Background: An association between pesticide exposure and cancer has been suggested. Infant leukemia is a rare neoplasm and its association with maternal pesticide exposure has been poorly explored.Objectives: We investigated the association between pesticide exposure during pregnancy and leukemia in children < 2 years of age.Methods: A hospital-based case–control study was carried out in 13 Brazilian states during 1999–2007. Mothers of 252 cases and those of 423 controls were interviewed. Information on pesticide exposures 3 months before pregnancy, throughout pregnancy, and during breastfeeding was obtained. Unconditional logistic regression was used to estimate adjusted odds ratios (aORs) for associations between pesticide exposures and leukemia.Results: Associations with ever use of pesticides during pregnancy were observed for acute lymphoid leukemia (ALL) (aOR = 2.10; 95% CI: 1.14, 3.86) and acute myeloid leukemia (AML) (aOR = 5.01; 95% CI: 1.97, 12.7) in children 0–11 months of age, and with ALL (aOR = 1.88; 95% CI: 1.05, 5.23) at 12–23 months of age. According to reported maternal exposure to permethrin, higher risk estimates were verified for children 0–11 months of age (aOR = 2.47; 95% CI: 1.17, 5.25 for ALL; and aOR = 7.28; 95% CI: 2.60, 20.38 for AML). Maternal pesticide exposure related to agricultural activities showed an aOR of 5.25 (95% CI: 1.83, 15.08) for ALL, and an aOR of 7.56 (95% CI: 1.83, 31.23) for AML.Conclusions: These results support the hypothesis that pesticide exposure during pregnancy may be involved in the etiology of acute leukemia in children < 2 years of age.

About 95% of HTLV-1 infected patients remain asymptomatic throughout life, and the risk factors associated with the development of related diseases, such as HAM/TSP and ATL, are not fully understood. The human leukocyte antigen-G molecule (HLA-G), a nonclassical HLA class I molecule encoded by MHC, is expressed in several pathological conditions, including viral infection, and is related to immunosuppressive effects that allow the virus-infected cells to escape the antiviral defense of the host. The 14-bp insertion/deletion polymorphism of exon 8 HLA-G gene influences the stability of the transcripts and could be related to HTLV-1-infected cell protection and to the increase of proviral load. The present study analyzed by conventional PCR the 14-bp insertion/deletion polymorphism of exon 8 HLA-G gene in 150 unrelated healthy subjects, 82 HTLV-1 infected patients with symptoms (33 ATL and 49 HAM), and 56 asymptomatic HTLV-1 infected patients (HAC). In addition, the proviral load was determined by quantitative real-time PCR in all infected groups and correlated with 14-bp insertion/deletion genotypes. The heterozygote genotype frequencies were significantly higher in HAM, in the symptomatic group, and in infected patients compared to control (p < 0.05). The proviral load was higher in the symptomatic group than the HAC group (p < 0.0005). The comparison of proviral load and genotypes showed that -14-bp/-14-bp genotype had a higher proviral load than +14-bp/-14-bp and +14-bp/+14-bp genotypes. Although HLA-G 14-bp polymorphism does not appear to be associated with HTLV-1 related disease development, it could be a genetic risk factor for susceptibility to infection.

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Objective: To analyze trends in childhood leukemia mortality in the state of Rio de Janeiro, Brazil, between 1980 and2006. Method: Gender-stratified leukemia mortality data for children aged < 15 years from 1980 to 2006 were retrieved from the Brazilian Mortality Information System for the state of Rio de Janeiro. Data were stratified by place of death (city of Rio de Janeiro proper, the state capital; Rio de Janeiro Metropolitan Region, excluding the capital; and rest of the state). Leukemia deaths were defined according to death certificate ICD-9 and ICD-10 coding (for deaths occurring in 1980-1995 and 1996-2006, respectively). Leukemia mortality rates were calculated by age and calendar year and age-adjusted to a standard world population. Polynomial linear regression with a 5% significance level was used to evaluate mortality trends in the study regions. Results:The three studied regions revealed similar trends, with a continuous downward pattern; the most substantial decline was detected in the municipality of Rio de Janeiro (city proper). In all studied areas, leukemia mortality was highest among males. Conclusions:A downward trend in childhood leukemia mortality was detected throughout the state of Rio de Janeiro. The most pronounced reduction occurred in the state capital. (CID-9), no período de 1980 a 1995, e segundo a CID-10 no período de 1996 a 2006. As taxas de mortalidade foram calculadas por faixa etária e ano de óbito, sendo, em seguida, ajustadas pela população mundial. Para análise de tendência, optou-se pelos modelos de regressão linear polinomial. Foi considerado um nível de significância de 5%. J Pediatr (Rio J)Resultados: As análises de tendência nas três localidades apresentaram perfis semelhantes, com um padrão decrescente e constante. Entretanto, a capital apresentou a maior queda em suas taxas. Analisando a tendência das taxas de mortalidade por leucemia infantil segundo o sexo, foi observado que, no sexo masculino, a incidência foi maior quando comparada ao sexo feminino nas três localidades analisadas. Conclusão:Foi observada uma tendência de declínio da mortalidade por leucemias na infância no estado do Rio de Janeiro, sendo mais acentuada na capital do que na região metropolitana e no interior do estado. J Pediatr (Rio J)

