Protocol for the ORION trial (RadiO fRequency ablatION for haemorrhoids): a randomised controlled trial.

BACKGROUND: Haemorrhoids are common and can significantly impact the personal and working lives of individuals. Those with more severe symptoms and those not responding to conservative management may require surgery. Current surgical techniques are associated with a degree of postoperative discomfort which may delay return to normal activity. Recurrence is lower in more radical procedures but resulting pain is higher. Radiofrequency ablation (RFA) is a new technique that is gaining popularity and has several hypothesised benefits, including reduced pain and recurrence. However, available evidence is limited. A recent overview from the National Institute for Health and Clinical Excellence recommended more research, in the form of randomised controlled trials, be carried out before further investment is made by national health services. Our aim is to assess whether RFA is at least as good in terms of recurrence as existing surgical interventions, but superior in terms of pain, for patients with symptomatic grade II and III haemorrhoids. METHODS: The RadiO fRequency ablatION for haemorrhoids (ORION) trial will be a pragmatic multicentre patient/assessor-blind parallel group-controlled trial with economic evaluation. The target sample size is 376 participants (188 per arm) and is based on two co-primary endpoints: (i) a non-inferiority design for recurrence and (ii) superiority design for pain at seven days. Participants with grade II or III haemorrhoids will be recruited in 16 National Health Service hospitals and randomised (1:1) to either RFA or surgeon's choice of surgery. CONCLUSIONS: Results will inform future practice for the treatment of grade II-III haemorrhoids and provide evidence for national health services on future investments in RFA. TRIAL REGISTRATION: ISRCTN14474552.

Change in diagnostic confidence brought about by using in utero MRI for fetal structural brain pathology: analysis of the MERIDIAN cohort.

AIM: To measure possible change in diagnostic confidence by performing in utero magnetic resonance imaging (iuMRI) studies on fetuses with brain abnormalities recognised on ultrasonography (US). MATERIALS AND METHODS: The analyses are based on the primary cohort from the prospective MERIDIAN study, which consisted of 570 fetuses with brain abnormalities detected on US, with iuMRI performed within 2 weeks of US and complete outcome reference data. The cohort was recruited between July 2011 and August 2014, and written informed consent was obtained for all participants. They all had indicators of diagnostic confidence measured on US by fetal medicine experts and iuMRI by the reporting radiologists. Three assessments were carried out using the conventional uncorrected (C2-C1%) method, the conventional (C2-C1%) with the Omary correction, and the score-based weighted average method. RESULTS: All three assessments showed statistically significant (p<0·0001) positive effects indicating that iuMRI was potentially beneficial when included in the diagnostic pathway for prenatal structural brain anomalies (in terms of diagnostic confidence). CONCLUSION: These results strongly support the routine clinical use of iuMRI as an adjunct to US when assessing fetuses with structural brain abnormalities.

Adjusting for treatment switching in randomised controlled trials - A simulation study and a simplified two-stage method.

Estimates of the overall survival benefit of new cancer treatments are often confounded by treatment switching in randomised controlled trials (RCTs) - whereby patients randomised to the control group are permitted to switch onto the experimental treatment upon disease progression. In health technology assessment, estimates of the unconfounded overall survival benefit associated with the new treatment are needed. Several switching adjustment methods have been advocated in the literature, some of which have been used in health technology assessment. However, it is unclear which methods are likely to produce least bias in realistic RCT-based scenarios. We simulated RCTs in which switching, associated with patient prognosis, was permitted. Treatment effect size and time dependency, switching proportions and disease severity were varied across scenarios. We assessed the performance of alternative adjustment methods based upon bias, coverage and mean squared error, related to the estimation of true restricted mean survival in the absence of switching in the control group. We found that when the treatment effect was not time-dependent, rank preserving structural failure time models (RPSFTM) and iterative parameter estimation methods produced low levels of bias. However, in the presence of a time-dependent treatment effect, these methods produced higher levels of bias, similar to those produced by an inverse probability of censoring weights method. The inverse probability of censoring weights and structural nested models produced high levels of bias when switching proportions exceeded 85%. A simplified two-stage Weibull method produced low bias across all scenarios and provided the treatment switching mechanism is suitable, represents an appropriate adjustment method.

The effectiveness and cost-effectiveness of donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer's disease (review of Technology Appraisal No. 111): a systematic review and economic model.

