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miR-Blood is a high-quality, small RNA expression atlas for the major components of human peripheral blood (plasma, erythrocytes, thrombocytes, monocytes, neutrophils, eosinophils, basophils, natural killer cells, CD4+ T cells, CD8+ T cells, and B cells). Based on the purified blood components from 52 individuals, the dataset provides a comprehensive repository for the expression of 4971 small RNAs from eight non-coding RNA classes., (© 2024. The Author(s).)

Introduction: Lung cancer remains the deadliest cancer in the world, and lung cancer survival is heavily dependent on tumor stage at the time of detection. Low-dose computed tomography screening can reduce mortality; however, annual screening is limited by low adherence in the United States of America and still not broadly implemented in Europe. As a result, less than 10% of lung cancers are detected through existing programs. Thus, there is a great need for additional screening tests, such as a blood test, that could be deployed in the primary care setting., Methods: We prospectively recruited 1384 individuals meeting the National Lung Screening Trial demographic eligibility criteria for lung cancer and collected stabilized whole blood to enable the pipetting-free collection of material, thus minimizing preanalytical noise. Ultra-deep small RNA sequencing (20 million reads per sample) was performed with the addition of a method to remove highly abundant erythroid RNAs, and thus open bandwidth for the detection of less abundant species originating from the plasma or the immune cellular compartment. We used 100 random data splits to train and evaluate an ensemble of logistic regression classifiers using small RNA expression of 943 individuals, discovered an 18-small RNA feature consensus signature (miLung), and validated this signature in an independent cohort (441 individuals). Blood cell sorting and tumor tissue sequencing were performed to deconvolve small RNAs into their source of origin., Results: We generated diagnostic models and report a median receiver-operating characteristic area under the curve of 0.86 (95% confidence interval [CI]: 0.84-0.86) in the discovery cohort and generalized performance of 0.83 in the validation cohort. Diagnostic performance increased in a stage-dependent manner ranging from 0.73 (95% CI: 0.71-0.76) for stage I to 0.90 (95% CI: 0.89-0.90) for stage IV in the discovery cohort and from 0.76 to 0.86 in the validation cohort. We identified a tumor-shed, plasma-bound ribosomal RNA fragment of the L1 stalk as a dominant predictor of lung cancer. The fragment is decreased after surgery with curative intent. In additional experiments, results of dried blood spot collection and sequencing revealed that small RNA analysis could potentially be conducted through home sampling., Conclusions: These data suggest the potential of a small RNA-based blood test as a viable alternative to low-dose computed tomography screening for early detection of smoking-associated lung cancer., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: Patients with advanced, non-oncogene-driven NSCLC with high programmed death-ligand 1 (PD-L1) expression are eligible for treatment with immunotherapy. There is, however, an urgent medical need for biomarkers identifying cases that require additional combination with chemotherapy. We previously uncovered a myeloid-based 5-microRNA (5-miRNA) signature that identified responders to immunotherapy in PD-L1 unstratified patients; however, its potential utility in treatment guidance for patients with PD-L1 high tumors remained unclear., Methods: We trained (n = 68) and validated (n = 56) a 5-miRNA multivariable Cox proportional hazards model predictive of overall survival on small RNA sequencing data of whole blood samples prospectively collected before the commencement of immunotherapy for stage IV NSCLC with PD-L1 tumor proportion score greater than or equal to 50%, treated with PD-1 inhibitor monotherapy (immunotherapy alone [IO]). Specificity was demonstrated in a control cohort treated with immunochemotherapy (ICT) (n = 31)., Results: The revised 5-miRNA risk score (miRisk) stratified IO-treated patients and identified a high-risk group with significantly shorter overall survival (hazard ratio = 5.24, 95% confidence interval: 2.17-12.66, p < 0.001). There was a significant interaction between the miRisk score and type of treatment (IO or ICT, p  = 0.036), indicating that the miRisk score may serve as a predictive biomarker for immunotherapy response. Furthermore, the miRisk score could identify a group of high-risk patients who may benefit from treatment with ICT as opposed to IO (hazard ratio = 0.35, 95% confidence interval: 0.15-0.82, p  = 0.018)., Conclusions: The miRisk score can distinguish a group of patients with PD-L1 high, stage IV NSCLC likely to benefit from adding chemotherapy to immunotherapy and may support treatment decisions as a blood-based complementary diagnostic., (© 2022 The Authors.)

Background: Accelerated reproductive aging, in women indicated by early natural menopause, is associated with increased coronary heart disease (CHD) risk in observational studies. Conversely, an adverse CHD risk profile has been suggested to accelerate menopause., Objectives: To study the direction and evidence for causality of the relationship between reproductive aging and (non-)fatal CHD and CHD risk factors in a bidirectional Mendelian randomization (MR) approach, using age at natural menopause (ANM) genetic variants as a measure for genetically determined reproductive aging in women. We also studied the association of these variants with CHD risk (factors) in men., Design: Two-sample MR, using both cohort data as well as summary statistics, with 4 methods: simple and weighted median-based, standard inverse-variance weighted (IVW) regression, and MR-Egger regression., Participants: Data from EPIC-CVD and summary statistics from UK Biobank and publicly available genome-wide association studies were pooled for the different analyses., Main Outcome Measures: CHD, CHD risk factors, and ANM., Results: Across different methods of MR, no association was found between genetically determined reproductive aging and CHD risk in women (relative risk estimateIVW = 0.99; 95% confidence interval (CI), 0.97-1.01), or any of the CHD risk factors. Similarly, no associations were found in men. Neither did the reversed analyses show evidence for an association between CHD (risk factors) and reproductive aging., Conclusion: Genetically determined reproductive aging is not causally associated with CHD risk (factors) in women, nor were the genetic variants associated in men. We found no evidence for a reverse association in a combined sample of women and men., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Immunotherapies have recently gained traction as highly effective therapies in a subset of late-stage cancers. Unfortunately, only a minority of patients experience the remarkable benefits of immunotherapies, whilst others fail to respond or even come to harm through immune-related adverse events. For immunotherapies within the PD-1/PD-L1 inhibitor class, patient stratification is currently performed using tumor (tissue-based) PD-L1 expression. However, PD-L1 is an accurate predictor of response in only ~30% of cases. There is pressing need for more accurate biomarkers for immunotherapy response prediction. We sought to identify peripheral blood biomarkers, predictive of response to immunotherapies against lung cancer, based on whole blood microRNA profiling. Using three well-characterized cohorts consisting of a total of 334 stage IV NSCLC patients, we have defined a 5 microRNA risk score (miRisk) that is predictive of overall survival following immunotherapy in training and independent validation (HR 2.40, 95% CI 1.37-4.19; P < 0.01) cohorts. We have traced the signature to a myeloid origin and performed miRNA target prediction to make a direct mechanistic link to the PD-L1 signaling pathway and PD-L1 itself. The miRisk score offers a potential blood-based companion diagnostic for immunotherapy that outperforms tissue-based PD-L1 staining., (© 2022. The Author(s).)

