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Objective: To determine the association between poor dental health and risk of oral cavity squamous cell cancer (OCSCC) at individual tumor subsites. Study Design: Case‐control and cross‐sectional Methods: A case‐control study was performed using a population‐based cohort in North Carolina (Carolina Head and Neck Cancer Epidemiology Study [CHANCE]). A secondary cross‐sectional analysis was performed with an institutional cohort (WashU/Siteman). Cases were adults with primary OCSCC and an identifiable tumor subsite. In the CHANCE cohort, controls were adults without head and neck cancer. In the Washington University/Siteman cohort, patients with tongue cancer served as the comparator group. We used number of missing teeth (categorized 0‐6, 7‐24, 25‐28) as a surrogate for poor dental health, which was self‐reported in CHANCE and measured on a pretreatment computed tomography scan in the WashU/Siteman study. Adjusted odds ratios (aORs) for missing teeth were estimated for each tumor subsite using binomial logistic regression models. Results: Near complete tooth loss (25‐28 teeth) was associated with a 3.5‐fold increased risk of alveolar ridge malignancy (aOR: 3.51; 95% confidence interval [CI]: 1.14‐11.01, P =.03) in the CHANCE study. This association was confirmed in our cross‐sectional analysis (WashU/Siteman study) where missing 25‐28 teeth was associated with an increased risk of alveolar ridge compared to tongue cancer (aOR: 4.60; 95% CI: 1.97‐11.10, P =.001). Conclusions: This study suggests an association between poor dental health and risk of alveolar ridge cancer independent of smoking, alcohol use, age, race, and sex. Future prospective and translational studies are needed to confirm this association and elucidate the mechanism of dental disease in alveolar ridge malignancies. [ABSTRACT FROM AUTHOR]

Introduction: Patients with bilateral vocal fold paralysis (BVFP) experience airway obstruction because of loss of abductor function of posterior cricoarytenoid (PCA) muscles. We previously reported that implantation of autologous muscle progenitor (stem) cells into thyroarytenoid muscles during reinnervation resulted in improved adductor function. In this study, that same approach was applied to treating PCA muscles in a canine model of BVFP. Design: Animal study. Methods: Two canines underwent baseline measures of glottal resistance (GR), then complete transection and suture repair of both recurrent laryngeal nerves. Muscle stem cells were isolated from skeletal muscle and cultured. Two months later, GR was measured, and then 107 stem cells were implanted into one PCA muscle of each animal. After four more months, GR and glottal opening force (GOF) were measured and the muscles were harvested for histologic study. One control dog underwent the same procedures without stem cell implantation, for comparison. Results: GR increased by 21%–25% over baseline at 2 months, but after stem cell implantation, improved to 10%–14% over baseline at 6 months. PCA muscle strength, as determined by GOF, was 61%–65% on control sides (no stem cells), and 78%–83% on treated sides (with stem cells). Histology confirmed survival of stem cells and a 50% higher rate of innervation of motor endplates in the stem cell treated sides. Conclusion: Autologous muscle progenitor (stem) cells show promise as a potential new therapy for patients with bilateral vocal fold paralysis. Additional studies are needed to determine the optimal number of cells, timing of implantation, and other variables before launching a clinical trial. Level of Evidence: NA (animal study) Laryngoscope, 134:324–328, 2024 [ABSTRACT FROM AUTHOR]

Objective: To evaluate the safety, immunogenicity, and efficacy of INO‐3107, a DNA immunotherapy designed to elicit targeted T‐cell responses against human papillomavirus (HPV) types 6 and 11, in adult patients with recurrent respiratory papillomatosis (RRP; NCT04398433). Methods: Eligible patients required ≥2 surgical interventions for RRP in the year preceding dosing. INO‐3107 was administered by intramuscular (IM) injection followed by electroporation (EP) on weeks 0, 3, 6, and 9. Patients underwent surgical debulking within 14 days prior to first dose, with office laryngoscopy and staging at screening and weeks 6, 11, 26, and 52. Primary endpoint was safety and tolerability, as assessed by treatment‐emergent adverse events (TEAEs). Secondary endpoints included frequency of surgical interventions post‐INO‐3107 and cellular immune responses. Results: An initial cohort of 21 patients was enrolled between October 2020 and August 2021. Fifteen (71.4%) patients had ≥1 TEAE; 11 (52.4%) were Grade 1, and 3 (14.3%) were Grade 3 (none treatment related). The most frequently reported TEAE was injection site or procedural pain (n = 8; 38.1%). Sixteen (76.2%) patients had fewer surgical interventions in the year following INO‐3107 administration, with a median decrease of 3 interventions versus the preceding year. The RRP severity score, modified by Pransky, showed improvement from baseline to week 52. INO‐3107 induced durable cellular responses against HPV‐6 and HPV‐11, with an increase in activated CD4 and CD8 T cells and CD8 cells with lytic potential. Conclusion: The data suggest that INO‐3107 administered by IM/EP is tolerable and immunogenic and provides clinical benefit to adults with RRP. Level of Evidence: 3 Laryngoscope, 133:3087–3093, 2023 [ABSTRACT FROM AUTHOR]

Objectives: Evaluate factors associated with adherence to ototoxicity monitoring among patients with head and neck cancer treated with cisplatin and radiation therapy at a tertiary care center. Methods: We performed a single‐institution retrospective cohort study on adults with head and neck cancer treated with cisplatin and radiation therapy who participated in an ototoxicity monitoring program. The primary outcomes were rates of post‐treatment audiograms at the following time points: one, three, six, 12, and greater than 12 months. Multivariable logistic regression was performed to identify risk factors associated with complete loss of follow‐up after pre‐treatment evaluation. Results: Two hundred ninety‐four head and neck cancer patients were analyzed. Overall, 220 (74.8%) patients had at least one post‐treatment audiogram; 58 (20.0%) patients had more than one audiogram. The time point with the highest follow‐up rate was at 3 months (n = 170, 57.8%); rates at the remaining times ranged from 7.1% to 14.3%. When controlling for covariates, patients without insurance and those with stage IV cancers were associated with complete loss of audiologic follow‐up (aOR = 7.18, 95% CI = 2.75–19.90; aOR = 1.96, 95% CI = 1.02–3.77, respectively). Among 156 patients recommended for a hearing aid, only 39 (24.8%) patients received one. Conclusions: Head and neck cancer patients enrolled in an ototoxicity monitoring program demonstrate moderately high follow‐up rates for at least one post‐treatment audiogram. However, follow‐up tapers dramatically after 6 months, and overall hearing aid utilization is low. Further research is needed to understand barriers to long‐term audiologic follow‐up and hearing aid utilization to decrease untreated hearing loss in cancer survivorship. Level of Evidence: Level 3 Laryngoscope, 133:3161–3168, 2023 [ABSTRACT FROM AUTHOR]

Introduction/Aims: Disease or injury can cause neuromuscular changes to the larynx that can affect voice, breathing, and swallowing. Motor nerve conduction studies have had limited use in the study of laryngeal neurophysiology, despite their importance in other anatomic sites. The aim of this study was to explore the feasibility of performing recurrent laryngeal motor nerve conduction studies (rlMNCS) in a rat model. Methods: rlMNCS were performed in 15 rats under anesthesia. A bipolar stimulating electrode was placed on the recurrent laryngeal nerve (RLN) 5 mm below the cricoid cartilage. Via direct laryngoscopy, a recording electrode was placed transorally into the thyroarytenoid muscle. The RLN was maximally stimulated to determine the compound muscle action potential (CMAP). Three consecutive trials were averaged. Results: The mean stimulating threshold to the RLN to achieve a CMAP from the thyroarytenoid was 1.7 ± 0.6 mA. RLN stimulation caused a visible adductor twitch of the vocal fold in all animals. The mean negative amplitude was 2.0 ± 0.8 mV, and the total area was 1.0 ± 0.4 mV ms. The CMAP latency and negative duration were 1.0 ± 0.1 ms and 0.9 ± 0.2 ms, respectively. Discussion: rlMNCS are feasible and may be useful in understanding laryngeal neurophysiology with disease or injury. This work could provide a tractable animal model for studying and monitoring treatment of neuromuscular conditions affecting voice, breathing, and swallowing. [ABSTRACT FROM AUTHOR]

