Faculty Bibliography

OBJECTIVE:Previous investigations demonstrated voice changes corresponding to menstrual cycle phases, but few explored longitudinal cycle-to-cycle variations. The aim of this longitudinal case study was to describe changes in acoustics, laryngeal kinematics, vocal effort, and ability to produce high soft phonation in relation to menstrual cycle phases over the course of multiple cycles in a single normally cycling individual. METHODS:Data were obtained from a 34-year-old professional voice user who had self-collected daily videostroboscopy, acoustics, vocal effort rating, and high soft phonation tasks for 394 days. Data were analyzed by cycle phase and across time for all cycles. RESULTS:Cycle length ranged from 24-32 days. All metrics demonstrated high cycle-to-cycle variability (±2 standard deviation or more). Greatest variability was during menses and luteal phases. The fertile window was the least variable and showed decreased glottal area index (GAI), asymmetry quotient, perceived vocal effort, and increased smoothed cepstral peak prominence, consistent with previous literature suggesting "best" voice quality during the periovulatory period. Perceived vocal effort and fundamental frequency were highest during the luteal phase. GAI was lowest during the luteal phase, and higher during estimated day of ovulation, which contradicts previous findings. CONCLUSION/CONCLUSIONS:This case study represents a unique, longitudinal data set demonstrating changes in phonatory characteristics across repeated menstrual cycles. In general, there was increased variability during rapid hormonal changes (menses, luteal phases) and less variability during hormonal stability (fertile window), suggesting that voice changes are sensitive to the rapid hormonal shifts. Future prospective studies should include multiple participants and concurrent hormone-level tracking. LEVEL OF EVIDENCE/METHODS:Level 4.

Remote access approaches to the neck have gained attention due to cosmetic concerns with conventional cervical incisions. Their safety, reproducibility, and oncologic outcomes remain to be fully validated. We retrospectively analyzed our initial experience with retroauricular robotic neck surgery using the Da Vinci system. Thirty-two patients were included. Data collected comprised demographics, procedure type, surgical features, and oncological follow-up. Thirty-five surgeries were performed: 13 posterolateral neck dissections (levels II-V) with central (VI), 5 modified radical dissections (I-V), 5 posterolateral dissections (II-V), and 1 super-selective neck dissection (I). Twelve neck dissections were combined with thyroidectomy. Additional procedures included 4 partial thyroidectomies, 3 submandibular gland resections, 3 schwannoma resections, and 1 branchial cyst excision, totaling 60 procedures. Twenty patients had malignant disease (62.5%). Median hospital stay was 2 days (range 1 9), similar to conventional approaches. Complications included 5 temporary nerve palsies, 1 lymphatic fistula, 1 transient hypoparathyroidism, and 1 minor flap necrosis, all managed conservatively; 1 hematoma required reoperation. Conversion to a conventional approach occured in 4 cases (6.7%). No additional intraoperative or postoperative complications were observed. The mean lymph node yield was 54 in posterolateral/radical dissections and 13 in central dissections. Median follow-up of malignant cases was 41.3 months (range 18-56), with a 3-year regional control rate of 94.7%. Our experience with 60 retroauricular robotic procedures demonstrates this approach to be safe, feasible, and oncologically effective, with complication rates, hospital stay, and oncological outcomes comparable to conventional surgery.

Oxytocin is a small, nine amino acid peptide synthesized and released mostly in the brain. It was discovered first as a hormone that facilitates labor and lactation but has since attracted interest for having important roles in social bonding. Although sometimes informally called a 'love hormone', this is erroneous and does not accurately reflect the biological action of oxytocin across different contexts. Here we provide an overview of the organization of the oxytocin system, which subserves different biological functions that ultimately coordinate physiological and behavioral states supporting reproductive success (Figure 1).