Background & Aims: Fecal immunochemical tests (FITs) are widely used for colorectal cancer (CRC) screening. FITs detect most CRCs. Although detection of CRC at early stages is most relevant for reducing CRC mortality, there is limited evidence for the stage-specific sensitivity of the FIT in CRC detection. We estimated stage- and location-specific sensitivities of a quantitative FIT in a large cohort of patients with CRC., Methods: Fecal samples were collected before treatment from 435 patients with newly diagnosed CRC. Sensitivities of a quantitative FIT (FOB Gold, Sentinel Diagnostics; Milano, Italy) for tumors of different T stages and overall TNM stages (according to Union for International Cancer Control) were calculated at the cutoff recommended by the manufacturer (17 μg/g feces) and at alternative cutoffs, ranging from 10 to 40 μg/g feces, overall and stratified by tumor location., Results: At the cutoff recommended by the manufacturer, the FIT detected T1 tumors with 52% sensitivity (95% CI, 37%-67%), T2 tumors with 79% sensitivity (95% CI, 68%-88%), T3 tumors with 93% sensitivity (95% CI, 89%-95%), and T4 tumors with 84% sensitivity (95% CI, 72%-92%) (P trend < .0001). The FIT detected stage I cancers with 68% sensitivity (95% CI, 57%-78%), stage II cancers with 92% sensitivity (95% CI, 87%-96%), stage III cancers with 82% sensitivity (95% CI, 73%-89%), and stage IV cancers with 89% sensitivity (95% CI, 80%-95%) (P trend 0.01). The FIT detected T1 colorectal tumors with sensitivity values that were 22%-52% lower than for tumors of other T stages and stage I CRC with sensitivity values that were 11%-33% lower than for later-stage CRCs, at any of the evaluated cutoff values. The FIT detected T1 and stage I CRCs in the distal colon with sensitivity values of 32% and 52%, respectively., Conclusions: Although the FIT identifies patients with CRC with overall high sensitivity, it can miss approximately one-third of stage I CRCs. Studies are needed to increase noninvasive detection of early-stage CRC., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: People with a first-degree relative with colorectal cancer (CRC) are recommended to start CRC screening at age 40. However, there is limited information on how many people in different age groups have a known family history of CRC and how many of them have had a colonoscopy., Methods: We set up a multicenter, cross-sectional, population-based study in Germany to determine what proportions of persons in age groups from 40 to 54 years old have a known family history of CRC. We invited 160,000 persons to participate in an online survey from 2015 through 2016. We investigated what proportions of persons in each age group reported a family history of CRC and what proportions of persons underwent a colonoscopy examination using descriptive statistics and multiple logistic regression models., Results: Of 28,711 responders to the online questionnaire (8428 were age 40-44 years, 9879 were age 45-49 years, and 10,404 were age 50-54 years), 2705 stated that they had a first-degree relative with CRC (9.4%). The prevalence of a first-degree relative with CRC increased with age: 7.5%, 9.6%, and 10.9% for people 40 to 44 years old, 45 to 49 years old, and 50 to 54 years old, respectively. The prevalence of a first-degree relative who received a diagnosis of CRC at age 70 years or older increased steadily with each age group. Although a greater proportion of people with a family history of CRC had undergone a colonoscopy examination (54.5%) than people without a family history of CRC (25.7%; P < .0001), large proportions of people within this risk group were not in compliance with the guidelines (54.8%, 47.6%, and 38.6% for ages 40-44 y, 45-49 y, and 50-54 y, respectively)., Conclusions: One in 10 persons in Germany age 40 to 54 years old has a first-degree relative with CRC. Guidelines recommend initiation of screening at ages 40 to 45 years for people with a family history, yet at this age many people do not have a family history of CRC yet, and almost half of persons 40 to 54 years old with a family history of CRC have not yet received a screening colonoscopy., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Blood-based protein biomarker signatures might be an alternative or supplement to existing methods for early detection of colorectal cancer (CRC) for population-based screening. The objective of this study was to derive a protein biomarker signature for early detection of CRC and its precursor advanced adenoma (AA). In a two-stage design, 270 protein markers were measured by liquid chromatography/multiple reaction monitoring/mass spectrometry in plasma samples of discovery and validation sets. In the discovery set consisting of 100 newly diagnosed CRC cases and 100 age- and sex-matched controls free of neoplasm at screening colonoscopy, the algorithms predicting the presence of early- or late-stage CRC were derived by Lasso regression and .632 + bootstrap. The prediction algorithms were then externally validated in an independent validation set consisting of participants of screening colonoscopy including 56 participants with CRC, 99 with AA and 99 controls without any colorectal neoplasms. Three different signatures for all-, early- and late-stage CRC consisting of five-, three- and eight-protein markers were obtained in the discovery set with areas under the curves (AUCs) after .632 + bootstrap adjustment of 0.85, 0.83 and 0.96, respectively. External validation in the representative screening population yielded AUCs of 0.79 (95% CI, 0.70-0.86), 0.79 (95% CI, 0.66-0.89) and 0.80 (95% CI, 0.70-0.89) for all-, early- and late-stage CRCs, respectively. The three-marker early-stage algorithm yielded an AUC of 0.65 (95% CI, 0.56-0.73) for detection of AA in the validation set. Although not yet competitive with available stool-based tests for CRC early detection, the identified proteins may contribute to the development of powerful blood-based tests for early detection of CRC and its precursors AAs., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Blood-based protein biomarkers may be an attractive option for early detection of colorectal cancer (CRC). Here, we used a two-stage design to measure 275 protein markers by proximity extension assay (PEA), first in plasma samples of a discovery set consisting of 98 newly diagnosed CRC cases and 100 age- and gender-matched controls free of neoplasm at screening colonoscopy. An algorithm predicting the presence of early- or late-stage CRC was derived by least absolute shrinkage and selection operator regression with .632+ bootstrap method, and the algorithms were then validated using PEA again in an independent validation set consisting of participants of screening colonoscopy with and without CRC (n = 56 and 102, respectively). Three different signatures for all-, early-, and late-stage CRC consisting of 9, 12, and 11 protein markers were obtained in the discovery set with areas under the curves (AUCs) after .632 + bootstrap adjustment of 0.92, 0.91, and 0.96, respectively. External validation among participants of screening colonoscopy yielded AUCs of 0.76 [95% confidence interval (95% CI), 0.67-0.84], 0.75 (95% CI, 0.62-0.87), and 0.80 (95% CI, 0.68-0.89) for all-, early-, and late-stage CRC, respectively. Although the identified protein markers are not competitive with the best available stool tests, these proteins may contribute to the development of powerful blood-based tests for CRC early detection in the future., (© 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Objective: Plasma protein biomarkers could be an efficient alternative for population-based screening for early detection of colorectal cancer (CRC). The objective of this study was to evaluate and validate plasma proteins individually and as a signature for early detection of CRC., Methods: In a three-stage design, proteins were measured firstly by liquid chromatography/multiple reaction monitoring-mass spectrometry (LC/MRM-MS) and later by proximity extension assay (PEA) in a discovery set consisting of 96 newly diagnosed CRC cases and 94 controls free of neoplasms at screening colonoscopy. Two algorithms (one for each measurement method) were derived by Lasso regression and .632+ bootstrap based on 11 proteins that were included in both the LC/MRM-MS and PEA measurements. Additionally, another algorithm was constructed from the same eleven biomarkers plus amphireglin, the most promising protein marker in the PEA measurements that had not been available from the LC/MRM-MS measurements. Lastly the three prediction signatures were validated with PEA in independent samples of participants of screening colonoscopy (CRC ( n = 56), advanced adenoma ( n = 101), and participants free of neoplasm ( n = 102))., Results: The same four proteins were included in all three prediction signatures; mannan binding lectin serine protease 1, osteopontin, serum paraoxonase lactonase 3 and transferrin receptor protein 1, and the third prediction signature additionally included amphiregulin. In the independent validation set from a true screening setting, the five-marker blood-based signature including AREG presented areas under the curves of 0.82 (95% CI, 0.74-0.89), 0.86 (95% CI, 0.77-0.92) and 0.76 (95% CI, 0.64-0.86) for all, early and late stages CRC, respectively., Conclusion: Two different measurement methods consistently identified four protein markers and an algorithm additionally including amphiregulin, a marker measured by PEA only, showed promising performance for detecting early stage CRC in an independent validation in a true screening setting. These proteins may be potential candidates for blood-based tests for early detection of CRC.