Simple Summary: In head and neck squamous cell carcinoma (HNSCC), a major challenge with treatments targeting the immune system is an incomplete understanding of rare immune cell subtypes. Several recent studies have explored these cell types, but these studies have not integrated cellular data with clinicopathologic or demographic features to place conclusions in an appropriate clinical context. We deconvolve transcriptomic data from HNSCC patients to infer proportions of immune cell subtypes and place these data in the context of demographic, clinical, pathologic, and genomic characteristics. Our analysis revealed a possible association of γδ T cells with poor survival in HNSCC and underscore the need to better understand the role of these rare cells in HNSCC, including whether the presence of γδ T cells may predict the need for adjuvant therapy. (1) Background: The role of rare immune cell subtypes in many solid tumors, chief among them head and neck squamous cell carcinoma (HNSCC), has not been well defined. The objective of this study was to assess the association between proportions of common and rare immune cell subtypes and survival outcomes in HNSCC. (2) Methods: In this cohort study, we utilized a deconvolution approach based on the CIBERSORT algorithm and the LM22 signature matrix to infer proportions of immune cell subtypes from 517 patients with untreated HPV-negative HNSCC from The Cancer Genome Atlas. We performed univariate and multivariable survival analysis, integrating immune cell proportions with clinical, pathologic, and genomic data. (3) Results: We reliably deconvolved 22 immune cell subtypes in most patients and found that the most common immune cell types were M0 macrophages, M2 macrophages, and memory resting CD4 T cells. In the multivariable analysis, we identified advanced N stage and the presence of γδ T cells as independently predictive of poorer survival. (4) Conclusions: We uncovered that γδ T cells in the tumor microenvironment were a negative predictor of survival among patients with untreated HNSCC. Our findings underscore the need to better understand the role of γδ T cells in HNSCC, including potential pro-tumorigenic mechanisms, and whether their presence may predict the need for alternative therapy approaches. [ABSTRACT FROM AUTHOR]

Background: HPV‐related oropharyngeal squamous cell carcinoma (OPSCC) is associated with a favorable prognosis, yet patients of color and low socioeconomic status (SES) continue to experience inferior outcomes. We aim to understand how the emergence of HPV has impacted race and SES survival disparities in OPSCC. Methods: A retrospective cohort of 18,362 OPSCC cases from 2010 to 2017 was assembled using the SEER (Surveillance, Epidemiology, and End Results) database. Cox proportional regression and Fine and Gray regression models were used to calculate hazard ratios (HRs) adjusting for race, SES, age, subsite, stage, and treatment. Results: Black patients had lower overall survival than patients of other races in HPV‐positive and HPV‐negative OPSCC (HR 1.31, 95% CI 1.13–1.53 and HR 1.23, 95% CI 1.09–1.39, respectively). Higher SES was associated with improved survival in all patients. Race had a diminished association with survival among high SES patients. Low SES Black patients had considerably worse survival than low SES patients of other races. Conclusion: Race and SES interact variably across cohorts. High SES was protective of the negative effects of race, although there remains a disparity in outcomes among Black and non‐Black patients, even in high SES populations. The persistence of survival disparities suggests that the HPV epidemic has not improved outcomes equally across all demographic groups. [ABSTRACT FROM AUTHOR]

Laryngeal dystonia is a potentially disabling task specific dystonia primarily affecting speech. The evaluation and diagnosis of laryngeal dystonia remain challenging, and often require a multi‐disciplinary approach, involving collaboration among speech language pathologists, neurologists and laryngologists (1–5). It is crucial to correctly differentiate between the types of laryngeal dystonia due to the distinct therapeutic approaches and responses to botulinum toxin therapy or speech therapy. For educational purposes, we have divided laryngeal dystonia into two main types: adductor and abductor dystonia. In this article, we describe a series of examination techniques that can assist movement disorders neurologists diagnosing this condition, and appropriately differentiating the most common forms of laryngeal dystonia. [ABSTRACT FROM AUTHOR]

Objective: The goal of this study is to better characterize the phenotypic heterogeneity of oromandibular dystonia (OMD) for the purpose of facilitating early diagnosis. Methods: First, we provide a comprehensive summary of the literature encompassing 1,121 cases. Next, we describe the clinical features of 727 OMD subjects enrolled by the Dystonia Coalition (DC), an international multicenter cohort. Finally, we summarize clinical features and treatment outcomes from cross-sectional analysis of 172 OMD subjects from two expert centers. Results: In all cohorts, typical age at onset was in the 50s and 70% of cases were female. The Dystonia Coalition cohort revealed perioral musculature was involved most commonly (85%), followed by jaw (61%) and tongue (17%). OMD more commonly appeared as part of a segmental dystonia (43%), and less commonly focal (39%) or generalized (10%). OMD was found to be associated with impaired quality of life, independent of disease severity. On average, social anxiety (LSA score: 33 ± 28) was more common than depression (BDI II score: 9.7 ± 7.8). In the expert center cohorts, botulinum toxin injections improved symptom severity by more than 50% in ~80% of subjects, regardless of etiology. Conclusions: This comprehensive description of OMD cases has revealed novel insights into the most common OMD phenotypes, pattern of dystonia distribution, associated psychiatric disturbances, and effect on QoL. We hope these findings will improve clinical recognition to aid in timely diagnosis and inform treatment strategies. [ABSTRACT FROM AUTHOR]

Objectives/Hypothesis: In‐office recurrent laryngeal nerve conduction studies (NCSs) are a technique that can potentially provide information about laryngeal innervation. NCS is essential in the management of other neuropathies including carpal tunnel syndrome and spinal cord injury. We hypothesize that laryngeal NCS may have similar utility in managing patients with vocal fold paralysis, atrophy, and neurodegenerative disease. NCSs are technically challenging because they require transcervical stimulation of the recurrent laryngeal nerve (RLN). This study combines radiographic data with cadaveric dissection to describe the anatomic parameters for optimal RLN stimulation. Study Design: Radiographic and Cadaveric Study. Methods: Fifty computed tomography scans were reviewed to determine the dimensions for ideal needle electrode placement. These values were compared to measurements from 12 fresh human cadaveric neck dissections. Ultrasound imaging was utilized in select cases. The neck was dissected to assess the accuracy of electrode placement. Results: Radiographically, the mean transcervical depth to the RLN was 33.2 mm ± 8.3 mm in males versus 29.4 mm ± 9.4 mm in females. The working space between the lateral trachea and carotid artery was 15.3 mm ± 3.6 mm on the right and 14.1 mm ± 2.9 mm on the left. After placement of stimulating electrodes into the cadaveric neck, the electrode tips were consistently within 8 mm of the RLN. Ultrasound guidance improved placement accuracy of the stimulating electrode. Conclusions: Laryngeal NCSs can provide detailed and objective information about laryngeal innervation that could dramatically improve the management of various neuropathies. In‐office NCSs require technical precision, and this study describes anatomic factors that may affect the feasibility of performing this technique. Level of Evidence: NA Laryngoscope, 131:1566–1569, 2021 [ABSTRACT FROM AUTHOR]

Background: For human papilloma virus positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC), management recommendations for patients with a single metastatic lymph node <6 cm in diameter remain nebulous, leading to treatment heterogeneity in this common subgroup of patients. Methods: We utilized the National Cancer Database to perform survival and multivariable analyses of patients with HPV+ OPSCC with one positive lymph node <6 cm and negative surgical margins. Results: We found that 5‐year survival is comparable between patients who receive surgery and adjuvant radiation versus surgery alone. In multivariable analyses, we found no significant difference in the hazard ratio of overall survival after adjusting for various potential confounders. Conclusions: These data suggest that patients with margin‐negative HPV+ OPSCC with a single positive lymph node <6 cm have comparable survival with or without adjuvant radiation. Future studies exploring outcomes for this specific group in randomized‐controlled trials will be critical for further evaluating these initial observations. [ABSTRACT FROM AUTHOR]

