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The gene fusions BCR-ABL1, TCF3-PBX1, and ETV6-RUNX1 are recurrent in B-cell acute lymphoblastic leukemia (B-ALL) and are found with low frequency in coexistence with CRLF2 (cytokine receptor-like factor 2) rearrangements and overexpression. There is limited information regarding the CRLF2 abnormalities and dominant-negative IKZF1 isoforms associated with surrogate markers of Jak2, ABL, and Ras signaling pathways. To assess this, we evaluated 24 Mexican children with B-ALL positive for recurrent gene fusions at diagnosis. We found CRLF2 rearrangements and/or overexpression, dominant-negative IKZF1 isoforms, and surrogate phosphorylated markers of signaling pathways coexisting with recurrent gene fusions. All the BCR-ABL1 patients expressed CRLF2 and were positive for pCrkl (ABL); most of them were also positive for pStat5 (Jak2/Stat5) and negative for pErk (Ras). TCF3-PBX1 patients with CRLF2 abnormalities were positive for pStat5, most of them were also positive for pCrkl, and two patients were also positive for pErk. One patient with ETV6-RUNX1 and intracellular CRLF2 protein expressed pCrkl. In some cases, the activated signaling pathways were reverted in vitro by specific inhibitors. We further analyzed a TCF3-PBX1 patient at relapse, identifying a clone with the recurrent gene fusion, P2RY8-CRLF2, rearrangement, and phosphorylation of the three surrogate markers that we studied. These results agree with the previous reports regarding resistance to treatment observed in patients with recurrent gene fusions and coexisting CRLF2 gene abnormalities. A marker phosphorylation signature was identified in BCR-ABL1 and TCF3-PBX1 patients. To obtain useful information for the assessment of treatment in B-ALL patients with recurrent gene fusions, we suggest that they should be evaluated at diagnosis for CRLF2 gene abnormalities and dominant-negative IKZF1 isoforms, in addition to the analyses of activation and inhibition of signaling pathways.

Ph-like subtypes with CRLF2 abnormalities are frequent among Hispano–Latino children with pre-B ALL. Therefore, there is solid ground to suggest that this subtype is frequent in Mexican patients. The genomic complexity of Ph-like subtype constitutes a challenge for diagnosis, as it requires diverse genomic methodologies that are not widely available in diagnostic centers in Mexico. Here, we propose a diagnostic strategy for Ph-like ALL in accordance with our local capacity. Pre-B ALL patients without recurrent gene fusions (104) were classified using a gene-expression profile based on Ph-like signature genes analyzed by qRT-PCR. The expressions of the CRLF2 transcript and protein were determined by qRT-PCR and flow cytometry. The P2RY8::CRLF2, IGH::CRLF2, ABL1/2 rearrangements, and Ik6 isoform were screened using RT-PCR and FISH. Surrogate markers of Jak2-Stat5/Abl/Ras pathways were analyzed by phosphoflow. Mutations in relevant kinases/transcription factors genes in Ph-like were assessed by target-specific NGS. A total of 40 patients (38.5%) were classified as Ph-like; of these, 36 had abnormalities associated with Jak2-Stat5 and 4 had Abl. The rearrangements IGH::CRLF2,P2RY8::CRLF2, and iAMP21 were particularly frequent. We propose a strategy for the detection of Ph-like patients, by analyzing the overexpression/genetic lesions of CRLF2, the Abl phosphorylation of surrogate markers confirmed by gene rearrangements, and Sanger sequencing.

BACKGROUND B-cell acute lymphoblastic leukemia (B-ALL) is the most commonly diagnosed childhood malignancy worldwide and is especially common in Mexico. Additionally, the number of cases has increased in recent years. Thus, it is very important to develop molecular strategies to diagnose leukemia. The aim of this study was to investigate MYB expression and to determine its impact on the diagnosis of B-ALL. METHODS We analyzed the B-ALL gene expression profile by microarray data mining. Bioinformatics analysis was performed to identify the genes that are overexpressed in leukemia. We determined that MYB was highly expressed in leukemia. Then, we validated MYB expression in 70 patients with B-ALL and in 16 healthy controls (HCs) using qRT-PCR. The results were statistically analyzed using the Kolmogorov-Smirnov Z test, Mann-Whitney U test, receiver operating characteristic curves, and the Youden index. RESULTS The microarrays showed that MYB was overexpressed in B-ALL patients with a fold change of 57.8728 and a P value of 2.56-195 . MYB expression showed great variability among the patients analyzed. However, compared to the HCs, the B-ALL patients had a P value

INTRODUCTION Development of inhibitors is the most serious complication in patients with haemophilia (PWH). The prevalence of inhibitors in patients with severe haemophilia A (HA) is approximately 25%-30%. Inhibitor prevalence differs among populations. Some studies report a prevalence of almost twice in Hispanic as compared to Caucasian patients. Most data available, on the prevalence of inhibitors and their predisposing factors, originate from centres in developed countries. AIM Establish the prevalence of inhibitors of FVIII and FIX in Mexico. METHODS This was an observational, cross-sectional and descriptive study. The records of all patients diagnosed with haemophilia A (HA) or B (HB), with and without inhibitors, were included. Clinical and demographical characteristics of patients with inhibitors were assessed. Statistical analysis was performed using IBM SPSS version 22. The Ethics Committees of the various participating institutions approved this study. RESULTS A total of 1455 patients from the 20 participating centres were recruited, from which 1208 (83.02%) had HA and 247 (16.97%) were diagnosed with HB. The presence of inhibitors in severe HA was reported in 93/777(11.96%), and 10/162 (6.17%) in severe HB. Of them, 91.7% exhibited high titres in HA and 100% in HB. CONCLUSION In Mexico, the general prevalence of inhibitors varies considerably among centres. This study established a basis of comparison for future development and advances in the treatment and follow-up of patients. These findings also augment our understanding of risk factors related to inhibitor development.

Background and Aims Occupational exposure of parents to carcinogens is of great interest in the etiology of leukemias. Evidence of the impact of such exposure on infants or small children is scarce. Here we estimated whether occupational exposure of parents to carcinogens could be a risk factor for leukemias in their children. Methods Cases of acute leukemia (AL) in infants ≤24 months old diagnosed in Mexico City (1998–2013) were included in a population-based, case-control study. Each of the 195 cases was matched with at least one healthy child ( n = 369). For each of four exposure windows studied, the degree of exposure to carcinogens was determined for both parents by using a validated occupational exposure index. An unconditional logistic regression was carried out. Results Odds ratios (OR) and the 95% confidence intervals (CI) of the overall occupational exposure for parents during the four exposure windows indicated no association with risk of AL in their children. Pre-conception, the OR by the father 0.77 (0.49–1.21), by the mother 1.03 (0.50–2.11); during pregnancy, father 0.66 (0.38–1.15), mother 1.79 (0.46–6.90); during breastfeeding, father 0.75 (0.43–1.30), mother 0.96 (0.21–4.30); and after birth, father 0.74 (0.45–1.22), mother 0.90 (0.24–3.32). The statistical power of the sample size to identify an OR ≥2 and an exposure of ≥10% among controls was 78%. Conclusions These data support the idea that parents' occupational exposure during any of the periods studied was not a risk factor contributing to the etiology of AL in infants ≤24 months of age.

The parental age at conception has been reported to be a risk factor for childhood acute leukaemia (AL); however, the relationship is controversial. The aim of the present study was to investigate the association between parental age at conception and the risk of AL in Mexican children, a population with a high incidence of the disease and a high prevalence of pregnancies in adolescents and young adults.A multicentre case-control study was conducted. Incident AL cases younger than 17 years of age diagnosed between 2010 and 2015 were included. Controls were matched with cases according to age, sex, and health institution. Using logistic regression analysis, adjusted odds ratios (aOR) and 95 % confidence intervals (95 % CI) were calculated for each maternal stratum after adjusting for paternal age at conception of index child. The maternal age between 25 and 29.99 years was selected as the reference category.In most strata where maternal and paternal ages were assessed, no association was found with the risk of developing acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML) in their offspring. An increased risk for AML was observed when the mother was between 20 and 24.99 years of age and the father aged 25-29.99 years (aOR, 1.94; 95 % CI, 1.03-3.67). In addition, there was a positive association for ALL when the mother´s age was between 20 and 24.99 years and the father was20 years of age, however, a very wide confidence interval was noted (aOR, 12.26; 95 % CI, 1.41-106.83).In the present study, maternal and paternal ages assessed in different strata showed little association with risk of developing ALL and AML in children. Positive associations between risk of both types of childhood AL were observed with younger paternal and maternal ages.

