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Treatment of chronic hypercapnic failure in COPD patients with home noninvasive ventilation (HNIV) remains unclear.To create a curated cohort of all COPD patients on HNIV in Catalonia, perform a cluster analysis, and evaluate mortality evolution.This study was a multicenter, observational study including all COPD patients on HNIV on 1st January of 2018. Patients were selected through the Catalan Health Service, and administrative and clinical data were obtained in the previous four years. Principal component analysis of mixed data and hierarchical clustering were performed to identify clusters of patients. Mortality was evaluated from 1 January 2018 until 31 December 2020.A total of 247 patients were enrolled. They were mostly male (78.1%), with a median (SD) age of 70.4 (9.4) years old. In 60%, 55% and 29% of patients, obesity, sleep apnea and heart failure coexisted, respectively. Cluster analysis identified four well-differentiated groups labeled for their clinical characteristics: (1) obese smokers, (2) very severe COPD, (3) sleep apnea and (4) older comorbid males. Patients belonging to Clusters (2) and (4) had a worse prognosis than patients in Clusters (1) and (3).A high heterogeneity in the prescription of HNIV was demonstrated. Cluster analysis identifies four different groups, of which only one had COPD as the main cause of ventilation, while the other three clusters showed a predominance of other comorbidities. This leads to different survival outcomes, including an overlapping phenotype of obesity-related disease and sleep apnea with better survival.

Background: Although an association between lung function and subclinical atherosclerosis has been reported, it remains unclear whether this association is only driven by tobacco smoking. We aimed to assess this in a population with at least one cardiovascular risk factor. Methods: We recruited 6209 subjects aged between 45 and 70 years with at least one cardiovascular risk factor (excluding diabetes mellitus) participating in the ILERVAS project 2015–2018. Lung function was determined by spirometry. Subclinical atherosclerosis was assessed with the ankle–brachial index (ABI) and the presence of carotid and femoral plaques measured by ultrasound. Results: A total of 5927 subjects were included: 49% male, median (p25–p75) age 57 years (52–62). Plaques were found in 4337 (73.2%) of the subjects. The patients with atherosclerosis showed worse lung function: median forced expiratory volume in one second (FEV1) 95% and forced vital capacity (FVC) 94% in the patients with plaques vs. 99% and 98% in the other patients (p < 0.001). Adjusted models stratified by smoking status showed that being in the lower quartiles of FEV1 % was associated with carotid and femoral plaques (OR 1.599, p = 0.005; and OR 1.654, p = 0.006), whereas FVC % was inversely associated with carotid plaques (OR 0.967, p = 0.041). A pathological ABI was associated with worse FEV1 (OR 1.971, p = 0.038) and the presence of airway obstruction (OR 1.658, p = 0.015). However, these differences were restricted to current smokers. Conclusions: Lung function impairment was correlated with subclinical atherosclerosis only in current smokers. This highlights the unique role of smoking-related vascular and pulmonary dysfunction in early stages of pulmonary and cardiovascular afflictions.

Introduction Classic cardiovascular risk factors do not explain all the cardiovascular events. Obstructive sleep apnoea (OSA) has been proposed as a potential and prevalent cardiovascular risk factor. Our study aimed to describe the prevalence of OSA in a middle-aged cohort with mild–moderate cardiovascular risk and evaluate its association with atherosclerotic disease. Methods This is an observational cross-sectional ancillary study of the ILERVAS project which was aimed to study subclinical arterial disease in a cohort with mild–moderate cardiovascular risk. In a sample of consecutive subjects, we performed a sleep study and evaluate OSA prevalence and its association with carotid and femoral atheroma plaques and atherosclerotic burden. Results Overall, 966 subjects with a median age of 57 years (25–75th percentile; 52–62) and a body mass index (BMI) of 28.5 kg/m2 (25.6–31.6) were included. Of these, 72.6% (69.7%–75.3%) had OSA (apnoea–hypopnoea index (AHI) ≥ 5/h); 35.7% (32.8%–38.8%) had mild OSA (AHI 5–14.9/h) and 36.9% (33.9%–39.9%) had moderate/severe OSA (AHI ≥ 15/h). Mean oxygen saturation and the percentage of time with oxygen saturation Conclusions This study confirms a high prevalence of OSA in patients with mild–moderate cardiovascular risk and shows an association between atherosclerotic burden, total and femoral plaque with CT90 and mean oxygen saturation, suggesting the importance of OSA-related hypoxaemia in the induction of atherosclerotic disease.

Purpose The determination of the Programmed Death Ligand-1 (PD-L1) expression is part of the diagnostic algorithm for advanced non-small-cell lung cancer (NSCLC) patients. We aimed to analyze the diagnostic performance of EBUS-TBNA performed as first-choice nodal staging procedure for the determination of PD-L1 expression in NSCLC patients.Methods Longitudinal-prospective study including NSCLC patients diagnosed between January 2018 and October 2019, for whom a primary tumor biopsy sample and an EBUS-TBNA cytological malignant sample were available. Samples with fewer than 100 malignant cells were considered inadequate. PDL-1 IHC 22C3 pharmDx antibody was used. The percentage of tumor cells expressing PD-L1, setting 1% and 50% as cutoff points, was collected. The weighted kappa coefficient was used to assess the concordance of PD-L1 expression. The PD-L1 expression was compared precision terms.Results From a total of 43 patients, 53 pairs of samples were obtained, of which 23 (43.4%) were adequate and included for analysis. The weighted kappa coefficient for PD-L1 expression was 0.41 (95% CI: 0.15–0.68) and 0.56 (95% CI: 0.23–0.9) for cutoff values ≥ 1% and ≥ 50%, respectively. In advanced stages, the weighted kappa coefficient was 0.6 (95% CI: 0.3–0.9) and 1 (95% CI: 1–1) for PD-L1 expression cutoff values ≥ 1% and ≥ 50%, respectively. EBUS-TBNA showed a sensitivity, specificity, positive predictive value, and negative predictive value of 1 to detect PDL-1 expression ≥ 50% in advanced stages.Conclusion EBUS-TBNA performed as first nodal staging procedure provides reliable specimens for the detection of PD-L1 expression ≥ 50% in advanced NSCLC patients and could guide immunotherapy.

We characterized the polysomnography (PSG) parameters associated with alterations in the circadian blood pressure (BP) pattern aiming to identify the main contributors to explain the nondipper profile in obstructive sleep apnea (OSA). This is an observational prospective-multicenter study that included participants referred to the sleep unit for suspected OSA. Following a PSG study, subjects with an apnea–hypopnea index (AHI) ≥5 events/hr were included. Two groups were established based on the 24-hr ambulatory blood pressure monitoring dipping ratio (DR; night/day BP ratio): dippers (DR ≤ 0.9) and nondippers (DR > 0.9). The cohort consisted of 299 patients: 131 (43.8%) dippers and 168 (56.2%) nondippers. A significant increase in the risk of presenting a nondipper BP pattern was found along with AHI gain [odds ratio (OR) (95% CI) = 1.71 (1.28 to 2.28)]. The best AHI cutoff for predicting nondipper status was 25.2 events/hr, increasing the OR (95% CI) to 3.50 (2.02 to 6.07). The hypopnea index [OR (95% CI) = 1.70 (1.27 to 2.26)], TSat90 [OR (95% CI) = 1.41 (1.06 to 1.87)], and respiratory arousal index [OR (95% CI) = 1.74 (1.30 to 2.34)] were individually associated with the risk of a nondipping pattern. Multivariate variable selection processes identified the respiratory arousal index as the most relevant risk factor for the nondipper profile, beyond classical clinical risk factors and usual PSG metrics.

