Prospective >12 Months Outcomes After Vocal Fold Injection Medialization With Silk Microparticle-Hyaluronic Acid Material.

OBJECTIVE: Vocal fold injection medialization (VFIM) is widely used as an initial treatment for unilateral vocal fold paralysis (UVFP). Current practices employ materials that share the limitation of temporary clinical effect from variable resorption rates. A novel silk protein microparticle-hyaluronic acid-based material (silk-HA) has demonstrated cellular infiltration and tissue deposition that may portend a durable medialization effect. We report on ≥12 months outcomes after VFIM with silk-HA. METHODS: Prospective open-label study of patients with UVFP that elected treatment with VFIM with silk-HA. Blinded experts rated laryngeal stroboscopic exams. RESULTS: Seventeen patients with UVFP underwent VFIM with silk-HA. Twelve of the 17 patients have ≥12 months follow-up. Seven patients demonstrated durable treatment benefit ≥12 months after injection with median improvement of 19 (p = 0.0156) in VHI-10. There was no significant change in VHI-10 between 1 and 12 months for these patients. Blinded ratings indicated that 5/7 patients with sustained improvements in VHI-10 exhibited complete or touch glottal closure at 12 months. Two of the seven patients exhibited a small (<1 mm) glottal gap at 12 months. Seven patients experienced initial benefit with later regression 3-4 months after injection. CONCLUSION: VFIM with silk-HA can offer durable improvement in voice-related outcomes for UVFP past 12 months. A subset of patients treated with silk-HA experienced early loss of effect around 3-4 months postinjection. Clinical factors predictive of sustained treatment response to silk-HA injection require further exploration. LEVEL OF EVIDENCE: 3 Laryngoscope, 2023.

Flexible Versus Rigid Laryngoscopy: A Prospective, Blinded Comparison of Image Quality.

OBJECTIVE: To compare flexible distal-chip laryngoscopy (FDL) and rigid telescopic laryngoscopy (RTL) in image quality and diagnostic ability. STUDY DESIGN: Prospective cohort study; blinded comparison. METHODS: Eighteen normal adult subjects were recruited to undergo both FDL and RTL and normalized videos were recorded. Three blinded laryngologists compared the videos for color fidelity, illumination, resolution, and vascularity, and indicated superiority with FDL, RTL, or no difference. Raters also reported if an abnormality was seen and in which video it was better visualized. Videos for two subjects were repeated to assess intra-rater reliability, making 20 video comparisons across 3 raters for a total of 60 ratings. Differences in responses were analyzed via Mann-Whitney U and Pearson Χ2. Inter-rater reliability was assessed via Fleiss' kappa, and intra-rater reliability was assessed via percent agreement. RESULTS: RTL was rated superior in all categories of image quality (47 vs 5 vs 8, P < 0.01; 47 vs 7 vs 6, P < 0.01; 51 vs 5 vs 4, P<0.01; 44 vs 9 vs 7, P < 0.01, respectively). An abnormality was seen 33 times with both modalities and 6 times with RTL only. When seen with both modalities, visualization was superior in RTL compared with FDL (29 vs 4, P <0.01). CONCLUSIONS: There was significant superiority of RTL in all categories of image quality, with slight inter-rater agreement for color fidelity, resolution, and vascularity. RTL was also significantly better for visualization of abnormalities. These findings suggest superior image quality in RTL compared with FDL, but further research is required to determine if this difference is clinically significant.

Systemic Bevacizumab for Treatment of Respiratory Papillomatosis: International Consensus Statement.

