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.

Construção e validação de História em Quadrinhos para crianças com leucemia linfoide aguda / Construcción y validación de Cómics a niños con leucemia linfocítica aguda / Construction and validation of Comics at children with acute lymphocytic leukemia

Resumo Introdução O câncer tem impacto na vida das crianças e seus familiares. As Histórias em Quadrinhos podem ser uma estratégia de fortalecer o vínculo e a comunicação entre profissional/paciente/família. Objetivo Desenvolver e validar um material instrucional/educativo, no formato de Histórias em Quadrinhos, voltada para crianças hospitalizadas com leucemia linfóide aguda. Metodologia Estudo metodológico desenvolvido em nove etapas: elaboração do projeto de pesquisa; definição e seleção do conteúdo; adaptação da linguagem; inclusão de ilustrações; construção de um material piloto; validação do material; layout; impressão final e disponibilização. A validação ocorreu com 10 especialistas entre março e maio de 2022, utilizando-se o Instrumento de Validação de Conteúdo Educativo em Saúde. Resultados Foram elaboradas 5 Histórias em Quadrinhos, com 6 personagens principais, sendo necessárias 63 horas de trabalho. Elas foram divididas por temáticas (distúrbios gastrointestinais; cistite hemorrágica; problemas relacionados a autoestima e autoimagem; risco de infecção e dor óssea) que obtiveram Índice de Validade de Conteúdo global satisfatório entre 0,78 e 0,87. Conclusões e implicações para a prática As histórias em quadrinhos podem ser utilizadas como fonte atrativa e confiável de informações sobre a doença, servindo como apoio às informações durante a internação hospitalar e o preparo para alta.

Resumen Introducción El cáncer tiene un impacto en la vida de los niños y sus familias. Los cómics pueden ser una estrategia para fortalecer el vínculo y la comunicación entre profesional/paciente/familia. Objetivo Desarrollar y validar un material didáctico/educativo, en formato de Historietas, dirigido a niños hospitalizados con leucemia linfocítica aguda. Metodología Estudio metodológico desarrollado en nueve etapas: elaboración del proyecto de investigación; definición y selección de contenidos; adaptación lingüística; inclusión de ilustraciones; construcción de un material piloto; validación del material; disposición; impresión final y disponibilidad. La validación se realizó con 10 especialistas entre marzo y mayo de 2022, utilizando el Instrumento de Validación de Contenido de Educación en Salud. Resultados Se crearon 5 Comics, con 6 personajes principales, requiriendo 63 horas de trabajo. Fueron divididos por temas (trastornos gastrointestinales; cistitis hemorrágica; problemas relacionados con la autoestima y la autoimagen; riesgo de infección y dolor óseo) que obtuvieron un Índice de Validez de Contenido global satisfactorio entre 0,78 y 0,87. Conclusiones e implicaciones para la práctica Los cómics pueden ser utilizados como una fuente atractiva y confiable de información sobre la enfermedad, apoyando información durante la hospitalización y preparación para el alta.

Abstract Introduction Cancer has an impact on the lives of children and their families. Comics can be a strategy to strengthen the bond and communication between professional/patient/family. Objective To develop and validate an instructional/educational material, in the format of Comics, aimed at children hospitalized with acute lymphocytic leukemia. Methodology Methodological study developed in nine stages: preparation of the research project; content definition and selection; language adaptation; inclusion of illustrations; construction of a pilot material; validation of the material; layout; final printing and availability. Validation took place with 10 specialists between March and May 2022, using the Health Education Content Validation Instrument. Results 5 Comics were created, with 6 main characters, requiring 63 hours of work. They were divided by themes (gastrointestinal disorders; hemorrhagic cystitis; problems related to self-esteem and self-image; risk of infection and bone pain) that obtained a satisfactory global Content Validity Index between 0.78 and 0.87. Conclusions and implications for practice Comics can be used as an attractive and reliable source of information about the disease, supporting information during hospitalization and preparation for discharge.

Avaliação da saúde bucal de crianças e adolescentes com leucemia atendidas no Hemorio / Evaluation of the oral health of children and adolescents with leukemia treated at Hemorio

Esta pesquisa transversal, descritiva e observacional objetivou avaliar a saúde bucal dos participantes infantojuvenis diagnosticados com leucemia, assistidos pela odontologia. Foram incluídas todas as crianças e adolescentes de 3 a 18 anos matriculadas no centro de referência hematológico e diagnosticados com leucemia, atendidos pela instituição, entre junho/2022 e janeiro/2023. Foram coletados os dados sociodemográfcos, médicos, odontológicos e laboratoriais, seguidos de uma avaliação clínica odontológica e registro fotográfco. Para avaliação da prevalência de cárie utilizou-se o índice de dentes cariados, perdidos, obturados, por dente e o índice de dentes decíduos cariados, indicado a extração e obturado. A avaliação das manifestações orais fo irealizada conforme protocolo da Organização Mundial de Saúde. Compuseram a pesquisa 25 participantes, 14 masculinos e 11 femininos, a média deidade foi de 10,12 anos (d.p. = 4,8).A leucemia linfoide aguda foi a mais prevalente (80%), a maioria dos participantes apresentou índice de cárie zero (60%), as manifestações orais foram diagnosticadas em 60% deles, sendo as mais frequentes: alteração de paladar (24%), mucosite (16%) e xerostomia (12%). Os participantes também apresentaram alta incidência de manifestações orais, condição de higiene bucal insatisfatória, porém baixo índice de cárie. Outrossim, observa-se a importância de os cirurgiões dentistas conhecerem as manifestações orais mais encontradas em crianças com leucemia, a necessidade da higiene bucal de qualidade, bem como a condição de saúde bucal total, buscando garantir que a boca não seja uma fonte de infecção que prejudique a condição de saúde geral e o tratamento oncológico.

