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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

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.

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.

Background: Granulin is a secreted, glycosylated peptide—originated by cleavage from a precursor protein—which is involved in cell growth, tumor invasion and angiogenesis. However, the specific prognostic impact of granulin in human colorectal cancer has only been studied to a limited extent. Thus, we wanted to assess the expression of granulin in colorectal cancer patients to evaluate its potential as a prognostic biomarker. Methods: Expressional differences of granulin in colorectal carcinoma tissue (n = 94) and corresponding healthy colon mucosa were assessed using qRT-PCR. Immunohistochemistry was performed in colorectal cancer specimens (n = 97), corresponding healthy mucosa (n = 47) and colorectal adenomas (n = 19). Subsequently, the results were correlated with histopathological and clinical patients’ data. HCT-116 cells were transfected with siRNA for invasion and migration assays. Results: Immunohistochemistry and qRT-PCR revealed tumoral over expression of granulin in colorectal cancer specimens compared to corresponding healthy colon mucosa and adenomas. Tumoral overexpression of granulin was associated with a significantly impaired overall survival. Moreover, downregulation of granulin by siRNA significantly diminished the invasive capacities of HCT-116 cells in vitro. Conclusion: Expression of granulin differs in colorectal cancer tissue, adenomas and healthy colon mucosa. Furthermore, granulin features invasive and migrative capabilities and overexpression of granulin correlates with a dismal prognosis. This reveals its potential as a prognostic biomarker and granulin could be a worthwhile molecular target for individualized anticancer therapy.

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.

To assess the putative impact of peridural analgesia on oncological outcome in patients undergoing resection of stages I–IV colon cancer. In a single-center study, 876 patients undergoing resection for primary colon cancer (AJCC stages I–IV) between 2001 and 2014 were analyzed. Mean follow-up of the entire cohort was 4.2 ± 3.5 years. Patients who did and did not receive peridural analgesia were compared using Cox regression and propensity score analyses. Overall, 208 patients (23.7%) received peridural analgesia. Patients’ characteristics were biased with regard to the use of peridural analgesia (propensity score 0.296 ± 0.129 vs. 0.219 ± 0.108, p

Purpose Smurf2 is a member of the homologous to E6-AP carboxyl terminus family of E3 ubiquitin ligases. Changes in their expression pattern are known to contribute to tumorigenesis. Smurf2 plays a decisive role in cell differentiation, proliferation, and migration and exhibits a dual role in cancer - functioning as both oncogene and tumor suppressor. Dysregulation of Smurf2 in different cancer types has been described, besides colorectal cancer (CRC). We therefore examined the expression and oncogenic potential of Smurf2 in human CRC patients. Materials and methods Expression levels of Smurf2 were analyzed via qRT-PCR in CRC specimens and healthy mucosa from 98 patients who had undergone surgery due to CRC. Spatial expression of Smurf2 was additionally studied by immunohistochemistry. siRNA-mediated knockdown of Smurf2 was applied for migration and invasion assays in DLD-1 and SW-480 cells. Results Smurf2 was significantly overexpressed in CRC tissue compared to corresponding healthy colon mucosa. Smurf2 expression levels differed significantly between microsatellite instable (MSI) and microsatellite stable (MSS) CRC. In patients suffering from MSS CRC, high tumoral expression of Smurf2 was significantly associated with impaired overall survival. Consistently, in vitro analysis revealed that knockdown of Smurf2 reduced the invasive and migratory potential of MSS CRC cells. Conclusion Smurf2 expression is upregulated in CRC specimens and affects survival dependent on patients' MSI status. Moreover, Smurf2 supports cancer cell migration and invasion, collectively suggesting an oncogenic function in CRC.

Purpose: Obesity is associated with increased incidence and mortality in rectal cancer (RC). However, an obesity paradox in the sense of a protective effect of obesity is discussed controversially. We evaluated whether adipose tissue distribution has an impact on medical (MC) and surgical complications (SC) after RC surgery. Methods: A total of 296 RC patients underwent oncological surgery and multidetector CT with quantification of total (TAT), visceral (VAT), and subcutaneous adipose tissue (SAT). Logistic regressions on SC (anastomotic leakage [n = 26], wound infection [n = 58], bleeding [n = 12], abscess [n = 32], bladder dysfunction [n = 24], burst abdomen [n = 10]), and MC (pulmonary [n = 22], cardiac [n = 18], urinary tract infection [n = 9], sepsis [n = 5]) were performed. Results: High pelvicVAT was associated with reduced risk for overall SC (OR = 0.915, p = 0.012) and anastomotic leakage (OR = 0.587, p = 0.024, CI: 0.369/0.934). In contrast, CT-quantified obesity was associated with increased risk for wound infection, bladder dysfunction, burst abdomen, overall MC, and cardiac complications (ORs up to 1.423). BMI was not associated with any SC or MC. Conclusion: An obesity paradox with a protective effect of CT-quantified adipose tissue was confirmed for anastomotic leakage and overall SC. In contrast, high adipose tissue was associated with higher risk for other SC and MC. These results show a more complex influence of body composition on MC and SC. CT-quantified obesity is able to provide deeper insights to explain the obesity paradox beyond BMI.

