Role of C3a as a Novel Regulator of 25(OH)D3 to 1α,25-Dihydroxyvitamin D3 Metabolism in Upper Airway Epithelial Cells.

In patients with chronic rhinosinusitis with nasal polyps, primary human sinonasal epithelial cell (HSNEC) 1α-hydroxylase levels are reduced, as is their ability to metabolize 25-hydroxycholecalciferol [25(OH)D3] to its active metabolite, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3]. In this study, we sought to identify the factor responsible for the regulation of HSNEC metabolism of 25(OH)D3, focusing on C3 and C3a. Multiple inhaled irritants trigger the release of complement components, C3 and C3a, leading to suppression of 1α-hydroxylase levels in HSNECs. Recombinant C3a was able to decrease 1α-hydroxylase and impair 25(OH)D3 to 1,25(OH)2D3 metabolism, while addition of a C3a receptor antagonist restored conversion. Conversely, 1,25(OH)2D3 suppressed Aspergillus fumigatus-induced C3 and C3a levels in HSNEC supernatant. Given the ability of 1,25(OH)2D3 to modulate LL37 in other cell types, we examined its regulation in HSNECs and relationship to C3a. 1,25(OH)2D3 stimulated the secretion of LL37, whereas A. fumigatus and C3a suppressed it. Conversely, LL37 reduced the release of C3/C3a by HSNECs. Lastly, oral steroid use and in vitro dexamethasone application both failed to increase 1α-hydroxylase or reduce C3a levels. In summary, in this article, we describe for the first time a novel relationship between complement activation and local vitamin D metabolism in airway epithelial cells. The presence of elevated C3/C3a in patients with asthma and/or chronic rhinosinusitis with nasal polyps may account for their impaired HSNEC 25(OH)D3 to 1,25(OH)2D3 metabolism and explain why they receive limited therapeutic benefit from oral vitamin D3 supplementation.

Transformation from Sinonasal Seromucinous Hamartoma to Adenocarcinoma: A Case Report.

OBJECTIVES: Sinonasal hamartomas are benign neoplasms composed of disorganized mature tissue elements. Epithelial variants include respiratory epithelial adenomatoid hamartoma (REAH) and seromucinous hamartoma (SMH). Malignant transformation of REAH is rarely reported; however, the malignant transformation of SMH to adenocarcinoma has not been described. We report the first case of a transformation from SMH to adenocarcinoma. METHODS: The medical records of a patient presenting with sinonasal SMH with malignant transformation to adenocarcinoma were reviewed. The NCBI database was queried for the literature regarding SMH and malignant transformation of sinonasal hamartomas. RESULTS: A 39-year-old man presented with a left nasal mass, nasal obstruction, and epistaxis. Computed tomography and magnetic resonance imaging demonstrated a nonaggressive and heterogeneous left nasal mass with involvement of the middle turbinate and posterior ethmoid sinuses. He underwent endoscopic sinus surgery with complete excision of the mass. Pathology revealed SMH with focal areas of transition to low-grade adenocarcinoma characterized by stromal invasion but no bony, perineural, or lymphovascular invasion. Adjuvant treatment was not recommended. Literature review revealed no reported cases of malignant transformation of SMH. CONCLUSION: We report the first case of malignant transformation of SMH. Patients with SMH must be counseled that there is an extremely rare and potentially unrecognized risk of malignancy that may influence treatment and postoperative monitoring.

Recalcitrant rhinosinusitis, innate immunity, and mannose-binding lectin.

