BackgroundThere is a paucity of research into interventions that help people with intellectual disabilities learn to read. This feasibility study examines whether an online reading programme, Headsprout, with additional support strategies and supervision (the intervention), can be delivered by support workers/family carers and the feasibility of conducting a later large-scale effectiveness trial.MethodsThe study used a 2-arm randomised controlled trial (RCT) design with an embedded process evaluation using a mixed methods approach.ResultsThirty-six adults with intellectual disabilities were recruited. Informed consent and data were obtained remotely. Progression criteria for recruitment, retention, randomisation and usual practice were met; intervention adherence and fidelity were poor. Pressure on support services was a key barrier.ConclusionsWhilst progression to a large-scale effectiveness trial was not recommended, the success of conducting an RCT and remotely obtaining informed consent and data from adults with intellectual disabilities opens opportunities for increased participation in research for a currently under-represented group. Registration: ISRCTN11409097ConclusionsWhilst progression to a large-scale effectiveness trial was not recommended, the success of conducting an RCT and remotely obtaining informed consent and data from adults with intellectual disabilities opens opportunities for increased participation in research for a currently under-represented group. Registration: ISRCTN11409097

Abstract Background Children with a learning disability experience a range of inequalities and adverse life events that put them at greater risk of mental health problems. The construct of emotional literacy has been shown to be a moderating factor of how life stress affects mental health. Teaching emotional literacy in schools may therefore be an effective way to promote positive mental health. There is an identified need for adapted emotional literacy programmes in special schools. Objectives To evaluate whether it is feasible to conduct a large-scale randomised controlled trial of the effectiveness and cost-effectiveness of an emotional literacy programme (Zippy’s Friends special educational needs and disabilities) for children with a learning disability in special schools. The key aims were to assess the acceptability and feasibility of participating in the trial, data collection and the Zippy’s Friends special educational needs and disabilities intervention through quantitative and qualitative data collection. Design A feasibility, cluster randomised controlled trial that aimed to recruit and randomise 12 special schools to either deliver the intervention over 1 academic year or continue with practice as usual and to collect data from 96 pupils at baseline (pre randomisation) and 12 months post randomisation. Setting Special schools in England and Scotland. Participants Pupils with a learning disability, aged 9–11 years, attending special schools in England. Follow-up interviews were conducted with 8 pupils, 4 parents/carers and 11 school staff members. Intervention Zippy’s Friends for Special Educational Needs and Disabilities is a manual-based, classroom-based emotional literacy programme focused on a problem-solving approach to develop and improve children’s emotional literacy. The mainstream programme has been adapted for children with a learning disability by simplifying the activities, shortening the sessions and introducing more repetition. Main outcome measures Feasibility and acceptability of: (1) participation in the research trial; (2) the collection of the outcome measure data and (3) the Zippy’s Friends for Special Educational Needs and Disabilities intervention. Results A total of 8 schools and 53 pupils were recruited. Retention of schools after randomisation (100%) and retention of pupils (100%) met the prespecified progression criteria. For recruitment of schools (20.5% of those approached), pupil engagement with the intervention (50%) and collection of outcome and service use data (62.3%) the criteria were partially met. Fidelity of the intervention delivery (48%) fell just below the progression criteria. Thus, the feasibility and acceptability outcome progression criteria were largely met, suggesting that progression to a full trial is warranted with amendments to the study design. Limitations This feasibility trial was conducted during the COVID-19 pandemic, resulting in unusually high absences of pupils and teachers, different classroom arrangements (bubbles) and unprecedented stress and emotional challenges for pupils, parents and teaching staff. The findings are therefore specific to that period and all three main outcomes of this feasibility trial were adversely affected. Conclusions The findings of this study indicate that a large-scale randomised controlled trial is feasible provided that a number of amendments to the study design are made to improve: (1) the timing of the project to suit the demands of special schools’ yearly timetable; (2) recruitment and (3) outcome and service use data collection. Future work On the basis of the current findings, an application for a full trial will be prepared and submitted with a number of amendments. Trial registration This trial is registered as ISRCTN83610691. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme (NIHR award ref: NIHR129064) and is published in full in Public Health Research; Vol. 12, No. 15. See the NIHR Funding and Awards website for further award information. Plain language summary Why this research is important Emotional literacy (the ability to understand, express and manage your own feelings and be aware of other people’s emotional needs) is important for mental health. There are no programmes where research tells us that emotional literacy programmes for children in special schools ‘work’. The programme Zippy’s Friends is an emotional literacy programme widely used in mainstream schools. Zippy’s Friends for Special Educational Needs and Disabilities is adapted for use in special schools. How we did it Eight special schools were involved. Five used Zippy’s Friends for Special Educational Needs and Disabilities in at least one class over a school year. They were compared with three that used standard teaching programmes only. Teachers, parents and children completed questionnaires to measure changes in children’s emotional literacy, mental health and behaviour over the school year. We also interviewed teachers, parents and children to find out about their experiences of taking part in the study and Zippy’s Friends for Special Educational Needs and Disabilities. This study was designed to find out: How willing schools are to take part If Zippy’s Friends for Special Educational Needs and Disabilities can be delivered as planned If the questionnaires are suitable. The results Fifty-three pupils were recruited; none dropped out. Teachers returned questionnaires for 62% of children at the end of the school year. Feedback on Zippy’s Friends for Special Educational Needs and Disabilities from pupils, parents/carers and teachers was very positive. What this means This study took place during the COVID-19 pandemic. Although this made it more difficult, it was feasible. The results tell us that a larger-scale version of this study can be done, provided that we make changes to improve: (1) the timing of contacting schools; (2) how we collect information and (3) how we work with parents/carers. With these improvements, a larger study may be able to tell us whether Zippy’s Friends for Special Educational Needs and Disabilities can improve emotional literacy in children in special schools to help them cope with problems and have better mental health. Scientific summary Background Children with a learning disability experience a range of inequalities that put them at risk of mental health problems in adulthood. Children and young