L-Asparaginase e perspectivas no tratamento da leucemia linfoblástica aguda: revisão de literatura / L-Asparaginase and perspectives in the treatment of leukemia acute lymphoblastic: literature review

Introdução: A L-asparaginase tem sido estudada como alternativa no tratamento da Leucemia Linfoblástica Aguda (LLA) uma vez que possui a capacidade de induzir apoptose em células leucêmicas sem causar danos às células normais. Estudos mostraram benefícios no tratamento da LLA, porém com o risco de desenvolver efeitos adversos. Objetivo: Este trabalho visa apresentar e explicar o histórico da L-asparaginase, desafios enfrentados pelo Brasil, mecanismos de ação que envolvem as formas da enzima e efeitos adversos de sua utilização. Métodos: Foram incluídos neste trabalho 54 artigos na língua portuguesa e inglesa consultados em bancos de artigos como PubMed e SciELO, entre o período de 1953 até 2021. Resultados: A L-asparaginase é uma enzima que converte asparagina em aspartato e amônia, isolada a partir de colônias de Escherichia coli e de Erwinia chrysanthemi, além disso foi polimerizada com polietilenoglicol. O uso de corticosteroides, anti-histamínicos e suplementação vitamínica se mostraram eficientes para amenizar os efeitos adversos. Conclusões: É necessário evitar um desabastecimento de L-Asparaginase no Brasil, principalmente por conta da dificuldade de comercialização e alto custo, mesmo sendo um medicamento presente na lista da Organização Mundial da Saúde, considerado essencial.

Introduction: L-asparaginase has been studied as an alternative in the treatment of Acute Lymphoblastic Leukemia (ALL) since it has the ability to induce apoptosis in leukemic cells without causing damage to normal cells. Studies have shown benefits in the treatment of ALL, but with the risk of developing adverse effects. Objective: This work aims to present and explain the history of L-asparaginase, challenges faced by Brazil, mechanisms of action involving the forms of the enzyme and adverse effects of its use. Methods: 54 articles in Portuguese and English were included in this work, consulted in article banks such as PubMed and SciELO, between the period of 1953 to 2021. Results: L-asparaginase is an enzyme that converts asparagine into aspartate and ammonia, isolated from from Escherichia coli and Erwinia chrysanthemi colonies, it was also polymerized with polyethylene glycol. The use of corticosteroids, antihistamines and vitamin supplementation proved to be efficient in mitigating adverse effects. Conclusions: It is necessary to avoid a shortage of L-Asparaginase in Brazil, mainly due to the difficulty of commercialization and high cost, even though it is a drug present on the World Health Organization list, considered essential.

Hallazgos moleculares y citogenéticos en pacientes pediátricos, diagnosticados de leucemia linfoide aguda: Un estudio de centro único / Molecular and cytogenetic findings in pediatric patients diagnosed with acute lymphoid leukemia: A single center study / Achados moleculares e citogenéticos em pacientes pediátricos com diagnóstico de leucemia linfóide aguda: um estudo de centro único

Introducción: La leucemia linfoblástica aguda (LLA) es la neoplasia maligna de mayor frecuencia en la infancia; advertir sus alteraciones moleculares y citogenéticas permite establecer el riesgo, el pronóstico asociado y además plantear esquemas terapéuticos apropiados; el objetivo de este estudio es conocer la prevalencia de estas alteraciones en nuestra población. Metodología: Estudio de tipo retrospectivo y transversal, basado en los registros de las alteraciones moleculares y citogenéticas de los pacientes pediátricos diagnosticados con leucemia linfoblástica aguda durante el periodo comprendido entre enero 2014 a diciembre de 2018, en el Hospital del Instituto Oncológico Nacional "Dr. Juan Tanca Marengo". Resultados: Se incluyeron 338 pacientes, de los cuales el principal grupo etario lo constituyo el de 0 a 4 años; el inmunofenotipo más observado fue el B-común. En el 24.56% de los casos se detectó altercaciones estructurales, principalmente por estudios de biología molecular; siendo la más común la translocación t(12;21). Se obtuvieron resultados por citogenética en 167 pacientes, en cuales la principal alteración numérica correspondió a la hiperdiploidía de entre 47 a 51 cromosomas. Conclusión: Los avances en la caracterización molecular y citogenética de la LLA, permiten mejorar la estratificación de su riesgo; y establecer estrategias terapéuticas que permitan una mejoría en la sobrevida.

