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和注射器的基础。 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基因突变表达的突变VHL蛋白保留了一些生化功能，但这种功能随着突变蛋白的加速分解而丧失。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。为了验证这一假设，我们招募了7名患有症状性中枢神经系统血管母细胞瘤的生殖系错义VHL患者。受试者接受400毫克/天的伏立诺治疗，连续7天，并手术切除血管母细胞瘤。采用免疫印迹、免疫组织化学和实时定量定量聚合酶链式反应等方法对血管母细胞瘤进行分析。我们发现，在与VHL相关的血管母细胞瘤中，使用旋涡剂的短期治疗增加了pVHL水平，并抑制了肿瘤进展。这些结果表明，HDACi治疗可以挽救生殖系错义突变的VHL患者的肿瘤pVHL，治疗可以阻止肿瘤的生长。 我们还分析了大量VHL患者中球后血管母细胞瘤的自然病史，以确定其表现、进展和处理。18例球后血管母细胞瘤患者接受了MRI检查，符合本研究的纳入标准。我们发现球后血管母细胞瘤可以在较长时间内保持稳定且无临床症状。新近生长和较大的肿瘤体积与症状的发生有关。症状性球后血管母细胞瘤的手术治疗是安全的，并且可以逆转相关的症状。 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。 为了深入了解NF2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269名NF2患者进行自然病史研究。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。这项前瞻性的自然病史研究应该有助于确定影响肿瘤生物学、症状形成和NF2最佳治疗时机的因素。 我们完成了一项纵向分析(未发表，在AANS 2017年年会上的口头演示)。我们试图前瞻性地分析FLAIR MRI在预测NF2患者听力损失方面的作用。我们在一组小的、未经治疗的VS(500mm3)患者中验证了这一假设，以避免手术或大肿瘤大小对迷宫FLAIR信号的影响。我们证实，没有听力损失的患者有正常的迷路FLAIR信号。然后我们发现，迷路FLAIR信号的变化早于听力损失2.7年。在任何情况下，FLAIR信号都没有从升高变为正常。这些有趣的发现为临床医生提供了一个机会，用一种非侵入性的听力损失预测生物标志物来监测NF2患者。 2型神经纤维瘤病(NF2)患者由于肿瘤局部压迫以及NF2单倍体功能不全介导的轴突神经病，容易出现周围神经病症状。我们最近分析了NF2患者中压迫性和全身性周围神经病变的患病率，并评估了手术在缓解神经病变症状方面的作用。我们发现，NF2患者由于肿瘤压迫和轴索神经病变而出现周围神经病症状。在肿瘤明显受压的情况下，保留神经束的手术切除可以缓解神经性症状。EMG/NCS研究有助于指导有周围神经病变症状的NF2患者的治疗。

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 and syringes. 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 expressed by a germline missense VHL gene mutation retains some biochemical function, but this function is lost through accelerated breakdown of the mutant protein. Vorinostat, a histone deacetylase inhibitor approved for the treatment of refractory cutaneous T-cell lymphoma (CTCL), experimentally slows the intracellular breakdown of the mutant VHL protein. To test this hypothesis, we enrolled seven germline missense VHL patients with symptomatic central nervous system hemangioblastomas. The subjects received 400 mg/day of vorinostat for seven days and surgical resection hemangioblastomas. Hemangioblastomas were analyzed using Western blot, immunohistochemistry and real-time qPCR. We found that short-duration treatment with vorinostat increased pVHL levels and suppressed tumor progression sigmaling in VHL-associated hemangioblastomas. These results indicate that HDACi treatment can rescue tumor pVHL in germline missense mutated VHL patients and treatment could arrest tumor growth. We also analyzed the natural history of retrobulbar hemangioblastomas in a large cohort of VHL patients in order to define presentation, progression and management. Eighteen patients with retrobulbar hemangioblastoma on surveillance MR imaging met the inclusion criteria for this study. We found that retrobulbar hemangioblastomas may remain stable and clinically asymptomatic for long durations. Recent growth and larger tumor volume were associated with symptom occurrence. Surgical treatment of symptomatic retrobulbar hemangioblastomas can be safe and may reverse the associated symptoms. 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 for predicting the future growth of a tumor and deciding on the best treatment of affected patients. To gain clinical and molecular insights into the effects of NF2 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 269 NF2 patients. 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 in NF2. We completing a longitudinal analysis (unpublished, Oral Presentation at AANS Annual Meeting 2017). We sought to prospectively analyze the utility of FLAIR MRI to predict hearing loss in patients with NF2. We tested the hypothesis in a cohort of patients with small, untreated VS (<500mm3) to avoid the effects of surgery or large tumor size on labyrinthine FLAIR signal. We confirmed that no patients with hearing loss had normal labyrinthine FLAIR signal. We then found that a change in labyrinthine FLAIR signal preceded hearing loss in that ear by 2.7 years. In no case did a FLAIR signal change reverse from elevated to normal. These interesting findings offer clinicians an opportunity to monitor patients with NF2 with a non-invasive predictive biomarker of hearing loss. Patients with neurofibromatosis type 2 (NF2) have a predisposition to develop peripheral neuropathic symptoms due to focal compression from tumors as well as due to NF2 haploinsufficiency mediated axonal neuropathy. We recently analyzed the prevalence of compressive and generalized peripheral neuropathies in patients with NF2, and evaluate the role of surgery in alleviating neuropathic symptoms. We found that patients with NF2 present with peripheral neuropathic symptoms due to compression from tumors and due to axonal neuropathy. In instances of distinct tumor compression, nerve fascicle sparing surgical resection leads to resolution of neuropathic symptoms. EMG/NCS studies help guide management of NF2 patients with peripheral neuropathic symptoms.