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Background & Aims: Colonoscopy-based surveillance to prevent colorectal cancer (CRC) causes substantial burden for patients and health care. Stool tests may help to reduce surveillance colonoscopies by limiting colonoscopies to individuals at increased risk of advanced neoplasia., Methods: This cross-sectional observational study included individuals aged 50-75 years with surveillance indication. Before bowel preparation, participants collected samples for a multitarget stool DNA test and 2 fecal immunochemical tests (FITs). Test accuracy was calculated for all surveillance indications. For the post-polypectomy indication only, which is the most common and is associated with a relatively low CRC risk, long-term impact of stool-based surveillance was evaluated with the Adenoma and Serrated Pathway to Colorectal Cancer (ASCCA) model. Stool-based strategies were simulated to tune each test's positivity threshold to obtain strategies at least as effective as colonoscopy surveillance., Results: There were 3453 individuals with results for all stool tests and colonoscopy; 2226 had previous polypectomy, 1003 had previous CRC, and 224 had a familial risk. Areas under the receiver operating characteristic curve for advanced neoplasia were 0.72 (95% CI, 0.69-0.75) for the multitarget stool DNA test, 0.61 (95% CI, 0.58-0.64) for the FIT OC-SENSOR (Eiken Chemical Co, Tokyo, Japan) and 0.59 (95% CI, 0.56-0.61) for the FIT FOB-Gold (Sentinel, Milan, Italy). Stool-based post-polypectomy surveillance strategies at least as effective as colonoscopy surveillance reduced the number of colonoscopies by 15%-41% and required 5.6-9.5 stool tests over a person's lifetime. Multitarget stool DNA-based surveillance was more costly than colonoscopy surveillance, whereas FIT-based surveillance saved costs., Conclusions: This study found that stool-based post-polypectomy surveillance strategies can be safe and cost-effective, with potential to reduce the number of colonoscopies by up to 41%., Clinicaltrials: gov, Number: NCT02715141., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Several automated programs have been developed to facilitate body composition analysis of images from abdominal computed tomography (CT) scans. External validation in patients with colorectal cancer is necessary for use in research and clinical practice. Our aim was to validate an automatic method (AutoMATiCA) of segmenting CT images at the third lumbar level (L3) from patients with colorectal cancer, by comparing with manual segmentation., Methods: Diagnostic abdominal CT scans of consecutive patients with stage I-III colorectal cancer were analysed to measure cross-sectional areas and tissue densities of skeletal muscle and intra-muscular, visceral, and subcutaneous adipose tissue. Trained analysts performed manual segmentation of L3 CT images using SliceOmatic. Automatic segmentation was performed using AutoMATiCA, an open-source software. The Dice similarity coefficient (DSC) was calculated to assess segmentation accuracy. Agreement of automatic with manual segmentation was evaluated using intra-class correlation coefficients (ICCs) and Bland-Altman plots with limits of agreement., Results: A total of 292 scans were included, of which 62% were from male patients. The agreement of AutoMATiCA with the manual segmentation was excellent, with median DSC values ranging from 0.900 to 0.991 and ICCs above 0.95 for all segmented areas. No systematic deviations were observed in Bland-Altman plots for all segmented areas, with overall narrow limits of agreement., Conclusions: AutoMATiCA provides an accurate segmentation of abdominal CT images from patients with colorectal cancer. Our findings support its use as a highly efficient automated tool for body composition analysis in research and potentially also in clinical practice., Competing Interests: Declaration of competing interest Judith de Vos-Geelen has served as a consultant for Amgen, AstraZeneca, MSD, Pierre Fabre, and Servier, and has received institutional research funding from Servier. All outside the submitted work., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Fatigue is prevalent in colorectal cancer (CRC) survivors, impacting their health-related quality of life (HRQoL). Inflammation-induced activation of the kynurenine pathway may play a role in cancer-related fatigue and HRQoL, but evidence is scarce. Therefore, we aimed to investigate longitudinal associations of plasma tryptophan, kynurenines, and ratios with fatigue and HRQoL in CRC survivors up to 12 months post-treatment. Repeated measurements at 6 weeks, 6 months, and 12 months post-treatment were performed in 249 stage I-III CRC survivors. Plasma tryptophan and eight kynurenines were analyzed using liquid chromatography-tandem mass spectrometry (LC/MS-MS). Fatigue and HRQoL outcomes were evaluated using validated questionnaires. Confounder-adjusted linear mixed models were conducted to analyze longitudinal associations, with false discovery rate (FDR) correction. Higher tryptophan (Trp), kynurenic acid (KA), and xanthurenic acid (XA) concentrations, as well as a higher kynurenic acid-to-quinolinic acid ratio (KA/QA), were associated with less fatigue and better functioning, while a higher kynurenine-to-tryptophan ratio (KTR) and 3-hydroxykynurenine ratio (HKr) were associated with more fatigue and worse functioning. Finally, higher KA and XA concentrations and a higher KA/QA ratio were associated with a higher overall HRQoL summary score, while a higher HKr was associated with a lower overall HRQoL summary score. In conclusion, we observed that tryptophan and several kynurenines were longitudinally associated with fatigue and HRQoL in CRC survivors up to 12 months post-treatment. Future research is needed to validate our findings and explore the potential of the kynurenine pathway as intervention target for reducing fatigue and enhancing HRQoL after CRC treatment., (© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: There is a growing population of survivors of colorectal cancer (CRC). Fatigue and insomnia are common symptoms after CRC, negatively influencing health-related quality of life (HRQoL). Besides increasing physical activity and decreasing sedentary behavior, the timing and patterns of physical activity and rest over the 24-h day (i.e. diurnal rest-activity rhythms) could also play a role in alleviating these symptoms and improving HRQoL. We investigated longitudinal associations of the diurnal rest-activity rhythm (RAR) with fatigue, insomnia, and HRQoL in survivors of CRC., Methods: In a prospective cohort study among survivors of stage I-III CRC, 5 repeated measurements were performed from 6 weeks up to 5 years post-treatment. Parameters of RAR, including mesor, amplitude, acrophase, circadian quotient, dichotomy index, and 24-h autocorrelation coefficient, were assessed by a custom MATLAB program using data from tri-axial accelerometers worn on the upper thigh for 7 consecutive days. Fatigue, insomnia, and HRQoL were measured by validated questionnaires. Confounder-adjusted linear mixed models were applied to analyze longitudinal associations of RAR with fatigue, insomnia, and HRQoL from 6 weeks until 5 years post-treatment. Additionally, intra-individual and inter-individual associations over time were separated., Results: Data were available from 289 survivors of CRC. All RAR parameters except for 24-h autocorrelation increased from 6 weeks to 6 months post-treatment, after which they remained relatively stable. A higher mesor, amplitude, circadian quotient, dichotomy index, and 24-h autocorrelation were statistically significantly associated with less fatigue and better HRQoL over time. A higher amplitude and circadian quotient were associated with lower insomnia. Most of these associations appeared driven by both within-person changes over time and between-person differences in RAR parameters. No significant associations were observed for acrophase., Conclusions: In the first five years after CRC treatment, adhering to a generally more active (mesor) and consistent (24-h autocorrelation) RAR, with a pronounced peak activity (amplitude) and a marked difference between daytime and nighttime activity (dichotomy index) was found to be associated with lower fatigue, lower insomnia, and a better HRQoL. Future intervention studies are needed to investigate if restoring RAR among survivors of CRC could help to alleviate symptoms of fatigue and insomnia while enhancing their HRQoL., Trial Registration: EnCoRe study NL6904 ( https://www.onderzoekmetmensen.nl/ )., (© 2024. The Author(s).)

