Morshed, Ramin A.

OBJECTIVE It is uncertain which cochlear dose parameters significantly impact hearing after stereotactic radiosurgery (SRS) for sporadic vestibular schwannoma (VS). The objective of this study was to determine the impact of cochlear dose parameters on hearing outcomes for patients with serviceable hearing (SH). METHODS This was a historical cohort study performed at a single tertiary center that included patients with sporadic VS and SH who underwent single-session Gamma Knife radiosurgery treatment from 2007 to 2022. Associations of cochlear dose parameters with time to non-SH and rates of change in pure-tone average (PTA) and word recognition score (WRS) following SRS were assessed. RESULTS A total of 205 patients with SH underwent SRS for a sporadic VS. At SRS, 54 (26%) tumors were confined to the internal auditory canal and 151 (74%) extended into the cerebellopontine angle. At 2, 5, and 10 years following SRS, 62%, 37%, and 15% of patients maintained SH, respectively. The median time to non-SH was 1.8 years. The median rates of change in PTA and WRS were 6.0 dB of hearing loss per year and −6.5% per year, respectively. In a multivariable analysis, each 1-Gy increase in minimum cochlear dose was significantly associated with time to non-SH (HR 1.5, 95% CI 1.2–1.9), rate of change in PTA decibel hearing loss per year (parameter estimate [PE] 3.4, 95% CI 0.6–6.2), and rate of change in WRS percentage per year (PE −6.4, 95% CI −11.2 to −1.5). The associations of each 1-Gy increase in mean cochlear dose with hearing outcomes were only significant among patients with class B hearing (time to non-SH HR 1.3, 95% CI 1.1–1.6; rate of change in PTA PE 3.6, 95% CI 1.2–5.9; and rate of change in WRS PE −5.7, 95% CI −9.7 to −1.7). CONCLUSIONS The minimum cochlear dose impacts hearing outcomes after SRS for VS and should be considered in radiosurgical treatment planning. In this cohort, the mean cochlear dose was only associated with hearing outcomes in the subgroup of patients with class B hearing at SRS.

Abstract Targeted gene expression profiling improves risk stratification for meningiomas, but the utility of this approach for low grade meningiomas is incompletely understood. To address this, 466 meningiomas that were initially used to validate a 34-gene expression biomarker were combined with 270 previously unpublished samples for an analysis of biomarker performance in newly diagnosed (n=691) or recurrent (n=45) WHO grade 1 meningiomas treated with gross total (GTR) or subtotal resection (STR), and newly diagnosed WHO grade 2 meningiomas treated with GTR. Prediction of local freedom from recurrence (LFFR) or overall survival (OS) was measured using Cox proportional hazards models and the Kaplan-Meier method. The cohort included 736 patients, 69.4% female, with a median age at diagnosis of 58 years. There were 635 WHO grade 1 meningiomas, 498 with GTR and 133 with STR, and 101 WHO grade 2 meningiomas with GTR. The median follow-up was 4.6 years, the local recurrence rate was 12.0% and the rate of death was 8.4%. The biomarker classified 51.5% of meningiomas as intermediate risk and 9.6% as high risk. Combining the biomarker with extent of resection identified 19.7% as unfavorable (intermediate molecular risk with STR or high molecular risk), including 7.4% of newly diagnosed WHO grade 1 meningiomas with GTR. The risk score was prognostic for LFFR overall (hazard ratio per 0.1 increase in risk score 1.89, 95% confidence interval 1.58-2.25) and across WHO grades, extents of resection, and newly diagnosed or recurrent settings. Gene expression risk groups were prognostic for LFFR, with improved outcomes among low molecular risk compared to intermediate molecular risk (Log-rank, p=0.0002) and high molecular risk meningiomas (Log-rank, p<0.0001). These data suggest that a targeted gene expression biomarker can identify low grade meningiomas that are more likely to recur after surgery, possibly changing management for approximately one-fifth of cases.