BACKGROUND: Mannose-binding lectin (MBL) is a protein produced by the liver that participates in innate immunity by tagging the surface of microbes for opsonization. Mannose-binding lectin deficiency is present in 7% of the population and has been implicated in recurrent respiratory tract infections in children. Mannose-binding lectin deficiency has not been explored in rhinosinusitis but is associated with increased mortality in adult pneumococcal infection. The purpose of this report is to describe a tertiary rhinology patient experience with MBL deficiency and recalcitrant rhinosinusitis. METHODS: This retrospective case series report characterizes predominantly adult patients with low MBL levels from January 2010 to June 2012. Indications for MBL testing, sinus culture data, immunological testing results, and treatments used to control rhinosinusitis are described. RESULTS: Mannose-binding lectin levels were deficient in 12 of 36 patients (33.3%) tested. IgG subclasses were abnormally low in 5 of 12 patients; IgA was normal in 11 of 12 patients; and IgM was normal in 11 of 12 patients. Staphylococcus aureus, coagulase-negative Staphylococcus species, and Pseudomonas aeruginosa, known to be "tagged" by MBL, were the most common organisms grown on culture. Treatments included culture directed systemic antimicrobial therapy and topical steroids/antibiotics. CONCLUSION: Mannose-binding lectin, an important component of the lectin complement pathway and innate immunity, is possibly associated with recalcitrant adult rhinosinusitis. Steroid/antibiotic irrigations appear to benefit patients with recalcitrant rhinosinusitis and possibly those with MBL deficiency. Given that the prevalence of MBL deficiency in this case series is 4 times that seen in the normal population, additional investigations are warranted to further elucidate the role of MBL deficiency in rhinosinusitis.

Case Report: Management of Acanthamoeba Rhinosinusitis in a Patient with Chronic Lymphocytic Leukemia.

Infections caused by free-living amoebae pose a significant public health threat owing to growing populations of immunocompromised hosts combined with diagnostic delays, treatment difficulties, and high case fatality rates. Nasopharyngeal infections caused by Acanthamoeba are rare and the optimal treatment is not well established. We report a case of Acanthamoeba rhinosinusitis in a patient with chronic lymphocytic leukemia who presented with headaches and chronic rhinosinusitis refractory to multiple courses of antibiotics. A diagnosis of Acanthamoeba rhinosinusitis was established through broad-range polymerase chain reaction testing on sinus tissue. The patient had a favorable response to treatment, which included surgical debridement, cessation of immunosuppressants, and a three-drug regimen consisting of miltefosine, fluconazole, and sulfadiazine.

Sinonasal and Skull Base Metastatic Renal Cell Carcinoma: A Case Series.

Metastatic lesions to the paranasal sinuses and skull base, while rare, carry a poor prognosis. Renal cell carcinoma has been reported in multiple case reports to be one of the most common distant malignancies to spread to the paranasal sinuses; however, it is often unrecognized by physicians, and thus treatment is delayed. To increase awareness of this disease process, we describe three cases of metastatic renal cell carcinoma to the sinonasal cavity, which is the largest case series in the literature to date.

The Transverse Turbinate Line: A Reliable Landmark for the Maxillary Sinus Natural Ostium.

OBJECTIVES: Approximating the maxillary sinus natural ostium's (MSNO) natural position during anterograde surgery is challenging, as only a single visual "landmark," the maxillary line, is routinely offered to guide the identification of the MSNO in three-dimensional space. Despite almost 40 years of endoscopic sinus surgery (ESS) experience in North America, maxillary recirculation and discontinuity between the natural and surgical ostia are commonly encountered during revision ESS. Consequently, we feel an additional visual landmark would assist in localizing the MSNO with or without image guidance. In this study, we aim to provide a second reliable landmark in the sinonasal cavity. METHODS: We present a cadaveric anatomical landmark series that provides a second visual landmark for the MSNO, which we have labeled the transverse turbinate line (TTL): a 2-millimeter zone of confidence for the craniocaudal positioning of the MSNO that can be combined with the anteroposterior (AP) landmark of the maxillary line. RESULTS: In our study, 40 cadaveric sinuses were dissected, and the TTL was found to correspond consistently with the zone between the superior and inferior aspects of the MSNO. CONCLUSION: We anticipate that this second relational landmark may decrease the time required for anterograde access to the MSNO in trainees, increase the accuracy of identification, and translate to lower long-term recirculation and maxillary surgery failure rates. LEVEL OF EVIDENCE: NA Laryngoscope, 133:3285-3291, 2023.

Sinonasal IgG4-related sclerosing disease: A rare entity and challenging diagnosis.

