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Introdução: A manipulação de antineoplásicos para ajuste de dose, como partição de comprimidos, e comum no tratamento de leucemias agudas de crianças e adolescentes. Objetivo: Identificar a frequência e descrever a pratica da partição domiciliar de comprimidos antineoplásicos utilizados no tratamento oral de crianças e adolescentes com leucemias agudas na fase de manutenção. Método: Trata-se de um estudo transversal descritivo, realizado em um hospital pertencente a rede de saúde publica do Distrito Federal com assistência especializada em pediatria. Foram incluídos no estudo crianças e adolescentes entre 1 e 18 anos, diagnosticados com leucemias agudas e em fase de manutenção do tratamento no período de estudo. Foi aplicado um questionário semiestruturado ao responsável principal pela administração dos medicamentos quimioterápicos via oral, podendo ser o cuidador ou a própria criança/adolescente. Foram coletadas variáveis sociodemográficas dos pacientes e cuidadores e variáveis sobre a pratica de partição de medicamentos antineoplásicos no domicilio. Resultados: Todos os 48 entrevistados no período do estudo relataram ter partido comprimidos antineoplásicos ao longo do tratamento de leucemias agudas, sendo estes mercaptopurina (n=45 [93,75%]) e tioguanina (n=3 [6,25%]). Conclusão: A partição de comprimidos antineoplásicos foi uma pratica unanime em virtude da necessidade referida de ajuste de dose individual para o tratamento de leucemias agudas de crianças e adolescentes, considerando a indisponibilidade de formulações adequadas. Os resultados reforçam a necessidade de a partição ser uniformizada e realizada de maneira a minimizar os riscos e a garantir a segurança para as crianças e adolescentes e seus cuidadores.

Acute leukemia (AL) is the most common type of childhood cancer and has two major subtypes: acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Historically, studies in this field have pointed out driver somatic mutations with different mechanisms of pathogenesis. Family-based and large-scale high-throughput sequencing studies have recently uncovered several genetic germline variants, indicating an inherited origin. Familial history of cancer (FHC) is associated with an increased risk of both ALL and AML. Herein we explore the excess of hematological malignancies (HM) in first-degree relatives of patients diagnosed under 21 years old and compare rates of FHC between AML and ALL cases. We revisited the registry of the Brazilian group Estudos Multi-Institucionais das Leucemias Infantis (EMiLI) comprised of 89 cancer centers from 2009 to 2019. Socio-demographic, immunomolecular, and self-reported FHC data were collected using a structured questionnaire at the beginning of the follow-up. Descriptive statistics were used to assess the frequency distribution and differences between cases. We used unconditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals to evaluate the estimated FHC predisposition to AL. From a total of 5,831 samples, 42.6% were from North/Northeast, 35.7% from South/Southeast, and 21.7% from Midwest macroregions. There was a high frequency of cases (p < 0.001) of Non-White ethnicity in North/Northeast and White ethnicity in South/Southeast. B-cell Precursor ALL was more frequent in Midwest, T-cell acute lymphoblastic leukemia in North/Northeast, and AML cases in South/Southeast. Among 3,618 individuals with AL, 472 had a positive FHC (13%). Of these, 96 (20.3%) reported HM as the origin of cancer. We observed a higher odds of having at least one relative with cancer in AML cases compared to ALL (OR 1.36; 95% CI 1.01-1.82; p = 0.040). When considering only first-degree relatives with any type of cancer, the risk was even more considerable for the AML group than ALL (OR 2.92; 95% CI 1.57-5.42; p = 0.001). With a statistical significance value (p= 0.02), we observed that AML cases present higher odds of having a first-degree relative with FHC with hematologic origin than ALL cases (OR 5.71; 95% CI 1.91-17.08). This effect was not observed analyzing second degree-relatives or relatives with non-hematological malignancies. Our findings suggest that AML is more associated with a positive FHC than ALL, particularly when having a first-degree relative with HM. Both genetic and environmental exposure factors could be involved in the AL subtypes epidemiology. Identifying children with a higher risk of AL would be beneficial by performing early targeted cancer screening and improving prevention and surveillance programs. Further genomic studies exploring Brazilian childhood AL cases with FHC are crucial to elucidate the role of genetic background and ancestry as risk factors associated with leukemogenesis. Citation Format: Daniela P. Mendes-de-Almeida, Francianne G. Andrade, Paulo Chagas-Neto, Maria do Perpétuo Socorro S. Carvalho, José C. Córdoba, Marcelo dos S. Souza, Logan G. Spector, Maria S. Pombo-de-Oliveira, Brazilian Collaborative Study of Childhood Leukemia, Acronym EMiLI. Acute leukemia excess in families [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 801.

