Neurotoxicidad subaguda por metotrexato en pacientes con enfermedad oncohematológica. Reporte de tres casos / Subacute methotrexate neurotoxicity in patients with oncohematological disease. A report of 3 cases

El metotrexato es un fármaco análogo del ácido fólico ampliamente utilizado en el tratamiento de enfermedades autoinmunes, leucemias y linfomas. Su uso puede ocasionar la aparición de múltiples efectos adversos entre los que se encuentran aquellos relacionados con la presencia de toxicidad neurológica, que puede presentarse de forma aguda, subaguda o crónica. La neurotoxicidad subaguda es aquella que ocurre típicamente entre los 2 y los 14 días posteriores a la administración y puede manifestarse con una amplia gama de síntomas neurológicos. En la mayoría de los casos, no recurre con futuras exposiciones al medicamento. Presentamos tres casos de neurotoxicidad subaguda por metotrexato con manifestaciones clínicas diferentes en pacientes oncohematológicos que se internaron entre los años 2018 y 2020. Dos de ellos presentaron recurrencia frente a la nueva administración del fármaco y todos evidenciaron lesiones en resonancia magnética nuclear.

Methotrexate is a folic acid analogue widely used in the treatment of autoimmune diseases, leukemias, and lymphomas. Methotrexate use may cause multiple adverse effects, including those related to the presence of neurological toxicity, which may be acute, subacute, or chronic. Subacute neurotoxicity typically occurs between 2 and 14 days after administration and may present as a wide range of neurological symptoms. In most cases, it does not recur with future exposures to the drug. Here we describe 3 cases of subacute methotrexate neurotoxicity with different clinical manifestations in patients with oncohematological disease who were hospitalized between 2018 and 2020. Two of them showed recurrence with a new drug administration. Lesions were observed in the magnetic resonance imaging tests of all of them.

Protective effect of linoleic acid on liver toxicity induced by methotrexate / Efecto protector del ácido linoleico sobre la toxicidad hepática inducida por metotrexato

SUMMARY: We aimed to investigate the protective effect of linoleic acid on liver toxicity induced by methotrexate. The study was carried out in partnership with the Department of Anatomy and Department of Medical Pharmacology of Çukurova University Faculty of Medicine, using the laboratory facilities of the Department of Medical Pharmacology. Human hepatocyte cell line (CRL- 11233) cells obtained from the American Type Culture Collection Organization (ATCC) were used. Expressions of apoptotic pathway markers, apoptosis inducing factor (AIF), BAX, BCL 2, GADD 153, 78-kDa glucose-regulated protein (GRP78), and CASPASE-3 were evaluated. All analyzes were examined in four groups (Group 1; control, Group 2; linoleic acid given, Group 3; methotrexate given and Group 4; linoleic acid and methotrexate given). The mean ± standard error values of the obtained results as nanogram / milliliter (ng / ml) are in Group I, Group II, Group III and Group IV, respectively; AIF values, 0.4150 ± 0.1208, 0.3633 ± 0.2389, 1.792 ± 0.3611 and 1.077 ± 0.1646, BAX values, 0.900 ± 0.1864, 1.002 ± 0.2098, 8.352 ± 1.467 and 4.295 ± 1.522, BCL 2 values, 13.93 ± 1.198, 13.92 ± 1.739, 2.938 ± 1.059 and 9.250 ± 1.492, GADD 153, 0.7333 ± 0.1751, 0.7067 ± 0.2115, 1.650 ± 0.2950 and 1.237 ± 0.1805, GRP78, 0.4767 ± 0.1804, 0.5233 ± 0.1590, 2.183 ± 0.2639 and 1.112 ± 0.2693, CASPASE-3 values , 1.127 ± 0.2033, 0.8317 ± 0.3392, 13.50 ± 1.871 and 8.183 ± 1.030. It was determined that linoleic acid has a protective effect on methotrexate-induced liver toxicity.

Nuestro objetivo fue investigar el efecto protector del ácido linoleico sobre la toxicidad hepática inducida por metotrexato. El estudio se llevó a cabo en colaboración con el Departamento de Anatomía y el Departamento de Farmacología Médica de la Facultad de Medicina de la Universidad de Çukurova, utilizando las instalaciones del laboratorio del Departamento de Farmacología Médica. Se usaron células de la línea celular de hepatocitos humanos (CRL-11233) obtenidas de la American Type Culture Collection Organisation (ATCC). Se evaluaron las expresiones de marcadores de vías apoptóticas, factor inductor de apoptosis (AIF), BAX, BCL 2, GADD 153, proteína regulada por glucosa de 78 kDa (GRP78) y CASPASE-3. Todos los análisis se examinaron en cuatro grupos (Grupo 1; control, Grupo 2; se administró ácido linoleico, Grupo 3; se administró metotrexato y Grupo 4; se administró ácido linoleico y metotrexato). Los valores medios ± error estándar de los resultados obtenidos como nanogramo/mililitro (ng/ml) se encuentran en el Grupo I, Grupo II, Grupo III y Grupo IV, respectivamente; Valores de AIF, 0,4150 ± 0,1208, 0,3633 ± 0,2389, 1,792 ± 0,3611 y 1,077 ± 0,1646, valores de Bax, 0,900 ± 0,1864, 1,002 ± 0,2098, 8,352 ± 1,467 y 4,295 ± 1,522, BCL 2 valores, 13,93 ± 1,199. 2,938 ± 1,059 y 9,250 ± 1,492, GADD 153, 0,7333 ± 0,1751, 0,7067 ± 0,2115, 1,650 ± 0,2950 y 1,237 ± 0,1805, Grp78, 0,4767 ± 0,1804, 0,5233 ± 0,1590, 2,183, ± 1,263. 1,127 ± 0,2033, 0,8317 ± 0,3392, 13,50 ± 1,871 y 8,183 ± 1,030. Se determinó que el ácido linoleico tiene un efecto protector sobre la toxicidad hepática inducida por metotrexato.

