Implementation of a roadmap for the comprehensive diagnosis, follow-up, and research of childhood leukemias in vulnerable regions of Mexico: results from the PRONAII Strategy.

The main objective of the National Project for Research and Incidence of Childhood Leukemias is to reduce early mortality rates for these neoplasms in the vulnerable regions of Mexico. This project was conducted in the states of Oaxaca, Puebla, and Tlaxcala. A key strategy of the project is the implementation of an effective roadmap to ensure that leukemia patients are the target of maximum benefit of interdisciplinary collaboration between researchers, clinicians, surveyors, and laboratories. This strategy guarantees the comprehensive management of diagnosis and follow-up samples of pediatric patients with leukemia, centralizing, managing, and analyzing the information collected. Additionally, it allows for a precise diagnosis and monitoring of the disease through immunophenotype and measurable residual disease (MRD) studies, enhancing research and supporting informed clinical decisions for the first time in these regions through a population-based study. This initiative has significantly improved the diagnostic capacity of leukemia in girls, boys, and adolescents in the regions of Oaxaca, Puebla, and Tlaxcala, providing comprehensive, high-quality care with full coverage in the region. Likewise, it has strengthened collaboration between health institutions, researchers, and professionals in the sector, which contributes to reducing the impact of the disease on the community.

Epidemiology of childhood acute leukemias in marginalized populations of the central-south region of Mexico: results from a population-based registry.

Introduction: Acute leukemias (AL) are the main types of cancer in children worldwide. In Mexico, they represent one of the main causes of death in children under 20 years of age. Most of the studies on the incidence of AL in Mexico have been developed in the urban context of Greater Mexico City and no previous studies have been conducted in the central-south of the country through a population-based study. The aim of the present work was to identify the general and specific incidence rates of pediatric AL in three states of the south-central region of Mexico considered as some of the marginalized populations of Mexico (Puebla, Tlaxcala, and Oaxaca). Methods: A population-based study was conducted. Children aged less than 20 years, resident in these states, and newly diagnosed with AL in public/private hospitals during the period 2021-2022 were identified. Crude incidence rates (cIR), standardized incidence rates (ASIRw), and incidence rates by state subregions (ASIRsr) were calculated. Rates were calculated using the direct and indirect method and reported per million children under 20 years of age. In addition, specific rates were calculated by age group, sex, leukemia subtype, and immunophenotype. Results: A total of 388 cases with AL were registered. In the three states, the ASIRw for AL was 51.5 cases per million (0-14 years); in Puebla, it was 53.2, Tlaxcala 54.7, and Oaxaca de 47.7. In the age group between 0-19 years, the ASIRw were 44.3, 46.4, 48.2, and 49.6, in Puebla, Tlaxcala, and Oaxaca, respectively. B-cell acute lymphoblastic leukemia was the most common subtype across the three states. Conclusion: The incidence of childhood AL in the central-south region of Mexico is within the range of rates reported in other populations of Latin American origin. Two incidence peaks were identified for lymphoblastic and myeloid leukemias. In addition, differences in the incidence of the disease were observed among state subregions which could be attributed to social factors linked to the ethnic origin of the inhabitants. Nonetheless, this hypothesis requires further investigation.

Subclassification of B-acute lymphoblastic leukemia according to age, immunophenotype and microenvironment, predicts MRD risk in Mexican children from vulnerable regions.

