Faculty Bibliography

Tumors of the paranasal sinus and nasal cavity (PNS/NC) are rare and exhibit diverse histology, anatomic subsite, and malignant potential. Early-stage disease is typically managed with surgery, and locally advanced disease is treated with a combination of surgery, radiotherapy, and chemotherapy. Clinical decision-making is commonly guided by limited retrospective evidence. To address this limitation, we performed a systematic review to inform evidence-based consensus for the management of common clinical scenarios, including the potential roles of radiation and systemic therapy to promote structural preservation, elective neck management, and radiation technique considerations. A librarian-mediated literature search identified 39 studies of adult patients with PNS/NC tumors treated with curative intent that met the study inclusion criteria. Search results were reported using the preferred reporting items for systematic reviews and meta-analyses (PRISMA) methodology. A modified-Delphi process was used to guide consensus for the appropriate use of various management strategies. Strong consensus existed for the appropriateness of primary surgery for early-stage disease, approaches to locally advanced disease with minimal periorbital fat invasion, and the use of induction chemotherapy with response-directed local therapy. Consensus regarding nodal treatment and the use of proton therapy in the adjuvant setting was less robust. The rarity and diversity of PNS/NC tumors limit randomized phase III trials to guide management. As such, this systematic review and appropriate-use consensus statements provide clinical guidance for the management of this challenging disease spectrum.

A key treatment for patients with multiple myeloma is high-dose melphalan followed by autologous stem cell transplant (ASCT). It can provide a deep response with long-term remission. However, some patients progress quickly, and it is not clear why that is. Here, we performed single-cell RNA and T-cell receptor (TCR) sequencing of the immune microenvironment of 40 patients before and after ASCT to determine if differences in the immune composition could define those who would progress. Clear differences in cell populations were identified in progressors, including increased T-cell infiltration, decreased TCR diversity, and decreased frequency of monocytes and CD56bright NK cells. We identified cell interactions that predicted progression including increased frequency of CD8+ exhausted T cells and stromal cells and decreased frequency of CD56bright NK cells and plasmacytoid dendritic cells. We propose and validate a model of progression that can also be determined by flow cytometry. Together these data highlight the importance of the immune microenvironment in understanding responses to ASCT.

Gliomas are a major cause of cancer-related deaths in adolescents and young adults (AYAs; ages 15-39 years). Different molecular alterations drive gliomas in children and adults, leading to distinct biology and clinical consequences, but the implications of pediatric- versus adult-type alterations in AYAs are unknown. Our population-based analysis of 1,456 clinically and molecularly characterized gliomas in patients aged 0-39 years addresses this gap. Pediatric-type alterations were found in 31% of AYA gliomas and conferred superior outcomes compared to adult-type alterations. AYA low-grade gliomas with specific RAS-MAPK alterations exhibited senescence, tended to arise in different locations and were associated with superior outcomes compared to gliomas in children, suggesting different cellular origins. Hemispheric IDH-mutant, BRAF p.V600E and FGFR-altered gliomas were associated with the risk of malignant transformation, having worse outcomes with increased age. These insights into gliomagenesis may provide a rationale for earlier intervention for certain tumors to disrupt the typical behavior, leading to improved outcomes.

Alston's singing mice (Scotinomys teguina) are highly vocal Central American rodents that produce structured "songs" (duration: 5-10 s),¹

OBJECTIVE:Observe if metal artifact reduction (MAR) techniques applied to magnetic resonance imaging (MRI) performed on patients with cochlear implants (CI) or auditory brainstem implants (ABI) improves image quality. STUDY DESIGN/METHODS:Retrospective review. SETTING/METHODS:Tertiary care center. PATIENTS/METHODS:Patients with auditory implants who underwent clinical MRI before and after the application of MAR techniques previously described. INTERVENTIONS/METHODS:From September 2022 to March 2023, patients who underwent brain or internal auditory canal (IAC) MRI with and without MAR were identified. Sequences included T1 and T2 weighted with turbo-spin-echo (TSE) correction and fluid-attenuation inversion recovery (FLAIR). Images were analyzed for visualization of intracranial structures by two neuroradiologists. MAIN OUTCOME MEASURES/METHODS:Visibility of 14 structures graded on a four-point Likert scale. Average scores per structure and sequence were compared using paired two-tailed t-tests and change in mode score. RESULTS:Ten patients underwent pre- and post-MAR MRI. Six had a unilateral CI, three had a unilateral ABI, and one had an ABI and CI. Three patients had four devices with the internal magnet removed for both scans. All structures had significantly improved visibility on post-MAR scan except ipsilateral parietal and occipital lobes and contralateral inner ear. Mode score increased from 2 to 4 for the ipsilateral occipital lobe and from 3 to 4 for the ipsilateral semicircular canals, brainstem, and cerebellar peduncles. Significant improvement was seen in all sequences except for ipsilateral structures on T1w axial precontrast and contralateral structures on T1w coronal postcontrast. ABIs did not improve as much as CIs because they scored better on the pre-MAR scan. CONCLUSIONS:MAR techniques improve image quality for patients with MRI-compatible implants with magnets. Benefits may be more evident in CIs than ABIs.

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.

