Neuro-oncology of Familial Neoplasia Syndromes

家族性肿瘤综合征的神经肿瘤学

• 批准号: 10915976
• 负责人: Prashant Chittiboina
• 金额: $ 54.99万
• 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/10915976
• 关键词: Acceleration; 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; Oral; Organ; Pancreas; Patient Monitoring; Patients; Pattern; Peripheral; Peripheral Nerves; Peripheral Nervous System Diseases; Peripheral Nervous System Neoplasms; Permeability; 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; 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.

von Hippel-Lindau病（VHL）： 我们在250例VHL患者的自然史研究中继续随访VHL患者（Lonser et al. 2014），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生长在一个跳跃模式的特点是生长期和静止期。 静止的肿瘤不需要治疗。 血管母细胞瘤更容易引起症状，如果它们与扩大的肿瘤囊肿有关，则需要手术治疗。血浆通过渗透性肿瘤血管外渗是形成瘤周囊肿和针筒的基础。 胚胎性成血管细胞是VHL相关CNS成血管细胞瘤的起源细胞。VHL相关的CNS血管母细胞瘤需要新的非侵入性治疗。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，但是这种功能通过突变蛋白的加速分解而丧失。伏立诺他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），实验上减缓了突变VHL蛋白的细胞内分解。为了验证这一假设，我们招募了7例有症状的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 mg/天的伏立诺他治疗7天，并进行血管母细胞瘤手术切除。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，在VHL相关的血管母细胞瘤中，伏立诺他短期治疗可增加pVHL水平并抑制肿瘤进展信号。这些结果表明HDACi治疗可以挽救生殖系错义突变VHL患者中的肿瘤pVHL，并且治疗可以阻止肿瘤生长。 我们还分析了一个大的VHL患者队列中球后血管母细胞瘤的自然病史，以确定其表现、进展和治疗。18例MR监测的球后血管母细胞瘤患者符合本研究的入选标准。 我们发现球后血管母细胞瘤可以长期保持稳定和无临床症状。近期生长和较大的肿瘤体积与症状发生相关。手术治疗有症状的球后血管母细胞瘤是安全的，并可逆转相关症状。 神经纤维瘤病2型（NF 2）： NF 2中中枢神经系统肿瘤的多变性以及对其自然史和症状形成的潜在机制的不完全理解导致治疗延迟至神经功能缺损发生后。基于这种治疗模式，治疗时的肿瘤通常较大，并且与不可逆的神经功能缺损和治疗诱导的发病风险增加相关。因此，与NF 2相关的肿瘤自然史的知识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。 为了获得NF 2基因突变对肿瘤发展/进展的影响的临床和分子见解，并确定与NF 2相关肿瘤症状演变相关的特征，我们正在对269名NF 2患者进行自然史研究。 分析这项研究数据将使我们能够更好地了解NF 2中CNS肿瘤的自然史。到目前为止，在许多受试者中观察到肿瘤生长的可变模式，包括口吃模式。初步研究表明，NF 2基因突变以外的遗传因素与NF 2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肿瘤生物学、症状形成和NF 2治疗最佳时机的因素。 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）。我们试图前瞻性分析FLAIR MRI预测NF 2患者听力损失的实用性。我们在一组患有小的未经治疗的VS（<500 mm 3）的患者中测试了这一假设，以避免手术或大肿瘤尺寸对乳腺FLAIR信号的影响。我们证实，没有听力损失的患者有正常的FLAIR信号。然后我们发现，在该耳听力损失前2.7年，耳FLAIR信号的变化。在任何情况下，FLAIR信号都没有从升高到正常的反向变化。这些有趣的发现为临床医生提供了一个机会，可以用听力损失的非侵入性预测生物标志物来监测NF 2患者。 患有2型神经纤维瘤病（NF 2）的患者由于来自肿瘤的局灶性压迫以及由于NF 2单倍不足介导的轴突神经病而具有发展周围神经病性症状的倾向。我们最近分析了NF 2患者压迫性和全身性周围神经病变的患病率，并评估了手术在减轻神经病变症状中的作用。我们发现NF 2患者由于肿瘤压迫和轴突神经病变而出现周围神经病变症状。在明显的肿瘤压迫的情况下，保留神经束的手术切除导致神经病理性症状的解决。EMG/NCS研究有助于指导伴有周围神经病变症状的NF 2患者的管理。

项目成果

Von Hippel-Lindau disease.

• DOI: 10.1016/b978-0-444-62702-5.00010-x
• 发表时间: 2015
• 期刊: Handbook of clinical neurology
• 作者: Chittiboina, Prashant;Lonser, Russell R
• 通讯作者: Lonser, Russell R

Resection of a conus medullaris hemangioblastoma: Case report.

髓圆锥血管母细胞瘤切除术：病例报告。

• DOI: 10.1016/j.inat.2020.100904
• 发表时间: 2021
• 期刊: Interdisciplinary neurosurgery : Advanced techniques and case management
• 作者: Alvarez,Reinier;Mastorakos,Panagiotis;Chittiboina,Prashant
• 通讯作者: Chittiboina,Prashant

Long-term natural history of neurofibromatosis Type 2-associated intracranial tumors.

• DOI: 10.3171/2012.3.jns111649
• 发表时间: 2012-07
• 期刊: Journal of neurosurgery
• 影响因子: 4.1
• 作者: Dirks MS;Butman JA;Kim HJ;Wu T;Morgan K;Tran AP;Lonser RR;Asthagiri AR
• 通讯作者: Asthagiri AR

Developmentally arrested structures preceding cerebellar tumors in von Hippel-Lindau disease.

• DOI: 10.1038/modpathol.2011.61
• 发表时间: 2011-08
• 期刊: Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc

Safe marginal resection of atypical neurofibromas in neurofibromatosis type 1.

• DOI: 10.3171/2019.7.jns191353
• 发表时间: 2020-11-01
• 期刊: Journal of neurosurgery
• 影响因子: 4.1
• 作者: Nelson CN;Dombi E;Rosenblum JS;Miettinen MM;Lehky TJ;Whitcomb PO;Hayes C;Scott G;Benzo S;Widemann BC;Chittiboina P
• 通讯作者: Chittiboina P