Publications by authors named "Roberto Rivera-Luna"

39 Publications

Childhood Acute Leukemias in Developing Nations: Successes and Challenges.

Curr Oncol Rep 2021 Mar 23;23(5):56. Epub 2021 Mar 23.

Centro de Investigación Biomédica de Oriente CIBIOR, Instituto Mexicano del Seguro Social Delegación Puebla, Km. 4.5 Carretera Atlixco-Metepec, 74360, Puebla, Mexico.

Purpose Of Review: Acute leukemias represent a tremendous threat to public health around the globe and the main cause of death due to disease in scholar age children from developing nations. Here, we review their current status in Mexico, as a paradigm of study, and the major challenges to control systemic diseases like childhood cancer.

Recent Findings: A unique molecular epidemiology, late/low precision diagnosis, limited access to treatment, toxicity associated with therapy, continuous exposure to environmental risk factors, and the high frequency of early relapses are some of the factors cooperating to low rates of survival in low-to-medium-income countries. Deliberative dialogues and exhaustive programs have emerged as promising means of advancing evidence-informed policy, by providing a structured forum for key stakeholders to integrate scientific and pragmatic knowledge about complex health concerns. A system-wide strategy based on the comprehensive leukemia identity is essential for a meaningful decline in early childhood mortality.
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http://dx.doi.org/10.1007/s11912-021-01043-9DOI Listing
March 2021

Does the Human Development Index relate with acute lymphoblastic leukemia incidence?

Bol Med Hosp Infant Mex 2021 Jan 26. Epub 2021 Jan 26.

Division of Hematology/Oncology. Instituto Nacional de Pediatría, Mexico City, Mexico.

Background: The association between childhood cancer and socioeconomic status has been widely studied. However, none of the results are conclusive. This study aimed to analyze the association between the Human Development Index (HDI) and the acute lymphoblastic leukemia (ALL) incidence in children under the Popular Medical Insurance Care.

Methods: We conducted an observational, descriptive, and population-based study covering 55% of the Mexican population (58 million).

Results: The most impoverished states were located in the south east region of Mexico, while the north was more homogeneous, with HDIs varying between 0.73 and 0.79. Our findings emphasize that the metropolitan area of Mexico City and the State of Nuevo Leon have the highest levels of HDI. Regions were graded from I to IV according to their HDIs in ascending order. The HDIs varied from 0.667 to 0.830/100,000 children/year, with a national average of 0.746. The leukemia incidence for regions I, II, III, and IV was 6.12, 6.53, 4.96, and 9.95. An analysis of ALL incidence in Mexico showed significant differences for region IV in comparison with the other regions based on the HDI values (p = 0.0001).

Conclusions: Further in-depth studies, including the economic aspects of the different geographic regions and their ethnographic characteristics, would give a more comprehensive panorama.
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http://dx.doi.org/10.24875/BMHIM.20000043DOI Listing
January 2021

Extremely Low-Frequency Magnetic Fields and the Risk of Childhood B-Lineage Acute Lymphoblastic Leukemia in a City With High Incidence of Leukemia and Elevated Exposure to ELF Magnetic Fields.

Bioelectromagnetics 2020 Dec 23;41(8):581-597. Epub 2020 Sep 23.

Unidad de Investigación Médica en Epidemiología Clínica, Unidad Médica de Alta Especialidad (UMAE), Hospital de Pediatría, Centro Médico Nacional (CMN) "Siglo XXI," Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico.

It is important to study the relationship between extremely low-frequency magnetic fields (ELF-MFs) and childhood leukemia, particularly in locations with a high incidence of this neoplasm in children and an elevated exposure to ELF-MF, such as Mexico City. The aim was to investigate the association between ELF-MF exposure and the risk of B-lineage acute lymphoblastic leukemia (B-ALL). A case-control study was conducted in Mexico City during the period from 2010 to 2011. Residential 24-h ELF-MF measurements were obtained for 290 incident B-ALL patients and 407 controls, aged less than 16 years. Controls were frequency-matched by sex, age (±18 months), and health institution. The adjusted odds ratios (aOR) and 95% confidence intervals (CIs) were calculated. ELF-MF exposure at <0.2 μT was used to define the reference group. ELF-MF exposure at ≥0.3 μT was observed in 11.3% of the controls. Different ELF-MF intensity cutoff values were used to define the highest exposure category; the highest exposure category for each cutoff value was associated with an increased risk of B-ALL compared with the corresponding lower exposure categories. The aORs were as follows: ≥0.2 μT = 1.26 (95% CI: 0.84-1.89); ≥0.3 μT = 1.53 (95% CI: 0.95-2.48); ≥0.4 μT = 1.87 (95% CI: 1.04-3.35); ≥0.5 μT = 1.80 (95% CI 0.95-3.44); ≥0.6 μT = 2.32 (95% CI: 1.10-4.93). ELF-MF exposure as a continuous variable (per 0.2 μT intervals) was associated with B-ALL risk (aOR = 1.06; 95% CI: 1.01-1.12). In the present study, the proportion of children exposed to ≥0.3 μT is among the highest reported worldwide. Additionally, an ELF-MF exposure ≥0.4 μT may be associated with the risk of B-ALL. Bioelectromagnetics. © 2020 Bioelectromagnetics Society.
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http://dx.doi.org/10.1002/bem.22295DOI Listing
December 2020

