Meningitis neoplásica en tumores sólidos: revisión actualizada de diagnóstico, pronóstico, manejo terapéutico y direcciones futuras / Neoplastic meningitis in solid tumours: Updated review of diagnosis, prognosis, therapeutic management, and future directions

La meningitis neoplásica (MN) es una complicación metastásica relativamente frecuente en pacientes con cáncer, con alta morbilidad neurológica y en general pobre pronóstico. La prevalencia está en torno al 5-15% de los tumores sólidos, y los más frecuentes son el cáncer de mama, el de pulmón y el melanoma. La clínica se produce por afectación de hemisferios cerebrales, nervios craneales, médula y raíces nerviosas, siendo en muchos casos multifocal, y presenta a menudo síntomas y signos de hipertensión intracraneal. Las principales herramientas diagnósticas son la exploración neurológica, la resonancia magnética cerebral y medular con contraste, y el análisis y la citología del líquido cefalorraquídeo (LCR), aunque recientemente se están investigando técnicas como la detección de células tumorales y ADN circulante en el LCR, que aumentan la sensibilidad diagnóstica. Con las terapias disponibles en la actualidad el objetivo del tratamiento no es curativo, sino retrasar y disminuir los síntomas y preservar la calidad de vida de los pacientes, e implica un enfoque multimodal que puede incluir radioterapia, quimioterapia intratecal y/o sistémica y cirugía. El tratamiento debe ser individualizado y se basa principalmente en guías y opiniones de expertos. Actualmente se están llevando a cabo ensayos clínicos prometedores de fármacos contra dianas moleculares e inmunoterápicos. Este artículo es una revisión actualizada de la MN, e incluye epidemiologia, presentación clínica, diagnóstico, pronóstico, manejo y opciones terapéuticas; se dirige al neurólogo general, y en particular al neurólogo que ejerce su práctica en centros con pacientes oncológicos. (AU)

Neoplastic meningitis (NM) is a relatively frequent metastatic complication of cancer associated with high levels of neurological morbidity and generally poor prognosis. It appears in 5%-15% of patients with solid tumours, the most frequent being breast and lung cancer and melanoma. Symptoms are caused by involvement of the cerebral hemispheres, cranial nerves, spinal cord, and nerve roots, and are often multifocal or present with signs and symptoms of intracranial hypertension. The main diagnostic tools are the neurological examination, brain and spinal cord contrast-enhanced magnetic resonance imaging, and cerebrospinal fluid analysis including cytology, although studies have recently been conducted into the detection of tumour cells and DNA in the cerebrospinal fluid, which increases diagnostic sensitivity. With the currently available therapies, treatment aims not to cure the disease, but to delay and ameliorate the symptoms and to preserve quality of life. Treatment of NM involves a multimodal approach that may include radiotherapy, intrathecal and/or systemic chemotherapy, and surgery. Treatment should be individualised, and is based mainly on clinical practice guidelines and expert opinion. Promising clinical trials are currently being conducted to evaluate drugs with molecular and immunotherapeutic targets. This article is an updated review of NM epidemiology, clinical presentation, diagnosis, prognosis, management, and treatment; it is aimed at general neurologists and particularly at neurologists practicing in hospital settings with oncological patients. (AU)

Miopericarditis inducida por altas dosis de citarabina: cuando el corazón se debilita, pero la lucha contra el cáncer se fortalece / High dose cytarabine induced myopericarditis: When the heart debilitates but the fight against cancer must be strong

Resumen La cardiotoxicidad por citarabina es un efecto adverso poco conocido. Se presenta el caso de un paciente de 51 años con antecedentes de Leucemia Mieloide Aguda manejada con altas dosis de citarabina y que presentó como consecuencia miopericarditis aguda. Luego del manejo de soporte en cuidados intensivos, se inició tratamiento cardioprotector específico para falla cardiaca y, dada la alta posibilidad de requerir citarabina en el manejo oncológico ulterior, se inició tratamiento con antinflamatorios no esteroideos y colchicina con el fin de reducir el riesgo de recurrencia de la miopericarditis. Se presenta el caso clínico, y una estrategia diagnóstica para pacientes con altas dosis de citarabina y compromiso pericárdico y miocárdico.

