P-glycoprotein inhibition with verapamil overcomes mometasone resistance in Chronic Sinusitis with Nasal Polyps.

BACKGROUND: P-glycoprotein (P-gp) is a membrane efflux pump which is overexpressed in Chronic Rhinosinusitis with Nasal Polyps (CRSwNP) and promotes Type 2 inflammation. Glucocorticoids (GC) are substrates of P-gp suggesting that overexpression may additionally contribute to GC resistance in CRSwNP. This study aims to determine whether P-gp inhibition using verapamil enhances mometasone retention and efficacy in nasal polyp explants. METHODOLOGY: IRB approved study in which organotypic polyp explants were exposed to mometasone (4.15 µg/mL) and verapa- mil (125 µg/mL) as mono and combination therapy. The effect of verapamil on mometasone tissue retention over time was deter- mined using HPLC. The effect of verapamil on mometasone anti-inflammatory function was determined using ELISA for secreted IL-5. Groups were compared using Kruskal-Wallis test. RESULTS: P-gp expression strongly and significantly inversely correlated with mometasone retention 1hr after exposure, with a ne- arly 6-fold reduction in tissue retention between the lowest and highest P-gp expressing polyp explants. P-gp inhibition reversed this effect and significantly improved mometasone retention at 1hr relative to mometasone alone. The combination of mome- tasone and verapamil significantly reduced IL-5 secretion relative to vehicle control and outperformed either treatment alone. CONCLUSIONS: Our study confirms that P-gp contributes to mometasone resistance. This P-gp mediated resistance was successfully reversed by addition of the P-gp inhibitor verapamil. Verapamil further significantly enhanced the anti-inflammatory effect of mometasone when given as a combination therapy.

Radioanatomic Characteristics of the Posteromedial Intraconal Space: Implications for Endoscopic Resection of Orbital Lesions.

BACKGROUND AND PURPOSE: Imaging is essential in the diagnostic work-up of patients with orbital lesions. The position of an orbital lesion relative to the inferomedial muscular trunk of the ophthalmic artery determines endoscopic resectability, anticipated technical difficulty, and patient morbidity. Although the inferomedial muscular trunk is not readily identifiable on preoperative imaging, we hypothesize that it is spatially approximate to the location where the ophthalmic artery crosses the optic nerve. Our aim was to determine whether the ophthalmic artery-optic nerve crosspoint anatomically approximates the inferomedial muscular trunk in a cadaver study and can be appreciated on imaging of known posteromedial orbital lesions. MATERIALS AND METHODS: Dissection was performed on 17 fresh-frozen cadaver orbits to assess the relationship between the inferomedial muscular trunk and ophthalmic artery-optic nerve crosspoint. Retrospective review of imaging in 9 patients with posteromedial orbital lesions assessed posteromedial orbital compartment characteristics and the ability to locate the ophthalmic artery-optic nerve crosspoint. RESULTS: In our cadaver study, the mean distance between the ophthalmic artery-optic nerve crosspoint and the inferomedial muscular trunk was 1.21 ± 0.64 mm. Retrospectively, the ophthalmic artery-optic nerve crosspoint was identifiable in 9/9 patients, whereas the inferomedial muscular trunk was not identifiable in any patient. Total or partial effacement of the posteromedial intraconal fat triangle was observed in 9/9 patients. CONCLUSIONS: This study of neurovascular relationships within the posteromedial orbit demonstrates that the ophthalmic artery-optic nerve crosspoint closely approximates the inferomedial muscular trunk and can be seen in patients with posteromedial orbital lesions. Posteromedial intraconal fat effacement may help to localize these lesions. These findings may facilitate multidisciplinary communication and help predict lesion resectability and patient outcomes.

Oral steroids and intraoperative bleeding during endoscopic sinus surgery.

OBJECTIVES: Our main objective was to investigate the effect of preoperative oral steroids on intraoperative bleeding and quality of the surgical field during endoscopic sinus surgery (ESS). Our second objective was to determine whether the osteitis score could be used to predict the volume of intraoperative bleeding. METHODOLOGY: This double-blinded, randomized trial included 65 patients with chronic rhinosinusitis with nasal polyps. The corticosteroid group received oral prednisolone (1 mg/kg), administered to patients once daily for 2 days and then tapered down, with treatment completed on the day 10. The control group received placebo before the operation. Endoscopic exams were recorded, and preoperative sinus computed tomography scans were scored. Intraoperative blood loss was recorded. Quality of the surgical field was assessed by the surgeon, using a linear scale from 1 to 10. RESULTS: The mean bleeding volume was 239 ml in the corticosteroid group and 203 ml in control group. There was no significant difference between the groups (p = 0.495). Surgical field quality scores were higher in the corticosteroid group than in the control group, but the difference was not significant (p = 0.36). There was no statistically significant relationship between the bleeding volume and Kennedy Osteitis Scores in corticosteroid group (r = 0.225, p = 0.186) and control group (r = 0.084, p = 0.663). CONCLUSION: Our findings suggest that using oral corticosteroids, which have rare but serious side effects, is not necessary in the preoperative period. Furthermore, we found that the radiological osteitis score was not a suitable marker for predicting intraoperative bleeding volumes.

Vitamin D3 correlates inversely with systemic dendritic cell numbers and bone erosion in chronic rhinosinusitis with nasal polyps and allergic fungal rhinosinusitis.

Vitamin D(3) (VD(3) ) is a steroid hormone that regulates bone health and numerous aspects of immune function and may play a role in respiratory health. We hypothesized that T helper type 2 (Th2) disorders, chronic rhinosinusitis with nasal polyps (CRSwNP) and allergic fungal rhinosinusitis (AFRS) would have VD(3) deficiencies, resulting in increased mature dendritic cells (DCs) and bone erosion. We conducted a retrospective study examining VD(3) levels in patients with AFRS (n = 14), CRSwNP (n = 9), chronic rhinosinusitis without nasal polyps (CRSsNP) (n = 20) and cerebrospinal fluid leak repair (non-diseased controls) (n = 14) at time of surgery. Circulating immune cell levels were determined by immunostaining and flow cytometric analysis. Plasma VD(3) and immune regulatory factors (granulocyte-macrophage colony-stimulating factor and prostaglandin E(2) ) were measured by enzyme-linked immunosorbent assay. It was observed that CRSwNP and AFRS demonstrated increased circulating DCs, while chronic rhinosinusitis without nasal polyps displayed increased circulating macrophages. CRSwNP and AFRS were to found to have insufficient levels of VD(3) which correlated inversely with circulating numbers of mature DCs, DC regulatory factors and bone erosion. CRSsNP displayed no change in circulating DC numbers or VD(3) status compared to control, but did display increased numbers of circulating macrophages that was independent of VD(3) status. Lastly, VD(3) deficiency was associated with more severe bone erosion. Taken together, these results suggest support a role for VD(3) as a key player in the immunopathology of CRSwNP and AFRS.