Learning Objectives: Introduction: Early congenital cholesteatoma is often undiagnosed and usually presents only when the tympanic membrane is breached and the ear chronically discharges. Early detection and intervention of congenital cholesteatoma should intuitively allow better surgical outcomes. Otitis media with effusion could be an early indicator of underlying cholesteatoma and children presenting with persistent unilateral effusion should be investigated. Method: Over a 5-year period from 1st March 2009 to 1st March 2014 every child with a persistent unilateral conductive loss, flat tympanometry for 6 months and normal tympanic membrane was listed for insertion of a ventilation tube. At follow up audiological evaluation, any child with persistent hearing loss underwent CT scanning to investigate for cholesteatoma and exploratory mastoid surgery where CT findings were suggestive.
INTRODUCTION: Diffuse intrinsic pontine glioma (DIPG) carries a high mortality rate secondary to its aggressive molecular characteristics, infiltrative nature, and lack of effective treatment options. Overall survival is only 9-11 months and median time to progression after radiotherapy is 5-6 months. Convection-enhanced delivery (CED) has demonstrated safety in phase-1 trials, but efficacy is indeterminate.METHODS: Sixty-three children with DIPG treated between 2010-2022 were retrospectively reviewed for first radiographic progression. All were treated using conventional external beam radiation (EBRT) and 31 (49%) were treated with CED of radiolabeled 124-Iodine-Omburtamab following EBRT (NCT01502917). Progression was codified by independent neuroradiologists according to anatomic location (local, contiguous, medulla, midbrain, middle cerebellar peduncle (MCP), and/or distant). Overall survival (OS) was assessed with Kaplan-Meier methodology and cumulative incidence of progression at each anatomic site was assessed in a cause-specific competing risk analysis with death as a competing event and were stratified based on CED treatment.RESULTS: Mean age at diagnosis was 7.1 (+/-3.4 years) with a median OS of 1.22 years for the cohort. Patients receiving CED demonstrated higher rates of progression in general, when considering progression at all anatomical sites (HR 1.79, p = 0.047) and no statistically significant difference was found in OS when stratified by CED treatment (p = 0.22). However, CED treatment was associated with significantly lower cumulative incidence of pontine and medullary progression (HR 0.43, p = 0.03; HR 0.15, p = 0.01, respectively) relative to non-CED treated patients. No statistically significant differences in progression were identified at other sites (contiguous, midbrain, MCP, or distant).CONCLUSIONS: MR-defined patterns of relapse provide evidence for locoregional control in children with DIPG treated with radioimmunotherapy administered by CED. These results prompt a consideration for modifying the design of future clinical trials by supplementing brain stem CED with whole neuroaxis treatment.
Mammalian inner ear hair cell loss leads to permanent hearing and balance dysfunction. In contrast to the cochlea, vestibular hair cells of the murine utricle have some regenerative capacity. Whether human utricular hair cells regenerate remains unknown. Here we procured live, mature utricles from organ donors and vestibular schwannoma patients, and present a validated single-cell transcriptomic atlas at unprecedented resolution. We describe previously unknown markers of 25 sensory and non-sensory cell types, with genes of hair cell and supporting cell subtypes displaying striking divergence between mice and humans. We further uncovered transcriptomes unique to hair cell precursors, which we validated to be 14-fold more robust in vestibular schwannoma utricles, representing ongoing regeneration in humans. Lastly, trajectory analysis of the supporting cell-hair cell axis revealed 5 distinct patterns of dynamic gene expression and associated pathways, including mTOR signaling and synaptogenesis. Our dataset constitutes a foundational resource, accessible via a web-based interface, serving to advance knowledge of the normal and diseased human inner ears and tools to stimulate human inner ear regeneration.
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