Faculty Bibliography

OBJECTIVE:To demonstrate the long-term benefits of implantation in patients with high-frequency sensorineural hearing loss, this report provides 5-year follow-up on a group of implant recipients who were subjects of the Cochlear™ Nucleus® Hybrid™ L24 Implant System pivotal clinical study. METHODS:The results of three related clinical studies were compiled to provide outcome data after 1, 3, and 5 years of implant use in a group of subjects who presented with preoperative high-frequency hearing loss and were implanted with a Nucleus Hybrid L24 (Cochlear Ltd., Sydney, Australia) cochlear implant. A subset of the 50 adult subjects (N = 32) who participated in the Hybrid L24 pivotal Investigational Device Exemption (IDE) completed comprehensive evaluations at 12 months postactivation, 3 years postactivation, and then as part of a postapproval study at 5 years postactivation. Testing included audiometric, speech perception, and subjective satisfaction measures. RESULTS:Mean unilateral speech perception performance was significantly improved at all postoperative intervals compared to preoperative best-aided results and has remained stable to 5 years postactivation. Ninety-four percent of subjects had measurable hearing, and 72% continued to use electric-acoustic stimulation in the implanted ear after 5 years of implant use. Subjective satisfaction results support objective performance improvements. CONCLUSION/CONCLUSIONS:Results demonstrate long-term success of patients with high-frequency hearing loss following Hybrid L24 (Cochlear) cochlear implantation. Benefits include speech perception abilities significantly better than those in the preoperative best-aided condition, with additional benefit in those using electric-acoustic stimulation in the implanted ear. LEVEL OF EVIDENCE/METHODS:2b. Laryngoscope, 2018.

LINE-1/L1 retrotransposon sequences comprise 17% of the human genome. Among the many classes of mobile genetic elements, L1 is the only autonomous retrotransposon that still drives human genomic plasticity today. Through its co-evolution with the human genome, L1 has intertwined itself with host cell biology. However, a clear understanding of L1's lifecycle and the processes involved in restricting its insertion and intragenomic spread remains elusive. Here we identify modes of L1 proteins' entrance into the nucleus, a necessary step for L1 proliferation. Using functional, biochemical, and imaging approaches, we also show a clear cell cycle bias for L1 retrotransposition that peaks during the S phase. Our observations provide a basis for novel interpretations about the nature of nuclear and cytoplasmic L1 ribonucleoproteins (RNPs) and the potential role of DNA replication in L1 retrotransposition.

OBJECTIVES/HYPOTHESIS/OBJECTIVE:To develop a clinically relevant model of oropharyngeal concurrent chemoradiation therapy (CCRT) in order to quantify the effects of CCRT on tongue function and structure. CCRT for advanced oropharyngeal cancer commonly leads to tongue base dysfunction and dysphagia. However, no preclinical models currently exist to study the pathophysiology of CCRT-related morbidity, thereby inhibiting the development of targeted therapeutics. STUDY DESIGN/METHODS:Animal model. METHODS:Twenty-one male Sprague-Dawley rats were randomized into three groups: 2 week (2W), 5 month (5M), and control (C). The 2W and 5M animals received cisplatin, 5-fluorouracil, and five fractions of 7 Gy to the tongue base; the C animals received no intervention. In vivo tongue strength and displacement, as well as hyoglossus muscle collagen content, were assessed. Analyses were conducted 2 weeks or 5 months following completion of CCRT in the 2W and 5M groups, respectively. RESULTS:Peak tetanic and twitch tongue forces were significantly reduced in both 2W and 5M animals compared to controls (tetanic: P = .0041, P = .0089, respectively; twitch: P = .0201, P = .0020, respectively). Twitch half-decay time was prolonged in 2W animals compared to controls (P = .0247). Tongue displacement was significantly reduced across all testing parameters in 5M animals compared to both the C and 2W groups. No differences in collagen content were observed between experimental groups. CONCLUSIONS:The current study is the first to describe a preclinical model of CCRT to the head and neck with an emphasis on clinical relevance. Tongue strength decreased at 2 weeks and 5 months post-CCRT. Tongue displacement increased only at 5 months post-CCRT. Fibrosis was not detected, implicating alternative causative factors for these findings. LEVEL OF EVIDENCE/METHODS:NA Laryngoscope, 2017.

Programmed cell death-1 (PD-1) is an essential inhibitory receptor in T cells. Antibodies targeting PD-1 elicit durable clinical responses in patients with multiple tumor indications. Nevertheless, a significant proportion of patients do not respond to anti-PD-1 treatment, and a better understanding of the signaling pathways downstream of PD-1 could provide biomarkers for those whose tumors respond and new therapeutic approaches for those whose tumors do not. We used affinity purification mass spectrometry to uncover multiple proteins associated with PD-1. Among these proteins, signaling lymphocytic activation molecule-associated protein (SAP) was functionally and mechanistically analyzed for its contribution to PD-1 inhibitory responses. Silencing of SAP augmented and overexpression blocked PD-1 function. T cells from patients with X-linked lymphoproliferative disease (XLP), who lack functional SAP, were hyperresponsive to PD-1 signaling, confirming its inhibitory role downstream of PD-1. Strikingly, signaling downstream of PD-1 in purified T cell subsets did not correlate with PD-1 surface expression but was inversely correlated with intracellular SAP levels. Mechanistically, SAP opposed PD-1 function by acting as a molecular shield of key tyrosine residues that are targets for the tyrosine phosphatase SHP2, which mediates PD-1 inhibitory properties. Our results identify SAP as an inhibitor of PD-1 function and SHP2 as a potential therapeutic target in patients with XLP.

