Cross validated serum small extracellular vesicle microRNAs for the detection of oropharyngeal squamous cell carcinoma.

BACKGROUND: Oropharyngeal squamous cell carcinoma (OPSCC) is often diagnosed at an advanced stage because the disease often causes minimal symptoms other than metastasis to neck lymph nodes. Better tools are required to assist with the early detection of OPSCC. MicroRNAs (miRNAs, miRs) are potential biomarkers for early head and neck squamous cell cancer diagnosis, prognosis, recurrence, and presence of metastatic disease. However, there is no widespread agreement on a panel of miRNAs with clinically meaningful utility for head and neck squamous cell cancers. This could be due to variations in the collection, storage, pre-processing, and isolation of RNA, but several reports have indicated that the selection and reproducibility of biomarkers has been widely affected by the methods used for data analysis. The primary analysis issues appear to be model overfitting and the incorrect application of statistical techniques. The purpose of this study was to develop a robust statistical approach to identify a miRNA signature that can distinguish controls and patients with inflammatory disease from patients with human papilloma virus positive (HPV +) OPSCC. METHODS: Small extracellular vesicles were harvested from the serum of 20 control patients, 20 patients with gastroesophageal reflux disease (GORD), and 40 patients with locally advanced HPV + OPSCC. MicroRNAs were purified, and expression profiled on OpenArray™. A novel cross validation method, using lasso regression, was developed to stabilise selection of miRNAs for inclusion in a prediction model. The method, named StaVarSel (for Stable Variable Selection), was used to derive a diagnostic biomarker signature. RESULTS: A standard cross validation approach was unable to produce a biomarker signature with good cross validated predictive capacity. In contrast, StaVarSel produced a regression model containing 11 miRNA ratios with potential clinical utility. Sample permutations indicated that the estimated cross validated prediction accuracy of the 11-miR-ratio model was not due to chance alone. CONCLUSIONS: We developed a novel method, StaVarSel, that was able to identify a panel of miRNAs, present in small extracellular vesicles derived from blood serum, that robustly cross validated as a biomarker for the detection of HPV + OPSCC. This approach could be used to derive diagnostic biomarkers of other head and neck cancers.

Does gene expression in laryngeal subsites differ between patients with laryngopharyngeal reflux and controls?

OBJECTIVE: To identify laryngeal mRNA gene changes in patients with laryngopharyngeal reflux (LPR). METHOD: Laryngeal biopsies from non-smoking LPR patients (n=10; Reflux Symptom Index (RSI) >12 and a Reflux Finding Score (RFS) >6) and controls (n=9; RSI <12 and RFS <6) were collected from four subsites (true vocal cord, false vocal cord, medial arytenoid and posterior commissure) of the larynx. qRT-PCR analyses were conducted on 20 reflux- and inflammation-related genes, including interleukins 6 and 8, cytokeratins 8 and 14, mucin genes MUC1, MUC2, MUC3B, MUC4, MUC5B, MUC6 and MUC7 and carbonic anhydrase III. Statistical analysis (Mann-Whitney U test) compared gene expression levels between LPR and control groups at each subsite. RESULTS: Site-specific differences in squamous metaplasia and gene expression were noted in LPR patients, with the majority present in the medial arytenoid region. Significant.differences were noted in genes related to mucosal defence and inflammation, including CRNN, CD1d, TGFß-1, MUC2, MUC5B and CDH1. CONCLUSION: Whilst the posterior commissure is commonly identified as the area demonstrating the most significant macroscopic change in LPR, the histological changes and genes assessed here showed more pronounced LPR associated differences in the medial arytenoid. We identified differences in expression of mucin genes, cytokeratin-14 and molecular markers of inflammation. Whilst some of these changes may be metaplasia-related, further evaluation of the mRNA expression of these genes may provide a useful biomarker panel for diagnosis and therapeutic monitoring of LPR.

Microbiology of otitis media in Indigenous Australian children: review.

