Faculty Bibliography

OBJECTIVES/OBJECTIVE:The role of locoregional radiotherapy for metastatic oropharyngeal squamous cell cancer (OPSCC) is unclear. We investigated the impact of head and neck radiotherapy on survival in de novo metastatic OPSCC patients who received systemic therapy. METHODS:We queried the NCDB from 2004-2015 for metastatic OPSCC patients at diagnosis with known HPV-status who received systemic therapy. The association of head and neck radiotherapy with overall survival was analyzed using the Kaplan-Meier method, Cox proportional hazards model, and propensity score-matched analysis adjusting for demographic and disease-specific prognostic factors. RESULTS:Of the 2,139 patients with metastatic OPSCC who presented with metastases and received systemic treatment, we identified 556 patients with known HPV-status. Among these 556 patients, 49% were HPV-positive and 56% received head and neck radiotherapy. With a median follow-up of 17.5 months (IQR 6.0-163.4 months), radiotherapy was associated with significantly improved 1-year OS (67% vs 58%, log-rank P < .001) which remained significant on MVA (HR 0.78 95% CI 0.62-0.97 P = .029). In HPV-status subgroup analysis, a survival benefit was identified in HPV-positive patients (1-year OS 77% vs 67%, log-rank P < .001) but not in HPV-negative patients. Results were consistent on a propensity score-matched analysis of 212 HPV-positive matched patients (HR 0.66, 95% CI 0.49-0.83, P < .001). CONCLUSION/CONCLUSIONS:The survival of metastatic OPSCC remains limited. In this large series of patients with known HPV-status, head and neck radiotherapy was associated with longer survival in those with HPV-associated disease. These data could guide management of this challenging group of patients for head and neck cancer practitioners. LEVEL OF EVIDENCE/METHODS:3 Laryngoscope, 2020.

OBJECTIVES/UNASSIGNED:(1) Determine the feasibility of obtaining a global, unbiased metabolomic profile on laryngeal muscle in a rat model; (2) evaluate the impact of biological aging on the laryngeal metabolome; and (3) characterize biochemical expression differences between aged and non-aged laryngeal and hindlimb muscle. METHODS/UNASSIGNED:Thyroarytenoid laryngeal muscle and plantaris hindlimb muscle were harvested from 5 young adult (9 months old) and 5 older adult (32 months old) F344BN rats. Tissue was processed and analyzed using LC-MS methods. Detected metabolites were compared to widely used metabolite databases and KEGG pathway enrichment was performed on significant metabolites. RESULTS/UNASSIGNED:The greatest differences in metabolite expression were between laryngeal and limb muscle with 126 different metabolites found between laryngeal and limb within the young group and 149 different metabolites within the old group. Significant hits between muscle groups highlighted amino acid differences between these tissues. There were more robust differences with age in limb muscle compared to laryngeal muscle. CONCLUSIONS/UNASSIGNED:Amino acid metabolism is a key difference between muscles of the limbs and larynx. Due to the number of differentially expressed metabolites between the 2 muscle groups, caution should be exercised when applying skeletal limb muscle physiology and biology concepts to the vocal muscles in both aged and non-aged musculoskeletal systems. Mechanisms underlying less robust effects of age on laryngeal muscle compared to limb muscle require elucidation.

The presence of spiral ganglion cells (SGCs) is widely accepted to be a prerequisite for successful speech perception with a cochlear implant (CI), because SGCs provide the only known conduit between the implant electrode and the central auditory system. By extension, it has been hypothesized that the number of SGCs might be an important factor in CI outcomes. An impressive body of work has been published on findings from the laborious process of collecting temporal bones from CI users and counting the number of SGCs to correlate those numbers with speech perception scores, but the findings thus far have been conflicting. We performed a meta-analysis of all published studies with the hope that combining existing data may help us reach a more definitive conclusion about the relationship between SGC count and speech perception scores in adults.

Oral cancer is a major public health problem, and there is an increasing trend for oral cancer to affect young men and women. Public awareness is poor, and many patients present with late-stage disease, contributing to high mortality. Oral cancer is often preceded by a clinical premalignant phase accessible to visual inspection, and thus there are opportunities for earlier detection and to reduce morbidity and mortality. Screening asymptomatic individuals by systematic visual oral examinations to detect the disease has been shown to be feasible. A positive screen includes both oral cancer and oral potentially malignant disorders. We review key screening studies undertaken, including 1 randomized clinical trial. Screening of high-risk groups is cost-effective. Strengths and weaknesses of oral cancer screening studies are presented to help guide new research in primary care settings and invigorated by the prospect of using emerging new technologies that may help to improve discriminatory accuracy of case detection. Most national organizations, including the US Preventive Services Task Force, have so far not recommended population-based screening due a lack of sufficient evidence that screening leads to a reduction in oral cancer mortality. Where health care resources are high, opportunistic screening in dental practices is recommended, although the paucity of research in primary care is alarming. The results of surveys suggest that dentists do perform oral cancer screenings, but there is only weak evidence that screening in dental practices leads to downstaging of disease. Where health care resources are low, the feasibility of using primary health care workers for oral cancer screening has been tested, and measures indicate good outcomes. Most studies reported in the literature are based on 1 round of screening, whereas screening should be a continuous process. This review identifies a huge potential for new research directions on screening for oral cancer.

