Faculty Bibliography

BACKGROUND:Virtual surgical planning has contributed to technical advancements in free fibula flap mandible reconstruction. The authors present the largest comparative study on the latest modification of this technology: the use of patient-specific, preoperatively customized reconstruction plates for fixation. METHODS:A retrospective chart review was performed on all patients undergoing mandibular reconstruction with virtually planned free fibula flaps at a single institution between 2008 and 2018. Patient demographics, perioperative characteristics, and postoperative outcomes were reviewed. Reconstructions using traditional fixation methods were compared to those using prefabricated, patient-specific reconstruction plates. RESULTS:A total of 126 patients (mean age, 48.5 ± 20.3 years; 61.1 percent male) underwent mandibular reconstruction with a free fibula flap. Mean follow-up time was 23.5 months. A customized plate was used in 43.7 percent of cases. Reconstructions with patient-specific plates had significantly shorter total operative times compared with noncustomized fixation methods (643.0 minutes versus 741.7 minutes; p = 0.001). Hardware complications occurred in 11.1 percent of patients, with a trend toward a lower rate in the customized plate group (5.5 percent versus 15.5 percent; p = 0.091). Multivariate regression showed that the use of customized plates was a significant independent predictor of fewer overall complications (p = 0.03), shorter operative time (p = 0.014), and shorter length of stay (p = 0.001). CONCLUSIONS:Compared to traditional fixation methods, patient-specific plates are associated with fewer complications, shorter operative times, and reduced length of stay. The use of customized reconstruction plates increases efficiency and represents the latest technological innovation in mandibular reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE:Therapeutic, III.

BACKGROUND:Lymph node yield (LNY) is a proposed quality indicator in neck dissection for oral cavity squamous cell carcinoma (OCSCC). METHODS:Retrospective series including 190 patients with OCSCC undergoing neck dissection between 2016 and 2018. A change in pathologic grossing protocol was initiated during the study period to assess residual adipose tissue. A generalized linear model was used to assess the impact of multiple variables on LNY. RESULTS:Mean LNY was 28.59 (SD = 17.65). The protocol identified a mean of 10.32 lymph nodes per case. Multivariable analysis identified associations between LNY and use of the pathology protocol (P = .02), number of dissected lymph node levels (P < .001), presence of pathologic lymph nodes (P = .002), body mass index (P = .02), prior neck surgery (P = .001), and prior neck radiation (P = .001). CONCLUSIONS:Assessment of residual adipose tissue within neck dissection specimens improves accuracy of LNY. LNY in neck dissection is influenced by multiple factors including methods of pathologic assessment.

Purpose Patients receive multiple bolus trials during a videofluoroscopic swallowing study (VFSS) to assess swallow function, inclusive of narrowing within the pharyngoesophageal segment (PES). While differences in the narrowest and widest segments are visualized, the ratio of distention across boluses is not well understood. Method A retrospective review of 50 consecutive VFSSs with five boluses of varied viscosity and volume was performed. Still images at maximal PES distention were captured and scaled using a 19-mm disk. Measurements of the narrowest and widest segments were obtained, and a distention ratio was calculated. Studies were categorized by PES phenotype as normal, esophageal web, cricopharyngeal bar, or narrow PES. PES distention ratios were evaluated across bolus trials and within PES phenotypes using a mixed-methods repeated-measures analysis of variance. Results Of the 50 studies, there were 11 normal, 16 web, 10 bar, and 13 narrow PES. Quantitative differences were present for the narrowest (p = .01) and widest (p = .002) points across bolus volumes. No difference was present in distention ratio (p = .2) across volumes. Evaluating the PES phenotype, web, normal, bar, and narrow PES distention ratios differed (p = .03). Bar and PES narrow distention ratios were lower compared to that of the normal group (p = .01 for normal vs. bar and p = .02 for normal vs. PES narrow). Conclusions PES distention ratio stability across varying bolus volumes and phenotypes suggests that a reduction in trials during a VFSS may permit an equivalent PES evaluation to traditional exams. Ultimately, this could improve our understanding and accurate diagnosis of PES dysfunction.