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.

Changes in the gut microbiome have already been associated with postoperative complications in major abdominal surgery. However, it is still unclear whether these changes are transient or a long-lasting effect. Therefore, the aim of this prospective clinical pilot study was to examine long-term changes in the gut microbiota and to correlate these changes with the clinical course of the patient. Methods: In total, stool samples of 62 newly diagnosed colorectal cancer patients undergoing primary tumor resection were analyzed by 16S-rDNA next-generation sequencing. Stool samples were collected preoperatively in order to determine the gut microbiome at baseline as well as at 6, 12, and 24 months thereafter to observe longitudinal changes. Postoperatively, the study patients were separated into two groups—patients who suffered from postoperative complications (n = 30) and those without complication (n = 32). Patients with postoperative complications showed a significantly stronger reduction in the alpha diversity starting 6 months after operation, which does not resolve, even after 24 months. The structure of the microbiome was also significantly altered from baseline at six-month follow-up in patients with complications (p = 0.006). This was associated with a long-lasting decrease of a large number of species in the gut microbiota indicating an impact in the commensal microbiota and a long-lasting increase of Fusobacterium ulcerans. The microbial composition of the gut microbiome shows significant changes in patients with postoperative complications up to 24 months after surgery.

Background Fusobacterium nucleatum (Fn), a bacterium associated with a wide spectrum of infections, has emerged as a key microbe in colorectal carcinogenesis. However, the underlying mechanisms and clinical relevance of Fn in colorectal cancer (CRC) remain incompletely understood. Patients and Methods We examined associations between Fn abundance and clinicopathologic characteristics among 105 treatment-naive CRC patients enrolled in the international, prospective ColoCare Study. Electronic medical charts, including pathological reports, were reviewed to document clinicopathologic features. Quantitative real-time polymerase chain reaction (PCR) was used to amplify/detect Fn DNA in preoperative fecal samples. Multinomial logistic regression was used to analyze associations between Fn abundance and patient sex, age, tumor stage, grade, site, microsatellite instability, body mass index (BMI), alcohol consumption, and smoking history. Cox proportional hazards models were used to investigate associations of Fn abundance with overall survival in adjusted models. Results Compared to patients with undetectable or low Fn abundance, patients with high Fn abundance (n = 22) were 3-fold more likely to be diagnosed with rectal versus colon cancer (odds ratio [OR] = 3.01; 95% confidence interval [CI], 1.06-8.57; P = .04) after adjustment for patient sex, age, BMI, and study site. Patients with high Fn abundance also had a 5-fold increased risk of being diagnosed with rectal cancer versus right-sided colon cancer (OR = 5.32; 95% CI, 1.23-22.98; P = .03). There was no statistically significant association between Fn abundance and overall survival. Conclusion Our findings suggest that Fn abundance in fecal samples collected prior to surgery varies by tumor site among treatment-naive CRC patients. Overall, fecal Fn abundance may have diagnostic and prognostic significance in the clinical management of CRC.

Importance: The incidence of early-onset colorectal cancer (younger than 50 years) is rising globally, the reasons for which are unclear. It appears to represent a unique disease process with different clinical, pathological, and molecular characteristics compared with late-onset colorectal cancer. Data on oncological outcomes are limited, and sensitivity to conventional neoadjuvant and adjuvant therapy regimens appear to be unknown. The purpose of this review is to summarize the available literature on early-onset colorectal cancer.Observations: Within the next decade, it is estimated that 1 in 10 colon cancers and 1 in 4 rectal cancers will be diagnosed in adults younger than 50 years. Potential risk factors include a Westernized diet, obesity, antibiotic usage, and alterations in the gut microbiome. Although genetic predisposition plays a role, most cases are sporadic. The full spectrum of germline and somatic sequence variations implicated remains unknown. Younger patients typically present with descending colonic or rectal cancer, advanced disease stage, and unfavorable histopathological features. Despite being more likely to receive neoadjuvant and adjuvant therapy, patients with early-onset disease demonstrate comparable oncological outcomes with their older counterparts.Conclusions and Relevance: The clinicopathological features, underlying molecular profiles, and drivers of early-onset colorectal cancer differ from those of late-onset disease. Standardized, age-specific preventive, screening, diagnostic, and therapeutic strategies are required to optimize outcomes.

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.

To determine associations between physical activity (PA), sedentary behavior (SB), and oxidative stress in colorectal cancer patients, ColoCare Study participants in Germany wore an accelerometer 6 and/or 12 months after surgery. Spearman partial correlations were used to assess associations between PA and urinary concentrations of oxidized guanine, a validated marker of oxidative stress. There were no significant associations between PA or SB and oxidized guanine in n = 76 measurements (ng/mg creatinine; r = 0.03, p = 0.76 for PA, r = –0.05, p = 0.69 for SB). Novelty Objectively measured PA was not associated with a marker of oxidative stress in colorectal cancer patients.

