Oncocytic papillary cystadenoma of the larynx: a case report.

BACKGROUND: Cystadenoma of the salivary glands is a rare benign clinical condition affecting both major and minor salivary glands equally. It constitutes approximately 2% of total neoplasms and 4.2-4.7% of benign formations in minor salivary glands. Typically presenting as a slow-growing, painless neoplasm, it can be distinguished from Cystadenolymphoma (Whartin's Tumor) by the absence of lymphoid elements in histological examination. While mostly located in the oral cavity and oropharynx, it can also be found in sinonasal mucosa, and rare cases have been identified in the larynx. CASE PRESENTATION: A 75-year-old Caucasian woman presented to the ear, nose, and throat department with complaints of dysphonia and headaches persisting for several months. Dysphonia had developed months after an unspecified vocal cord surgery elsewhere. Flexible laryngoscopy identified a left-sided cystic swelling affecting the supraglottic space, leading to respiratory obstruction and dysphonia. Head and neck computed tomography confirmed a 1.9 × 1.7 cm bilobed cystic mass originating from the left Morgagni ventricle. Microlaryngoscopy with CO2 laser excision and biopsy revealed a histopathological diagnosis of oncocytic papillary cystadenoma. Post-surgery, the patient fully recovered from dysphonia, with no significant complications noted. Long-term clinical surveillance was advised to detect potential recurrences promptly. CONCLUSION: Ectopic minor salivary gland tumors, both benign and malignant, should be taken into consideration as potential differential diagnosis for any swelling arising within the upper digestive tract mucosa. Ears, nose, and throat clinical examination completed by videolaryngoscopy can easily point out the location of the mass. Imaging is mandatory for differential diagnosis and for surgical planning. Surgical excision can provide both diagnosis and definitive cure.

Lifestyle changes in middle age and risk of cancer: evidence from the European Prospective Investigation into Cancer and Nutrition.

In this study, we aimed to provide novel evidence on the impact of changing lifestyle habits on cancer risk. In the EPIC cohort, 295,865 middle-aged participants returned a lifestyle questionnaire at baseline and during follow-up. At both timepoints, we calculated a healthy lifestyle index (HLI) score based on cigarette smoking, alcohol consumption, body mass index and physical activity. HLI ranged from 0 (most unfavourable) to 16 (most favourable). We estimated the association between HLI change and risk of lifestyle-related cancers-including cancer of the breast, lung, colorectum, stomach, liver, cervix, oesophagus, bladder, and others-using Cox regression models. We reported hazard ratios (HR) with 95% confidence intervals (CI). Median time between the two questionnaires was 5.7 years, median age at follow-up questionnaire was 59 years. After the follow-up questionnaire, we observed 14,933 lifestyle-related cancers over a median follow-up of 7.8 years. Each unit increase in the HLI score was associated with 4% lower risk of lifestyle-related cancers (HR 0.96; 95%CI 0.95-0.97). Among participants in the top HLI third at baseline (HLI > 11), those in the bottom third at follow-up (HLI ≤ 9) had 21% higher risk of lifestyle-related cancers (HR 1.21; 95%CI 1.07-1.37) than those remaining in the top third. Among participants in the bottom HLI third at baseline, those in the top third at follow-up had 25% lower risk of lifestyle-related cancers (HR 0.75; 95%CI 0.65-0.86) than those remaining in the bottom third. These results indicate that lifestyle changes in middle age may have a significant impact on cancer risk.

Diet and lifestyle in relation to small intestinal cancer risk: findings from the European Prospective Investigation into Cancer and Nutrition (EPIC).

PURPOSE: The incidence of small intestinal cancer (SIC) is increasing, however, its aetiology remains unclear due to a lack of data from large-scale prospective cohorts. We examined modifiable risk factors in relation to SIC overall and by histological subtype. METHODS: We analysed 450,107 participants enrolled in the European Prospective Investigation into Cancer and Nutrition cohort. Cox proportional hazards models were used to estimate univariable and multivariable hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: During an average of 14.1 years of follow-up, 160 incident SICs (62 carcinoids, 51 adenocarcinomas) were identified. Whilst univariable models revealed a positive association for current versus never smokers and SIC (HR, 95% CI: 1.77, 1.21-2.60), this association attenuated in multivariable models. In energy-adjusted models, there was an inverse association across vegetable intake tertiles for SIC overall (HRT3vsT1, 95% CI: 0.48, 0.32-0.71, p-trend: < 0.001) and for carcinoids (HRT3vsT1, 95% CI: 0.44, 0.24-0.82, p-trend: 0.01); however, these attenuated in multivariable models. Total fat was also inversely associated with total SIC and both subtypes but only in the second tertile (SIC univariable HRT2vsT1, 95% CI: 0.57, 0.38-0.84; SIC multivariable HRT2vsT1, 95% CI: 0.55, 0.37-0.81). Physical activity, intake of alcohol, red or processed meat, dairy products, or fibre were not associated with SIC. CONCLUSION: These exploratory analyses found limited evidence for a role of modifiable risk factors in SIC aetiology. However, sample size was limited, particularly for histologic subtypes; therefore, larger studies are needed to delineate these associations and robustly identify risk factors for SIC.