Background: Earlier age at menopause has been associated with increased risk of coronary heart disease (CHD), but the shape of association and role of established cardiovascular risk factors remain unclear. Therefore, we examined the associations between menopausal characteristics and CHD risk; the shape of the association between age at menopause and CHD risk; and the extent to which these associations are explained by established cardiovascular risk factors., Methods: We used data from EPIC-CVD, a case-cohort study, which includes data from 23 centres from 10 European countries. We included only women, of whom 10 880 comprise the randomly selected sub-cohort, supplemented with 4522 cases outside the sub-cohort. We conducted Prentice-weighted Cox proportional hazards regressions with age as the underlying time scale, stratified by country and adjusted for relevant confounders., Results: After confounder and intermediate adjustment, post-menopausal women were not at higher CHD risk compared with pre-menopausal women. Among post-menopausal women, earlier menopause was linearly associated with higher CHD risk [HRconfounder and intermediate adjusted per-year decrease = 1.02, 95% confidence interval (CI) = 1.01-1.03, p = 0.001]. Women with a surgical menopause were at higher risk of CHD compared with those with natural menopause (HRconfounder-adjusted = 1.25, 95% CI = 1.10-1.42, p < 0.001), but this attenuated after additional adjustment for age at menopause and intermediates (HR = 1.12, 95% CI = 0.96-1.29, p = 0.15). A proportion of the association was explained by cardiovascular risk factors., Conclusions: Earlier and surgical menopause were associated with higher CHD risk. These associations could partially be explained by differences in conventional cardiovascular risk factors. These women might benefit from close monitoring of cardiovascular risk factors and disease., (© The Author(s) 2019. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Importance: Fecal immunochemical tests for hemoglobin are widely used for colorectal cancer (CRC) screening. Observational studies suggested that sensitivity of fecal immunochemical tests for detecting advanced neoplasms could be increased by acetylsalicylic acid (aspirin), especially among men., Objective: To evaluate the potential to increase sensitivity of fecal immunochemical tests by administering a single 300-mg oral aspirin dose 2 days before stool sampling., Design, Setting, and Participants: A randomized, placebo-controlled, double-blind trial was conducted in 14 gastroenterology practices and 4 hospitals in Germany, and included 2422 men and women aged 40 to 80 years scheduled for colonoscopy, with no recent use of aspirin or other drugs with antithrombotic effects (enrollment from June 2013 to November 2016, and final follow-up January 27, 2017)., Interventions: Administration of a single tablet containing 300 mg of aspirin (n = 1208) or placebo (n = 1214) 2 days before fecal sampling for fecal immunochemical test., Main Outcome and Measures: The primary outcome was sensitivity of a quantitative fecal immunochemical test at 2 predefined cutoffs (10.2 and 17-μg Hb/g stool) for detecting advanced neoplasms (colorectal cancer or advanced adenoma)., Results: Among 2422 randomized patients (mean [SD] age, 59.6 [7.9] years; 1219, 50%, men), 2134 were included in the analysis (78% for primary screening colonoscopy, 22% for diagnostic colonoscopy). Advanced neoplasms were identified in 224 participants (10.5%), including 8 participants (0.4%) with CRC and 216 participants (10.1%) with advanced adenoma. Sensitivity was 40.2% in the aspirin group and 30.4% in the placebo group (difference 9.8%, 95% CI, -3.1% to 22.2%, P = .14) at cutoff 10.2-μg Hb/g stool and 28.6% in the aspirin and 22.5% in the placebo group (difference 6.0%, 95% CI, -5.7% to 17.5%, P = .32) at cutoff 17-μg Hb/g stool., Conclusions and Relevance: Among adults aged 40 to 80 years not using aspirin or other antithrombotic medications, administration of a single dose of oral aspirin prior to fecal immunochemical testing, compared with placebo, did not significantly increase test sensitivity for detecting advanced colorectal neoplasms at 2 predefined cutoffs of a quantitative fecal immunochemical test., Trial Registration: Deutsches Register Klinischer Studien Identifier: DRKS00003252; EudraCT Identifier: 2011-005603-32/DE.

