Body mass index and waist circumference in relation to risk of recurrence and progression after non-muscle invasive bladder cancer.

BACKGROUND: Obesity may be associated with increased risk of recurrence and progression in patients with non-muscle invasive bladder cancer (NMIBC), but evidence is limited and inconsistent. We examined the associations of body mass index (BMI), waist circumference, and waist-to-hip ratio (WHR) with risk of recurrence and progression among patients with NMIBC. METHODS: This prospective study included 1029 patients diagnosed with primary NMIBC between 2014 and 2017. Patients reported weight 2 years before diagnosis at baseline, and weight, waist and hip circumference at 3 months postdiagnosis. Associations were quantified using Cox proportional hazard analyses, adjusted for clinical and lifestyle characteristics. RESULTS: More than half of patients were overweight (49%) or obese (19%) after diagnosis. During a median follow-up time of 3.6 years, 371 patients developed ≥1 recurrence and 53 experienced progression. No associations with recurrence were observed for BMI (HRper 5 kg/m2 0.94; 95% CI 0.82, 1.07), waist circumference (HRper 10 cm 0.95; 95% CI 0.86, 1.05), or WHR (HRper 0.1 unit 0.90; 95% CI 0.76, 1.06). In contrast, higher BMI was associated with a 40% increased risk of progression, with only the 2-year prediagnosis association reaching statistical significance (HRper 5 kg/m2 1.42; 95% CI 1.09, 1.84). No associations for pre-to-postdiagnosis weight change were found. CONCLUSION: General and abdominal obesity were not associated with recurrence risk among patients with NMIBC, but might be associated with increased risk of progression. Studies with sufficient sample size to stratify by tumor stage and treatment are needed to better understand whether and how obesity could influence prognosis.

Operationalisation of a standardised scoring system to assess adherence to the World Cancer Research Fund/American Institute for Cancer Research cancer prevention recommendations in the UK biobank.

Introduction: In 2018, The World Cancer Research Fund (WCRF)/American Institute for Cancer Research (AICR) published ten evidence-based Cancer Prevention Recommendations designed to reduce the risk of cancer via improved lifestyle behaviours. In 2019, Shams-White and colleagues created the "2018 WCRF/AICR Score" which aimed to standardise how adherence to these recommendations is assessed. The standardised scoring system includes seven of the recommendations concerning weight, physical activity and diet, with an optional eighth recommendation on breastfeeding. To promote transparency and reproducibility, the present paper describes the methodology for operationalisation of the standardised scoring system in the UK Biobank. Methods: UK Biobank recruited >500,000 individuals aged 37-73 years, between 2006 and 2010. In 2021, we held a workshop with experts which aimed to reach consensus on how to operationalise the scoring system using data available within UK Biobank. We used data on anthropometric measurements, physical activity and diet to calculate adherence scores. 24 h dietary assessment data were used to measure adherence to the following recommendations: "Eat a diet rich in wholegrains, vegetables, fruit, and beans", "Limit consumption of "fast foods" and other processed foods high in fat, starches or sugars" and "Limit consumption of sugar-sweetened drinks"; food frequency questionnaire data were used to assess adherence to "Limit consumption of red and processed meat" and "Limit alcohol consumption". Participants were allocated points for meeting, partially meeting or not meeting each recommendation, using cut-offs defined in the standardised scoring system. Results: At our workshop, discussions included the use of national guidelines to assess adherence to the recommendation on alcohol consumption, as well as challenges faced including defining the adapted ultra-processed food variables. A total score was calculated for 158,415 participants (mean 3.9 points, range 0-7 points). We also describe the methodology to derive a partial 5-point adherence score using data from the food frequency questionnaire in 314,616 participants. Conclusion: We describe the methodology used to estimate adherence to the 2018 WCRF/AICR Cancer Prevention Recommendations for participants in the UK Biobank, including some of the challenges faced operationalising the standardised scoring system.

Adherence to lifestyle recommendations after non-muscle invasive bladder cancer diagnosis and risk of recurrence.