people with a learning disability experience negative life events and adversity more frequently. The construct of emotional literacy has been shown to be a distinct and moderating factor of how life stress affects mental health and well-being. Teaching emotional literacy in primary schools has been shown to be an effective way to promote positive mental health and help children cope with negative life experiences, resulting in the long term in better mental health in later life. In mainstream schools, the Zippy’s Friends (ZF) programme has been shown to be an effective way in which to improve emotional literacy, coping skills and mental health outcomes. Emotional literacy is underemphasised in the special educational needs and disabilities (SEND) curriculum and mainstream emotional literacy programmes (except ZF-SEND) do not have SEND adaptations. The National Institute for Health and Care Excellence recommends that help should be given to those most at risk of mental health problems. Lack of investment in mental health promotion in special schools has significant costs for society. There is, therefore, an identified need for SEND-adapted emotional literacy programmes in special schools. Objectives The objectives for this study were to: Assess intervention delivery, fidelity and adherence, and factors influencing implementation, mechanisms of impact and context using data from multiple sources, including teacher-completed session records, qualitative interviews and observations of ZF-SEND lessons. Explore how children, parents/carers and teachers experience the intervention and research participation through qualitative interviews. Investigate the validity and reliability of the self-report measure of mental health (‘Me and my School’) and its relationship with other (proxy report) measures of mental health and behaviour. Establish by survey what constitutes education as practice as usual (PAU) for emotional literacy in special schools for children with a learning disability. Undertake a nested ‘study within a trial’ to explore the acceptability of two different study designs: one where PAU does not come with the offer of delayed access to ZF-SEND, and one where it does. Review the feasibility study against predetermined progression criteria and ascertain whether progression to a large-scale randomised controlled trial is feasible. Methods Design Two-arm cluster (school) randomised feasibility trial of an adapted ZF programme (ZF-SEND) delivered by teachers to children in special schools. Setting Special schools for children with SEND in England. Population/inclusion Children with a learning disability attending special schools in years 5–6 (aged 9–11 years), their teachers and parents/carers. Exclusions Child already receiving similar manual-based emotional literacy intervention(s). Parents/carers whose level of English language is insufficient for participation in informed consent and structured interview. Intervention Usual practice with ZF-SEND, delivered by teachers. ZF-SEND is a manualised classroom-based emotional literacy programme comprising six modules, each with four session plans. Sessions are adapted to different levels of comprehension. Sessions include at least two activities to explore issues relating to emotional awareness, emotional expression, problem solving and coping skills. Comparator Practice as usual (without ZF-SEND). Primary outcomes (1) Feasibility and acceptability of participation in the study (recruitment, retention and randomisation); (2) feasibility and acceptability of data collection (potential outcome measures for a large-scale trial, quality of life measurement and service use data collection) and (3) feasibility and acceptability of the intervention (fidelity, adherence, attendance, experience of delivering or receiving the intervention and intervention costs). Secondary outcomes (baseline and 8–12 months post randomisation) Strengths and Difficulties Questionnaire (teacher and parent/carer completed); Nisonger Child Behaviour Rating Form (teacher completed); Emotional Literacy: Assessment and Intervention (teacher and parent completed); Me and My School (pupil completed); quality of life measures (pupil and parent/carer completed); service use. Sample Quantitative data collection A total of 8 schools (5 intervention and 3 control), comprising 53 pupils. Qualitative data collection Eight pupils from four ZF-SEND schools, four parents/carers (two from PAU and two from ZF-SEND schools), seven class teachers (three from PAU and four from ZF-SEND schools), four members of senior leadership with management/oversight roles (two from PAU and two from ZF-SEND schools). Randomisation Schools were randomised following completion of pupil recruitment and baseline assessments. Schools were allocated to PAU or ZF-SEND arm using minimisation with 80% random component and balanced by size of school. Analyses Primary (feasibility) outcomes were estimated with their associated 95% confidence intervals (CIs). To inform a future trial, effect sizes and 95% CIs were estimated around the between-group comparisons of clinical measures (secondary outcomes) collected as part of the study. This analysis was based on the intention-to-treat principle and controlled for the clustered nature of children within schools using two-level mixed models. The qualitative process evaluation data were analysed with a framework analysis. Results The results of this study were impacted by the COVID-19 pandemic. It is likely that the pandemic resulted in reduced capacity and interest of schools to participate in research, higher staff and pupil absence in schools, increased pressure on school management, teachers, children and parents/carers, difficult family dynamics and poorer response rates of teachers and parents/carers. Despite this, eight schools were recruited and followed-up with acceptable rates of recruitment of pupils (N = 53) and 100% retention. Acceptable response rates at baseline and follow-up for teachers on the outcome measures were also achieved. Moreover, data collection from pupils was feasible and acceptable with high response rates. However, response rates for parents fell below the progression criterion. Owing to the difficulties in recruiting schools during the COVID-19 pandemic, baseline data collection occurred later than originally planned, resulting in delayed randomisation and ZF-SEND schools starting the programme, and a shorter follow-up period of 8–12 months post randomisation. Only one school completed the programme. Observational and interview data suggest that stakeholders found ZF-SEND feasible and acceptable, and teachers were positive and enthusiastic about the programme. However, there were problematic issues with collecting data about programme delivery on the session checklists, which means that quantitative measures of fidelity, adherence and engagement need to be interpreted with caution. Conclusions This study indicates that a large-scale randomised controlled trial of ZF-SEND is feasible and could provide important evidence about emotional literacy interventions for children with a learning disability provided that the study design is enhanced by: (1) approaching schools earlier in the preceding academic year, randomising schools in the summer term, providing training to teachers in the ZF-SEND arm before the summer break and again early in the autumn term; (2) refining and reducing the outcome measures; (3) embedding data collection on ZF-SEND delivery into the programme and (4) engaging more with parents/carers or, alternatively, omitting parent/carer data collection from the study design. Trial registration This trial is registered as ISRCTN83610691. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme (NIHR award ref: NIHR129064) and is published in full in Public Health Research; Vol. 12, No. 15. See the NIHR Funding and Awards website for further award information.

