Faculty Bibliography

Gamma knife stereotactic radiosurgery is one of the most common procedures performed to manage patients with vestibular schwannoma. With a history that spans over 40 years, there has been continued evolution in radiosurgery technique and understanding of outcomes. The goal has always been to achieve long-term inactivation of tumor growth, commonly with tumor volumetric regression, and preservation of neurologic function. Challenges remain particularly pertaining to hearing preservation and other related symptoms such as those related to balance and tinnitus. Current discussions span a variety of topics including the importance of cochlear dose, the timing of the radiosurgery intervention as opposed to initial observation, the interpretation of imaging changes after radiosurgery, and the value of hearing augmentation strategies.

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.

The detection and tracking of metastatic cancer over the lifetime of a patient remains a major challenge in clinical trials and real-world care. Advances in deep learning combined with massive datasets may enable the development of tools that can address this challenge. We present NYUMets-Brain, the world's largest, longitudinal, real-world dataset of cancer consisting of the imaging, clinical follow-up, and medical management of 1,429 patients. Using this dataset we developed Segmentation-Through-Time, a deep neural network which explicitly utilizes the longitudinal structure of the data and obtained state-of-the-art results at small (<10 mm³) metastases detection and segmentation. We also demonstrate that the monthly rate of change of brain metastases over time are strongly predictive of overall survival (HR 1.27, 95%CI 1.18-1.38). We are releasing the dataset, codebase, and model weights for other cancer researchers to build upon these results and to serve as a public benchmark.

PURPOSE/OBJECTIVE:DNA methylation profiling stratifies isocitrate dehydrogenase (IDH)-mutant astrocytomas into methylation low-grade and high-grade groups. We investigated the utility of the T2-FLAIR mismatch sign for predicting DNA methylation grade and cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) homozygous deletion, a molecular biomarker for grade 4 IDH-mutant astrocytomas, according to the 2021 World Health Organization (WHO) classification. EXPERIMENTAL DESIGN/METHODS:Preoperative MRI scans of IDH-mutant astrocytomas subclassified by DNA methylation profiling (n=71) were independently evaluated by two radiologists for the T2-FLAIR mismatch sign. The diagnostic utility of T2-FLAIR mismatch in predicting methylation grade, CDKN2A/B status, copy number variation, and survival was analyzed. RESULTS:The T2-FLAIR mismatch sign was present in 21 of 45 (46.7%) methylation low-grade and 1 of 26 (3.9%) methylation high-grade cases (p<0.001), resulting in 96.2% specificity, 95.5% positive predictive value, and 51.0% negative predictive value for predicting low methylation grade. The T2-FLAIR mismatch sign was also significantly associated with intact CDKN2A/B status (p=0.028) with 87.5% specificity, 86.4% positive predictive value, and 42.9% negative predictive value. Overall multivariable Cox analysis showed that retained CDKN2A/B status remained significant for PFS (p=0.01). Multivariable Cox analysis of the histologic grade 3 subset, which was nearly evenly divided by CDKN2A/B status, CNV, and methylation grade, showed trends toward significance for DNA methylation grade with OS (p=0.045) and CDKN2A/B status with PFS (p=0.052). CONCLUSIONS:The T2-FLAIR mismatch sign is highly specific for low methylation grade and intact CDKN2A/B in IDH-mutant astrocytomas.

BACKGROUND:Isocitrate dehydrogenase (IDH) mutant astrocytoma grading, until recently, has been entirely based on morphology. The 5th edition of the Central Nervous System World Health Organization (WHO) introduces CDKN2A/B homozygous deletion as a biomarker of grade 4. We sought to investigate the prognostic impact of DNA methylation-derived molecular biomarkers for IDH mutant astrocytoma. METHODS:We analyzed 98 IDH mutant astrocytomas diagnosed at NYU Langone Health between 2014 and 2022. We reviewed DNA methylation subclass, CDKN2A/B homozygous deletion, and ploidy and correlated molecular biomarkers with histological grade, progression free (PFS), and overall (OS) survival. Findings were confirmed using 2 independent validation cohorts. RESULTS:There was no significant difference in OS or PFS when stratified by histologic WHO grade alone, copy number complexity, or extent of resection. OS was significantly different when patients were stratified either by CDKN2A/B homozygous deletion or by DNA methylation subclass (P value = .0286 and .0016, respectively). None of the molecular biomarkers were associated with significantly better PFS, although DNA methylation classification showed a trend (P value = .0534). CONCLUSIONS:The current WHO recognized grading criteria for IDH mutant astrocytomas show limited prognostic value. Stratification based on DNA methylation shows superior prognostic value for OS.

OBJECTIVE:To describe outcomes of patients with sporadic vestibular schwannoma (VS) who underwent repeat stereotactic radiosurgery (SRS) after primary SRS failure. STUDY DESIGN/METHODS:Multi-institutional historical cohort study. SETTING/METHODS:Five tertiary care referral centers. PATIENTS/METHODS:Adults ≥18 years old with sporadic VS. INTERVENTION/METHODS:Primary and repeat treatment with SRS. MAIN OUTCOME MEASURE/METHODS:Microsurgery-free survival after repeat SRS. RESULTS:Across institutions, 32 patients underwent repeat SRS after primary SRS. Most patients (74%) had tumors with cerebellopontine angle extension at primary SRS (median size, 13.5 mm [interquartile range, 7.5-18.8] mm). After primary SRS, patients underwent repeat SRS at a median of 4.8 years (interquartile range, 3.2-5.7 yr). For treatment modality, 30 (94%) patients received gamma knife for primary treatment and 31 (97%) patients received gamma knife as their repeat treatment. Median tumor volume increased from 0.970 cm3 at primary SRS to 2.200 cm3 at repeat SRS. Facial nerve function worsened in two patients after primary SRS and in two patients after repeat SRS. There were no instances of intracranial complications after repeat SRS. Microsurgery-free survival rates (95% confidence interval; number still at risk) at 1, 3, and 5 years after repeat SRS were 97% (90-100%, 24), 84% (71-100%, 13), and 68% (48-96%, 6), respectively. There was one occurrence of malignancy diagnosed after repeat radiosurgery. CONCLUSION/CONCLUSIONS:Overall, repeat SRS for sporadic VS has comparable risk profile, but lower rates of tumor control, compared with primary SRS.

