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.

Relationships Among Physical Activity, Sleep, and Cancer-related Fatigue: Results From the International ColoCare Study.

BACKGROUND: Risk factors for cancer-related fatigue are understudied in colorectal cancer. PURPOSE: This study aimed to address this critical gap in the literature by (a) describing changes in colorectal cancer-related fatigue and health behavior (physical activity, sleep problems) and (b) examining if physical activity and sleep problems predict fatigue trajectories from baseline (approximately at the time of diagnosis), to 6- and 12 months after enrollment. METHODS: Patients participating in the international ColoCare Study completed self-report measures at baseline (approximately time of diagnosis), 6-, and 12 months assessing physical activity using the International Physical Activity Questionnaire (IPAQ) and fatigue and sleep using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30). Mixed-effect models examined changes in physical activity, sleep problems, and fatigue. Cross-lagged panel models examined bidirectional relationships between physical activity or sleep and fatigue across time. RESULTS: Colorectal cancer patients (n = 649) had a mean age of 61 ± 13 years. Most were male (59%), non-Hispanic White (91%), diagnosed with Stages III-IV (56%) colon cancer (58%), and treated with surgery (98%). Within-person cross-lagged models indicated higher physical activity at Month 6 was associated with higher fatigue at Month 12 (ß = 0.26, p = .016). When stratified by cancer stage (I-II vs. III-IV), the relationship between physical activity at Month 6 and fatigue at Month 12 existed only for patients with advanced cancer (Stages III and IV, ß = 0.43, p = .035). Cross-lagged associations for sleep and fatigue from baseline to Month 6 were only observed in patients with Stages III or IV cancer, however, there was a clear cross-sectional association between sleep problems and fatigue at baseline and Month 6. CONCLUSIONS: Within-person and cross-lagged association models suggest fatiguability may become increasingly problematic for patients with advanced colorectal cancer the first year after diagnosis. In addition, sleep problems were consistently associated with higher fatigue in the first year, regardless of cancer stage. TRIAL REGISTRATION: The international ColoCare Study was registered on clinicaltrials.gov, NCT02328677, in December 2014.

Within-person and cross-lagged association models suggest fatiguability may become increasingly problematic for patients with advanced (Stages III and IV) colorectal cancer the first year after diagnosis.

Functional quality of life among newly diagnosed young adult colorectal cancer survivors compared to older adults: results from the ColoCare Study.

PURPOSE: Colorectal cancer (CRC) incidence and mortality are increasing among young adults (YAs) aged 18-39. This study compared quality of life (QOL) between YA and older adult CRC survivors in the ColoCare Study. METHODS: Participants were grouped by age (years) as follows: 18-39 (YA), 40-49, 50-64, and 65 + . Functional QOL (physical, social, role, emotional, cognitive) and global QOL were assessed with the EORTC-QLQ-C30 at enrollment, 3, 6, and 12 months. Average scores were compared between groups over time using longitudinal mixed-effect modeling. Proportions with clinically meaningful QOL impairment were calculated using age-relevant thresholds and compared between groups over time using logistic regression with mixed effects. RESULTS: Participants (N = 1590) were n = 81 YAs, n = 196 aged 40-49, n = 627 aged 50-64, and n = 686 aged 65 + . Average physical function was better among YAs than participants aged 50-64 (p = 0.010) and 65 + (p < 0.001), and average social function was worse among YAs than aged 65 + (p = 0.046). Relative to YAs, all age groups were less likely to report clinically meaningful social dysfunction (aged 40-49 OR = 0.13, 95%CI = 0.06-0.29; aged 50-64 OR = 0.10, 95%CI = 0.05-0.21; aged 65 + OR = 0.07, 95%CI = 0.04-0.15) and role dysfunction (aged 40-49 OR = 0.36, 95%CI = 0.18-0.75; aged 50-64 OR = 0.41, 95%CI = 0.22-0.78; aged 65 + OR = 0.32, 95%CI = 0.17-0.61). Participants aged 40-49 were also less likely to report physical dysfunction (OR = 0.42, 95%CI = 0.19-0.93). CONCLUSION: YA CRC survivors reported better physical and worse social function compared to older CRC survivors, and YA CRC survivors were more likely to report clinically meaningful social, role, and physical disfunction. Future work should further investigate QOL using age-relevant benchmarks to inform best practices for CRC survivorship care. TRIAL REGISTRATION: NCT02328677, registered December 2014.