OBJECTIVES/HYPOTHESIS/OBJECTIVE:Our laboratory and others hypothesized that Smad3 is a principle mediator of the fibrotic phenotype in the vocal folds (VFs), and we further posited that alteration of Smad3 expression through short interfering (si)RNA holds therapeutic promise, yet delivery remains challenging. To address this issue, we employed a novel synthetic oligomer, lipitoid, complexed with siRNA to improve stability and cellular uptake with the goal of increased efficiency of RNA-based therapeutics. STUDY DESIGN/METHODS:In vitro study and in vivo animal model. METHODS:In vitro, lipitoid cytotoxicity was quantified via colorimetric and LIVE/DEAD assays in immortalized human VF fibroblasts and primary rabbit VF fibroblasts. In addition, optimal incubation interval and solution for binding siRNA to lipitoid for intracellular delivery were determined. In vivo, a rabbit model of VF injury was employed to evaluate Smad3 knockdown following locally injected lipitoid-complexed siRNA. RESULTS:In vitro, lipitoid did not confer additional toxicity compared to commercially available reagents. In addition, 20-minute incubation in 1× phosphate-buffered saline resulted in maximal Smad3 knockdown. In vivo, Smad3 expression increased following VF injury. This response was significantly reduced in injured VFs at 4 and 24 hours following injection (P = .035 and .034, respectively). CONCLUSIONS:The current study is the first to demonstrate targeted gene manipulation in the VFs as well as the potential utility of lipitoid for localized delivery of genetic material in vivo. Ideally, these data will serve as a platform for future investigation regarding the functional implications of therapeutic gene manipulation in the VFs. LEVEL OF EVIDENCE/METHODS:NA Laryngoscope, 2017.

OBJECTIVE It is common for a medical disorder to be managed or researched by individuals who work within different specialties. It is known that both neurosurgeons and neurotologists manage vestibular schwannoma (VS) patients. While overlap in specialty focus has the potential to stimulate multidisciplinary collaboration and innovative thinking, there is a risk of specialties forming closed-communication loops, called knowledge silos, which may inhibit knowledge diffusion. This study quantitatively assessed knowledge sharing between neurosurgery and otolaryngology on the subject of VS. METHODS A broad Web of Science search was used to download details for 4439 articles related to VS through 2016. The publishing journal's specialty and the authors' specialties (based on author department) were determined for available articles. All 114,647 of the article references were categorized by journal specialty. The prevalence of several VS topics was assessed using keyword searches of titles. RESULTS For articles written by neurosurgeons, 44.0% of citations were from neurosurgery journal articles and 23.4% were from otolaryngology journals. The citations of otolaryngology authors included 11.6% neurosurgery journals and 56.5% otolaryngology journals. Both author specialty and journal specialty led to more citations of the same specialty, though author specialty had the largest effect. Comparing the specialties' literature, several VS topics had significantly different levels of coverage, including radiosurgery and hearing topics. Despite the availability of the Internet, there has been no change in the proportions of references for either specialty since 1997 (the year PubMed became publicly available). CONCLUSIONS Partial knowledge silos are observed between neurosurgery and otolaryngology on the topic of VS, based on the peer-reviewed literature. The increase in access provided by the Internet and searchable online databases has not decreased specialty reference bias. These findings offer lessons to improve cross-specialty collaboration, physician learning, and consensus building.

Objective To compare positive margin rates between the 2 most common subsites of oropharyngeal transoral robotic surgery (TORS), the base of tongue (BOT) and the tonsil, as well as identify preoperative imaging characteristics that predispose toward positive margins. Study Design Case series with chart review. Setting Tertiary care referral center. Subjects and Methods We compared the final and intraoperative positive margin rate between TORS resections for tonsil and BOT oropharyngeal squamous cell carcinoma (OPSCC), as well as the effect of margins on treatment. A blinded neuroradiologist examined the preoperative imaging of BOT tumors to measure their dimensions and patterns of spread and provided a prediction of final margin results. Results Between January 2010 and May 2016, a total of 254 patients underwent TORS for OPSCC. A total of 140 patients who underwent TORS for T1/T2 OPSCC met inclusion criteria. A final positive margin is significantly more likely for BOT tumors than tonsil tumors (19.6% vs 4.5%, respectively, P = .004) and likewise for intraoperative margins of BOT and tonsil tumors (35.3% vs 12.4%, respectively; P = .002). A positive final margin is 10 times more likely to receive chemoradiation compared to a negative margin, controlling for extracapsular spread and nodal status (odds ratio, 9.6; 95% confidence interval, 1.6-59.6; P = .02). Preoperative imaging characteristics and subjective radiologic examination of BOT tumors did not correlate with final margin status. Conclusion Positive margins are significantly more likely during TORS BOT resections compared to tonsil resections. More research is needed to help surgeons predict which T1/T2 tumors will be difficult to completely extirpate.