Background: Obstructive sleep apnea (OSA) is associated with a recurrent cardiovascular event (CVE) risk in patients with a first acute coronary syndrome (ACS). However, the pathological pathways by which OSA promotes this deleterious role are unknown. We aim to explore the proteomic profile associated with OSA that promote the recurrent CVE risk in severe OSA patients with ACS without previous cardiovascular diseases. Methods: This post-hoc analysis from the ISAACC study (NCT01335087) included 86 patients admitted for ACS. Patients underwent respiratory polygraphy for the first 24-72 h to OSA diagnosis. We analyzed of 276 cardiovascular and inflammatory related proteins in baseline fasting plasma samples using proximity expression assay technology (Olink®, Sweden). Protein levels were compared between severe OSA patients with/without recurrent CVEs during follow-up. Random forest was conducted to select relevant proteins and generate a predictive model of recurrent CVE. Results: We included 86 patients (median age: 61 years, median BMI: 29.4 kg/m2 and 86 % males) admitted for ACS with severe OSA (56 without recurrent CVE/30 with recurrent CVE). The plasma levels of 38 proteins were differentially expressed between groups. Additionally, 12 proteins had a significant association with respiratory polygraphy parameters. Three proteins discriminate with an AUC of 0.81 (95 % CI of 0.71-0.9) between severe OSA patients with and without recurrent CVE. These proteins were implicated in cell proliferation, communication and apoptosis, and regulation/response to the inflammatory and immune systems. Conclusion: In ACS patients with severe OSA, a proteomic profile was associated with recurrent CVEs. This proteomic profile was correlated with specific OSA parameters from respiratory polygraphy. Proteomic profiling may provide an new direction for patient risk stratification and clinical management. Instituto de Salud Carlos III (ISCIII) (PI10/02763, PI10/02745, PI18/00449, PI21/ 00337) (Spain), co-funded by the European Union, IRBLleida-Fundació Dr.Pifarré, CERCA Programme/Generalitat de Catalunya (Spain), SEPAR (Spain), ResMed Ltd. (Australia), Esteve-Teijin (Spain), Oxigen Salud (Spain), Associació Lleidatana de Respiratori (ALLER) (Spain), and Sociedad Española de Sueño (SES) (Spain). AZ held a predoctoral fellowship “Ajuts 2021 de Promoció de la Recerca en Salut-9ª edició” from IRBLleida/Diputació de Lleida. JdB acknowledges receiving financial support from ISCIII (Miguel Servet 2019: CP19/00108), co-funded by the European Social Fund (ESF), “Investing in your future”. MS has received financial support from a “Ramón y Cajal” grant (RYC2019-027831-I) from the “Ministerio de Ciencia e Innovación- Agencia Estatal de Investigación ” co-funded by the European Social Fund (ESF)/“Investing in your future”.

Background: Coffee contains many bioactive substances that can play a role on colorectal cancer. Epidemiological evidence of coffee intake and colorectal cancer is, however, inconsistent. Aim: To provide further information on the risk of colorectal cancer in relation to coffee consumption. Methods: Data derive from two companion case-control studies conducted in Italy and Spain within the European Union Project on Health Impacts of long-term exposure to disinfection by-products in Drinking Water and the Spanish Multi-Case Control study on Cancer. These included a total of 2289 incident cases with colorectal cancer and 3995 controls with information on coffee intake. Odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were derived from unconditional logistic regression models, adjusted for study centre, sex, age, education, smoking, and other covariates. Results: Compared with never coffee drinkers, the OR was 0.99 (95% CI 0.95-1.02) for total coffee consumption. There was no significant trend in risk with dose or duration, the ORs being 0.95 (95% CI 0.72-1.25) for an amount of five or more cups per day of coffee and 0.95 (95% CI 0.75-1.19) for a duration of consumption of 50 years or longer. The OR was 1.04 (95% CI 0.87-1.25) for two or more cups per day of decaffeinated coffee. There were no heterogeneity across strata of various covariates, as well as no apparent differences between various anatomical subsites. Conclusion: This large pooled analysis of two studies shows no association of coffee and decaffeinated coffee with colorectal cancer risk.

The etiology of prostate cancer (PCa) is not well-known, and the role of diet is not well established. We aimed to evaluate the role of the inflammatory power of the diet, measured by the Dietary Inflammatory Index (DIIA population-based multicase-control (MCC-Spain) study was conducted. Information was collected on sociodemographic characteristics, personal and family antecedents, and lifestyles, including diet from a Food Frequency Questionnaire. The inflammatory potential of the diet was assessed using the energy-adjusted Dietary Inflammatory Index (E-DII) based on 30 parameters (a higher score indicates a higher inflammatory capacity of the diet). Tertiles of E-DII were created using the cut-off points from the control group. The International Society of Urology Pathology (ISUP) was grouped as ISUP 1, ISUP 2, or ISUP 3-5. Unconditional logistic regression models were used to estimate adjusted odds ratios (aOR) and 95% confidence intervals (CI) for the association between E-DII score and PCa risk.A total of 928 PCa cases and 1278 population controls were included. Among PCa cases, the mean value of the E-DII score was 0.18 (SD: 1.9) vs. 0.07 (SD: 1.9) in the control group (p = 0.162). Cases with a more pro-inflammatory diet (3rd tertile) had the highest risk of PCa, aORA positive association was observed between consuming a pro-inflammatory diet and PCa in the MCC-Spain population, specifically for an ISUP grade greater or equal than 2.

Background: Recent studies have suggested that the population with a first event of acute coronary syndrome (ACS) is susceptible to the deleterious effects of obstructive sleep apnea (OSA)(Zapater, A. et al. Am J Respir Crit Care Med 2020; 202:1698-1706). Aim and objectives: We explore respiratory polygraphy parameters that are associated with an increased risk of recurrence cardiovascular events in this subgroup of patients with ACS. Methods: Post-hoc analysis of the ISAACC study, including 723 patients admitted for a first ACS (NCT01335087). A principal component analysis (PCA) was performed using six respiratory polygraphy parameters: apnea-hypopnea index (AHI), oxygen desaturation index, mean and minimum oxygen saturation (SaO2), average duration of events and percentage of time with SaO2 Results: PCA showed that two respiratory polygraphy patterns accounted for 70% of variance. A first pattern was mainly characterized by low mean SaO2 and events with severe desaturation (High Time with SaO2 Conclusions: A sleep apnea pattern, mainly characterized by high mean SaO2 and longer duration events with severe desaturation, is associated with a high risk of recurrent cardiovascular events in patients who have suffered a first ACS.

Background: Patients with acute respiratory distress syndrome (ARDS) due to COVID19 may present physical and functional respiratory sequelae at short term follow-up. Objective: To evaluate the impact of a pulmonary rehabilitation program (PRP) on clinical and functional respiratory alterations in COVID19 patients with ARDS after hospital discharge. Methodology: Prospective interventional study that included patients with clinical and/or functional respiratory alterations after 3 month of hospital discharge. Patients underwent a 9-week PRP, two sessions per week. The following variables were measured pre and post PRP: pulmonary function tests, 6’ walking test (6MWT), sit to stand test, dyspnea (mMRC), fatigue (FACIT-F), physical activity (IPAQ) and anxiety and depression (HADS) questionnaires. Results: 21 patients completed the PRP to date. They were mostly male (66.7%), with a mean age of 56.5±12 years old. 76.2% needed ICU admission and 43% required invasive mechanical ventilation. After PRP, there was a significant increase in the lung diffusing capacity (62±12% to 72±11%, p=0.04) as well as in the mean distance covered in the 6MWT (421±75 to 465±93 meters, p=0.03). We observed an improvement in dyspnea (p=0.01), in IPAQ (1574±1168 to 3045±1816 METS, p Conclusions: nine-week PRP could improve respiratory function, exercise capacity, and symptoms such as dyspnea or fatigue in patients with ARDS caused by COVID19 after hospital discharge. Supported in part by CIBERESUCICOVID (COV20/0011)

Although outdoor air pollution and particulate matter in outdoor air have been consistently linked with increased lung cancer risk, the evidence for associations at other cancer sites is limited. Bladder cancer shares several risk factors with lung cancer and some positive associations of ambient air pollution and bladder cancer risk have been observed. This study examined associations of ambient air pollution and bladder cancer risk in the large-scale Spanish Bladder Cancer Study. Estimates of ambient fine particulate matter (PM2.5 ) and nitrogen dioxide (NO2 ) concentrations were assigned to the geocoded participant residence of 938 incident bladder cancer cases and 973 hospital controls based on European multicity land-use regression models. Adjusted odds ratios (ORs) and 95% confidence intervals (CI) for associations of ambient air pollution and bladder cancer risk were estimated using unconditional logistic regression models. Overall, there was no clear association between either ambient PM2.5 (OR per 5.9 μg/m3 = 1.06, 95% CI 0.71-1.60) or NO2 (OR per 14.2 μg/m3 = 0.97, 95% CI 0.84-1.13) concentrations and incident bladder cancer risk. There was no clear evidence for effect modification according to age group, sex, region, education, cigarette smoking status, or pack-years. Results were also similar among more residentially stable participants and in two-pollutant models. Overall, there was no clear evidence for associations of ambient PM2.5 and NO2 concentrations and incident bladder cancer risk. Further research in other large-scale population studies is needed with detailed information on measured or modeled estimates of ambient air pollution concentrations and individual level risk factors.

