Initial Presentation of Granulomatosis with Polyangiitis as Progressive Skull Base Osteomyelitis.

A healthy man in his 30s presented with a 2-week history of severe bitemporal pain and pressure. He was initially treated for presumed acute rhinosinusitis, but his symptoms continued to worsen and underwent endoscopic sinus surgery at an outside community facility. He developed left abducens nerve palsy postoperatively, and magnetic resonance imaging (MRI) demonstrated evidence of extensive skull base osteomyelitis. He was initiated on intravenous (IV) broad-spectrum antibiotics but was subsequently found to have prostatic and submandibular sterile fluid collections. The patient subsequently developed new right abducens and left vagal nerve palsies and underwent revision endoscopic sinus surgery. Pathology revealed extensive inflammation, necrotizing granulomas, and evidence of small and medium vessel vasculitis. Extensive laboratory workup was negative, except for anti-PR-3 antibody positivity. Given the characteristic findings on pathology and laboratory findings, the patient was diagnosed with granulomatosis with polyangiitis (GPA). High-dose glucocorticoid therapy as well as rituximab infusion were promptly initiated. He had marked improvement in his symptoms and resolution of his right CN VI palsy but left-sided CN VI and CN X palsies persisted. This patient presented without the typical rhinologic manifestations of GPA, and rather presented with progressive sinusitis, skull base osteomyelitis with associated cranial neuropathies, and aseptic systemic abscesses. Prompt diagnosis of GPA is particularly important in those with otorhinolaryngological manifestations, as early initial immunosuppressive therapy has been linked to lower relapse and mortality rates. Vigilance and early differentiation between GPA and other forms of sinusitis is of critical importance, particularly when symptoms are refractory to standard rhinosinusitis therapies.

Immunotherapy Approaches Beyond PD-1 Inhibition: the Future of Cellular Therapy for Head and Neck Squamous Cell Carcinoma.

OPINION STATEMENT: In a span of a few years, the surprising early successes of programmed cell death 1 (PD-1) inhibitors across a vast range of tumor types have transformed our understanding of cancer immunogenicity and provided proof of principle that T cells, if manipulated, can mediate meaningful tumor regression. In head and neck cancer, only a minority of patients respond to PD-1 therapy, but these small outcomes have fueled the enthusiasm for the next generation of immunotherapy-adoptive cell therapy-which employs recent advances in genetic engineering and cell culturing methods to generate T cells with enhanced anti-tumor efficacy for infusion back into the patient. Head and neck cancer is comprised of biologically distinct cancers, HPV-positive and HPV-negative, and the clinical responses to PD-1 inhibitors in both HPV-positive and HPV-negative head and neck patients have showcased better than any other cancer type that there are distinct pathways to immunogenicity that may lend themselves to different therapeutic approaches. Thus, head and neck cancer is uniquely poised to benefit from the personalized approach of adoptive cell therapy as well as provide a valuable platform to explore contrasting T cell modalities. In this article, we will review the growing portfolio of trials of adoptive cell therapies in head and neck cancer and discuss the future directions of this emerging new field.

Surgical Options for Locally Advanced Oropharyngeal Cancer.

