30 Years of Experience with Non-Hodgkin Lymphoma in Children and Adolescents: a retrospective cohort study.

OBJECTIVE: Describe the clinical and demographic characteristics of pediatric patients with non-Hodgkin's lymphoma (NHL) enrolled in a tertiary unit of Pediatric Hematology between 1982-2015. PATIENTS AND METHODS: A retrospective cohort study of 140 patients aged 16 years or less with NHL. Demographic characteristics, data on diagnosis, and outcomes were analyzed. The overall survival (OS) analysis and stratification by the most frequent histological subtypes were performed using the Kaplan-Meier method. RESULTS: One hundred and thirty-six patients with de novo NHL and four with NHL as a second malignancy were analyzed. The median age at diagnosis was 6.4 years (interquartile range, 4.2 to 11.1 years); 101 patients were males. Four patients had primary immunodeficiency, four had human immunodeficiency virus, two post-liver transplantation, and one had autoimmune lymphoproliferative syndrome. The most frequent histological type was NHL of mature B- cell (B-NHL-B; 67.1%), with Burkitt's lymphoma being the most frequent subtype, and lymphoblastic lymphoma (LBL, 21.4%). The main clinical manifestation at the diagnosis was abdominal tumors (41.4%). During the follow-up time, 13 patients relapsed, but five of them reached a second remission. Thirty-five patients died, and 103 remained alive in clinical remission. No contact was possible for two patients. The OS at 5 years was 74.5% (± 3.8%). The OS estimated for patients with LBL, NHL-B, and the remaining was 80.4%±7.9%, 72.8%±4.7%, and 74.5%±11%, respectively (P = 0.58). CONCLUSION: Our results are comparable with cohorts from other middle-income countries.

30 Years of Experience with Non-Hodgkin Lymphoma in Children and Adolescents: a retrospective cohort study

SUMMARY OBJECTIVE Describe the clinical and demographic characteristics of pediatric patients with non-Hodgkin's lymphoma (NHL) enrolled in a tertiary unit of Pediatric Hematology between 1982-2015. PATIENTS AND METHODS A retrospective cohort study of 140 patients aged 16 years or less with NHL. Demographic characteristics, data on diagnosis, and outcomes were analyzed. The overall survival (OS) analysis and stratification by the most frequent histological subtypes were performed using the Kaplan-Meier method. RESULTS One hundred and thirty-six patients with de novo NHL and four with NHL as a second malignancy were analyzed. The median age at diagnosis was 6.4 years (interquartile range, 4.2 to 11.1 years); 101 patients were males. Four patients had primary immunodeficiency, four had human immunodeficiency virus, two post-liver transplantation, and one had autoimmune lymphoproliferative syndrome. The most frequent histological type was NHL of mature B- cell (B-NHL-B; 67.1%), with Burkitt's lymphoma being the most frequent subtype, and lymphoblastic lymphoma (LBL, 21.4%). The main clinical manifestation at the diagnosis was abdominal tumors (41.4%). During the follow-up time, 13 patients relapsed, but five of them reached a second remission. Thirty-five patients died, and 103 remained alive in clinical remission. No contact was possible for two patients. The OS at 5 years was 74.5% (± 3.8%). The OS estimated for patients with LBL, NHL-B, and the remaining was 80.4%±7.9%, 72.8%±4.7%, and 74.5%±11%, respectively (P = 0.58). CONCLUSION Our results are comparable with cohorts from other middle-income countries.

RESUMO OBJETIVO Descrever as características clínicas e demográficas de pacientes pediátricos com linfoma não Hodgkin (LNH) em uma unidade terciária de Hematologia Pediátrica entre 1982-2015. PACIENTES E MÉTODOS Estudo de coorte retrospectivo de dados de prontuários de 140 pacientes com idade até 16 anos com LNH. Características demográficas e dados relativos ao diagnóstico e evolução foram analisados. A sobrevida global (SG) e estratificada pelos subtipos histológicos mais frequentes foi analisada pelo método de Kaplan-Meier. RESULTADOS Dados de 136 pacientes com LNH de novo e quatro com LNH como segunda neoplasia foram analisados. A mediana de idade ao diagnóstico foi 6,4 anos (intervalo interquartil: 4,2 a 11,1 anos); 101 pacientes eram meninos. Onze pacientes apresentavam imunodeficiência (quatro primária, quatro secundária ao vírus da imunodeficiência humana adquirida, dois pós-transplante hepático e um com síndrome linfoproliferativa autoimune). Os tipos histológicos mais frequentes foram o LNH de células B madura (LNH-B, 67,1% dos pacientes), sendo o linfoma de Burkitt o subtipo mais frequente, e o linfoma linfoblástico (LL, 21,4%). A principal manifestação clínica ao diagnóstico foi massa abdominal (41,4%). A mediana de seguimento dos sobreviventes foi 7,7 anos (intervalo interquartil: 3,3 a 10,9 anos). Treze pacientes recidivaram (cinco alcançaram segunda remissão clínica), 35 faleceram, 103 permanecem vivos em remissão completa e dois perderam o seguimento. A probabilidade de SG em cinco anos foi 74,5%±3,8%. Para os pacientes com LL, LNH-B e os demais, a SG foi 80,4%±7,9%, 72,8%±4,7% e 74,5%±11%, respectivamente (P=0,58). CONCLUSÃO Nossos resultados são comparáveis aos de outros países de renda média.