The original version of this Article contained an error in the spelling of the author Manuela Gago-Dominguez, which was incorrectly given as Manuela G. Dominguez. This has now been corrected in both the PDF and HTML versions of the Article.

Background: Lung cancer is mainly diagnosed at advanced or locally advanced stages, usually when symptoms become evident. However, sometimes it may be diagnosed incidentally during routine care, while patients are still asymptomatic. Prognosis differences based on symptomatic presentation have been partially explored. Our aim was to analyze the prognostic value of the initial symptomatic state of the patients in a general lung cancer cohort. Methods: Observational ambispective study including patients consecutively diagnosed with primary lung cancer between January 2016 and December 2018 via the lung cancer Fast Diagnostic Track (FDT). Patients were followed up until death or the end of the study in September 2019. Asymptomatic patients were compared with patients presenting symptoms. Overall survival (OS) of both groups was compared using the log-rank test. Cox regression analysis was performed to clarify the effect of the symptomatic status at diagnosis on survival. Additionally, propensity score (PS) matching analysis was performed. Results: A total of 267 patients were analyzed; 83.5% were men, with a mean (SD) age at diagnosis of 68 (10.7) years. Incidental diagnosis was ascertained in 24.7% of cases. Asymptomatic patients presented more frequently stage I and II disease compared to symptomatic patients (51.5% vs. 14%), and exhibited a significantly better prognosis, with a 3-year OS of 63.6% (vs. 30.3%) and a median OS that was not reached during follow-up (vs. 10.3 months). With an adjusted multivariate Cox proportional hazard model, we obtained a HR (95% CI) of 2.63 (95% CI, 1.6-4.2; P

Background In anti-phospholipase A2 receptor (PLA2R) membranous nephropathy (MN) there is controversy whether spontaneous remission (SR) can be predicted using a single titre or by assessing the dynamic changes in anti-PLA2R antibody (ab) titres. The study objective was to identify the optimal dynamics of anti-PLA2Rab titres to predict SR in MN. Methods A total of 127 nephrotic patients with anti-PLA2R-MN were prospectively followed up for 6 months under conservative treatment. Anti-PLA2Rabs and proteinuria were assessed at diagnosis and monthly thereafter. The primary endpoint (PEP) was a reduction of proteinuria ≥50% at 6 months. Logistic models with baseline and evolutive anti-PLA2Rab titres were developed to predict the PEP. Results A total of 28 patients (22%) reached the PEP. These patients were more frequently female and had significantly lower baseline proteinuria and anti-PLA2Rab titres. An anti-PLA2R titre ≤97.5 RU/mL at diagnosis had a sensitivity of 71% and a specificity of 81% to predict the PEP. The model including baseline anti-PLA2Rabs and a reduction ≥15% at 3 months predicted the PEP with a sensitivity of 93% and a specificity of 80%, with an area under the curve that was significantly greater than that obtained with relative changes of proteinuria in the same period of time {odds ratio [OR] 0.95 [95% confidence interval (CI) 0.91–0.98 versus OR 0.79 [95% CI 0.70–0.88], respectively; P = 0.0013}. Conclusions Combining the baseline anti-PLA2Rab titres with their relative changes at 3 months after diagnosis gives the earliest prediction for achieving a reduction of urinary protein excretion ≥50% at 6 months in MN, thereby shortening the observation period currently recommended to make individualized decisions to start immunosuppressive therapy., Graphical Abstract Graphical Abstract

Experimental evidence indicates that exercise performed at different times of the day may affect circadian rhythms and circadian disruption has been linked to breast and prostate cancer. We examined in a population‐based case‐control study (MCC‐Spain) if the time‐of‐day when physical activity is done affects prostate and breast cancer risk. Lifetime recreational and household physical activity was assessed by in‐person interviews. Information on time‐of‐day of activity (assessed approximately 3 years after the assessment of lifetime physical activity and confounders) was available for 781 breast cancer cases, 865 population female controls, 504 prostate cases and 645 population male controls from 10 Spanish regions, 2008‐2013. We estimated odds ratios (ORs) and 95% confidence intervals (95% CI) for different activity timings compared to inactive subjects using unconditional logistic regression adjusting for confounders. Early morning (8‐10 am) activity was associated with a protective effect compared to no physical activity for both breast (OR = 0.74, 95% CI = 0.48‐1.15) and prostate cancer (OR = 0.73, 95% CI = 0.44‐1.20); meta‐OR for the two cancers combined 0.74 (95%CI = 0.53‐1.02). There was no effect observed for breast or prostate cancer for late morning to afternoon activity while a protective effect was also observed for evening activity only for prostate cancer (OR = 0.75, 95% CI = 0.45‐1.24). Protective effects of early morning activity were more pronounced for intermediate/evening chronotypes for both cancers. This is the first population‐based investigation identifying a differential effect of timing of physical activity on cancer risk with more pronounced effects for morning hour activity. Our results, if confirmed, may improve current physical activity recommendations for cancer prevention., What's new? Exercise protects against a variety of cancers, but does time of day matter? Disrupting the body's circadian rhythm can boost cancer risk. Here, the authors compared breast and prostate cancer risk among people who exercised in the early morning, late morning, afternoon, and evening. They conducted a population‐based case‐control study, in which participants filled out a questionnaire about their patterns of sleeping, eating, and exercising. Exercising in the early morning appeared to be more strongly protective against breast and prostate cancer than exercising later in the day. Evening exercise appeared to have a moderate protective effect on prostate cancer.

This research was supported by the “Acción Transversal del Cancer”, approved by the Spanish Council of Ministers on 11th October 2007, by the Instituto de Salud Carlos III-FEDER [grant number:PI08/1770, PI08/0533, PI08/1359, PS09/00773-Cantabria, PS09/01286-León, PS09/01903-Valencia, PS09/02078-Huelva, PS09/ 01662-Granada, PI11/01403, PI11/01889-FEDER, PI11/00226, PI11/01810, PI11/02213, PI12/00488, PI12/00265, PI12/01270, PI12/00715, PI12/00150, PI14/01219, PI14/0613, PI15/00069, PI15/00914, PI15/01032, PI11/01810, PI14/01219, PI11/02213, PIE16/00049, PI17/01179, PI17-00092], by the Fundación Marqués de Valdecilla [grant number: API 10/09], by the ICGC International Cancer Genome Consortium CLL (The ICGC CLL-Genome Project is funded by Spanish Ministerio de Economía y Competitividad (MINECO) through the Instituto de Salud Carlos III (ISCIII)), by the Red Temática de Investigación del Cáncer (RTICC) del ISCIII [grant number: RD12/0036/0036], by the Junta de Castilla y León [grant number: LE22A10-2], by the Consejería de Salud of the Junta de Andalucía [grant number: PI-0571-2009, PI-0306-2011, salud201200057018tra], by the Conselleria de Sanitat of the Generalitat Valenciana [grant number: AP_061/10], by the Recercaixa [grant number: 2010ACUP00310], by the Regional Government of the Basque Country, by the Consejería de Sanidad de la Región de Murcia, by the European Commission [grant number: FOOD-CT-2006-036224-HIWATE], by the Spanish Association Against Cancer (AECC) Scientific Foundation [grant number: GCTRA18022MORE], by the Catalan Government-Agency for Management of University and Research Grants (AGAUR) [grant number: 2014SGR647, 2014SGR850 and 2017SGR723], by the Fundación Caja de Ahorros de Asturias and by the University of Oviedo. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., There is evidence for the influence of socioeconomic status (SES) on healthy behaviours but the effect of social mobility (SM) is not yet well known. This study aims to analyse the influence of origin and destination SES (O-SES and D-SES) and SM on healthy behaviours and co-occurrence, from an integrated gender and age perspective. Data were obtained from the controls of MCC-Spain between 2008–2013 (3,606 participants). Healthy behaviours considered: healthy diet, moderate alcohol consumption, non-smoking and physical activity. SM was categorized as stable high, upward, stable medium, downward or stable low. Binary and multinomial logistic regression models were adjusted. Those aged, “Acción Transversal del Cancer” by the Spanish Council of Ministers, Instituto de Salud Carlos III-FEDER [grant number:PI08/1770, PI08/0533, PI08/1359, PS09/00773-Cantabria, PS09/01286-León, PS09/01903-Valencia, PS09/02078-Huelva, PS09/ 01662-Granada, PI11/01403, PI11/01889-FEDER, PI11/00226, PI11/01810, PI11/02213, PI12/00488, PI12/00265, PI12/01270, PI12/00715, PI12/00150, PI14/01219, PI14/0613, PI15/00069, PI15/00914, PI15/01032, PI11/01810, PI14/01219, PI11/02213, PIE16/00049, PI17/01179, PI17-00092, Fundación Marqués de Valdecilla [grant number: API 10/09], ICGC International Cancer Genome Consortium CLL (The ICGC CLL-Genome Project is funded by Spanish Ministerio de Economía y Competitividad (MINECO) through the Instituto de Salud Carlos III (ISCIII)), Red Temática de Investigación del Cáncer (RTICC) del ISCIII [grant number: RD12/0036/0036], Junta de Castilla y León [grant number: LE22A10-2], Consejería de Salud of the Junta de Andalucía [grant number: PI-0571-2009, PI-0306-2011, salud201200057018tra], Conselleria de Sanitat of the Generalitat Valenciana [grant number: AP_061/10], Recercaixa [grant number: 2010ACUP00310], Regional Government of the Basque Country, Consejería de Sanidad de la Región de Murcia, European Commission [grant number: FOOD-CT-2006-036224-HIWATE], Spanish Association Against Cancer (AECC) Scientific Foundation [grant number: GCTRA18022MORE, Catalan Government-Agency for Management of University and Research Grants (AGAUR) [grant number: 2014SGR647, 2014SGR850 and 2017SGR723], Fundación Caja de Ahorros de Asturias, University of Oviedo

