Coblation intracapsular tonsillectomy in a paediatric tertiary centre: Revision surgery rates over a nine-year period.

OBJECTIVES: Coblation intracapsular tonsillectomy (ICT) is increasingly being used in the paediatric population because of the rapid recovery and low rates of complications associated with it. There is, however, a risk of symptomatic regrowth with this technique. The objective of our study is to establish the rate of, and risks for, revision surgery over time in a major tertiary referral centre with a large cohort of paediatric Coblation ICT cases. METHODS: A retrospective review of all children (0-19 years) undergoing Coblation ICT from April 2013 to June 2022 was undertaken, using electronic databases and clinical records. Post-operative follow up was reviewed and revision cases were subsequently identified and examined. Statistical analysis was performed using a Chi-Squared test. RESULTS: 4111 patients underwent Coblation ICT during the studied period, with or without concomitant adenoidectomy. Of these, 135 (3.3 %) required revision tonsil surgery, primarily for recurrence of initial symptoms; two patients required two consecutive revision procedures (137 revision procedures in total). Eight-eight (n = 88) (64 %) of these were revised with a repeat Coblation ICT procedure and 49 (36 %) with bipolar diathermy extracapsular tonsillectomy (ECT) of remnant tonsil tissue. The revision rates after Coblation ICT declined steeply on a year-on-year basis since the commencement of this technique (from 10.6 % early on, to 0.3 % at the end of the study period P<0.001). A significantly higher revision rate was noted in children below the age of two at the time of primary surgery, compared to those older than two years of age (P<0.001). CONCLUSIONS: This study demonstrates real-world departmental revision rates over a nine-year period from the technique's commencement of use. With Coblation ICT, symptomatic re-growth occurs rarely, but may be clinically significant, with higher rates of recurrent symptoms seen in children under two years of age at the time of primary surgery. The revision rate apparently drops over time in parallel with overall experience of surgeons and formalised training.

Proteomics-based identification of cancer-associated proteins in chronic lymphocytic leukaemia

BACKGROUND: Chronic lymphocytic leukaemia (CLL) is a neoplasm of B-cells characterized by variable prognosis. Exploring the proteome of CLL cells may provide insights into the disease. Therefore, eleven proteomics experiments were conducted on eleven primary CLL samples. RESULTS: We reported a CLL proteome consisting of 919 proteins (false discovery rate (FDR) 1%) whose identification was based on the sequencing of two or more distinct peptides (FDR of peptide sequencing 1%). Mass spectrometry-based protein identification was validated for four different proteins using Western blotting and specific antibodies in different CLL samples. Small sizes of nucleolin (~57 kDa and ~68 kDa) showed a potential association with good prognosis CLL cells (n = 8, p < 0.01). Compared with normal B-cells, CLL cells over-expressed thyroid hormone receptor-associated protein 3 (THRAP3; n = 9; p = 0.00007), which is implicated in cell proliferation; and heterochromatin protein 1-binding protein 3 (HP1BP3; n = 10; p = 0.0002), which promotes cell survival and tumourogenesis. A smaller form of HP1BP3, which may correspond to HP1BP3 isoform-2, was specifically identified in normal B-cells (n = 10; p = 0.0001). HP1BP3 and THRAP3 predicted poor prognosis of CLL (p 0.05). Consistently, THRAP3 and HP1BP3 were found to be associated with cancer-related pathways (p 0.05). CONCLUSIONS: Our findings add to the known proteome of CLL and confirm the prognostic importance of two novel cancer-associated proteins in this disease.

Genome-wide association study identifies risk loci for progressive chronic lymphocytic leukemia.

Prognostication in patients with chronic lymphocytic leukemia (CLL) is challenging due to heterogeneity in clinical course. We hypothesize that constitutional genetic variation affects disease progression and could aid prognostication. Pooling data from seven studies incorporating 842 cases identifies two genomic locations associated with time from diagnosis to treatment, including 10q26.13 (rs736456, hazard ratio (HR) = 1.78, 95% confidence interval (CI) = 1.47-2.15; P = 2.71 × 10-9) and 6p (rs3778076, HR = 1.99, 95% CI = 1.55-2.55; P = 5.08 × 10-8), which are particularly powerful prognostic markers in patients with early stage CLL otherwise characterized by low-risk features. Expression quantitative trait loci analysis identifies putative functional genes implicated in modulating B-cell receptor or innate immune responses, key pathways in CLL pathogenesis. In this work we identify rs736456 and rs3778076 as prognostic in CLL, demonstrating that disease progression is determined by constitutional genetic variation as well as known somatic drivers.

