Perfil clínico-epidemiológico de pacientes pediátricos de um centro de oncohematologia de pernambuco / Clinical-epidemiological profile of pediatric patients at a center of oncohematology in Pernambuco / Perfil clínico-epidemiológico de pacientes pediátricos en un centro de oncohematología de Pernambuco

ntrodução:O câncer infantojuvenil corresponde a um grupo de várias doenças que têm em comum a proliferação descontrolada de células anormais e que pode ocorrer em qualquer local do organismo. Objetivo:Identificar os tipos de neoplasias mais frequentes na infância e adolescência e analisar o perfil clínico-epidemiológicodos pacientes. Metodologia:Estudo de transversal exploratório, de natureza aplicada com análise documental, realizado no Centro de Oncohematologia Pediátrica do Hospital Universitário Oswaldo Cruz, Recife, Pernambuco.Foram incluídos crianças e adolescentes diagnosticados com neoplasia e tratados por terapia antineoplásica.Os critérios de exclusão foram crianças e adolescentes normorreativas e/ou com doenças sistêmicas; prontuários ilegíveis ou com falta de informações clínicas.Resultados:Identificou-se que 54,21% dos pacientes eram dosexo feminino, seguido por 44,86% do sexo masculino.A faixa etária prevalente no estudo foi o de crianças de 5 a 14 anos (54,21%), ainda sobre o perfil dos pacientes, identificou-se que população autodeclarada como negra foi a mais prevalente representando 44,86% do total, seguido dos brancos com 43,93%. O diagnóstico que prevaleceu foi o de Leucemia Linfoide Aguda(23,36%), seguido pela Retinoblastoma (7,48%) e pela Rabdomiossarcoma embrionário (6,54%), e consequentemente o local da neoplasia primária que prevaleceu foi a Medula óssea (27,10%) seguido do olho (10,28%), deste total nota-se que o tratamento antineoplásico mais utilizado foi a quimioterapia (40,19%) seguido da quimioterapia associada à radioterapia(12,15%) e pela quimioterapia associada a cirurgia (10,28%). Conclusões:A leucemia linfoide aguda foi a neoplasia mais frequente na infância e adolescência, com prevalência na idade entre 5 e 14 anos, no sexo feminino e na etnia negra. A terapia antineoplásica mais utilizada foi a quimioterapia, seguida da associação entre quimioterapia e radioterapia (AU).

Introduction:Childhood cancer correspondsto a group of several diseases that have in common the uncontrolled proliferation of abnormal cells and that can occur anywhere in the body. Objective:Identify the most frequent types of neoplasms in childhood and adolescence and analyze the clinical-epidemiological profile of patients. Methodology:Exploratory cross-sectional study, applied in nature with document analysis, carried out at the Pediatric Oncohematology Center of Oswaldo Cruz University, Recife, Pernambuco. Children and adolescents diagnosed with neoplasia and treated with antineoplastic therapy were included. Exclusion criteria were normoreactive children and adolescents and/or with systemic diseases; illegible medical records or lacking clinical information. Results:It was identified that54.21% of the patients were female, followed by 44.86% male. The prevalent age group in the study was children from 5 to 14 years old (54.21%), still regarding the patients'profile , it was identified that the population self-declared as black was the most prevalent, representing 44.86% of the total, followed by of whites with 43.93%. The diagnosis that prevailed was Acute Lymphoid Leukemia (23.36%), followed by Retinoblastoma (7.48%) and Embryonic Rhabdomyosarcoma (6.54%), and consequently,the site of the primary neoplasm that prevailed was Bone marrow (27.10%) followed by the eye (10.28%), of this total it is noted that the most used anticancer treatment was chemotherapy (40.19%) followed by chemotherapy associated with radiotherapy (12.15% ) and chemotherapy associated with surgery (10.28%). Conclusions:Acute lymphoblastic leukemia was the most frequent neoplasm in childhood and adolescence, with a prevalence between 5 and 14 years of age, in females,and black ethnicity. The most used antineoplastic therapy was chemotherapy, followed by the association between chemotherapy and radiotherapy (AU).

ntroducción: El cáncer infantil corresponde a un grupo de varias enfermedades que tienen en común la proliferación descontrolada de células anormales y que pueden presentarse en cualquier parte del cuerpo. Objetivo: Identificar los tipos de neoplasias más frecuentes en la infancia y la adolescencia y analizar el perfil clínico-epidemiológico de los pacientes. Metodología: Estudio transversal exploratorio, aplicado en la naturaleza con análisis de documentos, realizado en el Centro de Oncohematología Pediátrica del Hospital Universitario Oswaldo Cruz, Recife, Pernambuco. Se incluyeron niños y adolescentes con diagnóstico de neoplasia y tratados con terapia antineoplásica. Los criterios de exclusión fueron niños y adolescentes normorreactivos y/o con enfermedades sistémicas; registros médicos ilegibles o carentes de información clínica. Resultados: Se identificó que el 54,21% de los pacientes eran del sexo femenino, seguido del 44,86% del masculino. El grupo etario prevalente en el estudio fueron los niños de 5 a 14 años (54,21%), en cuanto al perfil de los pacientes, se identificó que la población autodeclarada afrodescendiente fue la más prevalente, representando el 44,86% del total, seguido de los blancos con un 43,93%. El diagnóstico que predominó fue Leucemia Linfoide Aguda (23,36%), seguido de Retinoblastoma (7,48%) yRabdomiosarcoma Embrionario (6,54%), y en consecuencia el local de la neoplasia primaria que predominó fue Médula Ósea (27,10%) seguido de ocular (10,28%), de este total se destaca que el tratamiento anticancerígeno más utilizado fue la quimioterapia (40,19%) seguida de la quimioterapia asociada a radioterapia (12,15%) y la quimioterapia asociada a cirugía (10,28%). Conclusiones: La leucemia linfoblástica aguda fue la neoplasia más frecuente en la infancia y la adolescencia, con prevalencia entre los 5 y los 14 años, en el sexo femenino y en la etnia negra. La terapia antineoplásica más utilizada fue la quimioterapia, seguida de la asociación entre quimioterapia y radioterapia (AU).