Brain tumours (BTs) are one of the most frequent tumour types in young people. We explored the association between tap water, exposure to trihalomethanes (THM) and nitrate and neuroepithelial BT risk in young people. Analysis of tap water consumption were based on 321 cases and 919 appendicitis controls (10–24 years old) from 6 of the 14 participating countries in the international MOBI-Kids case-control study (2010–2016). Available historical residential tap water concentrations of THMs and nitrate, available from 3 countries for 86 cases and 352 controls and 85 cases and 343 for nitrate, respectively, were modelled and combined with the study subjects’ personal consumption patterns to estimate ingestion and residential exposure levels in the study population (both pre- and postnatal). The mean age of participants was 16.6 years old and 56% were male. The highest levels and widest ranges for THMs were found in Spain (residential and ingested) and Italy and in Korea for nitrate. There was no association between BT and the amount of tap water consumed and the showering/bathing frequency. Odds Ratios (ORs) for BT in relation to both pre- and postnatal residential and ingestion levels of THMs were systematically below 1 (OR = 0.37 (0.08–1.73)) for postnatal average residential THMs higher than 66 μg/L. For nitrate, all ORs were above 1 (OR = 1.80 (0.91–3.55)) for postnatal average residential nitrate levels higher than 8.5 mg/L, with a suggestion of a trend of increased risk of neuroepithelial BTs with increasing residential nitrate levels in tap water, which appeared stronger in early in life. This, to our knowledge, is the first study on this topic in young people. Further research is required to clarify the observed associations.

Aims: To study whether the consumption of ultra-processed foods and drinks is associated with breast, colorectal, and prostate cancers. Methods: Multicentric population-based case-control study (MCC-Spain) conducted in 12 Spanish provinces. Participants were men and women between 20 and 85 years of age with diagnoses of colorectal (n = 1852), breast (n = 1486), or prostate cancer (n = 953), and population-based controls (n = 3543) frequency-matched by age, sex, and region. Dietary intake was collected using a validated food frequency questionnaire. Foods and drinks were categorized according to their degree of processing based on the NOVA classification. Unconditional multivariable logistic regression was used to evaluate the association between ultra-processed food and drink consumption and colorectal, breast, and prostate cancer. Results: In multiple adjusted models, consumption of ultra-processed foods and drinks was associated with a higher risk of colorectal cancer (OR for a 10% increase in consumption: 1.11; 95% CI 1.04-1.18). The corresponding odds for breast (OR 1.03; 95% CI 0.96-1.11) and prostate cancer (OR 1.02; 95% CI 0.93-1.12) were indicative of no association. Conclusions: Results of this large population-based case-control study suggest an association between the consumption of ultra-processed foods and drinks and colorectal cancer. Food policy and public health should include a focus on food processing when formulating dietary guidelines. ? 2021 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

International audience; Medical diagnostic X-rays are an important source of ionizing radiation (IR) exposure in the general population; however, it is unclear if the resulting low patient doses increase lymphoma risk. We examined the association between lifetime medical diagnostic X-ray dose and lymphoma risk, taking into account potential confounding factors, including medical history. The international Epilymph study (conducted in the Czech-Republic, France, Germany, Ireland, Italy, and Spain) collected self-reported information on common diagnostic X-ray procedures from 2,362 lymphoma cases and 2,465 frequency-matched (age, sex, country) controls. Individual lifetime cumulative bone marrow (BM) dose was estimated using time period-based dose estimates for different procedures and body parts. The association between categories of BM dose and lymphoma risk was examined using unconditional logistic regression models adjusting for matching factors, socioeconomic variables, and the presence of underlying medical conditions (atopic, autoimmune, infectious diseases, osteoarthritis, having had a sick childhood, and family history of lymphoma) as potential confounders of the association. Cumulative BM dose was low (median 2.25 mGy) and was not positively associated with lymphoma risk. Odds ratios (ORs) were consistently less than 1.0 in all dose categories compared to the reference category (less than 1 mGy). Results were similar after adjustment for potential confounding factors, when using different exposure scenarios, and in analyses by lymphoma subtype and by type of control (hospital-, population-based). Overall no increased risk of lymphoma was observed. The reduced ORs may be related to unmeasured confounding or other sources of systematic bias.We found little evidence that chronic medical conditions confound lymphoma risk and medical radiation associations.

Purpose To evaluate the association between dietary fat and fat subtype and breast cancer development. Methods We conducted a case-control study with 1181 cases of incident breast cancer, diagnosed between 2007 and 2012, and 1682 population controls frequency matched (by age, sex, and region) from the Spanish multicenter case-control study MCC-Spain. Results We found a significant protective effect in premenopausal women of total fat intake [OR 0.51 95% CI (0.31-0.86) highest versus lowest tertile], but no effect was observed in menopausal women [OR 1.15 95% CI (0.83-1.60)]. Analyzing by type of fat, this protective effect persisted only for the monounsaturated fatty acids [OR 0.51 95% CI (0.32-0.82)]. In contrast, other fatty acids did not have a significant effect. In addition, a protection against risk of breast cancer was found when polyunsaturated fats were "substituted" by monounsaturated, maintaining the same total fat intake [OR 0.68 95% CI (0.47-0.99)]. Finally, analyzing by breast cancer subtype, we found no effect, except in premenopausal women where intake of moderate [OR 0.52 95% CI (0.33-0.82)] and high monounsaturated fatty acids [OR 0.47 95% CI (0.27-0.82)] maintains a protective effect against ER/PR + tumors. In contrast, in menopausal women, a high intake of monounsaturated fatty acids was associated with higher risk of HER2 + tumors [OR 2.00 95% CI (0.97-4.13)]. Conclusion Our study shows a differential effect of monounsaturated fatty acids according to menopausal status and breast cancer subtype.

