Faculty Bibliography

The prognosis and recurrence rate of inverted papilloma (IP) with concomitant cellular dysplasia are not well-delineated. Demographic, clinical and imaging data of all patients who were surgically treated for sinonasal inverted papilloma (SNIP) in our center between 1996 and 2013 were reviewed. Data regarding the coexistence of dysplastic changes or malignancy within the resected tissues were also retrieved. After the exclusion of malignant cases and patients who were lost for follow-up, 92 patients were included in the study. Five patients had coexisting cellular dysplasia (4.7%), four of them had severe dysplasia and one had mild-to-moderate dysplasia. All four cases with severe dysplasia recurred, three were primarily treated endoscopically and one by external approach. Only the case with mild to moderate dysplasia which had been treated by subcranial approach did not recur. Patients with dysplasia had significantly higher recurrence rate than patients without dysplasia (80 vs. 14%, p = 0.019). This significant relation between histology and recurrence remained even after adjustment to tumor extent. The adjusted odd ratio of dysplasia (dysplasia vs. no dysplasia) is 9.7, p = 0.043. SNIP with dysplasia should be treated aggressively and followed closely. The histopathologic investigation of SNIP specimens should always note the presence of dysplasia and its severity. Further investigation on the clinical behavior of SNIP with dysplasia is needed. Multicenter studies are warranted due to the rarity of dysplastic SNIP.

BACKGROUND:Measuring quality outcomes is an important prerequisite to improve quality of care. Rhinosinusitis represents a high value target to improve quality of care because it has a high prevalence of disease, large economic burden, and large practice variation. In this study we review the current state of quality measurement for management of both acute (ARS) and chronic rhinosinusitis (CRS). METHODS:The major national quality metric repositories and clearinghouses were queried. Additional searches included the American Academy of Otolaryngology-Head and Neck Surgery database, PubMed, and Google to attempt to capture any additional quality metrics. RESULTS:Seven quality metrics for ARS and 4 quality metrics for CRS were identified. ARS metrics focused on appropriateness of diagnosis (n = 1), antibiotic prescribing (n = 4), and radiologic imaging (n = 2). CRS quality metrics focused on appropriateness of diagnosis (n = 1), radiologic imaging (n = 1), and measurement of patient quality of life (n = 2). The Physician Quality Reporting System (PQRS) currently tracks 3 ARS quality metrics and 1 CRS quality metric. There are no outcome-based rhinosinusitis quality metrics and no metrics that assess domains of safety, patient-centeredness, and timeliness of care. CONCLUSIONS:The current status of quality measurement for rhinosinusitis has focused primarily on the quality domain of efficiency and process measures for ARS. More work is needed to develop, validate, and track outcome-based quality metrics along with CRS-specific metrics. Although there has been excellent work done to improve quality measurement for rhinosinusitis, there remain major gaps and challenges that need to be considered during the development of future metrics.

OBJECTIVE: Recent reports highlight the efficacy of small interfering RNA (siRNA) targeting SMAD3 to regulate transforming growth factor beta (TGF-beta)-mediated fibroplasia in vocal fold fibroblasts. The current study sought to investigate SMAD3 expression during wound healing in vivo and quantify the downstream transcriptional events associated with SMAD3 knockdown in vitro. STUDY DESIGN: In vivo and in vitro. METHODS: Unilateral vocal fold injury was created in a rabbit model. SMAD3 and SMAD7 mRNA expression was quantified at 1 hour and 1, 3, 7, 14, 30, 60, and 90 days following injury. In vitro, multi-gene analysis technology was employed in our immortalized human vocal-fold fibroblast cell line following TGF-beta1 stimulation +/- SMAD3 knockdown across time points. RESULTS: SMAD3 mRNA expression increased following injury; upregulation was significant at 3 and 7 days compared to control (both P < 0.001). SMAD7 mRNA was also upregulated at 3, 7, and 14 days (P = 0.02, P < 0.001, and P < 0.001, respectively). In vitro, SMAD3 knockdown reduced the expression of multiple profibrotic, TGF-beta signaling, and extracellular matrix metabolism genes at 6 and 24 hours following TGF-beta1 stimulation. CONCLUSION: Cumulatively, these data support SMAD3 as a potential master regulator of TGF-beta-mediated fibrosis. SMAD3 transcription peaked 7 days following injury. Multi-gene analysis indicated that the therapeutic effectiveness of SMAD3 knockdown may be related to regulation of downstream mediators of fibroplasia and altered TGF-beta signaling. LEVEL OF EVIDENCE: NA. Laryngoscope, 2017.