Novel mutations causing biotinidase deficiency in individuals identified by the newborn screening program in Minas Gerais, Brazil.

Biotinidase deficiency is an autosomal recessive inherited metabolic disorder caused by mutations in the BTD gene. Clinical manifestations can be treated and effectively prevented with pharmacological doses of biotin. Nine novel mutations in BTD are reported in 14 children diagnosed by the newborn screening program in Minas Gerais, Brazil, from June 2013 to December 2017. Serum BTD enzyme activity was determined for all cases and some parents. Two of the mutations are deletions and seven missense mutations located in the exonic region of the BTD gene, mostly in exon 4. Two newborns were profoundly biotinidase-deficient (one homozygous p.A534V [c.1601C > T] and another, double heterozygous for a novel mutation p.R211S [c.631C > A] co-inherited with an already described mutation p.T532 M [c.1595C > T]). Two mutations were associated with a partial deficiency of biotinidase (p.F361 V [c.1081 T > G] in two homozygous children, and p.S311 T [c.932G > C] in a compound heterozygous child who co-inherited a known severe mutation p.Y438X [c.1314 T > A]). The remaining five mutations were found in compound heterozygous children. Hence, a definitive conclusion about the degree of biotinidase deficiency is not possible yet. These results emphasize the importance of sequencing the BTD gene as an important tool to gain a better understanding of the correlation between biochemical phenotype and genotype.

Clinical and hematological profile in a newborn cohort with hemoglobin SC / Perfil clínico e hematológico em uma coorte neonatal com hemoglobina SC

Abstract Objectives: Hemoglobin SC is the second most common variant of sickle-cell disease worldwide, after hemoglobin SS. The objectives of the study were to describe the clinical and laboratory characteristics of hemoglobin SC disease in children from a newborn screening program and treated at a blood center. Methodology: This study assessed a cohort of 461 infants born between 01/01/1999 and 12/31/2012 and followed-up until 12/31/2014. Clinical events were expressed as rates for 100 patient-years, with 95% confidence intervals. Kaplan-Meier survival curves were created. Results: The median age of patients was 9.2 years; 47.5% were female. Mean values of blood tests were: hemoglobin, 10.5 g/dL; reticulocytes, 3.4%; white blood cells, 11.24 × 109/L; platelets, 337.1 × 109/L; and fetal hemoglobin, 6.3%. Clinical events: acute splenic sequestration in 14.8%, blood transfusion 23.4%, overt stroke in 0.2%. The incidence of painful vaso-occlusive episodes was 51 (48.9-53.4) per 100 patient-years and that of infections, 62.2 episodes (59.8-64.8) per 100 patient-years. Transcranial Doppler ultrasonography (n = 71) was normal given the current reference values for SS patients. Hydroxyurea was given to ten children, all of whom improvement of painful crises. Retinopathy was observed in 20.3% of 59 children who underwent ophthalmoscopy. Avascular necrosis was detected in seven of 12 patients evaluated, predominantly in the left femur. Echocardiogram compatible with pulmonary hypertension was recorded in 4.6% of 130 children, with an estimated average systolic pulmonary artery pressure of 33.5 mmHg. The mortality rate from all causes was 4.3%. Conclusions: Clinical severity is variable in SC hemoglobinopathy. Several children have severe manifestations similar to those with SS disease.

Resumo Objetivos: A hemoglobinopatia SC é a segunda variante mais comum da doença falciforme no mundo, após a hemoglobinopatia SS. Os objetivos do estudo foram descrever as características clínicas e laboratoriais da hemoglobinopatia SC em recém-nascidos diagnosticados por programa de triagem neonatal e encaminhados para acompanhamento em hemocentro. Metodologia: Coorte de 461 recém-nascidos SC nascidos entre 01/01/1999 e 31/12/2012 e seguidos até 31/12/2014. A incidência de eventos clínicos foi expressa por taxas relativas a 100 pacientes-ano, com limites de confiança a 95%. Curvas de sobrevida foram construídas segundo Kaplan-Meier. Resultados: Mediana de idade, 9,2 anos; 47,5%, feminino. Médias dos valores hematológicos: hemoglobina 10,5 g/dL; reticulócitos 3,4%; leucometria 11,24 x 109/L; plaquetometria 337,1x109/L; hemoglobina fetal 6,3%. Eventos clínicos: sequestro esplênico agudo em 14,8%, hemotransfusão 23,4%, AVC isquêmico 0,2%. A incidência de episódios vaso-oclusivos dolorosos foi de 51 (48,9-53,4) por 100 pacientes-ano; a de infecções, 62,2 episódios (59,8-64,8) por 100 pacientes-ano. Doppler transcraniano (n = 71) foi normal, se usados os valores de referência de crianças SS. Dez pacientes usaram hidroxiureia, todos com melhoria das crises dolorosas. Retinopatia foi observada em 20,3% das 59 crianças que fizeram fundoscopia. Necrose avascular foi detectada em 7 de 12 pacientes avaliados, com predomínio no fêmur esquerdo. Ecocardiograma compatível com hipertensão pulmonar foi registrado em 4,6% de 130 crianças, com média estimada de 33,5 mm Hg de pressão arterial pulmonar. A taxa de mortalidade por todas as causas foi de 4,3%. Conclusões: A hemoglobinopatia SC tem gravidade variável; várias crianças apresentam manifestações clínicas intensas, semelhantes às da hemoglobinopatia SS.