v-myb avian myeloblastosis viral oncogene homolog expression is a potential molecular diagnostic marker for B-cell acute lymphoblastic leukemia.

Asia Pac J Clin Oncol 2021 Feb 10;17(1):60-67. Epub 2020 Aug 10.

Experimental Oncology Laboratory, Research Department, National Institute of Pediatrics, Mexico City, Mexico.

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 . MYB expression showed great variability among the patients analyzed. However, compared to the HCs, the B-ALL patients had a P value < .0001, an area under the curve of 0.813, and a Youden index of 1.46, indicating the statistical significance.

Conclusion: MYB expression in B-ALL cells could be a potential molecular marker for childhood leukemia.
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http://dx.doi.org/10.1111/ajco.13406DOI Listing
February 2021

Maternal and paternal ages at conception of index child and risk of childhood acute leukaemia: A multicentre case-control study in Greater Mexico City.

Cancer Epidemiol 2020 08 19;67:101731. Epub 2020 May 19.

Coordinación de Investigación en Salud, CMN "Siglo XXI", IMSS. Av. Cuauhtemoc 330, Delegación Cuauhtémoc, Mexico City, 06720, Mexico; Unidad de Investigación Médica en Epidemiología Clínica, Unidad Médica de AltaEspecialidad (UMAE) Hospital de Pediatría, Centro Médico Nacional (CMN) "Siglo XXI", Instituto Mexicano del Seguro Social (IMSS). Av. Cuauhtemoc 330, Delegación Cuauhtémoc, Mexico City, 06720, Mexico; Laboratorio de Biología Molecular de las Leucemias, Unidad de Investigación en Genética Humana, UMAE, Hospital de Pediatría, CMN "Siglo XXI", IMSS. Av. Cuauhtemoc 330, Delegación Cuauhtémoc, Mexico City, 06720, Mexico. Electronic address:

Background: 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.

Methods: 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.

Results: 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 was <20 years of age, however, a very wide confidence interval was noted (aOR, 12.26; 95 % CI, 1.41-106.83).

Conclusion: 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.
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http://dx.doi.org/10.1016/j.canep.2020.101731DOI Listing
August 2020

Efficacy and safety of quinolones for the treatment of uncomplicated urinary tract infections in women: a network meta-analysis.

Int Urogynecol J 2021 Jan 24;32(1):3-15. Epub 2020 Feb 24.

Medical Research Unit, Instituto Nacional de Pediatría, Insurgentes Sur 3700-C, Col. Insurgentes Cuicuilco, Coyoacán, zip 04530, Mexico City, Mexico.

Introduction And Hypothesis: Uncomplicated urinary tract infection (uUTI) is defined as the presence of pathogenic organisms in the urinary tract without anatomical and functional abnormalities, is accompanied by inflammatory leukocytes and cytokines and may or may not develop clinical symptoms. The frequency of uncomplicated urinary tract infection is higher in young women. Several quinolone treatment regimens are available; however, since we do not know which is the best antibiotic regimen for the treatment of this urinary infection, we analyzed the published evidence and conducted a systematic review with network meta-analysis. The aim was to compare and hierarchize quinolones according to their efficacy and safety and to identify the best treatment for uncomplicated urinary tract infection in women through a systematic review with network meta-analysis.

Methods: Medline, Embase, LILACS, Cochrane CENTRAL and other databases were searched for trials. Bias in the trials was assessed using the Cochrane Collaboration tool. To analyze efficacy and adverse events, for direct comparisons, we obtained risk ratios and 95% confidence intervals by applying a fixed-effects model using tau and Q tests to calculate the heterogeneity. For the network meta-analysis, we analyzed the indirect comparisons by Bucher's method.

