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Immune responses to cancer are highly variable, with mismatch repair-deficient (MMRd) tumors exhibiting more anti-tumor immunity than mismatch repair-proficient (MMRp) tumors. To understand the rules governing these varied responses, we transcriptionally profiled 371,223 cells from colorectal tumors and adjacent normal tissues of 28 MMRp and 34 MMRd individuals. Analysis of 88 cell subsets and their 204 associated gene expression programs revealed extensive transcriptional and spatial remodeling across tumors. To discover hubs of interacting malignant and immune cells, we identified expression programs in different cell types that co-varied across tumors from affected individuals and used spatial profiling to localize coordinated programs. We discovered a myeloid cell-attracting hub at the tumor-luminal interface associated with tissue damage and an MMRd-enriched immune hub within the tumor, with activated T cells together with malignant and myeloid cells expressing T cell-attracting chemokines. By identifying interacting cellular programs, we reveal the logic underlying spatially organized immune-malignant cell networks.

BackgroundTo evaluate the association between postdiagnostic dairy intake and survival among patients with colorectal cancer (CRC).MethodsThis study analyzed data from the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). Postdiagnostic dairy intake and other dietary and lifestyle factors were obtained from validated questionnaires. Individual dairy items including milk, cheese, yogurt, and so on were reported, and total, high-fat, and low-fat dairy intakes were derived.ResultsA total of 1753 eligible CRC cases were identified until 2012, from which 703 deaths were documented after a median follow-up time of 8.2 y, and 242 were due to CRC. Overall, when comparing those who consumed 21+ servings/wk with

BackgroundBody mass index (BMI) and diabetes are established risk factors for colorectal cancer (CRC), likely through perturbations in metabolic traits (e.g. insulin resistance and glucose homeostasis). Identification of interactions between variation in genes and these metabolic risk factors may identify novel biologic insights into CRC etiology.MethodsTo improve statistical power and interpretation for gene-environment interaction (G × E) testing, we tested genetic variants that regulate expression of a gene together for interaction with BMI (kg/m2 ) and diabetes on CRC risk among 26 017 cases and 20 692 controls. Each variant was weighted based on PrediXcan analysis of gene expression data from colon tissue generated in the Genotype-Tissue Expression Project for all genes with heritability ≥1%. We used a mixed-effects model to jointly measure the G × E interaction in a gene by partitioning the interactions into the predicted gene expression levels (fixed effects), and residual G × E effects (random effects). G × BMI analyses were stratified by sex as BMI-CRC associations differ by sex. We used false discovery rates to account for multiple comparisons and reported all results with FDR

Background: Use of multivitamin supplements has been associated with lower incidence of colorectal cancer (CRC). However, its influence on CRC survival remains unknown. Methods: Among 2424 patients with stage I–III CRC who provided detailed information about multivitamin supplements in the Nurses' Health Study and Health Professionals Follow‐up Study, the authors calculated multivariable hazard ratios (HRs) of multivitamin supplements for all‐cause and CRC‐specific mortality according to post‐diagnostic use and dose of multivitamin supplements. Results: During a median follow‐up of 11 years, the authors documented 1512 deaths, among which 343 were of CRC. Compared to non‐users, post‐diagnostic users of multivitamin supplements at a dose of 3–5 tablets/week had lower CRC‐specific mortality (HR, 0.55; 95% confidence interval [CI], 0.36–0.83, p =.005), and post‐diagnostic users at doses of 3–5 and 6–9 tablets/week had lower all‐cause mortality (HR, 0.81; 95% CI, 0.67–0.99, p =.04; HR, 0.79; 95% CI, 0.70–0.88), p <.001). The dose–response analysis showed a curvilinear relationship for both CRC‐specific (pnonlinearity <.001) and all‐cause mortality (pnonlinearity =.004), with the maximum risk reduction observed at 3–5 tablets/week and no further reduction at higher doses. Compared to non‐users in both pre‐ and post‐diagnosis periods, new post‐diagnostic users at dose of <10 tablets/week had a lower all‐cause mortality (HR, 0.81; 95% CI, 0.71–0.94, p =.005), whereas new users at a dose of ≥10 tablets/week (HR, 1.58; 95% CI, 1.07–2.33) and discontinued users (HR, 1.35; 95% CI, 1.14–1.59) had a higher risk of mortality. Conclusions: Use of multivitamin supplements at a moderate dose after a diagnosis of nonmetastatic CRC is associated with lower CRC‐specific and overall mortality, whereas a high dose (≥10 tablets/week) use is associated with higher CRC‐specific mortality. In this prospective study of 2424 patients with stage I–III colorectal cancer (CRC), the authors observed a curvilinear relationship in the use of multivitamin supplements: compared to non‐users, users at a dose of 3–9 tablets/week had a lower risk of CRC‐specific and all‐cause mortality, whereas users at a dose higher than 10 tablets/week had a higher CRC‐specific mortality. [ABSTRACT FROM AUTHOR]

