Association of body shape phenotypes and body fat distribution indexes with inflammatory biomarkers in the European Prospective Investigation into Cancer and Nutrition (EPIC) and UK Biobank.

BACKGROUND: The allometric body shape index (ABSI) and hip index (HI), as well as multi-trait body shape phenotypes, have not yet been compared in their associations with inflammatory markers. The aim of this study was to examine the relationship between novel and traditional anthropometric indexes with inflammation using data from the European Prospective Investigation into Cancer and Nutrition (EPIC) and UK Biobank cohorts. METHODS: Participants from EPIC (n = 17,943, 69.1% women) and UK Biobank (n = 426,223, 53.2% women) with data on anthropometric indexes and C-reactive protein (CRP) were included in this cross-sectional analysis. A subset of women in EPIC also had at least one measurement for interleukins, tumour necrosis factor alpha, interferon gamma, leptin, and adiponectin. Four distinct body shape phenotypes were derived by a principal component (PC) analysis on height, weight, body mass index (BMI), waist (WC) and hip circumferences (HC), and waist-to-hip ratio (WHR). PC1 described overall adiposity, PC2 tall with low WHR, PC3 tall and centrally obese, and PC4 high BMI and weight with low WC and HC, suggesting an athletic phenotype. ABSI, HI, waist-to-height ratio and waist-to-hip index (WHI) were also calculated. Linear regression models were carried out separately in EPIC and UK Biobank stratified by sex and adjusted for age, smoking status, education, and physical activity. Results were additionally combined in a random-effects meta-analysis. RESULTS: Traditional anthropometric indexes, particularly BMI, WC, and weight were positively associated with CRP levels, in men and women. Body shape phenotypes also showed distinct associations with CRP. Specifically, PC2 showed inverse associations with CRP in EPIC and UK Biobank in both sexes, similarly to height. PC3 was inversely associated with CRP among women, whereas positive associations were observed among men. CONCLUSIONS: Specific indexes of body size and body fat distribution showed differential associations with inflammation in adults. Notably, our results suggest that in women, height may mitigate the impact of a higher WC and HC on inflammation. This suggests that subtypes of adiposity exhibit substantial variation in their inflammatory potential, which may have implications for inflammation-related chronic diseases.

Circulating free insulin-like growth factor-I and prostate cancer: a case-control study nested in the European prospective investigation into cancer and nutrition.

BACKGROUND: Circulating total insulin-like growth factor-I (IGF-I) is an established risk factor for prostate cancer. However, only a small proportion of circulating IGF-I is free or readily dissociable from IGF-binding proteins (its bioavailable form), and few studies have investigated the association of circulating free IGF-I with prostate cancer risk. METHODS: We analyzed data from 767 prostate cancer cases and 767 matched controls nested within the European Prospective Investigation into Cancer and Nutrition cohort, with an average of 14-years (interquartile range = 2.9) follow-up. Matching variables were study center, length of follow-up, age, and time of day and fasting duration at blood collection. Circulating free IGF-I concentration was measured in serum samples collected at recruitment visit (mean age 55 years old; standard deviation = 7.1) using an enzyme-linked immunosorbent assay (ELISA). Conditional logistic regressions were performed to examine the associations of free IGF-I with risk of prostate cancer overall and subdivided by time to diagnosis (≤ 14 and > 14 years), and tumor characteristics. RESULTS: Circulating free IGF-I concentrations (in fourths and as a continuous variable) were not associated with prostate cancer risk overall (odds ratio [OR] = 1.00 per 0.1 nmol/L increment, 95% CI: 0.99, 1.02) or by time to diagnosis, or with prostate cancer subtypes, including tumor stage and histological grade. CONCLUSIONS: Estimated circulating free IGF-I was not associated with prostate cancer risk. Further research may consider other assay methods that estimate bioavailable IGF-I to provide more insight into the well-substantiated association between circulating total IGF-I and subsequent prostate cancer risk.

Prediagnostic serum glyceraldehyde-derived advanced glycation end products and mortality among colorectal cancer patients.