Background: Race has been shown to have variable prognostic importance in nasopharyngeal carcinoma (NPC). However, previous studies are limited by a lack of comprehensive treatment, epidemiologic, and comorbidity data. Methods: This was a retrospective cohort study utilizing the National Cancer Database from 2004 to 2016. Multivariable Cox proportional hazards regressions were used to calculate adjusted hazard ratios (aHR) for overall survival. Results: A cohort of 9995 patients met inclusion and exclusion criteria. Race, insurance, comorbidity, treatment, stage, age, and histology were independent prognosticators. Among patients with keratinizing NPC, Asians and Hispanics had superior survival (aHR 0.58 [95% confidence interval (CI) 0.48–0.69], aHR 0.76 [95% CI 0.61–0.96]) compared to white patients. Among patients with non‐keratinizing differentiated NPC, Asians and black patients had improved survival (aHR 0.71 [95% CI 0.56–0.91], aHR 0.72 [95% CI 0.54–0.95]) compared to white patients. Race was not prognostic in non‐keratinizing undifferentiated NPC. Conclusion: The prognostic significance of race varies across histological subtypes of NPC. [ABSTRACT FROM AUTHOR]

Objectives/hypothesis: Recurrent laryngeal nerve (RLN) transection injuries may occur during thyroidectomy and other surgical procedures. Laser nerve welding has been shown to cause less technique-related axonal damage than the traditional suture method. We compared functional adductor results using these two methods of RLN repair.Study Design: Animal model.Methods: Canine hemilarynges underwent pretreatment testing of laryngeal adductor function, followed by RLN transection and repair using potassium titanyl phosphate (KTP) laser welding (n = 8) or microneural suture (n = 16) techniques. Six months later, adductor function was measured again and expressed as a proportion of the pretreatment value.Results: The mean laryngeal adductor pressure ratios were 82.4% (95% confidence interval [CI]: 72.8%-92.0%) for the laser repair group and 55.5% (95% CI: 49.4%-61.6%) for the suture control group, with a difference of 26.9% (95% CI: 15.3%-38.5%). Both spontaneous and stimulated glottic closure was observed in the laser welding and microsuture repair groups.Conclusions: Laser nerve welding resulted in greater strength of adduction than suture repair of an acutely transected RLN. Suture anastomosis may traumatize more axons than the laser. Stronger vocal fold adduction is associated clinically with better protection from aspiration and improved voice outcomes. KTP laser welding should be considered for anastomosis of the RLN and other nerves.Level Of Evidence: NA Laryngoscope, 130:1764-1769, 2020. [ABSTRACT FROM AUTHOR]

Objectives/hypothesis: Injection laryngoplasty has become valuable in treating laryngologic disorders including vocal cord atrophy, paralysis, and paresis. Although materials such as carboxymethylcellulose and calcium hydroxylapatite are Food and Drug Administration (FDA) approved, they are not without limitations. Juvederm (hyaluronic acid) is an alternative treatment that is not FDA approved. Although studies have examined Juvederm's longevity in cutaneous injections, there are limited data examining durability of Juvederm used in laryngoplasty. We aimed to determine the longevity and effectiveness of Juvederm used in injection laryngoplasty.Study Design: Retrospective cohort study.Methods: Subjects who underwent injection laryngoplasty using Juvederm were reviewed. Longevity was defined as the time between injection and the date that a patient first noted subjective deterioration of their voice. All subjects were subsequently followed using videostroboscopy to evaluate for Juvederm resorption. Longevity was analyzed using a Kaplan-Meier survival model, and effectiveness of laryngoplasty was determined using the Voice-Related Quality of Life index scores and analyzed using a Wilcoxon signed ranks test.Results: Fifty-nine subjects met inclusion criteria and underwent Juvederm injection laryngoplasty. Kaplan-Meier survival analysis revealed a mean longevity of 10.6 months (95% confidence interval: 9.1-12.0 months). Wilcoxon signed ranks analysis of the pre- and postinjection Voice Related Quality of Life (VRQOL) scores revealed improvement, with a mean preinjection VRQOL of 49.2 (standard deviation [SD] = 25.8) and mean postinjection VRQOL of 68.2 (SD = 27.5) (P < .001).Conclusions: Injection laryngoplasty using Juvederm is an effective treatment for vocal cord atrophy, paralysis, and paresis. Knowledge of the patient-defined duration of benefit following laryngoplasty using Juvederm plays an important role in counseling patients as well as in the planning of future interventions.Level Of Evidence: 4 Laryngoscope, 129:2744-2747, 2019. [ABSTRACT FROM AUTHOR]

Introduction: Unilateral vocal fold paralysis (UVFP) without an identifiable cause is termed idiopathic unilateral vocal fold paralysis (IUVFP). Some authors have postulated that select cases of IUVFP have a viral etiology, but the causality has not been established. We set out to review institutional cases of IUVFP and determine if there is a correlation between upper respiratory infection symptoms and presentation of IUVFP. Methods: Cases of IUVFP were reviewed over a 10-year period (2002-2012). The history was investigated to review presenting symptoms. We specifically reviewed for symptoms of upper respiratory infection at the onset of UVFP and tallied the frequency. Symptoms included sore throat, laryngitis, cough, influenza, bronchitis, pneumonia, otalgia, and sinusitis. The seasonal onset (if possible) was determined based on the history provided from the initial consultation. Study Design: Case series. Results: Overall, 107 patients presented with IUVFP; 35.5% of patients reported symptoms of upper respiratory infection at the onset of UVFP. Among these individuals, pharyngitis/laryngitis was the most common presenting symptom; 34.2% reported cough. In total, 40.0% of patients with IUVFP reported an onset of symptoms between December and February. Conclusions: This study suggests that symptoms of upper respiratory infection frequently occur with the presentation of IUVFP. The onset of symptoms tended to occur between December and February. The mechanism of viral-mediated UVFP has not been established. Future studies to explore this pathophysiology are needed. [ABSTRACT FROM AUTHOR]

Objective: Vocal fold paralysis is caused by injury to the recurrent laryngeal nerve (RLN). Current clinical measures of laryngeal innervation are often nonquantitative. Compound motor action potentials (CMAP) measure motor innervation. The goal of this study was to determine whether CMAP can quantify laryngeal innervation following acute nerve injury. Study Design: Animal study. Methods: Twelve canine hemilaryngeal preparations were used. The RLN was serially stimulated with increasing intensities until the nerve was maximally stimulated. The CMAP amplitude was measured for each intensity stimulation and correlated. Next, the RLN was incompletely transected, and the reduction in CMAP amplitude was correlated to the percentage of transected axons. The percentage of transected axons was determined using horseradish peroxidase (HRP) staining. Results: Combining all hemilaryngeal preparations, the submaximal stimulation of the RLN linearly correlated with the resultant CMAP amplitude (r = 0.83; 95% CI, 0.76-0.88). Following partial RLN transection, the percentage of remaining axons linearly correlated with the CMAP amplitude (r = 0.87; 95% CI, 0.34-0.98). Conclusions: CMAP amplitude is a quantitative measure that may correlate with the degree of vocal fold innervation in canines. Following RLN injury, CMAP may help clinicians quantify the number of intact axons, assess the likelihood of recovery, and counsel patients on their prognosis. [ABSTRACT FROM AUTHOR]

Objectives/hypothesis: In animal studies, intramuscular vincristine injections have been shown to block reinnervation of the denervated target muscle. This application could be used selectively to influence recovery patterns following injury of recurrent laryngeal nerves (RLNs). However, vincristine is currently Food and Drug Administration approved only for intravenous use. A formal toxicity trial of intramuscular injections was performed.Study Design: Animal study.Methods: Sixteen female canines underwent direct laryngoscopy with injection of moderate- (0.4 mg, n = 8) or high-dose (0.6 mg, n = 8) vincristine into the posterior cricoarytenoid (PCA) muscles. Plasma samples were collected at various time points postinjection and vincristine levels determined. At 24 hours (n = 7) or 14 days (n = 9) postinjection, animals were anesthetized and videolaryngoscopy documented vocal fold mobility and mucosal appearance. Adductor function was measured during stimulation of the RLN. Larynges were processed for histology.Results: Fifteen minutes after injection, plasma vincristine levels averaged 10.2% ± 6.7% of the intravenous maximum, suggesting about 90% of the vincristine remained within the PCA muscle. Plasma levels were usually below detectable limits within 24 hours. At the end points, all animals had grossly normal-appearing mucosa and full range of motion. Laryngeal adductor strength was normal in all cases. Histology showed moderate to severe acute inflammation in the submucosa only in the high-dose group at 24 hours. There was no necrosis of muscle or mucosa.Conclusions: Intramuscular vincristine injections into the canine PCA muscles resulted in no significant local toxicity, even at the maximum dose. It would be reasonable to evaluate this treatment strategy in a phase I human trial.Level Of Evidence: NA Laryngoscope, 128:E247-E250, 2018. [ABSTRACT FROM AUTHOR]

