Faculty Bibliography

BACKGROUND:Safe sampling of central nervous system tumor tissue for diagnostic purposes may be difficult if not impossible, especially in pediatric patients, and an unmet need exists to develop less invasive diagnostic tests. METHODS:We report our clinical experience with minimally invasive molecular diagnostics using a clinically validated assay for sequencing of cerebrospinal fluid (CSF) cell-free DNA (cfDNA). All CSF samples were collected as part of clinical care, and results reported to both clinicians and patients/families. RESULTS:We analyzed 64 CSF samples from 45 pediatric, adolescent and young adult (AYA) patients (pediatric = 25; AYA = 20) with primary and recurrent brain tumors across 12 histopathological subtypes including high-grade glioma (n = 10), medulloblastoma (n = 10), pineoblastoma (n = 5), low-grade glioma (n = 4), diffuse leptomeningeal glioneuronal tumor (DLGNT) (n = 4), retinoblastoma (n = 4), ependymoma (n = 3), and other (n = 5). Somatic alterations were detected in 30/64 samples (46.9%) and in at least one sample per unique patient in 21/45 patients (46.6%). CSF cfDNA positivity was strongly associated with the presence of disseminated disease at the time of collection (81.5% of samples from patients with disseminated disease were positive). No association was seen between CSF cfDNA positivity and the timing of CSF collection during the patient's disease course. CONCLUSIONS:We identified three general categories where CSF cfDNA testing provided additional relevant diagnostic, prognostic, and/or therapeutic information, impacting clinical assessment and decision making: (1) diagnosis and/or identification of actionable alterations; (2) monitor response to therapy; and (3) tracking tumor evolution. Our findings support broader implementation of clinical CSF cfDNA testing in this population to improve care.

OBJECTIVE:This study aims to refine Music Upper Limb Therapy - Integrated (MULT-I) to create a feasible enriched environment for stroke rehabilitation and compare its biological and behavioral effects to that of a home exercise program (HEP). DESIGN/METHODS:Randomized mixed-methods study of 30 adults with post-stroke hemiparesis. Serum brain derived neurotrophic factor (BDNF) and oxytocin levels measured biologic effects, and upper limb function, disability, quality of life and emotional well-being were assessed as behavioral outcomes. Participant experiences were explored using semi-structured interviews. RESULTS:MULT-I participants showed reduced depression from pre- to post- intervention as compared to HEP participants. BDNF levels significantly increased for MULT-I participants, but decreased for HEP participants, with a significant difference between groups after excluding those with post-stroke depression. MULT-I participants additionally improved quality of life and self-perceived physical strength, mobility, activity, participation, and recovery from pre- to post-intervention. HEP participants improved upper limb function. Qualitatively, MULT-I provided psychosocial support and enjoyment while HEP supported self-management of rehabilitation. CONCLUSIONS:Implementation of a music enriched environment is feasible, reduces post-stroke depression, and may enhance the neural environment for recovery via increases in BDNF levels. Self-management of rehabilitation through a home exercise program may further improve upper limb function.

BACKGROUND:For patients with vestibular schwannoma (VS), stereotactic radiosurgery (SRS) has proven effective in controlling tumor growth while hearing preservation remains a key goal. OBJECTIVE:To evaluate hearing outcomes in the modern era of cochlear dose restriction. METHODS:During the years 2013 to 2018, 353 patients underwent Gamma knife surgery for VS at our institution. We followed 175 patients with pre-SRS serviceable hearing (Gardner-Robertson Score, GR 1 and 2). Volumetric and dosimetry data were collected, including biological effective dose, integral doses of total and intracanalicular tumor components, and hearing outcomes. RESULTS:The mean age was 56 years, 74 patients (42%) had a baseline GR of 2, and the mean cochlear dose was 3.5 Gy. The time to serviceable hearing loss (GR 3-4) was 38 months (95% CI 26-46), with 77% and 62% hearing preservation in the first and second years, respectively. Patients optimal for best hearing outcomes were younger than 58 years with a baseline GR of 1, free canal space ≥0.041 cc (diameter of 4.5 mm), and mean cochlear dose <3.1 Gy. For such patients, hearing preservation rates were 92% by 12 months and 81% by 2 years, staying stable for >5 years post-SRS, significantly higher than the rest of the population. CONCLUSION/CONCLUSIONS:Hearing preservation after SRS for patients with VS with serviceable hearing is correlated to the specific baseline GR score (1 or 2), age, cochlear dose, and biological effective dose. Increased tumor-free canal space correlates with better outcomes. The most durable hearing preservation correlates with factors commonly associated with smaller tumors away from the cochlea.

