Role of Lymphovascular Invasion in Oral Cavity Squamous Cell Carcinoma Regional Metastasis and Prognosis.

OBJECTIVE: The overall 5-year survival for oral squamous cell carcinoma (OSCC) has not changed in the last 20 years despite advances in treatment. Lymphovascular invasion (LVI) has been shown to be a negative prognostic factor in other cancers, however its role in the prognosis of OSCC remains unclear. This study aims to determine if LVI is a predictor of cervical lymph node metastasis and/or recurrence in OSCC. METHODS: We conducted a retrospective cohort review of patients from our institutional cancer registry who were treated for OSCC between 2004 and 2018. Patient demographics, surgical pathology results, and clinical outcome data were collected. A multivariable logistic regression analysis was performed to determine if LVI was an independent predictor of cervical lymph node metastasis and/or recurrence. RESULTS: 442 patients were included, 32.8% were female and median age at time of diagnosis was 61.2 years. LVI was present in 32.8% of patients. When controlled for age, sex, t-classification, perineural invasion, depth of invasion (DOI), and margin status, LVI was a significant predictor of the presence of cervical node metastasis (OR: 3.42, CI: 2.17-5.39, P < .001). There was no significant association found between LVI and local recurrence (OR: 1.03, CI: 0.57-1.84, P = .92), regional recurrence (OR: 1.10, CI: 0.57-2.11, P = .78), or distant recurrence (OR: 1.59, CI: 0.87-2.94, P = .13). CONCLUSION: The results of this study suggest that LVI is a significant predictor of the presence of cervical lymph node metastasis at presentation independent of other known prognostic factors. LVI, however, was not found to be a significant independent predictor of locoregional or distant recurrence.Level of Evidence: Level III.

Development and evaluation of helper dependent adenoviral vectors for inner ear gene delivery.

Viral vector gene therapy is an attractive strategy to treat hearing loss. Since hearing loss is due to a variety of pathogenic signaling cascades in distinct cells, viral vectors that can express large or multiple genes in a cell-type specific manner are needed. Helper-dependent adenoviral vectors (HdAd) are safe viral vectors with a large packaging capacity (-36 kb). Despite the potential of HdAd, its use in the inner ear is largely unexplored. Therefore, to evaluate the utility of HdAd for inner ear gene therapy, we created two HdAd vectors that use distinct cellular receptors for transduction: HdAd Serotype Type 5 (HdAd5), the Coxsackie-Adenovirus Receptor (CAR) and a chimeric HdAd 5/35, the human CD46+ receptor (hCD46). We delivered these vectors through the round window (RW) or scala media in CBA/J, C57Bl6/J and hCD46 transgenic mice. Immunostaining in conjunction with confocal microscopy of cochlear sections revealed that multiple cell types were transduced using HdAd5 and HdAd 5/35 in all mouse models. Delivery of HdAd5 via RW in the C57Bl/6 J or CBA/J cochlea resulted in transduced mesenchymal cells of the peri­lymphatic lining and modiolar region while scala media delivery resulted in transduction of supporting cells and inner hair cells. Hd5/35 transduction was CD46 dependent and RW delivery of HdAd5/35 in the hCD46 mouse model resulted in a similar transduction pattern as HdAd5 in the peri­lymphatic lining and modiolar region in the cochlea. Our data indicate that HdAd vectors are promising vectors for use in inner ear gene therapy to treat some causes of hearing loss.

Comparison of Responses to DCN vs. VCN Stimulation in a Mouse Model of the Auditory Brainstem Implant (ABI).

