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Background: Dietary flavonoids are suggested to have antiobesity effects. Prospective evidence of an association between flavonoids and body mass index (BMI) is lacking in general populations.Objective: We assessed this association between 3 flavonoid subgroups and BMI over a 14-y period in 4280 men and women aged 55-69 y at baseline from the Netherlands Cohort Study.Design: Dietary intake was estimated at baseline (1986) by a validated food-frequency questionnaire. BMI was ascertained through self-reported height (in 1986) and weight (in 1986, 1992, and 2000). Analyses were based on sex-specific quintiles for the total intake of 6 catechins and of 3 flavonols/flavones. Linear mixed effect modeling was used to assess longitudinal associations in 3 adjusted models: age only, lifestyle (age, energy intake, physical activity, smoking status, alcohol intake, type 2 diabetes, and coffee consumption), and lifestyle and diet (vegetables, fruit, fiber, grains, sugar, dessert, and dieting habits).Results: After adjustment for age and confounders, the BMI (kg/m[2]) of women with the lowest intake of total flavonols/flavones and total catechins increased by 0.95 and 0.77, respectively, after 14 y. Women with the highest intake of total flavonols/flavones and total catechins experienced a significantly lower increase in BMI of 0.40 and 0.31, respectively (between group difference: P < 0.05). This difference remained after additional adjustment for dietary determinants and after stratification of median baseline BMI. In men, no significant differences in BMI change were observed over the quintiles of flavonoid intake after 14 y.Conclusion: Our results suggest that flavonoid intake may contribute to maintaining body weight in the general female population. © American Society for Nutrition [ABSTRACT FROM AUTHOR]

Background: An increasing number of studies in recent years investigate various dietary and lifestyle patterns and associated breast cancer (BC) risk., Objectives: This study aimed to comprehensively synthesize and grade the evidence on dietary and lifestyle patterns and BC risk., Methods: Databases were systematically searched up to 31 March, 2022, for evidence from RCTs and prospective cohort studies on adherence to a dietary pattern alone or in combination with lifestyle behaviors and incidence of or mortality from primary BC in adult females. Findings in all, premenopausal, and postmenopausal females were descriptively synthesized instead of meta-analyzed due to patterns heterogeneity. An independent Global Cancer Update Programme Expert Panel graded the strength of the evidence., Results: A total of 84 publications were included. Results for patterns reflecting both a healthy diet and lifestyle were more consistent than for patterns that included diet only. There was strong-probable evidence that a priori World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) and American Cancer Society (ACS) dietary and lifestyle scores may reduce BC risk in all and postmenopausal females, whereas in premenopausal females, less evidence was found contributing to limited-suggestive grade. There was also a limited-suggestive evidence that adherence to the Healthy Lifestyle Index and other diet and lifestyle scores may reduce BC risk in postmenopausal females; a posteriori Western/meat/alcohol dietary patterns may increase BC risk in postmenopausal females; and prudent/vegetarian/Mediterranean dietary patterns may reduce BC risk in all females. For the remaining patterns, evidence was graded as limited-no conclusions., Conclusions: Advice to adopt combined aspects of a healthy diet and lifestyle according to WCRF/AICR and ACS scores, encouraging a healthy weight, physical activity, alcohol and smoking avoidance, and a healthy diet rich in fruits, vegetables, (whole)grains and cereals and discouraging red and processed meat, can be proposed to females to lower BC risk. This review was registered at PROSPERO as ID CRD42021270129 (https://www.crd.york.ac.uk/prospero/display&#95;record.php?ID=CRD42021270129) on 28 August, 2021, and further updated on 4 May, 2022, in order to extend the search period., Competing Interests: Conflict of interest The authors report no conflicts of interests., (Copyright © 2024. Published by Elsevier Inc.)

