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Energy balance accounts for an individual’s energy intake, expenditure, and storage. Each aspect of energy balance has implications for the pharmacokinetics of cancer treatments and may impact an individual’s drug exposure and subsequently its tolerance and efficacy. However, the integrated effects of diet, physical activity, and body composition on drug absorption, metabolism, distribution, and excretion are not yet fully understood. This review examines the existing literature on energy balance, specifically the role of dietary intake and nutritional status, physical activity and energy expenditure, and body composition on the pharmacokinetics of cancer therapeutics. As energy balance and pharmacokinetic factors can be influenced by age-related states of metabolism and comorbidities, this review also explores the age-related impact of body composition and physiologic changes on pharmacokinetics among pediatric and older adult populations with cancer.

BACKGROUND: The inflammatory potential of the diet has been associated with colorectal cancer (CRC) risk, but its association with CRC prognosis is unclear. OBJECTIVE: To investigate the inflammatory potential of the diet in relation to recurrence and all-cause mortality among persons diagnosed with stage I to III CRC. METHODS: Data of the COLON study, a prospective cohort among CRC survivors were used. Dietary intake, 6 mo after diagnosis, was assessed by using a food frequency questionnaire and was available for 1631 individuals. The empirical dietary inflammatory pattern (EDIP) score was used as a proxy for the inflammatory potential of the diet. The EDIP score was created by using reduced rank regression and stepwise linear regression to identify food groups that explained most of the variations in plasma inflammatory markers (IL6, IL8, C-reactive protein, and tumor necrosis factor-α) measured in a subgroup of survivors (n = 421). Multivariable Cox proportional hazard models with restricted cubic splines were used to investigate the relation between the EDIP score and CRC recurrence and all-cause mortality. Models were adjusted for age, sex, BMI, PAL, smoking status, stage of disease, and tumor location. RESULTS: The median follow-up time was 2.6 y (IQR: 2.1) for recurrence and 5.6 y (IQR: 3.0) for all-cause mortality, during which 154 and 239 events occurred, respectively. A nonlinear positive association between the EDIP score and recurrence and all-cause mortality was observed. For example, a more proinflammatory diet (EDIP score +0.75) compared with the median (EDIP score 0) was associated with a higher risk of CRC recurrence (HR: 1.15; 95% CI: 1.03, 1.29) and all-cause mortality (HR: 1.23; 95% CI: 1.12, 1.35). CONCLUSIONS: A more proinflammatory diet was associated with a higher risk of recurrence and all-cause mortality in CRC survivors. Further intervention studies should investigate whether a switch to a more anti-inflammatory diet improves CRC prognosis.

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 AbsoluteIDQ 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, pFDR = 0.03; but not colon cancer: pFDR = 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.

Purpose Some dietary habits cluster together, and for this reason it is advised to study the impact of entire dietary patterns on human health, rather than that of individual dietary habits. The main objective of this study was to evaluate differences in gut microbiota composition and their predicted functional properties between people with a healthy (HDP) and western (WDP) dietary pattern. Methods A cross-sectional, observational study was carried out on 200 participants enrolled 2017–2018 in Poznań, Poland, equally distributed into HDP and WDP groups. Diet was estimated using 3-day food records and information on stool transit times was collected. Fecal microbiota composition was assessed by 16S rRNA gene sequencing and its functional properties were predicted by the PICRUSt2 workflow. Results The α-diversity did not differ between people with WDP and HDP, but β-diversity was associated with dietary pattern. People with HDP had higher relative abundances (RA) of Firmicutes and Faecalibacterium and lower RA of Bacteroidota and Escherichia–Shigella than participants with WDP. Only a small proportion of the variance in microbiota composition (1.8%) and its functional properties (2.9%) could be explained by dietary intake (legumes, simple sugars and their sources, like fruit, soft drinks) and stool transit characteristics. Conclusion Gut microbiota composition and predicted metabolic potential is shaped by overall diet quality as well as the frequency of defecation; however, the cumulative effect of these explain only a relatively low proportion of variance.

Contains fulltext : 290676.pdf (Publisher’s version ) (Open Access) The aim of this study was to evaluate our institutions airway management and complications after submandibular duct relocation (SMDR). We analysed a historic cohort of children and adolescents who were examined at the Multidisciplinary Saliva Control Centre between March 2005 and April 2016. Ninety-six patients underwent SMDR for excessive drooling. We studied details of the surgical procedure, postoperative swelling and other complications. Ninety-six patients, 62 males and 34 females, were treated consecutively by SMDR. Mean age at time of surgery was 14 years and 11 months. The ASA physical status was 2 in most patients. The majority of children were diagnosed with cerebral palsy (67.7%). Postoperative swelling of the floor of the mouth or tongue was reported in 31 patients (32.3%). The swelling was mild and transient in 22 patients (22.9%) but profound swelling was seen in nine patients (9.4%). In 4.2% of the patients the airway was compromised. In general, SMDR is a well-tolerated procedure, but we should be aware of swelling of the tongue and floor of the mouth. This may lead to a prolonged period of endotracheal intubation or a need for reintubation which can be challenging. After extensive intra-oral surgery such as SMDR we strongly recommend a extended perioperative intubation and extubation after the airway is checked and secure.

