Faculty Bibliography

BACKGROUND AND OBJECTIVES/OBJECTIVE:Hydrocephalus after Gamma Knife® stereotactic radiosurgery (SRS) for vestibular schwannomas is a rare but manageable occurrence. Most series report post-SRS communicating hydrocephalus in about 1% of patients, thought to be related to a release of proteinaceous substances into the cerebrospinal fluid. While larger tumor size and older patient age have been associated with post-SRS hydrocephalus, the influence of baseline ventricular anatomy on hydrocephalus risk remains poorly defined. METHODS:A single-institution retrospective cohort study examining patients who developed symptomatic communicating hydrocephalus after undergoing Gamma Knife® SRS for unilateral vestibular schwannomas from 2011 to 2021 was performed. Patients with prior hydrocephalus and cerebrospinal fluid diversion or prior surgical resection were excluded. Baseline tumor volume, third ventricle width, and Evans Index (EI)-maximum width of the frontal horns of the lateral ventricles/maximum internal diameter of the skull-were measured on axial postcontrast T1-weighted magnetic resonance imaging. RESULTS:A total of 378 patients met the inclusion criteria; 14 patients (3.7%) developed symptomatic communicating hydrocephalus and 10 patients (2.6%) underwent shunt placement and 4 patients (1.1%) were observed with milder symptoms. The median age of patients who developed hydrocephalus was 69 years (IQR, 67-72) and for patients younger than age 65 years, the risk was 1%. For tumor volumes <1 cm3, the risk of requiring shunting was 1.2%. The odds of developing symptomatic hydrocephalus were 5.0 and 7.7 times higher in association with a baseline EI > 0.28 (P = .024) and tumor volume >3 cm3 (P = .007), respectively, in multivariate analysis. Fourth ventricle distortion on pre-SRS imaging was significantly associated with hydrocephalus incidence (P < .001). CONCLUSION/CONCLUSIONS:Patients with vestibular schwannoma with higher baseline EI, larger tumor volumes, and fourth ventricle deformation are at increased odds of developing post-SRS hydrocephalus. These patients should be counseled regarding risk of hydrocephalus and carefully monitored after SRS.

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.

PURPOSE/OBJECTIVE:Mental health disorders, substance abuse, and tobacco use are prevalent in the US population. However, the association between these conditions and head and neck cancer (HNC) stage is poorly understood. This research aims to uncover the relationship between pre-existing mental health disorders, substance abuse, and tobacco use and HNC stage at diagnosis in patients receiving care in an integrated, public safety-net healthcare system. METHODS:This study was a secondary data analysis of linked hospital tumor registries and electronic health record (EHR) data. The study's primary independent variables were the comorbidities of mental health disorders, substance abuse, and tobacco use. The dependent variable was HNC stage at diagnosis, operationalized as early stage (i.e., stages I, II, and III) and advanced stage (stage IV, IVA, IVB, or IVC). The analysis included multivariable logistic regression adjusted for covariates of demographic variables, tumor anato RESULTS: The study population consisted of 357 patients with median age of 59 years, and was primarily male (77%), diverse (Black or African American 41%; Hispanic 22%), and from neighborhoods with low income (median average annual household income $39,785). Patients with a history of mental health disorders with or without tobacco use had significantly lower odds of advanced stage HNC at diagnosis (adjusted OR = 0.35, 95% Confidence Interval [CI]: 0.17-0.72.) while patients with a history of substance abuse with or without tobacco use had significantly higher odds of advanced stage HNC at diagnosis (adjusted OR 1.41, 95% CI: 1.01-1.98) than patients with no history of mental health disorders, substance abuse, or tobacco use. CONCLUSIONS:The relationship between HNC stage at diagnosis and the comorbidities of mental health disorders, substance abuse, or tobacco differs depending on the type and co-occurrence of these comorbidities. These findings demonstrate the need for innovative care delivery models and education initiatives tailored to meet the needs of patients with mental health disorders, substance abuse, and tobacco use that facilitate early detection of HNC.