Background: Long-term energy balance-related factors (i.e., lifestyle and physiologic factors that influence the equilibrium between energy intake and energy expenditure over an extended period) such as body mass index (BMI) are linked to colorectal cancer risk, but their impact on colorectal cancer survival is unclear. We explored associations between these long-term energy balance-related factors and survival and examined potential differences across metabolic Warburg-subtypes., Methods: Associations between long-term energy balance-related factors and survival in the total series of patients with colorectal cancer (n = 2,347) obtained from the prospective Netherlands Cohort Study, as well as according to Warburg-subtype (Warburg-low: n = 652, Warburg-moderate: n = 802, Warburg-high: n = 797), were investigated using Cox regression analysis., Results: Among the long-term energy balance-related factors studied, only increasing prediagnostic BMI was associated with a borderline significant poorer overall survival in patients with colorectal cancer [HR5kg/m2, 1.07; 95% confidence interval (CI), 0.99-1.15]. Stratified analyses showed that prediagnostic weight gain (HR5kg, 1.04; 95% CI, 0.99-1.09) and potentially increased height (HR5cm, 1.04; 95% CI, 0.98-1.11) were associated with poor overall survival only in patients with Warburg-high colorectal cancer. Increasing prediagnostic BMI was associated with poor survival only in patients with Warburg-moderate colorectal cancer (colorectal cancer-specific: HR5kg/m2, 1.12; 95% CI, 0.96-1.32; overall: HR5kg/m2, 1.20; 95% CI, 1.05-1.36). No consistent patterns were observed across energy restriction proxies., Conclusions: Maintaining a healthy prediagnostic BMI may be beneficial for colorectal cancer survival. Moreover, associations between prediagnostic BMI, weight change, early-life energy restriction, height, and colorectal cancer survival differed according to Warburg-subtypes., Impact: Understanding the biologic pathways involved in associations between energy balance-related factors and colorectal cancer survival could help refine prevention strategies in the future., (©2024 American Association for Cancer Research.)

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.)

Over the past years, insights in the cancer neuroscience field increased rapidly, and a potential role for neurons in colorectal carcinogenesis has been recognized. However, knowledge on the neuronal distribution, subtypes, origin, and associations with clinicopathological characteristics in human studies is sparse. In this study, colorectal tumor tissues from the Netherlands Cohort Study on diet and cancer (n = 490) and an in-cohort validation population (n = 529) were immunohistochemically stained for the pan-neuronal markers neurofilament (NF) and protein gene product 9.5 (PGP9.5) to study the association between neuronal marker expression and clinicopathological characteristics. In addition, tumor and healthy colon tissues were stained for neuronal subtype markers, and their immunoreactivity in colorectal cancer (CRC) stroma was analyzed. NF-positive and PGP9.5-positive nerve fibers were found within the tumor stroma and mostly characterized by the neuronal subtype markers vasoactive intestinal peptide and neuronal nitric oxide synthase, suggesting that inhibitory neurons are the most prominent neuronal subtype in CRC. NF and PGP9.5 protein expression were not consistently associated with tumor stage, sublocation, differentiation grade, and median survival. NF immunoreactivity was associated with a worse CRC-specific survival in the study cohort (P = .025) independent of other prognostic factors (hazard ratio, 2.31; 95% CI, 1.33-4.03; P = .003), but these results were not observed in the in-cohort validation group. PGP9.5, in contrast, was associated with a worse CRC-specific survival in the in-cohort validation (P = .046) but not in the study population. This effect disappeared in multivariate analyses (hazard ratio, 0.81; 95% CI, 0.50-1.32; P = .393), indicating that this effect was dependent on other prognostic factors. This study demonstrates that the tumor stroma of CRC patients mainly harbors inhibitory neurons and that NF as a single marker is significantly associated with a poorer CRC-specific survival in the study cohort but necessitates future validation., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Alterations within the tryptophan-kynurenine metabolic pathway have been linked to the etiology of colorectal cancer (CRC), but the relevance of this pathway for prognostic outcomes in CRC patients needs further elucidation. Therefore, we investigated associations between circulating concentrations of tryptophan-kynurenine pathway metabolites and all-cause mortality among CRC patients. This study utilizes data from 2102 stage I-III CRC patients participating in six prospective cohorts involved in the international FOCUS Consortium. Preoperative circulating concentrations of tryptophan, kynurenine, kynurenic acid (KA), 3-hydroxykynurenine (HK), xanthurenic acid (XA), 3-hydroxyanthranilic acid (HAA), anthranilic acid (AA), picolinic acid (PA), and quinolinic acid (QA) were measured by liquid chromatography-tandem mass spectrometry. Using Cox proportional hazards regression, we examined associations of above-mentioned metabolites with all-cause mortality, adjusted for potential confounders. During a median follow-up of 3.2 years (interquartile range: 2.2-4.9), 290 patients (13.8%) deceased. Higher blood concentrations of tryptophan, XA, and PA were associated with a lower risk of all-cause mortality (per doubling in concentrations: tryptophan: HR = 0.56; 95%CI:0.41,0.76, XA: HR = 0.74; 95%CI:0.64,0.85, PA: HR = 0.76; 95%CI:0.64,0.92), while higher concentrations of HK and QA were associated with an increased risk of death (per doubling in concentrations: HK: HR = 1.80; 95%CI:1.47,2.21, QA: HR = 1.31; 95%CI:1.05,1.63). A higher kynurenine-to-tryptophan ratio, a marker of cell-mediated immune activation, was associated with an increased risk of death (per doubling: HR = 2.07; 95%CI:1.52,2.83). In conclusion, tryptophan-kynurenine pathway metabolites may be prognostic markers of survival in CRC patients., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