Desenvolvimento e caracterização de lipossomas peguilados para veiculação de L-asparaginase / Development and characterization of peg-grafted liposomes for lasparaginase encapsulation

A Leucemia Linfoide Aguda (LLA) é um câncer de maior incidência em crianças, e tem a Lasparaginase (ASNase) como fármaco amplamente utilizado no tratamento dos afetados. A ASNase catalisa a hidrólise do aminoácido L-asparagina (Asn), presente na corrente sanguínea, a ausência do aminoácido no meio extracelular leva à morte células leucêmicas, que necessitam deste aminoácido para as funções celulares. Fatores envolvendo a eficiência do tratamento com ASNase como reações adversas e curta meia-vida, principalmente devido ao reconhecimento pelo sistema imune e degradação por proteases, limitam a sua eficácia. A encapsulação da enzima em lipossomas pode conferir proteção à degradação, melhorar seu perfil farmacocinético e diminuir os efeitos adversos, de forma a melhorar o tratamento da LLA sendo este o objetivo desse trabalho. Lipossomas de DOPC (1,2-dioleoil-sn-glicero-3-fosfocolina) e DMPC (1,2-dimiristoil-snglicero-3-fosfocolina) foram desenvolvidos empregando-se o método de hidratação do filme lipídico e diferentes protocolos de preparo contendo ou não diferentes concentrações de 18:0 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polietilenogicol)-2000] (DSPE-PEG). Os lipossomas produzidos foram utilizados para encapsular a ASNase e os sistemas contendo ou não ASNase encapsulada foram caracterizados por espalhamento de luz dinâmico (DLS), potencial zeta, microscopia eletrônica de transmissão (MET) e criomicroscopia de transmissão. Adicionalmente, foram avaliados a taxa de encapsulação e o perfil de permeabilidade das vesículas à L-asparagina. As análises de DLS mostraram que as nanoestruturas formadas empregando-se agitação magnética a partir de sistemas contendo 10% e 20% de DSPE-PEG possuem diâmetro hidrodinâmico menor (~ 25 nm a 60 nm) que os mesmos sistemas sem o fosfolipídio peguilado (~190 nm a 222 nm), demonstrando a relação entre a diminuição do tamanho e o aumento da quantidade de fosfolipídio peguilado e possível formação de estruturas micelares ou bicelares. O emprego de agitação em vórtex para hidratação do filme lipídico, adição do antioxidante -tocoferol e redução da concentração de DSPE-PEG (5% e 10%) levou à formação de sistemas com diâmetro hidrodinâmico maior, sendo esse protocolo e concentrações de PEG definidos como padrão. As análises de MET comprovaram a formação de lipossomas com diâmetro hidrodinâmico semelhante ao observado por DLS; com a utilização da criomicroscopia foi possível observar os lipossomas sem deformações. Os lipossomas de DMPC/DSPE-PEG 10% apresentaram maior permeabilidade à L-asparagina ao longo do tempo e, portanto, poderiam funcionar como nanoreatores, depletando o aminoácido da circulação. Estudos in vitro com células tumorais devem ser realizados e em seguida estudos in vivo, para confirmar este potencial

L-asparaginase (ASNase) is a first-choice drug, combined with other drugs, in therapeutic schemes to treat Acute Lymphoblastic Leukemia (ALL) in children and adolescents. ASNase catalyzes the hydrolysis of L-asparagine (Asn) in the bloodstream; since ALL cells cannot synthesize this amino acid, protein synthesis is impaired leading to leukemic cells death by apoptosis. In spite of its therapeutic importance, treatment with ASNase is associated to side effects, mainly hypersensitivity and immunogenicity. Another drawback refers to degradation by plasma proteases that altogether with immunogenicity shortens the enzyme half-life. Encapsulation of ASNase in liposomes, vesicular nanostructures formed by the self-aggregation of phospholipids, is an attractive alternative that possibly will protect the enzyme from plasma proteases, resulting on better pharmacokinetics profile. In this work, we prepared by thin film hydration liposomal formulations of the phospholipid 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) or 1,2-dimyristoyl-sn-glycero-3- phosphocholine (DMPC) containing or not different concentrations of 18:0 1,2-distearoyl-snglycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG), and encapsulated ASNase by electroporation. The systems containing or not ASNase were analyzed by Dynamic Light Scattering, zeta potential and Electron Microscopy. The encapsulation efficiency and vesicles permeability were also evaluated. According to the DLS analysis, the nanostructures formed by film hydration under magnetic stirring employing 10% or 20% DSPE-PEG presented smaller hydrodynamic diameter (~ 25 nm to 60 nm) than the same systems without the pegylated phospholipid (~ 190 nm to 222 nm), demonstrating the relation between size and the amount of pegylated phospholipid that results in formation of micellar or bicellar structures. The protocol was stabilize by hydration of the lipid film under vortex agitation, addition of the antioxidant - tocopherol and reduction of the concentration of DSPE-PEG (5% and 10%), what altogether led to the formation of nanostructures of higher hydrodynamic diameter and monodisperse systems. TEM analyzes confirmed the formation of liposomes with hydrodynamic diameter similar to that observed by DLS; with the use of cryomicroscopy it was possible to observe the liposomes without deformations. Liposomes of DMPC/DSPE-PEG 10% showed permeability to L-asparagine over time and, therefore, could function as nanoreactors, depleting the circulating amino acid

Análise Técnico-Econômica para a produção de biofármacos de L-asparaginase / Technical-Economic analysis for the production of L-asparaginase biopharmaceuticals

A enzima L-asparaginase é comumente utilizada como biofármaco para o tratamento da Leucemia Linfoblástica Aguda e possui altas taxas de cura com o medicamento disponível no mercado. Atualmente a aquisição deste biofármaco é fruto integral de importação, não sendo realizada produção nacional, muito embora existam grupos de pesquisas nacionais que trabalham em pesquisas e no desenvolvimento de biofármacos alternativos da L-asparaginase. Assim, a presente dissertação tem como objetivo realizar análises técnico-econômicas para avaliar a viabilidade de implementação industrial de bioprocessos para a produção da L-asparaginase do tipo Erwinase PEGuilada e não PEGuilada, que foram previamente desenvolvidos na FCF-USP. As análises técnico-econômicas foram conduzidas por meio do software SuperPro Design® (Intelligen, Inc.) e permitiram adaptar o processo laboratorial para um processo piloto e possibilitaram estimar os valores de custo de produção unitário (Unity Cost of Production - UPC) de US$ 12,37/mg e US$ 3,46/mg para a L-asparaginase monoPEGuilada e nativa obtida por processo similar, respectivamente. O custo unitário de produção para a enzima peguilada foi, portanto, estimado em cerca de 4 vezes o mesmo custo para a produção da enzima peguilada, sendo tal aumento de custo devido às operações de peguilação, já que ambas as plantas foram mantidas nas mesmas dimensões. Ainda, foram obtidos indicadores econômicos, que indicam a atratividade do processo desenvolvido, muito embora tenham sido identificados diversos gargalos de processo e fatores a serem otimizados e melhorados de forma a tornar o processo mais atrativo sob os pontos de vista técnico e econômico. Em uma análise de sensibilidade preliminar um aumento factível da densidade celular já mostra que é possível reduzir em mais de 30% o UPC. De toda forma, ainda que não otimizado, o processo apresentou valores e dados compatíveis com os biofármacos de L-asparaginase já disponíveis no mercado

