Neurooncology of Benign Central and Peripheral Nervous System Tumors

良性中枢和周围神经系统肿瘤的神经肿瘤学

• 批准号: 10018693
• 负责人: John Heiss
• 金额: $ 73.23万
• 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/10018693
• 关键词: 22q; Acoustic Neuroma; Affect; Auditory; Benign; Biological; Biological Markers; Blood; Central Nervous System Neoplasms; Clinical; Clinical assessments; Clinical/Radiologic; Code; Counseling; Cranial Nerves; Deglutition; Development; Disease Progression; Enrollment; Ependymoma; Evaluation; Evolution; Excision; Functional disorder; Future; Gene Mutation; Genes; Genomic Instability; Germ-Line Mutation; Glioma; Growth; Hearing; Intracranial Meningiomas; Knowledge; Longterm Follow-up; MRI Scans; Magnetic Resonance Imaging; Measurable; Medical; Methods; Molecular; Morbidity - disease rate; Natural History; Nature; Neoplasms; Nerve; Nervous system structure; Neurilemmoma; Neurofibromatosis 2; Neurofibromin 2; Neurologic Deficit; Numbness; Operative Surgical Procedures; Outcome; Outpatients; Paralysed; Participant; Patients; Pattern; Periodicity; Peripheral Nerves; Peripheral Nervous System; Peripheral Nervous System Diseases; Peripheral Nervous System Neoplasms; Plant Roots; Population; Production; Proteins; Publishing; Reporting; Risk; Serum; Speech; Spinal nerve structure; Structure; Symptoms; Syndrome; Testing; Therapeutic; Time; Treatment outcome; Tumor Biology; Tumor Burden; Tumor Suppressor Genes; Uncertainty; Vestibular Nerve; Visit; base; bilateral vestibular Schwannoma; cohort; deafness; exome sequencing; follow-up; hearing impairment; imaging biomarker; improved; injured; insight; meningioma; neoplastic cell; nerve injury; neuro-oncology; prevent hearing loss; prospective; relating to nervous system; tumor; tumor growth

The protean nature of the central nervous system tumors in NF2, incomplete understanding of their natural history, and undefined mechanism of symptom formation have resulted in a strategy of treating patients only after they develop neurologic deficits. By that time, tumors are typically large and neurological deficits irreversible. Surgical removal of large tumors often adds deficits. Better knowledge of NF2 natural history and tumor growth patterns could improve surgical timing and outcomes. We started a natural history study of NF2 patients 11 years ago to gain clinical and molecular insights into the effects of the type (missense, nonsense, deletion) of NF2 gene mutation on tumor development/progression and to identify features associated with symptom evolution in patients with NF2-associated tumors. The natural history study of NF2 initially enrolled 169 subjects, with the final subject completing follow-up evaluation in November 2018. This prospective natural history study identified factors that influenced tumor biology, symptom formation, and treatment outcome. Central nervous system tumors in NF2 usually contained many different populations of tumor cells. A saltatory growth pattern of periodic tumor growth was more often seen (59%) than linear (30%) or exponential growth (11%). Elevated intralabyrinthine protein and larger tumor size by MRI-scanning correlated with hearing loss. We published the first comprehensive whole exome sequencing study of NF2-related meningiomas. Sequencing of 2 adjacent intracranial meningiomas removed from the same patient showed that the second copy of the NF2 gene was inactivated in both tumors. The faster growing tumor, a Grade II meningioma, had a higher level of genomic instability than the slower-growing, Grade I meningioma. Long-term follow up of patients with NF2 was found to be essential in evaluating disease progression. However, because tumor growth and symptom production were unpredictable and new tumors developed in NF2 patients over their lifetime, we could not propose a better method for timing of tumor resection than the present practice of resecting only symptom-producing tumors. In February 2019, the study began enrollment of another 100 NF2 patients, who will undergo annual clinical and radiologic evaluations for 10 years as outpatients. Patients with NF2 have symptoms that significantly affect their lives, including hearing loss and speech/swallowing dysfunction. This previous stage of the NF2 natural history study helped us understand how these symptoms arise even from very small or quiescent tumors. In the ongoing study we seek to find better ways to prevent hearing loss and counsel patients about speech and swallowing problems. Auditory testing will be performed annually for participants with measurable hearing. Participants with initially untreated vestibular schwannomas will be followed annually with vestibular testing. Speech and swallowing reassessments will be performed if worsening of speech or swallowing is reported. Blood will be collected at each visit for blood biomarker testing. This recent cohort will allow us to further explore the biologic basis for speech and swallowing dysfunction in patients with NF2. We will study and report the strength of association of MRI findings, clinical assessments cranial nerve deficits and speech/swallowing dysfunction. We hope to identify imaging biomarkers of hearing loss in NF2. We will also explore other aspects of NF2, including attempting to discover the mode of peripheral neuropathy in patients with NF2 and to discover previously unknown serum biomarkers associated with high tumor burden in NF2.