Perfil de liberación de biomarcadores miocárdicos en pacientes con enfermedades hemato-oncológicas que reciben trasplante de progenitores hematopoyéticos / Profile or myocardial biomarkers release in patients with hemato-oncological diseases who receive hematopoietic stem cell transplantation / Perfil de liberação de biomarcadores miocárdicos em pacientes com doenças hemato-oncológicas que recebem transplante de células-tronco hematopoéticas

Introducción: las enfermedades cardiovasculares (CV) son la primera causa de muerte en quienes sobreviven al cáncer. Aunque el trasplante de progenitores hematopoyéticos (TPH) se asocia con grados variables de cardiotoxicidad, estas complicaciones han sido escasamente caracterizadas. Objetivo: analizar el perfil de liberación de biomarcadores miocárdicos como potenciales indicadores subclínicos de cardiotoxicidad en pacientes sometidos a TPH. Material y método: estudio descriptivo, analítico, prospectivo transversal y unicéntrico, reclutando pacientes derivados a la policlínica de cardio-oncología, con indicación de TPH en octubre de 2018-marzo de 2020. Se realizaron controles clínicos, ECG, bioquímicos (troponina I TnI y péptido natriurético del tipo BBNP) e imagenológicos según algoritmo de seguimiento. Las variables discretas se presentan como n (%) y las continuas mediante media ± DE o mediana RIQ. Los valores evolutivos de biomarcadores séricos se compararon mediante test de Friedman. La fracciónde eyección del VI (FEVI) basal se comparó con la de los 3 meses del TPH mediante test de Wilcoxon. Resultados: se incluyeron 19 pacientes, 37% mujeres, de 43,8 ± 15,7 años. No se detectaron modificaciones significativas de la FEVI en los controles evolutivos. En ningún caso se observó aumento de la TnI. Los valores de BNP aumentaron en 6 pacientes (32%), con diferencias significativas al mes postrasplante (basal: 13,6 1;6,1-30,9 vs. primer mes: 38,9 16,3-120,0 pg/ml, p = 0,036); con una mayor elevación en aquellos pacientes que recibieron antimetabolitos vs. otros fármacos (basal: 13,6 1;6,1-30,9 vs. al primer mes: 67,0 ;21,3-174,9 pg/ml, p = 0,039). El aumento de BNP no se asoció con el riesgo CV. Conclusión: la liberación de BNP posterior al TPH es un fenómeno frecuente (32% de los pacientes), alcanza un máximo al mes, independientemente de la FEVI. El subgrupo de pacientes que recibió antimetabolitos presentó una mayor liberación precoz de BNP.

Introduction: cardiovascular (CV) diseases are the leading cause of death in those who survive cancer. Although hematopoietic stem cell transplantation (HSCT) is associated with diverse grades of cardiotoxicity, these complications have been poorly characterized. Objective: to analyze the release profile of myocardial biomarkers as a potential subclinical marker of cardiotoxicity in patients undergoing HSCT. Material and method: descriptive, analytical, prospective, cross-sectional, single-center study, recruiting patients referred to the cardio-oncology polyclinic, with indication for HSCT in October 2018-March 2020. Clinical, ECG, biochemical and imaging controls were performed according to the algorithm of follow-up. The evolutionary values of serum biomarkers were compared using the Friedman test. Baseline LVEF was compared with that of 3 months after HSCT using the Wilcoxon test. Results: 19 patients were included, 37% women, aged 43.8 ± 15.7 years. No changes in LVEF were detected. In no case was an increase in TnI observed. BNP values increased in 6 patients (32%), with significant differences one month after transplantation (baseline: 13.6 ;6.1-30.9 vs. first month: 38.9 ;16.3-120.0, p = 0.036), detecting a greater elevation in those patients who received antimetabolites vs. other rugs (baseline: 13.6 ;6.1-30.9 vs. at the first month: 67.0 21.3-174.0, p = 0.039). The increase in BNP was not associated with CV risk. Conclusion: BNP release after HSCT is frequent (32% of our patients), reaching a maximum at one month, regardless of LVEF. The subgroup of patients who received antimetabolites had a greater early release of BNP.

Introdução: as doenças cardiovasculares (CV) são a principal causa de morte em pessoas que sobrevivem ao câncer. Embora o transplante de células-tronco hematopoéticas (TCTH) esteja associado à diverso grado de cardiotoxicidade, essas complicações têm sido mal caracterizadas. Objetivo: analisar o perfil de liberação de biomarcadores miocárdicos como potenciais marcadores subclínicos de cardiotoxicidade em pacientes submetidos ao TCTH. Material e método: estudo descritivo, analítico, prospectivo, transversal, unicéntrico, com recrutamento de pacientes encaminhados à policlínica de cardio-oncologia, com indicação de TCTH de outubro de 2018 a março de 2020. Foram realizados controles clínicos, eletrocardiográficos, bioquímicos e de imagem de acordo com o algoritmo de acompanhamento. Os valores evolutivos dos biomarcadores séricos foram comparados pelo teste de Friedman. A FEVE basal foi comparada com a de 3 meses após o TCTH usando o teste de Wilcoxon. Resultados: foram incluídos 19 pacientes, 37% mulheres, com idade de 43,8 ± 15,7 anos. Nenhuma mudança na LVEF foi detectada. Em nenhum caso foi observado um aumento de TnI. Os valores de BNP aumentaram um mês após o transplante (linha de base: 13,6 6,1-30,9; vs. primeiro mês: 38,9 16,3-120,0, p = 0,036), se detectou uma maior elevação nos pacientes que receberam antimetabólitos vs. outros medicamentos (linha de base: 13,6 ;6,1-30,9; vs. no primeiro mês: 67,0 ;21,3-174,0;, p = 0,039). O aumento do BNP não foi associado ao risco CV. Conclusão: a liberação do BNP após o TCTH é frequente (32% de nossos pacientes), podendo chegar a no máximo um mês, independente da FEVE. O subgrupo de pacientes que recebeu antimetabólitos apresentou maior liberação precoce de BNP.

