Dietary and genetic determinants of non-alcoholic fatty liver disease in coronary heart disease patients.

PURPOSE: A healthy diet reduces the risk of non-alcoholic fatty liver disease (NAFLD) in the general population, especially in individuals who are genetically predisposed to NAFLD. Little is known in patients who suffered from a myocardial infarction (MI). We examined the interaction between diet quality and genetic predisposition in relation to NAFLD in post-MI patients. METHODS: We included 3437 post-MI patients from the Alpha Omega Cohort. Diet quality was assessed with adherence to the Dutch Healthy Diet index 2015 (DHD15-index). A weighted genetic risk score (GRS) for NAFLD was computed using 39 genetic variants. NAFLD prevalence was predicted using the Fatty Liver Index. Prevalence ratios (PR) with 95% confidence intervals of DHD15-index and GRS in relation to NAFLD were obtained with multivariable Cox proportional hazards models. The interaction between DHD15-index and GRS in relation to NAFLD was assessed on an additive and multiplicative scale. RESULTS: Patients had a mean age of 69 (± 5.5) years, 77% was male and 20% had diabetes. The DHD15-index ranged from 28 to 120 with a mean of 73. Patients with higher diet quality were less likely to suffer from NAFLD, with a PR of 0.76 (0.62, 0.92) for the upper vs lower quintile of DHD15-index. No association between the GRS and NAFLD prevalence was found (PR of 0.92 [0.76, 1.11]). No statistically significant interaction between the DHD15-index and GRS was observed. CONCLUSION: In Dutch post-MI patients, adherence to the Dutch dietary guidelines was associated with a lower prevalence of NAFLD, as assessed by the FLI. This association was present regardless of genetic predisposition in this older aged cohort.

Associations between low- and high-fat dairy intake and recurrence risk in people with stage I-III colorectal cancer differ by sex and primary tumour location.

We previously demonstrated that intake of low-fat dairy, but not high-fat dairy, was associated with a decreased colorectal cancer (CRC) recurrence risk. These risks, however, may differ by sex, primary tumour location, and disease stage. Combining data from two similar prospective cohort studies of people with stage I-III CRC enabled these subgroup analyses. Participants completed a food frequency questionnaire at diagnosis (n = 2283). We examined associations between low- and high-fat dairy intake and recurrence risk using multivariable Cox proportional hazard models, stratified by sex, and primary tumour location (colon and rectum), and disease stage (I/II and III). Upper quartiles were compared to lower quartiles of intake, and recurrence was defined as a locoregional recurrence and/or metastasis. During a median follow-up of 5.0 years, 331 recurrences were detected. A higher intake of low-fat dairy was associated with a reduced risk of recurrence (hazard ratio [HR]: 0.60, 95% confidence interval [CI]: 0.43-0.83), which seemed more pronounced in men (HR: 0.51, 95% CI: 0.34-0.77) than in women (HR: 0.84, 95% CI: 0.47-1.49). A higher intake of high-fat dairy was associated with an increased risk of recurrence in participants with colon cancer (HR: 1.60, 95% CI: 1.03-2.50), but not rectal cancer (HR: 0.88, 95% CI: 0.54-1.45). No differences in associations were observed between strata of disease stage. Concluding, our findings imply that dietary advice regarding low-fat dairy intake may be especially important for men with CRC, and that dietary advice regarding high-fat dairy intake may be specifically important in people with colon cancer.

Coffee consumption is associated with a reduced risk of colorectal cancer recurrence and all-cause mortality.