Objective: We want to present information about response patterns obtained by Web-based survey in a large-scale epidemiological study., Study Design and Setting: Within the RAPS (Risk Adapted Prevention Strategies for colorectal cancer [CRC]) study, we invited 160,000 randomly selected persons aged 40-54 years in three large German cities from 2015 to 2016 to complete a Web-based questionnaire on CRC risk factors and screening (97 items, average time for completion 15 minutes). Invitation letters and up to two reminder letters were sent to each individual., Results: A total of 21.4% of women and 18.0% of men completed the questionnaire. Overall cumulative response rates were 7.5%, 14.3%, and 19.6% after the initial invitation letter, and the first and second reminder, respectively, with prevalence of and associations of key epidemiological parameters (such as family history of cancer, previous colonoscopy, etc.) being remarkably stable across waves of responses. For example, the sex and age distribution of the sample did not change with additional answers gained from additional letters., Conclusion: Web-based questionnaires are feasible, cost-effective, and time effective in the setting of large-scale epidemiological studies. Although response patterns were remarkably stable over several rounds of reminders with substantially increasing cumulative response rates, future research should address possibilities to further enhance response rates., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: Most studies identifying inflammatory markers for early detection of colorectal cancer (CRC) were conducted using clinically manifest cases. We aimed to identify circulating inflammatory biomarkers for early detection of CRC and validate them in both a clinical setting and a true screening setting., Study Design and Setting: A total of 92 inflammatory proteins were quantified in baseline plasma samples from individuals clinically diagnosed with CRC and neoplasm-free controls matched on age and sex (training set). A multimarker panel was selected and evaluated in samples from another clinical setting (validation set C) and a screening setting (validation set S)., Results: In the training set (N = 330), a five-biomarker signature was selected that provided an area under curve (AUC) of 0.85 and 60.9% sensitivity to detect CRC at 90% specificity. When this algorithm was applied to validation set C (N = 318), the AUC (0.80) and sensitivity (49.5%) at 90% specificity for CRC diagnosis were only slightly lower than those in the training set. By contrast, the diagnostic performance of the algorithm in validation set S (N = 126) from a true screening setting was much poorer, with an AUC of 0.59 and a sensitivity of 28.6% at 90% specificity., Conclusions: An inflammation-related protein panel with apparently good diagnostic properties for CRC detection was identified and confirmed in an independent clinical validation set. However, the biomarker combination performed substantially worse in a validation sample from a true screening setting. Our results underline the importance of validation in screening settings subsequently to novel signature discovery for cancer early detection., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Despite evidence that inflammation and metabolism play a crucial role in colorectal carcinogenesis, there have been few studies on the association of inflammatory and metabolic protein biomarkers in various stages of colorectal carcinogenesis., Methods: Ninety-two inflammatory and metabolic biomarkers were measured in plasma samples of participants of screening colonoscopy. Markers identified to be significantly associated with the presence of advanced colorectal neoplasia (ACN) in a discovery set (n = 204) were validated in an independent replication set (n = 422). Adjusted associations with the presence of non-advanced adenomas (NAA), advanced precancerous lesions (APL) and colorectal cancer (CRC) were quantified by multiple logistic regression., Results: Out of the 92 inflammatory proteins, 72 markers were evaluable and 8 showed statistically significant associations with the odds of ACN after full adjustment for potential risk factors for CRC in the discovery set. One of these, fibroblast growth factor 21 (FGF-21), could be validated in the replication set. The multivariable-adjusted odds ratio (OR) reached 2.65 (95% CI, 1.50-4.81) for individuals with FGF-21 levels within the highest tertile, compared to those within the lowest tertile (P trend across tertiles = 0.001). Separate models revealed fully adjusted ORs for NAA, APL and CRC of 2.99 (95% CI, 1.45-6.58, P trend  = 0.005), 2.24 (95% CI, 1.18-4.44, P trend  = 0.021) and 3.92 (95% CI, 1.51-12.18, P trend  = 0.003), respectively., Conclusions: Circulating FGF-21 level is associated with increased risk of early and late stages of colorectal carcinogenesis, supporting a role of inflammation and metabolism at all stages of colorectal carcinogenesis, and suggesting potential use of this biomarker for risk stratification in CRC screening.