Implantable cardioverter-defibrillator therapy to reduce sudden cardiac death in adults with congenital heart disease: A registry study.

INTRODUCTION: The adult congenital heart disease (ACHD) population is rapidly expanding. However, a significant proportion of these patients suffer sudden cardiac death. Recommending implantable cardioverter-defibrillator (ICD) insertion requires balancing the need for appropriate therapy in malignant arrhythmia against the consequences of inappropriate therapy and procedural complications. Here we present long-term follow-up data for ICD insertion in patients with ACHD from a large Level 1 congenital cardiac center. METHODS AND RESULTS: All patients with ACHD undergoing ICD insertion over an 18-year period were identified. Data were extracted for baseline characteristics including demographics, initial diagnosis, ventricular function, relevant medication, and indication for ICD insertion. Details regarding device insertion were gathered along with follow-up data including appropriate and inappropriate therapy and complications. A total of 136 ICDs were implanted during this period: 79 for primary and 57 for secondary prevention. The most common congenital cardiac conditions in both groups were tetralogy of Fallot and transposition of the great arteries. Twenty-two individuals in the primary prevention group received appropriate antitachycardia pacing (ATP), 14 underwent appropriate cardioversion, 17 received inappropriate ATP, and 15 received inappropriate cardioversion. In the secondary prevention group, 18 individuals received appropriate ATP, 8 underwent appropriate cardioversion, 8 received inappropriate ATP, and 7 were inappropriately cardioverted. Our data demonstrate low complication rates, particularly with leads without advisories. CONCLUSION: ICD insertion in the ACHD population involves a careful balance of the risks and benefits. Our data show a significant proportion of patients receiving appropriate therapy indicating that ICDs were inserted appropriately.

A laboratory-based scoring system predicts early treatment in Rai 0 chronic lymphocytic leukemia.

We present a laboratory-based prognostic calculator (designated CRO score) to risk stratify treatment-free survival in early stage (Rai 0) chronic lymphocytic leukemia (CLL) developed using a training-validation model in a series of 1,879 cases from Italy, the United Kingdom and the United States. By means of regression analysis, we identified five prognostic variables with weighting as follows: deletion of the short arm of chromosome 17 and unmutated immunoglobulin heavy chain gene status, 2 points; deletion of the long arm of chromosome 11, trisomy of chromosome 12, and white blood cell count >32.0x103/microliter, 1 point. Low-, intermediate- and high-risk categories were established by recursive partitioning in a training cohort of 478 cases, and then validated in four independent cohorts of 144 / 395 / 540 / 322 cases, as well as in the composite validation cohort. Concordance indices were 0.75 in the training cohort and ranged from 0.63 to 0.74 in the four validation cohorts (0.69 in the composite validation cohort). These findings advocate potential application of our novel prognostic calculator to better stratify early-stage CLL, and aid case selection in risk-adapted treatment for early disease. Furthermore, they support immunocytogenetic analysis in Rai 0 CLL being performed at the time of diagnosis to aid prognosis and treatment, particularly in today's chemofree era.

The use of a single chamber leadless pacemaker for the treatment of cardioinhibitory vasovagal syncope.

BACKGROUND: The use of pacemakers in the treatment of cardioinhibitory vasovagal syncope is controversial with a mixed message from the limited evidence base. Single chamber leadless pacemakers have been shown to be an effective alternative option to conventional pacemakers. OBJECTIVE: This study examines the use of leadless pacemakers in a cardioinhibitory vasovagal population in the United Kingdom. METHODS: Observational data on 32 patients implanted with the Micra Transcatheter Pacemaker System for vasovagal syncope are presented. Data was collected on implant indications, implant procedure and follow up data from 12 centres across the United Kingdom that had elected to use a Micra leadless pacemaker in this patient population. RESULTS: 32 patients aged 37 ±â€¯14 years (range 18 to 64 years) with 62% of the patients being female were recruited to the study. Vasovagal syncope was diagnosed clinically and with the support of Holter monitoring, tilt table testing and implantable loop recorders. The duration of symptoms was 8 ±â€¯8 yrs. with an average frequency of syncope being 4 ±â€¯6 times/year. The Micra pacemaker was successfully implanted in all patients with a major complication rate of 3.1%. Patients were followed up for 404 ±â€¯237 days (range 63-928 days). At follow up 28 (87%) patients were free from symptoms. CONCLUSIONS: This observational study suggests that the use of a single chamber leadless pacemaker in the treatment of cardioinhibitory vasovagal syncope might be a reasonable clinical option.