Metabolism and Recovery of Epithionitriles from Glucosinolates-A Human Intervention Study.

SCOPE: Epithionitriles can be main glucosinolate hydrolysis products in Brassica vegetables such as cabbage or pak choi. Here, for the first time, the bioavailability and metabolism of longer-chain epithionitriles (C4-C5) is studied in a human intervention study. METHODS AND RESULTS: After consumption of a white cabbage or pak choi sprouts beverage, rich in either 1-cyano-2,3-epithiopropane (CETP) or 1-cyano-3,4-epithiobutane (CETB) and 1-cyano-4,5-epithiopentane (CETPent), blood and urine samples of nine participants are taken and the metabolites are analyzed. The corresponding N-acetyl-S-(cyano-(methylthio)alkyl)-l-cysteine metabolites are identified and quantified by isotope dilution method using UHPLC-TOF-MS. The standards for N-acetyl-S-(cyano-(methylthio)alkyl)-l-cysteine metabolites from CETB and CETPent are synthesized for the first time and their structure confirmed by NMR spectroscopy. In contrast to the metabolites of CETP and CETPent, the expected metabolite of CETB is not detectable. The recoveries of the CETP and CETPent metabolites are 28 ± 9% for CETP and 12 ± 3% for CETPent in urine within 24 h. CONCLUSION: CETP and CETPent are quickly uptaken, metabolized via the mercapturic acid pathway, and excreted via urine, while for CETB the corresponding metabolite is not detectable. Therefore, an additional metabolization pathway seems to exist.

An experimental approach to training interoceptive sensitivity: study protocol for a pilot randomized controlled trial.

BACKGROUND: Eating in absence of hunger is quite common and often associated with an increased energy intake co-existent with a poorer food choice. Intuitive eating (IE), i.e., eating in accordance with internal hunger and satiety cues, may protect from overeating. IE, however, requires accurate perception and processing of one's own bodily signals, also referred to as interoceptive sensitivity. Training interoceptive sensitivity might therefore be an effective method to promote IE and prevent overeating. As most studies on eating behavior are conducted in younger adults and close social relationships influence health-related behavior, this study focuses on middle-aged and older couples. METHODS: The present pilot randomized intervention study aims at investigating the feasibility and effectiveness of a 21-day mindfulness-based training program designed to increase interoceptive sensitivity. A total of N = 60 couples participating in the NutriAct Family Study, aged 50-80 years, will be recruited. This randomized-controlled intervention study comprises three measurement points (pre-intervention, post-intervention, 4-week follow-up) and a 21-day training that consists of daily mindfulness-based guided audio exercises (e.g., body scan). A three-arm intervention study design is applied to compare two intervention groups (training together as a couple vs. training alone) with a control group (no training). Each measurement point includes the assessment of self-reported and objective indicators of interoceptive sensitivity (primary outcome), self-reported indicators of intuitive and maladaptive eating (secondary outcomes), and additional variables. A training evaluation applying focus group discussions will be conducted to assess participants' overall acceptance of the training and its feasibility. DISCUSSION: By investigating the feasibility and effectiveness of a mindfulness-based training program to increase interoceptive sensitivity, the present study will contribute to a deeper understanding of how to promote healthy eating in older age. TRIAL REGISTRATION: German Clinical Trials Register (DRKS), no. DRKS00024903. Retrospectively registered on April 21, 2021.

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.

Cigarette Smoking and Endometrial Cancer Risk: Observational and Mendelian Randomization Analyses.