Glyceraldehyde-derived advanced glycation end products (glycer-AGEs) could contribute to colorectal cancer development and progression due to their pro-oxidative and pro-inflammatory properties. However, the association of glycer-AGEs with mortality after colorectal cancer diagnosis has not been previously investigated. Circulating glycer-AGEs were measured by competitive ELISA. Multivariable Cox proportional hazards models were used to calculate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for associations of circulating glycer-AGEs concentrations with CRC-specific and all-cause mortality among 1034 colorectal cancer (CRC) cases identified within the European Prospective Investigation into Cancer and Nutrition (EPIC) study between 1993 and 2013. During a mean of 48 months of follow-up, 529 participants died (409 from CRC). Glycer-AGEs were statistically significantly positively associated with CRC-specific (HRQ5 vs Q1  = 1.53, 95% CI: 1.04-2.25, Ptrend  = .002) and all-cause (HRQ5 vs Q1  = 1.62, 95% CI: 1.16-2.26, Ptrend  < .001) mortality among individuals with CRC. There was suggestion of a stronger association between glycer-AGEs and CRC-specific mortality among patients with distal colon cancer (per SD increment: HRproximal colon  = 1.02, 95% CI: 0.74-1.42; HRdistal colon  = 1.51, 95% CI: 1.20-1.91; Peffect modification  = .02). The highest HR was observed among CRC cases in the highest body mass index (BMI) and glycer-AGEs category relative to lowest BMI and glycer-AGEs category for both CRC-specific (HR = 1.78, 95% CI: 1.02-3.01) and all-cause mortality (HR = 2.15, 95% CI: 1.33-3.47), although no statistically significant effect modification was observed. Our study found that prediagnostic circulating glycer-AGEs are positively associated with CRC-specific and all-cause mortality among individuals with CRC. Further investigations in other populations and stratifying by tumor location and BMI are warranted.

A nutritional biomarker score of the Mediterranean diet and incident type 2 diabetes: Integrated analysis of data from the MedLey randomised controlled trial and the EPIC-InterAct case-cohort study.

BACKGROUND: Self-reported adherence to the Mediterranean diet has been modestly inversely associated with incidence of type 2 diabetes (T2D) in cohort studies. There is uncertainty about the validity and magnitude of this association due to subjective reporting of diet. The association has not been evaluated using an objectively measured biomarker of the Mediterranean diet. METHODS AND FINDINGS: We derived a biomarker score based on 5 circulating carotenoids and 24 fatty acids that discriminated between the Mediterranean or habitual diet arms of a parallel design, 6-month partial-feeding randomised controlled trial (RCT) conducted between 2013 and 2014, the MedLey trial (128 participants out of 166 randomised). We applied this biomarker score in an observational study, the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study, to assess the association of the score with T2D incidence over an average of 9.7 years of follow-up since the baseline (1991 to 1998). We included 22,202 participants, of whom 9,453 were T2D cases, with relevant biomarkers from an original case-cohort of 27,779 participants sampled from a cohort of 340,234 people. As a secondary measure of the Mediterranean diet, we used a score estimated from dietary-self report. Within the trial, the biomarker score discriminated well between the 2 arms; the cross-validated C-statistic was 0.88 (95% confidence interval (CI) 0.82 to 0.94). The score was inversely associated with incident T2D in EPIC-InterAct: the hazard ratio (HR) per standard deviation of the score was 0.71 (95% CI: 0.65 to 0.77) following adjustment for sociodemographic, lifestyle and medical factors, and adiposity. In comparison, the HR per standard deviation of the self-reported Mediterranean diet was 0.90 (95% CI: 0.86 to 0.95). Assuming the score was causally associated with T2D, higher adherence to the Mediterranean diet in Western European adults by 10 percentiles of the score was estimated to reduce the incidence of T2D by 11% (95% CI: 7% to 14%). The study limitations included potential measurement error in nutritional biomarkers, unclear specificity of the biomarker score to the Mediterranean diet, and possible residual confounding. CONCLUSIONS: These findings suggest that objectively assessed adherence to the Mediterranean diet is associated with lower risk of T2D and that even modestly higher adherence may have the potential to reduce the population burden of T2D meaningfully. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12613000602729 https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=363860.

Food Processing and Risk of Crohn's Disease and Ulcerative Colitis: A European Prospective Cohort Study.

BACKGROUND & AIMS: Industrial foods have been associated with increased risks of several chronic conditions. We investigated the relationship between the degree of food processing and risks of Crohn's disease (CD) and ulcerative colitis (UC) in the European Prospective Investigation into Cancer and Nutrition cohort. METHODS: Analyses included 413,590 participants (68.6% women; mean baseline age, 51.7 y) from 8 European countries. Dietary data were collected at baseline from validated country-specific dietary questionnaires. Associations between proportions of unprocessed/minimally processed and ultraprocessed food intake and CD and UC risks were estimated using Cox models to obtain hazard ratios (HRs) and 95% CIs. Models were stratified by center, age, and sex, and adjusted for smoking status, body mass index, physical activity, energy intake, educational level, and alcohol consumption. RESULTS: During a mean follow-up period of 13.2 years, 179 incident cases of CD and 431 incident cases of UC were identified. The risk of CD was lower in people consuming high proportions of unprocessed/minimally processed foods (adjusted HR for the highest vs lowest quartile: 0.57; 95% CI, 0.35-0.93; P trend < .01), particularly fruits and vegetables (adjusted HRs, 0.54; 95% CI, 0.34-0.87 and 0.55; 95% CI, 0.34-0.91, respectively). There was no association between unprocessed/minimally processed food intake and the risk of UC. No association was detected between ultraprocessed food consumption and CD or UC risks. CONCLUSIONS: In the European Prospective Investigation into Cancer and Nutrition cohort, consumption of unprocessed/minimally processed foods was associated with a lower risk of CD. No association between UC risk and food processing was found.