OPINION STATEMENT: Oropharyngeal squamous cell carcinoma (OPSCC) incidence rates have been steadily increasing over the past several decades, and this has been largely attributed to human papillomavirus (HPV)-related OPSCC. The rise of HPV-related OPSCC and the observed distinct survival advantage it offers compared to HPV-unrelated OPSCC have resulted in the development of a new staging system specifically for OPSCC in the eighth edition of the AJCC Staging Manual for head and neck cancer. The observations on HPV-related OPSCC and its prognostic implications have coincided with increasing utilization of transoral surgical approaches to oropharyngeal tumors, such as transoral laser microsurgery (TLM) and transoral robotic surgery (TORS). These approaches were once thought to only be applicable to patients with low T-stage OPSCC tumors; however, they are being increasingly utilized in locally advanced OPSCC cases as several studies have shown that both of these transoral approaches are oncologically sound alternatives to concurrent chemoradiation therapy (CCRT), which was previously the standard-of-choice treatment in patients with locally advanced disease. Moreover, these transoral approaches have displayed better long-term swallowing outcomes compared to CCRT, as severe dysphagia is often the most bothersome functional impairment to OPSCC survivors who have undergone CCRT. While open surgical approaches were previously not utilized in the locally advanced OPSCC setting due to the risk of severe surgical complications compared to the potential benefits of organ preservation with CCRT and comparable survival rates after either treatment regimen, these approaches are still reasonable options for select patients in the salvage surgery setting, as they allow for maximum exposure to the deep oropharyngeal anatomy. Data from multiple clinical trials evaluating the potential for TORS to de-escalate radiation dose or CCRT regimen in certain settings will inform clinical decision-making for OPSCC patients for the next decade and allow for more personalized treatments tailored to an individual patient's disease burden.

Reducing margins of wide local excision in head and neck melanoma for function and cosmesis: 5-year local recurrence-free survival.

BACKGROUND: The proximity of head and neck (H&N) melanomas to critical anatomical structures requires that surgeons achieve a balance between adequate margins of excision and the functional and cosmetic needs of patients. This study sought to determine the risk associated with reducing margins of wide local excision (WLE) in H&N melanoma and to identify risk factors of recurrence. METHODS: Seventy-nine cases of primary, invasive H&N melanoma were treated by WLE and followed prospectively for local recurrence. Forty-two WLEs were performed according to current practice guidelines (1cm for lesions<1.0 mm thick, 1-2 cm for lesions 1.01-2.0 mm thick, and 2 cm for lesions >2.0 mm thick). Reduced margins (0.5 cm for lesions ≤1.0 mm thick, 0.5-1.0 cm for lesions 1.01-2.0 mm thick, and 1.0 cm for lesion >2.0 mm thick) were utilized in 37 cases to preserve critical anatomical structures such as the eyelid, nose, mouth and auricle. RESULTS: Overall local recurrence rate was 8.9% over a mean follow-up period of 71.3 months and a minimum of 60 months. Reducing margins of WLE did not increase local recurrence rates as demonstrated by local recurrence-free survival (90.4% vs. 91.9%, P = 0.806). CONCLUSION: Margins of WLE may be safely reduced in melanomas in close proximity to structures of the H&N without affecting local recurrence rates.

Olfaction Now and in the Future in CRSwNP.

BACKGROUND: Chronic rhinosinusitis (CRS) is the leading cause of olfactory dysfunction in the general population. Olfactory dysfunction is more common in patients with CRS with nasal polyposis (CRSwNP) compared to those without polyps. PURPOSE: The present review aims to summarize the current literature on the mechanism behind olfactory dysfunction in CRSwNP and the impact of therapy on olfactory outcomes in this patient population. METHODS: A comprehensive review of the available literature on olfaction in CRSwNP was performed. We evaluated the most recent evidence from studies on the mechanisms behind smell loss in CRSwNP and the impact of medical and surgical therapy for CRS on olfactory outcomes. RESULTS: The mechanism behind olfactory dysfunction in CRSwNP is not completely understood, but evidence from clinical research and animal models suggests both an obstructive component causing conductive olfactory loss and an inflammatory response in the olfactory cleft leading to sensorineural olfactory loss. Oral steroids and endoscopic sinus surgery have both shown efficacy in improving olfactory outcomes in CRSwNP in the short term; however, the long-term response of these treatments remains uncertain. Newer targeted biologic therapies, such as dupilumab, have also shown remarkable and durable improvement in smell loss for CRSwNP patients. CONCLUSION: Olfactory dysfunction is highly prevalent in the CRSwNP population. Although significant advances have been made in our understanding of olfactory dysfunction in the setting of CRS, additional studies are needed to elucidate cellular and molecular changes mediated by type 2-mediated inflammation in the olfactory epithelium with potential downstream effects on the central olfactory system. Further identification of these underlying basic mechanisms will be vital for developing future therapies targeted to improve olfactory dysfunction in patients with CRSwNP.