BACKGROUND: Current epidemiologic evidence indicates that smoking is associated with a lower endometrial cancer risk. However, it is unknown if this association is causal or confounded. To further elucidate the role of smoking in endometrial cancer risk, we conducted complementary observational and Mendelian randomization (MR) analyses. METHODS: The observational analyses included 286,415 participants enrolled in the European Prospective Investigation into Cancer and Nutrition and 179,271 participants in the UK Biobank, and multivariable Cox proportional hazards models were used. In two-sample MR analyses, genetic variants robustly associated with lifetime amount of smoking (n = 126 variants) and ever having smoked regularly (n = 112 variants) were selected and their association with endometrial cancer risk (12,906 cancer/108,979 controls from the Endometrial Cancer Association Consortium) was examined. RESULTS: In the observational analysis, lifetime amount of smoking and ever having smoked regularly were associated with a lower endometrial cancer risk. In the MR analysis accounting for body mass index, a genetic predisposition to a higher lifetime amount of smoking was not associated with endometrial cancer risk (OR per 1-SD increment: 1.15; 95% confidence interval: 0.91-1.44). Genetic predisposition to ever having smoked regularly was not associated with risk of endometrial cancer. CONCLUSIONS: Smoking was inversely associated with endometrial cancer in the observational analyses, although unsupported by the MR. Additional studies are required to better understand the possible confounders and mechanisms underlying the observed associations between smoking and endometrial cancer. IMPACT: The results from this analysis indicate that smoking is unlikely to be causally linked with endometrial cancer risk.

A New Evidence-Based Diet Score to Capture Associations of Food Consumption and Chronic Disease Risk.

Previously, the attempt to compile German dietary guidelines into a diet score was predominantly not successful with regards to preventing chronic diseases in the EPIC-Potsdam study. Current guidelines were supplemented by the latest evidence from systematic reviews and expert papers published between 2010 and 2020 on the prevention potential of food groups on chronic diseases such as type 2 diabetes, cardiovascular diseases and cancer. A diet score was developed by scoring the food groups according to a recommended low, moderate or high intake. The relative validity and reliability of the diet score, assessed by a food frequency questionnaire, was investigated. The consideration of current evidence resulted in 10 key food groups being preventive of the chronic diseases of interest. They served as components in the diet score and were scored from 0 to 1 point, depending on their recommended intake, resulting in a maximum of 10 points. Both the reliability (r = 0.53) and relative validity (r = 0.43) were deemed sufficient to consider the diet score as a stable construct in future investigations. This new diet score can be a promising tool to investigate dietary intake in etiological research by concentrating on 10 key dietary determinants with evidence-based prevention potential for chronic diseases.

Educational Attainment Is Associated With Kidney and Cardiovascular Outcomes in the German CKD (GCKD) Cohort.

Introduction: Prospective data on impact of educational attainment on prognosis in patients with chronic kidney disease (CKD) are scarce. We investigated the association between educational attainment and all-cause mortality, major adverse cardiovascular (CV) events (MACEs), kidney failure requiring dialysis, and CKD etiology. Methods: Participants (N = 5095, aged 18-74 years) of the ongoing multicenter German Chronic Kidney Disease (GCKD) cohort, enrolled on the basis of an estimated glomerular filtration rate (eGFR) of 30 to 60 ml/min (stages G3, A1-A3) or overt proteinuria (stages G1-G2, A3), were divided into 3 categories according to their educational attainment and were followed for 6.5 years. Results: Participants with low educational attainment (vs. high) had a higher risk for mortality (hazard ratio [HR] 1.48, 95% CI: 1.16-1.90), MACE (HR 1.37, 95% CI: 1.02-1.83), and kidney failure (HR 1.54, 95% CI: 1.15-2.05). Mediators between low educational attainment and mortality were smoking, CV disease (CVD) at baseline, low income, higher body mass index, and higher serum levels of CRP, high-density lipoprotein cholesterol, uric acid, NGAL, BAP, NT-proBNP, OPN, H-FABP, and urea. Low educational attainment was positively associated with diabetic nephropathy (odds ratio [OR] 1.65, 95% CI: 1.36-2.0) and CKD subsequent to acute kidney injury (OR 1.56, 95% CI: 1.03-2.35), but negatively associated with IgA nephropathy (OR 0.68, 95% CI: 0.52-0.90). Conclusion: Low educational attainment is associated with adverse outcomes and CKD etiology. Lifestyle habits and biomarkers mediate associations between low educational attainment and mortality. Recognition of the role of educational attainment and the associated health-relevant risk factors is important to optimize the care of patients with CKD and improve prognosis.

Lifestyle factors for the prevention of inflammatory bowel disease.

