Comparison of anticipated and actual control group outcomes in randomised trials in paediatric oncology provides evidence that historically controlled studies are biased in favour of the novel treatment

BACKGROUND: Historically controlled studies are commonly undertaken in paediatric oncology, despite their potential biases. Our aim was to compare the outcome of the control group in randomised controlled trials (RCTs) in paediatric oncology with those anticipated in the sample size calculations in the protocols. Our rationale was that, had these RCTs been performed as historical control studies instead, the available outcome data used to calculate the sample size in the RCT would have been used as the historical control outcome data. METHODS: A systematic search was undertaken for published paediatric oncology RCTs using the Cochrane Central Register of Controlled Trials (CENTRAL) database from its inception up to July 2013. Data on sample size assumptions and observed outcomes (timetoevent and proportions) were extracted to calculate differences between randomised and historical control outcomes, and a one-sample t-test was employed to assess whether the difference between anticipated and observed control groups differed from zero. RESULTS: Forty-eight randomised questions were included. The median year of publication was 2005, and the range was from 1976 to 2010. There were 31 superiority and 11 equivalence/noninferiority randomised questions with time-to-event outcomes. The median absolute difference between observed and anticipated control outcomes was 5.0% (range: -23 to +34), and the mean difference was 3.8% (95% CI: +0.57 to +7.0; P = 0.022). CONCLUSIONS: Because the observed control group (that is, standard treatment arm) in RCTs performed better than anticipated, we found that historically controlled studies that used similar assumptions for the standard treatment were likely to overestimate the benefit of new treatments, potentially leading to children with cancer being given ineffective therapy that may have additional toxicity. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/1745-6215-15-481) contains supplementary material, which is available to authorized users

Prognostic DNA Methylation Biomarkers in High-risk Non–muscle-invasive Bladder Cancer:A Systematic Review to Identify Loci for Prospective Validation

Context: High-risk non–muscle-invasive bladder cancer (HR-NMIBC) represents over 30% of all incident urothelial bladder cancers (BCs); patients are at risk of progression, and 20–30% will die from BC within 5 yr. Current guidelines recommend induction and maintenance of intravesical bacillus Calmette-Guérin (BCG) or upfront radical cystectomy for highest-risk disease, treatments with markedly different morbidity, mortality, and patient burden. There are no validated biomarkers to facilitate such treatment decisions. Alterations in DNA methylation are commonplace in BC; hence, measurable changes in DNA methylation represent an opportunity for the discovery of such biomarkers.Objective: To systematically assess the evidence regarding DNA methylation markers as prognosticators for HR-NMIBC.Evidence acquisition: Standard systematic review methods were employed with searches undertaken in MEDLINE, EMBASE, and PubMed up to January 2019. Studies that included patients with HR-NMIBC and investigated the utility of DNA methylation biomarkers as prognostic tools were included.Evidence synthesis: Of 63 prognostic biomarker studies identified, 21 met the protocol-driven inclusion criteria and were directly relevant to HR-NMIBC patient outcomes: tumour recurrence (TR), tumour progression (TP), disease-specific survival (DSS), and overall survival (OS). These studies described 140 methylation markers; of these, the most promising were cadherin-13 (CDH13; hazard ratios [HRs]: 5.1 for TR, 6.6 for TP, 3.8–8.0 for OS), protocadherins (PCDHs; HRs: 4.7 for TR, 2.5 for TP, 3.0–4.8 for OS), Runt domain transcription factor 3 (RUNX3; HR: 5.1 for TP), Homeobox 9 (HOXA9; HR: 1.9 for TR), Islet-1 (ISL1; HRs: 1.7 for TR, 3.3 for TP), and PAX6 (HR: 2.2 for TR).Conclusions: This systematic review identifies a number of potentially useful prognostic methylation markers for HR-NMIBC. These loci (CDH13, PCDHs, RUNX3, HOXA9, ISL1, and PAX6) should be validated in prospective studies in order to translate benefit to patients.Patient summary: Early bladder cancer represents a more complex spectrum of disease than can be assessed by conventional methods Emerging studies on molecular markers will improve our understanding of this disease, and may enable more precise and personalised treatment.</p

Prognostic DNA Methylation Biomarkers in High-risk Non–muscle-invasive Bladder Cancer:A Systematic Review to Identify Loci for Prospective Validation