Background Colorectal cancer (CRC) is the third-most-common cancer worldwide and its rates are increasing. Elevated body mass index (BMI) is an established risk factor for CRC, although the molecular mechanisms behind this association remain unclear. Using the Mendelian randomization (MR) framework, we aimed to investigate the mediating effects of putative biomarkers and other CRC risk factors in the association between BMI and CRC. Methods We selected as mediators biomarkers of established cancer-related mechanisms and other CRC risk factors for which a plausible association with obesity exists, such as inflammatory biomarkers, glucose homeostasis traits, lipids, adipokines, insulin-like growth factor 1 (IGF1), sex hormones, 25-hydroxy-vitamin D, smoking, physical activity (PA) and alcohol consumption. We used inverse-variance weighted MR in the main univariable analyses and performed sensitivity analyses (weighted-median, MR–Egger, Contamination Mixture). We used multivariable MR for the mediation analyses. Results Genetically predicted BMI was positively associated with CRC risk [odds ratio per SD (5 kg/m2) = 1.17, 95% CI: 1.08–1.24, P -value = 1.4 × 10−5] and robustly associated with nearly all potential mediators. Genetically predicted IGF1, fasting insulin, low-density lipoprotein cholesterol, smoking, PA and alcohol were associated with CRC risk. Evidence for attenuation was found for IGF1 [explained 7% (95% CI: 2–13%) of the association], smoking (31%, 4–57%) and PA (7%, 2–11%). There was little evidence for pleiotropy, although smoking was bidirectionally associated with BMI and instruments were weak for PA. Conclusions The effect of BMI on CRC risk is possibly partly mediated through plasma IGF1, whereas the attenuation of the BMI–CRC association by smoking and PA may reflect confounding and shared underlying mechanisms rather than mediation. [ABSTRACT FROM AUTHOR]

Identifying and distinguishing risk factors for heterogeneous disease subtypes has been of great interest. However, missingness in disease subtypes is a common problem in those data analyses. Several methods have been proposed to deal with the missing data, including complete-case analysis, inverse-probability weighting, and multiple imputation. Although extant literature has compared these methods in missing problems, none has focused on the competing risk setting. In this paper, we discuss the assumptions required when complete-case analysis, inverse-probability weighting, and multiple imputation are used to deal with the missing failure subtype problem, focusing on how to implement these methods under various realistic scenarios in competing risk settings. Besides, we compare these three methods regarding their biases, efficiency, and robustness to model misspecifications using simulation studies. Our results show that complete-case analysis can be seriously biased when the missing completely at random assumption does not hold. Inverse-probability weighting and multiple imputation estimators are valid when we correctly specify the corresponding models for missingness and for imputation, and multiple imputation typically shows higher efficiency than inverse-probability weighting. However, in real-world studies, building imputation models for the missing subtypes can be more challenging than building missingness models. In that case, inverse-probability weighting could be preferred for its easy usage. We also propose two automated model selection procedures and demonstrate their usage in a study of the association between smoking and colorectal cancer subtypes in the Nurses' Health Study and Health Professional Follow-Up Study. [ABSTRACT FROM AUTHOR]

Background Growing evidence indicates the adverse effect of ultra-processed food (UPF) consumption. However, it remains unknown whether UPF consumption influences the risk of colorectal cancer (CRC) precursors, namely conventional adenomas and serrated lesions. Methods We drew data from the Nurses' Health Study, Nurses' Health Study II, and Health Professionals Follow-up Study, comprising 142 052 participants who had undergone at least 1 lower gastrointestinal endoscopy during follow-up. To handle multiple records per participants, we used multivariable logistic regression for clustered data to calculate odds ratios (OR) and 95% confidence intervals (CIs) of colorectal polyps in relation to cumulative average consumption of UPFs. All statistical tests were 2-sided. Results We documented 11 644 patients with conventional adenomas and 10 478 with serrated lesions during 18-20 years of follow-up. Compared with participants in the lowest quintile of UPF consumption, those in the highest quintile had an increased risk of conventional adenomas (OR = 1.18, 95% CI = 1.11 to 1.26) and serrated lesions (OR = 1.20, 95% CI = 1.13 to 1.28). Similar results were found for high-risk polyps (ie, advanced adenomas and ≥10 mm serrated lesions; OR = 1.17, 95% CI = 1.07 to 1.28). These associations were slightly attenuated but remained statistically significant after further adjusting for body mass index, Western dietary pattern score, or individual dietary factors (fiber, folate, calcium, and vitamin D). The results remained essentially unchanged after excluding processed meat from total UPF intake. Conclusions Higher consumption of UPFs is associated with an increased risk of CRC precursors. UPFs might be a modifiable target for early prevention of CRC. [ABSTRACT FROM AUTHOR]