Risk factors and health behaviors associated with loneliness among cancer survivors during the COVID-19 pandemic.

Loneliness may exacerbate poor health outcomes particularly among cancer survivors during the COVID-19 pandemic. Little is known about the risk factors of loneliness among cancer survivors. We evaluated the risk factors of loneliness in the context of COVID-19 pandemic-related prevention behaviors and lifestyle/psychosocial factors among cancer survivors. Cancer survivors (n = 1471) seen at Huntsman Cancer Institute completed a survey between August-September 2020 evaluating health behaviors, medical care, and psychosocial factors including loneliness during COVID-19 pandemic. Participants were classified into two groups: 'lonely' (sometimes, usually, or always felt lonely in past month) and 'non-lonely' (never or rarely felt lonely in past month). 33% of cancer survivors reported feeling lonely in the past month. Multivariable logistic regression showed female sex, not living with a spouse/partner, poor health status, COVID-19 pandemic-associated lifestyle factors including increased alcohol consumption and marijuana/CBD oil use, and psychosocial stressors such as disruptions in daily life, less social interaction, and higher perceived stress and financial stress were associated with feeling lonely as compared to being non-lonely (all p < 0.05). A significant proportion of participants reported loneliness, which is a serious health risk among vulnerable populations, particularly cancer survivors. Modifiable risk factors such as unhealthy lifestyle behaviors and psychosocial stress were associated with loneliness. These results highlight the need to screen for unhealthy lifestyle factors and psychosocial stressors to identify cancer survivors at increased risk of loneliness and to develop effective management strategies.

Associations of combined physical activity and body mass index groups with colorectal cancer survival outcomes.

BACKGROUND: Physical activity and BMI have been individually associated with cancer survivorship but have not yet been studied in combinations in colorectal cancer patients. Here, we investigate individual and combined associations of physical activity and BMI groups with colorectal cancer survival outcomes. METHODS: Self-reported physical activity levels (MET hrs/wk) were assessed using an adapted version of the International Physical Activity Questionnaire (IPAQ) at baseline in 931 patients with stage I-III colorectal cancer and classified into 'highly active' and'not-highly active'(≥ / < 18 MET hrs/wk). BMI (kg/m2) was categorized into 'normal weight', 'overweight', and 'obese'. Patients were further classified into combined physical activity and BMI groups. Cox-proportional hazard models with Firth correction were computed to assess associations [hazard ratio (HR), 95% profile HR likelihood confidence interval (95% CI) between individual and combined physical activity and BMI groups with overall and disease-free survival in colorectal cancer patients. RESULTS: 'Not-highly active' compared to 'highly active' and 'overweight'/ 'obese' compared to 'normal weight' patients had a 40-50% increased risk of death or recurrence (HR: 1.41 (95% CI: 0.99-2.06), p = 0.03; HR: 1.49 (95% CI: 1.02-2.21) and HR: 1.51 (95% CI: 1.02-2.26), p = 0.04, respectively). 'Not-highly active' patients had worse disease-free survival outcomes, regardless of their BMI, compared to 'highly active/normal weight' patients. 'Not-highly active/obese' patients had a 3.66 times increased risk of death or recurrence compared to 'highly active/normal weight' patients (HR: 4.66 (95% CI: 1.75-9.10), p = 0.002). Lower activity thresholds yielded smaller effect sizes. CONCLUSION: Physical activity and BMI were individually associated with disease-free survival among colorectal cancer patients. Physical activity seems to improve survival outcomes in patients regardless of their BMI.

Trajectories and risk factors of fatigue following colorectal cancer diagnosis.

