Effects of PROtein enriched MEDiterranean Diet and EXercise on nutritional status and cognition in adults at risk of undernutrition and cognitive decline: the PROMED-EX Randomised Controlled Trial.

INTRODUCTION: Undernutrition leading to unplanned weight loss is common in older age and has been linked to increased dementia risk in later life. Weight loss can precede dementia by a decade or more, providing a unique opportunity for early intervention to correct undernutrition and potentially prevent or delay cognitive impairment. The combined effects of diet and exercise on undernutrition have not yet been evaluated. The objective of this trial is to determine the effect of a protein-enriched Mediterranean diet, with and without exercise, on nutritional status and cognitive performance in older adults at risk of undernutrition and cognitive decline. METHODS: One hundred and five participants aged 60 years and over at risk of undernutrition and with subjective cognitive decline will be recruited to participate in a 6-month, single-blind, parallel-group randomised controlled trial. Participants will be block randomised into one of three groups: group 1-PROMED-EX (diet+exercise), group 2-PROMED (diet only) and group 3-standard care (control). The primary outcome is nutritional status measured using the Mini Nutritional Assessment. Secondary outcomes include cognitive function, nutritional intake, body composition, physical function and quality of life. Mechanistic pathways for potential diet and exercise-induced change in nutritional status and cognition will be explored by measuring inflammatory, metabolic, nutritional and metabolomic biomarkers. ETHICS AND DISSEMINATION: The study is approved by the UK Office for Research Ethics Committee (ref: 21/NW/0215). Written informed consent will be obtained from participants prior to recruitment. Research results will be disseminated to the public via meetings and media and the scientific community through conference presentations and publication in academic journals. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT05166564).

Whole Dietary Patterns, Cognitive Decline and Cognitive Disorders: A Systematic Review of Prospective and Intervention Studies.

Dementia prevalence is a global public health concern. Adherence towards a healthy dietary pattern (DP) may reduce the risk of cognitive decline and dementia. This narrative systematic review aimed to synthesise prospective and intervention study data to evaluate the impact of a-posteriori and a-priori derived DPs on cognitive ageing, from cognitive decline to incident dementia. Ninety-three studies were included: 83 prospective studies and 10 randomised controlled trials (RCT). Most prospective studies (77%) examined a-priori DPs, with the Mediterranean diet examined most frequently. A total of 52% of prospective and 50% of RCTs reported a protective relationship between 'healthy' DPs and global cognitive decline. Overall, 59% of prospective studies reported positive associations between healthy DPs and risk of cognitive disorder. Incident cognitive disorder was examined by only one intervention study (subgroup analysis) which reported a beneficial effect of a low-fat diet on risk of probable dementia in women. Unhealthy DPs were examined less frequently (n = 17; 21%), with 41% of these studies reporting associations between adherence and poorer cognitive outcomes. Overall, there were mixed results for healthy and unhealthy DPs on cognition, likely due to between-study heterogeneity. Standardisation of diet exposure and cognitive outcome measurement would help to reduce this. Future research would benefit from investigating effects of culturally appropriate DPs on individual cognitive domains and incident cognitive disorders in diverse and high-risk populations.

PROtein enriched MEDiterranean diet to combat undernutrition and promote healthy neuroCOGnitive ageing in older adults: The PROMED-COG consortium project.

Dementia is a major public health challenge owing to its increasing prevalence and recognised impact on disability among older adults. Observational data indicate that weight loss is associated with increased dementia risk of 30%-40% and precedes a diagnosis of cognitive impairment or dementia by at least one decade. Although relatively little is known about the mechanisms of unintentional weight loss in dementia, this provides a window of opportunity to intervene with strategies to counteract undernutrition and delay, or prevent, the onset of dementia. This article provides an overview of the PROMED-COG project and associated work packages. The project aimes to (1) strengthen the epidemiologic evidence to better understand the potential benefits of combating undernutrition for healthy neurocognitive ageing; (2) increase scientific knowledge on the balance between a protein enriched Mediterranean diet (PROMED) and physical exercise to prevent undernutrition and promote healthy neurocognitive ageing, and generate data on mechanistic pathways; (3) stimulate collaboration and capacity building for nutrition and neurocognitive ageing research in Europe; and (4) develop public and practice recommendations to combat undernutrition and promote healthy neurocognitive ageing in older adults. Findings will provide new and critical insights into the role of undernutrition in neurocognitive ageing, how this role can differ by sex, genetic risk and timing of undernutrition exposure, and how modifications of dietary and physical activity behaviour can reduce the burden of undernutrition and neurodegeneration. The research outcomes will be useful to inform policy and practice about the dietary guidelines of older people and provide insight to industry for the development of food-based solutions to prevent undernutrition.