The enzyme L-asparaginase is commonly used as a biopharmaceutical in the treatment of Acute Lymphoblastic Leukemia, presenting high cure rates with the formulations available on the market. Nowadays, the acquisition of this biopharmaceutical is only from importation, given that there is no national production being carried out, although there are national research groups working on research and development of alternative L-asparaginase biopharmaceuticals. Thus, this project aims at carrying out technical-economic analyzes to evaluate the viability of industrial implementation of bioprocesses for the production of L-asparaginase of the PEGylated and non-PEGylated Erwinase type previously developed at FCF-USP. The technical-economic analyzes, conducted by means of the software SuperPro Design® (Intelligen, Inc.), allowed to adapt the laboratory process to a pilot process and made it possible to estimate the unit cost of production (UPC) values of US $ 12.37 / mg and US $ 3.56 / mg for monoPEGylated L-asparaginase and bare obtained by similar process, respectively. The unit cost of production for the pegylated enzyme was, therefore, estimated at about 4 times the same cost for the production of the pegylated enzyme, such an increase in cost due to pegylation operations, since both plants were maintained in the same dimensions. Moreover, economic indicators were obtained, which indicate the attractiveness of the developed process. However, several process bottlenecks and factors to be optimized and improved were identified to make the process more attractive from the technical and economic point of view. In a preliminary sensitivity analysis, a feasible increase in cell density already shows that it is possible to reduce UPC by more than 30%. Accordingly, although not optimized, the process presented values and data compatible with the L-asparaginase biopharmaceuticals already available on the market

Estudo da estabilidade e peguilação de L-asparaginase em soluções aquosas de líquidos iônicos de imidazólio / Study of the stability and pegylation of L-asparaginase in aqueous imidazole ionic liquid solutions

A enzima L-asparaginase de Escherichia coli (ASNase) é um biofármaco indicado para o tratamento de leucemia linfoblástica aguda, mas que pode causar reações de hipersensibilidade nos pacientes tratados. Na tentativa de amenizar esse efeito, foi desenvolvida a PEG-ASNase (enzima conjugada com polietilenoglicol) que apresenta a vantagem de ser menos imunogênica e ter maior meia-vida biológica. Mais recentemente, novas abordagens têm sido desenvolvidas visando aprimorar os processos de PEGuilação por meio de reações sítio dirigidas, por exemplo N-terminal, a fim de promover maior similaridade lote a lote e controle das características farmacocinéticas e farmacodinâmicas do biofármaco. Porém, existe ainda uma limitação associada à hidrólise do PEG reativo, desta forma surge a necessidade de procurar solventes alternativos para a PEGuilação que permitam manter a estabilidade das proteínas, aumentar o rendimento de PEGuilação e a estabilidade do PEG reativo. Nesse trabalho, líquidos iônicos foram investigados como solventes alternativos para a peguilação N-terminal de PEG-ASNase. Para tal, a estabilidade de ASNase em Lis foi investigada em LIs da família metil-imidazol, analisando a influência do aumento da cadeia alquílica e de diferentes ânions. A estabilidade da ASNase é favorecida quando em contato com Lis relativamente hidrofóbicos ([C2mim]Cl, [C4mim]Cl e [C6mim]Cl), mas sua a atividade é prejudicada quando o LI é muito polar, como o [C4mim][(CH3)2PO4] ou anfifílico como o [C12mim]Cl. Apesar de seu efeito desnaturante, o [C4mim][(CH3)2PO4] resultou no maior rendimento da reação de PEGuilação da ASNase (56%) quando empregado a 75% e a reação realizada em 10 min. O [C4mim]Cl resultou em rendimento semelhante ao tampão fosfato (~ 49%), mas ambos os LIs reduziram a poliPEGuilação. Portanto, os Lis [C4mim]Cl e [C4mim][(CH3)2PO4] fornecem uma alternativa viável à reação de PEGuilação pela redução na formação de espécies poliPEGuiladas, o que facilitaria os processos de purificação e permitiria maior controle lote a lote da reação, bem como pelo aumento do rendimento da reação no caso do [C4mim][(CH3)2PO4]

Escherichia coli L-asparaginase enzyme (ASNase) is a biopharmaceutical indicated for the treatment of acute lymphoblastic leukemia, but may cause hypersensitivity in the patients used. In an attempt to alleviate this effect, PEG-ASNase (polyethylene glycol conjugated enzyme) was developed, which has the advantage of being less immunogenic and having a longer biological half-life. More recently, new approaches have been applied to improve PEGylation processes through targeted sites, for example N-terminal, in order to promote greater similarity to the batch and control of the pharmacokinetic and pharmacodynamic characteristics of the biopharmaceutical. However, there is still a limitation associated with reactive PEG hydrolysis, thus increasing the need to look for alternative PEGylation solvents to maintain protein stability, increase PEGylation yield and use reactive PEG. In this work, ions were investigated as alternative solvents for the N-terminal PEG-ASNase. For example, a stability of ASNase in ILs was investigated in imidazole ILs by analyzing the influence of increased alkyl chain and different anions. ASNase stability is enhanced when in contact with relatively hydrophobic ILs ([C2min]Cl, [C4min]Cl and [C6min]Cl), but its activity is impaired when very polar ILs such as [C4min][(CH3)2PO4] or amphiphilic as [C12mim]Cl. Despite its denaturing effect, [C4min][(CH3)2PO4] resulted in higher yield of ASNase PEGylation reaction (56%) when employed at 75% and reaction performed in 10 min. [C4min]Cl yielded similar phosphate buffer yield (~ 49%), but both ILs reduced polyPEGylation. Therefore, [C4min]Cl and [C4min][(CH3)2PO4] Ils may use a viable alternative to the PEGylation reaction and reduce the formation of polyPEGylated species, or that facilitate purification processes and allow for greater batch use of the solution, as well as increased reaction yield in the case of [C4min][(CH3)2PO4]

Yin-Yang-1 decreases Fas-induced apoptosis in acute lymphoblastic leukemia under hypoxic conditions: its implications in immune evasion / YY1 induce la disminución de la apoptosis a través de Fas en la leucemia linfoblástica aguda en condiciones hipóxicas: implicaciones en la evasión de la respuesta inmunitaria