OBJECTIVES: To review research addressing the polymicrobial aetiology of otitis media in Indigenous Australian children in order to identify research gaps and inform best practice in effective prevention strategies and therapeutic interventions. METHODS: Literature review. RESULTS: Studies of aspirated middle-ear fluid represented a minor component of the literature reviewed. Most studies relied upon specimens from middle-ear discharge or the nasopharynx. Culture-based middle-ear discharge studies have found that non-typeable Haemophilus influenzae and Streptococcus pneumoniae predominate, with Moraxella catarrhalis, Staphylococcus aureus and Streptococcus pyogenes isolated in a lower proportion of samples. Alloiococcus otitidis was detected in a number of studies; however, its role in otitis media pathogenesis remains controversial. Nasopharyngeal colonisation is a risk factor for otitis media in Indigenous infants, and bacterial load of otopathogens in the nasopharynx can predict the ear state of Indigenous children. CONCLUSION: Most studies have used culture-based methods and specimens from middle-ear discharge or the nasopharynx. Findings from these studies are consistent with international literature, but reliance on culture may incorrectly characterise the microbiology of this condition. Advances in genomic technologies are now providing microbiologists with the ability to analyse the entire mixed bacterial communities ('microbiomes') of samples obtained from Indigenous children with otitis media.

Long-term quality-of-life outcomes following treatment for adult obstructive sleep apnoea: comparison of upper airway surgery, continuous positive airway pressure and mandibular advancement splints.

OBJECTIVE: Long-term quality-of-life (QOL) outcomes, complications and clinical effectiveness in patients undergoing treatment with upper airway surgery (UAS), continuous positive airway pressure (CPAP) and mandibular advancement splints (MAS) for adult obstructive sleep apnoea (OSA). DESIGN: Retrospective cohort study. SETTING: Multidisciplinary OSA clinic in University teaching hospital. PARTICIPANTS: Consecutive, simultaneously treated patients with OSA undergoing UAS (n = 83), CPAP (n = 83) and MAS (n = 79). MAIN OUTCOME MEASURES: Glasgow Benefit Inventory (GBI), Snoring Severity Scale (SSS), Epworth Sleepiness Score (ESS) and side-effects in all three groups were recorded at a mean of 34.5 months following start of treatment and compared via anova with Bonferroni's adjustment for pairwise comparisons. RESULTS: Upper airway surgery demonstrated a statistically significant QOL benefit over MAS. All three groups showed a significant improvement in SSS with CPAP significantly better than MAS, but equivalent to UAS. Uncomplicated UAS provided a greater QOL outcome than compliant MAS, non-compliant CPAP (P < 0.05) and comparable to compliant CPAP. Patients undergoing UAS with recorded complications still reported equivalent QOL outcomes to compliant CPAP and MAS, suggesting these surgical complications are relatively minor compared to the QOL benefit of OSA treatment. CONCLUSION: Upper airway surgery showed a significant improvement in QOL outcomes compared to non-compliant CPAP or MAS and equivalent benefit to compliant CPAP. This study strongly supports the role for contemporary UAS in OSA when CPAP is not or no longer an option.

Do tissue spears used to clear ear canal pus improve hearing? A case series study of hearing in remote Australian Aboriginal children with chronic suppurative otitis media before and after dry mopping with tissue spears.

OBJECTIVE: To determine whether the use of tissue spears to remove otorrhoea from Aboriginal children's ear canals improves hearing in the affected ear. DESIGN: Case series study with controls. METHODS: The study comprised 61 Aboriginal children from communities in the remote arid zone of South Australia who had otorrhoea obscuring the tympanic membrane in 1 or both ears. Eighty ears were treated with tissue spears, and hearing was assessed before and after treatment. RESULTS: Forty-two children had unilateral and 19 had bilateral active disease. An additional 13 ears without otorrhoea served as controls. Improvement by 5 dB HL or greater in a four-frequency pure tone average occurred in 41.3 per cent of treated ears. Subsequently, blinded audiologists made qualitative judgements that a functional improvement in hearing had occurred after tissue spear use in 28.4 per cent of ears. CONCLUSION: Tissue spears can improve hearing thresholds in a significant proportion of children with otorrhoea. However, the duration of the effect is unknown.

Validation of virtual-reality-based simulations for endoscopic sinus surgery.

