Mitiko Murao

Malnutrition as a prognostic factor in lymphoblastic leukaemia: a multivariate analysis.

One hundred and twenty eight Brazilian children with lymphoblastic leukaemia were intensively treated with a Berlin-Frankfurt-Munich based protocol. More children had a white cell count above 50 x 10(9)/l (31%) then observed in developed countries. After a median follow up of 31 months (11-58 months), the estimated probability of relapse free survival was 41% (7%) for the whole group. After adjustment in the Coxs multivariate model, malnutrition was the most significant adverse factor affecting duration of complete remission. Age above 8 years and high peripheral white cell count were also significant adverse factors. Among the nutritional indices, the height for age and weight for age z scores were both significant, whether the cut off points of z-2 or z = -1.28 were chosen to define malnutrition. A strong statistical association between the two indices was found; the contribution of height for age z score to the prediction of relapse free survival was more significant. Children with height for age z score < -2 had a relapse risk of 8.2 (95% confidence interval 3.1 to 21.9) relative to children with z score > -2. The results of this study suggest that socioeconomic and nutritional factors should be considered in the prognostic evaluation of children with leukaemia in developing countries.

Low socioeconomic status is a strong independent predictor of relapse in childhood acute lymphoblastic leukemia

The results of the treatment of acute lymphoblastic leukemia (ALL) in children depend not only on the biologic diversity of the leukemia cell, the multi‐drug treatment schedule and the individual variability of drug metabolism, but also on the socioeconomic and cultural background of the leukemic child. Social and cultural disparity is very marked in underdeveloped countries and has been increasing in industrialized nations. The prognostic influences of these factors are poorly documented and sometimes mistakenly attributed to differences in ethnic origin. We have investigated in Brazil the relative impact of malnutrition and socioeconomic status on the outcome of ALL, adjusting for the known influence of biologic factors. Children with ALL (n = 167) treated with a Berlin‐Frankfurt‐Munster‐based protocol were studied prospectively. At a median follow‐up of 1623 days, the estimated probability of disease‐free survival was 43 ± 4%. The main cause for interruption of remission was bone‐marrow relapse. Socioeconomic indicators of poverty (poor housing conditions, low per capita income and energy consumption) were significantly associated with a greater risk of relapse in univariate analysis. They were consolidated in a single index, socioeconomic status (SES), defined by the product of monthly per capita income times mean familial daily energy consumption. Other unfavorable findings included age, z score for the height for age at diagnosis (HAZ) below −1.28 and the z score for weight for age below −1.28. After adjustment in Coxs multivariate model, only HAZ and poor SES remained as predictive factors for relapse. Poor prognosis for leukemic children of low SES is just another indicator of social inequality. Int. J. Cancer Supplement 11:56–61, 1998.

Leucemia mielóide aguda na criança: experiência de 15 anos em uma única instituição

OBJETIVO: Verificar a sobrevida de criancas com leucemia mieloide aguda antes e apos a adocao de quimioterapia baseada no protocolo Berlim-Frankfurt-Munique-83. Analisar a influencia prognostica dos fatores idade, genero, estado nutricional, leucometria inicial e introducao da droga etoposida na fase de inducao da remissao. METODOS: Estudo prospectivo/retrospectivo com 83 criancas portadoras de leucemia mieloide aguda, diagnosticadas no Hospital das Clinicas da UFMG entre 1986 e 2000. Ate 1990, 15 criancas foram tratadas com dois a tres ciclos de citarabina e daunorrubicina, seguidos de esquemas variados de consolidacao/manutencao; de janeiro de 1991 a novembro de 1992, 15 pacientes em estudo piloto utilizaram etoposida na fase de inducao do protocolo alemao; de dezembro de 1992 a junho de 1999, a etoposida foi utilizada aleatoriamente. RESULTADOS: O tempo mediano de seguimento foi de cinco anos. As taxas de remissao iniciais foram de 40% e 66%, antes e apos a adocao do protocolo alemao (p = 0,11). O obito durante a inducao, causado por infeccoes e/ou hemorragia, foi a principal causa para nao se obter a remissao. As probabilidades estimadas de sobrevida e de remissao clinica completa aos cinco anos foram de 31%±5,4% e 49,7%±7,4%, respectivamente. Recidivas ocorreram em 22 casos, todas medulares. Criancas abaixo de seis anos de idade tiveram prognostico significativamente pior. Genero, leucometria inicial e estado nutricional nao influenciaram o prognostico. Criancas que aleatoriamente utilizaram a etoposida tiveram a duracao da remissao menor do que aquelas que nao a usaram. CONCLUSOES: A utilizacao de terapia baseada no protocolo alemao melhorou o prognostico. A administracao da etoposida foi desfavoravel, nao se encontrando explicacao plausivel para tal observacao.

