von Hippel-Lindau Disease (VHL) We are continuing to follow VHL patients in a natural history study of 250 VHL patients (Lonser et al. 2014) to gain further insights into the natural history of VHL-associated central nervous system (CNS) hemangioblastomas. So far, our findings confirm that most hemangioblastomas grow in a saltatory pattern characterized by periods of growth and quiescence. Quiescent tumors do not need treatment. Hemangioblastomas are more likely to cause symptoms and need surgical treatment if they are associated with enlarging tumor cysts. Plasma extravasation through permeable tumor vessels underlies the formation of peritumoral cysts. Embryologic hemangioblasts are the cells of origin of VHL-associated CNS hemangioblastomas. New, noninvasive treatments for VHL-associated CNS hemangioblastoma are needed. Our laboratory has documented that mutant VHL protein that results from a germline missense VHL gene mutation retains some biochemical function, but accelerated breakdown of the mutant protein eliminates this function. Vorinostat, a histone deacetylase inhibitor that is approved for the treatment of refractory cutaneous T-cell lymphoma (CTCL), experimentally slows the intracellular breakdown of the mutant VHL protein. An intramural clinical study (14-N-0067) is ongoing in which Vorinostat is given for 1 week to adult patients with known germline missense VHL gene mutation who require surgical resection of a hemangioblastoma. The study examines the presence and quantity of mutant VHL protein tumor in tumor specimens from surgery. The level of mutant VHL protein from Vorinostat-treated patients will be compared to levels of mutant VHL protein in tissue banked from previous surgical resections. Genetic expression of vascular endothelial growth factor (VEGF) and erythropoietin (EPO) in tumor is also measured. This study will provide preliminary data that may support a subsequent therapeutic clinical trial of Vorinostat in patients with missense VHL mutations. This year Surgical Neurology Branch members continued to publish articles explaining how peritumoral cyst formation in symptom produces symptoms in patients with VHL-related hemangioblastoma. We also showed that symptomatic tumors had erythropoietin signaling. Neurofibromatosis Type 2 (NF2) The protean nature of central nervous system tumors in NF2 and incomplete understanding of their natural history and underlying mechanisms of symptom formation have resulted in treatment being delayed until after the development of neurologic deficits. Based on this treatment paradigm, tumors at the time of treatment are typically large and associated with irreversible neurologic deficits and increased risk of treatment-induced morbidity. Subsequently, knowledge of the natural history of tumors associated with NF2 is critical in predicting the future growth of a tumor and deciding on the best treatment of affected patients. This year we reported that not all symptomatic peripheral nerve tumors that were surgically removed in the NF2 study were solely schwannomas, with 20% of tumors displaying histologic features of both schwannoma and neurofibroma. To gain clinical and molecular insights into the effects of NF-2 gene mutations on tumor development/progression and to identify features associated with symptom evolution in NF2-associated tumors, we are performing an ongoing natural history study of 169 NF2 patients. So far, 104 patients have completed the study by reaching the prescribed 5-year follow-up time point. We will continue to follow all enrolled patients until November 20, 2018, which is when the last enrollee will finish 5-years in the study. Analysis of this study data will allow us to gain a better understanding of the natural history of CNS tumors in NF2. So far, variable patterns of tumor growth, including a stuttering pattern, have been observed in many subjects. Preliminary studies suggest that genetic factors beyond the NF2 gene mutation are associated with increased meningioma aggressiveness in patients with NF2. This prospective natural history study should be useful in identifying the factors that affect tumor biology, symptom formation and, optimal timing of treatment.
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