The development of the spiral ganglion in the human foetus

The development of the spiral ganglion was studied in steps sections of 81 human temporal bones. By the 8th week, the spiral ganglion has already separated from the vestibular ganglion. At 13 weeks two distinct populations are observed that correspond to neuron and Schwann cells. At 15 weeks the spiral ganglion has increased its distance from the cochlear duct and is surrounded by mesenchyme near the scala tympani. At 14 weeks a gradual decrease in the nucleus-to-cell area ratio was observed in spiral ganglion neurons that may reflect a morphological adaptation to function. By the 23rd week the modiolus begins to ossify and the spiral ganglion is surrounded by bony trabeculae. The time course of spiral ganglion development follows that of the stria vascularis and organ of Corti, although maturation changes are still observed in the neuronal population even beyond 20 weeks

Longitudinal evaluation of quality of life in 288 patients with Neurofibromatosis 2

Advances in molecular biology have resulted in novel therapy for neurofibromatosis 2-related (NF2) tumours, highlighting the need for robust outcome measures. The disease-focused NF2 impact on quality of life (NFTI-QOL) patient questionnaire was assessed as an outcome measure for treatment in a multi-centre study. NFTI-QOL was related to clinician-rated severity (ClinSev) and genetic severity (GenSev) over repeated visits. Data were evaluated for 288 NF2 patients (n = 464 visits) attending the English national NF2 clinics from 2010 to 2012. The male-to-female ratio was equal and the mean age was 42.2 (SD 17.8) years. The analysis included NFTI-QOL eight-item score, ClinSev graded as mild, moderate, or severe, and GenSev as a rank order of the number of NF2 mutations (graded as mild, moderate, severe). The mean (SD) 8.7 (5.4) score for NFTI-QOL for either a first visit or all visits 9.2 (5.4) was similar to the published norm of 9.4 (5.5), with no significant relationships with age or gender. NFTI-QOL internal reliability was good, with a Cronbach’s alpha score of 0.85 and test re-test reliability r = 0.84. NFTI related to ClinSev (r = 0.41, p < 0.001; r = 0.46 for all visits), but weakly to GenSev (r = 0.16, p < 0.05; r = 0.15 for all visits). ClinSev related to GenSev (r = 0.41, p < 0.001; r = 0.42 for all visits). NFTI-QOL showed a good reliability and ability to detect significant longitudinal changes in the QOL of individuals. The moderate relationships of NFTI-QOL with clinician- and genetic-rated severity suggest that NFTI-QOL taps into NF2 patient experiences that are not encompassed by ClinSev rating or genotype

Evaluation of quality of life in adults with neurofibromatosis 1 (NF1) using the Impact of NF1 on Quality Of Life (INF1-QOL) questionnaire

Background Neurofibromatosis 1 (NF1) is an inherited, multi-system, tumour suppressor disorder with variable complications that cause psychological distress and social isolation. The study aim was to develop and validate a disease-specific questionnaire to measure quality of life (QOL) in NF1 that is suitable both as an assessment tool in clinical practice and in clinical trials of novel therapy. Methods The Impact of NF1 on Quality of Life (INF1-QOL) questionnaire was developed by a literature search for common terms, focus group (n=6), semi-structured interviews (n=21), initial drafts (n =50) and final 14 item questionnaire (n=50). Bivariate correlations between items, exploratory factor analysis, correlations with severity and EuroQol were employed. Results INF1-QOL showed good internal reliability (Cronbach’s alpha 0.87), mean total INF1-QOL score was 8.64 (SD 6.3), median 7.00, range 0-30 (possible range 0-42); no significant correlations with age or gender. The mean total EuroQol score was 7.38 (SD 2.87), median 6.5, mean global EuroQol score was 76.34 (SD 16.56), median 80. Total INF1-QOL score correlated with total EuroQol r=0.82, p<0.0001. The highest impact on QOL was moderate or severe problems with anxiety and depression (32%) and negative effects of NF1 on role and outlook on life (42%). The mean inter-relater reliability for grading of clinical severity scores was 0.71 (range 0.65-0.79), and intra-class correlation was 0.92. The mean clinical severity score was 1.95 (SD 0.65) correlating r=0.34 with total INF1-QOL score p<0.05 and correlated 0.37 with total EuroQol score p<0.01. The clinical severity score was mild in 17 (34%), moderate in 16 (32%) and 17 (34%) individuals had severe disease. Conclusions INF1-QOL is a validated, reliable disease specific questionnaire that is easy and quick to complete. Role and outlook on life and anxiety and depression have the highest impact on QOL indicating the variability, severity and unpredictability of NF1. INFI-QOL correlates moderately with clinical severity. The moderate relationship between INF1-QOL and physician rated severity emphasizes the difference between clinical and patient perception. INFI-QOL will be useful in individual patient assessment and as an outcome measure for clinical trials

Methods for the evaluation of biomarkers in patients with kidney and liver diseases: multicentre research programme including ELUCIDATE RCT