The association between body fatness and mortality among breast cancer survivors: results from a prospective cohort study.

Evidence linking body fatness to breast cancer (BC) prognosis is limited. While it seems that excess adiposity is associated with poorer BC survival, there is uncertainty over whether weight changes reduce mortality. This study aimed to assess the association between body fatness and weight changes pre- and postdiagnosis and overall mortality and BC-specific mortality among BC survivors. Our study included 13,624 BC survivors from the European Prospective Investigation into Cancer and Nutrition (EPIC) study, with a mean follow-up of 8.6 years after diagnosis. Anthropometric data were obtained at recruitment for all cases and at a second assessment during follow-up for a subsample. We measured general obesity using the body mass index (BMI), whereas waist circumference and A Body Shape Index were used as measures of abdominal obesity. The annual weight change was calculated for cases with two weight assessments. The association with overall mortality and BC-specific mortality were based on a multivariable Cox and Fine and Gray models, respectively. We performed Mendelian randomization (MR) analysis to investigate the potential causal association. Five-unit higher BMI prediagnosis was associated with a 10% (95% confidence interval: 5-15%) increase in overall mortality and 7% (0-15%) increase in dying from BC. Women with abdominal obesity demonstrated a 23% (11-37%) increase in overall mortality, independent of the association of BMI. Results related to weight change postdiagnosis suggested a U-shaped relationship with BC-specific mortality, with higher risk associated with losing weight or gaining > 2% of the weight annually. MR analyses were consistent with the identified associations. Our results support the detrimental association of excess body fatness on the survival of women with BC. Substantial weight changes postdiagnosis may be associated with poorer survival.

A longitudinal evaluation of alcohol intake throughout adulthood and colorectal cancer risk.

BACKGROUND: Alcohol intake is an established risk factor for colorectal cancer (CRC); however, there is limited knowledge on whether changing alcohol drinking habits during adulthood modifies CRC risk. OBJECTIVE: Leveraging longitudinal exposure assessments on alcohol intake at different ages, we examined the relationship between change in alcohol intake and subsequent CRC risk. METHODS: Within the European Prospective Investigation into Cancer and Nutrition, changes in alcohol intake comparing follow-up with baseline assessments were investigated in relation to CRC risk. The analysis included 191,180, participants and 1530 incident CRC cases, with exclusion of the first three years of follow-up to minimize reverse causation. Trajectory profiles of alcohol intake, assessed at ages 20, 30, 40, 50 years, at baseline and during follow-up, were estimated using latent class mixed models and related to CRC risk, including 407,605 participants and 5,008 incident CRC cases. RESULTS: Mean age at baseline was 50.2 years and the follow-up assessment occurred on average 7.1 years later. Compared to stable intake, a 12 g/day increase in alcohol intake during follow-up was positively associated with CRC risk (HR = 1.15, 95%CI 1.04, 1.25), while a 12 g/day reduction was inversely associated with CRC risk (HR = 0.86, 95%CI 0.78, 0.95). Trajectory analysis showed that compared to low alcohol intake, men who increased their alcohol intake from early- to mid- and late-adulthood by up to 30 g/day on average had significantly increased CRC risk (HR = 1.24; 95%CI 1.08, 1.42), while no associations were observed in women. Results were consistent by anatomical subsite. CONCLUSIONS: Increasing alcohol intake during mid-to-late adulthood raised CRC risk, while reduction lowered risk.

Plasma concentrations of advanced glycation end-products and colorectal cancer risk in the EPIC study.