Coffee consumption has been associated with a reduced risk of developing colorectal cancer (CRC). However, it is not clear whether coffee consumption is related to CRC progression. Hence, we assessed the association of coffee consumption with CRC recurrence and all-cause mortality using data from a prospective cohort study of 1719 stage I-III CRC patients in the Netherlands. Coffee consumption and other lifestyle characteristics were self-reported using questionnaires at the time of diagnosis. We retrieved recurrence and all-cause mortality data from the Netherlands Cancer Registry and the Personal Records Database, respectively. Cox proportional hazard regression models with and without restricted cubic splines were used to calculate hazard ratios (HR) and 95% confidence intervals (CI) adjusted for age, sex, education, smoking status, cancer stage and tumor location. We observed 257 recurrences during a 6.2-year median follow-up and 309 deaths during a 6.6-year median follow-up. Consuming more than 4 cups/d of coffee compared to an intake of <2 cups/d was associated with a 32% lower risk of CRC recurrence (95% CI: 0.49, 0.94,). The association between coffee consumption and all-cause mortality was U-shaped; coffee intake seemed optimal at 3-5 cups/d with the lowest risk at 4 cups/d (HR: 0.68, 95% CI: 0.53, 0.88). Our results suggest that coffee consumption may be associated with a lower risk of CRC recurrence and all-cause mortality. The association between coffee consumption and all-cause mortality appeared nonlinear. More studies are needed to understand the mechanism by which coffee consumption might improve CRC prognosis.

Allometric versus traditional body-shape indices and risk of colorectal cancer: a Mendelian randomization analysis.

BACKGROUND: Traditional body-shape indices such as Waist Circumference (WC), Hip Circumference (HC), and Waist-to-Hip Ratio (WHR) are associated with colorectal cancer (CRC) risk, but are correlated with Body Mass Index (BMI), and adjustment for BMI introduces a strong correlation with height. Thus, new allometric indices have been developed, namely A Body Shape Index (ABSI), Hip Index (HI), and Waist-to-Hip Index (WHI), which are uncorrelated with weight and height; these have also been associated with CRC risk in observational studies, but information from Mendelian randomization (MR) studies is missing. METHODS: We used two-sample MR to examine potential causal cancer site- and sex-specific associations of the genetically-predicted allometric body-shape indices with CRC risk, and compared them with BMI-adjusted traditional body-shape indices, and BMI. Data were obtained from UK Biobank and the GIANT consortium, and from GECCO, CORECT and CCFR consortia. RESULTS: WHI was positively associated with CRC in men (OR per SD: 1.20, 95% CI: 1.03-1.39) and in women (1.15, 1.06-1.24), and similarly for colon and rectal cancer. ABSI was positively associated with colon and rectal cancer in men (1.27, 1.03-1.57; and 1.40, 1.10-1.77, respectively), and with colon cancer in women (1.20, 1.07-1.35). There was little evidence for association between HI and colon or rectal cancer. The BMI-adjusted WHR and HC showed similar associations to WHI and HI, whereas WC showed similar associations to ABSI only in women. CONCLUSIONS: This large MR study provides strong evidence for a potential causal positive association of the allometric indices ABSI and WHI with CRC in both sexes, thus establishing the association between abdominal fat and CRC without the limitations of the traditional waist size indices and independently of BMI. Among the BMI-adjusted traditional indices, WHR and HC provided equivalent associations with WHI and HI, while differences were observed between WC and ABSI.

Hematocrit Is Associated with Cancer-Related Fatigue in Colorectal Cancer Survivors: A Longitudinal Analysis.

BACKGROUND: Cancer-related fatigue (CRF) is a frequent symptom in colorectal cancer survivors. It is unknown to what extent anemia may contribute to CRF in colorectal cancer survivors. This study aimed to investigate the association between hematocrit, as marker for anemia, and CRF among colorectal cancer survivors from diagnosis until two years thereafter. METHODS: The study population included 1,506 newly diagnosed colorectal cancer survivors at any stage of disease from a prospective cohort study. Hematocrit and CRF (EORTC QLQ-C30) were assessed at diagnosis, six months, and two years after diagnosis. Multivariable logistic regression or multivariable linear mixed models were used to assess the associations of hematocrit with CRF prevalence, or CRF severity over time, respectively. RESULTS: A low hematocrit (levels <40% men/<36% women) was present in a third of the survivors at diagnosis and six months thereafter, and among 16% two years after diagnosis. The prevalence of CRF was 15% at diagnosis, peaked at 27% at six months, and was 14% two years after diagnosis. Hematocrit was associated with the prevalence of CRF at diagnosis [OR, 0.92; confidence interval (CI), 0.88-0.95], 6 months (OR, 0.89; 95% CI, 0.86-0.92), and 2 years (OR, 0.91; CI, 0.87-0.96) after diagnosis. Lower hematocrit was associated with higher severity of CRF over time (beta-coefficient = 1.3; CI, 1.5-1.1). CONCLUSIONS: Lower hematocrit levels were longitudinally associated with a higher prevalence and severity of CRF in colorectal cancer. IMPACT: Our findings emphasize the importance of long-term anemia monitoring and a potential role of anemia in CRF among colorectal cancer survivors.