Use of the Polymerase Chain Reaction as a Complementary Method for the Detection of Central Nervous System Involvement in Children and Adolescents with Acute Lymphoblastic Leukemia.

BACKGROUND: Cytological analysis of the cerebrospinal fluid (CSF) remains the most widely used method for diagnosing central nervous system (CNS) involvement in acute lymphoblastic leukemia (ALL). This study aimed at evaluating the use of polymerase chain reaction (PCR), in comparison to other methods, for the assessment of the presence of blast cells in the CSF at the time of diagnosis of ALL. METHODS: This was a prospective, single-centre, study enrolling all patients up to the age of 18 years who were admitted to a university hospital between November 2011 and November 2014 with a diagnosis of ALL and from whom it was possible to draw a sufficient amount of CSF for analysis by conventional cytology (CT), immunophenotyping (IMP), and PCR. RESULTS: A total of 46 CSF samples from 44 ALL pediatric patients were included. CT was performed in all samples, IMP in 44, and PCR in 34. Thirteen (28.2%) samples showed positive results: two by CT, four by IMP, four by PCR, and three by both IMP and PCR. CONCLUSIONS: The results of this study showed that PCR should be considered a complementary method for the evaluation of the CSF in ALL patients at diagnosis.

Clinical and hematological profile in a newborn cohort with hemoglobin SC.

OBJECTIVES: Hemoglobin SC is the second most common variant of sickle-cell disease worldwide, after hemoglobin SS. The objectives of the study were to describe the clinical and laboratory characteristics of hemoglobin SC disease in children from a newborn screening program and treated at a blood center. METHODOLOGY: This study assessed a cohort of 461 infants born between 01/01/1999 and 12/31/2012 and followed-up until 12/31/2014. Clinical events were expressed as rates for 100 patient-years, with 95% confidence intervals. Kaplan-Meier survival curves were created. RESULTS: The median age of patients was 9.2 years; 47.5% were female. Mean values of blood tests were: hemoglobin, 10.5g/dL; reticulocytes, 3.4%; white blood cells, 11.24×109/L; platelets, 337.1×109/L; and fetal hemoglobin, 6.3%. Clinical events: acute splenic sequestration in 14.8%, blood transfusion 23.4%, overt stroke in 0.2%. The incidence of painful vaso-occlusive episodes was 51 (48.9-53.4) per 100 patient-years and that of infections, 62.2 episodes (59.8-64.8) per 100 patient-years. Transcranial Doppler ultrasonography (n=71) was normal given the current reference values for SS patients. Hydroxyurea was given to ten children, all of whom improvement of painful crises. Retinopathy was observed in 20.3% of 59 children who underwent ophthalmoscopy. Avascular necrosis was detected in seven of 12 patients evaluated, predominantly in the left femur. Echocardiogram compatible with pulmonary hypertension was recorded in 4.6% of 130 children, with an estimated average systolic pulmonary artery pressure of 33.5mmHg. The mortality rate from all causes was 4.3%. CONCLUSIONS: Clinical severity is variable in SC hemoglobinopathy. Several children have severe manifestations similar to those with SS disease.

Hospitalizations of children with sickle cell disease in the Brazilian Unified Health System in the state of Minas Gerais / Internações de crianças com doença falciforme no Sistema Único de Saúde no Estado de Minas Gerais

Abstract Objective: To identify and characterize hospital admissions and readmissions in the Brazilian Unified Public Health System (Sistema Único de Saúde [SUS]) in children with sickle cell disease diagnosed by the Minas Gerais Newborn Screening Program between 1999 and 2012. Methods: Hospital Admission Authorizations with the D57 (International Classification of Diseases-10) code in the fields of primary or secondary diagnosis were retrieved from the SUS Databank (1999-2012). There were 2991 hospitalizations for 969 children. Results: 73.2% of children had hemoglobin SS/Sβ0-thalassemia and 48% were girls. The mean age was 4.3 ± 3.2 years, the mean number of hospitalizations, 3.1 ± 3.3, and the hospital length of stay, 5 ± 3.9 days. Hospital readmissions occurred for 16.7% of children; 10% of admissions were associated with readmission within 30 days after discharge; 33% of readmissions occurred within seven days post-discharge. There were 41 deaths, 95% of which were in-hospital. Secondary diagnoses were not recorded in 96% of admissions, making it impossible to know the reason for admission. In 62% of cases, hospitalizations occurred in the child's county of residence. The total number of hospitalizations of children under 14 with sickle cell disease relative to the total of pediatric hospitalizations increased from 0.12% in 1999 to 0.37% in 2012. Conclusions: A high demand for hospital care in children with sickle cell disease was evident. The number of hospitalizations increased from 1999 to 2012, suggesting that the disease has become more "visible." Knowledge of the characteristics of these admissions can help in the planning of care for these children in the SUS.

