Faculty Bibliography

Inhibition of mTORC1 signaling has been shown to diminish growth of meningiomas and schwannomas in preclinical studies, and clinical data suggest that everolimus, an orally administered mTORC1 inhibitor, may slow tumor progression in a subset of NF2 patients with vestibular schwannoma (VS). To assess the pharmacokinetics, pharmacodynamics and potential mechanisms of treatment resistance, we performed a pre-surgical (phase 0) clinical trial of everolimus in patients undergoing elective surgery for VS or meningiomas. Eligible patients with meningioma or VS requiring tumor resection enrolled on study received everolimus 10 mg daily for 10 days immediately prior to surgery. Everolimus blood levels were determined immediately prior to and after surgery. Tumor samples were collected intraoperatively. Ten patients completed protocol therapy. Median pre- and post-operative blood levels of everolimus were found to be in a high therapeutic range (17.4 ng/ml and 9.4 ng/ml, respectively). Median tumor tissue drug concentration determined by mass spectrometry was 24.3 pg/mg (range 9.2-169.2). We observed only partial inhibition of phospho-S6 in the treated tumors, indicating incomplete target inhibition compared to control tissues from untreated patients (p=0.025). Everolimus led to incomplete inhibition of mTORC1 and downstream signaling. These data may explain the limited anti-tumor effect of everolimus observed in clinical studies for NF2 patients and will inform the design of future pre-clinical and clinical studies targeting mTORC1 in meningiomas and schwannomas.

BACKGROUND:Unlike medullary thyroid carcinoma in adults, the vast majority of pediatric medullary thyroid carcinoma is hereditary. Pediatric medullary thyroid carcinoma is known to have different genetic alterations driving tumorigenesis, but it is not known if pediatric medullary thyroid carcinoma has different clinicopathologic features. This study aims to identify which pediatric medullary thyroid carcinoma patients might warrant elective neck dissection. METHODS:We selected all patients ages 0 to 19 diagnosed with clinically evident medullary thyroid carcinoma in the National Cancer Database between 2004 to 2016. Clinicopathologic factors, treatments, and outcomes were analyzed and compared between this cohort and adults (ages ≥20) with medullary thyroid carcinoma. RESULTS:One hundred twenty-five pediatric medullary thyroid carcinoma (median age: 13) and 5,086 adult medullary thyroid carcinoma (median age: 57) patients were identified. Pediatric patients had smaller tumors (median diameter: 1.2 cm vs 2.0 cm; P < .001), lower rates of nodal metastases (n = 31, 36.9% vs 1,689, 50.4%; P = .02) but double the incidence of multifocal tumors (n = 70, 59.3%, vs 1,412, 29.9%; P < .001) compared with adults. Multifocal tumors conferred a significantly increased risk of nodal metastases in adult medullary thyroid carcinoma (64.4% vs 43.2%; P < .001) but not pediatric medullary thyroid carcinoma (37.7% vs 35.7%; P = .85). Nodal metastases were more frequent among older children (0-5 years: 0.0%, 6-12: 40.7%, 13-19: 41.7%; P = .04). However, rates of occult nodal metastases were similar between older children (6-19 years: n = 12, 21.4%) and adults (557, 25.8% P = .56). CONCLUSION/CONCLUSIONS:Pediatric medullary thyroid carcinoma has lower rates of lymph node metastases compared with adults. The risk of nodal disease was low among the youngest children, but older children ages 6 to 19 were at considerable risk for occult metastases. These findings could guide clinicians in selecting pediatric patients considered for elective lymph node dissection.

The majority of malignancies identified in indeterminate thyroid nodules (ITN) are low risk. Therefore, the need for total thyroidectomy or adjuvant treatment such as completion thyroidectomy or radioactive iodine (RAI) therapy in the treatment of ITNs is uncertain. This study aimed to analyze the likelihood of a need for total thyroidectomy and RAI therapy in the management of ITNs. All ITNs diagnosed on FNA cytology from 2014-2018 at NYU Langone Health were reviewed. ITNs managed with surgery were selected. Demographics, nodule characteristics, final pathology, treatment detail, and clinical outcomes were recorded. During the study period, 218 patients with surgically excised ITNs were identified. One hundred forty-two (65.1%) patients underwent thyroid lobectomy (TL), and 76 (34.9%) had total thyroidectomy (TT) upfront. In the lobectomy group, 26 (18.3%) had a malignant nodule on final surgical pathology, 8 (5.6%) underwent completion thyroidectomy, and 5 (3.5%) received RAI. In the total thyroidectomy group, 26 (34.2%) were diagnosed as malignant, and 14 (18.4%) received RAI. Follicular variant of papillary thyroid carcinoma (FVPTC) was the most common malignant diagnosis in both groups (TL: 20, 76.9%; TT: 12, 46.2%). Adenomatous nodule was the most common benign diagnosis (TL: 55, 72.5%; TT: 15, 51.2%). NIFTP accounted for 28.2% (40) of nodules treated with lobectomy and 27.6% (21) of nodules treated with upfront total thyroidectomy. In the entire cohort, only two (1%) patients had significant pathology in the contralateral lobe (1 [0.5%] with papillary thyroid carcinoma [PTC] and 1 [0.5%] with multifocal micro-PTC). Of all 218 ITNs, only 19 patients (8.7%) received RAI. With a median follow-up of 31.5 months (interquartile range = 21-39.5), no recurrences or progression was seen. The need for completion thyroidectomy or adjuvant RAI therapy in the treatment of ITN was low in our series. These data suggest that initial management of ITNs with lobectomy might be sufficient in the majority of cases