AIM: This study sought to identify groups of colorectal cancer patients based upon trajectories of fatigue and examine how demographic, clinical and behavioural risk factors differentiate these groups. METHOD: Patients were from six cancer centres in the United States and Germany. Fatigue was measured using the fatigue subscale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) at five time points (baseline/enrolment and 3, 6, 12 and 24 months after diagnosis). Piecewise growth mixture models identified latent trajectories of fatigue. Logistic regression models examined differences in demographic, clinical and behavioural characteristics between fatigue trajectory groups. RESULTS: Among 1615 participants (57% men, 86% non-Hispanic White, mean age 61 ± 13 years at diagnosis), three distinct groups were identified. In the high fatigue group (36%), fatigue significantly increased in the first 6 months after diagnosis and then showed statistically and clinically significant improvement from 6 to 24 months (P values < 0.01). Throughout the study period, average fatigue met or exceeded cutoffs for clinical significance. In the moderate (34%) and low (30%) fatigue groups, fatigue levels remained below or near population norms across the study period. Patients who were diagnosed with Stage II-IV disease and/or current smokers were more likely to be in the high fatigue than in the moderate fatigue group (P values < 0.05). CONCLUSION: A large proportion of colorectal cancer patients experienced sustained fatigue after initiation of cancer treatment. Patients with high fatigue at the time of diagnosis may benefit from early supportive care.

Factors associated with changes in exercise behaviors during the COVID-19 pandemic.

PURPOSE: There is limited information on how the COVID-19 pandemic has changed health behaviors among cancer patients. We examined changes in exercise behaviors since the pandemic and identified characteristics associated with these changes among cancer patients. METHODS: Cancer patients (n = 1,210) completed a survey from August to September 2020 to assess COVID-19 pandemic-related changes in health behaviors and psychosocial factors. Patients were categorized into three groups: exercising less, exercising did not change, and exercising more. Patient characteristics were compared by exercise groups. RESULTS: One-third of the patients reported a decreased amount of regular exercise, while 10% reported exercising more during the pandemic. Patients who exercised less were more likely to be unemployed/retired and have poor health status and psychosocial stressors such as disruptions in daily life while less likely to be former smokers (all p < 0.05). In contrast, patients who exercised more were younger, had stage IV diagnosis, and also reported disruptions in daily life (all p < 0.05). Patients who were living in rural areas were also more likely not to experience changes in exercise habits (all p < 0.05), although rural-urban status was not identified as a strong predictor. CONCLUSION: A significant proportion of cancer patients experienced changes in exercise habits, especially exercising less, during the first 6 months of the COVID-19 pandemic. Age, employment status, tumor stage, health status, smoking status, and psychosocial factors were associated with changes in exercise behaviors. Our results highlight the importance of promoting physical activity guidelines for cancer survivorship during the COVID-19 pandemic and may help improve the identification of cancer patients susceptible to exercising less.

Association of Sugar Intake with Inflammation- and Angiogenesis-Related Biomarkers in Newly Diagnosed Colorectal Cancer Patients.

Evidence suggests a positive association between sugar intake and colorectal cancer (CRC) outcomes. We sought to investigate inflammation and angiogenesis as underlying mechanisms behind increased sugar intake and worse CRC outcomes. Pre-surgery serum samples were obtained from 191 patients diagnosed with primary invasive stage I-IV CRC. Biomarkers of inflammation (CRP, SAA, IL-6, IL-8, MCP-1, TNFα) and angiogenesis (VEGFA, VEGFD, sICAM-1 and sVCAM-1) were analyzed (Meso-Scale-Discovery). Fructose, glucose, sucrose, and total sugar intake (calories/day, % total calories) were assessed by FFQ. Pearson's correlation and multiple linear regression analyses were performed. Patients were on average 64 years old, 64% were male, the majority was diagnosed with stage II-III (58%) cancers, and 67% were either overweight or obese. Among normal-weight individuals (BMI <25 kg/m2), we observed a significant inverse association between VEGFD and any type of sugar intake in cal/day (sucrose: p = 0.01, glucose and fructose: p < 0.001) and MCP-1 and fructose intake (p = 0.05). The magnitude of reduction in VEGF ranged between -1.24 for sucrose to 4.49 for glucose intake, and -2.64 for fructose intake for MCP-1 levels. Sugar intake was associated with some inflammation or angiogenesis biomarkers, among CRC patients; differences were observed by adiposity that warrant further investigation.Supplemental data for this article is available online at at 10.1080/01635581.2021.1957133.