Associations Between Dietary Patterns and Neuroimaging Markers: A Systematic Review.

Dementia is a complex, growing challenge for population health worldwide. Dietary patterns (DPs) may offer an opportunity to beneficially influence cognitive ageing and potentially reduce an individuals' risk of dementia through diet-related mechanisms. However, previous studies within this area have shown mixed results, which may be partly explained by the lack of sensitivity and accuracy within cognitive testing methods. Novel neuroimaging techniques provide a sensitive method to analyse brain changes preceding cognitive impairment which may have previously remained undetected. The purpose of this systematic review was to elucidate the role of DPs in relation to brain ageing processes, by summarising current prospective and intervention studies. Nine prospective studies met the inclusion criteria for the review, seven evaluated the Mediterranean diet (MeDi), one evaluated the Alternative Healthy Eating Index-2010, and one evaluated a posteriori derived DPs. No intervention studies were eligible for inclusion in this review. There was some evidence of an association between healthy DPs and neuroimaging markers including changes within these markers over time. Consequently, it is plausible that better adherence to such DPs may positively influence brain ageing and neurodegeneration. Future studies may benefit from the use of multi-modal neuroimaging techniques, to further investigate how adherence to a DP influences brain health. The review also highlights the crucial need for further intervention studies within this research area.

The feasibility of a peer support intervention to encourage adoption and maintenance of a Mediterranean diet in established community groups at increased CVD risk: the TEAM-MED EXTEND study: a pilot cluster randomised controlled trial.

This study aimed to evaluate the feasibility of a peer support intervention to encourage adoption and maintenance of a Mediterranean diet (MD) in established community groups where existing social support may assist the behaviour change process. Four established community groups with members at increased Cardiovascular Disease (CVD) risk and homogenous in gender were recruited and randomised to receive either a 12-month Peer Support (PS) intervention (PSG) (n 2) or a Minimal Support intervention (educational materials only) (MSG) (n 2). The feasibility of the intervention was assessed using recruitment and retention rates, assessing the variability of outcome measures (primary outcome: adoption of an MD at 6 months (using a Mediterranean Diet Score (MDS)) and process evaluation measures including qualitative interviews. Recruitment rates for community groups (n 4/8), participants (n 31/51) and peer supporters (n 6/14) were 50 %, 61 % and 43 %, respectively. The recruitment strategy faced several challenges with recruitment and retention of participants, leading to a smaller sample than intended. At 12 months, a 65 % and 76·5 % retention rate for PSG and MSG participants was observed, respectively. A > 2-point increase in MDS was observed in both the PSG and the MSG at 6 months, maintained at 12 months. An increase in MD adherence was evident in both groups during follow-up; however, the challenges faced in recruitment and retention suggest a definitive study of the peer support intervention using current methods is not feasible and refinement based on the current feasibility study should be incorporated. Lessons learned during the implementation of this intervention will help inform future interventions in this area.

Network methods to support user involvement in qualitative data analyses: an introduction to Participatory Theme Elicitation.

BACKGROUND: While Patient and Public Involvement (PPI) is encouraged throughout the research process, engagement is typically limited to intervention design and post-analysis stages. There are few approaches to participatory data analyses within complex health interventions. METHODS: Using qualitative data from a feasibility randomised controlled trial (RCT), this proof-of-concept study tests the value of a new approach to participatory data analysis called Participatory Theme Elicitation (PTE). Forty excerpts were given to eight members of a youth advisory PPI panel to sort into piles based on their perception of related thematic content. Using algorithms to detect communities in networks, excerpts were then assigned to a thematic cluster that combined the panel members' perspectives. Network analysis techniques were also used to identify key excerpts in each grouping that were then further explored qualitatively. RESULTS: While PTE analysis was, for the most part, consistent with the researcher-led analysis, young people also identified new emerging thematic content. CONCLUSIONS: PTE appears promising for encouraging user led identification of themes arising from qualitative data collected during complex interventions. Further work is required to validate and extend this method. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02455986 . Retrospectively Registered on 21 May 2015.

Statin use, candidate mevalonate pathway biomarkers, and colon cancer survival in a population-based cohort study.