Introduction: Colorectal cancer (CRC) survivors often experience neuropsychological symptoms, including anxiety and depression. Mounting evidence suggests a role for the kynurenine pathway in these symptoms due to potential neuroprotective and neurotoxic roles of involved metabolites. However, evidence remains inconclusive and insufficient in cancer survivors. Thus, we aimed to explore longitudinal associations of plasma tryptophan, kynurenines, and their established ratios with anxiety and depression in CRC survivors up to 12 months post-treatment., Methods: In 249 stage I-III CRC survivors, blood samples were collected at 6 weeks, 6 months, and 12 months post-treatment to analyze plasma concentrations of tryptophan and kynurenines using liquid-chromatography tandem-mass spectrometry (LC/MS-MS). At the same timepoints, anxiety and depression were assessed using the Hospital Anxiety and Depression Scale (HADS). Confounder-adjusted linear mixed models were used to analyze longitudinal associations. Sensitivity analyses with false discovery rate (FDR) correction were conducted to adjust for multiple testing., Results: Higher plasma tryptophan concentrations were associated with lower depression scores (β as change in depression score per 1 SD increase in the ln-transformed kynurenine concentration: -0.31; 95%CI: -0.56,-0.05), and higher plasma 3-hydroxyanthranilic acid concentrations with lower anxiety scores (-0.26; -0.52,-0.01). A higher 3-hydroxykynurenine ratio (HKr; the ratio of 3-hydroxykynurenine to the sum of kynurenic acid, xanthurenic acid, anthranilic acid, and 3-hydroxyanthranilic acid) was associated with higher depression scores (0.34; 0.04,0.63) and higher total anxiety and depression scores (0.53; 0.02,1.04). Overall associations appeared to be mainly driven by inter-individual associations, which were statistically significant for tryptophan with depression (-0.60; -1.12,-0.09), xanthurenic acid with total anxiety and depression (-1.04; -1.99,-0.10), anxiety (-0.51; -1.01,-0.01), and depression (-0.56; -1.08,-0.05), and kynurenic-acid-to-quinolinic-acid ratio with depression (-0.47; -0.93,-0.01). In sensitivity analyses, associations did not remain statistically significant after FDR adjustment., Conclusion: We observed that plasma concentrations of tryptophan, 3-hydroxyanthranilic acid, xanthurenic acid, 3-hydroxykynurenine ratio, and kynurenic-acid-to-quinolinic-acid ratio tended to be longitudinally associated with anxiety and depression in CRC survivors up to 12 months post-treatment. Future studies are warranted to further elucidate the association of plasma kynurenines with anxiety and depression., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Fatigue and insomnia, potentially induced by inflammation, are distressing symptoms experienced by colorectal cancer (CRC) survivors. Emerging evidence suggests that besides the nutritional quality and quantity, also the timing, frequency and regularity of dietary intake (chrono-nutrition) could be important for alleviating these symptoms. We investigated longitudinal associations of circadian eating patterns with sleep quality, fatigue and inflammation in CRC survivors. In a prospective cohort of 459 stage I-III CRC survivors, four repeated measurements were performed between 6 weeks and 24 months post-treatment. Chrono-nutrition variables included meal energy contribution, frequency (a maximum of six meals could be reported each day), irregularity and time window (TW) of energetic intake, operationalised based on 7-d dietary records. Outcomes included sleep quality, fatigue and plasma concentrations of inflammatory markers. Longitudinal associations of chrono-nutrition variables with outcomes from 6 weeks until 24 months post-treatment were analysed by confounder-adjusted linear mixed models, including hybrid models to disentangle intra-individual changes from inter-individual differences over time. An hour longer TW of energetic intake between individuals was associated with less fatigue ( β : -6·1; 95 % CI (-8·8, -3·3)) and insomnia ( β : -4·8; 95 % CI (-7·4, -2·1)). A higher meal frequency of on average 0·6 meals/d between individuals was associated with less fatigue ( β : -3·7; 95 % CI (-6·6, -0·8)). An hour increase in TW of energetic intake within individuals was associated with less insomnia ( β : -3·0; 95 % CI (-5·2, -0·8)) and inflammation ( β : -0·1; 95 % CI (-0·1, 0·0)). Our results suggest that longer TWs of energetic intake and higher meal frequencies may be associated with less fatigue, insomnia and inflammation among CRC survivors. Future studies with larger contrasts in chrono-nutrition variables are needed to confirm these findings.

