S. aureus biofilm properties correlate with immune B cell subset frequencies and severity of chronic rhinosinusitis.

Staphylococcus aureus mucosal biofilms are associated with recalcitrant chronic rhinosinusitis (CRS). However, S. aureus colonisation of sinus mucosa is frequent in the absence of mucosal inflammation. This questions the relevance of S. aureus biofilms in CRS etiopathogenesis. This study aimed to investigate whether strain-level variation in in vitro-grown S. aureus biofilm properties relates to CRS disease severity, in vitro toxicity, and immune B cell responses in sinonasal tissue from CRS patients and non-CRS controls. S. aureus clinical isolates, tissue samples, and matched clinical datasets were collected from CRS patients with nasal polyps (CRSwNP), CRS without nasal polyps (CRSsNP), and controls. B cell responses in tissue samples were characterised by FACS. S. aureus biofilms were established in vitro, followed by measuring their properties of metabolic activity, biomass, colony-forming units, and exoprotein production. S. aureus virulence was evaluated using whole-genome sequencing, mass spectrometry and application of S. aureus biofilm exoproteins to air-liquid interface cultures of primary human nasal epithelial cells (HNEC-ALI). In vitro S. aureus biofilm properties were correlated with increased CRS severity scores, infiltration of antibody-secreting cells and loss of regulatory B cells in tissue samples. Biofilm exoproteins from S. aureus with high biofilm metabolic activity had enriched virulence genes and proteins, and negatively affected the barrier function of HNEC-ALI cultures. These findings support the notion of strain-level variation in S. aureus biofilms to be critical in the pathophysiology of CRS.

Role of Vitamin D and Its Receptors in the Pathophysiology of Chronic Rhinosinusitis.

OBJECTIVES: Chronic rhinosinusitis (CRS) is a disease that represents a challenging therapeutic problem. Vitamin D and its receptors (VDR) are involved in the regulation of the immune system and may play role in CRS. Objectives of this study were to assess the relationships between the total concentration of vitamin D (25VD3) in sera, vitamin D receptor (VDR) expression, 1α-hydroxylase expression, and clinical data, including age, gender, Sino-Nasal Outcome Test (SNOT-22), computerized tomography (CT) scan, allergy status, and vitamin D supplementation in CRS patients with (CRSwNP) and without nasal polyps (CRSsNP), and in a control group. METHODS: The studied group comprised 52 patients with CRS without nasal polyps (sNP), 55 with CRS with nasal polyps (wNP), and 59 in the control group. The endpoints were determined by appropriate methods. We conducted immunohistochemical staining of gathered tissue from the ostiomeatal complex for determination of VDR and 1α-hydroxylase. Analytical results were compared with clinical data as already noted. RESULTS: A decrease in VDR nuclear staining occurred in CRS patients as compared to controls. Insignificant differences were observed in 1α-hydroxylase, expression in all studied groups, while VDR and cytochrome CYP27B1 protein expression (1α-hydroxylase) correlated with clinical data. CONCLUSIONS: The data provide evidence that indicates that vitamin D and its receptor and enzymes may play a role in CRS.

Identification and Functional Evaluation of miR-4633-5p as a Biomarker and Tumor Suppressor in Metastatic Melanoma.

BACKGROUND/AIMS: Sinonasal mucosal melanoma (SMM) is a rare but extremely aggressive disease. Interestingly, however, as lethal as SMM, a few patients could survive for over 5 years without metastasis. However, biomarkers for metastatic SMM are lacking. METHODS: Laser-capture microdissection combined with microRNA microarray and RT-qPCR was performed in formalin-fixed paraffin-embedded tissue samples from SMM patients whose follow-up studies were carried out in parallel. In vitro cell proliferation and invasion assays, gelatin zymography, western blot analysis and RT-qPCR were performed in melanoma cell lines. RESULTS: In the discovery stage, miR-4633-5p expressed differentially in sinonasal mucosal melanoma patients with short and long disease-specific survival. Subsequent large-sample validation revealed that expression of miR-4633-5p was lower in metastatic SMM than in non-metastatic patients (P< 0.001). Moreover, miR-4633-5plow was able to identify metastatic SMM with specificity of 100% (5/5) and sensitivity of 87.5% (21/24). Multivariate analysis further pinpointed miR-4633-5p as an independent marker for metastasis (relative risk: 54.22, P< 0.001). In vitro, overexpression of miR-4633-5p suppressed the growth and invasiveness of melanoma cells through inhibiting activation of Akt pathway and secretion of MMP2, while knockdown of miR-4633-5p reversed the inhibitory effects. CONCLUSION: Our findings underpin miR-4633-5p as a predictive biomarker in metastatic SMM and a pivotal tumor suppressor that negatively regulates the invasive growth of melanoma cells. Quantitative detection of miR-4633-5p can diagnostically predict the risk of metastasis in SMM patients, which, in turn, may lead to more personalized treatment with better prognosis.