Introduction: Acute lymphoblastic leukemia (ALL) is the most frequent malignant neoplasm in childhood; Noting its molecular and cytogenetic alterations allows to establish the risk, the associat-ed prognosis and also to propose appropriate therapeutic schemes; The objective of this study is to know the prevalence of these alterations in our population. Methods: Retrospective and cross-sectional study, based on the records of molecular and cytogenetic alterations of pediatric patients diagnosed with acute lymphoblastic leukemia during the period from January 2014 to December 2018, at the National Oncological Institute Hospital "Dr. Juan Tanca Marengo". Results: 338 patients were included, of which the main age group was made up of 0 to 4 years; the most observed immunophenotype was B-common. In 24.56% of the cases, structural alterations were detected, mainly by molecular biology studies; the most common being the t (12; 21) translocation. Cytogenetics results were obtained in 167 patients, in which the main numerical alteration corresponded to hyperdiploidy of between 47 and 51 chromosomes. Conclusions: Advances in the molecular and cytogenetic characterization of ALL make it possible to improve the stratification of its risk; and establish therapeutic strategies that achieve an improvement in survival.

Introdução: A leucemia linfoblástica aguda (LLA) é a neoplasia maligna mais comum na infância; Observar suas alterações moleculares e citogenéticas permite estabelecer o risco, o prognóstico associado e também propor esquemas terapêuticos adequados; O objetivo deste estudo é conhecer a prevalência dessas alterações em nossa população. Metodologia: Estudo retrospectivo e transversal, baseado nos registros de alterações moleculares e citogenéticas de pacientes pediátricos com diagnóstico de leucemia linfoblástica aguda no período de janeiro de 2014 a dezembro de 2018, no Hospital del Instituto Oncológico Nacional "Dr. Juan Tanca Marengo ". Resultados: Foram incluídos 338 pacientes, cuja faixa etária principal era de 0 a 4 anos; o imunofenótipo mais observado foi B-comum. Em 24,56% dos casos, foram detectadas alterações estruturais, principalmente por estudos de biologia molecular; o mais comum é a translocação t (12; 21). Os resultados citogenéticos foram obtidos em 167 pacientes, nos quais a principal alteração numérica correspondeu à hiperdiploidia entre 47 e 51 cromossomos. Conclusão: Os avanços na caracterização molecular e citogenética da LLA permitiram melhorar a estratificação de risco; e estabelecer estratégias terapêuticas que permitam uma melhora na sobrevida.

Ultraconserved long non-coding RNA uc 112 is highly expressed in childhood T versus B-cell acute lymphoblastic leukemia

ABSTRACT Aberrant expression of long non-coding RNAs (lncRNAs) has been detected in several types of cancer, including acute lymphoblastic leukemia (ALL), but lncRNA mapped on transcribed ultraconserved regions (T-UCRs) are little explored. The T-UCRs uc.112, uc.122, uc.160 and uc.262 were evaluated by quantitative real-time PCR in bone marrow samples from children with T-ALL (n = 32) and common-ALL/pre-B ALL (n = 30). In pediatric ALL, higher expression levels of uc.112 were found in patients with T-ALL, compared to patients with B-ALL. T-cells did not differ significantly from B-cells regarding uc.112 expression in non-tumor precursors from public data. Additionally, among B-ALL patients, uc.112 was also found to be increased in patients with hyperdiploidy, compared to other karyotype results. The uc.122, uc.160, and uc.262 were not associated with biological or clinical features. These findings suggest a potential role of uc.112 in pediatric ALL and emphasize the need for further investigation of T-UCR in pediatric ALL.

Childhood T-cell acute lymphoblastic leukemia in a single Latin American center: impact of improved treatment scheme and support therapy on survival

ABSTRACT Background and objective T-cell acute lymphoblastic leukemia (T-ALL) in children represents a high-risk disease. There is a lack of studies assessing the outcome of T-ALL in Hispanic populations, in which it is a rare malignancy. We report the characteristics and results of treatment for childhood T-cell ALL in children over 14 years at a Latin American reference center. Material and methods From January 2005 to December 2018, there occurred the analysis of twenty patients ≤ 16 years of age from a low-income open population diagnosed at a university hospital in Northeast Mexico. Clinical and laboratory characteristics, treatment regimens and outcomes were assessed by scrutinizing clinical records and electronic databases. Diagnosis was confirmed by flow cytometry, including positivity for CD-2, 5, 7 and surface/cytoplasmic CD3. Survival rates were assessed by the Kaplan-Meier method. Results There was a male preponderance (70 %), with a 2.3 male-to-female ratio (p= .074), the median age being 9.5 years. Leucocytes at diagnosis were ≥ 50 × 109/L in 13 (65 %) children, with CNS infiltration in 6 (30 %) and organomegaly in 10 (50 %). The five-year overall survival (OS) was 44.3 % (95 % CI 41.96-46.62), significantly lower in girls, at 20.8 % (95 % CI 17.32-24.51) vs. 53.1 % (95 % CI 50.30-55.82), (p= .035) in boys; there was no sex difference in the event-free survival (EFS) (p= .215). The survival was significantly higher after 2010 (p= .034). Conclusion The T-cell ALL was more frequent in boys, had a higher mortality in girls and the survival has increased over the last decade with improved chemotherapy and supportive care.