Determinants of Physical Activity among Patients with Colorectal Cancer: From Diagnosis to 5 Years after Diagnosis.

INTRODUCTION: Physical activity (PA) is associated with higher quality of life and probably better prognosis among colorectal cancer (CRC) patients. This study focuses on determinants of PA among CRC patients from diagnosis until 5 yr postdiagnosis. METHODS: Sociodemographic and disease-related factors of participants of two large CRC cohort studies were combined. Moderate-to-vigorous PA during sport and leisure time (MVPA-SL) was measured at diagnosis (T0) and 6, 12, 24, and 60 months (T6 to T60) postdiagnosis, using the SQUASH questionnaire. Mixed-effects models were performed to identify sociodemographic and disease-related determinants of MVPA-SL, separately for stage I-III colon (CC), stage I-III rectal cancer (RC), and stage IV CRC (T0 and T6 only). Associations were defined as consistently present when significant at ≥4 timepoints for the stage I-III subsets. MVPA-SL levels were compared with an age- and sex-matched sample of the general Dutch population. RESULTS: In total, 2905 CC, 1459 RC and 436 stage IV CRC patients were included. Patients with higher fatigue scores, and women compared with men had consistently lower MVPA-SL levels over time, regardless of tumor type and stage. At T6, having a stoma was significantly associated with lower MVPA-SL among stage I-III RC patients. Systemic therapy and radiotherapy were not significantly associated with MVPA-SL changes at T6. Compared with the general population, MVPA-SL levels of CRC patients were lower at all timepoints, most notably at T6. CONCLUSIONS: Female sex and higher fatigue scores were consistent determinants of lower MVPA-SL levels among all CRC patients, and MVPA-SL levels were lowest at 6 months postdiagnosis. Our results can inform the design of intervention studies aimed at improving PA, and guide healthcare professionals in optimizing individualized support.

Intake and biomarkers of folate and folic acid as determinants of chemotherapy-induced toxicities in patients with colorectal cancer: a cohort study.

BACKGROUND: Capecitabine is an oral chemotherapeutic drug showing antitumor activity through inhibition of thymidylate synthase, an enzyme involved in folate metabolism. There are concerns about the high intake of certain vitamins, and specifically folate, during chemotherapy with capecitabine. Whether folate or folic acid, the synthetic variant of the vitamin, impact treatment toxicity remains unclear. OBJECTIVE: We studied associations between intake and biomarkers of folate as well as folic acid and toxicities in patients with colorectal cancer (CRC) receiving capecitabine. METHODS: Within the prospective COLON (Colorectal cancer: Longitudinal, Observational study on Nutritional and lifestyle factors that influence recurrence, survival, and quality of life) cohort, 290 patients with stage II to III CRC receiving capecitabine were identified. Dietary and supplemental intake of folate and folic acid were assessed at diagnosis and during chemotherapy using questionnaires (available for 280 patients). Plasma folate and folic acid levels were determined by liquid chromatography tandem mass spectrometry (LC-MS/MS) and were available for 212 patients. Toxicities were defined as toxicity-related modifications of treatment, including dose reductions, regimen switches, and early discontinuation. Associations of intake and biomarkers of folate and folic acid with toxicities were determined using Cox proportional hazards regression adjusted for age and sex. RESULTS: In total, 153 (53%) patients experienced toxicities leading to modification of capecitabine treatment. Folate intake and plasma folate levels were not associated with risk of toxicities. However, use of folic acid-containing supplements during treatment (hazard ratio (HR) 1.81 and 95% confidence interval (CI) 1.15-2.85) and presence of folic acid in plasma at diagnosis (HR 2.09, 95% CI: 1.24, 3.52) and during treatment (HR 2.31, 95% CI: 1.29, 4.13) were associated with an increased risk of toxicities. CONCLUSIONS: This study suggests a potential association between folic acid and capecitabine-induced toxicities, providing a rationale to study diet-drug interactions and raise further awareness of the use of dietary supplements during oncological treatment. CLINICAL TRIAL DETAILS: This trial was registered at clinicaltrials.gov as NCT03191110.

