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Background:Physical activity and obesity are well-established factors of colorectal cancer risk and prognosis. Here, we investigate associations of individual and combined physical activity and body mass index (BMI) groups with proinflammatory biomarkers in colorectal cancer patients.Methods:Self-reported physical activity levels were classified as “active” (≥8.75 MET-hours/week) versus “inactive” (n = 579 stage I–IV colorectal cancer patients enrolled in the ColoCare Study. BMI [normal weight (≥18.5–2), overweight (≥25–2), and obese (≥30 kg/m2)] was abstracted from medical records. Patients were classified into four combinations of physical activity levels and BMI. Biomarkers [C-reactive protein (CRP), SAA, IL6, IL8, and TNFα] in presurgery serum samples were measured using the Mesoscale Discovery Platform. Regression models were used to compute relative percent differences in biomarker levels by physical activity and BMI groups.Results:“Inactive” patients had non-statistically significant higher IL6 levels compared with “active” patients (+36%, P = 0.10). “Obese” patients had 88% and 17% higher CRP and TNFα levels compared with “normal weight” patients (P = 0.03 and 0.02, respectively). Highest CRP levels were observed among “overweight or obese/inactive” compared with “normal weight/active” patients (P = 0.03).Conclusions:We provide evidence of associations between individual and combined physical activity and BMI groups with proinflammatory biomarkers. Although BMI was identified as the key driver of inflammation, biomarker levels were higher among “inactive” patients across BMI groups.Impact:This is the largest study in colorectal cancer patients investigating associations of energy balance components with inflammatory biomarkers. Our results suggest that physical activity may reduce obesity-induced inflammation in colorectal cancer patients and support the design of randomized controlled trials testing this hypothesis.

Supplementary Data from Associations of Individual and Combined Physical Activity and Body Mass Index Groups with Proinflammatory Biomarkers among Colorectal Cancer Patients

Background: Cell-to-cell adhesion and angiogenesis are hallmarks of cancer. No studies have examined associations of adhesion molecules and angiogenesis biomarkers with clinical outcomes in colorectal cancer. Methods: In presurgery serum from n = 426 patients with colorectal cancer (stage I–III), we investigated associations of CRP, SAA, adhesion molecules (sICAM-1, sVCAM-1), and angiogenesis markers (VEGF-A and VEGF-D) with overall survival (OS), disease-free survival (DFS), and risk of recurrence. We computed HRs and 95% confidence intervals; adjusted for age, sex, BMI, stage, site, and study site, stratified by tumor site in exploratory analyses. Results: N = 65 (15%) were deceased, and 39 patients (14%) had a recurrence after a median follow-up of 31 months. We observed significant associations of biomarkers with OS, DFS, and risk of recurrence on a continuous scale and comparing top to bottom tertile, with HRs ranging between 1.19 and 13.92. CRP was associated with risk of death and recurrence in patients in the top tertile compared with patients in the bottom tertile, for example, risk of recurrence HRQ3-Q1: 13.92 (1.72–112.56). Significant heterogeneity between biomarkers and clinical outcomes was observed in stratified analysis by tumor site for CRP, SAA, sICAM-1, sVCAM-1, and VEGF-D. VEGF-D was associated with a 3-fold increase in risk of death for rectal cancer (HRlog2: 3.26; 95% CI, 1.58–6.70) compared with no association for colon cancer (HRlog2: 0.78; 95% CI, 0.35–1.73; Pheterogenity = 0.01). Conclusions: Adhesion molecules and angiogenesis biomarkers are independent prognostic markers for colorectal cancer, with differences by tumor site. Impact: There is need for tailored treatment for colon and rectal cancer.

PDF file - 55K, Primer sequences used for qRT-PCR.

PDF file - 55K, Expression fold-change of EMT-associated genes and microRNAs between the four compartments liver (L). liver invasion front (LIF). tumor invasion frot (TIF) and tumor center (Tc). All samples were normalized to 18s expression and fold change expression was calculated according to the 2-��ct method as described previously (15). P-Values (P) were assessed by using the Wilcoxon signed-rank test. (LIF vs. L: expression fold-change of target gene in liver invasion front compared to liver. LIF vs TIF: expression fold-change of target gene in liver invasion front compared to tumor invasion front. LIF vs Tc: expression fold-change of target gene in liver invasion front compared to tumor center. TIF vs L: expression fold-change of target gene in tumor invasion front compared to liver. TIF vs Tc: expression fold-change of target gene in tumor invasion front compared to tumor center. L vs Tc: expression fold-change of target gene in liver compared to tumor center).