Treatment outcomes of children with acute lymphoblastic leukemia in a middle-income developing country: high mortalities, early relapses, and poor survival / Desfechos do tratamento de crianças com leucemia linfoblástica aguda em um paísem desenvolvimento de renda média: altas taxas de mortalidade, recidivas precocese baixa sobrevida

Abstract Objective Acute lymphoblastic leukemia is the most common childhood cancer, yet surprisingly, very few studies have reported the treatment outcomes and the relapse rate of patients from low/middle-income countries. Method This study was a 5-year retrospective cohort study. It was conducted at Oncology Center of Mansoura University in Egypt and aimed to estimate the treatment outcomes and the relapse rates of newly diagnosed acute lymphoblastic leukemia in children. Results Two hundred children suffering from acute lymphoblastic leukemia were studied; forty-six patients (23%) died during induction and most of those deaths were related to infection. Forty-one patients (27%) relapsed out of the 152 patients who achieved complete remission. The most common site of relapse was the bone marrow, followed by the isolated central nervous system, 53.7% and 31.7%, respectively. Seventy-eight percent of relapses occurred very early/early rather than later. The majority of relapse patients' deaths were related to infection and disease progression. The 5-year overall survival rate for patients was 63.1% (82.1% for non-relapsed compared to 36.6% for relapsed patients). Conclusion There was a high incidence of induction deaths related to infection and high percentages of very early/early relapses, with high mortalities and low 5-year overall survival rates. These findings suggest the urgent need for modification of chemotherapy regimens to be suitable for the local conditions, including implementation of supportive care and infection control policies. There is also a requirement for antimicrobial prophylaxis during induction period combined with the necessary increase in government healthcare spending to improve the survival of acute lymphoblastic leukemia in Egyptian children.

Resumo Objetivo Estimar os desfechos do tratamento e as taxas de recidiva de crianças recém-diagnosticadas com leucemia linfoblástica aguda. É o câncer infantil mais comum, mas surpreendentemente poucos estudos relataram os desfechos do tratamento e a taxa de recidiva em pacientes de países de renda baixa/média. Método Estudo de coorte retrospectivo de cinco anos. Foi feito no Centro de Oncologia da Universidade de Mansoura, no Egito. Resultados Foram estudadas 200 crianças com leucemia linfoblástica aguda, das quais 46 (23%) morreram durante a indução e a maioria dessas mortes estava relacionada à infecção. Dos 152 pacientes que alcançaram a remissão completa, 41 (27%) apresentaram recidiva. O local mais comum de recidiva foi a medula óssea, seguido pelo sistema nervoso central isolado, com 53,7% e 31,7% dos casos, respectivamente. Das recidivas, 78% ocorreram muito precocemente ou precocemente, em vez de tardiamente. A maioria das mortes de pacientes com recidiva estava relacionada à infecção e progressão da doença. A taxa de sobrevida global em cinco anos para os pacientes foi de 63,1% (82,1% para não recidivados em comparação com 36,6% para os recidivados). Conclusão Houve uma alta incidência de mortes na indução relacionadas à infecção e altos percentuais de recidivas muito precoces ou precoces, com altas taxas de mortalidade e baixas taxas de sobrevida global em cinco anos. Nossos achados sugerem a necessidade urgente de modificação dos esquemas quimioterápicos para adequação às nossas condições locais, implantação de políticas de cuidados de suporte e controle de infecções. Há também a necessidade de profilaxia antimicrobiana durante o período de indução, junto com um aumento necessário nos gastos governamentais com a saúde, para melhorar a capacidade de sobrevivência das crianças egípcias com leucemia linfoblástica aguda.

Eventos adversos en pacientes con diagnóstico de leucemia linfoblástica aguda, durante quimioterapia de inducción, atendidos en Hospital Nacional De Niños Benjamin Bloom, 1 de mayo del 2016 al 31 de mayo 2017 / Adverse events in patients diagnosed with acute lymphoblastic leukemia, during induction chemotherapy, treated at Benjamin Bloom National Children's Hospital, May 1, 2016 to May 31, 2017