Genome-Wide Gene-Environment Interaction Analyses to Understand the Relationship between Red Meat and Processed Meat Intake and Colorectal Cancer Risk.

BACKGROUND: High red meat and/or processed meat consumption are established colorectal cancer risk factors. We conducted a genome-wide gene-environment (GxE) interaction analysis to identify genetic variants that may modify these associations. METHODS: A pooled sample of 29,842 colorectal cancer cases and 39,635 controls of European ancestry from 27 studies were included. Quantiles for red meat and processed meat intake were constructed from harmonized questionnaire data. Genotyping arrays were imputed to the Haplotype Reference Consortium. Two-step EDGE and joint tests of GxE interaction were utilized in our genome-wide scan. RESULTS: Meta-analyses confirmed positive associations between increased consumption of red meat and processed meat with colorectal cancer risk [per quartile red meat OR = 1.30; 95% confidence interval (CI) = 1.21-1.41; processed meat OR = 1.40; 95% CI = 1.20-1.63]. Two significant genome-wide GxE interactions for red meat consumption were found. Joint GxE tests revealed the rs4871179 SNP in chromosome 8 (downstream of HAS2); greater than median of consumption ORs = 1.38 (95% CI = 1.29-1.46), 1.20 (95% CI = 1.12-1.27), and 1.07 (95% CI = 0.95-1.19) for CC, CG, and GG, respectively. The two-step EDGE method identified the rs35352860 SNP in chromosome 18 (SMAD7 intron); greater than median of consumption ORs = 1.18 (95% CI = 1.11-1.24), 1.35 (95% CI = 1.26-1.44), and 1.46 (95% CI = 1.26-1.69) for CC, CT, and TT, respectively. CONCLUSIONS: We propose two novel biomarkers that support the role of meat consumption with an increased risk of colorectal cancer. IMPACT: The reported GxE interactions may explain the increased risk of colorectal cancer in certain population subgroups.

Combining Asian and European genome-wide association studies of colorectal cancer improves risk prediction across racial and ethnic populations.

Polygenic risk scores (PRS) have great potential to guide precision colorectal cancer (CRC) prevention by identifying those at higher risk to undertake targeted screening. However, current PRS using European ancestry data have sub-optimal performance in non-European ancestry populations, limiting their utility among these populations. Towards addressing this deficiency, we expand PRS development for CRC by incorporating Asian ancestry data (21,731 cases; 47,444 controls) into European ancestry training datasets (78,473 cases; 107,143 controls). The AUC estimates (95% CI) of PRS are 0.63(0.62-0.64), 0.59(0.57-0.61), 0.62(0.60-0.63), and 0.65(0.63-0.66) in independent datasets including 1681-3651 cases and 8696-115,105 controls of Asian, Black/African American, Latinx/Hispanic, and non-Hispanic White, respectively. They are significantly better than the European-centric PRS in all four major US racial and ethnic groups (p-values < 0.05). Further inclusion of non-European ancestry populations, especially Black/African American and Latinx/Hispanic, is needed to improve the risk prediction and enhance equity in applying PRS in clinical practice.

Higher Plasma Creatinine Is Associated with an Increased Risk of Death in Patients with Non-Metastatic Rectal but Not Colon Cancer: Results from an International Cohort Consortium.

Colorectal cancer (CRC) is increasingly recognized as a heterogeneous disease. No studies have prospectively examined associations of blood metabolite concentrations with all-cause mortality in patients with colon and rectal cancer separately. Targeted metabolomics (Biocrates AbsoluteIDQ p180) and pathway analyses (MetaboAnalyst 4.0) were performed on pre-surgery collected plasma from 674 patients with non-metastasized (stage I-III) colon (n = 394) or rectal cancer (n = 283). Metabolomics data and covariate information were received from the international cohort consortium MetaboCCC. Cox proportional hazards models were computed to investigate associations of 148 metabolite levels with all-cause mortality adjusted for age, sex, tumor stage, tumor site (whenever applicable), and cohort; the false discovery rate (FDR) was used to account for multiple testing. A total of 93 patients (14%) were deceased after an average follow-up time of 4.4 years (60 patients with colon cancer and 33 patients with rectal cancer). After FDR adjustment, higher plasma creatinine was associated with a 39% increase in all-cause mortality in patients with rectal cancer. HR: 1.39, 95% CI 1.23-1.72, pFDR = 0.03; but not colon cancer: pFDR = 0.96. Creatinine is a breakdown product of creatine phosphate in muscle and may reflect changes in skeletal muscle mass. The starch and sucrose metabolisms were associated with increased all-cause mortality in colon cancer but not in rectal cancer. Genes in the starch and sucrose metabolism pathways were previously linked to worse clinical outcomes in CRC. In summary, our findings support the hypothesis that colon and rectal cancer have different etiological and clinical outcomes that need to be considered for targeted treatments.