Background Transoral robotic surgery (TORS) or transoral laser microsurgery (TLM) offer excellent oncological outcomes for oropharyngeal squamous cell carcinoma caused by human papillomavirus (HPV) infection. TORS may offer greater margin clearance around tumors than TLM. Objective To determine whether the differing energy sources used and surgical technique of TORS or TLM is associated with postoperative early swallowing function, feeding tube use, and specific factors related to quality of life. Design, Setting, and Participants This prespecified cohort study was performed within the Postoperative Adjuvant Treatment for HPV-Positive Tumours (PATHOS) randomized clinical trial at 40 centers in the UK, Germany, France, the US, and Australia between November 1, 2015, and August 31, 2023. PATHOS trial participants with HPV-positive oropharyngeal carcinoma of stages T1 to T3 and N0 to N2b M0 (TNM7) who underwent TLM or TORS were eligible. Of 989 consecutively recruited patients on the PATHOS trial, 508 were eligible for this substudy. Exposures The exposure of interest was TORS or TLM. Main Outcomes and Measures Preplanned outcome measures included nasogastric tube insertion rates within 4 weeks after surgery, length of in-hospital stay following surgery, specific scales from the MD Anderson Dysphagia Inventory (MDADI), 35-item European Organization for Research and Treatment of Cancer Head and Neck Questionnaire (H&N35), and 30-item Quality of Life Questionnaire (QLQ C30), water swallow test results, and videofluoroscopy scores. Results Of the 508 patients included in the analysis (390 [76.8%] male; median age, 58.3 [IQR, 52.8-63.6] years), 195 had TLM and 313 had TORS. Nasogastric tube insertion rates were higher after TORS than TLM (85 of 189 [45.0%] vs 10 of 126 [7.9%]; adjusted odds ratio [OR], 4.41 [95% CI, 1.01-19.32]). Mean scores favored TLM with small effect sizes in all MDADI domains and the H&N35 swallowing item at 4 weeks after surgery; between-group difference for the MDADI composite score was -4.89 (95% CI, -8.27 to -1.50); for the MDADI physical functioning score, -6.37 (95% CI, -10.15 to -2.59); for the MDADI global score, -10.02 (95% CI, -16.50 to -3.54); and for H&N35 swallowing score, 7.24 (95% CI, 2.17-12.30). No other measures showed evidence of clinically meaningful differences. Conclusions and Relevance In this cohort study, functional outcomes were moderately less impaired 4 weeks following TLM compared with TORS. Once the longer-term outcomes for these patients are known, these findings could aid the design and use of future head and neck-specific surgical robots.

