In vitro assessment of chemotherapy-induced neuronal toxicity.

Neurotoxicity is a major concern during drug development, and together with liver and cardio-toxicity, it is one of the main causes of clinical drug attrition. Current pre-clinical models may not sufficiently identify and predict the risk for central or peripheral nervous system toxicity. One such example is clinically dose-limiting neuropathic effects after the administration of chemotherapeutic agents. Thus, the need to establish novel in vitro tools to evaluate the risk of neurotoxicities, such as neuropathy, remains unmet in drug discovery. Though in vitro studies have been conducted using primary and immortalized cell lines, some limitations include the utility for higher throughput methodologies, method reproducibility, and species extrapolation. As a novel alternative, human induced-pluripotent stem cell (iPSC)-derived neurons appear promising for testing new drug candidates. These iPSC-derived neurons are readily available and can be manipulated as required. Here, we describe a novel approach to assess neurotoxicity caused by different classes of chemotherapeutics using kinetic monitoring of neurite dynamic changes and apoptosis in human iPSC-neurons. These studies show promising changes in neurite dynamics in response to clinical inducers of neuropathy, as well as the ability to rank-order and gather mechanistic insight into class-specific compound induced neurotoxicity. This platform can be utilized in early drug development, as part of a weight of evidence approach, to screen drug candidates, and potentially reduce clinical attrition due to neurotoxicity.

Sacral nerve stimulator revision due to somatic growth.

PURPOSE: Sacral nerve modulation is a Food and Drug Administration approved treatment for refractory urgency, frequency, urge incontinence and nonobstructive urinary retention in adults. The sparse literature on sacral nerve modulation in children focuses on its initial efficacy in patients with neurogenic bladder and dysfunctional elimination. We describe our initial experience with sacral nerve modulation and the phenomenon of growth spurts associated with lead malfunction that necessitates revision. MATERIALS AND METHODS: After receiving institutional review board approval we retrospectively reviewed the charts of pediatric patients who underwent sacral nerve modulation surgery at our institution. Charts were examined for patient demographics, subjective success, the need for further surgery and success after revision. RESULTS: Four patients underwent sacral nerve modulation at an average age of 12.1 years. All patients reported initial success, defined as greater than 50% symptom improvement. Subsequently 3 patients required a total of 5 revisions due to lead malfunction with an average of 1.5 years between surgeries. In those requiring revision the average somatic growth between revisions was 8.1 cm. Return of efficacy was reported after each revision. All patients had functioning nerve stimulators in place and continued to have a positive subjective response. CONCLUSIONS: The sparse data on sacral nerve modulation in children shows efficacy and safety similar to those in adults. Somatic growth may be associated with lead malfunction and require surgical revision. We report a small series showing that revision can be done successfully and safely. Informed consent for sacral nerve modulation in pediatric patients should include a discussion of somatic growth as a possible cause of lead malfunction necessitating revision.