Waldir Veiga Pereira

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.

Estimated number of cases, regional distribution and survival of patients diagnosed with acute myeloid leukemia between 1996 and 2000 in Rio Grande do Sul, Brazil

Rio Grande do Sul (RS), in South Brazil, with about 10 million inhabitants, is known for its agricultural activities and consequent increased human exposure to toxic agents. Patients with de novo acute myeloid leukemia (AML) were included based on information retrieved from all referral hospitals in RS between 1996 and 2000. A total of 532 patients were registered. Median age at diagnosis was 42 years. The estimated annual incidence was 1.11 cases/100 000 inhabitants/year. There was an estimated incidence of 0.5 – 1 case per 100 000 inhabitants up to the age of 45 years, and of 3.5 cases per 100 000 inhabitants aged 70 years and older, with no geographical clusters. The mean 5-year survival rate was 17% for all cases. There was an increased number of M3 cases, as already described for individuals of Latin-American and the mortality rate was similar to that described in the literature.

The association of ICAM-1 Exon 6 (E469K) but not of ICAM-1 Exon 4 (G241R) and PECAM-1 Exon 3 (L125V) polymorphisms with the development of differentiation syndrome in acute promyelocytic leukemia.

The use of all trans‐retinoic acid (ATRA) is the basis of treatment of acute promyelocytic leukemia (APL) and represents the paradigm of differentiation therapy. In general, ATRA is well‐tolerated but may be associated with a potentially lethal side‐effect, referred to as retinoic acid or differentiation syndrome (DS). The cellular and molecular mechanisms of DS are poorly understood and involve changes in the adhesive qualities and cytokine secretion of leukemic cells during ATRA‐induced differentiation. As leukocyte extravasation is a key event in DS pathogenesis, we analyzed the association between the polymorphisms at Exon 4 (G241R) and Exon 6 (E469K) of ICAM‐1 and Exon 3 (L125V) of PECAM‐1 genes with DS development in APL patients treated with ATRA and anthracyclines. DS was diagnosed in 23/127 (18.1%) APL patients at an average of 11.5 days after the start of ATRA. All patients presented respiratory distress associated with increased ground‐glass opacity in chest radiographies. Other accompanying symptoms were: fever not attributable to infection (65.2%), generalized edema (37.5%), weight gain (37.5%), and impairment of renal function (8.6%). We detected an association between development of DS and the AA genotype at Codon 469 of ICAM‐1 (odds ratio of 3.5; 95% confidence interval: 1.2–10.2). Conversely, no significant association was detected between G241R or L125V polymorphisms at Exon 4 of ICAM‐1 and Exon 3 of PECAM‐1, respectively. Our results suggest that susceptibility to DS in APL patients may be influenced by genetic variation in adhesion molecule loci.

Monoclonal Antibody Anti-MPO is Useful in Recognizing Minimally Differentiated Acute Myeloid Leukaemia

The enzyme myeloperoxidase (MPO) is the most specific marker of myeloid lineage. The recognition of acute myeloid leukaemia (AML) with minimally differentiation (AML-M0) is established with methods that include myeloid markers CD13/CD33 and detection of MPO in blast cells by immunological techniques or electron microscopy cytochemistry (EM). We have analysed the presence of MPO in leukaemic blast cells by conventional cytochemistry and immunological methods using a monoclonal antibody anti-MPO (CLB-MPO1) in 121 cases of acute leukaemia. The aim of the study was to investigate the sensitivity of this McAb to identify AML-M0, as CD13/CD33 can be expressed in some cases of acute lymphoblastic leukaemia (ALL) and EM cytochemistry is not always available in many laboratories. Anti-MPO was positive in all cases of AML (M1-M5) which were positive by Sudan Black B reaction in similar or higher percentage ratio for each case, although in some of them did not label with CD13/CD33 tested by IF and IPc techniques. Based on the anti-MPO positivity, 5 out of 10 cases called undifferentiated leukaemia (AUL) were reclassified as AML-M0, though 4 cases were CD13/CD33 negative. Furthermore, after analysing the anti-MPO expression among 32 cases of ALL, we had to reclassify four of them as acute biphenotypic leukaemia. We conclude that anti-MPO is a very sensitive and reliable tool in AML diagnosis and has an important role in distinguishing minimally differentiated AML and biphenotypic acute leukaemia from AUL and ALL.

In vitro evaluation of triazenes: DNA cleavage, antibacterial activity and cytotoxicity against acute myeloid leukemia cells

). The observation of intermolecular hydrogen bonding in the solid state of compound 3, based on the structural analysis by X-ray crystallography, as well as the results of IR and UV-Vis spectroscopic analyses of compounds 1, 2 and 3 are discussed in the present work.