OBJECTIVES/HYPOTHESIS: The purpose of this study is to develop consensus on key points that would support the use of systemic bevacizumab for the treatment of recurrent respiratory papillomatosis (RRP), and to provide preliminary guidance surrounding the use of this treatment modality. STUDY DESIGN: Delphi method-based survey series. METHODS: A multidisciplinary, multi-institutional panel of physicians with experience using systemic bevacizumab for the treatment of RRP was established. The Delphi method was used to identify and obtain consensus on characteristics associated with systemic bevacizumab use across five domains: 1) patient characteristics; 2) disease characteristics; 3) treating center characteristics; 4) prior treatment characteristics; and 5) prior work-up. RESULTS: The international panel was composed of 70 experts from 12 countries, representing pediatric and adult otolaryngology, hematology/oncology, infectious diseases, pediatric surgery, family medicine, and epidemiology. A total of 189 items were identified, of which consensus was achieved on Patient Characteristics (9), Disease Characteristics (10), Treatment Center Characteristics (22), and Prior Workup Characteristics (18). CONCLUSION: This consensus statement provides a useful starting point for clinicians and centers hoping to offer systemic bevacizumab for RRP and may serve as a framework to assess the components of practices and centers currently using this therapy. We hope to provide a strategy to offer the treatment and also to provide a springboard for bevacizumab's use in combination with other RRP treatment protocols. Standardized delivery systems may facilitate research efforts and provide dosing regimens to help shape best-practice applications of systemic bevacizumab for patients with early-onset or less-severe disease phenotypes. LEVEL OF EVIDENCE: 5 Laryngoscope, 131:E1941-E1949, 2021.

High-throughput screening identifies candidate drugs for the treatment of recurrent respiratory papillomatosis.

Recurrent respiratory papillomatosis (RRP) is a benign neoplasm of the larynx caused mainly by human papillomavirus type 6 or 11 and its standard treatment involves repeated surgical debulking of the laryngeal tumors. However, significant morbidity and occasional mortality due to multiple recurrences occur. Conditional reprogramming (CR) was used to establish a HPV-6 positive culture from an RRP patient, named GUMC-403. High-throughput screening was performed at the National Center for Advanced Technology (NCATS) to identify potential drugs to treat this rare but morbid disease. GUMC-403 cells were screened against the NPC library of >2800 approved drugs and the MIPE library of >1900 investigational drugs to identify new uses for FDA-approved drugs or drugs that have undergone significant research and development. From the two libraries, we identified a total of 13 drugs that induced significant cytotoxicity in RRP cells at IC50 values that were clinically achievable. We validated the efficacy of the drugs in vitro using CR 2D and 3D models and further refined our list of drugs to panobinostat, dinaciclib and forskolin as potential therapies for RRP patients.

Clinical Activity of Nivolumab for Human Papilloma Virus-Related Juvenile-Onset Recurrent Respiratory Papillomatosis.

BACKGROUND: Juvenile-onset recurrent respiratory papillomatosis (JO-RRP) is a human papilloma virus-mediated progressive benign neoplasm that affects children and young adults. Primary management consists of regular surgical debulking to maintain airway patency and vocal function. Like condyloma acuminata, JO-RRP is associated with immune dysregulation, and T cells isolated from papillomas express an anergic phenotype. Therefore, we hypothesized that programmed death protein 1 axis inhibition could stabilize tumor growth. MATERIALS AND METHODS: We treated two patients with refractory JO-RRP using nivolumab, with the primary objective of assessing clinical activity. We explored baseline papilloma features using immunohistochemistry and comprehensive genomic profiling. RESULTS: Both patients experienced symptomatic improvement, and interval laryngoscopies revealed a reduction in papillomatosis burden. One patient has not required subsequent surgical debridement for almost 2 years. On pathologic examination of pretreatment papillomas from both cases, infiltrating T cells were evident in the papilloma stroma, and papilloma programmed death ligand 1 expression was absent. Papilloma mutational load ranged between three and six mutations per megabase for each case. From on-treatment biopsy tissue, a higher amount of intraepithelial T cells and programmed death ligand 1 expression were detected in the papilloma. CONCLUSION: Nivolumab appears to have promising activity in JO-RRP, and further clinical investigation with more patients in clinical trials is warranted. IMPLICATIONS FOR PRACTICE: To the authors' knowledge, this article is the first report describing clinical activity with a programed cell death-1 (PD-1) inhibitor to treat a rare but detrimental type of respiratory tract epithelial neoplasm that afflicts young adults. Two patients were treated, and tumor features, such as mutational load, were examined with the intent to stimulate future hypotheses for translational research. The safety and activity of PD-1 inhibitors in this population still need to be corroborated in clinical trials and should not yet be adopted into clinical practice.

Voice Changes in the Elderly.

The impact of aging is as inevitable in the larynx as on all biologic systems. The muscles of larynx have the potential to atrophy, the elastin fibers of lamina propria thin with age, and mucous production diminishes. As a result, vocal folds fail to approximate appropriately and the stress on once-robust vocal folds increases. These changes present as poor voice quality, vocal tension, tremor, and altered fundamental frequency. Rather than consider presbyphonia as an immutable diagnosis, we must see it as an opportunity to elevate our standard of care and set goals to work for therapeutic improvement of voice quality.

