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Colorectal cancer (CRC) is increasingly recognized as a heterogeneous disease. No studies have prospectively examined associations of blood metabolite concentrations with all-cause mortality in patients with colon and rectal cancer separately. Targeted metabolomics (Biocrates AbsoluteIDQ p180) and pathway analyses (MetaboAnalyst 4.0) were performed on pre-surgery collected plasma from 674 patients with non-metastasized (stage I–III) colon (n = 394) or rectal cancer (n = 283). Metabolomics data and covariate information were received from the international cohort consortium MetaboCCC. Cox proportional hazards models were computed to investigate associations of 148 metabolite levels with all-cause mortality adjusted for age, sex, tumor stage, tumor site (whenever applicable), and cohort; the false discovery rate (FDR) was used to account for multiple testing. A total of 93 patients (14%) were deceased after an average follow-up time of 4.4 years (60 patients with colon cancer and 33 patients with rectal cancer). After FDR adjustment, higher plasma creatinine was associated with a 39% increase in all-cause mortality in patients with rectal cancer. HR: 1.39, 95% CI 1.23–1.72, pFDR = 0.03; but not colon cancer: pFDR = 0.96. Creatinine is a breakdown product of creatine phosphate in muscle and may reflect changes in skeletal muscle mass. The starch and sucrose metabolisms were associated with increased all-cause mortality in colon cancer but not in rectal cancer. Genes in the starch and sucrose metabolism pathways were previously linked to worse clinical outcomes in CRC. In summary, our findings support the hypothesis that colon and rectal cancer have different etiological and clinical outcomes that need to be considered for targeted treatments.

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.

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

INTRODUCTION: Telomere shortening, as seen with aging, can cause chromosomal instability and promote cancer progression. We investigated the association between circulating telomere length and overall and disease-free survival in a sub-cohort of patients with colorectal cancer. METHODS: Baseline genomic DNA from blood leukocytes was extracted from N=92 newly diagnosed stage I-IV patients with colorectal cancer enrolled at the ColoCare Study site in Heidelberg, Germany. Detailed information on clinicodemographic (including age) and lifestyle risk factors, and clinical outcomes (including recurrence and survival) was collected. Telomere length was measured in DNA using multiplex quantitative polymerase chain reaction. Kaplan Meier survival curves were generated comparing shorter to longer telomere lengths with log-rank testing. RESULTS: The mean T/S ratio for study patients was 0.5 (range: 0.3-0.9). Shorter telomeres were associated with older age at baseline. Patients with shorter telomeres experienced a worse overall and disease-free survival, although this association did not reach statistical significance. Kaplan-Meier survival curves for those with circulating telomere length below vs. above the median showed poorer overall (log-rank p=0.31) and disease-free survival (long-rank p=0.23). CONCLUSIONS: Our results suggest that individuals with shorter telomeres, as seen with aging, may experience a worse overall and disease-free survival after colorectal cancer diagnosis. Larger sample sizes with longer follow-up are needed to further evaluate telomere length as a prognostic biomarker in colorectal cancer progression.

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: Evidence suggests a positive association between sugar intake and colorectal cancer (CRC) outcomes. We sought to investigate inflammation and angiogenesis as underlying mechanisms behind increased sugar intake and worse CRC outcomes. METHOD: Pre-surgery serum samples were obtained from 191 patients diagnosed with primary invasive stage I-IV CRC. Biomarkers of inflammation (CRP, SAA, IL-6, IL-8, MCP-1, TNFα) and angiogenesis (VEGFA, VEGFD, sICAM-1 and sVCAM-1) were analyzed (Meso-Scale-Discovery). Fructose, glucose, sucrose, and total sugar intake (calories/day, % total calories) were assessed by FFQ. Pearson’s correlation and multiple linear regression analyses were performed. RESULTS: Patients were on average 64 years old, 64% were male, the majority was diagnosed with stage II-III (58%) cancers, and 67% were either overweight or obese. Among normalweight individuals (BMI