Encefalopatía subaguda reversible por metotrexato: notificación de un caso pediátrico / Methotrexate-induced stroke-like syndrome: A pediatric case report

Las leucemias son las neoplasias malignas más frecuentes en la infancia; la leucemia linfoblástica aguda (LLA) es la más frecuente. Desde principios de los 80, la adición de metotrexato intratecal a los esquemas de quimioterapia ha sido beneficiosa para prevenir la recidiva en el sistema nervioso central y evitar el uso de radioterapia. Su mecanismo de acción es la inhibición de la enzima dihidrofolato reductasa, por lo que posee múltiples efectos adversos (neurotoxicidad aguda, subaguda o crónica) después de la infusión intratecal o de dosis altas por vía intravenosa.Se presenta un paciente de 11 años con diagnóstico de LLA de línea T (LLA-T), que presenta hemiparesia faciobraquial y afasia de expresión de instauración aguda 8 días después de la administración intratecal de metotrexato. Luego de excluir otras patologías más frecuentes de origen vascular y la evolución típica del cuadro, con resolución espontánea ad integrum de los síntomas, se arribó al diagnóstico de encefalopatía subaguda reversible por metotrexato.

Leukemias are the most frequent malignant neoplasms in childhood; acute lymphoblastic leukemia (ALL) is the most frequent. The addition of intrathecal methotrexate to chemotherapy regimens has been beneficial in preventing relapse to the central nervous system and avoiding the use of radiation therapy. Due to its mechanism of action, by inhibiting the enzyme dihydrofolate reductase, when it is used systemically, it has multiple expected adverse effects such as mucositis, myelosuppression and it has also been observed after intrathecal administration or high intravenous doses, acute, subacute neurotoxicity where stroke like syndrome is found. We present an 11-year-old patient diagnosed with T-ALL, who manifested after 8 days of intrathecal administration of methotrexate, faciobrachial hemiparesis and acute onset expression aphasia. The diagnosis of subacute encephalopathy reversible by methotrexate was reached by excluding other more frequent pathologies and the typical evolution, with spontaneously ad integrum resolution of the symptoms

Avaliação do Efeito do Laser Preventivo na Mucosite Oral Quimioinduzida em Pacientes Submetidos a Altas Doses de Metotrexato / Evaluation of the Effect of Preventive Laser on Chemo-induced Oral Mucositis in Patients Submitted to High Doses of Methotrexate / Evaluación del Efecto del Láser Preventivo em la Mucositis Oral Inducida por Quimioterapia en Pacientes Sometidos a Altas Dosis de Metotrexato

Introdução: A quimioterapia, uma das formas de tratamento de neoplasias malignas, tem sua administração associada a inúmeras drogas, sendo uma delas o metotrexato (MTX), de alta toxicidade, responsável por inúmeros fatores agravantes para a saúde e bem-estar do paciente. Uma das principais complicações é a mucosite oral, manifestação clínica resultante do tratamento oncológico que pode interferir no tratamento e na cura. Objetivo: Avaliar, comparativamente, por meio de um estudo retrospectivo, o efeito do laser preventivo na ocorrência da mucosite oral quimioinduzida em pacientes com osteossarcoma não metastático submetidos a altas doses de MTX, bem como a intensidade da mucosite oral, utilizando o laser preventivo após os ciclos quimioterápicos contendo o medicamento MTX nos pacientes atendidos no Hospital de Câncer infantojuvenil de Barretos/SP. Método: Estudo de coorte com coleta retrospectiva em prontuários. Os pacientes foram divididos em dois grupos, um submetido à terapia profilática com laser de baixa intensidade após infusão do MTX e outro grupo não submetido a essa terapia. Resultados: Os dados obtidos mostraram que houve redução da gravidade da mucosite oral com o uso da laserterapia preventiva, com resultados estatisticamente significativos (p<0,001), corroborando os resultados encontrados na literatura. Conclusão: O uso da laserterapia é uma terapêutica auxiliar importante na prevenção e na redução da severidade da mucosite oral em pacientes submetidos a altas doses de MTX, diminuindo o número de internações por mucosite e os atrasos no protocolo terapêutico, o que reduz gastos e melhora o prognóstico para o paciente.

Introduction: Chemotherapy, one of the treatments for malignant neoplasms, is associated to innumerous drugs, one of them methotrexate (MTX), of high toxicity, responsible for several health damages and impact on the patient's well-being. One of the main complications is oral mucositis, a clinical manifestation resulting from the oncologic treatment that can interfere in the treatment and cure. Objective: To evaluate comparatively through a retrospective study, the effect of preventive laser in the occurrence of chemo-induced oral mucositis in patients with non-metastatic osteosarcoma submitted to high doses of methotrexate (MTX), and the intensity of oral mucositis, using the preventive laser after the chemotherapy cycles containing the drug methotrexate (MTX) in the patients treated at the Child and Adolescent Cancer Hospital of Barretos/SP. Method:Retrospective cohort study with charts review. The patients were divided in two groups, one submitted to low-intensity laser prophylaxis therapy after infusion of MTX and another group not submitted to prophylactic therapy. Results: The data obtained showed that preventive laser-therapy reduced the severity of oral mucositis with statistically significant results (p<0.001), corroborating the results found in the literature. Conclusion: The use of laser therapy is an important auxiliary therapy in the prevention and reduction of severity of oral mucositis in patients submitted to high doses of MTX, reducing the number of hospitalizations and delays in therapeutic protocol, which reduces costs and improves the patient prognosis.