PurposeThe overarching goal of the FOCUS (biomarkers related to folate-dependent one-carbon metabolism in colorectal cancer (CRC) recurrence and survival) Consortium is to unravel the effect of folate and folate-mediated one-carbon metabolism (FOCM) biomarkers on CRC prognosis to provide clinically relevant advice on folate intake to cancer patients and define future tertiary prevention strategies.ParticipantsThe FOCUS Consortium is an international, prospective cohort of 2401 women and men above 18 years of age who were diagnosed with a primary invasive non-metastatic (stages I–III) CRC. The consortium comprises patients from Austria, two sites from the Netherlands, Germany and two sites from the USA. Patients are recruited after CRC diagnosis and followed at 6 and 12 months after enrolment. At each time point, sociodemographic data, data on health behaviour and clinical data are collected, blood samples are drawn.Findings to dateAn increased risk of cancer recurrences was observed among patients with higher compared with lower circulating folic acid concentrations. Furthermore, specific folate species within the FOCM pathway were associated with both inflammation and angiogenesis pathways among patients with CRC. In addition, higher vitamin B6status was associated with better quality of life at 6 months post-treatment.Future plansBetter insights into the research on associations between folate and FOCM biomarkers and clinical outcomes in patients with CRC will facilitate the development of guidelines regarding folate intake in order to provide clinically relevant advice to patients with cancer, health professionals involved in patient care, and ultimately further tertiary prevention strategies in the future. The FOCUS Consortium offers an excellent infrastructure for short-term and long-term research projects and for combining additional biomarkers and data resulting from the individual cohorts within the next years, for example, microbiome data, omics and multiomics data or CT-quantified body composition data.

Aim To validate the predictive value of the European coLlaboration on Acute decompeNsated Heart Failure (ELAN-HF) score, and to assess the effect of self-care behaviour on readmission and mortality in patients after admission with acute decompensated heart failure (ADHF). Design Quantitative, prospective, single centre, cohort study. Methods N-Terminal pro–B-type natriuretic peptide (NT-proBNP) levels were measured on admission and discharge, and were used together with clinical and laboratory parameters to calculate the ELAN-HF score. Patients were stratified into four risk groups (low, intermediate, high, very high) according to their ELAN-HF score. The performance of the ELAN-HF score was evaluated and compared to the original study. Self-care behaviour was assessed by the European Heart Failure Self-care Behaviour Scale (EHFScBS-9). Survival analysis was used to estimate the association between both scores and re-admission for HF and/or all-cause mortality within 180 days. Results 88 patients were included. The median age of the study population was 75 years (IQR 69–83), 43% was female. NYHA III/IV functional class was present at discharge in 68 patients (85%) and 27 patients (34%) had a left ventricular ejection fraction p = 0.003). The median EHFScBS-9 score was 68.1 (IQR 58.3 – 77.8). There was no significant association between the EHFScBS-9 score and readmission and/or mortality p = 0.174). Conclusion This study confirms the validity and therefore the potential of the ELAN-HF score to triage patients with ADHF before discharge. Using this score may optimize the follow-up treatment on the nurse-led heart failure clinic in order to decrease readmission and mortality. Self-care behaviour was non-significantly associated with readmission and/or mortality in our study population. Trial Registration This study has been registered with the ethics committee MEC-U (Nieuwegein, The Netherlands), registration nr: V.160999/W18.208/HG/mk.

Introduction: Circulating levels of biomarkers indicating better B vitamin status appear to have a protective effect on various medical conditions, while they also contribute to the reduction in risk of some cancer entities, e.g. colorectal cancer (CRC). However, little is known about the associations of circulating vitamin B biomarkers with clinical outcomes among CRC patients, such as overall survival (OS), disease-free survival (DFS), and risk of recurrence. Recently, we showed that higher vitamin B6 status is associated with improved OS and DFS. In the present study, we further investigated associations of vitamin B1, B2, and B3 status with clinical outcomes in a prospective cohort of non-metastatic CRC patients. Materials and Methods: A total of 2,102 patients with stage I-III CRC participated in six cohorts in the international FOCUS Consortium. Circulating concentrations of vitamin B biomarkers (thiamine and thiamine monophosphate (representing vitamin B1), riboflavin (vitamin B2), and vitamin B3 markers N1-methylnicotinamide and nicotinamide were measured by liquid chromatography-tandem mass spectrometry in preoperative blood samples. Using Cox proportional hazards regression, we examined associations of vitamin B1, B2, B3 status, and related biomarkers with OS, DFS, and risk of recurrence. Models were adjusted for patient age, sex, circulating creatinine levels, tumor site, tumor stage, and study site. Results and Discussion: After a median follow-up of 3.2 years for OS, higher levels of thiamine monophosphate were associated with lower risk of all-cause mortality (HROS: 0.82; 95% CI, 0.71-0.95, p=0.008). Furthermore, higher riboflavin levels were associated with improved OS (HROS: 0.88; 95% CI, 0.78-0.98, p=0.03) and DFS (HRDFS: 0.91; 95% CI, 0.83-0.99, p=0.04). We did not observe any associations of thiamine, N1-methylnicotinamide, and nicotinamide with clinical outcomes among CRC patients. Conclusion: Findings from this multi-centre study of non-metastatic CRC patients yield important clinical information. We observed significantly improved OS among patients with higher levels of thiamine monophosphate after CRC diagnosis. Further, higher preoperative riboflavin may represent a promising predictor for OS and DFS among non-metastatic CRC patients. Citation Format: Biljana Gigic, Jennifer Ose, Stefanie Brezina, Anne JMR Geijsen, Arve Ulvik, Eline H. van Roekel, Andreana N. Holowatyj, Dieuwertje E. Kok, Fränzel JB van Duijnhoven, Victoria Damerell, Christopher I. Li, Nina Habermann, Alexis B. Ulrich, Matty P. Weijenberg, Andrea Gsur, Per M. Ueland, Ellen Kampman, Martin Schneider, Cornelia M. Ulrich. Circulating biomarkers of vitamin B1, B2, and B3 status and their associations with clinical outcomes among non-metastatic colorectal cancer patients: results from the FOCUS Consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1010.