BACKGROUND: Cachexia is a multifactorial metabolic syndrome associated with higher risk of mortality. The precise molecular mechanisms and biological pathways involved remain poorly characterized. A specific criterion of cachexia is loss of muscle mass. Myokines affect muscle mass and have profound effects on glucose and lipid metabolism, thus contributing to energy homeostasis and potentially cachexia. Only sparse data for patients with non-metastatic colorectal cancer exist. This study aims to investigate associations of systemic myokine concentrations with onset of cachexia in non-metastatic colorectal cancer patients. METHODS: Serum samples from n=125 colorectal cancer patients (stage I-III) recruited from the ColoCare Study site at Huntsman Cancer Institute were collected prior to surgery (baseline). Assays were run with the Milliplex Human Myokine Magnetic panel containing beads such as FABP3, Oncostatin M, and FGF21. Patients were defined as cachectic, pre-cachectic, or non-cachectic based on the criteria by Fearon et al. based on sex, BMI, and weight loss over a period of six months. ANOVA were applied to analyze associations of myokines with cachexia at 12 month after surgery, adjusted by age at diagnosis, sex, tumor stage, and tumor site. RESULTS: At the 12 months follow-up, 11% of patients were diagnosed with cachexia (n=14), 14% of patients with pre-cachexia (n=18), and 74% of patients were defined as non-cachectic. Patients with cachexia were more likely to be diagnosed with rectal cancer (57%) compared to pre-cachectic (17%) or non-cachectic patients (42%; p ONCLUSIONS: Cachectic patients presented higher FABP3 concentrations (p=0.02) which were associated with increased risk of cachexia, however these results were not significant after adjustment. In this study, cachectic patients were more likely to be diagnosed with rectal cancer. In summary, larger studies are needed to further evaluate FABP3 and other myokines as potential prognostic biomarkers for cachexia and consider differences by tumor site. Citation Format: Jennifer Ose, Ellen Beswick, Simon Ta Van, Richard H. Viskochil, Christy A. Warby, Jeffrey T. Yap, Matthew F. Covington, Anne H. Nguyen, Jordan W. Stanford, Tengda Lin, Anita R. Peoples, Sheetal Hardikar, Christopher I. Li, William M. Grady, David Shibatta, Adetunji T. Toriola, Martin Schneider, Jane C. Figueiredo, Daniel Jeong, Erin M. Siegel, Cornelia M. Ulrich, Biljana Gigic. Examination of systemic myokine concentrations with risk of cachexia in non-metastatic colorectal cancer patients - Results from the ColoCare Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 355.

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.

The COVID-19 pandemic has disrupted many facets of life. We evaluated pandemic-related health care experiences, COVID-19 prevention behaviors and measures, health behaviors, and psychosocial outcomes among rural and urban cancer patients.Among 1,472 adult cancer patients, who visited Huntsman Cancer Institute in the past 4 years and completed a COVID-19 survey (August-September 2020), we assessed the impact of the pandemic on medical appointments, prevention/health behaviors, and psychosocial factors, stratified by urbanicity.Mean age was 61 years, with 52% female, 97% non-Hispanic White, and 27% were residing in rural areas. Rural versus urban patients were more likely to be older, not employed, uninsured, former/current smokers, consume alcohol, and have pandemic-related changes/cancellations in surgery appointments (all P.05). Changes/cancellations in other health care access (eg, doctor's visits) were also common, particularly among urban patients. Urban versus rural patients were more likely to socially distance, use masks and hand sanitizer, and experience changes in exercise habits and in their daily lives (all P.05). Less social interaction and financial stress were common among cancer patients but did not differ by urbanicity.These findings suggest that the COVID-19 pandemic had a substantial impact on cancer patients, with several challenges specific to rural patients. This comprehensive study provides unique insights into the first 6 months of COVID-19 pandemic-related experiences and continuity of care among rural and urban cancer patients predominantly from Utah. Further research is needed to better characterize the pandemic's short- and long-term effects on rural and urban cancer patients and appropriate interventions.