Introduction: The decisive key to disease-free survival in B-cell precursor acute lymphoblastic leukemia in children, is the combination of diagnostic timeliness and treatment efficacy, guided by accurate patient risk stratification. Implementation of standardized and high-precision diagnostic/prognostic systems is particularly important in the most marginalized geographic areas in Mexico, where high numbers of the pediatric population resides and the highest relapse and early death rates due to acute leukemias are recorded even in those cases diagnosed as standard risk. Methods: By using a multidimensional and integrated analysis of the immunophenotype of leukemic cells, the immunological context and the tumor microenvironment, this study aim to capture the snapshot of acute leukemia at disease debut of a cohort of Mexican children from vulnerable regions in Puebla, Oaxaca and Tlaxcala and its potential use in risk stratification. Results and discussion: Our findings highlight the existence of a distinct profile of ProB-ALL in children older than 10 years, which is associated with a six-fold increase in the risk of developing measurable residual disease (MRD). Along with the absence of CD34+ seminal cells for normal hematopoiesis, this ProB-ALL subtype exhibited several characteristics related to poor prognosis, including the high expression level of myeloid lineage markers such as MPO and CD33, as well as upregulation of CD19, CD34, CD24, CD20 and nuTdT. In contrast, it showed a trend towards decreased expression of CD9, CD81, CD123, CD13, CD15 and CD21. Of note, the mesenchymal stromal cell compartment constituting their leukemic niche in the bone marrow, displayed characteristics of potential suppressive microenvironment, such as the expression of Gal9 and IDO1, and the absence of the chemokine CXCL11. Accordingly, adaptive immunity components were poorly represented. Taken together, our results suggest, for the first time, that a biologically distinct subtype of ProB-ALL emerges in vulnerable adolescents, with a high risk of developing MRD. Rigorous research on potential enhancing factors, environmental or lifestyle, is crucial for its detection and prevention. The use of the reported profile for early risk stratification is suggested.

Molecular and cellular markers for measurable residual disease in acute lymphoblastic leukemia.

Acute leukemia is the leading cause of death in children worldwide, particularly in developing countries where the growing number of cases with unfavorable prognosis and high risk of early relapse have positioned pediatric cancer as a priority. The late and imprecise diagnosis, malnutrition and unfavorable environmental conditions, and toxicity-associated therapy are some of the factors that compromise the success of the treatment and affect survival rates in vulnerable regions. An early and exhaustive classification of malignant neoplasms at the clinical debut and the proper follow-up of treatment's response constitute one of the most powerful prognostic factors. Remarkably, the ultrasensitive detection of residual and relapse clones that determine the minimal/measurable residual disease (MRD) has been a milestone in the comprehensive management of hematologic malignancies that favorably improve the complete remission cases. In this review, we discuss the scientific and technological advances applied to laboratory diagnosis in MRD determination: from the multiparametric immunophenotyping to next-generation sequencing and cytomics. As a result of multidisciplinary research in the main concentration oncology centers and laboratories, residual leukemia detection strategies that combine molecular analysis and cellular markers are recommended as the most valuable tools, making them the paradigm for stratification campaigns in vulnerable regions.

La leucemia aguda es la principal causa de muerte por enfermedad en la población infantil mundial, en particular en los países con economías en desarrollo, donde el creciente número de casos con pronóstico desfavorable y riesgo de recaídas tempranas ha posicionado a esta enfermedad como una prioridad de salud. El diagnóstico tardío y de baja precisión, la ausencia de condiciones favorables de alimentación y entorno ambiental, así como la toxicidad asociada a la terapia, son algunos de los factores que condicionan el éxito del tratamiento y afectan las tasas de supervivencia en las regiones más vulnerables. La clasificación temprana y exhaustiva del tumor maligno en la presentación clínica y durante el seguimiento de respuesta al tratamiento es uno de los más poderosos factores pronósticos. En especial, la detección ultrasensible de clonas residuales y reemergentes que determinan la enfermedad residual mínima medible ha sido un hito en el manejo integral de las neoplasias hematológicas y ha impactado favorablemente en las cifras de remisión completa. En esta revisión se comentan los avances científicos y tecnológicos aplicados al diagnóstico de laboratorio y a la determinación de la enfermedad residual mínima: desde la inmunofenotipificación multiparamétrica hasta la secuenciación y la citómica de última generación. Como resultado de las investigaciones multidisciplinarias en los principales centros oncológicos de concentración y los laboratorios de clase mundial, las estrategias de detección de la leucemia residual que combinan análisis moleculares y marcadores celulares han sido recomendadas como las de mayor utilidad, por lo que son el paradigma para las campañas de estratificación en las regiones vulnerables.