Purpose/Objective Transoral robotic surgery (TORS) has become a more popular technique than transoral laser microsurgery (TLM) for the treatment of oropharyngeal carcinoma (OPC), in particular for human papilloma virus (HPV) related OPC. The two techniques differ in terms of the energy source used and the resection philosophy. TLM commonly employs transtumoural cuts to assess the depth of a tumour, whereas TORS usually performs an en bloc resection, avoiding breaching the tumour. This could result in differences in post-operative healing and quality of life (QoL). The ongoing PATHOS trial is recruiting participants undergoing transoral surgery (technique is centre choice) for HPV-related OPC with the aim to analyse the oncological effectiveness of de-intensified adjuvant therapies. The trials’ QoL and functional data pre- and post-surgery present a unique opportunity to conduct this pre-planned sub-study comparing early post-operative functional and QoL outcomes following TLM and TORS. Material/Methods PATHOS trial participants who underwent TLM or TORS without re-resection or later, staged neck dissection, and who had 4 weeks post-surgery data available were included. The MD Anderson Dysphagia Inventory (MDADI), EORTC QLQC30 and H&N35, and 100mls Water Swallow Test (volume, capacity, speed) were administered pre-surgery and 4 weeks post-surgery. Data on length of in-hospital stay is collected post-surgery and nasogastric tube (NGT) use is collected at 12 months post-surgery.Data were analysed according to a pre-specified plan using mixed effects cox, linear and logistic regression models that included surgery type, age, anatomical site (lateral vs non-lateral), pathological T-stage, gender, smoking status, pre-surgery scores (for QoL/functional outcomes) and centre as a random effect. For the NGT analysis, only NGTs inserted within 4 weeks of surgery were considered as events and patients who had an NGT inserted pre-surgery were excluded. Results Between November 2015 and July 2023, 508 eligible patients were recruited from 40 centres in UK, Germany, France, USA, Australia. 313 (62%) underwent TORS, and 195 (38%) underwent TLM. There was no significant difference in length of hospital stay after surgery between patients undergoing TORS and TLM, when centre was taken in consideration (HR=0.89, 95%CI 0.69-1.16, p=0.401). NGT insertion rates were significantly higher after TORS than TLM (85/189 - 45.0% vs 10/126 - 7.9%, respectively, OR=4.41, 95%CI=1.01-19.3, p=0.049) but there was no difference in duration (median 5 (95% CI=0.5-12) days TLM, 6 (95% CI=4-6) days TORS; HR=1.05, 95%CI=0.52-2.12, p=0.897). Mean scores significantly favoured TLM (relative to TORS) in all MDADI domains and the H&N35 swallowing item at 4 weeks post-surgery (see table 1); between group difference (95% CI): MDADI composite -4.89 (8.27,-1.50), p=0.005; MDADI physical -6.37 (-10.15, -2.59), p=0.001; MDADI global -10.02 (-16.50, -3.54), p=0.002; H&N35 swallowing 7.24 (2.17, 12.30), p=0.005. There was a trend (p<0.1) for difference in EORTC H&N 35 pain score (4.58, 95%CI(-0.90, 9.96), p=0.095) and water swallow capacity (mL/second) (-1.51, 95%CI(-3.11, 0.10), p=0.067) favouring TLM. There was no significant difference between the following scores: EORTC C30 global, constipation, and summary; H&N35 opening mouth, pain killers, and weight loss. Conclusion PATHOS presents a unique opportunity to compare two different transoral surgical techniques. In this study population, TORS was associated with significantly higher rates of NGT use, worse H&N35 swallowing scores, and worse MDADI scores at 4 weeks post-surgery compared to TLM. There was also a trend (p<0.1) favouring TLM in H&N35 pain score and water swallow capacity. This is the largest comparative study of functional outcomes following TORS vs TLM. The recruiting institutions’ practices are likely to impact on length of stay and NGT use and has been accounted for in the analysis. This represents a non-randomised, unpowered sub-study for multiple secondary endpoints across which multiplicity was unadjusted. As such the results should be seen as hypothesis generating rather than confirmatory. Furthermore, the study has focused solely on the post-operative recovery period following surgery. It cannot comment on the impact of surgical philosophy (TORS vs TLM) on margins and how this may relate to the PATHOS randomised groups.Head and neck surgical oncologists may wish to reconsider the role that laser surgery, both as an energy source and a philosophy, has in the emerging field of robotic surgery.Funded by Cancer Research UK (Grant no: A25317), co-sponsored by Cardiff University and Velindre University NHS Trust.

BackgroundFour out of five people living with osteoarthritis (OA) also suffer with at least one other long-term health condition. The complex interaction between OA and multiple long-term conditions (MLTCs) can result in difficulties with self-care, restricted mobility, pain, anxiety, depression and reduced quality of life. The aim of the MulTI-domain Self-management in Older People wiTh OstEoarthritis and Multi-Morbidities (TIPTOE) trial is to evaluate the clinical and cost-effectiveness of the Living Well self-management support intervention, co-designed with people living with OA, integrated into usual care, in comparison to usual care alone.MethodsTIPTOE is a multi-centre, two-arm, individually randomised controlled trial where 824 individuals over 65 years old with knee and/or hip joint pain from their OA affected joint and at least one other long-term health condition will be randomised to receive either the Living Well Self-Management support intervention or usual care. Eligible participants can self-refer onto the trial via a website or be referred via NHS services across Wales and England. Those randomised to receive the Living Well support intervention will be offered up to six one-to-one coaching sessions with a TIPTOE-trained healthcare practitioner and a co-designed book. Participants will be encouraged to nominate a support person to assist them throughout the study. All participants will complete a series of self-reported outcome measures at baseline and 6- and 12-month follow-up. The primary outcome is symptoms and quality of life as assessed by the Musculoskeletal Health Questionnaire (MSK-HQ). Routine data will be used to evaluate health resource use. A mixed methods process evaluation will be conducted alongside the trial to inform future implementation should the TIPTOE intervention be found both clinically and cost-effective. An embedded 'Study Within A Project' (SWAP) will explore and address barriers to the inclusion of under-served patient groups (e.g. oldest old, low socioeconomic groups, ethnic groups).DiscussionTIPTOE will evaluate the clinical and cost-effectiveness of a co-designed, living well personalised self-management support intervention for older individuals with knee and/or hip OA and MLTCs. The trial has been designed to maximise inclusivity and access.Trial registrationISRCTN 16024745. Registered on October 16, 2023.

