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.

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.

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.

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.

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.

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.

Síndrome hemolítico-urêmica causada por gencitabina em uma paciente jovem com colangiocarcinoma / Hemolytic uremic syndrome due to gemcitabine in a young woman with cholangiocarcinoma

Resumo A gencitabina é um fármaco utilizado no tratamento de vários tipos de neoplasias malignas. Há poucas descrições de associação entre a droga e a síndrome hemolítico-urêmica (SHU), apesar de os pacientes em questão terem ido a óbito em pelo menos 50% dos casos. O presente artigo relata o caso de uma paciente com 25 anos de idade em remissão diagnosticada com colangiocarcinoma que apresentou anemia hemolítica microangiopática acompanhada de insuficiência renal aguda anúrica após cinco ciclos de quimioterapia com gencitabina; as manifestações eram condizentes com SHU causada pelos efeitos colaterais do medicamento. A administração de gencitabina foi interrompida, e a paciente foi tratada com hemodiálise, transfusões de sangue, trocas de plasma, corticosteroides, doxiciclina e rituximabe. Foi atingido um desfecho favorável; mais especificamente, a hemólise foi controlada e a função renal foi plenamente restabelecida.

Abstract Gemcitabine is a medication used to treat various types of malignant neoplasms. Its association with hemolytic uremic syndrome (HUS) has been described in few cases, although these cases have resulted in mortality rates of at least 50%. We report on the case of a 25-year-old patient with cholangiocarcinoma in remission who developed microangiopathic hemolytic anemia with acute anuric renal failure after receiving 5 cycles of gemcitabine chemotherapy; this condition was consistent with HUS caused by the side effects of this drug. The administration of gemcitabine was stopped, and hemodialysis, blood transfusions, plasma exchanges, steroids, doxycycline, and rituximab were used to treat the patient. A favorable outcome was achieved; in particular, hemolysis was controlled, and renal function was completely recovered.

Alanyl-glutamine attenuates 5-fluorouracil-induced intestinal mucositis in apolipoprotein E-deficient mice

Apolipoprotein E (APOE=gene, apoE=protein) is a known factor regulating the inflammatory response that may have regenerative effects during tissue recovery from injury. We investigated whether apoE deficiency reduces the healing effect of alanyl-glutamine (Ala-Gln) treatment, a recognized gut-trophic nutrient, during tissue recovery after 5-FU-induced intestinal mucositis. APOE-knockout (APOE-/-) and wild-type (APOE+/+) C57BL6J male and female mice (N=86) were given either Ala-Gln (100 mM) or phosphate buffered saline (PBS) by gavage 3 days before and 5 days after a 5-fluorouracil (5-FU) challenge (450 mg/kg, via intraperitoneal injection). Mouse body weight was monitored daily. The 5-FU cytotoxic effect was evaluated by leukometry. Intestinal villus height, villus/crypt ratio, and villin expression were monitored to assess recovery of the intestinal absorptive surface area. Crypt length, mitotic, apoptotic, and necrotic crypt indexes, and quantitative real-time PCR for insulin-like growth factor-1 (IGF-1) and B-cell lymphoma 2 (Bcl-2) intestinal mRNA transcripts were used to evaluate intestinal epithelial cell turnover. 5-FU challenge caused significant weight loss and leukopenia (P<0.001) in both mouse strains, which was not improved by Ala-Gln. Villus blunting, crypt hyperplasia, and reduced villus/crypt ratio (P<0.05) were found in all 5-FU-challenged mice but not in PBS controls. Ala-Gln improved villus/crypt ratio, crypt length and mitotic index in all challenged mice, compared with PBS controls. Ala-Gln improved villus height only in APOE-/- mice. Crypt cell apoptosis and necrotic scores were increased in all mice challenged by 5-FU, compared with untreated controls. Those scores were significantly lower in Ala-Gln-treated APOE+/+ mice than in controls. Bcl-2 and IGF-1 mRNA transcripts were reduced only in the APOE-/--challenged mice. Altogether our findings suggest APOE-independent Ala-Gln regenerative effects after 5-FU challenge.