Background: Trihalomethanes (THMs) are widespread disinfection by-products (DBPs) in drinking water, and long-term exposure has been consistently associated with increased bladder cancer risk. Objective: We assessed THM levels in drinking water in the European Union as a marker of DBP exposure and estimated the attributable burden of bladder cancer. Methods: We collected recent annual mean THM levels in municipal drinking water in 28 European countries (EU28) from routine monitoring records. We estimated a linear exposure-response function for average residential THM levels and bladder cancer by pooling data from studies included in the largest international pooled analysis published to date in order to estimate odds ratios (ORs) for bladder cancer associated with the mean THM level in each country (relative to no exposure), population-attributable fraction (PAF), and number of attributable bladder cancer cases in different scenarios using incidence rates and population from the Global Burden of Disease study of 2016. Results: We obtained 2005-2018 THM data from EU26, covering 75% of the population. Data coverage and accuracy were heterogeneous among countries. The estimated population-weighted mean THM level was 11.7 μg/L [standard deviation (SD) of 11.2]. The estimated bladder cancer PAF was 4.9% [95% confidence interval (CI): 2.5, 7.1] overall (range: 0-23%), accounting for 6,561 (95% CI: 3,389, 9,537) bladder cancer cases per year. Denmark and the Netherlands had the lowest PAF (0.0% each), while Cyprus (23.2%), Malta (17.9%), and Ireland (17.2%) had the highest among EU26. In the scenario where no country would exceed the current EU mean, 2,868 (95% CI: 1,522, 4,060; 43%) annual attributable bladder cancer cases could potentially be avoided. Discussion: Efforts have been made to reduce THM levels in the European Union. However, assuming a causal association, current levels in certain countries still could lead to a considerable burden of bladder cancer that could potentially be avoided by optimizing water treatment, disinfection, and distribution practices, among other possible measures. https://doi.org/10.1289/EHP4495. This work was funded by the EU Seventh Framework Programme EXPOsOMICS Project (grant agreement no. 308610), Human Genetics Foundation agreement 17-080 ISG, and CIBER Epidemiología y Salud Pública (CIBERESP). ISGlobal is a member of the Centres de Recerca de Catalunya (CERCA) Programme, Generalitat de Catalunya. We would like to thank the members of the European Programme for Intervention Epidemiology Training (EPIET) Alumni Network (EAN) for their assistance in identifying appropriate national focal points in specific countries. We would also like to thank the people from the national and local authorities and universities for the provision of THM data: Sofie Dewaele (Leefmilieu Brussel-BIM/Bruxelles Environnement–IBGE Afd. Inspectie en verontreinigde bodems, Dpt. Geïntegreerde controles, Brussels, Belgium), Steven Vanderwaeren (Team Watervoorziening-en gebruik, Vlaamse Milieumaatschappij, Afdeling Operationeel Waterbeheer, Brussels, Belgium), Jurica Štiglić (Croatian National Institute of Public Health, Zagreb, Croatia), Outi Zacheus (National Institute for Health and Welfare, Kuopio, Finland), Carmelo Massimo Maida (University of Palermo, Italy), Anna Norata (Agenzia di Tutela della Salute Citta’ Metropolitana Milano, Italy), Marco Chiesa (Agenzia di Tutela della Salute della Val Padana-Sede Territoriale di Mantova, Italy), Vincenzo Clasadonte (Agenzia di Tutela della Salute della Val Padana-Sede Territoriale Cremona, Italy), Emilia Guberti (Local Health Authority, Bologna, Italy), Cinzia Govoni (Local Health Authority, Ferrara, Italy), Paolo Pagliai (Local Health Authority Romagna, Italy), Daniela de Vita (Local Health Authority, Reggio Emilia, Italy), Danila Tortorici (Regional Health and Social Agency, Emilia Romagna, Italy), Marco Schintu (University of Cagliari, Italy), Paolo Montuori (University of Napoli Federico II, Italy), Audrius Dedele (Department of Environmental Sciences, Faculty of Natural Sciences, Vytautas Magnus University, Kaunas, Lithuania), Stefan Cachia (Water Services Corporation, Malta), Roel C.H. Vermuelen (Institute of Risk Assessment Sciences, Utrecht University, Utrecht, the Netherlands), the Chief Sanitary Inspectorate (Poland), Luís Simas (Water Quality Department, Entidade Reguladora, Dos Serviços De Águas e Resíduos, Lisboa, Portugal), and Christina Forslund (Food Control Department, National Food Agency, Uppsala, Sweden). Finally, we would like to thank Charles F. Lynch (University of Iowa, USA), Sylvaine Cordier (Université de Rennes, Inserm, École des hautes études en santé Publique (EHESP), Rennes, France), Will D. King (Queen’s University, Kingston, Ontario, Canada), and Kenneth P. Cantor (National Cancer Institute, National Institutes of Health, Bethesda, USA) for allowing us to use the dose–exposure data from their study. We are grateful to Xavier Basagaña (ISGlobal) for statistical assistance.

Prostate, breast and colorectal cancer are the most common tumours in Spain. The aim of the present study was to evaluate the association between adherence to nutrition-based guidelines for cancer prevention and prostate, breast and colorectal cancer, in the MCC-Spain case-control study. A total of 1,718 colorectal, 1,343 breast and 864 prostate cancer cases and 3,431 population-based controls recruited between 2007 and 2012, were included in the present study. The World Cancer Research Fund/American Institute for Cancer Research (WCRC/AICR) score based on six recommendations for cancer prevention (on body fatness, physical activity, foods and drinks that promote weight gain, plant foods, animal foods and alcoholic drinks; score range 0-6) was constructed. We used unconditional logistic regression analysis adjusting for potential confounders. One-point increment in the WCRF/AICR score was associated with 25% (95% CI 19-30%) lower risk of colorectal, and 15% (95% CI 7-22%) lower risk of breast cancer; no association with prostate cancer was detected, except for cases with a Gleason score ≥7 (poorly differentiated/undifferentiated tumours) (OR 0.87, 95% CI 0.76-0.99). These results add to the wealth of evidence indicating that a great proportion of common cancer cases could be avoided by adopting healthy lifestyle habits.

Introduction Preventable risk factors for chronic lymphocytic leukemia (CLL) remain largely unknown. The aim of this study was to evaluate the association between adherence to nutrition-based guidelines for cancer prevention and CLL, in the MCC-Spain case–control study. Methods A total of 318 CLL cases and 1293 population-based controls were included in the present study. The World Cancer Research Fund/American Institute for Cancer Research (WCRC/AICR) score based on the 2018 recommendations for cancer prevention (on body fatness, physical activity, and diet) was constructed. We used logistic regression analysis adjusting for potential confounders. Results Individuals in the highest tertile of the WCRF/AICR score had an odds ratio for CLL of 1.25 (95 % CI 0.91; 1.73) compared with individuals with low adherence (p-trend = 0.172). Each point increment in the score was associated with an OR for CLL of 1.06 (95 % CI 0.91; 1.23). Analyses by severity of disease did not show significant heterogeneity of effects. Conclusion Overall, our results do not support an association between the WCRF/AICR score and CLL, yet we might have been limited by statistical power and study design to detect modest associations. Further research, ideally with a prospective design, long follow-up, and including additional lymphoma subtypes, is warranted to confirm the impact of composite healthy lifestyle behaviors on lymphoma risk.

Instead of looking at individual nutrients or foods, dietary pattern analysis has emerged as a promising approach to examine the relationship between diet and health outcomes. Despite dietary patterns being compositional (i.e. usually a higher intake of some foods implies that less of other foods are being consumed), compositional data analysis has not yet been applied in this setting. We describe three compositional data analysis approaches (compositional principal component analysis, balances and principal balances) that enable the extraction of dietary patterns by using control subjects from the Spanish multicase-control (MCC-Spain) study. In particular, principal balances overcome the limitations of purely data-driven or investigator-driven methods and present dietary patterns as trade-offs between eating more of some foods and less of others., The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The study was partially funded by the ‘‘Accion Transversal del Cancer’’, approved by the Spanish Ministry Council on 11 October 2007; by the Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP); by the Instituto de Salud Carlos III-FEDER (grant nos PI08/1770, PI08/0533, PI08/1359, PS09/00773-Cantabria, PS09/01286-Leo´n, PS09/ 01903-Valencia, PS09/02078-Huelva, PS09/01662-Granada, PI11/01403, PI11/01810, PI11/02213, PI12/00488, PI14/01219, PI14/0613, PI15/00069, PI15/00914, PI15/01032, PI17/01280, PI09/0914, IJCI-2014-20900); by the Spanish Ministry of Health (grant no. CB06/02/1002); by the Spanish Ministry of Economy and Competitiveness (grant no. MTM2015-65016- C2-1-R); by the Catalan Government-Agency for Management of University and Research Grants (AGAUR) (grant nos 2014SGR551, 2017SGR656, 2017SGR733, 2017SGR723, 2017SGR1085); by the University of Girona (grant no. MPCUdG2016/069, GDRCompetUdG2017/19); by the Fundacio´n Marque´s de Valdecilla (grant no. API 10/09); by the Junta de Castilla y Leo´n (grant no. LE22A10-2); by the Consejerı´a de Salud of the Junta de Andalucı´a (grant nos PI-0571- 2009, PI-0306-2011, salud201200057018tra); by the Conselleria de Sanitat of the Generalitat Valenciana (grant no. AP_061/10); by the Regional Government of the Basque Country; by the Consejerı´a de Sanidad de la Regio´n de Murcia; by the European Commission (FOOD-CT-2006-036224-HIWATE); by the Spanish Association Against Cancer (AECC) Scientific Foundation; by the Fundacio´n Caja de Ahorros de Asturias; and by the University of Oviedo. ISGlobal is a member of the CERCA Programme, Generalitat de Catalunya.