Abstract Background: Acute lymphoblastic leukemia (ALL) is an aggressive malignant disease with high prevalence in pediatric patients. It has been shown that the downregulation of Fas expression is correlated with an inadequate response in ALL, although these mechanisms are still not well understood. Several reports demonstrated that hypoxia is involved in dysfunctional apoptosis. Yin-Yang-1 (YY1) transcription factor is involved in resistance to apoptosis, tumor progression, and it is increased in different types of cancer, including leukemia. The regulatory mechanism underlying YY1 expression in leukemia is still not understood, but it is known that YY1 negatively regulates Fas expression. The study aimed to evaluate the effect of YY1 on Fas expression under hypoxic conditions in ALL. Methods: Leukemia cell line RS4; 11 was cultured under normoxic and hypoxic conditions. YY1, Fas receptor, and hypoxia-inducible factor (HIF-1α) expression were analyzed. After treatment with a Fas agonist (DX2), apoptosis was analyzed through the detection of active caspase 3. Data were analyzed using Pearson’s correlation. Results: Leukemia cells co-expressed both HIF-1α and YY1 under hypoxia, which correlated with a downregulation of Fas expression. During hypoxia, the levels of apoptosis diminished after DX2 treatment. The analysis revealed that patients with high levels of HIF-1α also express high levels of YY1 and low levels of Fas. Conclusions: These results suggest that YY1 negatively regulates the expression of the Fas receptor, which could be involved in the escape of leukemic cells from the immune response contributing to the ALL pathogenesis.

Resumen Introducción: La leucemia linfoblástica aguda (LLA) es una enfermedad con alta prevalencia en la población pediátrica. El mecanismo por el cual el receptor de Fas participa en la regulación inmunitaria en los tumores es desconocido, pero se sabe que está subexpresado en LLA. El factor de transcripción Ying-Yang-1 (YY1) está involucrado en la resistencia a la apoptosis y la progresión tumoral; se encuentra aumentado en diferentes tumores, incluida la LLA. Aunque los mecanismos que regulan la expresión de YY1 en LLA son desconocidos, se sabe que YY1 regula la expresión del receptor de Fas. El objetivo de este trabajo fue evaluar el efecto de YY1 en la expresión de Fas en condiciones de hipoxia en la LLA. Métodos: Se cultivaron células RS4;11 en condiciones de hipoxia y se analizó la expresión de YY1, receptor de Fas y HIF-1α. La apoptosis fue inducida usando un agonista de Fas (DX2) y se analizó con la detección de caspasa 3 activa. Los datos se analizaron mediante correlación de Pearson. Resultados: Las células RS4;11 coexpresaron HIF-1αy YY1 en hipoxia, lo cual correlaciona con una baja expresión de Fas. La apoptosis se encontró disminuida durante condiciones de hipoxia, después del tratamiento con DX2. El análisis bioinformático mostró que los pacientes con altos niveles de HIF-1αpresentan YY1 elevado y bajos niveles del receptor de Fas. Conclusiones: Estos resultados sugieren que YY1 regula negativamente la expresión del receptor de Fas, lo cual podría estar involucrado en el escape de las células leucémicas a la respuesta inmunitaria, contribuyendo a la patogénesis de la LLA.

Retrospective evaluation and prediction of clearance and toxicity of high dose methotrexate in childhood acute lymphoblastic leukemia patients

To find the predictors of High Dose Methotrexate toxicities in childhood Acute Lymphoblastic Leukemia Patients. This study included 198 Childhood Acute Lymphoblastic Leukemia patients (303 infusions) who were treated with High Dose Methotrexate. Methotrexate levels at different time point were measured by modified enzyme multiplied immunoassay technique assay. The correlation between Methotrexate levels and toxicity was evaluated by Receiver Operating Characteristic curve. When the Methotrexate level at 42 h was lower than 0.76 µmol/L, the sensitivity for predicting thorough clearance at 66 h was 90.78%. When the Methotrexate level at 42 h was higher than1.5 µmol/L, the sensitivity for predicting delayed clearance was 82.17%. When the Methotrexate level at 66 h was higher than 0.5 µmol/L, the sensitivity for predicting Methotrexate toxicity was 89.09%. When the Methotrexate level at 66 h was lower than 0.1 µmol/L, the sensitivity for predicting Methotrexate nontoxicity was 92.73%. The Methotrexate level at 42 h could be predictor for delayed clearance. The Methotrexate level at 66 h could be predictor for toxicity.

Leucemia linfoblástica aguda en niños con síndrome de Down: análisis comparativo con pacientes sin síndrome de Down / Acute lymphoblastic leukemia in children with Down syndrome: Comparative analysis versus patients without Down syndrome

Introducción: Los niños con síndrome de Down (SD) tienen mayor frecuencia de leucemia linfoblástica aguda (LLA) y menor supervivencia que pacientes sin síndrome de Down (NSD). Analizamos las características clínicas, demográficas-biológicas y respuestas al tratamiento en SD-LLA versus NSD-LLA. Pacientes y métodos: Pacientes (0-19 años) con LLA desde enero de 1990 a noviembre de 2016. Se compararon características demográficas biológicas y respuestas al tratamiento con chi cuadrado y Wilcoxon rank sum. La supervivencia global y el intervalo libre de eventos (ILE) se analizaron con Kaplan-Meier y el test log-rank. Resultados: Se incluyeron 1795 pacientes, 54 con SD. Los SD-LLA presentaron edad mayor (p= 0,0189). T odos inmuno fenotipo precursor-B, con menor incidencia de anomalías recurrentes (p < 0,0001). Demostraron mejor tasa de respuesta a prednisona (p= 0,09) y mayor mortalidad en inducción y remisión completa (p < 0,0001). Todas las muertes de los SD-LLA fueron relacionadas con el tratamiento. La sobrevida libre de eventos en niños SD-LLA vs.NSD-LLA fue 47 (± 8)% vs. 73 (± 1)% (p= 0,006) y el ILE de los SD-LLA vs. NSD-LLA fue 54 (± 9)% vs. 75 (± 1)% (p= 0,0297). La tasa de recaídas fue similar en ambos grupos (p= 0,6894). El ILE de los SD-LLA fue menor en el grupo de 6-9 años: 39 (± 19)% (p= 0,7885). Conclusiones: Los niños de 6-9 años con SD-LLA años presentó menor sobrevida. Aunque estos niños presentaron una mejor respuesta temprana, la sobrevida libre de eventos e ILE fueron menores debido a la mortalidad relacionada con el tratamiento.