To compare the costs and clinical consequences of treating mild-to-moderate joint bleeds with recombinant activated factor VII (rFVIIa) versus plasma-derived activated prothrombin complex concentrate (pd-aPCC) in pediatric patients with hemophilia A with inhibitors in Mexico.A cost-effectiveness model was developed using TreeAge Pro v14.2.2 software (licensed in the USA) and adapted from a previously published model, with adjustments to reflect local clinical practice. Expert opinion was sought regarding patients' clinical management and resource utilization in Mexico to ensure that the current model was appropriate and relevant. The model compared rFVIIa and pd-aPCC for the treatment of mild-to-moderate joint bleeds in children14 years old (assumed average weight: 30 kg). The analysis outcome was incremental cost per resolved mild-to-moderate joint bleed. One-way sensitivity analysis and probabilistic sensitivity analysis were used to assess specific assumptions and to address any uncertainty in the model.The cost of treating mild-to-moderate joint bleeds was lower for rFVIIa versus pd-aPCC after 7 days (MX$105,581 vs. MX$132,024), assuming complete bleed resolution. After 48 hours, rFVIIa was associated with an 8% improvement in bleed resolution versus pd-aPCC, resulting in cost savings of MX$16,754. Probabilistic sensitivity analysis indicated that rFVIIa treatment was more cost-effective than pd-aPCC in 67% (at 7 days) and 72% (at 48 hours) of Monte Carlo simulations.Accounting for model uncertainty, rFVIIa provided cost savings over pd-aPCC for the Mexican public health care payer in the management of mild-to-moderate joint bleeds in pediatric hemophilia A with inhibitors.

In Mexico, due to the high rates of diabetes, overweight, and obesity, there has also been noted an increased newborn weight, which may be contributing to the elevated incidence rate of childhood acute leukemia (AL). We conducted a case–control study in public hospitals of Mexico City aimed to know whether a greater weight at birth is associated with a higher risk of developing leukemia. We included incident cases with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) diagnosed between 2010 and 2015. Controls were frequency‐matched to the cases by age, sex, and health institution. Logistic regression analysis was performed adjusting risks by child's sex, overcrowding index, birth order, and mother's age at the time of pregnancy. Adjusted odds ratios (aORs) and 95% confidence intervals were calculated. A total of 1455 cases and 1455 controls were included. An evident association between ALL and child's birthweight ≥2500 g was found (aOR 2.06; 95% CI: 1.59, 2.66) and also, in those with birthweight ≥3500 g (aOR 1.19; 95% CI: 1.00, 1.41). In AML patients with birthweight ≥2500 g and ≥3500 g, an aOR of 1.77 (95% CI: 1.07, 2.94) and 1.42 (95% CI: 1.03–1.95) was observed, respectively. No association was noticed with either type of AL and a birthweight ≥4000 g. To sum up, we found a moderate association between not having a low birthweight and an increased risk of acute leukemias. Birthweight ≥3500 g was also a risk factor for both types of leukemia. This suggests that a greater birthweight may increase the risk of acute leukemias in Mexican children.

Refractory severe aplastic anemia (RSAA) has poor prognosis. Eltrombopag is a therapeutic option in patients that failed to ATG+CyA; in countries with poor outcomes their use is limited. Described experience with low doses of Eltrombopag 25mg/d. CASE 1. Female 4 yo diagnosis SAA not responded after 2 cycles ATG, the first one with mesterolone for 6 months, continued pancytopenic with multiple transfusions (every 2/3 weeks) complicated by iron overload, and serious infections; presented CNS infection with secondary spastic paralysis, due chelation therapy development 2 cholestasis outbreak. Eltrombopag was started 25mg/d, after the first month, no more transfusion was needed with increase of neutrophils and platelet counts. After 7 months Eltrombopag for economic reasons was stopped with partial response. Hb >10g/dL, CAN >1000 m3 & platelets 99 X103. For 4 years; until now; she is doing well, no infections and no transfusions needed. CASE 2. Male 2 yo, SAA not responded ATG course, he was inpatient during 8 months with multiple infections, bleeding complications and consequence transfusion was needed. Iron overload required iron chelation therapy, the medical orders and CyA was irregularly administrated, the parents not accept considered BMT, so Eltrombopag 25mg/d was started, 6 weeks later no more transfusion was required, the bleeding stopped and no mores infections were observed; after 7 months had a partial response Hb > 11g/dL CAN > 1000m3 & platelets 45 x103, and Eltrombopag was stopped. This two patients use Eltrombopag as compassionate use, with good clinical results, in spite of low dose to get a partial hematological response. Low dose of Eltrombopag is useful to induce partial response rapidily with an excellent clinical results even when it is discontinued. Actually all patients with new SAA diagnostic are register in our Institution in a prospective protocol to receive ATG+CyA and start Eltrombopag 50mg/d with increase according to the response. The low dose could be a good option for patients with refractory aplastic anemia to get a partial response in development countries with less morbidity-mortality and a better quality of life. Disclosures No relevant conflicts of interest to declare.

B-cell acute lymphoblastic leukemia is the most commonly diagnosed childhood malignancy worldwide, more than 50% of these cases are diagnosed in Mexico. Although the five-year survival rate is &gt, 80%, 30% of patients experience relapse with poor prognosis. Cancer-associated gene expression profiles have been identified in several malignancies, and some transcripts have been used to predict disease prognosis. The human transcriptome is incompletely elucidated, moreover, more than 80% of transcripts can be processed via alternative splicing (AS), which increases transcript and protein diversity. The human transcriptome is divided, coding RNA accounts for 2%, and the remaining 98% is noncoding RNA. Noncoding RNA can undergo AS, promoting the diversity of noncoding transcripts. We designed specific primers to amplify previously reported alternative transcript variants of ZNF695 and showed that six ZNF695 transcript variants are co-expressed in cancer cell lines. The amplicons were sequenced and identified. Additionally, we analyzed the expression of these six transcript variants in bone marrow from B-cell acute lymphoblastic leukemia patients and observed that ZNF695 transcript variants one and three were the predominant variants expressed in leukemia. Moreover, our results showed the co-expression of coding and long noncoding RNA. Finally, we observed that long noncoding RNA ZNF695 expression predicted survival rates.

Acute myeloid leukemias represent the second most common childhood leukemia subtype. In Mexico, there are few studies on descriptive epidemiology for this disease.To report acute myeloid leukemia incidence for children less than 15 years of age in the Metropolitan Area of the Valley of Mexico for a period of five years (2010-2014) and to analyze whether there are differences in the incidence of acute myeloid leukemia by regions.A descriptive study was conducted in nine public hospitals in Mexico City. The crude annual average incidence rate and adjusted average annual incidence rate were calculated.A total of 190 patients with diagnosis of de novo acute myeloid leukemia were analyzed. Male sex (57.2%) and acute myeloid leukemia-M3 subtype (25.3%) were more frequent. The adjusted average annual incidence rates for Mexico City and for the Metropolitan Area of the Valley of Mexico were 8.18 and 7.74 per million children under 15 years old, respectively.It seems that childhood acute myeloid leukemia incidence is increasing in Mexico City, which makes the identification of associated risk factors imperative.