Resumo Objetivo: Identificar e caracterizar as internações e reinternações hospitalares pelo Sistema Único de Saúde (SUS) de crianças com doença falciforme, diagnosticadas pelo Programa de Triagem Neonatal de Minas Gerais entre 1999 e 2012. Métodos: Extraíram-se do banco de dados do SUS as Autorizações de Internação Hospitalar com o código D57 (Classificação Internacional de Doenças10) nos campos de diagnóstico primário ou secundário (1999-2012). Identificaram-se 969 crianças, total de 2.991 internações. Resultados: Das crianças, 73,2% tinham hemoglobina SS/Sβ0- talassemia e 48% eram meninas. A média foi de 4,3 ± 3,2 anos, a do número de internações, 3,1 ± 3,3 e a do tempo de permanência, 5 ± 3,9 dias. As readmissões hospitalares ocorreram em 16,7% das crianças; 10% das internações se associaram à readmissão em até 30 dias pós-alta; 33% das readmissões ocorreram em até 7 dias pós-alta. Ocorreram 41 óbitos, 95% em ambiente hospitalar. O diagnóstico secundário não foi registrado em 96% das internações, impossibilitou conhecer o motivo da internação. Em 62% dos casos, as internações ocorreram no município de residência da criança. O total de internações de crianças até 14 anos com doença falciforme em relação ao total das internações pediátricas passou de 0,12% em 1999 para 0,37% em 2012. Conclusões: Constatou-se elevada demanda por cuidados hospitalares, cujo aumento relativo entre 1999 e 2012 sugere incremento da "visibilidade" da doença falciforme. O conhecimento das características dessas internações pode contribuir para o planejamento do cuidado na rede assistencial do SUS.

Hospitalizations of children with sickle cell disease in the Brazilian Unified Health System in the state of Minas Gerais.

OBJECTIVE: To identify and characterize hospital admissions and readmissions in the Brazilian Unified Public Health System (Sistema Único de Saúde [SUS]) in children with sickle cell disease diagnosed by the Minas Gerais Newborn Screening Program between 1999 and 2012. METHODS: Hospital Admission Authorizations with the D57 (International Classification of Diseases-10) code in the fields of primary or secondary diagnosis were retrieved from the SUS Databank (1999-2012). There were 2991 hospitalizations for 969 children. RESULTS: 73.2% of children had hemoglobin SS/Sß0-thalassemia and 48% were girls. The mean age was 4.3±3.2 years, the mean number of hospitalizations, 3.1±3.3, and the hospital length of stay, 5±3.9 days. Hospital readmissions occurred for 16.7% of children; 10% of admissions were associated with readmission within 30 days after discharge; 33% of readmissions occurred within seven days post-discharge. There were 41 deaths, 95% of which were in-hospital. Secondary diagnoses were not recorded in 96% of admissions, making it impossible to know the reason for admission. In 62% of cases, hospitalizations occurred in the child's county of residence. The total number of hospitalizations of children under 14 with sickle cell disease relative to the total of pediatric hospitalizations increased from 0.12% in 1999 to 0.37% in 2012. CONCLUSIONS: A high demand for hospital care in children with sickle cell disease was evident. The number of hospitalizations increased from 1999 to 2012, suggesting that the disease has become more "visible." Knowledge of the characteristics of these admissions can help in the planning of care for these children in the SUS.

Shorter Maintenance Therapy in Childhood Acute Lymphoblastic Leukemia: The Experience of the Prospective, Randomized Brazilian GBTLI ALL-93 Protocol.

AIM: Maintenance therapy is an important phase of the childhood ALL treatment, requiring 2-year long therapy adherence of the patients and families. Weekly methotrexate with daily 6-mercaptopurine (6MP) constitutes the backbone of maintenance therapy. Reduction in the maintenance therapy could overweight problems related with poverty of children with ALL living in limited-income countries (LIC). OBJECTIVE: To compare, prospectively, the EFS rates of children with ALL treated according to two maintenance regimens: 18 vs. 24 months duration. MATERIALS AND METHODS: From October 1993 to September 1999, 867 consecutive untreated ALL patients <18 years of age were treated according to the Brazilian Cooperative Group for Childhood ALL Treatment (GBTLI) ALL-93 protocol. Risk classification was based exclusively on patient's age and leukocyte count (NCI risk group) and clinical extra medullary involvement of the disease. Data were analyzed by the intention-to-treat approach. RESULTS: Fourteen patients (1.6%) were excluded: wrong diagnosis (n = 7) and previous corticosteroid (n = 7). Of the 853 eligible patients, 421 were randomly allocated, at study enrollment, to receive 18-month (group 1) and 432 to receive 24-month (group 2) maintenance therapy. Complete remission rate was achieved in 96% of the patients (817/853). Twenty-eight patients (3.4%) died during the induction phase. Thirty-four patients (4.0%) were lost to follow-up. The overall EFS was 66.1 ± 1.7% at 15 years. No difference was seen according to maintenance: EFS15y was 65.8 ± 2.3% (group 1) and 66.3 ± 2.3% (group 2; p = 0.79). No difference between regimens was detected after stratifying the analyses according to factors associated with adverse prognosis in this study (age group <1 year or >10 years and high WBC at diagnosis). Overall death in remission rate was 6.85% (56 patients). Deaths during maintenance were 13 in group 1 and 12 in group 2, all due to infection. Over 15 years of follow-up, two patients both from group 2 presented a second malignancy (Hodgkin's disease and thyroid carcinoma) after 8.3 and 11 years off therapy, respectively. CONCLUSION: Six-month reduction of maintenance therapy in ALL children treated according to the GBTLI ALL-93 protocol provided the same overall outcome as 2-year duration regimen.