Context: High-risk non–muscle-invasive bladder cancer (HR-NMIBC) represents over 30% of all incident urothelial bladder cancers (BCs); patients are at risk of progression, and 20–30% will die from BC within 5 yr. Current guidelines recommend induction and maintenance of intravesical bacillus Calmette-Guérin (BCG) or upfront radical cystectomy for highest-risk disease, treatments with markedly different morbidity, mortality, and patient burden. There are no validated biomarkers to facilitate such treatment decisions. Alterations in DNA methylation are commonplace in BC; hence, measurable changes in DNA methylation represent an opportunity for the discovery of such biomarkers.Objective: To systematically assess the evidence regarding DNA methylation markers as prognosticators for HR-NMIBC.Evidence acquisition: Standard systematic review methods were employed with searches undertaken in MEDLINE, EMBASE, and PubMed up to January 2019. Studies that included patients with HR-NMIBC and investigated the utility of DNA methylation biomarkers as prognostic tools were included.Evidence synthesis: Of 63 prognostic biomarker studies identified, 21 met the protocol-driven inclusion criteria and were directly relevant to HR-NMIBC patient outcomes: tumour recurrence (TR), tumour progression (TP), disease-specific survival (DSS), and overall survival (OS). These studies described 140 methylation markers; of these, the most promising were cadherin-13 (CDH13; hazard ratios [HRs]: 5.1 for TR, 6.6 for TP, 3.8–8.0 for OS), protocadherins (PCDHs; HRs: 4.7 for TR, 2.5 for TP, 3.0–4.8 for OS), Runt domain transcription factor 3 (RUNX3; HR: 5.1 for TP), Homeobox 9 (HOXA9; HR: 1.9 for TR), Islet-1 (ISL1; HRs: 1.7 for TR, 3.3 for TP), and PAX6 (HR: 2.2 for TR).Conclusions: This systematic review identifies a number of potentially useful prognostic methylation markers for HR-NMIBC. These loci (CDH13, PCDHs, RUNX3, HOXA9, ISL1, and PAX6) should be validated in prospective studies in order to translate benefit to patients.Patient summary: Early bladder cancer represents a more complex spectrum of disease than can be assessed by conventional methods Emerging studies on molecular markers will improve our understanding of this disease, and may enable more precise and personalised treatment.</p

Correction to:The effectiveness and safety of proton beam radiation therapy in children and young adults with Central Nervous System (CNS) tumours: a systematic review

Correction to: J Neurooncolhttps://doi.org/10.1007/s11060-023-04510-

Correction to:The effectiveness and safety of proton beam radiation therapy in children and young adults with Central Nervous System (CNS) tumours: a systematic review

Correction to: J Neurooncolhttps://doi.org/10.1007/s11060-023-04510-

Administering anticipatory medications in end-of-life care: A qualitative study of nursing practice in the community and in nursing homes

Background: In the United Kingdom, an approach to improving end-of-life care has been the introduction of ‘just in case’ or ‘anticipatory’ medications. Nurses are often responsible for deciding when to use anticipatory medications, but little is known about their experiences. Aim: To examine nurses’ decisions, aims and concerns when using anticipatory medications. Design: An ethnographic study in two UK regions, using observations and interviews with nurses working in community and nursing home teams (n = 8). Findings: Observations (n = 83) and interviews (n = 61) with community nurses. Nurses identified four ‘conditions’ that needed to be established before they implemented anticipatory medications: (1) irreversibility; (2) inability to take oral medication; (3) where the patient was able, they should consent and (4) decision had to be independent of demands or requests from patient’s relatives. By using anticipation medications, nurses sought to enable patients to be ‘comfortable and settled’ by provision of gradual relief of symptoms at the lowest dose possible. They aimed to respond quickly to needs, seeking to avoid hospital admission or medical call-out, while adhering to local prescribing policies. Worries included distinguishing between pain and agitation, balancing risks of under- and over-medication and the possibility of hastening death. Conclusion: Nurses take a leading role in the administration of anticipatory medications. Nurses apply consideration and caution to the administration of anticipatory medications but some experience emotional burden. Education, training and experience played a role in the nurses’ confidence and should continue to be central to efforts to improving the quality of palliative care in the community and nursing homes