The role of malnutrition at diagnosis as a predictor of early mortality in Mexican leukemia children remains controversial. The objective of present study was to investigate whether malnutrition was a predictor of early mortality during the first year of treatment in Mexican acute lymphoblastic leukemia (ALL) children through the first population-based study. A total of 794 newly diagnosed ALL pediatric patients from public hospitals of Mexico City were enrolled. A multivariate Cox proportional hazards regression model was constructed and adjusted by patient’s age at diagnosis, gender, hospital of treatment, and socioeconomic status. Early mortality was high (12.1%) and malnutrition by different indicators was not associated with mortality at induction phase and at 6th month; a high risk of dying (RR = 2.08; 95% CI: 1.08–4.01) was observed in the group of malnourished children with a high-risk ALL.

WOS: 000376443500008, PubMed ID: 27223147, BACKGROUND The development of neutralizing anti-factor VIII alloantibodies (inhibitors) in patients with severe hemophilia A may depend on the concentrate used for replacement therapy. METHODS We conducted a randomized trial to assess the incidence of factor VIII inhibitors among patients treated with plasma-derived factor VIII containing von Willebrand factor or recombinant factor VIII. Patients who met the eligibility criteria (male sex, age = 5 Bethesda units). Inhibitors developed in 29 of the 125 patients treated with plasma-derived factor VIII (20 patients had high-titer inhibitors) and in 47 of the 126 patients treated with recombinant factor VIII (30 patients had high-titer inhibitors). The cumulative incidence of all inhibitors was 26.8% (95% confidence interval [CI], 18.4 to 35.2) with plasma-derived factor VIII and 44.5% (95% CI, 34.7 to 54.3) with recombinant factor VIII; the cumulative incidence of high-titer inhibitors was 18.6% (95% CI, 11.2 to 26.0) and 28.4% (95% CI, 19.6 to 37.2), respectively. In Cox regression models for the primary end point of all inhibitors, recombinant factor VIII was associated with an 87% higher incidence than plasma-derived factor VIII (hazard ratio, 1.87; 95% CI, 1.17 to 2.96). This association did not change in multivariable analysis. For high-titer inhibitors, the hazard ratio was 1.69 (95% CI, 0.96 to 2.98). When the analysis was restricted to recombinant factor VIII products other than second-generation full-length recombinant factor VIII, effect estimates remained similar for all inhibitors (hazard ratio, 1.98; 95% CI, 0.99 to 3.97) and high-titer inhibitors (hazard ratio, 2.59; 95% CI, 1.11 to 6.00). CONCLUSIONS Patients treated with plasma-derived factor VIII containing von Willebrand factor had a lower incidence of inhibitors than those treated with recombinant factor VIII. (Funded by the Angelo Bianchi Bonomi Foundation and others; ClinicalTrials.gov number, NCT01064284; EudraCT number, 2009-011186-88.), Angelo Bianchi Bonomi Foundation, Funded by the Angelo Bianchi Bonomi Foundation and others

After the long Spanish domination over Europe, and the decadence of Holland’s colonialism, Great Britain and France disputed his domination over the seas in the first half of Eighteenth century. The conflict was solved with the brutish victory over France during the Seven Years’ War (1756-1763) and marked the books’ edition in both countries for the knowledge, translation and dissemination of voyages’.narratives, in order to achieve new discoveries and anticipate next conquest and possessions. This article proposes make a description of theses conflicts from the military and publishing events, from the books of Museo Etnográfico de Buenos Aires’ Library. This library have a lot of English and French texts on voyages and explorations of colonial territories. These books show the important and mutual interest between Great Britain and France for the geographical, colonial and scientific achievement in the Eighteenth century. About these books, this article shows the intellectual, scientific and publishing competition further diplomatic and military rivalry between British and French colonialism. Besides, it analyses the importance of voyages’. Narratives for the advertising of colonial enterprise and its commercial and territorial aims to the public in order achieve his support.

Introduction: Acute lymphoblastic leukemia (ALL) is the most common subtype of leukemia diagnosed in children under 18 years. According to the statistics of the Popular Medical Insurance Program in Mexico, the ALL incidence is 79.8 cases per million per year, and it is significantly increasing. Recently, several SNPs of ARID5B gene have been associated with ALL susceptibility and are more strongly related with ALL risk in Hispanics. However, these observations are not necessarily representative of the situation in Mexico, since the proportion of Mexican patients included in these studies is unknown. It is essential for us to know if the genetic variants of ARID5B confer susceptibility to the development of the disease in our population and if these variants contribute to the higher incidence of childhood ALL in Mexico. Aim: The purpose of this study was to determine the association between the SNPs rs10821936, rs10994982, rs7089424, rs2393732, rs2393782, rs2893881, and rs4948488 of ARID5B gene with the susceptibility to develop ALL in Mexican children. Methods: The study included 384 controls and 298 children with ALL recruited at Instituto Nacional de Pediatria in Mexico city and Hospital de Especialidades Pediatricas de Tuxtla Gutierrez, Chiapas, Mexico. This study was reviewed and approved by the Institutional Research and Ethics Committees from both participant Institutions in accordance to the ethical principles of the Declaration of Helsinki. Volunteers, parents, or legal tutors of patients were previously informed about the study, and before the biological samples were collected, they provided a signed, written informed consent letter to participate. Genomic DNA was extracted from peripheral blood and saliva samples. Genotyping analysis was performed by real-time polymerase chain reaction (RT-PCR) using a pre-designed TaqMan assay for 7 SNPs (rs10821936, rs10994982, rs7089424, rs2393732, rs2393782, rs2893881, and rs4948488) of ARID5B. Genotypic and allelic frequencies were calculated to compare the differences between controls and patients (Fisher's exact test). The odds ratio (OR) was calculated to determine the association between SNPs and ALL susceptibility. Ancestry analysis was conducted for controls and patients (STRUCTURE program), and Haplotype analysis (Haploview program). Results: The estimated proportion of Native American and European ancestry was not statistically different between controls and patients; all SNPs in ARID5B were in Hardy-Weinberg equilibrium. The frequency of the risk alleles was higher in patients than in controls, but only 3 SNPs showed statistically significant differences (p Conslusions: The frequency of the risk alleles was higher than in Hispanic children with ALL. Each SNP of ARID5B confers an individual effect on the risk for developing the disease, and the CAG haplotype was strongly associated with ALL susceptibility. The genetic background of our population could be positively influencing the susceptibility to ALL development, specifically pre-B ALL. The SNPs rs10821936, rs10994982, rs7089424 and rs2393732 of ARID5B gene are significantly associated with an increased risk to develop childhood ALL and this could also explain in part the high incidence of childhood ALL in Mexico. Acknowledgments: This work was supported by the grants from Fondos del Presupuesto Federal para la Investigación (project 085/2012), Consejo Nacional de Ciencia y Tecnologia (CONACyT) - Desarrollo Cientifico para Atender Problemas Nacionales (project 216163), and in part by the Intramural Program of the National Cancer Institute. Conflict-of-interest disclosure: The authors state that there are no conflicts of interest. Disclosures No relevant conflicts of interest to declare.