Objectives: To describe the rare presentation, imaging and histological findings, and treatments in patients with IgG4-related disease (IgG4-RD) and diagnostic pitfalls and difficulties. Methods: Cases of sinonasal IgG4-RD were retrieved, and clinicopathological features were reviewed. Results: Seven cases of sinonasal IgG4-RD were identified over an 11-year period, including four males and three females, with an age range of 19-66 years (median 58 years). Patients presented with symptoms related to the mass effect of the lesions or the destructive nature of the disease including fullness, swelling, obstruction, and pain. Serum IgG and IgG4 levels, IgG/IgG4 ratios, storiform fibrosis, obliterative phlebitis, and plasma cell infiltration were seen in varying proportions. Bony erosion and tissue inflammation were present in some cases. Conclusion: Sinonasal IgG4-RD is exceedingly rare among other IgG4-RD and varied in its clinical presentation thus posing as a clinically difficult disease to diagnosis. Proper clinical, pathological, and immunohistopathological analysis is required for accurate diagnosis. Such disease should be considered in all cases of similar presentation to those in this study.Level of Evidence: 4.

Utilization of Nasal Mucus to Investigate the Pathophysiology of Chronic Rhinosinusitis.

BACKGROUND: Nasal mucus is proving to be a useful means by which to study the pathogenesis of chronic rhinosinusitis (CRS). Given the increase in publications examining nasal mucus and the lack of a review on this topic, we will focus on this noninvasive approach to studying CRS. Particular attention will be drawn towards inflammatory cytokines and biomarkers and their influence on disease severity. METHODS: A literature review of papers published in English pertaining to nasal mucus was performed using the PubMed database. The search utilized combinations of the following keywords: sinusitis, polyps, sample collection, nasal mucus, or nasal secretion. Studies solely on acute or bacterial sinusitis, allergic rhinitis, or cystic fibrosis were not included. RESULTS: A wide variety of materials and methods have been used to collect nasal mucus. Numerous assay types have been performed with the most common being ELISA, cytometric bead array, and proteomics. Most studies have focused on examining the levels of Th1/Th2 cytokines along with chemokines associated with type 2 immunity. Other factors identified include growth factors, senescence-associated proteins, complement, and antimicrobial defenses have also been identified. Nasal mucus cytokines have proven useful in cluster analysis and predicting postoperative improvement in Sino-nasal Outcome Test (SNOT-22) scores. One limitation of the use of nasal mucus is that some studies have suggested that nasal mucus does not always reflect the tissue microenvironment. CONCLUSIONS: Nasal mucus represents a critical tool by which to examine the sinonasal microenvironment in a noninvasive manner. Unlike studies of tissue, it can be utilized in both surgically and medically managed patients and avoids the trauma of biopsies. However, studies are still needed to determine the most effective method for nasal mucus collection. Studies should also take care to confirm that nasal mucus markers do, in fact, reflect the levels of the product studied in the tissue.

Detection of Microbiota in Post Radiation Sinusitis.

OBJECTIVES: A shift in the microbiota of chronic rhinosinusitis has been described after radiotherapy to the sinonasal cavity and skull base. There is a paucity of literature characterizing the bacteriology of post radiation sinusitis using next-generation gene sequencing techniques. This study aims to describe and compare the microbial flora of rhinosinusitis after radiotherapy using both culture and molecular techniques for microbial DNA detection. METHODS: The medical records of patients treated with external beam radiation for sinonasal, nasopharyngeal, or skull base malignancy were reviewed at a tertiary care facility. Patients' sinonasal cavities were swabbed for routine culture or brushed for molecular gene sequencing. Swab specimens were processed for standard microbial culture, and brush specimens were sent for gene sequencing at Micro GenX Laboratory (Lubbock, Texas, USA). RESULTS: Twenty-two patients were diagnosed with chronic sinusitis after undergoing radiotherapy. Staphylococcus aureus was the most common organism identified by both culture and gene sequencing, followed by Pseudomonas aeruginosa. Several additional organisms were detected by gene sequencing that were not isolated by routine culture techniques. Gene sequencing identified pathogens differing from culture results in 50% of patients examined. CONCLUSION: The bacteriology of post radiation sinusitis appears to resemble the microorganisms responsible for chronic sinusitis in healthy adults. Next generation gene sequencing techniques may reveal additional organisms responsible for sinusitis and provide complementary results that may impact the medical treatment of post radiation sinusitis.