Background FURVA, a randomised, double-blind Phase II trial, investigated whether the addition of vandetanib to fulvestrant improved progression-free survival (PFS) in patients with an aromatase inhibitor(AI)-resistant advanced breast cancer. Methods Postmenopausal women with oestrogen receptor-positive (ER+ve)/HER2-negative advanced breast cancer, who experienced disease progression on an AI, were randomised (1:1) to fulvestrant 500 mg (Q28) with vandetanib 300 mg od (f + v) or placebo (f + p) until disease progression or discontinuation. The primary endpoint was PFS; secondary endpoints included overall survival (OS) and the influence of REarranged during Transfection (RET) signalling on outcomes. Results In total, 165 participants were randomised to f + v ( n = 80) or f + p ( n = 85). Median PFS was 5.5 months (m) for f + v compared to 5.5 m for f + p (hazard ratio (HR) 0.88; 95% CI: 0.62–1.23; P = 0.22). Unexpectedly, high total RET expression was associated with a PFS advantage of 8.87 m vs 3.94 with low RET (HR 0.493: 95% CI 0.32–0.77; P = 0.002) independent of the treatment arm, supported by an OS advantage 21.95 m vs 18.04 (HR 0.584; 95% CI 0.34–1.00; P = 0.051) in the high-RET group. Conclusion The addition of vandetanib to fulvestrant does not improve PFS. However, high total RET expression was associated with improved PFS, suggesting RET may have a prognostic role in patients treated with fulvestrant. Clinical trial registration ClinicalTrials.gov, NCT02530411.

Background Capivasertib, an AKT inhibitor, added to fulvestrant, was previously reported to improve progression-free survival in women with aromatase inhibitor-resistant oestrogen receptor (ER)-positive, HER2-negative advanced breast cancer. The benefit appeared to be independent of the phosphoinositide 3-kinase (PI3K)/AKT/phosphatase and tensin homologue (PTEN) pathway alteration status of tumours, as ascertained using assays available at the time. Here, we report updated progression-free survival and overall survival results, and a prespecified examination of the effect of PI3K/AKT/PTEN pathway alterations identified by an expanded genetic testing panel on treatment outcomes. Methods This randomised, multicentre, double-blind, placebo-controlled, phase 2 trial recruited postmenopausal adult women aged at least 18 years with ER-positive, HER2-negative, metastatic or locally advanced inoperable breast cancer and an Eastern Cooperative Oncology Group performance status of 0-2, who had relapsed or progressed on an aromatase inhibitor, from across 19 hospitals in the UK. Participants were randomly assigned (1:1) to receive intramuscular fulvestrant 500 mg (day 1) every 28 days (plus a 500 mg loading dose on day 15 of cycle 1) with either capivasertib 400 mg or matching placebo, orally twice daily on an intermittent weekly schedule of 4 days on and 3 days off, starting on cycle 1 day 15. Treatment continued until disease progression, unacceptable toxicity, loss to follow-up, or withdrawal of consent. Treatment was allocated by an interactive web-response system using a minimisation method (with a 20% random element) and the following minimisation factors: measurable or non-measurable disease, primary or secondary aromatase inhibitor resistance, PIK3CA status, and PTEN status. The primary endpoint was progression-free survival in the intention-to-treat population. Secondary endpoints shown in this Article were overall survival and safety in the intention-to-treat population, and the effect of tumour PI3K/AKT/PTEN pathway status identified by an expanded testing panel that included next-generation sequencing assays. Recruitment is complete. The trial is registered with ClinicalTrials.gov, number NCT01992952. Findings Between March 16, 2015, and March 6, 2018, 183 participants were screened for eligibility and 140 (77%) were randomly assigned to receive fulvestrant plus capivasertib (n=69) or fulvestrant plus placebo (n=71). Median follow-up at the data cut-off of Nov 25, 2021, was 58.5 months (IQR 45.9-64.1) for participants treated with fulvestrant plus capivasertib and 62.3 months (IQR 62.1-70.3) for fulvestrant plus placebo. Updated median progression-free survival was 10.3 months (95% CI 5.0-13.4) in the group receiving fulvestrant plus capivasertib compared with 4.8 months (3.1-7.9) for fulvestrant plus placebo (adjusted hazard ratio [HR] 0.56 [95% CI 0.38-0.81]; two-sided p=0.0023). Median overall survival in the capivasertib versus placebo groups was 29.3 months (95% CI 23.7-39.0) versus 23.4 months (18.7-32.7; adjusted HR 0.66 [95% CI 0.45-0.97]; two-sided p=0.035). The expanded biomarker panel identified an expanded pathway-altered subgroup that contained 76 participants (54% of the intention-to-treat population). Median progression-free survival in the expanded pathway-altered subgroup for participants receiving capivasertib (n=39) was 12.8 months (95% CI 6.6-18.8) compared with 4.6 months (2.8-7.9) in the placebo group (n=37; adjusted HR 0.44 [95% CI 0.26-0.72]; two-sided p=0.0014). Median overall survival for the expanded pathway-altered subgroup receiving capivasertib was 38.9 months (95% CI 23.3-50.7) compared with 20.0 months (14.8-31.4) for those receiving placebo (adjusted HR 0.46 [95% CI 0.27-0.79]; two-sided p=0.0047). By contrast, there were no statistically significant differences in progression-free or overall survival in the expanded pathway non-altered subgroup treated with capivasertib (n=30) versus placebo (n=34). One additional serious adverse event (pneumonia) in the capivasertib group had occurred subsequent to the primary analysis. One death, due to atypical pulmonary infection, was assessed as possibly related to capivasertib treatment. Interpretation Updated FAKTION data showed that capivasertib addition to fulvestrant extends the survival of participants with aromatase inhibitor-resistant ER-positive, HER2-negative advanced breast cancer. The expanded biomarker testing suggested that capivasertib predominantly benefits patients with PI3K/AKT/PTEN pathway-altered tumours. Phase 3 data are needed to substantiate the results, including in patients with previous CDK4/6 inhibitor exposure who were not included in the FAKTION trial. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd.