Activation of naïve CD4+ T cells re-tunes STAT1 signaling to deliver unique cytokine responses in memory CD4+ T cells.

The cytokine IL-6 controls the survival, proliferation and effector characteristics of lymphocytes through activation of the transcription factors STAT1 and STAT3. While STAT3 activity is an ever-present feature of IL-6 signaling in CD4+ T cells, prior activation via the T cell antigen receptor limits IL-6's control of STAT1 in effector and memory populations. Here we found that phosphorylation of STAT1 in response to IL-6 was regulated by the tyrosine phosphatases PTPN2 and PTPN22 expressed in response to the activation of naïve CD4+ T cells. Transcriptomics and chromatin immunoprecipitation-sequencing (ChIP-seq) of IL-6 responses in naïve and effector memory CD4+ T cells showed how the suppression of STAT1 activation shaped the functional identity and effector characteristics of memory CD4+ T cells. Thus, tyrosine phosphatases induced by the activation of naïve T cells determine the way activated or memory CD4+ T cells sense and interpret cytokine signals.

Inhibitory-κB Kinase (IKK) α and Nuclear Factor-κB (NFκB)-Inducing Kinase (NIK) as Anti-Cancer Drug Targets.

The cellular kinases inhibitory-κB kinase (IKK) α and Nuclear Factor-κB (NF-κB)-inducing kinase (NIK) are well recognised as key central regulators and drivers of the non-canonical NF-κB cascade and as such dictate the initiation and development of defined transcriptional responses associated with the liberation of p52-RelB and p52-p52 NF-κB dimer complexes. Whilst these kinases and downstream NF-κB complexes transduce pro-inflammatory and growth stimulating signals that contribute to major cellular processes, they also play a key role in the pathogenesis of a number of inflammatory-based conditions and diverse cancer types, which for the latter may be a result of background mutational status. IKKα and NIK, therefore, represent attractive targets for pharmacological intervention. Here, specifically in the cancer setting, we reflect on the potential pathophysiological role(s) of each of these kinases, their associated downstream signalling outcomes and the stimulatory and mutational mechanisms leading to their increased activation. We also consider the downstream coordination of transcriptional events and phenotypic outcomes illustrative of key cancer 'Hallmarks' that are now increasingly perceived to be due to the coordinated recruitment of both NF-κB-dependent as well as NF-κB⁻independent signalling. Furthermore, as these kinases regulate the transition from hormone-dependent to hormone-independent growth in defined tumour subsets, potential tumour reactivation and major cytokine and chemokine species that may have significant bearing upon tumour-stromal communication and tumour microenvironment it reiterates their potential to be drug targets. Therefore, with the emergence of small molecule kinase inhibitors targeting each of these kinases, we consider medicinal chemistry efforts to date and those evolving that may contribute to the development of viable pharmacological intervention strategies to target a variety of tumour types.

Left atrial voltage, circulating biomarkers of fibrosis, and atrial fibrillation ablation. A prospective cohort study.

AIMS: To test the ability of four circulating biomarkers of fibrosis, and of low left atrial voltage, to predict recurrence of atrial fibrillation after catheter ablation. BACKGROUND: Circulating biomarkers potentially may be used to improve patient selection for atrial fibrillation ablation. Low voltage areas in the left atrium predict arrhythmia recurrence when mapped in sinus rhythm. This study tested type III procollagen N terminal peptide (PIIINP), galectin-3 (gal-3), fibroblast growth factor 23 (FGF-23), and type I collagen C terminal telopeptide (ICTP), and whether low voltage areas in the left atrium predicted atrial fibrillation recurrence, irrespective of the rhythm during mapping. METHODS: 92 atrial fibrillation ablation patients were studied. Biomarker levels in peripheral and intra-cardiac blood were measured with enzyme-linked immunosorbent assay. Low voltage (<0.5mV) was expressed as a proportion of the mapped left atrial surface area. Follow-up was one year. The primary endpoint was recurrence of arrhythmia. The secondary endpoint was a composite of recurrence despite two procedures, or after one procedure if no second procedure was undertaken. RESULTS: The biomarkers were not predictive of either endpoint. After multivariate Cox regression analysis, high proportion of low voltage area in the left atrium was found to predict the primary endpoint in sinus rhythm mapping (hazard ratio 4.323, 95% confidence interval 1.337-13.982, p = 0.014) and atrial fibrillation mapping (hazard ratio 5.195, 95% confidence interval 1.032-26.141, p = 0.046). This effect was also apparent for the secondary endpoint. CONCLUSION: The studied biomarkers do not predict arrhythmia recurrence after catheter ablation. Left atrial voltage is an independent predictor of recurrence, whether the left atrium is mapped in atrial fibrillation or sinus rhythm.