Introduction. Children with Down syndrome (DS) more commonly have acute lymphoblastic leukemia (ALL) and a lower survival rate than those without Down syndrome (WDS). We analyzed the clinical, demographic, and biological characteristics and treatment response of children with DS-ALL versus those WDS-ALL. Patients and methods: Patients with ALL between January 1990 and November 2016. The demographic and biologic characteristics and treatment response were compared using the χ² and Wilcoxon rank-sum tests. The overall survival and event-free interval (EFI) were analyzed using the Kaplan-Meier and log-rank tests. Results. 1795 patients were included; 54 had DS. Patients with DS-ALL were older (p= 0.0189). All had B-cell precursor immunophenotype and a lower incidence of recurrent abnormalities (p < 0.0001). They showed a better response rate to prednisone (p= 0.09) and a higher mortality in induction and complete remission (p < 0.0001). All deaths of patients with DS-ALL were treatment-related. The event-free survival (EFS) was 47% (± 8%) versus 73% (± 1%) (p= 0.006) and the EFI was 54% (± 9%) versus 75% (± 1%) (p= 0.0297) among patients with DS-ALL versus those WDS-ALL, respectively. The rate of relapse was similar in both groups (p= 0.6894). The EFI of patients with DS-ALL was lower in the group aged 6-9 years: 39% (± 19%) (p= 0.7885). Conclusions. A lower survival was observed among children aged 6-9 years with DS-ALL. Although these children showed a better early response, their EFS and EFI were lower due to treatment-related mortality.

Sinusitis aguda invasiva por Exserohilum rostratum en una paciente pediátrica con recaída medular de leucemia linfoblástica aguda / Invasive acute sinusitis by Exserohilum rostratum in a patient with medullary relapse of acute lymphoblastic leukemia

La infección fúngica invasora ha aumentado en frecuencia a lo largo de la última década, y la sinusitis fúngica es cada vez más habitual. Los hongos del género Exserohilum (familia Pleosporaceae, orden Pleosporales) son filamentosos y dematiáceos, de localización ubicua. Se trata de patógenos emergentes, que producen, en la mayoría de los casos, infecciones sistémicas que afectan, principalmente, a los senos paranasales y los pulmones. Son más frecuentes en pacientes inmunosuprimidos, aunque pueden presentarse en pacientes inmunocompetentes. El tratamiento de estas infecciones comprende el tratamiento antifúngico, resección quirúrgica y restitución de la inmunidad. Se presenta el caso de una paciente con recaída medular de leucemia linfoblástica aguda con sinusitis fúngica invasiva por Exserohilum rostratum.

Invasive fungal infection has increased in frequency over the last decade, with fungal sinusitis becoming more frequent. The fungi of the genus Exserohilum (family Pleosporaceae, order Pleosporales) are filamentous and dematiaceous of ubiquitous location. It is an emerging pathogen, which in most cases produces a systemic infection that mainly affects the paranasal sinuses and lungs. It is more common in immunosuppressed patients, although it may occur in immunocompetent patients. The treatment is based on three pillars: antifungal treatment, surgical debridement and restitution of immunity. We present the case of a patient with medullary relapse of acute lymphoblastic leukemia with invasive fungal sinusitis by Exserohilum rostratum.

Omics techniques and biobanks to find new biomarkers for the early detection of acute lymphoblastic leukemia in middle-income countries: a perspective from Mexico / Técnicas ómicas y biobancos para el hallazgo de nuevos biomarcadores para la detección temprana de leucemia linfoblástica aguda en países de ingresos medios: una perspectiva mexicana

Abstract: Acute lymphoblastic leukemia (ALL) affects the quality of life of many children in the world and particularly in Mexico, where a high incidence has been reported. With a proper financial investment and with well-organized institutions caring for those patients, together with solid platforms to perform high-throughput analyses, we propose the creation of a Mexican repository system of serum and cells from bone marrow and blood samples derived from tissues of pediatric patients with ALL diagnosis. This resource, in combination with omics technologies, particularly proteomics and metabolomics, would allow longitudinal studies, offering an opportunity to design and apply personalized ALL treatments. Importantly, it would accelerate the development of translational science and will lead us to further discoveries, including the identification of new biomarkers for the early detection of leukemia.

Resumen: La leucemia linfoblástica aguda (LLA) afecta la calidad de vida de una gran cantidad de individuos en edad pediátrica en todo el mundo; particularmente en México, donde se ha reportado una alta incidencia. Con un apropiado fondo de inversión financiera, así como instituciones adecuadamente organizadas al cuidado de los pacientes con LLA, en conjunto con plataformas sólidas para llevar a cabo análisis globales y de alto rendimiento, se propone la creación de un repositorio para la conservación de suero y células provenientes de médula ósea y sangre derivadas de pacientes pediátricos con LLA al diagnóstico. Estos recursos, en combinación con las tecnologías ómicas, en particular la proteómica y la metabolómica, podrían permitir el establecimiento de estudios longitudinales y ofrecer una oportunidad para el diseño y aplicación de tratamientos personalizados para la LLA. Esta estrategia permitiría acelerar el desarrollo de la ciencia traslacional, favoreciendo el hallazgo de importantes descubrimientos, incluyendo la identificación de nuevos biomarcadores para la detección temprana de la leucemia.

Leucemia linfoblástica aguda infantil: una aproximación genómica / Acute lymphoblastic leukemia: a genomic perspective

Resumen: En paralelo al proyecto de la secuenciación del genoma humano, se han desarrollado varias plataformas tecnológicas que están permitiendo ganar conocimiento sobre la estructura del genoma de las entidades humanas, así como evaluar su utilidad en el abordaje clínico del paciente. En la leucemia linfoblástica aguda (LLA), el cáncer infantil más común, las herramientas genómicas prometen ser útiles para detectar a los pacientes con alto riesgo de recaída, ya sea al diagnóstico o durante el tratamiento (enfermedad mínima residual), además de que permiten identificar los casos en riesgo de presentar reacciones adversas a los tratamientos antineoplásicos y ofrecer una medicina personalizada con esquemas terapéuticos diseñados a la medida del paciente. Un ejemplo claro de esto último es la identificación de polimorfismos de un solo nucleótido (SNPs) en el gen de la tiopurina metil transferasa (TPMT), donde la presencia de dos alelos nulos (homocigotos o heterocigotos compuestos) indica la necesidad de reducir la dosis de la mercaptopurina hasta en un 90% para evitar efectos tóxicos que pueden conducir a la muerte del paciente. En esta revisión se proporciona una visión global de la genómica de la LLA, describiendo algunas estrategias que contribuyen a la identificación de biomarcadores con potencial utilidad en la práctica clínica.