Advanced glycation end-products (AGEs) are a heterogeneous group of compounds formed by the non-enzymatic reaction between amino acids and reducing sugars, or dicarbonyls as intermediate compounds. Experimental studies suggest that AGEs may promote colorectal cancer, but prospective epidemiologic studies are inconclusive. We conducted a case-control study nested within a large European cohort. Plasma concentrations of three protein-bound AGEs-Nε-(carboxy-methyl)lysine (CML), Nε-(carboxy-ethyl)lysine (CEL) and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1)-were measured by ultra-performance liquid chromatography-tandem mass spectrometry in baseline samples collected from 1378 incident primary colorectal cancer cases and 1378 matched controls. Multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were computed using conditional logistic regression for colorectal cancer risk associated with CML, CEL, MG-H1, total AGEs, and [CEL+MG-H1: CML] and [CEL:MG-H1] ratios. Inverse colorectal cancer risk associations were observed for CML (OR comparing highest to lowest quintile, ORQ5 versus Q1 = 0.40, 95% CI: 0.27-0.59), MG-H1 (ORQ5 versus Q1 = 0.73, 95% CI: 0.53-1.00) and total AGEs (OR Q5 versus Q1 = 0.52, 95% CI: 0.37-0.73), whereas no association was observed for CEL. A higher [CEL+MG-H1: CML] ratio was associated with colorectal cancer risk (ORQ5 versus Q1 = 1.91, 95% CI: 1.31-2.79). The associations observed did not differ by sex, or by tumour anatomical sub-site. Although individual AGEs concentrations appear to be inversely associated with colorectal cancer risk, a higher ratio of methylglyoxal-derived AGEs versus those derived from glyoxal (calculated by [CEL+MG-H1: CML] ratio) showed a strong positive risk association. Further insight on the metabolism of AGEs and their dicarbonyls precursors, and their roles in colorectal cancer development is needed.

Circulating tryptophan metabolites and risk of colon cancer: Results from case-control and prospective cohort studies.

Dysregulation of tryptophan metabolism has been linked to colorectal tumorigenesis; however, epidemiological studies investigating tryptophan metabolites in relation to colorectal cancer risk are limited. We studied associations of plasma tryptophan, serotonin and kynurenine with colon cancer risk in two studies with cancer patients and controls, and in one prospective cohort: ColoCare Study (110 patients/153 controls), the Colorectal Cancer Study of Austria (CORSA; 46 patients/390 controls) and the European Prospective Investigation into Cancer and Nutrition (EPIC; 456 matched case-control pairs). Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for colon cancer risk. Tryptophan was inversely associated with colon cancer risk in ColoCare (OR per 1-SD = 0.44; 95% CI, 0.31-0.64) and EPIC (OR per 1-SD = 0.86; 95% CI, 0.74-0.99). Comparing detectable vs nondetectable levels, serotonin was positively associated with colon cancer in CORSA (OR = 6.39; 95% CI, 3.61-11.3) and EPIC (OR = 2.03; 95% CI, 1.20-3.40). Kynurenine was inversely associated with colon cancer in ColoCare (OR per 1-SD = 0.74; 95% CI, 0.55-0.98), positively associated in CORSA (OR per 1-SD = 1.79; 95% CI, 1.27-2.52), while no association was observed in EPIC. The kynurenine-to-tryptophan ratio was positively associated with colon cancer in ColoCare (OR per 1-SD = 1.38; 95% CI, 1.03-1.84) and CORSA (OR per 1-SD = 1.44; 95% CI, 1.06-1.96), but not in EPIC. These results suggest that higher plasma tryptophan may be associated with lower colon cancer risk, while increased serotonin may be associated with a higher risk of colon cancer. The kynurenine-to-tryptophan ratio may also reflect altered tryptophan catabolism during colon cancer development.

Lifestyle correlates of eight breast cancer-related metabolites: a cross-sectional study within the EPIC cohort.

BACKGROUND: Metabolomics is a promising molecular tool for identifying novel etiological pathways leading to cancer. In an earlier prospective study among pre- and postmenopausal women not using exogenous hormones, we observed a higher risk of breast cancer associated with higher blood concentrations of one metabolite (acetylcarnitine) and a lower risk associated with higher blood concentrations of seven others (arginine, asparagine, phosphatidylcholines (PCs) aa C36:3, ae C34:2, ae C36:2, ae C36:3, and ae C38:2). METHODS: To identify determinants of these breast cancer-related metabolites, we conducted a cross-sectional analysis to identify their lifestyle and anthropometric correlates in 2358 women, who were previously included as controls in case-control studies nested within the European Prospective Investigation into Cancer and Nutrition cohort and not using exogenous hormones at blood collection. Associations of each metabolite concentration with 42 variables were assessed using linear regression models in a discovery set of 1572 participants. Significant associations were evaluated in a validation set (n = 786). RESULTS: For the metabolites previously associated with a lower risk of breast cancer, concentrations of PCs ae C34:2, C36:2, C36:3, and C38:2 were negatively associated with adiposity and positively associated with total and saturated fat intakes. PC ae C36:2 was also negatively associated with alcohol consumption and positively associated with two scores reflecting adherence to a healthy lifestyle. Asparagine concentration was negatively associated with adiposity. Arginine and PC aa C36:3 concentrations were not associated to any of the factors examined. For the metabolite previously associated with a higher risk of breast cancer, acetylcarnitine, a positive association with age was observed. CONCLUSIONS: These associations may indicate possible mechanisms underlying associations between lifestyle and anthropometric factors, and risk of breast cancer. Further research is needed to identify potential non-lifestyle correlates of the metabolites investigated.