Study toward resolving the controversy over the definition of allergic fungal rhinosinusitis.

Dysbiosis of the microbiome on the airway mucosa leads to the development of chronic inflammatory and allergic disorders. The aim of this study was to consider the potential diagnostic criteria for allergic fungal rhinosinusitis (AFRS) and nonallergic fungal rhinosinusitis (FRS), and the role of fungal presence in an environment for the development of AFRS. In this study, 136 patients were divided into two groups: patients with positive specific immunoglobulin E (sIgE) and fungal finding (AFRS group), and patients with negative sIgE and positive fungal finding (FRS group). The study design included: anamnesis data, sIgE, eosinophil count and skin-prick test, rhinology and computerized tomography (CT) observation and mycological finding. Our results showed: (i) the prevalence in Serbia is: AFRS 1.3%, FRS 2.8%; (ii) 30.4% patients with sIgE+ had more often severe and recurrent chronic rhinosinusitis (CRS) (P = .005) and the presence of polyps (P = .025); (iii) 46.4% patients with sIgE+ had positive fungi on the sinonasal mucosa and were considered as AFRS; (iv) patients with AFRS had more frequent asthma (P = .024) and chronicity of CRS >10 years (P = .000). The persistent fungal presence and prolonged duration of CRS could be a silent threat for the progression of inflammation and development of FRS. Lavage with hypertonic-NaCl should be included in the everyday hygiene routine in an effort to decrease fungal load and antigenic exposure. The presence of allergological parameters and better response to corticosteroid therapy in AFRS patients should be considered as crucial diagnostic criteria for AFRS.

Optical Coherence Tomography as a Tool for Imaging the Sinonasal Mucosa in Patients: A Systematic Review.

Objectives: To summarize the current applications and potential uses of optical coherence tomography (OCT), a noninvasive imaging modality that uses near-infrared light to produce cross-sectional, high-resolution images of biologic tissues, for evaluating the sinonasal mucosa in patients. Methods: Original articles utilizing OCT to image the sinonasal mucosa in patients were identified from the PubMed, Embase, Cochrane Library, Web of Science, and Scopus databases using the search phrase: "Optical Coherence Tomography" AND (sinonasal OR intranasal OR sinus OR nose OR sinusitis OR rhinitis OR olfactory). Strength of evidence, quality of evidence, and risk of bias were measured using validated scales. Study results were qualitatively assessed. Results: Out of 1662 original records identified through database searching, 9 studies were included in the systematic review. Levels of evidence ranged from III to IV and quality of evidence ranged from moderate to very low. Endoscopic OCT systems as well as OCT systems integrated with surgical microscopes were described in the literature. Applications of OCT for imaging the sinonasal mucosa included identifying morphological patterns unique to individual diseases, detecting mucosal structural changes after medical therapies and procedures, and evaluating mucociliary clearance. Conclusions: Most studies investigating OCT imaging of the sinonasal mucosa featured small sample sizes and lacked control groups. While OCT imaging could be a useful adjunct for diagnosing sinonasal disorders and monitoring response to treatment in the future, additional high-quality studies are necessary to determine if the use of OCT imaging can lead to improved diagnostic accuracy and health outcomes for patients with sinonasal pathologies.

Pharmacokinetic Evidence of Steady and Sustained Drug Release from Long-Acting Implantable Corticosteroid Matrices for Chronic Rhinosinusitis.