Intra-cardiac and peripheral levels of biochemical markers of fibrosis in patients undergoing catheter ablation for atrial fibrillation.

AIMS: Measurement of circulating biomarkers of fibrosis may have a role in selecting patients and treatment strategy for catheter ablation. Pro-collagen type III N-terminal pro-peptide (PIIINP), C-telopeptide of type I collagen (ICTP), fibroblast growth factor 23 (FGF-23), and galectin 3 (gal-3) have all been suggested as possible biomarkers for this indication, but studies assessing whether peripheral levels reflect intra-cardiac levels are scarce. METHODS AND RESULTS: We studied 93 patients undergoing ablation for paroxysmal atrial fibrillation (AF) (n = 63) or non-paroxysmal AF (n = 30). Femoral venous, left and right atrial, and coronary sinus blood were analysed using ELISA to determine biomarker levels. Levels were compared with control patients (n = 36) and baseline characteristics, including left atrial voltage mapping data. C-telopeptide of type I collagen levels were higher in AF than in non-AF patients (P = 0.007). Peripheral ICTP levels were higher than all intra-cardiac levels (P < 0.001). Peripheral gal-3 levels were higher than left atrial levels (P = 0.001). Peripheral levels of FGF-23 and PIIINP were not significantly different from intra-cardiac levels. CS levels of ICTP were higher than right and left atrial levels (P < 0.001). gal-3 was higher in women vs. men (P ≤ 0.001) and with higher body mass index (P ≤ 0.001). ICTP levels increased with reducing ejection fraction (P ≤ 0.012). CONCLUSIONS: Atrial fibrillation patients have higher levels of circulating ICTP than matched non-AF controls. In AF ablation patients, intra-cardiac sampling of FGF-23 or PIIINP gives no further information over peripheral sampling. For gal-3 and ICTP, intra-cardiac sampling may be necessary to assess their association with intra-cardiac processes. None of the biomarkers is related to fibrosis assessed by left atrial voltage.

Cytomegalovirus infection does not impact on survival or time to first treatment in patients with chronic lymphocytic leukemia.

Human cytomegalovirus (HCMV) is a widely prevalent herpes virus which establishes a state of chronic infection. The establishment of CMV-specific immunity controls viral reactivation and leads to the accumulation of very large numbers of virus-specific T cells which come to dominate the immune repertoire. There is concern that this may reduce the immune response to heterologous infections and HCMV infection has been associated with reduced survival in elderly people. Patients with chronic lymphocytic leukemia (B-CLL) suffer from a state of immune suppression but have a paradoxical increase in the magnitude of the CMV-specific T cell and humoral immune response. As such, there is now considerable interest in how CMV infection impacts on the clinical outcome of patients with B-CLL. Utilizing a large prospective cohort of patients with B-CLL (n = 347) we evaluated the relationship between HCMV seropositivity and patient outcome. HCMV seropositive patients had significantly worse overall survival than HCMV negative patients in univariate analysis (HR = 2.28, 95% CI: 1.34-3.88; P = 0.002). However, CMV seropositive patients were 4 years older than seronegative donors and this survival difference was lost in multivariate modeling adjusted for age and other validated prognostic markers (P = 0.34). No significant difference was found in multivariate modeling between HCMV positive and negative patients in relation to the time to first treatment (HR = 1.12, 95% CI: 0.68-1.84; P = 0.65). These findings in a second independent cohort of 236 B-CLL patients were validated. In conclusion no evidence that HCMV impacts on the clinical outcome of patients with B-CLL was found. Am. J. Hematol. 91:776-781, 2016. © 2016 Wiley Periodicals, Inc.

Head and neck teratomas in children--A series of 23 cases at Great Ormond Street Hospital.