The auditory brainstem implant (ABI) is an auditory neuroprosthesis that provides hearing to deaf patients by electrically stimulating the cochlear nucleus (CN) of the brainstem. Whether such stimulation activates one or the other of the CN's two major subdivisions is not known. Here, we demonstrate clear response differences from the stimulation of the dorsal (D) vs. ventral (V) subdivisions of the CN in a mouse model of the ABI with a surface-stimulating electrode array. For the DCN, low levels of stimulation evoked multiunit responses in the inferior colliculus (IC) that were unimodally distributed with early latencies (avg. peak latency of 3.3 ms). However, high levels of stimulation evoked a bimodal distribution with the addition of a late latency response peak (avg. peak latency of 7.1 ms). For the VCN, in contrast, electrical stimulation elicited multiunit responses that were usually unimodal and had a latency similar to the DCN's late response. Local field potentials (LFP) from the IC showed components that correlated with early and late multiunit responses. Surgical cuts to sever the output of the DCN, the dorsal acoustic stria (DAS), gave insight into the origin of these early and late responses. Cuts eliminated early responses but had little-to-no effect on late responses. The early responses thus originate from cells that project through the DAS, such as DCN's pyramidal and giant cells. Late responses likely arise from the spread of stimulation from a DCN-placed electrode array to the VCN and could originate in bushy and/or stellate cells. In human ABI users, the spread of stimulation in the CN may result in abnormal response patterns that could hinder performance.

The utility of intra-oral ultrasound in improving deep margin clearance of oral tongue cancer resections.

OBJECTIVES: To investigate the potential utility of intra-oral ultrasound (IOUS) in guiding deep margin clearance and measuring depth of invasion (DOI) of oral tongue carcinomas (OTC). MATERIALS AND METHODS: Retrospective chart review of consecutive patients with T1-T3 OTC who underwent intraoperative ultrasound-guided resection and a comparator group that had undergone resection without the use of IOUS both by a single surgeon. Data was extracted from operative, pathology and radiology reports. Deep margins and DOI were reviewed by a dedicated head and neck pathologist. Correlation between histologic and ultrasound DOI was assessed using Pearson correlation. RESULTS: A total of 23 patients were included in the study cohort with a comparator group of 21 patients in the control group. None of the patients in the study cohort had a positive (cut-through) deep margin and the mean deep margin clearance was 8.5 ± 4.9 and 6.7 ± 3.8 for the IOUS and non-IOUS groups respectively (p-value 0.18) showing a non-significant improvement in the IOUS group. As a secondary outcome, there was a strong correlation between histologic and ultrasound DOI (0.9449). CONCLUSION: Ultrasound appears to be a potentially effective tool in guiding OTC resections. In this small series, IOUS facilitated deep margin clearance and resulted in a non-statistically significant increase in deep margin clearance. Intraoral ultrasound can accurately measure lesional DOI.

Advances in hearing preservation in cochlear implant surgery.

PURPOSE OF REVIEW: Advancements in cochlear implant surgical approaches and electrode designs have enabled preservation of residual acoustic hearing. Preservation of low-frequency hearing allows cochlear implant users to benefit from electroacoustic stimulation, which improves performance in complex listening situations, such as music appreciation and speech understanding in noise. Despite the relative high rates of success of hearing preservation, postoperative acoustic hearing outcomes remain unpredictable. RECENT FINDINGS: Thin, flexible, lateral wall arrays are preferred for hearing preservation. Both shortened and thin, lateral wall arrays have shown success with hearing preservation and the optimal implant choice is an issue of ongoing investigation. Electrocochleography can monitor cochlear function during and after insertion of the electrode array. The pathophysiology of hearing loss acutely after cochlear implant may differ from that involved in delayed hearing loss following cochlear implant. Emerging innovations may reduce cochlear trauma and improve hearing preservation. SUMMARY: Hearing preservation is possible using soft surgical techniques and electrode arrays designed to minimize cochlear trauma; however, a subset of patients suffer from partial to total loss of acoustic hearing months to years following surgery despite evidence of residual apical hair cell function. Early investigations in robotic-assisted insertion and dexamethasone-eluting implants show promise.

Margin Practices in Oral Cavity Cancer Resections: Survey of American Head and Neck Society Members.