Purpose:To investigate the clinical relevance of macrophages in liver metastasis of colorectal cancer and their influence on angiogenesis and patient survival. Moreover to evaluate specific blood monocytes as markers of disease recurrence.Experimental design: In a mouse model with spontaneous liver metastasis, the angiogenic characteristics of tumor- and metastasis (MAM)-associated macrophages were evaluated. Macrophages and the vasculature from 130 primary tumor (pTU) and 123 patients with liver metastasis were assessed. In vivo and in human samples, the clinical relevance of macrophage VEGFR1 expression was analyzed. Blood samples from patients (n = 157, 80 pTU and 77 liver metastasis) were analyzed for assessing VEGFR1-positive (VEGFR1+) cells as suitable biomarkers of disease recurrence.Results:The number of macrophages positively correlated with vascularization in metastasis. Both in the murine model as well as in primary isolated human cells, a subpopulation of MAMs expressing VEGFR1 were found highly angiogenic. While VEGFR1 expression in pTU patients did not predict prognosis; high percentage of VEGFR1+ cells in liver metastasis was associated with worse patient outcome. Interestingly, VEGFR1+-circulating monocytes in blood samples from patients with liver metastasis not only predicted progression but also site of recurrence.Conclusions:Our findings identify a new subset of proangiogenic VEGFR1+ MAMs in colorectal cancer that support metastatic growth and may become a liquid biomarker to predict disease recurrence in the liver.

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Solid tumors are rich ecosystems of numerous different cell types whose interactions lead to immune escape and resistance to immunotherapy in virtually all patients with metastatic cancer. Here, we have developed a 3D model of human solid tumor tissue that includes tumor cells, fibroblasts, and myeloid and lymphoid immune cells and can represent over a million cells over clinically relevant timeframes. This model accurately reproduced key features of the tissue architecture of human colorectal cancer and could be informed by individual patient data, yielding in silico tumor explants. Stratification of growth kinetics of these explants corresponded to significantly different overall survival in a cohort of patients with metastatic colorectal cancer. We used the model to simulate the effect of chemotherapy, immunotherapies, and cell migration inhibitors alone and in combination. We classified tumors according to tumor and host characteristics, showing that optimal treatment strategies markedly differed between these classes. This platform can complement other patient-specific ex vivo models and can be used for high-throughput screening of combinatorial immunotherapies.Significance: This patient-informed in silico tumor growth model allows testing of different cancer treatment strategies and immunotherapies on a cell/tissue level in a clinically relevant scenario. Cancer Res; 78(17); 5155–63. ©2018 AACR.

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Detailed information on the procedure of fitting the mathematical model to clinical data as well as details on treatment simulation.

Purpose: Epithelial-to-mesenchymal transition (EMT) plays a pivotal role in tumor invasion and dissemination. EMT occurs predominantly at the tumor edge where it is induced by cytokines, the extracellular matrix environment, or hypoxia. In the tumor cell, it is further mediated by several transcription factors and microRNAs. The aim of this study was to explore the expression of EMT-associated genes at the invasive front in colorectal cancer and to evaluate their prognostic significance.Experimental Design: We evaluated the expression of 13 EMT-associated genes at the invasion front of 30 colorectal liver metastases by quantitative real-time PCR. Immunostaining against zinc finger E-box–binding homeobox 2 (ZEB2) was carried out on 175 primary colorectal cancer specimens and 30 colorectal liver metastases and correlated to clinical and histopathologic data. DLD-1 cells were transfected with siRNA and subjected to migration and invasion assays.Results: Gene expression analysis and immunohistochemistry showed an upregulation of ZEB2 at the invasion front in primary colorectal cancer and liver metastases. Overexpression of ZEB2 at the invasion front correlated significantly with tumor stage in primary colorectal cancer. Moreover, univariate and multivariate analysis revealed overexpression of ZEB2 at the invasion front as an independent prognostic marker for cancer-specific survival. Downregulation of ZEB2 by siRNA decreased the migration and invasion capacity of DLD-1 cells in vitro.Conclusions: Overexpression of ZEB2 at the invasion front correlates with tumor progression and predicts cancer-specific survival in primary colorectal cancer. Therefore, ZEB2 may be interesting as biomarker and potential target for treatment of colorectal cancer. Clin Cancer Res; 17(24); 7654–63. ©2011 AACR.