OBJECTIVE: To estimate the proportion of cases of Crohn's disease (CD) and ulcerative colitis (UC) that could be prevented by modifiable lifestyle factors. DESIGN: In a prospective cohort study of US adults from the Nurses' Health Study (NHS; n=72 290), NHSII (n=93 909) and Health Professionals Follow-up Study (HPFS; n=41 871), we created modifiable risk scores (MRS; 0-6) for CD and UC based on established lifestyle risk factors, and healthy lifestyle scores (HLS; 0-9) derived from American healthy lifestyle recommendations. We calculated the population attributable risk by comparing the incidence of CD and UC between low-risk (CD-MRS≤1, UC-MRS≤2, HLS≥7) and high-risk groups. We externally validated our findings in three European cohorts: the Swedish Mammography Cohort (n=37 275), Cohort of Swedish Men (n=40 810) and European Prospective Investigation into Cancer and Nutrition (n=404 144). RESULTS: Over 5 117 021 person-years of follow-up (NHS, HPFS: 1986-2016; NHSII: 1991-2017), we documented 346 CD and 456 UC cases. Adherence to a low MRS could have prevented 42.9% (95% CI 12.2% to 66.1%) of CD and 44.4% (95% CI 9.0% to 69.8%) of UC cases. Similarly, adherence to a healthy lifestyle could have prevented 61.1% (95% CI 16.8% to 84.9%) of CD and 42.2% (95% CI 1.7% to 70.9%) of UC cases. In our validation cohorts, adherence to a low MRS and healthy lifestyle could have, respectively, prevented 43.9%-51.2% and 48.8%-60.4% of CD cases and 20.6%-27.8% and 46.8%-56.3% of UC cases. CONCLUSIONS: Across six US and European cohorts, a substantial burden of inflammatory bowel diseases risk may be preventable through lifestyle modification.

A Prospective Diet-Wide Association Study for Risk of Colorectal Cancer in EPIC.

BACKGROUND & AIMS: Evidence regarding the association of dietary exposures with colorectal cancer (CRC) risk is not consistent with a few exceptions. Therefore, we conducted a diet-wide association study (DWAS) in the European Prospective Investigation into Cancer and Nutrition (EPIC) to evaluate the associations between several dietary exposures with CRC risk. METHODS: The association of 92 food and nutrient intakes with CRC risk was assessed in 386,792 participants, 5069 of whom developed incident CRC. Correction for multiple comparisons was performed using the false discovery rate, and emerging associations were examined in the Netherlands Cohort Study (NLCS). Multiplicative gene-nutrient interactions were also tested in EPIC based on known CRC-associated loci. RESULTS: In EPIC, alcohol, liquor/spirits, wine, beer/cider, soft drinks, and pork were positively associated with CRC, whereas milk, cheese, calcium, phosphorus, magnesium, potassium, riboflavin, vitamin B6, beta carotene, fruit, fiber, nonwhite bread, banana, and total protein intakes were inversely associated. Of these 20 associations, 13 were replicated in the NLCS, for which a meta-analysis was performed, namely alcohol (summary hazard ratio [HR] per 1-SD increment in intake: 1.07; 95% confidence interval [CI], 1.04-1.09), liquor/spirits (HR per 1-SD increment in intake, 1.04; 95% CI, 1.02-1.06), wine (HR per 1-SD increment in intake, 1.04; 95% CI, 1.02-1.07), beer/cider (HR per 1-SD increment in intake, 1.06; 95% CI, 1.04-1.08), milk (HR per 1-SD increment in intake, 0.95; 95% CI, 0.93-0.98), cheese (HR per 1-SD increment in intake, 0.96; 95% CI, 0.94-0.99), calcium (HR per 1-SD increment in intake, 0.93; 95% CI, 0.90-0.95), phosphorus (HR per 1-SD increment in intake, 0.92; 95% CI, 0.90-0.95), magnesium (HR per 1-SD increment in intake, 0.95; 95% CI, 0.92-0.98), potassium (HR per 1-SD increment in intake, 0.96; 95% CI, 0.94-0.99), riboflavin (HR per 1-SD increment in intake, 0.94; 95% CI, 0.92-0.97), beta carotene (HR per 1-SD increment in intake, 0.96; 95% CI, 0.93-0.98), and total protein (HR per 1-SD increment in intake, 0.94; 95% CI, 0.92-0.97). None of the gene-nutrient interactions were significant after adjustment for multiple comparisons. CONCLUSIONS: Our findings confirm a positive association for alcohol and an inverse association for dairy products and calcium with CRC risk, and also suggest a lower risk at higher dietary intakes of phosphorus, magnesium, potassium, riboflavin, beta carotene, and total protein.

Excess Body Fatness during Early to Mid-Adulthood and Survival from Colorectal and Breast Cancer: A Pooled Analysis of Five International Cohort Studies.