Background: The tryptophan-kynurenine pathway is increasingly recognized to play a role in health-related quality of life (HRQoL) after cancer. Because tryptophan is an essential amino acid, and vitamins and minerals act as enzymatic cofactors in the tryptophan-kynurenine pathway, a link between diet and kynurenines is plausible., Objectives: This study aimed to investigate the longitudinal associations of macronutrient and micronutrient intake with metabolites of the kynurenine pathway in colorectal cancer (CRC) survivors up to 12 mo posttreatment., Methods: In a prospective cohort of stage I-III CRC survivors (n = 247), repeated measurements were performed at 6 wk, 6 mo, and 12 mo posttreatment. Macronutrient and micronutrient intake was measured by 7-d dietary records. Plasma concentrations of tryptophan and kynurenines were analyzed using liquid chromatography tandem mass spectrometry (LC/MS-MS). Longitudinal associations were analyzed using linear mixed models adjusted for sociodemographic, clinical, and lifestyle factors., Results: After adjustment for multiple testing, higher total protein intake was positively associated with kynurenic acid (KA) (β as standard deviation [SD] change in KA concentration per 1 SD increase in total protein intake: 0.12; 95% CI: 0.04, 0.20), xanthurenic acid (XA) (standardized β: 0.22; 95% CI: 0.11, 0.33), 3-hydroxyanthranilic acid (HAA) (standardized β: 0.15; 95% CI: 0.04, 0.27) concentrations, and the kynurenic acid-to-quinolinic acid ratio (KA/QA) (standardized β: 0.12; 95% CI: 0.02,0.22). In contrast, higher total carbohydrate intake was associated with lower XA concentrations (standardized β: -0.18; 95% CI: -0.30, -0.07), a lower KA/QA (standardized β: -0.23; 95% CI: -0.34, -0.13), and a higher kynurenine-to-tryptophan ratio (KTR) (standardized β: 0.20; 95% CI: 0.10, 0.30). Higher fiber intake was associated with a higher KA/QA (standardized β: 0.11; 95% CI: 0.02, 0.21) and a lower KTR (standardized β: -0.12; 95% CI: -0.20, -0.03). Higher total fat intake was also associated with higher tryptophan (Trp) concentrations (standardized β: 0.18; 95% CI: 0.06, 0.30) and a lower KTR (standardized β: -0.13; 95% CI: -0.22, -0.03). For micronutrients, positive associations were observed for zinc with XA (standardized β: 0.13; 95% CI: 0.04, 0.21) and 3-hydroxykynurenine (HK) (standardized β: 0.12; 95% CI: 0.03, 0.20) concentrations and for magnesium with KA/QA (standardized β: 0.24; 95% CI: 0.13, 0.36)., Conclusions: Our findings show that intake of several macronutrients and micronutrients is associated with some metabolites of the kynurenine pathway in CRC survivors up to 12 mo posttreatment. These results may be relevant for enhancing HRQoL after cancer through potential diet-induced changes in kynurenines. Further studies are necessary to confirm our findings., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: We investigated longitudinal associations of sedentary behavior, light-intensity physical activity (LPA) and moderate-to-vigorous physical activity (MVPA) with body composition in colorectal cancer (CRC) survivors, between 6 weeks and 24 months post treatment. In addition, we explored whether body composition mediated associations of sedentary behavior and MVPA with fatigue., Methods: A prospective cohort study was conducted in 459 stage I-III CRC patients recruited at diagnosis. Measurements were performed of accelerometer-assessed sedentary time (hours/day), self-reported LPA and MVPA (hours/week), anthropometric assessment of body mass index (BMI), waist circumference and fat percentage (measures of adiposity), and muscle circumference and handgrip strength (measures of muscle mass/function) repeated at 6 weeks, and 6, 12 and 24 months post treatment. Longitudinal associations of sedentary time and physical activity with body composition were analyzed using confounder-adjusted linear mixed models. Mediation analyses were performed to explore the role of body mass index (BMI) and handgrip strength as mediators in associations of sedentary time and MVPA with fatigue., Results: Less sedentary time and LPA were, independent of MVPA, longitudinally associated with increased handgrip strength, but not with measures of adiposity. More MVPA was associated with increased adiposity and increased handgrip strength. Higher BMI partly mediated associations between higher sedentary time and more fatigue., Conclusion: Within the first two years after CRC treatment, changes in sedentary behavior, physical activity and body composition are interrelated and associated with fatigue. Intervention studies are warranted to investigate causality., Trial Registration: The EnCoRe study is registered at trialregister.nl as NL6904 (former ID: NTR7099)., (© 2022. The Author(s).)

The underlying biological mechanisms causing persistent fatigue complaints after colorectal cancer treatment need further investigation. We investigated longitudinal associations of circulating concentrations of 138 metabolites with total fatigue and subdomains of fatigue between 6 weeks and 2 years after colorectal cancer treatment. Among stage I-III colorectal cancer survivors (n = 252), blood samples were obtained at 6 weeks, and 6, 12 and 24 months posttreatment. Total fatigue and fatigue subdomains were measured using a validated questionnaire. Tandem mass spectrometry was applied to measure metabolite concentrations (BIOCRATES AbsoluteIDQp180 kit). Confounder-adjusted longitudinal associations were analyzed using linear mixed models, with false discovery rate (FDR) correction. We assessed interindividual (between-participant differences) and intraindividual longitudinal associations (within-participant changes over time). In the overall longitudinal analysis, statistically significant associations were observed for 12, 32, 17 and three metabolites with total fatigue and the subscales "fatigue severity," "reduced motivation" and "reduced activity," respectively. Specifically, higher concentrations of several amino acids, lysophosphatidylcholines, diacylphosphatidylcholines, acyl-alkylphosphatidylcholines and sphingomyelins were associated with less fatigue, while higher concentrations of acylcarnitines were associated with more fatigue. For "fatigue severity," associations appeared mainly driven by intraindividual associations, while for "reduced motivation" stronger interindividual associations were found. We observed longitudinal associations of several metabolites with total fatigue and fatigue subscales, and that intraindividual changes in metabolites over time were associated with fatigue severity. These findings point toward inflammation and an impaired energy metabolism due to mitochondrial dysfunction as underlying mechanisms. Mechanistic studies are necessary to determine whether these metabolites could be targets for intervention., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

The tryptophan-kynurenine pathway has been linked to cancer aetiology and survivorship, and diet potentially affects metabolites of this pathway, but evidence to date is scarce. Among 247 stage I-III CRC survivors, repeated measurements were performed at 6 weeks, 6 months, and 1 year post-treatment. Adherence to the World Cancer Research Fund/ American Institute for Cancer Research (WCRF) and Dutch Healthy Diet (DHD) recommendations was operationalized using seven-day dietary records. Plasma kynurenines of nine metabolites were analysed. Longitudinal associations of adherence to these dietary patterns and plasma kynurenines were analysed using confounder-adjusted linear mixed-models. In general, higher adherence to the dietary WCRF/AICR and DHD recommendations was associated with lower concentrations of kynurenines with pro-oxidative, pro-inflammatory, and neurotoxic properties (3-hydroxykynurenine (HK) and quinolinic acid (QA)), and higher concentrations of kynurenines with anti-oxidative, anti-inflammatory, and neuroprotective properties (kynurenic acid (KA) and picolinic acid (Pic)), but associations were weak and not statistically significant. Statistically significant positive associations between individual recommendations and kynurenines were observed for: nuts with kynurenic-acid-to-quinolinic-acid ratio (KA/QA); alcohol with KA/QA, KA, and xanthurenic acid (XA); red meat with XA; and cheese with XA. Statistically significant inverse associations were observed for: nuts with kynurenine-to-tryptophan ratio (KTR) and hydroxykynurenine ratio; alcohol with KTR; red meat with 3-hydroxyanthranilic-to-3-hydroxykynurenine ratio; ultra-processed foods with XA and KA/QA; and sweetened beverages with KA/QA. Our findings suggest that CRC survivors might benefit from adhering to the dietary WCRF and DHD recommendations in the first year after treatment, as higher adherence to these dietary patterns is generally, but weakly associated with more favourable concentrations of kynurenines and their ratios. These results need to be validated in other studies.

