Introdução: O câncer em crianças e adolescentes com idade entre 0-19 anos configura-se como um problema de saúde pública tanto nos países desenvolvidos como nos países em desenvolvimento. É considerado raro e distinto quando comparado com o câncer em adultos. Apresenta padrões de incidência e mortalidade que variam em todo mundo, sendo que aproximadamente 80% dos cânceres infantis ocorrem nos países com baixo índice de desenvolvimento humano, com acesso aos serviços de cuidado à saúde de baixa qualidade. Objetivo: Apresentar um panorama geral do câncer em crianças e adolescentes com idade entre 0-19 anos com ênfase na descrição dos resultados de estudos de base populacional para incidência e mortalidade nas diferentes regiões geográficas no Mundo e no Brasil. Resultados: As taxas de incidência gerais para o câncer em crianças e adolescentes com idade entre 0-19 variaram entre 50 e 200 casos por milhão por ano em diferentes países e continentes. No Brasil, a mediana das taxas a incidência foi de 154,3 por milhão. A mortalidade apresentou declínio em várias partes do mundo, sendo considerada a segunda causa de morte em países desenvolvidos. Conclusão: As informações dos registros de câncer são indispensáveis no enfrentamento do câncer na população pediátrica, principalmente nos países em desenvolvimento, onde o impacto do câncer é pouco conhecido, ao passo que seu efeito sobre a população está aumentando. Melhorias na adoção de estratégias de tratamento integrado devem ser consideradas para melhorar as taxas de mortalidade por câncer em crianças e adolescentes no Brasil e no Mundo.
Background. Previous studies have suggested a variation in the incidence of acute promyelocytic leukemia (APL) among geographic regions with relatively higher percentages within the Latin American population. We aimed to describe the population burden of pediatric APL (p-APL) in Brazil assessing the incidence rates according to a hospital-based and population-based cancer (PBCR) registries. We also explored mutations in genes of the RAS pathway and the association of polymorphisms in genes of glutathione S-transferases (GSTs) with outcome. Our goal was to provide insights into the distribution of clinical-demographic data and the molecular epidemiology characteristics associated with APL outcome. Methods. One hundred and sixty-four p-APL cases (<19 years old) were identified from a dataset of a hospital-based registry based at a leukemia diagnostic central reference laboratory (2002-2018) and from 15 PBCR (2002-2009). Diagnostic criteria included morphological, immunophenotypic, and cytogenetic-molecular features. The PML-RARafusion gene was detected by FISH and/or RT-PCR. Additionally, mutations in FLT3 [D835 and internal tandem duplications (ITD)], KRAS, NRAS, and PTPN11 mutations were analyzed. We also evaluated the risk association of pharmacogenetically important GST deletion polymorphisms (GSTT1 and GSTM1) by multiplex-PCR, in a case-case analysis to test the effect of genetic susceptibility on overall survival (OS). Patients were treated with the inclusion of all-trans retinoic acid in chemotherapy with anthracyclines and cytarabine. Kaplan-Meier survival analysis was used to calculate the 5-year probabilities of OS (pOS), and estimated survival values were compared using the log-rank test. Cox proportional-hazard regression model estimated the hazard ratio (HR) and 95% confidence intervals (CI). All p-values were two-sided using significance level of 0.05. Results. From the hospital-based registry, APL patients represented 17.6% of the cohort (164 out of 933 acute myeloid leukemia cases), while in the PBCR, they represented 4.4% (35 out of 805 acute myeloid leukemia cases registered). The age-adjusted incidence rate was 0.32 per million persons during 2000-2009 based on PBCR. According to the hospital-based registry, we found similar distribution of patients among age ranges >2-10 and >10-21 years old (43.3% and 51.8%, respectively) and sex. RAS mutations were observed in 51.7% of APLs, including FLT3 (43.0%), NRAS (6.5%), and KRAS (2.2%). Variants in PTPN11 were silent amino acid substitutions (rs61736914; 4.9%). We observed a statistically significant association between FLT3 mutations and high white blood cell count at diagnosis (>10x109/L; 72.6%), low platelet count (<40×109/L; 83.0%), and the PML-RARa breakpoint cluster region 3 (90.5%). Death in the first ten days after diagnosis (early death) affected 17.5% (24/137) patients and these cases were excluded from the survival analysis. The mean of overall survival was 45.1 months (95% CI 40.1-50.1 months; pOS 66.9±5.8%). Univariate analysis did not show an association between variables and OS rates, except for APL patients carrying the GSTT1 polymorphism. GSTT1 null genotype conferred adverse prognosis compared to wild-type genotype (pOS 48.2±13.4% and 79.0±6.3%, p=0.024; hazard ratio 2.6, 95% CI 1.1-6.2, p=0.030; Figure 1). Conclusions. APL represented 17.6% of acute myeloid leukemia in our cohort of Latino patients, which is a higher proportion compared to Northern European countries and the United States (5-10%). GSTT1 polymorphism modulated outcome, suggesting that lower enzyme activity may impact response to therapy. Decreasing early death and inclusion of GSTT1 polymorphism in therapeutic protocols for chemotherapy dose modulation may allow patients to reach the same overall survival observed in the United States (>70%). Disclosures No relevant conflicts of interest to declare.
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.
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