RESUMO
Diffuse intrinsic pontine glioma (DIPG) is an incurable disease with a median overall survival of 10 months. Immune modulating antibodies have recently emerged as a highly promising treatment modality in multiple cancer types. We present results from the first study to evaluate the immune modulating antibody MDV9300 (pidilizumab) in pediatric patients with DIPG. All patients aged 3 years and older, diagnosed with DIPG between February 2014 and June 2015 in Israel, were offered to participate in the study. Enrolled patients were started on biweekly 6 mg/kg MDV9300 after radiation completion. Treatment was continued until disease progression on imaging. Patients were followed biweekly for the occurrence of neurological deficit toxicities and side effects. Secondary endpoints were event free survival and overall survival. Of 13 children diagnosed with DIPG during the study period, nine were enrolled in the study. The patients underwent radiotherapy and none had chemotherapy. A total of 83 cycles of MDV9300 (range 2-16) were applied. The main side effects were neutropenia (CTCAE grade 1-3), mild to moderate fatigue, and acute elevation of blood pressure. Four patients died within 1 year of the diagnosis, another three died within 2 years and two children are still alive nearly 30 months from diagnosis, with stable disease. The median event free survival is 9.3 months (range 6.8-24) and the median overall survival is 15.6 months (range 6.9-28). Preliminary results demonstrate that MDV9300 treatment is safe and may be effective in the treatment of children with DIPG.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias do Tronco Encefálico/tratamento farmacológico , Glioma/tratamento farmacológico , Adolescente , Neoplasias do Tronco Encefálico/imunologia , Neoplasias do Tronco Encefálico/radioterapia , Criança , Pré-Escolar , Terapia Combinada , Progressão da Doença , Feminino , Glioma/imunologia , Glioma/radioterapia , Humanos , Masculino , Intervalo Livre de Progressão , Estudos Prospectivos , Análise de SobrevidaRESUMO
C12orf65 participates in the process of mitochondrial translation and has been shown to be associated with a spectrum of phenotypes, including early onset optic atrophy, progressive encephalomyopathy, peripheral neuropathy, and spastic paraparesis.We used whole-genome homozygosity mapping as well as exome sequencing and targeted gene sequencing to identify novel C12orf65 disease-causing mutations in seven affected individuals originating from two consanguineous families. In four family members affected with childhood-onset optic atrophy accompanied by slowly progressive peripheral neuropathy and spastic paraparesis, we identified a homozygous frame shift mutation c.413_417 delAACAA, which predicts a truncated protein lacking the C-terminal portion. In the second family, we studied three affected individuals who presented with early onset optic atrophy, peripheral neuropathy, and spastic gait in addition to moderate intellectual disability. Muscle biopsy in two of the patients revealed decreased activities of the mitochondrial respiratory chain complexes I and IV. In these patients, we identified a homozygous splice mutation, g.21043 T>A (c.282+2 T>A) which leads to skipping of exon 2. Our study broadens the phenotypic spectrum of C12orf65 defects and highlights the triad of optic atrophy, axonal neuropathy and spastic paraparesis as its key clinical features. In addition, a clear genotype-phenotype correlation is anticipated in which deleterious mutations which disrupt the GGQ-containing domain in the first coding exon are expected to result in a more severe phenotype, whereas down-stream C-terminal mutations may result in a more favorable phenotype, typically lacking cognitive impairment.
Assuntos
Estudos de Associação Genética , Proteínas Mitocondriais/genética , Mutação , Fatores de Terminação de Peptídeos/genética , Fenótipo , Adolescente , Adulto , Processamento Alternativo , Sequência de Aminoácidos , Encéfalo/patologia , Criança , Consanguinidade , Análise Mutacional de DNA , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Atrofia Óptica/genética , Linhagem , Adulto JovemAssuntos
Isquemia Encefálica/complicações , Stents , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/cirurgia , Trombectomia/métodos , Doença Aguda , Idoso , Isquemia Encefálica/diagnóstico , Artéria Carótida Interna/diagnóstico por imagem , Artéria Carótida Interna/cirurgia , Estenose das Carótidas/complicações , Estenose das Carótidas/diagnóstico , Estenose das Carótidas/cirurgia , Feminino , Humanos , Acidente Vascular Cerebral/diagnóstico , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
OBJECTIVES: Spinal epidural lipomatosis, is a very rare condition, usually seen as an uncommon complication of Cushing's syndrome secondary to chronic steroid therapy leading to increased fat deposits in the epidural space. CASE REPORT: We report the first documented case of acute symptomatic spinal epidural lipomatosis in a patient with relapsed non-Hodgkin lymphoma. The patient underwent an allogeneic bone marrow transplantation (BMT) and a month of steroid treatment for acute graft vs. host disease (GvHD). He presented with a mild to moderate Cushing's syndrome and minimal obesity. He progressed rapidly to paraparesis, sensory deficit, urinary incontinence and finally respiratory arrest complicated with staphylococcal sepsis. CONCLUSION: Epidural lipomatosis, with subacute thecal sac compression, is a possible life-threatening complication of relatively short-term systemic glucocorticoid therapy for GvHD in BMT setting.