Objective: Muscle progenitor cells (MPCs) can be isolated from muscle samples and grown to a critical mass in culture. They have been shown to survive and integrate when implanted into rat laryngeal muscles. In this study, the ability of MPC implants to enhance adductor function of reinnervated thyroarytenoid muscles was tested in a canine model.Study Design: Animal study.Methods: Sternocleidomastoid muscle samples were harvested from three canines. Muscle progenitor cells were isolated and cultured to 107 cells over 4 to 5 weeks, then implanted into right thyroarytenoid muscles after ipsilateral recurrent laryngeal nerve transection and repair. The left sides underwent the same nerve injury, but no cells were implanted. Laryngeal adductor force was measured pretreatment and again 6 months later, and the muscles were harvested for histology.Results: Muscle progenitor cells were successfully cultured from all dogs. Laryngeal adductor force measurements averaged 60% of their baseline pretreatment values in nonimplanted controls, 98% after implantation with MPCs, and 128% after implantation with motor endplate-enhanced MPCs. Histology confirmed that the implanted MPCs survived, became integrated into thyroarytenoid muscle fibers, and were in close contact with nerve endings, suggesting functional innervation.Conclusion: Muscle progenitor cells were shown to significantly enhance adductor function in this pilot canine study. Patient-specific MPC implantation could potentially be used to improve laryngeal function in patients with vocal fold paresis/paralysis, atrophy, and other conditions. Further experiments are planned.Level Of Evidence: NA. Laryngoscope, 2017. [ABSTRACT FROM AUTHOR]

Objective: To determine whether injection laryngoplasty within 6 months following the onset of unilateral vocal fold paralysis (UVFP) decreases the rate of permanent thyroplasty in adults.Data Sources: Search strategies created by a medical librarian were implemented in multiple online research databases.Review Methods: Inclusion and exclusion criteria were designed to capture randomized clinical trials and cohort studies examining adults with UVFP who received injection laryngoplasty early in the course of treatment, within 6 months of onset, or who were observed. The primary outcome was the rate of thyroplasty. The Newcastle-Ottawa scale was used to assess quality of included cohort studies. Random effects meta-analysis was used to calculate an overall relative risk (RR). Heterogeneity was evaluated with the I2 statistic.Results: The search strategy resulted in 1,177 studies, of which four cohort studies remained for meta-analysis after applying inclusion and exclusion criteria. All studies were rated as 9 of 9 on the Newcastle-Ottawa scale. Meta-analysis of 275 patients with UVFP revealed that the overall pooled RR of undergoing thyroplasty in those receiving an early injection was 0.25 (95% confidence interval 0.14-0.45) compared to conservative management (late or no injection). The I2 overall was 62.4%.Conclusion: Otolaryngologists should offer injection laryngoplasty to patients with a diagnosis of UVFP within 6 months of diagnosis (recommendation based on grade C evidence with a preponderance of benefit over harm). Laryngoscope, 128:935-940, 2018. [ABSTRACT FROM AUTHOR]

Objectives/hypothesis: To evaluate outcomes for patients with pathological N3 (pN3) neck disease from human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) and determine variables predictive of survival.Study Design: Retrospective case series with chart review.Methods: This study was conducted between 1998 and 2013 and included patients with HPV-related OPSCC treated with surgery with or without adjuvant therapy and who had pN3 nodal disease. The primary outcome was disease-specific survival (DSS). Secondary outcomes included overall survival (OS), disease-free survival (DFS), adverse events, and gastrostomy tube rates.Results: Thirty-nine patients were included, of whom 36 (90%) underwent adjuvant therapy. Median follow-up was 39 months (range, 2-147 months). Mean age was 56 years, and 87% were male. Seventeen patients (44%) underwent selective neck dissection, whereas six (15%) underwent radical (n = 2) or extended radical (n = 4) neck dissection. Ninety-two percent had extracapsular extension. Five-year Kaplan-Meier estimated DSS, OS, and DFS were 89% (95% confidence interval [CI]: 79%-99%), 87% (95% CI: 75%-99%), and 84% (95% CI: 72%-96%), respectively. The disease recurrence rate was 10% (5% regional, 5% distant metastasis). Patients with less than 5 pathologically positive lymph nodes (P = .041) had improved DFS.Conclusions: Patients with HPV-related OPSCC and pN3 nodal disease treated with surgery and adjuvant therapy have very favorable long-term survival and regional control. Patients with five or more pathologically positive lymph nodes may be at higher risk for recurrence.Level Of Evidence: 4. Laryngoscope, 127:2033-2037, 2017. [ABSTRACT FROM AUTHOR]

Objectives/hypothesis: Cranial nerve transection during head and neck surgery is conventionally repaired with microsuture. Previous studies have demonstrated recovery with laser nerve welding (LNW), a novel alternative to microsuture. LNW has been reported to have poorer tensile strength, however. Laser-activated chitosan, an adhesive biopolymer, may promote nerve recovery while enhancing the tensile strength of the repair. Using a rat posterior tibial nerve injury model, we compared four different methods of nerve repair in this pilot study.Study Design: Animal study.Design: Animals underwent unilateral posterior tibial nerve transection. The injury was repaired by potassium titanyl phosphate (KTP) laser alone (n = 20), KTP + chitosan (n = 12), microsuture + chitosan (n = 12), and chitosan alone (n = 14). Weekly walking tracks were conducted to measure functional recovery (FR). Tensile strength (TS) was measured at 6 weeks.Results: At 6 weeks, KTP laser alone had the best recovery (FR = 93.4% ± 8.3%). Microsuture + chitosan, KTP + chitosan, and chitosan alone all showed good FR (87.4% ± 13.5%, 84.6% ± 13.0%, and 84.1% ± 10.0%, respectively). One-way analysis of variance was performed (F(3,56) = 2.6, P = .061). A TS threshold of 3.8 N was selected as a control mean recovery. Three groups-KTP alone, KTP + chitosan, and microsuture + chitosan-were found to meet threshold 60% (95% confidence interval [CI]: 23.1%-88.3%), 75% (95% CI: 46.8%-91.1%), and 100% (95% CI: 75.8%-100.0%), respectively.Conclusions: In the posterior tibial nerve model, all repair methods promoted nerve recovery. Laser-activated chitosan as a biopolymer anchor provided good TS and appears to be a novel alternative to microsuture. This repair method may have surgical utility following cranial nerve injury during head and neck surgery.Level Of Evidence: NA Laryngoscope, 127:E253-E257, 2017. [ABSTRACT FROM AUTHOR]

Objective: Compound motor action potential (CMAP) can quantitatively evaluate innervation following injury to the recurrent laryngeal nerve (RLN) in canines. CMAP duration (the total time of CMAP) and latency (the time between the nerve impulse and the onset of action potentials) have not been assessed following RLN injury.Study Design: Animal study.Methods: Twelve canine hemilaryngeal preparations were investigated. Baseline CMAP duration and latency were derived. Group A (n = 5) underwent RLN stretch injury, and group B (n = 7) underwent RLN transection/repair. The change in CMAP duration and latency was assessed between the baseline and 6-month measurements using receiver operator characteristic (ROC) curves for each group individually and combined.Results: Six months following injury, transection/repair injuries had the most significant increase in CMAP duration (2.8 ± 0.6 ms vs. 4.2 ± 0.8 ms, difference 1.4 ms 95% confidence interval [CI]: 0.43 to 2.40) and latency (2.6 ± 0.5 ms vs. 5.6 ± 1.5 ms, difference 3.0 ms 95% CI: 1.65 to 4.38). Stretch injuries also caused an increase in CMAP duration (2.3 ± 0.8 ms vs. 3.0 ± 0.6 ms, difference 0.7 ms 95% CI: -0.49 to 1.77) and latency (2.5 ± 0.8 ms vs. 4.7 ± 1.5 ms, difference 2.3 95% CI: 0.76 to 3.80). Using ROC curves, CMAP duration and latency differentiated between the baseline control and RLN injury at 6 months (area under the curve = 0.78 and 0.98, respectively).Conclusion: CMAP duration and latency are both quantitative measures that may have clinical utility as markers of RLN injury. CMAP latency had superior discrimination between injured and uninjured RLNs. Increased CMAP duration and latency may be explained by incomplete myelination and focal conduction block.Level Of Evidence: NA. Laryngoscope, 127:1855-1860, 2017. [ABSTRACT FROM AUTHOR]