Background: Obesity, defined by body mass index (BMI), measured at colorectal cancer (CRC) diagnosis has been associated with postoperative complications and survival outcomes. However, BMI does not allow for a differentiation between fat and muscle mass. Computed tomography (CT)-defined body composition more accurately reflects different types of tissue and their associations with health-related quality of life (HRQoL) during the first year of disease, but this has not been investigated yet. We studied the role of visceral and subcutaneous fat area (VFA and SFA) and skeletal muscle mass (SMM) on longitudinally assessed HRQoL in CRC patients. Methods: A total of 138 newly diagnosed CRC patients underwent CT scans at diagnosis and completed questionnaires prior to and six and twelve months post-surgery. We investigated the associations of VFA, SFA, and SMM with HRQoL at multiple time points. Results: A higher VFA was associated with increased pain six and twelve months post-surgery (&beta, = 0.06, p = 0.04 and &beta, = 0.07, p = 0.01) and with worse social functioning six months post-surgery (&beta, = &minus, 0.08, p = 0.01). Higher SMM was associated with increased pain twelve months post-surgery (&beta, = 1.03, p &lt, 0.01). Conclusions: CT-quantified body composition is associated with HRQoL scales post-surgery. Intervention strategies targeting a reduction in VFA and maintaining SMM might improve HRQoL in CRC patients during the first year post-surgery.

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

BACKGROUND The liver is the most common site of colorectal liver metastases (CRLM) and surgical resection improves overall survival in selected patients. Here, we investigate outcomes and relevant prognostic factors after repeated hepatic resections for CRLM. METHODS From a prospective database, 578 patients who underwent 788 resections of colorectal liver metastases were included into this study. In total, 169 patients underwent a second and 41 patients had a third operation due to intrahepatic metastatic recurrence. Univariate and multivariate analyses were performed to determine prognostic risk factors. RESULTS 5-year overall survival was 36.7% (95% CI: 30.2%; 43.2%) and 10-year survival was 20.3% (95% CI: 7.6%; 33.0%) in patients undergoing single resection. In patients undergoing a second or third resection, 5- and 10-year survival rates were 56.6% (95% CI: 45.0%; 68.2%) and 21.9% (95% CI: 6.8%; 37.0%) or 53.2% (95% CI: 32.4%; 74.0%) and 25.4%, respectively. In patients undergoing single resection, established markers (number, size and pattern of CRLM [p = 0.030/0.015/

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.

Anastomotic leakage is the most dreaded complication after rectal resection and total mesorectal excision, leading to increased morbidity and mortality. Formation of a diverting ileostomy is generally performed to protect anastomotic healing. Identification of variables predicting anastomotic leakage might help to select patients who are under increased risk for the development of anastomotic leakage prior to surgery. The objective of this study was to assess the applicability of a nomogram as prognostic model for the occurrence of anastomotic leakage after rectal resection in a cohort of rectal cancer patients. Nine hundred seventy-two consecutive patients who underwent surgery for rectal cancer were retrospectively analyzed. Univariate and multivariable Cox regression analyses were used to determine independent risk factors associated with anastomotic leakage. Receiver operating characteristics (ROC) curve analysis was performed to calculate the sensitivity, specificity, and overall model correctness of a recently published nomogram and an adopted risk score based on the variables identified in this study as a predictive model. Male sex (p = 0.042), obesity (p = 0.017), smoking (p = 0.012), postoperative bleeding (p = 0.024), and total protein level ≤ 5.6 g/dl (p = 0.007) were identified as independent risk factors for anastomotic leakage. The investigated nomogram and the adopted risk score failed to reach relevant areas under the ROC curve greater than 0.700 for the prediction of anastomotic leakage. The proposed nomogram and the adopted risk score failed to reliably predict the occurrence of anastomotic leakage after rectal resection. Risk scores as prognostic models for the prediction of anastomotic leakage, independently of the study population, still need to be identified.

Folate‐mediated one‐carbon metabolism (FOCM) is a key pathway essential for nucleotide synthesis, DNA methylation, and repair. This pathway is a critical target for 5‐fluorouracil (5‐FU), which is predominantly used for colorectal cancer (CRC) treatment. A comprehensive assessment of polymorphisms in FOCM‐related genes and their association with prognosis has not yet been performed. Within 1,739 CRC cases aged ≥30 years diagnosed from 2003 to 2007 (DACHS study), we investigated 397 single nucleotide polymorphisms (SNPs) and 50 candidates in 48 FOCM‐related genes for associations with overall‐ (OS) and disease‐free survival (DFS) using multiple Cox regression (adjusted for age, sex, stage, grade, BMI, and alcohol). We investigated effect modification by 5‐FU‐based chemotherapy and assessed pathway‐specific effects. Correction for multiple testing was performed using false discovery rates (FDR). After a median follow‐up time of 5.0 years, 585 patients were deceased. For one candidate SNP in MTHFR and two in TYMS, we observed significant inverse associations with OS (MTHFR: rs1801133, C677T: HR het = 0.81, 95% CI: 0.67–0.97; TYMS: rs1001761: HR het = 0.82, 95% CI: 0.68–0.99 and rs2847149: HR het = 0.82, 95% CI: 0.68–0.99). After FDR correction, one polymorphism in paraoxonase 1 (PON1; rs3917538) was significantly associated with OS (HR het = 1.28, 95% CI: 1.07–1.53; HR hzv = 2.02, 95% CI:1.46–2.80; HR logAdd = 1.31, pFDR = 0.01). Adjusted pathway analyses showed significant associations for pyrimidine biosynthesis (P = 0.04) and fluorouracil drug metabolism (P