Results: We included 18 trials (8765 women). For premenopausal women, ofloxacin had a 57% probability of achieving remission but an 83% frequency of adverse events. For postmenopausal women, ofloxacin was 82% more effective for remission, with a 49% frequency of adverse events, compared with other types of quinolones.

Conclusions: Compared with other quinolones, ofloxacin 200 mg once daily for a treatment duration < 3 days provides the highest clinical and bacteriological remission rates with the lowest relapse and resistance rates for the treatment of women with uUTIs. However, additional trials are needed to confirm our findings, especially when the treatment duration exceeds 3 days.
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http://dx.doi.org/10.1007/s00192-020-04255-yDOI Listing
January 2021

Expression of ZNF695 Transcript Variants in Childhood B-Cell Acute Lymphoblastic Leukemia.

Genes (Basel) 2019 09 16;10(9). Epub 2019 Sep 16.

Experimental Oncology Laboratory, Research Department, National Institute of Pediatrics, Mexico City 04530, Mexico.

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 >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.
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http://dx.doi.org/10.3390/genes10090716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771147PMC
September 2019

Variants in ARID5B gene are associated with the development of acute lymphoblastic leukemia in Mexican children.

Ann Hematol 2019 Oct 21;98(10):2379-2388. Epub 2019 Jun 21.

Laboratorio de Genética y Cáncer, Instituto Nacional de Pediatría, Insurgentes Sur 3700-C, Colonia Insurgentes Cuicuilco, C.P. 04530, Mexico City, Mexico.

A high impact of ARID5B SNPs on acute lymphoblastic leukemia (ALL) susceptibility has been described in Hispanic children; therefore, it is relevant to know if they influence the high incidence of childhood-ALL in Mexicans. Seven SNPs (rs10821936, rs10994982, rs7089424, rs2393732, rs2393782, rs2893881, rs4948488) of ARID5B were analyzed in 384 controls and 298 ALL children using genomic DNA and TaqMan probes. The SNPs were analyzed for deviation of Hardy-Weinberg equilibrium; Fisher's exact test was used to compare the genotypic and allelic frequencies between controls and patients. The association between SNPs and ALL susceptibility was calculated, and haplotype and ancestry analyses were conducted. All SNPs were associated with ALL, pre-B ALL, and hyperdiploid-ALL susceptibility (p < 0.05). No association with T-ALL and gene fusions was found (p > 0.05). The seven SNPs were associated with risk of pre-B ALL in younger children; however, rs2393732, rs2393782, rs2893881, and rs4948488 were not associated with susceptibility in older children and adolescents. The CAG haplotype (rs10821936, rs10994982, rs7089424) was strongly associated with ALL risk in our population (p < 0.00001). The frequency of all risk alleles in our ALL, pre-B, and hyperdiploid-ALL patients was higher than that in Hispanic children reported. This is the first report showing the association between rs2393732, rs2393782, and rs4948488 with pre-B hyperdiploid-ALL children. The G allele at rs2893881 confers major risk for pre-B hyperdiploid-ALL in Mexican (OR, 2.29) than in Hispanic children (OR, 1.71). The genetic background of our population could influence the susceptibility to ALL and explain its high incidence in Mexico.
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http://dx.doi.org/10.1007/s00277-019-03730-xDOI Listing
October 2019

Feeding difficulties and eating disorders in pediatric patients with cancer.

Bol Med Hosp Infant Mex 2019 ;76(3):113-119

Subdirección de Hematología/Oncología Instituto Nacional de Pediatría, Mexico City, Mexico.

Background: Feeding difficulties and disorders are a common problem in the pediatric population, which involve a series of deficient behaviors about nutrition processes that can adversely affect psychomotor, psychosocial, and physical development of children. This study aimed to describe the frequency of feeding difficulties or disorders in pediatric patients with cancer.

Methods: A prospective study which included 125 children from 1-19 years treated at the Department of Oncology of the Instituto Nacional de Pediatría, Mexico City, was conducted. The diagnosis of eating disorders and feeding difficulties was determined during the first 48 h since admission, and the age of the patient influenced the type of disorder and feeding difficulties.

Results: Children older than 11 years presented more frequently an intense resistance of feeding because of discomfort pain (fear of feeding) than younger children (11.4 ± 4.7 vs. 7.4 ± 4.9, p ≤ 0.001). The most frequent alteration associated with malnutrition was loss of appetite (odds ratio [OR]: 8.8, confidence interval [CI] 95% 2.9-26.9, p<0.001), followed by fear of feeding (OR: 3.14, CI 95% 1.24-7.9, p=0.015), and the organic causes showed the highest risk for malnutrition (OR: 3.1, CI 95% 0.98-9.7, p=0.054).

