Longitudinal associations of diurnal rest-activity rhythms with fatigue, insomnia, and health-related quality of life in survivors of colorectal cancer up to 5 years post-treatment.

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/ ).

Longitudinal associations of plasma kynurenines and ratios with fatigue and quality of life in colorectal cancer survivors up to 12 months post-treatment.

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.

Post-diagnosis adiposity, physical activity, sedentary behaviour, dietary factors, supplement use and colorectal cancer prognosis: Global Cancer Update Programme (CUP Global) summary of evidence grading.

Based on the World Cancer Research Fund Global Cancer Update Programme, we performed systematic reviews and meta-analyses to investigate the association of post-diagnosis adiposity, physical activity, sedentary behaviour, and dietary factors with colorectal cancer prognosis. We searched PubMed and Embase until 28th February, 2022. An independent expert committee and expert panel graded the quality of evidence. A total of 167 unique publications were reviewed, and all but five were observational studies. The quality of the evidence was graded conservatively due to the high risk of several biases. There was evidence of non-linearity in the associations between body mass index and colorectal cancer prognosis. The associations appeared reverse J-shaped, and the quality of this evidence was graded as limited (likelihood of causality: limited-no conclusion). The evidence on recreational physical activity and lower risk of all-cause mortality (relative risk [RR] highest vs. lowest: 0.69, 95% confidence interval [CI]: 0.62-0.77) and recurrence/disease-free survival (RR: 0.80, 95% CI: 0.70-0.92) was graded as limited-suggestive. There was limited-suggestive evidence for the associations between healthy dietary and/or lifestyle patterns (including diets that comprised plant-based foods), intake of whole grains and coffee with lower risk of all-cause mortality, and between unhealthy dietary patterns and intake of sugary drinks with higher risk of all-cause mortality. The evidence for other exposures on colorectal cancer outcomes was sparse and graded as limited-no conclusion. Analyses were conducted excluding cancer patients with metastases without substantial changes in the findings. Well-designed intervention and cohort studies are needed to support the development of lifestyle recommendations for colorectal cancer patients.

Post-diagnosis physical activity and sedentary behaviour and colorectal cancer prognosis: A Global Cancer Update Programme (CUP Global) systematic literature review and meta-analysis.

Low physical activity and high sedentary behaviour have been clearly linked with colorectal cancer development, yet data on their potential role in colorectal cancer survival is limited. Better characterisation of these relationships is needed for the development of post-diagnosis physical activity and sedentary behaviour guidance for colorectal cancer survivors. We searched PubMed and Embase through 28 February 2022 for studies assessing post-diagnosis physical activity, and/or sedentary behaviour in relation to all-cause and cause-specific mortality and recurrence after colorectal cancer diagnosis. Total and recreational physical activity were assessed overall and by frequency, duration, intensity, and volume using categorical, linear, and non-linear dose-response random-effects meta-analyses. The Global Cancer Update Programme (CUP Global) independent Expert Committee on Cancer Survivorship and Expert Panel interpreted and graded the likelihood of causality. We identified 16 observational studies on 82,220 non-overlapping patients from six countries. Physical activity was consistently inversely associated with colorectal cancer morbidity and mortality outcomes, with 13%-60% estimated reductions in risk. Sedentary behaviour was positively associated with all-cause mortality. The evidence had methodological limitations including potential confounding, selection bias and reverse causation, coupled with a limited number of studies for most associations. The CUP Global Expert panel concluded limited-suggestive evidence for recreational physical activity with all-cause mortality and cancer recurrence. Total physical activity and its specific domains and dimensions, and sedentary behaviour were all graded as limited-no conclusion for all outcomes. Future research should focus on randomised trials, while observational studies should obtain objective and repeated physical activity measures and better adjustment for confounders.

Post-diagnosis dietary factors, supplement use and colorectal cancer prognosis: A Global Cancer Update Programme (CUP Global) systematic literature review and meta-analysis.