ᅟ: Immunochemical fecal occult blood tests (iFOBTs) are increasingly used for colorectal cancer (CRC) screening. In our preceding observational study, sensitivity for detecting advanced colorectal neoplasms by iFOBT was 70.8% among users of low-dose acetylsalicylic acid compared with 35.9% among non-users (p = 0.001), whereas there were only very small differences in specificity. In receiver operating characteristics (ROC) analyses, the area under the curve (AUC) was much higher for acetylsalicylic acid users than for non-users, with particularly strong differences in men (0.87 versus 0.68, p = 0.003). These findings suggested that use of acetylsalicylic acid before conduct of iFOBT might be a promising approach to improve non-invasive screening for CRC., Methods/design: In this randomized, double-blind, placebo-controlled trial, the diagnostic performance of two iFOBTs for detecting advanced colorectal neoplasms after a single low-dose of acetylsalicylic acid (300 mg) compared to placebo is evaluated. Acetylsalicylic acid or placebo is administered at least 5 days before a planned, study-independent colonoscopic screening in 2400 participants aged 40 to 80 years. Stool samples are obtained before and on three different days after the single dose of acetylsalicylic acid or placebo. In addition, optional blood samples are taken for future biomarker analyses. The diagnostic performance of the iFOBTs will be compared to the results of the colonoscopy as a gold standard for the diagnosis of colorectal neoplasms. Additionally, gender-specific performance of the tests and gain in diagnostic performance by test application on multiple days will be evaluated., Discussion: If the findings from our preceding observational study will be confirmed in this large trial, the proposed low-risk, inexpensive intervention would considerably improve the diagnostic accuracy of iFOBTs and thus lead to enhanced early detection of colorectal neoplasms. Thus, the results of this trial may have a large public health impact., Trial Registration: This trial was registered before recruitment of the participants in www.clinicaltrialsregister.eu on the 30th of May 2012: EudraCT No.: 2011-005603-32 and in www.drks.de on 13th of March 2012: German Clinical Trials Register DRKS-ID: DRKS00003252 .

Background: People aged 40-60 years with a family history (FH) of colorectal cancer (CRC) in 1st degree relatives (FDRs) have a 2- to 4-fold increased risk of CRC compared to the average risk population. Therefore, experts recommend starting CRC screening earlier for this high-risk group. However, information on prevalence of relevant colonoscopic findings in this group is sparse, and no risk adapted screening offers are implemented in the German health care system. For example, screening colonoscopy is uniformly offered from age 55 on, regardless of family history. Thus, we initiated a multicenter epidemiological study - the RaPS study (Risk adapted prevention strategies for colorectal cancer) - with the following aims: to determine the prevalence of having a FH of CRC in FDR in the German population aged 40-54 years; to investigate the prevalence of colorectal neoplasms among people with a FDR; and to develop risk-adapted prevention strategies for this high-risk group based on the collected information., Methods/design: A random sample of 160.000 persons from the general population aged 40-54 years from the catchment areas of three study centers in Germany (Dresden, Munich and Stuttgart) are contacted to assess FH of CRC by an online-questionnaire. Those with a FH of CRC in FDRs are invited to the study centers for individual consultation regarding CRC prevention. Participants are asked to donate blood and stool samples and medical records of colonoscopies will be obtained. Prevalence of CRC and its precursors will be evaluated. Furthermore, genetic, epigenetic and proteomic biomarkers in blood and microbiomic biomarkers in stool will be investigated. Risk markers and their eligibility for risk adapted screening offers will be examined., Discussion: This study will provide data on the prevalence of colorectal neoplasms among persons with a FH of CRC in the age group 40-54 years, which will enable us to derive evidence based screening strategies for this high-risk group., Trial Registration: This trial was registered retrospectively in the German Clinical Trials Register (DRKS) on 29th of December 2016: German Clinical Trials Register DRKS-ID: DRKS00007842 .

Introduction: The relationship between circulating prolactin and invasive breast cancer has been investigated previously, but the association between prolactin levels and in situ breast cancer risk has received less attention., Methods: We analysed the relationship between pre-diagnostic prolactin levels and the risk of in situ breast cancer overall, and by menopausal status and use of postmenopausal hormone therapy (HT) at blood donation. Conditional logistic regression was used to assess this association in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, including 307 in situ breast cancer cases and their matched control subjects., Results: We found a significant positive association between higher circulating prolactin levels and risk of in situ breast cancer among all women [pre-and postmenopausal combined, ORlog2=1.35 (95% CI 1.04-1.76), Ptrend=0.03]. No statistically significant heterogeneity was found between prolactin levels and in situ cancer risk by menopausal status (Phet=0.98) or baseline HT use (Phet=0.20), although the observed association was more pronounced among postmenopausal women using HT compared to non-users (Ptrend=0.06 vs Ptrend=0.35). In subgroup analyses, the observed positive association was strongest in women diagnosed with in situ breast tumors<4 years compared to ≥4 years after blood donation (Ptrend=0.01 vs Ptrend=0.63; Phet=0.04) and among nulliparous women compared to parous women (Ptrend=0.03 vs Ptrend=0.15; Phet=0.07)., Conclusions: Our data extends prior research linking prolactin and invasive breast cancer to the outcome of in situ breast tumours and shows that higher circulating prolactin is associated with increased risk of in situ breast cancer.

Differentiated thyroid carcinoma (TC) is threefold more common in women than in men and, therefore, a role of female hormones in the etiology of differentiated TC has been suggested. We assessed these hypotheses in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Among 345,157 women (mean age 51) followed for an average of 11 years, 508 differentiated TC cases were identified. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression models. No significant associations were observed between differentiated TC risk and number of pregnancies, breast feeding, menopausal status, and age at menarche and at menopause. Significant associations were found with history of infertility problems (HR 1.70; 95% CI 1.12-2.60), a recent pregnancy (HR for ≤ 5 vs. >5 years before recruitment 3.87; 95% CI 1.43-10.46), menopause type (HR for surgical vs. natural menopause: 2.16; 95% CI 1.41-3.31), oral contraceptive (OC) use at recruitment (HR: 0.48; 95% CI 0.25-0.92) and duration of OC use (HR for ≥ 9 vs. ≤ 1 year: 0.66; 95% CI: 0.50-0.89). An increased risk was also found with hormone replacement therapy use at recruitment (HR = 1.30, 95% CI 1.02-1.67), but this was not significant after adjustment for type of menopause (HR = 1.22, 95% CI 0.95-1.57). Overall, our findings do not support a strong role of reproductive and menstrual factors, and female hormone use in the etiology of differentiated TC. The few observed associations may be real or accounted for by increased surveillance in women who had infertility problems, recent pregnancies or underwent surgical menopause., (© 2014 UICC.)

