Neuro-oncology of Familial Neoplasia Syndromes

家族性肿瘤综合征的神经肿瘤学

• 批准号: 10708611
• 负责人: Prashant Chittiboina
• 金额: $ 58.86万
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10708611
• 关键词: Adolescent; Adrenal Glands; Affect; Axonal Neuropathy; Biochemical; Cataract; Cells; Central Nervous System; Central Nervous System Neoplasms; Chromosomes; Clinical; Cranial Nerves; Cutaneous T-cell lymphoma; Cyst; Data; Development; Ear; Enrollment; Ependymoma; Evolution; Excision; Extravasation; Fascicle; Future; Gene Mutation; Genetic; Germ-Line Mutation; Glioma; Growth; HDAC4 gene; Hamartoma; Histone Deacetylase Inhibitor; Immunohistochemistry; Inherited; Kidney; Knowledge; Laboratories; Lesion; Magnetic Resonance Imaging; Mediating; Molecular; Morbidity - disease rate; Mutate; Natural History; Nature; Neoplasms; Nerve; Nervous System; Nervous System Neoplasms; Neurilemmoma; Neurofibromatosis 2; Neurologic Deficit; Neuropathy; Operative Surgical Procedures; Ophthalmology; Oral; Organ; Pancreas; Patient Monitoring; Patients; Pattern; Peripheral; Peripheral Nerves; Peripheral Nervous System Diseases; Peripheral Nervous System Neoplasms; Permeability; Plant Roots; Plasma; Predisposition; Prevalence; Proteins; Refractory; Resolution; Retina; Role; Signal Transduction; Spinal nerve structure; Stuttering; Symptoms; Syndrome; Syringes; Testing; Time; Tumor Biology; Tumor Suppressor Genes; Tumor Suppressor Proteins; Tumor Volume; VHL mutation; VHL protein; Vestibular Nerve; Visceral; Von Hippel-Lindau Syndrome; Vorinostat; Western Blotting; associated symptom; base; bilateral vestibular Schwannoma; body system; cohort; endolymphatic sac; hearing impairment; hemangioblastoma; inclusion criteria; insight; longitudinal analysis; meetings; meningioma; mutant; neuro-oncology; novel therapeutics; predictive marker; prospective; reproductive; symptom treatment; treatment duration; treatment risk; tumor; tumor growth; tumor progression

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 signaling 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 are 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.

希佩尔-林道病 (VHL)： 我们正在对 250 名 VHL 患者进行自然史研究（Lonser et al. 2014），继续追踪 VHL 患者，以进一步了解 VHL 相关中枢神经系统 (CNS) 血管母细胞瘤的自然史。 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模式生长，其特征是生长和静止期。 静止的肿瘤不需要治疗。 如果血管母细胞瘤与增大的肿瘤囊肿相关，则更有可能引起症状并需要手术治疗。血浆通过可渗透的肿瘤血管外渗是形成瘤周囊肿和注射器的基础。 胚胎成血管细胞是 VHL 相关中枢神经系统成血管细胞瘤的起源细胞。 VHL 相关中枢神经系统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，由种系错义VHL基因突变表达的突变VHL蛋白保留了一些生化功能，但该功能由于突变蛋白的加速分解而丧失。 Vorinostat 是一种组蛋白脱乙酰酶抑制剂，被批准用于治疗难治性皮肤 T 细胞淋巴瘤 (CTCL)，在实验上可减缓突变 VHL 蛋白的细胞内分解。为了检验这一假设，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种系错义 VHL 患者。受试者接受 400 毫克/天的伏立诺他治疗 7 天，并接受手术切除血管母细胞瘤。使用蛋白质印迹、免疫组织化学和实时 qPCR 分析血管母细胞瘤。我们发现伏立诺他的短期治疗可增加 VHL 相关血管母细胞瘤中的 pVHL 水平并抑制肿瘤进展信号。这些结果表明，HDACi 治疗可以挽救种系错义突变 VHL 患者的肿瘤 pVHL，并且治疗可以阻止肿瘤生长。 我们还分析了一大群 VHL 患者的球后血管母细胞瘤的自然史，以确定其表现、进展和治疗。 18 例监测 MR 成像的球后血管母细胞瘤患者符合本研究的纳入标准。 我们发现球后血管母细胞瘤可能长期保持稳定且临床无症状。最近的生长和较大的肿瘤体积与症状的发生相关。有症状的球后血管母细胞瘤的手术治疗是安全的，并且可以逆转相关症状。 2 型神经纤维瘤病 (NF2)： NF2 中枢神经系统肿瘤的千变万化的性质以及对其自然史和症状形成的潜在机制的不完全了解导致治疗被推迟到出现神经功能缺损之后。基于这种治疗模式，治疗时的肿瘤通常很大，并且与不可逆的神经功能缺损和治疗引起的发病风险增加相关。随后，了解与 NF2 相关的肿瘤的自然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/进展的影响，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 患者进行一项持续的自然史研究。 对这项研究数据的分析将使我们更好地了解 NF2 中 CNS 肿瘤的自然史。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。这项前瞻性自然史研究应该有助于确定影响 NF2 肿瘤生物学、症状形成和最佳治疗时机的因素。 我们正在完成一项纵向分析（未发表，2017 年 AANS 年会上的口头报告）。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效用。我们在一组未经治疗的小 VS (<500mm3) 患者中测试了这一假设，以避免手术或大肿瘤尺寸对迷路 FLAIR 信号的影响。我们确认没有听力损失患者的迷路 FLAIR 信号正常。然后我们发现，迷路 FLAIR 信号的变化先于该耳朵听力损失 2.7 年。在任何情况下，FLAIR 信号都不会从升高转为正常。这些有趣的发现为临床医生提供了利用非侵入性听力损失预测生物标志物监测 NF2 患者的机会。 2 型神经纤维瘤病 (NF2) 患者由于肿瘤的局灶性压迫以及 NF2 单倍体不足介导的轴突神经病变而容易出现周围神经病变症状。我们最近分析了 NF2 患者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中的作用。我们发现 NF2 患者因肿瘤压迫和轴突神经病变而出现周围神经病变症状。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病理性症状。 EMG/NCS 研究有助于指导具有周围神经病变症状的 NF2 患者的治疗。