Abstract Genomic alterations and molecular subgroups between extracranial disease sites and brain metastases often differ, yet the prevalence and clinical significance of divergent evolution in brain metastases is not fully understood. This study examined genomic alterations and molecular subgroup divergence rates between matched brain metastases and extracranial disease sites. A retrospective, two-center study was conducted on patients who underwent resection of brain metastases between 2014-2022 with clinical and matched genomic data and/or molecular markers available. The overall cohort comprised 256 patients with matched tumors from multiple cancer types, most commonly from breast (n=108, 42.2%), melanoma (n=83, 32.4%), and NSCLC (n=43, 16.8%). Targeted next-generation sequencing of over 500 oncogenes was performed on resected tumors as part of clinical care (n=41 patients with matched specimens). Molecular subgroups for breast, melanoma, and non-small cell lung cancer were also assessed by immunohistochemistry to evaluate rates of molecular subgroup discordance between sites. Subgroup discordance by immunohistochemistry was observed most frequently across breast cancer (22.2%, n=24/108) with loss of the estrogen receptor (ER) and progesterone receptor (PR) and gain of HER2 most frequently observed within brain metastases. Molecular subgroup discordance was rare within melanoma (7.3%, n=6/82) and NSCLC (14.0%, n=6/43) patients. When evaluating oncogenomic alterations from targeted DNA sequencing in 41 patients with matched specimens, 80.5% (33/41) of brain metastases demonstrated a unique oncogene alteration profile compared to an extracranial disease site. Fourteen patients (34.1%) had a gain of at least 1 targetable alteration within a brain metastasis that was not observed in an extracranial disease site. Brain metastases demonstrated high rates of genomic divergence compared to primary and extracranial metastatic disease sites. This data supports obtaining brain metastasis tissue and conducting molecular profiling of this tissue to help select optimal CNS penetrant systemic therapies for each patient.

Abstract BACKGROUND Brain metastases (BMs) are a significant cause of morbidity and mortality in metastatic breast cancer (MBC), yet prognostic and predictive biomarkers remain poorly understood. STUDY DESIGN 90 consecutive patients with breast cancer BMs who underwent surgical resection from 2006-2022 were retrospectively identified. Review of the electronic medical record and institutional cancer registry were completed to identify baseline clinical parameters and outcomes. BM mutation analysis was performed using a CLIA-certified targeted DNA mutation sequencing assay as part of routine clinical care. RESULTS All patients were female, median age at first BM resection was 57.9 years (range 27.0-81.3 years), and receptor subtypes included HR+/HER2- (n=27, 30.0%), HER2+ (n=33, 36.7%), and triple negative BC (TNBC; n=30, 33.3%). At time of first BM resection, most patients had a solitary BM (n=55, 61.1%), with anatomic locations including cerebellar (n=29, 32.2%), frontal (n=26, 28.9%), and parietal (n=17, 18.9%) sites. BM DNA mutation analysis (n= 20) revealed pathogenic alterations in TP53 (n=17, 85.0%), ERBB2 amplification (n=7, 35.0%), PIK3CA (n=4, 20.0%), BRCA1 (n=3, 15.0%), and BRCA2 (n=2, 10.0%). Most patients received postoperative radiation (n=82, 90.8%) and/or systemic therapy (n=67, 82.7%). Cerebellar location was significantly associated with the risk of developing leptomeningeal disease compared to other BM resection sites (HR = 2.75, p=0.02). Among all patients, median overall survival (OS) from first BM resection was 27.8 months (range 0.1-196.6 months). HR+/HER2- (median 37 months) or HER2+ (median 36 months) MBC was associated with significantly increased OS compared to TNBC (14.4 months) (p<0.01, log-rank test). CONCLUSIONS Patients with breast cancer BMs exhibited a median OS of >2 years following BM resection, and patients with TNBC had a significantly worse prognosis. Targetable mutations were observed in 40% of resected BM specimens, supporting the utility of molecular analysis of resected BMs to help guide clinical management.