This study aimed to evaluate the oral health of child and adolescent participants diagnosed with leukemia, assisted by dentistry. The research was configured a cross-sectional, descriptive and observational. All. All children and adolescents enrolled in the hematological reference center, aged 3 to 18 years, diagnosed with leukemia, treated by the institution, between June 2022 and January 2023 were included. Sociodemographic, medical, dental and laboratory data were collected; followed by a clinical dental evaluation and photographic recording. To assess the prevalence of caries, the index of decayed, missing,filled teeth per tooth and the index of decayed primary teeth, indicated for extraction and filling, were used. The evaluation of oral manifestations was carried out according to the World Health Organization protocol.The research included 25 participants, 14 male and 11 female and the average age was 10.12 years (SD = 4.8). Acute lymphoblastic leukemia was the most prevalent (80%). Regarding the caries index, the majority of participants had zero (60%) and oral side effects were diagnosed in 60% of them, the most frequent being:change in taste (24%), mucositis (16%) and xerostomia (12%). Participants also had a high incidence of oral manifestations, unsatisfactory oral hygiene, but a low rate of caries. Furthermore, it is important for dental surgeons to know the ora manifestations most commonly found in children with leukemia, the need for quality oral hygiene, as well as the oral health condition as a whole, seeking to ensure that the mouth is not a source of infection, which harms the general health condition and cancer treatment.

Subpoblaciones de linfocitos T en adultos mayores cubanos con leucemia linfoide crónica / Subpopulations of T lymphocytes in Cuban older adults with chronic lymphoid leukemia

Introducción: la inmunosenescencia está asociada con un mayor riesgo de desarrollo de cáncer. Dentro de las hemopatías malignas que afectan a este grupo de edad, está la leucemia linfoide crónica (LLC), caracterizada por trastornos en la inmunidad adaptativa que incluye las subpoblaciones de linfocitos T. Objetivo: Determinar la frecuencia de las subpoblaciones de linfocitos T en los pacientes adultos mayores con leucemia linfoide crónica evaluados en el Instituto de Hematología e Inmunología de Cuba. Métodos: Se realizó un estudio transversal en 30 adultos mayores con leucemia linfoide crónica. Se cuantificaron los linfocitos TCD3+CD4+ y TCD3+CD8+ en sangre periférica por citometría de flujo. Para la lectura y el análisis de los datos se empleó un citómetro de flujo Beckman Coulter Gallios. Se utilizaron los valores porcentuales, la media y la desviación estándar. Se consideró estadísticamente significativo si p≤0.05. Resultados: Hubo un predominio de hombres que representaron el 56,7 por ciento y del grupo de 70-79 años de edad. No se reportó ningún adulto mayor con LLC con valores altos ni normales de linfocitos TCD3+CD4+. Predominaron los hombres con valores bajos porcentuales de linfocitos TCD3+CD4+, TCD3+CD8+ e inversión del índice CD4/CD8 en relación con las mujeres. Conclusiones: Los adultos mayores con LLC presentan alteraciones en el número de las subpoblaciones de linfocitos T. La acción de estas células en relación al crecimiento de células B malignas aún es desconocido y resulta importante determinar si esto puede reflejar un intento de evasión de las células tumorales al control inmunológico(AU)

Introduction: Immunosenescence is associated with an increased risk of cancer development. Among the malignant hemopathies that affect this age group, it is chronic lymphoid leukemia (CLL), characterized by disorders in adaptive immunity, which include subpopulations of T lymphocytes. Objective: To determine frequency of T lymphocyte subpopulations in older adult patients with chronic lymphoid leukemia evaluated at the Institute of Hematology and Immunology of Cuba. Methods: A cross-sectional study was conducted in 30 older adults with chronic lymphoid leukemia. TCD3+CD4+ and TCD3+CD8+ lymphocytes were quantified in peripheral blood by flow cytometry. A Beckman Coulter Gallios flow cytometer was used to read and analyze the data. The percentage values, the mean and the standard deviation were used. It was considered statistically significant if p≤0.05. Results: There was a predominance of men who represented 56.7 percent and the age group of 70-79 years. No older adults with CLL with high or normal values of TCD3+CD4+ lymphocytes were reported. Men predominated with low percentage values of TCD3+CD4+, TCD3+CD8+ lymphocytes and inversion of the CD4/CD8 ratio in relation to women. Conclusions: Older adult with CLL present alterations in the number of T lymphocyte subpopulations. The role of these cells in relation to the growth of malignant B cells it is unknown and it turns out important to determine if this may reflect an attempt to evade tumor cells from immune control(AU)

Untargeted metabolomic and lipidomic analyses reveal lipid dysregulation in the plasma of acute leukemia patients.