MYB-activated models for testing therapeutic agents in adenoid cystic carcinoma.

OBJECTIVE: There are no effective systemic therapies for adenoid cystic cancer (ACC) and lack of tumor lines and mouse models have hindered drug development.We aim to develop MYB-activated models for testing new therapeutic agents. MATERIALS AND METHODS: We studied new ACC patient-derived xenograft (PDX) models and generated a matched cell line from one patient. In addition, we generated a genetically-engineered MYB-NFIB mouse model (GEMM) that was crossed with Ink4a+/-/Arf+/- mice to study tumor spectrum and obtain tumor lines. Using human and murine ACC-like tumor lines, we analyzed MYB expression by RNA-Seq and immunoblot and tested efficacy of new MYB inhibitors. RESULTS: We detected MYB-NFIB transcripts in both UFH1 and UFH2 PDX and observed tumor inhibition by MYB depletion using shRNA in vivo. We observed rapid loss of MYB expression when we cultured UFH1 in vitro, but were able to generate a UFH2 tumor cell line that retained MYB expression for 6 months. RNA-Seq expression detected an ACC-like mRNA signature in PDX samples and we confirmed an identical KMT2A/MLL variant in UFH2 PDX, matched cell line, and primary biopsy. Although the predominant phenotype of the MYB-NFIB GEMM was B-cell leukemia, we also generated a MYB-activated ACC-like mammary tumor cell line. We observed tumor inhibition using a novel MYB peptidomimetic in both human and murine tumor models. CONCLUSIONS: We generated and studied new murine and human MYB-activated tumor samples and detected growth inhibition with MYB peptidomimetics. These data provide tools to define treatment strategies for patients with advanced MYB-activated ACC.

Isolated leptomeningeal progression from sinonasal carcinomas: Implications for staging workup and treatment.

PURPOSE: To evaluate the rate and risk factors of isolated leptomeningeal progression in sinonasal carcinomas. METHODS: We retrospectively reviewed imaging and clinical records to determine progression patterns, and estimated rates using the Kaplan-Meier method. We evaluated risk factors using proportional hazard regression. RESULTS: We analyzed 120 patients who received adjuvant or primary radiotherapy for sinonasal carcinomas. Most patients had T4 disease (68%) and underwent surgery (84%) and chemotherapy (72%). Twenty-seven (23%) patients developed distant metastases (DM), including 20 (17%) with isolated DMs. Leptomeningeal progression was the most common site of isolated DMs (n = 9; 45%) with an average disease-free interval of 1.2 years (0.1-4.3 years). High-grade histology (P = 0.0003), intracranial invasion (P < 0.0001), and neuroendocrine histology (P = 0.06) were associated with increased risk. CONCLUSIONS: Isolated leptomeningeal progression is a common pattern of DM in advanced sinonasal carcinomas. We recommend adding cerebrospinal fluid cytology and contrast-enhanced spine MRI to routine staging evaluations for high-risk patients.

Significant orbital and intracranial complications from balloon sinus dilation as a stand-alone and powered dissector-assisted procedure.

Chronic rhinosinusitis is one of the most common chronic conditions affecting millions of people in the United States every year. Balloon sinus dilation is a minimally invasive intervention that was introduced as a possible alternative to endoscopic sinus surgery (ESS). In select patients, balloon dilation has been advocated as a relatively safe procedure with comparable efficacy to traditional ESS. Over the past 12 months, significant intracranial and intraorbital complications have been observed on five patients who underwent balloon sinus dilation as a stand-alone procedure, as well as what could be termed a power dissector-assisted balloon dilation procedure, obviating the need for a wide sinusotomy or any significant ethmoid surgery, which are typically performed to establish anatomical landmarks before the introduction of power instruments into dependent sinus cavities. Laryngoscope, 2455-2459, 2018.

Low-literacy interventions to promote discussion of prostate cancer: a randomized controlled trial.