Background: A major complication in severe hemophilia A is the formation of persistent neutralizing antibodies against factor(F) VIII, inhibitors, which render subsequent treatment ineffective. The presence of non-neutralizing anti-FVIII IgG antibodies (NNAs) before FVIII treatment initiation has been associated with subsequent development of inhibitors in previously untreated patients (PUPs) with severe hemophilia A in the frame of the SIPPET cohort (Cannavò A et al, Blood 2017). Up to 30% of PUPs develop neutralizing antibodies (inhibitors) within the first 20-30 exposure days (Eds) to FVIII concentrates, of which one third disappear spontaneously over a course of six months due to endogenous immune tolerance, and two thirds progress into persistent inhibitors that require immunotolerance therapy. The role of each anti-FVIII IgG subclasses (e.g., IgG1, IgG2, IgG3 and IgG4) and their possible prediction of persistent anti-FVIII inhibitors is not known yet. Aims: To investigate the predictive value of anti-FVIII IgG subclasses on persistence of the anti-FVIII inhibitor in PUPs with severe hemophilia A within 60 days from the first development of anti-FVIII inhibitor. Methods: From the 76 patients who developed inhibitors in the SIPPET cohort (Peyvandi et al., N Eng J Med 2016), anti-FVIII IgG subclasses were measured by an ELISA assay in 43 patients according to plasma availability (median age 18 months [IQR: 12-29]), median inhibitor titer: 16 Bethesda IU [IQR: 5-135]). For each IgG subclass, a cutoff of positivity was defined as the mean OD absorbance value + 5 SD, obtained by analyzing the plasma of 150 normal individuals. The association of number of anti-FVIII IgG subclasses and other possible risk factors (age at first treatment, type of FVIII product, number of EDs and type of F8 gene variation) with inhibitor persistence was first estimated by univariate analysis. Predictive associations were assessed by logistic regression, in which inhibitor persistence was the outcome, and number of anti-FVIII IgG subclasses (1= only one [always IgG1], 2 subclasses, 3 subclasses or all 4 subclasses) and age at first treatment with FVIII concentrates were the putative predictors that showed an association with inhibitor persistence. Other risk factors, such as type of FVIII product, number of EDs and type of F8 gene variation, were not associated with inhibitor persistence at univariate analysis. Relative risks (RR) and 95% confidence intervals (95% CI) were recalculated from odds ratios according to Zhang (JAMA, 1998). The predictive capacity was expressed as the area under the receiving operative characteristic (ROC) curve (AUC). Results: Of the 43 patients who developed an inhibitor (31 persistent, 12 transient), 3 had only one IgG subclass (IgG1), 15 two subclasses, 13 three subclasses and 12 were positive for all the four IgG subclasses. The presence of each subclass was associated with an increased risk of inhibitor persistence, both in univariate and multivariate analysis, with relative risks ranging from 1.3 to 1.8. The risk of inhibitor persistence progressively increased with the number of concomitant IgG subclasses. In the model containing also age at first treatment and taking the category with only IgG1 positivity as reference, the RR (95% CI) was 1.7 (0.2 to 2.9) for patients with two IgG subclasses, 2.6 (0.7 to 3.0) for those with three subclasses and 2.8 (1.2 to 3.0) for those with all the four subclasses. The odds of inhibitor persistence increased by 8% for every 1-month increase of age at first treatment (OR 1.08 [0.99 to 1.22]). The AUC of the predictive model was 0.82 (95% CI: 0.68 to 0.96) (Fig 1). Conclusions: The concomitant presence of more than one anti-FVIII IgG subclass within 60 days from the first development of anti-FVIII inhibitor in patients with severe hemophilia A was associated with an increased risk of persistence of the inhibitor. Age at first treatment also predicted inhibitor persistence. In conclusion, this predictive analysis showed a promising discriminative capability for clinicians to select patients with the highest risk of inhibitor persistence who could benefit from immunotolerance therapy. These results need to be confirmed in other cohorts of PUPs with severe hemophilia A. Figure 1. Figure 1. Disclosures Peyvandi: Novo Nordisk: Speakers Bureau; Octapharma US: Honoraria; Novo Nordisk: Speakers Bureau; Shire: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Roche: Speakers Bureau; Grifols: Speakers Bureau; Sobi: Speakers Bureau; Kedrion: Consultancy; Grifols: Speakers Bureau; Octapharma US: Honoraria; Sobi: Speakers Bureau; Grifols: Speakers Bureau; Grifols: Speakers Bureau; Kedrion: Consultancy; Octapharma US: Honoraria; Octapharma US: Honoraria; Kedrion: Consultancy; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Novo Nordisk: Speakers Bureau; Sobi: Speakers Bureau; Roche: Speakers Bureau; Shire: Speakers Bureau; Sobi: Speakers Bureau; Kedrion: Consultancy; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Shire: Speakers Bureau; Novo Nordisk: Speakers Bureau; Roche: Speakers Bureau; Shire: Speakers Bureau; Grifols: Speakers Bureau; Kedrion: Consultancy; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Shire: Speakers Bureau; Octapharma US: Honoraria; Sobi: Speakers Bureau; Roche: Speakers Bureau; Roche: Speakers Bureau; Novo Nordisk: Speakers Bureau. Palla:Grifols: Other: travel support; Pfizer: Other: travel support. Santagostino:Grifols: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Young:Novo Nordisk: Consultancy, Honoraria; Bioverativ: Consultancy, Honoraria; Bayer: Consultancy; CSL Behring: Consultancy, Honoraria; Kedrion: Consultancy; Genentech/Roche: Consultancy, Honoraria; Shire: Consultancy, Honoraria. Seth:Shire: Honoraria. Mancuso:Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kedrion: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biotest: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees. Mahlangu:Sanofi: Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; LFB: Consultancy; NovoNordisk: Consultancy, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Research Funding, Speakers Bureau; Chugai: Consultancy; Catalyst Biosciences: Consultancy, Research Funding; Biomarin: Research Funding, Speakers Bureau; Biogen: Research Funding, Speakers Bureau; Bayer: Research Funding; Amgen: Consultancy; Alnylam: Consultancy, Research Funding, Speakers Bureau; Shire: Consultancy, Research Funding, Speakers Bureau; Sobi: Research Funding, Speakers Bureau; Spark: Consultancy, Research Funding. Ewing:Hema Biologics: Honoraria; Novo Nordisk: Honoraria; CSL Behring: Honoraria; Grifols: Honoraria; Bayer: Honoraria; Shire: Honoraria; Genentech: Honoraria; Biogen: Research Funding. Male:Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octapharma: Speakers Bureau; Novo Nordisk: Speakers Bureau; Biotest: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Speakers Bureau; SOBI: Speakers Bureau; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Majumdar:NIMHD: Research Funding. Manco-Johnson:CSL Behring: Honoraria; Biogentek: Honoraria; Novo Nordisk: Honoraria; Bayer AG: Honoraria, Research Funding; Baxalta, now part of Shire: Honoraria. Mazzucconi:Baxalta-Shire: Consultancy, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Novartis,: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Novo Nordisk: Consultancy, Speakers Bureau; CSL Behring: Consultancy, Speakers Bureau. Neme:Shire: Consultancy, Honoraria; Novonordisk: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Grifols: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria. Prezotti:Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bioverative: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mannucci:Kedrion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Grifols: Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Baxalta/Shire: Speakers Bureau; Alexion: Speakers Bureau; Novo Nordisk: Speakers Bureau.

Worldwide, acute leukaemia (AL) is the commonest type of childhood malignancy with an annual incidence of 30–50 cases per million children (Curado et al, 2007); Mexico City has one of the highest rates, at 58.4 cases per million (Mejia-Arangure et al, 2005a). Among the identified risk factors, individuals with Down syndrome (DS) below 20 years of age have 10- to 20-fold greater risk of developing AL compared with the general population (Robison, 1992; Ross et al, 2005). According to the Greaves' hypotheses, late contact with infectious agents may lead to an abnormal or aberrant immune response that favors the development of acute lymphoblastic leukaemia (ALL) (Greaves, 2005). Correspondingly, early infections have a protective effect in ALL by promoting the physiological maturation of the immune system, whereas late infections promote an excessive proliferation of the lymphocytes (McNally and Eden, 2004; Menegaux et al, 2004; Greaves, 2006; O'Connor and Boneva, 2007). Children with DS, due to their increased susceptibility to AL, provide a natural and valuable model for evaluating the interaction between the susceptibility for AL and the environment. In this study, we assessed whether breastfeeding and early infection were associated with the risk of developing AL in children with DS. Mother's milk is an important modulator of the immune response in infants because, while by providing the child with antibodies and immune cells, it can also be a source of transmission of infectious agents (MacArthur et al, 2008).

