Evaluation of denosumab in adult oncology patients for the prevention of skeletal related events across a large academic health system.

INTRODUCTION: Denosumab (Xgeva®) and zoledronic acid (Zometa®) are widely utilized for prevention of skeletal related events (SREs) in oncology patients. Drug costs, renal function, ease and logistics of administration, and adverse effect profile are factors frequently considered by patients and/or providers when selecting an optimal agent. Given the significantly higher drug cost of denosumab compared to zoledronic acid, an evaluation of our institution's denosumab use and investigation into opportunities to shift denosumab administrations to zoledronic acid and/or to lower cost sites-of-care was warranted. METHODS: A single-center, multi-site, retrospective, observational analysis of the electronic medical record (EMR) was conducted for adult oncology patients who received denosumab 120 mg for prevention of SREs from October 1st, 2018 to September 30th, 2019 at three institutions within our health system. Additional information was collected to characterize the patient population based on cancer diagnosis, renal function, and concomitant calcium and vitamin D supplementation. Our primary objective was to evaluate if the use of denosumab met current formulary restrictions of the health system. RESULTS: In total, 304 adult oncology patients received 1411 doses of denosumab for the prevention of SREs. The majority of reviewed patients had a primary oncology diagnosis of breast (35%) or lung (24%) cancer. Of the patients who received denosumab, 278 (93%) met the health system's current formulary restrictions. The majority of patients who did not meet formulary restrictions were those with multiple myeloma (MM) (20/22; 91%). Of the 304 patients reviewed, 70 had the appropriate parameters in the EMR to calculate creatinine clearance (CrCl) using Cockcroft-Gault Equation. Of those 70 patients, 59 (84%) would have been eligible to receive zoledronic acid instead of denosumab given that their CrCl >30 mL/min with no documented intolerance to bisphosphonates. Concurrent use of calcium and vitamin D is recommended when using denosumab. Based on the most recent prior to admission (PTA) medication list obtained from the 304 patients evaluated, 222 (73%) had both calcium and vitamin D listed as "taking". CONCLUSIONS: Within our health system, denosumab is restricted to those who meet formulary restrictions. Additional education is recommended to help limit the use of denosumab, specifically in MM, to reduce drug costs when zoledronic acid is also an appropriate first-line agent.

Small-molecule screen identifies reactive oxygen species as key regulators of neutrophil chemotaxis.

Neutrophil chemotaxis plays an essential role in innate immunity, but the underlying cellular mechanism is still not fully characterized. Here, using a small-molecule functional screening, we identified NADPH oxidase-dependent reactive oxygen species as key regulators of neutrophil chemotactic migration. Neutrophils with pharmacologically inhibited oxidase, or isolated from chronic granulomatous disease (CGD) patients and mice, formed more frequent multiple pseudopodia and lost their directionality as they migrated up a chemoattractant concentration gradient. Knocking down NADPH oxidase in differentiated neutrophil-like HL60 cells also led to defective chemotaxis. Consistent with the in vitro results, adoptively transferred CGD murine neutrophils showed impaired in vivo recruitment to sites of inflammation. Together, these results present a physiological role for reactive oxygen species in regulating neutrophil functions and shed light on the pathogenesis of CGD.

Rapid appearance of resolvin precursors in inflammatory exudates: novel mechanisms in resolution.

Resolution of inflammation is essential. Although supplementation of omega-3 fatty acids is widely used, their availability at sites of inflammation is not known. To this end, a multidisciplinary approach was taken to determine the relationship of circulating omega-3 to inflammatory exudates and the generation of resolution signals. In this study, we monitored resolvin precursors in evolving exudates, which initially paralleled increases in edema and infiltrating neutrophils. We also prepared novel microfluidic chambers to capture neutrophils from a drop of blood within minutes that permitted single-cell monitoring. In these, docosahexaenoic acid-derived resolvin D1 rapidly stopped neutrophil migration, whereas precursor docosahexaenoic acid did not. In second organ injury via ischemia-reperfusion, resolvin metabolically stable analogues were potent organ protectors reducing neutrophils. Together, these results indicate that circulating omega-3 fatty acids rapidly appear in inflammatory sites that require conversion to resolvins that control excessive neutrophil infiltration, protect organs, and foster resolution.