East Midlands Research into Ageing Network (EMRAN) Discussion Paper Series

Academic geriatric medicine in Leicester . There has never been a better time to consider joining us. We have recently appointed a Professor in Geriatric Medicine, alongside Tom Robinson in stroke and Victoria Haunton, who has just joined as a Senior Lecturer in Geriatric Medicine. We have fantastic opportunities to support students in their academic pursuits through a well-established intercalated BSc programme, and routes on through such as ACF posts, and a successful track-record in delivering higher degrees leading to ACL post. We collaborate strongly with Health Sciences, including academic primary care. See below for more detail on our existing academic set-up. Leicester Academy for the Study of Ageing We are also collaborating on a grander scale, through a joint academic venture focusing on ageing, the ‘Leicester Academy for the Study of Ageing’ (LASA), which involves the local health service providers (acute and community), De Montfort University; University of Leicester; Leicester City Council; Leicestershire County Council and Leicester Age UK. Professors Jayne Brown and Simon Conroy jointly Chair LASA and have recently been joined by two further Chairs, Professors Kay de Vries and Bertha Ochieng. Karen Harrison Dening has also recently been appointed an Honorary Chair. LASA aims to improve outcomes for older people and those that care for them that takes a person-centred, whole system perspective. Our research will take a global perspective, but will seek to maximise benefits for the people of Leicester, Leicestershire and Rutland, including building capacity. We are undertaking applied, translational, interdisciplinary research, focused on older people, which will deliver research outcomes that address domains from: physical/medical; functional ability, cognitive/psychological; social or environmental factors. LASA also seeks to support commissioners and providers alike for advice on how to improve care for older people, whether by research, education or service delivery. Examples of recent research projects include: ‘Local History Café’ project specifically undertaking an evaluation on loneliness and social isolation; ‘Better Visits’ project focused on improving visiting for family members of people with dementia resident in care homes; and a study on health issues for older LGBT people in Leicester. Clinical Geriatric Medicine in Leicester We have developed a service which recognises the complexity of managing frail older people at the interface (acute care, emergency care and links with community services). There are presently 17 consultant geriatricians supported by existing multidisciplinary teams, including the largest complement of Advance Nurse Practitioners in the country. Together we deliver Comprehensive Geriatric Assessment to frail older people with urgent care needs in acute and community settings. The acute and emergency frailty units – Leicester Royal Infirmary This development aims at delivering Comprehensive Geriatric Assessment to frail older people in the acute setting. Patients are screened for frailty in the Emergency Department and then undergo a multidisciplinary assessment including a consultant geriatrician, before being triaged to the most appropriate setting. This might include admission to in-patient care in the acute or community setting, intermediate care (residential or home based), or occasionally other specialist care (e.g. cardiorespiratory). Our new emergency department is the county’s first frail friendly build and includes fantastic facilities aimed at promoting early recovering and reducing the risk of hospital associated harms. There is also a daily liaison service jointly run with the psychogeriatricians (FOPAL); we have been examining geriatric outreach to oncology and surgery as part of an NIHR funded study. We are home to the Acute Frailty Network, and those interested in service developments at the national scale would be welcome to get involved. Orthogeriatrics There are now dedicated hip fracture wards and joint care with anaesthetists, orthopaedic surgeons and geriatricians. There are also consultants in metabolic bone disease that run clinics. Community work Community work will consist of reviewing patients in clinic who have been triaged to return to the community setting following an acute assessment described above. Additionally, primary care colleagues refer to outpatients for sub-acute reviews. You will work closely with local GPs with support from consultants to deliver post-acute, subacute, intermediate and rehabilitation care services. Stroke Medicine 24/7 thrombolysis and TIA services. The latter is considered one of the best in the UK and along with the high standard of vascular surgery locally means one of the best performances regarding carotid intervention

Healthcare workers' attitudes towards working during pandemic influenza: A multi method study

Background: Healthcare workers (HCWs) will be key players in any response to pandemic influenza, and will be in the front line of exposure to infection. Responding effectively to a pandemic relies on the majority of medical, nursing, laboratory and hotel services staff continuing to work normally. Planning assumes that during a pandemic normal healthcare service levels will be provided, although it anticipates that as caseloads increase only essential care will be provided. The ability of the NHS to provide expected service levels is entirely dependent upon HCWs continuing to work as normal. Methods/design: This study is designed as a two-phase multi-method study, incorporating focus groups and a questionnaire survey. In phase one, qualitative methods will be used to collect the views of a purposive sample of HCWs, to determine the range of factors associated with their responses to the prospect of working through pandemic influenza. In phase two, the findings from the focus groups, combined with the available literature, will be used to inform the design of a survey to determine the generalisability of these factors, enabling the estimation of the likely proportion of HCWs affected by each factor, and how likely it is that they would be willing and/or able to continue to work during an influenza pandemic. Discussion: There are potentially greater than normal health risks for some healthcare workers working during a pandemic, and these workers may be concerned about infecting family members/ friends. HCWs will be as liable as other workers to care for sick family members and friends. It is vital to have information about how motivated HCWs will be to continue to work during such a crisis, and what factors might influence their decision to work/not to work. Through the identification and subsequent management of these factors it may be possible to implement strategies that will alleviate the concerns and fears of HCWs and remove potential barriers to working