Positron-emission tomography enhancement after vocal fold injection medialization.

The potential for the misinterpretation of positron-emission tomography (PET) scans in the context of a possible malignancy has been confirmed in a case report showing increased 18F-fluorodeoxyglucose (FDG) uptake after unilateral vocal fold augmentation medialization. We sought to expand these findings by investigating FDG uptake in a larger cohort of patients via a retrospective chart review. We examined the records of 15 adults-8 men and 7 women-who had undergone vocal fold augmentation for unilateral vocal fold paralysis and at least one subsequent PET scan. The differences in PET standard uptake value (SUV) between the injected and noninjected vocal folds were assessed via the Wilcoxon signed-rank test. A Spearman rank correlation coefficient was then used to estimate the relationship between differences in PET uptake and the length of time between the injection and the follow-up PET scan. The mean SUV of the injected vocal folds was 3.70, and the mean in the noninjected folds was 2.97. The difference did not achieve statistical significance (p = 0.34). In addition, the rank correlation coefficient with regard to the association between the difference in PET uptake and the duration between injection and PET was -0.24, suggesting an inverse relationship. However, the correlation coefficient did not differ significantly from zero (p = 0.34). We conclude that PET uptake after vocal fold augmentation medialization is variable and that it can increase substantially. This information should be considered in the context of the diagnostic accuracy of malignancy on PET.

Low-cost modular phonosurgery training station: development and validation.

OBJECTIVE: Phonosurgery requires technical precision and careful tissue handling. Typically, phonosurgical procedures require single-operator techniques, making it difficult for novice residents to develop necessary skills. We developed a low-cost phonosurgery simulator to allow practice and acquisition of microlaryngeal skills. STUDY DESIGN: Validation study assessing the simulator's face and content validity in surgical education. METHODS: For construction, the simulator is composed of a simulation station and laryngeal modules, each constructed with inexpensive, easily accessible materials including plywood and polyvinyl chloride pipe. Laryngeal modules were constructed using rubber bands, bacitracin, and plastic wrap to simulate layers of the true vocal fold. Three separate modules were developed to address specific skills: 1) basic instrumentation; 2) papilloma debulking; 3) subepithelial and epithelial lesion excision. Papillomas, subepithelial, and epithelial lesions were simulated with grapefruit, caulk, and suture, respectively. The Kantor-Berci video laryngoscope was used for visualization. For validation, face and content validity were assessed by attending otolaryngologists (n = 16), who performed the three specific skills using the simulation station and completed a 5-point Likert-type postsimulation questionnaire. RESULTS: Most participants (89%) strongly agreed that the simulator incorporates essential phonosurgery skills and that portions of the model simulated an actual case (content validity). All participants (100%) agreed that the simulator is an adequate training device to increase resident competency and would be interested in using it to train residents (face validity). CONCLUSION: This simulator has the potential to be an important component of phonosurgical education and preoperative preparation. Advantages include a realistic experience, modular design, and inexpensive construction. LEVEL OF EVIDENCE: N/A.

Use of reprogrammed cells to identify therapy for respiratory papillomatosis.

A patient with a 20-year history of recurrent respiratory papillomatosis had progressive, bilateral tumor invasion of the lung parenchyma. We used conditional reprogramming to generate cell cultures from the patient's normal and tumorous lung tissue. Analysis revealed that the laryngeal tumor cells contained a wild-type 7.9-kb human papillomavirus virus type 11 (HPV-11) genome, whereas the pulmonary tumor cells contained a 10.4-kb genome. The increased size of the latter viral genome was due to duplication of the promoter and oncogene regions. Chemosensitivity testing identified vorinostat as a potential therapeutic agent. At 3 months after treatment initiation, tumor sizes had stabilized, with durable effects at 15 months.

Hypopharyngeal diverticulum formation following anterior discectomy and fusion: case series.