Pre- and post-diagnostic dairy intake in relation to recurrence and all-cause mortality in people with stage I-III colorectal cancer.

PURPOSE: Higher dairy consumption is associated with a lower risk of colorectal cancer (CRC), but no studies thus far have investigated its relation with recurrence in CRC. Few studies have investigated total dairy in relation to mortality in CRC, and yielded inconsistent results. METHODS: In this prospective cohort study, people newly diagnosed with stage I-III CRC filled out a food frequency questionnaire at diagnosis (n = 1812) and six months after diagnosis (n = 1672). We examined associations between pre- and post-diagnostic intake of total dairy, low-fat dairy, high-fat dairy, milk, yoghurt, and cheese with recurrence and all-cause mortality using multivariable Cox proportional hazard models and restricted cubic splines (RCS). RESULTS: A total of 176 recurrences and 301 deaths occurred during a median follow-up of 3.0 and 5.9 years, respectively. Before diagnosis, a higher low-fat dairy intake was associated with a lower risk of recurrence (HRQ4vsQ1: 0.42, 95% CI 0.26-0.67; PRCS: 0.008) and all-cause mortality (HRQ4vsQ1: 0.58, 95% CI 0.41-0.81; PRCS < 0.001), whereas a higher high-fat dairy consumption tended to be associated with an increased all-cause mortality risk (HRQ4vsQ1: 1.41, 95% CI 0.98-2.01; PRCS: 0.030). After diagnosis, only the associations between low- and high-fat dairy in relation to all-cause mortality remained. CONCLUSIONS: This study demonstrated that higher pre- and post-diagnostic intakes of low-fat dairy were associated with a reduced all-cause mortality risk in people with stage I-III CRC, whereas higher intakes of high-fat dairy were associated with an increased all-cause mortality risk. Also, a higher pre-diagnostic low-fat dairy intake was associated with a reduced risk of recurrence. TRIAL REGISTRATION: Clinical Trials.gov identifier: NCT03191110.

The association between anastomotic leakage and health-related quality of life after colorectal cancer surgery.

AIM: Colorectal anastomotic leakage (AL) is a serious complication. Studies on the impact of AL on health-related quality of life (HRQoL) are scarce. We aimed to investigate the association between AL and HRQoL in colorectal cancer patients up to 2 years after diagnosis, and to evaluate whether AL is associated with a clinically relevant decrease in HRQoL over time. METHODS: Patients diagnosed with Stage I-III colorectal cancer undergoing elective surgical resection with primary anastomosis between 2010 and 2017 were included. HRQoL was evaluated using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30, represented by the summary score, and analysed at diagnosis and at 6 months and 2 years post-diagnosis. Multivariable linear regression was performed to assess the association between AL and HRQoL, while multivariable logistic regression was used to investigate the association between AL and a clinically relevant HRQoL decrease (≥10 points) during follow-up compared to the time of diagnosis. RESULTS: In total, 1197 patients were included of whom 63 (5%) developed AL. AL was not associated with HRQoL at 6 months post-diagnosis nor at 2 years post-diagnosis. However, having AL was associated with an increased risk of a clinically relevant decrease in HRQoL at 6 months post-diagnosis (OR 3.65, 95% CI 1.62-8.21) but not at 2 years after diagnosis (OR 1.91, 95% CI 0.62-5.93). CONCLUSION: Although AL was not associated with HRQoL at 6 months or 2 years post-diagnosis, AL was a determinant of a clinically relevant decrease in HRQoL at 6 months after diagnosis. Future work should identify feasible and effective strategies to prevent declines in QoL in this patient population.