Objective: Laryngeal adductor response (LAR) to air puff is used as a reliable method in evaluating sensation thresholds (ST) in human laryngeal sensory disorders. This method has been difficult to perform in small subjects such as rodents. The aims of this study were to 1) evaluate ST to air puff under binocular microlaryngoscopy in rats to evaluate laryngeal sensory disorders, 2) determine sensory thresholds at varying target locations, and 3) determine the ideal depth of anesthesia.Study Design: Animal study.Methods: Rats were induced with ketamine/xylazine. The level of anesthesia was monitored by spontaneous glottic closure and corneal reflex testing. Air puffs were delivered to the epiglottis, arytenoid, and piriform sinus at varied pressures with pulse time kept constant. Sensation thresholds were determined by direct visualization of the larynx using a binocular microscope. Topical lidocaine was then applied to the larynx and ST was determined. Trials were repeated in a small subset of animals.Results: Twenty-six trials were performed in 14 rats. Mean STs were 39 ± 9.7 mm Hg at the epiglottis, 48.8 ± 10.5 at the arytenoid, and not detectable at the pyriform sinus. Repeated trials demonstrated consistent results. Lidocaine effectively ablated the LAR in each trial. The LAR was difficult to induce while corneal reflex was absent and was difficult to distinguish from spontaneous glottic closures while under lighter sedation.Conclusion: Air pulse stimulation in rats is a simple, reliable, and effective way to determine laryngopharyngeal STs in rats and can be used as an efficient and affordable method for experimentation involving laryngeal sensory disorders.Level Of Evidence: NA. Laryngoscope, 127:E265-E269, 2017. [ABSTRACT FROM AUTHOR]

Unilateral vocal fold paralysis (UVP) occurs related to recurrent laryngeal nerve (RLN) impairment associated with impaired swallowing, voice production, and breathing functions. The majority of UVP cases occur subsequent to surgical intervention with approximately 12-42% having no known cause for the disease (i.e., idiopathic). Approximately two-thirds of those with UVP exhibit left-sided injury with the average onset at ≥50 yr of age in those diagnosed as idiopathic. Given the association between the RLN and the subclavian and aortic arch vessels, we hypothesized that changes in vascular tissues would result in increased aortic compliance in patients with idiopathic left-sided UVP compared with those without UVP. Gated MRI data enabled aortic arch diameter measures normalized to blood pressure across the cardiac cycles to derive aortic arch compliance. Compliance was compared between individuals with left-sided idiopathic UVP and age- and sex-matched normal controls. Three-way factorial ANOVA test showed that aortic arch compliance (P = 0.02) and aortic arch diameter change in one cardiac cycle (P = 0.04) are significantly higher in patients with idiopathic left-sided UVP compared with the controls. As previously demonstrated by other literature, our finding confirmed that compliance decreases with age (P < 0.0001) in both healthy individuals and patients with idiopathic UVP. Future studies will investigate parameters of aortic compliance change as a potential contributor to the onset of left-sided UVP. [ABSTRACT FROM AUTHOR]

Objectives/hypothesis: Cranial nerve transection during head and neck surgery is conventionally repaired by microsuture reanastomosis. Laser nerve welding (LNW), using CO2 laser to spot-weld the epineurium of transected nerve endings, has been shown in animal models to be a novel alternative to microsuture repair. This method avoids needle/suture material and minimizes instrumentation of the nerve. We hypothesized that potassium titanyl phosphate (KTP) laser would be superior to CO2 laser in repairing transected nerves. Using a rat posterior tibial nerve injury model, we compared CO2 laser, KTP laser, and microsuture reanastomosis.Study Design: Animal study.Methods: Animals underwent unilateral posterior tibial nerve transection. The injury was repaired by microsuture repair (n = 15), CO2 laser repair (n = 15), or KTP laser repair (n = 15). Weekly walking tracks were performed to measure functional recovery. Nerve segments were harvested for axon counting.Results: At 6 weeks, the KTP LNW had the best functional recovery (92.4 ± 8.6%) compared to microsuture repair (84.5 ± 10.2%, difference 7.9%, 95% confidence interval [CI]: 0.84%-14.96%). CO2 laser repair had a functional recovery of 86.8 ± 11.2%. KTP LNW had better axon recovery compared to transection/repair (difference 530.7 axons, 95% CI: 329.9-731.5). Operative time for the microsuture repair was 18.2 ± 6.8 minutes, compared to 5.8 ± 3.7 minutes for the LNW groups (difference 12.4 minutes, 95% CI: 8.6-16.2 minutes).Conclusions: KTP, CO2 , and microsuture repair all showed good functional recovery following complete transection of the posterior tibial nerve. Following complete nerve transection during head and neck surgery, KTP LNW may be a novel alternative to microsuture repair.Level Of Evidence: NA Laryngoscope, 127:1525-1530, 2017. [ABSTRACT FROM AUTHOR]

Objectives/hypothesis: To investigate the efficacy of paclitaxel, a potent microtubule inhibitor with a more favorable therapeutic index as compared with vincristine, in preventing post-traumatic nerve regeneration of the recurrent laryngeal nerve into the posterior cricoarytenoid muscle in a canine laryngeal model.Study Design: Experimental animal study.Methods: Forty-nine canine hemilaryngeal specimens were divided into five experimental groups. Under general anesthesia, a tracheostomy, recurrent laryngeal nerve (RLN) transection and repair, and laryngeal adductory pressures (LAP) were measured pre-RLN injury. The approach to the posterior cricoarytenoid (PCA) muscle for neurotoxin injection was transoral or open transcervical, at 0 or 3 months. At 6 months, postinjury LAPs were measured and the animals were sacrificed at 6 months to allow for laryngeal harvesting and analysis.Results: Paclitaxel demonstrated increased mean laryngeal adductory pressures (70.6%) as compared with saline control (55.5%). The effect of paclitaxel was the same as observed with vincristine at 0 months and with a delayed injection at 3 months. There was no difference between transoral or open injection groups.Conclusions: PCA muscle injection with paclitaxel resulted in improved strength of laryngeal adduction. This effect was similar to that of vincristine at both 0 and 3 months following nerve injury. A single intramuscular injection of paclitaxel was well tolerated. Additional human studies are needed to determine the degree of clinical benefit of this intervention.Level Of Evidence: NA Laryngoscope, 127:651-655, 2017. [ABSTRACT FROM AUTHOR]

Introduction: The strength of glottic closure with recurrent laryngeal nerve (RLN) stimulation has been indirectly measured experimentally by determining the squeezing pressure on a balloon inserted between the vocal folds, termed laryngeal adductory pressure (LAP). In this study, we sought to measure glottic closing force (GCF) directly and compare these results to LAP measures obtained with identical stimulation parameters. Methods: In canines, a method for measuring GCF was developed in which a suture was looped through a lateral thyrotomy hole, around the vocal process and back, then attached to a force gauge. The RLN was maximally stimulated and GCF recorded. The LAP was then measured as previously described, using the same stimuli. This process was repeated at 9 stimulation frequencies in 10-Hz intervals from 20 to 100 Hz. The GCF and LAP were compared using Pearson's correlation coefficient (PCC). Results: Both sides were measured in 16 dogs, resulting in 32 data sets. The LAP measures were obtained at all frequencies, while GCF was obtained in 246 of 288 (85.4%) attempts. The maximum GCF for each dog typically occurred at 80 to 100 Hz and averaged 0.287 ± 0.106 newtons. Plotting GCF versus LAP for each hemilaryngeal preparation, the mean PCC was 0.932 ± .042 (range, 0.802-0.987). The mean PCC did not differ between control (n = 26) and postoperative (n = 6) hemilarynges. Conclusion: This method for measuring GCF appears valid. The high Pearson's correlation coefficient indicates strong covariance between GCF and LAP, demonstrating that they are both measures of the same physical property. The LAP is easier to perform and more consistently obtained. [ABSTRACT FROM AUTHOR]