Purpose: Alcohol consumption is a major risk factor for colorectal cancer (CRC). It is currently poorly understood, however, how alcohol and different alcoholic beverage types are related to psychosocial outcomes in CRC survivors., Methods: We used data of N = 910 CRC survivors from the pooled EnCoRe and PROCORE cohorts and harmonized them into five time points: at diagnosis and 3, 6, 12, and 24 months post-diagnosis. Generalized estimated equation models were used to examine longitudinal associations of alcohol consumption, including consumption of beer, wine, and liquor, with anxiety, depression, and health-related quality of life (HRQoL), while correcting for sociodemographic, lifestyle, and clinical factors., Results: Survivors were on average 67 years and 37% was female. In the first 2 years post-diagnosis, survivors who consumed more alcoholic drinks/week reported lower anxiety and depressive symptoms and better HRQoL on all domains and symptom scales. This was the case for moderate and heavy amounts of alcohol and mostly for consuming beer and wine, but not for liquor. Associations were more often significant for men and for younger persons (< 67 years at baseline)., Conclusions: Generally, alcohol consumption was observed to be longitudinally related to less anxiety and depression and better HRQoL in CRC survivors., Implications for Cancer Survivors: Although alcohol consumption is generally unfavorable due to increased risk of carcinogenesis and worse prognosis after CRC, it seems to be associated with better psychosocial outcomes in the first 2 years after diagnosis and treatment. More research is needed to gain knowledge about reasons for drinking and causality., (© 2021. The Author(s).)

Background: Folate-mediated 1-carbon metabolism requires several nutrients, including vitamin B6. Circulating biomarker concentrations indicating high vitamin B6 status are associated with a reduced risk of colorectal cancer (CRC). However, little is known about the effect of B6 status in relation to clinical outcomes in CRC patients., Objectives: We investigated survival outcomes in relation to vitamin B6 status in prospectively followed CRC patients., Methods: A total of 2031 patients with stage I-III CRC participated in 6 prospective patient cohorts in the international FOCUS (folate-dependent 1-carbon metabolism in colorectal cancer recurrence and survival) Consortium. Preoperative blood samples were used to measure vitamin B6 status by the direct marker pyridoxal 5'-phosphate (PLP), as well as the functional marker HK-ratio (HKr)[3'-hydroxykynurenine: (kynurenic acid + xanthurenic acid + 3'-hydroxy anthranilic acid + anthranilic acid)]. Using Cox proportional hazards regression, we examined associations of vitamin B6 status with overall survival (OS), disease-free survival (DFS), and risk of recurrence, adjusted for patient age, sex, circulating creatinine concentrations, tumor site, stage, and cohort., Results: After a median follow-up of 3.2 y for OS, higher preoperative vitamin B6 status as assessed by PLP and the functional marker HKr was associated with 16-32% higher all-cause and disease-free survival, although there was no significant association with disease recurrence (doubling in PLP concentration: HROS, 0.68; 95% CI: 0.59, 0.79; HRDFS, 0.84; 95% CI: 0.75, 0.94; HRRecurrence, 0.96; 95% CI: 0.84, 1.09; HKr: HROS, 2.04; 95% CI: 1.67, 2.49; HRDFS, 1.56; 95% CI: 1.31, 1.85; HRRecurrence, 1.21; 95% CI: 0.96,1. 52). The association of PLP with improved OS was consistent across colorectal tumor site (right-sided colon: HROS, 0.75; 95% CI: 0.59, 0.96; left-sided colon: HROS, 0.71; 95% CI: 0.55, 0.92; rectosigmoid junction and rectum: HROS, 0.61; 95% CI: 0.47, 0.78)., Conclusion: Higher preoperative vitamin B6 status is associated with improved OS among stage I-III CRC patients., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.)

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 (β per SD 3.21, 95% confidence interval (CI), 1.42-5.01) and EORTC fatigue (β 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., (©2022 American Association for Cancer Research.)

Fatigue is a distressing complaint with high detriment to quality of life that persists in one-third of colorectal cancer survivors after cancer treatment. Previous studies in mixed groups of cancer patients have suggested sleep quality is associated with fatigue. We aimed to investigate this association in colorectal cancer survivors up until two years post-treatment. Data on n = 388 stage I-III colorectal cancer patients were utilized from the EnCoRe study. Sleep quality and fatigue were measured at 6 weeks and 6, 12, and 24 months post-treatment. Sleep quality was measured using the Pittsburgh Sleep Quality Index (cross-sectional analysis only) and the single-item insomnia scale from the EORTC QLQ-C30. Fatigue was measured by the Checklist Individual Strength. Linear and mixed-model regression analyses analysed associations between sleep quality and fatigue cross-sectionally and longitudinally. Longitudinal analysis revealed worsening sleep quality over time was significantly associated with increased levels of fatigue over time (β per 0.5 SD increase in the EORTC-insomnia score = 2.56, 95% Cl: 1.91, 3.22). Significant cross-sectional associations were observed between worse sleep quality and higher levels of fatigue at all time points. Worse sleep quality in colorectal cancer patients was associated with higher levels of fatigue during the first two years post-treatment.

Background: The increasing colorectal cancer (CRC) survivor population highlights the need for dietary recommendations in order to enhance health-related quality of life (HRQoL) and alleviate symptoms of fatigue, chemotherapy-induced peripheral neuropathy (CIPN), and gastrointestinal problems., Objectives: Because of the therapeutic potential of dietary fiber on the gut, we aim to assess longitudinal associations of postdiagnostic dietary fiber, fruit, and vegetable intake, a major source of dietary fiber, with HRQoL, fatigue, CIPN, and gastrointestinal symptoms in CRC survivors from 6 wk to 24 mo posttreatment., Methods: In a prospective cohort among stage I-III CRC survivors (n = 459), 5 repeated study measurements between diagnosis and 24 mo posttreatment were executed. Dietary fiber intake and fruit and vegetable intake were measured by 7-d dietary records. HRQoL, fatigue, CIPN, and gastrointestinal symptoms were measured by validated questionnaires. We applied confounder-adjusted linear mixed models to analyze longitudinal associations from 6 wk until 24 mo posttreatment and used hybrid models to disentangle the overall association into intraindividual changes and interindividual differences over time., Results: Higher dietary fiber intake and fruit and vegetable intake were longitudinally associated with statistically significant better physical functioning and less fatigue. Intraindividual analyses showed that an increase of 10 g/d in dietary fiber within individuals over time was associated with better physical functioning (β: 2.3; 95% CI: 0.1, 4.4), role functioning (ability to perform daily activities; 5.9; 1.5, 10.3), and less fatigue (-4.1; -7.7, -0.5). An average increase in fruit and vegetable intake of 100 g/d between individuals over time was predominantly associated with less fatigue (-2.2; -4.2, -0.3). No associations were found with CIPN and gastrointestinal symptoms., Conclusions: Our results suggest that increasing dietary fiber, fruit, and vegetable intake is related to better physical and role functioning and less fatigue in the first 2 y after the end of treatment for CRC., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Post-treatment adherence to the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) lifestyle recommendations were associated with health-related quality of life (HRQoL), fatigue, and chemotherapy-induced peripheral neuropathy (CIPN) in colorectal cancer (CRC) survivors. In a prospective cohort among CRC survivors ( n = 459), repeated home-visits were performed at 6 weeks, 6, 12, and 24 months post-treatment. Dietary intake, body composition, sedentary behaviour, and physical activity were assessed to construct a lifestyle score based on adherence to seven 2018 WCRF/AICR recommendations. Longitudinal associations of the lifestyle score with HRQoL, fatigue, and CIPN were analysed by confounder-adjusted linear mixed models. A higher lifestyle score was associated with better physical functioning and less activity-related fatigue, but not with CIPN. Adjustment for physical activity substantially attenuated observed associations, indicating its importance in the lifestyle score with regards to HRQoL. In contrast, adjustment for body composition and alcohol inflated observed associations, indicating that both recommendations had a counteractive influence within the lifestyle score. Our findings suggest that CRC survivors benefit from an overall adherence to the WCRF/AICR lifestyle recommendations in terms of HRQoL and fatigue, but not CIPN. Specific recommendations have a varying influence on these associations, complicating the interpretation and requiring further study.