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., (© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

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., (© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

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/m 2 ). The highest risk, relative to the nadir, was observed at both ends of the BMI distribution (18 and 38 kg/m 2 ), 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., (© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

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., (© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Purpose: To (1) identify the prevalence of sleep problems in cancer survivors across cancer types and survivorship durations compared to a normative population and (2) determine demographic, clinical, lifestyle, and psychosocial determinants., Method: Cancer survivors diagnosed between 2008 and 2015 (N = 6736) and an age- and sex-matched normative cohort (n = 415) completed the single sleep item of the EORTC QLQ-C30: Have you had trouble sleeping? Participants who responded with "quite a bit"/ "very much" were categorized as poor sleepers. A hierarchical multinomial logistic regression was used to identify determinants of sleep problems., Result: The prevalence of sleep problems was higher in cancer survivors (17%) compared to the normative population (11%) (p < 0.001), varied across cancer types (10-26%) and did not vary based on survivorship duration. The full model showed that survivors who were female (adjusted odds ratio (AOR) 2.26), overweight (AOR 1.50), had one (AOR 1.25) and ≥ 2 comorbidities (AOR 2.15), were former (AOR 1.30) and current (AOR 1.53) smokers and former alcohol drinkers (AOR 1.73), had a higher level of fatigue (AOR 1.05), anxiety (AOR 1.14), depression (AOR 1.11), and cognitive illness perceptions (AOR 1.02), had a higher odds for sleep problems. Higher education compared to lower education (AOR 0.67), having a partner (AOR 0.69), and obesity compared to normal BMI (AOR 0.86) were protective to sleep problems as well as high physical activity before adjusting for psychological factors (AOR 0.91)., Conclusion: Modifiable determinants of sleep problems include physical activity, fatigue, anxiety, depression, and illness perception., Implications for Cancer Survivors: Sleep problems after cancer deserve clinical attention. They may be improved by addressing modifiable lifestyle factors: increasing physical activity, stop smoking, and reducing alcohol consumption. As fatigue, depression, and illness perception seem related to sleep problems, lifestyle improvements may also improve these outcomes., (© 2024. The Author(s).)

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: Studies have shown that cancer survivors experience difficulties maintaining physical activity levels after participation in a supervised exercise rehabilitation program. This study aimed to assess the effectiveness of a six-month remote coaching intervention, following a supervised exercise oncology rehabilitation program on maintenance of PA levels; and improvement of aerobic capacity, muscle strength and patient-reported outcomes in cancer survivors., Methods: Ninety-seven participants from a Dutch University Hospital's exercise rehabilitation program were randomised to the COACH group (n = 46), receiving 6 months of remote coaching after completing the exercise program, or the CONTROL group (n = 50), receiving no additional intervention. Assessment of PA levels; sedentary time; aerobic capacity; muscle strength; fatigue; health-related quality of life (HRQoL); level of anxiety and depression; and return to work (RTW) rates were conducted at baseline (T0) and six months later (T1). Multiple linear regression was used for between-group statistical comparisons of all outcomes measures. Mean differences at T1 were estimated with corresponding 95% confidence intervals (95%CI)., Results: No significant between-group differences were observed for all outcomes at T1. An adjusted mean difference in weekly PA of 45 min (95%CI -50;140) was observed between the COACH group and the CONTROL group, favouring the COACH group, yet lacking statistical or clinical significance., Conclusions: Our six-month remote coaching intervention did not notably improve PA levels; sedentary time; aerobic capacity; muscle strength; HRQoL; fatigue; anxiety and depression symptoms and RTW rates after participation in a supervised exercise oncology program. Although the participants who received coaching showed slightly higher levels of PA, these differences were not significant. More research is needed to identify patients in need for follow-up interventions following supervised exercise program and to investigate the effectiveness of remote coaching interventions in these patients., Trial Registration: Dutch Trial Register NL7729, registered 13 may 2019, https://trialsearch.who.int/Trial2.aspx?TrialID=NL7729 ., (© 2024. The Author(s).)

