Hussaini, S. M. Qasim

68 Background: While immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, their high cost and limited global supply pose major challenges. Optimizing ICI dosing to achieve a minimum effective dose that has shown to maintain clinical benefit may be a potential solution with significant savings to the health system. We investigated potential savings in Medicare that could be attained from alternative ICI dosing. Methods: We conducted a literature review including original Phase 1/2 trials describing the minimal effective dose of three commonly used ICIs: Pembrolizumab (P), Nivolumab (N) and Atezolizumab (A). Alternate dosing strategies based on existing data for Pembrolizumab (2 mg/kg), Nivolumab (1 mg/kg) and Atezolizumab (4 mg/kg) were proposed. Publicly available CMS data on Medicare Part B expenditure for these therapies was utilized to obtain average cost per dosage unit, mg/dosage unit, and number of Medicare beneficiaries between 2018-2021. Average cost per dose and total cost per ICI was calculated based on current FDA approved dosing and alternate dosing strategies. Results: The average wholesale cost per fixed dose for P (200 mg), N (480 mg), and A were $9,242.00, $12,460.80, and $8,616.00, respectively. Implementing the proposed alternate dosing strategies led to a substantial reduction in drug costs: P ($7,393.60), N ($2,076.80), and A ($2,297.60). The ensuing cost savings were calculated based on the annual number of Medicare beneficiaries. From 2018-2021, the average total savings were estimated to be $95,545,182 for Pembrolizumab, $294,734,264 for Nivolumab, and $62,937,582 for Atezolizumab (Table). The cumulative average total cost savings from 2018-2021 exceeded $453 million. Conclusions: We demonstrate potential savings in Medicare with implementation of an alternative ICI dosing strategy. Our study underscores an urgent need to better understand clinical efficacy and cost savings from a patient perspective, and feasibility from a regulatory standpoint. This perspective may hold considerable global implications, providing a roadmap for cost-effective care in the domain of immunotherapy. [Table: see text]

e23082 Background: The hippocampus is one of two regions in the adult brain where new neurons are generated well into adulthood. Newborn neurons develop from neural stem cells, and are consequently integrated into the hippocampal circuitry to function in learning and memory. Temozolomide (TMZ) is a commonly used alkylating agent for treatment of malignant gliomas. In this study, we examine the effects of TMZ on adult neurogenesis and cognitive function in the murine model. Methods: Adult male mice (8-week-old) were injected daily with TMZ (25 mg/kg, i.p.) for 2, 2.5 and 3.5 weeks to estimate progenitor proliferation, neuronal maturation and animal behavior respectively. For progenitor proliferation, a single dose of BrdU (50mg/kg, i.p.) was injected at 2 weeks and the mice sacrificed 2 hours later. For maturation analysis, five separate doses of EdU (41.1 mg/kg, i.p.) were injected over five days starting at 2 weeks. Three weeks after first EdU injection mice were sacrificed. Both BrdU and EdU are novel thymidine analogues that label dividing cells. Immunostaining was performed on hippocampal brain slices to label progenitors at different stages of development. For behavioral analysis, daily tests measuring anxiety, memory and motor activity were started at 2 weeks into TMZ administration. Results: TMZ significantly reduced the resident radial glia-like and non-radial glia-like population (MCM2+Nestin+), as well as the overall proliferating progenitor pool (n = 2, p < 0.05). In addition, it significantly reduced the population of Type-3 neuroblasts (EdU+DCX+NeuN-) (n = 4, p < 0.05). During neuronal maturation, immature new neurons (EdU+DCX+NeuN+) and mature new neurons (EdU+DCX-NeuN+) were also reduced by TMZ (n = 4, p < 0.05). These effects of TMZ coincided with specific behavioral deficits. While TMZ had no effect on working memory and locomotor activity, mice that underwent TMZ administration showed significantly increased anxiety on the open field test (n = 7, p < 0.05). Conclusions: Our findings demonstrate TMZ significantly impairs cellular proliferation of neural stem cells and fate-committed neuroblasts, and increases anxiety with sparing of non-hippocampal-dependent memory. TMZ may thus be associated with specific deficits in hippocampal function in the adult brain, providing mechanistic insight into adverse effects that may be observed with TMZ treatment.

AbstractWnt signaling is a well‐known molecular pathway in age‐related pathogenesis and therapy of disease. While prior studies have mainly focused on Wnt ligands or Wnt activators, the in vivo functions of naturally secreted Wnt inhibitors are not clear, especially in brain aging. Using BubR1H/H mice as a novel mouse model of accelerated aging, we report that genetic inhibition of sFRP3 restores the reduced body and brain size observed in BubR1H/H mice. Furthermore, sFRP3 inhibition ameliorates hypomyelination in the corpus callosum and rescues neural progenitor proliferation in the hippocampal dentate gyrus of BubR1H/H mice. Taken together, our study identifies sFRP3 as a new molecular factor that cooperates with BubR1 function to regulate brain development, myelination, and hippocampal neurogenesis.