Despite the fact that the local immunological microenvironment shapes the prognosis of colorectal cancer, immunotherapy has shown no benefit for the vast majority of colorectal cancer patients. A better understanding of the complex immunological interplay within the microenvironment is required. In this study, we utilized wet lab migration experiments and quantitative histological data of human colorectal cancer tissue samples (n = 20) including tumor cells, lymphocytes, stroma, and necrosis to generate a multiagent spatial model. The resulting data accurately reflected a wide range of situations of successful and failed immune surveillance. Validation of simulated tissue outcomes on an independent set of human colorectal cancer specimens (n = 37) revealed the model recapitulated the spatial layout typically found in human tumors. Stroma slowed down tumor growth in a lymphocyte-deprived environment but promoted immune escape in a lymphocyte-enriched environment. A subgroup of tumors with less stroma and high numbers of immune cells showed high rates of tumor control. These findings were validated using data from colorectal cancer patients (n = 261). Low-density stroma and high lymphocyte levels showed increased overall survival (hazard ratio 0.322, P = 0.0219) as compared with high stroma and high lymphocyte levels. To guide immunotherapy in colorectal cancer, simulation of immunotherapy in preestablished tumors showed that a complex landscape with optimal stroma permeabilization and immune cell activation is able to markedly increase therapy response in silico. These results can help guide the rational design of complex therapeutic interventions, which target the colorectal cancer microenvironment. Cancer Res; 77(22); 6442–52. ©2017 AACR.

Supplementary methods, tables and supplementary figure legends Table S1. Patient characteristics. Table S2. Kind of neo-adjuvant therapy from LM patients included in the analysis of blood samples by flow cytometry. Table S3. Primer list used for qRT-PCR. Table S4. Association of circulating CD11b+ CD68+ VEGFR1+ cells with clinicopathologic variables in patients with liver metastasis of colorectal cancer. Table S5. Univariate analysis of factors associated with progression-free survival in patients with liver metastasis of CRC. Table S6. Multivariate analysis of factors associated with circulating VEGFR1+ macrophages and progression-free survival in LM patients.

This file contains all supplementary Tables and Figures. Supplementary Tables show detailed information on the model parameters and on the patient samples that were used in this study. Supplementary Figures show additional details on the model calibration process and on the model behavior and resulting phenotypes.

Background:Patients with colorectal cancer commonly suffer from complex psychological distress. Elevated distress may be linked to systemic biomarkers. We investigated associations of biomarkers of inflammation and angiogenesis with cancer-related distress (CTXD) score.Methods:N = 315 patients (stage I–IV) from 2 centers of the ColoCare Study were included: Huntsman Cancer Institute and University of Heidelberg. Biomarkers (e.g., IL6, VEGF-A, VEGF-D) were measured in serum collected pre-surgery and 12 months thereafter. The CTXD overall score and 4 subscales were collected 12 months after surgery and dichotomized to investigate biomarkers as predictors of distress 12 months after surgery; adjusted for age, sex, body mass index, tumor stage, center, and baseline levels of biomarkers.Results:Doubling of IL6 predicted future increased risk of overall distress [odds ratio (OR), 1.20; 95% confidence interval (CI), 1.02–1.41; P = 0.03]. VEGF-A–predicted future increased risk of high family strain (VEGF-A: OR, 1.21; 95% CI, 1.01–1.44; P = 0.04) and VEGF-D was associated with medical and financial demands (OR, 1.34; 95% CI, 1.01–1.74; P = 0.03).Conclusions:This is the first study to show that systemic biomarkers are significantly associated with future CTXD score. Distress was not measured at baseline; we cannot rule out ongoing associations of inflammation and distress throughout treatment versus a direct effect of inflammation on distress. Nonetheless, these data add to evidence that biobehavioral processes interact and that systemic biomarkers are associated with cancer-related distress one year after surgery.Impact:Exercise and diet interventions that lower systemic cytokine levels may impact longer-term CTXD score and improve quality of life of patients with colorectal cancer.