OBJECTIVES/HYPOTHESIS: National Cancer Care Network guidelines suggest consideration of adjuvant radiation even for early stage adenoid cystic carcinoma of the salivary glands. We used the National Cancer Data Base (NCDB) to analyze practice patterns and outcomes of postoperative radiotherapy for adenoid cystic carcinomas. STUDY DESIGN: Retrospective NCDB review. METHODS: Patients with nonmetastatic adenoid cystic carcinoma of the parotid, submandibular, or another major salivary gland from 2004 to 2012 were identified. Information was collected regarding receipt of postoperative radiation. The Kaplan-Meier method was used to assess overall survival and Cox regression analysis to assess impact of covariates. RESULTS: There were 1,784 patients included. Median age was 57 years old and median follow up was 47.5 months. Of the patients, 72.4% of underwent partial/total parotidectomy and 73.6% received postoperative radiation. The 5-year survival was 72.5% for those receiving surgery alone compared to 82.4% for those receiving postoperative radiation (P < .001). On subgroup analysis, this survival difference favoring postoperative radiation was significant for pT1-2N0 (P < .001), pT3-4N0 (P = .047), pTanyN+ (P < .001), and for positive margins (P = .001), but not for negative margins (P = .053). On multivariable analysis, postoperative radiation remained associated with improved overall survival (hazard ratio [HR] = 0.63, 95% confidence interval: 0.50-0.80, P < .001). The utilization of intensity modulated radiation therapy (IMRT) increased from 16.9% in 2004 to 56.3% in 2012 (P < .001). There was no survival benefit for IMRT over three-dimensional radiation therapy (HR = 0.84, P = .19). CONCLUSIONS: Postoperative radiation therapy for salivary adenoid cystic carcinoma was associated with improved survival even for those with early-stage disease. LEVEL OF EVIDENCE: 4 Laryngoscope, 127:2057-2062, 2017.

HYPOTHESIS: A novel smartphone-based software application can facilitate self-selection of frequency allocation tables (FAT) in postlingually deaf cochlear implant (CI) users. BACKGROUND: CIs use FATs to represent the tonotopic organization of a normal cochlea. Current CI fitting methods typically use a standard FAT for all patients regardless of individual differences in cochlear size and electrode location. In postlingually deaf patients, different amounts of mismatch can result between the frequency-place function they experienced when they had normal hearing and the frequency-place function that results from the standard FAT. For some CI users, an alternative FAT may enhance sound quality or speech perception. Currently, no widely available tools exist to aid real-time selection of different FATs. This study aims to develop a new smartphone tool for this purpose and to evaluate speech perception and sound quality measures in a pilot study of CI subjects using this application. METHODS: A smartphone application for a widely available mobile platform (iOS) was developed to serve as a preprocessor of auditory input to a clinical CI speech processor and enable interactive real-time selection of FATs. The application's output was validated by measuring electrodograms for various inputs. A pilot study was conducted in six CI subjects. Speech perception was evaluated using word recognition tests. RESULTS: All subjects successfully used the portable application with their clinical speech processors to experience different FATs while listening to running speech. The users were all able to select one table that they judged provided the best sound quality. All subjects chose a FAT different from the standard FAT in their everyday clinical processor. Using the smartphone application, the mean consonant-nucleus-consonant score with the default FAT selection was 28.5% (SD 16.8) and 29.5% (SD 16.4) when using a self-selected FAT. CONCLUSION: A portable smartphone application enables CI users to self-select frequency allocation tables in real time. Even though the self-selected FATs that were deemed to have better sound quality were only tested acutely (i.e., without long-term experience with them), speech perception scores were not inferior to those obtained with the clinical FATs. This software application may be a valuable tool for improving future methods of CI fitting.

