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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. Key points Head and neck cancer incidence is increasing and is projected to continue to rise, largely driven by increases in oropharyngeal cancer. Mortality rates have started to increase within the last decade, reflecting a rising incidence and static survival rates. Major risk factors that are associated with the risk of head and neck cancer are tobacco smoking and tobacco used in combination with alcohol consumption. Human papillomavirus is an additional major risk factor for oropharyngeal cancer. Cancers of the head and neck are clearly socioeconomically patterned but this socioeconomic risk is not entirely explained by smoking and alcohol behaviours.

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. 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. 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. 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. AstraZeneca and Cancer Research UK.

Background Four 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. Methods TIPTOE 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). Discussion TIPTOE 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 registration ISRCTN 16024745 . Registered on October 16, 2023.

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

Background: Socioeconomic inequalities in the relationship between lower socioeconomic status and circumstances with poorer survival of people with head and neck cancer have previously been described. However, the extent and nature of socioeconomic inequality in survival of people with head and neck cancer is poorly understood and explanations for these inequalities are yet to be thoroughly investigated. In particular, the underlying determinants of inequality in survival of people with head and neck cancer is yet to be explored by comparing factors that might be more modifiable with factors that might be more difficult to modify or control. In addition, no study exists from the United Kingdom (UK) that has explored socioeconomic inequality in survival of people with head and neck cancer using individual measurements of socioeconomic status, such as household income or education level, and few studies have investigated the long-term impact of inequality on survival of people with head and neck cancer beyond five-years. Finally, no studies have examined inequality in survival of people with head and neck cancer by utilising metrics of inequality. Further investigations into socioeconomic inequality in survival of people with head and neck cancer need to be conducted to describe and compare inequality with the aim to explain the underlying drivers of inequality in survival for people with head and neck cancer in the short-term, middle-term, and long-term follow-up. Aim: This thesis has the potential to shine a light on the issue of socioeconomic inequality in survival of people with head and neck cancer. This thesis aims to inform the patients, public, clinicians, and policy makers who are involved with head and neck cancer services on the magnitude of socioeconomic inequality in survival of people with head and neck cancer, and what factors can explain these inequalities. A series of epidemiological studies of existing UK cohort studies will be conducted to explore this topic from different angles with the aim to inform policy and practice to further the development and delivery of head and neck cancer services. The overall aim of this thesis is to: describe the trends in socioeconomic determinants and inequalities in survival from head and neck cancer over calendar time and follow-up time; to understand socioeconomic inequality in survival of people with head and neck cancer; and to explain the underlying determinants and explanations of socioeconomic inequality in survival of people with head and neck cancer. In addition, multiple measurements of survival will be utilised and compared, including overall survival, disease-specific survival, and net survival estimates, as well as measurements of inequality including the slope index of inequality and the relative index of inequality. Finally, both area-based measurements and individual measurements of socioeconomic status will be utilised and compared for their association with inequality in survival of people with head and neck cancer. Methods: Four studies were conducted with the aim to explore the magnitude, extent, and underlying determinants of survival and inequality in survival of people with head and neck cancer in the UK. Chapter 2 provides an overview analysis of socioeconomic determinants in survival by utilising data from the Scottish Cancer Registry of people diagnosed with head and neck cancer between 1986 to 2015. Due to the limitations around the availability of data in cancer registries, the explanations for socioeconomic inequality were not explored in this chapter and therefore, this chapter was an epidemiological analysis of the trends and magnitude of socioeconomic inequalities in survival over time. Chapter 3 analyses the determinants of survival from head and neck cancer by utilising the Scottish Audit of Head and Neck Cancer (SAHNC), a population-based clinical cohort study of people with head and neck cancer who were diagnosed between 1999 and 2001. Multiple patient, tumour, and treatment factors were examined for their predictive ability with survival, including area-based socioeconomic deprivation. Several methods of measuring survival were compared and contrasted in this chapter, including overall survival, disease-specific survival, and net survival estimates after one year, five years, and 12 years of a diagnosis of head and neck cancer. Chapter 4 also uses the SAHNC cohort and built upon Chapter 3by exploring the drivers and explanations for the socioeconomic inequality observed after one year, five years, and 12 years of a diagnosis of head and neck cancer. The patient, tumour, and treatment factors were individually examined for their relationship with socioeconomic factors with the aim of determining the underlying causes of socioeconomic inequality in survival of people with head and neck cancer. This chapter also explored these inequalities via different survival metrics-overall survival, disease-specific survival, and net survival estimates. Chapter 5 investigated the relationship of individual socioeconomic factors and explanations for these relationships using a cohort of people with head and neck cancer that were diagnosed between 2011 and 2014 in a population-based clinical cohort study in England; Head and Neck 5000 (HN5000). This part of the thesis aimed to undertake an in-depth exploration into the nature and extent of the socioeconomic inequality in survival of people with head and neck cancer by considering both area-based and individual dimensions of socioeconomic circumstances. Multiple demographic, health, behavioural, tumour, and treatment factors were considered to help understand the relationship between socioeconomic factors and head and neck cancer survival. This analysis built upon the previous chapters with multiple individual socioeconomic measurements and several additional potential explanatory factors collected as part of a more recent cohort study of people with head and neck cancer, including human papillomavirus (HPV) status. Results: As a whole, this thesis demonstrated strong and consistent socioeconomic inequalities in survival of people with head and neck cancer. These inequalities in survival of people with head and neck cancer appeared to become worse over calendar time and also across follow-up period after one year, five years, and ten years of a diagnosis of head and neck cancer (Chapter 2-Scottish Cancer Registry). Chapter 3 found that socioeconomic status was not an independent predictor of survival in a cohort of people with head and neck cancer who were diagnosed in Scotland between the years of 1999 and 2001(SAHNC), while Chapter 4 investigated the underlying factors that may explain the original inequality that was observed in overall survival, disease-specific survival, and net survival estimates(also the SAHNC). Chapter 4 highlighted that in models that were adjusted by various patient, tumour, and treatment factors, none of the factors could individually explain the socioeconomic inequality in survival alone, suggesting that socioeconomic inequality in survival of people with head and neck cancer is complex, with multiple factors having a combined effect, including background mortality in the long-term follow-up (via net survival estimates). The studies that were carried out in Chapter 2 to Chapter 4 only utilised area-based socioeconomic measurements -mainly Carstairs Deprivation Index. Chapter 5 added to this picture by exploring inequality by using both an area-based (Index of Multiple Deprivation (IMD)Category) and individual measurements of socioeconomic status including highest education level attained, number of years spent in education, annual household income, proportion of income from benefits, and financial concerns of living with or after cancer. Only data from England in the HN5000 cohort could be included in this analysis since it was not possible to pool and standardise the varying measurements of IMD (including Scottish IMD and Welsh IMD) across these countries of the UK. This study determined that inequalities were present for all of the measurements of socioeconomic status, however inequality in highest education level, number of years spent in education, and financial concerns of living with or after cancer were explained (fully attenuated) by other factors such as age and smoking status. Inequality across both annual household income and the proportion of income from benefits partly attenuated following the adjustment of all of the potential explanatory factors, however, even after full adjustment, the relationship with survival of these factors of socioeconomic status could not be fully explained by any of the potential patient, tumour, or treatment factors that were included in this study.