Postdiagnostic intake of a more proinflammatory diet is associated with a higher risk of recurrence and all-cause mortality in colorectal cancer survivors.

BACKGROUND: The inflammatory potential of the diet has been associated with colorectal cancer (CRC) risk, but its association with CRC prognosis is unclear. OBJECTIVE: To investigate the inflammatory potential of the diet in relation to recurrence and all-cause mortality among persons diagnosed with stage I to III CRC. METHODS: Data of the COLON study, a prospective cohort among CRC survivors were used. Dietary intake, 6 mo after diagnosis, was assessed by using a food frequency questionnaire and was available for 1631 individuals. The empirical dietary inflammatory pattern (EDIP) score was used as a proxy for the inflammatory potential of the diet. The EDIP score was created by using reduced rank regression and stepwise linear regression to identify food groups that explained most of the variations in plasma inflammatory markers (IL6, IL8, C-reactive protein, and tumor necrosis factor-α) measured in a subgroup of survivors (n = 421). Multivariable Cox proportional hazard models with restricted cubic splines were used to investigate the relation between the EDIP score and CRC recurrence and all-cause mortality. Models were adjusted for age, sex, BMI, PAL, smoking status, stage of disease, and tumor location. RESULTS: The median follow-up time was 2.6 y (IQR: 2.1) for recurrence and 5.6 y (IQR: 3.0) for all-cause mortality, during which 154 and 239 events occurred, respectively. A nonlinear positive association between the EDIP score and recurrence and all-cause mortality was observed. For example, a more proinflammatory diet (EDIP score +0.75) compared with the median (EDIP score 0) was associated with a higher risk of CRC recurrence (HR: 1.15; 95% CI: 1.03, 1.29) and all-cause mortality (HR: 1.23; 95% CI: 1.12, 1.35). CONCLUSIONS: A more proinflammatory diet was associated with a higher risk of recurrence and all-cause mortality in CRC survivors. Further intervention studies should investigate whether a switch to a more anti-inflammatory diet improves CRC prognosis.

Combining Asian-European Genome-Wide Association Studies of Colorectal Cancer Improves Risk Prediction Across Race and Ethnicity.

Polygenic risk scores (PRS) have great potential to guide precision colorectal cancer (CRC) prevention by identifying those at higher risk to undertake targeted screening. However, current PRS using European ancestry data have sub-optimal performance in non-European ancestry populations, limiting their utility among these populations. Towards addressing this deficiency, we expanded PRS development for CRC by incorporating Asian ancestry data (21,731 cases; 47,444 controls) into European ancestry training datasets (78,473 cases; 107,143 controls). The AUC estimates (95% CI) of PRS were 0.63(0.62-0.64), 0.59(0.57-0.61), 0.62(0.60-0.63), and 0.65(0.63-0.66) in independent datasets including 1,681-3,651 cases and 8,696-115,105 controls of Asian, Black/African American, Latinx/Hispanic, and non-Hispanic White, respectively. They were significantly better than the European-centric PRS in all four major US racial and ethnic groups (p-values<0.05). Further inclusion of non-European ancestry populations, especially Black/African American and Latinx/Hispanic, is needed to improve the risk prediction and enhance equity in applying PRS in clinical practice.

Longitudinal associations of fast foods, red and processed meat, alcohol and sugar-sweetened drinks with quality of life and symptoms in colorectal cancer survivors up to 24 months post-treatment.