This study was conducted to determine the frequency of the most common fusion genes in Mexican pediatric patients with acute lymphoblastic leukemia (ALL). Molecular analysis using RT-PCR was carried out in 53-blood samples: 52 patients with de novo ALL and one with relapsed ALL. The ETV6-RUNX1 fusion was found in 7 cases (13.5%), BCR-ABL fusion was detected in 2 cases (3.8%), and 6 patients (11.5%) expressed the chimeric gene E2A-PBX1. The prevalence of E2A-PBX1 is one of the highest that has been described thus far in childhood ALL. Furthermore, we detected both the BCR-ABL, and E2A-PBX1 fusion in the relapsed patient. With regards to the immunophenotype, ETV6-RUNX1 was expressed in both pre-B and T-cell cases, while the presence of E2A-PBX1 and BCR-ABL was associated with the pre-B ALL phenotype. The prevalence of E2A-PBX1 in Mexican pediatric cases supports the existence of ethnic differences in the frequency of molecular markers of ALL.

Background Controlled exposures of animals and humans to particulate matter (PM) or ozone air pollution cause an increase in plasma levels of endothelin-1, a potent vasoconstrictor that regulates pulmonary arterial pressure. Objectives The primary objective of this field study was to determine whether Mexico City children, who are chronically exposed to levels of PM and O3 that exceed the United States air quality standards, have elevated plasma endothelin-1 levels and pulmonary arterial pressures. Methods We conducted a study of 81 children, 7.9 ± 1.3 years of age, lifelong residents of either northeast (n = 19) or southwest (n = 40) Mexico City or Polotitlán (n = 22), a control city with PM and O3 levels below the U.S. air quality standards. Clinical histories, physical examinations, and complete blood counts were done. Plasma endothelin-1 concentrations were determined by immunoassay, and pulmonary arterial pressures were measured by Doppler echocardiography. Results Mexico City children had higher plasma endothelin-1 concentrations compared with controls (p < 0.001). Mean pulmonary arterial pressure was elevated in children from both northeast (p < 0.001) and southwest (p < 0.05) Mexico City compared with controls. Endothelin-1 levels in Mexico City children were positively correlated with daily outdoor hours (p = 0.012), and 7-day cumulative levels of PM air pollution < 2.5 μm in aerodynamic diameter (PM2.5) before endothelin-1 measurement (p = 0.03). Conclusions Chronic exposure of children to PM2.5 is associated with increased levels of circulating endothelin-1 and elevated mean pulmonary arterial pressure.

Southwest Metropolitan Mexico City (SWMMC) children are chronically exposed to complex mixtures of air pollutants. In a cross-sectional arm of our study, we investigated the association between exposure to SWMMC atmosphere and nasal abnormalities, hyperinflation, and interstitial markings assessed by chest X-rays, lung function changes, several serum cytokines, and endothelin-1 in 174 children aged 5-17 years vs. 27 control children residents in low-polluted areas. Control children had no nasal lesions, and only one child showed an abnormal chest X-ray. SWMMC children exhibited nasal abnormalities (22%), hyperinflation (67%), interstitial markings (49%), and a mild restrictive pattern by spirometry (10%). Interstitial markings were associated with a decrease in predicted values of FEF(25-75), FEF(75), and the FEV(1)/FVC ratio. Boys had a higher probability of developing interstitial markings with age (P = 0.004). Blood smear findings included toxic granulations in neutrophils and schistocytes. SWMMC children had more serum IL10 and IL6 and less IL8 than controls. In a longitudinal arm of our study, we found a significant seasonal drop in FVC and FEV(1) associated with a 6-month period of high ozone and PM(10) levels. Our data strongly suggest that a lifelong exposure to urban air pollution causes respiratory damage in children. Moreover, a cytokine network becomes imbalanced, with a shift towards upregulation of anti-inflammatory cytokines. Consequently, these children are potentially at risk for developing chronic lung disease and other systemic effects later in life.

Background Cytogenetic studies in acute lymphoblastic leukemia (ALL) have identified numerical and structural chromosomal abnormalities related to the disease's pathophysiologic characteristics. These findings correlate with prognosis and response to treatment in ALL patients. The purpose of this study was to define the frequency of chromosomal abnormalities in a group of Mexican children with ALL and to compare these data with those reported in the literature. Methods Bone marrow chromosome studies with GTG bands were performed in 150 pediatric patients with ALL who were naive to antileukemic treatment and aged from 5 months to 16 years; the majority was diagnosed as L1. Results Among 131 patients, 30 (22.9%) karyotypes were normal and the remaining 101 (77.1%) had abnormal karyotypes with numerical and/or structural abnormalities. Among patients with numerical abnormalities, the most frequent karyotypes were hyperdiploidy with 51–65 chromosomes (30 patients) and hyperdiploidy with 47–50 chromosomes (18 patients). Among recurrent, non-random, and primary structural abnormalities, the most frequent was t(9;22), followed by t(1;19). Aberrations involving band 11q23 were not detected, and only one of two patients with L3 had the t(8;14). Of the secondary non-random abnormalities, dup(1q), del(6q), and i(7)(q10) were found. Conclusions The frequency and type of chromosomal abnormalities found was comparable to those reported in the literature with similar methodology and pediatric populations; however, the number of cases analyzed should be increased to create a database of Mexican children with ALL, and several patients require molecular analysis to identify chromosomal abnormalities not detected through conventional cytogenetic studies.

OBJETIVO: Medir la tasa de incidencia de las leucemias agudas (LA) en las diferentes delegaciones políticas del Distrito Federal y evaluar si existe una tendencia significativa en dichos padecimientos en tales delegaciones. MATERIAL Y MÉTODOS: Estudio longitudinal descriptivo realizado en seis hospitales de la ciudad de México, los que atienden a cerca de 97.5% de todos los niños con cáncer de esta ciudad. Los datos se capturaron de 1995 a 1996, y se analizaron en 1999, en el Hospital de Pediatría del Centro Médico Nacional Siglo XXI, del Instituto Mexicano del Seguro Social. Para cada delegación se calcularon la tasa de incidencia anual promedio, la tasa estandarizada y la razón estandarizada de morbilidad (REM) con intervalos de confianza al 95% (IC 95%). La tendencia se evaluó con la tasa de cambio promedio. RESULTADOS: Se observó una tendencia al incremento en la incidencia de la leucemia aguda linfoblástica (LAL) en cinco delegaciones: Alvaro Obregón, Cuauhtémoc, Gustavo A. Madero, Iztacalco y Venustiano Carranza. En la leucemia aguda mieloblástica (LAM) no se notificaron cambios estadísticamente significativos en la incidencia en ninguna delegación política. Sólo con LAM se encontró una REM significativa y correspondió a la delegación Alvaro Obregón (REM= 2.91, IC 95% 1.63 - 4.80). Las REM más altas se encontraron en el sur y suroeste de la ciudad. CONCLUSIONES: Sólo se observó incremento en la incidencia de LAL en cinco delegaciones políticas. La incidencia más alta de LAM se encontró en la delegación Alvaro Obregón.OBJECTIVE: To measure the incidence rate and trend of acute leukemia (AL) in political districts of Mexico City. MATERIAL AND METHODS: Descriptive longitudinal study conducted at six hospitals that care for nearly 97.5% of all cancer cases among children in Mexico City. Study data were collected in 1995 and 1996, and were analyzed in 1999, at the National Medical Center "Siglo XXI" Children's Hospital, of the Mexican Institute for Social Security. Calculations of acute leukemia annual incidence rates, standardized rates, and standardized morbidity rates (SMR) with 95% confidence intervals, were obtained for each district. Morbidity trends were assessed through average change rates. RESULTS: In this study we observed an increasing trend of acute lymphoblastic leukemia (ALL) incidence in five districts: Alvaro Obregon, Cuauhtemoc, Gustavo A. Madero, Iztacalco, and Venustiano Carranza. Acute myeloblastic leukemia (AML) showed no significantly statistic increase of incidence in any district. AML did show a significant SMR in Alvaro Obregon district (SMR= 2.91, 95% CI 1.63 - 4.80). Higher SMRs were found in the south and southwest areas of the city. CONCLUSIONS: Increasing incidence of ALL was observed in five districts of Mexico City. AML incidence was the highest in Alvaro Obregon district.