Therapeutic switching: from antidermatophytic essential oils to new leishmanicidal products

This study examined whether the antidermatophytic activity of essential oils (EOs) can be used as an indicator for the discovery of active natural products against Leishmania amazonensis. The aerial parts of seven plants were hydrodistilled. Using broth microdilution techniques, the obtained EOs were tested against three strains of dermatophytes (Trichophyton mentagrophytes, Microsporum gypseum and Microsporum canis). To compare the EOs antifungal and antiparasitic effects, the EOs activities against axenic amastigotes of L. amazonensis were concurrently evaluated. For the most promising EOs, their antileishmanial activities against parasites infecting peritoneal macrophages of BALB/c mice were measured. The most interesting antifungal candidates were the EOs from Cymbopogon citratus, Otacanthus azureus and Protium heptaphyllum, whereas O. azureus, Piper hispidum and P. heptaphyllum EOs exhibited the lowest 50% inhibitory concentration (IC50) values against axenic amastigotes, thus revealing a certain correspondence between both activities. The P. hispidum EO was identified as the most promising product in the results from the infected macrophages model (IC50: 4.7 µg/mL, safety index: 8). The most abundant compounds found in this EO were sesquiterpenes, notably curzerene and furanodiene. Eventually, the evaluation of the antidermatophytic activity of EOs appears to be an efficient method for identifying new potential drugs for the treatment of L. amazonensis.

Predictors of fluid intravasation during operative hysteroscopy: a preplanned prospective observational study with 200 cases / Preditores de intravasamento durante histeroscopia cirúrgica: um estudo observacional prospectivo com 200 casos

PURPOSE: To verify the predictors of intravasation rate during hysteroscopy. METHODS: Prospective observational study (Canadian Task Force classification II-1). All cases (n=200 women; 22 to 86 years old) were treated in an operating room setting. Considering respective bag overfill to calculate water balance, we tested two multiple linear regression models: one for total intravasation (mL) and the other for absorption rate (mL.min-1). The predictors tested (independent variables) were energy (mono/bipolar), tube patency (with/without tubal ligation), hysterometry (cm), age≤50 years, body surface area (m2), surgical complexity (with/without myomectomy) and duration (min). RESULTS: Mean intravasation was significantly higher when myomectomy was performed (442±616 versus 223±332 mL; p<0.01). In the proposed multiple linear regression models for total intravasation (adjusted R2=0.44; p<0.01), the only significant predictors were myomectomy and duration (p<0.01).In the proposed model for intravasation rate (R2=0.39; p<0.01), only myomectomy and hysterometry were significant predictors (p=0.02 and p<0.01, respectively). CONCLUSIONS: Not only myomectomy but also hysterometry were significant predictors of intravasation rate during operative hysteroscopy. .

OBJETIVO: Testar preditores do ritmo de intravasamento durante histeroscopia cirúrgica. MÉTODOS: Estudo prospectivo observacional (classificação: Canadian Task Force II-1) incluindo casos conduzidos em centro cirúrgico (n=200 mulheres; 22 a 86 anos de idade). Considerando os erros de aferição nas embalagens de solução de irrigação para calcular o balanço hídrico, nós testamos dois modelos de regressão linear múltipla: um para intravasamento total (mL) e outro para ritmo de intravasamento (mL.min-1). Os preditores testados (variáveis independentes) foram energia (mono/bipolar), permeabilidade tubária (com/sem ligadura tubária), histerometria (cm), status ovariano (idade≤50 anos), área de superfície corporal (m2), complexidade de cirurgia (com/sem miomectomia) e tempo de ressecção (min). RESULTADOS: O intravasamento médio foi significativamente maior quando miomectomia foi realizada (442±616 versus 223±332 mL, p<0,01). No modelo proposto para intravasamento total (R2 ajustado=0,44; p<0,01), os únicos preditores significativos foram miomectomia e tempo de duração (p<0,01). No modelo proposto para a taxa de intravasamento (R2=0,39; p<0,01), somente miomectomia e histerometria foram preditores significativos (p=0,02 e p<0,01, respectivamente). CONCLUSÕES: Não só a miomectomia mas também a histerometria são preditores significativo da taxa de intravasamento durante histeroscopia cirúrgica. .