Conclusions: Over 90% of the studied population demonstrated at least one eating disorder or feeding difficulty. The principal effect is inadequate nutritional intake due to limited appetite and fear of feeding, which can result in undernutrition. For this reason, the identification of alterations in nutrition processes should be part of the comprehensive assessment of cancer patients.
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http://dx.doi.org/10.24875/BMHIM.19000072DOI Listing
February 2020

Nonclonal Chromosome Aberrations and Genome Chaos in Somatic and Germ Cells from Patients and Survivors of Hodgkin Lymphoma.

Genes (Basel) 2019 01 10;10(1). Epub 2019 Jan 10.

Subdirección de Hemato-Oncología, Instituto Nacional de Pediatría, Cd. De Mexico, P.O. Box 04530, Mexico.

Anticancer regimens for Hodgkin lymphoma (HL) patients include highly genotoxic drugs that have been very successful in killing tumor cells and providing a 90% disease-free survival at five years. However, some of these treatments do not have a specific cell target, damaging both cancerous and normal cells. Thus, HL survivors have a high risk of developing new primary cancers, both hematologic and solid tumors, which have been related to treatment. Several studies have shown that after treatment, HL patients and survivors present persistent chromosomal instability, including nonclonal chromosomal aberrations. The frequency and type of chromosomal abnormalities appear to depend on the type of therapy and the cell type examined. For example, MOPP chemotherapy affects hematopoietic and germ stem cells leading to long-term genotoxic effects and azoospermia, while ABVD chemotherapy affects transiently sperm cells, with most of the patients showing recovery of spermatogenesis. Both regimens have long-term effects in somatic cells, presenting nonclonal chromosomal aberrations and genomic chaos in a fraction of noncancerous cells. This is a source of karyotypic heterogeneity that could eventually generate a more stable population acquiring clonal chromosomal aberrations and leading towards the development of a new cancer.
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http://dx.doi.org/10.3390/genes10010037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357137PMC
January 2019

A greater birthweight increases the risk of acute leukemias in Mexican children-experience from the Mexican Interinstitutional Group for the Identification of the Causes of Childhood Leukemia (MIGICCL).

Cancer Med 2018 04 13;7(4):1528-1536. Epub 2018 Mar 13.

Health Research Coordination, Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico.

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.
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http://dx.doi.org/10.1002/cam4.1414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5911591PMC
April 2018

Current outlook of childhood cancer epidemiology in a middle-income country under a public health insurance program.

Pediatr Hematol Oncol 2017 Feb 13;34(1):43-50. Epub 2017 Mar 13.

b Department of Pediatric Oncology , National Institute of Pediatrics (NIP) , Mexico City , Mexico.

In Mexico, childhood cancer (0-18 years) is treated in a multidisciplinary way while providing care for more than half of the affected children through a public medical insurance. This insurance is given to all children who do not have any health care coverage in Mexico. This program is offered to the poorest of all Mexicans. All the children with this disease are submitted to pathology diagnosis and treatment according to national treatment protocols from 57 accredited medical institutions. From 2007 to 2015, a total of 24,039 children with cancer have been registered; the male gender predominates by 55%. The highest incidence was in the group aged between 0 and 4 years. Every year, there has been an increment in registration. In 2015, there were 3,433 new patients with an incidence of 150.1/million. In the same year, the incidence for all types of leukemia increased to 89.5/million. But for acute lymphoblastic leukemia, the incidence was found to be 79.8/million, which is extremely high. The mortality rate for all these patients in 2015 was 5.3/100,000. However, with regard to children aged between 15 and 18 years, the mortality rate was 8.5/100,000. Abandonment rate was 10%, and there were nine state institutions that had a mortality rate between 25% and 50% among their patients. Coincidentally, as per the Human Development Index, the parameters for education, health, and income were low for those nine institutions. The purpose of this work is to show the epidemiology and the burden we are facing due to this disease.
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http://dx.doi.org/10.1080/08880018.2016.1276236DOI Listing
February 2017

The burden of childhood cancer in Mexico: Implications for low- and middle-income countries.

Pediatr Blood Cancer 2017 06 1;64(6). Epub 2016 Dec 1.

Department of Pediatric Oncology, National Institute of Pediatrics (NIP), Mexico City, Mexico.

