Faculty Bibliography

Accumulation of phosphorylated tau is a key pathological feature of Alzheimer's disease. Phosphorylated tau accumulation causes synaptic impairment, neuronal dysfunction and formation of neurofibrillary tangles. The pathological actions of phosphorylated tau are mediated by surrounding neuronal proteins; however, a comprehensive understanding of the proteins that phosphorylated tau interacts with in Alzheimer's disease is surprisingly limited. Therefore, the aim of this study was to determine the phosphorylated tau interactome. To this end, we used two complementary proteomics approaches: (i) quantitative proteomics was performed on neurofibrillary tangles microdissected from patients with advanced Alzheimer's disease; and (ii) affinity purification-mass spectrometry was used to identify which of these proteins specifically bound to phosphorylated tau. We identified 542 proteins in neurofibrillary tangles. This included the abundant detection of many proteins known to be present in neurofibrillary tangles such as tau, ubiquitin, neurofilament proteins and apolipoprotein E. Affinity purification-mass spectrometry confirmed that 75 proteins present in neurofibrillary tangles interacted with PHF1-immunoreactive phosphorylated tau. Twenty-nine of these proteins have been previously associated with phosphorylated tau, therefore validating our proteomic approach. More importantly, 34 proteins had previously been associated with total tau, but not yet linked directly to phosphorylated tau (e.g. synaptic protein VAMP2, vacuolar-ATPase subunit ATP6V0D1); therefore, we provide new evidence that they directly interact with phosphorylated tau in Alzheimer's disease. In addition, we also identified 12 novel proteins, not previously known to be physiologically or pathologically associated with tau (e.g. RNA binding protein HNRNPA1). Network analysis showed that the phosphorylated tau interactome was enriched in proteins involved in the protein ubiquitination pathway and phagosome maturation. Importantly, we were able to pinpoint specific proteins that phosphorylated tau interacts with in these pathways for the first time, therefore providing novel potential pathogenic mechanisms that can be explored in future studies. Combined, our results reveal new potential drug targets for the treatment of tauopathies and provide insight into how phosphorylated tau mediates its toxicity in Alzheimer's disease.

PURPOSE/OBJECTIVE:The purpose of this study is to quantify dosimetric changes throughout the delivery of oropharyngeal cancer treatment and to investigate the application of statistical process control (SPC) for the management of significant deviations during the course of radiotherapy. METHODS:Thirteen oropharyngeal cancer patients with daily cone beam computed tomography (CBCT) were retrospectively reviewed. Cone beam computed tomography images of every other fraction were imported to the Velocity software and registered to planning CT using the 6 DOF (degrees of freedom) couch shifts generated during patient setup. Using Velocity "Adaptive Monitoring" module, the setup-corrected CBCT was matched to planning CT using a deformable registration. Volumes and dose metrics at each fraction were calculated and rated with plan values to evaluate interfractional dosimetric variations using a SPC framework. T-tests between plan and fraction volumes were performed to find statistically insignificant fractions. Average upper and lower process capacity limits (UCL, LCL) of each dose metric were derived from these fractions using conventional SPC guidelines. RESULTS:Gross tumor volume (GTV) and organ at risk (OAR) volumes in the first 13 fractions had no significant changes from the pretreatment planning CT. The GTV and the parotid glands subsequently decreased by 10% at the completion of treatment. There were 3-4% increases in parotid mean doses, but no significant differences in dose metrics of GTV and other OARs. The changes were organ and patient dependent. Control charts for various dose metrics were generated to assess the metrics at each fraction for individual patient. CONCLUSIONS:Daily CBCT could be used to monitor dosimetric variations of targets and OARs resulting from volume changes and tissue deformation in oropharyngeal cancer radiotherapy. Treatment review with the guidance of a SPC tool allows for an objective and consistent clinical decision to apply adaptive radiotherapy.

OBJECTIVES/UNASSIGNED:Recurrent respiratory papillomatosis can be treated in the office or operating room (OR). The choice of treatment is based on several factors, including patient and surgeon preference. However, there is little data to guide the decision-making. This study examines the available literature comparing operative treatment in-office versus OR. METHODS/UNASSIGNED:A systematic review was performed following Preferred Reporting Items for Systematic Reviews guidelines. Of 2,864 articles identified, 78 were reviewed full-length and 18 were included. Outcomes of interest were recurrence and complication rates, number of procedures, time interval between procedures, and cost. RESULTS/UNASSIGNED:Only one study compared outcomes of operative in-office to OR treatments. The weighted average complication rate for OR procedures was 0.02 (95% confidence interval [CI] 0.00-0.32), n = 8, and for office procedures, 0.17 (95% CI 0.08-0.33), n = 6. The weighted average time interval between OR procedures was 10.59 months (5.83, 15.35) and for office procedures 5.40 months (3.26-7.54), n = 1. The weighted average cost of OR procedures was $10,105.22 ($5,622.51-14,587.83), n = 2 versus $2,081.00 ($1,987.64-$2,174.36), n = 1 for office procedures. CONCLUSION/UNASSIGNED:Only one study compares office to OR treatment. The overall data indicate no differences aside from cost and imply that office procedures may be more cost-effective than OR procedures. However, the heterogeneous data limits any strong comparison of outcomes between office and OR-based treatment of laryngeal papillomas. More studies to compare the two treatment settings are warranted.