Hand and foot syndrome secondary to capecitabine.

A 55-year-old woman on treatment with capecitabine and paclitaxel for breast carcinoma presented with history of a tingling sensation in her hands and feet with a progressive burning sensation. She also noted discomfort, minimal pain and stiffness while holding objects. On examination, there was patchy hyperpigmentation of both the palms and soles, and the dorsa of hands and feet. This was accompanied by a thickening of the skin more over the knuckles and toes. In addition there was a moist desquamation around the toes and over the palmar creases and a bluish discoloration of the lunulae of both thumbnails. She was diagnosed with hand and foot syndrome and started on pyridoxine and emollients. The finding of keratoderma noted in our patient is not seen commonly in hand and foot syndrome.

Metotrexate como inductor en la producción de citocinas proinflamatorias en células epiteliales / Methotrexate as inducer of proinflammatory cytokines by epithelial cells

El metotrexate (MTX) es uno de los medicamentos frecuentemente utilizados en el cáncer infantil señalándose además, como agente citotóxico de la mucosa bucal, que puede desencadenar el proceso inflamatorio e incremento de la vascularidad en los tejidos epiteliales durante las fases iniciales de la mucositis oral. El presente trabajo tiene como objetivo determinar la producción de citocinas proinflamatorias IL-1b, IL-6 y TNF-a en cultivos de células epiteliales tratadas con MTX. Se realizaron cultivos de células epiteliales de laringe humana obtenidas de la línea celular Hep-2, con diferentes dosis de MTX en distintos tiempos de incubación, y a su vez se analizó la citotoxicidad del fármaco mediante el ensayo colorimétrico, el cual se basa en la reducción metabólica del bromuro de 3-(4,5- dimetiltiazol-2-ilo)-2,5-difeniltetrazol (MTT), y la producción de citocinas proinflamatorias mediante el ensayo inmuno enzimático indirecto (ELISA). En cuanto a los resultados se observó, que los cultivos de células Hep-2 presentaron aumento en la producción de las citocinas proinflamatorias a las 72 horas al utilizar las dosis de 0.32µM MTX. Estos resultados sugieren que la dosis y el tiempo de exposición del MTX alteran la fisiología de las células epiteliales humanas, lo cual podrían desempeñar un papel importante durante las fases de iniciación y de desarrollo de la mucositis oral.

Methotrexate (MTX), a drug commonly used in childhood cancer, has also been indicated as a cytotoxic agent of the oral mucosa, which can trigger the inflammatory process and increase the vascularity of epithelial tissues during the early stages of oral mucositis. The aim of this study was to determine the production of proinflammatory cytokines IL-1b, IL-6 y TNF-a in epithelial cell cultures treated with MTX. Epithelial cells of human larynx, obtained from the cell line Hep-2, were cultured with different doses of MTX during different incubation times. The drug cytotoxicity was analyzed by means of the colorimetric test, which is based on the metabolic reduction of the bromide of 3-(4, 5-dimetiltiazol-2-ilo)-2,5-difeniltetrazol (MTT); and the proinflammatory cytokines production by the test enzyme-linked immunosorbent assay (ELISA). Cultures of HEp-2 cells showed increased production of proinflammatory cytokines at 72 hours with 0.32µM of MTX. These results suggest that depending on the dose and exposure time, MTX alters the physiology of human epithelial cells, which may play an important role during the phases of initiation and development of oral mucositis.