Novel biomarkers for risk refinement and stratification in childhood acute lymphoblastic leukemia (ALL) are needed to optimize treatment results. We studied the expression of CASP8AP2 and H2AFZ associated with relapse and survival in bone marrow samples from newly diagnosed children with ALL. We found: (a) an increased risk for early relapse in those patients with low expression of CASP8AP2 (odds ratio [OR] 3.93, 95% confidence interval [CI] 1.40-11.02, p < 0.05) confirming its usefulness as a predictive risk marker, although H2AFZ did not present the same effect; (b) patients with low expressions of CASP8AP2 and H2AFZ had inferior survival rates (p < 0.001); (c) the predictive values regarding low expressions of H2AFZ and CASP8AP2 and high white blood cell count suggest that these features could help to identify more accurately patients at greater risk of relapse.

SummaryGermline mutations in patients with hemophilia B generally have arisen within the past 150 years. Evidence suggests that these germline mutations generally result from endogenous processes. However, a unique pattern would be expected if a population were exposed to a physiologically important germline mutagen since mutagens generally produce characteristic patterns, or “fingerprints”, of mutation. To determine the pattern of mutation in Mexican Hispanics, the regions of likely functional significance in the factor IX gene were screened by di-deoxy fingerprinting (ddF) in 31 families with hemophilia B. Mutations were found in 30 of these families. Haplotype analysis was performed on individuals with identical mutations to help distinguish independent, recurrent mutations from founder effects. Analysis of these 30 mutations, along with 7 mutations reported previously in Mexican Hispanic families, reveals a pattern of independent mutation that is similar to the pattern of mutation observed in 127 U. S. Caucasian families (p = 0.89). These results may reflect either an underlying pattern of germline mutation due to endogenous processes or the presence of an ubiquitous mutagen. Further analyses of the recurrent mutations revealed that two mutations, T296M and R248Q, accounted for 19% of the mutations found in the Mexicans. Haplotype data suggest that the multiple occurrences of T296M and R248Q are associated with founder effects and that screening for these mutations may allow rapid mutation detection and carrier diagnosis in a significant minority of Mexican families with hemophilia B. These two mutations also are associated with founder effects in the U. S. Caucasian population. However, the haplotypes are different in these two populations, indicating independent origins. The occurrence of identical founder mutations in distinct populations provides evidence for the previous hypothesis that the number of different mutations giving rise to mild or borderline mild/moderate hemophilia B is small compared to deleterious mutations causing more severe disease.

Environmental factors contributing to the development of childhood leukemia in children with Down's syndrome

Background and Aims. It has been suggested that acute leukemia (AL) can be the result of the interaction between inherited susceptibility to the disease and exposure to different carcinogenic facto...

BackgroundMedical research has not been able to establish whether a father's occupational exposures are associated with the development of acute leukemia (AL) in their offspring. The studies conducted have weaknesses that have generated a misclassification of such exposure. Occupations and exposures to substances associated with childhood cancer are not very frequently encountered in the general population; thus, the reported risks are both inconsistent and inaccurate. In this study, to assess exposure we used a new method, an exposure index, which took into consideration the industrial branch, specific position, use of protective equipment, substances at work, degree of contact with such substances, and time of exposure. This index allowed us to obtain a grade, which permitted the identification of individuals according to their level of exposure to known or potentially carcinogenic agents that are not necessarily specifically identified as risk factors for leukemia. The aim of this study was to determine the association between a father's occupational exposure to carcinogenic agents and the presence of AL in their offspring.MethodsFrom 1999 to 2000, a case-control study was performed with 193 children who reside in Mexico City and had been diagnosed with AL. The initial sample-size calculation was 150 children per group, assessed with an expected odds ratio (OR) of three and a minimum exposure frequency of 15.8%. These children were matched by age, sex, and institution with 193 pediatric surgical patients at secondary-care hospitals. A questionnaire was used to determine each child's background and the characteristics of the father's occupation(s). In order to determine the level of exposure to carcinogenic agents, a previously validated exposure index (occupational exposure index, OEI) was used. The consistency and validity of the index were assessed by a questionnaire comparison, the sensory recognition of the work area, and an expert's opinion.ResultsThe adjusted ORs and 95% confidence intervals (CI) were 1.69 (0.98, 2.92) during the preconception period; 1.98 (1.13, 3.45) during the index pregnancy; 2.11 (1.17, 3.78) during breastfeeding period; 2.17 (1.28, 3.66) after birth; and 2.06 (1.24, 3.42) for global exposure.ConclusionThis is the first study in which an OEI was used to assess a father's occupational exposure to carcinogenic agents as a risk factor for the development of childhood AL in his offspring. From our results, we conclude that children whose fathers have been exposed to a high level of carcinogenic agents seem to have a greater risk of developing acute leukemia. However, confounding factors cannot be disregarded due to an incomplete control for confounding.

RUNX1 over-representation is present in children with acute lymphoblastic leukemia. Although these cases have been related with poor outcome, not all reports describe patient follow-up. To understand its associated clinical features and prognosis, we report on 14 children with ALL and RUNX1 over-representation with laboratory data and outcomes compared to previous reports. Eighty-six children with RUNX1 over-representation have been described, including the 14 patients of this study. Most of them are between 6 and 15 years of age, have low leukocyte counts, pre-B immunophenotype, and three to eight RUNX1 copies. Of the 69 patients with follow-up data, 21 of them relapsed or died, suggesting that RUNX1 over-representation is associated to a poor outcome.