In Mexico, childhood cancer incidence and mortality have increased in the last decade. Through government actions since 2005, the Popular Medical Insurance (PMI) program for childhood cancer was created. The objective of PMI was to offer early cancer diagnosis, standardized treatment regimens, and numerous pediatric oncology residency programs. It has also accredited 55 national hospitals for the care of these children. Current problems still present under the PMI include shortage of pediatric oncologists and nurses and high rate of abandonment of treatment. Our aim is to describe the current scenario of childhood cancer care in Mexico, especially from the perspective of the PMI and how it has impacted human resources, infrastructure, and medical education.
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http://dx.doi.org/10.1002/pbc.26366DOI Listing
June 2017

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

Leuk Lymphoma 2017 04 26;58(4):898-908. Epub 2016 Aug 26.

b Unidad de Investigación Médica en Epidemiologia Clínica, UMAE Hospital de Pediatría, Centro Médico Nacional (CMN) 'Siglo XXI' , Instituto Mexicano del Seguro Social (IMSS) , México D.F , México.

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.
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http://dx.doi.org/10.1080/10428194.2016.1219904DOI Listing
April 2017

Expression of Ik6 and Ik8 Isoforms and Their Association with Relapse and Death in Mexican Children with Acute Lymphoblastic Leukemia.

PLoS One 2015 1;10(7):e0130756. Epub 2015 Jul 1.

Laboratorio de Cultivo de Tejidos, Departamento de Genética Humana, Instituto Nacional de Pediatría, México, DF, México.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0130756PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4488851PMC
April 2016

Descriptive Epidemiology in Mexican children with cancer under an open national public health insurance program.

BMC Cancer 2014 Oct 29;14:790. Epub 2014 Oct 29.

Head of the Division of Pediatric Hem/Oncology, National Institute of Pediatrics (NIP), Coordinator for the Technical Committee of the National Council for the Prevention and Treatment of Childhood Cancer, Mexico City, Mexico.

Background: All the children registered at the National Council for the Prevention and Treatment of Childhood Cancer were analyzed. The rationale for this Federal Government Council is to financially support the treatment of all children registered into this system. All patients are within a network of 55 public certified hospitals nationwide.

Methods: In the current study, data from 2007 to 2012 are presented for all patients (0-18 years) with a pathological diagnosis of leukemia, lymphoma and solid tumors. The parameters analyzed were prevalence, incidence, mortality, and abandonment rate.

Results: A diagnosis of cancer was documented in 14,178 children. The incidence was of 156.9/million/year (2012). The median age was 4.9. The most common childhood cancer is leukemia, which occurs in 49.8% of patients (2007-2012); and has an incidence rate of 78.1/million/year (2012). The national mortality rate was 5.3/100,000 in 2012, however in the group between 15 to 18 years it reaches a level of 8.6.

Conclusions: The study demonstrates that there is a high incidence of childhood cancer in Mexico. In particular, the results reveal an elevated incidence and prevalence of leukemia especially from 0 to 4 years. Only 4.7% of these patients abandoned treatment. The clinical outcome for all of the children studied improved since the establishment of this national program.
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http://dx.doi.org/10.1186/1471-2407-14-790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4228174PMC
October 2014

Pediatric oncology as the next global child health priority: the need for national childhood cancer strategies in low- and middle-income countries.

PLoS Med 2014 Jun 17;11(6):e1001656. Epub 2014 Jun 17.

Division of Pediatric Hematology/Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.

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http://dx.doi.org/10.1371/journal.pmed.1001656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4061014PMC
June 2014

Significance of CASP8AP2 and H2AFZ expression in survival and risk of relapse in children with acute lymphoblastic leukemia.

Leuk Lymphoma 2014 Oct 24;55(10):2305-11. Epub 2014 Feb 24.

Laboratorio de Cultivo de Tejidos, Instituto Nacional de Pediatría , México D.F. , México.

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.
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http://dx.doi.org/10.3109/10428194.2013.878458DOI Listing
October 2014

Consolidation treatment for high risk solid tumors in children with myeloablative chemotherapy and autologous hematopoietic progenitor stem cell transplantation.

Rev Bras Hematol Hemoter 2013 ;35(5):343-6

National Institute of Pediatrics - INP, Mexico City, AC, Mexico.

Background: In childhood cancer, consolidation treatment with chemotherapy followed by autologous hematopoietic progenitor stem cell transplantation is currently an accepted treatment modality in patients with high-risk solid tumors or in patients who have relapsed after conventional treatment.

Objectives: The objective of this study was to describe the results of transplantation of a group of children who had high-risk solid tumors or relapsed after conventional chemotherapy regimens.