OBJECTIVES/HYPOTHESIS:Acute supraglottitis is a potentially life-threatening condition due to rapid onset upper airway obstruction. The study aimed to characterize adult acute supraglottitis patients and to recognize factors associated with an aggressive disease course. STUDY DESIGN:Retrospective chart review. METHODS:All adult acute supraglottitis patients admitted to a single academic medical center between 2000 and 2014 were included and their medical charts reviewed. The main outcome measures were airway intervention and mortality. RESULTS:Three hundred fifty-eight patients were enrolled. Mean age was 53 years (range, 16-92 years), with 62.8% males. Sore throat (79%) and dysphagia (70.9%) were the most common symptoms. Stridor (3.6%), tachypnea (5.7%), and dyspnea (6.4%) were uncommon but significantly associated with airway intervention. The epiglottis was most commonly involved (67%). Involvement of the epiglottis and aryepiglottic folds showed a trend of correlation to airway intervention. Blood glucose levels, C-reactive protein (CRP) levels, and relative neutrophilia were significantly higher in patients admitted to the intensive care unit or requiring airway intervention. Thirty-four patients (9.5%) required intensive care unit admission. Sixteen patients (4.4%) required airway intervention. Recurrent episodes of supraglottitis, seen in 19 patients, were more common in males (P = .048), and tended to have a more severe clinical course, requiring more airway interventions (P = .005) and intensive care unit admissions (P = .016). CONCLUSIONS:The typical high risk patient-a male, with dyspnea and stridor, presenting with edema of the epiglottis and aryepiglottic folds, elevated CRP, hyperglycemia, and a history of recurrent episodes-should warrant more aggressive treatment and closer observation. LEVEL OF EVIDENCE:4 Laryngoscope, 127:2106-2112, 2017.

OBJECTIVES/HYPOTHESIS: NR4A1 was recently identified as an endogenous inhibitor of transforming growth factor (TGF)-beta-induced fibrosis, and the role of this nuclear receptor has not been elucidated in tissue health or the response to injury in the vocal folds. Given the clinical implications of vocal fold fibrosis, we investigated NR4A1 expression during vocal fold wound healing in vivo and the regulatory roles of NR4A1 on vocal fold fibroblasts (VFFs) in vitro with the ultimate goal of developing targeted therapies for this challenging patient population. STUDY DESIGN: In vivo and in vitro. METHODS: In vivo, the temporal pattern of NR4A1 mRNA expression was quantified following rat vocal fold injury. In vitro, the role of NR4A1 on TGF-beta1-mediated transcription of genes underlying fibrosis as well as myofibroblast differentiation and collagen gel contraction was quantified in our human VFF line. Small interfering RNA was employed to alter NR4A1 expression to further elucidate this complex system. RESULTS: Nr4a1 mRNA increased 1 day after injury and peaked at 7 days. Knockdown of NR4A1 resulted in upregulation of COL1A1 and TGF-beta1, with TGF-beta1 stimulation (both P < .001) in VFFs. NR4A1 knockdown also resulted in increased alpha-smooth muscle actin-positive cells (P = .013) and contraction (P = .002) in response to TGF-beta1. CONCLUSIONS: NR4A1 has not been described in vocal fold health or disease. Upregulation of TGF-beta following vocal fold injury was concurrent with increased NR4A1 expression. These data provide a foundation for the development of therapeutic strategies given persistent TGF-beta signaling in vocal fold fibrosis. LEVEL OF EVIDENCE: N/A Laryngoscope, 2017.

Cancer patients in pain require high doses of opioids and quickly become opioid-tolerant. Previous studies have shown that both chronic cancer pain and high dose opioid use lead to mu-opioid receptor down-regulation. In this study we explore down-regulation of OPRM1, the mu-opioid receptor gene, as a mechanism f,or opioid tolerance in the setting of opioid use for cancer pain. We demonstrate in a cohort of 84 cancer patients that high dose opioid use correlates with OPRM1 hypermethylation in peripheral leukocytes of these patients. We then reverse-translate our clinical findings by creating a mouse cancer pain model; we create opioid tolerance in the mouse cancer model to mimic opioid tolerance in the cancer patients. Using this model we determine the functional significance of OPRM1 methylation on cancer pain and opioid tolerance. We focus on two main cells within the cancer microenvironment: the cancer cell and the neuron. We show that targeted re-expression of mu-opioid receptor on cancer cells inhibits mechanical and thermal hypersensitivity, and prevents opioid tolerance, in the mouse model. The resultant analgesia and protection against opioid tolerance are likely due to preservation of mu-opioid receptor expression on the cancer-associated neurons.

Neocortical inhibitory neurons exhibit remarkably diverse morphology, physiological properties and connectivity. Genetic access to molecularly defined subtypes of inhibitory neurons has aided their functional characterization in recent years. These studies have established that, instead of simply balancing excitatory neuron activity, inhibitory neurons actively shape excitatory circuits in a subtype-specific manner. We review the emerging view that inhibitory neuron subtypes perform context-dependent modulation of excitatory activity, as well as regulate experience-dependent plasticity of excitatory circuits. We then review the roles of neuromodulators in regulating the subtype-specific functions of inhibitory neurons. Finally, we discuss the idea that dysfunctions of inhibitory neuron subtypes may be responsible for various aspects of neurological disorders.