The Utility of the Liverpool Adverse Drug Reaction Assessment Tools in the Evaluation of Chemotherapy-Induced Nausea and Vomiting in Children / Utilidade das Ferramentas de Avaliação de Reações Adversas a Medicamentos de Liverpool na Análise de Náuseas e Vômitos Induzidos por Quimioterapia em Crianças / La Utilidad de las Herramientas de Evaluación de Reacciones Adversas a Medicamentos de Liverpool en la Evaluación de Náuseas y Vómitos Inducidos por Quimioterapia en Niños

Introduction: Chemotherapy-induced nausea and vomiting (CINV) are common adverse drug reactions (ADR) experienced by children undergoing treatment for cancer. New paediatric ADR Assessment Causality and Avoidability tools (LCAT and LAAT) of Liverpool are suitable for categorizing factors related to ADR prevention and improving patient care. Still, no studies to date have compared the utility and results of its application for CINV in countries with different levels of development. Objective: To investigate the utility of the Liverpool Adverse Drug Reaction Causality and Avoidability Assessment Tools (LCAT and LAAT) in assessing CINV in children. Method: Prospective observational study of CINV assessment in children aged 4 to 16 years from Alder Hey Children's Hospital (Liverpool, UK) and "Instituto de Puericultura e Pediatria Martagão Gesteira" (Rio de Janeiro, Brazil). Children (helped by the parents) completed a symptom diary during chemotherapy and for 24 hours after treatment. Information regarding underlying diagnosis, past medical history, and medications administered was collected from the patient record. Case reports were prepared, and the temporal relationship between nausea and vomiting and exposure to chemotherapy, including any strategy to prevent CINV, was recorded. The causality and avoidability were assessed with LCAT and LAAT, respectively. Results: There were 26 reports of CINV in 36 chemotherapy cycles. The causality assessment was 'definite' for 24 cases. Twenty ADRs were deemed 'definitely avoidable' and four 'not avoidable'. Selection of inappropriate therapeutic options and non-administration of antiemetic were the most common factors observed in the hospitals studied. Conclusion: The LCAT and LAAT were helpful for assessing CINV in children in two different hospitals.

Introdução: Náuseas e vômitos induzidos por quimioterapia (NVIQ) são reações adversas a medicamentos (RAM) comuns em crianças em tratamento oncológico. Novas ferramentas de Avaliação de Causalidade e Evitabilidade de RAM de Liverpool (LCAT e LAAT) foram validadas e auxiliam a categorização de fatores de risco. Contudo, até o momento, nenhum estudo comparou a utilidade e os resultados de sua aplicação para NVIQ em países com diferentes níveis de desenvolvimento. Objetivo: Investigar a utilidade da LCAT e LAAT na avaliação de NVIQ. Método: Estudo observacional prospectivo com crianças de 4 a 16 anos do Alder Hey Children's Hospital (Liverpool, Reino Unido) e do Instituto de Puericultura e Pediatria Martagão Gesteira (Rio de Janeiro, Brasil). As crianças (ajudadas pelos pais) preencheram um diário de sintomas durante e até 24 horas após administração da quimioterapia. Informações sobre diagnóstico subjacente, história médica pregressa e medicamentos administrados foram coletadas do prontuário do paciente. Relatos de casos foram preparados e a relação temporal entre náuseas e vômitos e exposição à quimioterapia, incluindo qualquer estratégia para prevenir NVIQ, foi registrada para análise da causalidade e evitabilidade com o auxílio de LCAT e LAAT, respectivamente. Resultados: Houve 26 notificações de NVIQ em 36 ciclos de quimioterapia. A causalidade foi 'definida' para 24 casos. Foram consideradas 'definitivamente evitáveis' 20 RAM e 'não evitáveis', quatro. A seleção de opções terapêuticas inadequadas e a omissão de antieméticos foram os principais problemas evitáveis. Conclusão: O LCAT e o LAAT foram úteis para avaliar NVIQ em crianças em dois hospitais diferentes

Introducción: Las náuseas y vómitos inducidos por quimioterapia (NVIQ) son reacciones adversas a medicamentos (RAM) comunes en niños en tratamiento oncológico. Nuevas herramientas de Evaluación de Causalidad y Evitabilidad de RAM de Liverpool (LCAT y LAAT) han sido validadas y ayudan en la categorización de factores de riesgo. Sin embargo, ningún estudio ha comparado su utilidad y resultados para evaluación de NVIQ en países con diferentes niveles de desarrollo. Objetivo: Investigar la utilidad de LCAT y LAAT en la evaluación de NVIQ. Método: Estudio observacional prospectivo con niños de 4 a 16 años del Alder Hey Children's Hospital (Liverpool, Reino Unido) y del Instituto de Pediatría Martagão Gesteira (Río de Janeiro, Brasil). Los niños (ayudados por los padres) completaron un diario de síntomas durante y hasta 24 horas después de la quimioterapia. La información sobre el diagnóstico subyacente, la historia médica previa y los medicamentos se recopiló de la historia clínica médico del paciente. Se prepararon informes de casos y se registró la relación temporal entre las RAM y la exposición a la quimioterapia, incluyendo cualquier estrategia para prevenir NVIQ, para análisis de causalidad y evitabilidad con LCAT y LAAT, respectivamente. Resultados: Hubo 26 notificaciones de NVIQ en 36 ciclos de quimioterapia. La causalidad fue "definida" para 24 casos. Fueron consideradas "definitivamente evitables" 20 RAM y "no evitables", cuatro. La selección de opciones terapéuticas inadecuadas y la omisión de antieméticos fueron los principales problemas evitables. Conclusión: LCAT y LAAT fueron útiles para evaluar NVIQ en niños en dos hospitales diferentes

Embryonal sarcoma of the liver in a girl with Cockayne syndrome.