Introduction: Postoperative complications impact morbidity and mortality of colon cancer patients. Emerging evidence suggests that intestinal microbiota might play a critical role in the development of postoperative complications after gastrointestinal surgery. Here, we studied changes in fecal microbiota composition comparing samples collected before and after colon cancer surgery. Moreover, we examined whether the microbiota composition before surgery was associated with postoperative complications, and we explored potential determinants of the preoperative microbiota in colon cancer patients. Methods: For this study, two fecal samples were provided by 78 patients with colon cancer. The first (preoperative) sample was collected shortly after diagnosis and before (median and interquartile (IQR) range of 4 (2-6) days) colon cancer surgery. The second (postoperative) sample was collected approximately 6 weeks (median and IQR of 42 (37-47) days) after surgery and before start of adjuvant chemotherapy (whenever applicable). Based on 16S ribosomal RNA gene amplicon sequencing, the fecal microbiota diversity and composition were determined. Preoperative microbiota composition of patients who developed postoperative complications in the 30 days following surgery (n=18, 23%) was compared to those who did not (n=60, 77%) using univariate and multivariate analyses. Explorative random forest analyses were conducted to identify predictors of complication status, with relative abundance of the core genera, sex, age, fecal calprotectin levels, dietary fiber intake, body mass index, smoking status, ASA classification, cancer stage and tumor location being considered as potential predictors. Results: After surgery, microbial alpha diversity was reduced compared to the preoperative situation, whereas compositional changes over time only reached statistical significance for Lachnospiraceae NK4A136 and Coprococcus 1, which both decreased in relative abundance after surgery. Already before the start of surgery, relative abundance of the genera Bacteroides (10% vs 6%) and Lachnoclostridium (0.6% vs 0.2%) appeared to be higher in patients with complications versus those with uncomplicated recovery. In a prediction analysis, current smoking and relative abundance of Lachnoclostridium were identified as most profound predictors of complication status. Fecal calprotectin levels and current smoking status explained most (together 6%) of the overall variation in microbiota composition before surgery. Conclusion: In this study, higher relative abundances of the genera Bacteroides and Lachnoclostridium before surgery were associated with postoperative complications in patients with colon cancer. Future studies should expand on the potential causal and pathogenic routes underlying these observations. Citation Format: Dieuwertje E. Kok, Jannigje G. Kers, Hendriek C. Boshuizen, Niels Klaassen, Henk K. van Halteren, Flip M. Kruyt, Marjolein L. Smidt, Johannes H. De Wilt, Annemarie Boleij, Ellen Kampman, Erwin G. Zoetendal. Pre- and postoperative fecal microbiota and its association with complications after surgery in colon cancer patients. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4380.

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.

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.

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.

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

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.

In this article, the central issue is the interaction between Sandrart’s friendship networks, his art production and success in Amsterdam. His famous literary life’s work the Teutsche Academie, and Lebenslauf, his (auto) biography, will also be involved. Sandrart’s stay in Amsterdam (1637-1645) was the true springboard for his career. Upon arrival in Amsterdam, he immediately positioned himself in the network of influential entrepreneurs, connoisseurs and magistrates by moving into a patrician residence on the Keizersgracht. Sandrart’s wealthy bloedvrienden (family members) with important socio-political networks - the banker Johan de Neufville and the artist-agent Michel le Blon - further brokered easy access to the bourgeois elite network, which soon earned the aristocratic painter many important commissions. In the late 1630s and early 1640s, Sandrart was a pioneer in his use of the Van Dyckian way of portraying and a classicist Italian style in history painting. Although it took a further ten years before the change of style towards academism became definite in Amsterdam, Sandrart had been the artistic leader thereof. Moreover, he launched a new artists image and artistic lifestyle by positioning himself as the aristocratic-artist.

