Does Compliance or Cost Regulate Effectiveness of Notched Sound Therapy Phone Applications for Tinnitus Relief? Preliminary Data of a Prospective Randomized Control Trial.

OBJECTIVE: The objective of this study is to evaluate compliance with and effectiveness of notched sound therapy (NST) administered through a mobile application in improving symptoms of patients experiencing chronic tinnitus. STUDY DESIGN: A prospective randomized control trial was done. SETTING: The study was done at a tertiary referral center. PATIENTS: Adult patients with tinnitus were monitored. INTERVENTIONS: Patients were randomized at enrollment to either the NST or a standard of care (SOC) group. NST arm included, in addition to SOC, a free subscription to NST mobile application, whereas the SOC arm included NST at subscription cost. MAIN OUTCOME MEASURES: The main outcome measures were continued enrollment in study, compliance with the therapy, frequency and duration of therapy use, and change from the baseline in the Tinnitus Handicap Inventory (THI). RESULTS: Patients in the NST group were 2.25 times more likely to use the NST application for 3 months postenrollment. Only 33% of users in the NST group listened for the prescribed 2 h/d compared with 0% of users in the SOC group. There was a clinically relevant mean decrease in THI from a baseline of 13.5 in the NST group (p = 0.09) and of 14.8 in the SOC group (p = 0.02). There was a positive correlation between initial THI and decrease in THI after 3 months (p = 0.001). CONCLUSIONS: Monitoring tinnitus for 3 months leads to a decrease in subjective symptoms regardless of NST use. Patients who received a free subscription to the application were more likely to continue with therapy, but very few patients were able to comply with 2 hours of listening time per day.

Constitutive overexpression of the oncogene Rac1 in the airway of recurrent respiratory papillomatosis patients is a targetable host-susceptibility factor.

Recurrent respiratory papillomatosis (RRP) is caused by human papillomaviruses (HPVs), primarily types 6 and 11. The disease is characterized by multiple recurrences of airway papillomas, resulting in high levels of morbidity and significant mortality. The prevalence of latent HPV in the larynx of the general population is much greater than the prevalence of RRP, suggesting a host-susceptibility factor for disease. We report that the oncogene Rac1 and its downstream product cyclooxygenase-2 (COX-2) are both constitutively expressed at high levels throughout the airway of these patients, independent of active HPV infection. Use of the COX-2 inhibitor celecoxib in primary papilloma cell culture resulted in the downregulation of HPV transcription. Furthermore, a proof-of-principle study treating three patients with severe RRP with celecoxib resulted in remission of disease in all cases. Therefore, we have identified the first pharmacologically targetable host-susceptibility pathway that contributes to RRP recurrence.

Clinical trial of photodynamic therapy with meso-tetra (hydroxyphenyl) chlorin for respiratory papillomatosis.

OBJECTIVE: To determine the efficacy of photodynamic therapy (PDT) with meso-tetra (hydroxyphenyl) chlorin (m-THPC) photosensitizer for recurrent respiratory papillomatosis. DESIGN: Parallel-arm, randomized trial of patients requiring surgery at least 3 times yearly with single PDT 6 or 18 months after enrollment and 12-month follow-up. Disease extent was scored and papillomas were removed during direct endoscopy every 3 months after enrollment. SETTING: Tertiary medical centers. PATIENTS: Of 23 patients aged 4 to 60 years enrolled in the study, 15 patients, plus 2 in the late group without PDT owing to airway risk, completed the study. Six patients withdrew voluntarily after PDT. INTERVENTION: Intravenous administration of m-THPC 6 days before direct endoscopic PDT with 80 to 100 J of light for adults and 60 to 80 J for children. MAIN OUTCOME MEASURES: Difference in severity scores between the early and late groups and between pre- and post-PDT scores for all patients. Secondary measures were the associations between baseline characteristics and response and changes in immune response and the prevalence of latent viral DNA. RESULTS: There were significant differences between groups, with marked improvement in laryngeal disease across time after PDT (P = .006). Five of 15 patients were in remission 12 to 15 months after treatment, but there was recurrence of disease after 3 to 5 years. Tracheal disease was not responsive to PDT. No change occurred in the prevalence of latent human papillomavirus DNA. The immune response to virus improved with clinical response. CONCLUSIONS: Use of m-THPC PDT reduces the severity of laryngeal papillomas, possibly through an improved immune response. Failure to maintain remission with time suggests that this is not an optimal treatment.