Circulating tryptophan metabolites and risk of colon cancer: Results from case-control and prospective cohort studies.

Dysregulation of tryptophan metabolism has been linked to colorectal tumorigenesis; however, epidemiological studies investigating tryptophan metabolites in relation to colorectal cancer risk are limited. We studied associations of plasma tryptophan, serotonin and kynurenine with colon cancer risk in two studies with cancer patients and controls, and in one prospective cohort: ColoCare Study (110 patients/153 controls), the Colorectal Cancer Study of Austria (CORSA; 46 patients/390 controls) and the European Prospective Investigation into Cancer and Nutrition (EPIC; 456 matched case-control pairs). Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for colon cancer risk. Tryptophan was inversely associated with colon cancer risk in ColoCare (OR per 1-SD = 0.44; 95% CI, 0.31-0.64) and EPIC (OR per 1-SD = 0.86; 95% CI, 0.74-0.99). Comparing detectable vs nondetectable levels, serotonin was positively associated with colon cancer in CORSA (OR = 6.39; 95% CI, 3.61-11.3) and EPIC (OR = 2.03; 95% CI, 1.20-3.40). Kynurenine was inversely associated with colon cancer in ColoCare (OR per 1-SD = 0.74; 95% CI, 0.55-0.98), positively associated in CORSA (OR per 1-SD = 1.79; 95% CI, 1.27-2.52), while no association was observed in EPIC. The kynurenine-to-tryptophan ratio was positively associated with colon cancer in ColoCare (OR per 1-SD = 1.38; 95% CI, 1.03-1.84) and CORSA (OR per 1-SD = 1.44; 95% CI, 1.06-1.96), but not in EPIC. These results suggest that higher plasma tryptophan may be associated with lower colon cancer risk, while increased serotonin may be associated with a higher risk of colon cancer. The kynurenine-to-tryptophan ratio may also reflect altered tryptophan catabolism during colon cancer development.

Plasma metabolites associated with colorectal cancer stage: Findings from an international consortium.

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

Metabolomics profiling of visceral and abdominal subcutaneous adipose tissue in colorectal cancer patients: results from the ColoCare study.

PURPOSE: Underlying mechanisms of the relationship between body fatness and colorectal cancer remain unclear. This study investigated associations of circulating metabolites with visceral (VFA), abdominal subcutaneous (SFA), and total fat area (TFA) in colorectal cancer patients. METHODS: Pre-surgery plasma samples from 212 patients (stage I-IV) from the ColoCare Study were used to perform targeted metabolomics. VFA, SFA, and TFA were quantified by computed tomography scans. Partial correlation and linear regression analyses of VFA, SFA, and TFA with metabolites were computed and corrected for multiple testing. Cox proportional hazards were used to assess 2-year survival. RESULTS: In patients with metastatic tumors, SFA and TFA were statistically significantly inversely associated with 16 glycerophospholipids (SFA: pFDR range 0.017-0.049; TFA: pFDR range 0.029-0.048), while VFA was not. Doubling of ten of the aforementioned glycerophospholipids was associated with increased risk of death in patients with metastatic tumors, but not in patients with non-metastatic tumors (phet range: 0.00044-0.049). Doubling of PC ae C34:0 was associated with ninefold increased risk of death in metastatic tumors (Hazard Ratio [HR], 9.05; 95% confidence interval [CI] 2.17-37.80); an inverse association was observed in non-metastatic tumors (HR 0.17; 95% CI 0.04-0.87; phet = 0.00044). CONCLUSION: These data provide initial evidence that glycerophospholipids in metastatic colorectal cancer are uniquely associated with subcutaneous adiposity, and may impact overall survival.