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.

Background: Physical activity and obesity are well-established factors of colorectal cancer risk and prognosis. Here, we investigate associations of individual and combined physical activity and body mass index (BMI) groups with proinflammatory biomarkers in colorectal cancer patients. Methods: Self-reported physical activity levels were classified as “active” (≥8.75 MET-hours/week) versus “inactive” ( Results: “Inactive” patients had non-statistically significant higher IL6 levels compared with “active” patients (+36%, P = 0.10). “Obese” patients had 88% and 17% higher CRP and TNFα levels compared with “normal weight” patients (P = 0.03 and 0.02, respectively). Highest CRP levels were observed among “overweight or obese/inactive” compared with “normal weight/active” patients (P = 0.03). Conclusions: We provide evidence of associations between individual and combined physical activity and BMI groups with proinflammatory biomarkers. Although BMI was identified as the key driver of inflammation, biomarker levels were higher among “inactive” patients across BMI groups. Impact: This is the largest study in colorectal cancer patients investigating associations of energy balance components with inflammatory biomarkers. Our results suggest that physical activity may reduce obesity-induced inflammation in colorectal cancer patients and support the design of randomized controlled trials testing this hypothesis.

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: High numbers of lymphocytes in tumor tissue, including T regulatory cells (Treg), have been associated with better colorectal cancer survival. Tregs, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and therefore variants in genes related to Treg differentiation and function could be associated with colorectal cancer prognosis. Methods: In a prospective German cohort of 3,593 colorectal cancer patients, we assessed the association of 771 single-nucleotide polymorphisms (SNP) in 58 Treg-related genes with overall and colorectal cancer–specific survival using Cox regression models. Effect modification by microsatellite instability (MSI) status was also investigated because tumors with MSI show greater lymphocytic infiltration and have been associated with better prognosis. Replication of significant results was attempted in 2,047 colorectal cancer patients of the International Survival Analysis in Colorectal Cancer Consortium (ISACC). Results: A significant association of the TGFBR3 SNP rs7524066 with more favorable colorectal cancer–specific survival [hazard ratio (HR) per minor allele: 0.83; 95% confidence interval (CI), 0.74–0.94; P value: 0.0033] was replicated in ISACC (HR: 0.82; 95% CI, 0.68–0.98; P value: 0.03). Suggestive evidence for association was found with two IL7 SNPs, rs16906568 and rs7845577. Thirteen SNPs with differential associations with overall survival according to MSI in the discovery analysis were not confirmed. Conclusions: Common genetic variation in the Treg pathway implicating genes such as TGFBR3 and IL7 was shown to be associated with prognosis of colorectal cancer patients. Impact: The implicated genes warrant further investigation.

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

Background Based on two benchmark studies perioperative chemotherapy (CTx) has become standard treatment for locally advanced esophagogastric adenocarcinoma (EGA) in Europe. However, only half of the patients in both studies actually received postoperative CTx (aCTx). Thus, we evaluated the prognostic impact of preoperative CTx (nCTx) and aCTx combined versus nCTx alone. Furthermore, we aimed to identify subgroups potentially beneficial of aCTx and factors associated with its non-administration. Methods We retrospectively analyzed 299 consecutive patients with EGA, who underwent complete resection (all M0, R0) after nCTx in our institution and were eligible for aCTx. Patients with and without aCTx were compared regarding clinicopathological data, treatment, morbidity, and long-term prognosis. Results 129 patients (43.1%) did not receive aCTx. Administration of aCTx did not significantly improve overall (OS) and recurrence free survival (RFS) (median OS: 78.2 months vs. not reached, p = 0.331; RFS: 43.3 vs. 41.1 months, p = 0.118), but was an independent positive predictor of RFS (HR 1.6 95%CI 1.1–2.5, p = 0.024). aCTx improved RFS in non-intestinal tumors (p = 0.023) and patients receiving FLOT regimen (p = 0.038). By logistic regression analysis factors predictive of non-administration of aCTx were older age (>65 years: OR 3.2, p = 0.028), longer hospital stay (15–28 days: OR 2.6, p = 0.001; >28 days: OR 5.2, p Conclusion Advanced age, histopathologic non-response, and prolonged convalescence due to postoperative morbidity lead to omission of aCTx. However, this study could not provide evidence to support the beneficial role of aCTx in perioperative chemotherapy regimens for a selected patient collective with EGA and excellent prognosis.