Methods: A retrospective analysis was conducted from January 1998 to October 2004 of all children with pathologic diagnoses of high-risk solid tumors or children that had previously relapsed after conventional chemotherapy and that were subsequently submitted to autologous hematopoietic progenitor stem cell transplantation. The analysis included overall survival rates, event-free survival rates, mortality rates and chemotherapy complications.

Results: Nineteen patients were submitted to this approach. The age range was from 27 to 196 months with a median age of 52 months. The overall survival rate at 100 days was observed in 79%, the three-year event-free survival rate was 63%. The mortality rate secondary to the myeloablative chemotherapy regimen was 21% (n = 4). Only three patients (15.8%) relapsed with tumor progression after transplant.

Conclusion: Autologous hematopoietic progenitor stem cell transplantation is still a successful procedure in patients with solid tumors refractory to conventional chemotherapy.
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http://dx.doi.org/10.5581/1516-8484.20130099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3832315PMC
November 2013

Interleukin-1 receptor antagonist gene polymorphism increases susceptibility to septic shock in children with acute lymphoblastic leukemia.

Pediatr Infect Dis J 2013 Feb;32(2):136-9

Division of Pediatric Oncology, Hospital Infantil de Mexico Federico Gomez, Mexico City, Mexico.

Background: Interleukin-1 receptor antagonist polymorphism (ILRN) 2 (ILRN*2) has been associated with a poor outcome in septic patients because of an elevated production of anti-inflammatory cytokines. In >70% of patients, morbidity and mortality in childhood acute lymphoblastic leukemia is caused by infections. The aim of this study was to determine the association between this polymorphism and the frequency of septic shock from the time of diagnosis until completion of treatment.

Methods: This cohort study was conducted in 57 consecutive children with acute lymphoblastic leukemia. At the end of follow-up, children were stratified according to their IL1RN polymorphism (ILRN*1/ILRN*2), evaluating the impact of genotype on the severity of febrile neutropenic events during their treatment.

Results: Overall survival was 80% at 55 months after treatment. The average number of febrile neutropenic events in this cohort was 2.82 per patient. Genotype distribution was 50.9% for homozygote IL-1RN*1, 38.6% for heterozygote ILRN*1/ILRN*2 and 10.5% for homozygote IL-1RN*2. The risk of presenting septic shock for homozygote IL1RN*2/IL1RN*2 and heterozygote ILRN*1/ILRN*2 patients was significantly greater (odds ratio, 45; P = 0.001) adjusted for age, gender, risk of leukemia and presence of pathogenic bacteria. Genotype IL-1RN*2 is associated with the risk of development of septic shock in children with acute lymphoblastic leukemia. Further research in larger population-based studies is needed to replicate these findings.

Conclusions: This information would allow us to identify more predictive factors in this group of acute lymphoblastic leukemia patients in whom this information is lacking to establish an earlier and more aggressive approach.
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http://dx.doi.org/10.1097/INF.0b013e31827566ddDOI Listing
February 2013

Incidence of childhood cancer among Mexican children registered under a public medical insurance program.

Int J Cancer 2013 Apr 28;132(7):1646-50. Epub 2012 Aug 28.

Division of Pediatric Hem/Oncology, Coordinator for the Technical Committee of the National Council for the Prevention and Treatment of Childhood Cancer, National Institute of Pediatrics, Mexico City, Mexico.

Prior to 2005, 51% of children in Mexico diagnosed with cancer received no standardized optimal multidisciplinary medical care. A government-subsidized national cancer treatment program was therefore created for these patients and a National Cooperative Childhood Cancer Treatment Group was consequently formed for these patients. Pediatric patients with a proven diagnosis of leukemia, lymphoma or solid tumor and who were registered in the Popular Medical Insurance (PMI) program from January 2007 to December 2010, are described in this report. These patients had been enrolled and registered in one of the 49 nationwide certified medical institutions in Mexico. The national incidence and frequency data for childhood cancers were analyzed for the whole program. At the end of a 4-year study, the analysis revealed that 8,936 children from across Mexico had been diagnosed with cancer. The incidence rate for the PMI patients was 150.3/million/year (2010) for children of 0-18 years. The highest age incidence rate was 51.9 between 0 and 4 years and boys were the predominant group for all types of cancer. The leukemia incidence was 75.3/million/year (2010), and an average frequency of 50.75% throughout the 4 years. The overall mortality rate was measured at 5.4/100,000/year (2010). This study demonstrates a high frequency and incidence of childhood cancer and a beneficial impact of the PMI program over the quality of life in these children.
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http://dx.doi.org/10.1002/ijc.27771DOI Listing
April 2013

Childhood acute leukemias are frequent in Mexico City: descriptive epidemiology.