Scientific Advancements That Empower Us to Understand CRS Pathophysiology.

BACKGROUND: Chronic rhinosinusitis with nasal polyposis (CRSwNP) is a multifactorial inflammatory condition that remains poorly understood. Over the past decade, we have witnessed impressive scientific advancements that have allowed us to better understand the molecular and cellular mechanisms that underlie the inflammatory processes in mucosal diseases including asthma, allergic rhinitis, and CRSwNP. OBJECTIVE: The present review aims to summarize and highlight the most recent scientific advancements that have enriched our understanding of CRSwNP. METHODS: A comprehensive review of the available literature on the use of new scientific techniques in CRSwNP was performed. We evaluated the most recent evidence from studies using animal models, cell cultures, and genome sequencing techniques and their impact on our understanding of CRSwNP pathophysiology. RESULTS: Our understanding of CRSwNP has rapidly progressed with the development of newer scientific techniques to interrogate various pathways involved in its pathogenesis. Animal models remain powerful tools and have elucidated the mechanisms behind esinophilic inflammation in CRSwNP; however, animal models reproducing polyp formation are relatively sparse. 3D cell cultures have significant potential to better dissect the cellular interactions with the sinonasal epithelium and other cell types in CRS. Additionally, some groups are starting to utilize single-cell RNA sequencing to investigate RNA expression in individual cells with high resolution and on a genomic scale. CONCLUSION: These emerging scientific technologies represent outstanding opportunities to identify and develop more targeted therapeutics for different pathways that lead to CRSwNP. An additional understanding of these mechanisms will be critical for developing future therapies for CRSwNP.

Otolaryngology Considerations of Pituitary Surgery: What an Endocrinologist Should Know.

Endoscopic endonasal skull base surgery is the preferred surgical approach for the management of pituitary adenomas. Perioperative management of pituitary lesions requires multidisciplinary care and typically includes a dual surgeon team consisting of a neurosurgeon and an otolaryngologist. The involvement of the otolaryngologist allows for a safe surgical approach with excellent intraoperative visualization of the tumor to enable an effective resection of the tumor by the neurosurgeon. Detection and treatment of sinonasal pathology is essential prior to surgery. Patients may experience sinonasal complaints following endoscopic transsphenoidal surgery, although this is typically temporary. Sinonasal care in the postoperative period can expedite recovery to baseline. Here we discuss the perioperative factors of endoscopic pituitary surgery that endocrinologists should be aware of, ranging from preoperative patient selection and optimization to postoperative care, with a particular emphasis on anatomic and surgical factors.

Diagnosis, Prognosticators, and Management of Acute Invasive Fungal Rhinosinusitis: Multidisciplinary Consensus Statement and Evidence-Based Review with Recommendations.