Introducción: La quimioterapia, es uma de las formas de tratamiento de las neoplasias malignas, tiene su administración asociada a numerosas drogas siendo una de ellas el metotrexato (MTX), de alta toxicidad, responsable de numerosos factores agravantes para la salud y bienestar del paciente. Una de las principales complicaciones es la mucositis oral, manifestación clínica resultante del tratamiento oncológico que puede interferir en el tratamiento y cura. Objetivo: Evaluar, comparativamente, a través de um estudio retrospectivo, el efecto del láser preventivo em la aparición de la mucositis oral quimio inducida em pacientes com osteosarcoma no mestastásico sometido a altas dosis de MTX, bien como la intensidade de la mucositis oral, utilizando el láser preventivo después de los ciclos quimioterápicos que contiene el medicamento MTX en los pacientes antendidos en el Hospital del Cáncer Infantojuvenil de Barretos/SP. Método: Estudio de coorte con colección retrospectiva en prontuários. Los pacientes fueron divididos em dos grupos, uno sometido a terapia profiláctica con láser de baja intensidade después de la infusión de MTX y otro grupo no sometido a terapia profiláctica. Resultados: Los dados obtenidos mostraron que hubo una reducción en la severidad de la mucositis oral con el uso de la terapia láser preventiva, con resultados estáticamente significativos (p<0,001), corroborando los resultados encontrados em la literatura. Conclusión: El uso de la terapia con láser es una terapia auxiliar importante en la prevención y reducción de la severidad de la mucositis oral em pacientes sometidos a altas dosis de MTX, diminuendo el número de internaciones por mucositis y retrasos en el protocolo terapéutico, lo que reduce los gastos y mejora el pronóstico para el paciente.

Association between polymorphism of NUDT15 gene and hepatotoxicity induced by 6-MP in children with acute lymphoblastic leukemia / 中华医学遗传学杂志

OBJECTIVE@#To investigate the association between single nucleotide polymorphism of NUDT15 gene (SNP rs116855232) and hepatotoxicity in children with acute lymphocytic leukemia (ALL).@*METHODS@#A total of 135 children with ALL in Shandong Province were recruited in this study, and patients were divided into two groups based on the presence of liver injury. Genotypes of each patient were detected using PCR and Sanger sequencing. Clinical data and the average dose of 6-mercaptopurine (6-MP) were collected and analyzed by SPSS 19.0 software.@*RESULTS@#Respectively, 99 patients were found with CC genotype, 32 patients with CT genotype and 4 patients with TT genotype. Compared with ALL patients without hepatotoxicity, there was a difference in genotypes between the two groups in the initial stage of chemotherapy for leukemia (Chi@*CONCLUSION@#The polymorphism of rs116855232 in NUDT15 gene was associated with hepatotoxicity induced by 6-mercaptopurine in children with ALL, and ALL patients with TT genotype should take a lower dose of 6-MP to avoided hepatotoxicity.

The influence of platelet-rich plasma (PRP) on colonic anastomosis healing impaired by intraperitoneal 5-flourouracil application. An experimental study

Abstract Purpose 5-flourourasil (5-FU) is commonly used for early intraperitoneal chemotherapy in colorectal or appendiceal cancer patients with peritoneal carcinomatosis. Due to its effect, anastomosis healing can be impaired and leads to anastomotic leakage. In this study, we aimed to investigate the potential healing effect of platelet-rich plasma (PRP) on colonic anastomosis impaired by intraperitoneal 5-flourouracil application. Methods After ten rats were sacrificed for preparing PRP, forty Wistar-albino rats were subjected to colonic anastomosis, and randomly allocated into four groups including 10 rats each. According to receiving PRP and/or 5-FU application, the groups were formed as control (C), 5-FU without PRP (CT), anastomosis with PRP (C-PRP), and 5-FU with PRP (CT-PRP). CT and CT-PRP groups also received 5-FU intraperitoneally on postoperative day 1 (POD 1). All animals were euthanized on pod 7. The body weight change, anastomotic bursting pressure (ABP), tissue hydroxiprolin (TH) and histopathological examination of each group were analyzed. Results 5-FU application significantly reduced ABP levels when compared with group C, C-PRP and CT-PRP (for each comparison, p<0,01). PRP application in CT-PRP group raised the measure of ABP up to the levels of C group. Although tissue hydroxyproline levels (THL) levels of CT-PRP group were found higher than CT group, it was not significant (p=0.112). Microscopically, comparing with CT group, PRP application significantly promoted the healing of colonic anastomosis subjected to 5-FU application by improving tissue edema, necrosis, submucosal bridging and collagen formation (p<0.05). Tissue healing in CT-PRP group was observed as good as the control groups. (C, C-PRP, p=0.181, p=0.134; respectively). Conclusion PRP administration on colonic anastomosis significantly promotes the healing process of anastomosis in rats receiving 5-FU. This result encourages further clinical use of PRP to reduce the frequency of AL in patients receiving EPIC.

Significance of NUDT15 gene in individualized treatment with 6-mercaptopurine in children with acute lymphoblastic leukemia / 中国当代儿科杂志

As an important drug during maintenance treatment of acute lymphoblastic leukemia (ALL), 6-mercaptopurine (6-MP) has several side effects, including hepatotoxicity and bone marrow suppression. Since its tolerability varies from person to person, 6-MP treatment should be individualized. The deficiency of thiopurine methyltransferase (TPMT) enzyme activity is associated with 6-MP intolerance. There is a lower frequency of mutation in TPMT alleles among Asian patients. Recent studies have shown that in ALL patients with NUDT15 gene mutation, the maximum tolerated dose of 6-MP is lower than the conventional dose. The article reviews the significance of NUDT15 gene in individualized treatment with 6-MP in children with ALL.