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.

Purpose Anastomotic leakage constitutes a dreaded complication after colorectal surgery, leading to increased morbidity and mortality as well as prolonged hospitalization. Most leakages become clinically apparent about 8 days after surgery; however, early detection is quintessential to reduce complications and to improve patients’ outcome. We therefore investigated the significance of specific protein expression profiles as putative biomarkers, indicating anastomotic leakage. Methods In this single-center prospective cohort study serum and peritoneal fluid samples—from routinely intraoperatively inserted drainages—of colorectal cancer patients were collected 3 days after colorectal resection. Twenty patients without anastomotic leakage and 18 patients with an anastomotic leakage and without other complications were included. Protein expression of seven inflammatory markers in serum and peritoneal fluid was assessed by multiplex ELISA and correlated with patients’ clinical data. Results Monocyte chemoattractant protein 2 (CCL8/MCP-2), leukemia-inhibiting factor (LIF), and epithelial-derived neutrophil-activating protein (CXCL5/ENA-78) were significantly elevated in peritoneal fluid but not in serum samples from patients subsequently developing anastomotic leakage after colorectal surgery. No expressional differences could be found between grade B and grade C anastomotic leakages. Conclusion Measurement 3 days after surgery revealed altered protein expression patterns of the inflammatory markers CCL8/MCP2, LIF, and CXCL5/ENA-78 in peritoneal fluid from patients developing anastomotic leakage after colorectal surgery. Further studies with a larger patient cohort with inclusion of different variables are needed to evaluate their potential as predictive biomarkers for anastomotic leakage.

PURPOSE: Cancer-related distress is known to persist long after completion of treatment. Factors related to distress are largely unexplored in colorectal cancer (CRC) survivors. We examined changes over time and risk factors for distress in CRC patients over the first year after surgery. METHODS: We included 212 CRC patients with data at 6 and 12 months post-surgery from the ColoCare Study in Heidelberg, Germany. Sociodemographic and lifestyle factors, social support and health-related quality of life (HrQOL) prior to surgery were evaluated as predictors of cancer-related distress. Distress was measured with the Cancer and Treatment Distress instrument (CTXD). Linear regression analyses examined associations between risk factors and distress. RESULTS: Distress subscale scores varied significantly over time: health burden subscale score increased (P < .001), while finances (P = .004), medical demands (P < .001), and identity (P < .001) subscale scores decreased over time. Uncertainty and family strain subscale scores did not change. Younger age, lower income, advanced tumor stage, poorer social support, and poorer baseline HrQOL predicted higher level distress at 6 and 12 months. CONCLUSIONS: Cancer-related distress continues unresolved after surgery. Although some risk factors are difficult to alter, those at highest risk can be identified earlier for possible preventive strategies. IMPLICATIONS FOR CANCER SURVIVORS: Screening for risk factors pre-surgery would allow for targeted interventions including strategies to improve resources for those with low support, thereby reducing long-term distress in CRC survivors.