OBJECTIVES/HYPOTHESIS: To investigate the definition of a clear margin and the use of frozen section (FS) among practicing head and neck surgeons in oral cancer management. STUDY DESIGN: Cross-sectional survey. METHODS: We designed a survey that was sent to American Head and Neck Society (AHNS) members via an email link. RESULTS: A total of 185 (13% of 1,392) AHNS members completed our survey. Most surgeons surveyed (96.8%) use FS to supplement oral cavity squamous cell carcinoma resections. Fifty-five percent prefer a specimen-based approach. The majority of respondents believe FS is efficacious in guiding re-resection of positive margins, with 81% considering the new margin to be negative. More than half of respondents defined a distance of >5 mm on microscopic examination as a negative margin. CONCLUSIONS: To avoid oral cancer resections that result in positive margins on final analysis, and thus the need for additional therapy, most surgeons surveyed use FS. A majority of surveyed surgeons now prefer a specimen-based approach to margin assessment. Although there is a debate on what constitutes a negative margin, most surgeons surveyed believe it to be >5 mm on microscopic examination. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:782-787, 2021.

Three-Dimensional Surface Reconstruction of the Human Cochlear Nucleus: Implications for Auditory Brain Stem Implant Design.

Objective The auditory brain stem implant (ABI) is a neuroprosthesis placed on the surface of the cochlear nucleus (CN) to provide hearing sensations in children and adults who are not candidates for cochlear implantation. Contemporary ABI arrays are stiff and do not conform to the curved brain stem surface. Recent advancements in microfabrication techniques have enabled the development of flexible surface arrays, but these have only been applied in animal models. Herein, we measure the surface curvature of the human CN and adjoining regions to assist in the design and placement of next-generation conformable clinical ABI arrays. Three-dimensional (3D) reconstructions from ultrahigh T1-weighted brain magnetic resonance imaging (MRI) sequences and histologic reconstructions based on postmortem adult human brain stem specimens were used. Design This is a retrospective review of radiologic data and postmortem histologic axial sections. Setting This is set at the tertiary referral center. Participants Data were acquired from healthy adults. Main Outcome Measures The main outcome measures are principal curvature values (Kmin and Kmax) and global radius of curvature. Results The CN was successfully extracted and rendered as a 3D surface in all cases. Significant curvatures of the CN in both histologic and radiographic reconstructions were found with global radius of curvature ranging from 2.08 to 8.5 mm. In addition, local curvature analysis revealed that the surface is highly complex. Conclusion Detailed rendering of the human CN is feasible using histology and 3D MRI reconstruction and highlights complex surface topography that is not recapitulated by contemporary stiff ABI arrays.

Understanding approaches to measurement and impact of depth of invasion of oral cavity cancers: A survey of American Head and Neck Society Membership.

OBJECTIVES: To investigate methods used by head and neck surgeons to pre-operatively measure depth of invasion (DOI) in light of the new staging for oral cavity squamous cell carcinoma (OCSCC). MATERIALS AND METHODS: A survey was designed and sent to all American Head and Neck Society (AHNS) members via an email link. The last response was recorded on January 16, 2019. RESULTS: We received 185 (13.3%) responses from 184 surgeons and 1 radiation oncologist. The majority of surgeons correctly identified DOI (78.9%) and indicated measuring DOI pre-operatively (86%). The most common methods for measuring DOI were manual palpation (32.5%) and full thickness biopsy (25.2%). In addition, most surgeons (84.7%) reported using a DOI threshold (in mm) as their primary criterion in their decision to pursue a neck dissection in the N0 neck. The most common reported threshold was 4 mm (37.4% of those that reported using DOI), however, the range varied from 2 to >10 mm. Two-thirds of surgeons considered DOI an important indicator for adjuvant therapy. CONCLUSION: DOI is believed to be an important prognostic indicator guiding neck dissection and the need for adjuvant therapy. While most surgeons currently measure DOI pre-operatively, most use subjective methods. Future studies are needed to establish objective pre-operative DOI measurement techniques and to better inform the decision to perform prophylactic neck dissection, given the current majority practice of prophylactic neck dissection for DOI of 4 mm or greater.

Super-resolution Diffusion Tensor Imaging for Delineating the Facial Nerve in Patients with Vestibular Schwannoma.

