The mechanisms of action of metformin on head and neck cancer in the pre-clinical setting: a scoping review.

This scoping review identifies the mechanistic pathways of metformin when used to treat head and neck cancer cells, in the pre-clinical setting. Understanding the underlying mechanisms will inform future experimental designs exploring metformin as a potential adjuvant for head and neck cancer. This scoping review was conducted according to the Joanna-Briggs Institute framework. A structured search identified 1288 studies, of which 52 studies fulfilled the eligibility screen. The studies are presented in themes addressing hallmarks of cancer. Most of the studies demonstrated encouraging anti-proliferative effects in vitro and reduced tumor weight and volume in animal models. However, a few studies have cautioned the use of metformin which supported cancer cell growth under certain conditions.

Risk of airway fire with the use of KTP laser and high flow humidified oxygen delivery in a laryngeal surgery model.

Airway surgery presents a unique environment for operating room fire to occur. This study aims to explore the factors of combustion when using KTP laser with high flow oxygen in an ex-vivo model. The variables tested were varying tissue type, tissue condition, oxygen concentration, laser setting, and smoke evacuation in a stainless-steel model. Outcome measures were time of lasing to the first spark and/or flame. A multivariate Cox proportional hazard model was used to determine the risk of spark and flame across the different risk factors. For every 10% increase in oxygen concentration above 60% the risk of flame increased by a factor of 2.3. Continuous laser setting at 2.6 W increased the risk by a factor of 72.8. The risk of lasing adipose tissue is 7.3 times higher than that of muscle. Charred tissue increases the risk of flame by a factor of 92.8. Flame occurred without a preceding spark 93.6% of the time. Using KTP laser in the pulsed mode with low wattages, minimising lasing time, reducing the oxygen concentration and avoiding lasing adipose or charred tissue produce a relatively low estimated risk of spark or flame.

The role of biologics in chronic rhinosinusitis: a systematic review.

BACKGROUND: Chronic rhinosinusitis (CRS) refractory to medical and surgical treatment is challenging. It impacts patients' quality of life significantly. The pathophysiology of CRS has some similarities to allergic asthma and allergic rhinitis (AR) and includes eosinophilia, T-helper cell 2 cytokines, and local immunoglobilin E formation. Monoclonal antibody therapy has been used successfully in asthma and AR and more recently in CRS. Our was aim to systematically review the literature and identify the role of monoclonal antibodies (MAbs) in the treatment of CRS with polyps (CRSwNP) and without polyps (CRSsNP), especially with regard to comparability with current medical treatment, efficacy, and risk of complications. In addition, the role of surgery and biologics was evaluated. METHODS: We identified at total of 5341 relevant studies after a comprehensive database search. Six studies met the inclusion criteria, all 6 randomized, controlled trials. RESULTS: Treatment with omalizumab and mepolizumab demonstrated improvements in endoscopic nasal polyp score (EPS) and symptoms score in patients with CRSwNP when compared with placebo. Reslizumab reduced nasal polyp size in patients with raised intranasal interleukin-5 levels. Dupilumab treatment resulted in a 70% reduction in EPS compared with 20% in the placebo group (p < 0.001). These MAbs target different inflammatory markers involved in the pathophysiology of CRSwNP. None of the studies reported on CRSsNP or combined surgery with biologics. No severe adverse events were reported. CONCLUSION: Evidence demonstrates that use of MAbs leads to clinical improvement in CRSwNP. However, further research is required to determine their long-term effects, comparability to other medical treatments, and potential side effects.

National Surgical Quality Improvement Program risk calculator validity in South Australian laryngectomy patients.

BACKGROUND: Assessing an individual patient's post-operative risk profile prior to laryngectomy for cancer is difficult. The American College of Surgeons' National Surgical Quality Improvement Program (ACS-NSQIP) risk calculator was developed to better inform preoperative decision-making. The calculator uses patient-specific characteristics to estimate the risk of experiencing post-operative complications within 30 days of surgery. We investigated the ACS-NSQIP risk calculator's performance for Australian laryngectomy patients. METHODS: The ACS-NSQIP risk calculator was used to retrospectively calculate the 30-day post-operative predicted outcomes in patients who underwent laryngectomy for laryngeal, hypopharyngeal and thyroid cancers (with laryngeal involvement) in two institutions in South Australia. These data were compared against the actual mortality, morbidity, complications and length of stay (LOS) collected from a retrospective chart review. RESULTS: A total of 144 patients underwent surgical intervention for malignancies with laryngeal involvement. The median LOS was 25 days (range 13-197) compared to the predicted LOS of 6.5 days (range 3.5-12.5). Overall mortality was 2.78% with post-operative complications occurring in 63% of patients. The most common complication was wound infection, occurring in 33% of patients. Hosmer-Lemeshow plots demonstrated good agreement between predicted and observed rates for complications. CONCLUSION: The ACS-NSQIP risk calculator effectively predicted post-operative complication rates in South Australian laryngeal cancer patients undergoing laryngectomy. However, differences in predicted and actual LOS may limit the usefulness of the calculator's LOS predictions for Australian patients.