Acute leukemias (AL) are aggressive neoplasms with high mortality rates. Metabolomics and oxidative status have emerged as important tools to identify new biomarkers with clinical utility. To identify the metabolic differences between healthy individuals (HI) and patients with AL, a multiplatform untargeted metabolomic and lipidomic approach was conducted using liquid and gas chromatography coupled with quadrupole-time-of-flight mass spectrometry (LC-QTOF-MS or GC-QTOF-MS). Additionally, the total antioxidant capacity (TAC) was measured. A total of 20 peripheral blood plasma samples were obtained from patients with AL and 18 samples from HI. Our analysis revealed 135 differentially altered metabolites in the patients belonging to 12 chemical classes; likewise, the metabolic pathways of glycerolipids and sphingolipids were the most affected in the patients. A decrease in the TAC of the patients with respect to the HI was evident. This study conducted with a cohort of Colombian patients is consistent with observations from other research studies that suggest dysregulation of lipid compounds. Furthermore, metabolic differences between patients and HI appear to be independent of lifestyle, race, or geographic location, providing valuable information for future advancements in understanding the disease and developing more global therapies.

Association of the clinical profile and overall survival of pediatric patients with acute lymphoblastic leukemia.

Introduction: The clarification of etiopathology, the improvement of chemotherapy regimens and their risk stratifications, and the improvement in treatment support have increased the survival of children and adolescents affected by Acute Lymphoblastic Leukemia (ALL) past few years. This study aimed to estimate overall survival (OS) and event-free survival (EFS) in an onco-hematology treatment center in Brazil, reports the main clinical-laboratory characteristics of patients at diagnosis, verify the frequency of treatment-related adverse effects and the main causes of death. Material and methods: Retrospective analysis involving patients diagnosed with ALL, treated with the protocol of the Brazilian Group for Treatment of Leukemias in Childhood (GBTLI), between 2010 and 2020 was carried out; the outcomes (relapse, deaths, development of new neoplasms) were analyzed SPSS® software was used for the statistical analyses, and the p-value was considered significant when less than 0.05 for all analyses. Results: 109 patients were included in the study; the median age was 5 years, with a slight predominance of males. Sixty-six patients were classified as high-risk (HR) group and 43 patients were classified as low-risk (LR) group. After 5 years of diagnosis, the OS was 71.5%, and the EFS was 65%. No statistical difference was found between the HR and LR groups for OS and EFS, while leukocyte counts were statistically associated with the outcome of death (p = 0.028). Among the patients, 28 (25.6%) died due to infection accounting 46.4% of death causes. Among the 34 patients with unfavorable outcomes (death and/or relapse), 32 had no research for the minimal residual disease at the end of remission induction, and 25 were not investigated for the presence of chromosomal abnormalities. The most reported complications and treatment-related adverse effects were increased liver transaminases (85.9%), airway infection (79.4%), oral mucositis (67.2%), febrile neutropenia (64.4%), and diarrhea (36.4%). Conclusions: The rates of OS and EFS obtained in this cohort are similar to those obtained in the few previous similar studies in Brazil and lower than those carried out in developed countries. The unavailability of prognostic tests may have hindered risk stratification and influenced the results obtained.

Infections in patients with chronic lymphocytic leukemia

ABSTRACT Introduction: Infection is a major complication in patients with chronic lymphocytic leukemia (CLL). Newly diagnosed patients are at high risk of developing infection caused by encapsulated bacteria, such as Streptococcus pneumoniae and Haemophylus influenzae. Method and Results: However, once treatment is initiated, the spectrum of pathogens causing infection broadens, depending on the treatment regimens. With disease progression, cumulative immunosuppression occurs as a consequence of multiple treatment lines and the risk of infection further increases. On the other hand, the use of targeted therapies in the treatment of CLL have brought new risks of infection, with an increased incidence of invasive fungal diseases, particularly aspergillosis, in patients receiving Bruton kinase inhibitors. Conclusion: In this article, we review the epidemiology of infection in patients with CLL, taking into account the treatment regimen, and briefly discuss the management of infection.

Infections in patients with chronic lymphocytic leukemia.

INTRODUCTION: Infection is a major complication in patients with chronic lymphocytic leukemia (CLL). Newly diagnosed patients are at high risk of developing infection caused by encapsulated bacteria, such as Streptococcus pneumoniae and Haemophylus influenzae. METHOD AND RESULTS: However, once treatment is initiated, the spectrum of pathogens causing infection broadens, depending on the treatment regimens. With disease progression, cumulative immunosuppression occurs as a consequence of multiple treatment lines and the risk of infection further increases. On the other hand, the use of targeted therapies in the treatment of CLL have brought new risks of infection, with an increased incidence of invasive fungal diseases, particularly aspergillosis, in patients receiving Bruton kinase inhibitors. CONCLUSION: In this article, we review the epidemiology of infection in patients with CLL, taking into account the treatment regimen, and briefly discuss the management of infection.