Background Many individuals with intellectual disability (ID) have not learnt basic reading skills by the time that they reach adulthood, potentially limiting their access to critical information. READ-IT is an online reading programme developed from the Headsprout® Early Reading (HER®) intervention and supplemented by support strategies tailored for adults with ID. HER® has been successfully used to teach adults with ID to read in a forensic setting by trained staff. The aim of this study is to assess the feasibility of delivering READ-IT to adults with ID by family carers/support workers and will assess whether it would be feasible to conduct a later definitive randomised controlled trial (RCT) of the effectiveness of the programme. The study will aim to contribute to the evidence base on improving outcomes for adults with ID and their caregivers. Methods This study is a feasibility RCT, with embedded process evaluation. Forty-eight adults with ID will be recruited and allocated to intervention: control on a 1:1 basis. Intervention families will be offered the READ-IT programme immediately, continuing to receive usual practice and control participants will be offered the opportunity to receive READ-IT at the end of the trial follow-up period and will continue to receive usual practice. Data will be collected at baseline and 6 months post-randomisation. Discussion The results of this study will inform a potential future definitive trial, to evaluate the effectiveness of READ-IT to improve reading skills. Such a trial would have significant scientific impact internationally in the intellectual disability field. Trial registration ISRCTN11409097

Introduction Head and neck cancer appears to be increasing in incidence, with potential changes in aetiology proposed. This paper aims to provide a narrative overview of the epidemiological literature to describe the disease burden and trends in terms of incidence and mortality both in the UK and globally and to review the evidence on current risk factors.Methods A search was performed on multiple databases (PubMed and Epistemonikos), applying filters to identify systematic reviews and meta-analyses which investigated head and neck cancer incidence, mortality and risk factors. International and UK cancer registries and sources were searched for incidence and mortality data.Results Multiple definitions of head and neck cancer are employed in epidemiology. Globally, incidence rates have increased in recent decades, largely driven by oropharyngeal cancer. Mortality rates over the last decade have also started to rise, reflecting the disease incidence and static survival rates. Major risk factors include tobacco smoking alone and in combination with alcohol consumption, betel chewing (particularly in Southeast Asian populations) and the human papillomavirus in oropharyngeal cancer.Conclusions These epidemiological data can inform clinical and preventive service planning for head and neck cancer.

Background: Explanations for socioeconomic inequalities in survival of head and neck cancer (HNC) patients have had limited attention and are not well understood. Methods: The UK Head and Neck 5000 prospective clinical cohort study was analyzed. Survival relating to measures of socioeconomic status was explored including area-based and individual factors. Three-year overall survival was determined using the Kaplan-Meier method. All-cause mortality was investigated via adjusted Cox Proportional Hazard models. Results: A total of 3440 people were included. Three-year overall survival was 76.3% (95% CI 74.9, 77.7). Inequality in survival by deprivation category, highest education level, and financial concerns was explained by age, sex, health, and behavioral factors. None of the potential explanatory factors fully explained the inequality associated with annual household income or the proportion of income of benefits. Conclusion: These results support the interventions to address the financial issues within the wider care and support provided to HNC patients.

Background Single-modality treatment (surgery or radiotherapy [RT]) is a curative treatment option for early-stage oropharyngeal carcinoma (OPC) with comparable (excellent) oncological outcomes. This study aimed to compare self-reported swallowing function. Methods Participants with a T1-2N0-2bM0 OPC who were offered single-modality treatment and were recruited to the Head and Neck 5000 study were included. Prospectively collected self-reported swallowing function was compared between surgery and RT. Results Those offered RT (n = 150) had less favorable baseline characteristics than those offered surgery (n = 150). At 12-month follow up, RT participants reported more swallowing problems (35% vs 23%, RR 1.3; 95% CI 0.8-2.3,P= .277) in models adjusted for baseline characteristics. In those allocated to surgery who received adjuvant therapy (n = 78, 52%), the proportion with swallowing problems was similar to those allocated to RT alone. Conclusions Participants offered surgery alone had similar mortality but improved swallowing, although this was not statistically significant. However, over half of participants offered surgery alone received surgery and adjuvant therapy.

Background Smoking status, alcohol consumption and HPV infection (acquired through sexual activity) are the predominant risk factors for oropharyngeal cancer and are thought to alter the prognosis of the disease. Here, we conducted single-site and differentially methylated region (DMR) epigenome-wide association studies (EWAS) of these factors, in addition to ∼ 3-year survival, using Illumina Methylation EPIC DNA methylation profiles from whole blood in 409 individuals as part of the Head and Neck 5000 (HN5000) study. Overlapping sites between each factor and survival were then assessed using two-step Mendelian randomization to assess whether methylation at these positions causally affected survival. Results Using the MethylationEPIC array in an OPC dataset, we found novel CpG associations with smoking, alcohol consumption and ~ 3-year survival. We found no CpG associations below our multiple testing threshold associated with HPV16 E6 serological response (used as a proxy for HPV infection). CpG site associations below our multiple-testing threshold ( P Bonferroni < 0.05) for both a prognostic factor and survival were observed at four gene regions: SPEG (smoking), GFI1 (smoking), PPT2 (smoking) and KHDC3L (alcohol consumption). Evidence for a causal effect of DNA methylation on survival was only observed in the SPEG gene region (HR per SD increase in methylation score 1.28, 95% CI 1.14 to 1.43, P 2.12 × 10 −05 ). Conclusions Part of the effect of smoking on survival in those with oropharyngeal cancer may be mediated by methylation at the SPEG gene locus. Replication in data from independent datasets and data from HN5000 with longer follow-up times is needed to confirm these findings.