Nanocristais de flubendazol: preparação e caracterização físico-química / Flubendazole nanocrystals: preparation and physical-chemical characterization

Os nanocristais são partículas de fármacos cristalinos, com tamanho médio na faixa de submicrons, geralmente entre 200 e 500 nm, estabilizados por agentes estéricos ou eletrostáticos adsorvidos na superfície das partículas do fármaco. Sua dimensão reduzida proporciona propriedades especiais, como a adesividade às mucosas e o aumento de área superficial e da solubilidade de saturação, o que melhora significativamente a biodisponibilidade de fármacos pouco solúveis em água. Outra aplicação emergente dos nanocristais é na melhoria da entrega e da retenção de fármacos em tecidos e células tumorais. Estudos demonstraram que o flubendazol é um fármaco capaz de induzir a morte celular em tumores malignos e retardar o seu crescimento, por meio da alteração que provoca na estrutura dos microtúbulos e pela inibição da polimerização da tubulina. Foi demonstrada sua atividade antiproliferativa em linhagens de leucemia, mieloma, câncer intestinal, câncer de mama e neuroblastoma. O flubendazol é também um fármaco eficaz contra os helmintos, demonstrando atividade superior na eliminação dos vermes adultos, quando comparado com a dietilcarbamazina. Embora o flubendazol pareça ser uma molécula promissora, é um fármaco praticamente insolúvel em água (0,005 mg/mL). Para atingir o efeito terapêutico desejado, é necessário o desenvolvimento de uma formulação com melhores solubilidade e biodisponibilidade. Nesse sentido, o presente trabalho apresenta o preparo e a caracterização físico-química de nanocristais de flubendazol por meio da microfluidização. Foram realizados ensaios exploratórios para avaliar a performance de diferentes agentes estabilizantes nas suspensões: o polissorbato 80, o polaxamer 188 e o D-α tocoferol polietilenoglicol 1.000 succinato (TPGS). A avaliação da distribuição do tamanho de partícula foi realizada por espalhamento de luz laser (LLS), espalhamento de luz dinâmica (DLS), análise de rastreamento de nanopartículas (NTA) e microscopia eletrônica de varredura (MEV). A utilização do TPGS favoreceu a obtenção de uma nanossuspensão com o menor diâmetro hidrodinâmico médio das partículas, de 253,9 ± 3,0 nm. Nos estudos exploratórios, também foram determinados os parâmetros ótimos de moagem do microfluidizador, sendo estabelecidos: 35.000 psi de pressão, temperatura do produto de 30°C (± 5°C) e tempo de recirculação de 2 horas/100 gramas. Objetivando alcançar o menor diâmetro hidrodinâmico médio dos nanocristais, executou-se um planejamento estatístico no qual foi avaliada a influência da concentração de flubendazol (% p/p) e de TPGS (% p/p) na formulação. A análise revelou a significativa influência da concentração do TPGS na redução do tamanho de partícula e na estabilidade físico-química da nanossuspensão. Ensaios complementares de solubilidade demonstraram que o nanocristal proporcionou incremento na solubilidade de 2,3 e 3,2 e 5,2 vezes em HCl 0,1 N, tampão fosfato pH 6,8 e tampão fosfato salino pH 7,4, respectivamente. No ensaio de dissolução conduzido em HCl 0,1 N e 0,1% TPGS, observou-se significativo incremento, de 41% de fármaco dissolvido após 60 minutos, quando comparado com o flubendazol micronizado. As características do estado sólido do nanocristal foram avaliadas por meio de análise térmica (calorimetria exploratória diferencial e termogravimetria) e difratometria de raios X, não sendo observadas significativas alterações da estrutura cristalina. O presente trabalho também avaliou a efetividade dos nanocristais de flubendazol em tumores de pulmão, demonstrando sua expressiva capacidade de retardar o crescimento e diminuir o tamanho desses tumores em camundongos xenotransplantados