Obesity and obesity-driven cancer rates are continuing to rise worldwide. We hypothesize that adipocyte–colonocyte interactions are a key driver of obesity-associated cancers. To understand the clinical relevance of visceral adipose tissue in advancing tumor growth, we analyzed paired tumor-adjacent visceral adipose, normal mucosa, and colorectal tumor tissues as well as presurgery blood samples from patients with sporadic colorectal cancer. We report that high peroxisome proliferator-activated receptor gamma (PPARG) visceral adipose tissue expression is associated with glycoprotein VI (GPVI) signaling—the major signaling receptor for collagen—as well as fibrosis and adipogenesis pathway signaling in colorectal tumors. These associations were supported by correlations between PPARG visceral adipose tissue expression and circulating levels of plasma 4-hydroxyproline and serum intercellular adhesion molecule 1 (ICAM1), as well as gene set enrichment analysis and joint gene-metabolite pathway results integration that yielded significant enrichment of genes defining epithelial-to-mesenchymal transition—as in fibrosis and metastasis—and genes involved in glycolytic metabolism, confirmed this association. We also reveal that elevated prostaglandin-endoperoxide synthase 2 (PTGS2) colorectal tumor expression is associated with a fibrotic signature in adipose–tumor crosstalk via GPVI signaling and dendritic cell maturation in visceral adipose tissue. Systemic metabolite and biomarker profiling confirmed that high PTGS2 expression in colorectal tumors is significantly associated with higher concentrations of serum amyloid A and glycine, and lower concentrations of sphingomyelin, in patients with colorectal cancer. This multi-omics study suggests that adipose–tumor crosstalk in patients with colorectal cancer is a critical microenvironment interaction that could be therapeutically targeted. See related spotlight by Colacino et al., p. 803

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.

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.

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 (

We have previously shown that withdrawal of folic acid led to metabolic reprogramming and a less aggressive phenotype in a mouse cell model of triple-negative breast cancer (TNBC). Herein, we evaluate the effects of folic acid withdrawal on transcriptomic profiles in these cells. Murine cell lines were originally derived from a pool of spontaneous mammary tumors grown in MMTV-Wnt1 transgenic mice. Based on their differential molecular characteristics and metastatic potential, these cell lines were previously characterized as non-metastatic epithelial (E-Wnt), non-metastatic mesenchymal (M-Wnt) and metastatic mesenchymal (metM-Wnt(liver)) cells. Using custom two-color 180K Agilent microarrays, we have determined gene expression profiles for three biological replicates of each subtype kept on standard medium (2.2 μM folic acid) or folic acid-free medium for 72 hours. The analyses revealed that more genes were differentially expressed upon folic acid withdrawal in M-Wnt cells (1884 genes; Benjamini-Hochberg-adjusted P-value

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. Am J Clin Nutr 2022;116:303–313.

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.

Although some bacteria inhabiting the human gut synthesize folates, it has not yet been established whether bacterial folate biosynthesis can impact human folate status. The main objectives of this study were to evaluate associations between different lifestyle factors and the potential of fecal microbiota to produce folates, and to investigate whether this potential is associated with circulating folate and total homocysteine (tHcy) levels in humans. To this end, we carried out an observational study of two hundred adult participants, with high variance in dietary habits. Diet was determined using three-day food records. Fecal microbiota composition was assessed by 16S rRNA gene amplicon sequencing. To establish the folate-production potential of fecal bacteria, cultures containing feces were incubated under anaerobic conditions for 24 h, and the folate concentration was measured before and after incubation. The folate concentration in cultures was 185.4 ± 228.1 pg/ml/log(CFU/g) (2125.4 ± 2454.3 pg/ml) higher after incubation. This change in concentration was not associated with the healthy eating index that measures diet quality (r = -0.11, p = 0.11), but it was positively associated with low α-diversity (r = -0.18, p < 0.01), and high relative abundance of the Bacteroides, as well as Sutterella and Parasutterella genera. The gut microbiota's folate producing potential was associated neither with serum folate nor with plasma tHcy levels. In conclusion, some taxa of the native gut microbiota have the ability to synthesize folates under culture conditions, but this bacterial folate biosynthesis capacity does not predict human folate status.

Scope: Persistent DNA methylation changes may mediate the effects of early-life exposures on later-life health. However, because the length of the human lifespan is challenging for prospective studies, there are few relevant data from human longitudinal studies. Projecting data from mouse models of early-life exposure to existing human studies offers a potential tool to address this research challenge. Methods and Results: C57BL/6J mice were fed low or normal folate diets before and during pregnancy and lactation. Genome-wide promoter methylation was measured in male offspring livers at 17.5 days gestation and 28 weeks. Eight gene promoters were concurrently hypermethylated by folate depletion in fetuses and adults (>1.10 fold-change; pConclusion: Some persistent folate-induced methylation changes observed in mice were mirrored in humans. This demonstrates utility of mouse data in identifying human loci for interrogation as biomarkers of later-life health.

Folate is a B-vitamin with an important role in health and disease. The optimal folate status with regard to human health remains controversial. A low intake of natural folate as well as excessive intake of synthetic folic acid, were previously linked to an increased risk of colorectal cancer or with aberrant molecular pathways related to carcinogenesis in some studies. Importantly, most studies conducted so far, solely focused on dietary intake or circulating levels of folate in relation to cancer risk. Notably, diet or dietary supplements are not the only sources of folate. Several bacteria in the gastrointestinal tract can synthesize B-vitamins, including folate, in quantities that resemble dietary intake. The impact of bacterial folate biosynthesis concerning human health and disease remains unexplored. This review highlights current insights into folate biosynthesis by intestinal bacteria and its implications for processes relevant to cancer development, such as epigenetic DNA modifications and DNA synthesis. Moreover, we will reflect on the emerging question whether food-grade or intestinal bacteria can be considered a potential target to ensure sufficient levels of folate in the gastrointestinal tract and, hence the relevance of bacterial folate biosynthesis for disease prevention or treatment.Keywords: Folate, biosynthesis, colon, intestinal bacteria, colorectal cancer, DNA methylation, one-carbon metabolism