Carboplatin in the treatment of Ewing sarcoma: Results of the first Brazilian Collaborative Study Group for Ewing Sarcoma Family Tumors—EWING1

Large cooperative group studies have shown the efficacy of risk‐adapted treatment for Ewing sarcoma. However, validation and local adaptation by National cooperative groups is needed. A multicenter protocol to determine the efficacy and safety of a risk‐adapted intensive regimen was developed by the Brazilian cooperative group.

External auditory canal and middle ear relapse of acute promyelocytic leukemia treated with arsenic trioxide: case report and review of the literature.

Extramedullary involvement occurs infrequently in acute promyelocytic leukemia and is said to be more common after treatment with all-trans retinoic acid. We describe a 9-year-old girl who had an isolated external auditory canal and middle ear relapse after treatment with all-trans retinoic acid and chemotherapy. A patient with cytogenetically and molecularly confirmed acute promyelocytic leukemia developed isolated extramedullary relapse in the auditory canal and middle ear 4 years and 9 months after initial diagnosis, while in hematologic and molecular remission, successfully treated with arsenic trioxide alone.

Dipodascus capitatus (Geotrichum capitatum): infecção sistêmica fatal em paciente com leucemia mielocítica aguda

The infections caused by Dipodascus capitatus are rare, and the treatment is difficult. We reported a case of a patient with acute myeloid leukemia. The fungus was first isolated from hemocultures, and the phenotypic identification was based on mycological methods. The genotyping was carried out by sequencing the region D1/D2 from 26 rDNA. The susceptibility tests were assayed by Etest® and by the microdilution technique. None of the antifungal treatments employed were effective. The patient died on day 17 after the mycological diagnosis. The authors discussed the emergence of such infections as well as the difficulty regarding the diagnosis and treatment.

Leucemia Mielocítica Aguda da infância e adolescência: fracassos e vitórias

Embora estes sucessos fossem esporadi-cos, quebrava-se o paradigma da incurabilidade e nasciauma era de esperanca.A organizacao de grupos cooperativos para o trata-mento experimental desta doenca teve influencia definitivanos resultados animadores que hoje alcancamos. Como emoutras areas da terapeutica oncologica comecamos a dispordos farmacos mais importantes para tratar a LMA: a ARA-Ce os antraciclicos ja nos anos 1970. Nao sabiamos, porem, amelhor maneira de usa-los. Durante alguns anos, apesar dete-los ao nosso alcance, muitas vidas foram perdidas ate queestudos, na maioria prospectivos, nos conduziram a melho-res maneiras de maneja-las. Ate hoje continuam sendo a es-pinha dorsal do tratamento da LMA. Atualmente, em tornode metade destes pacientes podem ser curados quando en-caminhados, em tempo apropriado, a centros de excelenciapara o tratamento desta doenca.Foi, sem duvida, uma grande conquista, mas continuasendo um grande desafio avancar com a pesquisa basica eclinica para resgatar a outra metade. E por este motivo queos tratamentos devem, em grande parte das vezes, ser asso-ciados a grupos de investigadores experientes e institui-coes com capacidade de suporte para sustentar a opera-cionalizacao destes estudos cooperativos. Ainda com osmeios hoje disponiveis, ha controversias de qual a maneiramais apropriada de tratar a LMA. O fato de metade, ou mais,dos pacientes nao alcancarem a cura, o tratamento deveainda ser considerado em fase investigacional. As duvidasse estendem tanto ao tratamento de inducao de remissaocomo o de pos-remissao.Algumas questoes podem ser postas:Qual a intensidade da inducao? Sabe-se hoje que aassociacao ARA-C + antraciclico pode gerar remissao com-pleta em 70% a mais de 80% dos pacientes. E uma fase detratamento de grande morbidade em que devem ser bem pe-sados os ganhos e as perdas resultantes da maior ou menorintensidade do tratamento.A duracao de sete a dez dias consecutivos com ARA-Ce mais de tres com antraciclicos talvez nao eleve expressiva-mente os indices de remissao. A grande questao e se umtratamento mais intensivo com a adicao de outros farmacos,elevando doses, ou comprimindo o espaco de tempo entreos ciclos iniciais de quimioterapia, resultaria em maior redu-cao da Doenca Residual Minima (DRM) e eventual elevacaodo indice de cura. Um estudo do Grupo CCG Protocolo 2891revelou que os indices de sobrevida global eram superiorescom a inducao intensiva, baseada em intervalo curto e fixoentre os dois ciclos de inducao, em vez de intervalos comduracao suficiente para recuperacao medular.

Inherited factor V deficiency. Study of a Brazilian family.

Isolated Factor V deficiency is a very rare inherited coagulopathy. A genealogy of Brazilian Caucasians, where this disorder occurs, is reported. In this family, which was located because 2 affected individuals having the same surname were found by chance, the genealogical and laboratory data suggest an autosomal recessive pattern of inheritance. Nevertheless, the existence of deceased individuals who were reported as symptomatic seems to imply that some heterozygotes may present occasional bleeding episodes.