Os nanocristais são partículas de fármacos cristalinos, com tamanho médio na faixa de submicrons, geralmente entre 200 e 500 nm, estabilizados por agentes estéricos ou eletrostáticos adsorvidos na superfície das partículas do fármaco. Sua dimensão reduzida proporciona propriedades especiais, como a adesividade às mucosas e o aumento de área superficial e da solubilidade de saturação, o que melhora significativamente a biodisponibilidade de fármacos pouco solúveis em água. Outra aplicação emergente dos nanocristais é na melhoria da entrega e da retenção de fármacos em tecidos e células tumorais. Estudos demonstraram que o flubendazol é um fármaco capaz de induzir a morte celular em tumores malignos e retardar o seu crescimento, por meio da alteração que provoca na estrutura dos microtúbulos e pela inibição da polimerização da tubulina. Foi demonstrada sua atividade antiproliferativa em linhagens de leucemia, mieloma, câncer intestinal, câncer de mama e neuroblastoma. O flubendazol é também um fármaco eficaz contra os helmintos, demonstrando atividade superior na eliminação dos vermes adultos, quando comparado com a dietilcarbamazina. Embora o flubendazol pareça ser uma molécula promissora, é um fármaco praticamente insolúvel em água (0,005 mg/mL). Para atingir o efeito terapêutico desejado, é necessário o desenvolvimento de uma formulação com melhores solubilidade e biodisponibilidade. Nesse sentido, o presente trabalho apresenta o preparo e a caracterização físico-química de nanocristais de flubendazol por meio da microfluidização. Foram realizados ensaios exploratórios para avaliar a performance de diferentes agentes estabilizantes nas suspensões: o polissorbato 80, o polaxamer 188 e o D-α tocoferol polietilenoglicol 1.000 succinato (TPGS). A avaliação da distribuição do tamanho de partícula foi realizada por espalhamento de luz laser (LLS), espalhamento de luz dinâmica (DLS), análise de rastreamento de nanopartículas (NTA) e microscopia eletrônica de varredura (MEV). A utilização do TPGS favoreceu a obtenção de uma nanossuspensão com o menor diâmetro hidrodinâmico médio das partículas, de 253,9 ± 3,0 nm. Nos estudos exploratórios, também foram determinados os parâmetros ótimos de moagem do microfluidizador, sendo estabelecidos: 35.000 psi de pressão, temperatura do produto de 30°C (± 5°C) e tempo de recirculação de 2 horas/100 gramas. Objetivando alcançar o menor diâmetro hidrodinâmico médio dos nanocristais, executou-se um planejamento estatístico no qual foi avaliada a influência da concentração de flubendazol (% p/p) e de TPGS (% p/p) na formulação. A análise revelou a significativa influência da concentração do TPGS na redução do tamanho de partícula e na estabilidade físico-química da nanossuspensão. Ensaios complementares de solubilidade demonstraram que o nanocristal proporcionou incremento na solubilidade de 2,3 e 3,2 e 5,2 vezes em HCl 0,1 N, tampão fosfato pH 6,8 e tampão fosfato salino pH 7,4, respectivamente. No ensaio de dissolução conduzido em HCl 0,1 N e 0,1% TPGS, observou-se significativo incremento, de 41% de fármaco dissolvido após 60 minutos, quando comparado com o flubendazol micronizado. As características do estado sólido do nanocristal foram avaliadas por meio de análise térmica (calorimetria exploratória diferencial e termogravimetria) e difratometria de raios X, não sendo observadas significativas alterações da estrutura cristalina. O presente trabalho também avaliou a efetividade dos nanocristais de flubendazol em tumores de pulmão, demonstrando sua expressiva capacidade de retardar o crescimento e diminuir o tamanho desses tumores em camundongos xenotransplantados

Resultados de pacientes con linfoma del manto: impacto de terapias basadas en citarabina y trasplante hematopoyético / Cytarabine and hematopoietic cell transplantation for mantle cell lymphoma: analysis of 20 patients

Background: Mantle cell lymphoma (MCL) has high relapse and mortality rates. There is a survival benefit when treatment is intensified with cytarabine (AraC), hematopoietic cell transplantation (HCT) and maintenance with rituximab. Aim: To assess the outcomes of patients with MCL treated in a university hospital. Material and Methods: Review of an oncology center database and medical records identifying patients with MCL treated between 2006 and 2017. Death dates were obtained from the death certificate database of the National Identification Service. We analyzed the response rate, overall survival (OS) and progression-free survival (PFS). As a secondary objective, the survival impact of AraC, HCT and maintenance with rituximab, was also analyzed. Results: Information on 20 patients aged 62 ± 11 years, followed for a median of 45 months was retrieved. Eighty-five percent were diagnosed at an advanced stage. The most used first-line regime was R-CHOP in 11 patients, followed by R-HyperCVAD in five. Only 47% achieved complete response. 4-year PFS and OS were of 30 and 77% respectively. Mantle Cell Lymphoma International Prognostic Index (MIPI) significantly predicted PFS and OS. Maintenance with rituximab or HCT was associated with better PFS (48 vs 21 months, p < 0.01). The exposure to AraC or HCT, in refractory or relapsed disease, was associated with an increase in PFS from 9 to 28 months (p = 0,02) and 4-year OS from 40 to 100% (p = 0.05). OS increased even more, from 25 to 100% in those with high-risk MIPI (p = 0.04). Conclusions: The incorporation of AraC, HCT and maintenance with rituximab in the therapeutic backbone of MCL, especially for high-risk cases, was associated with improved survival.

Síndrome de degeneración combinada de la médula espinal y radiculopatía en dos pacientes por quimioterapia intratecal con metrotrexato y citarabina: casos clínicos / Spinal subacute combined degeneration after intrathecal chemotherapy: report of two cases

Intrathecal chemotherapy may be complicated with the development of myelopathies or toxic radiculopathies. This myeloradicular involvement, of toxic character, is unpredictable, since these patients have repeatedly received Intrathecal chemotherapy with the same drugs without apparent injury. The toxic effect should be mainly attributed to Cytarabine and not to methotrexate, since the central nervous system lacks Cytidine deaminase, the enzyme that degrades Cytarabine. We report two patients, an 18-year-old woman and a 16 years old male, who received systemic and intrathecal chemotherapy (methotrexate, cytarabine) for the treatment of an acute lymphoblastic leukemia and developed, in relation to this procedure, a spinal subacute combined degeneration. They had a proprioceptive and motor alteration of the lower extremities and neuroimaging showed selective rear and side spinal cord hyper intensity produced by central axonopathy. Two weeks later the woman developed a quadriplegia and the young man a flaccid paraplegia due to added root involvement.