The role of diet in colorectal cancer prognosis is not well understood and specific lifestyle recommendations are lacking. We searched for randomised controlled trials (RCTs) and longitudinal observational studies on post-diagnosis dietary factors, supplement use and colorectal cancer survival outcomes in PubMed and Embase from inception until 28th February 2022. Random-effects dose-response meta-analyses were conducted when at least three studies had sufficient information. The evidence was interpreted and graded by the CUP Global independent Expert Committee on Cancer Survivorship and Expert Panel. Five RCTs and 35 observational studies were included (30,242 cases, over 8700 all-cause and 2100 colorectal cancer deaths, 3700 progression, recurrence, or disease-free events). Meta-analyses, including 3-10 observational studies each, were conducted for: whole grains, nuts/peanuts, red and processed meat, dairy products, sugary drinks, artificially sweetened beverages, coffee, alcohol, dietary glycaemic load/index, insulin load/index, marine omega-3 polyunsaturated fatty acids, supplemental calcium, circulating 25-hydroxyvitamin D (25[OH]D) and all-cause mortality; for alcohol, supplemental calcium, circulating 25(OH)D and colorectal cancer-specific mortality; and for circulating 25(OH)D and recurrence/disease-free survival. The overall evidence was graded as 'limited'. The inverse associations between healthy dietary and/or lifestyle patterns (including diets that comprised plant-based foods), whole grains, total, caffeinated, or decaffeinated coffee and all-cause mortality and the positive associations between unhealthy dietary patterns, sugary drinks and all-cause mortality provided 'limited-suggestive' evidence. All other exposure-outcome associations provided 'limited-no conclusion' evidence. Additional, well-conducted cohort studies and carefully designed RCTs are needed to develop specific lifestyle recommendations for colorectal cancer survivors.

Post-diagnosis adiposity and colorectal cancer prognosis: A Global Cancer Update Programme (CUP Global) systematic literature review and meta-analysis.

The adiposity influence on colorectal cancer prognosis remains poorly characterised. We performed a systematic review and meta-analysis on post-diagnosis adiposity measures (body mass index [BMI], waist circumference, waist-to-hip ratio, weight) or their changes and colorectal cancer outcomes. PubMed and Embase were searched through 28 February 2022. Random-effects meta-analyses were conducted when at least three studies had sufficient information. The quality of evidence was interpreted and graded by the Global Cancer Update Programme (CUP Global) independent Expert Committee on Cancer Survivorship and Expert Panel. We reviewed 124 observational studies (85 publications). Meta-analyses were possible for BMI and all-cause mortality, colorectal cancer-specific mortality, and cancer recurrence/disease-free survival. Non-linear meta-analysis indicated a reverse J-shaped association between BMI and colorectal cancer outcomes (nadir at BMI 28 kg/m2). The highest risk, relative to the nadir, was observed at both ends of the BMI distribution (18 and 38 kg/m2), namely 60% and 23% higher risk for all-cause mortality; 95% and 26% for colorectal cancer-specific mortality; and 37% and 24% for cancer recurrence/disease-free survival, respectively. The higher risk with low BMI was attenuated in secondary analyses of RCTs (compared to cohort studies), among studies with longer follow-up, and in women suggesting potential methodological limitations and/or altered physiological state. Descriptively synthesised studies on other adiposity-outcome associations of interest were limited in number and methodological quality. All the associations were graded as limited (likelihood of causality: no conclusion) due to potential methodological limitations (reverse causation, confounding, selection bias). Additional well-designed observational studies and interventional trials are needed to provide further clarification.

Longitudinal associations of plasma kynurenines and ratios with anxiety and depression scores in colorectal cancer survivors up to 12 months post-treatment.

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 (ß 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.

Longitudinal associations of circadian eating patterns with sleep quality, fatigue and inflammation in colorectal cancer survivors up to 24 months post-treatment.

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 (ß: -6·1; 95 % CI (-8·8, -3·3)) and insomnia (ß: -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 (ß: -3·7; 95 % CI (-6·6, -0·8)). An hour increase in TW of energetic intake within individuals was associated with less insomnia (ß: -3·0; 95 % CI (-5·2, -0·8)) and inflammation (ß: -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.

Longitudinal associations of macronutrient and micronutrient intake with plasma kynurenines in colorectal cancer survivors up to 12 months posttreatment.