One-carbon metabolites, B vitamins and associations with systemic inflammation and angiogenesis biomarkers among colorectal cancer patients: results from the ColoCare Study.

B vitamins involved in one-carbon metabolism have been implicated in the development of inflammation- and angiogenesis-related chronic diseases, such as colorectal cancer (CRC). Yet, the role of one-carbon metabolism in inflammation and angiogenesis among CRC patients remains unclear. The objective of this study was to investigate associations of components of one-carbon metabolism with inflammation and angiogenesis biomarkers among newly diagnosed CRC patients (n 238) in the prospective ColoCare Study, Heidelberg. We cross-sectionally analysed associations between twelve B vitamins and one-carbon metabolites and ten inflammation and angiogenesis biomarkers from pre-surgery serum samples using multivariable linear regression models. We further explored associations among novel biomarkers in these pathways with Spearman partial correlation analyses. We hypothesised that pyridoxal-5'-phosphate (PLP) is inversely associated with inflammatory biomarkers. We observed that PLP was inversely associated with C-reactive protein (CRP) (r -0·33, Plinear < 0·0001), serum amyloid A (SAA) (r -0·23, Plinear = 0·003), IL-6 (r -0·39, Plinear < 0·0001), IL-8 (r -0·20, Plinear = 0·02) and TNFα (r -0·12, Plinear = 0·045). Similar findings were observed for 5-methyl-tetrahydrofolate and CRP (r -0·14), SAA (r -0·14) and TNFα (r -0·15) among CRC patients. Folate catabolite acetyl-para-aminobenzoylglutamic acid (pABG) was positively correlated with IL-6 (r 0·27, Plinear < 0·0001), and pABG was positively correlated with IL-8 (r 0·21, Plinear < 0·0001), indicating higher folate utilisation during inflammation. Our data support the hypothesis of inverse associations between PLP and inflammatory biomarkers among CRC patients. A better understanding of the role and inter-relation of PLP and other one-carbon metabolites with inflammatory processes among colorectal carcinogenesis and prognosis could identify targets for future dietary guidance for CRC patients.

Plasma metabolites associated with colorectal cancer: A discovery-replication strategy.

Colorectal cancer is known to arise from multiple tumorigenic pathways; however, the underlying mechanisms remain not completely understood. Metabolomics is becoming an increasingly popular tool in assessing biological processes. Previous metabolomics research focusing on colorectal cancer is limited by sample size and did not replicate findings in independent study populations to verify robustness of reported findings. Here, we performed a ultrahigh performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS) screening on EDTA plasma from 268 colorectal cancer patients and 353 controls using independent discovery and replication sets from two European cohorts (ColoCare Study: n = 180 patients/n = 153 controls; the Colorectal Cancer Study of Austria (CORSA) n = 88 patients/n = 200 controls), aiming to identify circulating plasma metabolites associated with colorectal cancer and to improve knowledge regarding colorectal cancer etiology. Multiple logistic regression models were used to test the association between disease state and metabolic features. Statistically significant associated features in the discovery set were taken forward and tested in the replication set to assure robustness of our findings. All models were adjusted for sex, age, BMI and smoking status and corrected for multiple testing using False Discovery Rate. Demographic and clinical data were abstracted from questionnaires and medical records.

Inflammation- and angiogenesis-related biomarkers are correlated with cancer-related fatigue in colorectal cancer patients: Results from the ColoCare Study.