Extracellular expression of Saccharomyces cerevisiae's L-asparaginase II in Pichia pastoris results in novel enzyme with better parameters.

L-asparaginase (ASNase) is an efficient inhibitor of tumor development, used in chemotherapy sessions against acute lymphoblastic leukemia (ALL) tumor cells; its use results in 80% complete remission of the disease in treated patients. Saccharomyces cerevisiae's L-asparaginase II (ScASNaseII) has a high potential to substitute bacteria ASNase in patients that developed hypersensitivity, but the endogenous production of it results in hypermannosylated immunogenic enzyme. Here we describe the genetic process to acquire the ScASNaseII expressed in the extracellular medium. Our strategy involved a fusion of mature sequence of protein codified by ASP3 (amino acids 26-362) with the secretion signal sequence of Pichia pastoris acid phosphatase enzyme; in addition, this DNA construction was integrated in P. pastoris Glycoswitch® strain genome, which has the cellular machinery to express and secrete high quantity of enzymes with humanized glycosylation. Our data show that the DNA construction and strain employed can express extracellular asparaginase with specific activity of 218.2 IU mg-1. The resultant enzyme is 40% more stable than commercially available Escherichia coli's ASNase (EcASNaseII) when incubated with human serum. In addition, ScASNaseII presents 50% lower cross-reaction with anti-ASNase antibody produced against EcASNaseII when compared with ASNase from Dickeya chrysanthemi.

Invasive Aspergillosis in Patients with Acute Leukemia: Comparison Between Acute Myeloid and Acute Lymphoid Leukemia.

BACKGROUND: The epidemiology of invasive aspergillosis (IA) in patients with acute lymphoid leukemia (ALL) has not been well characterized. OBJECTIVES: To identify potential peculiarities in the natural history, treatment response and outcome of IA diagnosed in patients with ALL and AML. METHODS: This is a retrospective cohort study conducted in seven tertiary-care hospitals between 2009 and 2017 of all consecutive episodes of IA occurring in adult patients with acute leukemia. Demographic characteristics, underlying disease and recent treatment, antifungal prophylaxis, neutropenia, receipt of corticosteroids, clinical and radiological findings, mycological results, antifungal therapy, and 6-week and 12-week survival were recorded. RESULTS: We identified 77 cases of IA in 54 patients with AML and 23 patients with ALL. The majority of patients developed IA in the context of induction chemotherapy for newly diagnosed (48.0%) or relapsed (41.6%) leukemia, with no differences between ALL and AML. Lung involvement was more frequent in AML (96.3% vs. 82.6%, p = 0.06) and rhinosinusitis was more common in ALL (43.5% vs. 24.1%, p = 0.09). Galactomannan was the microbiologic documentation of IA in 76.6%, with similar patterns of positivity in AML and ALL. The 6-week survival of IA in patients with AML and ALL was 63.0% and 56.5%, respectively (p = 0.60). CONCLUSIONS: The epidemiology, clinical presentation, diagnosis and outcome of IA in ALL patients are similar to patients with AML.

Biomarcadores genéticos de la leucemia linfoide aguda de linaje B / Genetic biomarkers of B - cell acute lymphoid leukemia

Introducción: La leucemia linfoide aguda es una proliferación y transformación maligna de las células progenitoras linfoides en la médula ósea, la sangre y los sitios extramedulares. Es la neoplasia más frecuente en la infancia. Constituye el 80 % de todas las leucemias agudas de la edad pediátrica y la más frecuente de las que se originan a partir del linaje de células B. Desde el punto de vista genético se presentan múltiples alteraciones moleculares y cromosómicas que son utilizadas para la estratificación pronóstica. Objetivo: Describir los biomarcadores genéticos de la leucemia linfoide aguda de linaje B y su implicación pronóstica. Métodos: Se realizó una revisión de la literatura en los idiomas inglés y español, a través del sitio web PubMed y el motor de búsqueda Google académico, de artículos publicados en los últimos cinco años. Se efectuaron un análisis y resumen de la bibliografía revisada. Conclusiones: En la leucemia linfoide aguda de linaje B se detectan múltiples alteraciones citogenéticas como las traslocaciones t(9;22) y la t(12;21), rearreglos en 11q23 que generan genes de fusión, así como otras aberraciones cromosómicas y mutaciones génicas. Este espectro genético involucra genes que participan en el desarrollo de las células linfoides y en la regulación del ciclo celular. El conocimiento de su biología, a partir del estudio de las alteraciones genéticas como biomarcadores predictivos, permite la estratificación de la leucemia linfoide aguda y la aplicación de tratamientos más personalizados para evitar recaídas.