Abstract Current standard of care for IDH-wildtype glioblastoma (GBM) includes maximal safe resection, adjuvant radiation, and chemotherapy with the alkylating agent temozolomide. A subset of gliomas treated with temozolomide develop somatic hypermutation with a predominance of C>T transitions due to the alkylation effects on DNA. However, the frequency of occurrence, clinical ramifications, and predictive biomarkers for developing temozolomide-induced hypermutation (TMZ-HM) in GBM are unknown. Here we performed comprehensive histopathologic, genomic, and epigenomic evaluation of paired initial and recurrent GBM from 106 patients. Seven patients (7%) developed hypermutation at time of first recurrence, while an additional five patients (5%) developed hypermutation at a subsequent recurrence. Patients who developed TMZ-HM had a significantly longer interval between initial surgery and first recurrence (27.8 vs. 9.9 months, p<0.001). In contrast to IDH-mutant gliomas where TMZ-HM is associated with poor prognosis, those patients with IDH-wildtype GBM who developed TMZ-HM had significantly longer overall survival from both initial surgery (67.9 vs. 20.3 months, p<0.001) and from time of recurrence after development of hypermutation (30.9 vs. 9.5 months, p=0.001). There was no difference in oncogenic alteration frequency in initial GBM that subsequently developed TMZ-HM. However, 4 specific CpG sites out of 12 total interrogated sites in the promoter region of MGMT (a DNA repair enzyme) and 5 specific CpG sites in the promoter region of KCNQ1DN (a negative regulator of c-Myc) were significantly more hypermethylated in those GBM that developed TMZ-HM. We then generated a weighted risk score across these CpG sites that can be used to prospectively identify GBM likely to develop TMZ-HM associated with favorable survival. In summary, patients with GBM that develop TMZ-HM follow a more favorable clinical course, and specific MGMT and KCNQ1DN promoter hypermethylation patterns could serve as a biomarker to identify these patients who may potentially benefit from extended alkylating chemotherapy treatment.

Abstract The prevalence of asymptomatic, incidental meningiomas is increasing due to greater frequency of brain imaging. This retrospective cohort study of adult patients presenting at a single institution from 1996-2020 integrated clinical data, serial magnetic resonance imaging (MRI) volumetrics, DNA methylation profiling, and targeted gene expression profiling to define the natural history and molecular architecture of incidental meningiomas. Volumetrics were calculated from contrast-enhanced brain MRIs at time of diagnosis compared to serial surveillance MRIs (average 3 MRIs per patient pre-intervention, range: 1-12) DNA methylation groups and gene expression risk scores were defined for 123 samples that underwent resection. Time-to-event analyses were performed for progression-free survival (PFS), symptom-free survival (SFS), and treatment-free survival (TFS). The cohort included 238 meningiomas from 207 patients. Median age at diagnosis was 59 years and 81.5% of patients were female. Median clinical and imaging follow-up were 9.1 and 6.7 years, respectively, during which time 50.8% progressed. Median maximum diameter and volume at diagnosis were 2.20 cm and 4.25 cm3, respectively, and median pre-treatment volumetric growth rate was 19.2% per year. Median pre-treatment PFS and TFS were 3.10 and 1.27 years, respectively, and median SFS and post-treatment PFS were not reached. Cox proportional hazards regression identified maximum diameter at diagnosis as a significant predictor of worse pre-treatment PFS (multivariate HR 1.65 per 1 cm [95% CI 1.19–2.28], p=0.0027) and worse TFS (multivariate HR 1.44 per 1 cm [95% CI 1.17–1.76], p<0.001). Skull base tumors had with worse SFS (multivariate HR 2.48 [95% CI 1.02–6.00], p=0.045). Molecular and histological features among incidental meningiomas that ultimately underwent resection (n=176, 74.0%) were reassuring (89.2% WHO grade 1, 10.2% WHO grade 2). These findings suggest maximum diameter at diagnosis of incidental meningiomas is significantly associated with earlier progression and eventual treatment, and skull base tumors have earlier symptom development.