Molecular and cellular markers for measurable residual disease in acute lymphoblastic leukemia / Marcadores celulares y moleculares para la enfermedad residual medible en la leucemia linfoblástica aguda

Abstract Acute leukemia is the leading cause of death in children worldwide, particularly in developing countries where the growing number of cases with unfavorable prognosis and high risk of early relapse have positioned pediatric cancer as a priority. The late and imprecise diagnosis, malnutrition and unfavorable environmental conditions, and toxicity-associated therapy are some of the factors that compromise the success of the treatment and affect survival rates in vulnerable regions. An early and exhaustive classification of malignant neoplasms at the clinical debut and the proper follow-up of treatment’s response constitute one of the most powerful prognostic factors. Remarkably, the ultrasensitive detection of residual and relapse clones that determine the minimal/measurable residual disease (MRD) has been a milestone in the comprehensive management of hematologic malignancies that favorably improve the complete remission cases. In this review, we discuss the scientific and technological advances applied to laboratory diagnosis in MRD determination: from the multiparametric immunophenotyping to next-generation sequencing and cytomics. As a result of multidisciplinary research in the main concentration oncology centers and laboratories, residual leukemia detection strategies that combine molecular analysis and cellular markers are recommended as the most valuable tools, making them the paradigm for stratification campaigns in vulnerable regions.

Resumen La leucemia aguda es la principal causa de muerte por enfermedad en la población infantil mundial, en particular en los países con economías en desarrollo, donde el creciente número de casos con pronóstico desfavorable y riesgo de recaídas tempranas ha posicionado a esta enfermedad como una prioridad de salud. El diagnóstico tardío y de baja precisión, la ausencia de condiciones favorables de alimentación y entorno ambiental, así como la toxicidad asociada a la terapia, son algunos de los factores que condicionan el éxito del tratamiento y afectan las tasas de supervivencia en las regiones más vulnerables. La clasificación temprana y exhaustiva del tumor maligno en la presentación clínica y durante el seguimiento de respuesta al tratamiento es uno de los más poderosos factores pronósticos. En especial, la detección ultrasensible de clonas residuales y reemergentes que determinan la enfermedad residual mínima medible ha sido un hito en el manejo integral de las neoplasias hematológicas y ha impactado favorablemente en las cifras de remisión completa. En esta revisión se comentan los avances científicos y tecnológicos aplicados al diagnóstico de laboratorio y a la determinación de la enfermedad residual mínima: desde la inmunofenotipificación multiparamétrica hasta la secuenciación y la citómica de última generación. Como resultado de las investigaciones multidisciplinarias en los principales centros oncológicos de concentración y los laboratorios de clase mundial, las estrategias de detección de la leucemia residual que combinan análisis moleculares y marcadores celulares han sido recomendadas como las de mayor utilidad, por lo que son el paradigma para las campañas de estratificación en las regiones vulnerables.

Poor Prognosis Biomolecular Factors Are Highly Frequent in Childhood Acute Leukemias From Oaxaca, Mexico.