BACKGROUND: Acute invasive fungal sinusitis (AIFS) is an aggressive disease that requires prompt diagnosis and multidisciplinary treatment given its rapid progression. However, there is currently no consensus on diagnosis, prognosis, and management strategies for AIFS, with multiple modalities routinely employed. The purpose of this multi-institutional and multidisciplinary evidence-based review with recommendations (EBRR) is to thoroughly review the literature on AIFS, summarize the existing evidence, and provide recommendations on the management of AIFS. METHODS: The PubMed, EMBASE, and Cochrane databases were systematically reviewed from inception through January 2022. Studies evaluating management for orbital, non-sinonasal head and neck, and intracranial manifestations of AIFS were included. An iterative review process was utilized in accordance with EBRR guidelines. Levels of evidence and recommendations on management principles for AIFS were generated. RESULTS: A review and evaluation of published literature was performed on 12 topics surrounding AIFS (signs and symptoms, laboratory and microbiology diagnostics, endoscopy, imaging, pathology, surgery, medical therapy, management of extrasinus extension, reversing immunosuppression, and outcomes and survival). The aggregate quality of evidence was varied across reviewed domains. CONCLUSION: Based on the currently available evidence, judicious utilization of a combination of history and physical examination, laboratory and histopathologic techniques, and endoscopy provide the cornerstone for accurate diagnosis of AIFS. In addition, AIFS is optimally managed by a multidisciplinary team via a combination of surgery (including resection whenever possible), antifungal therapy, and correcting sources of immunosuppression. Higher quality (i.e., prospective) studies are needed to better define the roles of each modality and determine diagnosis and treatment algorithms.

Impact of HPV status on immune responses in head and neck squamous cell carcinoma.

The main objective of our study was to understand the impact of immune cell composition and the tumor-reactivity of tumor infiltrating lymphocytes (TIL) in HPV-positive (HPV+) and HPV-negative (HPV-) head and neck squamous cell carcinoma (HNSCC). TIL cultures were established from primary HNSCC tumors, the T cell subsets were phenotypically characterized using flow cytometry, and Interferon (IFN)-γ ELISA assay was used to determine TIL function. NanoString Immune Profiler was used to determine an immune signature by HPV-status, and multiplex immunohistochemistry (MIHC) was used to quantify immune cell distributions and their spatial relationships. Results showed that HPV+ and HPV- HNSCC had similar capacity to expand IFN-γ reactive TIL populations, and these TIL populations had similar characteristics. NanoString analysis revealed increased differential expression of genes related to B cell functions in HPV+ HNSCC, which were significant at a Benjamini-Yekutieli adjusted p-value of < 0.001. MIHC also displayed increased CD8+ T cell and CD19/CD20+ B cell densities in the tumor region of HPV+ HNSCC as opposed to HPV- HNSCC (p < 0.01). Increases in a combined metric of tumor B cell content and stromal plasma cell content was associated with increased progression-free survival in HPV- HNSCC patients treated with immune checkpoint inhibitor therapy (p = 0.03). In summary, TIL populations expanded from HPV+ and HPV- HNSCC displayed similar IFN-γ reactivity. However, we identified a strong B-cell signature present within HPV+ HNSCC, and higher B and plasma cell content associated with improved PFS in HPV- HNSCC patients treated with immune checkpoint inhibitors.

Intratympanic Steroid Injection Complicated by Iatrogenic Perilymphatic Fistula: A Cautionary Tale.

Intratympanic (IT) steroid therapy is a mainstay treatment for sudden sensorineural hearing loss (SSNHL) for both initial therapy and salvage therapy. We report a rare case of iatrogenic perilymphatic fistula that resulted from trauma during an IT steroid injection for SSNHL. We discuss the diagnosis and treatment in the current case and compare it with previous reports from the literature. Laryngoscope, 131:2088-2090, 2021.

National Institutes of Health Funding for Obstructive Sleep Apnea: An Opportunity for Otolaryngologists.

OBJECTIVE: To describe current levels and trends of funding for the National Institutes of Health (NIH) in obstructive sleep apnea (OSA) and to recognize the current status of otolaryngologists in OSA research. STUDY DESIGN: Scientometric analysis. METHODS: The NIH RePORTER database was queried for the search term "obstructive sleep apnea" for all available years. Sex, degree, academic department, NIH funding source, geography, funding totals and years, and h-index of principal investigators (PIs) were collected and summarized. RESULTS: A total of 397 projects spanning 1242 total funding years were funded. Of the 273 individual PIs, 33.3% (91/273) were female. Regarding credentials, 52.4% of PIs (143/273) were MD or MD/PhD, and 41.0% (112/273) were PhD alone. Academic departments of PIs were most often medicine (34.1%), pediatrics (12.1%), cell biology/physiology (10.6%), and psychiatry (7.7%). Seven otolaryngology faculty members had received NIH funding for OSA research (2.6% of total PIs) since 2000. They accounted for 8 grants (0.25% of total grants) and $7,235,729 (1.5% of total dollars) of research funding. CONCLUSION: Despite studies showing increasing levels of OSA surgery being performed and major areas of research and clinical opportunity, otolaryngologists represent a small minority of OSA research funding. This information may help direct our specialty when setting priorities regarding research funding, as research into the basic science and clinical management of OSA represents a broad and interdisciplinary pursuit.

