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Abstract: This study compared the pharmacokinetics of azithromycin (AZI) following administration of extended-release (ER) and immediate-release (IR) formulations in plasma and sinus mucosa in patients with chronic rhinosinusitis. Patients (n =71) were randomised 1:1 to receive a single dose of AZI-ER 2g or up to three doses of AZI-IR 500mg daily. Paired plasma and sinus tissue samples were taken during endoscopic sinus surgery at 2–168h (four patients per time point) after the first dose. Samples were measured by a validated liquid chromatography/mass spectrometry assay. Pharmacokinetics were determined using composite concentration–time profiles. Comparison between formulations showed that within the first 24h, the AZI area under the plasma concentration–time curve (AUC24) for ER was 5.2- and 7.0-fold higher than IR in plasma and sinus tissue, respectively. Comparison between matrices showed that the AUC24 and AUC168 in sinus tissue were 28.2- and 62.2-fold higher than in plasma for the ER formulation, whilst the AUC24 in sinus tissue was 21.1-fold higher than in plasma for IR formulation. These results indicated that AZI has good penetration into sinus tissue regardless of formulation; however, dosing of AZI-ER (2g) increased AZI exposure within the first 24h compared with the Day 1 dose of 500mg IR regimen. [Copyright &y& Elsevier]

We implemented a streamlined care pathway for patients undergoing endoscopic transsphenoidal (TSA) pituitary surgery. Select patients are recovered in the postanesthesia care unit and transferred to a step-down unit for intermediate neurologic care (INCU), with clinicians trained to manage cerebrospinal fluid leak, diabetes insipidus (DI), and other complications. We evaluated all TSA surgeries performed at 1 academic medical center from 7th January, 2017 to 30th March, 2020, collecting patient factors, tumor characteristics, cost variables, and outcomes. The INCU pathway was implemented on 7th January 2018. Pathway patients were compared with nonpathway patients across the study period. Outcomes were assessed using multivariate regression, adjusting for patient and surgical characteristics, including intraoperative cerebrospinal fluid leak, postoperative DI, and tumor dimensions. One hundred eighty-seven patients were identified. Seventy-nine were on the INCU pathway. Mean age was 53.5 years. Most patients were male (66%), privately insured (62%), and white (66%). Mean total cost of admission was $27,276. Mean length of stay (LOS) was 3.97 days. Use of the INCU pathway was associated with total cost reduction of $6376.33 (P < 0.001, 95% confidence interval [CI]: $3698.21–$9054.45) and LOS reduction by 1.27 days (P = 0.008, 95% CI: 0.33–2.20). In-hospital costs were reduced across all domains, including $1964.87 in variable direct labor costs (P < 0.001, 95% CI: $1142.08–$2787.64) and $1206.52 in variable direct supply costs (P < 0.001, 95% CI: $762.54–$1650.51). Pathway patients were discharged earlier despite a higher rate of postoperative DI (25% vs. 11%, P = 0.011), with fewer readmissions (0% vs. 6%, P = 0.021). A streamlined care pathway following TSA surgery can reduce in-hospital costs and LOS without compromising patient outcomes. [ABSTRACT FROM AUTHOR]

Rathke cleft cysts (RCCs) arise from the development of the Rathke pouch. Recurrence is common after either drainage or cyst removal. The endoscopic endonasal approach (EEA) is increasingly utilized for the management of RCC. Various techniques have been described to try to reduce the rates of recurrence. We studied the effect of fenestration with a nasoseptal flap (NSF) on recurrence rates by comparing a cohort of patients undergoing this technique to a cohort of patients undergoing conventional drainage. Patients who underwent EEA for RCC between 2011 and 2020 were identified and divided into 2 cohorts: conventional fenestration versus fenestration with NSF. Surgical approach, reconstructive method, and recurrences were recorded. Primary end point was symptomatic or radiographic recurrence. 21 patients were identified undergoing EEA. An NSF was used to line the cyst cavity in 11 cases. Conventional fenestration without mucosal reconstruction was performed in the remaining 10 cases. In the cases without NSF, 5 (50%) developed recurrence requiring revision surgery, while there was only one recurrence in the NSF group (P < 0.05). In patients requiring revision, all had an NSF placed and none had a second recurrence of their RCC. NSF placement into a fenestrated RCC is useful to prevent cyst reaccumulation and reoperation. Typical fenestration carries an unacceptably high rate of recurrence. [ABSTRACT FROM AUTHOR]

