A phase I/IIa safety and efficacy trial of intratympanic gamma-secretase inhibitor as a regenerative drug treatment for sensorineural hearing loss.

Inhibition of Notch signalling with a gamma-secretase inhibitor (GSI) induces mammalian hair cell regeneration and partial hearing restoration. In this proof-of-concept Phase I/IIa multiple-ascending dose open-label trial (ISRCTN59733689), adults with mild-moderate sensorineural hearing loss received 3 intratympanic injections of GSI LY3056480, in 1 ear over 2 weeks. Phase I primary outcome was safety and tolerability. Phase lla primary outcome was change from baseline to 12 weeks in average pure-tone air conduction threshold across 2,4,8 kHz. Secondary outcomes included this outcome at 6 weeks and change from baseline to 6 and 12 weeks in pure-tone thresholds at individual frequencies, speech reception thresholds (SRTs), Distortion Product Otoacoustic Emissions (DPOAE) amplitudes, Signal to Noise Ratios (SNRs) and distribution of categories normal, present-abnormal, absent and Hearing Handicap Inventory for Adults/Elderly (HHIA/E). In Phase I (N = 15, 1 site) there were no severe nor serious adverse events. In Phase IIa (N = 44, 3 sites) the average pure-tone threshold across 2,4,8 kHz did not change from baseline to 6 and 12 weeks (estimated change -0.87 dB; 95% CI -2.37 to 0.63; P = 0.252 and -0.46 dB; 95% CI -1.94 to 1.03; P = 0.545, respectively), nor did the means of secondary measures. DPOAE amplitudes, SNRs and distribution of categories did not change from baseline to 6 and 12 weeks, nor did SRTs and HHIA/E scores. Intratympanic delivery of LY3056480 is safe and well-tolerated; the trial's primary endpoint was not met.

Hearing loss in Paget's disease: a temporal bone histopathology study.

BACKGROUND: Hearing loss in Paget's disease of bone (PDB) is typically mixed and bilateral. Although different mechanisms have been proposed, the pathophysiology of hearing impairment remains unclear. OBJECTIVE: The purpose of this study is to describe the histopathologic findings of temporal bones in patients with PDB and elucidate possible pathologic mechanisms related to hearing impairment. METHODS: This is an archival human temporal bone study of 8 subjects diagnosed with Paget's disease from the temporal bone collection of the UCL Ear Institute. RESULTS: A fractured stapes footplate was observed in 1 temporal bone and stapes footplate fixation in 2 other specimens. Obliteration of Cotugno's canal by extensive bone remodeling was observed in 78% of temporal bones. An intracochlear vestibular schwannoma was observed in 1 specimen (previously reported in the literature). Other findings include microfissures and microfractures of the otic capsule, bleeding in the scalae, strial atrophy, and cystic lesions in the spiral ligament. CONCLUSION: This study is the first to report a fractured stapes footplate, as a causative lesion of conductive hearing loss in PDB. Extensive bone remodeling around Cotugno canal also was a frequent finding, not reported before in the literature. We hypothesize that sensorineural hearing loss in patients with PDB of the temporal bone may, in some cases, be attributed to obliteration of Cotugno's canal by remodeling pagetoid bone, thus obstructing the venous drainage of the cochlea, with a subsequent effect on the function of stria vascularis and spiral ligament. This seems to be consistent with experimental studies in animals.

Bilateral squamous cell carcinoma of the temporal bones.

We report a case of bilateral squamous cell carcinoma of the temporal bones in a 66-year-old woman who underwent a left subtotal petrosectomy and a right lateral temporal bone resection. Hearing rehabilitation was successfully achieved by fitting a bone-anchored hearing aid (BAHA) on the right side. We feel that in cases where the extent of the tumor permits a lateral temporal bone resection in at least one side, fitting of a BAHA can achieve a good outcome without resorting to tympanoplasty techniques that may compromise the medial end of the surgical resection.