BACKGROUND: Professional organizations recommend that physicians discuss prostate cancer with patients to make individual screening decisions. However, few studies have tested strategies to encourage such discussions, particularly among high-risk populations. We examined the effects of two low-literacy interventions on the frequency of prostate cancer discussion and screening. DESIGN: Randomized, blinded, controlled trial with concealed allocation. SETTING/PARTICIPANTS: Inner-city primary care clinic, serving a predominately African-American population. Participants were men aged 45-70 with no history of prostate cancer, presenting for a regular appointment. INTERVENTIONS: While waiting to see their physician, patients received a patient education handout on prostate cancer screening (PtEd), a handout simply encouraging patients to talk to their doctor about prostate cancer (Cue), or a control handout. The interventions did not advocate for or against screening. MEASURES: Patient-reported discussion of prostate cancer with the physician and chart reviews determine prostate-specific antigen (PSA) test orders and performance of digital rectal examination (DRE). Adjusted odds ratios (aOR) and 95% confidence intervals (CI) were computed. Data were collected in 2003, and analyses were completed in 2006. RESULTS: Most of the 250 subjects (90.4%) were African American and 78.8% read below the ninth grade level. Overall, 48.4% reported discussing prostate cancer during the appointment. Compared to the control group (37.3%), discussions were significantly more common in the Cue group (58.0%, aOR=2.39 [1.26-4.52]), as well as in the PtEd group (50.0%, aOR=1.92 [1.01-3.65]). When prostate cancer was discussed, patients in the intervention groups more commonly initiated the conversation (47.6% PtEd and 40.0% Cue, vs 9.7% control, p<0.01 for each comparison to control). Compared to the control group (2.4%), PSA test orders increased in the PtEd group (14.1%, aOR=7.62 [1.62-35.83]) and in the Cue group (12.3%, aOR=5.86 [1.24-27.81]). Documentation of DRE did not change significantly (4.7% PtEd, 6.2% Cue, and 6.0% control). CONCLUSIONS: Two simple low-literacy interventions significantly increased discussion of prostate cancer and PSA test orders but not performance of DRE. Both interventions were effective in empowering low-literacy patients to initiate conversations about prostate cancer with their physician.

Spontaneous cerebrospinal fluid leak from the optic canal.

OBJECTIVE: To present a case of successful repair of a spontaneous cerebrospinal fluid leak in a previously unreported anatomic site. METHODS: Retrospective chart review. RESULTS: A 48-year-old woman developed a spontaneous cerebrospinal fluid leak from the optic nerve sheath and underwent a multilayer endoscopic closure with no damage to the optic nerve. CONCLUSION: Endoscopic surgeons can successfully repair cerebrospinal fluid leaks from the optic nerve sheath without causing loss of vision.

Outcomes of Sinonasal Cancer Treated With Proton Therapy.

PURPOSE: To report disease outcomes after proton therapy (PT) for sinonasal cancer. METHODS AND MATERIALS: Eighty-four adult patients without metastases received primary (13%) or adjuvant (87%) PT for sinonasal cancers (excluding melanoma, sarcoma, and lymphoma). Common histologies were olfactory neuroblastoma (23%), squamous cell carcinoma (22%), and adenoid cystic carcinoma (17%). Advanced stage (T3 in 25% and T4 in 69%) and high-grade histology (51%) were common. Surgical procedures included endoscopic resection alone (45%), endoscopic resection with craniotomy (12%), or open resection (30%). Gross residual disease was present in 26% of patients. Most patients received hyperfractionated PT (1.2 Gy [relative biological effectiveness (RBE)] twice daily, 99%) and chemotherapy (75%). The median PT dose was 73.8 Gy (RBE), with 85% of patients receiving more than 70 Gy (RBE). Prognostic factors were analyzed using Kaplan-Meier analysis and proportional hazards regression for multiple regression. Dosimetric parameters were evaluated using logistic regression. Serious, late grade 3 or higher toxicity was reported using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4. The median follow-up was 2.4 years for all patients and 2.7 years among living patients. RESULTS: The local control (LC), neck control, freedom from distant metastasis, disease-free survival, cause-specific survival, and overall survival rates were 83%, 94%, 73%, 63%, 70%, and 68%, respectively, at 3 years. Gross total resection and PT resulted in a 90% 3-year LC rate. The 3-year LC rate was 61% for primary radiation therapy and 59% for patients with gross disease. Gross disease was the only significant factor for LC on multivariate analysis, whereas grade and continuous LC were prognostic for overall survival. Six of 12 local recurrences were marginal. Dural dissemination represented 26% of distant recurrences. Late toxicity occurred in 24% of patients (with grade 3 or higher unilateral vision loss in 2%). CONCLUSIONS: Dose-intensified, hyperfractionated PT with or without concurrent chemotherapy results in excellent LC after gross total resection, and results in patients with gross disease are encouraging. Patients with high-grade histology are at greater risk of death from distant dissemination. Continuous LC is a major determinant of survival justifying aggressive local therapy in nearly all cases.