We conducted an umbrella review to synthesize the evidence on the diagnostic performance of liquid biopsy tests for detection of head and neck squamous cell carcinoma (HNSCC). Systematic reviews (SRs) were searched in Medline, Embase, and Google Scholar through December 6, 2023. The Joanna Briggs Institute Critical Appraisal Tool for Systematic Reviews was used to assess methodological quality. Two independent reviewers extracted data. We examined the pooled sensitivity and specificity of biomarker classes. We also statistically pooled sensitivity and specificity of individual biomarkers for oral SCC in cases where meta-analysis was not yet published, since most HNSCC occurs in the oral cavity. Performance was also assessed by specimen type (saliva, serum, plasma, and whole blood). Thirty-one SRs met inclusion criteria and 21 included meta-analyses on transcriptomic, proteomic, genomic, or metabolomic biomarkers. Overall methodologic quality was moderate to high. Primary study overlap was ≥ 15 % in 9.3 % of SR pairwise comparisons. MicroRNA (miRNA) was the biomarker class represented in the most SRs (n = 19) and individual studies (n = 106). Among these, the highest sensitivity was 77 % (95 % CI, 68-84 %), observed in miRNA-21. Hypermethylated DNA was the biomarker class with the highest pooled sensitivity (86 %; 95 % CI, 60-96 %) and specificity (92 %; 95 % CI, 80-97 %) overall, and with superior performance when used in panels compared to individual markers. In studies focused on OSCC detection, no other biomarker class or fluid type demonstrated superior performance over others. In future clinical studies, panels including hypermethylated DNA merit more rigorous evaluation to establish high specificity in addition to sufficient sensitivity.

OBJECTIVE:To better understand the distance relationship of the stapes to the round window, to assist in intraoperative round window identification. STUDY DESIGN/METHODS:Retrospective review of CT temporal bone imaging and multiplanar image reformat analysis. SETTING/METHODS:Tertiary referral center. PATIENTS/METHODS:Patients above 18 years of age who underwent cochlear implantation between January 2020 and April 2025 and had preoperative computed tomography (CT) imaging of the temporal bone. Patients were excluded if they had prior surgical procedures that could distort the stapes superstructure (eg, stapedectomy) or if image quality/resolution precluded adequate visualization of the stapes crus. INTERVENTION/METHODS:None. MAIN OUTCOME MEASURE/METHODS:Prediction accuracy of the stapes intercrural width to locate the level of the round window. RESULTS:There were 102 ears that were studied, including 51 (50%) left and 51 (50%) right ears. The average measured intercrural width was 2.1 mm (SD: 0.17 mm). The maximum intercrural distance was found to be 2.6 mm, and the minimum distance was 1.7 mm. In all 102 (100%) ears, the intercrural distance of the stapes accurately predicted the level of the RW on image analysis. CONCLUSION/CONCLUSIONS:The stapes intercrural width can be utilized as an accurate predictor of the round window level and is a simple and intuitive intraoperative tool surgeons can utilize to safely gain access to the cochlea.

PURPOSE/OBJECTIVE:This prospective, non-randomized phase II single-arm pilot trial aimed to explore favorable mid-treatment nodal response (FMNR) through CT imaging to guide de-escalated chemoradiation therapy (CRT) in patients with favorable risk, node-positive HPV-associated oropharyngeal cancer (OPC). MATERIALS AND METHODS/METHODS:. At week 4, CT imaging evaluated nodal response: ≥40% reduction warranted de-escalation to 60 Gy, while <40% reduction continued standard CRT. Primary endpoint was 2-year PFS from initiation of dose de-escalated CRT. Tissue tumor modified viral (TTMV) HPV DNA samples and DW-MRI were collected at baseline and week 4. MDADI questionnaires were collected at baseline, 1, 3, 6, 12, and 24 months. RESULTS:Of 39 patients, 26 had FMNR and underwent de-escalated treatment. 13 pts had slow mid-treatment nodal shrinkage and received standard dose. At a median follow-up of 47.4 months, the 2-year PFS was 92.1% (95% CI: 0.72-0.98) for the deescalated dose group and 92.3% for the standard dose patients (95% CI: 0.57-0.99), p=0.96. With a median survival follow up of 48.9 months (range: 16.7-77.8 months), there were no deaths or distant failures. FMNR was associated with rapid TTMV HPV DNA clearance, reduced TTMV HPV DNA flare, lower baseline and week 4 MRI diffusivity, and higher baseline and week 4 MRI diffusional kurtosis. No differences in acute or late maximum grade 3-4 toxicity by patient were noted. MDADI composite scores showed minimal clinical important difference (MCID) in the de-escalated group at 1-month post-treatment while the standard group had MCID up to 1-year post-treatment. No patients required feeding tube placement. CONCLUSIONS:De-escalated CRT using CT-based mid-treatment nodal response in favorable risk, node-positive HPV-associated OPC achieved excellent 2-year PFS and OS rates and represents a potential approach in better selecting patients for treatment de-escalation.