A significant proportion of healthy seniors report difficulty swallowing, thought to result from age-related decline in muscle bulk/function. Effortful Swallowing (ES) is used both as a compensatory maneuver to improve pharyngeal propulsion/clearance and has been proposed as an exercise to improve pharyngeal strength. This study sought to quantify the immediate kinematic, temporal, and functional changes during an ES maneuver to quantify its exercise potential to combat age-related changes in swallowing. Videofluoroscopy data were collected from 44 healthy seniors (21 male) over 65 years old (mean = 76.9, SD = 7.1). Each participant swallowed six 5 ml boluses of Varibar nectar-thick liquids: three with regular effort and three using ES. Individual swallows (n = 260) were measured on pharyngeal constriction, pharyngeal shortening, laryngeal closure duration, hyoid movement duration, UES opening duration, stage transition duration, pharyngeal transit time, pharyngeal response duration, Normalized Residue Ratio Scale (NRRS), and the Penetration-Aspiration Scale (PAS). Non-parametric Wilcoxon Rank Sum for repeated measures tested the effect of ES on each outcome. Exact p-values were calculated based on permutation methods, individual p values < 0.008 was deemed to be significant. The ES maneuver significantly prolonged all temporal variables. While we found no significant differences for pharyngeal constriction, significantly less (i.e., worse) pharyngeal shortening was observed in ES condition compared with regular effort swallows. Further, significantly worse pyriform sinus residue (NRRSv) was observed in the ES condition. No differences between ES and regular effort swallows were noted for pharyngeal constriction, NRRSv or PAS. We speculate that these negative manifestations of worse kinematics (less pharyngeal shortening) and function (increase in NRRSp) may be the result of forced volitional manipulation of swallowing in the ES condition in an otherwise normal elderly swallow.

Importance: Otoplasty is performed to correct prominauris, one of the most common head and neck congenital deformities. Advances in combination hybrid approaches enable surgeons to achieve greater precision and accuracy. Objective: To describe a hybrid cartilage-modifying approach and evaluate the procedure's effectiveness and safety. Design, Setting, and Participants: Medical record review including patients undergoing otoplasty by the present technique from January 2006 to December 2016 as performed by the senior author at a tertiary academic referral center. Twenty-three patients underwent 24 total procedures including both bilateral (n = 17) and unilateral (n = 7) procedures. Two procedures were revisions. Interventions: Hybrid cartilage-modifying otoplasty procedure. Main Outcomes and Measures: Preoperative and postoperative measurements were recorded. Paired sample t testing was performed to assess changes between preoperative superior, middle, and inferior helical measurements and corresponding postoperative measurements for all operated ears. Two-tailed, independent sample t testing was performed to compare postoperative differences between right and left ears within separate superior, middle, and inferior measurements in patients undergoing bilateral otoplasty. Results: Twenty-four surgeries were performed on 23 patients. The mean (SD) age at surgery was 16.3 (13.6) years with 13 patients (58%) between the ages of 4 and 10 years. Preoperatively, the mean (SD) superior, middle, and inferior helical rim-to-mastoid distance of the 41 discrete ears measured 16.5 (3.1) mm, 24.1 (3.8) mm, and 19.3 (4.4) mm, respectively. Mean (SD) postoperative measurements were 12.1 (2.4) mm, 14.7 (2.5) mm, and 14.0 (2.8) mm, respectively, for mean (SD) decreases of 4.4 (2.7) mm, 9.4 (3.4) mm, and 5.3 (3.6) mm. For the 17 bilateral procedures, the mean (standard error) postoperative scores between ears measured 0.7 (0.9) mm for the superior, 0.5 (0.9) mm for the middle, and 0.2 (1.0) mm for the inferior. The unaffected ear was measured in 4 of 7 (57%) of patients undergoing unilateral otoplasty, and the mean (SD) postoperative differences between left and right ears were 1.3 (0.8) mm, 3.0 (1.2) mm, and 1.0 (0.7) mm for the superior, middle, and inferior, respectively. Preoperative-to-postoperative differences for all ears (n = 41) were significant (P < .001 for all) for superior, middle, and inferior measurements. There were no significant absolute differences identified for superior (P = .41), middle (P = .58), and inferior (P = .88) measurements regarding left vs right postoperative comparisons for bilateral otoplasties. One patient undergoing bilateral repair required subsequent revision surgery of 1 ear. Two patients developed chronic suture site irritation, and 1 patient developed a hematoma. Conclusions and Relevance: The present technique allows multiple opportunities to adjust the auricular parameters. The results indicate a low revision rate and high degree of symmetry. Level of Evidence: 4.