Evidence that human papillomavirus causes inverted papilloma is sparse.

BACKGROUND: Controversy exists regarding the pathogenesis of inverted papilloma as it relates to the involvement of human papillomavirus (HPV). The purpose of this report is to describe the prevalence of HPV in nondysplastic, "early inverted papilloma" and to summarize HPV detection rates in the general population and in other HPV related neoplasia. METHODS: This case series report characterizes consecutive inverted papilloma patients from January 2005 to August 2012 with regard to smoking history, dysplasia, and HPV detection rates. Presence or absence of low/high risk HPV was determined by standardized in situ hybridization DNA probes. Medline literature review was performed to determine the prevalence of HPV in inverted papilloma without moderate or severe dysplasia. RESULTS: Thirty-six consecutive patients were identified with an average age of 63.6 (range, 40-84) years; gender: 23 men, 13 women. More than half (55%) were active or former smokers (14% active and 41% former). High/low risk HPV was present in 1 in 36 (2.7%) patients and 1 in 36 (2.7%) had mild dysplasia. In the literature review: (1) HPV was detected in 16.4% of inverted papilloma without dysplasia; (2) oral cavity HPV detection was 4.2% to 11.4% in the normal population; and (3) HPV was normally detected in 85% to 95% of HPV-related neoplasia. CONCLUSION: Given histological features of inverted papilloma and comparatively low detection rates of HPV in inverted papilloma without dysplasia (2.7%), as well as the summary of the world literature, HPV is not related to the initial pathogenesis of inverted papilloma or inverted papilloma's tendency to persist or recur. It is postulated that since inverted papilloma is more an inflammatory polyp, it is susceptible to secondary HPV infection because of its metaplasia. Tobacco and other causes of respiratory epithelium remodeling are more plausible explanations for the initial tissue transformation to inverted papilloma.

An update on attitudes and use of image-guided surgery.

BACKGROUND: The aim of this study was to compare 2010 access to, usage of, and attitudes toward image-guided surgery (IGS) for endoscopic sinus surgery and anterior skull-base surgery to those in 2005. METHODS: A mail survey of American Rhinologic Society (ARS) members was performed in January 2010. Results were compared to results from the same survey mailed in January 2005. RESULTS: Significantly more respondents in 2010 had access to IGS compared to 2005 (94.6% vs 86%, p = 0.002). Compared to 2005, IGS was used in a greater percentage of cases in 2010 (p < 0.0001). More respondents in 2010 felt that IGS is indicated for primary anterior ethmoidectomy, revision anterior ethmoidectomy, primary total ethmoidectomy, Lothrop procedure, cerebrospinal fluid (CSF) leak repair, tumor surgery, orbital decompression, and optic nerve decompression (all p < 0.05). Similar to 2005, region, residency completion date, and availability of IGS in residency had no measureable effect on attitudes toward IGS. As in 2005, availability of IGS was associated with a greater feeling of its necessity in 2010. CONCLUSION: IGS availability has grown significantly and nearly all ARS members now have access. Estimates of use by respondents have also increased over the last 5 years, particularly for ethmoid and advanced procedures. Revision surgery and advanced procedures continue to be chief indications for IGS use. As in 2005, the results of this survey reflect the opinion of the respondents, and do not necessarily reflect the views of the ARS or of practicing otolaryngologists in general.