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) (ß 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 ß: 0.22; 95% CI: 0.11, 0.33), 3-hydroxyanthranilic acid (HAA) (standardized ß: 0.15; 95% CI: 0.04, 0.27) concentrations, and the kynurenic acid-to-quinolinic acid ratio (KA/QA) (standardized ß: 0.12; 95% CI: 0.02,0.22). In contrast, higher total carbohydrate intake was associated with lower XA concentrations (standardized ß: -0.18; 95% CI: -0.30, -0.07), a lower KA/QA (standardized ß: -0.23; 95% CI: -0.34, -0.13), and a higher kynurenine-to-tryptophan ratio (KTR) (standardized ß: 0.20; 95% CI: 0.10, 0.30). Higher fiber intake was associated with a higher KA/QA (standardized ß: 0.11; 95% CI: 0.02, 0.21) and a lower KTR (standardized ß: -0.12; 95% CI: -0.20, -0.03). Higher total fat intake was also associated with higher tryptophan (Trp) concentrations (standardized ß: 0.18; 95% CI: 0.06, 0.30) and a lower KTR (standardized ß: -0.13; 95% CI: -0.22, -0.03). For micronutrients, positive associations were observed for zinc with XA (standardized ß: 0.13; 95% CI: 0.04, 0.21) and 3-hydroxykynurenine (HK) (standardized ß: 0.12; 95% CI: 0.03, 0.20) concentrations and for magnesium with KA/QA (standardized ß: 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.

The Relation of Lifestyle with Inflammation at the Time of Diagnosis in Patients with Colorectal Cancer.

Colorectal cancer is one of the most common lifestyle-related types of cancer. The exact pathophysiologic mechanism in the relation between (visceral) adipose tissue, systemic inflammation and colorectal cancer remains unknown. This study aimed to assess the association of lifestyle with markers of systemic inflammation at the time of diagnosis in stage I-III colorectal cancer patients. Patients (n = 298) with stage I-III colorectal cancer from three Dutch hospitals were included at diagnosis. Several lifestyle-related variables (MUST nutritional status score, WCRF/AICR healthy lifestyle score, active smoking, alcohol consumption and BMI) and inflammatory markers (plasma levels of IL-6, IL-8, IL-10, TNFα and 'high sensitive' hsCRP) were measured at the time of diagnosis. Confounder-adjusted multivariable linear regression models were used to analyse how the lifestyle variables were associated with the inflammatory markers. Statistically significant associations were found between a better WCRF/AICR lifestyle score and lower levels of IL-6 and hsCRP. A medium and high risk of malnutrition according to the MUST score was associated with elevated levels of both IL-8 and hsCRP. An overall unhealthier lifestyle indicated by a lower WCRF/AICR lifestyle score and a higher risk of malnutrition according to the MUST score at the time of diagnosis was associated with elevated levels of inflammatory markers. These findings can contribute to formulating lifestyle advice to improve treatment outcomes and prognosis in patients having CRC in the future.

Using mediators to understand effect modification and interaction.

Effect modification and interaction are key concepts within epidemiologic research. They refer to situations where the magnitude and/or direction of the causal effect of some exposure variable on an outcome depends on the level of a second variable (effect modification) or on the effect of a second variable (interaction). Interest in case of effect modification is primarily in one exposure variable, with its effects varying across subgroups, whereas primary interest in case of interaction is in the interplay of effects of two exposure variables. Distinctions between the concepts of effect modification and interaction are subtle. The goal of this article is to clarify these distinctions by using the concept of mediation, which focuses on elucidating mechanisms of causal effects.

Longitudinal associations of sedentary behavior and physical activity with body composition in colorectal cancer survivors up to 2 years post treatment.

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).

Longitudinal associations of plasma metabolites with persistent fatigue among colorectal cancer survivors up to 2 years after treatment.

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.

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.

Longitudinal Associations of Adherence to the Dietary World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) and Dutch Healthy Diet (DHD) Recommendations with Plasma Kynurenines in Colorectal Cancer Survivors after Treatment.

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.

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.

Higher vitamin B6 status is associated with improved survival among patients with stage I-III colorectal cancer.

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.