BMC Cancer 2011 Aug 17;11:355. Epub 2011 Aug 17.

Unidad de Investigación en Epidemiología Clínica, Unidad Médica de Alta Especialidad UMAE Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexicano de Seguridad Social, México DF, México.

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.
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http://dx.doi.org/10.1186/1471-2407-11-355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3171387PMC
August 2011

Analysis of gene rearrangements using a fluorescence in situ hybridization method in Mexican patients with acute lymphoblastic leukemia: experience at a single institution.

Cancer Genet Cytogenet 2008 Jul;184(2):94-8

Department of Research in Human Genetics, Instituto Nacional de Pediatría, Insurgentes Sur 3700-C, Col. Insurgentes Cuicuilco, Mexico City DF 04530, Mexico.

We evaluated the prevalence of BCR/ABL, MLL, and ETV6/RUNX1 rearrangements as well as CDKN2A (alias p16) deletion in a group of Mexican children with acute lymphoblastic leukemia (ALL) to determine whether the changes coexist, and to compare the incidences found with other reports in the literature. To increase the detection of these abnormalities, we combined conventional cytogenetics and fluorescence in situ hybridization (FISH) analysis. Bone marrow samples were obtained from 59 consecutive children with ALL. FISH detected a total of 63 abnormalities with the selected probes, 34 of which were related to the conventional cytogenetic results. The most common abnormality was the p16 deletion (22.8%), followed by MLL and ETV6/RUNX1 rearrangements (8.7%), and the BCR/ABL fusion was the least frequent (2.7%). The coexistence of two recurrent abnormalities with specific prognostic significance in the same patient was not found. A lesser proportion of the p16 deletion in T-ALL patients was observed, probably related to the low prevalence of this subtype in our population. In addition, we confirmed the low frequency of the ETV6/RUNX1 fusion observed in Hispanics. Due to the different prevalence of these abnormalities in the Mexican population, similar studies should be conducted analyzing new rearrangements, to improve the adequate classification of the abnormalities and the stratification in prognostic groups.
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http://dx.doi.org/10.1016/j.cancergencyto.2008.04.003DOI Listing
July 2008

[Medulloblastoma in pediatrics. Current prognosis and treatment].

Gac Med Mex 2007 Sep-Oct;143(5):415-20

Hematooncología Pediátrica, Instituto Nacional de Pediatriá, SSA, México DF, México.

In Mexico, Central Nervous System (CNS) tumors are the third most common childhood cancers. Medulloblastoma constitutes 20% of the primary CNS tumors and 40% of all cerebellar tumors, the single most common brain tumor among children. It originates over the external granular layer that normally migrates from the vermis to the surface of the cerebellum hemispheres and from there to the deep portions of the internal granular layer. These tumors infiltrate profusely the cerebellar cortex. The dissemination process can occur through the spinal fluid with seeding along the subarachnoidal space and around the spinal chord They eventually produce metastasis mainly to bone, liver, and bone marrow. There is a group of well identified prognostic factors that are relevant for each individual patient and that can be applied for multidisciplinary treatment purposes. The objective of the present review is to emphasize on new research findings and the overall survival that can be achieved with modern treatment programs.
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May 2008

Early death in children with acute lymphoblastic leukemia: does malnutrition play a role?

Pediatr Hematol Oncol 2008 Jan-Feb;25(1):17-26

Division of Hem-Oncology, National Institute of Pediatrics (Instituto Nacional de Pediatría), Mexico City, Mexico.

The study aim was to correlate malnutrition and early death in children with acute lymphoblastic leukemia (ALL). A study was conducted in 100 consecutive children with ALL. An analysis included clinical and laboratory parameters as well as co-morbidity factors. Forty patients were standard risk and 60 high risk. Multivariate analysis showed variables of statistical importance, including female gender (p 010), ALL high-risk (p 04), and infection (p 036). Malnutrition (p 1.0) and poverty (p 0.5) did not influence. Early mortality was documented in 15/100 (15%) patients. The study shows that high-risk ALL and infection represent the leading causes of early mortality.
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http://dx.doi.org/10.1080/08880010701774132DOI Listing
April 2008

Multiple copies of RUNX1: description of 14 new patients, follow-up, and a review of the literature.

Cancer Genet Cytogenet 2008 Jan;180(2):129-34

Departamento de Investigación en Genética Humana, Instituto Nacional de Pediatría, Insurgentes Sur No. 3700-C, Col. Insurgentes Cuicuilco, CP 04530 México, DF.

