Faculty Bibliography

INTRODUCTION/UNASSIGNED:Skull base surgery is a highly innovative, multidisciplinary field that brings together teams of neurosurgeons, otolaryngology-head and neck surgeons (OHNS), plastic surgeons, ophthalmologists, radiation oncologists, and others. However, not long ago, the nascent field was instead characterized by isolated individual brilliance. METHODS/UNASSIGNED:This paper explores the contributions of several key players toward breaking silos and transforming the field into what it is today. Our analysis centers on the formation of the North American Skull Base Society (NASBS), and the instrumental role that it played in the development of skull base surgery. We interviewed 12 past presidents of the NASBS and 2 prominent figures in skull base surgery. The contents of those 20 hours and 38 minutes of interviews and documents from initial NASBS meetings were analyzed. Key moments were segmented into short video clips, which complement this manuscript and are available on the NASBS website. RESULTS/UNASSIGNED:A compelling narrative of collaboration, mentorship, and tenacity emerged from our analysis. In the 20th century, the field of skull base surgery was characterized mainly by courageous but isolated efforts by neurosurgeons and OHNS surgeons. Through mentorship, collaboration, and incredible innovation, it has since grown into a multidisciplinary, cutting-edge specialty that utilizes the strengths of several medical specialties. This transformation was largely facilitated by the formation of the NASBS in 1989, which enabled worldwide communication and collaboration among those dedicated to advancing the field. CONCLUSION/UNASSIGNED:The growth of skull base surgery in North America and the instrumental role of the NASBS highlight the power of collaboration and innovation. It is important to recognize and celebrate the key players who facilitated the creation and success of the NASBS, which continues to unite young members across countless disciplines under one banner.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Hypofractionated Gamma Knife radiosurgery (hfGKRS) is increasingly considered for treating large or near-critical structure meningiomas because of potential safety advantages. However, data on optimal fractionation and long-term outcomes remain limited. This study evaluated the longer-term tumor control and toxicity after hfGKRS for intracranial meningiomas at 2 large centers, supplemented by a systematic review and meta-analysis of existing literature. METHODS:The analysis included 34 patients (site 1 = 25, site 2 = 9, median age 62.6 years) with 40 tumors (median volume 11.2 cm3). 62% was low-grade (World Health Organization grade 0-1) and 38% was high-grade (World Health Organization grade 2-3). The most common fractionation schemes were 20 Gy in 5 fractions for low-grade and 21 Gy in 3 fractions for high-grade tumors. The mean follow-up was 28.8 months. RESULTS:Only 6 of 34 patients did not have any previous treatment including surgery and/or radiotherapy. 82% of patient patients had neurological deficits before stereotactic radiosurgery. The estimated rate of 5-year tumor progression for low-grade and high-grade tumors was 7.7% (95% CI 0.41%-30%) and 36% (95% CI 12%-62%). Symptoms improved in 12 patients (35%) and worsened in 6 patients (16%), with 1 case attributed to tumor progression and no significant visual deterioration in 16 tumors within 3 mm of the optic apparatus. There was no statistically significant association between fractionation (3 vs 5) scheme and tumor control (P = .07) or survival (P = .12). Karnofsky Performance Status performance was a significant predictor of death (HR 0.89, P = .012) and tumor progression (HR 0.93, P = .048). The combined meta-analysis revealed a 5-year tumor control rate of 91.6% for low-grade and 37.9% for high-grade meningiomas. CONCLUSION/CONCLUSIONS:hfGKRS demonstrates durable control and acceptable safety for low-grade intracranial meningiomas. High-grade tumors showed less favorable outcomes comparable with single-session Gamma Knife radiosurgery historical data. Further prospective data are needed to confirm these findings and optimize fractionation strategies.