Objectives/hypothesis: A simple, safe and effective surgical alternative for treating adductor spasmodic dysphonia (ADSD) would appeal to many patients. This study evaluates a new option, using radiofrequency-induced thermotherapy (RFITT) of the thyroarytenoid muscle (TA) via the minithyrotomy approach to reduce the force of adduction.Methods: Fifteen dogs were used. In part 1, the optimal RFITT power settings, exposure time, probe location, and number of passes were determined. Part 2 compared laryngeal adductor pressures (LAPs) at baseline; immediately postintervention; and at 1, 3, or 6 months postintervention. Interventions included RFITT via the transcervical minithyrotomy approach (n = 15), transoral RFITT (n = 3), botulinum toxin (Botox) injection (n = 3), or no-intervention controls (n = 3). Postintervention induced phonation and histologic analyses were performed as well.Results: In the minithyrotomy RFITT group, the mean LAP was 30.3% of baseline immediately posttreatment. At 1, 3, and 6 months postoperatively, the mean LAPs were 24.9%, 44.8%, and 43.5%, respectively. Transoral RFITT reduced LAP to 56.6% of baseline immediately posttreatment, but returned to normal in the 1 and 3 month animals. The Botox injections dropped the LAP to 57% of baseline at 1 month, but returned to normal at 3 months. Mucosal waves, based on induced phonation stroboscopy, were present at the terminal date in all animals. Thirteen of 15 transcervical RFITT preparations (87%) showed no injury to the lamina propria, whereas 80% showed evidence of TA muscle atrophy and fibrosis.Conclusion: Minithyrotomy RFITT is a feasible technique that shows encouraging long-term results for the potential treatment of patients with ADSD.Level Of Evidence: N/A. Laryngoscope, 126:2325-2329, 2016. [ABSTRACT FROM AUTHOR]

Objective: To investigate the efficacy of a novel adductor muscle-releasing technique designed to decrease the force of vocal fold adduction, as a potential surgical therapy for patients with adductor spasmodic dysphonia (ADSD). Study Design: Experimental animal study. Methods: A canine laryngeal model was used to assess the acute and sustained efficacy of a lateral cricoarytenoid (LCA) muscle release. A total of 34 canine hemilaryngeal preparations were divided among 7 experimental groups. The LCA muscle was separated from its cricoid cartilage origin via an open, anterior, submucosal approach. The laryngeal adductory pressures (LAP) were assessed pre- and post-muscle release via direct recurrent laryngeal nerve stimulation. Measurements were repeated at 1.5, 3, or 6 months postoperatively. Another study evaluated release of the thyroarytenoid (TA) muscle from its thyroid cartilage origin. Results: Releasing the LCA muscle demonstrated a significant decrease in LAP acutely and was maintained at all 3 time points with the aid of a barrier (P < .05). Without the barrier, the LCA muscle reattached to the cricoid. Acute release of the TA muscle did not significantly decrease the LAP. Conclusions: The proposed LCA release procedure may provide patients with a permanent treatment option for ADSD. However, longer-term studies and human trials are needed. [ABSTRACT FROM AUTHOR]

Objectives/hypothesis: When the recurrent laryngeal nerve (RLN) is injured, functional recovery may be limited by the number of axons that regrow across the site of injury, and by the proportions of these axons that reinnervate the antagonistic muscle (synkinesis). This process was investigated in a computer model of RLN recovery.Study Design: Computer simulation.Methods: The developed computer program accepted as inputs: number of RLN axons; proportions of axons originally innervating adductor versus abductor, fraction of axons transected, fraction of axons that grow back, and width of 1 standard deviation about the mean. The program employed random sampling from a normal distribution to model various degrees of recovery, using random numbers to assign each axon to the correct muscle, an incorrect muscle, or no recovery. Each simulation was run 1,000×, and the mean, highest, and lowest degrees of synkinesis were determined.Results: More severe injuries were associated with greater degrees of synkinesis. Extremes of synkinesis were possible but were rare. One example result, for a 50% injury with a 50% recovery rate, found: in the adductor muscles, 74.8% of axons will be innervated, of which 49.2% are the original uninjured axons, 19.4% are recovered adductor axons, and 6.2% are misdirected abductor axons. In the posterior cricoarytenoid (PCA), these values were 75.7%, 50.8%, 6.1%, and 18.8%, respectively. Results of many such simulations are plotted.Conclusions: Laryngeal synkinesis can be simulated based on known anatomic ratios and estimated recovery rates. The PCA is invariably much more affected by synkinetic reinnervation than are the adductor muscles.Level Of Evidence: NA Laryngoscope, 126:1600-1605, 2016. [ABSTRACT FROM AUTHOR]

Objective: The compound motor action potential (CMAP) is the summated action potential from multiple muscle fibers activated by a single nerve impulse. The utility of laryngeal muscle CMAP for quantifying innervation following recurrent laryngeal nerve (RLN) injury was investigated. Method: In a series of 21 canine hemi-laryngeal preparations, RLNs were exposed and a stimulating electrode placed. Maximum CMAP amplitudes and area under the curve from the thyroarytenoid (TA) muscles were obtained at baseline and at 6 months following injury to the RLN. Injury mechanisms included crush, stretch, cautery, and complete transection with microsuture repair. Results: Prior to injury, baseline CMAP amplitudes and area under the curve were 15.81 mV and 15.49mVms, respectively. Six months following injury, CMAP amplitude and area under curve were 105.1% and 102.1% of baseline for stretch, 98.7% and 112.7% for crush, 93.3% and 114.3% for cautery. The CMAP amplitude and area under the curve in the transection/repair group had a 54.3% and 69.4% recovery, respectively, which were significantly different than baseline (P < .01, P < .05). These values were correlated with vocal fold motion. Conclusion: The CMAP is a measure of vocal fold innervation. The technique could be further developed for clinical and experimental applications. [ABSTRACT FROM AUTHOR]

Objective: To determine the impact of prior open neck biopsy on the prognosis of patients with human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) who are subsequently treated with a definitive surgical paradigm, including adjuvant therapy when indicated.Study Design: Retrospective cohort.Setting: Tertiary care university hospital.Subjects and Methods: Patients with open neck biopsies who were treated with definitive surgery, with or without adjuvant therapy, for HPV-related OPSCC between 1998 and 2012 were compared with a matched control group who did not undergo open neck biopsy. Outcomes were disease-free survival, overall survival, disease-specific survival, incidence of tumor deposit in dermal scar, patterns of recurrence, and neck dissection complications.Results: Forty-five patients who underwent open neck biopsy were compared with 90 matched controls. Tumor deposits in dermal scars from the prior open neck biopsy were found in 3 patients (7%) during completion neck dissection. Overall complications of the neck dissection were not significantly increased in the open biopsy group over matched controls (20% vs 12%, respectively; P > .05). Five-year Kaplan-Meier estimates for disease-free survival, overall survival, and disease-specific survival were not significantly different between the open biopsy and control groups (93% vs 91%, 98% vs 97%, 98% vs 99%, respectively; all P > .05). Recurrence rates were also not significantly different between groups.Conclusions: Patients with HPV-related OPSCC who have undergone a prior open neck biopsy can be successfully treated with a definitive surgical paradigm. Although needle biopsy is preferable to establish a diagnosis, previous open neck biopsy does not affect prognosis in these patients. [ABSTRACT FROM AUTHOR]