While several trials have compared laparoscopic to open surgery for colon cancer showing similar oncological results, oncological quality of laparoscopic versus open rectal resection is not well investigated. A systematic literature search for randomized controlled trials was conducted in MEDLINE, the Cochrane Library, and Embase. Qualitative and quantitative meta-analyses of short-term (rate of complete resections, number of harvested lymph nodes, circumferential resection margin positivity) and long-term (recurrence, disease-free and overall survival) oncologic results were conducted. Fourteen randomized controlled trials were identified including 3528 patients. Patients in the open resection group had significantly more complete resections (OR 0.70; 95% CI 0.51–0.97; p = 0.03) and a higher number of resected lymph nodes (mean difference − 0.92; 95% CI − 1.08 to 0.75; p

The present study compared the prognostic value of the lymph node ratio (LNR) and the 6th and the 7th TNM edition as three different lymph node classifications for rectal cancer patients.A total of 630 patients who underwent total mesorectal excision for primary rectal cancer between October 2001 and December 2007 were included. Prognostic factors of overall survival were analyzed using Cox proportional hazards models.The median follow-up was 36.1 months and the 5-year overall survival rate was 70.3 ± 4.7%. The median number of lymph nodes was 15.0 (12.0-19.0). All three lymph node evaluations correlated with survival (p 0.0001). The assessment of nodal status in the 7th TNM edition enabled further prognostic stratification. The prognostic value of the three classifications were independent of neoadjuvant therapy and lymph node count. On multivariate analyses, the N2 stage of the 6th TNM edition (Hazard ratio 2.08; 95% confidence interval 1.21-3.58) and the N2b stage of the 7th TNM edition (2.18; 1.17-4.07) correlated with poor survival. A LNR of 0.42-0.69 was also associated with unfavorable prognosis (2.97; 1.46-6.03), as was an LNR 0.69 (2.51; 1.04-6.05). The LNR did not provide prognostic information in addition to the N stage of the TNM classifications.The evaluated lymph node classifications were of comparable prognostic utility in patients with rectal cancer. The LNR did not provide prognostic information in addition to the N stage of the TNM classifications.

Salinomycin, a polyether antibiotic, is a well-known inhibitor of human cancer stem cells. Chemical modification of the allylic C20 hydroxyl of salinomycin has enabled access to synthetic analogs that display increased cytotoxic activity compared to the native structure. The aim of this study was to investigate the activity of a cohort of C20-O-acyl analogs of salinomycin on human colorectal cancer cell lines in vitro. Two human colorectal cancer cell lines (SW480 and SW620) were exposed to three C20-O-acylated analogs and salinomycin. The impact of salinomycin and its analogs on tumor cell number, migration, cell death, and cancer stem cell specifity was analyzed. Exposure of human colorectal cancer cells to the C20-O-acylated analogs of salinomycin resulted in reduced tumor cell number and impaired tumor cell migration at lower concentrations than salinomycin. When used at higher (micromolar) concentrations, these effects were accompanied by induction of apoptotic cell death. Salinomycin analogs further expose improved activity against cancer stem cells compared to salinomycin.

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.