Primary hepatic non-Hodgkin's lymphoma in children: a case report and review of the literature.

Non-Hodgkins lymphomas presenting exclusively in the liver are rather uncommon in adults and extremely rare in children. We describe a six-year-old white boy with jaundice, abdominal pain, and weight loss of two weeks duration. Physical examination disclosed asthenia, jaundice, abdominal swelling, large hepatomegaly, and ascitis. Aminotransferases bilirubin, and alkaline phosphatase were significantly elevated. Bone marrow aspiration, cerebrospinal fluid, chest x-ray, renal function tests, and uric acid were normal. Abdominal ultrasound showed liver enlargement with irregular regular borders, many parenchymal nodules in both liver lobes, a large hypoechogenic mass in the inferior segment of the liver, normal biliary ducts and two pancreatic nodules resembling those in the liver. Liver needle biopsy disclosed diffuse lymphomatous infiltration. Blast cells were positive for leukocyte common antigen (CD 45). Immunohistochemistry study for T or B cell lineage differentiation was not done. The child showed an excellent response to chemotherapy based on the BFM-83 protocol for B cell non-Hodgkins lymphomas. The patient had his therapy discontinued in June 1995 and remains in first complete remission as of May 20th, 1996.

Thiopurine S-methyltransferase (TPMT) gene polymorphism in Brazilian children with acute lymphoblastic leukemia: association with clinical and laboratory data.

The frequency of allele variants of gene TPMT*2, *3A, *3B, and *3C was estimated in a population of 116 Brazilian children with acute lymphoblastic leukemia. The association between genotype and clinical and laboratory data obtained during chemotherapy maintenance phase and the correlation of intraerythrocyte concentration of 6-mercaptopurine metabolites (6-tioguanine nucleotide nucleotides and methylmercaptopurine) were analyzed. A multiplex amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) was used in DNA amplification. Twelve patients presented TPMT gene mutation, all in heterozygous form. The most frequent allele variation was TPMT*3A (3.9%), followed by *3C (0.9%), *2 (0.4%), and *3B (0%). There was no significant association between clinical and laboratory data and the presence of mutation in TPMT gene. Of the 36 patients who were monitored for 6-mercaptopurine metabolite levels, only 1 had the mutation. In this patient, high 6-tioguanine nucleotide and low methylmercaptopurine concentrations were found. Event-free survival (EFS) for the whole group was 73.4%. There was no significant difference in event-free survival in the comparison between the groups with and without mutation (P = 0.06).

