RESUMEN
TOPIC: Children and adults with neurofibromatosis type 1 (NF1), a common autosomal dominant condition, manifest a variety of ophthalmologic conditions. Plexiform neurofibromas (PNs) involving the eyelid, orbit, periorbital, and facial structures (orbital-periorbital plexiform neurofibroma [OPPN]) can result in significant visual loss in children. Equally important, OPPNs can cause significant alteration in physical appearance secondary to proptosis, ptosis, and facial disfigurement, leading to social embarrassment and decreased self-esteem. CLINICAL RELEVANCE: Although NF1 is a relatively common disease in which routine ophthalmologic examinations are required, no formal recommendations for clinical care of children with OPPNs exist. Although medical and surgical interventions have been reported, there are no agreed-on criteria for when OPPNs require therapy and which treatment produces the best outcome. METHODS: Because a multidisciplinary team of specialists (oculofacial plastics, pediatric ophthalmology, neuro-ophthalmology, medical genetics, and neuro-oncology) direct management decisions, the absence of a uniform outcome measure that represents visual or aesthetic sequelae complicates the design of evidence-based studies and feasible clinical trials. RESULTS: In September 2013, a multidisciplinary task force, composed of pediatric practitioners from tertiary care centers experienced in caring for children with OPPN, was convened to address the lack of clinical care guidelines for children with OPPN. CONCLUSIONS: This consensus statement provides recommendations for ophthalmologic monitoring, outlines treatment indications and forthcoming biologic therapy, and discusses challenges to performing clinical trials in this complicated condition.
Asunto(s)
Neoplasias de los Párpados/terapia , Neurofibroma Plexiforme/terapia , Neurofibromatosis 1/complicaciones , Neoplasias Orbitales/terapia , Niño , Consenso , Prestación Integrada de Atención de Salud , Manejo de la Enfermedad , Neoplasias de los Párpados/patología , Humanos , Comunicación Interdisciplinaria , Neurofibroma Plexiforme/patología , Guías de Práctica Clínica como AsuntoRESUMEN
BACKGROUND: Neurofibromatosis type 1 (NF1) is an inherited disease predisposing affected patients to variable numbers of benign neurofibromas. To date there are no effective chemotherapeutic drugs available for this slow growing tumor. Molecularly targeted agents that aim to slow neurofibroma growth are being tested in clinical trials. So preclinical models for testing potential therapies are urgently needed to prioritize drugs for clinical trials of neurofibromas. PROCEDURE: We used magnetic resonance imaging (MRI) to monitor neurofibroma development in the Nf1(flox/flox) ;DhhCre mouse model of GEM grade I neurofibroma. Based on studies implicating mTOR and Raf signaling in NF1 mutant cells, we tested the therapeutic effect of RAD001 and Sorafenib in this model. Mice were scanned to establish growth rate followed by 8 weeks of drug treatment, then re-imaged after the last dose of drug treatment. Tumor volumes were determined by volumetric measurement. RESULTS: We found that rate of tumor growth varied among mice, as it does in human patients. RAD001 inhibited its predicted target pS6K, yet there was no significant decrease in the tumor volume in RAD001 treated mice compared to the vehicle control group. Sorafenib inhibited cyclinD1 expression and cell proliferation in tumors, and volumetric measurements identified significant decreases in tumor volume in some mice. CONCLUSION: The data demonstrate that volumetric MRI analysis can be used to monitor the therapeutic effect in the preclinical neurofibroma drug screening, and suggest that Sorafenib might have clinical activity in some neurofibromas.
Asunto(s)
Bencenosulfonatos/uso terapéutico , Modelos Animales de Enfermedad , Proteínas Hedgehog/fisiología , Imagen por Resonancia Magnética , Neurofibroma Plexiforme/tratamiento farmacológico , Neurofibroma Plexiforme/patología , Neurofibromina 1/fisiología , Piridinas/uso terapéutico , Sirolimus/análogos & derivados , Animales , Antineoplásicos/sangre , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Bencenosulfonatos/sangre , Bencenosulfonatos/farmacocinética , Western Blotting , Proliferación Celular/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Evaluación Preclínica de Medicamentos , Everolimus , Femenino , Humanos , Técnicas para Inmunoenzimas , Inmunosupresores/uso terapéutico , Integrasas/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Piridinas/sangre , Piridinas/farmacocinética , Transducción de Señal , Sirolimus/uso terapéutico , Sorafenib , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Distribución Tisular , Carga TumoralRESUMEN
INTRODUCTION: Measurement of tumor response by standard response criteria is challenging in thymic malignancies, especially when the pleura is involved, as it often is in stage IV disease. In this study, we aimed to determine the effectiveness of volumetric response evaluation criteria in solid tumors (volumetrics) for evaluating response in patients with thymic malignancies treated on a phase II study of belinostat. METHODS: We evaluated the tumor responses of 25 patients with thymic cancer using computed tomography-based RECIST, World Health Organization (WHO), modified RECIST, and volumetrics. As a control, we assessed 37 patients with non-small cell lung cancer (NSCLC) with RECIST and volumetrics. RESULTS: Agreement analyses in 23 patients with thymic cancer at the time of RECIST-determined progressive disease (PD) compared volumetrics with RECIST, modified RECIST, and WHO criteria. Use of volumetrics was associated with 22% discordance compared with RECIST, 15% versus modified RECIST, and 22% versus WHO criteria. Volumetrics revealed PD 72 days earlier than RECIST (p = 0.016). In another cohort of 35 patients with NSCLC, there was 9% discordance between volumetrics and RECIST at the time of PD. Volumetrics demonstrated PD 32 days earlier than RECIST in NSCLC (p = 0.0078). CONCLUSIONS: Our study suggests that volumetrics might improve detection of PD. Prospective evaluation of this technique in a larger series of patients with thymic malignancies will be required.