Objective: High-throughput metabolomics assays can generate thousands of biomarker measurements and provide novel opportunities for prognostic modeling in colorectal cancer (CRC) research. The high dimensionality of metabolic data brings unforeseen statistical challenges and traditional variable selection methods may not perform well due to simultaneous challenges of computational expediency, statistical accuracy, and algorithmic stability. The Iterative Sure Independence Screening (ISIS) has demonstrated superior theoretical properties in handling such situations, and may be a viable alternative. Methods: In a prospective study of 77 newly diagnosed CRC patients (stage I-IV), pre-surgical urinary samples were analyzed on a gas chromatography-mass spectrometry platform. After exclusion of metabolites with >30% coefficient of variation, 168 metabolites remained for statistical analysis. Raw measures were processed following a standard normalization pipeline. The primary outcome was overall survival (OS) as measured from date of cancer diagnosis. In addition to metabolomics data, the predictor set included baseline clinical characteristics, such as age, sex, body mass index, tumor site, tumor stage, and receipt of neo-adjuvant and/or adjuvant treatment. We applied the ISIS method with Lasso penalty on a Cox regression model (ISIS-Lasso) to identify features associated with OS. Cox models with either Lasso regularization or backward selection were also considered as competing methods. The performance of the models was assessed through two standard performance matrices: Uno's time-dependent Area Under the Curve (tAUC) and Brier's score, both with resample-based validation. Results: Based on bootstrapped tAUC curves, we demonstrated that the screening step in ISIS can significantly improve model performance, since its predicted mean (and median) AUC are larger across clinically relevant follow-up time points (2 and 5 years after diagnosis) relative to the corresponding measures from the other two models. The prediction error based on Brier's score with 0.632+ bootstrap from ISIS-Lasso was also noticeably lower compared to the model from backward selections. Based on the ISIS-Lasso model, we identified two features, that were predictive of OS in CRC patients: tumor stage and cystine. When fixing all other clinical measures, patients with early stage (I-III) had 52% lower risk of death, compared to late stage (IV); 1 standard deviation of increase of cystine level was associated with 62% increased risk of death. Conclusion: We have demonstrated the feasibility and effectiveness of an ISIS-based method to improve selection of prognostic models derived from metabolomics data. This may be especially useful for studies with moderate sample sizes. We have identified cystine as a potentially important prognostic biomarker. Citation Format: Tengda Lin, Biljana Gigic, Kenneth Boucher, Ben Haaland, David Liesenfeld, Robert Owen, Petra Schrotz-King, Jourgen Boehm, Anita Peoples, Augustin Scalbert, Martin Schneider, Jane Figueiredo, William Grady, Christopher Li, David Shibata, Erin Siegel, Adetunji Toriola, Alexis Ulrich, Neli Ulrich, Jincheng Shen, Jennifer Ose. Application of iterative sureindependence screening to improve urinary metabolomics-based prediction of survival in colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 892.

Smoking tobacco is a known risk factor for the development of colorectal cancer, and for mortality associated with the disease. Smoking has been reported to be associated with changes in DNA methylation in blood and in lung tumour tissues, although there has been scant investigation of how epigenetic factors may be implicated in the increased risk of developing colorectal cancer. To identify epigenetic changes associated with smoking behaviours, we performed epigenome-wide analysis of DNA methylation in colorectal tumours from 36 never smokers, 47 former smokers and 13 active smokers, and adjacent mucosa from 49 never smokers, 64 former smokers and 18 active smokers. Our analyses identified 15 CpG sites within the APC 1A promoter that were significantly hypermethylated and 14 CpG loci within the NFATC1 gene body that were significantly hypomethylated (pLIS

To investigate the association of serum 25-hydroxyvitamin D (25(OH)D3) with survival in a large prospective cohort study of colorectal cancer (CRC) patients. The study population consisted of 2,910 patients diagnosed with CRC between 2003 and 2010 who participated in the DACHS study, a multicenter study from Germany with comprehensive long-term follow-up. 25(OH)D3 was determined in serum samples collected shortly after cancer diagnosis by High Performance Liquid Chromatography-Electro Spray Ionization-Mass Spectrometry. Analyses of survival outcomes were performed using Cox regression with comprehensive adjustment for relevant confounders. The majority (59%) of CRC patients were vitamin D deficient (serum 25(OH)D3 levels 45.20 nmol/L), those in the lowest 25(OH)D3 quintile (

Background Recurrence of colorectal liver metastases after a first hepatectomy is common (4–48% of patients). This review investigates the utility of repeated hepatic resection of colorectal liver metastases. Methods A systematic search of the literature was performed in the Cochrane Library, MEDLINE, EMBASE, and trial registers. All studies comparing repeated hepatic resection for colorectal liver metastases with patients who underwent only one hepatectomy were eligible. Outcome criteria were safety parameters and survival rates. Data were analyzed using the random-effects model. Results In eight observational clinical studies, 450 patients with repeated hepatic resection were compared with 2669 single hepatic resections. Morbidity such as hepatic insufficiency (OR [95% CI] 1.46 [0.69; 3.08], p = 0.32) and biliary leakage and fistula (OR [95% CI] 1.22 [0.80; 1.85], p = 0.35) was comparable between the two groups. Mortality (OR [95% CI] 1.13 [0.46; 2.74], p = 0.79) and overall survival (HR [95% CI] 1.00 [0.63; 1.60], p = 0.99) were not significantly different between the two groups. Discussion Repeated hepatic resection for colorectal liver metastases is safe in selected patients. A prospective, multicenter high-quality trial or register study of repeated hepatic resection will be required to clarify patient-oriented outcomes such as overall survival and quality of life.

Ventral incisional hernia is the most common long-term complication after an abdominal operation. Among newly diagnosed colorectal cancer patients, we screened the preoperative plasma proteome to explore predictive markers for the development of an incisional hernia.We utilized preoperative plasma samples of 72 newly diagnosed colorectal cancer patients who underwent midline incision for tumor resection between 2010 and 2013. A total of 21 patients with incisional hernia occurrence were matched with 51 patients with at least 18 months follow-up without an incisional hernia by sex, age, and body mass index. To assess predictive markers of incisional hernia risk, we screened the plasma proteome for2,000 distinct proteins using a well-validated antibody microarray test. Paired t tests were used to compare protein levels between cases and controls. A gene-set-enrichment analysis (Gene Ontology and Kyoto Encyclopedia of Genes and Genomes) was applied to test for differences in signaling pathways between the 2 groups.The proteome screen identified 25 proteins that showed elevated or reduced plasma levels in the hernia group compared to the control group (nominal P values .05). Several proteins were in pathways associated with wound healing (CCL21, SHBG, BRF2) or cell adhesion (PCDH15, CDH3, EPCAM).Our study shows that there are multiple individual and groups of plasma proteins that could feasibly predict the personal hernia risk prior to undergoing an operation. Further investigations in larger, independent sample sets are warranted to replicate findings and validate clinical utility of potential biomarkers. After validation, such a biomarker could be incorporated into a multifactorial risk model to guide clinical decision-making.