OBJECTIVE: Head and neck teratomas are rare and malignant change is rarer still. This is a report detailing all of the teratomas treated by the ear, nose and throat or craniofacial teams over the last 28 years at our institution. Examining the common presenting and radiological features as well as our success rates compared to the current literature. METHOD: A retrospective review of all cases presenting to our institution with a head and neck teratoma were analysed. Data regarding the following characteristics were collected: antenatal history, clinical features, biological serum makers, radiological and pathological characteristics. Surgical treatment, rates of reoccurrence and the degree of post-operative follow up were also analysed. RESULTS: 23 cases in total were included: 8 cervical, 6 nasopharyngeal, 5 thyroid, 2 thymus, 2 temporal. One had malignant change. The majority of children presented at birth with respiratory distress, 5 cases were picked up antenatally and one case presented at 10 years of age. All were treated surgically; with complete excision in 20 patients. No clinical recurrence occurred but further surgery was performed for radiologically suspected residual disease in one case. DISCUSSION: This is the largest detailed case series in literature in regard to head and neck teratomas. Illustrating that this is frequently a benign disease process disease in the head and neck region and has an excellent long term prognosis following surgery. In the situation of incomplete resection careful meticulous follow up with radiological imaging and a multidisciplinary team approach is a safe and viable alternative.

A series of parapharyngeal glial heterotopia mimicking lymphatic malformation.

Otolaryngologists will most frequently encounter extra-cranial glial tissue within the nasal cavity, where it is known as a 'nasal glioma', and may communicate with the dura. However, glial tissue can also present extra-nasally in the form of a neck mass with no intracranial connection. In these rare cases, they can present soon after birth as an enlarging neck mass, causing compressive symptoms with airway obstruction and feeding difficulties. In this way, it is often initially misdiagnosed as a more common lesion such as a lymphatic malformation, teratoma, branchial anomaly or vascular malformation. As with many congenital head and neck masses, offering the most the appropriate management relies heavily on radiological imaging and, where possible, histopathology from a diagnostic biopsy. Once the diagnosis of extra-nasal glial heterotopia has been confirmed, the gold standard management is complete surgical excision. We review three cases of extra-nasal glial heterotopia presenting to our institution over an eleven year period as a large neck mass, which mimicked other congenital neck lumps, and discuss them in the context of those in the literature. We highlight how their clinical and radiological features can easily be confused with lymphatic malformations, and the potential implications of misdiagnosis. Raising awareness of this diagnostic confusion will highlight the need for management of these cases within an appropriate paediatric multidisciplinary setting.

Primary cervical ganglioneuroblastoma.

OBJECTIVES: Ganglioneuroblastomas represent a histological subgroup of the rare neuroblastic tumours with intermediate malignant potential arising from neural crest progenitor cells of sympathetic nerves. Diagnosis can often be difficult based on imaging alone. We describe 4 cases of children presenting with a solitary neck mass with histology ultimately revealing ganglioneuroblastoma. METHODS: A retrospective case note review was carried out of all patients with cervical ganglioneuroblastoma seen at Great Ormond Street Hospital, UK. RESULTS: Mean age at presentation was 5 years. Based on imaging, the initial diagnoses for three of the cases were: lymphatic malformation, carotid body tumour, paraganglioma, respectively, whilst the remaining case had an immediate incisional biopsy revealing the correct diagnosis. All cases were managed by surgical excision with no evidence of recurrence after a median follow up of 6 years. CONCLUSION: Otolaryngologists should be aware of ganglioneuroblastoma when establishing the differential diagnosis of a child presenting with a neck mass. Biopsy is recommended as the gold standard investigation to avoid an incorrect diagnosis.

Small-molecule inhibitors of 25-hydroxyvitamin D-24-hydroxylase (CYP24A1): synthesis and biological evaluation.

The synthesis of imidazole styrylbenzamide, tert-butyl styrylimidazole, and tert-butyl styrylsulfonate derivatives is described. Evaluation of binding affinity and inhibitory activity against CYP24A1 identified the imidazole styrylbenzamides as potent inhibitors of CYP24A1, having selectivity with respect to CYP27B1 comparable with or greater than that of the standard ketoconazole. Further evaluation of the 3,5-dimethoxy and 3,4,5-trimethoxy derivatives in chronic lymphocytic leukemia cells revealed that co-treatment of 1α,25-dihydroxyvitamin D3 plus inhibitor coordinately upregulated GADD45α and CDKN1A. Docking experiments on the inhibitors in the CYP24A1 enzyme active site suggest the compounds reach the active site through the vitamin D access tunnel and are exposed to multiple hydrophobic residues. The imidazole styrylbenzamides are optimally positioned to allow interaction of the imidazole with the heme, and, in the case of the methoxy derivatives, a hydrogen bond between the 3-methoxy group and Gln82 stabilizes the molecule in a favorable active conformation.