BACKGROUND: Statin use after colorectal cancer diagnosis may improve survival but evidence from observational studies is conflicting. The anti-cancer effect of statins may be restricted to certain molecular subgroups. In this population-based cohort study, the interaction between p53 and 3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMGCR) expression, KRAS mutations, and the association between statin use and colon cancer survival was assessed. METHODS: The cohort consisted of 740 stage II and III colon cancer patients diagnosed between 2004 and 2008. Statin use was determined through clinical note review. Tissue blocks were retrieved to determine immunohistochemical expression of p53 and HMGCR in tissue microarrays and the presence of KRAS mutations in extracted DNA. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for colorectal cancer-specific and overall survival. RESULTS: Statin use was not associated with improved cancer-specific survival in this cohort (HR=0.91, 95% CI 0.64-1.28). Statin use was also not associated with improved survival when the analyses were stratified by tumour p53 (wild-type HR=1.31, 95% CI 0.67-2.56 vs aberrant HR=0.80, 95% CI 0.52-1.24), HMGCR (HMGCR-high HR=0.69, 95% CI 0.40-1.18 vs HMGCR-low HR=1.10, 95% CI 0.66-1.84), and KRAS (wild-type HR=0.73, 95% CI 0.44-1.19 vs mutant HR=1.21, 95% CI 0.70-2.21) status. CONCLUSIONS: Statin use was not associated with improved survival either independently or when stratified by potential mevalonate pathway biomarkers in this population-based cohort of colon cancer patients.

Evaluation of PTGS2 Expression, PIK3CA Mutation, Aspirin Use and Colon Cancer Survival in a Population-Based Cohort Study.

OBJECTIVES: The association between aspirin use and improved survival after colorectal cancer diagnosis may be more pronounced in tumors that have PIK3CA mutations or high PTGS2 expression. However, the evidence of a difference in association by biomarker status lacks consistency. In this population-based colon cancer cohort study the interaction between these biomarkers, aspirin use, and survival was assessed. METHODS: The cohort consisted of 740 stage II and III colon cancer patients diagnosed between 2004 and 2008. Aspirin use was determined through clinical note review. Tissue blocks were retrieved to determine immunohistochemical assessment of PTGS2 expression and the presence of PIK3CA mutations. Cox proportional hazards models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for colorectal cancer-specific and overall survival. RESULTS: In this cohort aspirin use was associated with a 31% improvement in cancer-specific survival compared to non-use (adjusted HR=0.69, 95% CI 0.47-0.98). This effect was more pronounced in tumors with high PTGS2 expression (PTGS2-high adjusted HR=0.55, 95% CI 0.32-0.96) compared to those with low PTGS2 expression (PTGS2-low adjusted HR=1.19, 95% CI 0.68-2.07, P for interaction=0.09). The aspirin by PTGS2 interaction was significant for overall survival (PTGS2-high adjusted HR=0.64, 95% CI 0.42-0.98 vs. PTGS2-low adjusted HR=1.28, 95% CI 0.80-2.03, P for interaction=0.04). However, no interaction was observed between aspirin use and PIK3CA mutation status for colorectal cancer-specific or overall survival. CONCLUSIONS: Aspirin use was associated with improved survival outcomes in this population-based cohort of colon cancer patients. This association differed according to PTGS2 expression but not PIK3CA mutation status. Limiting adjuvant aspirin trials to PIK3CA-mutant colorectal cancer may be too restrictive.

Back to the future: routine morphological assessment of the tumour microenvironment is prognostic in stage II/III colon cancer in a large population-based study.

AIMS: Both morphological and molecular approaches have highlighted the biological and prognostic importance of the tumour microenvironment in colorectal cancer (CRC). Despite this, microscopic assessment of the tumour microenvironment has not been adopted into routine practice. The study aim was to identify those tumour microenvironmental features that are most likely to provide prognostic information and be feasible to use in routine pathology reporting practice. METHODS AND RESULTS: On the basis of existing evidence, we selected specific morphological features relating to peritumoral inflammatory and stromal responses, agreed criteria for scoring, and assessed these in representative haematoxylin and eosin (H&E)-stained whole tumour sections from a population-based cohort of 445 stage II/III colon cancer cases. Moderate/severe peritumoral diffuse lymphoid inflammation and Crohn's disease-like reaction were associated with significantly reduced risks of CRC-specific death [adjusted hazard ratio (HR) 0.48, 95% confidence interval (CI) 0.31-0.76, and HR 0.60, 95% CI 0.42-0.84, respectively]. The presence of >50% tumour stromal percentage, as assessed by global evaluation of tumour area, was associated with a significantly increased risk of CRC-specific death (HR 1.60 95% CI 1.06-2.41). A composite 'fibroinflammatory score' (0-3), combining dichotomized scores of these three features, showed a highly significant association with survival outcomes. Those with a score of ≥2 had an almost 2.5-fold increased risk of CRC-specific death (HR 2.44, 95% CI 1.56-3.81) as compared with those scoring zero. These associations were stronger in microsatellite instability (MSI)-high tumours, potentially identifying a subset of MSI-high colon cancers that lack characteristic morphological features and have an associated worse prognosis. CONCLUSIONS: In summary, reporting on H&E staining of selected microscopic features of the tumour microenvironment, independently or in combination, offers valuable prognostic information in stage II/III colon cancer, and may allow morphological correlation with developing molecular classifications of prognostic and predictive relevance.