BACKGROUND: Alzheimer's disease (AD) is the most commonly occurring form of dementia. It is predominantly a disease of later life, affecting 5% of those over 65 in the UK. OBJECTIVES: Review and update guidance to the NHS in England and Wales on the clinical effectiveness and cost-effectiveness of donepezil, galantamine, rivastigmine [acetylcholinesterase inhibitors (AChEIs)] and memantine within their licensed indications for the treatment of AD, which was issued in November 2006 (amended September 2007 and August 2009). DATA SOURCES: Electronic databases were searched for systematic reviews and/or metaanalyses, randomised controlled trials (RCTs) and ongoing research in November 2009 and updated in March 2010; this updated search revealed no new includable studies. The databases searched included The Cochrane Library (2009 Issue 4, Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials), MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, PsycINFO, EconLit, ISI Web of Science Databases--Science Citation Index, Conference Proceedings Citation Index, and BIOSIS; the Centre for Reviews and Dissemination (CRD) databases--NHS Economic Evaluation Database, Health Technology Assessment, and Database of Abstracts of Reviews of Effects. REVIEW METHODS: The clinical effectiveness systematic review was undertaken following the principles published by the NHS CRD. We included RCTs whose population was people with AD. The intervention and comparators depended on disease severity, measured by the Mini Mental State Examination (MMSE). INTERVENTIONS: mild AD (MMSE 21-26)--donepezil, galantamine and rivastigmine; moderate AD (MMSE 10-20)--donepezil, galantamine, rivastigmine and memantine; severe AD (MMSE < 10)--memantine. Comparators: mild AD (MMSE 21-26)--placebo or best supportive care (BSC); moderate AD (MMSE 10-20)--donepezil, galantamine, rivastigmine, memantine, placebo or BSC; severe AD (MMSE < 10)--placebo or BSC. The outcomes were clinical, global, functional, behavioural, quality of life, adverse events, costs and cost-effectiveness. Where appropriate, data were pooled using pair-wise meta-analysis, multiple outcome measures, metaregression and mixedtreatment comparisons. The decision model was based broadly on the structure of the three-state Markov model described in the previous technology assessment report, based upon time to institutionalisation, parameterised with updated estimates of effectiveness, costs and utilities. RESULTS: Notwithstanding the uncertainty of our results, we found in the base case that the AChEIs are probably cost saving at a willingness-to-pay (WTP) of £'30,000 per qualityadjusted life-year (QALY) for people with mild-to-moderate AD. For this class of drugs, there is a > 99% probability that the AChEIs are more cost-effective than BSC. These analyses assume that the AChEIs have no effect on survival. For the AChEIs, in people with mild to moderate AD, the probabilistic sensitivity analyses suggested that donepezil is the most cost-effective, with a 28% probability of being the most cost-effective option at a WTP of £'30,000 per QALY (27% at a WTP of £'20,000 per QALY). In the deterministic results, donepezil dominates the other drugs and BSC, which, along with rivastigmine patches, are associated with greater costs and fewer QALYs. Thus, although galantamine has a slightly cheaper total cost than donepezil (£'69,592 vs £'69,624), the slightly greater QALY gains from donepezil (1.616 vs 1.617) are enough for donepezil to dominate galantamine.The probability that memantine is cost-effective in a moderate to severe cohort compared with BSC at a WTP of £'30,000 per QALY is 38% (and 28% at a WTP of £'20,000 per QALY). The deterministic ICER for memantine is £'32,100 per/QALY and the probabilistic ICER is £'36,700 per/QALY. LIMITATIONS: Trials were of 6 months maximum follow-up, lacked reporting of key outcomes, provided no subgroup analyses and used insensitive measures. Searches were limited to English language, The model does not include behavioural symptoms and there is uncertainty about the model structure and parameters. CONCLUSIONS: The additional clinical effectiveness evidence identified continues to suggest clinical benefit from the AChEIs in alleviating AD symptoms, although there is debate about the magnitude of the effect. Although there is also new evidence on the effectiveness of memantine, it remains less supportive of this drug's use than the evidence for AChEIs. The conclusions concerning cost-effectiveness are quite different from the previous assessment. This is because both the changes in effectiveness and costs between drug use and non-drug use underlying the ICERs are very small. This leads to highly uncertain results, which are very sensitive to change. RESEARCH PRIORITIES: RCTs to include mortality, time to institutionalisation and quality of life, powered for subgroup analysis. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

The risk of febrile neutropenia in patients with non-small-cell lung cancer treated with docetaxel: a systematic review and meta-analysis.