Abstract: In parallel to the human genome sequencing project, several technological platforms have been developed that let us gain insight into the genome structure of human entities, as well as evaluate their usefulness in the clinical approach of the patient. Thus, in acute lymphoblastic leukemia (ALL), the most common pediatric malignancy, genomic tools promise to be useful to detect patients at high risk of relapse, either at diagnosis or during treatment (minimal residual disease), and they also increase the possibility to identify cases at risk of adverse reactions to chemotherapy. Therefore, the physician could offer patient-tailored therapeutic schemes. A clear example of the useful genomic tools is the identification of single nucleotide polymorphisms (SNPs) in the thiopurine methyl transferase (TPMT) gene, where the presence of two null alleles (homozygous or compound heterozygous) indicates the need to reduce the dose of mercaptopurine by up to 90% to avoid toxic effects which could lead to the death of the patient. In this review, we provide an overview of the genomic perspective of ALL, describing some strategies that contribute to the identification of biomarkers with potential clinical application.

Minimal residual disease detection in Tunisian B-acute lymphoblastic leukemia based on immunoglobulin gene rearrangements

IGH gene rearrangement and IGK-Kde gene deletion can be used as molecular markers for the assessment of B lineage acute lymphoblastic leukemia (B-ALL). Minimal residual disease detected based on those markers is currently the most reliable prognosis factor in B-ALL. The aim of this study was to use clonal IGH/IGK-Kde gene rearrangements to confirm B-ALL diagnosis and to evaluate the treatment outcome of Tunisian leukemic patients by monitoring the minimal residual disease (MRD) after induction chemotherapy. Seventeen consecutive newly diagnosed B-ALL patients were investigated by multiplex PCR assay and real time quantitative PCR according to BIOMED 2 conditions. The vast majority of clonal VH-JH rearrangements included VH3 gene. For IGK deletion, clonal VK1f/6-Kde recombinations were mainly identified. These rearrangements were quantified to follow-up seven B-ALL after induction using patient-specific ASO. Four patients had an undetectable level of MRD with a sensitivity of up to 10-5. This molecular approach allowed identification of prognosis risk group and adequate therapeutic decision. The IGK-Kde and IGH gene rearrangements might be used for diagnosis and MRD monitoring of B-ALL, introduced for the first time in Tunisian laboratories.

Acute lymphoblastic leukemia presenting with bilateral serous macular detachment / Leucemia linfoblástica aguda com descolamento macular seroso bilateral

ABSTRACT Acute lymphoblastic leukemia is a malignant hematopoietic neoplasia, which is rare in adults. Although ocular fundus alterations may be commonly observed in the course of the disease, such alterations are rarely the presenting signs of the disease. Here we describe the case of a patient with painless and progressive loss of visual acuity (right eye, 2/10; left eye, 3/10) developing over two weeks, accompanied by fever and cervical lymphadenopathy. Fundus examination showed bilateral macular serous detachment, which was confirmed by optical coherence tomography. Fluorescein angiography revealed hyperfluorescent pinpoints in the posterior poles. The limits of the macular detachment were revealed in the late phase of the angiogram. The results of blood count analysis triggered a thorough, systematic patient examination. The diagnosis of acute lymphoblastic leukemia B (CD10+) was established, and intensive systemic chemotherapy was immediately initiated. One year after the diagnosis, the patient remains in complete remission without any ophthalmologic alterations.

RESUMO A leucemia linfoblástica aguda é uma neoplasia maligna das células hematopoiéticas, incomum em adultos. Apesar da maioria dos casos apresentar alterações no fundo ocular no decurso da doença, estas são raramente forma de apresentação da mesma. Descreve-se o caso de uma doente com diminuição progressiva e indolor da acuidade visual (OD 2/10 e OE 3/10), que apresentava concomitantemente febre e adenopatias cervicais, com duas semanas de evolução. À oftalmoscopia apresentava descolamento seroso macular bilateral, confirmado por tomografia de coerência ótica. A angiografia fluoresceínica revelou pequenas lesões hiperfluorescentes tipo pinpoints no polo posterior. Nos tempos médios e tardios do exame adivinham-se os limites da bolsa do descolamento do neuroepitélio. As alterações encontradas no hemograma suscitaram um estudo sistêmico extenso. O diagnóstico de leucemia linfoblástica aguda B (CD10+) foi efetuado, iniciando-se, de imediato, quimioterapia sistêmica intensiva. Um ano após o diagnóstico a doente continua em remissão e sem alterações oftalmológicas de novo.

Relationship between complaints presented by emergency patients and the final outcome / Relação entre queixas apresentadas por pacientes na urgência e o desfecho final / Relación entre las quejas presentadas por pacientes en la urgencia y el desenlace final

AbstractObjective: to relate complaints presented by emergency room patients, classified using the Manchester Triage System, with the final outcome (discharge/death/transfer).Methods: prospective cohort study, involving 509 patients who were admitted to the emergency room and remained there for more than 24 hours after admission, being monitored to the final outcome. Data were analyzed with a statistical program using descriptive and analytical statistics.Results: the mean age of the patients was 59.1 years and 59.3% were male. The main complaints were unwell adult (130 - 22.5%), shortness of breath in adults (81 - 14.0%), abdominal pain in adults (58 - 10.0%) and behaving strangely (34 - 5.9%), with 87% of the patients being discharged. More deaths were found in the patients classified in the severe colors, with 42.8% classified as red, 17.0% as orange and 8.9% as yellow. Among the patients classified as green, 9.6% died.Conclusion: in the various colors of the Manchester Triage System, death prevailed in patients that presented the complaints of unwell adult, shortness of breath, head injury, major trauma, diarrhea and vomiting. The higher the clinical priority the greater the prevalence of death.

ResumoObjetivo:relacionar queixas apresentadas pelos pacientes classificados pelo Sistema de Triagem de Manchester em um pronto-socorro com o desfecho final (alta/óbito/transferência).Métodos:estudo de coorte prospectivo, realizado com 509 pacientes que deram entrada no pronto-socorro e que nele permaneceram por mais de 24 horas após a admissão, sendo acompanhados até o desfecho final. Os dados foram digitados e analisados com estatística descritiva e analítica em um pacote estatístico.Resultados:entre os pacientes, 59,3% eram do sexo masculino, com idade média de 59,1 anos. As queixas principais eram de mal-estar no adulto (130-22,5%), dispneia em adulto (81-14,0%), dor abdominal em adulto (58-10,0%), alterações de comportamento (34-5,9%), sendo que, desses, 87% recebeu alta. Foram encontrados mais óbitos nos pacientes classificados nas cores mais graves, sendo 42,8% classificados como vermelho, 17,0% laranja e 8,9% como amarelo. Entre os pacientes classificados como verde, 9,6% evoluiu para óbito.Conclusão:nas diversas cores do Sistema de Triagem Manchester, o óbito prevaleceu nos pacientes que apresentaram a queixa de mal-estar no adulto, dispneia, sofreram trauma craniano, trauma maior, diarreia e vômito. Quanto maior a prioridade clínica maior a prevalência de óbito.