BACKGROUND: Here, we explore the association between excess weight during early to mid-adulthood and survival in patients diagnosed with breast and colorectal cancer, using a pooled analysis of five cohort studies and study participants from 11 countries. METHODS: Participant-level body mass index (BMI) trajectories were estimated by fitting a growth curve model using over 2 million repeated BMI measurements from close to 600,000 cohort participants. Cumulative measures of excess weight were derived. Data from over 23,000 patients with breast and colorectal cancer were subsequently analyzed using time-to-event models for death with the date of diagnosis as start of follow-up. Study-specific results were combined through a random effect meta-analysis. RESULTS: We found a significant dose-response relationship (P trend = 0.013) between the average BMI during early and mid-adulthood and death from breast cancer, with a pooled HR of 1.31 (1.07-1.60) and the time to death shortened by 16% for average BMI above 25 kg/m2 compared with average BMI less than or equal to 22.5 kg/m2, respectively. Similar results were found for categories of cumulative time spent with excess weight. There was no association between excess body fatness during early to mid-adulthood and death in patients with colorectal cancer. CONCLUSIONS: Excess body fatness during early to mid-adulthood is associated not only with an increased risk of developing cancer, but also with a lower survival in patients with breast cancer. IMPACT: Our results emphasize the importance of public health policies aimed at reducing overweight during adulthood and inform future studies on the relationship between excess weight and cancer outcomes.

Prediagnostic alterations in circulating bile acid profiles in the development of hepatocellular carcinoma.

Bile acids (BAs) play different roles in cancer development. Some are carcinogenic and BA signaling is also involved in various metabolic, inflammatory and immune-related processes. The liver is the primary site of BA synthesis. Liver dysfunction and microbiome compositional changes, such as during hepatocellular carcinoma (HCC) development, may modulate BA metabolism increasing concentration of carcinogenic BAs. Observations from prospective cohorts are sparse. We conducted a study (233 HCC case-control pairs) nested within a large observational prospective cohort with blood samples taken at recruitment when healthy with follow-up over time for later cancer development. A targeted metabolomics method was used to quantify 17 BAs (primary/secondary/tertiary; conjugated/unconjugated) in prediagnostic plasma. Odd ratios (OR) for HCC risk associations were calculated by multivariable conditional logistic regression models. Positive HCC risk associations were observed for the molar sum of all BAs (ORdoubling  = 2.30, 95% confidence intervals [CI]: 1.76-3.00), and choline- and taurine-conjugated BAs. Relative concentrations of BAs showed positive HCC risk associations for glycoholic acid and most taurine-conjugated BAs. We observe an association between increased HCC risk and higher levels of major circulating BAs, from several years prior to tumor diagnosis and after multivariable adjustment for confounders and liver functionality. Increase in BA concentration is accompanied by a shift in BA profile toward higher proportions of taurine-conjugated BAs, indicating early alterations of BA metabolism with HCC development. Future studies are needed to assess BA profiles for improved stratification of patients at high HCC risk and to determine whether supplementation with certain BAs may ameliorate liver dysfunction.

Co-benefits from sustainable dietary shifts for population and environmental health: an assessment from a large European cohort study.

BACKGROUND: Unhealthy diets, the rise of non-communicable diseases, and the declining health of the planet are highly intertwined, where food production and consumption are major drivers of increases in greenhouse gas emissions, substantial land use, and adverse health such as cancer and mortality. To assess the potential co-benefits from shifting to more sustainable diets, we aimed to investigate the associations of dietary greenhouse gas emissions and land use with all-cause and cause-specific mortality and cancer incidence rates. METHODS: Using data from 443 991 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) study, a multicentre prospective cohort, we estimated associations between dietary contributions to greenhouse gas emissions and land use and all-cause and cause-specific mortality and incident cancers using Cox proportional hazards regression models. The main exposures were modelled as quartiles. Co-benefits, encompassing the potential effects of alternative diets on all-cause mortality and cancer and potential reductions in greenhouse gas emissions and land use, were estimated with counterfactual attributable fraction intervention models, simulating potential effects of dietary shifts based on the EAT-Lancet reference diet. FINDINGS: In the pooled analysis, there was an association between levels of dietary greenhouse gas emissions and all-cause mortality (adjusted hazard ratio [HR] 1·13 [95% CI 1·10-1·16]) and between land use and all-cause mortality (1·18 [1·15-1·21]) when comparing the fourth quartile to the first quartile. Similar associations were observed for cause-specific mortality. Associations were also observed between all-cause cancer incidence rates and greenhouse gas emissions, when comparing the fourth quartile to the first quartile (adjusted HR 1·11 [95% CI 1·09-1·14]) and between all-cause cancer incidence rates and land use (1·13 [1·10-1·15]); however, estimates differed by cancer type. Through counterfactual attributable fraction modelling of shifts in levels of adherence to the EAT-Lancet diet, we estimated that up to 19-63% of deaths and up to 10-39% of cancers could be prevented, in a 20-year risk period, by different levels of adherence to the EAT-Lancet reference diet. Additionally, switching from lower adherence to the EAT-Lancet reference diet to higher adherence could potentially reduce food-associated greenhouse gas emissions up to 50% and land use up to 62%. INTERPRETATION: Our results indicate that shifts towards universally sustainable diets could lead to co-benefits, such as minimising diet-related greenhouse gas emissions and land use, reducing the environmental footprint, aiding in climate change mitigation, and improving population health. FUNDING: European Commission (DG-SANCO), the International Agency for Research on Cancer (IARC), MRC Early Career Fellowship (MR/M501669/1).