Burnout phenomenon in U.S. plastic surgeons: risk factors and impact on quality of life.

BACKGROUND: Recent studies by the American College of Surgeons reveal that nearly 40 percent of U.S. surgeons exhibit signs of burnout. The authors endeavored to quantify the incidence of burnout among U.S. plastic surgeons, determine identifiable risk factors, and evaluate its impact on quality of life. METHODS: All U.S. residing members of the American Society of Plastic Surgeons were invited to complete an anonymous survey between September of 2010 and August of 2011. The survey contained a validated measure of burnout (Maslach Burnout Inventory) and evaluated surgeon demographics, professional and personal risk factors, career satisfaction, self-perceived medical errors, professional impairment, and family-home conflicts. RESULTS: Of the 5942 surgeons invited, 1691 actively practicing U.S. plastic surgeons (28.5 percent) completed the survey. The validated rate of burnout was 29.7 percent. Significant risk factors for burnout included subspecialty, number of hours worked and night calls per week, annual income, practice setting, and academic rank. Approximately one-fourth of plastic surgeons had significantly lower quality-of-life scores than the U.S. population norm, and this risk increases in burned out surgeons. In addition to having lower career satisfaction and more work-home conflicts, plastic surgeons with burnout also had a nearly two-fold increased risk of self-reported medical errors and self-reported impairment. CONCLUSIONS: Over one-fourth of plastic surgeons in the United States experience validated burnout, with concomitant attenuated career satisfaction and quality of life. Multivariate analysis identified predisposing factors that may aid in better understanding risk profiles that lead to burnout; therefore, efforts to understand and thereby avoid this burnout phenomenon are warranted.

National trends in retropharyngeal abscess among adult inpatients with peritonsillar abscess.

OBJECTIVES: To describe national trends in retropharyngeal abscess (RPA) complicating peritonsillar abscess (PTA) and to determine factors associated with RPA in patients with PTA. STUDY DESIGN: Cross-sectional analysis. SETTING: Nationwide Inpatient Sample, 2003-2010. SUBJECTS AND METHODS: PTA patients ≥18 years old, with or without RPA, were extracted according to ICD-9-CM codes. The cohort was analyzed with descriptive statistics and multivariate regression modeling to identify factors associated with RPA. RESULTS: Of the 91,647 (95% CI: 86,433-95,449) patients identified with PTA, 885 (1.0%) also had a concurrently coded RPA. The annual rate of concomitant RPA increased from 0.5% (95% CI: 0.3%-0.8%) to 1.4% (95% CI: 1.0%-2.0%) between 2003 and 2010 (P < .001). PTA patients with RPA more frequently underwent tonsillectomy (23.5% vs 11.1%), endotracheal intubation (7.1% vs 1.5%), and mechanical ventilation (13.2% vs 2.0%) than those without RPA (all P < .001). PTA patients with RPA were significantly older (41 vs 34 years old), had a longer hospital stay (6.4 vs 2.5 days), and had more procedures (2.5 vs 0.9) when compared to patients without RPA (all P < .001). Upon multivariate regression analysis, factors associated with RPA included the age groups of 40 to 64 years (odds ratio, 2.256; P < .001) and 65 and older (odds ratio, 2.086; P = .045). Median total charges for PTA inpatients with concomitant RPA were approximately $8700 greater (P < .001) when compared to patients with PTA alone. CONCLUSIONS: The incidence of RPA among adult inpatients with PTA is increasing, and patients with RPA have higher in-hospital resource utilization. Further studies may help validate factors predictive of RPA to enable prevention or earlier identification.

