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: 10708620
• 负责人: Prashant Chittiboina
• 金额: $ 17.24万
• 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/10708620
• 关键词: 22q; Affect; Attention; Benign; Biological Markers; Central Nervous System Neoplasms; Cephalic; Code; Counseling; Cranial Nerves; Cross-Sectional Studies; Data; Deglutition; Development; Disease; Disease Progression; Ependymoma; Excision; Exons; Fascicle; Functional disorder; Future; Genes; Genomics; Genotype; Germ-Line Mutation; Glioma; Goals; Growth; Hearing; Image; Infratentorial Neoplasms; Intervention; Karnofsky Performance Status; Knowledge; Location; Longterm Follow-up; Magnetic Resonance Imaging; Measurement; Measures; Medical; Methods; Monitor; Morbidity - disease rate; Mutation; Natural History; Nature; Neoplasms; Nerve; Nervous System; Neurilemmoma; Neurofibromatosis 2; Neurofibromin 2; Neurologic Deficit; Neuropathy; Numbness; Operative Surgical Procedures; Paralysed; Patient Self-Report; Patients; Pattern; Penetrance; Performance; Perilymph; Peripheral Nerve Schwannoma; Peripheral Nerves; Peripheral Nervous System; Peripheral Nervous System Diseases; Peripheral Nervous System Neoplasms; Pharmacotherapy; Phenotype; Plant Roots; Population; Proteins; Protocols documentation; RNA Splicing; Radiation therapy; Reporting; Resolution; Risk; Severities; Severity of illness; Site; Speech; Spinal nerve structure; Structure; Symptoms; Syndrome; Therapeutic; Time; Treatment outcome; Tumor Biology; Tumor Burden; Tumor Suppressor Genes; Uncertainty; Variant; Vestibular Nerve; base; bilateral vestibular Schwannoma; cohort; deafness; hearing impairment; insertion/deletion mutation; longitudinal analysis; meningioma; neoplastic cell; nerve injury; neuro-oncology; prevent hearing loss; prospective; research clinical testing; tool; trend; tumor; tumor growth

This ongoing natural history study has resulted in significant improvements in the understanding how NF2 affects patients. We found that central nervous system tumors in NF2 demonstrate a stepwise growth pattern. We also found that these tumors are made of many different populations of tumor cells. These findings emphasize the need for long term follow up of patients with NF2 to evaluate disease progression. Patients with NF2 have symptoms that significantly affect their lives such as hearing loss and speech/swallowing dysfunction. This natural historya study has helped us understand how these symptoms arise even when the tumors are very small or quiescent. These findings will help clinicians find better ways to prevent hearing loss and to counsel patients about speech and swallowing problems. Using the current cohort of subjects with NF2, we confirmed the presence of increased protein within perilymph by MRI imaging as FLAIR hyperintensity. In this cross sectional study, a close correlation between increased protein and hearing loss was demonstrated. This study validated MRI imaging as a method to detect increased protein within perilymph, and as a marker for hearing loss. We now have a convenient, non-invasive tool for monitoring of perilymph protein content. MRI imaging can be performed repeatedly and over long periods to detect changes in perilymph protein with time and with changes in hearing. In another analysis, we found that a large proportion of patients with NF2 report speech and swallow deficits that are not evident on objective measurements. We also found hypoglossal neuropathy unrelated to prior surgical interventions. Our findings suggest that swallowing and speech in problems in NF2 are associated with lower cranial nerve neuropathy, some due to compressive effects of posterior fossa tumors. We found that patients with NF2 present with neuropathy related to peripheral nerve schwannomas as well as unexplained EMG/NCS findings. In instances of distinct schwannoma growth along peripheral nerves, nerve fascicle sparing surgical resection leads to resolution of neuropathic symptoms. EMG/NCS studies and imaging helps guide the management of NF2 patients with high degree of certainty. Neurofibromatosis type 2 (NF2) presents with central and peripheral nervous system tumors and non-neoplastic manifestations including peripheral neuropathy and a large variation in penetrance and severity. Although germline nonsense and frameshift NF2 mutations are hypothesized to confer severe disease, the relationship between mutation type and manifestations of this disease is not completely understood. In this study, our goal was to deeply investigate phenotypes of NF2 patients and examine relationships between the effects of germline genotype on disease severity. Deep phenotypic profiles were created (serially for 5 years) including clinical evaluations, self-reported functional measures, lifetime interventions (surgical, radiation and drug treatments), and imaging (tumor number, type and volume using volumetric MRI of the neuroaxis). Validated germline mutation data (n = 68) was used to examine relationships between genotype and phenotype with attention to NF2 mutation type (indel/large deletion), genomic effect (missense/nonsense/frameshift), predicted protein effect (truncating/non-truncating) and location (exonic/intronic/splice-site). We found that tumor burden varied greatly between patients (total tumors on MRI median 24, interquartile range 8-52). Tumor burden on initial MRI was associated with number of surgeries during the protocol period (p < 0.0001). We found that cranial meningiomas were a major determinant of total tumor burden. Total tumor burden (number and volume) was associated with worse Karnofsky Performance Scale (KPS) and decline in KPS over the study protocol (p < 0.0001). We found that truncating mutations in exons 11-12 were associated with more severe disease in terms of tumor number on MRI (p = 0.0439). We concluded that this is the first large scale study to deeply phenotype patients with NF2 including longitudinal analysis and demonstrates several previously unrecognized trends related to germline mutations type, imaging findings, and measures of disease severity.