Proteomics-based strategies to identify proteins relevant to chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL), a malignant B-cell disorder, is characterized by a heterogeneous clinical course. Two-dimensional nano liquid chromatography (2D-nano-LC) coupled with matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometry (MALDI-TOF/TOF MS) (LC-MALDI) was used to perform qualitative and quantitative analysis on cellular extracts from 12 primary CLL samples. We identified 728 proteins and quantified 655 proteins using isobaric tag-labeled extracts. Four strategies were used to identify disease-related proteins. First, we integrated our CLL proteome with published gene expression data of normal B-cells and CLL cells to highlight proteins with preferential expression in the transcriptome of CLL. Second, as CLL's outcome is heterogeneous, our quantitative proteomic data were used to indicate heterogeneously expressed proteins. Third, we used the quantitative data to identify proteins with differential abundance in poor prognosis CLL samples. Fourth, hierarchical cluster analysis was applied to identify hidden patterns of protein expression. These strategies identified 63 proteins, and 4 were investigated in a CLL cohort (39 patients). Thyroid hormone receptor-associated protein 3, T-cell leukemia/lymphoma protein 1A, and S100A8 were associated with high-risk CLL. Myosin-9 exhibited reduced expression in CLL samples from high-risk patients. This study shows the usefulness of proteomic approaches, combined with transcriptomics, to identify disease-related proteins.

Investigation strategy in the management of metastatic adenocarcinoma of unknown primary presenting as cervical lymphadenopathy.

CONCLUSION: Computed tomography (CT) of the neck, chest, abdomen and pelvis is the most appropriate initial investigation following a fine needle aspiration cytology (FNAC) diagnosis of metastatic adenocarcinoma in cervical lymph nodes with unknown primary. PET-CT should be considered as the next step if the initial CT fails to identify the primary site, but its true value is yet to be determined. OBJECTIVE: To review investigation strategies for metastatic adenocarcinoma of unknown primary presenting as cervical lymphadenopathy, and to develop a management algorithm. METHODS: This was a retrospective case note study from two regional head and neck cancer centres in the UK. Adult patients with FNAC diagnosis of metastatic adenocarcinoma in cervical lymph nodes between 1998 and 2008, with a minimum 5-year follow-up, were included. Patients with a clinically obvious primary tumour or a previous history of adenocarcinoma were excluded. RESULTS: This study examined 41 cases. CT of the neck, chest, abdomen and pelvis was the most useful initial investigation. It identified the primary tumour site in 16/28 cases (57%), detected the primary tumour and led to revision of the FNAC diagnosis in 1 case (2.4%), and was necessary for the final diagnosis of true unknown primary in 12 cases (29.3%). Targeted imaging was not helpful.

Reducing inappropriate referrals to secondary care: our experiences with the ENT Emergency clinic.

INTRODUCTION: In the current financial climate faced by the NHS, it is important that we reduce the amount of inappropriate referrals made to secondary care specialties. ENT Emergency Clinics are one-stop clinics provided by many UK ENT departments to allow more rapid access to ENT services from primary care. However, many referrals to these clinics were considered to be inappropriate, overloading the clinic and delaying referrals to more specialist clinics. We conducted a service improvement project through introduction of referral guidelines and liaising with local GPs. METHODS: We carried out an initial audit of ENT referrals over a one-month period, which suggested that 31% (69/225) of referrals were inappropriate. We developed a guideline referral proforma that included six specific conditions and details of subspecialist clinics available. This was circulated among GPs and A&E doctors and backed up by hospital teaching sessions. Two months later we repeated the audit. RESULTS: Following introduction of guidelines there was a significant reduction in inappropriate referrals from 31% (69/225) to 16% (28/179), p<0.01. Despite significant improvements overall, the proportion of inappropriate referrals from GPs remained higher than those from the local A&E department in both Cycle 1 (42% vs.24%, p<0.01) and Cycle 2 (23% vs. 5%, p<0.01). DISCUSSION AND CONCLUSION: Devising and circulating guideline proformas in conjunction with local education for referring doctors may help reduce the number of inappropriate ENT referrals. This simple and cheap intervention could be used more widely and developed in primary care departments in partnership with local hospitals. Our study also highlights the challenges encountered when introducing new guidelines that affect referrals from doctors in the community. Increasing opportunities for GP trainees to gain some exposure to common conditions presenting to primary care might reduce inappropriate ENT referrals in the future.