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.)

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.

Purpose: Tumor location and tumor node metastasis (TNM) stage guide treatment decisions in colorectal cancer (CRC) patients. However, patients with the same disease stage do not benefit equally from adjuvant therapy. Hence, there remains an urgent clinical need to identify prognostic and/or predictive biomarker(s) to personalize treatment decisions. In this exploratory study, we investigated whether our previously defined metabolic Warburg-subtypes can predict which CRC patients might derive survival benefit from adjuvant therapy., Methods: Information regarding treatment (surgery only: n = 1451; adjuvant radiotherapy: n = 82; or adjuvant chemotherapy: n = 260) and Warburg-subtype (Warburg-low: n = 485, -moderate: n = 641, or -high: n = 667) was available for 1793 CRC patients from the Netherlands Cohort Study (NLCS). Kaplan-Meier curves and Cox regression models were used to investigate survival benefit from adjuvant therapy compared to surgery-only for the different Warburg-subtypes., Results: Patients with Warburg-moderate CRC (HR CRC-specific 0.64; 95% CI 0.47-0.86, HR overall 0.61; 95% CI 0.47-0.80), and possibly Warburg-high CRC (HR CRC-specific 0.86; 95% CI 0.65-1.14, HR overall 0.82; 95% CI 0.64-1.05), had survival benefit from adjuvant therapy. No survival benefit was observed for patients with Warburg-low CRC (HR CRC-specific 1.07; 95% CI 0.76-1.52, HR overall 0.95; 95% CI 0.70-1.30). There was a significant interaction between Warburg-subtype and adjuvant therapy for CRC-specific survival (p = 0.049) and overall survival (p = 0.035)., Conclusion: Our results suggest that Warburg-subtypes may predict survival benefit from adjuvant therapy in CRC patients. A survival benefit from adjuvant therapy was observed for patients with Warburg-moderate and possibly Warburg-high CRC, but not for patients with Warburg-low CRC. Future prospective studies are necessary to validate our findings., (© 2023. The Author(s).)

Background: Evaluating the criterion validity and responsiveness of the self-reported FitMáx©-questionnaire, Duke Activity Status Index (DASI) and Veterans Specific Activity Questionnaire (VSAQ) to monitor aerobic capacity in cancer survivors., Methods: Cancer survivors participating in a 10-week supervised exercise program were included. The FitMáx©-questionnaire, DASI, VSAQ and a cardiopulmonary exercise test (CPET) were completed before (T 0 ) and after (T 1 ) the program. Intraclass correlation coefficients (ICC) were calculated between VO 2peak estimated by the questionnaires (questionnaire-VO 2peak ) and VO 2peak measured during CPET (CPET-VO 2peak ), at T 0 to examine criterion validity, and between changes in questionnaire-VO 2peak and CPET-VO 2peak (ΔT 0 -T 1 ) to determine responsiveness. Receiver operating characteristic (ROC) analyses were performed to examine the ability of the questionnaires to detect true improvements (≥ 6%) in CPET-VO 2peak ., Results: Seventy participants were included. Outcomes at T 1 were available for 58 participants (83%). Mean CPET-VO 2peak significantly improved at T 1 (Δ1.6 mL·kg - 1 ·min - 1 or 8%). Agreement between questionnaire-VO 2peak and CPET-VO 2peak at T 0 was moderate for the FitMáx©-questionnaire (ICC = 0.69) and VSAQ (ICC = 0.53), and poor for DASI (ICC = 0.36). Poor agreement was found between ΔCPET-VO 2peak and Δquestionnaire-VO 2peak for all questionnaires (ICC 0.43, 0.19 and 0.18 for the FitMáx©-questionnaire, VSAQ and DASI, respectively). ROC analysis showed that the FitMáx©-questionnaire was able to detect improvements in CPET-VO 2peak (area under the curve, AUC = 0.77), when using a cut-off value of 1.0 mL·kg - 1 ·min - 1 , while VSAQ (AUC = 0.66) and DASI (AUC = 0.64) could not., Conclusion: The self-reported FitMáx©-questionnaire has sufficient validity to estimate aerobic capacity in cancer survivors at group level. The responsiveness of the FitMáx©-questionnaire for absolute change is limited, but the questionnaire is able to detect whether aerobic capacity improved. The FitMáx©-questionnaire showed substantial better values of validity and responsiveness compared to DASI and VSAQ., (© 2023. The Author(s).)