Unhealthy dietary habits can contribute to the development of colorectal cancer (CRC). Such habits may also be associated with post-treatment symptoms experienced by CRC survivors. Therefore, we aimed to assess longitudinal associations of post-treatment unhealthy dietary habits, i.e. intake of ultra-processed foods (UPF), red and processed meat, alcohol and sugar-sweetened drinks, with health-related quality of life (HRQoL), fatigue and chemotherapy-induced peripheral neuropathy (CIPN) in CRC survivors from 6 weeks up to 24 months post-treatment. In a prospective cohort among stage I-III CRC survivors (n 396), five repeated home visits from diagnosis up to 24 months post-treatment were executed. Dietary intake was measured by 7-d dietary records to quantify consumption of UPF, red and processed meat, alcohol and sugar-sweetened drinks. HRQoL, fatigue and CIPN were measured by validated questionnaires. We applied confounder-adjusted linear mixed models to analyse longitudinal associations from 6 weeks until 24 months post-treatment. We applied a post hoc time-lag analysis for alcohol to explore the directionality. Results showed that higher post-treatment intake of UPF and sugar-sweetened drinks was longitudinally associated with worsened HRQoL and more fatigue, while higher intake of UPF and processed meat was associated with increased CIPN symptoms. In contrast, post-treatment increases in alcohol intake were longitudinally associated with better HRQoL and less fatigue; however, time-lag analysis attenuated these associations. In conclusion, unhealthy dietary habits are longitudinally associated with lower HRQoL and more symptoms, except for alcohol. Results from time-lag analysis suggest no biological effect of alcohol; hence, the longitudinal association for alcohol should be interpreted with caution.

Cohort profile: Biomarkers related to folate-dependent one-carbon metabolism in colorectal cancer recurrence and survival - the FOCUS Consortium.

PURPOSE: The overarching goal of the FOCUS (biomarkers related to folate-dependent one-carbon metabolism in colorectal cancer (CRC) recurrence and survival) Consortium is to unravel the effect of folate and folate-mediated one-carbon metabolism (FOCM) biomarkers on CRC prognosis to provide clinically relevant advice on folate intake to cancer patients and define future tertiary prevention strategies. PARTICIPANTS: The FOCUS Consortium is an international, prospective cohort of 2401 women and men above 18 years of age who were diagnosed with a primary invasive non-metastatic (stages I-III) CRC. The consortium comprises patients from Austria, two sites from the Netherlands, Germany and two sites from the USA. Patients are recruited after CRC diagnosis and followed at 6 and 12 months after enrolment. At each time point, sociodemographic data, data on health behaviour and clinical data are collected, blood samples are drawn. FINDINGS TO DATE: An increased risk of cancer recurrences was observed among patients with higher compared with lower circulating folic acid concentrations. Furthermore, specific folate species within the FOCM pathway were associated with both inflammation and angiogenesis pathways among patients with CRC. In addition, higher vitamin B6 status was associated with better quality of life at 6 months post-treatment. FUTURE PLANS: Better insights into the research on associations between folate and FOCM biomarkers and clinical outcomes in patients with CRC will facilitate the development of guidelines regarding folate intake in order to provide clinically relevant advice to patients with cancer, health professionals involved in patient care, and ultimately further tertiary prevention strategies in the future. The FOCUS Consortium offers an excellent infrastructure for short-term and long-term research projects and for combining additional biomarkers and data resulting from the individual cohorts within the next years, for example, microbiome data, omics and multiomics data or CT-quantified body composition data.

External validation and updating of prediction models for estimating the 1-year risk of low health-related quality of life in colorectal cancer survivors.

OBJECTIVES: Timely identification of colorectal cancer (CRC) survivors at risk of experiencing low health-related quality of life (HRQoL) in the near future is important for enabling appropriately tailored preventive actions. We previously developed and internally validated risk prediction models to estimate the 1-year risk of low HRQoL in long-term CRC survivors. In this article, we aim to externally validate and update these models in a population of short-term CRC survivors. STUDY DESIGN AND SETTING: In a pooled cohort of 1,596 CRC survivors, seven HRQoL domains (global QoL, cognitive/emotional/physical/role/social functioning, and fatigue) were measured prospectively at approximately 5 months postdiagnosis (baseline for prediction) and approximately 1 year later by a validated patient-reported outcome measure (European Organization for Research and Treatment of Cancer Quality of life Questionnaire-Core 30). For each HRQoL domain, 1-year scores were dichotomized into low vs. normal/high HRQoL. Performance of the previously developed multivariable logistic prediction models was evaluated (calibration and discrimination). Models were updated to create a more parsimonious predictor set for all HRQoL domains. RESULTS: Updated models showed good calibration and discrimination (AUC ≥0.75), containing a single set of 15 predictors, including nonmodifiable (age, sex, education, time since diagnosis, chemotherapy, radiotherapy, stoma, and comorbidities) and modifiable predictors (body mass index, physical activity, smoking, anxiety/depression, and baseline fatigue and HRQoL domain scores). CONCLUSION: Externally validated and updated prediction models performed well for estimating the 1-year risk of low HRQoL in CRC survivors within 6 months postdiagnosis. The impact of implementing the models in oncology practice to improve HRQoL outcomes in CRC survivors needs to be evaluated.