The blood metabolome of incident kidney cancer: A case-control study nested within the MetKid consortium.

BACKGROUND: Excess bodyweight and related metabolic perturbations have been implicated in kidney cancer aetiology, but the specific molecular mechanisms underlying these relationships are poorly understood. In this study, we sought to identify circulating metabolites that predispose kidney cancer and to evaluate the extent to which they are influenced by body mass index (BMI). METHODS AND FINDINGS: We assessed the association between circulating levels of 1,416 metabolites and incident kidney cancer using pre-diagnostic blood samples from up to 1,305 kidney cancer case-control pairs from 5 prospective cohort studies. Cases were diagnosed on average 8 years after blood collection. We found 25 metabolites robustly associated with kidney cancer risk. In particular, 14 glycerophospholipids (GPLs) were inversely associated with risk, including 8 phosphatidylcholines (PCs) and 2 plasmalogens. The PC with the strongest association was PC ae C34:3 with an odds ratio (OR) for 1 standard deviation (SD) increment of 0.75 (95% confidence interval [CI]: 0.68 to 0.83, p = 2.6 × 10-8). In contrast, 4 amino acids, including glutamate (OR for 1 SD = 1.39, 95% CI: 1.20 to 1.60, p = 1.6 × 10-5), were positively associated with risk. Adjusting for BMI partly attenuated the risk association for some-but not all-metabolites, whereas other known risk factors of kidney cancer, such as smoking and alcohol consumption, had minimal impact on the observed associations. A mendelian randomisation (MR) analysis of the influence of BMI on the blood metabolome highlighted that some metabolites associated with kidney cancer risk are influenced by BMI. Specifically, elevated BMI appeared to decrease levels of several GPLs that were also found inversely associated with kidney cancer risk (e.g., -0.17 SD change [ßBMI] in 1-(1-enyl-palmitoyl)-2-linoleoyl-GPC (P-16:0/18:2) levels per SD change in BMI, p = 3.4 × 10-5). BMI was also associated with increased levels of glutamate (ßBMI: 0.12, p = 1.5 × 10-3). While our results were robust across the participating studies, they were limited to study participants of European descent, and it will, therefore, be important to evaluate if our findings can be generalised to populations with different genetic backgrounds. CONCLUSIONS: This study suggests a potentially important role of the blood metabolome in kidney cancer aetiology by highlighting a wide range of metabolites associated with the risk of developing kidney cancer and the extent to which changes in levels of these metabolites are driven by BMI-the principal modifiable risk factor of kidney cancer.

Association of Cycling With All-Cause and Cardiovascular Disease Mortality Among Persons With Diabetes: The European Prospective Investigation Into Cancer and Nutrition (EPIC) Study.