ResumenObjetivo:relacionar las quejas presentadas por los pacientes clasificados por el Sistema de Clasificación de Manchester, en un servicio de urgencia, con el desenlace final (alta/muerte/ transferencia).Métodos:estudio de cohorte prospectiva, realizado con 509 pacientes que dieron entrada en el servicio de urgencia y que en él permanecieron por más de 24 horas después de la admisión, siendo seguidos hasta el desenlace final. Los datos fueron introducidos y analizados con estadística descriptiva y analítica, en un programa estadístico.Resultados:entre los pacientes, 59,3% eran del sexo masculino, con edad promedio de 59,1 años. Las quejas principales eran de malestar en adulto (130-22,5%), disnea en adulto (81-14,0%), dolor abdominal en adulto (58- 10,0%), alteraciones de comportamiento (34-5,9%), siendo que, de estos, 87% recibió alta. Fueron encontradas más muertes entre los pacientes clasificados con los colores más graves, siendo 42,8% clasificados como rojo, 17,0% naranja y 8,9% como amarillo. Entre los pacientes clasificados como verde, 9,6% evolucionó para la muerte.Conclusión:en los diversos colores del Sistema de Clasificación Manchester, la muerte prevaleció en los pacientes que presentaron la queja de malestar en adulto, disnea, sufrieron trauma craniano, trauma mayor, diarrea y vómito. Cuanto mayor es la prioridad clínica mayor es la prevalencia de la muerte.

Leucemia linfoblástica aguda em lactentes: 20 anos de experiência / Acute lymphoblastic leukemia in infants: 20 years of experience

OBJETIVO: Analisar pacientes com menos de dois anos de idade com leucemia linfoblástica aguda atendidos no período de 1990 a 2010, em um centro de referência estadual. MÉTODOS: Estudo clínico, epidemiológico, transversal, descritivo e observacional. Pacientes incluídos tinham menos de dois anos de idade, com leucemia linfoblástica aguda, tratados no período de 1990 a 2010 na unidade de oncologia pediátrica de um centro de referência estadual, totalizando 41 casos. RESULTADOS: Todos os pacientes eram Caucasianos e 60,9% eram do sexo feminino. Com relação à idade, 24,38% tinham menos de seis meses, 17,07% tinham entre seis meses e um ano e 58,53% mais do que um ano de idade. A idade de seis meses foi estatisticamente significante para o desfecho de óbito. Os sinais e sintomas predominantes foram febre, hematomas e petéquias. Uma contagem de leucócitos superior a 100.000 foi observada em 34,14% dos casos; hemoglobina inferior a 11 em 95,13% e contagem de plaquetas inferior a 100.000, em 75,61% dos casos. Infiltração do sistema nervoso central estava presente em 12,91% dos pacientes. Em relação à linhagem, a linhagem B predominou (73%), mas a linhagem de células T foi estatisticamente significativa para o óbito. Trinta e nove por cento dos pacientes tiveram recorrência da doença. Em relação ao estado vital, 70,73% dos pacientes morreram, sendo choque séptico a principal causa. CONCLUSÕES: leucemia linfoblástica aguda em crianças tem uma alta taxa de mortalidade, principalmente em crianças menores de um ano e linhagem derivada de células T.

OBJECTIVE: To analyze patients younger than 2 years with acute lymphoblastic leukemia, treated in the period between 1990 and 2010 in a state reference center. METHODS: This was a clinical-epidemiological, cross-sectional, observational, and descriptive study. It included patients younger than 2 years with acute lymphoblastic leukemia, treated in the period of 1990 to 2010 in a pediatric oncology unit of a state reference center, totaling 41 cases. RESULTS: All patients were white ethnicity, and 60.9% were females. Regarding age, 24.38% were younger than 6 months, 17.07% were between 6 months and 1 year, and 58.53% were older than 1 year. The age of 6 months was statistically significant for the outcome of death. Predominant signs and symptoms were fever, bruising, and petechiae. A leukocyte count > 100,000 was found in 34.14% of cases, hemoglobin count < 11 in 95.13%, and platelet count < 100,000 in 75.61. Infiltration of central nervous system was present in 12.91% of patients. According to the lineage, B-cell lineage predominated (73%), but the T-cell line was statistically significant for death. 39% of patients had disease recurrence. In relation to vital status, 70.73% of the patients died; septic shock was the main cause. CONCLUSIONS: Acute lymphoblastic leukemia in infants has a high mortality rate, especially in children under 1 year and those with T-cell derived lineage.

Factors Related to Decreased Bone Mineral Density in Childhood Cancer Survivors

The risk of osteoporosis or osteopenia is known to increase after childhood cancer treatment. The purpose of this study was to evaluate patterns of bone mineral density (BMD) and to identify factors related to the decreased BMD in childhood cancer survivors. We studied 78 patients (34 boys, 44 girls) treated for childhood cancer. Twenty (25.7%) patients had lumbar BMD (LBMD) standard deviation score (SDS) lower than -2. Nineteen (24.4%) patients had femur neck BMD (FNBMD) SDS lower than -2. The patients treated with hematopoietic stem cell transplantation had lower LBMD SDS (-1.17 +/- 1.39 vs -0.43 +/- 1.33, P = 0.025). The risk of having LBMD SDS < -2 was higher in the patients treated with glucocorticoid (GC) for graft-versus-host disease (GVHD) (36.6% vs 13.5%; odds ratio [OR], 3.7; P = 0.020). In multivariate logistic regression analysis, longer duration of GC treatment for GVHD (OR, 1.12; 95% confidence interval [CI], 1.05-1.20) and lower body mass index (BMI) SDS (OR, 0.59; 95% CI, 0.36-0.95) were associated with decreased LBMD SDS. These findings suggest that prolonged GC use and reduction in BMI are risk factors for decreased BMD in childhood cancer survivors. Anticipatory follow-up and appropriate treatment are necessary, especially for the patients with risk factors.

Isolated relapse in the oral cavity of a child with t-lineage acute lymphoblastic leukemia

Despite high cure rates, approximately 20% of patients with acute lymphoblastic leukemia (ALL) have disease relapse. Isolated recurrence in oral cavity is extremely unusual. The aim of this paper is to report a case of an isolated relapse occurred in a child with T-lineage ALL. Clinical picture included swelling and pain in the right upper gingiva of the oral cavity, with no other clinical or hematological alterations. Diagnosis was confirmed by biopsy and immunohistochemical staining. Bone marrow aspiration was normal. Five months later leukemic infiltration of the bone marrow was detected and systemic chemotherapy was reintroduced. This case report highlights the relevance of dental care during and after chemotherapy, not only to treat lesions in the oral cavity resulting from the disease itself or from treatment side effects, but also to detect unusual sites of ALL relapse.