Síndrome de Stevens-Johnson asociado al tratamiento con metotrexato de la leucemia linfoblástica aguda: a propósito de un caso / Stevens-Johnson Syndrome associated with methotrexate treatment for acute lymphoblastic leukemia: a case report

La necrólisis epidérmica tóxica y el síndrome de StevensJohnson son enfermedades mucocutáneas raras que están asociadas a una evolución prolongada y a un desenlace potencialmente mortal. Principalmente están inducidas por fármacos y las tasas de mortalidad son muy elevadas. Aunque la piel es la más comprometida, también pueden estar afectados múltiples aparatos o sistemas como el cardiovascular, pulmonar, gastrointestinal y urinario. En este artículo, describimos el caso de un paciente con síndrome de Stevens-Johnson asociado al tratamiento con metotrexato, quien desarrolló insuficiencia cardíaca aguda y hemorragia gastrointestinal además de las manifestaciones en la piel. El paciente recibió un tratamiento satisfactorio con metilprednisolona e inmunoglobulina por vía intravenosa y continuó la quimioterapia con metotrexato.

Toxic epidermal necrolysis and Stevens-Johnson syndrome are rare mucocutaneous diseases which are associated with a prolonged course and potentially lethal outcome. They are mostly drug induced and mortality rates are very high. Although mostly skin is involved, multiple organ systems such as cardiovascular, pulmonary, gastrointestinal, and urinary systems may be affected. Here, we report a case of StevensJohnson Syndrome associated with methotrexate treatment who developed acute cardiac failure and gastrointestinal hemorrhage beside skin findings. He had been treated with intravenous immunglobulin and methylprednisolone succesfully and continued chemotherapy with methotrexate treatment again.

Oncological outcomes in extended time intervals between preoperative chemoradiotherapy with capecitabine and surgery in operable rectal adenocarcinoma / Resultados oncológicos en intervalos extendidos de tiempo entre quimioradioterapia preoperatoria con capecitabina y cirugía en adenocarcinoma rectal operable

Objective: To assess whether extended time intervals (8-12, 13-20 and >20 weeks) between the end of neoadjuvant chemoradiotherapy and surgery affect overall survival, disease-free survival. Materials and methods: Retrospective study in 120 patients with rectal adenocarcinoma without evidence of metastasis (T1-4/N0-2/M0) at the time of diagnosis that underwent surgery with curative intent after neoadjuvant chemoradiotherapy with capecitabine and obtained R0 or R1 resection between January 2010 to December 2014 at the National Cancer Institute of Peru. Dates were evaluated by Kaplan-Meier method, log- rank test and Cox regression analysis. Results: Of the 120 patients, 70 were women (58%). The median age was 63(26-85) years. All received neoadjuvant chemoradiotherapy. No significant difference was found between the association of the median radial (0.6, 0.7 and 0.8 cm; p=0.826) and distal edge (3.0, 3.5 and 4.0 cm; p=0.606) with time interval groups and similarly the mean resected (18.8, 19.1 and 16.0; p=0.239) and infiltrated nodules (1.05, 1.29 and 0.41); p=0.585). The median follow-up time of overall survival and desease free survival was 40 and 37 months, respectively. No significant differences were observed in overall survival (79.0%, 74.6% and 71.1%; p=0.66) and disease-free survival (73.7%, 68.1% and 73.6%; p=0.922) according to the three groups studied at the 3-year of follow-up. Conclusions: We found that widening the time intervals between the end of neoadjuvant chemoradiotherapy and surgery at 24 weeks does not affect the overall survival, disease-free survival and pathological outcomes. It allows to extend the intervals of time for future studies that finally will define the best time interval for the surgery

Objetivo: Evaluar si los intervalos de tiempo extendidos (8-12, 13-20 y >20 semanas) entre el fin de la quimioradioterapia neoadyuvante y la cirugía afectan la sobrevida global, y la sobrevida libre de enfermedad. Material y métodos: Estudio retrospectivo de 120 pacientes con adenocarcinoma rectal sin evidencia de metástasis (T1-4/N0-2/M0) al momento del diagnóstico que se sometieron a cirugía con intención curativa luego de quimioradioterapia neoadyuvante con capecitabina y tuvieron resección R0 o R1 entre enero 2010 y diciembre 2014 en el Instituto Nacioanal de Enfermedades Neoplásicas de Perú. El análisis se hizo con el método de Kaplan-Meier, la prueba log-rank y la regresión de Cox. Resultados: De 120 pacientes, 70 fueron mujeres (58%). La mediana de la edad fue 63 años (26-85 años). Todos recibieron quimioradioterapia neoadyuvante. No hubo diferencia significativa entre la asociación de las medianas de los bordes radial (0,6, 0.7 y 0,8 cm; p=0,826) y distal (3,0, 3,5 y 4,0 cm; p=0,606) con los intervalos de tiempo de los grupos y similarmente con la media de los ganglios resecados (18,8, 19,1 y 16,0; p=0,239) e infiltrados (1,05, 1,29 y 0,41; p=0,585). No se observaron diferencias significativas en sobrevida global (79,0%, 74,6% y 71,1%; p=0,66) y sobrevida libre de enfermedad (73,7%, 68,1% y 73,6%; p=0,922), en los tres grupos estudiados a 3 años de seguimiento. Conclusiones: Encontramos que aumentar los intervalos de tiempo entre el fin de la quimioradioterapia neoadyuvante y la cirugía hasta 24 semanas no afecta la sobrevida global, sobrevida libre de enfermedad ni los desenlaces patológicos. Esto permitiría extender los intervalos de tiempo en estudios futuros para definir el mejor intervalo de tiempo para la cirugía

Research progress of neoadjuvant therapy for locally advanced rectal cancer / 中华胃肠外科杂志