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.

Background: Strategies to increase physical activity (PA) and improve nutrition would contribute to substantial health benefits in the population, including reducing the risk of several types of cancers. The increasing accessibility of digital technologies mean that these tools could potentially facilitate the improvement of health behaviours among young people., Objective: We conducted a review of systematic reviews to assess the available evidence on digital interventions aimed at increasing physical activity and good nutrition in sub-populations of young people (school-aged children, college/university students, young adults only (over 18 years) and both adolescent and young adults (<25 years))., Methods: Searches for systematic reviews were conducted across relevant databases including KSR Evidence (www.ksrevidence.com), Cochrane Database of Systematic Reviews (CDSR) and Database of Abstracts of Reviews of Effects (DARE; CRD). Records were independently screened by title and abstract by two reviewers and those deemed eligible were obtained for full text screening. Risk of bias (RoB) was assessed with the Risk of Bias Assessment Tool for Systematic Reviews (ROBIS) tool. We employed a narrative analysis and developed evidence gap maps., Results: Twenty-four reviews were included with at least one for each sub-population and employing a range of digital interventions. The quality of evidence was limited with only one of the 24 of reviews overall judged as low RoB. Definitions of "digital intervention" greatly varied across systematic reviews with some reported interventions fitting into more than one category (i.e., an internet intervention could also be a mobile phone or computer intervention), however definitions as reported in the relevant reviews were used. No reviews reported cancer incidence or related outcomes. Available evidence was limited both by sub-population and type of intervention, but evidence was most pronounced in school-aged children. In school-aged children eHealth interventions, defined as school-based programmes delivered by the internet, computers, tablets, mobile technology, or tele-health methods, improved outcomes. Accelerometer-measured (Standardised Mean Difference [SMD] 0.33, 95% Confidence Interval [CI]: 0.05 to 0.61) and self-reported (SMD: 0.14, 95% CI: 0.05 to 0.23) PA increased, as did fruit and vegetable intake (SMD: 0.11, 95% CI: 0.03 to 0.19) (review rated as low RoB, minimal to considerable heterogeneity across results). No difference was reported for consumption of fat post-intervention (SMD: -0.06, 95% CI: -0.15 to 0.03) or sugar sweetened beverages(SSB) and snack consumption combined post-intervention (SMD: -0.02, 95% CI:-0.10 to 0.06),or at the follow up (studies reported 2 weeks to 36 months follow-up) after the intervention (SMD:-0.06, 95% CI: -0.15 to 0.03) (review rated low ROB, minimal to substantial heterogeneity across results). Smartphone based interventions utilising Short Messaging Service (SMS), app or combined approaches also improved PA measured using objective and subjective methods (SMD: 0.44, 95% CI: 0.11 to 0.77) when compared to controls, with increases in total PA [weighted mean difference (WMD) 32.35 min per day, 95% CI: 10.36 to 54.33] and in daily steps (WMD: 1,185, 95% CI: 303 to 2,068) (review rated as high RoB, moderate to substantial heterogeneity across results). For all results, interpretation has limitations in terms of RoB and presence of unexplained heterogeneity., Conclusions: This review of reviews has identified limited evidence that suggests some potential for digital interventions to increase PA and, to lesser extent, improve nutrition in school-aged children. However, effects can be small and based on less robust evidence. The body of evidence is characterised by a considerable level of heterogeneity, unclear/overlapping populations and intervention definitions, and a low methodological quality of systematic reviews. The heterogeneity across studies is further complicated when the age (older vs. more recent), interactivity (feedback/survey vs. no/less feedback/surveys), and accessibility (type of device) of the digital intervention is considered. This underscores the difficulty in synthesising evidence in a field with rapidly evolving technology and the resulting challenges in recommending the use of digital technology in public health. There is an urgent need for further research using contemporary technology and appropriate methods., Competing Interests: KM, CN, RW and JK, were employed by Kleijnen Systematic Reviews Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 McDermott, Noake, Wolff, Bauld, Espina, Foucaud, Steindorf, Thorat, Weijenberg, Schüz and Kleijnen.)