Hydration status regulates sodium flux and inflammatory pathways through epithelial sodium channel (ENaC) in the skin.

Although it is known that the inflammatory response that results from disruption of epithelial barrier function after injury results in excessive scarring, the upstream signals remain unknown. It has also been observed that epithelial disruption results in reduced hydration status and that the use of occlusive dressings that prevent water loss from wounds decreases scar formation. We hypothesized that hydration status changes sodium homeostasis and induces sodium flux in keratinocytes, which result in activation of pathways responsible for keratinocyte-fibroblast signaling and ultimately lead to activation of fibroblasts. Here, we demonstrate that perturbations in epithelial barrier function lead to increased sodium flux in keratinocytes. We identified that sodium flux in keratinocytes is mediated by epithelial sodium channels (ENaCs) and causes increased secretion of proinflammatory cytokines, which activate fibroblast via the cyclooxygenase 2 (COX-2)/prostaglandin E2 (PGE2) pathway. Similar changes in signal transduction and sodium flux occur by increased sodium concentration, which simulates reduced hydration, in the media in epithelial cultures or human ex vivo skin cultures. Blockade of ENaC, prostaglandin synthesis, or PGE2 receptors all reduce markers of fibroblast activation and collagen synthesis. In addition, employing a validated in vivo excessive scar model in the rabbit ear, we demonstrate that utilization of either an ENaC blocker or a COX-2 inhibitor results in a marked reduction in scarring. Other experiments demonstrate that the activation of COX-2 in response to increased sodium flux is mediated through the PIK3/Akt pathway. Our results indicate that ENaC responds to small changes in sodium concentration with inflammatory mediators and suggest that the ENaC pathway is a potential target for a strategy to prevent fibrosis.

Fibroblast Growth Factor 19 Activates the Unfolded Protein Response and Mitogen-Activated Protein Kinase Phosphorylation in H-69 Cholangiocyte Cells.

BACKGROUND: Cholangiocytes are injured in many biliary tract diseases that result in cirrhosis, cholangiocarcinoma and need for liver transplantation. Recent studies demonstrate that the hormone Fibroblast Growth Factor 19 (FGF19) is produced in the ileum and regulates hepatic gene expression via the enterohepatic circulation. However, the role of FGF19 on cholangiocytes remains largely unknown. The purpose of this study was to elucidate the effect of FGF19 on cholangiocyte gene and protein expression. METHODS: Cultured human cholangiocyte-derived H69 cells were treated with FGF19 (0-50ng/ml) and expression of genes and proteins involved in the Unfolded Protein Response (UPR) and mitogen-activated protein kinase (MAPK) pathways were studied using RT-PCR and Western blot analysis. RESULTS: FGF19-induced gene and protein expression of the UPR genes BiP and CHOP increased in a dose-responsive pattern. The UPR protein P-eIF2a displayed a bimodal pattern of protein expression, with 10ng/ml of FGF19 maximally reducing and 50ng/ml maximally increasing expression. MAPK pathway protein expression (P-JNK, P-ERK, P-38) displayed a similar bimodal pattern of expression with 2.5ng/ml of FGF19 decreasing expression and 25ng/ml of FGF19 increasing expression. CONCLUSIONS: FGF19 treatment of H69 cells selectively activates BiP and CHOP in a dose-dependent manner. FGF19 also regulates P-eIF2a and MAPK protein expression with a bimodal response. We speculate that FGF19 has an important role in the pathogenesis of many human cholangiopathies and cholestatic liver disorders.