这项正在进行的自然史研究在理解NF 2如何影响患者方面取得了重大进展。我们发现NF 2中的中枢神经系统肿瘤表现出逐步生长的模式。我们还发现这些肿瘤是由许多不同的肿瘤细胞群组成的。这些发现强调需要对NF 2患者进行长期随访以评估疾病进展。NF 2患者有明显影响其生活的症状，如听力损失和言语/吞咽功能障碍。这项自然史研究帮助我们理解了这些症状是如何出现的，即使肿瘤很小或静止。这些发现将帮助临床医生找到更好的方法来预防听力损失，并为患者提供有关语言和吞咽问题的咨询。 使用目前的NF 2受试者队列，我们通过MRI成像证实了外淋巴液中蛋白质增加的存在，表现为FLAIR高信号。在这项横断面研究中，证明了蛋白质增加与听力损失之间的密切相关性。本研究验证了MRI成像作为检测外淋巴液中蛋白质增加的方法，并作为听力损失的标志物。我们现在有一个方便的，非侵入性的工具，用于监测外淋巴蛋白含量。MRI成像可以重复进行，并在很长一段时间内检测外淋巴蛋白随时间的变化和听力的变化。 在另一项分析中，我们发现大部分NF 2患者报告的语言和吞咽缺陷在客观测量中并不明显。我们还发现舌下神经病变与既往手术干预无关。我们的研究结果表明，NF 2患者的吞咽和言语问题与下颅神经病变有关，有些是由于后颅窝肿瘤的压迫作用。 我们发现NF 2患者表现为与周围神经鞘瘤相关的神经病变以及无法解释的EMG/NCS结果。在神经鞘瘤沿着周围神经生长的情况下，保留神经束的手术切除导致神经病理性症状的解决。EMG/NCS研究和成像有助于指导高度确定性的NF 2患者的管理。 神经纤维瘤病2型（NF 2）表现为中枢和外周神经系统肿瘤和非肿瘤性表现，包括周围神经病变和在发病率和严重程度上的巨大变化。虽然假设种系无义和移码NF 2突变赋予严重的疾病，突变类型和这种疾病的表现之间的关系并不完全清楚。在这项研究中，我们的目标是深入调查NF 2患者的表型，并检查生殖基因型对疾病严重程度的影响之间的关系。创建了深度表型特征（连续5年），包括临床评价、自我报告的功能测量、终身干预（手术、放疗和药物治疗）和成像（使用神经轴的体积MRI的肿瘤数量、类型和体积）。使用经验证的种系突变数据（n = 68）检查基因型与表型之间的关系，注意NF 2突变类型（插入缺失/大缺失）、基因组效应（错义/无义/移码）、预测的蛋白质效应（截短/非截短）和位置（外显子/内含子/剪接位点）。我们发现患者之间的肿瘤负荷差异很大（MRI上的肿瘤总数中位数为24，四分位数间距为8-52）。初始MRI上的肿瘤负荷与方案期间的手术次数相关（p < 0.0001）。我们发现脑膜瘤是肿瘤总负荷的主要决定因素。总肿瘤负荷（数量和体积）与研究方案中更差的Karnofsky性能量表（KPS）和KPS下降相关（p < 0.0001）。我们发现外显子11-12的截短突变与MRI上肿瘤数量更严重的疾病相关（p = 0.0439）。我们的结论是，这是第一个大规模的研究，深入表型与NF 2患者，包括纵向分析，并证明了一些以前未被认识到的趋势与种系突变类型，影像学表现，和疾病严重程度的措施。