Pharyngoesophageal diverticulum is a rare complication following anterior cervical discectomy and fusion (ACDF). Dysphagia is a well-documented complication associated with ACDF. It may result postoperatively from a variety of etiologies, including hardware displacement, pharyngeal edema, or vocal fold paresis. One rare cause of persistent dysphagia is the formation of a hypopharyngeal diverticulum, reported in the literature in 9 previous cases. Such diverticula after ACDF surgery may have pathogenesis that is distinct from that of typical Zenker diverticula. We report 3 new cases of hypopharyngeal diverticula in patients who underwent revision ACDFs. Variables assessed included age, sex, level of fusion, ACDF-related complications, and diverticulum management. Two patients underwent successful open surgical diverticulectomy and cricopharyngeal myotomy. In the third case, the patient had a small diverticulum close to the surgical hardware and minimal symptoms and was managed conservatively. Our cases, combined with the 9 previous cases, demonstrate commonalities, particularly with regard to the risk of revision spinal surgery and infection and subsequent hypopharyngeal diverticula development. Hypopharyngeal diverticulum can occur as a complication of ACDF and should be considered in patients with persistent dysphagia after surgery. In this patient population, open resection and cricopharyngeal myotomy are recommended.

Segmental hemangiomas of the upper airway.

OBJECTIVES/HYPOTHESIS: To characterize the anatomic distribution of segmental hemangiomas of the larynx and to describe indications for treatment modalities. STUDY DESIGN: Retrospective chart review. METHODS: We performed a retrospective chart review of patients with cutaneous hemangiomas at a tertiary care center over a 4-year period. Only patients with upper airway hemangiomas were studied. We reviewed the anatomic distribution of hemangiomas within the upper airway and the treatment course of each patient. RESULTS: Of 1,226 patients with cutaneous hemangiomas, 108 (9%) were segmental in distribution. There were 56 patients (52%) who had a V3 distribution pattern, and 16 patients (29%) with upper airway involvement. All of these patients had associated V3 or mandibular segmental hemangiomas. As with the cutaneous manifestation, the distribution of hemangioma within the upper airway was segmental. This included the following anatomic sites: oral cavity, oropharynx, hypopharynx, intrinsic structures of the larynx, and subglottis. Many of these patients had diffuse mucosal involvement, including tracheal involvement. A total of 13 out of 16 patients underwent medical intervention, and seven also required surgical intervention. Medical management included systemic (12 patients) and intralesional (two patients) steroids. One patient received chemotherapy prior to referral. Surgical treatment included tracheostomy (four patients prior to referral) and laser ablation of subglottic involvement (total of four patients). CONCLUSIONS: A high percentage of patients with V3 cutaneous hemangiomas (29%) will manifest with upper airway involvement, the distribution of which is segmental. Treatment should take this diffuse pattern of involvement into consideration.

Clinical experience with angiotensin-converting enzyme inhibitor-induced angioedema.

OBJECTIVES: To understand the presentation and clinical course of angiotensin-converting enzyme (ACE) inhibitor-induced angioedema and to determine management factors associated with progression to airway compromise. STUDY DESIGN AND SETTING: Retrospective chart review of patients taking ACE inhibitors who presented to the emergency department with angioedema between December 1999 and July 2004 (n = 228). Clinical presentation, treatment, and clinical course were analyzed. RESULTS: The oral cavity was the most common location of upper-airway angioedema. Twenty-two (10%) patients required intubation, and all were intubated within 12 hours of presentation. Of the patients who required intubation, those who were started on an H(1)-blocker were extubated earlier than those not on an H(1)-blocker (P = 0.05). CONCLUSION: The locations of swelling and drooling on admission are predictive of the need for intubation. Other aspects of presentation, treatment, and disposition can help in management decisions for this potentially fatal condition. SIGNIFICANCE: This is the largest series to date of ACE inhibitor-related angioedema that challenges theories on the etiology and treatment of this condition.

Management of the post-tracheostomy scar.

Tracheostomy scar management is aimed at filling lost deep tissue bulk, the correction of tracheal skin tug, and a tension-free closure that falls more naturally into the neck folds. Three cases are used to illustrate the major principles involved in the correction of tracheostomy scars. Those reconstructive principles are 1) re-approximation of individual layers of the neck for improved contour and release of tracheal skin tug, 2) filling of tissue deficit, using scar de-epithelialization, muscle flaps, or acellular dermal grafts, 3) excision of hypertrophic scarring or keloids, and 4) horizontal wound closure using simple closure or local skin flaps such as z-plasty. The goals and techniques outlined can resolve skin adherence to the trachea and can improve scar appearance in this noticeable location.