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

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

Background: Folate-mediated 1-carbon metabolism requires several nutrients, including vitamin B6. Circulating biomarker concentrations indicating high vitamin B6 status are associated with a reduced risk of colorectal cancer (CRC). However, little is known about the effect of B6 status in relation to clinical outcomes in CRC patients. Objectives: We investigated survival outcomes in relation to vitamin B6 status in prospectively followed CRC patients. Methods: A total of 2031 patients with stage I–III CRC participated in 6 prospective patient cohorts in the international FOCUS (folate-dependent 1-carbon metabolism in colorectal cancer recurrence and survival) Consortium. Preoperative blood samples were used to measure vitamin B6 status by the direct marker pyridoxal 5'-phosphate (PLP), as well as the functional marker HK-ratio (HKr)[3'hydroxykynurenine: (kynurenic acid + xanthurenic acid + 3'-hydroxy anthranilic acid + anthranilic acid)]. Using Cox proportional hazards regression, we examined associations of vitamin B6 status with overall survival (OS), disease-free survival (DFS), and risk of recurrence, adjusted for patient age, sex, circulating creatinine concentrations, tumor site, stage, and cohort. Results: After a median follow-up of 3.2 y for OS, higher preoperative vitamin B6 status as assessed by PLP and the functional marker HKr was associated with 16–32% higher all-cause and disease-free survival, although there was no significant association with disease recurrence (doubling in PLP concentration: HROS, 0.68; 95% CI: 0.59, 0.79; HRDFS, 0.84; 95% CI: 0.75, 0.94; HRRecurrence, 0.96; 95% CI: 0.84, 1.09; HKr: HROS, 2.04; 95% CI: 1.67, 2.49; HRDFS, 1.56; 95% CI: 1.31, 1.85; HRRecurrence, 1.21; 95% CI: 0.96,1. 52). The association of PLP with improved OS was consistent across colorectal tumor site (right-sided colon: HROS, 0.75; 95% CI: 0.59, 0.96; left-sided colon: HROS, 0.71; 95% CI: 0.55, 0.92; rectosigmoid junction and rectum: HROS, 0.61; 95% CI: 0.47, 0.78). Conclusion: Higher preoperative vitamin B6 status is associated with improved OS among stage I–III CRC patients. Am J Clin Nutr 2022;116:303–313.

Purpose There is limited information on how the COVID-19 pandemic has changed health behaviors among cancer patients. We examined the impact of the pandemic on changes in exercise behaviors and identified characteristics associated with these changes among cancer patients. Methods Cancer patients (n = 1,361) completed a survey from August-September 2020 to assess COVID-19 pandemic-related changes in health behaviors and psychosocial factors. Patients were categorized into 3 groups: exercising less, exercising did not change, and exercising more. Patient characteristics were compared by exercise groups. Results One-third of the patients reported a decreased amount of regular exercise, while 11% reported exercising more during the pandemic. Patients who exercised less were more likely to be unemployed/retired, undergoing active treatment, and had increased pandemic-related alcohol consumption and psychosocial stressors such as loneliness and financial stress (all p p p

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.

Context Adipose tissue inflammation and dysregulated energy homeostasis are key mechanisms linking obesity and cancer. Distinct adipose tissue depots strongly differ in their metabolic profiles; however, comprehensive studies of depot-specific perturbations among patients with cancer are lacking. Objective We compared transcriptome profiles of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) from patients with colorectal cancer and assessed the associations of different anthropometric measures with depot-specific gene expression. Design Whole transcriptomes of VAT and SAT were measured in 233 patients from the ColoCare Study, and visceral and subcutaneous fat area were quantified via CT. Results VAT compared with SAT showed elevated gene expression of cytokines, cell adhesion molecules, and key regulators of metabolic homeostasis. Increased fat area was associated with downregulated lipid and small molecule metabolism and upregulated inflammatory pathways in both compartments. Comparing these patterns between depots proved specific and more pronounced gene expression alterations in SAT and identified unique associations of integrins and lipid metabolism–related enzymes. VAT gene expression patterns that were associated with visceral fat area poorly overlapped with patterns associated with self-reported body mass index (BMI). However, subcutaneous fat area and BMI showed similar associations with SAT gene expression. Conclusions This large-scale human study demonstrates pronounced disparities between distinct adipose tissue depots and reveals that BMI poorly correlates with fat mass–associated changes in VAT. Taken together, these results provide crucial evidence for the necessity to differentiate between distinct adipose tissue depots for a correct characterization of gene expression profiles that may affect metabolic health of patients with colorectal cancer.