OBJECTIVE: To investigate the cellular and molecular epidemiology of acute leukemias in vulnerable populations of children and adolescents in Oaxaca de Juarez, Mexico. MATERIAL AND METHODS: Descriptive, cross-sectional and retrospective study, conducted from 2014 to 2018 in which profiles of molecular and immunophenotypic aberrations were investigated in children and adolescents diagnosed with acute leukemia, by evaluating 28 molecular abnormalities by HemaVision-Q28 multiplex RT-PCR kit and standardized EuroFlow Immunophenotyping of bone marrow cells. RESULTS: We included 218 patients, with 82.5% younger than 14 years and 17.5% adolescents. The median age was 9 years and a main peak of incidence was recorded at age of 4 to 5 years. B-cell acute lymphoblastic leukemia was diagnosed in 70.64% of all cases, acute myeloid leukemia was in 22.48%, T-cell acute lymphoblastic leukemia in 6.42%, and mixed lineage acute leukemia in 0.46% of cases. Overall, chromosomal translocations were positive in 29.82% of cases. While 65.31% of patients with acute myeloid leukemia reported aberrancies, only in 18.83% of B-cell acute lymphoblastic leukemia cases genetic abnormalities were obvious. Surprisingly, most prevalent translocations in B-cell acute lymphoblastic leukemia were t(9;22) in 20.7%, followed by t(4;11) in 17.2% and t(6;11) in 13.8%, whereas patients with acute myeloid leukemia showed t(15;17) in 40.6% and t(8;21) in 21.9%. In contrast, an homogeneous expression of t(3;21) and t(6;11) was recorded for T-cell acute lymphoblastic leukemia and mixed lineage acute leukemia cases, respectively. Except for t(1;19), expressed only by pre-B cells, there was no association of any of the studied translocations with differentiation stages of the B-leukemic developmental pathway. CONCLUSION: Our findings identify near 50% of patients with acute lymphoblastic leukemia at debut with high-risk translocations and poor prognosis in B-cell acute lymphoblastic leukemia as well as an unexpected increase of acute myeloid leukemia cases in young children, suggesting a molecular shift that support a higher incidence of poor prognosis cases in Oaxaca.

[Allergies as a target of interest in the era of immunotherapy]. / Las alergias como blanco de interés en la era de la inmunoterapia.

Exacerbated immune system reactions often trigger allergy pathologies, which include asthma, rhinitis, urticaria, food and drug allergies, insect bites, and may sometimes have fatal outcomes. In Mexico, more than 20% of open population, present allergic symptoms with notable increase in the last twenty years, especially in children. The Mexican Institute for Social Security (IMSS, according to its initials in Spanish) provides attention to around 7000 patients per year, mainly due to allergies deriving from therapeutic drugs and certain foods. Pharmacotherapy has been effective in reducing classical allergy symptoms, although treatment does not stop disease progression. In addition, the constant use of drugs represents a remarkable socioeconomic impact. Strategies based on the modification of immune responses in the course of allergic reactions through immunotherapy started more than 100 years ago, and some have provided cure to the disease. On the occasion of the Nobel Prize in Physiology or Medicine 2018, it was awarded to James P. Allison and Tasuku Honjo for their contributions in the regulation of the immune system against cancer, through a new generation of immunotherapy. In this review we analyzed current immunotherapeutic options, including its benefits, limitations and perspectives for the best clinical management of allergies.

Las reacciones exacerbadas del sistema inmunológico a menudo disparan patologías por cuadros alérgicos que, entre otros, incluyen asma, rinitis, urticaria, alergia a alimentos, fármacos y picaduras de insectos, y en ocasiones tienen desenlaces fatales. En México, más del 20% de la población general presenta cuadros alérgicos, con un notable incremento en los últimos veinte años, especialmente en la población pediátrica. Tan solo el Instituto Mexicano del Seguro Social (IMSS) atiende alrededor de 7000 pacientes por año, principalmente por alergias a medicamentos y algunos alimentos. La farmacoterapia ha sido muy efectiva en la disminución de los síntomas, aunque el tratamiento no detiene la progresión de la enfermedad. Además, el uso constante de fármacos representa un remarcable impacto socioeconómico. Las estrategias basadas en la modificación de respuestas inmunes en el curso de las reacciones alérgicas a través de inmunoterapia comenzaron hace más de 100 años y algunas de ellas han dado solución a este grupo de padecimientos. En ocasión de la entrega del Premio Nobel de Medicina y Fisiología 2018, este fue otorgado a los doctores James P. Allison y Tasuku Honjo por sus contribuciones en la regulación del sistema inmune contra el cáncer, por medio de una nueva generación de inmunoterapia. En esta revisión analizamos las opciones inmunoterapéuticas actuales e incluimos sus beneficios, limitantes y perspectivas para el mejor manejo clínico de las alergias.