Searched for: school:SOM
Department/Unit:Otolaryngology
Association of tumor microbiome with survival in resected early-stage PDAC
Meng, Yixuan; Wang, Chan; Usyk, Mykhaylo; Kwak, Soyoung; Peng, Chengwei; Hu, Kenneth S; Oberstein, Paul E; Krogsgaard, Michelle; Li, Huilin; Hayes, Richard B; Ahn, Jiyoung
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.
PMID: 40013793
ISSN: 2379-5077
CID: 5801172
Ultra-rapid droplet digital PCR enables intraoperative tumor quantification
Murphy, Zachary R; Bianchini, Emilia C; Smith, Andrew; Körner, Lisa I; Russell, Teresa; Reinecke, David; Maarouf, Nader; Wang, Yuxiu; Golfinos, John G; Miller, Alexandra M; Snuderl, Matija; Orringer, Daniel A; Evrony, Gilad D
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.
PMID: 40010345
ISSN: 2666-6340
CID: 5801032
Improving Real-Time Feedback During Cochlear Implantation: The Auditory Nerve Neurophonic/Cochlear Microphonic Ratio
Bester, Christofer; O'Leary, Stephen John; Venail, Frédéric; Büchner, Andreas; Félix, Tiago Rocha; Lai, Wai Kong; Boccio, Carlos; Choudhury, Baishakhi; Tejani, Viral; Mylanus, Emmanuel; Sicard, Marielle; Lenarz, Thomas; Birman, Catherine; Di Lella, Frederico; Roland, J Thomas; Gantz, Bruce; Plant, Kerrie; English, Ruth; Arts, Remo; Beynon, Andy
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.
PMID: 39789698
ISSN: 1538-4667
CID: 5805252
A crucial role for the cortical amygdala in shaping social encounters
Aubry, Antonio V; Durand-de Cuttoli, Romain; Karpman, Elizabeth; Fisher-Foye, Rachel L; Parise, Lyonna F; Cathomas, Flurin; Burnett, C Joseph; Yang, Yewon; Yuan, Chongzhen; LaBanca, Alexa R; Chan, Kenny L; Winston, Kion T; Lin, Hsiao-Yun; Dackour, Farah; Tavallaei, Arman A; Alvarez, Johana; Nishioka, Tadaaki; Morishita, Hirofumi; Froemke, Robert C; Li, Long; Russo, Scott J
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 (COAplEsr1) exhibit increased activity during attack behaviour and during bouts of investigation that precede an attack, in male mice only. Chemogenetic or optogenetic inhibition of COAplEsr1 cells in male aggressors reduces aggression and increases pro-social investigation without affecting social reward and reinforcement behaviour. We further show that COAplEsr1 projections to the ventromedial hypothalamus and central amygdala are necessary for these behaviours. Collectively, these data suggest that, in aggressive males, COAplEsr1 cells respond specifically to social stimuli, thereby enhancing their salience and promoting attack behaviour.
PMID: 39939764
ISSN: 1476-4687
CID: 5793682
DNA immunotherapy for recurrent respiratory papillomatosis (RRP): phase 1/2 study assessing efficacy, safety, and immunogenicity of INO-3107
Morrow, Matthew P; Gillespie, Elisabeth; Sylvester, Albert; Amin, Milan R; Belafsky, Peter C; Best, Simon R; Friedman, Aaron D; Klein, Adam M; Lott, David G; Mau, Ted; Paniello, Randal C; Pransky, Seth M; Saba, Nabil F; Tan, Grace S; Wisotsky, Sadie; Marcus, Sarah A; Reuschel, Emma L; Reed, Katherine S; Weiner, David B; Dallas, Michael; Skolnik, Jeffrey M
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.
PMCID:11821913
PMID: 39939590
ISSN: 2041-1723
CID: 5793672
A Level-Adjusted Cochlear Frequency-to-Place Map for Estimating Tonotopic Frequency Mismatch With a Cochlear Implant
Sagi, Elad; Svirsky, Mario A
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.
PMID: 39930567
ISSN: 1538-4667
CID: 5793252
Optimal Timing of Primary Radiosurgical Treatment of Growing Vestibular Schwannoma: Insights From Salvage Microsurgery Outcomes
Marinelli, John P; Herberg, Hans A; Moore, Lindsay S; Yancey, Kristen L; Kay-Rivest, Emily; Casale, Garrett G; Durham, Allison; Khandalavala, Karl R; Lund-Johansen, Morten; Kosaraju, Nikitha; Lohse, Christine M; Patel, Neil S; Gurgel, Richard K; Babu, Seilesh C; Golfinos, John G; Roland, J Thomas; Hunter, Jacob B; Kutz, J Walter; Santa Maria, Peter L; Link, Michael J; Tveiten, Øystein V; Carlson, Matthew L
OBJECTIVE:Limited evidence guides the optimal timing of treatment after the detection of tumor growth during the observation of sporadic vestibular schwannoma (VS). The current work aimed to inform the timing of radiosurgical intervention based on an analysis of patient outcomes among those who ultimately failed stereotactic radiosurgery (SRS) and underwent salvage microsurgery. STUDY DESIGN/METHODS:A historical cohort study. SETTING/METHODS:Seven centers across the United States and Norway. METHODS:Adults with sporadic VS who underwent salvage microsurgery following failed primary SRS were included. The primary outcome of interest was the association between tumor size at the time of primary SRS and the ability to achieve gross total resection (GTR) and maintain postoperative House-Brackmann (HB) facial nerve grade I at the last follow-up after salvage microsurgery. RESULTS:Among 96 patients, the median (interquartile range [IQR]) cerebellopontine angle (CPA) tumor size at primary SRS was 14.5 mm (10.0-19.0). Each 1-mm increase in CPA tumor size at the time of primary SRS was associated with a 13% increased likelihood of near-total/subtotal resection or most recent postoperative HB grade >I (odds ratio [OR] 1.13, 95% confidence interval [CI] 1.05-1.21, P = .001), with an optimal tumor size threshold to distinguish this outcome of 12 mm of CPA extension (c-index 0.73). Similarly, for each 1-mm increase in CPA tumor size at the time of primary SRS, a 9% increase in any postoperative complication with salvage microsurgery was observed (OR 1.09, 95% CI 1.02-1.15, P = .009). CONCLUSION/CONCLUSIONS:Corroborated by size threshold surveillance data informing the timing of primary microsurgical resection, the current study suggests that VS outcomes are optimized when primary radiosurgical intervention is undertaken on growing tumors when they harbor 10-15 mm of cerebellopontine angle extension or less.
