Sustained release of neurotrophin-3 via calcium phosphate-coated sutures promotes axonal regeneration after spinal cord injury.

Because of the dynamics of spinal cord injury (SCI), the optimal treatment will almost certainly be a combination approach to control the environment and promote axonal growth. This study uses peripheral nerve grafts (PNGs) as scaffolds for axonal growth while delivering neurotrophin-3 (NT-3) via calcium phosphate (CaP) coatings on surgical sutures. CaP coating was grown on sutures, and NT-3 binding and release were characterized in vitro. Then, the NT-3-loaded sutures were tested in a complete SCI model. Rats were analyzed for functional improvement and axonal growth into the grafts. The CaP-coated sutures exhibited a burst release of NT-3, followed by a sustained release for at least 20 days. Functionally, the rats with PNGs + NT-3-loaded sutures and the rats treated with PNGs scored significantly higher than controls on day 56 postoperatively. However, functional scores in rats treated with PNGs + NT-3-loaded suture were not significantly different from those of rats treated with PNGs alone. Cholera toxin subunit B (CTB) labeling rostral to the graft was not observed in any controls, but CTB labeling rostral to the graft was observed in almost all rats that had had a PNG. Neurofilament labeling on transverse sections of the graft revealed that the rats treated with the NT-3-loaded sutures had significantly more axons per graft than rats treated with an NT-3 injection and rats without NT-3. These data demonstrate that PNGs serve as scaffolds for axonal growth after SCI and that CaP-coated sutures can efficiently release NT-3 to increase axonal regeneration. © 2016 Wiley Periodicals, Inc.

Glasdegib: A Novel Hedgehog Pathway Inhibitor for Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is an aggressive myeloid disorder that is associated with a generally poor prognosis. Effective treatment options have been limited for older patients with AML who are not able to undergo intensive remission induction chemotherapy due to advanced age or comorbidities. New and novel agents are needed to improve treatment outcomes for this patient population. Glasdegib is a novel Hedgehog signaling pathway inhibitor approved by the U.S. Food & Drug Administration for the treatment of patients with newly diagnosed AML who are 75 years of age or older or who have comorbidities that preclude intensive induction chemotherapy. Glasdegib is approved in combination with low-dose cytarabine (LDAC). This approval is based on the results of a multicenter, open-label, randomized trial of glasdegib plus LDAC vs. LDAC monotherapy in which the addition of glasdegib resulted in an improvement in median overall survival.

Evaluation of Montelukast for the Prevention of Infusion-related Reactions With Daratumumab.

BACKGROUND: Daratumumab is an anti-CD38 monoclonal antibody indicated for the treatment of multiple myeloma. Infusion-related reactions (IRRs) are among the most common adverse events associated with daratumumab. IRRs are most common with the first infusion of daratumumab. Recommended premedications to be given prior to the daratumumab dose include acetaminophen, diphenhydramine, and a corticosteroid. There is emerging data to suggest that the addition of montelukast to this premedication regimen can lower the incidence of daratumumab-related IRRs. PATIENTS AND METHODS: This was a single-center, retrospective chart review conducted at a large, multistate health system with several different hematology/oncology practice sites. Eligible patients included those with a primary diagnosis of a plasma cell disorder who received at least 1 dose of daratumumab. The primary outcome was the incidence of IRRs with the first daratumumab infusion. RESULTS: A total of 141 patients receiving daratumumab-based therapy were included in this study. All patients received acetaminophen, diphenhydramine, and a corticosteroid as premedications prior to the first infusion of daratumumab. Overall, 46 (33%) patients experienced an IRR with the first infusion of daratumumab. The incidence of IRR was lower in patients that received montelukast as a premedication compared with those that did not (montelukast, n = 25 [27%]; no montelukast, n = 21 [45%]; P = .0371). Patients in each arm experienced similar rates of overall, composite pulmonary, gastrointestinal, and systemic IRR manifestations. CONCLUSION: The use of montelukast prior to the first daratumumab infusion led to a reduction in the incidence of IRRs in our experience.

Immunohistochemical assessment of rat nerve isografts and immunosuppressed allografts.

OBJECTIVE: Autologous peripheral nerve grafts are commonly used clinically as a treatment for peripheral nerve injuries. However, in research using an autologous graft is not always feasible due to loss of function, which in many cases is assessed to determine the efficacy of the peripheral nerve graft. In addition, using allografts for research require the use of an immunosuppressant, which creates unwanted side effects and another variable within the experiment that can affect regeneration. The objective of this study was to analyze graft rejection in peripheral nerve grafts and the effects of cyclosporine A (CSA) on axonal regeneration. METHODS: Peripheral nerve grafts in inbred Lewis rats were compared with Sprague-Dawley (SD) rats to assess graft rejection, CSA side effects, immune responses, and regenerative capability. Macrophages and CD8+ cells were labeled to determine graft rejection, and neurofilaments were labeled to determine axonal regeneration. RESULTS: SD rats without CSA had significantly more macrophages and CD8+ cells compared to Lewis autografts, Lewis isografts, and SD allografts treated with CSA. Lewis autografts, Lewis isografts, and SD autografts had significantly more regenerated axons than SD rat allografts. Moreover, allografts in immunosuppressed SD rats had significantly less axons than Lewis rat autograft and isografts. DISCUSSION: Autografts have long been the gold standard for treating major nerve injuries and these data suggest that even though CSA is effective at reducing graft rejection, axon regeneration is still superior in autografts versus immunosuppressed allografts.