Cerebellar dysfunction leads to postural instability. Recent work in freely moving rodents has transformed investigations of cerebellar contributions to posture. However, the combined complexity of terrestrial locomotion and the rodent cerebellum motivate new approaches to perturb cerebellar function in simpler vertebrates. Here, we adapted a validated chemogenetic tool (TRPV1/capsaicin) to describe the role of Purkinje cells - the output neurons of the cerebellar cortex - as larval zebrafish swam freely in depth. We achieved both bidirectional control (activation and ablation) of Purkinje cells while performing quantitative high-throughput assessment of posture and locomotion. Activation modified postural control in the pitch (nose-up/nose-down) axis. Similarly, ablations disrupted pitch-axis posture and fin-body coordination responsible for climbs. Postural disruption was more widespread in older larvae, offering a window into emergent roles for the developing cerebellum in the control of posture. Finally, we found that activity in Purkinje cells could individually and collectively encode tilt direction, a key feature of postural control neurons. Our findings delineate an expected role for the cerebellum in postural control and vestibular sensation in larval zebrafish, establishing the validity of TRPV1/capsaicin-mediated perturbations in a simple, genetically tractable vertebrate. Moreover, by comparing the contributions of Purkinje cell ablations to posture in time, we uncover signatures of emerging cerebellar control of posture across early development. This work takes a major step towards understanding an ancestral role of the cerebellum in regulating postural maturation.

OBJECTIVE:This study aims to describe current practices among otolaryngology-trained microtia surgeons in the United States. STUDY DESIGN/METHODS:Survey. SETTING/METHODS:A tertiary care center. METHODS:A 22-question anonymous digital survey of practice patterns and surgical methods was distributed to all members of the American Academy of Facial Plastic and Reconstructive Surgery (AAFPRS) and the American Society of Pediatric Otolaryngology (ASPO). Responses were analyzed using descriptive statistics and linear regression models. RESULTS:Of 1730 eligible members, 83 (4.8%) responses were collected. Forty-three (51.8%) were AAFPRS members, 39 (47.0%) were ASPO members, and 1 (1.2%) reported dual membership. Respondents had multiple practice settings, were at different stages in their experience, and were well-distributed geographically. Forty (48.2%) don't perform microtia repair and half (52.5%) refer to an FPRS-trained colleague. Among microtia surgeons, most (N = 30, 69.8%) received fellowship training. Autologous reconstruction was the most popular method for training and practice; however, most perform multiple methods (N = 33, 76.7%). Autologous rib training was positively correlated with experience of >20 years. Those with combined autologous/alloplastic practice were more frequently trained by PO fellowship. Surgical site infection was the most frequent complication and was seen more often by those trained via residency alone (OR 12.8, P < .05). Those who trained in autologous rib alone were less likely to encounter postoperative graft exposure (OR 5.0, P < .05); however, they were more likely to encounter skin and soft tissue infection (OR 0.07, P < .05). CONCLUSION/CONCLUSIONS:Otolaryngology-trained microtia surgeons come from a variety of academic backgrounds and progress to varied practices. They are trained and practice both alloplastic and autologous repair methods, although autologous methods remain the most common.

OBJECTIVE:The purpose of this study is to characterize patients who work professionally as musical performers and undergo potassium titanyl phosphate (KTP) laser ablation of vocal fold lesions in the outpatient setting. METHODS:A retrospective chart review of patients who are vocal performers and underwent in-office KTP laser ablation of benign vocal fold lesions at a single academic institution between 2012 and 2023 was conducted. Demographics including occupation, were descriptively reviewed. Acoustic measures, including cepstral peak prominence (CPP) and mean fundamental frequency variance (F0CoV), were analyzed. Vocal fold vibratory amplitude and mucosal wave were evaluated on videostroboscopy utilizing the voice vibratory assessment with laryngeal imaging. Preablation and postablation outcome measures were compared via Wilcoxon signed rank and McNemar's test. RESULTS:26 patients who identified as singers successfully underwent single-treatment in-office KTP laser ablation of vocal fold polyps. Ten patients (38.5%) identified as professional performers, and all patients continued their occupation after ablation. 84.2% of patients had either complete recovery or mildly reduced mucosal wave and amplitude of the treated vocal fold following KTP laser ablation. Additionally, CPP vowel improved following in-office KTP laser ablation, and F0CoV decreased following the ablation. All patients were able to continue their occupation in the same capacity. CONCLUSION/CONCLUSIONS:In-office KTP ablation is a valuable, safe, and feasible intervention for professional performers with benign vocal fold polyps. This study provides insight into vocal outcomes in the largest cohort of professional performers with apt follow-up.

We often exert greater cognitive resources (i.e., listening effort) to understand speech under challenging acoustic conditions. This mechanism can be overwhelmed in those with hearing loss, resulting in cognitive fatigue in adults and potentially impeding language acquisition in children. However, the neural mechanisms that support listening effort are uncertain. Evidence from human studies suggests that the cingulate cortex is engaged under difficult listening conditions and may exert top-down modulation of the auditory cortex (AC). Here, we asked whether the gerbil cingulate cortex (Cg) sends anatomical projections to the AC that facilitate perceptual performance. To model challenging listening conditions, we used a sound discrimination task in which stimulus parameters were presented in either "Easy" or "Hard" blocks (i.e., long or short stimulus duration, respectively). Gerbils achieved statistically identical psychometric performance in Easy and Hard blocks. Anatomical tracing experiments revealed a strong, descending projection from layer 2/3 of the Cg1 subregion of the cingulate cortex to superficial and deep layers of the primary and dorsal AC. To determine whether Cg improves task performance under challenging conditions, we bilaterally infused muscimol to inactivate Cg1 and found that psychometric thresholds were degraded for only Hard blocks. To test whether the Cg-to-AC projection facilitates task performance, we chemogenetically inactivated these inputs and found that performance was only degraded during Hard blocks. Taken together, the results reveal a descending cortical pathway that facilitates perceptual performance during challenging listening conditions.