La leucemia aguda es la primera causa de cáncer en niños menores de 15 años en el mundo, siendo la leucemia linfoblástica aguda (LLA), la malignidad pediátrica más común, existe una clasificación de riesgo de pacientes que se someten a quimioterapia, catalogándolos como de Alto, Estándar y Bajo riesgo, siguiendo, de acuerdo a estándares internacionales, 3 fases de tratamiento, que son: Inducción, Consolidación y Mantenimiento. En el análisis del protocolo AHOPCA LLA 2015, la muerte por inducción es de un 3%. Se define como evento adverso a aquel evento que se ve relacionado con el perfil de toxicidad de la droga quimioterapéutica usada en determinada fase de tratamiento, siendo más frecuentes en la fase de inducción, y con mayor potencial de mortalidad. Dichos eventos adversos se reportan mediante la escala CTCAE (Common terminology criteria for adverse events), en grados del 0 al 5. El objetivo principal del presente estudio es estimar la prevalencia de eventos adversos grados 3,4 y 5, según escala CTACE, asociados a quimioterapia de inducción, en pacientes con diagnóstico de Leucemia Linfoblástica Aguda, atendidos en el Hospital Nacional de Niños Benjamín Bloom, mayo 2016 ­ mayo 2017. Mediante un estudio descriptivo y retrospectivo, de 73 pacientes, el presente trabajo determinó un porcentaje de eventos adversos en pacientes con LLA en quimioterapia de inducción del 35.6%, con una prevalencia en pacientes con LLA con enfermedad activa recibiendo quimioterapia del 6%, siendo los eventos adversos infecciosos los más frecuentes con un 40%, seguidos de los eventos trombóticos no cerebrales y hepatobiliares con un 13.33%. Según gravedad por escala CTCAE, fueron más frecuentes los eventos grado 3 con un 73.3%. Un 42.3% de pacientes con eventos adversos presentó enfermedad de Riesgo Alto y Moderado, observándose una mortalidad del 4.1%

Linfocitose extrema associada à leucemia linfoblástica aguda (LLA) de células T em um cão jovem: relato de caso / Extreme lymphocytosis associated with acute T-cell lymphoblastic leukemia (ALL) in a young dog: case report

A leucemia linfoblástica aguda (LLA) é uma enfermidade de origem linfóide e consiste na proliferação de células neoplásicas na medula óssea. O objetivo desse trabalho é relatar o caso de um cão macho, sem raça definida, de apenas um ano de idade, atendido no Hospital Universitário de Medicina Veterinária Prof. Firmino Mársico Filho (HUVET) da Universidade Federal Fluminense (UFF) com queixa principal de inapetência e diarreia há três dias e que foi diagnosticado com essa neoplasia por meio da sintomatologia clínica, resultados do hemograma e do mielograma. O paciente apresentava valores exacerbados de linfócitos (553.094 células/µL), além de anemia, trombocitopenia, hipoalbuminemia e elevação da atividade das enzimas fosfatase alcalina e ALT. Foram observadas manchas de Gümprecht, linfócitos atípicos apresentando anisocitose, anisocariose, intensa basofilia citoplasmática e monócitos ativados. O mielograma apresentou também um aumento de linfócitos e contagem de linfoblastos superior a 30% na medula, confirmando o diagnóstico de leucemia linfoblástica aguda. Ademais, posteriormente, foi realizado exame de Reação em Cadeia de Polimerase (PCR) para rearranjos de receptores de antígenos e foi detectado clonalidade para linfócitos T. O animal foi submetido à quimioterapia (protocolo com ciclofosfamida, vincristina e prednisona) mas não resistiu à gravidade do quadro, vindo a óbito após a primeira sessão, pouco tempo após o diagnóstico.

Acute lymphoblastic leukemia (LLA) is a disease with a lymphoid origin and consists of the proliferation of neoplastic cells in the bone marrow. The aim of this study was to report the case of only one year old mixed breed male dog, attended at the University Hospital of Veterinary Medicine Prof. Firmino Mársico Filho (HUVET) from Universidade Federal Fluminense (UFF), with major complaint of inappetence and diarrhea three days ago and which was diagnosed with this neoplasm through clinical symptoms, complete blood count and myelogram results. The patient had increased values of lymphocytes (553,094 cells/µL), in addition to anemia, thrombocytopenia, hypoalbuminemia and elevated alkaline phosphatase and ALT activities. Gümprecht shadows, atypical lymphocytes presenting anisocytosis, anisocariosis, and severe cytoplasmic basophilia and activated monocytes were observed. Myelogram also showed an increase in lymphocytes and a lymphoblastic count greater than 30% in the marrow, confirming the diagnosis of LLA. In addition, polymerase chain reaction (PCR) for antigen receptor rearrangements was performed and clonality for T lymphocytes was detected. The animal underwent chemotherapy (protocol with cyclophosphamide, vincristine and prednisone), but did not withstand the severity of the disease, coming to death after the first session, shorly after diagnosis.

