Infections and risk factors for infection-related mortality after pediatric allogeneic hematopoietic stem cell transplantation in Mexico: A single center retrospective study.

OBJECTIVE: To identify the type of infections and risk factors for infection-related mortality (IRM) after allogeneic hematopoietic stem cell transplantation (HSCT). METHODS: Retrospective cohort study of patients <16 years of age treated in 2010-2019 was conducted. Unadjusted hazard ratios (HR) and adjusted hazard ratios (aHR) with 95% confidence intervals (95% CIs) were estimated using Cox regression. Cumulative incidence was calculated. RESULTS: Data for 99 pediatric patients were analyzed. The myeloablative conditioning was the most used regimen (78.8%) and the hematopoietic stem cell source was predominantly peripheral blood (80.8%). Primary graft failure occurred in 19.2% of patients. Frequency of acute graft-versus-host disease was 46.5%. Total of 136 infectious events was recorded, the most common of which were bacterial (76.4%) followed by viral infection (15.5%) and then fungal infection (8.1%). The best predictors for infection subtypes where the following: a) for bacterial infection (the age groups of 10.1-15 years: aHR = 3.33; 95% CI: 1.62-6.85 and. >15 years: aHR = 3.34; 95% CI: 1.18-9.45); b) for viral infection (graft versus host disease: aHR = 5.36; 95% CI: 1.62-17.68), however, for fungal infection statistically significant predictors were not identified. Related mortality was 30% (n = 12). Increased risk for infection-related mortality was observed in patients with unrelated donor and umbilical cord stem cells recipients (HR = 3.12; 95% CI: 1.00-9.85). CONCLUSIONS: Frequencies of infections and infection-related mortality appear to be similar to those reported. Unrelated donors and stem cells from umbilical cord recipients were associated with a high risk of mortality.

Persistently high incidence rates of childhood acute leukemias from 2010 to 2017 in Mexico City: A population study from the MIGICCL.

Introduction: Over the years, the Hispanic population living in the United States has consistently shown high incidence rates of childhood acute leukemias (AL). Similarly, high AL incidence was previously observed in Mexico City (MC). Here, we estimated the AL incidence rates among children under 15 years of age in MC during the period 2010-2017. Methods: The Mexican Interinstitutional Group for the Identification of the Causes of Childhood Leukemia conducted a study gathering clinical and epidemiological information regarding children newly diagnosed with AL at public health institutions of MC. Crude age incidence rates (cAIR) were obtained. Age-standardized incidence rates worldwide (ASIRw) and by municipalities (ASIRm) were calculated by the direct and indirect methods, respectively. These were reported per million population <15 years of age; stratified by age group, sex, AL subtypes, immunophenotype and gene rearrangements. Results: A total of 903 AL cases were registered. The ASIRw was 63.3 (cases per million) for AL, 53.1 for acute lymphoblastic leukemia (ALL), and 9.4 for acute myeloblastic leukemia. The highest cAIR for AL was observed in the age group between 1 and 4 years (male: 102.34 and female: 82.73). By immunophenotype, the ASIRw was 47.3 for B-cell and 3.7 for T-cell. The incidence did not show any significant trends during the study period. The ASIRm for ALL were 68.6, 66.6 and 62.8 at Iztacalco, Venustiano Carranza and Benito Juárez, respectively, whereas, other municipalities exhibited null values mainly for AML. Conclusion: The ASIRw for childhood AL in MC is among the highest reported worldwide. We observed spatial heterogeneity of rates by municipalities. The elevated AL incidence observed in Mexican children may be explained by a combination of genetic background and exposure to environmental risk factors.

Transcriptome Analysis Identifies LINC00152 as a Biomarker of Early Relapse and Mortality in Acute Lymphoblastic Leukemia.

Evidence showing the role of long non-coding RNAs (lncRNAs) in leukemogenesis have emerged in the last decade. It has been proposed that these genes can be used as diagnosis and/or prognosis biomarkers in childhood acute lymphoblastic leukemia (ALL). To know if lncRNAs are associated with early relapse and early mortality, a microarray-based gene expression analysis in children with B-lineage ALL (B-ALL) was conducted. Cox regression analyses were performed. Hazard ratios (HR) and 95% confidence intervals (95% CI) were calculated. LINC00152 and LINC01013 were among the most differentially expressed genes in patients with early relapse and early mortality. For LINC00152 high expression, the risks of relapse and death were HR: 4.16 (95% CI: 1.46-11.86) and HR: 1.99 (95% CI: 0.66-6.02), respectively; for LINC01013 low expression, the risks of relapse and death were HR: 3.03 (95% CI: 1.14-8.05) and HR: 6.87 (95% CI: 1.50-31.48), respectively. These results were adjusted by NCI risk criteria and chemotherapy regimen. The lncRNA-mRNA co-expression analysis showed that LINC00152 potentially regulates genes involved in cell substrate adhesion and peptidyl-tyrosine autophosphorylation biological processes. The results of the present study point out that LINC00152 could be a potential biomarker of relapse in children with B-ALL.