Cancer-related fatigue is one of the most common side effects of colorectal cancer treatment and is affected by biomedical factors. We investigated the association of inflammation- and angiogenesis-related biomarkers with cancer-related fatigue. Pre-surgery (baseline) serum samples were obtained from n = 236 newly diagnosed colorectal cancer patients. Meso Scale Discovery assays were performed to measure levels of biomarkers for inflammation and angiogenesis (CRP, SAA, IL-6, IL-8, MCP-1, sICAM-1, sVCAM-1, TNFα, VEGFA and VEGFD). Cancer-related fatigue was assessed with the EORTC QLQ-30 questionnaire at baseline and 6 and 12 months post-surgery. We tested associations using Spearman's partial correlations and logistic regression analyses, adjusting for age, sex and body mass index. sICAM-1 and VEGFD showed a significant positive correlation with cancer-related fatigue at baseline and 6-, and 12-month follow-up (sICAM-1: r = 0.19, p = 0.010; r = 0.24, p = 0.004; r = 0.25, p = 0.006; VEGFD: r = 0.20, p = 0.006; r = 0.15, p = 0.06; r = 0.23, p = 0.01 respectively). Biomarkers of inflammation and angiogenesis measured prior to surgery are associated with cancer-related fatigue in colorectal cancer patients throughout various time points. Our results suggest the involvement of overexpressed sICAM-1 and VEGFD in the development of fatigue.

Associations Between Dietary Patterns and Longitudinal Quality of Life Changes in Colorectal Cancer Patients: The ColoCare Study.

Quality of life (QoL) is an important clinical outcome in cancer patients. We investigated associations between dietary patterns and QoL changes in colorectal cancer (CRC) patients. The study included 192 CRC patients with available EORTC QLQ-C30 data before and 12 months post-surgery and food frequency questionnaire data at 12 months post-surgery. Principal component analysis was used to identify dietary patterns. Multivariate regression models assessed associations between dietary patterns and QoL changes over time. We identified four major dietary patterns: "Western" dietary pattern characterized by high consumption of potatoes, red and processed meat, poultry, and cakes, "fruit&vegetable" pattern: high intake of vegetables, fruits, vegetable oils, and soy products, "bread&butter" pattern: high intake of bread, butter and margarine, and "high-carb" pattern: high consumption of pasta, grains, nonalcoholic beverages, sauces and condiments. Patients following a "Western" diet had lower chances to improve in physical functioning (OR = 0.45 [0.21-0.99]), constipation (OR = 0.30 [0.13-0.72]) and diarrhea (OR: 0.44 [0.20-0.98]) over time. Patients following a "fruit&vegetable" diet showed improving diarrhea scores (OR: 2.52 [1.21-5.34]. A "Western" dietary pattern after surgery is inversely associated with QoL in CRC patients, whereas a diet rich in fruits and vegetables may be beneficial for patients' QoL over time.

Smoking is associated with hypermethylation of the APC 1A promoter in colorectal cancer: the ColoCare Study.

Smoking tobacco is a known risk factor for the development of colorectal cancer and for mortality associated with the disease. Smoking has been reported to be associated with changes in DNA methylation in blood and in lung tumour tissues, although there has been scant investigation of how epigenetic factors may be implicated in the increased risk of developing colorectal cancer. To identify epigenetic changes associated with smoking behaviours, we performed epigenome-wide analysis of DNA methylation in colorectal tumours from 36 never-smokers, 47 former smokers, and 13 active smokers, and in adjacent mucosa from 49 never-smokers, 64 former smokers, and 18 active smokers. Our analyses identified 15 CpG sites within the APC 1A promoter that were significantly hypermethylated and 14 CpG loci within the NFATC1 gene body that were significantly hypomethylated (pLIS < 1 × 10-5 ) in the tumours of active smokers. The APC 1A promoter was hypermethylated in 7 of 36 tumours from never-smokers (19%), 12 of 47 tumours from former smokers (26%), and 8 of 13 tumours from active smokers (62%). Promoter hypermethylation was positively associated with duration of smoking (Spearman rank correlation, ρ = 0.26, p = 0.03) and was confined to tumours, with hypermethylation never being observed in adjacent mucosa. Further analysis of adjacent mucosa revealed significant hypomethylation of four loci associated with the TNXB gene in tissue from active smokers. Our findings provide exploratory evidence for hypermethylation of the key tumour suppressor gene APC being implicated in smoking-associated colorectal carcinogenesis. Further work is required to establish the validity of our observations in independent cohorts. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

CT-based compartmental quantification of adipose tissue versus body metrics in colorectal cancer patients.