BACKGROUND: Virtual reality (VR) simulators provide an alternative to real patients for practicing surgical skills but require validation to ensure accuracy. Here, we validate the use of a virtual reality sinus surgery simulator with haptic feedback for training in Otorhinolaryngology - Head & Neck Surgery (OHNS). METHODS: Participants were recruited from final-year medical students, interns, resident medical officers (RMOs), OHNS registrars and consultants. All participants completed an online questionnaire after performing four separate simulation tasks. These were then used to assess face, content and construct validity. anova with post hoc correlation was used for statistical analysis. RESULTS: The following groups were compared: (i) medical students/interns, (ii) RMOs, (iii) registrars and (iv) consultants. Face validity results had a statistically significant (P < 0.05) difference between the consultant group and others, while there was no significant difference between medical student/intern and RMOs. Variability within groups was not significant. Content validity results based on consultant scoring and comments indicated that the simulations need further development in several areas to be effective for registrar-level teaching. However, students, interns and RMOs indicated that the simulations provide a useful tool for learning OHNS-related anatomy and as an introduction to ENT-specific procedures. CONCLUSIONS: The VR simulations have been validated for teaching sinus anatomy and nasendoscopy to medical students, interns and RMOs. However, they require further development before they can be regarded as a valid tool for more advanced surgical training.

Bleeding following coblation tonsillectomy: a 10-year, single-surgeon audit and modified grading system.

OBJECTIVE: Coblation tonsillectomy can be controversial. This study assessed post-tonsillectomy haemorrhage outcomes for patients operated on by a single experienced coblation-trained ENT surgeon. STUDY DESIGN: A retrospective audit of coblation tonsillectomies was performed using the Flinders modification of Stammberger criteria for post-tonsillectomy haemorrhage. METHOD: Case note review, interview and database interrogation were utilised to obtain the dataset. Haemorrhage results were compared to reports in the current literature. RESULTS: Of those who underwent coblation tonsillectomy, 3.4 per cent were readmitted to hospital with haemorrhage and 1.3 per cent returned to the operating theatre (0.4 per cent primary haemorrhage and 0.9 per cent secondary haemorrhage). Younger children had a lower risk of returning to the operating theatre than older children or adults (0.3 per cent under the age of 12 years vs 2.0 per cent aged 12 years or older). CONCLUSION: Coblation can be a safe method for tonsillectomy with low complication rates when performed by an experienced ENT surgeon. The Flinders modification of the Stammberger criteria for post-tonsillectomy haemorrhage provides a simple system for data comparison.

Surgical management of airway stenosis by radiofrequency coblation.

BACKGROUND: Acquired airway stenosis can be challenging to manage endoscopically because of difficult field visualisation, instrument limitations and the risk of laser fire. At our institution, radiofrequency coblation has been successfully used for the resection of subglottic and tracheal stenosis in adults. This paper presents our experience with this technique. METHOD: A retrospective case note analysis of all cases of airway stenosis in adults from 2007 to 2012 was performed. RESULTS: Ten adult patients underwent coblation resection for airway stenosis. All lesions were classified as McCaffrey stage I (i.e. less than 1 cm long). Causes of stenosis included: idiopathic stenosis (40 per cent), previous tracheostomy (30 per cent) and endotracheal intubation (20 per cent). Six patients (60 per cent) required a single procedure and 4 (40 per cent) required multiple interventions. All patients reported significant improvement in their symptoms following treatment. All patients were alive at the time of writing and none have required open resection. CONCLUSION: Radiofrequency coblation is an attractive alternative technique for the treatment of idiopathic or acquired airway stenosis in adults.

Role of subtotal tonsillectomy ('tonsillotomy') in children with sleep disordered breathing.

INTRODUCTION: Sleep disordered breathing in children causes disturbance in behaviour and also in cardiorespiratory and neurocognitive function. Subtotal tonsillectomy ('tonsillotomy') has been performed to treat sleep disordered breathing, with outcomes comparable to established therapies such as total tonsillectomy or adenoidectomy. This review critically assesses the role of subtotal tonsillectomy in a paediatric setting. METHOD: The Medline database (1966 to October 2012) was electronically searched using key terms including subtotal or intracapsular tonsillectomy, tonsillotomy, tonsillectomy, paediatrics, and sleep disordered breathing. RESULTS: Eighteen papers were identified and reviewed. Subtotal tonsillectomy would appear to have an efficacy equal to that of total tonsillectomy for the treatment of sleep disordered breathing, and has significant benefits in reducing post-operative pain and analgesia use. Subtotal tonsillectomy patients appear to have less frequent post-operative haemorrhage compared with total tonsillectomy patients. CONCLUSION: In children, subtotal tonsillectomy is associated with fewer post-operative complications whilst having a comparable effect in improving sleep disordered breathing, compared with total tonsillectomy.