Clinical course of autoimmune hemolytic anemia: an observational study

OBJECTIVE Autoimmune hemolytic anemia is characterized by the production of autoantibodies against erythrocyte membrane antigens. This study was carried out to identify the clinical, immunological and outcome characteristics of autoimmune hemolytic anemia patients treated at the (HC-UFMG) Pediatric Hematology Unit and the Hemocentro de Belo Horizonte. METHODS We evaluated 17 patients younger than 15 years old admitted from 1988 to 2003 were evaluated. Autoimmune hemolytic anemia diagnosis was based on the presence of acquired hemolysis and confirmed by positive direct Coombs polyspecific test results. Clinical, laboratory, and outcome data were obtained from patient records. RESULTS The median age at diagnosis was 10.5 months. The direct Coombs polyspecific test was positive in 13 and negative in four patients. Monospecific testing was performed for 14 patients. The most frequent red cell autoantibody was IgG (five patients), followed by IgM in two. Thirteen patients had severe anemia and needed blood transfusions. Underlying diseases were identified in four patients: systemic lupus erythematosus, Hodgkins lymphoma, autoimmune hepatitis and Langerhans cell histiocytosis. The remaining patients were classified as having primary disease. The median follow-up period was 11 months (5 to 23 months). Three children died, two after splenectomy and one with complications of the underlying disease. CONCLUSION Autoimmune hemolytic anemia is rare in children and adolescents. Although patients usually respond to corticosteroids and/or immunoglobulin, fatal cases can occur. Prognosis is worse in patients with chronic underlying diseases.

Traço falciforme: heterozigose para hemoglobina S

Hemoglobin S (HbS) is one of the most common hereditary hematological alterations. In Brazil, the frequency of the sickle cell trait (HbAS) varies from 2% to 8%. Thus, there is an estimate of more than two million carriers of the HbAS sickle cell trait in Brazil. Different to homozygous carriers for Hb S (Hb SS), individuals with the sickle cell trait do not present with vaso-occlusive symptoms under physiologic conditions. Some clinical signals associated to the sickle cell trait only occur under conditions that favor the sickling process, including hypoxia, acidosis and dehydration. Life expectancy is similar to the general population. Hence, the condition of asymptomatic carrier should not affect the style and quality of life.Hemoglobin S (HbS) is one of the most common hereditary hematological alterations. In Brazil, the frequency of the sickle cell trait (HbAS) varies from 2% to 8%. Thus, there is an estimate of more than two million carriers of the HbAS sickle cell trait in Brazil. Different to homozygous carriers for Hb S (Hb SS), individuals with the sickle cell trait do not present with vaso-occlusive symptoms under physiologic conditions. Some clinical signals associated to the sickle cell trait only occur under conditions that favor the sickling process, including hypoxia, acidosis and dehydration. Life expectancy is similar to the general population. Hence, the condition of asymptomatic carrier should not affect the style and quality of life.

Curso clínico da anemia hemolítica auto-imune: um estudo descritivo

OBJETIVO: A anemia hemolitica auto-imune e caracterizada pela producao de auto-anticorpos contra antigenos de superficie das hemacias. O objetivo do estudo foi identificar as caracteristicas clinicas, imunologicas e evolutivas dos pacientes com anemia hemolitica auto-imune acompanhados no servico de hematologia pediatrica do HC-UFMG e no Hemocentro de Belo Horizonte. METODOS: Foram avaliadas 17 criancas menores de 15 anos, diagnosticadas entre 1988 e 2003. O diagnostico de anemia hemolitica auto-imune foi baseado no quadro de hemolise adquirida e confirmado por meio do teste de Coombs direto poliespecifico. Os dados clinicos, demograficos, laboratoriais e referentes a evolucao dos pacientes foram obtidos retrospectivamente nos prontuarios medicos. RESULTADOS: A mediana de idade ao diagnostico foi de 10,5 meses. O teste de Coombs direto poliespecifico foi positivo em 13 pacientes e negativo em quatro. Em 14 pacientes, foi realizado o teste de Coombs direto monoespecifico. Nestes, a classe de anticorpo mais frequente foi IgG (cinco pacientes), seguida pela IgM em dois. Em 13 (76%) pacientes, a anemia foi considerada grave, o que tornou necessaria a hemotransfusao. Em quatro pacientes, foi identificada uma doenca de base: lupus eritematoso sistemico, linfoma de Hodgkin, hepatite auto-imune e histiocitose de celulas de Langerhans. Os demais casos foram considerados como primarios. A mediana de seguimento foi de 11 meses (5 a 23 meses). Ocorreram tres obitos, sendo dois apos esplenectomia e um pela doenca de base. CONCLUSAO: A anemia hemolitica auto-imune e rara em criancas e adolescentes. Apesar de apresentar resposta ao corticoide e imunoglobulina, casos fatais tem sido relatados. O prognostico e pior na presenca de uma doenca cronica de base.

