Neurofibromatosis type 2 (NF2) is an autosomal-dominant disease that results in the formation of bilateral vestibular schwannomas (VSs) and multiple meningiomas. Treatment options for NF2-associated tumors are limited, and to date, no medical therapies are FDA approved. The ideal chemotherapeutic agent would inhibit both VS and meningiomas simultaneously. The objectives of this study are (1) to test the efficacy of AR42, a novel histone deacetylase inhibitor, to inhibit VS and meningioma growth and (2) to investigate this drug's mechanisms of action. Primary cultures of human VS and meningioma cells were established. Nf2-deficient mouse schwannoma and benign human meningioma Ben-Men-1 cells were also cultured. Cells were treated with AR42, and the drug's effects on proliferation and the cell cycle were analyzed using a methanethiosulfonate assay and flow cytometry, respectively. Human phospho-kinase arrays and Western blots were used to evaluate the effects of AR42 on intracellular signaling. The in vivo efficacy of AR42 was investigated using schwannoma xenografts. Tumor volumes were quantified using high-field, volumetric MRI, and molecular target analysis was performed using immunohistochemistry. AR42 inhibited the growth of primary human VS and Nf2-deficient mouse schwannoma cells with a half maximal inhibitory concentration (IC(50)) of 500 nM and 250-350 nM, respectively. AR42 also inhibited primary meningioma cells and the benign meningioma cell line, Ben-Men-1, with IC(50) values of 1.5 µM and 1.0 µM, respectively. AR42 treatment induced cell-cycle arrest at G(2) and apoptosis in both VS and meningioma cells. Also, AR42 exposure decreased phosphorylated Akt in schwannoma and meningioma cells. In vivo treatment with AR42 inhibited the growth of schwannoma xenografts, induced apoptosis, and decreased Akt activation. The potent growth inhibitory activity of AR42 in schwannoma and meningioma cells suggests that AR42 should be further evaluated as a potential treatment for NF2-associated tumors.

Objective/Hypothesis Recent studies indicate that vestibular schwannomas (VS) rely on PI3-kinase/AKT activation to promote cell proliferation and survival; therefore, targeting AKT may provide new therapeutic options. We have previously shown that AR42, a novel histone deacetylase inhibitor, potently suppresses VS growth in vitro at doses correlating with AKT inactivation. The objectives of the current study were translational: 1) to examine the end biologic effects of AR42 on tumor growth in vivo, 2) to validate AKT as its in vivo molecular target, 3) to determine whether AR42 penetrates the blood brain barrier (BBB), and 4) to study AR42’s pharmacotoxicity profile. Study Design In vivo mouse studies Methods AR42 was dosed orally in murine schwannoma allografts and human vestibular schwannoma xenografts. MRI was used to quantify changes in tumor volume while intracellular molecular targets were analyzed using immunohistochemistry. Blood-brain barrier (BBB) penetration was assayed, and both blood chemistry measurements and histology studies were used to evaluate toxicity. Results Growth of schwannoma implants was dramatically decreased by AR42 at doses correlating with AKT dephosphorylation, cell cycle arrest, and apoptosis. AR42 penetrated the BBB, and wild-type mice fed AR42 for 6-months behaved normally and gained weight appropriately. Blood chemistry studies and organ histology performed after 3- and 6-months of AR42 treatment demonstrated no clinically significant abnormalities. Conclusions AR42 suppresses schwannoma growth at doses correlating with AKT pathway inhibition. This orally bioavailable drug penetrates the BBB, is well tolerated, and represents a novel candidate for translation to human VS clinical trials.

Objective While urinary leukotriene E4 (uLTE4) is a validated biomarker for the cysteinyl leukotriene pathway, which is central to the pathophysiology of asthma, atopy, and chronic rhinosinusitis (CRS), the contributions of comorbid asthma and atopy to uLTE4 levels in various CRS subtypes have not been previously characterized. We sought to (1) identify reference values for uLTE4 in subjects with and without CRS and (2) determine how the presence of comorbid atopy and asthma affects uLTE4 levels in CRS. Setting Tertiary referral medical center. Subjects and Methods A prospective case-control study was conducted to compare uLTE4 levels between patients with CRS and healthy controls. Urinary LTE4 levels were measured by enzyme immunoassay and were adjusted for urinary creatinine concentrations (pg/mg Cr). Patients with CRS were stratified by the clinical comorbidities to determine normative uLTE4 values for patients with CRS with and without comorbid asthma or atopy. Results A total of 153 patients (mean age, 47.3; 47.1% female) were included in the study. Patients with CRS demonstrated significantly higher concentrations of uLTE4 than healthy controls (1652 vs 1065 pg/mg Cr, P = .032). Within the group of patients with CRS, comorbid asthma also individually correlated with elevated uLTE4 levels (1597 pg/mg Cr, P = .0098). Patients with CRS who did not have comorbid allergy and asthma, in contrast, did not have statistically higher uLTE4 levels than healthy controls (1142 pg/mg Cr, P = .61). Conclusion Urinary LTE4 serves as a noninvasive measure of the inflammatory state in CRS. Comorbid asthma and atopy contribute to elevated uLTE4 levels in CRS.

BACKGROUND Postoperative prophylactic antibiotics are commonly used in pituitary surgery, but evidence supporting their use is lacking, which has implications for antibiotic stewardship. OBJECTIVE To evaluate whether receipt of postoperative oral antibiotics results in superior sinonasal quality of life (QOL) compared with placebo among patients who undergo endoscopic endonasal transsphenoidal pituitary surgery. METHODS Patients were randomized to receive either oral placebo or cefdinir (trimethoprim-sulfamethoxazole in patients intolerant to cefdinir) for 7 d after surgery. They were monitored for 12 wk. The primary outcome measure was sinonasal QOL at 2 wk on the Anterior Skull Base Nasal Inventory-12. Supplementary end points included sinonasal QOL reported on the Sinonasal Outcome Test-22 and objective endoscopy scores to assess nasal healing according to the Lund-Kennedy method. RESULTS A total of 461 patients were screened, 131 were randomized, and 113 (placebo arm: 55; antibiotic arm: 58) were analyzed. There was no clinically meaningful or statistically significant difference in sinonasal QOL at any measured time point (P ≥ .24) using either instrument. Nasal cavity endoscopy scores were not significantly different at 1 to 2 wk after surgery (P = .25) or at 3 to 4 wk after surgery (P = .08). CONCLUSION Postoperative prophylactic oral antibiotics did not result in superior sinonasal QOL compared with placebo among patients who underwent standard endoscopic transsphenoidal surgery.