Chronic inflammation plays a role in the development of chronic lymphocytic leukaemia (CLL), and diet might modulate chronic inflammation. This study aims to evaluate the association between the dietary inflammatory index (DII&reg, ) and CLL. A total of 366 CLL cases and 1643 controls of the Spanish multicase-control (MCC) Spain study were included. The inflammatory potential of the diet was assessed using the energy-adjusted dietary inflammatory index (E-DII) based on 30 items from a validated semi-quantitative food frequency questionnaire. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression models controlling for potential confounders. Overall, a modest, non-statistically significant, positive association was observed between CLL and E-DII scores (OR for a one-unit increase in E-DII: 1.05 (CI 95%: 0.99, 1.12), p-value = 0.09 and by tertiles: ORT2vsT1: 1.20 (CI 95%: 0.90, 1.59), OR T3vsT1: 1.21 (CI 95%: 0.90, 1.62), p trend = 0.21). These results were independent from disease severity (p-het: 0.70), time from diagnosis (p-het: 0.67) and CLL treatment received (p-het: 0.56). No interactions were detected. In conclusion, the consumption of a diet with high pro-inflammatory components was not significantly associated with CLL. Changes towards a more pro-inflammatory dietary pattern in younger generations not included here warrant future research.

Inflammation and antioxidant capacity have been associated with colorectal and breast cancer. We computed the dietary inflammatory index (DII&reg, ), and the total dietary non-enzymatic antioxidant capacity (NEAC) and associated them with colorectal and breast cancer risk in the population-based multi case-control study in Spain (MCC-Spain). We included 1852 colorectal cancer and 1567 breast cancer cases, and 3447 and 1486 population controls, respectively. DII score and NEAC were derived using data from a semi-quantitative validated food frequency questionnaire. Unconditional logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (95%CI) for energy-adjusted DII (E-DII), and a score combining E-DII and NEAC. E-DII was associated with colorectal cancer risk (OR = 1.93, highest quartile versus lowest, 95%CI:1.60&ndash, 2.32, p-trend: &lt, 0.001), this increase was observed for both colon and rectal cancer. Less pronounced increased risks were observed for breast cancer (OR = 1.22, highest quartile versus lowest, 95%CI:0.99&ndash, 1.52, p-trend: &gt, 0.10). The combined score of high E-DII scores and low antioxidant values were associated with colorectal cancer risk (OR = 1.48, highest quartile versus lowest, 95%CI: 1.26&ndash, 1.74, 0.001), but not breast cancer. This study provides evidence that a pro-inflammatory diet is associated with increased colorectal cancer risk while findings for breast cancer were less consistent.

Background: Swimming in pools is a healthy activity that entails exposure to disinfection by-products (DBPs), some of which are irritant and genotoxic. Objectives: We evaluated exposure to DBPs during swimming in a chlorinated pool and the association with short-term changes in genotoxicity and lung epithelium permeability biomarkers. Methods: Non-smoker adults (N = 116) swimming 40 min in an indoor pool were included. We measured a range of biomarkers before and at different times after swimming: trihalomethanes (THMs) in exhaled breath (5 min), trichloroacetic acid (TCAA) in urine (30 min), micronuclei in lymphocytes (1 h), serum club cell protein (CC16) (1 h), urine mutagenicity (2 h) and micronuclei in reticulocytes (4 days in a subset, N = 19). Several DBPs in water and trichloramine in air were measured, and physical activity was extensively assessed. We estimated interactions with polymorphisms in genes related to DBP metabolism. Results: Median level of chloroform, brominated and total THMs in water was 37.3, 9.5 and 48.5, μg/L, respectively, and trichloramine in air was 472.6 μg/m3. Median exhaled chloroform, brominated and total THMs increased after swimming by 10.9, 2.6 and 13.4, μg/m3, respectively. Creatinine-adjusted urinary TCAA increased by 3.1 μmol/mol. Micronuclei in lymphocytes and reticulocytes, urine mutagenicity and serum CC16 levels remained unchanged after swimming. Spearman correlation coefficients showed no association between DBP exposure and micronuclei in lymphocytes, urine mutagenicity and CC16. Moderate associations were observed for micronuclei in reticulocytes and DBP exposure. Conclusions: The unchanged levels of the short-term effect biomarkers after swimming and null associations with personal estimates of exposure to DBPs suggest no measurable effect on genotoxicity in lymphocytes, urine mutagenicity and lung epithelium permeability at the observed exposure levels. The moderate associations with micronuclei in reticulocytes require cautious interpretation given the reduced sample size. © 2019 The Authors, We are grateful to all volunteers and the swimming pool facility. This work was funded by the EU 7th Framework Programme EXPOSOMICS Project (grant agreement 308610 ). We thank the Parc de Salut Mar Biobank (MARBiobanc) for providing support to the project. MARBiobanc is supported by grants from Instituto de Salud Carlos III / FEDER ( RD09/0076/00036 and PT13/0010/0005 ) and the “Xarxa de Bancs de tumors” sponsored by Pla Director d'Oncologia de Catalunya (XBTC). ISGlobal is a member of the CERCA Programme, Generalitat de Catalunya. We appreciate the work by Kate Jones (Health & Safety Laboratory, UK) for urinary TCAA analysis.

Purpose Although there is convincing evidence that red and processed meat intake increases the risk of colorectal cancer (CRC), the potential role of meat cooking practices has not been established yet and could partly explain the current heterogeneity of results among studies. Therefore, we aimed to investigate the association between meat consumption and cooking practices and the risk of CRC in a population-based case-control study. Methods A total of 1671 CRC cases and 3095 controls recruited in Spain between September 2008 and December 2013 completing a food frequency questionnaire with a meat-specific module were included in the analyses. Odds ratios (OR) and confidence intervals (CI) were estimated by logistic regression models adjusted for known confounders. Results Total meat intake was associated with increased risk of CRC (OR (T3-T1) 1.41; 95% CI 1.19-1.67; p (trend) < 0.001), and similar associations were found for white, red and processed/cured/organ meat. Rare-cooked meat preference was associated with low risk of CRC in red meat (ORrare vs. medium 0.66; 95% CI 0.51-0.85) and total meat (ORrare vs. medium 0.56; 95% CI 0.37-0.86) consumers, these associations being stronger in women than in men. Griddle-grilled/barbecued meat was associated with an increased CRC risk (total meat: OR 1.45; 95% CI 1.13-1.87). Stewing (OR 1.25; 95% CI 1.04-1.51) and oven-baking (OR 1.18; 95% CI 1.00-1.40) were associated with increased CRC risk of white, but not red, meat. Conclusion Our study supports an association of white, red, processed/cured/organ and total meat intake with an increased risk of CRC. Moreover, our study showed that cooking practices can modulate such risk.