Circulating microRNAs in head and neck cancer: a scoping review of methods.

Circulating microRNAs have been described as head and neck cancer biomarkers in multiple anatomical subsites including the oral cavity, nasopharynx, larynx, salivary glands and the skin. While there is an expanding volume of published literature showing the significance of individual or panels of microRNAs, the clinical validation of candidate biomarkers is lacking. The various methods used to collect, store, process and interpret these microRNAs are likely introducing bias and contributing to the inconsistent results. A systematic scoping review was conducted using PRISMA standards to identify published English literature between 2007 and 2018. Pubmed and EMBASE databases were searched using specific keyword combinations related to head and neck cancer, circulating samples (whole blood, plasma or serum) and microRNA. Following the title and abstract review, two primary authors appraised the articles for their suitability to include in the review based on the detail of methodological descriptions. Thirty suitable articles were identified relating to nasopharyngeal carcinoma, oral cavity, oropharyngeal and laryngeal squamous cell carcinoma as well as primary salivary gland malignancies. Comprehensive methodological analysis identified poor reporting of detailed methodology, variations in collection, storage, pre-processing, RNA isolation and relative quantification including normalisation method. We recommend standardising the pre-processing, RNA isolation, normalisation and relative quantitation steps at biomarker discovery phase. Such standardisation would allow for bias minimisation and effective progression into clinical validation phases.

Effectiveness of endoscopic versus external surgical approaches in the treatment of orbital complications of rhinosinusitis: a systematic review protocol.

OBJECTIVE: This review aims to investigate and compare the effectiveness of endoscopic drainage techniques against external drainage techniques for the treatment of orbital and subperiosteal abscesses as a complication of rhinosinusitis. INTRODUCTION: Transnasal endoscopic drainage and external drainage techniques have been used in the management of subperiosteal orbital abscesses secondary to rhinosinusitis. Each of these approaches has its own advantages and disadvantages, with extensive literature describing each technique separately. However, there is a lack of guidance in the studies on assessing and comparing the safety, effectiveness and suitability of these techniques. This review aims to compare the effectiveness of these techniques based on measuring outcomes in the literature such as: length of postoperative hospital stay, rate of revision surgery and complication rates. INCLUSION CRITERIA: Eligible studies will include people of all ages diagnosed with subperiosteal abscess, orbital abscess or cavernous sinus thrombosis (Chandler stages III-V) secondary to rhinosinusitis disease, who have also undergone drainage via either an endoscopic approach, external approach or combined surgical approach. METHODS: A comprehensive search of both published and unpublished literature will be performed to uncover studies meeting the inclusion criteria. Reference lists of studies included in final analyses will also be manually searched and subject matter experts contacted to investigate other sources of literature. Two reviewers will screen studies and a third reviewer will resolve disagreements. Studies will, where possible, be pooled in statistical meta-analysis with heterogeneity of data being assessed using the standard Chi-squared and I tests.

Nasal mucosa expression of lactoferrin in patients with chronic rhinosinusitis.

OBJECTIVE/HYPOTHESIS: Antimicrobial peptides, such as lactoferrin, are an important component of the innate immune system. They offer the body a first line defense against a wide range of invading pathogens. The diverse antipathogenic action of lactoferrin has been well characterized; however, the role that this peptide plays in chronic conditions such as rhinosinusitis remains largely unknown. This study aims to examine the level of lactoferrin expression in the nasal mucosa of patients with chronic rhinosinusitis (CRS). STUDY DESIGN/METHODS: Nasal biopsies of 85 chronic rhinosinusitis patients, subclassified into allergic fungal sinusitis (AFS), nonallergic fungal eosinophilic sinusitis (NAFES), nonallergic, nonfungal eosinophilic sinusitis (NANFES), and CRS were studied by quantitative real-time reverse-transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay for their expression of lactoferrin at an mRNA and protein level, respectively. RESULTS: All groups of patients with CRS showed a decrease in lactoferrin mRNA expression relative to controls (median fold-change of CRS relative to controls, 0.1550; AFS, 0.1800; NANFES, 0.1900; and NAFES, 0.2100). All groups also showed a decreased expression of lactoferrin protein (controls, 163.3 ng/mL; CRS, 82.19 ng/mL; AFS, 104.1 ng/mL; NANFES, 118.9 ng/mL; and NAFES, 74.33 ng/mL). The most significant reduction was evident in the CRS subgroup as well as in patients with nasal polyposis at the time of surgery. CONCLUSIONS: This is the first study of its kind to objectively examine lactoferrin expression in the nasal mucosa of CRS patients. We report a reduction in the expression of this important antimicrobial peptide at both the mRNA and protein level. Such a defect in the innate immune system may explain the predisposition of certain individuals to develop CRS and nasal polyposis, providing further insight into the pathogenesis of such conditions.