Chondrosarcomas of the skull base are rare tumors most commonly treated surgically with or without adjuvant radiation therapy. Using the National Cancer Database (NCDB), we analyzed overall survival (OS), treatment modalities, and prognosticators. The NCDB was queried for all cases of histologically confirmed skull base chondrosarcoma treated between 2004 and 2015, excluding patients with more than 1 malignant tumor, on palliative care, receiving unrelated concurrent treatments, or having less than 1 month of follow-up. The χ2 test for categorical variables, Cox proportional hazards models, and Kaplan-Meier log-rank analysis were used to test associations with the use of adjuvant radiation, OS, and survival time. A total of 498 patients with skull base chondrosarcoma were identified in the NCDB. Of them, 224 (45.0%) and 198 (39.8%) were treated with either surgery alone or surgery with adjuvant radiation therapy, respectively. Patients more likely to undergo surgery with adjuvant radiation had higher tumor grade (P = 0.008), later year of diagnosis (P = 0.002), positive surgical margins (P < 0.001), and treatment at an academic institution (P = 0.02). Patient, tumor, and socioeconomic factors associated with worse OS on multivariate analysis included the Charlson/Deyo Comorbidity Score ≥2 (P = 0.017), as well as clear cell (P = 0.02) and dedifferentiated (P = 0.006) histology. Age, tumor grade, tumor size, treatment modality, insurance status, facility type, and urban/rural population did not show a statistically significant impact on OS. The mainstay of treatment for skull base chondrosarcoma is surgery, with consideration of adjuvant radiation. This study demonstrated worse overall survival associated with more frail patients and aggressive histology types. It is important to consider these factors when planning the clinical management of these patients. [ABSTRACT FROM AUTHOR]

Esthesioneuroblastoma (ENB) is a rare sinonasal malignancy arising from olfactory neuroepithelium. Recurrence typically occurs locoregionally at the primary site or in the form of cervical metastasis. Delayed local recurrence away from the initial primary site is exceedingly rare. Retrospective review of 4 patients with histologically confirmed extraprimary local recurrence of ENB was performed with review of the literature. All cases initially presented with ENB isolated to the cribriform plate(s) treated with primary surgical resection and adjuvant radiotherapy. The first patient had ENB recurrence 8 years posttreatment involving the right orbit. She later developed metastases to the spine, neck, and mandible requiring composite resection and 4 courses of radiotherapy. The second patient had ENB recurrence of the dorsal septum 9 years posttreatment with cervical metastases requiring septectomy, bilateral neck dissection, and radiotherapy. The third patient had ENB recurrence 7 years posttreatment in the posterior nasopharynx requiring endonasal nasopharyngectomy. Finally, the fourth patient had ENB recurrence 12 years posttreatment in the sphenopalatine foramen, which was endoscopically resected. At the time of this review, all 4 patients were disease free at 32, 21, 4, and 24 months posttreatment follow-ups, respectively. This case series describes the rare phenomenon of delayed extraprimary local recurrence of histologically confirmed ENB. Treatment of extraprimary recurrences, analogous to other forms of ENB, should include primary surgical resection with adjuvant radiotherapy for generally favorable outcomes. Long-term close follow-up based on symptoms, endoscopy, and imaging is essential because of the risk of delayed recurrence. [ABSTRACT FROM AUTHOR]