BACKGROUND:Pituitary neuroendocrine tumors (PitNETs) are the most common intracranial neuroendocrine tumors. PitNETs can be challenging to classify, and current recommendations include a large immunohistochemical panel to differentiate among 14 WHO-recognized categories. METHODS:In this study, we analyzed clinical, immunohistochemical and DNA methylation data of 118 PitNETs to develop a clinico-molecular approach to classifying PitNETs and identify epigenetic classes. RESULTS:CNS DNA methylation classifier has an excellent performance in recognizing PitNETs and distinguishing the three lineages when the calibrated score is ≥0.3. Unsupervised DNA methylation analysis separated PitNETs into two major clusters. The first was composed of silent gonadotrophs, which form a biologically distinct group of PitNETs characterized by clinical silencing, weak hormonal expression on immunohistochemistry, and simple copy number profile. The second major cluster was composed of corticotrophs and Pit1 lineage PitNETs, which could be further classified using DNA methylation into distinct subclusters that corresponded to clinically functioning and silent tumors and are consistent with transcription factor expression. Analysis of promoter methylation patterns correlated with lineage for corticotrophs and Pit1 lineage subtypes. However, the gonadotrophic genes did not show a distinct promoter methylation pattern in gonadotroph tumors compared to other lineages. Promoter of the NR5A1 gene, which encodes SF1, was hypermethylated across all PitNETs clinical and molecular subtypes including gonadotrophs with strong SF1 protein expression indicating alternative epigenetic regulation. CONCLUSION/CONCLUSIONS:Our findings suggest that classification of PitNETs may benefit from DNA methylation for clinicopathological stratification.

BACKGROUND:Molecular aberrations have been incorporated into tumour classification guidelines of meningioma. TERT-promoter (TERTp) mutation is associated with worse prognosis and is designated a WHO grade 3 biomarker. However, it remains unclear whether TERTp mutation is context-dependent, with other co-occurring genetic alterations potentially driving its association with prognosis. We sought to characterise the role of TERTp mutation in meningioma and guide TERTp sequencing. METHODS:We identified 1492 patients of all ages who had previously received surgery for meningioma across 14 medical centres in the USA, Canada, and Germany. Patients were eligible if they had post-surgical clinical or radiographical assessment of the resection site, and TERTp status evaluated by Nov 1, 2024. Multi-modal profiling was used to assess TERTp mutation, focal gene alterations-including CDKN2A/B loss-and copy number alterations. An adjusted WHO grade was calculated for TERTp-mutant meningiomas, incorporating all WHO criteria except TERTp status. Kaplan-Meier curves and multivariable Cox proportional hazards models were used to quantify the effect of TERTp mutation on the endpoints of overall survival and recurrence-free survival across adjusted WHO grade and co-occurring molecular alterations. FINDINGS/RESULTS:64 (4·3%) of 1492 meningiomas were TERTp-mutant and 1428 (95·7%) were TERTp-wildtype. Of the TERTp-mutant meningiomas, 33 (51·6%) were from female patients and 31 (48·4%) were from male patients, and the overall median age was 67 years (IQR 60-75). Of the wildtype meningiomas, 965 (67·6%) were from female patients and 463 (32·4%) were from male patients, and the overall median age of the patients was 59 years (IQR 48-70). Data on race was inconsistently reported and thus excluded. The TERTp-mutant patients had a 5-year overall survival (49·4% [95% CI 33·7-72·4]) and 5-year recurrence-free survival (27·6% [95% CI 16·8-45·5]) resembling that of patients with WHO grade 3 TERTp-wildtype tumours (5-year overall survival 32·3% [95% CI 17·2-60·5], p=0·28, 5-year recurrence-free survival 14·3% [5·8-35·2], p=0·28). However, the TERTp-mutant group had heterogenous histological grading and was enriched for aggressive molecular features, with 1p loss present in 44 (77·2%) of 57 profiled tumours and CDKN2A/B loss in 24 (41·4%) of the 58 profiled tumours. Adjusting tumour grade revealed a subset of TERTp-mutant meningiomas that were more molecularly and clinically benign. Among TERTp-mutant tumours, CDKN2A/B loss played a defining role in stratifying tumour behaviour. Multivariable analysis confirmed this, with CDKN2A/B loss being significantly associated with shorter overall survival (HR 3·04 [95% CI 1·67-5·52], p=0·00026) and faster time to recurrence (HR 5·22 [95% CI 3·10-8·79], p<0·0001), while TERTp-mutation did not independently affect overall survival (HR 1·00 [95% CI 0·53-1·87], p=0·99) or recurrence-free survival (1·17 [95% CI 0·75-1·83], p=0·49). Sequencing for TERTp-mutation demonstrated clinical impact only among histologically WHO grade 2 meningiomas. INTERPRETATION/CONCLUSIONS:The indolent behaviour of certain TERTp-mutant meningiomas suggests that TERTp mutation is not sufficient to assign the most aggressive meningioma grade. Instead, TERT sequencing might offer prognostic utility in identifying high-risk cases among WHO grade 2 meningiomas. FUNDING/BACKGROUND:National Institutes of Health, National Institute of Neurological Disorders and Stroke, Friedberg Charitable Foundation, Courtney Meningioma Research Fund, Fleming Meningioma Research Fund, and the Gray Family Foundation.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Iatrogenic cerebrovascular injury can cause intracranial hemorrhage and pseudoaneurysm formation, putting patients at high risk for postoperative bleeding. No consensus for management exists. This study describes endovascular treatment of these acute injuries with flow diverter stents. METHODS:Electronic medical records were retrospectively reviewed for injury type and etiology, timing of diagnosis, and endovascular management, including antiplatelet regimens, embolization results, and clinical outcome. RESULTS:Six patients were included. Three suffered an injury to the internal carotid artery, 1 suffered an injury to the left anterior cerebral artery, 1 suffered an injury to the right posterior cerebral artery, and 1 suffered an injury to the basilar artery. Four of the 6 injuries occurred during attempted tumor resection, 1 occurred during cerebrospinal fluid leak repair, and 1 occurred during an ophthalmic artery aneurysm clipping. All injuries resulted in pseudoaneurysm formation. Four were immediately detected on angiography; 2 were initially negative on imaging. Five were treated with a pipeline embolization device, and 1 was treated with a Silk Vista Baby. Two were treated with 2 pipeline embolization devices telescopically overlapped across the pseudoaneurysm. All devices deployed successfully. No pseudoaneurysm recurrence or rebleeding occurred. No parent artery occlusion or stenosis was observed, and complete pseudoaneurysm occlusion was observed in 4 patients (in 2 patients, follow-up imaging could not be obtained). CONCLUSION/CONCLUSIONS:With proper antiplatelet regimens, flow diverter stents can be used safely to successfully treat complex acute iatrogenic injuries. Early repeat angiogram is needed when immediate postinjury imaging does not discover the point of vessel injury.