It remains unknown whether maintenance of a healthy lifestyle after endoscopic polypectomy could still confer benefit for colorectal cancer (CRC) incidence and mortality. In this study, we defined a healthy lifestyle score based on body mass index, smoking, physical activity, alcohol consumption and diet (range, 0‐5). We used Cox proportional hazards regression to estimate the hazard ratios (HRs) for the associations of healthy lifestyle score and individual lifestyle factors with CRC incidence and all‐cause mortality. During a median of 10 years of follow‐up of 24 668 participants who underwent endoscopic polypectomy, we documented 161 CRC cases and 4857 all‐cause deaths. A higher healthy lifestyle score after endoscopic polypectomy was associated with lower risk of CRC and all‐cause mortality. Compared with individuals with 0 to 1 healthy lifestyle factors, those with 2, 3 and 4 to 5 healthy lifestyle factors had a HR for CRC risk of 0.86 (95% confidence interval [CI], 0.60‐1.24), 0.73 (95% CI, 0.47‐1.14) and 0.52 (95% CI, 0.27‐1.01), respectively (Ptrend =.03). The corresponding HR (95% CI) for all‐cause mortality was 0.83 (95% CI, 0.76‐0.90), 0.63 (95% CI, 0.56‐0.70) and 0.56 (95% CI, 0.48‐0.65), respectively (Ptrend <.0001). In the joint analysis of pre‐ and postpolypectomy periods, patients with a healthy postpolypectomy lifestyle had a lower incidence of CRC regardless of their prepolypectomy exposure, whereas those with a healthy lifestyle in both periods had a lower mortality than those with an unhealthy lifestyle in either period. In conclusion, adherence to a healthy lifestyle after polypectomy may confer significant benefit for CRC prevention and reduction in all‐cause mortality. [ABSTRACT FROM AUTHOR]

Background: Although high T cell density is a strong favourable prognostic factor in colorectal cancer, the significance of the spatial distribution of T cells is incompletely understood. We aimed to evaluate the prognostic significance of tumour cell-T cell co-localisation and T cell densities.Methods: We analysed CD3 and CD8 immunohistochemistry in a study cohort of 983 colorectal cancer patients and a validation cohort (N = 246). Individual immune and tumour cells were identified to calculate T cell densities (to derive T cell density score) and G-cross function values, estimating the likelihood of tumour cells being co-located with T cells within 20 µm radius (to derive T cell proximity score).Results: High T cell proximity score associated with longer cancer-specific survival in both the study cohort [adjusted HR for high (vs. low) 0.33, 95% CI 0.20-0.52, Ptrend < 0.0001] and the validation cohort [adjusted HR for high (vs. low) 0.15, 95% CI 0.05-0.45, Ptrend < 0.0001] and its prognostic value was independent of T cell density score.Conclusions: The spatial point pattern analysis of tumour cell-T cell co-localisation could provide detailed information on colorectal cancer prognosis, supporting the value of spatial measurement of T cell infiltrates as a novel, robust tumour-immune biomarker. [ABSTRACT FROM AUTHOR]

Emerging evidence implicates the importance of perinatal and early-life exposures in colorectal cancer (CRC) development. However, it remains unclear whether being breastfed in infancy is associated with CRC risk in adult life, particularly early adulthood. We prospectively investigated the association between history of being breastfed and risk of CRC and its precursor lesions among 66,634 women 46–93 years of age from the Nurses' Health Study and 92,062 women 27–68 years of age from the Nurses' Health Study II. Cox regression and logistic regression for clustered data were used to estimate hazard ratios for CRC and odds ratios for CRC precursors, respectively. During 3.5 million person-years of follow-up, we identified 1490 incident cases of CRC in 2 cohorts. Having been breastfed was associated with a 23% (95% confidence interval [CI], 10% to 38%) increased risk of CRC. The risk of CRC increased with duration of being breastfed (P trend <.001). These findings were validated using breastfeeding information from the mothers of a subset of participants. Among younger participants from the Nurses' Health Study II, a significant association was observed between being breastfed and increased risk of high-risk adenomas under 50 years of age (odds ratio, 1.46; 95% CI, 1.16 to 1.83). Consistently, having been breastfed was associated with increased risk of CRC among participants ≤55 years of age (hazard ratio, 1.38; 95% CI, 1.06 to 1.80). Being breastfed in infancy was associated with increased risk of CRC in adulthood, including among younger adults. However, further research is needed to understand the underlying biological mechanisms, as this association does not establish causation. [ABSTRACT FROM AUTHOR]