Surfactant protein d expression in chronic rhinosinusitis patients and immune responses in vitro to Aspergillus and alternaria in a nasal explant model.

OBJECTIVES/HYPOTHESIS: Common fungi have been implicated in the pathogenesis of chronic rhinosinusitis (CRS) with eosinophilic mucus (EMCRS). Surfactant protein (SP)-D plays an important role in the immune response to Aspergillus fumigatus in the lungs. We sought to determine whether SP-D is expressed in nasal mucosa and investigated the response of SP-D in vitro to fungal allergens. STUDY DESIGN AND METHODS: 1) Nasal biopsies from 59 CRS and EMCRS patients, stratified into allergic fungal sinusitis (AFS), nonallergic fungal eosinophilic sinusitis (NAFES), and nonallergic nonfungal eosinophilic sinusitis (NANFES) were studied by quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR), immunostaining and enzyme-linked immunosorbent assay (ELISA). 2) Nasal tissue from three CRS and three NANFES patients was cultured with fungal allergens in a nasal explant in vitro model for 24 hours at increasing concentrations and mRNA SP-D secreted SP-D protein levels in response to the fungi determined by qRT-PCR and ELISA. RESULTS: Staining for SP-D was detected in the submucosal glands from the nasal biopsies in all patient groups except for AFS. By ELISA, SP-D was undetectable in AFS and decreased in NAFES, NANFES, and CRS compared with controls. CRS patients in vitro cultured with Aspergillus and Alternaria allergens in a nasal tissue explant model induced up-regulation of SP-D by qRT-PCR. In contrast, NANFES nasal tissue explants cultured with Aspergillus allergens induced down-regulation of SP-D. CONCLUSIONS: We report for the first time the expression of SP-D in both diseased and normal nasal mucosa. SP-D expression in CRS patients is up-regulated by fungal allergens in an in vitro model. These results may provide potential novel therapy for treatment of CRS.

Scoping review of pediatric tonsillectomy quality of life assessment instruments.

OBJECTIVES/HYPOTHESIS: Sleep-disordered breathing or recurrent tonsillitis have detrimental effects on the child's physical health and quality of life. Tonsillectomy is commonly performed to treat these common conditions and improve the child's quality of life. This scoping review aims to present a comprehensive and descriptive analysis of quality of life questionnaires as a resource for clinicians and researchers when deciding which tool to use when assessing the quality of life effects after tonsillectomy. STUDY DESIGN: A comprehensive search strategy was undertaken across MEDLINE (PubMed), CINAHL, Embase, and Cochrane CENTRAL. METHODS: Quality of life questionnaires utilized in studies investigating pediatric patients undergoing tonsillectomy for chronic tonsillitis or sleep-disordered breathing were included. Methodological quality and data extraction were conducted as per Joanna Briggs Institute methodology. RESULTS: Ten questionnaires were identified, consisting of six generic and four disease-specific instruments. The Pediatric Quality of Life Inventory was the most commonly utilized generic questionnaire. The Obstructive Sleep Apnea-18 was the most commonly utilized disease-specific questionnaire. CONCLUSIONS: This review identified a range of generic and disease-specific quality of life questionnaires utilized in pediatric patients who have undergone tonsillectomy with or without adenoidectomy for sleep-disordered breathing or chronic tonsillitis. Important aspects of each questionnaire have been summarized to aid researchers and clinicians in choosing the appropriate questionnaire when evaluating the quality of life effects of tonsillectomy. LEVEL OF EVIDENCE: NA Laryngoscope, 127:2399-2406, 2017.

Swallowing outcomes following primary surgical resection and primary free flap reconstruction for oral and oropharyngeal squamous cell carcinomas: A systematic review.