Objectives/hypothesis: Following acute injury to the recurrent laryngeal nerve (RLN), laryngeal electromyography (LEMG) is increasingly being used to determine prognosis for recovery. The LEMG findings change during the recovery process, but the timing of these changes is not well described. In this canine study, LEMGs were obtained serially following model RLN injuries.Study Design: Animal Study.Methods: Thirty-six canine RLNs underwent crush (n = 6), complete transection with reanastomosis (n = 6), half-transection half-crush (n = 5), cautery (n = 5), stretch (n = 5), inferior crush (n = 4), or inferior transection with reanastomosis (n = 5) injuries. Injuries were performed 5 cm from cricoid or were 5 cm further inferior. Under light sedation, LEMG of thyroarytenoid muscles was performed monthly for 6 months following injury. At 6 months, spontaneous and induced vocal fold motion was assessed.Results: Except for the stretch injury, the remaining groups showed very similar recovery patterns. Fibrillation potentials (FPs) and/or positive sharp waves (PSWs; signs of bad prognosis) were seen in all cases at 1 month and lasted on average for 2.26 months (range = 1-4 months). Motor unit potentials of at least 2+ (scale = 0-4+; signs of good prognosis) were seen beginning at 3.61 months (range = 2-6 months). The stretch injury was less severe, with 3 of 5 showing no FPs/PSWs at 1 month; all recovered full mobility. Ten of the 36 thyroarytenoid muscles (27.8%) had 1 electromyograph showing both bad prognosis and good prognosis signs simultaneously at 2 to 4 months postinjury.Conclusions: LEMG can be used to predict RNL recovery, but timing is important and LEMG results earlier than 3 months may overestimate a negative prognosis.Level Of Evidence: NA Laryngoscope, 126:651-656, 2016. [ABSTRACT FROM AUTHOR]

Objectives/Hypothesis Development of an academic career easily follows a clinical course for which there are multiple role models; however, development of an academic research career involves few role models, and rarely do instructional guides reach out to the new faculty. The purpose of this article is to present the cumulative experiences of previously and currently funded authors to serve as a guide to young as well as older faculty for developing their research careers. Study Design Cumulative experiences of research-dedicated faculty. Methods This article is the result of lessons learned from developing a Triological Society National Physician-Scientist Program and Network, as well as the cumulative experiences of the authors. Results Table I illustrates key elements in developing a serious research career. Table II records the career courses of five surgeon-scientists, highlighting the continued theme focus with theme-specific publications and progressive grants. These cumulative experiences have face validity but have not been objectively tested. The value added is a composite of 50 years of experiences from authors committed to research career development for themselves and others. Conclusion Crucial elements in developing a research career are a desire for and commitment to high-quality research, a focus on an overall theme of progressive hypothesis-driven investigations, research guidance, a willingness to spend the time required, and an ability to learn from and withstand failure. Level of Evidence 5. [ABSTRACT FROM AUTHOR]

Objectives/hypothesis: Functional recovery after a recurrent laryngeal nerve or facial nerve injury may be impaired due to aberrant reinnervation. Previous work in a rat peripheral nerve injury model found vincristine to be a potent inhibitor of reinnervation, and it has since been used to effectively block neural regeneration in other animal models. However, vincristine's narrow therapeutic index may limit its utility; therefore, another microtubule inhibitor, paclitaxel, which has a higher therapeutic index, was tested.Study Design: Animal (rat) study.Methods: After controlled injury to the rat posterior tibial (PT) nerve, the gastrocnemius/soleus complex was injected with saline (control, n = 14), vincristine (n = 30), or paclitaxel (n = 20). Injections without a crush injury were performed using saline (n = 5) or paclitaxel (n = 9). The functional recovery (FR) of the PT nerve was assessed using walking track analysis.Results: At 6 weeks, controls had already recovered to baseline (FR = 1.0), whereas the paclitaxel group had FR = 0.724 ± 0.064 and the vincristine group had FR = 0.709 ± 0.078. At 6 months, the paclitaxel rats had FR = 0.798 ± 0.167 and the vincristine rats had FR = 0.754 ± 0.240. These differences were significantly different from baseline, but the two agents were not different from each other. Paclitaxel did not affect the FR in the absence of a nerve injury.Conclusions: Intramuscular paclitaxel and vincristine both significantly inhibit regeneration of the PT nerve after crush injury for at least 6 months. Potential clinical uses of inhibition of reinnervation are discussed.Level Of Evidence: NA [ABSTRACT FROM AUTHOR]

The article presents a study which determines the effects of vincristine on the laryngeal adductor function of posterior cricoarytenoid (PCA) muscle following a recurrent laryngeal nerve (RLN) injury. The study uses canine animal as subject of the experiment. The study reveals that vincristine injection in PCA muscle blocks the antagonist muscle against synkinetic reinnervation.

We previously reported that nab-paclitaxel-based induction chemotherapy ( IC) and concurrent chemoradiotherapy resulted in low relapse rates (13%) and excellent survival in head and neck squamous cell carcinoma ( HNSCC). We compare the disease-specific survival ( DSS) and overall survival ( OS) between patients given nab-paclitaxel, cisplatin, and fluorouracil with cetuximab ( APF-C) and historical controls given docetaxel, cisplatin, and fluorouracil with cetuximab ( TPF-C). Patients with locally advanced HNSCC were treated with APF-C ( n = 30) or TPF-C ( n = 38). After 3 cycles of IC, patients were scheduled to receive cisplatin concurrent with definitive radiotherapy. T and N classification and smoking history were similar between the two groups and within p16-positive and p16-negative subsets. The median duration of follow-up for living patients in the APF-C group was 43.5 (range: 30-58) months versus 52 (range: 13-84) months for TPF-C. The 2-year DSS for patients treated with APF-C was 96.7% [95% Confidence Interval ( CI): 85.2%, 99.8%] and with TPF-C was 77.6% ( CI: 62.6%, 89.7%) ( P = 0.0004). Disease progression that resulted in death was more frequent in the TPF-C group (39%) compared with the APF-C group (3%) when adjusted for competing risks of death from other causes (Gray's test, P = 0.0004). In p16 positive OPSCC, the 2-year DSS for APF-C was 100% and for TPF-C was 74.6% ( CI: 47.4%, 94.6%) ( P = 0.0019) and the 2-year OS for APF-C was 94.1% ( CI: 65.0%, 99.2%) and for TPF-C was 74.6% ( CI: 39.8%, 91.1%) ( P = 0.013). In p16 negative HNSCC, the 2-year DSS for APF-C was 91.7% ( CI: 67.6%, 99.6%) and for TPF-C was 82.6% ( CI: 64.4%, 94.8%) ( P = 0.092). A 2-year DSS and OS were significantly better with a nab-paclitaxel-based IC regimen ( APF-C) compared to a docetaxel-based IC regimen ( TPF-C) in p16-positive OPSCC. [ABSTRACT FROM AUTHOR]

Objectives/Hypothesis A new treatment for acute unilateral vocal-fold paralysis (UVFP) was proposed in which a drug is injected into the posterior cricoarytenoid muscle (PCA) shortly after nerve injury, before the degree of natural recovery is known, to prevent antagonistic synkinetic reinnervation. This concept was tested in a series of canine experiments using vincristine as the blocking agent. Study Design Animal experiments. Methods Laryngeal adductor function was measured at baseline and at 6 months following experimental recurrent laryngeal nerve (RLN) injuries, including complete transection, crush injury, and cautery. In the treatment animals, the PCA was injected with vincristine at the time of RLN injury. Results Adductor function in the vincristine-treated hemilarynges was significantly improved compared with injury-matched noninjected controls (total n = 43). Transection/repair controls recovered 56.1% of original adductor strength; vincristine-treated hemilarynges recovered to 73.1% ( P = 0.002). Cautery injuries also improved with vincristine block (60.7% vs. 88.7%; P = 0.031). Crush injuries recovered well even without vincristine (104.8% vs. 111.2%; P = 0.35). Conclusion These findings support a new paradigm of early, preemptive blockade of the antagonist muscle (PCA) to improve ultimate net adductor strength, which could potentially improve functional recovery in many UVFP patients and avoid the need for medialization procedures. Possible clinical aspects of this new approach are discussed. Level of Evidence N/A. Laryngoscope, 125:655-660, 2015 [ABSTRACT FROM AUTHOR]

Unilateral vocal-fold paralysis (UVP) occurs when one of the vocal folds becomes paralyzed due to damage to the recurrent laryngeal nerve (RLN). Individuals with UVP experience problems with speaking, swallowing, and breathing. Nearly two-thirds of all cases of UVP is associated with impaired function of the left RLN, which branches from the vagus nerve within the thoracic cavity and loops around the aorta before ascending to the larynx within the neck. We hypothesize that this path predisposes the left RLN to a supraphysiological, biomechanical environment, contributing to onset of UVP. Specifically, this research focuses on the identification of the contribution of the aorta to onset of left-sided UVP. Important to this goal is determining the relative influence of the material properties of the RLN and the aorta in controlling the biomechanical environment of the RLN. Finite element analysis was used to estimate the stress and strain imposed on the left RLN as a function of the material properties and loading conditions. The peak stress and strain in the RLN were quantified as a function of RLN and aortic material properties and aortic blood pressure using Spearman rank correlation coefficients. The material properties of the aortic arch showed the strongest correlation with peak stress [ρ = 0.63, 95% confidence interval (CI), -1.00 to -0.25] and strain (ρ = 0.62, 95% CI, -0.99 to -0.24) in the RLN. Our results suggest an important role for the aorta in controlling the biomechanical environment of the RLN and potentially in the onset of left-sided UVP that is idiopathic. [ABSTRACT FROM AUTHOR]