Liver metastasis is a major cause of mortality in patients with advanced stages of colorectal cancer (CRC). The gut microbiota has been demonstrated to influence the progression of liver diseases, potentially providing novel perspectives for diagnosis, treatment and research. However, the gut microbial characteristics in CRC with liver metastasis (LM) and with no liver metastasis (NLM) have not yet been fully established. In the present study, high-throughput 16S RNA sequencing technology was employed, in order to examine the gut microbial richness and composition in patients with CRC with LM or NLM. A discovery cohort (cohort 2; LM=18; NLM=36) and a validation cohort (cohort 3; LM=13; NLM=41) were established using fresh feces. In addition, primary carcinoma tissue samples were also analyzed (LM=8 and NLM=10) as a supplementary discovery cohort (cohort 1). The findings of the present study indicated that the intestinal microbiota richness and diversity were increased in the LM group as compared to the NLM group. A significant difference was observed in species composition between the LM and NLM group. In the two discovery cohorts with two different samples, the dominant phyla were consistent, but varied at lower taxonomic levels. Phylum Fusobacteria presented consistent and significant enrichment in LM group in both discovery cohorts. Furthermore, with the application of a random forest model and receiver operator characteristic curve analysis, Fusobacteria was identified as a potential biomarker for LM. Moreover, Fusobacteria was also a poor prognosis factor for survival. Importantly, the findings were reconfirmed in the validation cohort. On the whole, the findings of the present study demonstrated that CRC with LM and NLM exhibit distinct gut microbiota characteristics. Fusobacteria detection thus has potential for use in predicting LM and a poor prognosis of patients with CRC. [ABSTRACT FROM AUTHOR]

Simple Summary: In this cross-sectional study, the global incidence, death, and DALY rates of early-onset colorectal cancer (CRC) increased from 1990 to 2019, with large variations in the regional and national levels. A low-milk or low-calcium diet and alcohol use were the leading possible risk factors in 2019. The importance of high body mass index and high fasting plasma glucose increased among both males and females from 1990 to 2019, while the importance of smoking and a low-fiber diet decreased among both sexes, but especially among females. These findings provide policymakers with an accurate quantification of the burden of early-onset CRC, and may help to identify and target high-risk individuals to mitigate the burden of early-onset CRC. Background: The incidence of early-onset colorectal cancer (CRC) diagnosed before age 50 has been increasing over the past decades. Hence, we examined the global, regional, and national burden of early-onset CRC and its risk factors from 1990 to 2019. Methods: Using data from the Global Burden of Disease (GBD) Study 2019, we reported the incidence, deaths, and disability-adjusted life-years (DALYs) attributable to the risk factors of early-onset CRC. All estimates were reported with 95% uncertainty intervals (UIs). Results: The global numbers of early-onset CRC for incidence, deaths, and DALYs in 2019 were 225,736 (95% UI, 207,658 to 246,756), 86,545 (80,162 to 93,431), and 4,259,922 (3,942,849 to 4,590,979), respectively. Despite large variations at the regional and national levels, the global incidence rate, death rate, and DALY rate increased from 1990 to 2019. Diets low in milk, diets low in calcium, and alcohol use were the leading risk factors in 2019. From 1990 to 2019, a high body mass index and high fasting plasma glucose ranked remarkably higher among males and females, while smoking and diets low in fiber ranked lower among both sexes, with a more profound change among females. Conclusions: Despite large variations in regional and national levels, the global incidence rate, death rate, and DALY rate increased during the past three decades. These findings may provide policymakers with an accurate quantification of the burden of early-onset CRC and targeted identification of those most at risk to mitigate the burden of early-onset CRC. [ABSTRACT FROM AUTHOR]