Patient-derived cancer xenografts (PDX) are widely used to identify and evaluate novel therapeutic targets, and to test therapeutic approaches in preclinical mouse avatar trials. Despite their widespread use, potential caveats of PDX models remain considerably underappreciated. Here, we demonstrate that EBV-associated B-lymphoproliferations frequently develop following xenotransplantation of human colorectal and pancreatic carcinomas in highly immunodeficient NOD.Cg-Prkdcscid Il2rgtm1Wjl /SzJ (NSG) mice (18/47 and 4/37 mice, respectively), and in derived cell cultures in vitro. Strikingly, even PDX with carcinoma histology can host scarce EBV-infected B-lymphocytes that can fully overgrow carcinoma cells during serial passaging in vitro and in vivo. As serial xenografting is crucial to expand primary tumor tissue for biobanks and cohorts for preclinical mouse avatar trials, the emerging dominance of B-lymphoproliferations in serial PDX represents a serious confounding factor in these models. Consequently, repeated phenotypic assessments of serial PDX are mandatory at each expansion step to verify "bona fide" carcinoma xenografts.

Cachexia is a multifactorial syndrome that is characterized by loss of skeletal muscle mass in cancer patients. The biological pathways involved remain poorly characterized. Here, we compare urinary metabolic profiles in newly diagnosed colorectal cancer patients (stage I&ndash, IV) from the ColoCare Study in Heidelberg, Germany. Patients were classified as cachectic (n = 16), pre-cachectic (n = 13), or non-cachectic (n = 23) based on standard criteria on weight loss over time at two time points. Urine samples were collected pre-surgery, and 6 and 12 months thereafter. Fat and muscle mass area were assessed utilizing computed tomography scans at the time of surgery. N = 152 compounds were detected using untargeted metabolomics with gas chromatography&ndash, mass spectrometry and n = 154 features with proton nuclear magnetic resonance spectroscopy. Thirty-four metabolites were overlapping across platforms. We calculated differences across groups and performed discriminant and overrepresentation enrichment analysis. We observed a trend for 32 compounds that were nominally significantly different across groups, although not statistically significant after adjustment for multiple testing. Nineteen compounds could be identified, including acetone, hydroquinone, and glycine. Comparing cachectic to non-cachectic patients, higher levels of metabolites such as acetone (Fold change (FC) = 3.17, p = 0.02) and arginine (FC = 0.33, p = 0.04) were observed. The two top pathways identified were glycerol phosphate shuttle metabolism and glycine and serine metabolism pathways. Larger subsequent studies are needed to replicate and validate these results.

Background Results of previous studies on the association of the CpG island methylator phenotype (CIMP) with colorectal cancer (CRC) prognosis were inconsistent and mostly based on different CIMP definitions. The current study aimed to comprehensively investigate the associations between DNA methylation on genes previously used to define CIMP status with CRC survival. Results Patients with CRC followed up for a median of 5.2 years were divided into a study cohort (n = 568) and a validation cohort (n = 308). DNA methylation was measured in tumor tissue using the Illumina Infinium HumanMethylation450 BeadChip and restricted to 43 genes used to define CIMP status in previous studies. Cox proportional hazard regression models were used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) of survival after CRC, including adjustment for tumor stage, microsatellite instability, and BRAF mutation status. In the study cohort, ten CpG sites were identified to be associated with CRC survival. Seven of these ten CpG sites were also associated with CRC survival in the validation cohort and were used to construct a prognostic score. CRC patients with a prognostic score of the lowest methylation level showed poorer disease-specific survival compared with patients with the highest methylation level in both the study cohort and the validation cohort (HR = 3.11 and 95% CI = 1.97–4.91, and HR = 3.06 and 95% CI = 1.71–5.45, respectively). Conclusions A CpG panel consisting of seven CpG sites was found to be strongly associated with CRC survival, independent from important clinical factors and mutations associated with CIMP. Further studies are required to confirm these findings. Electronic supplementary material The online version of this article (10.1186/s13148-019-0703-4) contains supplementary material, which is available to authorized users.