OBJECTIVES/HYPOTHESIS: Dysphagia is still a treatment-related morbidity, despite advances in treatment modalities for oral and oropharyngeal squamous cell carcinoma. This systematic review aimed to analyze the effects of swallowing outcomes of patients with oral or oropharyngeal squamous cell carcinoma treated with primary surgery with primary free flap reconstruction, with or without adjuvant therapy, for patients undergoing treatment with curative intent. STUDY DESIGN: A comprehensive search strategy was undertaken across MEDLINE, CINAHL, Embase, and Scopus. Gray literature was sought through Cochrane Central Register of Controlled Trials, MedNar, and ProQuest. METHODS: Studies included patients with oral cavity or oropharyngeal squamous cell carcinoma treated with primary surgery with primary free flap reconstruction. Swallowing function was the primary outcome, evaluated at 6 months or later following surgery. Methodological quality and data extraction was conducted as per the Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument and standardized data extraction tool. RESULTS: Fifteen articles comprising eight cohort studies and seven case series were included. Postoperative radiotherapy and oropharyngeal resections were demonstrated to be associated with increased dysphagia. CONCLUSION: Advanced tumor-node-metastasis stage and use of adjuvant radiotherapy has been shown to have negative impacts on swallowing function. The majority of patients were able to have gastrostomy tubes removed at 6 months following curative therapy. Larger flap mass for the reconstruction of oral and oropharyngeal defects appeared to improve swallowing outcomes. A protocol for the identification of patients at high and low risk of developing dysphagia is proposed. LEVEL OF EVIDENCE: N/A. Laryngoscope, 126:1572-1580, 2016.

Management of lateral sinus thrombosis: update and literature review.

The management of four cases of lateral sinus thrombosis (LST) over a four-year period at the Royal Darwin Hospital is presented in this retrospective review. The patients were aboriginal and presented with otalgia, otorrhoea and sepsis. Two cases had an associated complication of an otitic hydrocephalus and a subperiosteal abscess. Cholesteatoma was found in three cases. Computed tomography (CT) scan confirmed the LST in three cases. Three patients were anaemic and thrombocytopenic. All patients had positive blood cultures. The organisms were predominantly mixed anaerobes and Bacteroides species. Three patients were managed surgically as a two-stage procedure. One patient was managed as a single-stage procedure with a modified radical mastoidectomy. Therapeutic anticoagulation was utilized in one case. There were no deaths. The prognosis of LST is good if treatment is instituted early with broad-spectrum intravenous antibiotics and surgery. The role of clot removal at surgery and the use of anticoagulation are discussed in this paper.

Intralesional corticosteroid injection and dilatation provides effective management of subglottic stenosis in Wegener's granulomatosis.

OBJECTIVES/HYPOTHESIS: To describe our experience with the use of intralesional corticosteroid injection and dilatation (ILCD) in the management of subglottic stenosis (SGS). STUDY DESIGN: Retrospective chart review. METHODS: A retrospective chart review was performed of all patients with SGS requiring ILCD, from 2003 to 2008, at the Department of Otolaryngology-Head and Neck Surgery, Mount Sinai Hospital, Toronto, Canada. RESULTS: Twelve patients with SGS underwent 36 ILCD operations with a mean of three procedures per patient. We identified eight patients with Wegener's granulomatosis (WG) and four patients without WG. The eight WG patients received an average of 3.37 procedures, whereas non-WG patients required an average of 2.25 procedures. This maintained airway patency and symptom control for an average of 11.9 and 8.1 months, respectively. Only one complication was identified, and no long-term sequelae were found. No patients required new tracheotomies and one patient with a previous tracheotomy was successfully decannulated. CONCLUSIONS: Our data supports the use of ILCD as a safe and effective treatment of SGS in both WG and non-WG patients.

Innate immunity in the paranasal sinuses: a review of nasal host defenses.

BACKGROUND: Chronic rhinosinusitis (CRS) is a common inflammatory disorder of the paranasal sinuses. An abnormal host response to common bacterial or fungal pathogens is thought to be an important factor in the disease process. Host sinonasal epithelium plays an important role in initially recognizing the presence of microbes and responding by increasing production of antimicrobial peptides and cytokines, with recruitment of phagocytes and lymphocytes of the adaptive immune system, to eliminate the infection. Recently, the innate immune system and its complex interplay with the adaptive immune system are increasingly being recognized as important in the pathogenesis of chronic inflammatory diseases such as asthma and CRS. METHODS: Review of recent findings on innate immunity in the pathogenesis of CRS. RESULTS: New areas of research into potentially novel therapies for CRS are highlighted in this review, with emphasis on toll-like receptors, antimicrobial peptides (cathelicidins and defensins), and surfactant proteins. CONCLUSION: This review provides an overview of innate immunity in the sinonasal tract and discusses potential use of innate immune peptides as treatments against fungi, biofilms, and superantigens in CRS.

