Metformin for the Treatment of Recurrent Respiratory Papillomatosis.

OBJECTIVES: Metformin is an oral agent used for the management of type 2 diabetes. As a result of its ability to alter cellular metabolic requirements, metformin also possesses antiproliferative properties. Metformin has been shown to reduce mutagenesis in several malignancies, however has never been described as a treatment option for recurrent respiratory papillomatosis (RRP). The aim of this study is to present a case series of non-diabetic patients with adult-onset RRP who were treated with metformin. METHODS: Case series. RESULTS: Five patients (age 48 ± 17.82, range 35-68, 4 males, 1 female) were identified with a history of laryngeal RRP who were treated with 500 mg of metformin twice daily. Follow-up time ranged from 11 to 105 months. Two patients had spontaneous regression of RRP lesions within months of starting metformin. Four patients had reduced time intervals between surgical procedures after starting metformin. All patients tolerated metformin well with only minor side effects of self-limiting light-headedness, facial flushing or gastrointestinal upset. CONCLUSION: Metformin is a low-risk medication that was used to reduce progression and burden of disease in 5 patients with RRP. Further studies should investigate the sole or adjunct use of metformin for treatment of RRP.

Association of Laryngeal Botulinum Neurotoxin Injection With Work Productivity for Patients With Spasmodic Dysphonia.

Importance: A disordered voice can affect an individual across both work and non-work-related life domains. There is insufficient research on the effect of spasmodic dysphonia or its treatment with botulinum neurotoxin (BoNT) injections on work productivity. Objective: To assess whether employed patients with spasmodic dysphonia experience voice-related work productivity impairment before BoNT injection, and had a 10% or greater improvement in productivity 1 month after treatment with BoNT injection. Design, Setting, and Particpants: This prospective case series carried out in 2 laryngology outpatient clinics from November 1, 2015, to August 30, 2018 included a consecutive sample of adult employed patients diagnosed with spasmodic dysphonia. Analysis was conducted between November 1, 2015, to July 31, 2018. Exposures: Treatment with BoNT injection into the intrinsic laryngeal musculature. Main Outcomes and Measures: Eligible participants completed the following validated outcomes instruments immediately before and 1 month after outpatient laryngeal BoNT injection: the Work Productivity and Activity Impairment instrument (WPAI), Voice Handicap Index (VHI), and WorkHoarse. Demographic, comorbidity, and occupational voice use data were also collected at baseline. The changes in outcome measures (primary, WPAI Work Productivity Impairment domain) were tested using a paired 2-tailed t test. Exploratory subgroup analyses were analyzed with multivariable linear regression, adjusting for demographic, comorbidity, and voice use variables. Results: Of the 101 patients enrolled, 75 completed the study. The mean (SD) age of the 75 completing participants was 55.7 (11.8) years and 53 (71%) were women. The participants who completed the study had mean (SD) voice-related work productivity impairment of 43% (27%) at baseline and 22% (23%) at 1 month after BoNT injection (difference, 20% [27%] improvement; 95% CI, 14%-27%; effect size, 0.74). Conclusions and Relevance: This case series study found that employed patients with spasmodic dysphonia reported voice-related work productivity impairment, which improved significantly 1 month after treatment with BoNT injection. The association of spasmodic dysphonia with voice-related work productivity appeared greater in women than men with comparable outcomes with BoNT treatment, but this exploratory sex-associated difference requires independent validation.

Safety and Feasibility of a Novel Esophageal Balloon for Circumferential Cytologic Sampling.

OBJECTIVES: A prior publication introduced the Strome-Blitzer balloon's ability to obtain circumferential esophageal cytologic sampling. This GLP study was requisite for FDA approval to determine if equivalent cell capture and cellularity was observed with the balloon compared to surface sampling brushes and to determine the balloon's usability for naive otolaryngologists. METHODS: Three naïve users tested the Hobbs brush and Strome-Blitzer balloon on 4 Yorkshire swine. Four anatomical sites were sampled, beginning distally and ending proximally. In 2 animals, the balloon was used first distally and in the remaining 2, 4 new Hobbs brushes were used distally first. Moving proximally, the balloon and brushes were sequentially alternated. In follow-the-leader fashion, the balloon was introduced trans-orally followed by an endoscope to the desired site. The balloon was inflated exposing the abrasive strips to contact the esophageal mucosa. Moving the balloon 1 to 2 cm superiorly and inferiorly effected circumferential cell capture. The balloon was collapsed and removed, preserving the cellularity. The Hobbs brush was passed through the scope's channel. Four brushes, 1 per quadrant, obtained the samples at an anatomical site. The balloon was rated as pass/fail on the following: delivery, kinking, usability, and malfunction. A blinded veterinary pathologist evaluated the cytology. RESULTS: There was no device malfunction, mucosal trauma, or difficulty with device use. Balloon cytologic samples were comparable in cellularity and quality to the brush. CONCLUSION: A single balloon sampling was comparable to 4 brushes in capturing diagnostically relevant cellular volumes and architecture. Naïve users easily performed the procedures after reading the guidelines. LEVEL OF EVIDENCE: 3.