Background and Aims The biological characterization of childhood acute myeloid leukemia (c-AML) is an important outcome predictor. In Brazil, very little is known about the frequency of AML subgroups, although c-AML accounts for about 18% of leukemias. We carried out this study to investigate the contribution of type I and II gene mutations in the probability of overall survival (pOS) of c-AML in Brazil. Methods Seven hundred and three de novo pediatric AML cases (2000–2015) were assessed throughout a multicentric network study. Mutations in hotspot regions of FLT3 , NRAS , KRAS , PTPN11 , and c- KIT genes were analyzed as well as fusion genes ( RUNX1 - RUNX1T1 , MLL / KMT2A -r, CBFβ - MYH11 , and PML - RARα ) associated with AML. Patients were treated out of the clinical trial although following the BFM-AML2004 protocol. Acute promyelocytic leukemia (APL) was treated differently. AML with Down syndrome was excluded. Results There were significant differences in gene mutations among age ranges (≤2 years-old; >2–10 years old and ≥11 years old) and the nonrandom association between type I/II mutations. Lower white blood cell count (≤50 × 10 9 /L) was associated with RUNX1 - RUNX1T1 , whereas higher WBC with CBFβ-MYH11 ( p p = 0.03). pOS differences were observed between Brazilian regions. The South-Southeast regions had a better 5-year pOS, whereas the Midwest region presented the poorest pOS (23.7 ± 4.9%). PTPN11 mutations conferred an adverse prognosis as an independent prognostic factor. Conclusions Identification of genetic subgroups contributes to the molecular epidemiology and biology of AML worldwide, reflecting the profile of pediatric AML cases in Brazil.

Transient myeloproliferative disorder is a form of self-limited leukemia that occurs almost exclusively in neonates with Down syndrome. The authors report an unusual case of a newborn without constitutional trisomy 21 who developed undifferentiated leukemia and subsequently achieved clinical and molecular remission without chemotherapy. Cytogenetics and molecular analysis have shown trisomy 21 and GATA1 mutation restricted to leukemic cells. G-to-T transversion was detected, which is predicted to result in a premature stop codon (c.119G>T; pGlu67X) in diagnosis samples. These findings emphasize that there must be a powerful interaction between GATA1 and trisomy 21 in leukemogenesis process.

Os autores descrevem as caracteristicas biologicas de 1.459 criancas com leucemias agudas no Brasil, para comparar os efeitos de diferentes perfis imunofenotipicos com fatores ambientais que podem estar associados a etiologia das leucemias linfoblasticas agudas (LLA). As classificacoes morfologicas e imunofenotipicas combinadas foram aplicadas em 96% dos casos. Nestes, 55% foram classificados como LLA de celulas B precursoras (LLA-Bp) que compreendem LLA-pro-B e LLA-comum, 15% LLA-T, e 1,6% LLA-B. A proporcao de LLA-Bp e LLA-T difere entre si quanto a raca, com 59% das LLA-Bp em criancas brancas, enquanto 60,7% LLA-T em criancas nao-brancas. No entanto, as analises proporcionais de brancos versus nao brancos para cada subtipo, quando ajustadas por idade, sao semelhantes em criancas maiores de 6 anos (60,3% LLA-Bp e 59,3% LLA-T), mas diferem substancialmente em criancas menores, com 63,6% de LLA-Bp e 37,3% de LLA-T em brancos (0,0001). Estes resultados sao consistentes com excesso de LLA-Bp em criancas brancas mais jovens, embora a distribuicao entre LLA-Bp e LLA-T em cada regiao seja semelhante sem significado estatistico. As taxas de incidencias de LLA calculadas para cada regiao variaram de 2,2, 2,6 e 3,3/105 casos por ano para Bahia, Rio de Janeiro e Brasilia, respectivamente. Para avaliar se o pico de incidencia observado de LLA-Bp estaria relacionado com incidencia de infecao viral, nos observamos que LLA-Bp apresentou uma curva ascedente de casos no verao e inverno, enquanto LLA-T apresentou pico de incidencia no outono. Este estudo adiciona informacoes sobre epidemiologia de leucemias agudas no Brasil, no qual sugere que o subtipo LLA-comum poderia estar associado com tempo de exposicao a infeccao viral requerendo futuras analises especificas.