Purpose: Inflammation and angiogenesis are hallmarks of cancer development and progression. No studies have prospectively examined association of angiogenesis-related biomarkers with clinical outcomes in colon and rectal cancer. Patients and Methods: In pre-surgery serum samples from n=426 non-metastatic colorectal cancer (CRC) patients (stage I-III), we investigated associations of inflammatory (e.g., CRP, SAA, sICAM-1, sVCAM-1) and angiogenesis biomarkers (VEGF-A, VEGF-D) with overall survival (OS), disease-free survival (DFS), and risk of recurrence. We computed hazard ratios (HR) and 95% confidence intervals (CI). Analyses were adjusted for age, sex, body mass index, stage, tumor site, and study site, and also exploratory stratified by tumor site (colon vs. rectum). Results: N=65 patients (15%) were deceased and n=59 patients (15%) had a recurrence after a median follow-up of 31 months. Overall, doubling of CRP was associated with a ~24% increase in risk of death (OS: HRlog2: 1.24; 95% CI: 1.11-1.40), a 19% increase in risk of recurrence: HRlog2: 1.19; 95% CI: 1.08-1.32, and a non-statistically-significant 12% increase for DFS HRlog2: 1.12; 95% CI: 0.98-1.28. Similar associations were observed for SAA. Doubling of sICAM-1 was associated with a 4-fold increase in risk of death (OS: HRlog2: 4.05; 95% CI: 2.35-6.98). For the angiogenesis marker VEGF-D, significant heterogeneity was observed in analyses stratified by tumor site: doubling was associated with a 3-fold increase in risk of death for rectal cancer (OS: HR: 3.26; 95% CI: 1.58-6.70) and a 22% reduction in mortality for colon cancer (OS: HR: 0.78; 95% CI: 0.35-1.73; pheterogenity Conclusion: Our data suggest that some biomarkers of inflammation and angiogenesis are prognostic markers for stage I-III CRC patients, with potential differences by tumor site for angiogenesis markers. Citation Format: Jennifer Ose, Tengda Lin, Caroline Himbert, Christy A. Warby, Sheetal Hardikar, Juergen Boehm, Biljana Gigic, Petra Schrotz-King, Martin Schneider, Alexis B. Ulrich, David Shibata, Jane C. Figueiredo, Erin M. Siegel, Christopher I. Li, Adetunji T. Toriola, Cornelia M. Ulrich. Prognostic role of systemic inflammation in colon and rectal cancer patients: Results from the ColoCare Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3227.

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

Background 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.

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.

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.

Obesity and excess adiposity account for approximately 20% of all cancer cases; however, biomarkers of risk remain to be elucidated. While fibroblast growth factor-2 (FGF2) is emerging as an attractive candidate biomarker for visceral adipose tissue mass, the role of circulating FGF2 in malignant transformation remains unknown. Moreover, functional assays for biomarker discovery are limited. We sought to determine if human serum could stimulate the 3D growth of a non-tumorigenic cell line. This type of anchorage-independent 3D growth in soft agar is a surrogate marker for acquired tumorigenicity of cell lines. We found that human serum from cancer-free men and women has the potential to stimulate growth in soft agar of non-tumorigenic epithelial JB6 P+ cells. We examined circulating levels of FGF2 in humans in malignant transformation in vitro in a pilot study of n = 33 men and women. Serum FGF2 levels were not associated with colony formation in epithelial cells (r = 0.05, p = 0.80); however, a fibroblast growth factor receptor-1 (FGFR1) selective inhibitor significantly blocked serum-stimulated transformation, suggesting that FGF2 activation of FGFR1 may be necessary, but not sufficient for the transforming effects of human serum. This pilot study indicates that the FGF2/FGFR1 axis plays a role in JB6 P+ malignant transformation and describes an assay to determine critical serum factors that have the potential to promote tumorigenesis.