Non-pharmacological interventions for cognitive impairment due to systemic cancer treatment.

BACKGROUND: It is estimated that up to 75% of cancer survivors may experience cognitive impairment as a result of cancer treatment and given the increasing size of the cancer survivor population, the number of affected people is set to rise considerably in coming years. There is a need, therefore, to identify effective, non-pharmacological interventions for maintaining cognitive function or ameliorating cognitive impairment among people with a previous cancer diagnosis. OBJECTIVES: To evaluate the cognitive effects, non-cognitive effects, duration and safety of non-pharmacological interventions among cancer patients targeted at maintaining cognitive function or ameliorating cognitive impairment as a result of cancer or receipt of systemic cancer treatment (i.e. chemotherapy or hormonal therapies in isolation or combination with other treatments). SEARCH METHODS: We searched the Cochrane Centre Register of Controlled Trials (CENTRAL), MEDLINE, Embase, PUBMED, Cumulative Index of Nursing and Allied Health Literature (CINAHL) and PsycINFO databases. We also searched registries of ongoing trials and grey literature including theses, dissertations and conference proceedings. Searches were conducted for articles published from 1980 to 29 September 2015. SELECTION CRITERIA: Randomised controlled trials (RCTs) of non-pharmacological interventions to improve cognitive impairment or to maintain cognitive functioning among survivors of adult-onset cancers who have completed systemic cancer therapy (in isolation or combination with other treatments) were eligible. Studies among individuals continuing to receive hormonal therapy were included. We excluded interventions targeted at cancer survivors with central nervous system (CNS) tumours or metastases, non-melanoma skin cancer or those who had received cranial radiation or, were from nursing or care home settings. Language restrictions were not applied. DATA COLLECTION AND ANALYSIS: Author pairs independently screened, selected, extracted data and rated the risk of bias of studies. We were unable to conduct planned meta-analyses due to heterogeneity in the type of interventions and outcomes, with the exception of compensatory strategy training interventions for which we pooled data for mental and physical well-being outcomes. We report a narrative synthesis of intervention effectiveness for other outcomes. MAIN RESULTS: Five RCTs describing six interventions (comprising a total of 235 participants) met the eligibility criteria for the review. Two trials of computer-assisted cognitive training interventions (n = 100), two of compensatory strategy training interventions (n = 95), one of meditation (n = 47) and one of physical activity intervention (n = 19) were identified. Each study focused on breast cancer survivors. All five studies were rated as having a high risk of bias. Data for our primary outcome of interest, cognitive function were not amenable to being pooled statistically. Cognitive training demonstrated beneficial effects on objectively assessed cognitive function (including processing speed, executive functions, cognitive flexibility, language, delayed- and immediate- memory), subjectively reported cognitive function and mental well-being. Compensatory strategy training demonstrated improvements on objectively assessed delayed-, immediate- and verbal-memory, self-reported cognitive function and spiritual quality of life (QoL). The meta-analyses of two RCTs (95 participants) did not show a beneficial effect from compensatory strategy training on physical well-being immediately (standardised mean difference (SMD) 0.12, 95% confidence interval (CI) -0.59 to 0.83; I(2)= 67%) or two months post-intervention (SMD - 0.21, 95% CI -0.89 to 0.47; I(2) = 63%) or on mental well-being two months post-intervention (SMD -0.38, 95% CI -1.10 to 0.34; I(2) = 67%). Lower mental well-being immediately post-intervention appeared to be observed in patients who received compensatory strategy training compared to wait-list controls (SMD -0.57, 95% CI -0.98 to -0.16; I(2) = 0%). We assessed the assembled studies using GRADE for physical and mental health outcomes and this evidence was rated to be low quality and, therefore findings should be interpreted with caution. Evidence for physical activity and meditation interventions on cognitive outcomes is unclear. AUTHORS' CONCLUSIONS: Overall, the, albeit low-quality evidence may be interpreted to suggest that non-pharmacological interventions may have the potential to reduce the risk of, or ameliorate, cognitive impairment following systemic cancer treatment. Larger, multi-site studies including an appropriate, active attentional control group, as well as consideration of functional outcomes (e.g. activities of daily living) are required in order to come to firmer conclusions about the benefits or otherwise of this intervention approach. There is also a need to conduct research into cognitive impairment among cancer patient groups other than women with breast cancer.