Importance: Premature death from all causes and cardiovascular disease (CVD) causes is higher among persons with diabetes. Objective: To investigate the association between time spent cycling and all-cause and CVD mortality among persons with diabetes, as well as to evaluate the association between change in time spent cycling and risk of all-cause and CVD mortality. Design, Setting, and Participants: This prospective cohort study included 7459 adults with diabetes from the European Prospective Investigation into Cancer and Nutrition study. Questionnaires regarding medical history, sociodemographic, and lifestyle information were administered in 10 Western European countries from 1992 through 2000 (baseline examination) and at a second examination 5 years after baseline. A total of 5423 participants with diabetes completed both examinations. The final updated primary analysis was conducted on November 13, 2020. Exposures: The primary exposure was self-reported time spent cycling per week at the baseline examination. The secondary exposure was change in cycling status from baseline to the second examination. Main Outcomes and Measures: The primary and secondary outcomes were all-cause and CVD mortality, respectively, adjusted for other physical activity modalities, diabetes duration, and sociodemographic and lifestyle factors. Results: Of the 7459 adults with diabetes included in the analysis, the mean (SD) age was 55.9 (7.7) years, and 3924 (52.6%) were female. During 110 944 person-years of follow-up, 1673 deaths from all causes were registered. Compared with the reference group of people who reported no cycling at baseline (0 min/wk), the multivariable-adjusted hazard ratios for all-cause mortality were 0.78 (95% CI, 0.61-0.99), 0.76 (95% CI, 0.65-0.88), 0.68 (95% CI, 0.57-0.82), and 0.76 (95% CI, 0.63-0.91) for cycling 1 to 59, 60 to 149, 150 to 299, and 300 or more min/wk, respectively. In an analysis of change in time spent cycling with 57 802 person-years of follow-up, a total of 975 deaths from all causes were recorded. Compared with people who reported no cycling at both examinations, the multivariable-adjusted hazard ratios for all-cause mortality were 0.90 (95% CI, 0.71-1.14) in those who cycled and then stopped, 0.65 (95% CI, 0.46-0.92) in initial noncyclists who started cycling, and 0.65 (95% CI, 0.53-0.80) for people who reported cycling at both examinations. Similar results were observed for CVD mortality. Conclusion and Relevance: In this cohort study, cycling was associated with lower all-cause and CVD mortality risk among people with diabetes independent of practicing other types of physical activity. Participants who took up cycling between the baseline and second examination had a considerably lower risk of both all-cause and CVD mortality compared with consistent noncyclists.

Soft Drink and Juice Consumption and Renal Cell Carcinoma Incidence and Mortality in the European Prospective Investigation into Cancer and Nutrition.

BACKGROUND: Renal cell carcinoma (RCC) accounts for more than 80% of kidney cancers in adults, and obesity is a known risk factor. Regular consumption of sweetened beverages has been linked to obesity and several chronic diseases, including some types of cancer. It is uncertain whether soft drink and juice consumption is associated with risk of RCC. We investigated the associations of soft drink and juice consumption with RCC incidence and mortality in the European Prospective Investigation into Cancer and Nutrition (EPIC). METHODS: A total of 389,220 EPIC participants with median age of 52 years at recruitment (1991-2000) were included. Cox regression yielded adjusted HRs and 95% confidence intervals (CI) for RCC incidence and mortality in relation to intakes of juices and total, sugar-sweetened, and artificially sweetened soft drinks. RESULTS: A total of 888 incident RCCs and 356 RCC deaths were identified. In models including adjustment for body mass index and energy intake, there was no higher risk of incident RCC associated with consumption of juices (HR per 100 g/day increment = 1.03; 95% CI, 0.97-1.09), total soft drinks (HR = 1.01; 95% CI, 0.98-1.05), sugar-sweetened soft drinks (HR = 0.99; 95% CI, 0.94-1.05), or artificially sweetened soft drinks (HR = 1.02; 95% CI, 0.96-1.08). In these fully adjusted models, none of the beverages was associated with RCC mortality (HR, 95% CI per 100 g/day increment 1.06, 0.97-1.16; 1.03, 0.98-1.09; 0.97, 0.89-1.07; and 1.06, 0.99-1.14, respectively). CONCLUSIONS: Consumption of juices or soft drinks was not associated with RCC incidence or mortality after adjusting for obesity. IMPACT: Soft drink and juice intakes are unlikely to play an independent role in RCC development or mortality.

Low adherence to CKD-specific dietary recommendations associates with impaired kidney function, dyslipidemia, and inflammation.

BACKGROUND/OBJECTIVES: A diet following chronic kidney disease (CKD)-specific recommendations is considered essential for optimal management of patients with CKD. However, data on the adherence to these recommendations and its implications for health-relevant biomarkers are lacking. The objectives were to estimate adherence to CKD-specific dietary recommendations, to identify characteristics and lifestyle variables associated with poor adherence, and to investigate the relationship of adherence with biomarkers. METHODS: In this cross-sectional analysis, average dietary intake was estimated in 3193 participants with moderately severe CKD enrolled into the observational multicenter German CKD study using a food frequency questionnaire. A CKD diet score was developed to assess adherence to CKD-specific dietary recommendations based on intake of sodium, potassium, fiber, protein, sugar, and cholesterol. The associations of dietary adherence with characteristics, lifestyle variables, and biomarker levels were determined. RESULTS: Logistic regression analysis revealed younger age, higher body mass index, male gender, lower educational attainment, various lifestyle variables (cigarette smoking, infrequent alcohol consumption, low physical activity), and lower estimated glomerular filtrate rate associated with lower adherence to dietary recommendations. Low adherence to dietary recommendations was further associated with dyslipidemia, higher uric acid, and C-reactive protein levels. Associations between low dietary adherence and biomarkers were mostly driven by low intake of fiber and potassium, and high intake of sugar and cholesterol. CONCLUSIONS: This study revealed differential characteristics and biomarkers associated with lower adherence to CKD-specific dietary recommendations. Promotion of CKD-specific dietary recommendations may help to mitigate the adverse prognosis in CKD patients.