PURPOSE/OBJECTIVE:To investigate how adults with unilateral vestibular hypofunction and healthy controls incorporate visual and auditory cues for postural control in an abstract visual environment. METHODS:] components in low [0, 0.25 Hz], mid [0.25, 0.5 Hz] and high [0.5, 1 Hz] frequencies in the anterior-posterior direction. We used linear mixed-effects models to compares healthy controls (n = 41, mean age 52 years, range 22-78) to participants with unilateral peripheral vestibular hypofunction (n = 28, 61.5, 27-82), adjusting for age. RESULTS:Variance and low PSD: we observed a significant vestibular by visual load interaction in the presence of sounds, such that the vestibular group had significantly higher sway than controls only on dynamic visuals in the presence of sounds. Mid PSD: the vestibular group had significantly higher sway than controls regardless of condition. High PSD: the vestibular group had significantly higher sway than controls, except for the presence of sounds on static visuals. CONCLUSIONS:Patients with vestibular hypofunction used sounds to reduce sway in a static abstract environment and were somewhat destabilized by it in a dynamic environment. This suggests that sounds, when played from headphones, may function as an auditory anchor under certain level of challenge and specific tasks regardless of whether it's stationary or moving. Our results support that increased sway in middle frequencies reflects vestibular dysfunction.

The pancreas tumor microbiota may influence tumor microenvironment and influence survival in early-stage pancreatic ductal adenocarcinoma (PDAC); however, current studies are limited and small. We investigated the relationship of tumor microbiota to survival in 201 surgically resected patients with localized PDAC (Stages I-II), from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) cohorts. We characterized the tumor microbiome using RNA-sequencing data. We examined the association of the tumor microbiome with overall survival (OS), via meta-analysis with the Cox PH model. A microbial risk score (MRS) was calculated from the OS-associated microbiota. We further explored whether the OS-associated microbiota is related to host tumor immune infiltration. PDAC tumor microbiome α- and β-diversities were not associated with OS; however, 11 bacterial species, including species of Gammaproteobacteria, confirmed by extensive resampling, were significantly associated with OS (all Q < 0.05). The MRS summarizing these bacteria was related to a threefold change in OS (hazard ratio = 2.96 per standard deviation change in the MRS, 95% confidence interval = 2.26-3.86). This result was consistent across the two cohorts and in stratified analyses by adjuvant therapy (chemotherapy/radiation). Identified microbiota and the MRS also exhibited association with memory B cells and naïve CD4⁺ T cells, which may be related to the immune landscape through BCR and TCR signaling pathways. Our study shows that a unique tumor microbiome structure, potentially affecting the tumor immune microenvironment, is associated with poorer survival in resected early-stage PDAC. These findings suggest that microbial mechanisms may be involved in PDAC survival, potentially informing PDAC prognosis and guiding personalized treatment strategies.IMPORTANCEMuch of the available data on the PDAC tumor microbiome and survival are derived from relatively small and heterogeneous studies, including those involving patients with advanced stages of pancreatic cancer. There is a critical knowledge gap in terms of the tumor microbiome and survival in early-stage patients treated by surgical resection; we expect that advancements in survival may initially be best achieved in these patients who are treated with curative intent.

BACKGROUND:The diagnosis and treatment of tumors often depend on molecular-genetic data. However, rapid and iterative access to molecular data is not currently feasible during surgery, complicating intraoperative diagnosis and precluding measurement of tumor cell burdens at surgical margins to guide resections. METHODS:Here, we introduce Ultra-Rapid droplet digital PCR (UR-ddPCR), a technology that achieves the fastest measurement, to date, of mutation burdens in tissue samples, from tissue to result in 15 min. Our workflow substantially reduces the time from tissue biopsy to molecular diagnosis and provides a highly accurate means of quantifying residual tumor infiltration at surgical margins. FINDINGS/RESULTS: = 0.995). CONCLUSIONS:The technology and workflow developed here enable intraoperative molecular-genetic assays with unprecedented speed and sensitivity. We anticipate that our method will facilitate novel point-of-care diagnostics and molecularly guided surgeries that improve clinical outcomes. FUNDING/BACKGROUND:This study was funded by the National Institutes of Health and NYU Grossman School of Medicine institutional funds. Reagents and instruments were provided in kind by Bio-Rad.