BACKGROUND: Patients with non-muscle invasive bladder cancer (NMIBC) are at a high risk of tumor recurrence. It has not been previously investigated if adherence to cancer prevention recommendations lowers the risk of recurrence. OBJECTIVES: We examined whether the standardized lifestyle score measuring adherence to the 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) cancer prevention recommendations was associated with the risk of recurrence and progression among patients with NMIBC. METHODS: The study population included patients diagnosed with primary NMIBC between 2014 and 2017 from the prospective cohort UroLife. Lifestyle was assessed at baseline (n = 979; reflecting the prediagnosis period) and 3-mo postdiagnosis (n = 885). The standardized 2018 WCRF/AICR score was constructed based on recommendations for body weight, physical activity, diet, and alcohol intake. We computed multivariable-adjusted HRs and 95% CIs using Cox proportional hazard regression models. RESULTS: During a median follow-up time of 3.7 y, 320 patients developed ≥1 recurrence(s) and 49 experienced progression. Patients in the highest compared with the lowest tertile of postdiagnosis WCRF/AICR scores had a lower risk of first bladder cancer recurrence (HR: 0.74; 95% CI: 0.56, 0.98). No associations were observed for multiple recurrences (HR: 0.90; 95% CI: 0.70, 1.15) or for the baseline score with either first (HR: 1.07; 95% CI: 0.82, 1.40) or multiple recurrences (HR: 1.04; 95% CI: 0.82, 1.31). Improving lifestyle after diagnosis (per 1-point increase) was not significantly associated with the risk of first or multiple recurrence(s) (HR: 0.87; 95% CI: 0.74, 1.02; HR: 0.93; 95% CI: 0.80, 1.08, respectively). No associations were observed for bladder cancer progression, but the power was limited. CONCLUSIONS: Better adherence to the WCRF/AICR cancer prevention recommendations 3 mo after NMIBC diagnosis, but not before diagnosis, is associated with a decreased risk of first bladder cancer recurrence. More studies evaluating postdiagnosis lifestyles are needed to provide solid support for lifestyle recommendations for cancer survivors.

Longitudinal associations of adherence to lifestyle recommendations and health-related quality of life in patients with non-muscle invasive bladder cancer.

Although the role of lifestyle in health-related quality of life (HRQoL) outcomes has been increasingly recognized for various types of cancer, evidence in patients with non-muscle invasive bladder cancer (NMIBC) is very limited. We aimed to evaluate the longitudinal association between adherence to the 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) lifestyle recommendations and HRQoL in patients with NMIBC. This study included 1029 patients with NMIBC recruited between May 2014 and April 2017 from the Dutch multi-centre prospective cohort study UroLife. Lifestyle and HRQoL data were collected at 6 weeks (baseline), 3 months and 15 months after diagnosis. Information on body mass index (BMI), physical activity, diet and alcohol was used to compute the standardized WCRF/AICR adherence score (0-7). HRQoL outcomes were evaluated by the EORTC QLQ-C30. Linear mixed models were used to assess longitudinal confounder-adjusted associations between the WCRF/AICR adherence score and HRQoL outcomes. Adherence to each additional WCRF/AICR recommendation was associated with better global quality of life, physical, role and social functioning, and less fatigue. We found stronger inter-individual than intra-individual associations, suggesting that associations were mainly driven by between-subject differences. Higher adherence to the BMI, physical activity and dietary recommendations was associated with better scores for most HRQoL outcomes, while adherence to the alcohol recommendation (ie, non-consumption) was associated with worse HRQoL. Following the WCRF/AICR lifestyle recommendations may improve HRQoL in patients with NMIBC. Intervention studies are needed to establish whether the association between lifestyle and HRQoL is causal.

Identification of Lifestyle Behaviors Associated with Recurrence and Survival in Colorectal Cancer Patients Using Random Survival Forests.