Tumor‐associated macrophages (TAMs) have a unique favorable effect on the prognosis of colorectal cancer (CRC), although their association with stage‐specific outcomes remains unclear. We assessed the densities of CD68+ and CD163+ TAMs at the invasive front of resected CRC stage III CRC from 236 patients, 165 of whom received post‐surgical FOLFOX treatment, and their relationship with disease‐free survival (DFS). Associations between macrophage mRNAs and clinical outcome were investigated in silico in 59 stage III CRC and FOLFOX‐treated patients from The Cancer Genome Atlas (TCGA). Biological interactions of SW480 and HT29 cells and macrophages with FOLFOX were tested in co‐culture models. Low TAM densities were associated with shorter DFS among patients receiving FOLFOX (CD68+, p = 0.0001; CD163+, p = 0.0008) but not among those who were untreated. By multivariate Cox analysis, only low TAM (CD68+, p = 0.001; CD163+, p = 0.002) and nodal status (CD68+, p = 0.009; CD163+, p = 0.007) maintained an independent predictive value. In the TCGA cohort, high CD68 mRNA levels were associated with better outcome (p = 0.02). Macrophages enhanced FOLFOX cytotoxicity on CRC cells (p < 0.01), and drugs oriented macrophage polarization from M2‐ to M1‐phenotype. Low TAM densities identify stage III CRC patients at higher risk of recurrence after adjuvant therapy, and macrophages can augment the chemo‐sensitivity of micro‐metastases. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is a heterogeneous disease with evidence of distinct tumor types that develop through different somatically altered pathways. To better understand the impact of the host genome on somatically mutated genes and pathways, we assessed associations of germline variations with somatic events via two complementary approaches. We first analyzed the association between individual germline genetic variants and the presence of non-silent somatic mutations in genes in 1375 CRC cases with genome-wide SNPs data and a tumor sequencing panel targeting 205 genes. In the second analysis, we tested if germline variants located within previously identified regions of somatic allelic imbalance were associated with overall CRC risk using summary statistics from a recent large scale GWAS (n≃125 k CRC cases and controls). The first analysis revealed that a variant (rs78963230) located within a CNA region associated with TLR3 was also associated with a non-silent mutation within gene FBXW7. In the secondary analysis, the variant rs2302274 located in CDX1/PDGFRB frequently gained/lost in colorectal tumors was associated with overall CRC risk (OR = 0.96, p = 7.50e-7). In summary, we demonstrate that an integrative analysis of somatic and germline variation can lead to new insights about CRC. [ABSTRACT FROM AUTHOR]

Background Recent preclinical research strongly suggests that dietary sugars can enhance colorectal tumorigenesis by direct action, particularly in the proximal colon that unabsorbed fructose reaches. Objectives We aimed to examine long-term consumption of sugar-sweetened beverages (SSBs) and total fructose in relation to incidence and mortality of colorectal cancer (CRC) by anatomic subsite. Methods We followed 121,111 participants from 2 prospective US cohort studies, the Nurses' Health Study (1984–2014) and Health Professionals Follow-Up Study (1986–2014), for incident CRC and related death. Cox proportional hazards regression was used to compute HRs and 95% CIs. Results During follow-up, we documented 2733 incident cases of CRC with a known anatomic location, of whom 901 died from CRC. Positive associations of SSB and total fructose intakes with cancer incidence and mortality were observed in the proximal colon but not in the distal colon or rectum (P heterogeneity ≤ 0.03). SSB consumption was associated with a statistically significant increase in the incidence of proximal colon cancer (HR per 1-serving/d increment: 1.18; 95% CI: 1.03, 1.34; P trend = 0.02) and a more pronounced elevation in the mortality of proximal colon cancer (HR: 1.39; 95% CI: 1.13, 1.72; P trend = 0.002). Similarly, total fructose intake was associated with increased incidence and mortality of proximal colon cancer (HRs per 25-g/d increment: 1.18; 95% CI: 1.03, 1.35; and 1.42; 95% CI: 1.12, 1.79, respectively). Moreover, SSB and total fructose intakes during the most recent 10 y, rather than those from a more distant period, were associated with increased incidence of proximal colon cancer. Conclusions SSB and total fructose consumption were associated with increased incidence and mortality of proximal colon cancer, particularly during later stages of tumorigenesis. [ABSTRACT FROM AUTHOR]