Protease-activated receptor 2 (PAR-2) is activated by secreted proteases from immune cells or fungi. PAR-2 is normally expressed basolaterally in differentiated nasal ciliated cells. We hypothesized that epithelial remodeling during diseases characterized by cilial loss and squamous metaplasia may alter PAR-2 polarization. Here, using a fluorescent arrestin assay, we confirmed that the common fungal airway pathogen Aspergillus fumigatus activates heterologously-expressed PAR-2. Endogenous PAR-2 activation in submerged airway RPMI 2650 or NCI-H520 squamous cells increased intracellular calcium levels and granulocyte macrophage-colony-stimulating factor, tumor necrosis factor α, and interleukin (IL)-6 secretion. RPMI 2650 cells cultured at an air-liquid interface (ALI) responded to apically or basolaterally applied PAR-2 agonists. However, welldifferentiated primary nasal epithelial ALIs responded only to basolateral PAR-2 stimulation, indicated by calcium elevation, increased cilia beat frequency, and increased fluid and cytokine secretion. We exposed primary cells to disease-related modifiers that alter epithelial morphology, including IL-13, cigarette smoke condensate, and retinoic acid deficiency, at concentrations and times that altered epithelial morphology without causing breakdown of the epithelial barrier to model early disease states. These altered primary cultures responded to both apical and basolateral PAR-2 stimulation. Imaging nasal polyps and control middle turbinate explants, we found that nasal polyps, but not turbinates, exhibit apical calcium responses to PAR-2 stimulation. However, isolated ciliated cells from both polyps and turbinates maintained basolateral PAR-2 polarization, suggesting that the calcium responses originated from nonciliated cells. Altered PAR-2 polarization in disease-remodeled epithelia may enhance apical responses and increase sensitivity to inhaled proteases. [ABSTRACT FROM AUTHOR]

Bitter taste receptors (taste family 2 bitter receptor proteins; T2Rs), discovered in many tissues outside the tongue, have recently become potential therapeutic targets. We have shown previously that airway epithelial cells express several T2Rs that activate innate immune responses that may be important for treatment of airway diseases such as chronic rhinosinusitis. It is imperative to more clearly understand what compounds activate airway T2Rs as well as their full range of functions. T2R isoforms in airway motile cilia (T2R4, -14, -16, and -38) produce bactericidal levels of nitric oxide (NO) that also increase ciliary beating, promoting clearance of mucus and trapped pathogens. Bacterial quorum-sensing acyl-homoserine lactones activate T2Rs and stimulate these responses in primary airway cells. Quinolones are another type of quorum-sensing molecule used by Pseudomonas aeruginosa. To elucidate whether bacterial quinolones activate airway T2Rs, we analyzed calcium, cAMP, and NO dynamics using a combination of fluorescent indicator dyes and FRET-based protein biosensors. T2R-transfected HEK293T cells, several lung epithelial cell lines, and primary sinonasal cells grown and differentiated at the air--liquid interface were tested with 2-heptyl-3-hydroxy-4-quinolone (known as Pseudomonas quinolone signal; PQS), 2,4-dihydroxyquinolone, and 4-hydroxy-2-heptylquinolone (HHQ). In HEK293T cells, PQS activated T2R4, -16, and -38, whereas HHQ activated T2R14. 2,4-Dihydroxyquinolone had no effect. PQS and HHQ increased calcium and decreased both baseline and stimulated cAMP levels in cultured and primary airway cells. In primary cells, PQS and HHQ activated levels of NO synthesis previously shown to be bactericidal. This study suggests that airway T2R-mediated immune responses are activated by bacterial quinolones as well as acyl-homoserine lactones. [ABSTRACT FROM AUTHOR]