The identification of patients at high-risk for colorectal cancer (CRC) recurrence remains an unmet clinical need. The aim of this study was to investigate associations of metabolites with risk of recurrence in stage II/III CRC patients. A targeted metabolomics assay (128 metabolites measured) was performed on pre-surgery collected EDTA plasma samples from n = 440 newly diagnosed stage II/III CRC patients. Patients have been recruited from four prospective cohort studies as part of an international consortium: Metabolomic profiles throughout the continuum of CRC (MetaboCCC). Cox proportional hazard models were computed to investigate associations of metabolites with recurrence, adjusted for age, sex, tumor stage, tumor site, body mass index, and cohort, false discovery rate (FDR) was used to account for multiple testing. Sixty-nine patients (15%) had a recurrence after a median follow-up time of 20 months. We identified 13 metabolites that were nominally associated with a reduced risk of recurrence. None of the associations were statistically significant after controlling for multiple testing. Pathway topology analyses did not reveal statistically significant associations between recurrence and alterations in metabolic pathways (e.g., sphingolipid metabolism p = 0.04, pFDR = 1.00). To conclude, we did not observe statistically significant associations between metabolites and CRC recurrence using a well-established metabolomics assay. The observed results require follow-up in larger studies.

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.

Objectives This study aims to evaluate the medium to long-term (1–12 years) effectiveness of two-duct ligation (2-DL) in patients with nonprogressive neurodisabilities. Methods Main outcomes included a Visual Analogue Scale (VAS), Drooling Severity (DS) and Drooling Frequency (DF), collected at baseline, 32 weeks postintervention and 1–12 years postintervention. Secondary outcomes were adverse events (AEs), and satisfaction. Results Forty-two patients were analyzed (mean age 17 years, mean baseline VAS 82). VAS decreased significantly from baseline to long-term (n = 30. Mean difference −36.5, CI -47.0 to −26.0, p ≤ 0.001; −26.1, CI -36.2 to −15.9, p ≤ 0.001). However, long-term VAS significantly increased compared to VAS at 32 weeks (+10.4, CI 1.0–19.8, p = 0.031). Out of 42 patients, 64% would recommend 2-DL to peers. Conclusion There is a significant subjective 2-DL effect on drooling severity in the medium to long-term as reported by patients and caregivers, but there is also a certain degree of recurrence in this time span, and 33% of the patients required subsequent treatment. However, the majority of patients and/or caregivers would recommend 2-DL to peers.

Aim To compare the effect of bilateral submandibular duct ligation and botulinum neurotoxin A (BoNT‐A) on drooling severity and its impact on daily life and care in children and adolescents with moderate‐to‐severe drooling. Method This was a randomized, interventional, controlled trial in which 53 children and adolescents (31 males, 22 females, mean age 11y, range 8–22y, SD 2y 10mo) with cerebral palsy (58.5%) or other non‐progressive developmental disorders (41.5%) were randomized to BoNT‐A (n=26) or bilateral submandibular duct ligation (n=27). A parent questionnaire on the severity of drooling in specific positions and daily activities and the impact of drooling on daily life and care was filled out at baseline and 8 and 32 weeks posttreatment. Results Both BoNT‐A and bilateral submandibular duct ligation had a positive effect on daily care, damage to electronic equipment and/or furniture, social interactions, and self‐esteem. However, bilateral submandibular duct ligation had a significant greater and longer‐lasting short‐ (8wks) and medium‐term (32wks) effect on daily care, reducing damage to electronic devices, and improving social interactions and satisfaction with life in general. Interpretation This randomized controlled trial confirms reduced drooling by both BoNT‐A and bilateral submandibular duct ligation, but provides new evidence on improved well‐being through a reduction in drooling. Even though there is a greater risk of complications and morbidity after bilateral submandibular duct ligation, compared to BoNT‐A there was a significantly greater and longer‐lasting positive effect on most outcomes. What this paper adds Bilateral botulinum neurotoxin A (BoNT‐A) and submandibular duct ligation had a positive effect on the well‐being of individuals with moderate‐to‐severe drooling.Bilateral submandibular duct ligation had a greater effect on the impact of drooling during daily care than BoNT‐A.Bilateral submandibular duct ligation reduced damage to electronic devices and improved social interactions and satisfaction with life., What this paper adds Bilateral botulinum neurotoxin A (BoNT‐A) and submandibular duct ligation had a positive effect on the well‐being of individuals with moderate‐to‐severe drooling.Bilateral submandibular duct ligation had a greater effect on the impact of drooling during daily care than BoNT‐A.Bilateral submandibular duct ligation reduced damage to electronic devices and improved social interactions and satisfaction with life. This article's abstract has been translated into Spanish and Portuguese. Follow the links from the abstract to view the translations.

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.