High Incidence of Biotinidase Deficiency from a Pilot Newborn Screening Study in Minas Gerais, Brazil.

OBJECTIVE: To assess the incidence of biotinidase deficiency among newborns and their clinical outcome up to one year of age in a large pilot screening study in Minas Gerais, Brazil. METHODS: A prospective cohort study was conducted from September 2007 to June 2008 with heel-prick blood samples collected on filter paper for the purpose of newborn screening. A qualitative colorimetric test was used as the primary screening method. Colorimetric-positive cases were further tested with a serum confirmatory assay. Gene sequencing was performed for eight children suspected with biotinidase deficiency and for some of their parents. Positive cases were daily supplemented with oral biotin and were followed up for approximately six years. RESULTS: Out of 182,891 newborns screened, 129 were suspected of having biotinidase deficiency. Partial deficiency was confirmed in seven children (one was homozygous for p.D543E) and profound deficiency in one child (homozygous p.H485Q). Thus the incidence was one in 22,861 live births (95% confidence interval 1:13,503 to 1:74,454) for profound and partial biotinidase deficiency combined. Two novel mutations were detected: p.A281V and p.E177K. In silico analysis and estimation of the enzyme activity in the children and their parents showed that p.A281V is pathogenic and p.E177K behaves like p.D444H. CONCLUSION: The incidence of biotinidase deficiency in newborn screening in Minas Gerais was higher than several international studies. The sample size should be larger for final conclusions. Oral daily biotin apparently precluded clinical symptoms, but it may have been unnecessary in some newborns.

Deficiência de ferro em lactentes brasileiros com doença falciforme / Iron deficiency in Brazilian infants with sickle cell disease

OBJETIVO: Avaliar a deficiência ou sobrecarga de ferro em lactentes com doença falciforme, a fim de embasar a decisão de recomendar (ou não) a suplementação profilática de ferro nessa população. MÉTODOS: Estudo retrospectivo transversal envolvendo 135 lactentes menores de 2 anos (66 meninos e 69 meninas), com genótipos SS e SC (77/58), nascidos entre 2005 e 2006 em Minas Gerais. Os indicadores de uma possível deficiência de ferro foram: volume corpuscular médio (VCM), hemoglobina corpuscular média (HCM), saturação da transferrina (ST) e ferritina. Dezessete lactentes [12,6 por cento, intervalo de confiança de 95 por cento (IC95 por cento) 7,0-18,2 por cento] haviam recebido hemotransfusão antes da coleta dos exames. RESULTADOS: ST e ferritina estavam significativamente mais baixas nos lactentes com hemoglobina SC (p < 0,001). Quando dois indicadores foram utilizados para definir a deficiência de ferro (VCM ou HCM baixos mais ST ou ferritina baixas), 17,8 por cento das crianças (IC95 por cento 11,3-24,3 por cento) tinham deficiência de ferro, predominando naquelas com perfil SC (p = 0,003). Análise das crianças que não haviam sido transfundidas (n = 118) mostrou prevalência de ferropenia em 19,5 por cento. Constatou-se aumento de ferritina em 15 lactentes (11,3 por cento; IC95 por cento 5,9-16,7 por cento); a maioria havia sido transfundida. CONCLUSÕES: A maior parte dos lactentes com doença falciforme não desenvolve deficiência de ferro, mas alguns têm déficit significativo. Este estudo indica que lactentes com doença falciforme, principalmente aqueles com hemoglobinopatia SC, talvez possam receber ferro profilático; no entanto, a suplementação deve ser suspensa após a primeira hemotransfusão.