OBJECTIVE:There is a debate regarding the durability of fat implants. Our experience and recent publications suggest fat implantation may deliver a long-lasting improvement. This study aims to present the long-term outcomes for vocal fold fat augmentation using strict harvesting, preparing, and implantation protocols. STUDY DESIGN/METHODS:A prospective cohort conducted between 2014 and 2020 (recruitment 2014-2017). SETTING/METHODS:An academic tertiary referral center. SUBJECTS AND METHODS/METHODS:Twenty-two patients with glottic insufficiency were enrolled: 11 had unilateral vocal fold paralysis (UVFP), and 11 had atrophy or scar. Harvested fat was injected unilaterally or bilaterally into multiple sites. Six of these patients also had simultaneous microlaryngoscopic removal of other benign glottic lesions. Outcome measurements included video stroboscopy; Grade, Roughness, Breathiness, Asthenia, Strain (GRBAS) score; Voice Handicap Index (VHI); and acoustic analysis, performed preoperatively, 3, 12, 24, and 36 months after surgery. RESULTS:= .012. Stroboscopic analysis revealed statistically significant improvement in mucosal wave propagation, phase closure, and phase symmetry. Best results were achieved in the UVFP subgroup. Computed tomography scans demonstrated long-term viability of the implanted adipose tissue. CONCLUSION/CONCLUSIONS:Fat is an excellent source of autologous graft. With careful patient selection and proper surgical technique, fat is suitable for long-term correction of glottic insufficiency. Fat augmentation should be considered as a long-lasting or even permanent solution, rather than temporary.

As the world's geriatric population continues to grow at an unprecedented rate, an increasing number of elderly patients are seeking hearing rehabilitation strategies, including cochlear implantation (CI). However, CI surgery in elderly patients has been met with trepidation given fears of physical and cognitive complications associated with general anesthesia. Cochlear implant surgery under local anesthesia with conscious sedation (LA-CS) in the elderly population is a safe and feasible alternative to general anesthesia. Elderly patients who are too infirm for general anesthesia or who choose not to pursue CI due to fears of the cognitive or medical consequences of general anesthesia should be counseled on the option of doing it under LA-CS by experienced CI surgeons. This article provides an overview of the surgical technique and technical nuances of performing CI surgery under LA-CS.

BACKGROUND:Prior studies have shown an advantage for electro-acoustic stimulation (EAS) in cochlear implant (CI) patients with residual hearing, but the degree of benefit can vary. The objective was to explore which factors relate to performance with and acceptance of EAS for CI users with conventional-length electrodes. METHODS:A retrospective chart review was conducted for adults with an average threshold of 75 dB hearing loss or better across 250 and 500 Hz preoperatively (n = 83). All patients underwent cochlear implantation with a conventional-length electrode. Low-frequency audiometric thresholds were measured at initial activation as well as 3 and 12 months postoperatively to determine who met the criteria for EAS. Speech perception for CNC words and AzBio sentences in quiet and +10 dB SNR noise was evaluated 3 and 12 months after activation. RESULTS:Speech perception in quiet and noise was similar regardless of whether or not the patient was eligible for EAS. Less than half of the patients who met the EAS criteria chose to use it, citing reasons such as physical discomfort or lack of perceived benefit. EAS users performed better on CNC words but not sentence recognition than EAS nonusers. CONCLUSIONS:EAS use is dependent on audiologic and nonaudiologic issues. Hearing preservation is possible with conventional electrodes, but hearing preservation alone does not guarantee superior speech perception.

OBJECTIVE:To evaluate the effect of definitive radiotherapy dose on survival in patients with human papillomavirus positive oropharyngeal carcinoma. METHODS:Human papillomavirus positive oropharyngeal carcinoma patients staged T1-3 and N0-2c, who received definitive radiotherapy (fraction sizes of 180 cGy to less than 220 cGy), were identified from the National Cancer Database 2010-2014 and stratified by radiation dose (50 Gy to less than 66 Gy, or 66 Gy or more). RESULTS:A total of 2173 patients were included, of whom 124 (6 per cent) received a radiation dose of 50 Gy to less than 66 Gy. With a median follow up of 33.8 months, patients had a 3-year overall survival rate of 88.6 per cent (95 per cent confidence interval = 87.1-90.1 per cent). On multivariate Cox analysis, a radiotherapy dose of 50 Gy to less than 66 Gy (hazard ratio = 0.95, 95 per cent confidence interval = 0.52-1.74, p = 0.86) was not a predictor of increased mortality risk. CONCLUSION/CONCLUSIONS:Human papillomavirus positive oropharyngeal carcinoma patients had excellent outcomes with definitive radiotherapy doses of 50 Gy to less than 66 Gy. These results further support patients enrolling into clinical trials for radiation dose de-escalation.