Linfocitose extrema associada à leucemia linfoblástica aguda (LLA) de células T em um cão jovem: relato de caso / Extreme lymphocytosis associated with acute T-cell lymphoblastic leukemia(ALL) in a young dog: case report

A leucemia linfoblástica aguda (LLA) é uma enfermidade de origem linfóide e consiste na proliferação de células neoplásicas na medula óssea. O objetivo desse trabalho é relatar o caso de um cão macho, sem raça definida, de apenas um ano de idade, atendido no Hospital Universitário de Medicina Veterinária Prof. Firmino Mársico Filho (HUVET) da Universidade Federal Fluminense (UFF) com queixa principal de inapetência e diarreia há três dias e que foi diagnosticado com essa neoplasia por meio da sintomatologia clínica, resultados do hemograma e do mielograma. O paciente apresentava valores exacerbados de linfócitos (553.094 células/µL), além de anemia, trombocitopenia, hipoalbuminemia e elevação da atividade das enzimas fosfatase alcalina e ALT. Foram observadas manchas de Gümprecht, linfócitos atípicos apresentando anisocitose, anisocariose, intensa basofilia citoplasmática e monócitos ativados. O mielograma apresentou também um aumento de linfócitos e contagem de linfoblastos superior a 30% na medula, confirmando o diagnóstico de leucemia linfoblástica aguda. Ademais, posteriormente, foi realizado exame de Reação em Cadeia de Polimerase (PCR) para rearranjos de receptores de antígenos e foi detectado clonalidade para linfócitos T. O animal foi submetido à quimioterapia (protocolo com ciclofosfamida, vincristina e prednisona), mas não resistiu à gravidade do quadro, vindo a óbito após a primeira sessão, pouco tempo após o diagnóstico.

Acute lymphoblastic leukemia (LLA) is a disease with a lymphoid origin and consists of the proliferation of neoplastic cells in the bone marrow. The aim of this study was to report the case of only one year old mixed breed male dog, attended at the University Hospital of Veterinary Medicine Prof. Firmino Mársico Filho (HUVET) from Universidade Federal Fluminense (UFF), with major complaint of inappetence and diarrhea three days ago and which was diagnosed with this neoplasm through clinical symptoms, complete blood count and myelogram results. The patient had increased values of lymphocytes (553,094 cells/μL), in addition to anemia, thrombocytopenia, hypoalbuminemia and elevated alkaline phosphatase and ALT activities. Gümprecht shadows, atypical lymphocytes presenting anisocytosis, anisocariosis, and severe cytoplasmic basophilia and activated monocytes were observed. Myelogram also showed an increase in lymphocytes and a lymphoblastic count greater than 30% in the marrow, confirming the diagnosis of LLA. In addition, polymerase chain reaction (PCR) for antigen receptor rearrangements was performed and clonality for T lymphocytes was detected. The animal underwent chemotherapy (protocol with cyclophosphamide, vincristine and prednisone), but did not withstand the severity of the disease, coming to death after the first session, shortly after diagnosis.

Hallazgos Inmunofenotípicos, Morfológicos y Citogenéticos de las Leucemias Linfoblásticas Agudas en Pediatría / Immunophenotypic, Morphological and Cytogenetic Findings of Acute Lymphoblastic Leukemia in Pediatrics

Introducción: Las leucemias linfoblásticas agudas (LLA) son proliferaciones clónales malignas de células en distintos grados de diferenciación y representan las neoplasias más frecuentes en la edad pediátrica. El objetivo de este estudio es determinar las principales características inmunofenotípicas, biológicas y moleculares de las LLA en nuestro medio. Métodos: Se realiza un estudio retrospectivo, de tipo no experimental, descriptivo, y longitudinal de los pacientes diagnosticados de LLA durante el periodo comprendido entre 2004 a 2009 en el Instituto Oncológico Nacional "Dr. Juan Tanca Marengo" Solca, Guayaquil. Resultados: Se analizaron un total de 316 pacientes, con una edad promedio de 6 años. Por sus características morfológicas fueron clasificados como FAB L1 en 90.5 % de los casos (n=286). En base a su inmunofenotipo 91.8 % (n=290) de los mismos correspondieron a una LLA de fenotipo B y un 8.2 % (n=26) a una de fenotipo T, el con un predominio de la variedad B común. Se reportaron 45 casos de translocaciones, siendo a más común la t(12;21). En relación al cariotipo este se reportó como normal en 229 casos (72.5 %) y se evidenciaron gran variabilidad de alteraciones en el restante 27.5 %, prevaleciendo las hiperdiploidías. Conclusión: Una mejor clasificación y estatificación de los pacientes, por medio de la correlación de los hallazgos inmunofenotípicos, morfológicos y citogenéticos permitirá establecer nuevas estrategias terapéuticas con una mejor sobrevida.

