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Previous studies have suggested a variation in the incidence of acute promyelocytic leukemia (APL) among the geographic regions with relatively higher percentages in the Latin American population. We aimed to explore the population burden of pediatric APL, gathering information from the population-based cancer registry (PBCR) and the diagnosis of APL obtained through incident cases from a hospital-based cohort. The homozygous deletion in glutathione S-transferases (GSTs) leads to a loss of enzyme detoxification activity, possibly affecting the treatment response. Mutations in the RAS pathway genes are also considered to be a key component of the disease both in the pathogenesis and in the outcomes. We have assessed mutations in a RAS–MAP kinase pathway (FLT3, PTPN11, and K-/NRAS) and GST variant predisposition risk in the outcome. Out of the 805 children and adolescents with acute myeloid leukemia (AML) who are registered in the PBCR, 35 (4.3%) were APL cases. The age-adjusted incidence rate (AAIR) was 0.03 per 100,000 person-years. One-hundred and sixty-three patients with APL were studied out of 931 AML cases (17.5%) from a hospital-based cohort. Mutations in FLT3, KRAS, and NRAS accounted for 52.1% of the cases. Patients with APL presented a 5-year probability of the overall survival (OS) of 67.3 ± 5.8%. A GST-theta 1 (GSTT1) null genotype conferred adverse prognosis, with an estimated hazard ratio of 2.8, 95% confidence interval (CI) 1.2–6.9. We speculate that the GSTT1 polymorphism is associated with therapeutics and would allow better OS of patients with APL with a GSTT1 null genotype.

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.

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.