Objectives Predicting the course of cranial nerves (CNs) VII and VIII in the cerebellopontine angle on preoperative imaging for vestibular schwannoma (VS) may help guide surgical resection and reduce complications. Diffusion magnetic resonance imaging dMRI is commonly used for this purpose, but is limited by its resolution. We investigate the use of super-resolution reconstruction (SRR), where several different dMRIs are combined into one dataset. We hypothesize that SRR improves the visualization of the CN VII and VIII. Design Retrospective case review. Setting Tertiary referral center. SRR was performed on the basis of axial and parasagittal single-shot epiplanar diffusion tensor imaging on a 3.0-tesla MRI scanner. Participants Seventeen adult patients with suspected neoplasms of the lateral skull base. Main Outcome Measures We assessed separability of the two distinct nerves on fractional anisotropy (FA) maps, the tractography of the nerves through the cerebrospinal fluid (CSF), and FA in the CSF as a measure of noise. Results SRR increases separability of the CN VII and VIII (16/17 vs. 0/17, p = 0.008). Mean FA of CSF surrounding the nerves is significantly lower in SRRs (0.07 ± 0.02 vs. 0.13 ± 0.03 [axial images]/0.14 ± 0.05 [parasagittal images], p = 0.00003/ p = 0.00005). Combined scanning times (parasagittal and axial) used for SRR were shorter (8 minute 25 seconds) than a comparable high-resolution scan (15 minute 17 seconds). Conclusion SRR improves the resolution of CN VII and VIII. The technique can be readily applied in the clinical setting, improving surgical counseling and planning in patients with VS.

Microstructured thin-film electrode technology enables proof of concept of scalable, soft auditory brainstem implants.

Auditory brainstem implants (ABIs) provide sound awareness to deaf individuals who are not candidates for the cochlear implant. The ABI electrode array rests on the surface of the cochlear nucleus (CN) in the brainstem and delivers multichannel electrical stimulation. The complex anatomy and physiology of the CN, together with poor spatial selectivity of electrical stimulation and inherent stiffness of contemporary multichannel arrays, leads to only modest auditory outcomes among ABI users. Here, we hypothesized that a soft ABI could enhance biomechanical compatibility with the curved CN surface. We developed implantable ABIs that are compatible with surgical handling, conform to the curvature of the CN after placement, and deliver efficient electrical stimulation. The soft ABI array design relies on precise microstructuring of plastic-metal-plastic multilayers to enable mechanical compliance, patterning, and electrical function. We fabricated soft ABIs to the scale of mouse and human CN and validated them in vitro. Experiments in mice demonstrated that these implants reliably evoked auditory neural activity over 1 month in vivo. Evaluation in human cadaveric models confirmed compatibility after insertion using an endoscopic-assisted craniotomy surgery, ease of array positioning, and robustness and reliability of the soft electrodes. This neurotechnology offers an opportunity to treat deafness in patients who are not candidates for the cochlear implant, and the design and manufacturing principles are broadly applicable to implantable soft bioelectronics throughout the central and peripheral nervous system.

Semiautomated Motion Tracking for Objective Skills Assessment in Otologic Surgery: A Pilot Study.

Perioperative teaching and feedback of technical performance are essential during surgical training but are limited by competing demands on faculty time, resident work-hour restrictions, and desire for efficient operating room utilization. The increasing use of high-definition video microscopy and endoscopy in otolaryngology offers opportunities for trainees and faculty to evaluate performance outside the operating room but still requires faculty time. Our hypothesis is that automated motion tracking via video analysis offers a way forward to provide more consistent and objective feedback for surgical trainees. In this study, otolaryngology trainees at various levels were recorded performing a cortical mastoidectomy on cadaveric temporal bones using standard surgical instrumentation and high-definition video cameras coupled to an operating microscope. Videos were postprocessed to automatically track the tip of otologic dissection instruments. Data were analyzed for key metrics potentially applicable to the global rating scale used in the Accreditation Council for Graduate Medical Education's Objective Structured Assessments of Technical Skills.

Does Clearance of Positive Margins Improve Local Control in Oral Cavity Cancer? A Meta-analysis.