BACKGROUND: The efficacy of topical corticosteroids is limited in chronic rhinosinusitis (CRS) due to rapid clearance from the nasal cavity and insufficient drug delivery to inflamed sinonasal passages. LYR-210 is an implantable corticosteroid matrix designed to provide up to 24 weeks of treatment to patients with CRS by locally delivering mometasone furoate (MF) to the sinonasal mucosa. In a randomized, controlled, dose-ranging LANTERN study, LYR-210 (7500 µg) achieved clinically relevant improvement in CRS cardinal symptom composite scores, the 22-item Sinonasal Outcome Test (SNOT-22), ethmoid opacification, and the need for rescue treatment at 24 weeks. OBJECTIVE: As the plasma MF concentrations of LYR-210 (2500 µg) and LYR-210 (7500 µg) were evaluated at weeks 4, 12, and 24 in the LANTERN study (data on file at Lyra Therapeutics, Inc.), this study aims to characterize the pharmacokinetic profiles of both doses of LYR-210 at earlier timepoints post-placement in patients with CRS. METHODS: Twenty-four surgically naïve adult patients with CRS were enrolled in an open-label, multicenter study and underwent in-office bilateral administration of LYR-210 (2500 µg) (n = 12 patients) or LYR-210 (7500 µg) (n = 12 patients) into the middle meatus. Plasma MF concentrations were determined pre-placement and 1-h post-placement (day 1), and on days 2, 3, 7, 14, 21, 28, 42, and 56 by liquid chromatography-tandem mass spectrometry. RESULTS: Both LYR-210 doses were well-tolerated with no serious adverse events. Systemic MF levels were dose-dependent and lower than reported values of other respiratory MF products. Plasma MF concentrations showed steady drug release from LYR-210 (2500 µg) and LYR-210 (7500 µg) that persisted through day 56. CONCLUSION: LYR-210 achieved dose-dependent, continuous local MF delivery at a steady rate with low systemic exposure for months.

Sinonasal blue nevus: a case report and review.

Blue nevus is a type of uncommon benign pigmented lesion in the skin or the mucosa of human body which is featured by pigmented dendritic melanocytes and spindled melanocytic cells. Sinonasal blue nevus is extremely rare. We reported a sinonasal blue nevus case with the background of pituitary adenoma, type 2 diabetes mellitus, and hypertension (including endoscopic and histological pictures). Further, the existing literature about blue nevus is reviewed. This paper puts a spotlight on the potential correlation between blue nevus with the endocrine system disorder and provides support for further experimental research.

P-glycoprotein regulates Staphylococcus aureus enterotoxin B-stimulated interleukin-5 and thymic stromal lymphopoietin secretion in organotypic mucosal explants.

BACKGROUND: T-helper 2 (Th2) inflammation is a hallmark of chronic rhinosinusitis with nasal polyps (CRSwNP) although the pathogenesis is poorly understood. P-glycoprotein (permeability glycoprotein, P-gp) is an efflux pump that is capable of regulating cytokine transport and is expressed within sinonasal mucosa. The purpose of this study was to examine if the oversecretion of interleukin 5 (IL-5) and thymic stromal lymphopoietin (TSLP) in CRSwNP could be explained through P-gp-mediated secretory pathways. METHODS: Fifteen ethmoid mucosal explants were harvested from patients with CRS (n = 10) and CRSwNP (n = 10) and stimulated with Staphylococcus aureus enterotoxin B (SEB). P-gp was inhibited using zosuquidar trihydrochloride (herein Zosuquidar). P-gp expression was measured using real-time polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). IL-5, IL-8, and TSLP secretion were quantified using ELISA. RESULTS: P-gp protein was overexpressed in CRSwNP (28.32 ± 25.94 ng/mL per mg explant) as compared to CRS (10.74 ± 8.61; p = 0.01, 2-tailed Mann-Whitney U test). There was no difference in messenger RNA (mRNA) expression. SEB induced a significant increase in IL-5 and TSLP but not IL-8 secretion relative to control in the CRSwNP explants only. Subsequent P-gp inhibition significantly reduced IL-5 and TSLP secretion (p = 0.04 for both, 2-tailed Student t test) to control levels. The concentration of IL-5 and TSLP secretion were strongly and significantly correlated to the concentration of P-gp within the same explant (IL-5: r = 0.791, p = 0.001; TSLP: r = 0.687, p = 0.003; 2-tailed Spearman's rank-order correlation). CONCLUSION: P-gp protein is expressed at higher concentrations in CRSwNP as compared to CRS. This overexpression directly contributes to the relative hypersecretion of IL-5 and TSLP. These findings suggest a novel mechanism for Th2 skewing in CRSwNP.

Malignant melanoma of the nasal cavity.

Malignant melanomas of the sinonasal mucosa are very uncommon, presenting frequently in advanced stages with usually a fatal course. Diagnosis becomes more difficult if it is amelanotic variety. Radical surgery is constrained because of increased morbidity & cosmesis, moreover radiotherapy and chemotherapy have little role if any to play. A case of 60 years old male who presented with nasal mass and epistaxis finally diagnosed as melanoma on histolopathology. Some other important aspects of this rare tumor are discussed here.