Dacryocystorhinostomy with a thulium:YAG laser-a case series.

We conducted a retrospective chart review of 27 patients-7 men and 20 women, aged 47 to 94 years (mean: 71.3)-with symptomatic epiphora secondary to dacryostenosis who had undergone thulium: YAG (Tm:YAG) laser dacryocystorhinostomy (DCR). Among them, dacryostenosis had been documented in 35 eyes by dacryocystography. The Tm:YAG procedure involved the administration of local anesthesia, after which a 600-µm laser fiber was inserted into the lacrimal canaliculi and then into the nasolacrimal duct. Under endoscopic visualization, the DCR was performed anterior and inferior to the middle turbinate, which created an opening. Silicone stents were then inserted and tied intranasally. In the immediate postoperative period, all 27 patients noted initial improvement. During a follow-up of 22 days to 25 months (mean: 11.3 mo), 24 of the 27 patients (89%) remained symptom-free, while the remaining 3 patients (11%) experienced a treatment failure and required revision surgery. To the best of our knowledge, only two articles on thulium laser therapy for DCR have been previously published, both approximately 25 years ago; both involved the use of a thulium along with holmium and chromium in cadavers. As far as we know, our case series is the largest in the English-language literature that has documented the use of the thulium in laser therapy for DCR, and it is the only in vivo study. We found that DCR with the Tm:YAG laser was an effective and affordable option for patients with symptomatic epiphora secondary to lacrimal obstruction.

Steering Sheath for 2-Nostril Transnasal Office Laryngoscopy.

OBJECTIVE: The aim was to study the feasibility of performing office-based laryngeal procedures employing a flexible hollow steerable sheath placed contralateral to the nostril through which a standard flexible video endoscope is placed. METHODS: The study design included simulation of transnasal endoscopic laryngeal procedures evaluating the use of a flexible steering sheath in laboratory and clinic settings. Transnasal laryngeal procedures were performed in an otolaryngology office setting employing an airway-management-trainer mannequin and then repeated in a human cadaver lab with standard transnasal flexible video laryngoscopy. Video documentation assessed use of a lever-manipulated deflecting ureteral access sheath with an inner diameter of 2.97 mm, an outer diameter of 4.95 mm, and a length of 45 cm. Simulated transnasal laryngoscopy procedures deployed devices through the deflecting sheath to mimic vocal fold needle injection, biopsy with forceps, balloon dilation, and laser treatment to identify strengths and shortcomings to the technology and technique. RESULTS: Simulation was successful in appropriately directing instrumentation for all procedures tested. Shortcomings included limitations in steering capacity, greater length to the sheath than desirable for laryngeal procedures, and the need for additional assistants to perform procedures. CONCLUSION: Steering sheath technology is applicable to enhance in-office transnasal laryngoscopy procedures.

Metformin Prevents the Progression of Dysplastic Mucosa of the Head and Neck to Carcinoma in Nondiabetic Patients.

OBJECTIVE: Metformin is an oral anti-hyperglycemic agent used to treat type 2 diabetes mellitus (DM). In vitro and animal models have shown that metformin can prevent the progression of oral lesions to carcinoma; however, there is conflicting data in the clinical literature regarding risk reduction for malignancy in head and neck cancer (HNC). STUDY DESIGN: Case series. METHODS: We present 3 cases in which adjuvant metformin therapy was used to treat recurrent and multifocal dysplastic lesions in previously treated nondiabetic HNC patients. RESULTS: Patients included 1 with a history of oral cavity squamous cell carcinoma (SCC) and 2 with a history of laryngeal SCC. Follow-up time ranged between 3 and 33 months. All 3 patients showed complete or partial regression of the remaining mucosal lesions and did not require any additional surgeries. CONCLUSION: We present 3 cases of nondiabetic HNC patients with field cancerization who showed a good response to adjuvant therapy with metformin. The nondiabetic population is not affected by confounding factors such as increased risk of malignancy and decreased overall survival that is itself associated with abnormal glucose metabolism and is therefore an excellent cohort in which to study the use of adjuvant metformin therapy in HNC patients.