Overweight and obesity as predictors of early mortality in Mexican children with acute lymphoblastic leukemia: a multicenter cohort study.

BACKGROUND: Mexico City has one of the highest incidences and mortality rates of acute lymphoblastic leukemia (ALL) in the world and a high frequency of early relapses (17%) and early mortality (15%). Otherwise, childhood overweight and obesity are reaching epidemic proportions. They have been associated with poor outcomes in children with ALL. The aim of present study was to identify if overweight and obesity are predictors of early mortality and relapse in Mexican children with ALL. METHODS: A multicenter cohort study was conducted. ALL children younger than 15 years old were included and followed-up during the first 24 months after diagnosis. Overweight and obesity were classified according World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) criteria. Early mortality and early relapses were the main outcomes. RESULTS: A total of 1070 children were analyzed. Overweight/obesity at diagnosis were predictors of early mortality (WHO: HR = 1.4, 95%CI:1.0-2.0; CDC: HR = 1.6, 95%CI:1.1-2.3). However, no associations between overweight (WHO: HR = 1.5, 95%CI:0.9-2.5; CDC: HR = 1.0; 95% CI:0.6-1.6) and obesity (WHO: HR = 1.5, 95%CI:0.7-3.2; CDC: HR = 1.4; 95%CI:0.9-2.3) with early relapse were observed. CONCLUSIONS: Overweight and obese patients embody a subgroup with high risk of dying during leukemia treatment.

Identification and Characterization of Novel Fusion Genes with Potential Clinical Applications in Mexican Children with Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia is the most common type of childhood cancer worldwide. Mexico City has one of the highest incidences and mortality rates of this cancer. It has previously been recognized that chromosomal translocations are important in cancer etiology. Specific fusion genes have been considered as important treatment targets in childhood acute lymphoblastic leukemia (ALL). The present research aimed at the identification and characterization of novel fusion genes with potential clinical implications in Mexican children with acute lymphoblastic leukemia. The RNA-sequencing approach was used. Four fusion genes not previously reported were identified: CREBBP-SRGAP2B, DNAH14-IKZF1, ETV6-SNUPN, ETV6-NUFIP1. Although a fusion gene is not sufficient to cause leukemia, it could be involved in the pathogenesis of the disease. Notably, these new translocations were found in genes encoding for hematopoietic transcription factors which are known to play an important role in leukemogenesis and disease prognosis such as IKZF1, CREBBP, and ETV6. In addition, they may have an impact on the prognosis of Mexican pediatric patients with ALL, with the potential to be included in the current risk stratification schemes or used as therapeutic targets.

[Perception of quality of life related with health and depression in patients with hemophilia]. / Percepción de la calidad de vida relacionada con la salud y la depresión en pacientes con hemofilia.

BACKGROUND: Hemophilia is a hemorrhagic disease characterized by the deficiency of either coagulation factor VIII or IX. It impacts negatively in people's quality of life and it causes side effects, such as depression. The objective was to describe and analyze the health-related quality of life (HRQoL) and depression levels in a group of 50 pediatric patients with hemophilia (PPwH) and their parents. The specific objectives were: to analyze the correlation between HRQoL levels reported by patients and their parents, and to analyze the correlation between HRQoL levels and depression in PPwH. METHODS: Descriptive, cross-sectional and correlational study with a group of 50 PPwH and their parents. The Pediatric Life Quality Questionnaire [PedsQLTM 4.0] was completed by PPwH and their parents and the Children's Depression Inventory (CDI) was answered only by PPwH. RESULTS: The average age of PPwH was 10.66 years (SD = 2.61) and that of parents was 36.28 years (SD = 6.4). 82% suffered from hemophilia A and 70% suffered from severe hemophilia. 78% of participants felt at risk or at high risk with regards to their quality of life, and, concerning their depression levels, we found moderate symptoms in 54% and severe symptoms in 10%. CONCLUSIONS: The HRQoL and depression levels we found are alarming. They show the importance of evaluating objective and subjective indicators; in addition, we emphasize the need of assisting the severe cases detected and suggest the activities to face these health issues.