The most widely used fluorophore in glioma-resection surgery, 5-aminolevulinic acid (5-ALA), is thought to cause the selective accumulation of fluorescent protoporphyrin IX (PpIX) in tumour cells. Here we show that the clinical detection of PpIX can be improved via a microscope that performs paired stimulated Raman histology and two-photon excitation fluorescence microscopy (TPEF). We validated the technique in fresh tumour specimens from 115 patients with high-grade gliomas across four medical institutions. We found a weak negative correlation between tissue cellularity and the fluorescence intensity of PpIX across all imaged specimens. Semi-supervised clustering of the TPEF images revealed five distinct patterns of PpIX fluorescence, and spatial transcriptomic analyses of the imaged tissue showed that myeloid cells predominate in areas where PpIX accumulates in the intracellular space. Further analysis of external spatially resolved metabolomics, transcriptomics and RNA-sequencing datasets from glioblastoma specimens confirmed that myeloid cells preferentially accumulate and metabolize PpIX. Our findings question 5-ALA-induced fluorescence in glioma cells and show how 5-ALA and TPEF imaging can provide a window into the immune microenvironment of gliomas.

OBJECTIVE:Pediatric data regarding treatment via an auditory brainstem implant (ABI) remains sparse. The authors aimed to describe their experience at their institution and to delineate associated demographic data, audiometric outcomes, and surgical parameters. METHODS:An IRB-approved, retrospective chart review was conducted among the authors' pediatric patients who had undergone auditory brainstem implantation between 2012 and 2021. Demographic information including sex, age, race, coexisting syndrome(s), history of cochlear implant placement, average duration of implant use, and follow-up outcomes were collected. Surgical parameters collected included approach, intraoperative findings, number of electrodes activated, and complications. RESULTS:A total of 19 pediatric patients had an ABI placed at the authors' institution, with a mean age at surgery of 4.7 years (range 1.5-17.8 years). A total of 17 patients (89.5%) had bilateral cochlear nerve aplasia/dysplasia, 1 (5.3%) had unilateral cochlear nerve aplasia/dysplasia, and 1 (5.3%) had a hypoplastic cochlea with ossification. A total of 11 patients (57.9%) had a history of cochlear implants that were ineffective and required removal. The mean length of implant use was 5.31 years (0.25-10 years). Two patients (10.5%) experienced CSF-related complications requiring further surgical intervention. The most recent audiometric outcomes demonstrated that 15 patients (78.9%) showed improvement in their hearing ability: 5 with sound/speech awareness, 5 able to discriminate among speech and environmental sounds, and 5 able to understand common phrases/conversation without lip reading. Nine patients (47.4%) are in a school for the deaf and 7 (36.8%) are in a mainstream school with support. CONCLUSIONS:The authors' surgical experience with a multidisciplinary team demonstrates that the retrosigmoid approach for ABI placement in children with inner ear pathologies and severe sensorineural hearing loss is a safe and effective treatment modality. Audiometric outcome data showed that nearly 79% of these patients had an improvement in their environmental and speech awareness. Further multicenter collaborations are necessary to improve these outcomes and potentially standardize/enhance electrode placement.

PURPOSE/OBJECTIVE:Although ongoing studies are assessing the efficacy of new systemic therapies for patients with triple negative breast cancer (TNBC), the overwhelming majority have excluded patients with brain metastases (BM). Therefore, we aim to characterize systemic therapies and outcomes in a cohort of patients with TNBC and BM managed with stereotactic radiosurgery (SRS) and delineate predictors of increased survival. METHODS:We used our prospective patient registry to evaluate data from 2012 to 2023. We included patients who received SRS for TNBC-BM. A competing risk analysis was conducted to assess local and distant control. RESULTS:Forty-three patients with 262 tumors were included. The median overall survival (OS) was 16 months (95% CI 13-19 months). Predictors of increased OS after initial SRS include Breast GPA score > 1 (p < 0.001) and use of immunotherapy such as pembrolizumab (p = 0.011). The median time on immunotherapy was 8 months (IQR 4.4, 11.2). The median time to new CNS lesions after the first SRS treatment was 17 months (95% CI 12-22). The cumulative rate for development of new CNS metastases after initial SRS at 6 months, 1 year, and 2 years was 23%, 40%, and 70%, respectively. Thirty patients (70%) underwent multiple SRS treatments, with a median time of 5 months (95% CI 0.59-9.4 months) for the appearance of new CNS metastases after second SRS treatment. CONCLUSIONS:TNBC patients with BM can achieve longer survival than might have been previously anticipated with median survival now surpassing one year. The use of immunotherapy is associated with increased median OS of 23 months.