OBJECTIVE:To identify the molecular signaling pathways underlying sudden unexpected death in epilepsy (SUDEP) and high-risk SUDEP compared to epilepsy control patients. METHODS:For proteomics analyses, we evaluated the hippocampus and frontal cortex from microdissected post-mortem brain tissue of 12 SUDEP and 14 non-SUDEP epilepsy patients. For transcriptomics analyses, we evaluated hippocampus and temporal cortex surgical brain tissue from mesial temporal lobe epilepsy (MTLE) patients: 6 low-risk and 8 high-risk SUDEP as determined by a short (< 50 seconds) or prolonged (≥ 50 seconds) postictal generalized EEG suppression (PGES) that may indicate severely depressed brain activity impairing respiration, arousal, and protective reflexes. RESULTS:In autopsy hippocampus and cortex, we observed no proteomic differences between SUDEP and non-SUDEP epilepsy patients, contrasting with our previously reported robust differences between epilepsy and non-epilepsy control patients. Transcriptomics in hippocampus and cortex from surgical epilepsy patients segregated by PGES identified 55 differentially expressed genes (37 protein-coding, 15 lncRNAs, three pending) in hippocampus. CONCLUSION/CONCLUSIONS:The SUDEP proteome and high-risk SUDEP transcriptome were similar to other epilepsy patients in hippocampus and frontal cortex, consistent with diverse epilepsy syndromes and comorbidities associated with SUDEP. Studies with larger cohorts and different epilepsy syndromes, as well as additional anatomic regions may identify molecular mechanisms of SUDEP.

BACKGROUND:Financial toxicity (FT) can be devastating to cancer patients, and solutions are urgently needed. We investigated the impact of financial counseling (FC) on FT in head and neck cancer (HNC) patients. METHODS:Via a single-institution database, we reviewed the charts of HNC patients who underwent definitive or post-operative radiotherapy, from October 2013 to December 2020. Of these patients, 387 had provided baseline and post-treatment information regarding financial difficulty. In July 2018, a dedicated financial counselor was provided for radiation therapy patients and we subsequently examined the impact of FC on financial difficulty scores. RESULTS:= 0.035). On average, patients who received FC had a 0.2 units lower change in financial difficulty score as compared with those with the same gender and nodal stage but without FC. CONCLUSIONS:Providing a dedicated financial counselor significantly increased the proportion of HNC receiving FC, resulting in the stabilization of financial difficulty scores post-treatment. Based on a multiple linear regression model, FC was independently associated with reduced financial difficulty. The employment of a financial counselor may be a viable, hospital-based approach to begin to address FT in HNC.

OBJECTIVE:The purpose of this study was to evaluate the feasibility of intraoperative navigation (ION) using adhesive fiducials and high-resolution computed tomography (HRCT) of the temporal bone in pediatric patients undergoing atresiaplasty for congenital aural atresia (CAA). METHODS:From June 2018 to August 2019, a retrospective review was performed on pediatric patients with unilateral or bilateral CAA who underwent atresiaplasty with or without concurrent bone anchored implant (BAI) placement. Single stage atresiaplasty was performed at a tertiary referral center with ION linked to image-guidance compatible HRCT non-contrast temporal bone images. Up to six adhesive fiducials were placed for navigation. Patient demographics were collected including Schuknecht classification type and Jahrsdoerfer score. Main outcome measures included the number of useable adhesive fiducials for navigation, navigation system registration accuracy, operative time, intraoperative complications, and postoperative outcomes including facial nerve function, surgical site infection rate, restenosis rate, and audiometric data. RESULTS:Five patients (3 male, 1 AU atresia, 2 AS atresia, all Schuknecht type C) with an average age of 9.2 years (range 6.8-11.8 years) underwent single sided atresiaplasty with ION. Two patients underwent concurrent BAI placement. Average Jahrsdoerfer score was 8.6 (range 7-10). Preoperative audiogram demonstrated a mean air-bone gap (ABG) of 45 dB (range 35-54 dB). The navigation system registration accuracy ranged from 0.08 to 1.80 mm (mean 1.00 mm). Mean operative time was 268 min (range 217-307 min). There were no intraoperative complications. At an average follow up of 7.2 months (range 2-15 months), postoperative facial nerve function was normal in all patients and no patients developed postoperative stenosis or surgical site infections. Four patients underwent postoperative audiogram at an average of 4 months after surgery (range 2-5 months) and all demonstrated an ABG of less than 30 dB (mean 20 dB, range 15-26 dB) with an average improvement in ABG of 23 dB (range 11-39 dB). The one patient who did not undergo postoperative pure tone audiometry underwent AzBio speech perception testing and demonstrated an improvement from 81% to 89%. CONCLUSIONS:The use of ION in otologic surgery is uncommon. Inherent aberrant temporal bone anatomy in CAA makes this a unique population to study the value of this technology. The use of adhesive fiducials is feasible, with navigation registration accuracy and surgical outcomes comparable to those in the literature. More data is necessary regarding the impact of ION on long-term surgical and audiometric outcomes.