Current lifestyle recommendations for cancer survivors are the same as those for the general public to decrease their risk of cancer. However, it is unclear which lifestyle behaviors are most important for prognosis. We aimed to identify which lifestyle behaviors were most important regarding colorectal cancer (CRC) recurrence and all-cause mortality with a data-driven method. The study consisted of 1180 newly diagnosed stage I-III CRC patients from a prospective cohort study. Lifestyle behaviors included in the current recommendations, as well as additional lifestyle behaviors related to diet, physical activity, adiposity, alcohol use, and smoking were assessed six months after diagnosis. These behaviors were simultaneously analyzed as potential predictors of recurrence or all-cause mortality with Random Survival Forests (RSFs). We observed 148 recurrences during 2.6-year median follow-up and 152 deaths during 4.8-year median follow-up. Higher intakes of sugary drinks were associated with increased recurrence risk. For all-cause mortality, fruit and vegetable, liquid fat and oil, and animal protein intake were identified as the most important lifestyle behaviors. These behaviors showed non-linear associations with all-cause mortality. Our exploratory RSF findings give new ideas on potential associations between certain lifestyle behaviors and CRC prognosis that still need to be confirmed in other cohorts of CRC survivors.

Association of Habitual Preoperative Dietary Fiber Intake With Complications After Colorectal Cancer Surgery.

IMPORTANCE: Postoperative complications are associated with increased morbidity and mortality among patients with colorectal cancer. As a modifiable factor associated with gut health, dietary fiber intake is of interest with regard to the risk of complications after surgery for colorectal cancer. OBJECTIVE: To examine the association between preoperative dietary fiber intake and risk of complications after surgery for colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS: This cohort study used data from the Colorectal Longitudinal, Observational Study on Nutritional and Lifestyle Factors (COLON) study, which recruited adult patients with colorectal cancer at any stage at diagnosis from 11 hospitals in the Netherlands between August 2010 and December 2017. The present study included patients with stage I to IV colorectal cancer who underwent elective abdominal surgery. Data were analyzed between December 2019 and September 2020. EXPOSURES: Habitual dietary fiber intake was assessed at diagnosis using a 204-item food frequency questionnaire. MAIN OUTCOMES AND MEASURES: Any complications, surgical complications, and anastomotic leakage occurring during the 30 days after surgery for colorectal cancer. The association between fiber intake and risk of postoperative complications was assessed using logistic regression analyses. Additional analyses stratified by sex, tumor location, and fiber source were performed. RESULTS: Among the 1399 patients included in the analysis, the median age at inclusion was 66 years (interquartile range, 61-72 years) and 896 (64%) were men. Any complications occurred in 397 patients (28%), and surgical complications occurred in 235 patients (17%). Of 1237 patients with an anastomosis, 67 (5%) experienced anastomotic leakage. Higher dietary fiber intake (per 10 g per day) was associated with a lower risk of any complications (odds ratio [OR], 0.75; 95% CI, 0.62-0.92) and surgical complications (OR, 0.76; 95% CI, 0.60-0.97), whereas no association with anastomotic leakage was found (OR, 0.97; 95% CI, 0.66-1.43). Among women, higher dietary intake was associated with any complications (OR, 0.64; 95% CI, 0.44-0.94), whereas there was no association among men (OR, 0.79; 95% CI, 0.63-1.01). Fiber intake from vegetables (per 1 g per day) was inversely associated with any (OR, 0.90; 95% CI, 0.83-0.99) and surgical (OR, 0.87; 95% CI, 0.78-0.97) complications. CONCLUSIONS AND RELEVANCE: In this cohort study, higher habitual dietary fiber intake before surgery was associated with a lower risk of postoperative complications among patients with colorectal cancer. The findings suggest that improving preoperative dietary fiber intake may be considered in future prehabilitation programs for patients undergoing surgery for colorectal cancer.

Levels of Inflammation Markers Are Associated with the Risk of Recurrence and All-Cause Mortality in Patients with Colorectal Cancer.

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

Lifestyle after colorectal cancer diagnosis in relation to recurrence and all-cause mortality.

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

Sufficient 25-Hydroxyvitamin D Levels 2 Years after Colorectal Cancer Diagnosis are Associated with a Lower Risk of All-cause Mortality.