Directed balloon cytology of the esophagus: A novel device for obtaining circumferential cytologic sampling.

OBJECTIVE: Current methods of obtaining esophageal cytology include brush biopsy and blind balloon sampling, among others. These methods can be time-consuming if performed in accordance with acknowledged standards. Further, exact site localization can prove to be difficult. We describe a novel device for esophageal sampling using an esophageal balloon with debriding strips contained within the pleats of the balloon. Inflation brings the latter in contact with the surface to be sampled. Cell capture was compared with the commonly used brush technique in a pig model. METHODS: Separate balloon and standard brush cytology samples were collected from a pig model. Smear and cell pellet preparations were compared regarding cell density and total volume. RESULTS: Adequate samples were obtained with both the brush and balloon. On the cell smear preparations, the cell density was greater when obtained with balloon sampling. Further, the cell pellet volume was significantly greater with the latter as well. The intact morphology of individual rafts of squamous epithelial cells also was comparable between the two methods. In addition, the balloon provided precise mapping of the cytology sites in contrast to the standard brush technique. CONCLUSION: We present an innovative new balloon technology for esophageal sampling, which demonstrated a decreased sampling time interval, precise mapping, and increased cellular volume when compared to a commonly used brush technique. LEVEL OF EVIDENCE: NA. Laryngoscope, 127:1032-1035, 2017.

Botulinum Toxin in Secondarily Nonresponsive Patients with Spasmodic Dysphonia.

Chemodenervation with botulinum toxin (BoNT) has been effective and well tolerated for all types of dystonia for >30 years. We reviewed outcomes of our patients treated with BoNT serotype A (BoNT-A) for spasmodic dysphonia (SD) who became secondarily nonresponsive. We found that 8 of 1400 patients became nonresponsive to BoNT-A (0.57%), which is lower than the secondary nonresponse rate in other dystonias. After a cessation period, 4 of our patients resumed BoNT-A injections, and recurrence of immunoresistance was not seen in any of them. When compared with patients with other dystonias, patients with SD receive extremely low doses of BoNT. Small antigen challenge may explain the lower rate of immunoresistance and long-lasting efficacy after BoNT-A is restarted among secondary nonresponsive patients with SD.

Functional Anatomy and Oncologic Barriers of the Larynx.

Laryngeal barriers to tumor spread are a product of laryngeal development, anatomic barriers, and enzymatic activity. Supraglottic and glottic/subglottic development is distinct and partially explains the metastatic behavior of laryngeal carcinoma. Dense connective tissues and elastic fibers provide anatomic barriers within the larynx. Laryngeal cartilage contains dense cartilage, enzyme inhibitors, and an intact perichondrium making it relatively resistant to tumor invasion; however, focal areas of vulnerability are created by ossified cartilage and natural interruptions in the perichondrium. Local inflammation and the enzymatic interplay between tumor and host are important factors in the spread of laryngeal tumor.

Multilevel airway stenosis in patients with granulomatosis with polyangiitis (Wegener's).

OBJECTIVES: To describe the presentation and clinical course of subglottic stenosis (SGS), in particular the development of concurrent airway lesions, in patients with Granulomatosis with Polyangiitis (Wegener's) (GPA). MATERIALS AND METHODS: Retrospective review of clinical data from all patients presenting to our institution from 2000 to 2012 with SGS and GPA. RESULTS: Thirty-five patients were identified. The average age at diagnosis was 33 years old. Eleven patients (31%) presented with SGS as part their initial manifestation of GPA. The remaining patients developed SGS later, at a median of 2.5 years from diagnosis (range 6 months to 14 years). Twelve patients (34%) were noted to have multilevel airway involvement. Seven patients (20%) had documentation of cricoarytenoid joint fixation and vocal cord immobility. This was typically progressive in nature and occurred at an average of two years following the diagnosis of SGS. Six patients (17%) had mid/distal tracheal stenosis and four (11%) had bronchial stenosis. The majority of patients (86%) had evidence of concurrent sinonasal involvement, ten patients (29%) had evidence of otologic involvement and eight (23%) had ocular involvement. CONCLUSIONS: Cricoarytenoid joint fixation and distal stenosis occur not infrequently in patients with GPA and SGS, resulting in progressive multilevel airway stenosis in about one third of patients. It is critical to identify multilevel stenosis when managing the airways of these patients.

The effect of different angiolytic lasers on resolution of subepithelial mucosal hematoma in an animal model.