Background: Experimental and epidemiologic data suggest that higher circulating prolactin is associated with breast cancer risk; however, how various risk factors for breast cancer influence prolactin levels in healthy women is not clear., Methods: We analyzed cross-sectional associations between several suggested reproductive and lifestyle risk factors for breast cancer and circulating prolactin among pre- and postmenopausal women, taking into account the use of current postmenopausal hormone therapy, among 2,560 controls from a breast cancer nested case-control study within the EPIC cohort., Results: Adjusted geometric mean prolactin levels were significantly higher among premenopausal women, and among postmenopausal women using hormone therapy compared with nonusers (8.2, 7.0, and 6.3 ng/mL, respectively; Pcat = <0.0001). Furthermore, prolactin levels were significantly higher among users of combined estrogen-progestin hormone therapy compared with users of estrogen-alone hormone therapy (6.66 vs. 5.90 ng/mL; Pcat = 0.001). Prolactin levels were lower among parous women compared with nulliparous women (8.61 vs. 10.95 ng/mL; Pcat = 0.0002, premenopausal women); the magnitude of this difference depended on the number of full-term pregnancies (22.1% lower, ≥3 vs. 1 pregnancy, Ptrend = 0.01). Results for parity were similar but lower in magnitude among postmenopausal women. Prolactin did not vary by other studied factors, with the exception of lower levels among postmenopausal smokers compared with never smokers., Conclusions: Our study shows that current hormone therapy use, especially the use of combined hormone therapy, is associated with higher circulating prolactin levels in postmenopausal women, and confirms prior findings of lower circulating prolactin in parous women., Impact: Our study extends the knowledge linking various breast cancer risk factors with circulating prolactin., (©2014 American Association for Cancer Research.)

Background and Purpose: Because primary prevention of stroke is a priority, our aim was to assess the primary preventive potential of major lifestyle risk factors for stroke in middle-aged women and men., Methods: Among 23,927 persons, 551 (195 women and 356 men) had a first diagnosis of stroke during an average follow-up of 12.7 years. Using Cox proportional hazards models, we estimated the associations of adiposity, smoking, physical activity, alcohol consumption, and diet with risk of developing stroke. A competing risk model built from cause-specific proportional hazards models accounting for concurrent risk of death was used to calculate relative and absolute reductions in stroke occurrences that could have been achieved by maintaining a healthy lifestyle pattern., Results: Obesity, smoking, alcohol consumption, diet, and physical inactivity were each identified as modifiable lifestyle risk factors for stroke. About 38% of stroke cases were estimated as preventable through adherence to a healthy lifestyle profile (never smoking, maintaining optimal body mass index and waist circumference, performing physical exercise, consuming a moderate quantity of alcohol, and following a healthy dietary pattern). Age-specific estimates of 5-year incidence rates for stroke in the actual cohort and in a hypothetical, comparable cohort of individuals following a healthy lifestyle would be reduced from 153 to 94 per 100,000 women and from 261 to 161 per 100,000 men for the age group 60 to 65 years., Conclusions: Our analysis confirms the strong primary prevention potential for stroke based on avoidance of excess body weight, smoking, heavy alcohol consumption, unhealthy diet, and physical inactivity., (© 2014 American Heart Association, Inc.)

Results from prospective studies on premenopausal serum hormone levels in relation to breast cancer risk have been inconclusive, especially with regard to tumor subtypes. Using a case-control study nested within the prospective European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (801 breast cancer cases and 1,132 matched control subjects), we analyzed the relationships of prediagnostic serum estradiol, free estradiol, progesterone, testosterone, free testosterone and sex hormone-binding globulin (SHBG) levels with the risk of breast cancer by estrogen and progesterone receptor-positive and -negative breast tumors and by age at diagnoses. Higher prediagnostic serum levels of testosterone and free testosterone were associated with an increased overall risk of breast cancer [ORQ4-Q1  = 1.56 (95% CI 1.15-2.13), ptrend  = 0.02 for testosterone and ORQ4-Q1  = 1.33 (95% CI 0.99-1.79), ptrend  = 0.04 for free testosterone], but no significant risk association was observed for estradiol, free estradiol, progesterone and SHBG. Tests for heterogeneity between receptor-positive and -negative tumors were not significant. When analysis were stratified by age at tumor diagnosis, the odds ratios observed for estradiol were stronger and borderline significant for breast cancer diagnosed at age less than 50 [ORQ4-Q1  = 1.32 (95% CI 0.87-2.01), ptrend  = 0.05] compared to breast cancer diagnosed at age 50 or above [ORQ4-Q1  = 0.94 (95% CI 0.60-1.47), ptrend  = 0.34, phet  = 0.04]. In conclusion, our data indicate that higher premenopausal circulating testosterone levels are associated with an increased risk of developing breast cancer, but do not show a significant association of estradiol or progesterone with breast cancer risk, overall, by menstrual cycle phase or by tumor receptor status, although a possible risk increase with higher estradiol levels for tumors diagnosed before age 50 was seen., (© 2013 UICC.)

Background: The association of reproductive factors with hormone receptor (HR)-negative breast tumors remains uncertain., Methods: Within the EPIC cohort, Cox proportional hazards models were used to describe the relationships of reproductive factors (menarcheal age, time between menarche and first pregnancy, parity, number of children, age at first and last pregnancies, time since last full-term childbirth, breastfeeding, age at menopause, ever having an abortion and use of oral contraceptives [OC]) with risk of ER-PR- (n = 998) and ER+PR+ (n = 3,567) breast tumors., Results: A later first full-term childbirth was associated with increased risk of ER+PR+ tumors but not with risk of ER-PR- tumors (≥35 vs. ≤19 years HR: 1.47 [95% CI 1.15-1.88] p(trend) < 0.001 for ER+PR+ tumors; ≥35 vs. ≤19 years HR: 0.93 [95% CI 0.53-1.65] p(trend) = 0.96 for ER-PR- tumors; P(het) = 0.03). The risk associations of menarcheal age, and time period between menarche and first full-term childbirth with ER-PR-tumors were in the similar direction with risk of ER+PR+ tumors (p(het) = 0.50), although weaker in magnitude and statistically only borderline significant. Other parity related factors such as ever a full-term birth, number of births, age- and time since last birth were associated only with ER+PR+ malignancies, however no statistical heterogeneity between breast cancer subtypes was observed. Breastfeeding and OC use were generally not associated with breast cancer subtype risk., Conclusion: Our study provides possible evidence that age at menarche, and time between menarche and first full-term childbirth may be associated with the etiology of both HR-negative and HR-positive malignancies, although the associations with HR-negative breast cancer were only borderline significant.