Longitudinal Associations between Inflammatory Markers and Fatigue up to Two Years after Colorectal Cancer Treatment.

BACKGROUND: Fatigue is often reported by colorectal cancer survivors and largely impacts their quality of life. Inflammation has been linked to fatigue mainly in patients with breast cancer. Therefore, we investigated how inflammation is longitudinally associated with fatigue in colorectal cancer survivors, up to 2 years posttreatment. METHODS: A total of 257 patients from the ongoing Energy for life after ColoRectal cancer cohort study were included in the analysis. Plasma levels of IL6, IL8, IL10, TNFα, high-sensitivity C-reactive protein (hsCRP), and fatigue were measured at 6 weeks, 6, 12, and 24 months posttreatment. Fatigue was measured through the validated Checklist Individual Strength (CIS; total, 20-140), consisting of four subscales - subjective fatigue (8-56), motivation (4-28), physical activity (3-21), and concentration (5-35), and the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 fatigue subscale (0-100). Linear mixed-models were used to assess the confounder-adjusted longitudinal associations between inflammatory markers and overall fatigue along with the subscales. RESULTS: Mean levels of CIS fatigue decreased from 62.9 at 6 weeks to 53.0 at 24 months. In general, levels of inflammatory markers also decreased over time. No statistically significant longitudinal associations were found between IL6, IL8, IL10, TNFα, and fatigue. Higher levels of hsCRP were associated with more CIS fatigue (ß per SD 3.21, 95% confidence interval (CI), 1.42-5.01) and EORTC fatigue (ß 2.41, 95% CI, 0.72-4.10). CONCLUSIONS: Increased levels of hsCRP are longitudinally associated with more posttreatment fatigue in colorectal cancer survivors. IMPACT: These findings suggest that low-grade inflammation may play a role in fatigue reported by colorectal cancer survivors up to 2 years posttreatment.

Genome-Wide Interaction Analysis of Genetic Variants With Menopausal Hormone Therapy for Colorectal Cancer Risk.

BACKGROUND: The use of menopausal hormone therapy (MHT) may interact with genetic variants to influence colorectal cancer (CRC) risk. METHODS: We conducted a genome-wide, gene-environment interaction between single nucleotide polymorphisms and the use of any MHT, estrogen only, and combined estrogen-progestogen therapy with CRC risk, among 28 486 postmenopausal women (11 519 CRC patients and 16 967 participants without CRC) from 38 studies, using logistic regression, 2-step method, and 2- or 3-degree-of-freedom joint test. A set-based score test was applied for rare genetic variants. RESULTS: The use of any MHT, estrogen only and estrogen-progestogen were associated with a reduced CRC risk (odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.64 to 0.78; OR = 0.65, 95% CI = 0.53 to 0.79; and OR = 0.73, 95% CI = 0.59 to 0.90, respectively). The 2-step method identified a statistically significant interaction between a GRIN2B variant rs117868593 and MHT use, whereby MHT-associated CRC risk was statistically significantly reduced in women with the GG genotype (OR = 0.68, 95% CI = 0.64 to 0.72) but not within strata of GC or CC genotypes. A statistically significant interaction between a DCBLD1 intronic variant at 6q22.1 (rs10782186) and MHT use was identified by the 2-degree-of-freedom joint test. The MHT-associated CRC risk was reduced with increasing number of rs10782186-C alleles, showing odds ratios of 0.78 (95% CI = 0.70 to 0.87) for TT, 0.68 (95% CI = 0.63 to 0.73) for TC, and 0.66 (95% CI = 0.60 to 0.74) for CC genotypes. In addition, 5 genes in rare variant analysis showed suggestive interactions with MHT (2-sided P < 1.2 × 10-4). CONCLUSION: Genetic variants that modify the association between MHT and CRC risk were identified, offering new insights into pathways of CRC carcinogenesis and potential mechanisms involved.