Otitis media in Indigenous Australian children: review of epidemiology and risk factors.

BACKGROUND: Otitis media represents a major health concern in Australian Indigenous children ('Indigenous children'), which has persisted, despite public health measures, for over 30 years. METHODS: Global searches were performed to retrieve peer-reviewed and 'grey' literature investigating the epidemiology of and risk factors for otitis media in Indigenous children, published between 1985 and 2012. RESULTS: In Indigenous children, the prevalence of otitis media subtypes is 7.1-12.8 per cent for acute otitis media, 10.5-30.3 per cent for active chronic otitis media and 31-50 per cent for tympanic membrane perforation. The initial onset of otitis media in Indigenous children occurs earlier and persists for longer after the first year of life, compared with non-Indigenous children. Indigenous children are colonised by otopathogens more frequently, at younger ages and with a higher bacterial load. Poor community and domestic infrastructure, overcrowding and exposure to tobacco smoke increase the risk of otitis media in Indigenous children; however, the availability of swimming pools plays no role in the prevention or management of otitis media. CONCLUSION: Despite awareness of the epidemiological burden of otitis media and its risk factors in Indigenous children, studies undertaken since 1985 demonstrate that otitis media remains a significant public health concern in this population.

Bisphosphonate-associated osteonecrosis of the external auditory canal.

BACKGROUND: Osteonecrosis is a benign condition characterised by necrotic exposed bone, and is associated with bisphosphonate use. Osteonecrosis of the external auditory canal is rare, with only a few reported cases. METHOD: Two case reports of temporal bone osteonecrosis are presented. RESULTS: A 64-year-old man with a history of immunoglobulin G kappa multiple myeloma developed a right external auditory canal ulcer 6 years after commencement on clodronate. A 72-year-old woman taking alendronate for osteoporosis, initially diagnosed and treated for right-sided otitis externa, was found to have underlying exposed bone in the right external auditory canal, with a computed tomography scan confirming destruction of the temporal bone. CONCLUSION: With increasing use of both oral and intravenous bisphosphonates in the community for benign conditions such as osteoporosis and for malignant conditions such as breast cancer and multiple myeloma, the diagnosis of bisphosphonate-associated osteonecrosis should always be considered in patients with a temporal bone lesion, and a relevant drug history taken.

Micro-ribonucleic acids in head and neck cancer: an introduction.

BACKGROUND AND METHODS: Head and neck cancer is the sixth most common cancer worldwide. Advances in management have not greatly altered overall survival. Over the last decade, there have been significant scientific advances in our knowledge of cell cycle regulation and the complex oncogenic processes. MicroRNAs are small, non-coding RNAs which are integral to the regulation of gene expression and which play a part in carcinogenesis. The literature on the role of microRNA in head and neck cancer is reviewed. OBJECTIVE: To introduce the role and significance of microRNAs in head and neck cancer. RESULTS: The possibilities of incorporating microRNAs into clinical practice are discussed, including their potential role in diagnosis, prognosis, prediction of metastatic spread, therapy and tumour surveillance. CONCLUSION: Discoveries in expression profiling of microRNA in head and neck oncology promise advancements in the diagnosis, prognosis and therapy of these cancers.

Lysozyme expression is increased in the sinus mucosa of patients with chronic rhinosinusitis.

BACKGROUND: The presence of fungi and bacteria in the paranasal sinuses may contribute to ongoing inflammation. Lysozyme is an innate immune peptide with bactericidal and fungicidal activity. The expression of lysozyme in chronic rhinosinusitis (CRS) is poorly understood and deficiencies in lysozyme expression may contribute to the ongoing inflammation in CRS patients. OBJECTIVE: Determine lysozyme expression in sinus mucosa of normal and CRS patients with (CRSwNP) and without (CRSsNP) nasal polyps. METHODOLOGY: Sinus mucosa specimens (n = 82) were processed for standard histology, immunohistochemical localisation of lysozyme, immunofluorescent localisation of fungi, and qPCR analysis of lysozyme expression. RESULTS: CRS specimens displayed high-levels of lysozyme immunoreactivity in many of the abundant serous cells. Moderate levels were detected in some epithelial cells and inflammatory cells. Low levels were detected in some subepithelial glands of control specimens. No difference in immunoreactivity was detected between CRSwNP and CRSsNP specimens. Fungal elements were not visualised in any sinus specimen. qPCR analysis demonstrated variable lysozyme expression between individuals. CONCLUSIONS: Lysozyme protein expression is increased in patients with CRS, suggesting a defect in lysozyme expression is not responsible for the microbial colonisation often associated with CRS. The functional activity of lysozyme in CRS patients needs to be further investigated.