Anastomotic leakage is one of the most worrisome complications in colorectal surgery. An expert meeting was organized to discuss and find a consensus on various aspects of the surgical management of colorectal disease with a possible impact on anastomotic leakage. A three-step Delphi-method was used to find consensus recommendations. Strong consensus was achieved for the use of mechanical bowel preparation and oral antibiotics prior to colorectal resections, the abundance of non-selective NSAIDs, the preoperative treatment of severe iron deficiency anemia, and for attempting to improve the patients’ general performance in the case of frailty. Concerning technical aspects of rectal resection, there was a strong consensus in regard to routinely mobilizing the splenic flexure, to dividing the inferior mesenteric vein, and to using air leak tests to check anastomotic integrity. There was also a strong consensus on not to oversew the stapled anastomoses routinely, to use protective ileostomies for low rectal and intersphincteric, but not for high-rectal anastomoses. Furthermore, a consensus was reached in regard to using CT-scans with rectal contrast enema to evaluate suspected anastomotic leakage as well as measuring C-reactive protein routinely to monitor the postoperative course after colorectal resections. No consensus was found concerning the indication and technique for testing bowel perfusion, the routine use of endoscopy to check the integrity of the anastomosis, the placement of transanal drains for rectal anastomoses and the management of anastomotic leakage with peritonitis. Consensus could be found for several practice details in the perioperative management in colorectal surgery that might have an influence on anastomotic leakage.

Background: Xenobiotic-metabolizing enzymes (XME) play a critical role in the activation and detoxification of several carcinogens. However, the role of XMEs in colorectal carcinogenesis is unclear. Methods: We investigated the expression of XMEs in human colorectal tissues among patients with stage I–IV colorectal cancer (n = 71) from the ColoCare Study. Transcriptomic profiling using paired colorectal tumor and adjacent normal mucosa tissues of XMEs (GSTM1, GSTA1, UGT1A8, UGT1A10, CYP3A4, CYP2C9, GSTP1, and CYP2W1) by RNA microarray was compared using Wilcoxon rank-sum tests. We assessed associations between clinicopathologic, dietary, and lifestyle factors and XME expression with linear regression models. Results: GSTM1, GSTA1, UGT1A8, UGT1A10, and CYP3A4 were all statistically significantly downregulated in colorectal tumor relative to normal mucosa tissues (all P ≤ 0.03). Women had significantly higher expression of GSTM1 in normal tissues compared with men (β = 0.37, P = 0.02). By tumor site, CYP2C9 expression was lower in normal mucosa among patients with rectal cancer versus colon cancer cases (β = −0.21, P = 0.0005). Smokers demonstrated higher CYP2C9 expression levels in normal mucosa (β = 0.17, P = 0.02) when compared with nonsmokers. Individuals who used NSAIDs had higher GSTP1 tumor expression compared with non-NSAID users (β = 0.17, P = 0.03). Higher consumption of cooked vegetables (>1×/week) was associated with higher CYP3A4 expression in colorectal tumor tissues (β = 0.14, P = 0.007). Conclusions: XMEs have lower expression in colorectal tumor relative to normal mucosa tissues and may modify colorectal carcinogenesis via associations with clinicopathologic, lifestyle, and dietary factors. Impact: Better understanding into the role of drug-metabolizing enzymes in colorectal cancer may reveal biological differences that contribute to cancer development, as well as treatment response, leading to clinical implications in colorectal cancer prevention and management.

Early-onset colorectal cancer has been on the rise in Western populations. Here, we compare patient characteristics between those with early- (&lt, 50 years) vs. late-onset (≥50 years) disease in a large multinational cohort of colorectal cancer patients (n = 2193). We calculated descriptive statistics and assessed associations of clinicodemographic factors with age of onset using mutually-adjusted logistic regression models. Patients were on average 60 years old, with BMI of 29 kg/m2, 52% colon cancers, 21% early-onset, and presented with stage II or III (60%) disease. Early-onset patients presented with more advanced disease (stages III–IV: 63% vs. 51%, respectively), and received more neo and adjuvant treatment compared to late-onset patients, after controlling for stage (odds ratio (OR) (95% confidence interval (CI)) = 2.30 (1.82–3.83) and 2.00 (1.43–2.81), respectively). Early-onset rectal cancer patients across all stages more commonly received neoadjuvant treatment, even when not indicated as the standard of care, e.g., during stage I disease. The odds of early-onset disease were higher among never smokers and lower among overweight patients (1.55 (1.21–1.98) and 0.56 (0.41–0.76), respectively). Patients with early-onset colorectal cancer were more likely to be diagnosed with advanced stage disease, to have received systemic treatments regardless of stage at diagnosis, and were less likely to be ever smokers or overweight.