Ingested nitrate leads to the endogenous synthesis of N-nitroso compounds (NOCs), animal carcinogens with limited human evidence. We aimed to evaluate the risk of colorectal cancer (CRC) associated with nitrate exposure in drinking water and diet. A case-control study in Spain and Italy during 2008-2013 was conducted. Hospital-based incident cases and population-based (Spain) or hospital-based (Italy) controls were interviewed on residential history, water consumption since age 18, and dietary information. Long-term waterborne ingested nitrate was derived from routine monitoring records, linked to subjects' residential histories and water consumption habits. Dietary nitrate intake was estimated from food frequency questionnaires and published food composition databases. Odd ratios (OR) were calculated using mixed models with area as random effect, adjusted for CRC risk factors and other covariables. Generalized additive models (GAMs) were used to analyze exposure-response relationships. Interaction with endogenous nitrosation factors and other covariables was also evaluated. In total 1,869 cases and 3,530 controls were analyzed. Average waterborne ingested nitrate ranged from 3.4 to 19.7 mg/day, among areas. OR (95% CIs) of CRC was 1.49 (1.24, 1.78) for >10 versus ≤5 mg/day, overall. Associations were larger among men versus women, and among subjects with high red meat intake. GAMs showed increasing exposure-response relationship among men. Animal-derived dietary nitrate was associated with rectal, but not with colon cancer risk. In conclusion, a positive association between CRC risk and waterborne ingested nitrate is suggested, mainly among subgroups with other risk factors. Heterogeneous effects of nitrate from different sources (water, animal and vegetables) warrant further research.

Background Airway obstruction (AO) is associated with hypoxemia, systemic inflammation and oxidative stress. These conditions can favor the formation of Advanced Glycation End-products (AGEs) and induce mitochondrial stress. The latter can alter metabolite intermediates in the Krebs cycle leading to the formation of the cysteine-fumarate adduct S-(2-succino) cysteine (2SC) in proteins (protein succination). Protein succination has not been described in airways diseases. Research question To assess differences in levels of AGEs and 2SC between patients with AO and normal spirometry. Study design and Methods: In this case-control study, we investigated 35 moderate to severe AO patients and 31 subjects with normal spirometry, matched for age, gender, body mass index (BMI), tobacco history, prediabetes and adherence to Mediterranean diet. Plasma 2SC and AGEs concentrations were measured by GS/MS, and AGEs in skin were determined measuring autofluorescence (SAF). Multivariate logistic regression models explored the association between AGEs in the skin, 2SC and the presence of AO. Results The population was predominantly middle-age (mean of 58.7 years-old), overweight (median of BMI 26.7 kg/m2) and male subjects (69.7%). Patients with AO showed higher values of SAF (p = 0.04) and 2SC (p = 0.047). No differences were observed for plasma AGEs. SAF and 2SC were significantly associated with the presence of AO after adjusting for age, gender, smoking history, BMI and Mediterranean diet score (p = 0.041 and p = 0.038, respectively). Interpretation Skin AGEs and 2SC are increased in patients with moderate to severe AO and independently associated with its presence. Further studies should confirm these findings and explore their potential role as a biomarker for the disease.

Predoctoral contract to MS (CIBERESP), Spanish Ministry of Economy and Competitiveness Juan de la Cierva de Incorporación grant IJCI-2014-20900. Spanish Ministry of Economy and Competitiveness - Carlos III Institute of Health cofunded by FEDER funds/European Regional Develpment Fund (ERDF) - a way to build Europe [(grants PI17/01280, PI11/01810, PI14/01219, PI11/02213, PI09/1662, PI15/00966, RCESP C03/09, RTICESP C03/10, RTIC RD06/0020/0095, RD12/0036/0056, Rio Hortega CM13/00232, SV-09-CLINIC-1 and Centro de Investigación Biomédica en Red: Epidemiología y Salud Pública (CIBERESP))] and the Agència de Gestió d'Ajuts Universitaris i de Recerca AGAUR (2017SGR1085, 2014SGR756). The ICGC CLL-Genome Project was funded by Spanish Ministerio de Economía y Competitividad (MINECO) through the Instituto de Salud Carlos III (ISCIII), PMP15/00007 and Centro de Investigación Biomédica en Red: Oncología (CIBERONC)., Solans, M., Castelló, A., Benavente, Y., Marcos-Gragera, R., Amiano, P., Gracia-Lavedan, E., Costas, L., Robles, C., Gonzalez-Barca, E., Banda, E.L., Alonso, E., Aymerich, M., Campo, E., Dierssen-Sotos, T., Fernández-Tardón, G., Olmedo-Requena, R., Gimeno, E., Castaño-Vinyals, G., Aragonés, N., Kogevinas, M., Sanjose, S., Pollán, M., Casabonne, D.

Zinc is a key trace element in normal prostate cell metabolism, and is decreased in neoplastic cells. However, the association between dietary zinc and prostate cancer (PC) in epidemiologic studies is a conflicting one. Our aim was to explore this association in an MCC-Spain case-control study, considering tumor aggressiveness and extension, as well as genetic susceptibility to PC. 733 incident cases and 1228 population-based controls were included for this study. Dietary zinc was assessed using a food frequency questionnaire, and genetic susceptibility was assessed with a single nucleotide polymorphisms (SNP)-based polygenic risk score (PRS). The association between zinc intake and PC was evaluated with mixed logistic and multinomial regression models. They showed an increased risk of PC in those with higher intake of zinc (Odds Ratio (OR) tertile 3vs1: 1.39, 95% Confidence interval (CI):1.00&ndash, 1.95). This association was mainly observed in low grade PC (Gleason = 6 RRR tertile 3vs1: 1.76, 95% CI:1.18&ndash, 2.63) as well as in localized tumors (cT1-cT2a RRR tertile 3vs1: 1.40, 95% CI:1.00&ndash, 1.95) and among those with higher PRS (OR tertile 3vs1: 1.50, 95% CI:0.89&ndash, 2.53). In conclusion, a higher dietary zinc intake could increase the risk of low grade and localized tumors. Men with higher genetic susceptibility might also have a higher risk of PC associated with this nutrient intake.

BACKGROUND: Exposure to trihalomethanes (THMs) in drinking water has consistently been associated with an increased risk of bladder cancer, but evidence on other cancers including the breast is very limited. OBJECTIVES: We assessed long-term exposure to THMs to evaluate the association with female breast cancer (BC) risk. METHODS: A multi case-control study was conducted in Spain from 2008 to 2013. We included 1003 incident BC cases (women 20-85years old) recruited from 14 hospitals and 1458 population controls. Subjects were interviewed to ascertain residential histories and major recognized risk factors for BC. Mean residential levels of chloroform, brominated THMs (Br-THMs) and the sum of both as total THM (TTHMs) during the adult-lifetime were calculated. RESULTS: Mean adult-lifetime residential levels ranged from 0.8 to 145.7μg/L for TTHM (median=30.8), from 0.2 to 62.4μg/L for chloroform (median=19.7) and from 0.3 to 126.0μg/L for Br-THMs (median=9.7). Adult-lifetime residential chloroform was associated with BC (adjusted OR=1.47; 95%CI=1.05, 2.06 for the highest (>24μg/L) vs. lowest (31μg/L vs. 48μg/L vs.

We reviewed the comments on our publication sent by S.M.J. Mortazavi and would like to clarify some of the concerns from this reader, especially those due to misunderstanding of our study methods.

Background: Bulky DNA adducts reflect genotoxic exposures, have been associated with lower birth weight, and may predict cancer risk. Objective: We selected factors known or hypothesized to affect in utero adduct formation and repair and examined their associations with adduct levels in neonates. Methods: Pregnant women from Greece, Spain, England, Denmark, and Norway were recruited in 2006–2010. Cord blood bulky DNA adduct levels were measured by the 32P-postlabeling technique (n = 511). Diet and maternal characteristics were assessed via questionnaires. Modeled exposures to air pollutants and drinking-water disinfection by-products, mainly trihalomethanes (THMs), were available for a large proportion of the study population. Results: Greek and Spanish neonates had higher adduct levels than the northern European neonates [median, 12.1 (n = 179) vs. 6.8 (n = 332) adducts per 108 nucleotides, p < 0.001]. Residence in southern European countries, higher maternal body mass index, delivery by cesarean section, male infant sex, low maternal intake of fruits rich in vitamin C, high intake of dairy products, and low adherence to healthy diet score were statistically significantly associated with higher adduct levels in adjusted models. Exposure to fine particulate matter and nitrogen dioxide was associated with significantly higher adducts in the Danish subsample only. Overall, the pooled results for THMs in water show no evidence of association with adduct levels; however, there are country-specific differences in results with a suggestion of an association in England. Conclusion: These findings suggest that a combination of factors, including unknown country-specific factors, influence the bulky DNA adduct levels in neonates. Citation: Pedersen M, Mendez MA, Schoket B, Godschalk RW, Espinosa A, Landström A, Villanueva CM, Merlo DF, Fthenou E, Gracia-Lavedan E, van Schooten FJ, Hoek G, Brunborg G, Meltzer HM, Alexander J, Nielsen JK, Sunyer J, Wright J, Kovács K, de Hoogh K, Gutzkow KB, Hardie LJ, Chatzi L, Knudsen LE, Anna L, Ketzel M, Haugen M, Botsivali M, Nieuwenhuijsen MJ, Cirach M, Toledano MB, Smith RB, Fleming S, Agramunt S, Kyrtopoulos SA, Lukács V, Kleinjans JC, Segerbäck D, Kogevinas M. 2015. Environmental, dietary, maternal, and fetal predictors of bulky DNA adducts in cord blood: a European mother–child study (NewGeneris). Environ Health Perspect 123:374–380; http://dx.doi.org/10.1289/ehp.1408613