A randomised controlled trial to evaluate the efficacy of a 6-month dietary and physical activity intervention for patients receiving androgen deprivation therapy for prostate cancer.

PURPOSE: Treatment of prostate cancer with androgen deprivation therapy (ADT) is associated with an increased fat mass, decreased lean mass, increased fatigue and a reduction in quality of life (QoL). The aim of this study was to evaluate the efficacy of a 6-month dietary and physical activity intervention for prostate cancer patients receiving ADT, to help minimise these side effects. METHODS: Patients (n = 94) were recruited to this study if they were planned to receive ADT for prostate cancer for at least 6 months. Men randomised to the intervention arm received a dietary and exercise intervention, commensurate with UK healthy eating and physical activity recommendations. The primary outcome of interest was body composition; secondary outcomes included fatigue, QoL, functional capacity, stress and dietary change. RESULTS: The intervention group had a significant (p < 0.001) reduction in weight, body mass index and percentage fat mass compared to the control group at 6 months; the between-group differences were -3.3 kg (95% confidence interval (95% CI) -4.5, -2.1), -1.1 kg/m(2) (95% CI -1.5, -0.7) and -2.1% (95% CI -2.8, -1.4), respectively, after adjustment for baseline values. The intervention resulted in improvements in functional capacity (p < 0.001) and dietary intakes but did not significantly impact fatigue, QoL or stress scores at endpoint. CONCLUSIONS: A 6-month diet and physical activity intervention can minimise the adverse body composition changes associated with ADT. IMPLICATIONS FOR CANCER SURVIVORS: This study shows that a pragmatic lifestyle intervention is feasible and can have a positive impact on health behaviours and other key outcomes in men with prostate cancer receiving ADT.

A randomised controlled trial to evaluate the efficacy of a 6 month dietary and physical activity intervention for prostate cancer patients receiving androgen deprivation therapy.

BACKGROUND: Treatment with Androgen Deprivation Therapy (ADT) for prostate cancer is associated with changes in body composition including increased fat and decreased lean mass; increased fatigue, and a reduction in quality of life. No study to date has evaluated the effect of dietary and physical activity modification on the side-effects related to ADT. The aim of this study is to evaluate the efficacy of a 6-month dietary and physical activity intervention for prostate cancer survivors receiving ADT to minimise the changes in body composition, fatigue and quality of life, typically associated with ADT. METHODS: Men are recruited to this study if their treatment plan is to receive ADT for at least 6 months. Men who are randomised to the intervention arm receive a home-based tailored intervention to meet the following guidelines a) > or = 5 servings vegetables and fruits/day; b) 30%-35% of total energy from fat, and < 10% energy from saturated fat/day; c) 10% of energy from polyunsaturated fat/day; d) limited consumption of processed meats; e) 25-35 gm of fibre/day; f) alcoholic drinks < or = 28 units/week; g) limited intake of foods high in salt and/or sugar. They are also encouraged to include at least 30 minutes of brisk walking, 5 or more days per week. The primary outcomes are change in body composition, fatigue and quality of life scores. Secondary outcomes include dietary intake, physical activity and perceived stress. Baseline information collected includes: socio-economic status, treatment duration, perceived social support and health status, family history of cancer, co-morbidities, medication and supplement use, barriers to change, and readiness to change their health behaviour. Data for the primary and secondary outcomes will be collected at baseline, 3 and 6 months from 47 intervention and 47 control patients. DISCUSSION: The results of this study will provide detailed information on diet and physical activity levels in prostate cancer patients treated with ADT and will test the feasibility and efficacy of a diet and physical activity intervention which could provide essential information to develop guidelines for prostate cancer patients to minimise the side effects related to ADT. TRIAL REGISTRATION: ISRCTN trial number ISCRTN75282423.