Introduction: Acute lymphoblastic leukemias (ALL) are malignant clonic proliferations of cells at different degrees of differentiation and represent the most frequent neoplasms in pediatric age. The objective of this study is to determine the main immunophenotypic, biological and molecular characteristics of ALL in our environment. Methods: A retrospective, non-experimental, descriptive and longitudinal study of patients diagnosed with ALL during the period between 2004 and 2009 is carried out in the pediatric area of the National Oncology Institute "Dr. Juan Tanca Marengo "Solca, Guayaquil. Results: A total of 316 patients were analyzed, with an average age of 6 years. Due to their morphological characteristics, they were classified as FAB L1 in 90.5% of cases (n = 286). According to their immunophenotype, 91.8% (n = 290) of them corresponded to an ALL of the phenotype B and 8.2% (n = 26) to one of the phenotype T, with a predominance of the common variety B. 45 cases of translocations, the most common being t (12; 21). In relation to the karyotype, this was reported as normal in 229 cases (72.5%) and there was a great variability in the alterations in the rest of 27.5%, with hyperdiploidías prevailing. Conclusion: A better classification and staging of patients, through the correlation of immunophenotypic, morphological and cytogenetic findings, will allow the establishment of new therapeutic strategies with better survival.

Infección por Rhodotorula rubra en el lactante con leucemia linfoblástica aguda. Reporte de un caso / Rhodotorula rubra infection in infants with acute lymphoblastic leukemia. Case report

Rhodotorula especies (spp.) son levaduras comensales de la familia Sporidiobolaceae. Rhodotorula rubra es un patógeno oportunista y emergente que tiene la habilidad de colonizar e infectar a los pacientes susceptibles como son los que padecen de enfermedades hematológicas malignas, y está asociado con el uso de catéteres venosos centrales. Hay pocos reportes de casos en niños inmunocomprometidos. Presentamos el caso de una paciente lactante con diagnóstico de leucemia linfoblástica aguda (LLA) B común, que presentó infección fúngica por Rhodotorula rubra.

Rhodotorula species (spp.) are commensal yeasts of the family Sporidiobolaceae. Rhodotorula rubra is an opportunistic and emerging pathogen with the ability to colonize and infect susceptible patients like patients with malignant haematological diseases and it is associated with the use of central venous catheters. Only a few reports have linked found in immunocompromised children. In this article we present the case report of a lactating patient with a diagnosis of common acute lymphoblastic leukemia (B), who presented a fungal infection by Rhodotorula rubra.

Plan nacional para la atención integral de la leucemia linfática aguda en pacientes de 1 a 21 años (Plan Salvador: 2017- 2021) (R.M. Nº 383-2017/MINSA) / National plan for the comprehensive care of acute lymphatic leukemia in patients aged 1 to 21 years (Plan Salvador: 2017-2021) (R.M. No. 383-2017 / MINSA)

El plan describe las pautas para mejorar el diagnóstico precoz, referencia oportuna de los casos; así como la mejora del tratamiento y estrategias para la reducción del abandono del tratamiento, con la participación plena de todos los actores alrededor de esta enfermedad.

Evaluación ecocardiográfica longitudinal en pacientes con leucemia linfoide aguda que recibieron antraciclinas durante la edad pediátrica / Longitudinal ecocardiographic assesment in patients with acute lymphoid leukemia that received anthracyclines during childhood

Introducción: La cardiotoxicidad tardía causada por el tratamiento del cáncer puede ser un problema frecuente en los sobrevivientes por lo que se decidió realizar un estudio ecocardiográfico longitudinal de la función cardiovascular con el objetivo de detectar las alteraciones causadas por la administración de antraciclinas en pacientes que tuvieron una leucemia linfoide aguda en la edad pediátrica. Métodos: se incluyeron todos los pacientes atendidos por esta leucemia en el Servicio de Pediatría del Instituto de Hematología e Inmunología ,desde abril de 2002 hasta febrero de 2015, que además debían tener al menos 2 evaluaciones ecocardiográficas posteriores a la conclusión del tratamiento. A todos se les realizó examen físico, se tomaron datos generales de las historias clínicas, se les calculó la dosis acumulativa de antraciclinas y el tiempo transcurrido hasta la realización de la evaluación. De los ecocardiogramas realizados se tomaron las medidas de aurícula izquierda, ventrículo derecho, fracción de eyección y fracción de acortamiento. Resultados : predominaron los signos de cardiotoxicidad tardía subclínica con una media de 9 años después de suspendido el tratamiento y estuvieron afectados ambos sexos por igual. En el primer ecocardiograma realizado, tres años después de la suspensión, la mayor frecuencia de alteraciones estuvieron en las medidas de aurícula izquierda y ventrículo derecho. Los estudios se repitieron cada tres años y en el tercer estudio fue más frecuente la afectación de las fracciones de eyección y de acortamiento. Se encontró que había relación estadísticamente significativa entre el uso de mayores dosis de antraciclinas y las alteraciones ecocardiográficas. Conclusiones: las afectaciones de la función cardiovascular fueron ligeras y aumentaron durante el seguimiento(AU)