Background: Protein biomarkers with associations with the activity and outcomes of diseases are being identified by modern proteomic technologies. They may be simple, accessible, cheap and safe tests that can inform diagnosis, prognosis, treatment selection, monitoring of disease activity and therapy and may substitute for complex, invasive and expensive tests. However, their potential is not yet being realised. Design and methods: The study consisted of three workstreams to create a framework for research: workstream 1, methodology – to define current practice and explore methodology innovations for biomarkers for monitoring disease; workstream 2, clinical translation – to create a framework of research practice, high-quality samples and related clinical data to evaluate the validity and clinical utility of protein biomarkers; and workstream 3, the ELF to Uncover Cirrhosis as an Indication for Diagnosis and Action for Treatable Event (ELUCIDATE) randomised controlled trial (RCT) – an exemplar RCT of an established test, the ADVIA Centaur® Enhanced Liver Fibrosis (ELF) test (Siemens Healthcare Diagnostics Ltd, Camberley, UK) [consisting of a panel of three markers – (1) serum hyaluronic acid, (2) amino-terminal propeptide of type III procollagen and (3) tissue inhibitor of metalloproteinase 1], for liver cirrhosis to determine its impact on diagnostic timing and the management of cirrhosis and the process of care and improving outcomes. Results: The methodology workstream evaluated the quality of recommendations for using prostate-specific antigen to monitor patients, systematically reviewed RCTs of monitoring strategies and reviewed the monitoring biomarker literature and how monitoring can have an impact on outcomes. Simulation studies were conducted to evaluate monitoring and improve the merits of health care. The monitoring biomarker literature is modest and robust conclusions are infrequent. We recommend improvements in research practice. Patients strongly endorsed the need for robust and conclusive research in this area. The clinical translation workstream focused on analytical and clinical validity. Cohorts were established for renal cell carcinoma (RCC) and renal transplantation (RT), with samples and patient data from multiple centres, as a rapid-access resource to evaluate the validity of biomarkers. Candidate biomarkers for RCC and RT were identified from the literature and their quality was evaluated and selected biomarkers were prioritised. The duration of follow-up was a limitation but biomarkers were identified that may be taken forward for clinical utility. In the third workstream, the ELUCIDATE trial registered 1303 patients and randomised 878 patients out of a target of 1000. The trial started late and recruited slowly initially but ultimately recruited with good statistical power to answer the key questions. ELF monitoring altered the patient process of care and may show benefits from the early introduction of interventions with further follow-up. The ELUCIDATE trial was an ‘exemplar’ trial that has demonstrated the challenges of evaluating biomarker strategies in ‘end-to-end’ RCTs and will inform future study designs. Conclusions: The limitations in the programme were principally that, during the collection and curation of the cohorts of patients with RCC and RT, the pace of discovery of new biomarkers in commercial and non-commercial research was slower than anticipated and so conclusive evaluations using the cohorts are few; however, access to the cohorts will be sustained for future new biomarkers. The ELUCIDATE trial was slow to start and recruit to, with a late surge of recruitment, and so final conclusions about the impact of the ELF test on long-term outcomes await further follow-up. The findings from the three workstreams were used to synthesise a strategy and framework for future biomarker evaluations incorporating innovations in study design, health economics and health informatics

The NFTI-QOL: a disease-specific quality of life questionnaire for neurofibromatosis 2

The objective of this study was to develop a reliable, validated disease-specific score measuring quality of life (QOL) in clinical practice and treatment trials in Neurofibromatosis 2 (NF2) individuals. In NF2 patients, qualitative interviews (n = 15) and a focus group session (n = 30) generated items for a pilot questionnaire. This was tested and refined (n = 20). The final version (NFTI-QOL) was validated (n = 50) with two generic QOL questionnaires (SF-36 and EuroQOL). The NFTI-QOL was also administered to patients with solitary vestibular schwannoma (SVS) (n = 30) and normal controls (n = 30). The participants were NF2 patients, SVS patients, and normal controls. NFTI-QOL score, SF-36 score, and EuroQOL score were the main outcome measures. Mean NFTI-QOL score was 9.4 (range: 0 to 20, maximum possible score = 24). The NFTI-QOL score correlated strongly with EuroQOL (r = 0.71, p < 0.001) and SF-36 (r = 0.81, p < 0.001). NF2 individuals were significantly worse than the SVS patients, who in turn were worse than the controls on the NIFTI-QOL. The NFTI-QOL showed good internal reliability (Cronbach's α = 0.87). We developed an eight-item disease-specific QOL score for NF2 patients, validated against SF-36 and EuroQOL. It correlated strongly with clinician-rated disease severity in NF2, with better correlation than the SF-36 in this regard

Classification and management of cervical paragangliomas

INTRODUCTION: Cervical paragangliomas are slow-growing tumours that eventually cause lower cranial nerve palsies and infiltrate the skull base. Surgical treatment may cause the same deficits and, in some, risks more serious neurological deficits. We describe a classification used to guide investigation, consent and management of cervical paragangliomas based on extensive experience. METHODS: The case notes of patients managed by the senior author at a tertiary referral skull base unit between 1987 and 2010 were reviewed retrospectively. A total of 87 cervical paragangliomas were identified in 70 patients (mean age: 46 years, range: 13–77 years). Of these, 35 patients had 36 vagal paragangliomas, 43 patients had 50 carotid body paragangliomas and 8 had both. One cervical paraganglioma arose from neither the carotid body nor the nodose ganglion. The main outcome measures were death, stroke, gastrostomy and tracheotomy. RESULTS: All tumours were classified pre-operatively based on their relationship to the carotid artery, skull base and lower cranial nerves. Type 1 tumours were excised with a transcervical approach, type 2 with a transcervical-parotid approach and type 3 with a combined transcervical-parotid and infratemporal fossa approach. Type 4 patients underwent careful assessment and genetic counselling before any treatment was undertaken. There were no peri-operative deaths; two patients had strokes, one required a long-term feeding gastrostomy and none required a tracheotomy. CONCLUSIONS: The use of a pre-operative classification system guides management and surgical approach, improves accuracy of consent, facilitates audit and clarifies which patients should be referred to specialised centres