OBJECTIVES/HYPOTHESIS/OBJECTIVE:Singers have high vocal demands and are at increased risk of developing voice disorders. Different singing genres place different technical demands on the voice. However, differences in laryngeal pathology based on genre have not been well-researched. The purpose of this study was to determine the prevalence of laryngeal pathology in different genres of professional and amateur singers who present with a voice complaint. STUDY DESIGN/METHODS:Retrospective review. METHODS:Retrospective review of patients seen at a tertiary laryngology practice. Self-identified singers who reported their primary singing genre and categorized their singing as a full-time job, part-time job, or amateur involvement were included. Type and prevalence of pathology were calculated based on genre and professional status. RESULTS:Of the 302 self-identified singers, 54% (n = 164) had laryngeal pathology. Among those with pathology, the most common finding was fibrotic lesion (38.4%, 63/164). Genres in which a majority of singers had pathology were other (69.2%, 9/13), choral (64.7%, 11/17), pop (63.2%, 12/19), musical theater (61.4%, 43/70), country (100%, 4/4), and Latin (100%, 2/2). The highest prevalence of pathology was seen in part-time professional singers (62.2%, 41/66) and full-time professionals (60.8%, 62/102), compared to amateurs (45.1%, 60/133). CONCLUSIONS:Laryngeal pathology is prevalent in singers presenting with a voice complaint. Regardless of genre or professional status, fibrotic lesions were the most common pathological finding. This study provides preliminary data on the prevalence of different laryngeal pathologies found in singers by genre and degree of professional involvement. LEVEL OF EVIDENCE/METHODS:4 Laryngoscope, 2020.

OBJECTIVES/HYPOTHESIS/OBJECTIVE:Novel laryngotracheal wound coverage devices are limited by complex anatomy, smooth surfaces, and dynamic pressure changes and airflow during breathing. We hypothesize that a bioinspired mucoadhesive patch mimicking how geckos climb smooth surfaces will permit sutureless wound coverage and also allow drug delivery. STUDY DESIGN/METHODS:ex-vivo. METHODS:Polycaprolactone (PCL) fibers were electrospun onto a substrate and polyethylene glycol (PEG) - acrylate flocks in varying densities were deposited to create a composite patch. Sample topography was assessed with laser profilometry, material stiffness with biaxial mechanical testing, and mucoadhesive testing determined cohesive material failure on porcine tracheal tissue. Degradation rate was measured over 21 days in vitro along with dexamethasone drug release profiles. Material handleability was evaluated via suture retention and in cadaveric larynges. RESULTS:concentration was maintained over 21 days. Optimized PCL-PEG-2XFLK density flocked patches were easy to maneuver endoscopically in laryngeal evaluation. CONCLUSIONS:This novel, sutureless, patch is a mucoadhesive platform suitable to laryngeal and tracheal anatomy with drug delivery capability. LEVEL OF EVIDENCE/METHODS:N/A Laryngoscope, 2020.

Vocal fold polyp (VFP) is an exophytic gelatinous lesion with an atrophic epithelium. After behavioral and conservative management, phonomicrosurgery is the treatment of choice for VFPs with excellent outcomes in terms of lesion resolution and postoperative vocal function. Office-based potassium titanyl phosphate (KTP) laser ablation is a new treatment modality for VFPs but its efficacy for professional singers has yet to be validated. Reported is a consecutive series of six professional singers (with seven episodes of VFP) who, based on patient and provider preference, underwent in-office KTP laser ablation of VFP. Two polyps required two ablation procedures; otherwise, a single treatment was successful in resolution of VFP at a mean resolution time of 44 days. Singing voice handicap index 10 improved from a mean of 30.8 (range 4-40) to 6.0 (range 0-22). All patients resumed their professional singing careers without vocal limitations. Posttreatment videos were reviewed by three blinded fellowship trained laryngologists, who were not able to accurately predict the laterality of the polyp (52% correct, p = 0.99).