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Background: Different event-free survival rates (EFS) of childhood ALL treatment regarding race, were published in the literature. However, a better consensus exists considering the bad prognosis of undernutrition. Taking into account the social economic reality of a low-income country such as Brazil, the systematic evaluation of these variables is of utmost importance, while inserted in a modern ALL treatment protocol. Objective: To compare, prospectively, the long-term EFS rates of previously untreated children with ALL, according to race and nutritional status at diagnosis. Methods: Patients were classified as Low Risk and High Risk according to NCI Criteria. Treatment schedule: Low Risk group: Remission induction therapy with DEXA 6mg/m2/d × 28 days, VCR 1.5 mg/m2/wk × 4, Daunomycin 25 mg/m2/wk × 4, L-ASP 10.000 U/m2/dose × 8, Ara-C 75mg/m2/dose × 8 and TIT therapy (day 0,28 and 42). Intensification therapy with MTX 2g/m2/wk × 4, 24 h continuous infusion with LCV rescue 15mg/m2/dose × 4, 6MP-50mg/m2 d × 21days and TIT therapy (x 4). Re-induction therapy: Dexa 6mg/m2 d × 21days, VCR 1.5mg/m2/wk × 4, L-ASP 10.000 U/m2/d × 4, 6-MP 50mg/m2/d × 14days, Ara-C 75 mg/m2/d × 4 and TIT therapy (x3). Central randomization was done for maintenance therapy duration (130 vs 103 wk). Maintenance: 6-MP 50mg/m2/d, MTX 25mg/m2/wk and TIT therapy every 8 weeks during all treatment. No CNS radiation was done. For High Risk patients, an induction intensification with intermediate dose of AraC (750 mg/m2/d × 6) was introduced, as well as, a rotational maintenance therapy with different pair of drugs were proposed (AraC 750mg/m2 × 4/Asp 6 000 U; Dexa/VCR/wk × 3 and 6-MP 75 mg/m2/d × 21 days/MTX 40 mg/m2/wk × 3). Prophylatic CNS radiation(18Gy) was done at wks 19–21 of therapy. Statistical analysis: EFS is defined as the time from diagnosis till any failure, relapse, death, or the development of a second malignancy. Continuous complete remission duration (CCR) is defined as EFS, contingent upon induction of a complete remission. EFS and CCR rates have been estimated by Kaplan and Meier’s method. Results: From October 1993 to September 1999, 867 patients were consecutively enrolled in the protocol GBTLI ALL-93. Fourteen pts were excluded (1.5%), due to wrong diagnosis or previous corticosteroid treatment. 853 pts were evaluated in this study. 447 pts were classified as Low Risk group (52%) and 406(48%) as High Risk. According to race, 226 pts (26.5%)were classified as black and 627 (73.5%) as white. Overall undernutrition was diagnosed among 7.0 % of the patients. In the black population 10.4% were undernourished, comparing with 5.7% in the white group. The 14yrs-EFS for all the study patients is 80% ± 2% and 55% ± 2.5% for the Low Risk and High Risk pts, respectively. Concerning race, the 14yrs-EFS is of 71.7% ± 4.5% for the black children, comparatively to 83% ± 2.1% for the white ones (p=0.01). According to the nutritional status, the EFS is of 70.2%± 1.7% and 53.0%± 6.8% for the nourished and undernourished children, respectively. Malnutrition had the worst desfavorable impact among the High Risk pts, with a 14yrs-EFS of 40.1% ± 8.7%, compared to those without malnutrition of 57.8% ± 2.7% (p = 0.05). Social and economical issues directly involved with treatment, were provided by means of free medical attention and drugs supplies. Treatment abandon was &lt; 1%. Conclusion: The black race and undernutrition had significant adverse effect on the long-term EFS among the patients of this study.