Background Epigenetic clocks are biomarkers of ageing derived from DNA methylation levels at a subset of CpG sites. The difference between age predicted by these clocks and chronological age, termed “epigenetic age acceleration”, has been shown to predict age-related disease and mortality. We aimed to assess the prognostic value of epigenetic age acceleration and a DNA methylation-based mortality risk score with all-cause mortality in a prospective clinical cohort of individuals with head and neck cancer: Head and Neck 5000. We investigated two markers of intrinsic epigenetic age acceleration ( IEAAHorvath and IEAAHannum ), one marker of extrinsic epigenetic age acceleration ( EEAA ), one optimised to predict physiological dysregulation ( AgeAccelPheno ), one optimised to predict lifespan ( AgeAccelGrim ) and a DNA methylation-based predictor of mortality ( ZhangScore ). Cox regression models were first used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for associations of epigenetic age acceleration with all-cause mortality in people with oropharyngeal cancer ( n  = 408; 105 deaths). The added prognostic value of epigenetic markers compared to a clinical model including age, sex, TNM stage and HPV status was then evaluated. Results IEAAHannum and AgeAccelGrim were associated with mortality risk after adjustment for clinical and lifestyle factors (HRs per standard deviation [SD] increase in age acceleration = 1.30 [95% CI 1.07, 1.57; p  = 0.007] and 1.40 [95% CI 1.06, 1.83; p  = 0.016], respectively). There was weak evidence that the addition of AgeAccelGrim to the clinical model improved 3-year mortality prediction (area under the receiver operating characteristic curve: 0.80 vs. 0.77; p value for difference = 0.069). Conclusion In the setting of a large, clinical cohort of individuals with head and neck cancer, our study demonstrates the potential of epigenetic markers of ageing to enhance survival prediction in people with oropharyngeal cancer, beyond established prognostic factors. Our findings have potential uses in both clinical and non-clinical contexts: to aid treatment planning and improve patient stratification.

BackgroundFURVA, 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.MethodsPostmenopausal 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.ResultsIn 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.ConclusionThe 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 registrationClinicalTrials.gov, NCT02530411.

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.

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.