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.
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http://dx.doi.org/10.1016/j.cancergencyto.2007.10.004DOI Listing
January 2008

Long-term survival in children under 3 years of age with low-grade astrocytoma.

Childs Nerv Syst 2007 May 17;23(5):543-7. Epub 2007 Jan 17.

Division of Hem/Oncology and Radiotherapy, National Institute of Pediatrics [Instituto Nacional de Pediatría], Insurgentes Sur no. 3700-C, Mexico City, D F, 04530, México.

Objective: The purpose of this study is to analyze clinical aspects and disease-free survival (DFS) in children less than 3 years of age diagnosed with low-grade astrocytoma.

Methods: In a period of 24 years (1980-2004), a total of 43 (5.4%) children were registered with these characteristics. Twenty-three patients had pilocytic astrocytoma, 18 diffused, and 2 mixed. Thirty-one (72.1%) children had incomplete surgical tumor resection and 12 (27.9%) had a complete tumor resection. Twelve (27.9%) patients had cranial radiotherapy and 17 (39.5%) received chemotherapy. Overall survival was recorded in 23 (53%). DFS was 50% at 250 months of follow-up for the whole group. DFS for the supratentorial group was 60% at 250 months, whereas, for the infratentorial, it was 22% at 120 months (p = 0.008).

Conclusion: The only favorable prognostic pattern was the supratentorial presentation. Radiotherapy and chemotherapy did not alter the outcome.
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http://dx.doi.org/10.1007/s00381-006-0287-0DOI Listing
May 2007

[Molecular hemato-oncology and new specific treatment strategies for leukemia].

Gac Med Mex 2006 Mar-Apr;142(2):145-50

Departamento de Genética y Biología Molecular, CINVESTA V-IPN, Mexico DF, Mexico.

Leukemia-associated fusion genes are detected in a significant proportion of newly diagnosed cases, where genes encoding transcription factors are usually found at one of the breakpoints. Activated fusion proteins such as Pml-Raralpha have been shown to inhibit cellular differentiation by recruitment of nuclear corepressor complexes, which maintain local histone deacetylase (HDAC) in a variety of hematologic lineage-specific gene promoters. This HDAC-dependent transcriptional repression appears as a common pathway in the development of leukemia and could constitute an important target for new therapeutic agents. Alternatively, the Bcr-Abl oncoprotein shows high tyrosine kinase activity and deregulates signal transduction pathways normally involved in both apoptosis and proliferation. This aberrant activity is affected by signal transduction inhibitors (STIs), which block or prevent the oncogenic pathway. In this review, we shed some light on our understanding of both the reversible transcriptional repression controlled by HDAC and the deregulated Bcr-Abl signal transduction pathway. In addition, the administration of low molecular weight drugs for human leukemia treatment based on this knowledge brings about a significant long-term clinical remission and an acceptable risk of toxic effects that should increase the cure rate.
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September 2006

Survival in extra-orbital metastatic retinoblastoma:treatment results.

Clin Transl Oncol 2006 Jan;8(1):39-44

Department of Oncology, Instituto Nacional de Pediatría, Mexico DF, Mexico.

Introduction: Retinoblastoma (RB) is the most frequent malignant eye tumor in childhood. In developing countries advanced stages are common. The purpose of this paper is to present our 21-year clinical experience with metastatic extra ocular RB patients treated with 5 different chemotherapy schemas at a single Mexican Pediatric referral center.

Materials And Methods: A retrospective analysis was carried out reviewing the clinical characteristics of patients with metastatic RB. The information analyzed included the delay in diagnosis after first symptoms, age, sex, ocular staging, and anatomic site of metastases, treatment scheme, initial response and status at the last contact or date of death.

Results: Eighty-one patients were included; age range was from 3 to 80 months. The most common site of metastasis was central nervous system (83.9%). From those patients treated with chemotherapy (n = 74), 89.2% presented a complete initial response (n = 66). Early mortality occurred in 7 cases before any treatment. Fifty-six received treatment and died with progressive disease. All patients without radiotherapy died with tumor activity (n = 15). The use of cisplatin was related with longer disease free intervals; no other variable was related with survival. Four patients were alive and disease free at 33 to 144.3 months of follow up from diagnosis. The prevalent cause of death was tumor progression.

Conclusions: In our experience, metastatic RB has a very high mortality rate in spite of the use of different chemotherapy regimens.
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http://dx.doi.org/10.1007/s12094-006-0093-xDOI Listing
January 2006