Introduction: Acute lymphoid leukemia is a proliferation and malignant transformation of lymphoid progenitor cells in the bone marrow, blood and extramedullary sites. It is the most common neoplasm in childhood; it constitutes 80% of all acute leukemias in children; and the most frequent of those that originate from the B cell lineage. From the genetic point of view, there are multiple molecular and chromosomal alterations. Objective: To describe the genetic biomarkers of the disease and its prognostic implication. Methods: A review of the literature in English and in Spanish was carried out, in the PubMed website and using the search engine of Google Scholar, for articles published in the last five years. We performed analysis and summary of the reviewed bibliography. Conclusions: In acute lymphoid leukemia, multiple cytogenetic alterations are detected, such as translocation t(9;22), t(12;21), rearrangements in 11q23 that generate fusions genes as well as other chromosomal aberrations and gene mutation. This genetic spectrum involves genes that participate in the development of lymphoid cells and in the regulation of the cell cycle. Knowledge of its biology, based on the study of genetic alterations as predictive biomarkers, allows the stratification of Acute lymphoid leukemia and the application of more personalized treatments to avoid relapses.

Escala pediátrica de disfunción multiorgánica secuencial: validación en pacientes pediátricos graves con leucemia linfoide aguda / Pediatric sequential multiorgan dysfunction scale: validation in critical pediatric patients with acute lymphocytic leukemia

Introducción: Los pacientes que ingresan a la unidad de cuidados intensivos pediátricos son aquellos con alto riesgo de mortalidad que pueden presentar síndrome de disfunción orgánica múltiple. Los pacientes que padecen leucemia linfoide aguda forman parte de este grupo. Objetivos: Validar la escala pediátrica de evaluación del fallo multiorgánico secuencial (pSOFA) en pacientes cubanos graves con diagnóstico de leucemia linfoide aguda. Métodos: Se realizó un estudio observacional, prospectivo, multicéntrico, en unidades de cuidados intensivos de hospitales cubanos con 92 pacientes y 184 ingresos. Se calcularon las puntuaciones de las escalas de disfunción multiorgánica secuencial, riesgo de mortalidad e índice de mortalidad pediátrica, y se evaluó la presencia de disfunción orgánica en las primeras 24 h y a las 48 h. Resultados: La puntuación pSOFA fue mayor en los no supervivientes (p < 0,001) y la mortalidad se incrementó de modo progresivo en los subgrupos con las puntuaciones pSOFA más altas. El análisis de las curvas de las características operativas del receptor (ROC) mostró que el área bajo la curva (AUC) para la predicción de la mortalidad con la puntuación pSOFA fue de 0,89, comparado con 0,84 y 0,79 con las escalas PRISM-3 y PIM-2, respectivamente. Conclusiones: La escala pSOFA mostró ser útil para establecer los criterios disfunción orgánica y su especificidad en el riesgo de mortalidad en los pacientes pediátricos cubanos críticos con diagnóstico de leucemia linfoide aguda(AU)

Introduction: Patients admitted to the pediatric intensive care unit (PICU) are those with a high risk of mortality who may present multiple organ dysfunction syndrome. Patients with acute lymphoid leukemia are part of this group. Objectives: To validate the pediatric sequential multi-organ failure assessment scale (pSOFA) in severe Cuban patients diagnosed with acute lymphoid leukemia. Methods: An observational, prospective, multicenter study was carried out in intensive care units of Cuban hospitals with 92 patients and 184 admissions. The scores of the sequential multiple organ dysfunction, mortality risk and pediatric mortality index scales were calculated, and the presence of organ dysfunction was evaluated in the first 24 hours and at 48 hours. Results: The pSOFA score was higher in non-survivors (p <0.001) and mortality progressively increased in the subgroups with the highest pSOFA scores. The analysis of the receiver operating characteristics (ROC) curves showed that the area under the curve (AUC) for the prediction of mortality with the pSOFA score was 0.89, compared to 0.84 and 0.79 with the PRISM-3 and PIM-2 scales, respectively. Conclusions: The pSOFA scale proved useful to establish the criteria for organ dysfunction and its specificity in the risk of mortality in critical Cuban pediatric patients diagnosed with acute lymphoid leukemia(AU)

The Role of SLC22A1 and Genomic Ancestry on Toxicity during Treatment in Children with Acute Lymphoblastic Leukemia of the Amazon Region.

In Brazil, Acute lymphoid leukemia (ALL) is the leading cause of cancer deaths in children and adolescents. Treatment toxicity is one of the reasons for stopping chemotherapy. Amerindian genomic ancestry is an important factor for this event due to fluctuations in frequencies of genetic variants, as in the NUDT15 and SLC22A1 genes, which make up the pharmacokinetic and pharmacodynamic pathways of chemotherapy. This study aimed to investigate possible associations between NUDT15 (rs1272632214) and SLC22A1 (rs202220802) gene polymorphism and genomic ancestry as a risk of treatment toxicities in patients with childhood ALL in the Amazon region of Brazil. The studied population consisted of 51 patients with a recent diagnosis of ALL when experiencing induction therapy relative to the BFM 2009 protocol. Our results evidenced a significant association of risk of severe infectious toxicity for the variant of the SLC22A1 gene (OR: 3.18, p = 0.031). Genetic ancestry analyses demonstrated that patients who had a high contribution of African ancestry had a significant protective effect for the development of toxicity (OR: 0.174; p = 0.010), possibly due to risk effects of the Amerindian contribution. Our results indicate that mixed populations with a high degree of African ancestry have a lower risk of developing general toxicity during induction therapy for ALL. In addition, individuals with the SLC22A1 variant have a higher risk of developing severe infectious toxicity while undergoing the same therapy.

Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular Consensus on genetically modified cells. II: CAR-T cell therapy for patients with CD19+ acute lymphoblastic leukemia.

Chimeric antigen receptor T (CAR-T) cell therapy is a novel therapeutic modality for acute lymphoblastic leukemia (ALL) with robust outcomes in patients with refractory or relapsed disease. At the same time, CAR-T cell therapy is associated with unique and potentially fatal toxicities, such as cytokine release syndrome (CRS) and neurological toxicities (ICANS). This manuscript aims to provide a consensus of specialists in the fields of Hematology Oncology and Cellular Therapy to make recommendations on the current scenario of the use of CAR-T cells in patients with ALL.

Disfunción orgánica en pacientes pediátricos con leucemia linfoide aguda en el Instituto de Hematología e Inmunología / Organic dysfunction in pediatric patients with acute lymphoid leukemia at the Institute of Hematology and Immunology

Introducción: El pronóstico de las enfermedades hematológicas malignas ha experimentado un importante avance en las últimas décadas, sobre todo por las nuevas combinaciones de quimioterapia. Estos hechos han propiciado que muchos de estos pacientes, en algún momento de su enfermedad, sean tratados en unidades de cuidados intensivos, lo que no era frecuente hace dos décadas. Objetivo: Describir el desarrollo de la disfunción múltiple de órganos en pacientes pediátricos con leucemia linfoide aguda en terapia intensiva en el Instituto de Hematología e Inmunología. Métodos: Se realizó un estudio clínico, observacional, transversal en el que se incluyeron los pacientes pediátricos con leucemia linfoblástica aguda y disfunción múltiple de órganos, atendidos en el servicio de terapia intensiva en el periodo 2018 a 2020. Se analizaron las variables: sociodemográficas, estado nutricional, diagnóstico al ingreso, puntaje del score pSOFA, conducta fármaco-terapéutica. Resultados: El grupo de edad más afectado fue el de 1 a 4 años, en su mayoría normopesos, con complicaciones de choque séptico, distrés respiratorio, y con 33 por ciento de mortalidad mayor en aquellos pacientes con score pSOFA con más de 10 puntos. La conducta terapéutica más utilizada fue la administración de oxígeno, fluidoterapia y antibióticos de tercera y cuarta generación en la primera hora de ingreso al servicio. Conclusiones: Si el puntaje del score pSOFA es mayor de 10 puntos existe mayor riesgo de muerte y mortalidad pediátrica (90 por ciento )(AU)

Introduction: The prognosis of hematological malignancies has undergone an important advance in the last decades, mainly due to the new chemotherapy combinations. These facts have led many of these patients to be treated in intensive care units at some point during their illness. Objective: To describe the development of multiple organ dysfunction in pediatric patients with acute lymphoid leukemia in intensive care at the Institute of Hematology and Immunology. Methods: A clinical, observational, cross-sectional study was carried out that included pediatric patients with acute lymphoblastic leukemia and multiple organ dysfunction, treated in the intensive care service in the period from 2018 to 2020. The variables were analyzed: sociodemographic, nutritional status, diagnosis on admission, pSOFA score, drug-therapeutic behavior. Results: The most affected age group was 1 to 4 years old, mostly normal weight, with complications of septic shock, respiratory distress, and 33 percent higher mortality in those patients with a pSOFA score with more than 10 points. The most used therapeutic approach was the administration of oxygen, fluid therapy and third and fourth generation antibiotics in the first hour of admission to the service. Conclusions: If the pSOFA score is greater than 10 points, there is a greater risk of death and pediatric mortality (90 percent)(AU).

Actualidades terapéuticas en la leucemia linfoide crónica / Therapeutic news in chronic lymphoid leukemia

Introducción: La leucemia linfoide crónica es una neoplasia linfoproliferativa crónica caracterizada por el aumento de una población clonal linfoide disfuncional con inmunofenotipo B (> 95 por ciento) y excepcionalmente T (< 5 por ciento) que afecta sobre todo a personas mayores de 55 años de edad y se incrementa su frecuencia hacia la séptima década de vida. Objetivo: Analizar las principales modalidades terapéuticas para el manejo de la leucemia linfoide crónica. Métodos: Se realizó una revisión de la literatura, en inglés y español, a través del sitio web PubMed y el motor de búsqueda Google académico de artículos publicados en los últimos 5 años. Se hizo un análisis y resumen de la bibliografía revisada. Análisis y síntesis de la información: La leucemia linfoide crónica se consideró durante décadas una enfermedad del paciente añoso, en general de curso indolente, con una evolución impredecible e incurable. El tratamiento de esta enfermedad en los últimos 30 años ha sufrido cambios muy significativos que han repercutido favorablemente en el incremento de la supervivencia global y libre de enfermedad de los pacientes que la padecen. Conclusión: Se debe mantener un adecuado seguimiento de los pacientes con leucemia linfoide crónica, pues esto permitirá disminuir en lo posible las complicaciones, la progresión y un aumento de la supervivencia global(AU)