Chronic rhinosinusitis has a significant impact on patient quality of life, creates billions of dollars of annual healthcare costs, and accounts for ~20% of adult antibiotic prescriptions in the United States. Because of the rise of resistant microorganisms, there is a critical need to better understand how to stimulate and/or enhance innate immune responses as a therapeutic modality to treat respiratory infections. We recently identified bitter taste receptors (taste family type 2 receptors, or T2Rs) as important regulators of sinonasal immune responses and potentially important therapeutic targets. Here, we examined the immunomodulatory potential of flavones, a class of flavonoids previously demonstrated to have antibacterial and anti-inflammatory effects. Some flavones are also T2R agonists. We found that several flavones inhibit Muc5AC and inducible NOS up-regulation as well as cytokine release in primary and cultured airway cells in response to several inflammatory stimuli. This occurs at least partly through inhibition of protein kinase C and receptor tyrosine kinase activity. We also demonstrate that sinonasal ciliated epithelial cells express T2R14, which closely co-localizes (<7 nm) with the T2R38 isoform. Heterologously expressed T2R14 responds to multiple flavones. These flavones also activate T2R14-driven calcium signals in primary cells that activate nitric oxide production to increase ciliary beating and mucociliary clearance. TAS2R38 polymorphisms encode functional (PAV: proline, alanine, and valine at positions 49, 262, and 296, respectively) or nonfunctional (AVI: alanine, valine, isoleucine at positions 49, 262, and 296, respectively) T2R38. Our data demonstrate that T2R14 in sinonasal cilia is a potential therapeutic target for upper respiratory infections and that flavones may have clinical potential as topical therapeutics, particularly in T2R38 AVI/AVI individuals. [ABSTRACT FROM AUTHOR]

The article describes three cases of intravascular papillary endothelial hyperplasia of the skull base and intracranial compartment. The first case involves a 56-year-old woman who presented with chronic, recurrent sinus infections. The second case involves a 39-year-old woman who presented with multiple syncopal episodes and chose surgical removal of the lesion. The third case involves a 73-year-old man who presented with intractable seizures.

Abstract: Introduction: Postoperative CSF leak is the most common complication of endoscopic endonasal approach (EEA) to skull base lesions. Endoscopic multilayer closure of skull base defect using pedicled nasoseptal flaps (NSF) based off the sphenopalatine artery reduces CSF leaks. EEA robustly expands in surgical arena, yet postoperative imaging evaluation remains poorly studied. This work illustrates normal MR imaging appearance of skull base reconstruction utilizing NSFs during immediate postoperative period. Methods: We retrospectively identified patients who had skull base reconstructions utilizing NSFs following EEAs and immediate postoperative-enhanced brain MRI. NSFs and free grafts were evaluated for signal intensity, thickness, configuration, enhancement, vascular pedicle of NSF, relationship in multilayer reconstruction, and defect coverage. Imaging findings were correlated with surgical technique and CSF leaks. Results: Twenty-eight patients had 26 multilayer reconstructions and 34 NSFs. Twenty-nine NSFs showed enhancing C-shaped arc at the skull base. Of those, 26 flaps (90%) were confidently identified by visualization of their vascular pedicles, 3 were not distinguishable from adjacent mucosa and pedicles were not identified. Five NSFs showed no enhancement (1 CSF leak). Twenty-seven enhancing NSFs approximated defects with close abutment to free grafts. One flap was displaced; one incompletely covered the defect (2 CSF leaks). Fisher exact test demonstrated an association between incomplete defect coverage and displacement of NSFs with CSF leak (P =0.05). Conclusion: Endoscopic skull base reconstruction utilizing NSF has characteristic MR imaging appearance. Non-enhancing mucosal gap or displacement of NSF may indicate incomplete defect coverage, identifying patients at risk for CSF leak. [Copyright &y& Elsevier]

This case video demonstrates a multidisciplinary approach to resection of a juvenile nasopharyngeal angiofibroma highlighting direct intratumoral onyx embolization. The patient is a 14-year-old boy who presented with a 1-month history of worsening epistaxis and nasal congestion. Preoperative magnetic resonance imaging demonstrated a 4.5 x 3 x 3 cm lobulated mass in the right pterygomaxillary space, sphenoid, and the nasopharynx adjacent to the cavernous carotid. Given the high vascularity of the lesion, intratumoral onyx embolization was undertaken, which significantly reduced intraoperative blood loss in this case. The present video demonstrates the technique for safe direct intratumoral onyx embolization and its role in significantly reducing intraoperative blood loss (Video 1). Postoperatively, the patient made an uncomplicated recovery. The patient consented to the procedure. [ABSTRACT FROM AUTHOR]