The first reported malignancy associated with Cockayne syndrome.

Childhood Malignant Brain Tumors: Balancing the Bench and Bedside.

Brain tumors are the leading cause of childhood cancer deaths in developed countries. They also represent the most common solid tumor in this age group, accounting for approximately one-quarter of all pediatric cancers. Developments in neuro-imaging, neurosurgical techniques, adjuvant therapy and supportive care have improved survival rates for certain tumors, allowing a future focus on optimizing cure, whilst minimizing long-term adverse effects. Recent times have witnessed a rapid evolution in the molecular characterization of several of the common pediatric brain tumors, allowing unique clinical and biological patient subgroups to be identified. However, a resulting paradigm shift in both translational therapy and subsequent survival for many of these tumors remains elusive, while recurrence remains a great clinical challenge. This review will provide an insight into the key molecular developments and global co-operative trial results for the most common malignant pediatric brain tumors (medulloblastoma, high-grade gliomas and ependymoma), highlighting potential future directions for management, including novel therapeutic options, and critical challenges that remain unsolved.

Pharmacological Management of Childhood-Onset Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a rare, severe, multisystem autoimmune disorder. Childhood-onset SLE (cSLE) follows a more aggressive course with greater associated morbidity and mortality than adult-onset SLE. Its aetiology is yet to be fully elucidated. It is recognised to be the archetypal systemic autoimmune disease, arising from a complex interaction between the innate and adaptive immune systems. Its complexity is reflected by the fact that there has been only one new drug licensed for use in SLE in the last 50 years. However, biologic agents that specifically target aspects of the immune system are emerging. Immunosuppression remains the cornerstone of medical management, with glucocorticoids still playing a leading role. Treatment choices are led by disease severity. Immunosuppressants, including azathioprine and methotrexate, are used in mild to moderate manifestations. Mycophenolate mofetil is widely used for lupus nephritis. Cyclophosphamide remains the first-line treatment for patients with severe organ disease. No biologic therapies have yet been approved for cSLE, although they are being used increasingly as part of routine care of patients with severe lupus nephritis or with neurological and/or haematological involvement. Drugs influencing B cell survival, including belimumab and rituximab, are currently undergoing clinical trials in cSLE. Hydroxychloroquine is indicated for disease manifestations of all severities and can be used as monotherapy in mild disease. However, the management of cSLE is hampered by the lack of a robust evidence base. To date, it has been principally guided by best-practice guidelines, retrospective case series and adapted adult protocols. In this pharmacological review, we provide an overview of current practice for the management of cSLE, together with recent advances in new therapies, including biologic agents.

Expression of Toll-like receptors and their detection of nuclear self-antigen leading to immune activation in JSLE.

OBJECTIVES: Toll-like receptors (TLRs) essential in the functioning of the immune system have been implicated in the development of autoimmunity. TLR3, 7, 8 and 9 are capable of recognizing nucleic autoantigens typical of SLE. Their expression correlates positively with disease activity in adult-onset SLE. This study aimed to determine the role of TLRs in JSLE and whether apoptotic neutrophils are a source of nuclear autoantigen being detected through TLR3, 7, 8 and 9, leading to an inflammatory response. METHODS: TLR3, 7, 8 and 9 mRNA and protein expression were measured in peripheral blood mononuclear cells (PBMCs) in JSLE patients compared with JIA and non-inflammatory controls. Activation of the TLRs by JSLE serum-induced apoptotic neutrophils was detected by measuring IFN-α mRNA and protein expression, and confirmed using myeloid differentiation factor 88 (MyD88) and TIR domain-containing adapter-inducing IFN-ß (TRIF) inhibitors. RESULTS: JSLE patients have increased TLR3, 8 and 9 mRNA and protein expression compared with controls (P < 0.05). Incubation of PBMCs with apoptotic neutrophils demonstrated a dose-response relationship for IFN-α mRNA expression. Inhibition of TLR signalling by blocking MyD88 and TRIF signalling decreased IFN-α mRNA expression in PBMCs incubated with apoptotic neutrophils (P < 0.05). CONCLUSIONS: This study demonstrated significantly increased TLR expression in JSLE compared with controls. Our data indicate that apoptotic neutrophils trigger TLR activation through their presentation of autoantigens. The role of TLRs in this inflammatory response was demonstrated by a dose-response relationship to apoptotic neutrophil concentration and confirmed by a decrease in IFN-α production after inhibition of TLR signalling.