Apesar dos altos índices de cura, cerca de 20% dos pacientes com leucemia linfóide aguda (LLA) apresentam recidiva da doença. Recidiva isolada na cavidade oral é extremamente incomum. O objetivo deste trabalho é relatar um caso de recidiva isolada em criança com LLA de linhagem T. A apresentação clínica foi quadro de edema e dor na cavidade oral, na região superior da gengiva à direita, sem outras alterações clínicas ou hematológicas. O diagnóstico foi confirmado por meio de biópsia e imuno-histoquímica. O mielograma era normal. Cinco meses após a manifestação inicial na cavidade oral, foi detectada infiltração leucêmica na medula óssea. O tratamento com quimioterapia sistêmica foi reintroduzido. Este relato de caso ressalta a importância do acompanhamento clínico e odontológico durante e após o tratamento quimioterápico, não somente com o objetivo de tratar as alterações na cavidade oral decorrentes da própria doença ou dos efeitos adversos do tratamento, mas para que sejam detectadas apresentações incomuns de recidiva na LLA.

Overt testicular disease at diagnosis in childhood acute lymphoblastic leukemia: Prognostic significance and role of testicular irradiation.

Objective. To analyze the prognostic impact of overt testicular disease (OTD) at diagnosis and role of testicular irradiation in the same. Methods. Data of 579 boys treated at our center over 16 years was reviewed. Results. Fourteen (2.4%) males had OTD. 10 (71.4%) of these had high-risk disease. Patients with OTD, had a significantly higher incidence of mediastinal-adenopathy (p=0.001), hyperleucocytosis (p=0.004) and CNS disease at presentation (p<0.0001) compared to patients in continuous complete remission (CCR). 4 of the 11 patients with OTD, who opted for therapy, had relapse; 2 are in CCR. Although, survival in patients with OTD was inferior (p=0.183) compared to patients without OTD, it was not an independent prognostic factor (p=0.47). In the entire study cohort, symptom-diagnosis interval (p=0.006), white cell (p=0.001) and platelet count (p=0.001) at presentation were significantly associated with survival (Cox multivariate regression analysis). Conclusions. OTD was not an independent prognostic factor, despite association with high-risk features. Survival outcome was inferior. The observations indicate the need of revaluation of the present protocol with incorporation of intermediate dose and subsequently high-dose methotrexate (after assessment for toxicity and tolerance), risk-stratified therapy and plausibly omission of testicular irradiation.

Leucemia linfoblástica aguda: evaluación clínico terapéutica del protocolo total XV modificado: Hospital Universitario de Caracas 2003-2007: [revisión] / Acute lymphoblastic leukemia: clinical and therapeutic evaluation of the XV total protocol: Hospital Universitario of Caracas 2003-2007: [review]

La leucemia linfoblástica aguda (LLA) se caracteriza por la proliferación clonal y acumulación de células linfoides malignas en médula ósea y en sangre periférica. Identificar los aspectos clínico-hematológicos, evolución terapéutica y morbimortalidad en niños con LLA de novo tratados con el Protocolo Total XV modificado, en el Servicio de Hematología del Hospital Universitario de Caracas (HUC) entre 2003-2007. Estudio clínico-epidemiológico, descriptivo y retrospectivo mediante la revisión de historias clínicas de pacientes menores de18 años. Los síntomas clínicos al diagnóstico fueron hipertermia, astenia, cefalea, hiporexia, sangrado y dolor óseo; los signos: adenopatías, hepatoesplenomegalia y fiebre; mayor prevalencia en el género masculino: 64,7% y entre 1 a 10 años (67,7%). La mayoría presentó anemia, leucocitosis y trombocitopenia. La infiltración del SNC fue del 5,9%. Se obtuvo un 79,4% de remisión completa (RC)en la fase de inducción, la morbilidad principal fue por neutropenia febril y 8,7% de mortalidad. En la fase de consolidación, se mantuvo la tasa de RC (79,9%), la morbilidad fue por hepatotoxicidad y 6,8% de mortalidad. En la fase de mantenimiento, se mantuvo la tasa de RC 80% pero se presentó un 11,6% de recaídas, mayor morbilidad infecciosa y 19,2% de mortalidad. La sobrevida global (SG) y la sobrevida libre de enfermedad (SLE) con una mediana de seguimiento de 24 meses, fue: 57% y 18,8%, respectivamente. La estrategia para adaptar el Protocolo Total XV modificado en el Servicio de Hematología, no fue efectiva para mejorar la SG ni SLE al compararlo con la literatura internacional.

Acute lymphoblastic leukemia (ALL) is characterized by clonal proliferation and accumulation of malignant lymphoidcells in bone marrow and peripheral blood. To identify clinical and hematological aspects, therapeutic outcome and morbid mortality in children with de novo ALL treated with the modified Total Protocol XV, in the Department of Hematology, Hospital Universitario de Caracas (HUC) between 2003-2007. Clinical and epidemiological, descriptive, retrospective study by reviewing medical records of patients under 18 years. Clinical symptoms at diagnosis were hyperthermia, fatigue, headache, anorexia, bleeding and bone pain. Signs were lymphadenopathy, hepatosplenomegaly and fever, more prevalent in male 64.7% and in patients between 1 and 10 years (67.7 %). Mosthad anemia, leukocytosis and thrombocytopenia. CNS infiltration was present in 5.9%. We obtained a 79.4% complete remission (CR) in the induction phase, the major morbidity was febrile neutropenia and 8.7% mortality. In the consolidation phase, CR rate remained thesame (79.9%), morbidity was 6.8% for hepatotoxicity and mortality. In the maintenance phase, CR rate was 80% but there was an 11.6% relapse, and the infectious morbidity and mortality rate increased to 19.2%. Overall survival (OS) and disease-free survival (DFS) with a median follow-up of 24 months was 57% and 18.8% respectively. The strategy to adapt the Total Protocol XV modified in the Hematology Department was not effective in improving the OS and SLE when compared with international literature.

Acute Lymphoblastic Leukemia Presented as Multiple Breast Masses

Breast metastases in cases leukemia are very rare and occur primarily in patients with acute myeloid leukemia. We report the involvement of breast metastases in a 30-year-old woman with acute T cell lymphoblastic leukemia. The patient's mammograms revealed an extremely dense pattern with ill-defined, denser mass-like lesions in both breasts. A bilateral breast ultrasonographic evaluation revealed lobular-shaped and partly ill-defined hypoechoic masses with a multi-septated nodular (mottled) appearance.