OBJECTIVE: Vocal fold hematoma is traditionally managed with a period of voice rest, in the order of weeks, to allow natural resolution. This study is designed to examine the efficacy and safety of a number of hemoglobin-avid (vascular) lasers when used in the setting of acute vocal fold hematoma. METHODS: Venous blood drawn from 4 white rabbits was used to create an array of subepithelial hematomas in the buccal cavities of each animal. Laser energy from I of 3 different lasers (532-nm pulsed potassium titanyl phosphate [KTP], 532-nm diode KTP, and 940-nm diode laser) was applied to each of the test hematomas at varying energy levels. Hematoma sites were photographed at days 0, 1, 5, 7, 9, and 12. Two animals were sacrificed on day 7 and the remainder on day 12. Histological evaluation of collateral tissue damage and residual hematoma was performed on biopsy specimens. RESULTS: Macroscopic and microscopic ulceration at laser-treated sites was mostly resolved by day 7. Inflammatory cell infiltrate was present in laser-treated and hematoma-only sites. Laser-treated samples showed alterations in vascularity. CONCLUSION: Hemoglobin-avid lasers may be beneficial in accelerating subepithelial hematoma resolution with a favorable tissue damage profile.

Hoarseness evaluation: a transatlantic survey of laryngeal experts.

OBJECTIVES/HYPOTHESIS: Hoarseness is a symptom of laryngeal dysfunction, without an existing consensus regarding its appropriate evaluation. A survey of laryngeal specialists is proposed to establish expert opinion on the methodology for evaluation of hoarseness, and to identify divergence of opinion regarding appropriate management. STUDY DESIGN: Cross-sectional survey. METHODS: A 13-item questionnaire was submitted electronically to the membership of the American Laryngological Association, the American Broncho-Esophagological Association, and the European Laryngological Society. Responses were collated anonymously and subjected to cross-tabulated data analysis. RESULTS: A total of 195 responses were included for review. The majority of respondents identified themselves as laryngologists/phoniatricians (54.9%). Two-thirds (64.1%) of the providers dedicated more than 25% of their practice to voice management, and 48.8% managed more than 10 dysphonic patients weekly. Most respondents defined hoarseness and dysphonia as symptoms and not diseases. The panel recommended a mandated time to laryngoscopy of 1 week to 1 month from the onset of symptoms for most acutely dysphonic patients, regardless of risk factors for malignancy, while it was not advised to defer laryngoscopy beyond 2 months of symptom persistence in any situation. A majority (96.2%) felt that an otolaryngologist ought to perform the initial laryngoscopy of a newly hoarse patient. CONCLUSION: This survey demonstrates an agreement to expedite specialized laryngeal visualization for cases of hoarseness not subsiding within 1 month, and exemplifies controversies stemming from a recently published clinical practice guideline. Ongoing research and practice evaluation will contribute to set forth improved standards of care and to appropriately counsel dysphonic patients.

Development and validation of a new clinically-meaningful rating scale for measuring lateral canthal line severity.

BACKGROUND: Several scales have been employed for evaluating the effects of cosmetic treatments in the periorbital area. The Food and Drug Administration (FDA) has recently issued new recommendations specifying a rigorous process to validate new aesthetic scales. OBJECTIVES: The authors describe and validate a new clinical rating scale: the Investigator's Global Assessment of Lateral Canthal Line (IGA-LCL) severity scale. METHODS: The new FDA recommendations were utilized to validate the new scale. The first step was concept elicitation (based on direct input from clinicians, patients, and literature) and evaluation of content validity (appropriateness of concepts). The resulting five-point scale provided detailed descriptions of the lateral canthal lines (LCL), including quantitative assessment of LCL length and depth. Performance parameters, including intra- and interrater reproducibility and construct validity, were then evaluated in clinical studies. Finally, the scale's threshold for clinically-meaningful benefit and the ability of the scale to detect change were confirmed in two Phase 2b clinical studies involving a total of 270 subjects. RESULTS: Content validity was established and the IGA-LCL scale showed excellent interrater reliability (weighted Kappa = 0.89) and interrater reliability (weighted Kappa = 0.77; Kendall's coefficient of concordance = 0.89). In clinical trials, the scale was sensitive enough to detect clinically-meaningful one- and two-point changes in LCL severity following treatment with topical botulinum toxin type A (BoNT-A). The authors observed statistically-significant correlations between the physician-rated IGA-LCL results and patient-reported outcomes. CONCLUSIONS: The IGA-LCL scale was shown to be reliable, appropriate, and clinically meaningful for measuring LCL severity.

Results of a randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of a botulinum toxin type A topical gel for the treatment of moderate-to-severe lateral canthal lines.