BACKGROUND: Whether changes in 25 hydroxy vitamin D3 (25(OH)D3) levels after colorectal cancer diagnosis influence clinical outcomes is unclear. We investigated the association of trajectories of 25(OH)D3 levels with recurrence and all-cause mortality. METHODS: In total, 679 patients were included in our data analyses. Trajectories of 25(OH)D3 levels were defined on the basis of vitamin D status at diagnosis, at 6 months, and 2 years after diagnosis. Observed trajectories of 25(OH)D3 levels were consistent deficient levels (20%), consistent sufficient levels (39%), increasing levels (20%), and a temporary drop in levels (13%). Associations of trajectories of 25(OH)D3 with recurrence and all-cause mortality were assessed using multivariable Cox proportional hazards regression models. RESULTS: During a follow-up time of 2.2 years for recurrence and 3.5 years for all-cause mortality, 31 and 65 events occurred, respectively. No statistically significant associations were observed for vitamin D trajectories and the risk of recurrence. Patients who were consistently sufficient compared with patients who were consistently deficient had a lower risk of all-cause mortality [HR 0.39; 95% confidence interval (CI), 0.21-0.73]. The risk of all-cause mortality seems lower in patients with increasing levels or a temporary drop in levels (HR 0.54; 95% CI, 0.27-1.10 and HR 0.40 95% CI, 0.17-0.93) relative to patients with consistent deficient levels. CONCLUSIONS: Patients with colorectal cancer following a trajectory characterized by sufficient levels of 25(OH)D3 2 years after diagnosis all appeared to have a lower risk of all-cause mortality compared with patients having consistent deficient levels. IMPACT: Further studies should investigate how trajectories of 25(OH)D3 levels are associated with colorectal cancer recurrence.

Diet quality indices and dietary patterns are associated with plasma metabolites in colorectal cancer patients.

PURPOSE: Emerging evidence suggests that diet is linked to survival in colorectal cancer patients, although underlying mechanisms are not fully understood. The aim of this study was to evaluate whether dietary exposures are associated with metabolite concentrations in colorectal cancer patients. METHODS: Concentrations of 134 metabolites of the Biocrates AbsoluteIDQ p180 kit were quantified in plasma samples collected at diagnosis from 195 stage I-IV colorectal cancer patients. Food frequency questionnaires were used to calculate adherence to the World Cancer Research Fund (WCRF) dietary recommendations and the Dutch Healthy Diet (DHD15) index as well as to construct dietary patterns using Principal Component Analysis. Multivariable linear regression models were used to determine associations between dietary exposures and metabolite concentrations. All models were adjusted for age, sex, body mass index, smoking status, analytical batch, cancer stage, and multiple testing using false discovery rate. RESULTS: Participants had a mean (SD) age of 66 (9) years, were mostly men (60%), and mostly diagnosed with stage II and III cancer. For the dietary pattern analyses, Western, Carnivore, and Prudent patterns were identified. Better adherence to the WCRF dietary recommendations was associated with lower concentrations of ten phosphatidylcholines. Higher intake of the Carnivore pattern was associated with higher concentrations of two phosphatidylcholines. The DHD15-index, Western pattern, or Prudent pattern were not associated with metabolite concentrations. CONCLUSION: In the current study, the WCRF dietary score and the Carnivore pattern are associated with phosphatidylcholines. Future research should elucidate the potential relevance of phosphatidylcholine metabolism in the colorectal cancer continuum. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov Identifier: NCT03191110.

The association between the adapted dietary inflammatory index and colorectal cancer recurrence and all-cause mortality.