The clinical application of novel chemotherapeutic drugs including oral 5-FU and targeted drugs and preoperatively accurate imaging grading has brought challenges to the indication criteria developed by NCCN and ESMO for neoadjuvant chemoradiotherapy in locally advanced rectal cancer (LARC). Extended hotspots have focused on the effectiveness of using capecitabine instead of fluorouracil infusion, the combination of multiple drugs and the feasibility of using neoadjuvant chemotherapy instead of neoadjuvant chemoradiotherapy for selective patients. Traditionally, the evaluation of the effect of neoadjuvant therapy has been based on the effect on the pathological complete remission (pCR) rate. However, current studies recommend the disease-free survival (DFS) as a more important outcome. Besides, seeking for effective biomarkers as predictive markers for neoadjuvant therapies or as prognostic markers remains a hotspot in the field of neoadjuvant chemoradiotherapy. The "watch and wait" approach refers to taking a close follow-up strategy instead of direct operation for patients achieving clinically complete remission (cCR) after neoadjuvant therapy. However, there is no unified evaluation criteria and time point for the evaluation of cCR following neoadjuvant therapy. Therefore, there remain a lot of controversies regarding the clinical application of neoadjuvant chemoradiotherapy in LARC. In this manuscript, research progress in the indication for neoadjuvant therapy, improvement in the neoadjuvant therapeutic schedule, advancement of the efficacy evaluation criteria of neoadjuvant therapy, the "watch and wait" approach and other hot topics is summarized to provide references for clinical practice.

Predicting Therapeutic Response by Lymphocyte Level at 28th Day after DAC Treatment in Patients with MDS / 中国实验血液学杂志

OBJECTIVE@#To investigate a reliable clinical indication for predicting the therapeutic response of decitabine therapy in the patients with myelodysplastic syndromes (MDS).@*METHODS@#The clinical efficacy of decitabine for 55 cases of MDS was analyzed retrospectively. According to the lymphocyte level at d28 after the first time treatment with decitabine, the patients were divided into high lymphocyte level group (H-Lym≥1.2×10/L) and low lymphocyte level group (L-Lym<1.2×10/L), and the overall response rate (ORR) and the progression-free survival (PFS) time in 2 groups were compared.@*RESULTS@#As compared with L-Lym group, the ORR and PFS time in H-Lym group were significantly enhanced ［(76.0% vs 50.0%) (P<0.05) and median time (15.7 months vs 8.5 months)(P<0.05), respectively］;the ratio of platelet level ≥100×10/L in H-Lym group was very significantly higher than that in L-Lym group (72.0% vs 20.0%)(P<0.01). Multivariat analysis showed that the risk of disease progression in L-Lym group was 4.45-fold of H-Lym group (95% CI:1.58-12.59)(P<0.05).@*CONCLUSION@#The patients with lymphocyte level ≥1.2×10/L at day 28 after the first time treatment with decitabine show the higher ORR and longer PFS time, therefore. the lymphocyte level at day 28 after first time treatment with decitabine can be used as an early clinical indicator for predecting the response to decitabine treatment.

Hemangioendotelioma epitelioide pulmonar: Reporte de un caso / Lung epithelioid hemangioendothelioma: Report of one case

Epithelioid hemangioendothelioma is a multifocal tumor that rarely metastasizes. It is difficult to diagnose, most often it is an incidental finding in young asymptomatic women. The radiologic pattern is heterogeneous. Histologic confirmation of Weibel-Palade bodies or immunohistochemistry based on specific tumor markers such as factor VIII and CD34 are the most important finding to confirm the diagnosis. We report a 21 years old woman Presenting with cough and dyspnea. A chest X ray was suggestive of tuberculosis. Sputum smears were negative for acid fat bacilli and the tuberculin test was negative. A chest CAT scan showed multiple nodular lesions. A surgical biopsy of the lesions confirmed the presence of a hemangioendothelioma. The patient was initially treated with prednisone and azathioprine without response. Thereafter, the patient is without treatment and without evidence of disease progression.

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.

Adverse effects of high-dose methotrexate therapy / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To investigate the adverse effects of high-dose methotrexate (HDMTX) therapy, and to provide a theoretical basis for optimizing clinical treatment.</p><p><b>METHODS</b>A retrospective analysis was performed for the clinical data of 120 children with acute lymphoblastic leukemia or non-Hodgkin lymphoma who underwent 601 times of HDMTX therapy. The adverse effects of various systems were analyzed according to the WHO criteria for the classification of adverse effects of anticancer drugs.</p><p><b>RESULTS</b>Almost all the children experienced bone marrow suppression, and 93.3% had granulocytopenia. The most common adverse effects in the digestive system and urinary system were elevated glutamic-pyruvic transaminase (60.4%) and proteinuria (9.2%) respectively. For skin symptoms, skin erythema had the highest incidence rate (7.2%). The adverse effects in the nervous system (hyperpathia, numbness of extremities, or headache) were only observed in 7 cases. Serious adverse effects were only seen in the blood system and digestive system. Compared with the 3 g/mmethotrexate (MTX) group, the 5 g/mHDMTX group had a significantly higher 24-hour plasma MTX concentration, significant reductions in hemoglobin and platelet count, and significantly higher incidence rates of oral mucositis, proteinuria, and skin symptoms (P<0.05).</p><p><b>CONCLUSIONS</b>Serious adverse effects of HDMTX therapy mainly involve the blood system and digestive system, and the adverse effects such as bone marrow suppression, oral mucositis, proteinuria, and skin symptoms occur in a dose-dependent manner.</p>

Research advances in pharmacogenomics of mercaptopurine / 中国当代儿科杂志

Mercaptopurine is a common chemotherapeutic drug and immunosuppressive agent and plays an important role in the treatment of acute lymphoblastic leukemia and inflammatory bowel disease. It may cause severe adverse effects such as myelosuppression, which may result in the interruption of treatment or complications including infection or even threaten patients' lives. However, the adverse effects of mercaptopurine show significant racial and individual differences, which reveal the important role of genetic diversity. Recent research advances in pharmacogenomics have gradually revealed the genetic nature of such differences. This article reviews the recent research advances in the pharmacogenomics and individualized application of mercaptopurine.