We aimed to assess the incidence of febrile neutropenia in patients with non small cell lung cancer treated with docetaxel as second line chemotherapy by systematic review and meta-analysis of clinical studies. Published studies were retrieved and included if they considered docetaxel at the licensed dose after a previous chemotherapy regimen, and reported the proportion of patients getting FN. Meta-analysis was conducted to estimate the proportion of patients who experience one or more episodes of FN. The pooled, random effects meta-analysis estimate for the proportion of patients who experience one or more episodes of FN on docetaxel was 5.95% (95% CI 4.22-8.31) based on 13 studies, comprising 1609 patients. No significant differences were seen either between studies that permitted the use of prophylactic granulocyte colony-stimulating factors or between phase II and phase III trials.Evidence from randomised controlled trials suggests that the incidence of FN with docetaxel is around 6% and therefore an important factor to consider in the choice of the chemotherapy regimen.

The clinical effectiveness and cost-effectiveness of enzyme replacement therapy for Gaucher's disease: a systematic review.

OBJECTIVES: The aim of this review is to determine the clinical effectiveness and cost-effectiveness of enzyme replacement therapy (ERT) in the treatment of symptomatic Gaucher's disease. DATA SOURCES: Major electronic databases were searched from their inception to August 2003; and updated from January 2003 to July/August 2004. REVIEW METHODS: Databases were searched for studies that met the criteria and selected data were extracted and evaluated. Studies were assessed for their relevance to the UK context and the review objective. The bibliographic databases were also searched to identify existing cost studies, economic evaluations and models. A Markov decision model was constructed based on patients moving between states defined by the modified Severity Score Index (SSI). Most of the parameters were derived from the published literature. ERT was assumed to restore patients to full health in the base case. RESULTS: Sixty-three studies were included, all suggestive of benefit with ERT. However, the way in which the effects translate into patient well-being and survival or the need for services and resources has not been reliably estimated. Quality of life improvements with ERT have been reported. Nonetheless, studies based on the Short Form 36 (SF-36) indicate that patients treated with ERT continue to have reduced health-related quality of life (HRQoL) compared with the general population. No study attached utility values to quality of life measures for ERT-treated patients. Thirty-one studies relevant to the natural history of the disease were found. Sixteen looked at multiple clinical characteristics of a cohort of patients with type I Gaucher's disease. There was considerable within-study and between-study heterogeneity, but all showed that Gaucher's disease was a progressive condition. Some suggested that the disease may become more indolent in adulthood; however, studies were discrepant on this point. Most disease is diagnosed in adulthood, although about one-quarter presented in childhood, these patients having the most severe symptoms and greatest rate of progression. Modelling of natural history was undertaken using the five papers that reported the SSI for each patient, along with patient-level data on age, age at diagnosis, splenectomy status and genotype, to address the question of whether disease stabilises in adulthood and the degree of correlation between phenotype and genotype. Analysis of the available data suggested that disease progression is likely to slow markedly in adulthood and that genotype is a useful predictor of clinical expression of the disease. Five studies looked at quality of life. Data on this topic were also obtained from the registries. The evidence suggests that the vast majority of the clinical characteristics of type I Gaucher's disease have little impact on subjective HRQoL and that therefore for the majority of people with type I Gaucher's disease this may not be a severe condition. Bone and skeletal symptoms contribute most to the morbidity of the disease and can lead to severe pain and immobility. The mean cost per patient treated was approximately pounds sterling 86,000 per annum in England and Wales. The cost per patient varied considerably by dose. Four existing economic evaluations were found, all of which calculated a very high cost per quality-adjusted life-year (QALY). Using the Markov decision model, ERT was assumed to restore patients to full health in the base case. The estimated incremental cost per QALY [incremental cost-effectiveness ratio (ICER)] in the base case ranged from pounds sterling 380,000 to pounds sterling 476,000 per QALY, depending on genotype. Univariate sensitivity analyses examined ERT not restoring full health, more severe disease progression in the untreated cohort, and only treating the most severely affected patients. These produced ICERs of approximately pounds sterling 1.4 million, pounds sterling 296,000 and pounds sterling 275,000 per QALY, respectively. The base-case unit cost of the drug is pounds sterling 2.975. The unit cost would have had to be reduced ten-fold, to pounds sterling 0.30, to obtain an ICER of pounds sterling 30,000 per QALY. At a unit cost of pounds sterling 1 the ICER would be pounds sterling 120,000 per QALY. CONCLUSIONS: Although ERT for treating the 'average' Gaucher's disease patient exceeds the normal upper threshold for cost-effectiveness seen in NHS policy decisions by over ten-fold, some argue that since orphan drug legislation encouraged the manufacture of Cerezyme, and Gaucher's disease can be defined as an orphan disease, the NHS has little option but to provide it, despite its great expense. More information is required before the generalisability of the findings can be determined. Although data from the UK have been used wherever possible, these were very thin indeed. Nonetheless, even large errors in estimates of the distribution of genotype, genotype--phenotype associations, effectiveness and numbers of patients will not reduce the ICER to anywhere near the upper level of treatments usually considered cost-effective. Further research could help to clarify the many uncertainties that exist. However, although doing so will be of clinical interest, it is questionable whether, within the current pricing environment, such research would have any substantive impact on policy decisions. It is highly improbable that, whatever the findings of such research, the ICER could be brought down by the orders of magnitude required to make ERT an efficient use of health service resources. (The possible exception to this would be investigating the most efficient alternative treatment strategies for using ERT in a paediatric population only.) Moreover, if under equity considerations for orphan diseases the NHS feels it is important to provide this drug, regardless of its cost-effectiveness, then refining the precision of the ICER estimate also becomes superfluous.