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.

Background Prostate-specific antigen (PSA) testing for early detection of prostate cancer is low-value when it is not indicated by guidelines and the harms outweigh the benefits. In this retrospective cohort study, we identify provider and patient factors associated with PSA testing, particularly in situations where testing would be low-value. Methods We used electronic health record data from 2011 to 2018 representing 1,738,021 health system encounters in the United States. Using logistic generalized estimating equation models, we examined patient factors (age, comorbid illness, family history, race and prior PSA results), provider factors (gender, specialty, graduation year and medical school rank), and overall time trends associated with PSA testing in low-value and appropriate settings. Results Comorbid illness (odds ratio (OR) 0.0 for 3+ conditions vs none) and no prior PSA testing (OR 0.2) were associated with a lower likelihood of PSA testing in low-value situations, while family history of prostate cancer (OR 1.6) and high prior PSA test results (OR 2.2 for PSA > 6 vs 0–1) were associated with a greater likelihood. Men aged 55–65 years were at greatest risk for PSA testing in low-value situations. The provider factor associated with PSA testing in low-value situations was specialty, with urologists being most likely (OR 2.3 versus advanced practice providers). Internal medicine physicians were more likely to perform PSA testing during low-value situations (OR 1.3 versus advanced practice providers) but much more likely to order a PSA test where appropriate (OR 2.2). All PSA testing decreased since 2011. Conclusion We identified several patient and provider factors associated with PSA testing in low-value settings. Some aspects suggest attention to relevant factors for PSA testing in low-value settings (e.g. comorbid illness), while others may encourage PSA testing in low-value settings (e.g. family history). The greatest likelihood of PSA testing in low-value settings is among men within the age range most commonly recommended by guidelines.

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.

The application of metabolomics technology to epidemiological studies is emerging as a new approach to elucidate disease etiology and for biomarker discovery. However, analysis of metabolomics data is complex and there is an urgent need for the standardization of analysis workflow and reporting of study findings. To inform the development of such guidelines, we conducted a survey of 47 cohort representatives from the Consortium of Metabolomics Studies (COMETS) to gain insights into the current strategies and procedures used for analyzing metabolomics data in epidemiological studies worldwide. The results indicated a variety of applied analytical strategies, from biospecimen and data pre-processing and quality control to statistical analysis and reporting of study findings. These strategies included methods commonly used within the metabolomics community and applied in epidemiological research, as well as novel approaches to pre-processing pipelines and data analysis. To help with these discrepancies, we propose use of open-source initiatives such as the online web-based tool COMETS Analytics, which includes helpful tools to guide analytical workflow and the standardized reporting of findings from metabolomics analyses within epidemiological studies. Ultimately, this will improve the quality of statistical analyses, research findings, and study reproducibility.

Purpose: The COVID-19 pandemic has substantially changed social practices, economic stability, and access to medical care that may significantly affect cancer patients, especially those undergoing active treatment. We characterized the pandemic's influence on healthcare delivery, behavioral health, and financial stress in cancer patients. Methods: We included data from N = 1,253 adult cancer patients, who visited HCI in the last 4 years, consented to the Total Cancer Care study, and completed a COVID-19 survey as part of the COPES consortium. The survey was administered between Aug and Sept 2020 and included questions on change/cancellation of medical visits, change in exercise and alcohol consumption, daily life, social interactions, and financial stress since March 2020. Results: The cohort's mean age was 60.4 (19–92) years, with 54% female, 68% non-Hispanic White, 41% retired, 43% employed full or part-time, and 24% living in rural counties. Among the 27% of patients who reported receiving current treatment at HCI, 30% had to change or cancel a medical visit due to the pandemic, with 2% reported a change/cancellation in a biopsy, surgery, radiotherapy, and chemotherapy; 5% reported a change/cancellation in imaging; and 3% and 23% reported a change/cancellation in cancer screening and doctor's visit, respectively. 18% rescheduled an appointment to a telehealth visit. Changes in exercise habits due to the pandemic were common (47%), with 10% no longer exercising regularly, 21% exercising less, and 11% exercising more than before. 5% reported increased alcohol consumption, while 6% reported a decrease. Most patients (84%) experienced a change in their daily lives (ranging from somewhat to a lot of change). 69% had fewer social interactions, and 49% reported financial stress due to the pandemic, with 11% reporting being quite a bit/very much financially stressed. Conclusions: These findings suggest that within approximately the first 6 months, the COVID-19 pandemic had a substantial impact on cancer patients' lives, with adverse effects on health behaviors and financial stress. Healthcare delivery continued for essential cancer care but was disrupted for other services, such as cancer screening. Further analyses are underway. Funding: U01CA206110 and R01CA211705.