OBJECTIVE:Current clinical practice guidelines recommend a laryngoscopic referral for patients who present with hoarseness for longer than 28 days and earlier for patients with certain high-risk factors. The goal of this study was to identify additional possible concomitant health conditions in individuals with chronic (>28 days) hoarseness to improve early detection of chronic voice problems. METHODS:Using data from the 2012 National Health Interview Survey, four health conditions were selected: Swallowing problems, respiratory problems, hormonal-cycle problems, and physical activity limitations. Multivariable logistic regressions controlling for age, gender, race, and smoking status, were used to calculate the odds ratios for the association of each of these four health conditions to chronic versus acute voice problems. RESULTS:Of the 2,746 respondents who reported a voice disorder within the last year, 736 reported a voice problem lasting longer than 4 weeks in duration. After controlling for covariates, individuals reporting swallowing problems and physical activity limitations were more likely to report a chronic voice problem versus an acute voice problem, odds ratios with 95% confidence intervals of 1.983 (1.619, 2.430) and 1.716 (1.355, 2.173), respectively. No significant associations were found for respiratory or hormonal-cycle problems. CONCLUSION/CONCLUSIONS:Individuals who present with both a voice problem and a swallowing problem or physical activity limitation may be at increased risk for developing a chronic voice problem. Therefore, these two health conditions should be included as high-risk factors when determining the escalation of care for a patient presenting with acute dysphonia.

OBJECTIVE:Meningiomas that arise primarily within the cavernous sinus are often believed to be more indolent in their growth pattern. Despite this perceived growth pattern, disabling symptoms can arise even with small tumors. While research has been done on cavernous sinus meningiomas (CSMs) and their treatment, very little is known about their natural growth rates. With a better understanding of the growth rate of CSM, patient treatment and guidance can be can optimized and individualized. The goal of this study was to determine volumetric growth rates of untreated CSMs. METHODS:Thirty-seven patients with 166 MR images obtained between May 2004 and September 2019 were reviewed, with a range of 2-13 MR images per patient (average of 4.5 MR images per patient). These scans were obtained over an average follow-up period of 45.9 months (median 33.8, range 2.8-136.9 months). All imaging prior to any intervention was included in this analysis. Volumetric measurements were performed and assessed over time. RESULTS:The estimated volumetric growth rate was 23.3% per year (95% CI 10.2%-38.0%, p < 0.001), which is equivalent to an estimated volume doubling time (VDT) of 3.3 years (95% CI 2.1-7.1 years). There was no significant relationship between growth rate and patient age (p = 0.09) or between growth rate and patient sex (p = 0.78). The median absolute growth rate was 41% with a range of -1% to 1793%. With a definition of "growth" as an increase of greater than 20% during the observed period, 65% of tumors demonstrated growth within their observation interval. Growth rates for each tumor were calculated and tumors were segmented based on growth rate. Of 37 patients, 22% (8) demonstrated no growth (< 5% annual growth, equivalent to a VDT > 13.9 years), 32% (12) were designated as slow growth (annual growth rate 5%-20%, VDT 3.5-13.9 years), 38% (14) were found to have medium growth (annual growth rate 20%-100%, VDT 0.7-3.5 years), and 8% were considered fast growing (annual growth rate > 100%, VDT < 0.7 years). CONCLUSIONS:This study evaluated CSM volumetric growth rates. A deeper understanding of the natural history of untreated CSMs allows for better counseling and management of patients.

OBJECTIVE:In this study, the authors aimed to clarify the relationship between hearing loss and tumor volumetric growth rates in patients with untreated vestibular schwannoma (VS). METHODS:Records of 128 treatment-naive patients diagnosed with unilateral VS between 2012 and 2018 with serial audiometric assessment and MRI were reviewed. Tumor growth rates were determined from initial and final tumor volumes, with a median follow-up of 24.3 months (IQR 8.5-48.8 months). Hearing changes were based on pure tone averages, speech discrimination scores, and American Academy of Otolaryngology-Head and Neck Surgery hearing class. Primary outcomes were the loss of class A hearing and loss of serviceable hearing, estimated using the Kaplan-Meier method and with associations estimated from Cox proportional hazards models and reported as hazard ratios. RESULTS:Larger initial tumor size was associated with an increased risk of losing class A (HR 1.5 for a 1-cm3 increase; p = 0.047) and serviceable (HR 1.3; p < 0.001) hearing. Additionally, increasing volumetric tumor growth rate was associated with elevated risk of loss of class A hearing (HR 1.2 for increase of 100% per year; p = 0.031) and serviceable hearing (HR 1.2; p = 0.014). Hazard ratios increased linearly with increasing growth rates, without any evident threshold growth rate that resulted in a large, sudden increased risk of hearing loss. CONCLUSIONS:Larger initial tumor size and faster tumor growth rates were associated with an elevated risk of loss of class A and serviceable hearing.