Measurement of the clinical and cost-effectiveness of non-invasive diagnostic testing strategies for deep vein thrombosis.

OBJECTIVES: To estimate the diagnostic accuracy of non-invasive tests for proximal deep vein thrombosis (DVT) and isolated calf DVT, in patients with clinically suspected DVT or high-risk asymptomatic patients, and identify factors associated with variation in diagnostic performance. Also to identify practical diagnostic algorithms for DVT, and estimate the diagnostic accuracy, clinical effectiveness and cost-effectiveness of each. DATA SOURCES: Electronic databases (to April 2004). A postal survey of hospitals in the UK. REVIEW METHODS: Selected studies were assessed against validated criteria. A postal survey of hospitals in the UK was undertaken to describe current practice and availability of tests, and identify additional diagnostic algorithms. Pooled estimates of sensitivity, specificity and likelihood ratios were obtained for each test using random effects meta-analysis. The effect of study-level covariates was explored using random effects metaregression. A decision-analytic model was used to combine estimates from the meta-analysis and estimate the diagnostic performance of each algorithm in a theoretical population of outpatients with suspected DVT. The net benefit of using each algorithm was estimated from a health service perspective, using cost--utility analysis, assuming thresholds of willingness to pay of pound 20,000 and pound 30,000 per quality-adjusted life-year (QALY). The model was analysed probabilistically and cost-effectiveness acceptability curves were generated to reflect uncertainty in estimated cost-effectiveness. RESULTS: Individual clinical features are of limited diagnostic value, with most likelihood ratios being close to 1. Wells clinical probability score stratifies proximal, but not distal, DVT into high-, intermediate- and low-risk categories. Unstructured clinical assessment by experienced clinicians may have similar performance to Wells score. In patients with clinically suspected DVT, D-dimer has 91% sensitivity and 55% specificity for DVT, although performance varies substantially between assays and populations. D-dimer specificity is dependent on pretest clinical probability, being higher in patients with a low clinical probability of DVT. Plethysmography and rheography techniques have modest sensitivity for proximal DVT, poor sensitivity for distal DVT, and modest specificity. Ultrasound has 94% sensitivity for proximal DVT, 64% sensitivity for distal DVT and 94% specificity. Computed tomography scanning has 95% sensitivity for all DVT (proximal and distal combined) and 97% specificity. Magnetic resonance imaging has 92% sensitivity for all DVT and 95% specificity. The diagnostic performance of all tests is worse in asymptomatic patients. The most cost-effective algorithm discharged patients with a low Wells score and negative D-dimer without further testing, and then used plethysmography alongside ultrasound, with venography in selected cases, to diagnose the remaining patients. However, the cost-effectiveness of this algorithm was dependent on assumptions of test independence being met and the ability to provide plethysmography at relatively low cost. Availability of plethysmography and venography is currently limited at most UK hospitals, so implementation would involve considerable reorganisation of services. Two algorithms were identified that offered high net benefit and would be feasible in most hospitals without substantial reorganisation of services. Both involved using a combination of Wells score, D-dimer and above-knee ultrasound. For thresholds of willingness to pay of pound 10,000 or pound 20,000 per QALY the optimal strategy involved discharging patients with a low or intermediate Wells score and negative D-dimer, ultrasound for those with a high score or positive D-dimer, and repeat scanning for those with positive D-dimer and a high Wells score, but negative initial scan. For thresholds of pound 30,000 or more a similar strategy, but involving repeat ultrasound for all those with a negative initial scan, was optimal. CONCLUSIONS: Diagnostic algorithms based on a combination of Wells score, D-dimer and ultrasound (with repeat if negative) are feasible at most UK hospitals and are among the most cost-effective. Use of repeat scanning depends on the threshold for willingness to pay for health gain. Further diagnostic testing for patients with a low Wells score and negative D-dimer is unlikely to represent a cost-effective use of resources. Recommendations for research include the evaluation of the costs and outcomes of using the optimal diagnostic algorithms in routine practice, the development and evaluation of algorithms appropriate for specific groups of patients with suspected DVT, such as intravenous drug abusers, pregnant patients and those with previous DVT, the evaluation of the role of plethysmography: interaction with other diagnostic tests, outcome of low-risk patients with negative plethysmography and measurement of the costs of providing plethysmography, and methodological research into the incorporation of meta-analytic data into decision-analytic modelling.