BMI and BMI change following incident type 2 diabetes and risk of microvascular and macrovascular complications: the EPIC-Potsdam study.

AIMS/HYPOTHESIS: Studies suggest decreased mortality risk among people who are overweight or obese compared with individuals with normal weight in type 2 diabetes (obesity paradox). However, the relationship between body weight or weight change and microvascular vs macrovascular complications of type 2 diabetes remains unresolved. We investigated the association between BMI and BMI change with long-term risk of microvascular and macrovascular complications in type 2 diabetes in a prospective cohort study. METHODS: We studied participants with incident type 2 diabetes from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort, who were free of cancer, cardiovascular disease and microvascular disease at diagnosis (n = 1083). Pre-diagnosis BMI and relative annual change between pre- and post-diagnosis BMI were evaluated in multivariable-adjusted Cox models. RESULTS: There were 85 macrovascular (myocardial infarction and stroke) and 347 microvascular events (kidney disease, neuropathy and retinopathy) over a median follow-up of 10.8 years. Median pre-diagnosis BMI was 29.9 kg/m2 (IQR 27.4-33.2), and the median relative annual BMI change was -0.4% (IQR -2.1 to 0.9). Higher pre-diagnosis BMI was positively associated with total microvascular complications (multivariable-adjusted HR per 5 kg/m2 [95% CI]: 1.21 [1.07, 1.36], kidney disease 1.39 [1.21, 1.60] and neuropathy 1.12 [0.96, 1.31]) but not with macrovascular complications (HR 1.05 [95% CI 0.81, 1.36]). Analyses according to BMI categories corroborated these findings. Effect modification was not evident by sex, smoking status or age groups. In analyses according to BMI change categories, BMI loss of more than 1% indicated a decreased risk of total microvascular complications (HR 0.62 [95% CI 0.47, 0.80]), kidney disease (HR 0.57 [95% CI 0.40, 0.81]) and neuropathy (HR 0.73 [95% CI 0.52, 1.03]), compared with participants with a stable BMI; no clear association was observed for macrovascular complications (HR 1.04 [95% CI 0.62, 1.74]). The associations between BMI gain compared with stable BMI and diabetes-related vascular complications were less apparent. Associations were consistent across strata of sex, age, pre-diagnosis BMI or medication but appeared to be stronger among never-smokers compared with current or former smokers. CONCLUSIONS/INTERPRETATION: Among people with incident type 2 diabetes, pre-diagnosis BMI was positively associated with microvascular complications, while a reduced risk was observed with weight loss when compared with stable weight. The relationships with macrovascular disease were less clear.

Blood Metal Levels and Amyotrophic Lateral Sclerosis Risk: A Prospective Cohort.

OBJECTIVE: Metals have been suggested as a risk factor for amyotrophic lateral sclerosis (ALS), but only retrospective studies are available to date. We compared metal levels in prospectively collected blood samples from ALS patients and controls, to explore whether metals are associated with ALS mortality. METHODS: A nested ALS case-control study was conducted within the prospective EPIC (European Prospective Investigation into Cancer and Nutrition) cohort. Cases were identified through death certificates. We analyzed metal levels in erythrocyte samples obtained at recruitment, as a biomarker for metal exposure from any source. Arsenic, cadmium, copper, lead, manganese, mercury, selenium, and zinc concentrations were measured by inductively coupled plasma-mass spectrometry. To estimate ALS risk, we applied conditional logistic regression models. RESULTS: The study population comprised 107 cases (65% female) and 319 controls matched for age, sex, and study center. Median time between blood collection and ALS death was 8 years (range = 1-15). Comparing the highest with the lowest tertile, cadmium (odds ratio [OR] = 2.04, 95% confidence interval [CI] = 1.08-3.87) and lead (OR = 1.89, 95% CI = 0.97-3.67) concentrations suggest associations with increased ALS risk. Zinc was associated with a decreased risk (OR = 0.50, 95% CI = 0.27-0.94). Associations for cadmium and lead remained when limiting analyses to noncurrent smokers. INTERPRETATION: This is the first study to compare metal levels before disease onset, minimizing reverse causation. The observed associations suggest that cadmium, lead, and zinc may play a role in ALS etiology. Cadmium and lead possibly act as intermediates on the pathway from smoking to ALS. ANN NEUROL 20209999:n/a-n/a.