OBJECTIVE: To assess iron deficiency or overload in infants with sickle cell disease in order to support the decision to recommend (or not) iron prophylactic supplementation in this population. METHODS: Cross-sectional and retrospective study with 135 infants below 2 years old (66 boys and 69 girls), 77 with SS and 58 with SC hemoglobin, born between 2005 and 2006 in Minas Gerais, Brazil. Indicators of possible iron deficiency were: mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), transferrin saturation (TS), and ferritin. Blood transfusions had been given to 17 infants (12.6 percent, 95 percent confidence interval [95 percentCI] 7.0-18.2 percent) before laboratory tests were done. RESULTS: Ferritin and TS were significantly lower in SC infants (p < 0.001). When two indices were considered for the definition of iron deficiency (low MCV or MCH plus low ferritin or TS), 17.8 percent of children (95 percentCI 11.3-24.3 percent) presented iron deficiency, mainly those with SC hemoglobin (p = 0.003). An analysis of infants who were not given transfusions (n = 118) showed that 19.5 percent presented iron deficiency. Fifteen infants (11.3 percent, 95 percentCI 5.9-16.7 percent) presented increased ferritin; the majority had been transfused. CONCLUSIONS: Most infants with sickle cell disease do not develop iron deficiency, though some have a significant deficit. This study indicates that infants with sickle cell disease, mainly those with SC hemoglobin, may receive prophylactic iron; however, supplementation should be withdrawn after the first blood transfusion.

Iron deficiency in Brazilian infants with sickle cell disease.

OBJECTIVE: To assess iron deficiency or overload in infants with sickle cell disease in order to support the decision to recommend (or not) iron prophylactic supplementation in this population. METHODS: Cross-sectional and retrospective study with 135 infants below 2 years old (66 boys and 69 girls), 77 with SS and 58 with SC hemoglobin, born between 2005 and 2006 in Minas Gerais, Brazil. Indicators of possible iron deficiency were: mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), transferrin saturation (TS), and ferritin. Blood transfusions had been given to 17 infants (12.6%, 95% confidence interval [95%CI] 7.0-18.2%) before laboratory tests were done. RESULTS: Ferritin and TS were significantly lower in SC infants (p < 0.001). When two indices were considered for the definition of iron deficiency (low MCV or MCH plus low ferritin or TS), 17.8% of children (95%CI 11.3-24.3%) presented iron deficiency, mainly those with SC hemoglobin (p = 0.003). An analysis of infants who were not given transfusions (n = 118) showed that 19.5% presented iron deficiency. Fifteen infants (11.3%, 95%CI 5.9-16.7%) presented increased ferritin; the majority had been transfused. CONCLUSIONS: Most infants with sickle cell disease do not develop iron deficiency, though some have a significant deficit. This study indicates that infants with sickle cell disease, mainly those with SC hemoglobin, may receive prophylactic iron; however, supplementation should be withdrawn after the first blood transfusion.

Benefits of the intermittent use of 6-mercaptopurine and methotrexate in maintenance treatment for low-risk acute lymphoblastic leukemia in children: randomized trial from the Brazilian Childhood Cooperative Group--protocol ALL-99.

PURPOSE To describe event-free survival (EFS) and toxicities in children with low-risk acute lymphoblastic leukemia (ALL) assigned to receive either continuous 6-mercaptopurine (6-MP) and weekly methotrexate (MTX) or intermittent 6-MP with intermediate-dose MTX, as maintenance treatment. PATIENTS AND METHODS Between October 1, 2000, and December 31, 2007, 635 patients with low-risk ALL were enrolled onto Brazilian Childhood Cooperative Group for ALL Treatment (GBTLI) ALL-99 protocol. Eligible children (n = 544) were randomly allocated to receive either continuous 6-MP/MTX (group 1, n = 272) or intermittent 6-MP (100 mg/m(2)/d for 10 days, with 11 days resting) and MTX (200 mg/m(2) every 3 weeks; group 2, n = 272). RESULTS The 5-year overall survival (OS) and EFS were 92.5% +/- 1.5% SE and 83.6% +/- 2.1% SE, respectively. According to maintenance regimen, the OS was 91.4% +/- 2.2% SE (group 1) and 93.6% +/- 2.1% SE (group 2; P = .28) and EFS 80.9% +/- 3.2% SE (group 1) and 86.5% +/- 2.8% SE (group 2; P = .089). Remarkably, the intermittent regimen led to significantly higher EFS among boys (85.7% v 74.9% SE; P = .027), while no difference was seen for girls (87.0% v 88.8% SE; P = .78). Toxic episodes were recorded in 226 and 237 children, respectively. Grade 3 to 4 toxic events for groups 1 and 2 were, respectively, 273 and 166 for hepatic dysfunction (P = .002), and 772 and 636 for hematologic episodes (P = .005). Deaths on maintenance were: seven (group 1) and one (group 2). CONCLUSION The intermittent use of 6-MP and MTX in maintenance is a less toxic regimen, with a trend toward better long-term EFS. Boys treated with the intermittent schedule had significantly better EFS.

A simplified minimal residual disease polymerase chain reaction method at early treatment points can stratify children with acute lymphoblastic leukemia into good and poor outcome groups.