Purpose Persistent fatigue among colorectal cancer (CRC) patients might be associated with unfavorable body composition, but data are sparse and inconsistent. We studied how skeletal muscle index (SMI), skeletal muscle radiodensity (SMR), visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) at diagnosis are associated with fatigue up to 24 months post-diagnosis in stage I–III CRC patients. Methods SMI, SMR, VAT, and SAT were assessed among 646 CRC patients using pre-treatment computed tomography images. Fatigue at diagnosis, at 6, and 24 months post-diagnosis was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire. The association of SMI, SMR, VAT, and SAT with fatigue (yes/no) was assessed using confounder-adjusted restricted cubic spline analyses. Results Prevalence of fatigue at diagnosis was 18%, at 6 months 25%, and at 24 months 12%. At diagnosis, a significant (p = 0.01) non-linear association of higher levels of SAT with higher prevalence of fatigue was observed. Lower levels of SMR were linearly associated with higher prevalence of fatigue at 6 months post-diagnosis (overall association p = 0.02). None of the body composition parameters were significantly associated with fatigue at 24 months. Conclusion Having more SAT was associated with more fatigue at diagnosis, while low levels of SMR were associated with more fatigue at 6 months post-diagnosis. Implications for Cancer Survivors Our results suggest that it may be interesting to investigate whether interventions that aim to increase SMR around the time of diagnosis may help to lower fatigue. However, more knowledge is needed to understand the mechanisms behind the association of SMR with fatigue.

Simple Summary 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 what kind of lifestyle behaviors are important for prognosis after a cancer diagnosis. In an observational study among 1180 colorectal cancer patients, we aimed to identify which lifestyle behaviors were most important regarding cancer recurrence and all-cause mortality. We simultaneously evaluated lifestyle behaviors, related to diet, physical activity, adiposity, alcohol use, and smoking. 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 important lifestyle behaviors. Our exploratory findings identified several lifestyle behaviors related to prognosis after colorectal cancer. These findings should be confirmed in other observational studies before they can be translated into clinical practice. Abstract 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.

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.

Contains fulltext : 220748.pdf (Publisher’s version ) (Open Access) PURPOSE: Body weight and body composition may change during and after adjuvant or neo-adjuvant chemotherapy for breast cancer. However, most studies did not include a comparison group of women without cancer, thus could not assess whether observed changes differed from age-related fluctuations in body weight and body composition over time. We assessed changes in body composition during and after chemotherapy in breast cancer patients compared with age-matched women not diagnosed with cancer. METHODS: We recruited 181 patients with stage I-IIIb breast cancer and 180 women without cancer. In patients, we assessed body composition using a dual-energy X-ray scan before start of chemotherapy (T1), shortly after chemotherapy (T2), and 6 months after chemotherapy (T3); for the comparison group, the corresponding time points were recruitment (T1) and 6 (T2) and 12 (T3) months. RESULTS: Fifteen percent of patients and 8% of the comparison group gained at least 5% in body weight between T1 and T3. Among the comparison group, no statistically significant changes in body weight, or body composition were observed over time. Body weight of patients significantly increased from baseline (72.1 kg +/- 0.4 kg) to T2 (73.3 kg +/- 0.4 kg), but decreased to 73.0 kg +/- 0.4 kg after chemotherapy (T3). Lean mass of patients significantly increased from 43.1 kg +/- 0.5 kg at baseline to 44.0 kg +/- 0.5 kg at T2, but returned to 43.1 kg +/- 0.5 kg at T3. There were no differential changes in fat mass over time between patients and the comparison group. CONCLUSIONS: Changes in body weight and body composition during and after chemotherapy for early stage breast cancer were modest, and did not differ substantially from changes in body weight and body composition among women without cancer.

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&ndash, 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, TNF&alpha, 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, &beta, &minus, 2.22, 95%CI &minus, 3.65, 0.78). In the population of analysis for the mediation analyses (n = 551), the total association between lifestyle and fatigue was (&beta, 2.17, 95% CI &minus, 4.60, 0.25). A statistically significant indirect association via inflammation was observed (&beta, 0.97, 95% CI &minus, 1.92, 0.21), explaining 45% of the total association between lifestyle and fatigue (&minus, 0.97/&minus, 2.17 &times, 100). Thus, inflammation is probably one of the underlying mechanisms linking lifestyle to fatigue.

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 (β −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 (β −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.

Contains fulltext : 218303.pdf (Publisher’s version ) (Open Access) 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 mug/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.

Contains fulltext : 225116.pdf (Publisher’s version ) (Open Access) Bordetella pertussis vaccine escape mutants that lack expression of the pertussis antigen pertactin (Prn) have emerged in vaccinated populations in the last 10-20 years. Additionally, clinical isolates lacking another acellular pertussis (aP) vaccine component, filamentous hemagglutinin (FHA), have been found sporadically. Here, we show that both whole-cell pertussis (wP) and aP vaccines induced protection in the lungs of mice, but that the wP vaccine was more effective in nasal clearance. Importantly, bacterial populations isolated from the lungs shifted to an FHA-negative phenotype due to frameshift mutations in the fhaB gene. Loss of FHA expression was strongly selected for in Prn-deficient strains in the lungs following aP but not wP vaccination. The combined loss of Prn and FHA led to complete abrogation of bacterial surface binding by aP-induced serum antibodies. This study demonstrates vaccine- and anatomical site-dependent adaptation of B. pertussis and has major implications for the design of improved pertussis vaccines.

