Clinical and molecular analysis of smoothened inhibitors in Sonic Hedgehog medulloblastoma.

BACKGROUND: Smoothened inhibitors (SMOi) have shown activity in Sonic Hedgehog (SHH) medulloblastoma, however this therapeutic class was not developed in children due to severe effects reported on growth. We hereby report long-term follow-up of young patients treated with SMOi for recurrent medulloblastoma. METHODS: Clinical data on response and toxicity from patients treated with vismodegib or sonidegib from 2011 to 2019 for a SHH medulloblastoma were retrospectively reviewed. Methylation analysis and whole exome sequencing were performed whenever possible. RESULTS: All patients with a somatic PTCH1 mutation responded to SMOi (6/8), including 2 prolonged complete responses. One patient was free of disease 8.2 years after treatment. SMOi was challenged again for 3 patients. Two of them had a response, one with SMOi alone, the other one in combination with temozolomide despite previous progression under monotherapy. SMO resistance mutations were found in patients from biopsy at relapse. Combination with temozolomide or surgery plus radiotherapy was associated with very long disease control in 2 patients. The most severe adverse events were myalgia and growth plate fusion with metaphyseal sclerosis. Normal growth velocity was recovered for 1 patient although her final height was below estimated target height. CONCLUSIONS: Targeting SMO in mutated PTCH1 is an interesting strategy for long-term responses. Combination of SMOi with chemotherapy or surgery and local radiotherapy is an appealing strategy to prevent early resistance and diminish SMOi exposure, especially in young patients. Inhibition of SHH pathway causes growth and development impairment but partial recovery of the growth velocity is possible.

Robust age estimation of southern sea otters from multiple morphometrics.

Reliable age estimation is an essential tool to assess the status of wildlife populations and inform successful management. Aging methods, however, are often limited by too few data, skewed demographic representation, and by single or uncertain morphometric relationships. In this study, we synthesize age estimates in southern sea otters Enhydra lutris nereis from 761 individuals across 34 years of study, using multiple noninvasive techniques and capturing all life stages from 0 to 17 years of age. From wild, stranded, and captive individuals, we describe tooth eruptions, tooth wear, body length, nose scarring, and pelage coloration across ontogeny and fit sex-based growth functions to the data. Dental eruption schedules provided reliable and identifiable metrics spanning 0.3-9 months. Tooth wear was the most reliable predictor of age of individuals aged 1-15 years, which when combined with total length, explained >93% of observed age. Beyond age estimation, dental attrition also indicated the maximum lifespan of adult teeth is 13‒17 years, corresponding with previous estimates of life expectancy. Von Bertalanffy growth function model simulations of length at age gave consistent estimates of asymptotic lengths (male Loo  = 126.0‒126.8 cm, female Loo  = 115.3‒115.7 cm), biologically realistic gestation periods (t 0 = 115 days, SD = 10.2), and somatic growth (male k = 1.8, SD = 0.1; female k = 2.1, SD = 0.1). Though exploratory, we describe how field radiographic imaging of epiphyseal plate development or fusions may improve aging of immature sea otters. Together, our results highlight the value of integrating information from multiple and diverse datasets to help resolve conservation problems.