Introduction The International Agency for Research on Cancer classified radiofrequency (RF) electromagnetic fields (EMF) as possibly carcinogenic based on limited evidence in human studies of cell phone use and in animal experiments, while occupational evidence was found inadequate due in part to limitations in exposure assessment. This study assesses possible associations between occupational exposure to RF or intermediate frequency (IF) EMF in INTEROCC participants using novel exposure assessment methodologies. Methods A plausible index of cumulative exposure to RF and IF EMF was calculated using a source-exposure matrix and detailed interviews on work with or nearby EMF sources, both overall and in specific exposure time windows. Conditional logistic regression was used to investigate associations with glioma and meningioma risk. Results Only ~10% (n=769) of participants (n=7,330) were ever exposed to RF and ~1% (n=44) to IF EMF sources. Overall, there was no positive association between exposure to RF or IF EMF and glioma or meningioma risk, and the majority of odds ratios (ORs) were th ) for both RF electric fields and IF magnetic fields in the 1–4 year exposure time window for glioma, but were not statistically significant. Conclusions Lifetime occupational RF and IF exposures based on our index were not associated with the risk of glioma or meningioma. Further work should include more exposed participants and examine alternative exposure or dose indices such as those incorporating thresholds on biological effects or combinations of static and RF magnetic fields.

Background: Disinfection by-products (DBPs) constitute a complex mixture of prevalent chemicals in drinking water and there is evidence of neurotoxicity for some of them. Objectives: We evaluated the association between estimates of DBP exposure during pregnancy and child neuropsychological outcomes at 1 and 4–5 years of age. Methods: We conducted a population-based mother-child cohort study in Spain with recruitment at first trimester of gestation (INMA Project, 2003–2008). Neuropsychological development was measured at 1 year of age using the Bayley Scales of Infant Development and at 4–5 years with the McCarthy Scales of Children's Abilities. Modeled tap water concentrations of trihalomethanes (THM) were combined with personal ingestion, showering and bathing habits to estimate exposure as ingestion uptake, all route (showering, bathing, ingestion) uptake (μg/day) and crude levels (μg/l) in the residence. Chloroform, brominated THMs (bromodichloromethane, dibromochloromethane, bromoform) and total THMs (chloroform and brominated THMs) were analysed separately. Nine haloacetic acids levels were available in one of the areas. Linear regression was used to estimate associations in 1855 subjects adjusting for covariables. Results: The median concentration of total THMs, chloroform, brominated THMs, total haloacetic acids, dichloroacetic acid, and trichloroacetic acid were, respectively 30.3 μg/L, 9.4 μg/L, 11.6 μg/L, 10.5 μg/L, 2.7 μg/L, and 3.1 μg/L. The associations between THM exposure and neuropsychological outcomes were null, except for total and brominated THM uptake though all routes and the general cognitive score at 4–5 years, with a decrease in − 0.54 points (95%CI − 1.03, − 0.05) and − 0.64 (95%CI − 1.16, − 0.12), respectively, for doubling total and brominated THM uptake. A positive association found between dichloroacetic acid and the mental score at 1 year did not persist at 4–5 years. Conclusions: Minor associations observed between DBP exposure during gestation and child neuropsychological development at 1 year disappeared at 4–5 years. Although a suggestive association is identified for exposure to brominated THMs and the cognitive score at 4–5 years, chance cannot be ruled out. This study was funded by Grants from UE (FP7-ENV-2011 cod 282957 and HEALTH.2010.2.4.5-1), and from Spain: Instituto de Salud Carlos III (Red INMA G03/176, CB06/02/0041, FIS-FEDER 03/1615, 04/1509, 04/1112, 04/1931, PI041436, FIS-PI042018, 05/1079, 05/1052, 06/1213, FIS-PI06/0867, 07/0314, 081151, 09/02647, 09/02311, 09/00090, 11/0178, 11/02591, 11/02038, 13/1944, 13/2032, 13/02429, 13/02187, 14/0891, 14/1687, CP14/00108, CP16/00261 and Miguel Servet-FEDER MS15/0025, MS13/00054, CP0610034, MS14/00108), CIBERESP (Ref. AA08_012), the Conselleria de Sanitat de la Generalitat Valenciana, Generalitat de Catalunya (CIRIT 1999SGR 00241), Fundació La Marató de TV3 (090430), Obra Social Cajastur/Fundación Liberbank, Universidad de Oviedo, Department of Health of the Basque Government (2005111093, 2009111069, 2013111089 and 2015111065), and the Provincial Government of Gipuzkoa (DFG06/002, DFG08/001 and DFG15/221). Annual agreements with the city council of the study area in Gipuzkoa (Zumarraga, Urretxu, Legazpi, Azkoitia y Azpeitia y Beasain). ISGlobal is a member of the CERCA Programme, Generalitat de Catalunya.

Objective To externally validate the previously identified effect on breast cancer risk of the Western, Prudent and Mediterranean dietary patterns. Study design MCC-Spain is a multicase-control study that collected epidemiological information on 1181 incident cases of female breast cancer and 1682 control cases from 10 Spanish provinces. Three dietary patterns derived in another Spanish case-control study were analysed in the MCC-Spain study. These patterns were termed Western (high intakes of fatty and sugary products and red and processed meat), Prudent (high intakes of low-fat dairy products, vegetables, fruits, whole grains and juices) and Mediterranean (high intake of fish, vegetables, legumes, boiled potatoes, fruits, olives, and vegetable oil, and a low intake of juices). Their association with breast cancer was assessed using logistic regression models with random province-specific intercepts considering an interaction with menopausal status. Risk according to tumour subtypes ? based on oestrogen (ER), progesterone (PR) and human epidermal growth factor 2 (HER2) receptors (ER+/PR+&HER2-; HER2+; ER-/PR-&HER2-) ? was evaluated with multinomial regression models. Main outcome measures Breast cancer and histological subtype. Results Our results confirm most of the associations found in the previous case-control study. A high adherence to the Western dietary pattern seems to increase breast cancer risk in both premenopausal women (OR4thvs.1stquartile(95%CI):1.68(1.02;2.79); OR1SD-increase(95%CI): 1.19(1.01;1.40)) and postmenopausal women (OR4thvs.1stquartile(95%CI):1.48(1.07;2.05); OR1SD-increase(95%CI): 1.14(1.01;1.28)). While high adherence to the Prudent pattern did not show any effect on breast cancer, the Mediterranean dietary pattern seemed to be protective, but only among postmenopausal women (OR4thvs.1stquartile (95%CI):0.72(95% CI 0.53;0.98); p-int = 0.075). There were no significant differences by tumour subtype. Conclusion Dietary recommendations based on a departure from the Western dietary pattern in favour of the Mediterranean diet could reduce breast cancer risk in the general population. The study was funded by Carlos III Institute of Health grants (PI12/00488, PI12/00265, PI12/00715, PI12/01270, PI09/00773 and PI08/1770), by the Spanish Ministry of Economy and Competitiveness (IJCI-2014-20900) and by Consejería de Salud de la Junta de Andalucía (PI-0571- 2009 and PI-0306-2011) competitive calls including peer review for scientific quality. Additional funding was provided by the Spanish Federation of Breast Cancer Patients (FECMA: EPY 1169- 10), the Association of Women with Breast Cancer from Elche (AMACMEC:EPY 1394/15), the Marqués de Valdecilla foundation (grant API 10/09), ) and by Acción Transversal del Cancer, approved by the Spanish Ministry Council on October 11, 2007. None of the funders played any role in conducting research or writing the paper.