Objectives/Hypothesis Most patients with unilateral vocal fold paralysis experience some degree of spontaneous reinnervation, which depends upon the type and severity of recurrent laryngeal nerve (RLN) injury. After partial recovery, the paretic vocal fold may or may not adduct adequately to allow glottic closure, which in turn affects phonatory and swallowing outcomes. This process was studied in a series of canine laryngeal nerve injury models. Study Design Animal (canine) experiments. Methods Maximum stimulable laryngeal adductor pressure (LAP) was measured pretreatment (baseline) and at 6 months following experimental RLN injuries (total n = 59). The nine study groups were designed to simulate a range of severities of RLN injury. Results The greatest LAP recovery, at 108% of original baseline, was seen in a 50% transection model; the least recovery was seen when the RLN underwent complete transection with repair, at 56% with precise alignment and 50% with alignment reversed. Intermediate models (partial RLN injuries) gave intermediate results. Crush models recovered 105% of LAP, whereas a half-transection, half-crush injury recovered 72%, and cautery injuries recovered 61%. Controls (complete transection without repair) had no measurable recovery. Conclusions The injured RLN has a strong tendency to recover. Restoration of adductor strength, as determined by the LAP, was predictably related to the severity of RLN injury. The model RLN injuries studied provide a range of expected outcomes that can be used for future experiments exploring interventions that may improve postinjury adductor function. Level of Evidence NA Laryngoscope, 125:E67-E72, 2015 [ABSTRACT FROM AUTHOR]

Background Hyperbaric oxygen (HBO) therapy is sometimes used to assist in wound healing after major head and neck cancer surgery. However, there is concern that HBO treatments might enhance the growth of any residual microscopic disease. This was studied in a mouse model of squamous cell carcinoma (SCC). Methods SCC-VII/SF tumor cells were cultured, and then injected (3 × 103 cells) into C3H/HeJ mice in 5 groups: subcutaneous (SQ) control ( n = 13), SQ-immediate ( n = 12), SQ-delayed ( n = 13), tail vein control ( n = 8), and tail vein immediate ( n = 9). The 3 experimental groups were subjected to HBO therapy, 2.4 atm for 90 minutes, 5 days per week for 4 weeks, starting on postinjection day 3 ('immediate') or 10 ('delayed'). Tumors in the SQ mice were measured 3 times per week. Lung metastases in the tail vein mice were counted at necropsy. Results At postimplantation day 28, when the immediate group completed its HBO therapy, the tumor volume in the SQ-immediate group was 49.1% higher than the control group, and the SQ-delayed group was 105.1% higher than controls ( p < .05). Two weeks later, the SQ-immediate group and SQ-delayed group tumor volumes were still significantly higher than controls, but the difference was smaller (18.4% and 43.8%, respectively; p < .05 only for the delayed group). The tail vein groups had similar numbers of lung metastases, with a mean of 8.7 metastases in the control group and 9.0 metastases in the HBO group (not significant [NS]). Conclusion This study suggests that HBO therapy does accelerate the growth of microscopic foci of SCCs. This finding differs from some earlier studies and warrants further study. © 2014 Wiley Periodicals, Inc. Head Neck 36: 1743-1746, 2013 [ABSTRACT FROM AUTHOR]

Objective: To determine the etiology, laterality, and time to presentation of unilateral vocal fold paralysis (UVFP) at a tertiary care institution over 10 years.Study Design: Case series with chart review.Setting: Academic medical center.Subjects and Methods: All patients seen between 2002 and 2012 by the Department of Otolaryngology at the Washington University School of Medicine (WUSM), with a diagnosis of unilateral vocal fold paralysis, were included. Medical records were reviewed for symptom onset date, presentation date(s), and etiology of UVFP.Results: Of the patients, 938 met inclusion criteria and were included. In total, 522 patients (55.6%) had UVFP due to surgery; 158 (16.8%) were associated with thyroid/parathyroid surgery, while 364 (38.8%) were due to nonthyroid surgery. Of the patients, 416 (44.4%) had nonsurgical etiologies, 124 (13.2%) had idiopathic UVFP, and 621 (66.2%) had left-sided UVFP. The diagnosis was more common on the left side in cases of intrathoracic surgeries and malignancies, as expected, but also in idiopathic, carotid endarterectomy, intubation, and skull base tumors. In total, 9.8% of patients presented first to an outside otolaryngologist at a median time of 2.1 months after onset, but these patients presented to WUSM at a median time of 9.5 months. Overall, 70.6% of patients presented to a WUSM otolaryngologist within 3 months of onset.Conclusion: Iatrogenic injury remains the most common cause of UVFP. Thyroidectomy remains the leading cause of surgery-related UVFP. Patients are typically seen within 3-4 months of onset; however, a significant delay exists for those referred to WUSM. [ABSTRACT FROM AUTHOR]

Noncompliance with federal regulations, as monitored through institutional review boards for the ethical conduct of clinical research, can occur, even to seasoned investigators. The cause of this noncompliance can be that an investigator is overloaded, does not know the regulations, or does not take the time to pay attention to the details. Sometimes it happens just because of inevitable human error that can befall us all at any time. The authors begin by citing the inherent differences between clinical practice and clinical research. This is followed by an illustration of common noncompliance errors, with examples, followed by general and specific concepts and methods to minimize noncompliance events. The objective of this article is to condense the myriad details involved in conducting clinical research into a set of manageable recommendations that can be recalled easily before and during the research. The material supporting these recommendations comes from years of institutional review board work at several institutions and consultation with experienced principal investigators and their research coordinators. [ABSTRACT FROM PUBLISHER]

Although coding variants in THAP1 have been causally associated with primary dystonia, the contribution of noncoding variants remains uncertain. Herein, we examine a previously identified Intron 1 variant (c.71+9C>A, rs200209986). Among 1672 subjects with mainly adult-onset primary dystonia, 12 harbored the variant in contrast to 1/1574 controls ( P < 0.01). Dystonia classification included cervical dystonia ( N = 3), laryngeal dystonia (adductor subtype, N = 3), jaw-opening oromandibular dystonia ( N = 1), blepharospasm ( N = 2), and unclassified ( N = 3). Age of dystonia onset ranged from 25 to 69 years (mean = 54 years). In comparison to controls with no identified THAP1 sequence variants, the c.71+9C>A variant was associated with an elevated ratio of Isoform 1 (NM_018105) to Isoform 2 (NM_199003) in leukocytes. In silico and minigene analyses indicated that c.71+9C>A alters THAP1 splicing. Lymphoblastoid cells harboring the c.71+9C>A variant showed extensive apoptosis with relatively fewer cells in the G2 phase of the cell cycle. Differentially expressed genes from lymphoblastoid cells revealed that the c.71+9C>A variant exerts effects on DNA synthesis, cell growth and proliferation, cell survival, and cytotoxicity. In aggregate, these data indicate that THAP1 c.71+9C>A is a risk factor for adult-onset primary dystonia. [ABSTRACT FROM AUTHOR]

“Comparative effectiveness research” (CER) is not a new concept; however, recently it has been popularized as a method to develop scientifically sound actionable data by which patients, physicians, payers, and policymakers may make informed health care decisions. Fundamental to CER is that the comparative data are derived from large diverse populations of patients assembled from point-of-care general primary care practices and that measured outcomes include patient value judgments. The challenge is to obtain scientifically valid data to be acted upon by decision-making stakeholders with potentially quite diversely different agenda. The process requires very thoughtful research designs modulated by complex statistical and analytic methods. This article is composed of a guiding narrative with an extensive set of tables outlining many of the details required in performing and understanding CER. It ends with short discussions of three example papers, limitations of the method, and how a practicing physician may view such reports. [ABSTRACT FROM PUBLISHER]