OBJECTIVES: To compare local recurrence-free survival (LRFS) in early oral cavity cancer (OCC) patients with positive/close frozen section (FS) cleared with further resection (R1 to R0) or positive FS not cleared (R1) to those with negative margins on initial FS analysis (R0). DATA SOURCES: PubMed, EMBASE, and Cochrane. REVIEW METHODS: We followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) for reporting in our study. Only English-language articles that included patients with OCC and local recurrence (LR) comparisons between R0 and initially R1 to final R0 or final R1 groups were included. We requested the raw data from the corresponding authors of eligible studies and performed an individual participant data (IPD) meta-analysis of LRFS outcomes across groups. RESULTS: Pooled LRFS data from 8 studies showed that patients in the R1 to R0 group had worse LRFS compared to the R0 group (hazard ratio [HR] = 2.897, P < .001). Patients in the R1 group were also found to have worse LRFS compared to the R0 group (HR = 3.795, P < .001). When compared to final R1 group, the initially R1 to final R0 only showed a trend toward better LRFS. CONCLUSION: Margin revision of initially positive margins to "clear" based on FS guidance does not equate to an initially negative margin and does not significantly improve local control. These findings call into question the effectiveness of the current methodology of intraoperative FS in OCC resections and call for a prospective study to determine what system of resected specimen analysis best predicts completeness of resection.

Utility of intraoral ultrasound in managing oral tongue squamous cell carcinoma: Systematic review.

OBJECTIVES/HYPOTHESIS: Adequate surgical resection of early stage oral tongue cancer provides the best chance at preventing locoregional disease recurrence. Determination of tumor dimensions and margin location is challenging and can lead to inadequate resections with close/positive margins. Ultrasonography has proven its utility in determining the thickness and extent of tongue tumors. Preoperative tumor dimension measurements carry increased significance with the addition of depth of invasion (DOI) to the eighth edition of the American Joint Committee on Cancer (AJCC) TNM staging system. We report the results of a systematic review of the literature pertaining to the use of ultrasound in the diagnosis and management of oral tongue carcinoma. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-analysis statement checklist was used to inform the design of this systematic review. All studies that utilized ultrasound in the diagnosis/management of primary carcinoma of the oral tongue were included. PubMed, Embase, and Cochrane were reviewed to identify eligible studies. RESULTS: Nineteen articles were included in our analysis. Six hundred seventy-eight patients were studied in the articles included. Ultrasound tumor thickness measurements correlate well with those on histopathology and show promise as a predictor of cervical lymph node metastasis. Ultrasound can be safely used intraoperatively for deep margin assessment. CONCLUSIONS: Ultrasound is useful in the evaluation of oral tongue malignancies. More experience is needed to determine if it is reliable in determining preoperative DOI in light of the role this tumor parameter plays in the eighth edition of the AJCC staging manual. Laryngoscope, 129:662-670, 2019.

Ancestral Adeno-Associated Virus Vector Delivery of Opsins to Spiral Ganglion Neurons: Implications for Optogenetic Cochlear Implants.

Optogenetics is a transformative technology based on light-sensitive microbial proteins, known as opsins, that enable precise modulation of neuronal activity with pulsed radiant energy. Optogenetics has been proposed as a means to improve auditory implant outcomes by reducing channel interaction and increasing electrode density, but the introduction of opsins into cochlear spiral ganglion neurons (SGNs) in vivo has been challenging. Here we test opsin delivery using a synthetically developed ancestral adeno-associated virus (AAV) vector called Anc80L65. Wild-type C57BL/6 mouse pups were injected via the round window of cochlea with Anc80L65 carrying opsin Chronos under the control of a CAG promoter. Following an incubation of 6-22 weeks, pulsed blue light was delivered to cochlear SGNs via a cochleosotomy approach and flexible optical fiber. Optically evoked auditory brainstem responses (oABRs) and multiunit activity in inferior colliculus (IC) were observed. Post-experiment cochlear histology demonstrated opsin expression in SGNs (mean = 74%), with an even distribution of opsin along the cochlear basal/apical gradient. This study is the first to describe robust SGN transduction, opsin expression, and optically evoked auditory electrophysiology in neonatal mice. Ultimately, this work may provide the basis for a new generation of cochlear implant based on light.