BACKGROUND & AIMS: The inflammatory potential of the diet has been linked to colorectal cancer (CRC) development and mortality. However, it is unknown whether it is also associated with CRC recurrence. Therefore, the aim of this study was to investigate the associations between the inflammatory potential of the diet and plasma inflammation markers as well as recurrence and all-cause mortality in CRC patients. METHODS: Data of the Colorectal cancer, Observational, LONgitudinal (COLON) study, a prospective cohort study, was used. Dietary intake, assessed using a semi-quantitative food frequency questionnaire, was available for 1478 patients at diagnosis and for 1334 patients six months after diagnosis. Dietary intake data were used to calculate the adapted dietary inflammatory index (ADII). Data about cancer recurrence and all-cause mortality, were assessed through linkage with the Netherlands Cancer Registry and the Municipal Personal Records Database, respectively. The association between the ADII (continuous) and inflammation markers (Interleukin (IL)6, IL8, IL10, Tumor Necrosis Factor (TNF)α, high sensitivity C-reactive protein (hsCRP) and a summary inflammatory z-score), measured with a multiplex assay using electrochemiluminiscence detection, was assessed using quantile regression analyses. Restricted cubic splines (RCS) analyses and multivariable Cox proportional hazard models were used to explore the relationship between the ADII and CRC outcomes. RESULTS: During a median follow-up time of 3.2 years (Interquartile range (IQR) 2.0-4.1) for recurrence and 4.8 years (IQR 3.5-5.9) for all-cause mortality, 228 recurrences and 279 deaths occurred. A more pro-inflammatory diet at diagnosis as well as six months after diagnosis was associated with higher levels of TNFα, hsCRP and the summary inflammatory z-score. Results of RCS showed no relationship between the ADII and CRC outcomes at both time points. Also results of the Cox proportional hazard models showed no associations between the ADII at both time points and recurrence (HR (95%CI) 0.98 (0.94-1.04) & 0.96 (0.91-1.02) or all-cause mortality (HR (95%CI) 1.03 (0.98-1.07) & 1.00 (0.95-1.05)). CONCLUSION: Our study did not show an association between the ADII and recurrence and all-cause mortality in CRC patients. Further research should also take into account molecular tumor subtypes, as the effect of the inflammatory potential of the diet on cancer recurrence and mortality is more likely to be present in tumors with an inflammatory signature. CLINICAL TRIAL REGISTRY NUMBERS AND WEBSITE: The colon study: NCT03191110; clinical trials.gov.

Inflammation Is a Mediating Factor in the Association between Lifestyle and Fatigue in Colorectal Cancer Patients.

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

Circulating Folate and Folic Acid Concentrations: Associations With Colorectal Cancer Recurrence and Survival.

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

The association between circulating levels of vitamin D and inflammatory markers in the first 2 years after colorectal cancer diagnosis.

BACKGROUND: Calcitriol, the active form of vitamin D, may inhibit colorectal cancer (CRC) progression, which has been mechanistically linked to an attenuation of a pro-inflammatory state. The present study investigated the associations between circulating 25 hydroxy vitamin D3 (25(OH)D3) levels and inflammatory markers (IL10, IL8, IL6, TNFα and hsCRP) in the 2 years following CRC diagnosis. METHODS: Circulating 25(OH)D3 levels and inflammatory markers were assessed at diagnosis, after 6, 12 and 24 months from 798 patients with sporadic CRC participating in two prospective cohort studies. Associations between 25(OH)D3 levels and individual inflammatory markers as well as a summary inflammatory z-score were assessed at each time point by multiple linear regression analyses. To assess the association between 25(OH)D3 and inflammatory markers over the course of 2 years, linear mixed model regression analyses were conducted. RESULTS: Higher 25(OH)D3 levels were associated with lower IL6 levels at diagnosis, at 6 months after diagnosis and over the course of 2 years (ß -0.06, 95% CI -0.08 to -0.04). In addition, 25(OH)D3 levels were inversely associated with the summary inflammatory z-score at diagnosis and over the course of 2 years (ß -0.17, 95% CI -0.25 to -0.08). In addition, a significant inverse association between 25(OH)D3 levels and IL10 was found over the course of 2 years. Intra-individual analyses showed an inverse association between 25(OH)D3 and IL10, IL6 and TNFα. No statistically significant associations between 25(OH)D3 and IL8 and hsCRP levels were observed. CONCLUSIONS: Serum 25(OH)D3 levels were inversely associated with the summary inflammatory z-score and in particular with IL6 in the years following CRC diagnosis. This is of potential clinical relevance as IL6 has an important role in chronic inflammation and is also suggested to stimulate cancer progression. Further observational studies should investigate whether a possible 25(OH)D3-associated reduction of inflammatory mediators influences treatment efficacy and CRC recurrence.

Vitamin D, magnesium, calcium, and their interaction in relation to colorectal cancer recurrence and all-cause mortality.

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

Associations of Abdominal Skeletal Muscle Mass, Fat Mass, and Mortality among Men and Women with Stage I-III Colorectal Cancer.