Prospective analysis of circulating metabolites and endometrial cancer risk.

BACKGROUND: Endometrial cancer is strongly associated with obesity and dysregulation of metabolic factors such as estrogen and insulin signaling are causal risk factors for this malignancy. To identify additional novel metabolic pathways associated with endometrial cancer we performed metabolomic analyses on pre-diagnostic plasma samples from 853 case-control pairs from the European Prospective Investigation into Cancer and Nutrition (EPIC). METHODS: A total of 129 metabolites (acylcarnitines, amino acids, biogenic amines, glycerophospholipids, hexoses, and sphingolipids) were measured by liquid chromatography-mass spectrometry. Conditional logistic regression estimated the associations of metabolites with endometrial cancer risk. An analysis focusing on clusters of metabolites using the bootstrap lasso method was also employed. RESULTS: After adjustment for body mass index, sphingomyelin [SM] C18:0 was positively (OR1SD: 1.18, 95% CI: 1.05-1.33), and glycine, serine, and free carnitine (C0) were inversely (OR1SD: 0.89, 95% CI: 0.80-0.99; OR1SD: 0.89, 95% CI: 0.79-1.00 and OR1SD: 0.91, 95% CI: 0.81-1.00, respectively) associated with endometrial cancer risk. Serine, C0 and two sphingomyelins were selected by the lasso method in >90% of the bootstrap samples. The ratio of esterified to free carnitine (OR1SD: 1.14, 95% CI: 1.02-1.28) and that of short chain to free acylcarnitines (OR1SD: 1.12, 95% CI: 1.00-1.25) were positively associated with endometrial cancer risk. Further adjustment for C-peptide or other endometrial cancer risk factors only minimally altered the results. CONCLUSION: These findings suggest that variation in levels of glycine, serine, SM C18:0 and free carnitine may represent specific pathways linked to endometrial cancer development. If causal, these pathways may offer novel targets for endometrial cancer prevention.

Polyphenol intake and differentiated thyroid cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.

Polyphenols are bioactive compounds with several anticarcinogenic activities; however, human data regarding associations with thyroid cancer (TC) is still negligible. Our aim was to evaluate the association between intakes of total, classes and subclasses of polyphenols and risk of differentiated TC and its main subtypes, papillary and follicular, in a European population. The European Prospective Investigation into Cancer and Nutrition cohort included 476,108 men and women from 10 European countries. During a mean follow-up of 14 years, there were 748 incident differentiated TC cases, including 601 papillary and 109 follicular tumors. Polyphenol intake was estimated at baseline using validated center/country-specific dietary questionnaires and the Phenol-Explorer database. In multivariable-adjusted Cox regression models, no association between total polyphenol and the risks of overall differentiated TC (HRQ4 vs. Q1 = 0.99, 95% confidence interval [CI] 0.77-1.29), papillary (HRQ4 vs. Q1 = 1.06, 95% CI 0.80-1.41) or follicular TC (HRQ4 vs. Q1 = 1.10, 95% CI 0.55-2.22) were found. No associations were observed either for flavonoids, phenolic acids or the rest of classes and subclasses of polyphenols. After stratification by body mass index (BMI), an inverse association between the intake of polyphenols (p-trend = 0.019) and phenolic acids (p-trend = 0.007) and differentiated TC risk in subjects with BMI ≥ 25 was observed. In conclusion, our study showed no associations between dietary polyphenol intake and differentiated TC risk; although further studies are warranted to investigate the potential protective associations in overweight and obese individuals.

Blood pressure and risk of cancer in the European Prospective Investigation into Cancer and Nutrition.