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).)

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

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.)

Background: Previous research suggests that Warburg-subtypes are related to potentially important survival differences in colorectal cancer (CRC) patients. In the present study, we investigated whether mutational subgroups based on somatic mutations in RAS, BRAF, PIK3CA, and MET, which are known to promote the Warburg-effect, as well as mismatch repair (MMR) status, hold prognostic value in CRC. In addition, we investigated whether Warburg-subtypes provide additional prognostic information, independent of known prognostic factors like TNM stage., Methods: CRC patients (n = 2344) from the prospective Netherlands Cohort Study (NLCS) were classified into eight mutually exclusive mutational subgroups, based on observed mutations in RAS, BRAF, PIK3CA, and MET, and MMR status: All-wild-type + MMR proficient , KRAS mut  + MMR proficient , KRAS mut  + PIK3CA mut  + MMR proficient , PIK3CA mut  + MMR proficient , BRAF mut  + MMR proficient , BRAF mut  + MMR deficient , other + MMR proficient , and other + MMR deficient . Kaplan-Meier curves and Cox regression models were used to investigate associations between mutational subgroups and survival, as well as associations between our previously established Warburg-subtypes and survival within these mutational subgroups., Results: Compared to patients with all-wild-type + MMR proficient CRC, patients with KRAS mut  + MMR proficient , KRAS mut  + PIK3CA mut  + MMR proficient , BRAF mut  + MMR proficient , or other + MMR proficient CRC had a statistically significant worse survival (HR CRC-specific ranged from 1.29 to 1.88). In contrast, patients with other + MMR deficient CRC had the most favorable survival (HR CRC-specific 0.48). No statistically significant survival differences were observed for the Warburg-subtypes within mutational subgroups., Conclusion: Our results highlight the prognostic potential of mutational subgroups in CRC. Warburg-subtypes did not provide additional prognostic information within these mutational subgroups. Future larger-scale prospective studies are necessary to validate our findings and to examine the potential clinical utility of CRC subtyping based on mutational subgroups., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

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.

KRAS mutations (KRAS mut ), PIK3CA mut , BRAF mut , and deficient DNA mismatch repair (dMMR) have been associated with the Warburg effect. We previously reported differential associations between early-life energy balance-related factors (height, energy restriction, body mass index [BMI]) and colorectal cancer (CRC) subtypes based on the Warburg effect. We now investigated associations of early-life energy balance-related factors and the risk of CRC subgroups based on mutation and MMR status. Data from the Netherlands Cohort Study was used. KRAS mut , PIK3CA mut, BRAF mut, and MMR status were available for 2349 CRC cases, and complete covariate data for 1934 cases and 3911 subcohort members. Multivariable-adjusted Cox regression was used to estimate associations of height, energy restriction proxies (exposure to Dutch Hunger Winter, Second World War, Economic Depression), and early adult BMI (age 20 years) with risk of CRC based on individual molecular features and combinations thereof (all-wild-type+MMR-proficient [pMMR]; any-mutation/dMMR). Height was positively associated with any-mutation/dMMR CRC but not all-wild-type+pMMR CRC, with the exception of rectal cancer in men, and with heterogeneity in associations observed for colon cancer in men (p-heterogeneity = 0.049) and rectal cancer in women (p-heterogeneity = 0.014). Results on early-life energy restriction proxies in relation to the risk of CRC subgroups did not show clear patterns. Early adult BMI was positively, but not significantly, associated with KRAS mut colon cancer in men and with BRAF mut and dMMR colon cancer in women. Our results suggest a role of KRAS mut , PIK3CA mut , BRAF mut , and dMMR in the etiological pathway between height and CRC risk. KRAS mut might potentially play a role in associations of early adult BMI with colon cancer risk in men, and BRAF mut and dMMR in women., (© 2022 The Authors. Molecular Carcinogenesis published by Wiley Periodicals LLC.)