OBJECTIVE Imaging surveillance with serial MRI, or a "wait-and-scan" approach, is a management option for patients with small or medium-sized vestibular schwannomas (VSs). Prior publications have indicated no distinct quality of life advantage to upfront treatment compared with initial wait-and-scan management. However, imaging surveillance is dependent on patient adherence to follow-up. In this study, the authors aimed to identify rates and predictors of patient loss to follow-up during wait-and-scan management of sporadic VS. METHODS A single-center study was conducted including all patients from 2013 to 2018 who had undergone upfront imaging surveillance of sporadic VS. Patient data were retrospectively obtained from the electronic medical record. Outcomes of interest included loss to follow-up unrelated to death and inconsistent adherence to imaging surveillance recommendations. Logistic regression analyses were conducted to evaluate factors associated with loss to follow-up. RESULTS Over a 6-year study period, 270 patients underwent initial imaging surveillance of a sporadic VS. The median tumor diameter was 8.6 mm (range 1–28.9 mm). At the time of censoring, 106 patients (39.3%) had received treatment, 157 (58.1%) had been advised to continue follow-up, and 7 (2.6%) had died of non–VS-related causes. In total, 73 patients (27.0%) were completely lost to follow-up prior to the first treatment or death. Additionally, 60 patients (22.2%) missed at least 1 MRI follow-up or imaging follow-up was delayed by more than 1 year. Multivariable logistic regression identified an out-of-state residence (OR 3.05, 95% CI 1.58–5.89, p = 0.0009) and a smaller tumor size (unit OR per 1-mm increase in size, OR 0.88, 95% CI 0.83–0.95, p = 0.0006) to be associated with loss to follow-up. Patients living ≥ 350 miles from the hospital or with tumors ≤ 3 mm at the time of initial clinic evaluation were most likely to be lost to follow-up. Only a smaller tumor size was associated with an increased risk of inconsistent imaging follow-up (unit OR per 1-mm increase in size, OR 0.92, 95% CI 0.87–0.98, p = 0.007). CONCLUSIONS Patients undergoing imaging surveillance of VS are at risk for loss to follow-up and inconsistent imaging surveillance. Patients with smaller tumors or those living farther away from the treating institution are at highest risk for being lost to follow-up.

BACKGROUND AND OBJECTIVES: The trans-sinus transglabellar and bifrontal approaches offer direct access to the anterior cranial fossa. However, these approaches present potential drawbacks. We propose the biportal endoscopic transfrontal sinus (BETS) approach, adapting endoscopic endonasal approach (EEA) techniques for minimally invasive access to the anterior fossa, reducing tissue manipulation, venous sacrifice, and brain retraction. METHODS: Six formalin specimens were used. BETS approach involves 2 incisions over the medial aspect of both eyebrows from the supraorbital notch to the medial end of the eyebrow. A unilateral pedicled pericranial flap is harvested. A craniotomy through the anterior table of the frontal sinus (FS) and a separate craniotomy through the posterior table are performed. Two variants of the approach (preservative vs cranialization) are described for opening and reconstruction of the FS based on the desired pathology to access. Bone flap replacement can be performed with titanium plates and filling of the external table defect with bone cement. RESULTS: Like in EEA, this approach provides access for endoscope and multiple working instruments to be used simultaneously. The approach allows wide access to the anterior cranial fossa, subfrontal, and interhemispheric corridors, all the way up to the suprachiasmatic corridor and through the lamina terminalis to the third ventricle. BETS provides direct access to the anterior fossa, minimizing the level of frontal lobe retraction and providing potentially less tissue disruption and improved cosmesis. Cerebrospinal fluid fistula risk remains one of the major concerns as the narrow corridor limits achieving a watertight closure which can be mitigated with a pedicled flap. Mucocele risk is minimized with full cranialization or reconstruction of the FS. CONCLUSION: The BETS approach is a minimally invasive approach that translates the concepts of EEA to the FS. It allows excellent access to the anterior cranial fossa structures with minimal frontal lobe retraction.