How should we diagnose suspected deep-vein thrombosis?

BACKGROUND: Many different approaches are used to diagnose suspected deep-vein thrombosis (DVT), but there has been little formal comparison of strategies. AIM: To identify the most cost-effective strategy for the UK National Health Service (NHS). DESIGN: Systematic review, meta-analysis and cost-effectiveness analysis. METHODS: We identified 18 strategies and estimated the diagnostic performance of constituent tests by systematic review and meta-analysis. Outcomes of testing and treatment were estimated from published data or by an expert panel. Costs were estimated from NHS reference costs and published data. We built a decision-analysis model to estimate, for each strategy, the overall accuracy, costs, and outcomes (valued as quality-adjusted life-years, QALYs), compared to a 'no testing, no treatment' alternative. Probabilistic analysis estimated the net benefit of each strategy at varying thresholds for willingness to pay for health gain. RESULTS: At the thresholds for willingness to pay recommended by the National Institute for Clinical Excellence (20,000 pounds sterling-30,000 pounds sterling per QALY), the optimal strategy was to discharge patients with a low or intermediate Wells score and negative D-dimer, limiting ultrasound to those with a high score or positive D-dimer. Strategies using radiological testing for all patients were only cost-effective at 40,000 pound sterling per QALY or more. DISCUSSION: The optimal strategy for DVT diagnosis is to use ultrasound selectively in patients with a high clinical risk or positive D-dimer. Radiological testing for all patients does not appear to be a cost-effective use of health service resources.

The cost-effectiveness of influenza vaccination of healthy adults 50-64 years of age.

Influenza can cause significant morbidity and mortality. Influenza vaccination is an effective and safe strategy in the prevention of influenza. Currently the National Health Service (NHS) vaccinates 'at-risk' individuals only. This definition includes everyone over 65 years of age but excludes individuals 50-64 years of age unless they have an additional risk factor, such as underlying heart disease or lung disease. In order to examine the cost-effectiveness of an extension of the vaccination policy to include this age group we constructed an economic model to estimate the costs and benefits of vaccination from both a health service and a societal perspective. Data to populate the model was obtained from the literature and the outcome measure used was the quality adjusted life year (QALY). Influenza vaccination prevented an estimated 4508 cases (95% CI: 2431-7606) per 100,000 vaccinees per influenza season for a net cost to the NHS of pound653,221 (95% CI: 354,575-1,072,257). The net cost increased to pound1,139,069 (95% CI 27,052-2,030,473) when non-NHS costs were included and the estimated cost-per-QALY were pound6174 and pound10,766 for NHS and all costs respectively. Extension of the current immunisation policy has the potential to generate a significant health benefit at a comparatively low cost.

Systematic review and economic decision modelling for the prevention and treatment of influenza A and B.

OBJECTIVES: To establish the clinical and cost-effectiveness of amantadine, oseltamivir and zanamivir compared to standard care for the treatment and prevention of influenza. DATA SOURCES: Electronic databases. Reference lists of identified articles and key publications. Relevant trials. REVIEW METHODS: A systematic review and meta-analysis of the randomised evidence was undertaken to investigate the effectiveness of oseltamivir and zanamivir compared to standard care for treatment and prophylaxis use for influenza A and B. An additional systematic review of the effectiveness of amantadine for treatment and prophylaxis use for influenza A in children and the elderly was also undertaken. Economic decision models were constructed to examine the cost-effectiveness and cost-utility of the alternative strategies for treating and preventing influenza A and/or B. This was informed by the systematic reviews outlined above and additional sources of information where required. RESULTS: The systematic review of the treatment of influenza found that oseltamivir reduced the median duration of symptoms in the influenza positive group by 1.38 days for the otherwise healthy adult population, 0.5 day for the high-risk population, and 1.5 days for the children population. This compared to 1.26 days, 1.99 days, and 1.3 for the similar groups for inhaled zanamivir. The systematic review of the prevention of influenza found that the relative risk reduction for oseltamivir was between approximately 75 and 90% and approximately 70 and 90% for inhaled zanamivir depending on the strategy adopted and the population under consideration. For the economic model a base case was constructed that focussed primarily on the health benefits generated by shortening the period of influenza illness. This base case found that, compared to standard care, the estimated cost per quality-adjusted life year ranged from pound 6190 to pound 31,529 for healthy adults, from pound 4535 to pound 22,502 for the 'high-risk' group, from pound 6117 to pound 30,825 for children, and from pound 5057 to pound 21,781 for the residential care elderly population. The base case model included valuations of the health effects of pneumonia (and otitis media in the children's model) based on observed rates in the trials. However it does not include the cost of hospitalisations as only very limited data was available for the effects of antivirals on hospitalisation rates. As for mortality rates, deaths from influenza were rare in trials of neuraminidase inhibitors (NIs). Therefore, suitable data on mortality were not available from these sources. As avoided hospitalisation costs and avoided mortality are potentially important we also carried out sensitivity analysis that involved extrapolating the observed reductions in pneumonias in the NI trials to hospitalisations and deaths. In all four models the cost-effectiveness of NIs is substantially improved by this extrapolation. For prophylaxis, antiviral drugs were compared with vaccination as preventative strategies. In all cases the cost-effectiveness ratios for vaccination were either low or cost-saving. In the base case the cost-effectiveness of antivirals was relatively unfavourable, there were scenarios relating to the elderly residential care model where antivirals as an additional strategy could be cost-effective. CONCLUSIONS: The cost-effectiveness varies markedly between the intervention strategies and target populations. The estimate of cost effectiveness is also sensitive to variations in certain key parameters of the model, for example the proportion of all influenza-like illnesses that are influenza. The effectiveness literature that was used to inform the economic decision model spans many decades and hence great caution should be exercised when interpreting the results of indirect intervention comparisons from the model. Further randomised trials making direct comparisons would be valuable to verify the model's findings.

A systematic review of molecular and biological markers in tumours of the Ewing's sarcoma family.

The aims of this study were to perform the first systematic review of molecular and biological tumour markers in tumours of the Ewing's sarcoma family (ESFT), and evaluate the current evidence for their clinical use. A well-defined, reproducible search strategy was used to identify the relevant literature from 1966 to February 2000. Papers were independently assessed for tumour markers used in the screening, diagnosis, prognosis or monitoring of patients with ESFT. Eighty-four papers studying the use of 70 different tumour markers in ESFT's were identified. Low-quality, inconsistent reporting limited meta-analysis to that of prognostic data for 28 markers. Patients with tumours lacking S-100 protein expression have a better overall survival (OS) (hazard ratio (HR)=0.41, 95% confidence interval (CI) 0.19, 0.89) than those with expression; patients with high levels of serum LDH had a worse OS and disease-free survival (DFS) (OS: HR=2.92, CI 2.16, 3.94, DFS: HR=3.38, 95% CI 2.28, 4.99); patients with localised disease and tumours expressing type 1 EWS-FLI1 fusion transcripts had an improved DFS compared with those with other fusion transcript types (HR=0.17, 95% CI 0.079, 0.37). The knowledge base formed should facilitate more informative future research. Improved statistical reporting and large, multicentre prospective studies are advocated.