Introduction Cancer therapy could cause frequent cardiac toxicity, so we decided to perform an echocardiographic longitudinal study of the late effects caused by anthracyclines administration in patients that were treated for acute lymphoid leukemia during childhood. Methods All the patients admitted in the Pediatric Service of Institute of Hematology and Immunology, with acute lymphoid leukemia since april 2002 until february 2015 and that have at least two echocardiographic studies after finishing therapy. A complete physical exammination was performed to all of them and the cumulative dose of anthracyclines received was calculated and also time until evaluation. From the echocardiograms were taken the measurements of left auricle, right ventricle, ejection fraction and shortening fraction. Results: the main findings were signs of late subclinical cardiotoxicity with a mean of 9 years after therapy completion and there were no sex predominance. In the first echocardiogram performed three years after stopping therapy there were more alterations in the measures of left auricle and right ventricle. The studies were repeated every three years and in the third one there were more alterations in ejection fraction and shortening fraction and there also were a statiscally significative relation between cumulative anthracyclines doses and echocardiographic findings. Conclusions: There were found subclinical cardiac dysfunction that increases as time goes by(AU)

Outcome of children and adolescents with lymphoblastic lymphoma / Evolução de crianças e adolescentes com linfoma linfoblástico

Summary Introduction: lymphoblastic lymphoma (LBL) is the second most common subtype of non-Hodgkin lymphoma in children. The aim of this study was to characterize the clinical course of children and adolescents with LBL treated at a tertiary center. Methods: this is a retrospective cohort study of 27 patients aged 16 years or younger with LBL admitted between January 1981 and December 2013. Patients were treated according to the therapy protocol used for acute lymphoblastic leucemia. Diagnosis was based on biopsy of tumor and/or cytological examination of pleural effusions. The overall survival was analyzed using the Kaplan-Meier method. Results: the median age at diagnosis was 11.6 years (interquartile range, 4.6- 13.8). LBL had T-cell origin in 16 patients (59%). The most common primary manifestation in T-cell LBL was mediastinal involvement, in 9 patients (56%). Intra-abdominal tumor was the major site of involvement in patients with precursor B-LBL. Most patients had advanced disease (18 patients – 67%) at diagnosis. Twenty-four patients (89%) achieved complete clinical remission. After a median follow-up of 43 months (interquartile range, 6.4-95), 22 patients (81%) were alive in first complete remission. Five children (18.5%) died, three of them soon after admission and two after relapsing. The probability of survival at five years for 20 patients with de novo LBL was 78% (SD 9.4). Conclusion: our findings confirm the favorable prognosis of children with LBL with an intensive chemotherapy regimen derived from ALL therapy.

Resumo Objetivos: linfoma linfoblástico (LL) é o segundo subtipo mais comum de linfoma não Hodgkin em crianças. O objetivo deste estudo foi caracterizar a evolução clínica de crianças e adolescentes com LL em um centro terciário. Métodos: estudo de coorte retrospectivo de 27 pacientes com idade de até 16 anos com LL admitidos entre janeiro de 1981 e dezembro de 2013. Os pacientes foram tratados de acordo com o protocolo de tratamento para leucemia linfoblástica aguda (LLA). O diagnóstico foi baseado em biópsia do tumor e/ou no exame citológico de derrame pleural. A sobrevida global foi analisada pelo método de Kaplan-Meier. Resultados: a média de idade ao diagnóstico foi de 11,6 anos (variação interquartil, 4,6-13,8). Linfoma linfoblástico de células T foi identificado em 16 pacientes (59%) e a manifestação primária mais comum foi o acometimento mediastinal (56%). Tumor intra-abdominal foi a manifestação clínica principal nos pacientes com LL de células pré- -B. A maioria dos pacientes apresentava doença avançada (18 pacientes, 67%) ao diagnóstico. Vinte e quatro pacientes (89%) alcançaram remissão clínica completa. Após um período de acompanhamento médio de 43 meses (intervalo interquartil, 6,4-95), 22 pacientes (81%) continuam vivos em primeira remissão clínica completa. Cinco crianças (18,5%) morreram, três delas logo após a admissão e duas após recidiva. A probabilidade de sobrevida em cinco anos para 20 pacientes com LL de novo foi de 78% (DP 9,4). Conclusão: os resultados confirmam o prognóstico favorável de crianças com LL tratadas com regime de quimioterapia intensiva derivado da terapia de LLA.