Epstein-Barr virus (EBV) causes nasopharyngeal carcinoma (NPC) in endemic regions, where almost every tumor is EBV-positive. In Western populations, NPC is rare, and human papillomavirus infection (HPV) has been suggested as another viral cause. We validated multiplex serology with molecular tumor markers, to define EBV-positive, HPV-positive and EBV-/HPV-negative NPCs in the United Kingdom, and analyzed survival differences between those groups. Sera from NPC cases (n = 98) and age- and sex-matched controls (n = 142) from the Head and Neck 5000 clinical cohort study were analyzed. IgA and IgG serum antibodies against 13 EBV antigens were measured and compared with EBER in situ hybridization (EBER-ISH) data of 41 NPC tumors (29 EBER-ISH positive, 12 negative). IgG antibodies to EBV LF2 correctly diagnosed EBV-positive NPCs in 28 of 29 cases, while all EBER-ISH negative NPCs were seronegative to LF2 IgG (specificity = 100%, sensitivity = 97%). HPV early antigen serology was compared to HPV molecular markers (p16 expression, HPV DNA and RNA) available for 41 NPCs (13 positive, 28 negative). Serology matched molecular HPV markers in all but one case (specificity = 100%, sensitivity = 92%). EBV and HPV infections were mutually exclusive. Overall, 67% of the analyzed NPCs were defined as EBV-positive, 18% as HPV-positive and 14% as EBV/HPV-negative. There was no statistical evidence of a difference in survival between the three groups. These data provide evidence that both, EBV-positive and HPV-positive NPCs are present in a low incidence country, and that EBV and HPV serum antibodies correlate with the viral status of the tumor.

Background DNA methylation (DNAm) variation is an established predictor for several traits. In the context of oropharyngeal cancer (OPC), where 5-year survival is ~ 65%, DNA methylation may act as a prognostic biomarker. We examined the accuracy of DNA methylation biomarkers of 4 complex exposure traits (alcohol consumption, body mass index [BMI], educational attainment and smoking status) in predicting all-cause mortality in people with OPC. Results DNAm predictors of alcohol consumption, BMI, educational attainment and smoking status were applied to 364 individuals with OPC in the Head and Neck 5000 cohort (HN5000; 19.6% of total OPC cases in the study), followed up for median 3.9 years; inter-quartile range (IQR) 3.3 to 5.2 years (time-to-event—death or censor). The proportion of phenotypic variance explained in each trait was as follows: 16.5% for alcohol consumption, 22.7% for BMI, 0.4% for educational attainment and 51.1% for smoking. We then assessed the relationship between each DNAm predictor and all-cause mortality using Cox proportional-hazard regression analysis. DNAm prediction of smoking was most consistently associated with mortality risk (hazard ratio [HR], 1.38 per standard deviation (SD) increase in smoking DNAm score; 95% confidence interval [CI] 1.04 to 1.83; P 0.025, in a model adjusted for demographic, lifestyle, health and biological variables). Finally, we examined the accuracy of each DNAm predictor of mortality. DNAm predictors explained similar levels of variance in mortality to self-reported phenotypes. Receiver operator characteristic (ROC) curves for the DNAm predictors showed a moderate discrimination of alcohol consumption (area under the curve [AUC] 0.63), BMI (AUC 0.61) and smoking (AUC 0.70) when predicting mortality. The DNAm predictor for education showed poor discrimination (AUC 0.57). Z tests comparing AUCs between self-reported phenotype ROC curves and DNAm score ROC curves did not show evidence for difference between the two (alcohol consumption P 0.41, BMI P 0.62, educational attainment P 0.49, smoking P 0.19). Conclusions In the context of a clinical cohort of individuals with OPC, DNAm predictors for smoking, alcohol consumption, educational attainment and BMI exhibit similar predictive values for all-cause mortality compared to self-reported data. These findings may have translational utility in prognostic model development, particularly where phenotypic data are not available.

OBJECTIVES:To compare risk factors and survival in people with oropharyngeal cancer (OPC) and cancer unknown primary (CUP).MATERIALS AND METHODS:We recruited 5511 people with head and neck cancer between 2011 and 2014. We collected data on age, gender, smoking, sexual behaviour, treatment intent, stage, co-morbidity, p16 protein overexpression and biological samples. We assessed human papillomavirus (HPV) status using serological response and p16 immunohistochemistry. We followed up participants to identify those who had died. We used Cox proportional hazards regression models to estimate survival and adjust for confounders.RESULTS:Of the 4843 people with squamous cell cancer 196 had CUP - a prevalence of 4.0% (95% CI 3.5% to 4.6%). Of those people with OPC and CUP 69% (1150/1668) and 60% (106/178) respectively had HPV driven tumours. People with HPV driven tumours were likely to be younger, male, non-smokers, with higher stage disease, a history of oral sex and less co-morbidity. People with HPV negative CUP and HPV driven CUP had the survival of people with a stage II/III HPV negative OPC and a stage I/II HPV driven OPC respectively. The adjusted hazard ratio for HPV driven OPC and CUP compared with HPV negative OPC and CUP was 0.46 (95% CI 0.35 to 0.59) and 0.34 (95% CI 0.14 to 0.82) respectively.CONCLUSION:HPV driven CUP is likely to be HPV driven OPC. Identifying effective methods of detecting occult OPC could improve CUP management and allow the detection of early lesions in high risk groups.