Introduction: Chronic lymphoid leukemia is a chronic lymphoproliferative neoplasm characterized by the increase of a dysfunctional lymphoid clonal population with immunophenotype B (> 95 percent) and exceptionally T (<5 percent), it mainly affects people over 55 years of age, increasing towards the seventh decade of life. Objective: To analyze the main therapeutic modalities for the management of chronic lymphoid leukemia. Methods: A literature review was carried out, in English and Spanish, through the PubMed website and the academic search engine Google for articles published in the last 5 years. An analysis and summary of the revised bibliography was made. Analysis and synthesis of the information: Chronic lymphoid leukemia was considered for decades a disease of the elderly patient, generally of an indolent course, unpredictable and incurable evolution. The treatment of this disease has undergone in the last 30 years very significant changes that have had a favorable impact on the increase in the overall and disease-free survival of patients who suffer from it. Conclusion: Adequate follow-up of patients with chronic lymphoid leukemia must be maintained, as this will make it possible to reduce complications, progression and increase overall survival as much as possible(AU)

Eventos adversos a medicamentos durante el tratamiento de inducción de la leucemia linfoide aguda en niños / Adverse drug events during the induction treatment of acute lymphoblastic leukemia in children

Introducción: Durante el tratamiento de inducción de la leucemia linfoide aguda en niños no siempre se identifican las reacciones adversas a medicamentos. Objetivo: Describir los eventos adversos y las reacciones adversas a medicamentos durante el tratamiento de inducción de la leucemia linfoide aguda, en niños tratados en el Instituto de Hematología e Inmunología de Cuba, durante 2012-2017. Método: Estudio observacional, descriptivo, transversal, de series de casos en farmacovigilancia, se utilizó la farmacovigilancia activa. Variables: sexo, edad, grupo pronóstico, semana de tratamiento, tipo de evento adverso, sistema de órgano afectado, severidad e imputabilidad. La información se obtuvo del registro nacional del protocolo ALLIC-BFM 2009 y las historias clínicas. Resultados: Se incluyeron 69 niños, 55,1 por ciento (38 casos) fueron masculinos, 56,5 por ciento (39 niños) tenía entre uno y seis años. El 52,2 por ciento (36 pacientes) pertenecían al grupo pronóstico intermedio. Se registraron 471 eventos adversos. El 50,5 por ciento (238/471) ocurrió en la primera semana de tratamiento. Los más frecuentes: anemia (17,8 por ciento; 84/471), neutropenia (16,1 por ciento; 76/471) y trombocitopenia (15,9 por ciento; 75/471). Los sistemas de órganos más afectados: hemolinfopoyético (57,54 por ciento; 271/471) y gastrointestinal (15,71 por ciento; 74/471). El 93,2 por ciento (439/471) se clasificó en reacciones adversas posibles. Según gravedad el 72,4 por ciento (330/456) fueron moderadas y el 27,4 por ciento (125/456) graves. Conclusiones: Todos los casos presentaron eventos adversos, predominaron las alteraciones hematológicas y los eventos reportados para fármacos incluidos en la quimioterapia. Se identificaron reacciones adversas clasificadas como posibles, con predominio de las moderadas y graves(AU)

Introduction: During the induction treatment of acute lymphoid leukemia in children, adverse drug reactions are not always identified. Aims: Describe the demographic and clinical characteristics of children with acute lymphoid leukemia who receive induction treatment at the Institute of Hematology and Immunology between 2012-2017. Characterize adverse events that occur during induction treatment. Describe adverse drug reactions during induction. Methods: Observational, descriptive, cross-sectional study of case series in pharmacovigilance, used active pharmacovigilance. Variables: sex, age, prognosis group, week of treatment, type of adverse event, organ system affected, severity and imputability. The information was obtained from the national register of the ALLIC-BFM 2009 protocol and the medical records. Results: 69 children were included, 55.1 percent belonged to the male sex, 56.5 percent were between one and six years old. 52.2 percent (36 children) belonged to the intermediate prognosis group. 471 events were recorded. 50.5 percent occurred in the first week of treatment. The most frequent: anemia (17.8 percent), neutropenia (16.1 percent) and thrombocytopenia (15.9 percent). The most affected organ systems: hemolinfopoietic (57.5 percent) and gastrointestinal (15.7 percent). According to the severity, 72.4 percent were moderate and 27.4 percent severe. Conclusions: The whole presented adverse events, hematological alterations and reported events for drugs included in chemotherapy predominated. Adverse reactions classified as possible were identified, moderate and severe predominated(AU)

