Early phase clinical studies of AR-42, a histone deacetylase inhibitor, for neurofibromatosis type 2-associated vestibular schwannomas and meningiomas.

OBJECTIVES: Two pilot studies of AR-42, a pan-histone deacetylase inhibitor, in human neurofibromatosis type 2 (NF2), vestibular schwannomas (VS), and meningiomas are presented. Primary endpoints included safety, and intra-tumoral pharmacokinetics (PK) and pharmacodynamics (PD). METHODS: Pilot 1 is a subset analysis of a phase 1 study of AR-42 in solid tumors, which included NF2 or sporadic meningiomas. Tumor volumes and treatment-related adverse events (TRAEs) are reported (NCT01129193).Pilot 2 is a phase 0 surgical study of AR-42 assessing intra-tumoral PK and PD. AR-42 was administered for 3 weeks pre-operatively. Plasma and tumor drug concentrations and p-AKT expression were measured (NCT02282917). RESULTS: Pilot 1: Five patients with NF2 and two with sporadic meningiomas experienced a similar incidence of TRAEs to the overall phase I trial. The six evaluable patients had 15 tumors (8 VS, 7 meningiomas). On AR-42, tumor volume increased in six, remained stable in eight, and decreased in one tumor. The annual percent growth rate decreased in eight, remained stable in three, and increased in four tumors. Pilot 2: Four patients with sporadic VS and one patient with meningioma experienced no grade 3/4 toxicities. Expression of p-AKT decreased in three of four VS. All tumors had higher AR-42 concentrations than plasma. CONCLUSIONS: AR-42 is safe. Tumor volumes showed a mixed response, but most slowed growth. On a 40-mg regimen, drug concentrated in tumors and growth pathways were suppressed in most tumors, suggesting this may be a well-tolerated and effective dose. A phase 2 study of AR-42 for NF2-associated tumors appears warranted. LEVEL OF EVIDENCE: 1b, 4.

Assessment of Pain and Analgesic Use in Children Following Otologic Surgery.

OBJECTIVE: To compare postoperative pain and analgesic use in children following transcanal endoscopic ear surgery (TEES) vs non-transcanal endoscopic ear surgery (non-TEES). STUDY DESIGN: Prospective case series. SETTING: Tertiary care center. METHODS: Surveys using the Wong-Baker FACES Pain Rating Scale and recording the frequency and dosage of consumed analgesics were administered prospectively to caregivers of children undergoing otologic surgery between May 2018 to February 2020. Pain intensity and medication use were recorded twice daily for 6 days, starting on postoperative day 0. Mean pain scores and mean number of consumed analgesic doses were compared between groups. RESULTS: Survey response rate was 57.9%. Among 53 patients who completed the survey, 35 (66.0%) underwent TEES and 18 (34.0%) underwent non-TEES. Mean pain ratings on postoperative days 0 and 1 were significantly lower among children undergoing TEES (2.2 and 2.1) vs non-TEES (4.0 and 4.1), P = .045 and P = .008, respectively (Mann-Whitney U test). The mean pain ratings across the 6 days were similar in TEES (1.7) and non-TEES (2.6) (P = .140, Mann-Whitney U test). The mean number of analgesic doses consumed per half-day over the 6 days was significantly lower among children undergoing TEES (0.3) vs non-TEES (0.6; P = .049, Mann-Whitney U test). CONCLUSION: Postoperative pain following TEES and non-TEES in children was overall low. Children undergoing TEES had a small but statistically significant decrease in pain on postoperative days 0 and 1 and decreased use of pain medications compared to non-TEES.

Topical fibroblast growth factor-2 for treatment of chronic tympanic membrane perforations.

OBJECTIVE: To determine the efficacy of fibroblast growth factor-2 (FGF-2) in treating chronic nonhealing tympanic membrane (TM) perforations. METHOD: Double-blinded, randomized placebo controlled phase 2 clinical trial for patients with chronic TM perforations of more than 3 months duration with a cross-over arm. Patients received either FGF-2 or placebo (sterile water) saturated gelatin sponge in the perforation after rimming the perforation under topical anesthesia. The perforation was then covered with Tisseel fibrin glue. The primary endpoint was complete closure of the TM perforation. Secondary end points included change in hearing and partial TM closure rates. The TM was examined every 3 weeks with otoendoscopy for closure. The treatment was repeated if there was incomplete closure every 3 weeks up to a total of three treatments per arm. RESULTS: Seventy four patients were recruited for the study. Fifty seven met eligibility criteria and fifty four completed the study. Ten of 14 perforations closed completely in the placebo group (71.4%) and 23 of 40 perforations closed completely in the FGF-2 treatment group (57.5%), P value = .36. Pure tone averages and word recognition scores were not statistically significantly different between study groups post-treatment. After initial complete closure, re-perforation occurred in seven FGF-2 treated patients and two placebo patients making the effective final closure rate 40% for FGF and 57% for placebo, respectively. CONCLUSION: No statistically significant difference in tympanic membrane perforation closure rate was found between the FGF-2 and placebo groups. There were no differences in hearing outcomes between the groups. LEVEL OF EVIDENCE: 1b.

Differential perception and tolerance of chronic rhinosinusitis symptoms as a confounder of gender-disparate disease burden.

BACKGROUND: Previous studies have consistently shown that females with chronic rhinosinusitis (CRS) have a greater CRS symptom burden than males with CRS. Our objective was to determine whether differential disease perception could explain this phenomenon. METHODS: A total of 500 participants (239 males, 261 females) with CRS were recruited. CRS symptom burden was assessed with the 22-item Sino-Nasal Outcome Test (SNOT-22). General health-related quality of life was assessed with the visual analog scale of the 5-dimensional EuroQol questionnaire (EQ-5D VAS). Participants were asked to rate their CRS symptom control as "Not at all," "A little," "Somewhat," "Very," and "Completely." "Not at all," "A little," and "Somewhat" controlled symptoms were considered to reflect poorly controlled symptoms. RESULTS: SNOT-22 score was significantly more severe (p < 0.001) among females (mean, 44.0; standard deviation [SD], 22.5) than males (mean, 36.3; SD, 20.2). However, there was no significant difference in male- vs female-reported CRS symptom control (p = 0.154). In addition, there was no significant difference (p = 0.109) in EQ-5D VAS score between males (mean, 70.9; SD, 19.0) and females (mean, 68.4; SD, 19.5). Although a SNOT-22 score of ≥25 was predictive of poorly controlled symptoms in males (sensitivity, 82.6%; specificity, 62.5%), a SNOT-22 score of ≥30 was predictive of poorly controlled symptoms in women (sensitivity, 82.4%; specificity, 64.5%). CONCLUSION: Females with CRS reported more severe SNOT-22 scores, despite reporting a similar level of symptom control and general health-related quality of life as men. Women had a higher SNOT-22 threshold for poorly controlled symptoms. Female CRS patients may have greater perception and tolerance of CRS symptoms without a corresponding significant, disparate downstream impairment.