PURPOSE: While obesity is considered a prognostic factor in colorectal cancer (CRC), there is increasing evidence that not simply body mass index (BMI) alone but specifically abdominal fat distribution is what matters. As part of the ColoCare study, this study measured the distribution of adipose tissue compartments in CRC patients and aimed to identify the body metric that best correlates with these measurements as a useful proxy for adipose tissue distribution. MATERIALS AND METHODS: In 120 newly-diagnosed CRC patients who underwent multidetector computed tomography (CT), densitometric quantification of total (TFA), visceral (VFA), intraperitoneal (IFA), retroperitoneal (RFA), and subcutaneous fat area (SFA), as well as the M. erector spinae and psoas was performed to test the association with gender, age, tumor stage, metabolic equivalents, BMI, waist-to-height (WHtR) and waist-to-hip ratio (WHR). RESULTS: VFA was 28.8 % higher in men (pVFA<0.0001) and 30.5 % higher in patients older than 61 years (pVFA<0.0001). WHtR correlated best with all adipose tissue compartments (rVFA=0.69, rTFA=0.84, p<0.0001) and visceral-to-subcutaneous-fat-ratio (VFR, rVFR=0.22, p=<0.05). Patients with tumor stages III/IV showed significantly lower overall adipose tissue than I/II. Increased M. erector spinae mass was inversely correlated with all compartments. CONCLUSION: Densitometric quantification on CT is a highly reproducible and reliable method to show fat distribution across adipose tissue compartments. This distribution might be best reflected by WHtR, rather than by BMI or WHR. KEY POINTS: • Densitometric quantification of adipose tissue on CT is highly reproducible and reliable. • Waist-to-height ratio better correlates with adipose tissue compartments and VFR than BMI or waist-to-hip ratio. • Men have higher a higher visceral fat area than women. • Patients older than 61 years have higher visceral fat area. • Patients with tumor stages III/IV have significantly lower adipose tissue than those in stages I/II.

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.

Impact of genetic polymorphisms on adenoma recurrence and toxicity in a COX2 inhibitor (celecoxib) trial: results from a pilot study.

OBJECTIVE: Chemoprevention trials have shown that celecoxib reduces adenoma recurrence but can cause cardiovascular toxicity. In this pilot study, we evaluated associations between genetic variation in several candidate pathways (e.g. prostaglandin synthesis) and adenoma recurrence and cardiovascular and gastrointestinal toxicities. METHODS: Genotyping analysis was carried out on 117 Israeli colorectal adenoma patients who participated in the Prevention of Colorectal Sporadic Adenomatous Polyps trial. Reassessment followed after 3 years on celecoxib and after 2 years from termination of treatment with celecoxib. Efficacy (absence of colorectal adenomas) was measured by colonoscopy at years 1, 3, and 5. Toxicities were assessed by investigators during celecoxib treatment and by self-report post-treatment. A linkage disequilibrium-based selection algorithm (r2≥0.90, MAF≥4%) identified 255 tagSNPs in 25 analyzed candidate genes. Genotyping was performed by using Illumina GoldenGate technology. RESULTS: Multiple genetic variants were associated with adenoma recurrence and toxicity. Genetic variability in COX1, COX2, and ALOX12/15 genes played a role in adenoma recurrence, particularly among patients on placebo. More gene variants (especially variants in PGES, CRP, SRC, and GPX3) were associated with increased risk for cardiovascular toxicity and symptoms, compared with gastrointestinal toxicity and symptoms. The increased risk for cardiovascular toxicity/symptoms associated with the SRC gene variants (rs6017996, rs6018256, rs6018257) ranged from 6.61 (95% confidence interval 1.66-26.36, P<0.01) to 10.71 (95% confidence interval 1.96-58.60, P<0.01). CONCLUSION: Genetic polymorphisms in multiple inflammation-related genes appear to interact with celecoxib on adenoma recurrence and its attendant toxicity, particularly cardiovascular toxicity/symptoms. Larger studies validating these pharmacogenetic relationships are needed.