PMID: 39927827
ISSN: 1097-6817
CID: 5793172
Differential behavioral engagement of inhibitory interneuron subtypes in the zebra finch brain
Hozhabri, Ellie; Corredera Asensio, Ariadna; Elmaleh, Margot; Kim, Jeong Woo; Phillips, Matthew B; Frazel, Paul W; Dimidschstein, Jordane; Fishell, Gord; Long, Michael A
Inhibitory interneurons are highly heterogeneous circuit elements often characterized by cell biological properties, but how these factors relate to specific roles underlying complex behavior remains poorly understood. Using chronic silicon probe recordings, we demonstrate that distinct interneuron groups perform different inhibitory roles within HVC, a song production circuit in the zebra finch forebrain. To link these functional subtypes to molecular identity, we performed two-photon targeted electrophysiological recordings of HVC interneurons followed by post hoc immunohistochemistry of subtype-specific markers. We find that parvalbumin-expressing interneurons are highly modulated by sensory input and likely mediate auditory gating, whereas a more heterogeneous set of somatostatin-expressing interneurons can strongly regulate activity based on arousal. Using this strategy, we uncover important cell-type-specific network functions in the context of an ethologically relevant motor skill.
PMID: 39644901
ISSN: 1097-4199
CID: 5781772
Saccade subtypes: Eyes on the prize
Bellegarda, Celine; Schoppik, David
Current models of eye movement control propose that motor neurons responsible for moving the eyes contribute to all eye movements, regardless of context. A recent study in larval zebrafish has instead identified specialized neural circuits, including subtypes of motor neurons, for two different types of fast eye movement, one for exploration and the other for hunting.
PMID: 39904313
ISSN: 1879-0445
CID: 5783892
The Relationship between Chronic Unilateral Hearing Loss, Balance Function, and Falls Is Not Informed by Vestibular Status
Lubetzky, Anat V; Kelly, Jennifer L; Scigliano, Katherine; Morris, Brittani; Cheng, Kristyn; Harel, Daphna; Cosetti, Maura
OBJECTIVES/OBJECTIVE:Recent studies suggest that hearing loss is associated with balance dysfunction and an increased risk of falls. The purpose of this study was to investigate whether adults with unilateral hearing loss (UHL) have an underlying vestibular dysfunction and whether vestibular testing explains balance function and fall risk. STUDY DESIGN/METHODS:Cross-sectional. SETTING/METHODS:Urban otology practice and a human motion laboratory. PATIENTS/METHODS:We recruited 41 healthy controls (mean age, 52 years; range, 22-78 years) and 29 adults with stable UHL (mean age, 53 years; range, 18-80 years) who denied symptoms of dizziness (Dizziness Handicap Inventory average, 1.86; range, 0-14). UHL occurred an average of 4 years (range from sudden loss, 4 months to 27.5 years) prior to testing. INTERVENTIONS/METHODS:We conducted the caloric portion of the videonystagmography test, video head impulse test (vHIT), and a battery of balance tests: standing on foam with eyes closed, timed up and go test, four square step test, 10-meter walk, and a virtual reality (VR) assessment of postural control. MAIN OUTCOME MEASURES/METHODS:Hearing was quantified by four-frequency pure-tone average (PTA). Caloric weakness was defined as asymmetry greater than 25%. Participants self-reported falls over the past 12 months and history of vertigo. Performance on balance tests was quantified by time to completion or duration of hold. Performance on the VR assessment was quantified by root-mean-square velocity of head sway. RESULTS:Proportion of unilateral caloric weakness was significantly higher in the UHL group (25%) than the control group (12%). Five participants with UHL refused caloric testing. vHIT gains of lateral canals were normal in both groups. The majority of participants in the UHL group experienced vertigo at the onset of hearing loss (72%). There were five fallers in the UHL group (17%) and three in the control group (7%). Participants with caloric weakness or vertigo at onset did not differ from those without in age or in any of the balance tests. Participants with history of falls differed in head sway and duration of hold standing on foam with eyes closed. CONCLUSIONS:Individuals with UHL are more likely to have caloric weakness than healthy controls; however, these findings are not correlated with functional outcomes or history of falls. Postural control testing using virtual reality or standing on foam with eyes closed may help detect those at a risk for falls.
PMCID:11726057
PMID: 39663801
ISSN: 1537-4505
CID: 5778252