Neuro-oncology of Familial Neoplasia Syndromes

冯·希佩尔-林道病(VHL) 我们正在继续对250名VHL患者进行自然病史研究(Lonser等人)。2014)以进一步了解VHL相关的中枢神经系统(CNS)血管母细胞瘤的自然历史。到目前为止，我们的研究结果证实，大多数血管母细胞瘤以跳跃式生长为特征，其特点是生长和停滞。静止的肿瘤不需要治疗。如果血管母细胞瘤伴有肿瘤囊增大，则更有可能出现症状，需要手术治疗。通过可渗透的肿瘤血管的血浆外渗是形成瘤周囊肿的基础。 胚胎学血管母细胞是VHL相关中枢神经系统血管母细胞瘤的起源细胞。VHL相关的CNS血管母细胞瘤需要新的非侵入性治疗方法。我们的实验室已经证明，由胚系错义VHL基因突变引起的突变VHL蛋白保留了一些生化功能，但突变蛋白的加速分解消除了这一功能。伏立诺是一种组蛋白去乙酰酶抑制剂，被批准用于治疗难治性皮肤T细胞淋巴瘤(CTCL)，它在实验上减缓了突变的VHL蛋白的细胞内分解。一项内部临床研究(14-N-0067)正在进行中，在该研究中，Vorinostat被用于已知的胚系错义VHL基因突变的成年患者，这些患者需要手术切除血管母细胞瘤。这项研究检查了手术切除的肿瘤标本中突变的VHL蛋白肿瘤的存在和数量。Vorinostat治疗患者的突变VHL蛋白水平将与以前手术切除的组织中突变VHL蛋白的水平进行比较。同时检测肿瘤组织中血管内皮生长因子(VEGF)和促红细胞生成素(EPO)的基因表达。这项研究将提供初步数据，可能支持Vorinostat在VHL错义突变患者中的后续临床治疗试验。 今年外科神经病学分会继续发表文章，解释VHL相关血管母细胞瘤患者瘤周囊肿形成的症状是如何产生症状的。我们还发现，有症状的肿瘤有促红细胞生成素信号。 神经纤维瘤病2型(NF2) NF2中枢神经系统肿瘤的多变性质，以及对其自然病史和潜在症状形成机制的不完全了解，导致治疗被推迟到神经功能缺陷发展之后。根据这种治疗模式，肿瘤在治疗时通常很大，并与不可逆转的神经功能障碍和增加治疗引起的发病率增加有关。因此，了解与NF2相关的肿瘤的自然病史对于预测肿瘤的未来生长和决定受影响患者的最佳治疗至关重要。今年，我们报道了在NF2研究中手术切除的所有有症状的周围神经肿瘤并不都是单纯的神经鞘瘤，20%的肿瘤同时表现出神经鞘瘤和神经纤维瘤的组织学特征。 为了深入了解NF-2基因突变对肿瘤发生/发展的影响，并确定与NF2相关肿瘤症状演变相关的特征，我们正在对169名NF2患者进行自然病史研究。到目前为止，104名患者已经完成了研究，达到了规定的5年随访时间点。我们将继续跟踪所有登记的患者，直到2018年11月20日，也就是最后一名参与者完成为期5年的研究。对这项研究数据的分析将使我们更好地了解NF2中中枢神经系统肿瘤的自然历史。到目前为止，在许多受试者中观察到了不同的肿瘤生长模式，包括口吃模式。初步研究表明，NF2基因突变以外的遗传因素与NF2患者脑膜瘤侵袭性增加有关。这项前瞻性的自然历史研究应该有助于确定影响肿瘤生物学、症状形成和最佳治疗时机的因素。

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.