Purpose: The COVID-19 pandemic has disrupted many facets of life for rural and urban patients with cancer. Here, we characterize the impact of the pandemic on social and health behaviors of rural and urban cancer patients. Methods: N=1,326 adult cancer patients, who visited HCI in the last 4 years and enrolled in either Total Cancer Care or Precision Exercise Prescription studies, completed a COVID-19 survey. The survey was administered between Aug and Sept 2020 and included questions on demographic and clinical information as well as employment status, health behaviors, and COVID-19 prevention measures. Results: The mean age was 61 (19-92) years, with 54% female, 97% non-Hispanic White, 80% stage I-III, 42% employed full or part-time, 25% living in rural counties, and 85% reporting good to excellent overall health. Cancer patients in rural compared to urban counties were more likely to be older (rural=63 vs. urban=60 years; p=0.01), retired or not employed (rural=63% vs. urban=56%; p=0.04), not have health insurance coverage (rural=4% vs. urban=2%; p=0.01), and have ever smoked (rural=35% vs. urban=24%; p=0.001). However, urban patients reported “somewhat” to “a lot” of change in their daily lives more frequently than rural patients (urban=86% vs. rural=77%; p Citation Format: Bailee Daniels, Caroline Himbert, Cassandra A. Hathway, Tengda Lin, Karen Salas, Anjelica Ashworth, Anne C. Kirchhoff, Anna Beck, Cindy Matsen, Courtney Scaife, Cristina Christenson, Douglas Grossman, Howard Colman, Jason P. Hunt, Jennifer Ose, Jonathan Tward, Kevin B. Jones, Michael Deininger, Mikaela Larson, Paul LaStayo, Thomas Varghese, Tracy Onega, Wallace L. Akerley, Frank J. Penedo, Erin M. Siegel, Cornelia M. Ulrich, Shelley S. Tworoger, Anita R. Peoples. Impact of the COVID-19 pandemic on social and health behaviors among rural and urban cancer patients at Huntsman Cancer Institute (HCI) [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2021 Feb 3-5. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(6_Suppl):Abstract nr S04-03.

As clock signals are usually supplied by external rigid ICs, they may limit mechanical flexibility of devices fabricated on plastic. Reported in this letter is a full-swing clock generating circuit that is integrated on a plastic substrate. The clock signal is generated by a 13-stages ring oscillator (RO), which is implemented by n-type-only dual-gate amorphous-indium–gallium-zinc-oxide thin-film transistors. By combining bootstrapping and pseudo-CMOS inverting, an output peak-peak voltage ( $V_{\textrm {p-p}}$ ) that reaches the supply voltage ( $V_{\textrm {DD}}$ ) and a high speed, reaching an output frequency of 360 kHz, are achieved. In addition, a phase modulating capacitor is implemented in the RO to increase the high voltage level holding time and the addition of a buffer in the circuit is also studied for the achievement of two antiphase outputs.