Fungal allergens induce cathelicidin LL-37 expression in chronic rhinosinusitis patients in a nasal explant model.

BACKGROUND: Fungus is thought to play an important role in some subgroups of chronic rhinosinusitis (CRS) patients with eosinophilic mucus (EMCRS). The cathelicidin LL-37 is an important innate defense peptide with antimicrobial activity but its responses in CRS and EMCRS patients have not been established. We investigated the innate immune responses of LL-37 in nasal tissue from CRS and EMCRS patients to fungal allergen challenge. METHODS: The levels of LL-37 produced by nasal tissue and secreted in response to fungal allergen challenge were determined by a nasal tissue explant in vitro model. LL-37 mRNA and protein levels were quantified by real-time reverse-transcriptase-polymerase chain reaction and immunoassay methods. RESULTS: LL-37 mRNA expression in CRS, but not EMCRS patients, is significantly upregulated by Aspergillus (mean fourfold increase) and Alternaria (mean sixfold increase) extracts in a dose-response manner (p < 0.001). LL-37 peptide levels in the nasal tissue from CRS patients are increased in response to Alternaria (p < 0.05). In contrast, with EMCRS patients, the expression of LL-37 peptide in nasal tissue is increased with Aspergillus (p < 0.001) but is reduced with Alternaria. We also observed a trend where levels of secreted LL-37 were decreased with higher doses of Alternaria and Aspergillus extracts. CONCLUSION: LL-37 is significantly up-regulated at the mRNA and protein level in CRS patients in response to fungal allergens. However, EMCRS patients do not show increased LL-37 at either the mRNA or the protein level in response to Alternaria.

Human cathelicidin antimicrobial peptide is up-regulated in the eosinophilic mucus subgroup of chronic rhinosinusitis patients.

BACKGROUND: Eosinophilic mucus chronic rhinosinusitis (EMCRS) patients are a subgroup of CRS with a poorer prognosis due to frequent recurrences of disease. The cathelicidin antimicrobial peptide (CAMP) is an important innate defense peptide but its role in CRS is not well characterized. The purpose of this study was to investigate CAMP mRNA and protein expression from EMCRS, CRS, and normal control patients. METHODS: Biopsy specimens of nasal mucosa and nasal polyps were taken from 59 CRS patients and 9 controls. CAMP mRNA and protein levels were analyzed by real-time quantitative reverse-transcriptase polymerase chain reaction, immunoassay, Western blot, and immunohistochemistry. RESULTS: The expression of CAMP mRNA was significantly increased in EMCRS patients compared with CRS patients (p = 0.0004). By immunohistochemistry, expression of CAMP was localized to nasal epithelial, submucosal glands, and inflammatory subepithelial cells. Western blotting confirmed the presence of CAMP in EMCRS, CRS, and control patients. However, we did not detect statistically significant differences in the protein levels in tissue homogenates between EMCRS, CRS, and control patients. CONCLUSION: This study shows expression of CAMP in nasal mucosa supporting its role in innate defenses against inhaled pathogens. Although CAMP mRNA was up-regulated in EMCRS patients, there were no statistically significant differences in protein levels in the nasal mucosa of EMCRS compared with CRS patients and controls.

Th2 immunological inflammation in allergic fungal sinusitis, nonallergic eosinophilic fungal sinusitis, and chronic rhinosinusitis.

BACKGROUND: Noninvasive fungal sinusitis is a heterogenous group of conditions including allergic fungal sinusitis (AFS) and nonallergic eosinophilic fungal sinusitis (NEFS). Th2-mediated cascades have been postulated to be the major inflammatory response in patients with AFS although other mechanisms also may be involved. The detailed mucosal Th2 cytological status of NEFS still has not been studied in great depth. METHODS: Using a meticulous patient selection algorithm over a 2-year period, infundibular mucosal tissue from patients with AFS, NEFS, chronic rhinosinusitis (CRS), and normal controls was studied (n = 59). Immunohistochemistry for mast cells, eosinophils, and immunoglobulin E (IgE) cells was performed and cell counts per unit area were measured. RESULTS: Mast cell, eosinophil, and IgE+ cell numbers were significantly raised in patients with AFS, NEFS, and CRS when compared with controls. There was no significant difference between cell numbers in patients with AFS and NEFS. CONCLUSION: Patients with AFS exhibit a classic Th2 inflammatory response in nasal mucosal tissue with NEFS and CRS patients showing evidence of a similar Th2 cascade, including the presence of IgE+ cells.