Susceptibility to thiopurine toxicity by TPMT and NUDT15 variants in Colombian children with acute lymphoblastic leukemia / Asociación de variantes genéticas en TPMT y NUDT15 con los eventos de toxicidad durante la terapia de mantenimiento en niños colombianos con Leucemia Linfoide Aguda

Abstract Objective: This study aimed to correlate the genetic profile of the NUDT15 and TPMT genes with the side effects of the treatment of pediatric patients with acute lymphoid leukemia who were undergoing maintenance therapy at a tertiary care hospital in 2017. Methods: This was an analytical, longitudinal, observational study in which the genotypes of the genes of interest were determined by PCR allelic discrimination with TaqMan® probes in patients receiving chemotherapy during the maintenance phase in the Pediatric Hematology and Oncology Unit in 2017. Sociodemographic and clinical data corresponding to the first six months of their maintenance chemotherapy were collected, and the correlation between the genotypes obtained and the development of side effects during the maintenance phase of chemotherapy in these patients was evaluated. Results: Seventy pediatric patients were included in the study. Genetic analyses were carried out of these for NUDT15 and TPMT (rs1800462 and rs1800460) on 68 patients, while for the rs1142345 polymorphism, typing was achieved in 42 patients. 4/68 patients were heterozygous for NUDT15, and the same number of patients were heterozygous for rs1800462 and rs1142345, while for rs1800460, 6 heterozygous patients were identified. No statistically significant association was identified between the genetic variants and the outcomes of interest. Conclusion: Studies with a larger population size are needed and the evaluation of other genetic variants that may influence the development of side effects during maintenance chemotherapy.

Resumen Objetivo: la finalidad de este estudio fue evaluar las asociaciones entre los perfiles de los genes NUDT15 y TPMT con los efectos adversos del tratamiento de mantenimiento en pacientes pediátricos con Leucemia Linfoblástica Aguda atendidos en un hospital de referencia durante el 2017. Métodos: Este fue un estudio observacional analítico, de corte longitudinal en el que los genotipos de los genes de interés fueron determinados mediante PCR de discriminación alélica con sondas TaqMan® en pacientes que estaban recibiendo quimioterapia de mantenimiento en la Unidad de Oncohematología Pediátrica durante el 2017. Los datos clínicos y sociodemográficos correspondientes a los primeros 6 meses de sus tratamientos de mantenimiento fueron colectados, y se evaluó la correlación entre los genotipos identificados y el desarrollo de efectos secundarios en estos pacientes. Resultados: setenta pacientes fueron incluidos en el estudio, de estos, los análisis genéticos para NUDT15 y TPMT (rs1800462 and rs1800460) fueron realizados en 68 pacientes, en tanto que para el polimorfismo rs1142345 se logró la tipificación en 42 pacientes. 4/68 pacientes fueron heterocigotos para NUDT15 y el mismo número de pacientes fueron heterocigotos para rs1800462 and rs1142345, mientras que para rs1800460, 6 pacientes heterocigotos fueron identificados. No se identificaron asociaciones estadísticamente significantes entre las variants genéticas y los resultados clínicos de interés. Conclusiones: Estos hallazgos resaltan la importancia de realizar estudios de este tipo con un mayor número de sujetos de estudio, así como plantean la necesidad de evaluar otras variantes genéticas que podrían tener algún impacto en el desarrollo de efectos secundarios durante la quimioterapia de mantenimiento.

Molecular dynamics simulations of human L-asparaginase1: Insights into structural determinants of enzymatic activity.

The l-asparaginase enzyme is used in cancer therapy, mainly acute lymphoid leukemia (ALL). Commercial enzymes (EcASNase2) cause adverse reactions during treatment, such as immunogenicity. A human enzyme could be a non-immunogenic substitute. However, no candidate was found showing efficient kinetic properties. HASNase1 is an l-asparaginase that comes from the N-terminal domain of a protein called 60 kDa-lysophospholipase and its 3D structure has not been resolved. HASNase1 is homologous to EcASNase1 and gpASNase1, and this last one has shown efficient kinetic properties. Homology modeling was used to find the 3D structure of hASNase1, so one could submit it to Molecular Dynamics (MD), in order to understand structural differences that lead to different catalytic efficiency compared to EcASNase2 and gpASNase1. The interaction potential between L-Asn and active site residues showed that the substrate can rotate in the site when Region1 is open. Region1 residues sequence favors deformations and movements as shown in MD. Region2-A is linear in gpASNase1, and it features a helix portion in hASNase1, which leaves the Tyr308 position projected to the active site ratifying its role in catalytic efficiency. Analysis of Lys188 orientation and movement showed the effect of positive cooperativity in hASNase1. It was found that the presence of Asn at the allosteric site helps, not only in Region1 stabilization, but also in Lys188 stabilization for the maintenance of the triad. Despite structural similarities in hASNase1, gpASNase1, and EcASNase2, there are differences in structural determinants that, in addition to allosterism, may explain the different kinetic properties.