Coelhos inoculados com tripomastigotas da cepa Ernestina do Trypanosoma cruzi tiveram parasitemias, demonstradas pelo xenodiagnóstico, até cinco meses e meio após a infecção. O tratamento de alguns desses coelhos com benzonidazol, na dose de 8mg/kg durante sessenta dias, após dois meses de infecção, resultou na negativação dos xenos após 30 dias de uso da medicação. Os coelhos chagásicos crônicos, após seis meses de infecção, já tinham a parasitemia subpatente quando foram submetidos a tratamento idêntico àqueles da fase aguda. Em ambos os casos, os coelhos tratados com benzonidazol tiveram títulos de anticorpos humorais semelhantes àqueles verificados nos coelhos chagásicos não- tratados, inclusive durante a quimioterapia. A não alteração da imunidade humoral em coelhos tratados foi comprovada quando animais chagásicos e não chagásicos submetidos ao tratamento produziram títulos de anticorpos hemolíticos idênticos àqueles verificados nos animais não-tratados. Em acentuado contraste, a função imune timo-dependente foi severamente alterada pelo uso do benzonidazol. As reações de hipersensibilidade tardia contra um antígeno sub- celular do T. cruzi foram suprimidas durante a vigência do tratamento dos coelhos chagásicos. Paralelamente, estas reações eram intensas nos coelhos chagásicos não-tratados e negativas em coelhos controles normais. Todavia, as reações cutâneas tornaram-se novamente positivas 10 dias após o tratamento. Foi interessante notar que as reações de hipersensibilidade tardia in vivo, em coelhos imunizados com BCG e testados com PPD ou em coelhos sensibilizados com DNCB também foram suprimidas durante o tratamento com o benzonidazol. Contudo, as reações de imunidade celular contra estes antígenos também reverteram aos valores normais 7 a 10 dias após a suspensão do benzonidazol. Resultados semelhantes foram relatados em relação ao nifurtimox, outra droga utilizada no tratamento da doença de Chagas. 0 benzonidazol e o nifurtimox são compostos nitro-aromáticos cuja nitrorredução resulta na formação de metabólitos intermediários potencialmente citotóxicos para o protozoário e para as células do hospedeiro.Rabbits inoculated with trypomastigotes of the Ernestina strain of Trypanosoma cruzi showed parasitemias, which were demonstrated by xenodiagnosis during five and half months of the infection. The administration of 8mg/kg/day for 2 months of benznidazole in rabbits with two months infection resulted in persistently negative xenodiagnoses after 30 days of chemotherapy. Also rabbits with chronic Chagas' disease showing negative parasitemia six months after infection were treated with benznidazole. Both groups of rabbits that received intraperitoneal injections of the drug had titers of serum antibodies to the parasite similar to those shown in untreated T. cruzi-infected rabbits. That the humoral antibody response is not altered by the benznidazole was demonstrated in other experiments, which showed that the animals under chemotherapy can produce hemolytic antibody titers as high as those found in Controls as wellas in T. cruzi-infected untreated rabbits. In marked contrast, the thymus-dependent immune function was severely affected by benznidazole. The delayed-type hypersensitivity reaction against a T. cruzi subcellular antigen was suppressed during chemotherapy, whereas the reaction was consistently present in untreated T. cruzi-infected rabbits. However, delayed-type hypersensitivity against the parasite antigen could be elicited 10 days after cessation of treatment. Also delayed hypersensitivity in rabbits immunised with BCG and tested using PPD or in rabbits sensitised to DNCB were also suppressed by benznidazole treatment. It has been shown therefore that both drugs used for treating Chagas' disease can produce profound alterations in the thymus-dependent immune response. Benznidazole and nifurtimox are nitro-aromatic compounds that undergo enzymatic reduction with production of intermediate metabolites that can be strongly cytotoxic for the T. cruzi and for the mammalian cells.