Core auditory cortex (AC) neurons encode slow fluctuations of acoustic stimuli with temporally patterned activity. However, whether temporal encoding is necessary to explain auditory perceptual skills remains uncertain. Here, we recorded from gerbil AC neurons while they discriminated between a 4-Hz amplitude modulation (AM) broadband noise and AM rates >4 Hz. We found a proportion of neurons possessed neural thresholds based on spike pattern or spike count that were better than the recorded session's behavioral threshold, suggesting that spike count could provide sufficient information for this perceptual task. A population decoder that relied on temporal information outperformed a decoder that relied on spike count alone, but the spike count decoder still remained sufficient to explain average behavioral performance. This leaves open the possibility that more demanding perceptual judgments require temporal information. Thus, we asked whether accurate classification of different AM rates between 4 and 12 Hz required the information contained in AC temporal discharge patterns. Indeed, accurate classification of these AM stimuli depended on the inclusion of temporal information rather than spike count alone. Overall, our results compare two different representations of time-varying acoustic features that can be accessed by downstream circuits required for perceptual judgments.

INTRODUCTION/BACKGROUND:Cochlear implantation (CI) is a reliable and safe means by which sensorineural hearing loss can be ameliorated in the elderly population. However, a high degree of variation exists in postimplantation hearing outcomes for which some modifiable factors of the daily natural auditory environment may be contributory. In this study, we analyze the relationship between cochlear implant patient age, natural auditory environment, and postimplantation speech perception among older adults. METHODS:Data log from automatic environment classification enabled sound processors of postlingually deafened CI recipients ≥50 years old (n = 115) were obtained retrospectively and analyzed for time spent (hours per day) in listening environment and loudness (SPL dB). Speech perception testing was assessed in a subset of patients (n = 27) using open-set word recognition in quiet Consonant-Nucleus-Consonant in the short and intermediate postoperative period. RESULTS:The mean subject age was 70 years (range, 53-99 years). Average daily implant use was 10.8 h and was not significantly correlated with age (p = 0.23, Spearman's rho). Age was positively correlated with the percentage of hours spent at <40 and 40-50 dB and negatively correlated to proportional CI use at higher volume (60-70, 70-80, and >80 dB; rs = 0.21, 0.20, -0.20, -0.35, -0.43; p = 0.021, 0.036, 0.033, <0.001, <0.001, respectively). Age was positively correlated with CI use in the quiet scene (rs = 0.26, p = 0.006) and negatively correlated with scenes containing speech and noise (rs = -0.19, -0.25; p = 0.046, 0.007). Total hours of device use and time spent at <40, 40-50 dB, and quiet environments were significantly correlated with improved CNC word scores (rs = 0.48, 0.48, 0.51; p = 0.01, 0.01, <0.01, Spearman's rho). While all speech (speech in noise + speech) was not significantly correlated to improvements in speech perception, a medium effect size was observed (rs = 0.37, p = 0.057). DISCUSSION/CONCLUSION/CONCLUSIONS:This study supports a relationship between auditory environment and age, with older CI recipients spending a greater proportion of time in quiet. Older CI users demonstrated greater improvements in speech perception with longer daily device use. Additional examination of the relationship between auditory environment and speech perception is necessary to conclusively guide future auditory rehabilitation efforts.

Erythropoiesis involves complex interrelated molecular signals influencing cell survival, differentiation, and enucleation. Diseases associated with ineffective erythropoiesis, such as β-thalassemias, exhibit erythroid expansion and defective enucleation. Clear mechanistic determinants of what make erythropoiesis effective are lacking. We previously demonstrated that exogenous transferrin ameliorates ineffective erythropoiesis in β-thalassemic mice. In the current work, we utilize transferrin treatment to elucidate a molecular signature of ineffective erythropoiesis in β-thalassemia. We hypothesize that compensatory mechanisms are required in β-thalassemic erythropoiesis to prevent apoptosis and enhance enucleation. We identify pleckstrin-2-a STAT5-dependent lipid binding protein downstream of erythropoietin-as an important regulatory node. We demonstrate that partial loss of pleckstrin-2 leads to worsening ineffective erythropoiesis and pleckstrin-2 knockout leads to embryonic lethality in β-thalassemic mice. In addition, the membrane-associated active form of pleckstrin-2 occurs at an earlier stage during β-thalassemic erythropoiesis. Furthermore, membrane-associated activated pleckstrin-2 decreases cofilin mitochondrial localization in β-thalassemic erythroblasts and pleckstrin-2 knockdown in vitro induces cofilin-mediated apoptosis in β-thalassemic erythroblasts. Lastly, pleckstrin-2 enhances enucleation by interacting with and activating RacGTPases in β-thalassemic erythroblasts. This data elucidates the important compensatory role of pleckstrin-2 in β-thalassemia and provides support for the development of targeted therapeutics in diseases of ineffective erythropoiesis.