PURPOSE/UNASSIGNED:To report a case of delayed diagnosis of a pituitary tumor impacting vision. The patient had undergone bilateral cataract surgery with multifocal lenses, and even an intraocular lens (IOL) exchange for persistent visual dissatisfaction, which was ultimately due to the tumor and not the visually significant cataracts or the intra-ocular lens. METHODS/UNASSIGNED:Single case report and narrative review. RESULTS/UNASSIGNED:An 81-year-old male patient presented with visually significant nuclear sclerotic cataracts that were consistent with his chief complaint of decreased visual acuity and colors not being vivid. About one month after uneventful sequential cataract phacoemulsification with multifocal IOL insertion, he complained of bilateral visual dissatisfaction, primarily with color and contrast issues. This was attributed to his non-adaption to the bilateral multifocal intra-ocular lenses. A unilateral IOL exchange of the multifocal lens to a monofocal lens occurred without complication. Still, the persistence of visual dissatisfaction after a unilateral IOL exchange prompted consultation with neuro-ophthalmology where he was diagnosed with a pituitary macroadenoma. CONCLUSION/UNASSIGNED:Prior to performing an IOL exchange in patients with persistent visual dissatisfaction after multifocal lens placement, other causes of visual dissatisfaction should be thoroughly investigated.

OBJECTIVES/OBJECTIVE:To assess a decade of experience of treating patients with high hearing risk cerebellopontine angle (CPA) epidermoid lesions and examine factors influencing postoperative outcomes, particularly hearing preservation. STUDY DESIGN/METHODS:Retrospective chart review. SETTING/METHODS:Single tertiary-referral center. PATIENTS/METHODS:Adults with CPA epidermoid lesions who presented with hearing loss or evidence of lesion involving vestibulocochlear nerve. INTERVENTIONS/METHODS:The studied intervention was microsurgical resection. MAIN OUTCOME MEASURES/METHODS:Main outcome measures included extent of resection, hearing preservation rate for patients with postoperative audiograms, and disease progression. RESULTS:Twenty-three adults with an average tumor volume of 15.63 ± 16.2 cm3 were included. Five lesions (22%) involved the full internal auditory canal (IAC), 11 (48%) had partial involvement, and 5 (22%) were IAC sparing. Most patients with IAC involvement (88%) had circumferential invasion of the canal. Patients underwent either a retrosigmoid (18, 79%) or combined retrolabyrinthine transpetrosal approach (5, 22%), and gross total resection was achieved in most cases (13, 57%). Of 12 patients with postoperative audiograms, 10 (83%) had preoperative hearing preserved. There was no statistically significant change in hearing scores with treatment based on preoperative extent of IAC involvement. Ten patients (43%) had residual lesions postoperatively, and 6 exhibited progression. One patient ultimately required reoperation 6 years after initial surgery. CONCLUSIONS:Preoperative hearing was preserved in the majority of the patients who underwent resection of CPA epidermoids via a retrosigmoid or transpetrosal approach. CPA epidermoids often invaded the IAC; however, degree of invasion was not associated with hearing outcomes.