OBJECTIVES:There are many potential advantages to combined electric and acoustic stimulation (EAS) with a cochlear implant (CI), including benefits for hearing in noise, localization, frequency selectivity, and music enjoyment. However, performance on these outcome measures is variable, and the residual acoustic hearing may not be beneficial for all patients. As such, we propose a measure of spectral resolution that might be more predictive of the usefulness of the residual hearing than the audiogram alone. In the following experiments, we measured performance on spectral resolution and speech perception tasks in individuals with normal hearing (NH) using low-pass filters to simulate steeply sloping audiograms of typical EAS candidates and compared it with performance on these tasks for individuals with sensorineural hearing loss with similar audiometric configurations. Because listeners with NH had similar levels of audibility and bandwidth to listeners with hearing loss, differences between the groups could be attributed to distortions due to hearing loss. DESIGN:Listeners with NH (n = 12) and those with hearing loss (n = 23) with steeply sloping audiograms participated in this study. The group with hearing loss consisted of 7 EAS users, 14 hearing aid users, and 3 who did not use amplification in the test ear. Spectral resolution was measured with the spectral-temporal modulated ripple test (SMRT), and speech perception was measured with AzBio sentences in quiet and noise. Listeners with NH listened to stimuli through low-pass filters and at two levels (40 and 60 dBA) to simulate low and high audibility. Listeners with hearing loss listened to SMRT stimuli unaided at their most comfortable listening level and speech stimuli at 60 dBA. RESULTS:Results suggest that performance with SMRT is significantly worse for listeners with hearing loss than for listeners with NH and is not related to audibility. Performance on the speech perception task declined with decreasing frequency information for both listeners with NH and hearing loss. Significant correlations were observed between speech perception, SMRT scores, and mid-frequency audiometric thresholds for listeners with hearing loss. CONCLUSIONS:NH simulations describe a "best case scenario" for hearing loss where audibility is the only deficit. For listeners with hearing loss, the likely broadening of auditory filters, loss of cochlear nonlinearities, and possible cochlear dead regions may have contributed to distorted spectral resolution and thus deviations from the NH simulations. Measures of spectral resolution may capture an aspect of hearing loss not evident from the audiogram and be a useful tool for assessing the contributions of residual hearing post-cochlear implantation.

BACKGROUND:We examine the prognostic implications of mid-course nodal response in oropharyngeal cancer (OPX) to radiation therapy. METHODS:In 44 patients with node-positive OPX undergoing concurrent chemoradiation, nodal volumes were measured on cone beam CTs from days 1, 10, 20, and 35. Nodal decrease (ND) was based on percent shrinkage from day 1. RESULTS:At a median follow-up of 17 months, the 2-year disease-free survival (DFS), locoregional control (LRC), distant metastasis-free survival (DMFS), and overall survival (OS) were 87%, 92%, 89%, and 92%, respectively. Patients with ND ≥43% at D20 had improved LRC (100% vs 78.4%, P = .03) compared to D20 ND <43%. On multivariate analysis, D20 ≥43% was independently prognostic for LRC (HR 1.17, P = .05). CONCLUSION/CONCLUSIONS:Patients with low-risk oropharynx cancer with ND of ≥43% by treatment day 20 had significantly improved LRC. The prognostic benefit of ND may assist in identifying candidates for treatment de-escalation.

Cerebral cavernous malformations are common vascular anomalies consisting of a cluster of capillaries without intervening brain tissue.1 A variety of approaches for resection have been undertaken,2 and a handful of case reports have described the endoscopic, endonasal, transclival approach.3 We present a case of a 51-yr-old woman with lupus and hepatitis B-associated cirrhosis who presented with diplopia, dysphagia, and ataxia. She had a left abducens nerve palsy and magnetic resonance imaging (MRI) showed a left pontine cavernous malformation. After a repeat hemorrhage, she consented to surgical resection. The lesion appeared to come to the medial pontine pial surface. Tractography indicated a rightward displacement of the left corticospinal tract. Therefore, an endoscopic, transnasal, transclival approach was chosen. A lumbar drain was placed preoperatively. The clivus and ventral petrous bone were drilled using the vidian canal to help identify the anterior genu of the petrous carotid artery. The clival dura was opened, revealing the abducens nerve exiting the ventral pons. The cavernoma was visible on the surface lateral to the nerve. It was removed using blunt dissection and the remaining cavity inspected. The skull base was reconstructed using an abdominal dermal-fat graft and Alloderm covered by a nasoseptal flap. Postoperatively she had transient swallowing difficulty. The lumbar drain was kept open for 5 d. Cerebrospinal fluid (CSF) leak was ruled out using an intrathecal fluorescein injection. She was discharged home, but presented 2 wk postoperatively with aseptic meningitis, which was treated supportively. Postoperative imaging did not show residual cavernoma.

