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: 10915985
• 负责人: Prashant Chittiboina
• 金额: $ 15.84万
• 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/10915985
• 关键词: 22q; Affect; Attention; Benign; Central Nervous System; 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; 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; autosome; bilateral vestibular Schwannoma; biomarker identification; cohort; deafness; hearing impairment; improved; insertion/deletion mutation; longitudinal analysis; meningioma; neoplastic cell; nerve injury; neuro-oncology; prevent hearing loss; prospective; research clinical testing; tool; trend; tumor; tumor growth; validation studies

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历史研究显着提高了人们对 NF2 如何影响患者的理解。我们发现 NF2 中的中枢神经系统肿瘤表现出逐步生长模式。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 NF2 患者进行长期随访以评估疾病进展。 NF2 患者的症状会严重影响他们的生活，例如听力丧失和言语/吞咽功能障碍。这项自然史研究帮助我们了解即使肿瘤非常小或处于静止状态，这些症状也是如何出现的。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，并就言语和吞咽问题向患者提供咨询。 使用当前 NF2 受试者队列，我们​​通过 MRI 成像证实外淋巴内蛋白质增加，即 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。这项研究验证了 MRI 成像作为检测外淋巴内蛋白质增加的方法以及作为听力损失的标志物的方法。我们现在拥有一种方便、非侵入性的工具来监测外淋巴蛋白含量。 MRI 成像可以长期重复进行，以检测外淋巴蛋白随时间和听力变化的变化。 在另一项分析中，我们发现很大一部分 NF2 患者存在言语和吞咽缺陷，而客观测量结果并不明显。我们还发现舌下神经病变与之前的手术干预无关。我们的研究结果表明，NF2 中的吞咽和言语问题与下颅神经神经病变有关，部分原因是后颅窝肿瘤的压迫作用。 我们发现 NF2 患者出现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可以缓解神经病理性症状。 EMG/NCS 研究和影像学有助于高度确定地指导 NF2 患者的治疗。 2 型神经纤维瘤病 (NF2) 表现为中枢和周围神经系统肿瘤和非肿瘤表现，包括周围神经病变以及外显率和严重程度的巨大差异。尽管假设种系无义突变和 NF2 移码突变会导致严重疾病，但突变类型与该疾病表现之间的关系尚不完全清楚。在这项研究中，我们的目标是深入研究 NF2 患者的表型，并检查种系基因型对疾病严重程度的影响之间的关系。创建了深度表型图谱（连续 5 年），包括临床评估、自我报告的功能测量、终生干预（手术、放射和药物治疗）和成像（使用神经轴体积 MRI 的肿瘤数量、类型和体积）。使用经过验证的种系突变数据 (n = 68) 检查基因型和表型之间的关系，重点关注 NF2 突变类型（插入/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 24，四分位数范围为 8-52）。初始 MRI 的肿瘤负荷与方案期间的手术次数相关 (p < 0.0001)。我们发现颅脑膜瘤是总肿瘤负荷的主要决定因素。总肿瘤负荷（数量和体积）与较差的卡诺夫斯基性能量表（KPS）以及研究方案中 KPS 的下降相关（p < 0.0001）。我们发现，就 MRI 上的肿瘤数量而言，外显子 11-12 的截短突变与更严重的疾病相关（p = 0.0439）。我们得出的结论是，这是第一个对 NF2 患者进行深入表型分析的大规模研究，包括纵向分析，并展示了与种系突变类型、影像学结果和疾病严重程度测量相关的几个先前未被认识的趋势。

项目成果

Audiologic Natural History of Small Volume Cochleovestibular Schwannomas in Neurofibromatosis Type 2.

2 型神经纤维瘤病中小体积耳蜗前庭神经鞘瘤的听力学自然史。

• DOI: 10.1097/mao.0000000000001690
• 发表时间: 2018
• 期刊: Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology
• 作者: deTorres,AlvinT;Brewer,CarmenC;Zalewski,ChrisK;King,KellyA;Walker,Robert;Scott,GretchenC;Asthagiri,AshokR;Chittiboina,Prashant;Kim,HungJeffrey
• 通讯作者: Kim,HungJeffrey

First insight into the somatic mutation burden of neurofibromatosis type 2-associated grade I and grade II meningiomas: a case report comprehensive genomic study of two cranial meningiomas with vastly different clinical presentation.

• DOI: 10.1186/s12885-017-3127-6
• 发表时间: 2017-02-13
• 期刊: BMC cancer
• 影响因子: 3.8
• 作者: Dewan R;Pemov A;Dutra AS;Pak ED;Edwards NA;Ray-Chaudhury A;Hansen NF;Chandrasekharappa SC;Mullikin JC;Asthagiri AR;NISC Comparative Sequencing Program;Heiss JD;Stewart DR;Germanwala AV
• 通讯作者: Germanwala AV

Eccrine spiradenoma mimicking a painful traumatic neuroma: case report.

小汗腺螺旋腺瘤模仿痛苦的创伤性神经瘤：病例报告。

• DOI: 10.3171/2017.5.jns162999
• 发表时间: 2018
• 期刊: Journal of neurosurgery
• 影响因子: 4.1
• 作者: Donaldson,Katelyn;Scott,Gretchen;Cantor,FredricK;Patronas,NicholasJ;Quezado,Martha;Heiss,JohnD
• 通讯作者: Heiss,JohnD

Flexible thecoscopy for extensive spinal arachnoiditis.

• DOI: 10.3171/2021.4.spine21483
• 发表时间: 2022-02-01
• 期刊: JOURNAL OF NEUROSURGERY-SPINE
• 影响因子: 2.8
• 作者: Mastorakos, Panagiotis;Pomeraniec, I. Jonathan;Bryant, Jean-Paul;Chittiboina, Prashant;Heiss, John D.
• 通讯作者: Heiss, John D.

Diagnosis of a growing radiation-induced skull lesion in a patient: an unusual scar.

患者因放射引起的颅骨病变不断增长的诊断：不寻常的疤痕。

• DOI: 10.3171/2015.7.jns15989
• 发表时间: 2016
• 期刊: Journal of neurosurgery
• 影响因子: 4.1
• 作者: Perera,AndreaP;Mehta,GautamU;Pratt,Drew;Quezado,MarthaM;Gilbert,MarkR;Heiss,JohnD
• 通讯作者: Heiss,JohnD