Background and Aims: With the introduction of the national bowel cancer screening program, the detection of sessile and flat colonic lesions ≥20 mm in size, defined as large nonpedunculated colorectal polyps (LNPCPs), has increased. The aim of this study was to examine the quality of endoscopic treatment of LNPCPs in the Dutch screening program., Methods: This investigation comprised 2 related, but separate, substudies (1 with a cross-sectional design and 1 with a longitudinal design). The first examined prevalence and characteristics of LNPCPs in data from the national Dutch screening cohort from February 2014 until January 2017. The second, with screening data from 5 endoscopy units in the Southern part of the Netherlands from February 2014 until August 2015, examined performance on important quality indicators (technical and clinical successes, recurrence rate, adverse event rate, and surgery referral rate). All patients were part of the national Dutch screening cohort., Results: In the national cohort, an LNPCP was detected in 8% of participants. Technical and clinical success decreased with increasing LNPCP size, from 93% and 96% in 20- to 29-mm lesions to 85% and 86% in 30- to 39-mm lesions and to 74% and 81% in ≥40-mm lesions (P < .001; P = .034). The cumulative recurrence rate at 12 months increased with LNPCP size, from 9% to 22% and 26% in the respective size groups (P = .095). The adverse event rate was 5%. The overall surgical referral rate for noninvasive LNPCPs was 7%., Conclusions: In this performance of 2 substudies, it was shown that quality parameters for endoscopic resection of large polyps in the Dutch screening cohort are not reached, especially in ≥30-mm polyps. Endoscopic resection of large polyps could benefit from additional training, quality monitoring, and centralization either within or between centers., (Copyright © 2021 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Introduction: Given the growing population of colorectal cancer (CRC) survivors, identifying ways to enhance health-related quality of life (HRQoL) and alleviate complaints of fatigue and chemotherapy-induced peripheral neuropathy (CIPN) is essential., Purpose: We aimed to assess longitudinal associations of sedentary behavior (SB) and moderate to vigorous physical activity (MVPA) independently, as well as their joint association, with HRQoL, fatigue, and CIPN in CRC survivors., Methods: In a prospective cohort among stage I-stage III CRC survivors (n = 396), five repeated home visits from diagnosis up to 24 months posttreatment were executed. SB was measured using triaxial accelerometers, and MVPA, HRQoL, fatigue, and CIPN were measured by validated questionnaires. We applied confounder-adjusted linear mixed models to analyze longitudinal associations from 6 wk until 24 months posttreatment., Results: Average time in prolonged SB (accumulated in bouts of duration ≥30 min) was 5.3 ± 2.7 h·d-1, and approximately 82% of survivors were classified as sufficiently active (≥150 min·wk-1 of MVPA) at 6 wk posttreatment. Decreases in SB and increases in MVPA were independently associated with better HRQoL and less fatigue over time. No associations were found for CIPN complaints. A synergistic interaction was observed between prolonged SB and MVPA in affecting functioning scales. Relative to CRC survivors with low prolonged SB and high MVPA, survivors with high prolonged SB and low MVPA reported a stronger decrease in physical functioning and role functioning over time than expected based on the independent associations of prolonged SB and MVPA., Conclusion: Our longitudinal results show that less SB and more MVPA are beneficial for CRC survivors' HRQoL and fatigue levels. Our findings regarding interaction underscore that joint recommendations to avoid prolonged sitting and accumulate MVPA are important., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American College of Sports Medicine.)

Purpose: Alcohol consumption can lead to worse prognosis and mortality among colorectal cancer (CRC) patients. We investigated alcohol consumption of CRC survivors up to 2 years post-diagnosis, and how sociodemographic, lifestyle, and clinical factors were associated longitudinally with these habits., Methods: We pooled longitudinal data of 910 CRC survivors from the ongoing PROCORE and EnCoRe studies with data collected at diagnosis (baseline) and 3, 6, 12, and 24 months post-diagnosis. Both studies assessed alcohol consumption, including beer, wine, and liquor. Generalized estimated equation models were used to examine changes over time in alcohol consumption and multivariable longitudinal associations of sociodemographic, lifestyle, and clinical factors with alcohol consumption., Results: At baseline, participants were on average 67 years old, 332 (37%) were female, and alcohol was consumed by 79%. Most survivors (68-71%) drank less at all follow-ups. Beer, wine, and liquor were consumed by 51%, 58%, and 25% at baseline, respectively, and these declined over time. Males consumed more alcohol, and higher education, more physical activity, and not having a (permanent) stoma were associated with consuming more alcohol., Conclusion: CRC survivors decreased their alcohol consumption in the 2 years post-diagnosis. Future studies should take the significant factors that were associated with alcohol post-diagnosis consumption into account, when they investigate CRC health outcomes or for identifying subgroups for interventions. Males with higher education, more physical activity, and no stoma should be reminded after diagnosis for reducing their alcohol consumption., (© 2021. The Author(s).)

We investigated longitudinal associations of moderate-to-vigorous physical activity (MVPA) and light-intensity physical activity (LPA) with plasma concentrations of 138 metabolites after colorectal cancer (CRC) treatment. Self-reported physical activity data and blood samples were obtained at 6 weeks, and 6, 12 and 24 months post-treatment in stage I-III CRC survivors (n = 252). Metabolite concentrations were measured by tandem mass spectrometry (BIOCRATES AbsoluteIDQp180 kit). Linear mixed models were used to evaluate confounder-adjusted longitudinal associations. Inter-individual (between-participant differences) and intra-individual associations (within-participant changes over time) were assessed as percentage difference in metabolite concentration per 5 h/week of MVPA or LPA. At 6 weeks post-treatment, participants reported a median of 6.5 h/week of MVPA (interquartile range:2.3,13.5) and 7.5 h/week of LPA (2.0,15.8). Inter-individual associations were observed with more MVPA being related (FDR-adjusted q-value < 0.05) to higher concentrations of arginine, citrulline and histidine, eight lysophosphatidylcholines, nine diacylphosphatidylcholines, 13 acyl-alkylphosphatidylcholines, two sphingomyelins, and acylcarnitine C10:1. No intra-individual associations were found. LPA was not associated with any metabolite. More MVPA was associated with higher concentrations of several lipids and three amino acids, which have been linked to anti-inflammatory processes and improved metabolic health. Mechanistic studies are needed to investigate whether these metabolites may affect prognosis.