Summary Knowledge about cytarabine induced cardiotoxicity is scarce. We present the clinical case of a 51-year-old patient with past medical history of Acute Myeloid Leukemia managed with high doses of cytarabine and who developed acute myopericarditis as a complication. After support management in intensive care unit, specific cardioprotective heart failure therapy was started and, due to the high possibility of requiring high doses of cytarabine in subsequent oncological management, therapy with Non-Steroidal Anti-inflammatory drugs and colchicine was given to reduce the risk of myopericarditis recurrence. We present the clinical case and a diagnostic strategy for patients with high doses of cytarabine and pericardial and myocardial involvement.

Reacción adversa a Citarabina con compromiso cutáneo: reporte de caso / Adverse reaction to Cytarabine with skin involvement: case report: case report

RESUMEN Presentamos el caso de una paciente de 67 años con un diagnóstico clínico de reacción adversa cutánea al uso del agente quimioterapéutico citarabina, el cual recibió en el contexto del tratamiento médico por leucemia mieloide aguda. Se realiza la descripción epidemiológica, signos clínicos, evolución médica y realizamos la comparación con casos similares previamente descritos. Para excluir otros diagnósticos diferenciales se realizó estudio histopatológico y su correlación con el examen clínico.

ABSTRACT We report the case of a 67-year-old female patient with a medical diagnosis of cutaneous adverse reaction to the use of the chemotherapeutic agent cytarabine, which she received in the context of medical treatment for acute myeloid leukemia. Epidemiological description, clinical signs, medical evolution, and comparison with similar cases previously described. In order to exclude other differential diagnoses, histopathological study and its correlation with the clinical examination were performed.

Neoplastic meningitis in solid tumours: updated review of diagnosis, prognosis, therapeutic management, and future directions.

Neoplastic meningitis (NM) is a relatively frequent metastatic complication of cancer associated with high levels of neurological morbidity and generally poor prognosis. It appears in 5%-15% of patients with solid tumours, the most frequent being breast and lung cancer and melanoma. Symptoms are caused by involvement of the cerebral hemispheres, cranial nerves, spinal cord, and nerve roots, and are often multifocal or present with signs and symptoms of intracranial hypertension. The main diagnostic tools are the neurological examination, brain and spinal cord contrast-enhanced magnetic resonance imaging, and cerebrospinal fluid analysis including cytology, although studies have recently been conducted into the detection of tumour cells and DNA in the cerebrospinal fluid, which increases diagnostic sensitivity. With the currently available therapies, treatment aims not to cure the disease, but to delay and ameliorate the symptoms and to preserve quality of life. Treatment of NM involves a multimodal approach that may include radiotherapy, intrathecal and/or systemic chemotherapy, and surgery. Treatment should be individualised, and is based mainly on clinical practice guidelines and expert opinion. Promising clinical trials are currently being conducted to evaluate drugs with molecular and immunotherapeutic targets. This article is an updated review of NM epidemiology, clinical presentation, diagnosis, prognosis, management, and treatment; it is aimed at general neurologists and particularly at neurologists practicing in hospital settings with oncological patients.

Neoplastic meningitis in solid tumours: Updated review of diagnosis, prognosis, therapeutic management, and future directions. / Meningitis neoplásica en tumores sólidos: revisión actualizada de diagnóstico, pronóstico, manejo terapéutico y direcciones futuras.

Neoplastic meningitis (NM) is a relatively frequent metastatic complication of cancer associated with high levels of neurological morbidity and generally poor prognosis. It appears in 5%-15% of patients with solid tumours, the most frequent being breast and lung cancer and melanoma. Symptoms are caused by involvement of the cerebral hemispheres, cranial nerves, spinal cord, and nerve roots, and are often multifocal or present with signs and symptoms of intracranial hypertension. The main diagnostic tools are the neurological examination, brain and spinal cord contrast-enhanced magnetic resonance imaging, and cerebrospinal fluid analysis including cytology, although studies have recently been conducted into the detection of tumour cells and DNA in the cerebrospinal fluid, which increases diagnostic sensitivity. With the currently available therapies, treatment aims not to cure the disease, but to delay and ameliorate the symptoms and to preserve quality of life. Treatment of NM involves a multimodal approach that may include radiotherapy, intrathecal and/or systemic chemotherapy, and surgery. Treatment should be individualised, and is based mainly on clinical practice guidelines and expert opinion. Promising clinical trials are currently being conducted to evaluate drugs with molecular and immunotherapeutic targets. This article is an updated review of NM epidemiology, clinical presentation, diagnosis, prognosis, management, and treatment; it is aimed at general neurologists and particularly at neurologists practicing in hospital settings with oncological patients.