Purpose: Previous studies have shown that > 50% of colorectal cancer (CRC) patients treated with adjuvant chemotherapy gain weight after diagnosis. This may affect long-term health. Therefore, prevention of weight gain has been incorporated in oncological guidelines for CRC with a focus on patients that undergo adjuvant chemotherapy treatment. It is, however, unknown how changes in weight after diagnosis relate to weight before diagnosis and whether weight changes from pre-to-post diagnosis are restricted to chemotherapy treatment. We therefore examined pre-to-post diagnosis weight trajectories and compared them between those treated with and without adjuvant chemotherapy. Methods: We included 1184 patients diagnosed with stages I–III CRC between 2010 and 2015 from an ongoing observational prospective study. At diagnosis, patients reported current weight and usual weight 2 years before diagnosis. In the 2 years following diagnosis, weight was self-reported repeatedly. We used linear mixed models to analyse weight trajectories. Results: Mean pre-to-post diagnosis weight change was −0.8 (95% CI −1.1, −0.4) kg. Post-diagnosis weight gain was + 3.5 (95% CI 2.7, 4.3) kg in patients who had lost ≥ 5% weight before diagnosis, while on average clinically relevant weight gain after diagnosis was absent in the groups without pre-diagnosis weight loss. Pre-to-post diagnosis weight change was similar in patients treated with (−0.1 kg (95%CI −0.8, 0.6)) and without adjuvant chemotherapy (−0.9 kg (95%CI −1.4, −0.5)). Conclusions: Overall, hardly any pre-to-post diagnosis weight change was observed among CRC patients, because post-diagnosis weight gain was mainly observed in patients who lost weight before diagnosis. This was observed independent of treatment with adjuvant chemotherapy.

To gain a comprehensive understanding of the multidimensional complex systems structure of the stress response and related health outcomes, we utilized network analysis in a sample of 328 healthy participants in two steps. In a first step, we focused on associations between measures of basal hypothalamic-pituitary-adrenal axis functioning and subjective stress perceptions. In a second step, we linked these diverse stress-related measures to biomarkers and self-reports of health and sleep. Overall, measures clustered depending on their method of assessment, with high correlations between different saliva-based indices of diurnal cortisol regulation, between cortisol and cortisone levels in hair, between different biological health indicators (systemic inflammatory activity and body mass index), between state (experience sampling) and trait (questionnaire-based) self-reports of stress and wellbeing, and between different self-reports of sleep. Bridges between clusters suggested that if individuals perceive stress throughout their daily lives this is reflected in their total salivary cortisol output possibly contributing to long-term cortisol accumulation in hair. Likewise, earlier awakening time may contribute to cortisol accumulation in hair via an influence on awakening cortisol processes. Our results show that while meaningful connections between measures exist, stress is a highly complex construct composed of numerous aspects. We argue that network analysis is an integrative statistical approach to address the multidimensionality of the stress response and its effects on the brain and body. This may help uncover pathways to stress-related disease and serve to identify starting points for prevention and therapeutic intervention.

The aging process is associated with diminished colonic health. In this study, we applied an integrative approach to reveal potential interactions between determinants of colonic health in aging C57BL/6J mice. Analysis of gut microbiota composition revealed an enrichment of various potential pathobionts, including Desulfovibrio spp., and a decline of the health-promoting Akkermansia spp. and Lactobacillus spp. during aging. Intraluminal concentrations of various metabolites varied between ages and we found evidence for an increased gut permeability at higher age. Colonic gene expression analysis suggested that during the early phase of aging (between 6 and 12 months), expression of genes involved in epithelial-to-mesenchymal transition and (re)organization of the extracellular matrix were increased. Differential expression of these genes was strongly correlated with Bifidobacterium spp. During the later phase of aging (between 12 and 28 months), gene expression profiles pointed towards a diminished antimicrobial defense and were correlated with an uncultured Gastranaerophilales spp. This study demonstrates that aging is associated with pronounced changes in gut microbiota composition and colonic gene expression. Furthermore, the strong correlations between specific bacterial genera and host gene expression may imply that orchestrated interactions take place in the vicinity of the colonic wall and potentially mediate colonic health during aging.

The literature concerning biological influences on positive social behavior shows that, in nonthreatening contexts, tonic oxytocin (OT) and respiratory sinus arrhythmia (RSA) each predict positive, affiliative behaviors toward certain others and are associated with positive health outcomes. The purpose of this investigation was to determine the degree to which the positive affiliative correlates of OT and RSA can be distinguished when observed at the level of everyday life events. A sample of midlife adults (N = 73) provided tonic indices of these biological characteristics, as well as perceptions of a variety of common life events alongside reports of their emotions during those events. OT and RSA each independently moderated the link between perceived event sociality and positive emotions, whereas only RSA predicted the probability of being with other people during an event. These findings suggest that OT and RSA may each be linked to positive social experiences in complementary yet distinct ways. (PsycINFO Database Record