BACKGROUND: Injections of botulinum toxin type A are commonly used to treat facial wrinkles; however, undesirable effects are associated with injections (e.g., pain, bruising, ptosis, immunogenicity, and needle aversion). To address these issues, RT001 Botulinum Toxin Type A Topical Gel is being developed for the treatment of lateral canthal lines. OBJECTIVES: To assess the safety and efficacy of RT001 for the treatment of lateral canthal lines in a randomized, double-blind, placebo-controlled study. MATERIALS & METHODS: Adult subjects were enrolled to receive a single treatment of RT001 (n=45) or placebo (n=45) applied topically in the lateral canthal area. The primary endpoint was the composite of the Investigator Global Assessment of Lateral Canthal Line Severity (IGA-LCL) and the Patient Severity Assessment of lateral canthal line severity (PSA) defined as a 2-point or greater improvement on both scales. RESULTS: At four weeks, 44.4 percent of subjects treated with RT001 achieved a 2-point or greater improvement on a rigorous composite of both the IGA-LCL and PSA scales compared to 0.0% for the placebo subjects (P<0.0001). At four weeks, 88.9 percent of subjects achieved clinically relevant improvement by investigator assessment. Adverse events were mild in severity and unrelated to study treatment. CONCLUSIONS: RT001 appears to be a safe and well-tolerated treatment for improvement of lateral canthal lines.

Topical Application of Green Tea Polyphenol (-)-Epigallocatechin-3-gallate (EGCG) for Prevention of Recurrent Oral Neoplastic Lesions.

OBJECTIVE: A preliminary study was conducted to investigate feasibility of using an oral cancer chemopreventive agent (-)-epigallocatechin-3-gallate (EGCG), the most biologically active component in the green tea extract, in a form of 'swish-and-spit' mouthwash. Such application of EGCG is beneficial as it maximizes exposure of the oral mucosa to the agent but minimizes systemic side effect. STUDY DESIGN: The study was conducted on individuals suspected to have oral field cancerization who are at a high risk for developing recurrent oral precancerous and carcinomatous lesions. EGCG was used as a daily mouthwash for 7 days. EGCG's ability to modulate target molecules implicated in oral carcinogenesis was assessed by measuring the change in expression level of biomarkers. RESULTS: Immunohistochemical expression of phosphoactivated epidermal growth factor receptor (pEGFR), cyclooxygenase-2 (cox-2) and ki-67 were evaluated at baseline and at the endpoint (day 8). Although not statistically significant, overall decrease in expression levels of pEGFR (27.5%), cox-2 (15.9%) and ki-67 positive cells (51.8%) were observed following EGCG treatment. Moreover, a detectable level of EGCG was found in saliva but not in plasma after the one-week treatment regime, demonstrating local availability of EGCG in oral mucosa without significant systemic absorption. CONCLUSION: To best of our knowledge this is the first study to explore use of oral cancer chemopreventive agent in a form of mouthwash in patients with oral field cancerization. Although a definitive conclusion was not reached due to limited sample size, if proven effective, EGCG therapy may offer a non-invasive preventive modality for oral field cancerization.

Laryngeal manifestations of relapsing polychondritis and a novel treatment option.

OBJECTIVES: Laryngotracheal involvement in relapsing polychondritis (RP) is rare. However, it is one of the most common causes of death in this patient population. We present three patients who primarily presented with laryngeal manifestations of RP and a novel treatment option for bamboo nodules. STUDY DESIGN: Retrospective chart review and comprehensive review of the literature. RESULTS: Two patients first presented to an otolaryngologist because of hoarseness and chronic cough that eventually progressed to dyspnea upon exertion. Laryngeal examination revealed subglottic stenoses. Upon rheumatologic workup both were diagnosed with RP. After treatment with steroids and immunosuppressive drugs, one of the patient's laryngeal symptoms improved, whereas the other required dilation procedures. Neither patient had classic auricular or nasal symptoms upon initial presentation. The third patient was being treated for spasmodic dysphonia and was noted to have bamboo nodules with accompanying dysphonia. Rheumatologic workup revealed RP and systemic treatment ensued. Unfortunately, her symptoms of hoarseness persisted despite systemic treatment. A pulsed-potassium-titanyl-phosphate (KTP) laser was applied to the bilateral bamboo nodules, which eventually caused resolution of her vocal fold lesions and dysphonia. CONCLUSIONS: We present three patients with RP, all of whom sought health care by an otolaryngologist primarily. Awareness of this disease entity and the possibility for early laryngeal involvement is crucial for proper care of those with this life-threatening disease.