A virtual-reality subtotal tonsillectomy simulator.

OBJECTIVES: To develop a virtual-reality subtotal tonsillectomy simulation for surgical training. MATERIALS AND METHODS: Computer models of a male patient's head and throat, and the surgical instrument, were created. These models were combined with custom-built simulation software. Recently developed tissue simulation technology that exploits recent developments in programmable graphics processing units was used to model tonsillar tissue in a way that allows surgical interaction whilst providing accurate tactile feedback. Current real-time rendering techniques were used to provide realistic visuals. Iterative refinements were made to the simulation, and in particular the tissue simulation, in consultation with relevantly experienced surgeons. RESULTS: We have used newly developed tissue simulation technology to developed a novel virtual-reality subtotal tonsillectomy simulation for surgical training, the first of its kind. CONCLUSION: Early feedback suggests that this simulator can help surgeons to rapidly acquire subtotal tonsillectomy surgical skills in a risk-free and realistic virtual environment.

Biomarkers and laryngopharyngeal reflux.

Laryngopharyngeal reflux is a controversial but increasingly made diagnosis used in patients with a collection of often non-specific laryngeal symptoms. It is a clinical diagnosis, and its pathophysiology is currently poorly understood. Previous reflux research has focused on injurious agents, acid, pepsin and biomarker expression. Failure of intrinsic defences in the larynx may cause changes in laryngeal epithelia, particularly alterations in carbonic anhydrases and E-cadherin. Carbonic anhydrase III levels vary in the larynx in response to laryngopharyngeal reflux, depending on location. Expression of E-cadherin, a known tumour suppressor, is reduced in the presence of reflux. Mucin expression also varies according to the severity of reflux. Further research is required to define the clinical entity of laryngopharyngeal reflux, and to identify a definitive mechanism for mucosal injury. Understanding this mechanism should allow the development of a comprehensive model, which would enable future diagnostic and therapeutic interventions to be developed.

Coblation for epistaxis management in patients with hereditary haemorrhagic telangiectasia: a multicentre case series.

OBJECTIVE: To propose radiofrequency coblation as a potential treatment modality for mild to moderate epistaxis in patients with hereditary haemorrhagic telangiectasia. METHOD: Case reports and review of the world literature concerning coblation and other treatment modalities for epistaxis in patients with hereditary haemorrhagic telangiectasia. RESULTS: Effective epistaxis control was achieved in four out of five cases of hereditary haemorrhagic telangiectasia. In the fifth case, we struggled to achieve haemostasis due to disease severity. CONCLUSION: Radiofrequency coblation is a novel technique, which was found to be a safe, effective, quick and well tolerated treatment option for epistaxis management in patients with hereditary haemorrhagic telangiectasia.

Radiofrequency coblation for treatment of advanced laryngotracheal recurrent respiratory papillomatosis.

BACKGROUND: A variety of treatment modalities are currently used to treat recurrent respiratory papillomatosis. We aimed to study the efficacy of radiofrequency cold ablation (coblation) for the treatment of laryngotracheal recurrent respiratory papillomatosis, by comparing treatment intervals for coblation and CO2 laser vaporisation. METHOD: Retrospective case series of adult patients with advanced laryngotracheal recurrent respiratory papillomatosis. RESULTS: Six patients were treated for at least two years by CO2 laser vaporisation with or without intralesional cidofovir. All six subsequently underwent treatment with radiofrequency coblation with or without intralesional cidofovir. Coblation resulted in longer periods between interventions, compared with CO2 laser (p = 0.03). CONCLUSION: Radiofrequency coblation appears to be an attractive alternative technique to CO2 laser for the surgical treatment of advanced laryngotracheal papillomata.