[Mantle cell lymphoma, response to treatment and prognosis in 45 patients]. / Linfoma de células del manto. Respuesta al tratamiento y pronóstico en 45 pacientes.

BACKGROUND AND PURPOSE: Mantle cell lymphoma (MCL) is a rare lymphoproliferative disorder, with frequent relapses and a poor prognosis. This study analyzes response to treatment and prognosis in a series of MCL patients. PATIENTS AND METHOD: Retrospective study of MCL patients diagnosed in a single institution between 1996 and 2013. The cohort was divided according to the treatment received. RESULTS: Forty-five patients were included (32 male) with a median age of 66 years old. Twenty-one received intensive chemotherapy or chemoimmunotherapy (based on high-dose cytarabine), 13 semi-intensive (without high-dose cytarabine), 8 not intensive and 3 did not require treatment. Overall response rate was 85% in the intensive and 77% in the semi-intensive treatment groups. In multivariate analysis, intensive treatment was correlated with a longer progression-free survival (hazard ratio 9.8 [95% CI 2.7-35.5], P=.001) and overall survival (4.5 [1.2-17.8], P=.03). CONCLUSIONS: In this retrospective series of MCL patients, intensive treatment was correlated with better outcomes than the other treatment modalities.

[Liposomal cytarabine for the treatment of leptomeningeal dissemination of central nervous system tumours in children and adolescents]. / Citarabina liposomal para el tratamiento de la diseminación leptomeníngea en tumores del sistema nervioso central en niños y adolescentes.

Leptomeningeal dissemination in paediatric central nervous system (CNS) tumours is associated with a poor outcome, and new therapeutic strategies are desperately needed. One of the main difficulties in the treatment of CNS tumours is blood brain barrier penetration. Intrathecal therapy has shown to be effective in several paediatric tumours. The aim of this article is to review the data available on the use of liposomal cytarabine for paediatric patients with leptomeningeal dissemination of CNS tumours, including the pharmacology, administration route, safety and efficacy data.

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.

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.(AU)

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.(AU)

Efeitos da ingestão de diferentes fontes lipídicas na mucosite em camundongos submetidos à quimioterapia com ARA-C / Effects of the intake of different lipid sources in mucositis in mice undergoing chemotherapy with ARA-C

Os lipídeos desempenham importante papel no metabolismo, na composição estrutural, transmissão de sinais celulares e na função imunológica do organismo. Os diferentes ácidos graxos que compõem os triacilgliceróis e fosfolípides vão ditar o tipo de resposta orgânica. Os agentes antineoplásicos são drogas amplamente utilizadas no tratamento de diversos tipos de câncer, tratamento este que, muitas vezes, resulta em efeitos colaterais responsáveis pela restrição da dose e sucesso da quimioterapia. Assim, dietas que previnam os efeitos deletérios da quimioterapia poderiam ser utilizadas como coadjuvantes no tratamento do câncer ou quimioterapia. Este trabalho teve por objetivo verificar a ação do consumo de diferentes fontes lipídicas à base de ácidos graxos ômega-3 (óleo de linhaça), triacilgliceróis de cadeia média (gordura de coco) e ácidos graxos trans (gordura vegetal hidrogenada) no trofismo intestinal de camundongos submetidos a tratamento com o quimioterápico (citarabina). Analisando o efeito da citarabina neste estudo, verificou-se que essa droga agrediu o organismo, causando perda de peso dos camundongos, diminuição da massa celular intestinal (sugerida pela redução no teor de DNA da mucosa intestinal) e relativo aumento da proteína na mucosa intestinal, principalmente nos animais alimentados com óleo de soja. As demais fontes lipídicas não alteraram os efeitos vistos pelo uso da citarabina. Os resultados sugerem, nas condições realizadas, não haver na utilização das fontes lipídicas citadas concomitantemente à aplicação da citarabina influência benéfica sobre e tratamento, sendo que a ingestão de óleo de soja pela sua riqueza em ácidos graxos ômega-6, poderia piorar o processo inflamatório decorrente da quimioterapia.