Diffusion Tensor Imaging of Central Auditory Pathways in Patients with Sensorineural Hearing Loss: A Systematic Review.

Objective The radiologic evaluation of patients with hearing loss includes computed tomography and magnetic resonance imaging (MRI) to highlight temporal bone and cochlear nerve anatomy. The central auditory pathways are often not studied for routine clinical evaluation. Diffusion tensor imaging (DTI) is an emerging MRI-based modality that can reveal microstructural changes in white matter. In this systematic review, we summarize the value of DTI in the detection of structural changes of the central auditory pathways in patients with sensorineural hearing loss. Data Sources PubMed, Embase, and Cochrane. Review Methods We used the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement checklist for study design. All studies that included at least 1 sensorineural hearing loss patient with DTI outcome data were included. Results After inclusion and exclusion criteria were met, 20 articles were analyzed. Patients with bilateral hearing loss comprised 60.8% of all subjects. Patients with unilateral or progressive hearing loss and tinnitus made up the remaining studies. The auditory cortex and inferior colliculus (IC) were the most commonly studied regions using DTI, and most cases were found to have changes in diffusion metrics, such as fractional anisotropy, compared to normal hearing controls. Detectable changes in other auditory regions were reported, but there was a higher degree of variability. Conclusion White matter changes based on DTI metrics can be seen in patients with sensorineural hearing loss, but studies are few in number with modest sample sizes. Further standardization of DTI using a prospective study design with larger sample sizes is needed.

Intraoperative Ultrasound in Oral Tongue Cancer Resection: Feasibility Study and Early Outcomes.

The current standard of care in oral tongue cancer surgery is complete resection with a target of 5-mm microscopic clearance at all margins on final pathologic review. While current methods of resection are often successful at determining the mucosal margins of the lesion, they may be limited when attempting to achieve an adequate deep margin. A number of previous studies suggested that ultrasound is superior to manual palpation and other imaging modalities (computed tomography, magnetic resonance imaging) at demarcating the margins of tongue lesions. Recent clinical reports of the intraoperative use of this modality have used an invasive method to mark the proposed deep resection margin. In this communication, we report our initial experience with the use of intraoperative ultrasound as an adjunct to oral tongue cancer surgery without the use of an invasive method to mark the deep resection margin.

Toward Optimizing Cervical Vestibular Evoked Myogenic Potentials (cVEMP): Combining Air-Bone Gap and cVEMP Thresholds to Improve Diagnosis of Superior Canal Dehiscence.

OBJECTIVE: To develop a novel approach combining low-frequency air-bone gap (ABG) and cervical vestibular evoked myogenic potential (cVEMP) thresholds to improve screening for superior canal dehiscence (SCD) syndrome. STUDY DESIGN: Retrospective study. SETTING: Tertiary care center. PATIENTS: One hundred forty patients with SCD and 21 healthy age-matched controls were included. Ears for each patient were divided into three groups based on computed tomography (CT) findings: 1) dehiscent, 2) thin, or 3) unaffected. MAIN OUTCOME MEASURES: cVEMP and audiometric thresholds were analyzed and differences among groups were evaluated. RESULTS: We define the third window indicator (TWI) as the cVEMP thresholds at 500, 750, and 1000 Hz adjusted for the ABG at 250 Hz (i.e., subtracting ABG from cVEMP threshold). The TWI differentiates between dehiscent and nondehiscent control ears with a sensitivity of 82% and specificity of 100%, corresponding to a positive predictive value of 100%. ABGs and cVEMP thresholds were similar for healthy controls and patients with thin bone over the superior canal. CONCLUSION: This is the largest study to date examining the usefulness of cVEMPs in the diagnosis of SCD. Our "third window indicator" (TWI) combines cVEMP thresholds with the ABG at 250 Hz to improve the ability to screen patients with SCD symptoms.