The Childhood Cancer Diagnosis (CCD) Study: a UK observational study to describe referral pathways and quantify diagnostic intervals in children and young people with cancer

Introduction: Childhood cancer is diagnosed in 400 000 children and young people (CYP) aged 0–19 years worldwide annually. In the UK, a child’s cumulative cancer risk increases from 1 in 4690 from birth to aged 1, to 1 in 470 by age 15. Once diagnosed, access to treatments offers survival to adulthood for over 80%. Tumour diagnoses are at a later stage and mortality is higher when compared with those in other parts of Europe. This means higher risk, more intensive therapies for a cure. Some CYPs are known to experience delays to diagnosis which may further contribute to poor outcomes. This study aims to understand the current pathway of childhood cancer referrals and diagnosis and quantify diagnostic intervals in the UK.Methods and analysis: This is a prospective multicentre observational study including all tertiary childhood cancer treatment centres in the UK. CYP (0–18 years) with a new diagnosis of cancer over the study period will be invited to participate. Data will be collected at initial diagnosis and 5 years after diagnosis. Data will include demographic details, clinical symptoms, tumour location, stage and clinical risk group. In addition, key diagnostic dates and referral routes will be collected to calculate the diagnostic intervals. At 5 years’ follow-up, data will be collected on refractory disease, relapse and 1-year and 5-year survival. Population characteristics will be presented with descriptive analyses with further analyses stratified by age, geographical region and cancer type. Associations between diagnostic intervals/delay and risk factors will be explored using multiple regression and logistic regression.Ethics: The study has favourable opinion from the York and Humber, Leeds West REC (19/YH/0416).Dissemination: Results will be presented at academic conferences, published in peer-reviewed journals and disseminated through public messaging in collaboration with our charity partners through a national awareness campaign (ChildCancerSmart).Study registration: researchregistry.com (researchregistry5313)

Childhood bone tumours in primary care: helping GPs to identify ‘the needle in the haystack’

In 2018, the World Health Organization declared childhood cancer as a global disease burden, launching a Global Initiative to improve survival to 60% worldwide by 2030. If achieved, it is estimated that an extra 1 million children’s lives will be saved. In the UK, childhood cancer is the largest illness cause of death in childhood in 1–19-year-olds and the incidence continues to rise. Unlike in adult cancers, there are no modifiable risk factors or cost-effective screening options and so early diagnosis is key to reducing morbidity, mortality, and late effects from treatment burden

Can I go home now? : The safety and efficacy of a new UK paediatric febrile neutropenia protocol for risk-stratified early discharge on oral antibiotics

OBJECTIVE: To evaluate a new protocol of risk stratification and early discharge for children with febrile neutropenia (FN). DESIGN: Prospective service evaluation from 17 April 2020 to 16 April 2021. SETTING: 13 specialist centres in the UK. PATIENTS: 405 children presenting with FN. INTERVENTION: All children received intravenous antibiotics at presentation. Risk stratification was determined using the Australian-UK-Swiss (AUS) rule and eligibility for homecare assessed using criteria including disease, chemotherapy, presenting features and social factors. Those eligible for homecare could be discharged on oral antibiotics after a period of observation proportional to their risk group. MAIN OUTCOME MEASURES: Median duration of admission and of intravenous antibiotics, and percentage of patients with positive blood cultures, significant infection, readmission within 7 days of initial presentation, intensive care unit (ICU) admission, death from infection and death from other causes. RESULTS: 13 centres contributed 729 initial presentations of 405 patients. AUS rule scores were positively correlated with positive blood cultures, significant infection, ICU admission and death. 20% of children were eligible for homecare with oral antibiotics, of which 55% were low risk (AUS 0-1). 46% low-risk homecare eligible patients were discharged by 24 hours vs 2% homecare ineligible. Homecare readmission rates were 14% overall and 16% for low-risk cases (similar to a meta-analysis of previous studies). No child eligible for homecare was admitted to ICU or died. CONCLUSIONS: Use of the AUS rule and homecare criteria allow for safe early outpatient management of children with FN

Research priorities for children's cancer : a James Lind Alliance Priority Setting Partnership in the UK