// Dieuwertje E.G. Kok 1 , Lambertus A.L.M. Kiemeney 2, 3 , Gerald W. Verhaegh 3 , Jack A. Schalken 3 , Emile N.J.T. van Lin 4 , J.P. Michiel Sedelaar 3 , J. Alfred Witjes 3 , Christina A. Hulsbergen - van de Kaa 5 , Pieter van ’t Veer 1 , Ellen Kampman 1, 2 , Lydia A. Afman 1 1 Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands 2 Department for Health Evidence, Radboud University Medical Center, Nijmegen, The Netherlands 3 Department of Urology, Radboud university Medical Center, Nijmegen, The Netherlands 4 Strahlentherapie Bonn Rhein Sieg, Wesel, Germany 5 Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands Correspondence to: Lydia A. Afman, email: lydia.afman@wur.nl Keywords: selenium, prostatic neoplasms, gene expression, microarray, EMT Received: February 06, 2016 Accepted: December 16, 2016 Published: January 06, 2017 ABSTRACT In parallel with the inconsistency in observational studies and chemoprevention trials, the mechanisms by which selenium affects prostate cancer risk have not been elucidated. We conducted a randomized, placebo-controlled trial to examine the effects of a short-term intervention with selenium on gene expression in non-malignant prostate tissue. Twenty-three men received 300 µg selenium per day in the form of selenized yeast (n=12) or a placebo (n=11) during 5 weeks. Prostate biopsies collected from the transition zone before and after intervention were analysed for 15 participants (n=8 selenium, n=7 placebo). Pathway analyses revealed that the intervention with selenium was associated with down-regulated expression of genes involved in cellular migration, invasion, remodeling and immune responses. Specifically, expression of well-established epithelial markers, such as E-cadherin and epithelial cell adhesion molecule EPCAM, was up-regulated, while the mesenchymal markers vimentin and fibronectin were down-regulated after intervention with selenium. This implies an inhibitory effect of selenium on the epithelial-to-mesenchymal transition (EMT). Moreover, selenium was associated with down-regulated expression of genes involved in wound healing and inflammation; processes which are both related to EMT. In conclusion, our explorative data showed that selenium affected expression of genes implicated in EMT in the transition zone of the prostate.

Contains fulltext : 205420.pdf (Publisher’s version ) (Open Access) Cancer treatments, toxicities and their effects on lifestyle, may impact levels of vitamin D. The aim of this study was to determine serum 25-hydroxyvitamin D3 (25(OH)D3) levels before, directly after and 6 months after chemotherapy in breast cancer patients (n = 95), and a comparison group of women (n = 52) not diagnosed with cancer. Changes in 25(OH)D3 levels over time were compared using linear mixed models adjusted for age and season of blood sampling. Before start of chemotherapy, 25(OH)D3 levels were lower in patients (estimated marginal mean 55.8 nmol/L, 95% confidence interval (95%CI) 51.2-60.4) compared to the comparison group (67.2 nmol/L, 95%CI 61.1-73.3, P = 0.003). Directly after chemotherapy, 25(OH)D3 levels were slightly decreased (-5.1 nmol/L, 95%CI -10.7-0.5, P = 0.082), but ended up higher 6 months after chemotherapy (10.9 nmol/L, 95%CI 5.5-16.4, P < 0.001) compared to pre-chemotherapy values. In women without cancer, 25(OH)D3 levels remained stable throughout the study. Use of dietary supplements did not explain recovery of 25(OH)D3 levels after chemotherapy. We reported lower 25(OH)D3 levels in breast cancer patients, which decreased during chemotherapy, but recovered to levels observed in women without cancer within 6 months after chemotherapy. Suboptimal 25(OH)D3 levels in the majority of the participants highlight the relevance of monitoring in this vulnerable population.

Purpose Initial dose of chemotherapy is planned based on body surface area, which does not take body composition into account. We studied the association between fat mass (kg and relative to total body weight) as well as lean mass (kg and relative to total body weight) and toxicity-induced modifications of treatment in breast cancer patients receiving chemotherapy. Methods In an observational study among 172 breast cancer patients (stage I–IIIB) in the Netherlands, we assessed body composition using dual-energy X-ray scans. Information on toxicity-induced modifications of treatment, defined as dose reductions, cycle delays, regimen switches, or premature termination of chemotherapy, was abstracted from medical records. Adjusted hazard ratios and 95% confidence intervals (95% CI) were calculated to assess associations between body composition and the risk of toxicity-induced modifications of treatment. Results In total, 95 out of 172 (55%) patients experienced toxicity-induced modifications of treatment. Higher absolute and relative fat mass were associated with higher risk of these modifications (HR 1.14 per 5 kg; 95% CI 1.04–1.25 and HR 1.21 per 5%; 95% CI 1.05–1.38, respectively). A higher relative lean mass was associated with a lower risk of modifications (HR 0.83 per 5%; 95% CI 0.72–0.96). There was no association between absolute lean mass and risk of toxicity-induced modifications of treatment. Conclusions A higher absolute and a higher relative fat mass was associated with an increased risk of toxicity-induced modifications of treatment. Absolute lean mass was not associated with risk of these treatment modifications, while higher relative lean mass associated with lower risk of modifications. These data suggest that total fat mass importantly determines the risk of toxicities during chemotherapy in breast cancer patients. Electronic supplementary material The online version of this article (10.1007/s10549-018-5014-5) contains supplementary material, which is available to authorized users.