Several studies have reported associations of hypertension with cancer, but not all results were conclusive. We examined the association of systolic (SBP) and diastolic (DBP) blood pressure with the development of incident cancer at all anatomical sites in the European Prospective Investigation into Cancer and Nutrition (EPIC). Hazard ratios (HRs) (95% confidence intervals) were estimated using multivariable Cox proportional hazards models, stratified by EPIC-participating center and age at recruitment, and adjusted for sex, education, smoking, body mass index, physical activity, diabetes and dietary (in women also reproductive) factors. The study included 307,318 men and women, with an average follow-up of 13.7 (standard deviation 4.4) years and 39,298 incident cancers. We confirmed the expected positive association with renal cell carcinoma: HR = 1.12 (1.08-1.17) per 10 mm Hg higher SBP and HR = 1.23 (1.14-1.32) for DBP. We additionally found positive associations for esophageal squamous cell carcinoma (SCC): HR = 1.16 (1.07-1.26) (SBP), HR = 1.31 (1.13-1.51) (DBP), weaker for head and neck cancers: HR = 1.08 (1.04-1.12) (SBP), HR = 1.09 (1.01-1.17) (DBP) and, similarly, for skin SCC, colon cancer, postmenopausal breast cancer and uterine adenocarcinoma (AC), but not for esophageal AC, lung SCC, lung AC or uterine endometroid cancer. We observed weak inverse associations of SBP with cervical SCC: HR = 0.91 (0.82-1.00) and lymphomas: HR = 0.97 (0.93-1.00). There were no consistent associations with cancers in other locations. Our results are largely compatible with published studies and support weak associations of blood pressure with cancers in specific locations and morphologies.

Ascertainment of Dementia Cases in the Spanish European Prospective Investigation into Cancer and Nutrition-Murcia Cohort.

BACKGROUND: Cohort studies generally focus on a particular disease, although they offer the possibility of evaluating different outcomes with minimal additional investment. The objective of this study was to describe the methodology used to assess dementia in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Murcia study. METHODS: The EPIC-Murcia cohort consists of 8,515 healthy participants (68% women, aged 30-70 years), recruited between 1992 and 1996 and followed up for over 20 years. Incident cases were ascertained by a 2-step protocol: a record linkage with health databases to identify potential events and a review of medical records of potential cases to validate incident cases. RESULTS: Overall, 1,202 potential cases were identified, and 275 dementia cases were validated. Medical reports were the source of information in 243 cases, with complete neurological information in 227, and a high degree of certainty of the diagnosis in 229 cases. P70 (dementia code) and/or antidementia drugs and/or ICD codes identified 259 cases (sensitivity: 94.2%, 95% CI 90.7-96.6; specificity: 98.1%, 95% CI 97.8-98.4). CONCLUSION: Ascertainment of incident dementia in the EPIC-Murcia cohort study was feasible using information from medical records. This systematic 2-step validation protocol is proposed as a feasible way to ascertain dementia in cohort studies originally designed for other endpoints.

Separate and combined associations of obesity and metabolic health with coronary heart disease: a pan-European case-cohort analysis.

Aims: The hypothesis of 'metabolically healthy obesity' implies that, in the absence of metabolic dysfunction, individuals with excess adiposity are not at greater cardiovascular risk. We tested this hypothesis in a large pan-European prospective study. Methods and results: We conducted a case-cohort analysis in the 520 000-person European Prospective Investigation into Cancer and Nutrition study ('EPIC-CVD'). During a median follow-up of 12.2 years, we recorded 7637 incident coronary heart disease (CHD) cases. Using cut-offs recommended by guidelines, we defined obesity and overweight using body mass index (BMI), and metabolic dysfunction ('unhealthy') as ≥ 3 of elevated blood pressure, hypertriglyceridaemia, low HDL-cholesterol, hyperglycaemia, and elevated waist circumference. We calculated hazard ratios (HRs) and 95% confidence intervals (95% CI) within each country using Prentice-weighted Cox proportional hazard regressions, accounting for age, sex, centre, education, smoking, diet, and physical activity. Compared with metabolically healthy normal weight people (reference), HRs were 2.15 (95% CI: 1.79; 2.57) for unhealthy normal weight, 2.33 (1.97; 2.76) for unhealthy overweight, and 2.54 (2.21; 2.92) for unhealthy obese people. Compared with the reference group, HRs were 1.26 (1.14; 1.40) and 1.28 (1.03; 1.58) for metabolically healthy overweight and obese people, respectively. These results were robust to various sensitivity analyses. Conclusion: Irrespective of BMI, metabolically unhealthy individuals had higher CHD risk than their healthy counterparts. Conversely, irrespective of metabolic health, overweight and obese people had higher CHD risk than lean people. These findings challenge the concept of 'metabolically healthy obesity', encouraging population-wide strategies to tackle obesity.

Evaluation of risk prediction models to select lung cancer screening participants in Europe: a prospective cohort consortium analysis.