NF2中中枢神经系统肿瘤的蛋白质性质，对其自然历史的不完全了解以及症状形成不确定的机制，才导致了仅在患者发展神经系统缺陷后治疗的策略。到那时，肿瘤通常很大，神经系统缺陷不可逆。 大型肿瘤的手术切除通常会增加缺陷。 对NF2自然史和肿瘤生长模式的更好了解可以改善手术时机和结果。 11年前，我们开始对NF2患者进行的自然史研究，以获得NF2基因突变对NF2相关肿瘤患者的临床和分子见解。 NF2的自然历史研究最初招募了169名受试者，最终受试者在2018年11月完成了后续评估。这项前瞻性自然史研究确定了影响肿瘤生物学，症状形成和治疗结果的因素。 NF2中的中枢神经系统肿瘤通常包含许多不同的肿瘤细胞群体。与线性（30％）或指数生长（11％）相比，周期性肿瘤生长的盐生长模式更常见（59％）。 通过MRI扫描与听力丧失相关的升钙内蛋白和较大的肿瘤大小升高。 我们发表了第一项与NF2相关脑膜瘤的全面外显子组测序研究。 从同一患者中去除的2个相邻颅内脑膜瘤的测序表明，在两个肿​​瘤中，NF2基因的第二个副本均失活。比生长较慢的I级脑膜瘤具有更快的生长肿瘤，即II级脑膜瘤，具有更高的基因组不稳定性。 发现NF2患者的长期随访对于评估疾病进展至关重要。 但是，由于肿瘤的生长和症状产生是不可预测的，并且在NF2患者一生中发展了新的肿瘤，因此，我们不能比目前仅切除症状肿瘤的实践更好地进行肿瘤切除的时间。 2019年2月，这项研究开始入学100名NF2患者，他们将接受10年的年度临床和放射学评估10年。 NF2患者的症状显着影响其生活，包括听力损失和言语/吞咽功能障碍。 NF2自然史研究的上一个阶段有助于我们了解这些症状是如何从很小或静止的肿瘤中引起的。在正在进行的研究中，我们试图找到更好的方法来防止听力损失，并为患者提供有关言语和吞咽问题的咨询。 听觉测试将每年为具有可测量听力的参与者进行。每年将进行前庭测试，最初进行前庭sch瘤的参与者将进行。 如果报道了言语或吞咽恶化，将进行言语和吞咽重新评估。每次访问时都会收集血液进行血液生物标志物测试。这一最近的队列将使我们能够进一步探索NF2患者的言语和吞咽功能障碍的生物学基础。我们将研究和报告MRI发现的关联，临床评估的颅神经缺陷和语音/吞咽功能障碍的力量。我们希望确定NF2中听力损失的生物标志物。我们还将探索NF2的其他方面，包括试图在NF2患者中发现周围神经病的模式，并发现NF2中与高肿瘤负担相关的先前未知的血清生物标志物。