Background We conducted an investigator-driven, multicenter, open label, randomized study to establish whether the source of factor VIII (FVIII) replacement (plasma-derived, pd; or recombinant, r) affects the rate of inhibitory alloantibodies in previously untreated patients (PUPs) with severe hemophilia A. Methods Between 2010 and 2014, 303 PUPs who provided consent through their tutors were screened at 42 participating sites in 14 countries from Africa, the Americas, Asia and Europe. The original aim was to screen 300 patients, randomize 270 (10% screening failure) and follow them for 50 exposure days (ED) or 3 years. Once the intended numbers were included, follow-up was terminated due to logistic and budgetary reasons. Screening criteria were age 5 BU/ml) were a secondary outcome. Patients were censored at the end of the follow-up (50 EDs, 3 years or study end), at inhibitor development or drop-out. Kaplan-Meier and Cox regression survival analyses took into account as putative confounders FVIII gene mutations, ethnicity, hemophilia and inhibitor family history, previous blood component exposure, therapeutic regimen, age at first treatment and country site. Results Of 303 screened patients, 39 were screening failures, and 13 were excluded because 3 patients had received >5 treatments with blood components and 10 were not infused after randomization. The remaining 251 patients were analysed and 35 had truncated follow-up (25 dropout, 10 study termination). Patients were aged 0-81 months at randomization (median 14 months) and received between 1 and 50 infusions of FVIII concentrates (median 22). Of those who did not develop an inhibitor, over 70% had >20 ED. 76 patients developed an inhibitor, of which 50 were high-titred. The cumulative inhibitor incidence was 35.4% (95% confidence interval (CI95) 28.9-41.9%). 90% of inhibitors developed within 20 EDs, both for all and high-titre inhibitors. After randomization 125 patients received pdFVIII and 126 rFVIII. The putative confounders were equally divided between the two product class arms. There were 29 inhibitors (20 high-titred) in the group treated with the class of pdFVIII and 47 (30 high-titred) in those treated with rFVIII. The cumulative inhibitor incidence was 26.7% (CI95 18.3-35.1%) for pdFVIII and 44.5% (CI95 34.7-54.3%) for rFVIII (Figure). For high-titre inhibitors the cumulative incidence was 18.5% (CI95 12.1-26.9%) for pdFVIII and 28.4% (CI95 19.6-37.2%) for rFVIII. By univariate Cox regression analysis rFVIII was associated with an 87% higher incidence of inhibitors than pdFVIII (hazard ratio (HR) 1.87, CI95 1.18-2.97). For high-titre inhibitors the rate was 70% increased (HR 1.70, CI95 0.96-2.99). The associations did not materially change after adjustment for putative confounders: in adjusted models the rate remained 70-90% elevated for rFVIII vs pdFVIII. When analysis was restricted to sites that had not randomized patients to a second generation full length rFVIII or pdFVIII (n=131 patients, 25 inhibitors), the risk of other rFVIII concentrates vs pdFVIII was still twofold increased (HR 1.99, CI95 1.00-3.99). Conclusions The rFVIII product class was associated with a 1.87-fold higher incidence of inhibitors than the pdFVIII class. This difference remained even when second generation full length rFVIII concentrate was excluded from the analyses. The results of this randomized study have implications in the choice of product for management of PUPs, as inhibitor development remains a major challenge in the management of haemophilia A. (Funded by the Angelo Bianchi Bonomi Foundation, Italian Ministry of Health, Grifols, Kedrion and LFB - Registed at EudraCT 2009-001186-88). Figure 1. Figure 1. Disclosures Peyvandi: Octapharma: Other: Investigator; LFB, Kedrion, Novonordisk, Bayer, Roche, CSL Behring.: Consultancy, Honoraria, Research Funding. Mannucci:Novonordisk, Grifols, Kedrion, Bayer, Biotest, Baxalta: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Karimi:Octapharma: Other: Investigator. Young:Baxter, Grifols: Consultancy, Honoraria. Santagostino:Roche: Speakers Bureau; Bayer: Speakers Bureau; Baxter/Baxalta: Speakers Bureau; Octapharma: Speakers Bureau; Biotest: Speakers Bureau; Novo Nordisk: Speakers Bureau; Kedrion: Speakers Bureau; Biogen/Sobi: Speakers Bureau; CSL Behring: Speakers Bureau; Pfizer: Research Funding, Speakers Bureau. Mancuso:Baxter, Pfizer, CSL Behring, Baxter, Sobi/Biotest: Consultancy; Novo Nordisk, Bayer: Speakers Bureau. Mahlangu:Biogen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Research Funding; NovoNordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bonanad:Baxalta: Research Funding. Ewing:Baxter, Novo Nordisk, Grifols, Bayer, Kedrion: Honoraria. Owaidah:King abdulaziz city for science, Novo Nordisk, Bayer: Honoraria, Research Funding. Kobrinsky:Octapharma: Speakers Bureau; CSL Behring: Speakers Bureau; Sanofi: Speakers Bureau; Kedrion Biopharma: Membership on an entity's Board of Directors or advisory committees. Kavakli:Baxter: Other: advisory board member and received educational and investigational support; Bayer: Other: advisory board member and received educational and investigational support; Novo Nordisk: Other: advisory board member and received educational and investigational support; Pfizer: Other: advisory board member and received educational and investigational support; Bio Products Laboratory: Other: received educational and investigational support; CSL Behring: Other: received educational and investigational support; Octapharma: Other: received educational and investigational support. Manco-Johnson:Baxter, bayer, biogen, CSL Behring, NovoNordish: Honoraria. Neme:Novo Nordisk and Pfizer: Other: fees for speaking. Wicklund:NovoNordisk, Bayer, Baxter (now Baxalta), Biogen-Idec, CSL-Behring, National Hemophilia Foundation: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zulfikar:Eczacýbaþý-Baxter, Pfizer, Novo Nordisk: Consultancy, Honoraria, Research Funding.

Expression of the 6 and 8 dominant-negative Ikaros isoforms in pediatric patients with acute lymphoblastic leukemia has been associated with a high risk of relapse and death; due to these isoforms disrupting the differentiation and proliferation of lymphoid cells. The aim of this study was to know the frequency of Ik6 and Ik8 in 113 Mexican ALL-children treated within the National Popular Medical Insurance Program to determine whether there was an association with relapse-free survival, event-free survival and overall survival, and to assess its usefulness in the initial stratification of patients. The expression of these isoforms was analyzed using specific primer sets and nested RT-PCR. The detected transcripts were classified according to the isoforms's sizes reported. A non-expected band of 300 bp from one patient was analyzed by sequencing. Twenty-six patients expressed Ik6 and/or Ik8 and one of them expressed a variant of Ik8 denominated Ik8-deleted. Although the presence of them was not statistically associated with lower relapse free survival (p = 0.432), event free survival (p = 0.667) or overall survival (p = 0.531), inferior overall survival was observed in patients that expressed these isoforms and showed high or standard risk by age and white blood-cell count at diagnosis. Of the 26 patients Ik6+ and/or Ik8+, 14 did not present adverse events; from them 6 were exclusively Ik6+ and/or Ik8+, and 8 were positive for the other Ikaros isoforms (Ik1, Ik2, Ik5, Ik3A, Ik4, Ik4A, Ik7). In the patients studied, the expression of Ik6 and Ik8 did not constitute an independent prognostic factor for relapse or death related to disease; therefore, they could not be used in the initial risk stratification.

The t(12;21) produces the gene fusion ETV6/RUNX1 and is a frequent rearrangement in childhood ALL, associated with a good prognosis. In Mexico its prevalence has not been reported. This study evaluated a group of consecutive Mexican children with newly diagnosed ALL, to detect the fusion using fluorescence in situ hybridization (FISH). Seventy-one bone marrow samples were analyzed with FISH, using ETV6/RUNX1 DNA probes. Abnormalities of ETV6, RUNX1, or both were found in 31 of the 71 (44%) patients. Six showed ETV6/RUNX1 fusion and 17, with extra RUNX1 copies, presented an additional chromosome 21 or dup(21)(q22). Five patients had structural changes in ETV6, and three patients showed extra copies of ETV6 and RUNX1 from polysomy of chromosomes 12 and 21. Our results revealed a fusion in 8.5% of the 71 cases analyzed. This frequency is lower than that observed in other populations (9.5-32%). The structural rearrangements resulting in RUNX1 extra copies were found in 9.8% of patients, which is close to the range reported (1.5-9.7%) by other authors. Due to the prevalence of RUNX1 overrepresentation in our population and its unknown prognostic significance, further studies should be conducted in consecutive children with ALL, to correlate this abnormality with the patients' follow-up.

Southwest Metropolitan Mexico City (SWMMC) children are chronically exposed to complex mixtures of air pollutants. In a cross-sectional arm of our study, we investigated the association between exposure to SWMMC atmosphere and nasal abnormalities, hyperinflation, and interstitial markings assessed by chest X-rays, lung function changes, several serum cytokines, and endothelin-1 in 174 children aged 5-17 years vs. 27 control children residents in low-polluted areas. Control children had no nasal lesions, and only one child showed an abnormal chest X-ray. SWMMC children exhibited nasal abnormalities (22%), hyperinflation (67%), interstitial markings (49%), and a mild restrictive pattern by spirometry (10%). Interstitial markings were associated with a decrease in predicted values of FEF(25-75), FEF(75), and the FEV(1)/FVC ratio. Boys had a higher probability of developing interstitial markings with age (P = 0.004). Blood smear findings included toxic granulations in neutrophils and schistocytes. SWMMC children had more serum IL10 and IL6 and less IL8 than controls. In a longitudinal arm of our study, we found a significant seasonal drop in FVC and FEV(1) associated with a 6-month period of high ozone and PM(10) levels. Our data strongly suggest that a lifelong exposure to urban air pollution causes respiratory damage in children. Moreover, a cytokine network becomes imbalanced, with a shift towards upregulation of anti-inflammatory cytokines. Consequently, these children are potentially at risk for developing chronic lung disease and other systemic effects later in life.