Early efficacy trial of anakinra in corticosteroid-resistant autoimmune inner ear disease.

BACKGROUND: Autoimmune inner ear disease (AIED) is a rare disease that results in progressive sensorineural hearing loss. Patients with AIED initially respond to corticosteroids; however, many patients become unresponsive to this treatment over time, and there is no effective alternative therapy for these individuals. METHODS: We performed a phase I/II open-label, single-arm clinical trial of the IL-1 receptor antagonist anakinra in corticosteroid-resistant AIED patients. Given that the etiology of corticosteroid resistance is likely heterogeneous, we used a Simon 2-stage design to distinguish between an unacceptable (≤10%) and an acceptable (≥30%) response rate to anakinra therapy. Subjects received 100 mg anakinra by subcutaneous injection for 84 days, followed by a 180-day observational period. RESULTS: Based on patient responses, the Simon 2-stage rule permitted premature termination of the trial after 10 subjects completed the 84-day drug period, as the target efficacy for the entire trial had been achieved. Of these 10 patients, 7 demonstrated audiometric improvement, as assessed by pure tone average (PTA) and word recognition score (WRS). In these 7 responders, reduced IL-1ß plasma levels correlated with clinical response. Upon discontinuation of treatment, 3 subjects relapsed, which correlated with increased IL-1ß plasma levels. CONCLUSION: We demonstrated that IL-1ß inhibition in corticosteroid-resistant AIED patients was effective in a small cohort of patients and that IL-1ß plasma levels associated with both clinical hearing response and disease relapse. These results suggest that a larger phase II randomized clinical trial of IL-1ß inhibition is warranted. TRIAL REGISTRATION: ClinicalTrials.gov NCT01267994. FUNDING: NIH, Merrill & Phoebe Goodman Otology Research Center, and Long Island Hearing & Speech Society.

Latent Human Papillomavirus infection is comparable in the larynx and trachea.

Recurrent respiratory papillomas are benign airway tumors caused by Human Papillomaviruses (HPVs) types 6 and 11. The disease is characterized by multiple recurrences of papillomas following surgical removal, caused by activation of latent HPV DNA. Most patients have laryngeal disease, while only a small subset has tracheal involvement. We have asked whether the lower frequency of tracheal papillomas was due to reduced prevalence of latent/subclinical tracheal HPV infection or reduced likelihood of activation to clinically apparent disease. A total of 121 biopsies of clinically normal laryngeal and tracheal tissues from 61 patients with laryngeal papillomas were analyzed for HPV DNA by polymerase chain reaction, confirmed by Southern blot hybridization. Patients were followed for 3-18 years (mean = 5.5 +/- 4.4), with only one developing subsequent tracheal disease. There was no significant difference in prevalence of latent HPV DNA between larynx and trachea, analyzing either those patients with a single biopsy or those with more than one biopsy of larynx, trachea, or both. There was also no significant difference between tracheal latency with HPV 6 and HPV 11. We conclude that HPV infects tracheal mucosa and is maintained as a latent infection in the trachea as efficiently as in the larynx. Therefore, we propose that the low frequency of tracheal disease reflects a lower frequency of HPV activation, and postulate that cellular factors that differ between the stratified squamous epithelium of the larynx and the ciliated pseudo-stratified columnar epithelium of the trachea contribute to this difference.

Polymorphism of transporter associated with antigen presentation 1 as a potential determinant for severity of disease in recurrent respiratory papillomatosis caused by human papillomavirus types 6 and 11.

Recurrent respiratory papillomatosis (RRP) is a rare disease caused by human papillomaviruses (HPVs). It is characterized by multiple recurrences of benign neoplasms and has a variable clinical course, ranging from infrequent recurrence to acute airway obstruction. One way in which HPV subverts the immune system in RRP is by interfering with TAP1 (transporter associated with antigen presentation 1). We examined whether a known TAP1 polymorphism in the ATPase domain altered the severity of disease in patients with RRP. The presence of this polymorphism was significantly correlated with severity of disease (P=.015). Because of the proximity of the TAP1 gene to human leukocyte antigen (HLA) class II genes on chromosome 6, we postulated that a linkage disequilibrium may exist. Of the patients with polymorphic TAP1, 36% were positive for HLA-DRB1*0102 (P=.021; P=.147 with Bonferroni's correction). However, this association appeared to mitigate the severity of disease (P=.04). Therefore, severity of disease in a patient with RRP might be determined by sequencing TAP1, in conjunction with HLA class II genes.