Colorectal cancer (CRC) survivors need evidence-based guidelines pertaining to post-treatment body composition, which could benefit health-related quality of life (HRQoL). We aimed to describe the course of several body composition measures, and to assess longitudinal associations of these measures with HRQoL, fatigue and chemotherapy-induced peripheral neuropathy (CIPN). In a prospective cohort among stage I-III CRC survivors (n = 459), five repeated home visits from diagnosis up to 24 months post-treatment were executed. Body mass index (BMI), waist circumference and fat percentage were assessed as measures of adiposity, and muscle arm circumference and handgrip strength as measures of muscle mass and function. We applied linear mixed-models to describe changes in body composition over time and to analyze overall longitudinal associations. Of included participants, 44% was overweight and 31% was obese at diagnosis. All body composition measures followed similar trends, decreasing from diagnosis to 6 weeks and then increasing up to 24 months post-treatment. In confounder-adjusted mixed models, increases in adipose tissue and muscle function were longitudinally associated with better HRQoL and less fatigue, regardless of pre-treatment body composition. With regards to improving HRQoL, decreasing fatigue and CIPN, clinical practice should also focus on restoring body tissues after CRC treatment.Trial registration: NTR7099.

Background: We investigated whether preoperative and postoperative levels of inflammation markers, which have mechanistically been linked to colorectal cancer progression, were associated with recurrence and all-cause mortality in patients with colorectal cancer., Methods: Data of two prospective cohort studies were used. For the current analysis, patients with stage I to III colorectal cancer were considered. Data on inflammation [IL6, IL8, IL10, TNFα, high-sensitivity C-reactive protein (hsCRP), and a combined inflammatory z -score] were available for 747 patients before surgery and for 614 patients after surgery. The associations between inflammation marker levels and colorectal cancer recurrence and all-cause mortality were examined using multivariable Cox proportional hazard regression models, considering patient characteristics and clinical and lifestyle factors., Results: Higher preoperative and postoperative hsCRP levels were associated with a higher risk of recurrence [HR per doubling (95% CI), 1.15 (1.02-1.30) and 1.34 (1.16-1.55)] and all-cause mortality [HR per doubling (95% CI) 1.13 (1.01-1.28) and 1.15 (0.98-1.35)]. A doubling in IL8 levels (preoperative levels HR = 1.23; 95% CI, 1.00-1.53 and postoperative levels HR = 1.61; 95% CI, 1.23-2.12) and a higher combined inflammatory z -score (preoperative HR per doubling = 1.39; 95% CI, 1.03-1.89 and postoperative HR per doubling = 1.56; 95% CI, 1.06-2.28) were associated with a higher risk of all-cause mortality, but not recurrence. No associations between IL6, IL10, and TNFα and recurrence or all-cause mortality were observed., Conclusions: Preoperative and postoperative levels of specific inflammation markers were associated with recurrence and/or all-cause mortality., Impact: The complex role of inflammation in cancer recurrence merits further elucidation by investigating local inflammation at the tumor site., (©2021 American Association for Cancer Research.)

Background: An unhealthy lifestyle is associated with the risk of colorectal cancer (CRC), but it is unclear whether overall lifestyle after a CRC diagnosis is associated with risks of recurrence and mortality., Objectives: To examine associations between postdiagnosis lifestyle and changes in lifestyle after a CRC diagnosis with risks of CRC recurrence and all-cause mortality., Methods: The study population included 1425 newly diagnosed, stage I-III CRC patients from 2 prospective cohort studies enrolled between 2010 and 2016. Lifestyle, including BMI, physical activity, diet, and alcohol intake, was assessed at diagnosis and at 6 months postdiagnosis. We assigned lifestyle scores based on concordance with 2 sets of cancer prevention guidelines-from the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) and the American Cancer Society (ACS)-and national disease prevention guidelines. Higher scores indicate healthier lifestyles. We computed adjusted HRs and 95% CIs using Cox regression., Results: We observed 164 recurrences during a 2.8-year median follow-up and 171 deaths during a 4.4-year median follow-up. No associations were observed for CRC recurrence. A lifestyle more consistent with the ACS recommendations was associated with a lower all-cause mortality risk (HR per +1 SD, 0.85; 95% CI: 0.73-0.995). The same tendency was observed for higher WCRF/AICR (HR, 0.92; 95% CI: 0.78-1.08) and national (HR, 0.90; 95% CI: 0.77-1.05) lifestyle scores, although these associations were statistically nonsignificant. Generally, no statistically significant associations were observed for BMI, physical activity, diet, or alcohol. Improving one's lifestyle after diagnosis (+1 SD) was associated with a lower all-cause mortality risk for the ACS (HR, 0.80; 95% CI: 0.67-0.96) and national (HR, 0.84; 95% CI: 0.70-0.999) scores, yet was statistically nonsignificant for the WCRF/AICR score (HR, 0.94; 95% CI: 0.78-1.13)., Conclusions: A healthy lifestyle after CRC diagnosis and improvements therein were not associated with the risk of CRC recurrence, but were associated with a decreased all-cause mortality risk., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: B vitamins have been associated with the risk and progression of colorectal cancer (CRC), given their central roles in nucleotide synthesis and methylation, yet their association with quality of life in established CRC is unclear., Objectives: To investigate whether quality of life 6 months postdiagnosis is associated with: 1) circulating concentrations of B vitamins and related biomarkers 6 months postdiagnosis; 2) changes in these concentrations between diagnosis and 6 months postdiagnosis; 3) B-vitamin supplement use 6 months postdiagnosis; and 4) changes in B-vitamin supplement use between diagnosis and 6 months postdiagnosis., Methods: We included 1676 newly diagnosed stage I-III CRC patients from 3 prospective European cohorts. Circulating concentrations of 9 biomarkers related to the B vitamins folate, riboflavin, vitamin B6, and cobalamin were measured at diagnosis and 6 months postdiagnosis. Information on dietary supplement use was collected at both time points. Health-related quality of life (global quality of life, functioning scales, and fatigue) was assessed by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 6 months postdiagnosis. Confounder-adjusted linear regression analyses were performed, adjusted for multiple testing., Results: Higher pyridoxal 5'-phosphate (PLP) was cross-sectionally associated with better physical, role, and social functioning, as well as reduced fatigue, 6 months postdiagnosis. Associations were observed for a doubling in the hydroxykynurenine ratio [3-hydroxykynurenine: (kynurenic acid + xanthurenic acid + 3-hydroxyanthranilic acid + anthranilic acid); an inverse marker of vitamin B6] and both reduced global quality of life (β = -3.62; 95% CI: -5.88, -1.36) and worse physical functioning (β = -5.01; 95% CI: -7.09, -2.94). Dose-response relations were observed for PLP and quality of life. No associations were observed for changes in biomarker concentrations between diagnosis and 6 months. Participants who stopped using B-vitamin supplements after diagnosis reported higher fatigue than nonusers., Conclusions: Higher vitamin B6 status was associated with better quality of life, yet limited associations were observed for the use of B-vitamin supplements. Vitamin B6 needs further study to clarify its role in relation to quality of life., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: Whether changes in 25 hydroxy vitamin D 3 (25(OH)D 3 ) levels after colorectal cancer diagnosis influence clinical outcomes is unclear. We investigated the association of trajectories of 25(OH)D 3 levels with recurrence and all-cause mortality., Methods: In total, 679 patients were included in our data analyses. Trajectories of 25(OH)D 3 levels were defined on the basis of vitamin D status at diagnosis, at 6 months, and 2 years after diagnosis. Observed trajectories of 25(OH)D 3 levels were consistent deficient levels (20%), consistent sufficient levels (39%), increasing levels (20%), and a temporary drop in levels (13%). Associations of trajectories of 25(OH)D 3 with recurrence and all-cause mortality were assessed using multivariable Cox proportional hazards regression models., Results: During a follow-up time of 2.2 years for recurrence and 3.5 years for all-cause mortality, 31 and 65 events occurred, respectively. No statistically significant associations were observed for vitamin D trajectories and the risk of recurrence. Patients who were consistently sufficient compared with patients who were consistently deficient had a lower risk of all-cause mortality [HR 0.39; 95% confidence interval (CI), 0.21-0.73]. The risk of all-cause mortality seems lower in patients with increasing levels or a temporary drop in levels (HR 0.54; 95% CI, 0.27-1.10 and HR 0.40 95% CI, 0.17-0.93) relative to patients with consistent deficient levels., Conclusions: Patients with colorectal cancer following a trajectory characterized by sufficient levels of 25(OH)D 3 2 years after diagnosis all appeared to have a lower risk of all-cause mortality compared with patients having consistent deficient levels., Impact: Further studies should investigate how trajectories of 25(OH)D 3 levels are associated with colorectal cancer recurrence., (©2021 American Association for Cancer Research.)