Gemcitabine-Induced Hemolytic Uremic Syndrome in Pancreatic Cancer: A Case Report and Review of the Literature

Hemolytic uremic syndrome (HUS) is a rare thrombotic complication characterized by a triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. HUS may be caused by several different conditions, including infection, malignancy, and chemotherapeutic agents, such as mitomycin, cisplatin, and most recently, gemcitabine. The outcome of gemcitabine-induced HUS is poor, and the disease has a high mortality rate. This study reports a case of gemcitabine-induced HUS in a patient with pancreatic cancer in Korea.

Chemotherapy induced liver abnormalities: an imaging perspective

Treating patients undergoing chemotherapy who display findings of liver toxicity, requires a solid understanding of these medications. It is important for any clinician to have an index of suspicion for liver toxicity and be able to recognize it, even on imaging. Cancer chemotherapy has evolved, and newer medications that target cell biology have a different pattern of liver toxicity and may differ from the more traditional cytotoxic agents. There are several hepatic conditions that can result and keen clinical as well as radiographic recognition are paramount. Conditions such as sinusoidal obstructive syndrome, steatosis, and pseudocirrhosis are more commonly associated with chemotherapy. These conditions can display clinical signs of acute hepatitis, liver cirrhosis, and even liver failure. It is important to anticipate and recognize these adverse reactions and thus appropriate clinical action can be taken. Often times, patients with these liver manifestations can be managed with supportive therapies, and liver toxicity may resolve after discontinuation of chemotherapy.

Citarabina y reacciones cutáneas en leucemia aguda mieloide / Cytarabine and skin reactions in acute myeloid leukemia

La citarabina es un antimetabolito utilizado en el tratamiento de las leucemias agudas mieloides (LAM). Esta droga presenta numerosos efectos adversos (mielosupresión, toxicidad en sistema nervioso central, hepática, gastrointestinal, ocular y cutánea). La toxicidad dermatológica es habitualmente descrita como rara, sin embargo existen diferencias en la incidencia comunicada. Se realizó un estudio retrospectivo donde se incluyeron todas las LAM tratadas con quimioterapia que incluía citarabina, entre el 1º de julio 2006 y el 1° de julio 2012. Se incluyeron 46 pacientes con una mediana de edad de 55 años. La incidencia global de reacciones cutáneas fue de 39% (n = 18). La presencia de lesiones cutáneas no se asoció con sexo, edad, antecedentes de atopía, de reacciones medicamentosas, tipo de LAM ni dosis de citarabina utilizada. Las lesiones se observaron entre 2 a 8 días de iniciado el tratamiento. En cuanto al grado lesional, 27.8% presentaron grado 1, 38.9% grado 2 y 33.3% grado 3. No existieron lesiones grado 4 ni muerte vinculada a toxicidad cutánea. En cuanto al tipo de lesiones, 55.6% se presentaban con máculas, 22.2% con pápulas y 22.2% con eritema. Con respecto a la distribución de las lesiones, 52% de los pacientes presentaron una distribución difusa, 39.3% acral y 8.7% a nivel flexural. Las reacciones adversas cutáneas con la administración de citarabina son frecuentes en nuestro medio, en algunos casos con afectación grave. Si bien suelen resolverse espontáneamente, pueden determinar mayor riesgo de infección, así como comprometer la calidad de vida.