Simple Summary: This paper presents an extended version of the Cox regression model to examine heterogeneous effects of risk factors on disease subtypes defined by a continuous biomarker. This approach can be easily applied to cancer studies and is accessible to researchers via user-friendly R scripts. Molecular pathologic diagnosis is important in clinical (oncology) practice. Integration of molecular pathology into epidemiological methods (i.e., molecular pathological epidemiology) allows for investigating the distinct etiology of disease subtypes based on biomarker analyses, thereby contributing to precision medicine and prevention. However, existing approaches for investigating etiological heterogeneity deal with categorical subtypes. We aimed to fully leverage continuous measures available in most biomarker readouts (gene/protein expression levels, signaling pathway activation, immune cell counts, microbiome/microbial abundance in tumor microenvironment, etc.). We present a cause-specific Cox proportional hazards regression model for evaluating how the exposure–disease subtype association changes across continuous subtyping biomarker levels. Utilizing two longitudinal observational prospective cohort studies, we investigated how the association of alcohol intake (a risk factor) with colorectal cancer incidence differed across the continuous values of tumor epigenetic DNA methylation at long interspersed nucleotide element-1 (LINE-1). The heterogeneous alcohol effect was modeled using different functions of the LINE-1 marker to demonstrate the method's flexibility. This real-world proof-of-principle computational application demonstrates how the new method enables visualizing the trend of the exposure effect over continuous marker levels. The utilization of continuous biomarker data without categorization for investigating etiological heterogeneity can advance our understanding of biological and pathogenic mechanisms. [ABSTRACT FROM AUTHOR]

Identification of new genetic markers may improve the prediction of colorectal cancer prognosis. Our objective was to examine genome-wide associations of germline genetic variants with disease-specific survival in an analysis of 16,964 cases of colorectal cancer. We analyzed genotype and colorectal cancer-specific survival data from a consortium of 15 studies. Approximately 7.5 million SNPs were examined under the log-additive model using Cox proportional hazards models, adjusting for clinical factors and principal components. Additionally, we ran secondary analyses stratifying by tumor site and disease stage. We used a genome-wide p-value threshold of 5 × 10–8 to assess statistical significance. No variants were statistically significantly associated with disease-specific survival in the full case analysis or in the stage-stratified analyses. Three SNPs were statistically significantly associated with disease-specific survival for cases with tumors located in the distal colon (rs698022, HR = 1.48, CI 1.30–1.69, p = 8.47 × 10–9) and the proximal colon (rs189655236, HR = 2.14, 95% CI 1.65–2.77, p = 9.19 × 10–9 and rs144717887, HR = 2.01, 95% CI 1.57–2.58, p = 3.14 × 10–8), whereas no associations were detected for rectal tumors. Findings from this large genome-wide association study highlight the potential for anatomical-site-stratified genome-wide studies to identify germline genetic risk variants associated with colorectal cancer-specific survival. Larger sample sizes and further replication efforts are needed to more fully interpret these findings. [ABSTRACT FROM AUTHOR]

The proximal and distal subsites of colorectal cancer (CRC) have distinct differences in their embryonic origin, epidemiology, and prognosis. Therefore, they are not considered as the same disease. However, the possible difference in microbial characterization of the two subsites of CRC is still unclear. In this study, we explored tumor microbiota diversity and composition difference in patients with proximal (N = 187) and distal CRCs (N = 142). This was carried out on cancer tissues and adjacent tissues using bacterial 16S rRNA sequencing. The Kaplan–Meier method was used to analyze the correlation between differential flora and overall survival rate of the patients. It was found that there were significant differences in tumor microbial characteristics between the proximal and distal CRC tissues. The microbiota communities were distinctly richer in the proximal colon tumor tissues than in the distal CRC tissues. Microbial diversity and structure were relatively constant in the paracancerous normal tissues of the proximal and distal colorectum. Generally, microbial communities of CRC tumor tissues were composed of Proteobacteria, Firmicutes, Actinobacteria, and Bacteroidetes. Alpha diversity in the proximal and distal CRC tumor tissues was closely related to specific microflora. The abundance of Fusobacteria was associated with age of patient, tumor diameter, and tumor microsatellite instability (MSI) status of the patients. Moreover, Fusobacteria enrichment was associated with poor prognosis especially in patients with proximal colon cancers, but not in patients with distal CRC. In conclusion, proximal and distal subsites of the CRC present distinct microbiota diversity and community structures. The differences indicate that there are different risk factors across anatomical subsites of CRC, which may provide a new strategy for precise prevention and treatment of CRC in the future. [ABSTRACT FROM AUTHOR]