BACKGROUND: Minimal residual disease is an important independent prognostic factor in childhood acute lymphoblastic leukemia. The classical detection methods such as multiparameter flow cytometry and real-time quantitative polymerase chain reaction analysis are expensive, time-consuming and complex, and require considerable technical expertise. DESIGN AND METHODS: We analyzed 229 consecutive children with acute lymphoblastic leukemia treated according to the GBTLI-99 protocol at three different Brazilian centers. Minimal residual disease was analyzed in bone marrow samples at diagnosis and on days 14 and 28 by conventional homo/heteroduplex polymerase chain reaction using a simplified approach with consensus primers for IG and TCR gene rearrangements. RESULTS: At least one marker was detected by polymerase chain reaction in 96.4% of the patients. By combining the minimal residual disease results obtained on days 14 and 28, three different prognostic groups were identified: minimal residual disease negative on days 14 and 28, positive on day 14/negative on day 28, and positive on both. Five-year event-free survival rates were 85%, 75.6%, and 27.8%, respectively (p<0.0001). The same pattern of stratification held true for the group of intensively treated children. When analyzed in other subgroups of patients such as those at standard and high risk at diagnosis, those with positive B-derived CD10, patients positive for the TEL/AML1 transcript, and patients in morphological remission on a day 28 marrow, the event-free survival rate was found to be significantly lower in patients with positive minimal residual disease on day 28. Multivariate analysis demonstrated that the detection of minimal residual disease on day 28 is the most significant prognostic factor. CONCLUSIONS: This simplified strategy for detection of minimal residual disease was feasible, reproducible, cheaper and simpler when compared with other methods, and allowed powerful discrimination between children with acute lymphoblastic leukemia with a good and poor outcome.

Acute splenic sequestration in a cohort of children with sickle cell anemia / Sequestro esplênico agudo em coorte de crianças com anemia falciforme

OBJETIVO: Analisar o sequestro esplênico agudo (SEA) em crianças com anemia falciforme, provindas da triagem neonatal de Minas Gerais e acompanhadas pelo Hemominas de Belo Horizonte (MG). MÉTODOS: Coorte retrospectiva de 255 crianças com hemoglobinopatia SS/Sβº, nascidas entre 01/01/2000 e 31/12/2004 e acompanhadas até 31/12/2006. Os dados foram extraídos dos prontuários médicos. RESULTADOS: Oitenta e nove pacientes apresentaram 173 eventos de SEA (10,2 primeiros eventos por 100 pacientes/ano), sendo que 75% dos primeiros episódios de SEA ocorreram até 2 anos de vida. A probabilidade estimada de ocorrência do primeiro episódio de SEA foi de 40%. A recorrência atingiu 57,3%. Após o primeiro episódio de SEA, a esplenectomia foi indicada em apenas 12,4% dos casos; após o segundo, em 60,4% dos casos. Após o terceiro episódio, 41,7% dos casos ainda permaneceram sob observação clínica. A mediana do tempo entre indicação e realização da esplenectomia foi de 2 meses. Nesse intervalo, 37,2% das crianças tiveram novo episódio de SEA e uma delas faleceu. A letalidade no primeiro episódio foi de 1,1% e de 7,8% em episódios subsequentes. Entre as 255 crianças ocorreram 19 óbitos: 36,8% devido a infecções e 26,3% após SEA. CONCLUSÕES: O SEA é um evento comum na anemia falciforme, principalmente nos 2 primeiros anos de vida, com recidiva em mais da metade dos casos. Predominou conduta conservadora na indicação da esplenectomia. Embora a letalidade tenha sido baixa, o SEA representou a segunda causa de óbito. Isso aponta para fragilidades estruturais do sistema de saúde de MG e para a necessidade de melhor capacitação profissional na abordagem do problema.

OBJECTIVE: To analyze acute splenic sequestration (ASS) in children with sickle cell anemia diagnosed through a newborn screening program in the state of Minas Gerais, Brazil, and followed up at the hematology center in the city of Belo Horizonte, Minas Gerais, Brazil. METHODS: Retrospective cohort of 255 children with sickle cell anemia (Hb SS/Sβº) born between January 01, 2000, and December 31, 2004, and followed up until December 31, 2006. Data were abstracted from the patients' medical records. RESULTS: A total of 89 patients had 173 episodes of ASS (10.2 first episodes per 100 patient-years); 75% of the first episodes occurred before 2 years of age. The estimated probability of occurrence of the first episode of ASS during the study period was 40%. Recurrence rate reached 57.3%. After the first episode, splenectomy was indicated in only 12.4% of the cases; after the second, in 60.4% of the cases. After the third episode, 41.7% of the patients remained under clinical observation. The median time between indication for splenectomy and the actual surgical procedure was 2 months. During the intervening period, 37.2% of the children suffered a new episode of ASS and one child died. Case-fatality rate was 1.1% for the first episode and 7.8% for the subsequent episodes. Among a total of 255 children, 19 died: 36.8% due to infections and 26.3% after ASS. CONCLUSIONS: ASS is relatively common in sickle cell anemia, mainly in the first 2 years of life; relapse occurs in more than half of the cases. Conservative management instead of immediate splenectomy was the method of choice. Although the case-fatality rate was low, ASS was the second most common cause of death. These results disclose some fragilities of the health system in the state of Minas Gerais and the need for better professional education to approach ASS crises.