Cytarabine is an antimetabolite used in the treatment of acute myeloid leukemia (AML). It has many adverse effects as: myelosuppression, toxic reactions involving central nervous system, liver, gastrointestinal tract, eyes or skin. Dermatologic toxicity is often described as rare; nevertheless there are differences in the reported frequency. We performed a retrospective study including all AML treated with chemotherapy that involved cytarabine between 1st July of 2006 and 1st July of 2012; 46 patients were included with a median age of 55 years. The overall incidence of skin reactions was 39% (n = 18). Sex, age, history of atopy, history of drug reactions, or dose of cytarabine used, were not associated with them. Skin reactions were observed from 2 to 8 days after treatment started. Considering injury degree: 27.8% had grade 1, 38.9% grade 2 and 33.3% grade 3. We did not find any injury grade 4 or death associated with skin toxicity. As for the type of injury: 55.6% presented macules, 22.2% papules and 22.2% erythema. Lesions distribution was diffuse in 52% of patients, acral in 39.3%, and at flexural level in 8.7%. Adverse cutaneous reactions secondary to the administration of cytarabine are frequent in our service and include some cases with severe involvement. Although these reactions usually resolve spontaneously, they determine an increased risk of infection and a compromise of the patient quality of life.

Síndrome hemolítico-urémico asociado al uso de gemcitabina: Caso clínico / Hemolytic-uremic syndrome associated with gemcitabine use: Report of one case

Gemcitabine is a widely used drug in the treatment of advanced pancreatic cancer and other malignancies. It is generally well tolerated and exceptionally its use has been associated with hemolytic-uremic syndrome, causing acute kidney injury, hipertension, chronic renal failure requiring dialysis, and death. We report a 60-year-old man with pancreatic carcinoma and regional lymph node invasion, whom after four months of therapy with gemcitabine and after dose number 11, suddenly developed an acute nephritic syndrome with moderate renal impairment, associated with severe anemia (hemoglobin 6.0 g/dL) and thrombocytopenia (20,000 mm³). Renal biopsy showed the classic findings of thrombotic micro angiopathy Gemcitabine was discontinued and renal function and hematological parameters gradually improved.

Síndrome mão-pé induzida por quimioterapia: relato de um caso / Hand-foot syndrome induced by chemotherapy: a case study / Síndrome mano-pie inducida por quimioterapia: relato de un caso

Objetivou-se relatar um caso de uma paciente que apresentou síndrome mão-pé de grau 3, decorrente do uso do quimioterápico Capecitabina e para a qual foi utilizada massagem local com creme hidratante aquoso à base de aloe vera. A capacidade funcional da paciente foi avaliada utilizando-se a Escala de Performance ECOG e as lesões fotografadas durante as consultas de enfermagem que ocorreram em intervalos de dez dias, totalizando quarenta dias de acompanhamento. Observou-se melhora significativa da integridade tissular, com regressão total dos sintomas, importante ganho em qualidade de vida, e retorno imediato ao tratamento quimioterápico. Acredita-se que o aloe vera pode ser um importante coadjuvante na assistência de enfermagem a pacientes submetidos à quimioterapia antineoplásica.

The study was aimed at reporting a case of a patient who developed Hand-Foot Syndrome (HFS) grade 3 due the use of capecitabine and for which massage was used with aqueous-based moisturizer, aloe vera. The patient's functional capacity was assessed using the ECOG Performance Scale and the lesions were photographed during nursing appointment that occurred at intervals of ten days, totaling forty days of monitoring. There was significant improvement in tissue integrity, with total regression of symptoms, an important gain in quality of life, and immediate return to chemotherapy. It is believed that aloe vera can be an important component in nursing care in patients undergoing cancer chemotherapy.

El estudio tiene como objetivo presentar un caso de una paciente que desarrolló la Síndrome Pie-Mano de grado 3 debido al uso de capecitabina y en que se utilizó el masaje con crema hidratante aloe vera, en base acuosa. La capacidad funcional de la paciente se evaluó mediante la Escala de Desempeño ECOG y las lesiones fueran fotografiadas durante las consultas de enfermería que ocurrirán a intervalos de diece días, con un total de cuarenta días de seguimiento. Hubo una mejora significativa en la integridad de los tejidos, con la regresión total de los síntomas, un aumento importante en la calidad de vida, y el retorno inmediato a la quimioterapia. Se cree que el aloe vera puede ser un componente importante en los cuidados de enfermería en pacientes sometidos a quimioterapia contra el cáncer.