Although many internalized G protein-coupled receptors (GPCRs) continue to signal, the mechanisms and outcomes of intracellular GPCR signaling are uncertain due to the challenges of measuring organelle-specific signals and of selectively antagonizing receptors in intracellular compartments. Herein, genetically encoded biosensors targeted to the plasma membrane and early endosomes were used to analyze compartmentalized signaling of protease-activated receptor 2 (PAR₂); the propensity of nanoparticles (NPs) to accumulate in endosomes was leveraged to preferentially antagonize intracellular PAR₂ signaling of pain. PAR₂ agonists evoked sustained activation of PAR₂, Gαq, and β-arrestin-1 in early endosomes and activated extracellular signal regulated kinase (ERK) in the cytosol and nucleus, measured with targeted biosensors. Fluorescent dendrimer and core-shell polymeric NPs accumulated in endosomes of HEK293T cells, colonic epithelial cells, and nociceptors, detected by confocal microscopy. NPs efficiently encapsulated and slowly released AZ3451, a negative allosteric PAR₂ modulator. NP-encapsulated AZ3451, but not unencapsulated AZ3451, rapidly and completely reversed PAR₂, Gαq, and β-arrestin-1 activation in early endosomes and ERK activation in the cytosol and nucleus. When administered into the mouse colon lumen, fluorescent dendrimer NPs accumulated in endosomes of colonocytes and polymeric NPs accumulated in neurons, sites of PAR₂ expression. Both NP formulations of AZ3451, but not unencapsulated AZ3451, caused long-lasting analgesia and normalized aberrant behavior in preclinical models of inflammatory bowel disease. These results provide evidence that PAR₂ endosomal signaling mediates pain and that nanomedicines that antagonize PAR₂ in endosomes effectively relieve pain. NP-mediated delivery may improve the efficacy of other GPCR antagonists for treatment of diverse diseases.

OBJECTIVE/UNASSIGNED:We sought to consolidate the anatomical findings from radiologic research and prior surgical literature to develop a stepwise surgical approach utilizing cadaveric specimens which can serve to improve the accuracy and scalability of surgical apical cochleostomies in the future. METHODS/UNASSIGNED:Cadaveric temporal bone dissections, with subsequent image documentation and distance measurements to confirm surgical accuracy. RESULTS/UNASSIGNED:All four temporal bones (100%) that were drilled utilizing the newly developed surgical approach had an accurately placed apical cochleostomy. No inadvertent entry into the middle turn of the cochlea occurred. There was no violation of the labyrinthine facial nerve, or carotid artery. CONCLUSIONS/UNASSIGNED:Preliminary findings are promising for the described steps to achieve a substantial improvement in apical cochleostomy accuracy, with reduced trauma compared to historically taught techniques.

BACKGROUND:Pituitary neuroendocrine tumors (PitNETs) are the most common intracranial neuroendocrine tumors. PitNETs can be challenging to classify, and current recommendations include a large immunohistochemical panel to differentiate among 14 WHO-recognized categories. METHODS:In this study, we analyzed clinical, immunohistochemical and DNA methylation data of 118 PitNETs to develop a clinico-molecular approach to classifying PitNETs and identify epigenetic classes. RESULTS:CNS DNA methylation classifier has an excellent performance in recognizing PitNETs and distinguishing the three lineages when the calibrated score is ≥0.3. Unsupervised DNA methylation analysis separated PitNETs into two major clusters. The first was composed of silent gonadotrophs, which form a biologically distinct group of PitNETs characterized by clinical silencing, weak hormonal expression on immunohistochemistry, and simple copy number profile. The second major cluster was composed of corticotrophs and Pit1 lineage PitNETs, which could be further classified using DNA methylation into distinct subclusters that corresponded to clinically functioning and silent tumors and are consistent with transcription factor expression. Analysis of promoter methylation patterns correlated with lineage for corticotrophs and Pit1 lineage subtypes. However, the gonadotrophic genes did not show a distinct promoter methylation pattern in gonadotroph tumors compared to other lineages. Promoter of the NR5A1 gene, which encodes SF1, was hypermethylated across all PitNETs clinical and molecular subtypes including gonadotrophs with strong SF1 protein expression indicating alternative epigenetic regulation. CONCLUSION/CONCLUSIONS:Our findings suggest that classification of PitNETs may benefit from DNA methylation for clinicopathological stratification.