OBJECTIVES: To engage children who have experienced cancer, childhood cancer survivors, their families and professionals to systematically identify and prioritise research questions about childhood cancer to inform the future research agenda. DESIGN: James Lind Alliance Priority Setting Partnership. SETTING: UK health service and community. METHODS: A steering group oversaw the initiative. Potential research questions were collected in an online survey, then checked to ensure they were unanswered. Shortlisting via a second online survey identified the highest priority questions. A parallel process with children was undertaken. A final consensus workshop was held to determine the Top 10 priorities. PARTICIPANTS: Children and survivors of childhood cancer, diagnosed before age 16, their families, friends and professionals who work with this population. RESULTS: Four hundred and eighty-eight people submitted 1299 potential questions. These were refined into 108 unique questions; 4 were already answered and 3 were under active study, therefore, removed. Three hundred and twenty-seven respondents completed the shortlisting survey. Seventy-one children submitted questions in the children's surveys, eight children attended a workshop to prioritise these questions. The Top 5 questions from children were taken to the final workshop where 23 questions in total were discussed by 25 participants (young adults, carers and professionals). The top priority was 'can we find effective and kinder (less burdensome, more tolerable, with fewer short and long-term effects) treatments for children with cancer, including relapsed cancer?' CONCLUSIONS: We have identified research priorities for children's cancer from the perspectives of children, survivors, their families and the professionals who care for them. Questions reflect the breadth of the cancer experience, including diagnosis, relapse, hospital experience, support during/after treatment and the long-term impact of cancer. These should inform funding of future research as they are the questions that matter most to the people who could benefit from research

Second asymptomatic carotid surgery trial (ACST-2): a randomised comparison of carotid artery stenting versus carotid endarterectomy

Background: Among asymptomatic patients with severe carotid artery stenosis but no recent stroke or transient cerebral ischaemia, either carotid artery stenting (CAS) or carotid endarterectomy (CEA) can restore patency and reduce long-term stroke risks. However, from recent national registry data, each option causes about 1% procedural risk of disabling stroke or death. Comparison of their long-term protective effects requires large-scale randomised evidence. Methods: ACST-2 is an international multicentre randomised trial of CAS versus CEA among asymptomatic patients with severe stenosis thought to require intervention, interpreted with all other relevant trials. Patients were eligible if they had severe unilateral or bilateral carotid artery stenosis and both doctor and patient agreed that a carotid procedure should be undertaken, but they were substantially uncertain which one to choose. Patients were randomly allocated to CAS or CEA and followed up at 1 month and then annually, for a mean 5 years. Procedural events were those within 30 days of the intervention. Intention-to-treat analyses are provided. Analyses including procedural hazards use tabular methods. Analyses and meta-analyses of non-procedural strokes use Kaplan-Meier and log-rank methods. The trial is registered with the ISRCTN registry, ISRCTN21144362. Findings: Between Jan 15, 2008, and Dec 31, 2020, 3625 patients in 130 centres were randomly allocated, 1811 to CAS and 1814 to CEA, with good compliance, good medical therapy and a mean 5 years of follow-up. Overall, 1% had disabling stroke or death procedurally (15 allocated to CAS and 18 to CEA) and 2% had non-disabling procedural stroke (48 allocated to CAS and 29 to CEA). Kaplan-Meier estimates of 5-year non-procedural stroke were 2·5% in each group for fatal or disabling stroke, and 5·3% with CAS versus 4·5% with CEA for any stroke (rate ratio [RR] 1·16, 95% CI 0·86–1·57; p=0·33). Combining RRs for any non-procedural stroke in all CAS versus CEA trials, the RR was similar in symptomatic and asymptomatic patients (overall RR 1·11, 95% CI 0·91–1·32; p=0·21). Interpretation: Serious complications are similarly uncommon after competent CAS and CEA, and the long-term effects of these two carotid artery procedures on fatal or disabling stroke are comparable. Funding: UK Medical Research Council and Health Technology Assessment Programme

Research priorities for children’s cancer: a James Lind Alliance priority setting partnership in the United Kingdom

Objectives: to engage children who have experienced cancer, childhood cancer survivors, their families, and professionals to systematically identify and prioritise research questions about childhood cancer to inform the future research agenda.Design: James Lind Alliance Priority Setting Partnership.Setting: UK health service and community.Methods: a steering group oversaw the initiative. Potential research questions were collected in an online survey, then checked to ensure they were unanswered. Shortlisting via a second online survey identified the highest priority questions. A parallel process with children was undertaken. A final consensus workshop was held to determine the Top 10 priorities.Participants: children and survivors of childhood cancer, diagnosed before age 16, their families, friends, and professionals who work with this population.Results: four hundred and eighty-eight people submitted 1299 potential questions. These were refined into 108 unique questions; four were already answered and three were under active study, therefore removed. Three hundred and twenty-seven respondents completed the shortlisting survey. Seventy-one children submitted questions in the children’s surveys, eight children attended a workshop to prioritise these questions. The Top 5 questions from children were taken to the final workshop where 23 questions in total were discussed by 25 participants (young adults, carers and professionals). The top priority was, ‘Can we find effective and kinder (less burdensome, more tolerable, with fewer short- and long-term effects) treatments for children with cancer, including relapsed cancer?’Conclusions: we have identified research priorities for children’s cancer from the perspectives of children, survivors, their families, and the professionals who care for them. Questions reflect the breadth of the cancer experience, including diagnosis, relapse, hospital experience, support during/after treatment and the long-term impact of cancer. These should inform funding of future research as they are the questions that matter most to the people who could benefit from research