BACKGROUND: Lung cancer risk prediction models might efficiently identify individuals who should be offered lung cancer screening. However, their performance has not been comprehensively evaluated in Europe. We aimed to externally validate and evaluate the performance of several risk prediction models that predict lung cancer incidence or mortality in prospective European cohorts. METHODS: We analysed 240 137 participants aged 45-80 years with a current or former smoking history from nine European countries in four prospective cohorts from the pooled database of the Lung Cancer Cohort Consortium: the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (Finland), the Nord-Trøndelag Health Study (Norway), CONSTANCES (France), and the European Prospective Investigation into Cancer and Nutrition (Denmark, Germany, Italy, Spain, Sweden, the Netherlands, and Norway). We evaluated ten lung cancer risk models, which comprised the Bach, the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial 2012 model (PLCOm2012), the Lung Cancer Risk Assessment Tool (LCRAT), the Lung Cancer Death Risk Assessment Tool (LCDRAT), the Nord-Trøndelag Health Study (HUNT), the Optimized Early Warning Model for Lung Cancer Risk (OWL), the University College London-Death (UCLD), the University College London-Incidence (UCLI), the Liverpool Lung Project version 2 (LLP version 2), and the Liverpool Lung Project version 3 (LLP version 3) models. We quantified model calibration as the ratio of expected to observed cases or deaths and discrimination using the area under the receiver operating characteristic curve (AUC). For each model, we also identified risk thresholds that would screen the same number of individuals as each of the US Preventive Services Task Force 2021 (USPSTF-2021), the US Preventive Services Task Force 2013 (USPSTF-2013), and the Nederlands-Leuvens Longkanker Screenings Onderzoek (NELSON) criteria. FINDINGS: Among the participants, 1734 lung cancer cases and 1072 lung cancer deaths occurred within five years of enrolment. Most models had reasonable calibration in most countries, although the LLP version 2 overpredicted risk by more than 50% in eight countries (expected to observed ≥1·50). The PLCOm2012, LCDRAT, LCRAT, Bach, HUNT, OWL, UCLD, and UCLI models showed similar discrimination in most countries, with AUCs ranging from 0·68 (95% CI 0·59-0·77) to 0·83 (0·78-0·89), whereas the LLP version 2 and LLP version 3 showed lower discrimination, with AUCs ranging from 0·64 (95% CI 0·57-0·72) to 0·78 (0·74-0·83). When pooling data from all countries (but excluding the HUNT cohort), 33·9% (73 313 of 216 387) of individuals were eligible by USPSTF-2021 criteria, which included 74·8% (1185) of lung cancers and 76·3% (730) of lung cancer deaths occurring over 5 years. Fewer individuals were selected by USPSTF-2013 and NELSON criteria. After applying thresholds to select a population of equal size to USPSTF-2021, the PLCOm2012, LCDRAT, LCRAT, Bach, HUNT, OWL, UCLD, and UCLI, models identified 77·6%-79·1% of future cases, although they selected slightly older individuals compared with USPSTF-2021 criteria. Results were similar for USPSTF-2013 and NELSON. INTERPRETATION: Several lung cancer risk prediction models showed good performance in European countries and might improve the efficiency of lung cancer screening if used in place of categorical eligibility criteria. FUNDING: US National Cancer Institute, l'Institut National du Cancer, Cancer Research UK.

Nitrosyl-heme and Heme Iron Intake from Processed Meats and Risk of Colorectal Cancer in the EPIC-Spain Cohort.

BACKGROUND: The International Agency for Research on Cancer classified processed meats (PM) as "carcinogenic" and red meat as "probably carcinogenic" for humans. The possible relationship between colorectal cancer risk and the mechanisms involved in the carcinogenesis of PMs have not been established yet. Nitrosyl-heme and heme iron have been proposed as potential-related compounds. The aim of this study was to determine the association between nitrosyl-heme and heme iron intake and colorectal cancer risk among participants from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Spain study. METHODS: This prospective study included 38,262 men and women from the EPIC-Spain study. Food consumption was assessed using diet history and food composition tables. Heme iron and nitrosyl-heme intake were determined by estimating the intake of PM items and conducting laboratory analyses. HR estimates were obtained by proportional hazard models, stratified by age at recruitment and study center and adjusted for sex, total energy intake, education, smoking, body mass index, waist size, physical activity, lifetime alcohol, fibre, calcium, and familiar colorectal cancer history. RESULTS: During a mean follow-up of 16.7 years, 577 participants were diagnosed with colorectal cancer. We found no overall association between nitrosyl-heme [HRT3vsT1, 0.98; 95% confidence interval (CI), 0.79-1.21] or heme iron intakes (HRT3vsT1, 0.88; 95% CI, 0.70-1.10) with colorectal cancer risk, nor according to tumor subtypes. CONCLUSIONS: Our study found no evidence supporting a link between nitrosyl-heme or heme iron intake and colorectal cancer risk in Spanish subjects. IMPACT: As research on nitrosyl-heme is preliminary, more heterogeneous studies are necessary to provide more convincing evidence on their role in colorectal cancer carcinogenesis.

Nitrosyl-Heme and Heme Iron Intake from Processed Meats in Subjects from the EPIC-Spain Cohort.

BACKGROUND: The consumption of processed meats (PMs) and red meats are linked to the likelihood of developing colorectal cancer. Various theories have been proposed to explain this connection, focusing on nitrosyl-heme and heme iron intake. We hypothesized that differences in nitrosyl-heme and heme iron intakes will be associated with various sociodemographic and lifestyle factors. METHODS: The study included 38,471 healthy volunteers (62% females) from five Spanish regions within the EPIC-Spain cohort. High-Performance Liquid Chromatography (HPLC) determined nitrosyl-heme and heme iron levels in the 39 most consumed PMs. Food intake was assessed using validated questionnaires in interviews. Nitrosyl-heme and heme iron intakes, adjusted for sex, age, body mass index (BMI), center, and energy intake, were expressed as geometric means due to their skewed distribution. Variance analysis identified foods explaining the variability of nitrosyl-heme and heme iron intakes. RESULTS: The estimated intakes were 528.6 µg/day for nitrosyl-heme and 1676.2 µg/day for heme iron. Significant differences in nitrosyl-heme intake were found by sex, center, energy, and education level. Heme iron intake varied significantly by sex, center, energy, and smoking status. "Jamón serrano" and "jamón cocido/jamón de York" had the highest intake values, while "morcilla asturiana" and "sangrecilla" were key sources of nitrosyl-heme and heme iron. CONCLUSIONS: This is the first study to estimate levels of nitrosyl-heme intake directly in PMs for a large sample, revealing variations based on sex, BMI, smoking, and activity. Its data aids future exposure estimations in diverse populations.

Dietary index based on the Food Standards Agency nutrient profiling system and risk of Crohn's disease and ulcerative colitis.

BACKGROUND: Nutri-score is now widely available in food packages in Europe. AIM: To study the overall nutritional quality of the diet in relation to risks of Crohn's disease (CD) and ulcerative colitis (UC), in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort METHODS: We collected dietary data at baseline from validated food frequency questionnaires. We used a dietary index based on the UK Food Standards Agency modified nutrient profiling system (FSAm-NPS-DI) underlying the Nutri-Score label, to measure the nutritional quality of the diet. We estimated the association between FSAm-NPS-DI score, and CD and UC risks using Cox models stratified by centre, sex and age; and adjusted for smoking status, BMI, physical activity, energy intake, educational level and alcohol intake. RESULTS: We included 394,255 participants (68.1% women; mean age at recruitment 52.1 years). After a mean follow-up of 13.6 years, there were 184 incident cases of CD and 459 incident cases of UC. Risk of CD was higher in those with a lower nutritional quality, that is higher FSAm-NPS-DI Score (fourth vs. first quartile: aHR: 2.04, 95% CI: 1.24-3.36; p-trend: <0.01). Among items of the FSAm-NPS-DI Score, low intakes of dietary fibre and fruits/vegetables/legumes/nuts were associated with higher risk of CD. Nutritional quality was not associated with risk of UC (fourth vs. first quartile of the FSAm-NPS-DI Score: aHR: 0.91, 95% CI: 0.69-1.21; p-trend: 0.76). CONCLUSIONS: A diet with low nutritional quality as measured by the FSAm-NPS-DI Score is associated with a higher risk of CD but not UC.

Altered plasma metabolite levels can be detected years before a glioma diagnosis.

Genetic and metabolic changes in tissue and blood are reported to occur several years before glioma diagnosis. Since gliomas are currently detected late, a liquid biopsy for early detection could affect the quality of life and prognosis of patients. Here, we present a nested case-control study of 550 prediagnostic glioma cases and 550 healthy controls from the Northern Sweden Health and Disease study (NSHDS) and the European Prospective Investigation into Cancer and Nutrition (EPIC) study. We identified 93 significantly altered metabolites related to glioma development up to 8 years before diagnosis. Out of these metabolites, a panel of 20 selected metabolites showed strong disease correlation and a consistent progression pattern toward diagnosis in both the NSHDS and EPIC cohorts, and they separated future cases from controls independently of biological sex. The blood metabolite panel also successfully separated both lower-grade glioma and glioblastoma cases from controls, up to 8 years before diagnosis in patients within the NSHDS cohort and up to 2 years before diagnosis in EPIC. Pathway enrichment analysis detected metabolites related to the TCA cycle, Warburg effect, gluconeogenesis, and cysteine, pyruvate, and tyrosine metabolism as the most affected.