Acute splenic sequestration in a cohort of children with sickle cell anemia.

OBJECTIVE: To analyze acute splenic sequestration (ASS) in children with sickle cell anemia diagnosed through a newborn screening program in the state of Minas Gerais, Brazil, and followed up at the hematology center in the city of Belo Horizonte, Minas Gerais, Brazil. METHODS: Retrospective cohort of 255 children with sickle cell anemia (Hb SS/Sbeta(0)) born between January 01, 2000, and December 31, 2004, and followed up until December 31, 2006. Data were abstracted from the patients' medical records. RESULTS: A total of 89 patients had 173 episodes of ASS (10.2 first episodes per 100 patient-years); 75% of the first episodes occurred before 2 years of age. The estimated probability of occurrence of the first episode of ASS during the study period was 40%. Recurrence rate reached 57.3%. After the first episode, splenectomy was indicated in only 12.4% of the cases; after the second, in 60.4% of the cases. After the third episode, 41.7% of the patients remained under clinical observation. The median time between indication for splenectomy and the actual surgical procedure was 2 months. During the intervening period, 37.2% of the children suffered a new episode of ASS and one child died. Case-fatality rate was 1.1% for the first episode and 7.8% for the subsequent episodes. Among a total of 255 children, 19 died: 36.8% due to infections and 26.3% after ASS. CONCLUSIONS: ASS is relatively common in sickle cell anemia, mainly in the first 2 years of life; relapse occurs in more than half of the cases. Conservative management instead of immediate splenectomy was the method of choice. Although the case-fatality rate was low, ASS was the second most common cause of death. These results disclose some fragilities of the health system in the state of Minas Gerais and the need for better professional education to approach ASS crises.

Púrpura trombocitopênica imune da criança: experiência de 12 anos em uma única instituição brasileira / Childhood immune thrombocytopenic purpura: 12-year experience of a single Brazilian institution

O objetivo deste trabalho foi determinar a frequência dos quadros clínicos da púrpura trombocitopênica imune e sua associação com contagem de plaquetas, taxa de resposta à esplenectomia e fatores preditivos do desfecho e da evolução para a cronicidade. Realizou-se estudo retrospectivo com 187 crianças diagnosticadas no Hospital das Clínicas da UFMG, entre 04/1988 e 12/2001. Quadros assintomáticos e leves corresponderam a 76 por cento do total. Hemorragias exclusivamente cutâneas ocorreram em 96 por cento dos casos sintomáticos. A gravidade dos sintomas associou-se à intensidade da plaquetopenia. Evolução aguda foi apresentada por 123 pacientes (70,7 por cento) e crônica por 51 (29,3 por cento). A apresentação insidiosa (26,2 por cento) associou-se a um maior número de esplenectomias (p=4x10-7), a uma menor taxa de resposta à corticoterapia (p=0,003) e constituiu-se, juntamente com a ausência de resposta à corticoterapia (p<1x10-7), em fator preditivo da cronicidade (p=1x10-7). Taxa de resposta de 74,5 por cento foi alcançada com a esplenectomia. Remissão foi o desfecho final em 80,2 por cento dos pacientes. Foram preditivos de remissão final: gênero masculino (p=0,02), número baixo de plaquetas ao diagnóstico (p=0,004), resposta à corticoterapia (p=0,003) e ocorrência de uma primeira remissão (p<1x10-7). Confirmou-se que a doença na criança é benigna e autolimitada. Houve associação entre gravidade dos sintomas e intensidade da plaquetopenia. Constituíram-se fatores preditivos da cronicidade: apresentação insidiosa e ausência de resposta à corticoterapia. Constituíram-se fatores associados à remissão final: gênero masculino, número mais baixo de plaquetas ao diagnóstico, resposta à corticoterapia inicial e ocorrência de uma primeira remissão.

The objective of this work was to determine the frequency of clinical manifestations of immune thrombocytopenic purpura and its association with platelet count, response to splenectomy and predictive factors for response and chronicity. This retrospective study included 187 children diagnosed at Hospital das Clínicas, Federal University of Minas Gerais, Brazil, between April 1988 and December 2001. About 76 percent of the cases had asymptomatic or clinically mild disease. Cutaneous bleeding alone was seen in 96 percent of the symptomatic cases. Severity of symptoms was associated with low platelet count. The acute disease was observed in 123 patients (70.7 percent) and 51 (29.3 percent) developed the chronic disease. Insidious presentation (26.2 percent) was associated with a larger number of splenectomies (p=4x10-7) and with a reduced response to steroids (p=0.003). Additionally, the lack of response to steroids (p<1x10-7) and insidious presentation were predictive factors for chronicity (p=1x10-7). Splenectomy resulted in remission in 74.5 percent. Remission was the final outcome for 80.2 percent of patients. Remission-associated factors included being male (p=0.02), a lower platelet count at diagnosis (p=0.004), response to steroids (p=0.003), and the occurrence of a first remission (p<1x10-7). The disease in childhood is benign and self-limiting with severity of symptoms being associated with a low platelet count.