Introducción: la hemofilia es una enfermedad hemorrágica caracterizada por la deficiencia del factor VIII o IX de la coagulación. Impacta negativamente la calidad de vida de las personas y tiene efectos como la depresión. El objetivo fue describir y analizar los niveles de calidad de vida relacionada con la salud (CVRS) y depresión en una muestra de 50 pacientes pediátricos con hemofilia (PPcH) y sus padres. Los objetivos específicos fueron analizar la correlación entre los niveles de CVRS reportada por PPcH y sus padres, y analizar la correlación entre la CVRS y la depresión en PPcH. Métodos: estudio descriptivo, transeccional y correlacional. Participaron 50 PPcH y sus progenitores, los cuales asistieron a consulta en un hospital del tercer nivel. Se aplicó el Cuestionario de Calidad de Vida Pediátrica (PedsQLTM 4.0) a PPcH y padres, y el Cuestionario de Depresión Infantil (CDI) solo a PPcH. Resultados: la media de edad de los pacientes fue de 10.66 años (desviación estándar [DE] = 2.61) y la de los padres 36.28 (DE = 6.4); el 82% padecía hemofilia A y el 70% tenía hemofilia severa. El 78% de los participantes se sintió en riesgo o alto riesgo respecto a su calidad de vida y en cuanto a los niveles de depresión se encontró sintomatología moderada en el 54% y sintomatología severa en el 10%. Conclusiones: los niveles de CVRS y depresión encontrados son preocupantes. Se evidencia la importancia de evaluar indicadores objetivos y subjetivos, y además se deben canalizar los casos graves detectados y se sugieren actividades para atender estos problemas.

[Leading causes of death during the induction therapy in pediatric patients with acute lymphoblastic leukemia]. / Principales causas de mortalidad durante la fase de inducción a la remisión en los pacientes pediátricos con leucemia linfoblástica aguda.

BACKGROUND: Leukemias are the leading cause of childhood cancer. In most developed countries 1-2% of patients die during remission induction; however, in developing countries, this figure is higher and the causes of death apparently vary among the populations studied. The aim was to determine the cause of death during remission induction in pediatric patients with acute lymphoblastic leukemia (ALL) in the hospital "Dr. Gaudencio González Garza" of Centro Médico Nacional La Raza from January 1, 2009, to December 31, 2014. METHODS: A retrospective cohort study was carried out and a descriptive statistical analysis was performed. RESULTS: During the study period, a total of 463 patients with ALL were diagnosed, out of which 5.4% died (n = 25). Among the patients who died, 64% (n = 16) were female and 60% had high-risk clinical features at diagnosis. The main causes of death were septic shock and bleeding. CONCLUSIONS: Early mortality was five times higher than the one reported for developed countries, while the causes of death did not differ. Close monitoring is necessary to detect and promptly treat complications secondary to chemotherapy toxicity in Mexican pediatric patients with ALL.

Introducción: las leucemias son la principal causa de cáncer en la infancia. En la mayoría de países desarrollados fallecen entre 1 y 2% de los pacientes durante la inducción a la remisión; sin embargo, en países en vías de desarrollo, esta cifra al parecer es superior y las causas de muerte varían entre las poblaciones estudiadas. El objetivo fue determinar la causa de mortalidad durante la fase de inducción a la remisión en los pacientes pediátricos con diagnóstico de leucemia linfoblástica aguda (LLA) en el Hospital General "Dr. Gaudencio González Garza" del Centro Médico Nacional La Raza del 1 de enero de 2009 al 31 de diciembre de 2014. Métodos: se realizó un estudio de cohorte retrospectivo y se utilizó estadística descriptiva. Resultados: se diagnosticaron un total de 463 pacientes con LLA durante el periodo de estudio, de los cuales falleció el 5.4% (n = 25). Entre los pacientes que fallecieron, el 64% (n = 16) eran del sexo femenino y el 60% tenía características clínicas de alto riesgo al momento del diagnóstico. Entre las principales causas de muerte estuvieron el choque séptico y las hemorragias. Conclusiones: la frecuencia de mortalidad temprana en los pacientes con LLA fue cinco veces más elevada que la reportada para países desarrollados, mientras que las causas de muerte no difieren. Se requiere de una vigilancia estrecha para detectar y tratar oportunamente las complicaciones secundarias a toxicidad por quimioterapia en pacientes pediátricos mexicanos con LLA.

Early mortality in children with acute lymphoblastic leukemia in a developing country: the role of malnutrition at diagnosis. A multicenter cohort MIGICCL study.

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.

[Descriptive epidemiology of children with acute myeloid leukemia residing in Mexico City: a report from the Mexican Inter-Institutional Group for Identifying Childhood Leukemia Causes]. / Epidemiología descriptiva de la leucemia mieloide aguda (LMA) en niños residentes de la Ciudad de México: reporte del Grupo Mexicano Interinstitucional para la Identificación de las Causas de la Leucemia en Niños.

INTRODUCTION: Acute myeloid leukemias represent the second most common childhood leukemia subtype. In Mexico, there are few studies on descriptive epidemiology for this disease. AIMS: 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. MATERIAL AND METHODS: 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. RESULTS: 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. CONCLUSIONS: It seems that childhood acute myeloid leukemia incidence is increasing in Mexico City, which makes the identification of associated risk factors imperative.