Evaluación de la actividad antiproliferativa y proapoptótica de compuestos kauranos sobre líneas celulares de leucemia humana / Evaluation of the antiproliferative and proapoptotic activity of kauran compounds on human leukemia cell lines

En Venezuela y el mundo, el cáncer es la segunda causa de morbi-mortalidad, y la leucemia es uno de los tipos de cáncer que afecta a nuestra población. La principal características de las celulas linfoides y mieloides presentes en la leucemia es que son pocos funcionales y además no responden a las señales proapoptóticas. Por lo tanto, en la búsqueda de compuestos de mejor perfil terapéutico, se evaluó el efecto de compuestos de tipo seco ent-kauranos aislados de plantas terrestres en las lineas celulares jurka E6.1 y HL60 sobre el crecimiento celular a través del método colorimétrico del MTT, la inducción de apoptosis a través del uso de la microscopia confocal, la citometría de flujo y los micro arreglos de proteínas; y sobre el ciclo celular, la actividad de la vía del NFkB y la diferenciación celular también a través de la citometría de flujo. Se determino que el ácido de casacasina, y la caracasina, disminuyeron la proliferación cecular, indujeron el arresto del ciclo celular, provocaron la externalización de la fosfatidilserina y la activación de las capasas 3, 7, 8 y 9, a la vez que promovieron la disminución del potencial mitocondrial, incrementaron la expresión de las proteínas proapoptóticas en ambas líneas celulares, disminuyeron la activación de la vía de señalización del NFkB en la línea celular Jurkat E6.1, y ademas indujeron la expresión de la proteína CD40 e incrementaron la producción de especies reactivas de oxigeno en la línea celular HL60, por lo que estos compuestos ent-kauranos poseen un alto potencial anticancerígeno para la leucemia linfocítica aguda de células T y para la leucemia promielocítica

Immunoglobulin heavy chain gene rearrangement in non B-cell haematological malignancies / Reordenamiento del gen de la cadena pesada de inmunoglobulina en las neoplasias hematológicas de linfocitos no B

PURPOSE: Clonality detection through amplifying immunoglobulin heavy chain (IGH) gene rearrangements by polymerase chain reaction (PCR) is a useful tool in diagnosis of various B-lymphoid malignancies. Immunoglobulin heavy chain gene rearrangement can be an optimal target for clonality detection in B-lymphoid malignancies. In the present study, we evaluated the presence of IGH gene rearrangement in non B-cell haemato-oncologypatients including T-cell acute lymphoblastic leukaemia (T-ALL), acute myeloblastic leukaemia (AML) and biphenotypic leukaemia. METHODS: We studied 18 cases of haematological malignancies which comprised five patients with TALL, 12 patients with AML and one with biphenotypic leukaemia. RESULTS: We found that the incidence of IGH gene rearrangement in T-ALL and AML were three (60%) and two (16.7%), respectively. The patient with biphenotypic leukaemia was negative for IGH gene rearrangement. CONCLUSION: Immunoglobulin gene rearrangement, which occurs in almost all haematological malignancies of B-cell lineage, also presents in a very small proportion of T-cell or myeloid malignancies.

OBJETIVO: La detección de la clonalidad mediante amplificación de los reordenamientos del gen de la cadena pesada (IGH) de inmunoglobulina por reacción en cadena de la polimerasa (RCP) es una herramienta útil en el diagnóstico de varios tumores malignos linfoides de células B. El reordenamiento del gen de la cadena pesada de inmunoglobulina puede ser un objetivo óptimo de la detección de la clonalidad en tumores malignos linfoides de células B. En el presente estudio, se evaluó la presencia de reordenamiento del gen IGH en pacientes de hemato-oncología de células no B, incluyendo la leucemia linfoblástica aguda de células T (LLA-T), leucemia mieloblástica aguda (LMA), y leucemia bifenotípica. MÉTODOS: Se estudiaron 18 casos de neoplasias malignas hematológicas que abarcaron cinco pacientes con (LLA-T), 12pacientes con AML y uno con leucemia bifenotípica. CONCLUSIÓN: Reordenamiento del gen de la inmunoglobulina que ocurre en casi todas las neoplasias malignas hematológicas del linaje de las células B, también se presenta en una proporción muy pequeña de células T o las neoplasias mieloides.

Intrachromosomal amplification of chromosome 21 (iAMP21) detected by ETV6/RUNX1 FISH screening in childhood acute lymphoblastic leukemia: a case report

Chromosome abnormalities that usually define high-risk acute lymphoblastic leukemia are the t(9;22)/ breakpoint cluster region protein-Abelson murine leukemia viral oncogene homolog 1, hypodiploid with < 44 chromosomes and 11q23/ myeloid/lymphoid leukemia gene rearrangements. The spectrum of acute lymphoblastic leukemia genetic abnormalities is nevertheless rapidly expanding. Therefore, newly described chromosomal aberrations are likely to have an impact on clinical care in the near future. Recently, the rare intrachromosomal amplification of chromosome 21 started to be considered a high-risk chromosomal abnormality. It occurs in approximately 2-5% of pediatric patients with B-cell precursor acute lymphoblastic leukemia. This abnormality is associated with a poor outcome. Hence, an accurate detection of this abnormality is expected to become very important in the choice of appropriate therapy. In this work the clinical and molecular cytogenetic evaluation by fluorescence in situ hybridization of a child with B-cell precursor acute lymphoblastic leukemia presenting the rare intrachromosomal amplification of chromosome 21 is described.