Evidence on the association between dietary flavonoids and lignans and breast cancer (BC) risk is inconclusive, with the possible exception of isoflavones in Asian countries. Therefore, we investigated prospectively dietary total and subclasses of flavonoid and lignan intake and BC risk according to menopause and hormonal receptor status in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. The study included 334,850 women, mostly aged between 35 and 70 years from ten European countries. At baseline, country-specific validated dietary questionnaires were used. A flavonoid and lignan food composition database was developed from the US Department of Agriculture, the Phenol-Explorer and the UK Food Standards Agency databases. Cox regression models were used to analyse the association between dietary flavonoid/lignan intake and the risk of developing BC. During an average 11.5-year follow-up, 11,576 incident BC cases were identified. No association was observed between the intake of total flavonoids [hazard ratio comparing fifth to first quintile (HRQ5-Q1) 0.97, 95 % confidence interval (CI): 0.90-1.04; P trend = 0.591], isoflavones (HRQ5-Q1 1.00, 95 % CI: 0.91-1.10; P trend = 0.734), or total lignans (HRQ5-Q1 1.02, 95 % CI: 0.93-1.11; P trend = 0.469) and overall BC risk. The stratification of the results by menopausal status at recruitment or the differentiation of BC cases according to oestrogen and progesterone receptors did not affect the results. This study shows no associations between flavonoid and lignan intake and BC risk, overall or after taking into account menopausal status and BC hormone receptors.

Background: In 2007, the World Cancer Research Fund (WCRF) and the American Institute for Cancer Research (AICR) issued recommendations on diet, physical activity, and weight management for cancer prevention on the basis of the most comprehensive collection of available evidence., Objective: We investigated whether concordance with WCRF/AICR recommendations is related to risk of death., Design: The current study included 378,864 participants from 9 European countries enrolled in the European Prospective Investigation into Cancer and Nutrition study. At recruitment (1992-1998), dietary, anthropometric, and lifestyle information was collected. A WCRF/AICR score, which incorporated 6 of the WCRF/AICR recommendations for men [regarding body fatness, physical activity, foods and drinks that promote weight gain, plant foods, animal foods, and alcoholic drinks (score range: 0-6)] and 7 WCRF/AICR recommendations for women [plus breastfeeding (score range: 0-7)], was constructed. Higher scores indicated greater concordance with WCRF/AICR recommendations. Associations between the WCRF/AICR score and risks of total and cause-specific death were estimated by using Cox regression analysis., Results: After a median follow-up time of 12.8 y, 23,828 deaths were identified. Participants within the highest category of the WCRF/AICR score (5-6 points in men; 6-7 points in women) had a 34% lower hazard of death (95% CI: 0.59, 0.75) compared with participants within the lowest category of the WCRF/AICR score (0-2 points in men; 0-3 points in women). Significant inverse associations were observed in all countries. The WCRF/AICR score was also significantly associated with a lower hazard of dying from cancer, circulatory disease, and respiratory disease., Conclusion: Results of this study suggest that following WCRF/AICR recommendations could significantly increase longevity.

Flavour development and overall eating quality of pan-fried pork chops of longissimus dorsi from eight different raw meat qualities aged for 4 and 15 days were assessed by a trained sensory panel. The raw meat qualities were obtained through combinations of strategic feeding/fasting (control vs. low glycogen concentration), slaughter live-weight (84kg vs. 110kg), and gender (female vs. castrate). The flavour development was investigated for possible correlation with the concentrations of selected individual flavour precursors present in the raw meat: monosaccharides, IMP and degradation products, fatty acids, lactate and thiamine. Differences in precursor concentrations between the raw meat qualities were observed with feeding/fasting and ageing as the main factors with the largest influence of all experimental factors. However, the concentrations of the precursors could not explain the differences in sensory perception of the pan-fried pork chops. Overall, the differences were small.

Sensory analysis of meatballs was carried out to monitor the warmed-over flavour (WOF) development in cooked, cold-stored (at 4°C for 0, 2 and 4days) and reheated meatballs derived from M. longissimus dorsi (LD) and M. semimembranosus (SM) of pigs fed a standard diet supplemented with either 3% of rapeseed oil or 3% of palm oil. This was performed in combination with measurement of volatile compounds using a solid-state-based gas sensor array system (electronic nose) and gas chromatography/mass spectrometry together with measurement of thiobarbitoric acid reactive substances (TBARS). Subsequently, to elucidate the relations and predictability between the obtained data, the gas sensor responses were correlated with chemical (volatile and non-volatile secondary lipid oxidation products) and sensory data (flavour and odour attributes), using partial least squares regression modelling (PLSR). The TBARS, hexanal, pentanal, pentanol and nonanal all correlated to the sensory attributes associated to WOF formation. Moreover, the responses from eight of the MOS (metal oxide semiconductor) sensors within the electronic nose proved to be significantly related to WOF characteristics detected by both sensory and chemical analysis, while six of the MOSFET (metal oxide semiconductor field effect transistor) sensors were related to freshly cooked meat attributes determined by sensory analysis. The obtained results show the potential of the present gas sensor technology to monitor WOF formation in pork.