Multidisciplinary treatment of rectal cancer, including neoadjuvant treatment, total mesorectal excision, and adjuvant chemotherapy, have improved oncological outcome. Preoperative radiation therapy is advocated by national and international guidelines in all patients with AJCC stage II and III rectal cancer. Although this treatment reduces local recurrence rates with no effect on overall survival, there are possible short- and long-term side effects of radiation exposure, so patients should be carefully selected for neoadjuvant radiation therapy. We analyzed whether ventral or dorsal tumor location affects local recurrence rates following radical rectal resection. Patients who underwent radical rectal resection for mid or low rectal cancer in our department between October 2001 and December 2013 were included. Prognostic indicators for local recurrence were analyzed using univariate and multivariate analyses. Overall, 480 patients met the inclusion criteria. Univariate analysis identified surgical procedure (hazard ratio [HR] 1.9, p = 0.006), ventral tumor location (HR 3.8, p

BACKGROUND AND OBJECTIVES Despite advances in early detection of colon cancer, a minority of patients still require urgent surgery. Whether such urgent conditions result in poor outcome remains a topic of debate. METHODS Using a prospectively maintained database, patients suffering exclusively from colon cancer and receiving either elective or emergent resection between 2001 and 2014 were analyzed with respect to overall, disease-specific, and relative survival using Cox regression and propensity score analyses. RESULTS From a total of 877 patients analyzed, 2.7% (24) presented with complications requiring urgent surgery. Propensity-scoring identified strongly biased patient characteristics (0.097 ± 0.069 vs 0.028 ± 0.043; P < 0.001). An unadjusted Cox proportional hazards regression analysis revealed urgent surgery as a statistically significant prognostic factor with an approximately 207% increased risk of mortality (hazard ratio [HR] = 3.07; 95% confidence interval [CI]: 1.62-5.81; P = 0.003). After adjusting the data according to the propensity score analysis, urgent surgery was not associated with a decreased overall (HR = 1.67; 95%CI; 0.84-3.36; P = 0.174), disease-specific (HR = 1.62; 95% CI; 0.81-3.24; P = 0.201) or relative survival (HR = 1.86; 95% CI: 0.92-3.79; P = 0.086). CONCLUSIONS After risk-adjustment, using multivariable Cox regression and propensity score analyses, no significant disadvantage could be noted with regard to overall, disease-specific, or relative survival in patients with exclusively colon cancer who received emergent oncological resection.

OncoImmunology 8(9), e1626193 (2019). doi:10.1080/2162402X.2019.1626193, Published by Taylor & Franics, Abingdon

Background Studies on the association between body mass index (BMI) and colorectal cancer (CRC) prognosis after diagnosis have yielded inconsistent results. Few studies have investigated associations between prediagnostic BMI change and CRC prognosis. Objective The associations of BMI at diagnosis and prediagnostic BMI change with relevant prognostic outcomes were evaluated in a large population-based cohort of CRC patients. Design A total of 3130 patients diagnosed with CRC between 2003 and 2010 were interviewed on sociodemographic and lifestyle factors, medication, and comorbidities. Cancer recurrence, vital status, and cause of death were documented for a median follow-up time of 4.9 y. With the use of Cox proportional hazards regression, associations between BMI at diagnosis and BMI change (difference between 1-10 y before diagnosis and at diagnosis) and overall, CRC-specific, recurrence-free, and disease-free survival were analyzed. Results Compared with normal weight, overweight [BMI (in kg/m2): 25 to 5 was associated with poorer prognosis for all survival outcomes (overall survival-aHR: 1.83; 95% CI: 1.43, 2.34; CRC-specific survival-aHR: 1.78; 95% CI: 1.33, 2.39), and associations were particularly pronounced in men (overall survival-aHR: 2.31; 95% CI: 1.65, 3.22; CRC-specific survival-aHR: 2.56; 95% CI: 1.72, 3.81; P-interaction = 0.08). Conclusions Overweight and obesity are associated with enhanced survival after a CRC diagnosis. A major decrease in BMI in the years before diagnosis is a strong independent predictor of decreased survival. This trial was registered at www.studybox.de as ST-D066.

// Robin Schmitz 1 , Aida Freire Valls 1, 2 , Rosario Yerbes 2 , Sophie von Richter 1 , Christoph Kahlert 3 , Sonja Loges 4 , Jurgen Weitz 3 , Martin Schneider 1 , Carmen Ruiz de Almodovar 2 , Alexis Ulrich 1 , Thomas Schmidt 1 1 Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, University Heidelberg, Heidelberg, Germany 2 Biochemistry Center, University of Heidelberg, Heidelberg, Germany 3 Department of Visceral, Thoracic and Vascular Surgery, University of Dresden, Dresden, Germany 4 Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany Correspondence to: Thomas Schmidt, email: thomas.schmidt1@med.uni-heidelberg.de Keywords: colorectal cancer, tyro3, Mer, Gas6, macrophages Received: January 25, 2016 Accepted: June 26, 2016 Published: July 28, 2016 ABSTRACT Purpose: CRC remains the third most common cancer worldwide with a high 5-year mortality rate in advanced cases. Combined with chemotherapy, targeted therapy is an additional treatment option. However as CRC still escapes targeted therapy the vigorous search for new targets is warranted to increase patients´ overall survival. Results: In this study we describe a new role for Gas6/protein S-TAM receptor interaction in CRC. Gas6, expressed by tumor-infiltrating M2-like macrophages, enhances malignant properties of tumor cells including proliferation, invasion and colony formation. Upon chemotherapy macrophages increase Gas6 synthesis, which significantly attenuates the cytotoxic effect of 5-FU chemotherapy on tumor cells. The anti-coagulant protein S has similar effects as Gas6. In CRC patient samples Tyro3 was overexpressed within the tumor. In-vitro inhibition of Tyro3 and Mer reduces tumor cell proliferation and sensitizes tumor cells to chemotherapy. Moreover high expression of Tyro3 and Mer in tumor tissue significantly shortens CRC patients´ survival. Experimental design: Various in vitro models were used to investigate the role of Gas6 and its TAM receptors in human CRC cells, by stimulation (rhGas6) and knockdown (siRNA) of Axl, Tyro3 and Mer. In terms of a translational research, we additionally performed an expression analysis in human CRC tissue and analyzed the medical record of these patients. Conclusions: Tyro3 and Mer represent novel therapeutic targets in CRC and warrant further preclinical and clinical investigation in the future.