Lipids play an important role in metabolism, in the structural composition, in the transmission of cellular signals and in the body immune function. The different fatty acids that make up lhe triacylglycerols and phospholipids will dictate the type of organic response. The antineoplastic agents are widely used drugs in the treatment of various cancers, a treatment that often results in side effects responsible for restricting the rate and success of the chemotherapy. Thus, diets that prevent the deleterious effects of chemotherapy could be used as adjunct treatment of cancer or chemotherapy. This work was aimed at investigating the effects of the consumption of several lipid-based omega-3 (flaxseed oil), medium chain triglycerides (coconut) and Trans fatty acids (hydrogenated vegetable fat) in the intestinal tropism of mice treated with chemotherapy (cytarabine). Analyzing the effect of cytarabine in this study, it was found that this drug damaged the body, causing weight loss in mice, decreased intestinal cell mass (suggested by the reduction in the DNA content of the intestinal mucosa) and relative increase of protein in the intestinal mucosa mainly in animals fed with soybean oil. The other fat sources did not alter the effect seen by the use of cytarabine. The results suggest, in the existing conditions, that there is no beneficial influence on the treatment due to the use of the mentioned lipid sources concomitantly to the application on the cytarabine, and the intake of soybean oil, for its richness in Omega-6, could exacerbate the inflammatory process resulting from the chemotherapy.

Avaliação retrospectiva dos pacientes portadores de leucemia mielóide aguda tratados no serviço de hematologia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo entre 1978 e 2007 / Retrospetive evaluation of acute myeloid leukemia patients treated in University of Sao Paulo General Hospital between 1978 and 2007

A leucemia mielóide aguda ainda apresenta altos índices de mortalidade em adultos, exceção feita à leucemia promielocítica. A otimização dos protocolos de tratamento tem sido muito discutida há 3 décadas, com resultados ainda insatisfatórios. Fatores prognósticos como idade, cariótipo e tolerância à consolidação com altas doses de citarabina guardam relação com a melhor sobrevida. Com o objetivo de avaliar diferentes protocolos de tratamento e validar estes e outros fatores prognósticos, conduzimos um estudo retrospectivo no Hospital das Clínicas da Universidade de São Paulo, analisando prontuários médicos e os eventos relacionados à leucemia mielóide aguda, de 1978 a 2007. Analisamos 400 pacientes tratados curativamente e achamos que idade abaixo de 60 anos (27% vs 7%), cariótipo favorável (53% vs 28% vs 5%) e administração de doses totais de citarabina, principalmente se acima da mediana de 45,45 gramas (68% vs 44% vs 21%) tem impacto positivo na sobrevida global em 5 anos, sendo o uso de altas doses de citarabina um fator independente. A positividade para mieloproxidase, classificação FAB e protocolo de tratamento não mostraram associação estatisticamente significante para melhores índices de sobrevida. Pudemos concluir que, se os protocolos de indução não apresentam diferenças estatísticas, a consolidação intensiva com altas doses de citarabina em pacientes abaixo de 60 anos tem impacto independente na sobrevida global, com resultados ainda melhores quando a dose total é maior ou igual a 45,45 gramas. O cariótipo também foi validado em nossa população.

Acute myeloid leukemia in adults is still a highly fatal disease, except for acute promyelocitic leukemia. The optimization of treatment protocols has been debated for three decades, without satisfactory results. Prognostic factors like age, kariotype and consolidation with cytarabine in high dosis seem to correlact with a better overall survival. We conducted a retrospective study in the General Hospital of University of Sao Paulo analyzing medical records and acute myeloid leukemia outcomes to compare different treatment protocols used through 1978 to 2007. We also intended to validate international prognostic factors as the ones cited in our population. We analyzed 400 patients treated with curative intention and found better overall survival in 5 years regarding age less than 60 years (27% vs 7%), favorable karyotipe (53% vs 28% vs 5%) and high dosis cytarabine in consolidation, meanly if total dose was at least the median of 45,45 g (68% vs 44% vs 21%). Consolidation with high dosis cytarabine was an independent predictor of better overall survival. No estatistical differences were seen regarding myeloperoxidase positivity, induction protocol and FAB classification. We concluded that, if the induction protocols seem to be no different in results, consolidation with high dosis cytarabine for patients under 60 years has impact in overall survival, being even better when the total dosis is at least 45,45 g. Karyotipe has also been validated in our study population.