Mapping the human genetic architecture of COVID-19

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3–7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease

Second asymptomatic carotid surgery trial (ACST-2): a randomised comparison of carotid artery stenting versus carotid endarterectomy

Background: Among asymptomatic patients with severe carotid artery stenosis but no recent stroke or transient cerebral ischaemia, either carotid artery stenting (CAS) or carotid endarterectomy (CEA) can restore patency and reduce long-term stroke risks. However, from recent national registry data, each option causes about 1% procedural risk of disabling stroke or death. Comparison of their long-term protective effects requires large-scale randomised evidence. Methods: ACST-2 is an international multicentre randomised trial of CAS versus CEA among asymptomatic patients with severe stenosis thought to require intervention, interpreted with all other relevant trials. Patients were eligible if they had severe unilateral or bilateral carotid artery stenosis and both doctor and patient agreed that a carotid procedure should be undertaken, but they were substantially uncertain which one to choose. Patients were randomly allocated to CAS or CEA and followed up at 1 month and then annually, for a mean 5 years. Procedural events were those within 30 days of the intervention. Intention-to-treat analyses are provided. Analyses including procedural hazards use tabular methods. Analyses and meta-analyses of non-procedural strokes use Kaplan-Meier and log-rank methods. The trial is registered with the ISRCTN registry, ISRCTN21144362. Findings: Between Jan 15, 2008, and Dec 31, 2020, 3625 patients in 130 centres were randomly allocated, 1811 to CAS and 1814 to CEA, with good compliance, good medical therapy and a mean 5 years of follow-up. Overall, 1% had disabling stroke or death procedurally (15 allocated to CAS and 18 to CEA) and 2% had non-disabling procedural stroke (48 allocated to CAS and 29 to CEA). Kaplan-Meier estimates of 5-year non-procedural stroke were 2·5% in each group for fatal or disabling stroke, and 5·3% with CAS versus 4·5% with CEA for any stroke (rate ratio [RR] 1·16, 95% CI 0·86–1·57; p=0·33). Combining RRs for any non-procedural stroke in all CAS versus CEA trials, the RR was similar in symptomatic and asymptomatic patients (overall RR 1·11, 95% CI 0·91–1·32; p=0·21). Interpretation: Serious complications are similarly uncommon after competent CAS and CEA, and the long-term effects of these two carotid artery procedures on fatal or disabling stroke are comparable. Funding: UK Medical Research Council and Health Technology Assessment Programme

Second asymptomatic carotid surgery trial (ACST-2) : a randomised comparison of carotid artery stenting versus carotid endarterectomy

Background: Among asymptomatic patients with severe carotid artery stenosis but no recent stroke or transient cerebral ischaemia, either carotid artery stenting (CAS) or carotid endarterectomy (CEA) can restore patency and reduce long-term stroke risks. However, from recent national registry data, each option causes about 1% procedural risk of disabling stroke or death. Comparison of their long-term protective effects requires large-scale randomised evidence. Methods: ACST-2 is an international multicentre randomised trial of CAS versus CEA among asymptomatic patients with severe stenosis thought to require intervention, interpreted with all other relevant trials. Patients were eligible if they had severe unilateral or bilateral carotid artery stenosis and both doctor and patient agreed that a carotid procedure should be undertaken, but they were substantially uncertain which one to choose. Patients were randomly allocated to CAS or CEA and followed up at 1 month and then annually, for a mean 5 years. Procedural events were those within 30 days of the intervention. Intention-to-treat analyses are provided. Analyses including procedural hazards use tabular methods. Analyses and meta-analyses of non-procedural strokes use Kaplan-Meier and log-rank methods. The trial is registered with the ISRCTN registry, ISRCTN21144362. Findings: Between Jan 15, 2008, and Dec 31, 2020, 3625 patients in 130 centres were randomly allocated, 1811 to CAS and 1814 to CEA, with good compliance, good medical therapy and a mean 5 years of follow-up. Overall, 1% had disabling stroke or death procedurally (15 allocated to CAS and 18 to CEA) and 2% had non-disabling procedural stroke (48 allocated to CAS and 29 to CEA). Kaplan-Meier estimates of 5-year non-procedural stroke were 2·5% in each group for fatal or disabling stroke, and 5·3% with CAS versus 4·5% with CEA for any stroke (rate ratio [RR] 1·16, 95% CI 0·86-1·57; p=0·33). Combining RRs for any non-procedural stroke in all CAS versus CEA trials, the RR was similar in symptomatic and asymptomatic patients (overall RR 1·11, 95% CI 0·91-1·32; p=0·21). Interpretation: Serious complications are similarly uncommon after competent CAS and CEA, and the long-term effects of these two carotid artery procedures on fatal or disabling stroke are comparable

Mapping the human genetic architecture of COVID-19

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3,4,5,6,7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease