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To report a prospectively planned analysis of two randomised controlled trials with embedded comparisons of prednisolone versus tetracosactide depot for the treatment of infantile epileptic spasms syndrome (IESS). Individual patient data from patients randomly allocated to prednisolone or tetracosactide depot were analysed from two trials (UKISS, ICISS). The comparison was embedded within trials in which some patients also received vigabatrin but only patients receiving monotherapy with randomly allocated hormonal treatments are included in this analysis. The main outcome was cessation of spasms (Days 13–14 after randomisation). Lead time to treatment and underlying aetiology were taken into account. Cessation of spasms on Days 14–42 inclusive, electroclinical response (EEG Day 14), plus developmental and epilepsy outcomes (at 14 months in UKISS and 18 months in ICISS) are also reported. Minimum treatment was prednisolone 40 mg per day for two weeks or tetracosactide depot 0·5 mg IM on alternate days for two weeks, all followed by a reducing dose of prednisolone over two weeks. 126 infants were included in this study. On tetracosactide depot, 47 of 62 (76%) were free of spasms on Days 13–14 compared to 43 of 64 (67%) on prednisolone (difference 9%, 95% CI -7·2% to +25·2%, chi square 1·15, p = 0·28). For Day 14–42 cessation of spasms, on tetracosactide depot, 41 of 61 (67%) were free of spasms compared to 35 of 62 (56%) on prednisolone (difference 11%, 95% CI -6·4% to +28·4%, chi square 1·51, p = 0·22). There was no significant difference in mean VABS score between infants who received prednisolone compared with those who received tetracosactide depot (74·8 (SD 18·3) versus 78·0 (SD 20·2) t = −0·91 p = 0·36). The proportion with ongoing epilepsy at the time of developmental assessment was 20 of 61 (33%) in the tetracosactide group compared with 26 out of 63 (41%) in the prednisolone group (difference 8%, 95% CI -9·2% to +25·2%, Chi [2] 0·95, p = 0·33). With hormone monotherapy, either prednisolone or tetracosactide depot may be recommended for infantile epileptic spasms syndrome. • Embedding a second randomisation in trials effectively provides additional information about trial treatments. • There was no significant difference between prednisolone and tetracosactide depot in those achieving early spasm cessation. • There was no significant difference between trial treatments in those free of epileptic seizures at 14 and 18 months. • Developmental outcome was similar in both treatment groups. • Either prednisolone or tetracosactide depot can be recommended when using hormonal treatment as monotherapy. [ABSTRACT FROM AUTHOR]

Introduction There is increasing recognition of the long-term sequelae of brain tumours treated in childhood. Five year survival rates now exceed 75% and assessing the quality of survival (QoS) in multiple domains is essential to any comparison of the benefits and harms of treatment regimens. Aim The aim of this position statement is to rationalise assessments and facilitate collection of a common data set across Europe. Sufficient numbers of observations can then be made to enable reliable comparisons between outcomes following different tumour types and treatments. Methods This paper represents the consensus view of the QoS working group of the Brain Tumour group of the European Society of Paediatric Oncology regarding domains of QoS to prioritise for assessment in clinical trials. This consensus between clinicians and researchers across Europe has been arrived at by discussion and collaboration over the last eight years. Results Areas of assessment discussed include core medical domains (e.g. vision, hearing, mobility, endocrine), emotion, behaviour, adaptive behaviour and cognitive functioning. Conclusions A ‘core plus’ approach is suggested in which core assessments (both direct and indirect tests) are recommended for all clinical trials. The core component is a relatively brief screening assessment that, in most countries, is a sub-component of routine clinical provision. The ‘plus’ components enable the addition of assessments which can be selected by individual countries and/or tumour-, age-, and location-specific groups. The implementation of a QoS protocol common to all European clinical studies of childhood brain tumours is also discussed [ABSTRACT FROM AUTHOR]

Highlights: [•] The proliferation of GBM cell lines displayed different sensitivities towards oligomycin or 2DG. [•] Differential sensitivities of GBM cell lines towards oligomycin were correlated with the activation of AMPKα. [•] Combining oligomycin and 2DG has drastic synergistic effects on suppressing cell growth and motility. [Copyright &y& Elsevier]

The amplitude values of transient-evoked otoacoustic emissions, recorded from a large sample of neonates, were used to examine the asymmetry between ears tested and the differences due to the sex of the subject. Whilst the sex difference, with females having larger responses than males, has been a consistent finding in previous reports, the right/left ear difference, with the right ear giving a larger response than the left, has produced variable results that differed between laboratories. In this study, the sex difference was confirmed with females giving a 1.2 dB greater response than males. It was not affected by the age of the neonate. A significant effect of test order was found. The measured right/left difference was enhanced when the right ear was tested first but was diminished when the left ear was tested first. If the left ear is tested first then the measured right/left difference would be about 0.5 dB whereas, if the right ear is tested first, the measured right/left difference would be about 1.5 dB. When male/female comparisons were made for right and left ears separately and for the same ear tested first, the sex differences were the same for all four conditions. The sex and right/left differences have been confirmed as statistically significant effects and the order effect could explain the discrepancies and variability of the right/left differences reported in the literature. [Copyright &y& Elsevier]