Flavour development and overall eating quality of pork semimembranosus were investigated with regard to different raw meat qualities (feeding/fasting strategy; control/low glycogen level, gender; castrate/female, slaughter live-weight; 84kg/110kg) combined with frying temperature (150°C/240°C). It was further investigated whether the precursor levels of glycogen, IMP, inosine, and hypoxanthine in the raw meat were correlated to the raw meat quality and fried/grilled attributes. Pork schnitzels were fried on a pan (155°C) or grill-pan (240-250°C) to a core temperature of 70°C. Frying temperature was the one factor with greatest influence on the sensory attributes, and pan-grilled schnitzels had significantly higher scores in fried/grilled attributes regardless of meat quality compared to pan-fried schnitzels. Texture was not appreciably influenced by any treatment. There was no correlation between precursor levels and raw meat qualities or fried sensory attributes. Gender and slaughter live-weight had no pronounced influence on flavour and overall eating quality.

The objective of the present study was to investigate the effect of a diet with a low content of digestible starch, slaughter weight and subsequent aging time on meat colour and colour stability. Pork colour was determined as the extent of blooming of M. longissimus thoracis (LT) and M. semimembranosus (SM) after 1, 2, 4, 8 and 15 days postmortem and as colour stability during a subsequent storage period in air for 6 days. Compared to the control diet, the experimental diet resulted in a significantly lower postmortem muscle temperature (1°C; p<0.0001). Moreover, high slaughter weight (110kg) resulted in a higher postmortem temperature in LT (p<0.001) compared to low weight (85kg). Independent of feeding strategy and slaughter weight, the extent of blooming decreased during the first 2-4 days of aging in LT, however, the effect was more pronounced in meat from experimentally fed pigs and pigs with high slaughter weight. This effect was not seen in SM, where a gradual increase in blooming took place throughout the aging period. The colour stability was found to be superior in aged pork from experimentally fed pigs. The discoloration rate was faster in SM compared to LT. In conclusion, the present study shows that the diet composition can be used as a tool to control meat colour and colour stability in pork.

The influence of two diets with different fatty acid compositions has been studied with regard to overall pork quality and significance of specific fatty acids on sensory attributes in fried chops and oven roasts. Twenty castrates and 20 females were in a balanced experimental set-up fed with a standard diet supplemented with α-tocopherol (200mg/kg feed) where the fat source was either 3% of palm oil or 3% rapeseed oil. After slaughter, despite differences in lipid composition and sensory attributes, no significant difference in overall meat quality parameters and flavour precursors was found. Comparison of the two diets showed that supplementation with rapeseed oil resulted in a significantly higher content of C18:3n-3 (polar lipid (PL), neutral lipid (NL)), C18:2n-6c (NL) and C20:2 (NL) in LD and C18:1n-9c, C18:2n-6c, C18:3n-3, C20:3n-3, C22:5n-3 in backfat, while supplementation with palm oil resulted in a higher content of C16:0 (NL), C16:1 (PL), C18:1n-9t (NL) in LD and C16:0, C17:0, C18:0, C16:1, C20:4n-6 in backfat. A positive and significant correlation between the contents of C18:2n-6c, C20:3n-6 in the PL fraction and the sensory attributes fried meat odour and sweet odour were found in fried pork chops from female pigs. Likewise, positive correlations were seen between the content of C18:1n-9c in the PL fraction and sensory attributes such as sourish odour, piggy odour and piggy flavour in whole oven roasts. These data substantiate the view that specific fatty acids in the PL fraction influences flavour attributes in pork.

Inosine monophosphate (IMP) and its degradation products, ribose and hypoxanthine, are all considered to be important constituents in meat flavor formation and development. The present study explored the fate of IMP during the aging of two qualities of pork (pH >5.7 and 5.5 < pH < 5.6) and the potential relationship between IMP, hypoxanthine, and sensory attributes of pork registered both as retronasal and basic taste responses in whole meat, meat juice, and the remaining meat residue. During aging the concentration of IMP decreased with a simultaneous increase in the concentrations of inosine, hypoxanthine, and ribose. The rates at which IMP was degraded to inosine and inosine to hypoxanthine during aging were found to be in agreement with the known rate constants of the dephosphorylation of IMP and the hydrolysis of inosine, respectively. Moreover, high-pH pork resulted in a significantly higher concentration of hypoxanthine throughout storage compared with low-pH pork due to an initially higher concentration of IMP in high-pH meat. The sensory analysis showed increasing intensity in bitterness and saltiness of pork as a function of aging, with the intensity being most pronounced in the meat juice. The increasing bitterness of the pork as a function of aging coincided with the higher content of hypoxanthine in these samples, thereby suggesting that degradation of IMP to hypoxanthine might influence pork flavor. In contrast, IMP was associated with nonaged meat and the sensory attributes meaty and brothy.

The objective of the present study was to elucidate the significance of a muscle-glycogen-reducing finishing diet containing a high ratio of rapeseed and grass meal on fat colour and pork colour compared with a control diet. Pork colour was determined as the extent of blooming of M. longissimus dorsi (LD) and M. semimembranosus (SM) after 1, 2, 4, 8 and 15 days of aging, while fat colour was measured on back fat and stripped bacon the day after slaughter. The muscle-glycogen-reducing diet significantly decreased the glycogen content measured 1min after slaughter in LD. This was reflected as decrease in early post-mortem temperature, as well as a tendency to higher initial pH in both muscles. Moreover ultimate pH was significantly higher in LD from strategically fed pigs compared to the control group and the same tendency was found in SM. Independent of muscle and time of aging, the colour of bloomed pork from pigs fed the control diet had higher chroma and L(∗), a(∗) and b(∗) values compared with pork from the pigs fed the muscle-glycogen-reducing diet with the effect being most pronounced in LD. This can be explained by the slightly higher pH(45min) in the muscles from the pigs fed the muscle-glycogen-reducing finishing diet, which sustain the metmyoglobin reductase activity and the oxygen consumption potential in the muscle and hereby minimise the degree of blooming. The more pronounced influence of the experimental diet on the degree of blooming in LD compared to SM may be explained by the lower T(45min) in LD, which minimise denaturation of the enzymatic processes. This clearly shows that the diet composition can be used to control the extent of blooming in pork. Finally, despite the high content of grass meal in the muscle-glycogen-reducing finishing diet, this diet had negligible influence on the colour of the back fat and stripped bacon fat.