UNLABELLED:The superior hypophyseal arteries (SHAs) are well known in anatomical and surgical literature, with a well-established role in supply of the anterior hypophysis and superjacent optic apparatus. However, due to small size and overlap with other vessels, in vivo imaging by any modality has been essentially non-existent. Advances in high resolution cone beam CT angiography (CBCTA) now enables this deficiency to be addressed. This paper presents, to the best of our knowledge, the first comprehensive in vivo imaging evaluation of the SHAs. METHODS:Twenty-five CBCTA studies of common or internal carotid arteries were obtained for a variety of clinical reasons. Dedicated secondary reconstructions of the siphon were performed, recording the presence, number, and supply territory of SHAs. A spectrum approach, emphasizing balance with adjacent territories (inferior hypophyseal, ophthalmic, posterior and communicating region arteries) was investigated. RESULTS:The SHAs were present in all cases. Supply of the anterior pituitary was nearly universal (96%) and almost half (44%) originated from the 'cave' region, in excellent agreement with surgical literature. Optic apparatus supply was more difficult to adjudicate, but appeared present in most cases. The relationship with superior hypophyseal aneurysms was consistent. Patency following flow diverter placement was typical, despite a presumably rich collateral network. Embryologic implications with respect to the ophthalmic artery and infraoptic course of the anterior cerebral artery are intriguing. CONCLUSIONS:SHAs are consistently seen with CBCTA, allowing for correlation with existing anatomical and surgical literature, laying the groundwork for future in vivo investigation.

BACKGROUND AND OBJECTIVES/OBJECTIVE:The management of World Health Organization (WHO) grade 2 meningiomas is complicated by their diverse clinical behaviors. Stereotactic radiosurgery (SRS) can be an effective management option. Literature on SRS dose selection is limited but suggests that a higher dose is better for tumor control. We characterize the predictors of post-SRS outcomes that can help guide planning and management. METHODS:We reviewed a cohort of consecutive patients with pathologically-proven WHO grade 2 meningiomas who underwent SRS at a single institution between 2011 and 2023. RESULTS:Ninety-nine patients (median age 62 years) underwent SRS, 11 of whom received hypofractionated SRS in 5 fractions. Twenty-two patients had received previous irradiation. The median follow-up was 49 months. The median overall survival was 119 months (95% CI 92-NA) with estimated 5- and 10-year survival of 83% and 27%, respectively. The median progression-free survival (PFS) was 40 months (95% CI 32-62), with 3- and 5-year rates at 54% and 35%, respectively. The median locomarginal PFS was 63 months (95% CI 51.8-NA) with 3- and 5-year rates at 65% and 52%. Nine (9%) patients experienced adverse events, 2 Common Terminology Criteria for Adverse Events grade 3 and 7 grade 2, consisting of worsening neurologic deficit from edema. In the single-session cohort, Ki-67 significantly predicted both overall survival and intracranial PFS. Tumors with Ki-67 >10% had 2.17 times the risk of locomarginal progression compared with Ki-67 ≤10% (P = .018) adjusting for covariates. Sex, prescription dose, tumor volume, and location also predicted tumor control. In tumors with Ki-67 >10%, margin dose ≥14 Gy was associated with significantly better tumor control but not for tumors with Ki-67 ≤10%. CONCLUSION/CONCLUSIONS:The management of WHO grade 2 meningiomas requires a multimodality approach. This study demonstrates the value of a targeted SRS approach in patients with limited disease and further establishes predictive biomarkers that can guide planning through a personalized approach.