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., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: To describe changes in physical performance and patient-reported outcomes in cancer survivors who participated in an exercise program as part of usual-care multidisciplinary rehabilitation and the influence of training adaptations during the coronavirus-19 (COVID-19) pandemic., Methods: In an observational cohort study, cancer survivors underwent usual-care multidisciplinary rehabilitation including a 10-week exercise program. During the COVID-19 pandemic, the exercise program was adapted with reduced training time and frequency. Mean changes and 95% confidence intervals in physical performance (peak oxygen uptake (VO 2 peak), peak work rate during a steep ramp test (SRT-WRpeak), 6-min walking distance, muscle strength) and patient-reported outcomes (health-related quality of life, fatigue, anxiety, and depression) were assessed between the start and the end of the exercise program. Linear regression analysis, adjusting for baseline levels of outcomes, was used to investigate differences in changes in outcomes between participants who underwent the original and the adapted program., Results: All outcomes statistically significantly improved over time, regardless of adaptations in the exercise program. VO 2 peak increased with 9.6% and 7.7% in the original and adapted program, respectively. Significant smaller improvements were observed in SRT-WRpeak (- 3.9%) and upper body muscle strength (- 10.8%) after participation in the adapted compared to the original program. No significant between-group differences were observed for other outcomes., Conclusion: Physical performance and patient-reported outcomes statistically and clinically significantly improved in cancer survivors who participated in an exercise program as part of usual-care multidisciplinary rehabilitation. Improvements of performance outcomes were smaller since the training adaptations, though only significant for SRT-WRpeak and upper body strength., (© 2022. The Author(s).)

Introduction: KRAS mutations (KRAS mut ), PIK3CA mut , BRAF mut , and mismatch repair deficiency (dMMR) have been associated with the Warburg-effect. We previously observed differential associations between energy balance-related factors (BMI, clothing-size, physical activity) and colorectal cancer (CRC) subtypes based on the Warburg-effect. We now investigated whether associations between energy balance-related factors and risk of CRC differ between subgroups based on mutation and MMR status., Methods: Information on molecular features was available for 2349 incident CRC cases within the Netherlands Cohort Study (NLCS), with complete covariate data available for 1934 cases and 3911 subcohort members. Multivariable-adjusted Cox-regression was used to estimate associations of energy balance-related factors with risk of CRC based on individual molecular features (KRAS mut ; PIK3CA mut ; BRAF mut ; dMMR) and combinations thereof (all-wild-type + MMR-proficient (pMMR); any-mutation/dMMR)., Results: In men, BMI and clothing-size were positively associated with risk of colon, but not rectal cancer, regardless of molecular features subgroups; the strongest associations were observed for PIK3CA mut colon cancer. In women, however, BMI and clothing-size were only associated with risk of KRAS mut colon cancer (p-heterogeneity KRASmut versus all-wild-type+pMMR  = 0.008). Inverse associations of non-occupational physical activity with risk of colon cancer were strongest for any-mutation/dMMR tumors in men and women, and specifically for PIK3CA mut tumors in women. Occupational physical activity was inversely associated with both combination subgroups of colon cancer in men., Conclusion: In men, associations did not vary according to molecular features. In women, a role of KRAS mutations in the etiological pathway between adiposity and colon cancer is suggested, and of PIK3CA mutations between physical activity and colon cancer., (© 2022. The Author(s).)

Purpose: The aim of this study is to assess the societal burden of colorectal cancer (CRC) survivorship 2-10 years post-diagnosis in terms of (1) societal costs, and (2) quality of life/utilities, and to analyze associated patient characteristics., Methods: This is a cross-sectional, bottom-up prevalence-based burden of disease study, conducted from a societal perspective in the Netherlands. In total, 155 CRC survivors were included. Utilities were measured by the EQ-5D-5L, using the Dutch tariffs. A cost questionnaire was developed to obtain cost information. Subgroup analyses were performed, based on patient characteristics and sensitivity analyses., Results: Of all CRC survivors, 81(54%) reported no problems for mobility, 133(88%) for self-care, 98(65%) for daily activities, 59(39%) for pain/discomfort, and 112(74%) for anxiety/depression on the EQ-5D-5L. The average EQ-5D-5L utility score was 0.82 (SD = 0.2) on a scale from 0 (death) to 1 (perfect health). Significant differences in utility score were found for gender, tumor stage, number of comorbidities, and lifestyle score. The average societal costs per CRC survivor per 6 months were estimated at €971 (min = €0, max = €32,425). Significant differences in costs were found for the number of comorbidities., Conclusions: This study shows a considerable burden of CRC survivors 2-10 years after diagnosis, in comparison with survivors sooner after diagnosis and with healthy individuals in the Netherlands., Implications for Cancer Survivors: Long-term care of CRC survivors should focus on improving the societal burden by identifying modifiable factors, as summarized in the WCRF/AICR lifestyle score, including body composition, physical activity, and diet., (© 2021. The Author(s).)