Fatigue is very common among colorectal cancer (CRC) patients. We examined the association between adherence to the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) lifestyle recommendations and fatigue among stage I-III CRC patients, and whether inflammation mediated this association. Data from two prospective cohort studies were used. Adherence to the WCRF/AICR recommendations was expressed as a score ranging from 0-7, and assessed shortly after diagnosis. Six months post-diagnosis, fatigue was assessed with the European Organization for Research and Treatment of Cancer quality of life questionnaire C30 (EORTC QLQ-C30), and in a subpopulation, the plasma levels of inflammation markers (IL6, IL8, TNFα, and hsCRP) were assessed. Multiple linear regression analyses were performed to investigate the association between adherence to the WCRF/AICR recommendations and fatigue. To test mediation by inflammation, the PROCESS analytic tool developed by Hayes was used. A higher WCRF/AICR adherence score was associated with less fatigue six months after diagnosis ( n = 1417, β -2.22, 95%CI -3.65; -0.78). In the population of analysis for the mediation analyses ( n = 551), the total association between lifestyle and fatigue was (β -2.17, 95% CI -4.60; 0.25). A statistically significant indirect association via inflammation was observed (β -0.97, 95% CI -1.92; -0.21), explaining 45% of the total association between lifestyle and fatigue (-0.97/-2.17 × 100). Thus, inflammation is probably one of the underlying mechanisms linking lifestyle to fatigue.

Background: Folates, including folic acid, may play a dual role in colorectal cancer development. Folate is suggested to be protective in early carcinogenesis but could accelerate growth of premalignant lesions or micrometastases. Whether circulating concentrations of folate and folic acid, measured around time of diagnosis, are associated with recurrence and survival in colorectal cancer patients is largely unknown., Methods: Circulating concentrations of folate, folic acid, and folate catabolites p-aminobenzoylglutamate and p-acetamidobenzoylglutamate were measured by liquid chromatography-tandem mass spectrometry at diagnosis in 2024 stage I-III colorectal cancer patients from European and US patient cohort studies. Multivariable-adjusted Cox proportional hazard models were used to assess associations between folate, folic acid, and folate catabolites concentrations with recurrence, overall survival, and disease-free survival., Results: No statistically significant associations were observed between folate, p-aminobenzoylglutamate, and p-acetamidobenzoylglutamate concentrations and recurrence, overall survival, and disease-free survival, with hazard ratios ranging from 0.92 to 1.16. The detection of folic acid in the circulation (yes or no) was not associated with any outcome. However, among patients with detectable folic acid concentrations (n = 296), a higher risk of recurrence was observed for each twofold increase in folic acid (hazard ratio = 1.31, 95% confidence interval = 1.02 to 1.58). No statistically significant associations were found between folic acid concentrations and overall and disease-free survival., Conclusions: Circulating folate and folate catabolite concentrations at colorectal cancer diagnosis were not associated with recurrence and survival. However, caution is warranted for high blood concentrations of folic acid because they may increase the risk of colorectal cancer recurrence., (© The Author(s) 2020. Published by Oxford University Press.)

Colorectal cancer is the second most common cause of cancer-related death globally, with marked differences in prognosis by disease stage at diagnosis. We studied circulating metabolites in relation to disease stage to improve the understanding of metabolic pathways related to colorectal cancer progression. We investigated plasma concentrations of 130 metabolites among 744 Stages I-IV colorectal cancer patients from ongoing cohort studies. Plasma samples, collected at diagnosis, were analyzed with liquid chromatography-mass spectrometry using the Biocrates AbsoluteIDQ™ p180 kit. We assessed associations between metabolite concentrations and stage using multinomial and multivariable logistic regression models. Analyses were adjusted for potential confounders as well as multiple testing using false discovery rate (FDR) correction. Patients presented with 23, 28, 39 and 10% of Stages I-IV disease, respectively. Concentrations of sphingomyelin C26:0 were lower in Stage III patients compared to Stage I patients (p FDR  < 0.05). Concentrations of sphingomyelin C18:0 and phosphatidylcholine (diacyl) C32:0 were statistically significantly higher, while citrulline, histidine, phosphatidylcholine (diacyl) C34:4, phosphatidylcholine (acyl-alkyl) C40:1 and lysophosphatidylcholines (acyl) C16:0 and C17:0 concentrations were lower in Stage IV compared to Stage I patients (p FDR  < 0.05). Our results suggest that metabolic pathways involving among others citrulline and histidine, implicated previously in colorectal cancer development, may also be linked to colorectal cancer progression., (© 2019 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Vitamin D status may be an important determinant of health-related quality of life of colorectal cancer survivors. The current study investigated longitudinal associations between serum 25-hydroxyvitamin D 3 (25OHD 3 ) concentrations and quality of life in stage I-III colorectal cancer survivors up to 2 years after treatment., Methods: Patients with colorectal cancer ( n = 261) were included upon diagnosis. Home visits (including blood sampling) were performed at diagnosis and at 6 weeks, 6 months, 1 year, and 2 years after treatment. Serum 25OHD 3 concentrations were measured using LC/MS-MS and adjusted for season. Validated questionnaires were used to assess global quality of life and cognitive functioning (EORTC-QLQ-C30), fatigue (EORTC-QLQ-C30 and Checklist Individual Strength, CIS), and depression and anxiety (Hospital Anxiety and Depression Scale). Statistical analyses were performed using linear mixed models and adjusted for sex, age, time since diagnosis, therapy, comorbidities, physical activity, and body mass index., Results: At diagnosis, 45% of patients were vitamin D deficient (<50 nmol/L). After treatment, 25OHD 3 concentrations increased on average with 3.1 nmol/L every 6 months. In confounder-adjusted models, 20 nmol/L increments in 25OHD 3 were longitudinally associated with increased global quality of life [β 2.9; 95% confidence interval (CI), 1.5-4.3] and reduced fatigue (EORTC-QLQ-C30 subscale: β -3.5; 95% CI, -5.3 to -1.8 and CIS: β -2.8; 95% CI, -4.7 to -0.9). Observed associations were present both within and between individuals over time., Conclusions: Higher concentrations of 25OHD 3 were longitudinally associated with better global quality of life and less fatigue in colorectal cancer survivors., Impact: This study suggests that higher 25OHD 3 concentrations may be beneficial for colorectal cancer survivors. Future intervention studies are needed to corroborate these findings., (©2020 American Association for Cancer Research.)