Hemophagocytic lymphohistiocytosis: a case series of a Brazilian institution

Objective To describe the clinical and laboratory presentation of hemophagocytic lymphohistiocytosis in children treated at a referral institution. Methods A retrospective descriptive study was carried out of seven children diagnosed with hemophagocytic lymphohistiocytosis between 2010 and 2012. The criteria for diagnosis were those proposed by the Histiocyte Society. When indicated, immunochemotherapy was prescribed according to the HLH94 and HLH2004 protocols of the Histiocyte Society. Results The patients’ ages at diagnosis ranged from one month to nine years. All patients had splenomegaly, fever, anemia, thrombocytopenia, hyperferritinemia and hypertriglyceridemia. Bone marrow hemophagocytosis was detected in six patients. In six cases, infectious diseases triggered the syndrome. In two cases, associated with visceral leishmaniasis, remission was achieved after treatment of the underlying infection. Three patients, who had Epstein–Barr-related hemophagocytic lymphohistiocytosis, required treatment with immunochemotherapy. They are alive and in remission; one patient had symptoms of juvenile rheumatoid arthritis and another, who was suspected of having primary hemophagocytic lymphohistiocytosis, entered into remission after bone marrow transplantation. Two deaths (28.6%) occurred in patients with suspected primary hemophagocytic lymphohistiocytosis; one whose clinical picture was triggered by cytomegalovirus infection did not respond to immunochemotherapy and the other died before any specific treatment was provided. Conclusion As reported before, hemophagocytic lymphohistiocytosis has a multifaceted presentation with nonspecific signs and symptoms. In secondary forms, remission may be achieved by treating the underlying disease. In the primary forms, remission may be achieved with immunochemotherapy, but bone marrow transplantation is required for cure.

Incidence and risk factors for central nervous system relapse in children and adolescents with acute lymphoblastic leukemia

Background Despite all the advances in the treatment of childhood acute lymphoblastic leukemia, central nervous system relapse remains an important obstacle to curing these patients. This study analyzed the incidence of central nervous system relapse and the risk factors for its occurrence in children and adolescents with acute lymphoblastic leukemia. Methods This study has a retrospective cohort design. The studied population comprised 199 children and adolescents with a diagnosis of acute lymphoblastic leukemia followed up at Hospital das Clinicas, Universidade Federal de Minas Gerais (HC-UFMG) between March 2001 and August 2009 and submitted to the Grupo Brasileiro de Tratamento de Leucemia da Infância - acute lymphoblastic leukemia (GBTLI-LLA-99) treatment protocol. Results The estimated probabilities of overall survival and event free survival at 5 years were 69.5% (± 3.6%) and 58.8% (± 4.0%), respectively. The cumulative incidence of central nervous system (isolated or combined) relapse was 11.0% at 8 years. The estimated rate of isolated central nervous system relapse at 8 years was 6.8%. In patients with a blood leukocyte count at diagnosis ≥ 50 x 109/L, the estimated rate of isolated or combined central nervous system relapse was higher than in the group with a count < 50 x 109/L (p-value = 0.0008). There was no difference in cumulative central nervous system relapse (isolated or combined) for the other analyzed variables: immunophenotype, traumatic lumbar puncture, interval between diagnosis and first lumbar puncture and place where the procedure was performed. Conclusions These results suggest that a leukocyte count > 50 x 109/L at diagnosis seems to be a significant prognostic factor for a higher incidence of central nervous system relapse in childhood acute lymphoblastic leukemia.