Background: It remains unknown whether the benefit of colonoscopy screening against colorectal cancer (CRC) and the optimal age to start screening differ by CRC risk profile.Methods: Among 75 873 women and 42 875 men, we defined a CRC risk score (0-8) based on family history, aspirin, height, body mass index, smoking, physical activity, alcohol, and diet. We calculated colonoscopy screening-associated hazard ratios and absolute risk reductions (ARRs) for CRC incidence and mortality and age-specific CRC cumulative incidence according to risk score. All statistical tests were 2-sided.Results: During a median of 26 years of follow-up, we documented 2407 CRC cases and 874 CRC deaths. Although the screening-associated hazard ratio did not vary by risk score, the ARRs in multivariable-adjusted 10-year CRC incidence more than doubled for individuals with scores 6-8 (ARR = 0.34%, 95% confidence interval [CI] = 0.26% to 0.42%) compared with 0-2 (ARR = 0.15%, 95% CI = 0.12% to 0.18%, Ptrend < .001). Similar results were found for CRC mortality (ARR = 0.22%, 95% CI = 0.21% to 0.24% vs 0.08%, 95% CI = 0.07% to 0.08%, Ptrend < .001). The ARR in mortality of distal colon and rectal cancers was fourfold higher for scores 6-8 than 0-2 (distal colon cancer: ARR = 0.08%, 95% CI = 0.07% to 0.08% vs 0.02%, 95% CI = 0.02% to 0.02%, Ptrend < .001; rectal cancer: ARR = 0.08%, 95% CI = 0.08% to 0.09% vs 0.02%, 95% CI = 0.02% to 0.03%, Ptrend < .001). When using age 45 years as the benchmark to start screening, individuals with risk scores of 0-2, 3, 4, 5, and 6-8 attained the threshold CRC risk level (10-year cumulative risk of 0.47%) at age 51 years, 48 years, 45 years, 42 years, and 38 years, respectively.Conclusions: The absolute benefit of colonoscopy screening is more than twice higher for individuals with the highest than lowest CRC risk profile. Individuals with a high- and low-risk profile may start screening up to 6-7 years earlier and later, respectively, than the recommended age of 45 years. [ABSTRACT FROM AUTHOR]

Most risk prediction models for colorectal cancer (CRC) are based on questionnaires and show a modest discriminatory ability. Therefore, we aim to develop risk prediction models incorporating plasma biomarkers for CRC to improve discrimination. We assessed the predictivity of 11 biomarkers in 736 men in the Health Professionals Follow‐up Study and 639 women in the Nurses' Health Study. We used stepwise logistic regression to examine whether a set of biomarkers improved the predictivity on the basis of predictors in the National Cancer Institute's (NCI) Colorectal Cancer Risk Assessment Tool. Model discrimination was assessed using C‐statistics. Bootstrap with 500 randomly sampled replicates was used for internal validation. The models containing each biomarker generated a C‐statistic ranging from 0.50 to 0.59 in men and 0.50 to 0.54 in women. The NCI model demonstrated a C‐statistic (95% CI) of 0.67 (0.62‐0.71) in men and 0.58 (0.54‐0.63) in women. Through stepwise selection of biomarkers, the C‐statistic increased to 0.70 (0.66‐0.74) in men after adding growth/differentiation factor 15, total adiponectin, sex hormone binding globulin and tumor necrosis factor receptor superfamily member 1B (P for difference = 0.008); and increased to 0.62 (0.57‐0.66) in women after further including insulin‐like growth factor 1 and insulin‐like growth factor‐binding protein 3 (P for difference =.06). The NCI + selected biomarkers model was internally validated with a C‐statistic (95% CI) of 0.73 (0.70‐0.77) in men and 0.66 (0.61‐0.70) in women. Circulating plasma biomarkers may improve the performance of risk factor‐based prediction model for CRC. What's new? Most risk prediction models for colorectal cancer are based on questionnaires and have shown a modest discriminatory ability. Based on data from two U.S. cohorts, here the authors present a risk prediction model using questionnaire information and plasma biomarker measurements. Adding growth/differentiation factor 15, total adiponectin, sex hormone binding globulin, and tumour necrosis factor receptor superfamily member 1B for men and insulin‐like growth factor 1 and insulin‐like growth factor‐binding protein 3 for women slightly increased the discriminatory accuracy. These results provide proof of principle for the inclusion of biomarkers into colorectal cancer risk assessment to improve early detection and surveillance. [ABSTRACT FROM AUTHOR]