The methodological factors involved in screening neonates for hearing loss, using transient-evoked otoacoustic emissions (TEOAEs) and automated auditory brainstem responses, have been evaluated from a large sample of neonates. The risk factors, commonly used to select babies for a targeted screen, have very little correlation with failing TEOAE testing. The parameters used to determine passing or failing the TEOAE test and the false alarm rate change markedly with age in the first few days of life as, of course, did the percentage of babies who failed the test. The stimulus level used was the default setting for the Otodynamics equipment but the stimulus level measured in the ear canal decreased over the first 140 h of life. It is thought that this reflects the impedance changes in outer and middle ears and possible changes in middle ear dynamics. The methodological variables investigated here can illuminate some of the differences in previous reports of neonatal screening, in particular the reported hit and false alarm rates. [Copyright &y& Elsevier]

Background: Infantile spasms constitutes a severe infantile epilepsy syndrome that is difficult to treat and has a high morbidity. Hormonal therapies or vigabatrin are the most commonly used treatments. We aimed to assess whether combining the treatments would be more effective than hormonal therapy alone.Methods: In this multicentre, open-label randomised trial, 102 hospitals (Australia [three], Germany [11], New Zealand [two], Switzerland [three], and the UK [83]) enrolled infants who had a clinical diagnosis of infantile spasms and a hypsarrhythmic (or similar) EEG no more than 7 days before enrolment. Participants were randomly assigned (1:1) by a secure website to receive hormonal therapy with vigabatrin or hormonal therapy alone. If parents consented, there was an additional randomisation (1:1) of type of hormonal therapy used (prednisolone or tetracosactide depot). Block randomisation was stratified for hormonal treatment and risk of developmental impairment. Parents and clinicians were not masked to therapy, but investigators assessing electro-clinical outcome were masked to treatment allocation. Minimum doses were prednisolone 10 mg four times a day or intramuscular tetracosactide depot 0·5 mg (40 IU) on alternate days with or without vigabatrin 100 mg/kg per day. The primary outcome was cessation of spasms, which was defined as no witnessed spasms on and between day 14 and day 42 from trial entry, as recorded by parents and carers in a seizure diary. Analysis was by intention to treat. The trial is registered with The International Standard Randomised Controlled Trial Number (ISRCTN), number 54363174, and the European Union Drug Regulating Authorities Clinical Trials (EUDRACT), number 2006-000788-27.Findings: Between March 7, 2007, and May 22, 2014, 766 infants were screened and, of those, 377 were randomly assigned to hormonal therapy with vigabatrin (186) or hormonal therapy alone (191). All 377 infants were assessed for the primary outcome. Between days 14 and 42 inclusive no spasms were witnessed in 133 (72%) of 186 patients on hormonal therapy with vigabatrin compared with 108 (57%) of 191 patients on hormonal therapy alone (difference 15·0%, 95% CI 5·1-24·9, p=0·002). Serious adverse reactions necessitating hospitalisation occurred in 33 infants (16 on hormonal therapy alone and 17 on hormonal therapy with vigabatrin). The most common serious adverse reaction was infection occurring in five infants on hormonal therapy alone and four on hormonal therapy with vigabatrin. There were no deaths attributable to treatment.Interpretation: Hormonal therapy with vigabatrin is significantly more effective at stopping infantile spasms than hormonal therapy alone. The 4 week period of spasm cessation required to achieve a primary clinical response to treatment suggests that the effect seen might be sustained, but this needs to be confirmed at the 18 month follow-up.Funding: The Castang Foundation, Bath Unit for Research in Paediatrics, National Institute of Health Research, the Royal United Hospitals Bath NHS Foundation Trust, the BRONNER-BENDUNG Stifung/Gernsbach, and University Children's Hospital Zurich. [ABSTRACT FROM AUTHOR]

Summary: Background: Infantile spasms is a severe infantile seizure disorder that is difficult to treat and has a high morbidity. Absence of spasms on days 13 and 14 after randomisation is more common in infants allocated hormone treatments than in those allocated vigabatrin. We sought to assess whether early control of spasms is associated with improved developmental or epilepsy outcomes. Methods: Infants enrolled in the United Kingdom Infantile Spasms Study (UKISS) were randomly assigned hormone treatment (n=55) or vigabatrin (n=52) and were followed up until clinical assessment at 12–14 months of age. We assessed neurodevelopment with the Vineland adaptive behaviour scales (VABS) at 14 months of age on an intention to treat basis. Findings: Of 107 infants enrolled, five died and 101 survivors reached both follow-up assessments. Absence of spasms at final clinical assessment (hormone 41/55 [75%] vs vigabatrin 39/51 [76%]) was similar in each treatment group (difference 1·9%, 95% CI −18·3% to 14·4%; χ2=0·05; p=0·82). Mean VABS score did not differ significantly (hormone 78·6 [SD 16·8] vs vigabatrin 77·5 [SD 12·7]; difference 1·0, 95% CI −4·9 to 7·0; t99 =0·35, p=0·73). In infants with no identified underlying aetiology, the mean VABS score was higher in those allocated hormone treatment than in those allocated vigabatrin (88·2 [17·3] vs 78·9 [14·3]; difference 9·3, 95% CI 1·2 to 17·3; t95 =2·28, p=0·025). Interpretation: Hormone treatment controls spasms better than does vigabatrin initially, but not at 12–14 months of age. Better initial control of spasms by hormone treatment in those with no identified underlying aetiology may lead to improved developmental outcome. [Copyright &y& Elsevier]