The destruction of the World Trade Center (WTC) towers on the 11th of September, 2001 released a vast amount of aerosolized dust and smoke resulting in acute and chronic exposures to community members as well as responders. The WTC Environmental Health Center (WTC EHC) is a surveillance and treatment program for a diverse population of community members, including local residents and local workers with WTC dust exposure. Many of these patients have reported persistent lower respiratory symptoms (LRS) despite treatment for presumed asthma. Our goal was to identify conditions associated with persistent uncontrolled LRS despite standard asthma management. We recruited 60 patients who were uncontrolled at enrollment and, after a three-month run-in period on high-dose inhaled corticosteroid and long acting bronchodilator, reassessed their status as Uncontrolled or Controlled based on a score from the Asthma Control Test (ACT). Despite this treatment, only 11 participants (18%) gained Controlled status as defined by the ACT. We compared conditions associated with Uncontrolled and Controlled status. Those with Uncontrolled symptoms had higher rates of upper airway symptoms. Many patients had persistent bronchial hyper-reactivity (BHR) and upper airway hyper-reactivity as measured by paradoxical vocal fold movement (PVFM). We found a significant increasing trend in the percentage of Controlled with respect to the presence of BHR and PVFM. We were unable to identify significant differences in lung function or inflammatory markers in this small group. Our findings suggest persistent upper and lower airway hyper-reactivity that may respond to standard asthma treatment, whereas others with persistent LRS necessitate additional diagnostic evaluation, including a focus on the upper airway.

Sensory-driven decisions are formed by accumulating information over time. Although parietal cortex activity is thought to represent accumulated evidence for sensory-based decisions, recent perturbation studies in rodents and non-human primates have challenged the hypothesis that these representations actually influence behavior. Here, we asked whether the parietal cortex integrates acoustic features from auditory cortical inputs during a perceptual decision-making task. If so, we predicted that selective inactivation of this projection should impair subjects' ability to accumulate sensory evidence. We trained gerbils to perform an auditory discrimination task and obtained measures of integration time as a readout of evidence accumulation capability. Minimum integration time was calculated behaviorally as the shortest stimulus duration for which subjects could discriminate the acoustic signals. Direct pharmacological inactivation of parietal cortex increased minimum integration times, suggesting its role in the behavior. To determine the specific impact of sensory evidence, we chemogenetically inactivated the excitatory projections from auditory cortex to parietal cortex and found this was sufficient to increase minimum behavioral integration times. Our signal-detection-theory-based model accurately replicated behavioral outcomes and indicated that the deficits in task performance were plausibly explained by elevated sensory noise. Together, our findings provide causal evidence that parietal cortex plays a role in the network that integrates auditory features for perceptual judgments.

Oral cancer patients experience pain at the site of the primary cancer. Patients with metastatic oral cancers report greater pain. Lack of pain identifies patients at low risk of metastasis with sensitivity = 0.94 and negative predictive value = 0.89. In the same cohort, sensitivity and negative predictive value of depth of invasion, currently the best predictor, were 0.95 and 0.92, respectively. Cancer pain is attributed to cancer-derived mediators that sensitize neurons and is associated with increased neuronal density. We hypothesized that pain mediators would be overexpressed in metastatic cancers from patients reporting high pain. We identified 40 genes overexpressed in metastatic cancers from patients reporting high pain (n=5) compared to N0 cancers (n=10) and normal tissue (n=5). The genes are enriched for functions in extracellular matrix organization and angiogenesis. They have oncogenic and neuronal functions and are reported in exosomes. Hierarchical clustering according to expression of neurotrophic and axon guidance genes also separated cancers according to pain and nodal status. Depletion of exosomes from cancer cell line supernatant reduced nociceptive behavior in a paw withdrawal assay, supporting a role for exosomes in cancer pain. The identified genes and exosomes are potential therapeutic targets for stopping cancer and attenuating pain.

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.