Not only a therapeutic target; mTOR in Hodgkin lymphoma and acute lymphoblastic leukemia.

Introduction: The mechanistic/mammalian target of rapamycin (mTOR) is a serine/threonine kinase, which is downregulated or upregulated and is implicated in different types of cancer including hematologic neoplasms, skin prostate, and head and neck cancer. Aim: The aim of this study was to explore the current knowledge of mTOR signaling in acute lymphoblastic leukemia and Hodgkin lymphoma. Methods: A systematic review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, searching PubMed, Discovery Service for National Autonomous University of Mexico, Registro Nacional de Instituciones y Empresas Científicas y Tecnológicas (RENIECYT), and Scientific Electronic Library Online (SciELO) from 1994 to 2023. A total of 269 papers were identified for acute lymphoblastic leukemia, but based on specific criteria, 15 were included; for Hodgkin lymphoma, 110 papers were identified, but 5 were included after manual searching. Results: A total of 20 papers were evaluated, where mTOR activity is increased in patients with Hodgkin lymphoma and acute lymphoblastic leukemia by different molecular mechanisms. Conclusions: mTOR activity is increased in patients with both hematologic neoplasms and NOTCH; interleukin 4, 7, and 9, and nuclear proteins have been studied for their role in the activation of mTOR signaling.

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.

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.

Parental Exposure to Workplace Carcinogens and the Risk of Development of Acute Leukemia in Infants. Case-Control Study.

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.

Role of Genetic Polymorphisms of Deoxycytidine Kinase and Cytidine Deaminase to Predict Risk of Death in Children with Acute Myeloid Leukemia.

Cytarabine is one of the most effective antineoplastic agents among those used for the treatment of acute myeloid leukemia. However, some patients develop resistance and/or severe side effects to the drug, which may interfere with the efficacy of the treatment. The polymorphisms of some Ara-C metabolizing enzymes seem to affect outcome and toxicity in AML patients receiving cytarabine. We conducted this study in a cohort of Mexican pediatric patients with AML to investigate whether the polymorphisms of the deoxycytidine kinase and cytidine deaminase enzymes are implicated in clinical response and toxicity. Bone marrow and/or peripheral blood samples obtained at diagnosis from 27 previously untreated pediatric patients with de novo AML were processed for genotyping and in vitro chemosensitivity assay, and we analyzed the impact of genotypes and in vitro sensitivity on disease outcome and toxicity. In the multivariate Cox regression analysis, we found that age at diagnosis, wild-type genotype of the CDA A79C polymorphism, and wild-type genotype of the dCK C360G polymorphism were the most significant prognostic factors for predicting the risk of death.

Prevalence of gene rearrangements in Mexican children with acute lymphoblastic leukemia: a population study-report from the Mexican Interinstitutional Group for the identification of the causes of childhood leukemia.

Mexico has one of the highest incidences of childhood leukemia worldwide and significantly higher mortality rates for this disease compared with other countries. One possible cause is the high prevalence of gene rearrangements associated with the etiology or with a poor prognosis of childhood acute lymphoblastic leukemia (ALL). The aims of this multicenter study were to determine the prevalence of the four most common gene rearrangements [ETV6-RUNX1, TCF3-PBX1, BCR-ABL1, and MLL rearrangements] and to explore their relationship with mortality rates during the first year of treatment in ALL children from Mexico City. Patients were recruited from eight public hospitals during 2010-2012. A total of 282 bone marrow samples were obtained at each child's diagnosis for screening by conventional and multiplex reverse transcription polymerase chain reaction to determine the gene rearrangements. Gene rearrangements were detected in 50 (17.7%) patients. ETV6-RUNX1 was detected in 21 (7.4%) patients, TCF3-PBX1 in 20 (7.1%) patients, BCR-ABL1 in 5 (1.8%) patients, and MLL rearrangements in 4 (1.4%) patients. The earliest deaths occurred at months 1, 2, and 3 after diagnosis in patients with MLL, ETV6-RUNX1, and BCR-ABL1 gene rearrangements, respectively. Gene rearrangements could be related to the aggressiveness of leukemia observed in Mexican children.

Estímulo iatrotrópico y tiempo al diagnóstico en pacientes pediátricos con leucemia linfoblástica aguda / Iatrotropic stimulus and lag time for pediatric patients with acute lymphoblastic leukemia

Introducción. La leucemia linfoblástica aguda (LLA) es una enfermedad potencialmente curable en la que el éxito del tratamiento depende de la detección oportuna de la enfermedad; por lo anterior, resulta relevante identificar los factores que influyen en el periodo previo al diagnóstico. El objetivo de este estudio es describir el intervalo entre el inicio de los síntomas atribuibles a la enfermedad y la confirmación diagnóstica, en términos del tiempo transcurrido (lag-time), del estímulo iatrotrópico y de la atención médica recibida, así como estimar la asociación de estos factores con la mortalidad. Métodos. Se revisaron los expedientes clínicos de 182 pacientes pediátricos con LLA en 9 centros de atención oncológica en la República Mexicana y se realizaron entrevistas a sus familiares para reconstruir el periodo previo al diagnóstico. Resultados. Se incluyeron 99 pacientes vivos y 83 que fallecieron, con una media de edad de 7.3 ± 4.7 años. El promedio de tiempo entre el inicio de los síntomas y el diagnóstico fue de 43.5 ± 22.5 días y acudieron a un promedio de 2.3 consultas antes de la confirmación diagnóstica. Los principales motivos para solicitar la atención médica fueron: astenia y adinamia (47.4%), fiebre (44.8%), palidez (44.3%), hiporexia/anorexia (20.9%) y cefalea (19.9%). El número de médicos especialistas no oncólogos consultados y de consultas previas al diagnóstico resultaron factores protectores para la mortalidad (OR 0.77 y 0.64, respectivamente). Conclusiones. El tiempo de espera entre el inicio de los síntomas y la confirmación diagnóstica es mayor al reportado en países desarrollados; esto se debe, principalmente, a la atención médica recibida. El número de médicos y de consultas previas resultaron factores protectores para mortalidad, probablemente como consecuencia de la detección oportuna y la vigilancia médica de los síntomas inespecíficos que orientan a la presencia de la enfermedad.

Background. Acute lymphoblastic leukemia (ALL) is a potentially curable disease where success of the treatment depends on the timely detection of the disease; therefore, it is important to identify those influencing factors during the prediagnostic period. The objective of this study was to describe the interval time from onset of symptoms attributable to the disease to the diagnostic confirmation in terms of elapsed time (lag-time), iatrotropic stimulus and received medical care, as well as to estimate the association of these factors with mortality. Methods. We reviewed 182 clinical files from pediatric patients with ALL in nine cancer treatment centers in Mexico and conducted interviews with their families to rebuild the run-up time until diagnosis. Results. We included 99 living patients and 83 patients who died; average age of the patients was 7.3 ± 4.7 years. The average time between symptom onset and diagnosis was 43.5 ± 22.5 days. Patients had an average of 2.3 consultations prior to diagnostic confirmation. The main reasons for requesting medical attention were asthenia and adynamia (47.4%), fever (44.8%), pallor (44.3%), hyperoxia/anorexia (20.9%) and headache (19.9%). The number of non-oncological physicians surveyed and number of consultations until diagnosis were protective factors for mortality (OR 0.77 and 0.64, respectively). Conclusions. Time between symptom onset and diagnostic confirmation is longer than what has been reported in developed countries mainly due to medical attention received. The number of physicians and number of prior consultations were protective factors for mortality, probably as a result of early detection and medical surveillance of nonspecific symptoms that lead to the presence of the disease.

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

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.