OBJECTIVES/OBJECTIVE:Real-time monitoring of cochlear function to predict the loss of residual hearing after cochlear implantation is now possible. Current approaches monitor the cochlear microphonic (CM) during implantation from the electrode at the tip of the implant. A drop in CM response of >30% is associated with poorer hearing outcomes. However, there is prior evidence that CM amplitude can fluctuate in a manner unrelated to hearing trauma, leading to false positives. By monitoring another cochlear response, the auditory nerve neurophonic (ANN), a differentiation between CM drops that result in reduced cochlear output from false positives may be possible. The hypothesis tested in the present work was that ANN/CM ratios measured during a CM drop will increase during drops not associated with postoperative hearing loss. DESIGN/METHODS:Twenty-eight adult participants with known CM drops during implantation were taken from a larger data set. This contains adult cochlear implant candidates scheduled to receive a Cochlear Nucleus cochlear implant with either the slim-straight or slim-modiolar electrode array with preoperative audiometric low-frequency average thresholds of ≤80 dB HL at 500, 750, and 1000 Hz in the ear to be implanted. Patients were recruited from eight international implant sites. Pure-tone audiometry was measured postoperatively and 4 to 6 weeks after implantation. Electrocochleography was measured during and immediately after the implantation of the array in response to a 500-Hz, 6-msec pure-tone pip at 110 dB HL. RESULTS:The ANN/CM ratio rose during CM drops in 19 of these patients and decreased in 9. At the follow-up timepoint, patients with a decreasing ANN/CM ratio had a median hearing loss of 29.0 dB, significantly worse than the group with increasing ratio at 13.3 dB ( p = 0.004). Considering only the change in ANN amplitude during a CM drop led to smaller groups (ANN drop during CM drop N = 17, ANN increasing during CM drop N = 6) due to 5 patients having undetectable ANN during the CM drop. Using the ANN alone also led to as poorer prediction of hearing preservation, with median hearing preservation in the ANN increasing group of 12.9 dB, significantly better than the ANN decreasing group of 25 dB ( p = 0.02). The group with a decreasing ANN/CM ratio had maximum CM amplitude immediately after insertion lower than the maximum amplitude reached during insertion (mean maximum postinsertion amplitude of 98% of during-insertion amplitude). In comparison, the ANN/CM ratio increasing group tended to have a larger CM amplitude immediately after insertion (mean maximum CM amplitude postinsertion of 164% of the maximum during-insertion amplitude). CONCLUSIONS:These data show that the ANN/CM ratio is a measure that can differentiate between patients with CM drops that lead to a loss of residual hearing and those that do not. The ANN/CM ratio is easily measured and responds rapidly during a CM drop, showing clinical promise for improving current and developing approaches to intraoperative monitoring.

Aggression is an evolutionarily conserved behaviour that controls social hierarchies and protects valuable resources. In mice, aggressive behaviour can be broken down into an appetitive phase, which involves approach and investigation, and a consummatory phase, which involves biting, kicking and wrestling¹. Here, by performing an unsupervised weighted correlation network analysis on whole-brain FOS expression in mice, we identify a cluster of brain regions, including hypothalamic and amygdalar subregions and olfactory cortical regions, that are highly co-activated in male but not in female aggressors. The posterolateral cortical amygdala (COApl)-an extended olfactory structure-was found to be a hub region, on the basis of the number and strength of correlations with other regions in the cluster. Our data also show that oestrogen receptor 1 (Esr1)-expressing cells in the COApl (COApl^Esr1) exhibit increased activity during attack behaviour and during bouts of investigation that precede an attack, in male mice only. Chemogenetic or optogenetic inhibition of COApl^Esr1 cells in male aggressors reduces aggression and increases pro-social investigation without affecting social reward and reinforcement behaviour. We further show that COApl^Esr1 projections to the ventromedial hypothalamus and central amygdala are necessary for these behaviours. Collectively, these data suggest that, in aggressive males, COApl^Esr1 cells respond specifically to social stimuli, thereby enhancing their salience and promoting attack behaviour.