Background: Few large studies describe initial disease trajectories and subsequent mortality in people with head and neck cancer. This is a necessary first step to identify the need for palliative care and associated services. Aim: To analyse data from the Head and Neck 5000 study to present mortality, place and mode of death within 12 months of diagnosis. Design: Prospective cohort study. Participants: In total, 5402 people with a new diagnosis of head and neck cancer were recruited from 76 cancer centres in the United Kingdom between April 2011 and December 2014. Results: Initially, 161/5402 (3%) and 5241/5402 (97%) of participants were treated with ‘non-curative’ and ‘curative’ intent, respectively. Within 12 months, 109/161 (68%) in the ‘non-curative’ group died compared with 482/5241 (9%) in the ‘curative’ group. Catastrophic bleed was the terminal event for 10.4% and 9.8% of people in ‘non-curative’ and ‘curative’ groups, respectively; terminal airway obstruction was recorded for 7.5% and 6.3% of people in the same corresponding groups. Similar proportions of people in both groups died in a hospice (22.9% ‘non-curative’; 23.5% ‘curative’) and 45.7% of the ‘curative’ group died in hospital. Conclusion: In addition to those with incurable head and neck cancer, there is a small but significant ‘curative’ subgroup of people who may have palliative needs shortly following diagnosis. Given the high mortality, risk of acute catastrophic event and frequent hospital death, clarifying the level and timing of palliative care services engagement would help provide assurance as to whether palliative care needs are being met.

Background We investigated long-term survival from head and neck cancer (HNC) using different survival approaches. Methods Patients were followed-up from the Scottish Audit of Head and Neck Cancer. Overall survival and disease-specific survival were calculated using the Kaplan-Meier method. Net survival was calculated by the Pohar-Perme method. Mutually adjusted Cox proportional hazards models were used to determine the predictors of survival. Results A total of 1820 patients were included in the analyses. Overall survival at 12 years was 26.3% (24.3%, 28.3%). Disease-specific survival at 12 years was 56.9% (54.3%, 59.4%). Net survival at 12 years was 41.4% (37.6%, 45.1%). Conclusion Determinants associated with long-term survival included age, stage, treatment modality, WHO performance status, alcohol consumption, smoking behavior, and anatomical site. We recommend that net survival is used for long-term outcomes for HNC patients-it disentangles other causes of death, which are overestimated in overall survival and underestimated in disease-specific survival.

Background: Socioeconomic inequalities impact on the survival of head and neck cancer (HNC) patients, but there is limited understanding of the explanations of the inequality, particularly in long-term survival. Methods: Patients were recruited from the Scottish Audit of Head and Neck Cancer between 1999 and 2001 and were linked to mortality data as at 30th September 2013. Socioeconomic status was determined using the area-based Carstairs 2001 index. Overall and disease-specific survival were calculated using the Kaplan-Meier method with 95% confidence intervals (CI's) at 1-, 5-, and 12-years. Net survival at 1-, 5-, and 12-years was also computed with 95% CIs. Cox proportional hazard models with 95% CIs were used to determine the explanations for the inequality in survival by all-cause mortality and disease-specific mortality with 95% CIs. Results: Most patients were from the most deprived group, and were more likely to smoke, drink, have cancer of a higher stage and have a lower WHO Performance Status. A clear gradient across Carstairs fifths for unadjusted overall and disease-specific survival was observed at 1-, 5-, and 12-years for patients with HNC. Following the adjustment for multiple patient, tumor and treatment factors, the inequality in survival for patients with HNC had attenuated and was no longer statistically significant at 1-, 5-, and 12-years. Conclusion: A clear gradient across Carstairs fifths for unadjusted overall, disease-specific and net survival was observed at 1-, 5-, and 12-years for HNC patients in Scotland from 1999 to 2001. This study concludes that explanations for the inequality in the survival of patients with HNC are not straightforward, and that many factors including various patient, tumor and treatment factors play a part in the inequality in the survival of patients with HNC.

OBJECTIVES:This paper aims to provide contemporary epidemiological data on squamous cell carcinoma (SCC) of the nasal cavity, which represents a rare type of head and neck cancer.DESIGN, SETTING & PARTICIPANTS:A descriptive analysis of people with nasal cavity SCC treated with curative intent from the Head and Neck 5000 study; a multicentre clinical cohort study of people from the UK with head and neck cancer. People with tumours of the nasopharynx, paranasal sinuses and other sub-sites of the head and neck were excluded.MAIN OUTCOME MEASURES:Demographic data and treatment details are presented for all participants. The main outcomes were overall survival and survival according to categories of characteristics (eg, smoker vs non-smoker); these were explored using Kaplan-Meier plots.RESULTS:Thirty people with nasal cavity SCC were included in the study, of which most were male (67%) and current or ex-smokers (70%). The majority (70%) presented with early-stage (T1/2, N0) tumours. Cervical lymph node metastases at presentation were rare, occurring in only one person. Nine people died during the follow-up period (30%). Worse survival outcomes were seen in people with moderate or severe co-morbidities.CONCLUSIONS:This paper provides epidemiological data on nasal cavity SCC in the UK. Patterns of disease and survival outcomes are described, identifying high-risk groups. Further studies should explore whether primary treatment modality alters survival.