BACKGROUND Deletions in IKZF1 are found in approximately 15% of children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL). There is strong evidence for the poor prognosis of the most common IKZF1 deletions affecting exons 4-7 (DEL 4-7) and exons 1-8 (DEL 1-8), but evidence for the remaining 33% of cases harboring other variants of IKZF1 deletions is lacking. In an international multi-centre study we analyzed the prognostic value of these rare variants. METHODS Multiplex ligation-dependent probe amplification (MLPA) assays were performed on genomic DNA from patients’ bone marrow aspirates at diagnosis by the national study groups. Each IKZF1-deleted case was matched to three wild-type controls based on cytogenetic subtype, treatment protocol, stratification arm, white blood cell count and age at diagnosis. Known high-risk factors age <1 year (infants), BCR-ABL1-positive, and MLL-rearranged cases were excluded. We compared the cumulative incidence of relapse with death as competing event (CIR) between cases and their controls using Gray’s test. Matched pair Cox regression was used for event-free survival (EFS) analysis, and the hazard ratio (HR) with 95% confidence interval (CI) was reported. RESULTS We included 134 BCP-ALL cases with a rare IKZF1 deletion and 402 matched controls. Of these cases, 26 (19%) had a deletion in exon 2 to 3 (DEL 2-3), 32 (24%) in exon 2 to 7 (DEL 2-7), 15 (11%) in exon 2 to 8 (DEL 2-8), 27 (20%) in exon 4 to 8 (DEL 4-8), and 34 (25%) belonged to the remaining group (DEL-Other). All rare IKZF1 deletion variants together had a higher 5-year CIR compared with the matched wild-type controls (40% vs. 22%, p<0.001), and a lower matched pair EFS (HR 1.8, 95% CI: 1.4-2.3; p<0.001). Analysis of cases and matched controls within their own risk group (56 standard risk, 33 intermediate risk and 45 high risk cases), showed an unfavorable effect for rare IKZF1 deletions in all stratification groups. Rare IKZF1 deletions were found in all BCP-ALL subtypes. The frequency of ETV6-RUNX1-positive (12 cases, 9%), high-hyperdiploid (21 cases, 16%), and unclassified BCP-ALL (13 cases, 10%) was relatively low among rare IKZF1-deleted cases. Most cases were found in the B-other group (88 cases, 66%). These B-other cases had a higher 5-year CIR compared with wild-type controls (47% vs. 27%, p<0·001), which translated into a lower EFS (HR 1·8, 95% CI: 1·3-2·4, p=<0·001). CIR and EFS analysis of high-hyperdiploid cases revealed a weak trend for an adverse outcome associated with rare IKZF1 deletions (5-year CIR 29% vs. 18%, p=0·1 and HR 2·4, 95% CI: 0·8-6·7, p=0·1). No prognostic impact was seen for rare IKZF1 deletions in ETV6-RUNX1-positive BCP-ALL Separate analyses per IKZF1 deletion type showed a higher 5-year CIR for DEL 2-7 (38% vs. 18%, p=0.05), for DEL 2-8 (60% vs. 31%, p=0.02), and for DEL-Other cases (45% vs. 24%, p=0.04). Matched pair analysis of EFS revealed a poor prognosis for DEL 2-7 (HR 2·0, p=0·03), DEL 2-8 (HR 2·2, p=0·002), and DEL-Other (HR 2·2, p<0·001). The CIR and EFS of DEL 2-3 cases displayed a trend for unfavorable outcome (5-year CIR 28% vs. 17%, p=0.06; HR 1.8, p=0.1) but not for DEL 4-8 (34% vs. 26%, p>0.1; HR 1.0, p>0.1). The prognosis of each rare variant, including DEL 2-3 and DEL 4-8, was equal or worse compared with the most frequently observed and unfavorable prognostic DEL 4-7 and DEL 1-8 variants. CONCLUSIONS All types of rare IKZF1 deletions, with the possible exception of DEL 4-8 cases, had a significantly increased risk of relapse and poorer EFS compared with their matched wild-type controls. The prognosis of DEL 4-8 cases was as poor as those of the other rare variants and that of the known high-risk variants DEL 4-7 and DEL 1-8. We therefore conclude that all variants of IKZF1 deletions are equivalent in terms of their prognostic impact. Disclosures No relevant conflicts of interest to declare.

The IL7/IL7R mediated signaling is essential for normal development and homeostasis of T cell precursors. Early studies have shown that around 10% of patients with Acute lymphoblastic leukemia T cell (T-ALL) have mutations in the alpha chain of the receptor for IL7 (IL-7Ralpha) driving constitutive signaling via JAK1 and independent of IL-7, gamma-chain or JAK3. Some genetic changes are important factors to initiate leukemia, but in many cases these changes are insufficient to achieve the complete leukemic phenotype, suggesting that collaborative oncogenic mutations may be present. To identify candidate mutations that work in collaboration with the oncogenic IL7R, we performed exome sequencing and SNP-CNV-Array assay on a group of eight primary T-ALL samples carrying the IL7R mutation (T-ALL-IL7Rmut). The microarray was performed using Cytoscan HD - Affymetrix and CNVs were detected by ChAs software, version 2.0.1.2. For exome sequencing we used Illumina Hiseq2000 platform and Agilent SureSelect V4 51M Capture kit (mean sequencing depths of 80X / 50X for leukemia and remission samples, respectively). Somatic Single Nucleotide Variants (SNVs) and Small Insertion/Deletion (InDels) were detected using VarScan, and mutations were functionally annotated using ANNOVAR. All somatic mutations detected were manually curated. We found 17 genes recurrently mutated (in ≥ 2 cases) and chose five of them for further analyses due to their previous involvement in ALL (PHF6, RB1, CTCF, SGK223 and DNM2). Ongoing experiments are being conducted to determine whether these recurrent mutations can collaborate functionally with mutIL7R by co-transfection into immature murine thymocytes, transplanting into mice and determining incidence of leukemia. Disclosures No relevant conflicts of interest to declare.