OBJECTIVE:Spontaneous tumor shrinkage during wait-and-scan management of sporadic vestibular schwannoma is generally considered an uncommon phenomenon. However, most data informing this understanding stem from single-slice linear tumor measurements taken in the axial imaging plane. The objective of the current work was to characterize the regression capacity of sporadic vestibular schwannomas using volumetric tumor measurements. STUDY DESIGN/METHODS:Retrospective cohort study using slice-by-slice, three-dimensional volumetric tumor measurements. SETTING/METHODS:Three tertiary referral centers. PATIENTS/METHODS:Patients with sporadic vestibular schwannoma. INTERVENTIONS/METHODS:Wait-and-scan. MAIN OUTCOME MEASURES/METHODS:Regression-free survival rates with regression defined as a decrease of at least 20% of the tumor volume. RESULTS:Among 952 patients undergoing a total of 3,505 magnetic resonance imaging studies during observation, 123 experienced volumetric tumor regression after diagnosis at a median of 1.2 years (interquartile range, 0.6-2.9 yr). Volumetric regression-free survival rates (95% confidence interval; number still at risk) at 1, 3, and 5 years after diagnosis were 94% (92-95%; 662), 86% (83-89%; 275), and 78% (73-82%; 132), respectively. Among 405 patients who demonstrated an initial period of tumor growth but continued wait-and-scan management, 48 experienced volumetric regression at a median of 1.2 years (interquartile range, 0.8-2.6 yr) after initial growth. Volumetric regression-free survival rates at 1, 3, and 5 years after initial growth were 94% (92-97%; 260), 84% (79-89%; 99), and 75% (67-83%; 43), respectively. Ultimately, only 82 of the 952 patients studied showed exclusively volumetric tumor regression (i.e., without any periods of tumor growth) by the time of last follow-up. CONCLUSION/CONCLUSIONS:Spontaneous volumetric tumor shrinkage during wait-and-scan management occurs more frequently than suggested by previous studies using linear tumor measurements and can even occur after previous episodes of documented tumor growth. These data further highlight the dynamic nature of vestibular schwannoma growth. To this end, the application of natural history data to patient management requires a nuanced approach that parallels the complex tumor behavior of vestibular schwannoma.

BACKGROUND:Previous studies comparing hearing outcomes in patients managed with stereotactic radiosurgery (SRS) and a watch-and-wait strategy were limited by small sample sizes that prevented controlling for potential confounders, including initial hearing status, tumor size, and age. OBJECTIVE:To compare hearing outcomes for patients with vestibular schwannomas (VS) managed with observation and SRS while controlling for confounders with propensity score matching. METHODS:Propensity score matching was used to compare 198 patients with unilateral VS with initial serviceable hearing (99 treated with SRS and 99 managed with observation alone) and 116 with initial class A hearing (58 managed with SRS and 58 with observation), matched by initial hearing status, tumor volume, age, and sex. Kaplan-Meier survival methods were used to compare risk of losing class A and serviceable hearing. RESULTS:Between patients with VS managed with SRS or observation alone, there was no significant difference in loss of class A hearing (median time 27.2 months, 95% CI 16.8-43.4, and 29.2 months, 95% CI 20.4-62.5, P = .88) or serviceable hearing (median time 37.7 months, 95% CI 25.7-58.4, and 48.8 months, 95% CI 38.4-86.3, P = .18). For SRS patients, increasing mean cochlear dose was not related to loss of class A hearing (hazard ratio 1.3, P = .17) but was associated with increasing risk of serviceable hearing loss (hazard ratio of 1.5 per increase in Gy, P = .017). CONCLUSION/CONCLUSIONS:When controlling for potential confounders, there was no significant difference in loss of class A or serviceable hearing between patients managed with SRS or with observation alone.

OBJECTIVE:To evaluate the ability of the transimpedance matrix (TIM) measurement to detect cochlear implant electrode tip foldover by comparing results to a "gold standard," the intraoperative plain film radiograph. STUDY DESIGN/METHODS:Retrospective case series. SETTING/METHODS:Tertiary referral hospital. PATIENTS/METHODS:One hundred three patients who underwent cochlear implantation between June 2020 and August 2021. INTERVENTIONS/METHODS:Intraoperative electrophysiologic monitoring (electrode impedances, neural response telemetry, and TIM measurement) and modified Stenver's view plain film radiographs. MAIN OUTCOME MEASURES/METHODS:Identification of tip foldover on both TIM and plain films. RESULTS:In total, 103 patients (117 ears) had both a TIM measurement and intraoperative X-ray available for review, including 68 adults and 35 children. One hundred patients (85%) received the Cochlear Slim Modiolar electrode. Tip foldovers were noted in three of 117 implants (2.5%). In all cases, TIM was able to detect the foldover, and the electrode arrays were reinserted with the patients still under anesthesia, with repeat X-ray demonstrating a normal configuration. Two other abnormal TIM patterns were identified. One was in a patient with an obstructed cochlea in whom only 10 electrodes could be inserted, the other was in a patient with a common cavity abnormality. One additional patient underwent electrode repositioning intraoperatively because of overinsertion. In this patient, the TIM appeared to be within normal limits, but the over-insertion was apparent on X-ray. Overall, the sensitivity and specificity of TIM measurements in detecting electrode tip foldover were both 100%. CONCLUSION/CONCLUSIONS:TIM measurements were able to accurately identify tip foldovers. More research is needed to define the adjunctive role of TIM as an intraoperative measure.