Background: Fusobacterium nucleatum (Fn) plays an active role in normal host physiology and has been associated with colorectal carcinogenesis. To date, the role of Fn in newly diagnosed colorectal cancer patients is unclear. This is the first study to evaluate associations between Fn abundance and clinicopathologic characteristics among neoadjuvant chemotherapy naïve colorectal cancer patients. Methods: We used presurgery collected fecal stool samples from n=101 prospectively followed, newly diagnosed colorectal cancer patients from the ColoCare Cohort. Quantitative real-time polymerase chain reaction was used to amplify/detect Fn DNA in neoadjuvant chemotherapy-naïve patients, not using antibiotics for at least 1 month. Patients were classified into Fn-high (n=50) or Fn-low (n=51) groups based on median Fn Cycle thresholding (Ct) values (low≤16.72; high>16.72) in fecal DNA. Multivariable regression was utilized to analyze associations between Fn and clinicopathologic characteristics such as tumor stage, tumor site, and tumor grade. Results: We did not observe statistically significant differences in clinicopathologic or demographic characteristics by Fn abundance groups. Compared to the Fn-low patient group, Fn-high patients were 69% more likely to be diagnosed with stage III colorectal cancer (odds ratio [OR]=1.69, 95% confidence interval [CI] 1.56-15.93, P=0.0067), while there was no difference for stage I or II. Conclusion: Human gut microbial composition, including Fusobacterium nucleatum abundance, may be linked to colorectal cancer progression. Citation Format: Patrick Mallea, Christy A. Warby, W. Zac Stephens, Biljana Gigic, Kate Buhrke, Tengda Lin, Juergen Boehm, Sheetal Hardikar, Elisa K. Santori, Petra Schrotz-King, Martin Schneider, Alexis Ulrich, Eric A. Swanson, Adetunji T. Toriola, June Round, Cornelia M. Ulrich, Andreana N. Holowatyj, Jennifer Ose. Fusobacterium nucleatum and clinicopathologic features of colorectal carcinoma: Results from the ColoCare Cohort [abstract]. In: Proceedings of the AACR Special Conference on Modernizing Population Sciences in the Digital Age; 2019 Feb 19-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(9 Suppl):Abstract nr A05.

Background: Increased physical activity (PA) and higher overall tumor lymphocytic reaction score (LRS) are independently associated with improved outcomes in colorectal cancer (CRC) patients. However, the contribution of immune function to energy balance effects on CRC prognosis remains unclear. Methods: PA was self-reported prior to surgery (baseline) from nineteen stage I-III CRC patients enrolled in the ColoCare Study and computed into metabolic equivalent (MET) hr/week using the VITAL questionnaire. Objective PA measures were assessed using accelerometers (Actigraph GT3X+) worn 24 hr/day for 4+ consecutive days 12 months post-surgery. PA volume and intensity were derived from raw accelerometer data using ActiLife software and Freedson activity cut-points (moderate to vigorous exercise in bouts of >10 min). Clinicodemographic features were assessed by medical chart review. Clinical tumor blocks were pathologically scored for components of lymphocytic reaction (Crohn's-like reaction, peritumoral reaction, intratumoral periglandular reaction, and tumor-infiltrating lymphocytes [TILs]; individually scored: 0-3) and overall LRS (sum score: 0-12). Patients were categorized by mean overall LRS into low (0-4) and high (5-12) LRS groups. Mean and standard deviation values were calculated for PA and clinicodemographic features, and compared by overall LRS group using ANOVA tests. Spearman correlation coefficients were calculated to investigate the association between PA and lymphocytic reaction. Results: CRC patients were on average 58 years old, obese (mean body mass index=31.1 kg/m2), had a mean overall LRS of 4, reported 13.4 baseline MET hr/week and 11.5 MET hr/week 12 months post-surgery. Baseline body mass index was inversely correlated with intratumoral periglandular reaction (r=-0.32, p=0.002) and overall LRS (r=-0.62, p=0.005). Self-reported baseline MET hr/week had a strong positive correlation with overall LRS (r=0.83, p Conclusion: Together, findings from this pilot study suggest a correlation of energy balance components (PA and body composition) with lymphocytic reaction to colorectal cancer. Citation Format: Andreana N. Holowatyj, Richard Viskochil, Caroline Himbert, Tengda Lin, Jennifer Ose, Anita R. Peoples, Lyen C. Huang, Bartley Pickron, Courtney Scaife, Juergen Boehm, Sheetal Hardikar, Mary Bronner, Jane C. Figueiredo, Christopher Li, Martin Schneider, David Shibata, Erin Siegel, Adetunji T. Toriola, Maria Pletneva, Eric A. Swanson, Cornelia M. Ulrich. Physical activity is associated with lymphocytic reaction to colorectal cancer: A pilot study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5745.