Recurrent respiratory papillomatosis (RRP) is a chronic airway disease caused by Human Papillomavirus (HPV). INO-3107, DNA immunotherapy designed to elicit T-cells against HPV-6 and HPV-11, was evaluated in a 52-week Phase 1/2 study for efficacy, safety, and immunogenicity (NCT04398433). Thirty-two eligible adults with HPV-6 and/or HPV-11 RRP, requiring ≥2 surgical interventions in the year preceding dosing were enrolled between October 2020 and November 2021 and administered 4 INO-3107 doses by intramuscular injection followed by electroporation. The primary endpoint was safety and tolerability, as assessed by treatment-emergent adverse events (TEAEs). Secondary endpoints included surgical intervention frequency and change in RRP Severity Score (modified) post-INO-3107 and assessment of immune responses. 81% (26/32) of patients experienced surgery reduction following INO-3107 compared with the year prior to treatment. Blood assessments revealed HPV-6 and HPV-11 antigen-specific T-cell induction. RNA sequencing identified an inflammatory response in papillomas, inclusive of cytolytic CD8 + T-cell signatures. T-cell receptor sequencing revealed emergent T-cell clones in blood and confirmed trafficking to papillomas. Treatment-related adverse events (AEs) were reported in 13/32 (41%) patients, all low-grade. INO-3107 provides clinical benefit to HPV-6 and/or HPV-11-associated RRP adults and is well-tolerated. Importantly, treatment-induced peripheral T-cell responses traffic to airway tissue and are associated with clinical response.

OBJECTIVES/OBJECTIVE:To provide a level-adjusted correction to the current standard relating anatomical cochlear place to characteristic frequency (CF) in humans, and to re-evaluate anatomical frequency mismatch in cochlear implant (CI recipients considering this correction. It is proposed that a level-adjusted place-frequency function may represent a more relevant tonotopic benchmark for CIs in comparison to the current standard. DESIGN/METHODS:The present analytical study compiled data from 15 previous animal studies that reported isointensity responses from cochlear structures at different stimulation levels. Extracted outcome measures were CFs and centroid-based best frequencies at 70 dB SPL input from 47 specimens spanning a broad range of cochlear locations. A simple relationship was used to transform these measures to human estimates of characteristic and best frequencies, and nonlinear regression was applied to these estimates to determine how the standard human place-frequency function should be adjusted to reflect best frequency rather than CF. The proposed level-adjusted correction was then compared with average place-frequency positions of commonly used CI devices when programmed with clinical settings. RESULTS:The present study showed that the best frequency at 70 dB SPL (BF70) tends to shift away from CF. The amount of shift was statistically significant (signed-rank test z = 5.143, p < 0.001), but the amount and direction of shift depended on cochlear location. At cochlear locations up to 600° from the base, BF70 shifted downward in frequency relative to CF by about 4 semitones on average. Beyond 600° from the base, BF70 shifted upward in frequency relative to CF by about 6 semitones on average. In terms of spread (90% prediction interval), the amount of shift between CF and BF70 varied from relatively no shift to nearly an octave of shift. With the new level-adjusted place-frequency function, the amount of anatomical frequency mismatch for devices programmed with standard-of-care settings is less extreme than originally thought and may be nonexistent for all but the most apical electrodes. CONCLUSIONS:The present study validates the current standard for relating cochlear place to CF, and introduces a level-adjusted correction for how best frequency shifts away from CF at moderately loud stimulation levels. This correction may represent a more relevant tonotopic reference for CIs. To the extent that it does, its implementation may potentially enhance perceptual accommodation and speech understanding in CI users, thereby improving CI outcomes and contributing to advancements in the programming and clinical management of CIs.