BACKGROUND: The associations of abdominal skeletal muscle mass index (SMI), visceral and subcutaneous adipose tissue (VAT and SAT, respectively), and mortality among patients with stage I-III colorectal cancer may differ for men and women, but only few studies stratified their data into men and women. We investigated associations of abdominal SMI, VAT, and SAT with overall mortality among men and among women with stage I-III colorectal cancer. METHODS: SMI, VAT, and SAT were assessed from abdominal CT images for 1,998 patients with stage I-III colorectal cancer diagnosed between 2006 and 2015. Restricted cubic splines (RCS) were used to investigate associations of SMI, VAT, and SAT with overall mortality. RESULTS: Average age of the participants was 67.9 ± 10.6 years and 58% were men. During a median follow-up of 4.3 years, 546 (27%) patients died. Among men, the association of SMI and mortality was statistically significant in a nonlinear way in the RCS analyses, with lower SMI levels associated with higher mortality. SMI was not associated with mortality among women. SAT was associated with mortality in a nonlinear way for men and for women, with lower SAT levels being associated with higher mortality. VAT was not significantly associated with mortality in men or women. CONCLUSION: Associations of abdominal skeletal muscle mass with mortality among patients with colorectal cancer were not the same for men and for women. IMPACT: This study stresses the importance for more attention on sex-related differences in body composition and cancer outcomes.

Chemotherapy and vitamin D supplement use are determinants of serum 25-hydroxyvitamin D levels during the first six months after colorectal cancer diagnosis.

Vitamin D metabolites, including 25-hydroxyvitamin D3 (25(OH)D3), may inhibit colorectal cancer (CRC) progression. Here we investigated cross-sectional and longitudinal associations of demographic, lifestyle and clinical characteristics with 25(OH)D3 serum concentrations in CRC patients at diagnosis and six months later. In 1201 newly-diagnosed stage I-III CRC patients, 25(OH)D3 levels were analysed twice. Multivariable linear regression was used to assess demographic, lifestyle and clinical determinants of 25(OH)D3 levels at diagnosis and six months later. Linear mixed models were used to assess characteristics associated with changes in 25(OH)D3 levels over time. Results of our study showed that vitamin D intake from diet or supplements, use of calcium supplements, BMI and disease stage were associated with 25(OH)D3 levels at both time points. Six months after diagnosis, gender and having received chemo- and/or radiotherapy were also associated with 25(OH)D3 levels. A stronger decrease in 25(OH)D3 levels was observed in patients who underwent chemotherapy, compared to surgery only (ß-6.9 nmol/L 95 %CI -9.8; -4.0). Levels of 25(OH)D3 levels increased in patients using vitamin D supplements compared to non-users (ß 4.0 nmol/L 95 %CI 1.2; 6.8). In conclusion, vitamin D supplement use and treatment appear to be important determinants of 25(OH)D3 levels during the first six months after CRC diagnosis, although the difference in 25(OH)D3 levels was minor. ClinicalTrials.gov Identifier: NCT03191110.

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.

Are Ergothioneine Levels in Blood Associated with Chronic Peripheral Neuropathy in Colorectal Cancer Patients Who Underwent Chemotherapy?

Objective: Chronic Chemotherapy-Induced Peripheral Neuropathy (CIPN) is highly prevalent among colorectal cancer (CRC) patients. Ergothioneine (ET) - a dietary antioxidant -protected against CIPN in experimental models, but human studies are lacking. We explored whether whole blood ET levels were associated with chronic peripheral neuropathy among CRC patients who had completed chemotherapy.Methods: At diagnosis, median ET-concentration in whole blood of 159 CRC patients was 10.2 µg/ml (7.2-15.8). Patients completed questionnaires on peripheral neuropathy 6 months after completion of chemotherapy. We calculated prevalence ratios (PR) to assess associations of ET-concentrations and prevalence of peripheral neuropathy and used linear regression to assess associations with severity of peripheral neuropathy.Results: Prevalence of total and sensory peripheral neuropathy were both 81%. Higher ET-concentrations tended to be associated with lower prevalence of total and sensory peripheral neuropathy, but not statistically significant (highest versus lowest tertile of ET: PR = 0.93(0.78, 1.11) for total neuropathy, and PR = 0.84(0.70, 1.02) for sensory neuropathy). ET-concentrations were not associated with severity of neuropathy.Conclusion: Statistically significant associations were not observed, possibly because of limited sample size. Although data may putatively suggest higher levels of ET to be associated with a lower prevalence of neuropathy, analyses should be repeated in larger populations with larger variability in ET-concentrations.