OBJETIVO: Medir la tasa de incidencia de las leucemias agudas (LA) en las diferentes delegaciones políticas del Distrito Federal y evaluar si existe una tendencia significativa en dichos padecimientos en tales delegaciones. MATERIAL Y MÉTODOS: Estudio longitudinal descriptivo realizado en seis hospitales de la ciudad de México, los que atienden a cerca de 97.5% de todos los niños con cáncer de esta ciudad. Los datos se capturaron de 1995 a 1996, y se analizaron en 1999, en el Hospital de Pediatría del Centro Médico Nacional Siglo XXI, del Instituto Mexicano del Seguro Social. Para cada delegación se calcularon la tasa de incidencia anual promedio, la tasa estandarizada y la razón estandarizada de morbilidad (REM) con intervalos de confianza al 95% (IC 95%). La tendencia se evaluó con la tasa de cambio promedio. RESULTADOS: Se observó una tendencia al incremento en la incidencia de la leucemia aguda linfoblástica (LAL) en cinco delegaciones: Alvaro Obregón, Cuauhtémoc, Gustavo A. Madero, Iztacalco y Venustiano Carranza. En la leucemia aguda mieloblástica (LAM) no se notificaron cambios estadísticamente significativos en la incidencia en ninguna delegación política. Sólo con LAM se encontró una REM significativa y correspondió a la delegación Alvaro Obregón (REM= 2.91, IC 95% 1.63 - 4.80). Las REM más altas se encontraron en el sur y suroeste de la ciudad. CONCLUSIONES: Sólo se observó incremento en la incidencia de LAL en cinco delegaciones políticas. La incidencia más alta de LAM se encontró en la delegación Alvaro Obregón.

We report four children with acute megakaryoblastic leukemia (AML-M7) and t(1;22)(p13;q13), two of them with Down syndrome; their ages were 7 months, and 6, 7, and 10 years. These findings differ from those reported in children with M7 and t(1;22) at the age of presentation (exclusively under 1-year-old) and in the two cases associated with Down syndrome (t[1;22],+21c) that may be due to the high heterogeneity of the chromosomal changes in children with AML. We cannot disregard ethnic difference distribution of chromosomal changes and age of presentation in Mexican children with AML.

The factor IX gene (F9) is an advantageous system for analyzing recent spontaneous germline mutation in humans. Herein, the male:female ratio of mutation ("r") in F9 have been estimated by Bayesian analysis from 59 germline origin families. The overall "r" in F9 was estimated at 3.75. The "r"s varied with the type of mutation. The "r"s ranged from 6.65 and 6.10 for transitions at CpG and A:T to G:C transitions at non-CpG dinucleotides, respectively, to 0.57 and 0.42 for microdeletions/microinsertions and large deletions (>1 kb), respectively. The "r" for the two subtypes of non-CpG transitions differed (6.10 for A:T to G:C vs 0.80 for G:C to A:T). Somatic mosaicism was detected in 11% of the 45 origin individuals for whom the causative mutation was visualized directly by genomic sequencing of leukocyte DNA (estimated sensitivity of approximately one part in 20). Four of the five defined somatic mosaics had G:C to A:T transitions at non-CpG dinucleotides, hinting that this mutation subtype may occur commonly early in embryogenesis. The age at conception was analyzed for 41 US Caucasian families in which the age of the origin parent and the year of conception for the first carrier/hemophiliac were available. No evidence for a paternal age effect was seen. However, an advanced maternal age effect was observed (P=0.03) and was particularly prominent for transversions (average of the 79th percentile when maternal age was normalized for the year of conception). This suggests that an increased maternal age results in a higher rate of transmitted mutation, whereas the increased number of mitotic replications associated with advanced paternal age has little, if any, effect on the rate of transmitted mutation.

Background Worldwide, acute leukemia is the most common type of childhood cancer. It is particularly common in the Hispanic populations residing in the United States, Costa Rica, and Mexico City. The objective of this study was to determine the incidence of acute leukemia in children who were diagnosed and treated in public hospitals in Mexico City. Methods Included in this study were those children, under 15 years of age and residents of Mexico City, who were diagnosed in 2006 and 2007 with leukemia, as determined by using the International Classification of Childhood Cancer. The average annual incidence rates (AAIR), and the standardized average annual incidence rates (SAAIR) per million children were calculated. We calculated crude, age- and sex-specific incidence rates and adjusted for age by the direct method with the world population as standard. We determined if there were a correlation between the incidence of acute leukemias in the various boroughs of Mexico City and either the number of agricultural hectares, the average number of persons per household, or the municipal human development index for Mexico (used as a reference of socio-economic level). Results Although a total of 610 new cases of leukemia were registered during 2006-2007, only 228 fit the criteria for inclusion in this study. The overall SAAIR was 57.6 per million children (95% CI, 46.9-68.3); acute lymphoblastic leukemia (ALL) was the most frequent type of leukemia, constituting 85.1% of the cases (SAAIR: 49.5 per million), followed by acute myeloblastic leukemia at 12.3% (SAAIR: 6.9 per million), and chronic myeloid leukemia at 1.7% (SAAIR: 0.9 per million). The 1-4 years age group had the highest SAAIR for ALL (77.7 per million). For cases of ALL, 73.2% had precursor B-cell immunophenotype (SAAIR: 35.8 per million) and 12.4% had T-cell immunophenotype (SAAIR 6.3 per million). The peak ages for ALL were 2-6 years and 8-10 years. More than half the children (58.8%) were classified as high risk. There was a positive correlation between the average number of persons per household and the incidence of the pre-B immunophenotype (Pearson's r, 0.789; P = 0.02). Conclusions The frequency of ALL in Mexico City is among the highest in the world, similar to those found for Hispanics in the United States and in Costa Rica.

Imatinib mesylate is the standard treatment for chronic phase CML. Imatinib combinations with interferon alpha or Ara-C has shown synergistic anti-proliferative effects. In an attempt to improve the rate of cytogenetic responses we compare the use of IA vs. IMAC as initial therapy in EP (< 12 months) Ph+ CML patients (pts). The study was conducted in 48 Ph+ CML pts recruited within 12 months from diagnosis with no treatment other than alkylating agents and were randomized to receive IA 400 mg/day (N= 23) or imatinib 400 mg/day plus Ara-C (subcutaneous injection) 10 mg/m2/BSA daily for 10 days monthly (N= 25). Median age for IA group is 44 years (18–75) and 38 years (20–57) for IMAC group. Median time from diagnosis of CML to inclusion was 8 months (1–12). Complete Hematologic Response (CHR) was achieved in 20 pts. (86.9%) for the IA group and in 24 patients (96%) of the IMAC group in a median time of 3 weeks (range: 1–6). With a median follow-up of 9 months (range 3–12 months) Cytogenetic Responses (CgR) in group IA were achieved in 69%: Major Cytogenetic Responses (MCgR) (Bcr/Abl 1–35%) assessed by Bone Marrow Fluorescence in situ Hybridization (FISH) (performed pretreatment and at month 3 and 6) were obtained in 11 pts (47.8%) and minor Cytogenetic Response (mCgR) (Bcr/Abl 36–90%) in 5 pts (21.7%). In the IMAC group Cytogenetic Responses were achieved in 92%: MCgR in 16 (64%) and mCgR in 7(28%). Toxicity grade III neutropenia was present in 2 pts (8.6%) of IA group and in 3 pts (12%) for the IMAC group and grade I –II nausea and edema were the most frequent adverse reactions for both groups in about 30 % of cases. Six pts (26.3%) from the IA group has no response compared with 2 (8%) from the IMAC group. Two patients from the IMAC group and 1 from IA were removed due to Cytogenetic Clonal Evolution and lost of CgR. From these preliminary results we suggest that CHR and Global Cytogenetic Response are higher in the IMAC group, meanwhile there is a lower CgR and high rate of Pts with no cytogenetic response (26.3 vs. 8%) in the IA group. It is too early to conclude definitive differences in the cytogenetic responses at this time, but it appears to be a trend to greater CgR rate for the IMAC group. Data collection and patient accrual are ongoing and results with a 18 months follow up will be presented. Preliminary Results Response Imatinib Alone Imatinib + Ara-C CHR: Complete Hematologic Response, MCgR: Major Cytogenetic Response, mCgR: Minor Cytogenetic Response, CCgR: Complete Cytogenetic Response. CHR 20/23 (89.9%) 24/25 (96%) MCgR 11 (47.8%) 16 (64%) mCgR 5 (21.7%) 7 (28%) CCgR 0 0