Background: Calcitriol, the active form of vitamin D, may inhibit colorectal cancer (CRC) progression, which has been mechanistically linked to an attenuation of a pro-inflammatory state. The present study investigated the associations between circulating 25 hydroxy vitamin D 3 (25(OH)D 3 ) levels and inflammatory markers (IL10, IL8, IL6, TNFα and hsCRP) in the 2 years following CRC diagnosis., Methods: Circulating 25(OH)D 3 levels and inflammatory markers were assessed at diagnosis, after 6, 12 and 24 months from 798 patients with sporadic CRC participating in two prospective cohort studies. Associations between 25(OH)D 3 levels and individual inflammatory markers as well as a summary inflammatory z -score were assessed at each time point by multiple linear regression analyses. To assess the association between 25(OH)D 3 and inflammatory markers over the course of 2 years, linear mixed model regression analyses were conducted., Results: Higher 25(OH)D 3 levels were associated with lower IL6 levels at diagnosis, at 6 months after diagnosis and over the course of 2 years (β -0.06, 95% CI -0.08 to -0.04). In addition, 25(OH)D 3 levels were inversely associated with the summary inflammatory z -score at diagnosis and over the course of 2 years (β -0.17, 95% CI -0.25 to -0.08). In addition, a significant inverse association between 25(OH)D 3 levels and IL10 was found over the course of 2 years. Intra-individual analyses showed an inverse association between 25(OH)D 3 and IL10, IL6 and TNFα. No statistically significant associations between 25(OH)D 3 and IL8 and hsCRP levels were observed., Conclusions: Serum 25(OH)D 3 levels were inversely associated with the summary inflammatory z -score and in particular with IL6 in the years following CRC diagnosis. This is of potential clinical relevance as IL6 has an important role in chronic inflammation and is also suggested to stimulate cancer progression. Further observational studies should investigate whether a possible 25(OH)D 3 -associated reduction of inflammatory mediators influences treatment efficacy and CRC recurrence., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest., (© The Author(s), 2020.)

Vitamin D metabolites, including 25-hydroxyvitamin D 3 (25(OH)D 3 ), may inhibit colorectal cancer (CRC) progression. Here we investigated cross-sectional and longitudinal associations of demographic, lifestyle and clinical characteristics with 25(OH)D 3 serum concentrations in CRC patients at diagnosis and six months later. In 1201 newly-diagnosed stage I-III CRC patients, 25(OH)D 3 levels were analysed twice. Multivariable linear regression was used to assess demographic, lifestyle and clinical determinants of 25(OH)D 3 levels at diagnosis and six months later. Linear mixed models were used to assess characteristics associated with changes in 25(OH)D 3 levels over time. Results of our study showed that vitamin D intake from diet or supplements, use of calcium supplements, BMI and disease stage were associated with 25(OH)D 3 levels at both time points. Six months after diagnosis, gender and having received chemo- and/or radiotherapy were also associated with 25(OH)D 3 levels. A stronger decrease in 25(OH)D 3 levels was observed in patients who underwent chemotherapy, compared to surgery only (β-6.9 nmol/L 95 %CI -9.8; -4.0). Levels of 25(OH)D 3 levels increased in patients using vitamin D supplements compared to non-users (β 4.0 nmol/L 95 %CI 1.2; 6.8). In conclusion, vitamin D supplement use and treatment appear to be important determinants of 25(OH)D 3 levels during the first six months after CRC diagnosis, although the difference in 25(OH)D 3 levels was minor. ClinicalTrials.gov Identifier: NCT03191110., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Higher concentrations of 25-hydroxyvitamin D3 [25(OH)D3] at diagnosis are associated with a lower mortality risk in colorectal cancer (CRC) patients. However, magnesium and calcium are important in vitamin D metabolism., Objectives: We aimed to investigate 25(OH)D3, magnesium, or calcium and their interaction among patients with CRC in relation to recurrence and all-cause mortality., Methods: The study population included 1169 newly diagnosed stage I-III CRC patients from 2 prospective cohorts. Associations between 25(OH)D3 concentrations, magnesium or calcium intake through diet and/or supplements at diagnosis, and recurrence and all-cause mortality were evaluated using multivariable Cox proportional hazard models. The interaction between 25(OH)D3 and magnesium or calcium was assessed by investigating 1) joint compared with separate effects, using a single reference category; and 2) the effect estimates of 1 factor across strata of another., Results: Serum 25(OH)D3, calcium, and magnesium, alone and their interactions, were not associated with recurrence. Serum 25(OH)D3 concentrations seemed to be associated with all-cause mortality. An inverse association between magnesium intake (HRQ3 vs. Q1: 0.55; 95% CI: 0.32, 0.95 and HRQ4 vs. Q1: 0.65; 95% CI: 0.35, 1.21), but not calcium intake, and all-cause mortality was observed. When investigating the interaction between 25(OH)D3 and magnesium, we observed the lowest risk of all-cause mortality in patients with sufficient vitamin D concentrations (≥50 nmol/L) and a high magnesium intake (median split) (HR: 0.53; 95% CI: 0.31, 0.89) compared with patients who were vitamin D deficient (<50 nmol/L) and had a low magnesium intake. No interactions between calcium and vitamin D in relation to all-cause mortality were observed., Conclusions: Our findings suggest that the presence of an adequate status of 25(OH)D3 in combination with an adequate magnesium intake is essential in lowering the risk of mortality in CRC patients, yet the underlying mechanism should be studied. In addition, diet and lifestyle intervention studies are needed to confirm our findings. The COLON study was registered at clinicaltrials.gov as NCT03191110. The EnCoRe study was registered at trialregister.nl as NTR7099., (Copyright © The Author(s) 2020.)