BCL2L1) and tumor suppressors (TP53, RB1, RPH3AL) were identified. In addition, eight focal deletions were detected at 4q34, defining a sharp peak region around the noncoding RNA LINC00290 gene. Although non-Brazilian tumors with a mutated TP53 were similar to Brazilian tumors, those with a wild-type TP53 displayed distinct genomic profiles, with significantly fewer rearrangements (P = 0.019). In particular, three alterations (LOH of chromosome 17, +9q33-q34, and -4q34) were significantly more frequent in TP53-mutated samples. Finally, two of four TP53 wild-type tumors displayed as sole rearrangement a copy-neutral LOH of the imprinted region at 11p15, supporting a major role for this region in ACT development. CONCLUSIONS: Our findings highlight potential driver genes and cellular pathways implicated in childhood ACT and demonstrate the existence of different oncogenic routes in this pathology.

Molecular epidemiology of adrenocortical tumors in southern Brazil.

The high frequency of TP53 R337H carriers in southern Brazil is responsible for the highest known incidence of childhood adrenocortical tumor (ACT). Our aims were to examine other contributing mutations, age-related risk factors, epidemiological differences in ACT and to shed light on a method for increasing the survival rate of children. The fetal zone of the adrenal cortex is believed to be one of the tissues most susceptible to adenoma or carcinoma formation due to loss of p53 function. The founder germline R337H mutation is found in 95% of ACTs of young children, a much greater proportion than in adults. Despite intense educational campaigns about the high incidence of ACT in Paraná State, advanced cases remain common. Four advanced ACT cases (4/5) were admitted to a single institution in the first 6months of 2011 in Paraná State, none of the families knew about ACT, and 2 reported no familial cancer syndrome. Curative resection is possible when a small ACT is detected early.