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.)

Early-life (childhood to adolescence) energy balance-related factors (height, energy restriction, BMI) have been associated with adult colorectal cancer (CRC) risk. Warburg-effect activation via PI3K/Akt-signaling might explain this link. We investigated whether early-life energy balance-related factors were associated with risk of Warburg-subtypes in CRC. We used immunohistochemistry for six proteins involved in the Warburg-effect (LDHA, GLUT1, MCT4, PKM2, P53, and PTEN) on tissue microarrays of 2399 incident CRC cases from the prospective Netherlands Cohort Study (NLCS). Expression levels of all proteins were combined into a pathway-based sum score and categorized into three Warburg-subtypes (Warburg-low/-moderate/-high). Multivariable Cox-regression analyses were used to estimate associations of height, energy restriction proxies (exposure to Dutch Hunger Winter; Second World War [WWII]; Economic Depression) and adolescent BMI with Warburg-subtypes in CRC. Height was positively associated with colon cancer in men, regardless of Warburg-subtypes, and with Warburg-low colon and Warburg-moderate rectal cancer in women. Energy restriction during the Dutch Hunger Winter was inversely associated with colon cancer in men, regardless of Warburg-subtypes. In women, energy restriction during the Hunger Winter and WWII was inversely associated with Warburg-low colon cancer, whereas energy restriction during the Economic Depression was positively associated with Warburg-high colon cancer. Adolescent BMI was positively associated with Warburg-high colon cancer in men, and Warburg-moderate rectal cancer in women. In conclusion, the Warburg-effect seems to be involved in associations of adolescent BMI with colon cancer in men, and of energy restriction during the Economic Depression with colon cancer in women. Further research is needed to validate these results., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

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.)

Previous research has suggested that the expression of proteins related to the Warburg effect may have prognostic value in colorectal cancer (CRC), but results remain inconsistent. Our objective was to investigate the relationship between Warburg-subtypes and patient survival in a large population-based series of CRC patients. In the present study, we investigated the expression of six proteins related to the Warburg effect (LDHA, GLUT1, MCT4, PKM2, p53, PTEN) by immunohistochemistry on tissue microarrays (TMAs) from 2,399 incident CRC patients from the prospective Netherlands Cohort Study. Expression levels of the six proteins were combined into a pathway-based sum-score and patients were categorised into three Warburg-subtypes (low/moderate/high). The associations between Warburg-subtypes and CRC-specific and overall survival were investigated using Kaplan-Meier curves and Cox regression models. CRC patients were classified as Warburg-low (n = 695, 29.0%), Warburg-moderate (n = 858, 35.8%) or Warburg-high (n = 841, 35.1%). Patients with Warburg-high CRC had the poorest CRC-specific [hazard ratio (HR) 1.17; 95% CI 1.00-1.38] and overall survival (HR 1.19; 95% CI 1.05-1.35), independent of known prognostic factors. In stratified analyses, this was particularly true for patients with tumour-node-metastasis (TNM) stage III CRC (HR CRC-specific 1.45; 95% CI 1.10-1.92 and HR overall 1.47; 95% CI 1.15-1.87), and cancers located in the rectum (HR overall 1.56; 95% CI 1.15-2.13). To our knowledge, this is the first study to identify the prognostic value of immunohistochemistry-based Warburg-subtypes in CRC. Our data suggest that Warburg-subtypes are related to potentially important differences in CRC survival. Further research is required to validate our findings and to investigate the potential clinical utility of these Warburg-subtypes in CRC., (© 2021 The Authors. The Journal of Pathology: Clinical Research published by The Pathological Society of Great Britain and Ireland and John Wiley & Sons Ltd.)