Demographic, lifestyle and biospecimen-related factors at the time of blood collection can influence metabolite levels in epidemiological studies. Identifying the major influences on metabolite concentrations is critical to designing appropriate sample collection protocols and considering covariate adjustment in metabolomics analyses. We examined the association of age, sex, and other short-term pre-blood collection factors (time of day, season, fasting duration, physical activity, NSAID use, smoking and alcohol consumption in the days prior to collection) with 133 targeted plasma metabolites (acylcarnitines, amino acids, biogenic amines, sphingolipids, glycerophospholipids, and hexoses) among 108 individuals that reported exposures within 48 h before collection. The differences in mean metabolite concentrations were assessed between groups based on pre-collection factors using two-sided t-tests and ANOVA with FDR correction. Percent differences in metabolite concentrations were negligible across season, time of day of collection, fasting status or lifestyle behaviors at the time of collection, including physical activity or the use of tobacco, alcohol or NSAIDs. The metabolites differed in concentration between the age and sex categories for 21.8% and 14.3% metabolites, respectively. In conclusion, extrinsic factors in the short period prior to collection were not meaningfully associated with concentrations of selected endogenous metabolites in a cross-sectional sample, though metabolite concentrations differed by age and sex. Larger studies with more coverage of the human metabolome are warranted.

Background: Fusobacterium nucleatum (Fn), an oral commensal involved in a wide spectrum of infections, has recently been implicated in colorectal cancer (CRC) etiology. However, the role of Fn in treatment-naïve CRC patients remains unclear. Therefore, we assessed whether Fn abundance is associated with clinicopathologic characteristics among treatment-naïve CRC patients enrolled in the prospective ColoCare Study. Methods: Quantitative real-time PCR was used to amplify and detect Fn DNA in fecal samples collected prior to surgery from 105 patients. We utilized multivariable regression analysis to investigate associations between Fn abundance and sex, age at surgery, BMI, tumor stage, tumor grade, tumor site, infection with H. pylori, microsatellite instability, alcohol consumption, and smoking history by adjusting for sex, age at surgery, cohort, and BMI. Results: Compared to patients with undetectable or low abundance of Fn, patients with higher abundance of Fn were more likely to be diagnosed with rectal cancer than colon cancer (Odds Ratio [OR] = 3.01, 95% CI 1.06-8.57 P=0.04). Categorizing the colon into right-sided (proximal) and left-sided (distal) showed that patients with a high abundance of Fn were also more likely to be diagnosed with rectal cancer compared to right-sided colon cancer (OR=5.32, 95% CI 1.23-22.98 P=0.03), thus suggesting an increasing risk of cancer diagnosis along the bowel towards the rectum. Conclusion: Our study sheds light on the association of high abundance of Fn in fecal biospecimen with colorectal carcinogenesis, which may support future preventive or diagnostic measures. Citation Format: Yannick Eisele, Patrick M. Mallea, Biljana Gigic, W. Zac Stephens, Christy A. Warby, Kate Buhrke, Tengda Lin, Petra Schrotz-King, Sheetal Hardikar, Lyen C. Huang, T. Bartley Pickron, Courtney Scaife, Torsten Koelsch, Anita R. Peoples, Maria A. Pletneva, Mary Bronner, Martin Schneider, Alexis B. Ulrich, Eric A. Swanson, Adetunji T. Toriola, Hans Hauner, June Round, Cornelia M. Ulrich, Andreana N. Holowatyj, Jennifer Ose. Fusobacterium nucleatum and clinicopathologic features of colorectal carcinoma: Results from the ColoCare Study [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr A01.