Analysis of Thiopurine S-Methyltransferase Deficient Alleles in Acute Lymphoblastic Leukemia Patients in Mexican Patients.

BACKGROUND AND AIMS: It has been demonstrated that heterozygote and homozygote thiopurine S-methyltransferase (TPMT) mutant allele carriers are at high risk to develop severe and potentially fatal hematopoietic toxicity after treatment with standard doses of 6-mercaptopurine (6-MP) and methotrexate (MX). Those drugs are the backbone of acute lymphoblastic leukemia (ALL) and several autoimmune disease treatments. We undertook this study to determine the frequency of the TPMT deficient alleles in children with ALL and non-ALL subjects from Mexico City and Yucatan, Mexico. METHODS: We included 849 unrelated subjects, of which 368 ALL children and 342 non-ALL subjects were from Mexico City, and 60 ALL cases and 79 non-ALL individuals were from Yucatan. Genotyping of the rs1800462, rs1800460 and rs1142345 SNPs was performed by 5'exonuclease technique using TaqMan probes (Life Technologies Foster City, CA). RESULTS: The mutant TPMT alleles were present in 4.8% (81/1698 chromosomes) and only 0.2% were homozygote TPMT*3A/TPMT*3A. We did not find statistically significant differences in the distribution of the mutant alleles between patients from Mexico City and Yucatan in either ALL cases or non-ALL. Nonetheless, the TPMT*3C frequency in ALL patients was higher than non-ALL subjects (p = 0.03). To note, the null homozygous TPMT*3A/TPMT*3A genotype was found in 2.5% of the non-ALL subjects. CONCLUSIONS: TPMT mutant alleles did not exhibit differential distribution between both evaluated populations; however, TPMT*3C is overrepresented in ALL cases in comparison with non-ALL group. Assessing the TPMT mutant alleles could benefit the ALL children and those undergoing 6-MP and MX treatment.

Survival of Mexican children with acute myeloid leukaemia who received early intensification chemotherapy and an autologous transplant.

BACKGROUND: In Mexico and other developing countries, few reports of the survival of children with acute leukaemia exist. Objective. We aimed at comparing the disease-free survival of children with acute myeloid leukaemia who, in addition to being treated with the Latin American protocol of chemotherapy and an autologous transplant, either underwent early intensified chemotherapy or did not undergo such treatment. PROCEDURE: This was a cohort study with a historical control group, forty patients, less than 16 years old. Group A (20 patients), diagnosed in the period 2005-2007, was treated with the Latin American protocol of chemotherapy with an autologous transplant plus early intensified chemotherapy: high doses of cytarabine and mitoxantrone. Group B (20 patients), diagnosed in the period 1999-2004, was treated as Group A, but without the early intensified chemotherapy. RESULTS: Relapse-free survival for Group A was 90% whereas that for Group B it was 60% (P = 0.041). Overall survival for Group A (18, 90%) was higher than that for Group B (60%). Complete remission continued for two years of follow-up. CONCLUSIONS: Relapse-free survival for paediatric patients treated with the Latin American protocol of chemotherapy with an autologous transplant plus early intensified chemotherapy was higher than that for those who did not receive early intensified chemotherapy.

Pancitopenia periférica / Peripheral pancytopenia

El síndrome de pancitopenia periférica tiene gran interés en clínica pediátrica ya que frecuentemente señala una afección grave de los tejidos sanguíneos, la cual debe ser diagnosticada y tratada oportunamente. Etiopatogenia. Se comentan 6 grupos de padecimientos que pueden cursar con pancitopenia periférica; se describen brevemente sus características clínicas y fisiopatológicas principales. Conclusiones. El pronóstico de los pacientes con pancitopenia periférica pueden mejorarse si se diagnóstica temprana y se instala el tratamiento adecuado para la enfermedad primaria

Actualización de los criterios del tratamiento de la deficiencia de hierro / Update on iron deficiency treatment criteria

La deficiencia de hierro constituye un problema de salud pública. Recientemente se han desarrollado nuevos protocolos para la profilaxis y tratamiento de esta carencia nutricional. Biología molecular del hierro orgánico. Se revisa la relación del hierro con importantes macromoléculas que captan, transportan y utilizan el hierro. Factores que determinan el estado nutricional relativo al hierro. El balance del hierro se ve influido por la pérdida crónica de sangre, los altos requerimentos de hierro en la lactancia, la adolescencia y el embarazo. Estrategias para la profilaxis y el tratamiento de la deficiencia de hierro. Se comenta la importancia de la determinación del receptor soluble de la transferrina; así como los programas para suplementar a los lactantes con leche fortificada con hierro o azúcar fortificada con la sal ferrosa de EDTA sódico, o bien tabletas de sulfato ferroso en protocolo de dosis bisemanal