Nach Einfuhrung der totalen mesorektalen Exzision (TME) in der kurativen Behandlung des Rektumkarzinoms hat sich die Rolle der neoadjuvanten Therapie gewandelt. Durch die verbesserte Operationstechnik konnte die Lokalrezidivrate allein durch die Chirurgie nach den TME-Kriterien auf unter 8 % gesenkt werden. Auch wenn die lokale Kontrolle mittels praoperativer Bestrahlung weiter verbessert werden konnte, hat dies nicht zu einem allgemeinen Uberlebensvorteil vorbestrahlter Patienten gefuhrt. Leitliniengerecht sollten alle Patienten im UICC-II- und -III-Stadium vorbehandelt werden. Die stadienbasierte Indikationsstellung zur neoadjuvanten Therapie hat jedoch Schwachen. Zum einen stellen die Patienten mit T3-Tumoren eine prognostisch sehr heterogene Gruppe dar, zum anderen ist die praoperative Lymphknotendiagnostik zu ungenau. Im Gegensatz dazu hat sich in den letzten Jahren der zirkumferenzielle Resektionsrand (CRM) als wichtiger prognostischer Parameter etabliert. Patienten, bei denen eine grose Nahe/Infiltration der Hullfaszie (positiver CRM) zum/durch den Tumor besteht, haben eine hohere Lokalrezidivrate und ein schlechteres Uberleben. Mit hochauflosender MRT-Untersuchung des Beckens kann bei Patienten mit Rektumkarzinom der praoperative CRM mit einer hohen Sensitivitat und Spezifitat bestimmt werden. Das mittels MRT verbesserte T‑Staging bzw. die Vorhersage der Resektionsrander konnen ein wichtiges Kriterium zur Selektion von Patienten fur studienbasierte Therapieansatze ohne neoadjuvante Therapie sein.

// Hermann Brenner 1, 2, 3 , Lina Jansen 1 , Alexis Ulrich 4 , Jenny Chang-Claude 5 , Michael Hoffmeister 1 1 Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany 2 Division of Preventive Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany 3 German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany 4 Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany 5 Unit of Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany Correspondence to: Hermann Brenner, e-mail h.brenner@dkfz.de Keywords: colonoscopy, colorectal cancer, fecal occult blood test, screening, survival Received: March 07, 2016 Accepted: April 26, 2016 Published: May 17, 2016 ABSTRACT Background: An increasing proportion of colorectal cancer (CRC) patients are diagnosed by screening rather than symptoms. Aims: We aimed to assess and compare prognosis of patients with screen-detected CRC and symptom-detected CRC. Methods: Overall and CRC specific mortality over a median follow-up of 4.8 years was assessed according to mode of diagnosis (symptoms, screening colonoscopy, fecal occult blood test [FOBT], other) in a multi-center cohort of 2,450 CRC patients aged 50-79 years recruited in Germany in 2003-2010. Results: 68%, 11% and 10% were detected by symptoms, screening colonoscopy and FOBT, respectively. The screen-detected cancers had a more favorable stage distribution than the symptom-detected cancers (68% versus 50% in stage I or II). Age- and sex adjusted hazard ratios (HRs) of total mortality with 95% confidence intervals (95% CIs) compared to symptom-detected cancers were 0.35 (0.24-0.50) and 0.36 (0.25-0.53) for screening colonoscopy and FOBT detected CRCs, respectively. HRs were only slightly attenuated and remained highly significant after adjustment for stage and multiple other covariates (0.50 (0.34-0.73) and 0.54 (0.37-0.80), respectively). Even stronger associations were seen for CRC specific mortality. Patients with screen-detected stage III CRC had as good CRC specific survival as patients with symptom-detected stage I or II CRC. Conclusions: Patients with screen-detected CRC have a very good prognosis far beyond the level explained by their more favorable stage distribution. Mode of detection is an important, easy-to-obtain proxy indicator for favorable diagnosis beyond earlier stage at diagnosis and as such may be useful for risk stratification in treatment decisions.