Background: The influence of a high sugar diet on colorectal cancer (CRC) survival is unclear.Methods: Among 1463 stage I-III CRC patients from the Nurses' Health Study and Health Professionals Follow-up Study, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for CRC-specific and all-cause mortality in relation to intake of post-diagnosis sugar-sweetened beverages (SSB), artificially sweetened beverages (ASB), fruit juice, fructose and other sugars.Results: Over a median 8.0 years, 781 cases died (173 CRC-specific deaths). Multivariable-adjusted HRs for post-diagnosis intake and CRC-specific mortality were 1.21 (95% CI: 0.87-1.68) per 1 serving SSBs per day (serving/day) and 1.24 (95% CI: 0.95-1.63) per 20 grams fructose per day. Significant positive associations for CRC-specific mortality were primarily observed ≤5 years from diagnosis (HR per 1 serving/day of SSBs = 1.59, 95% CI: 1.06-2.38). Significant inverse associations were observed between ASBs and CRC-specific and all-cause mortality (HR for ≥5 versus <1 serving/week = 0.44, 95% CI: 0.26-0.75 and 0.70, 95% CI: 0.55-0.89, respectively).Conclusions: Higher post-diagnosis intake of SSBs and sugars may be associated with higher CRC-specific mortality, but only up to 5 years from diagnosis, when more deaths were due to CRC. The inverse association between ASBs and CRC-specific mortality warrants further examination. [ABSTRACT FROM AUTHOR]

Background: The role of poor diet quality in the rising incidence of colorectal cancer (CRC) diagnosed younger than age 50 years has not been explored. Based on molecular features of early-onset CRC, early-onset adenomas are emerging surrogate endpoints.Methods: In a prospective cohort study (Nurses' Health Study II), we evaluated 2 empirical dietary patterns (Western and prudent) and 3 recommendation-based indexes (Dietary Approaches to Stop Hypertension [DASH], Alternative Mediterranean Diet [AMED], and Alternative Healthy Eating Index [AHEI]-2010) with risk of early-onset adenoma overall and by malignant potential (high-risk: ≥1 cm, tubulovillous or villous histology, high-grade dysplasia, or ≥3 adenomas), among 29 474 women with 1 or more lower endoscopy before age 50 years (1991-2011). Multivariable logistic regressions were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs).Results: We documented 1157 early-onset adenomas with 375 at high risk. Western diet was positively associated, whereas prudent diet, DASH, AMED, and AHEI-2010 were inversely associated with risk of early-onset adenoma. The associations were largely confined to high-risk adenomas (the highest vs lowest quintile: Western, OR = 1.67, 95% CI = 1.18 to 2.37; prudent, OR = 0.69, 95% CI = 0.48 to 0.98; DASH, OR = 0.65, 95% CI = 0.45 to 0.93; AMED, OR = 0.55, 95% CI = 0.38 to 0.79; AHEI-2010, OR = 0.71, 95% CI = 0.51 to 1.01; all Ptrend ≤ .03), driven by those identified in the distal colon and rectum (all Ptrend ≤ .04, except AMED: Ptrend = .14).Conclusion: Poor diet quality was associated with an increased risk of early-onset distal and rectal adenomas of high malignant potential. These findings provide preliminary but strong support to the role of diet in early-onset CRC. [ABSTRACT FROM AUTHOR]

Background: Healthy lifestyle and screening represent 2 major approaches to colorectal cancer (CRC) prevention. It remains unknown whether the CRC-preventive benefit of healthy lifestyle differs by endoscopic screening status, and how the combination of healthy lifestyle with endoscopic screening can improve CRC prevention.Methods and Findings: We assessed lifestyle and endoscopic screening biennially among 75,873 women (Nurses' Health Study, 1988 to 2014) and 42,875 men (Health Professionals Follow-up Study, 1988 to 2014). We defined a healthy lifestyle score based on body mass index, smoking, physical activity, alcohol consumption, and diet. We calculated hazard ratios (HRs) and population-attributable risks (PARs) for CRC incidence and mortality in relation to healthy lifestyle score according to endoscopic screening. Participants' mean age (standard deviation) at baseline was 54 (8) years. During a median of 26 years (2,827,088 person-years) follow-up, we documented 2,836 incident CRC cases and 1,013 CRC deaths. We found a similar association between healthy lifestyle score and lower CRC incidence among individuals with and without endoscopic screening, with the multivariable HR per one-unit increment of 0.85 (95% CI, 0.80 to 0.90) and 0.85 (95% CI, 0.81 to 0.88), respectively (P-interaction = 0.99). The fraction of CRC cases that might be prevented (PAR) by endoscopic screening alone was 32% (95% CI, 31% to 33%) and increased to 61% (95% CI, 42% to 75%) when combined with healthy lifestyle (score = 5). The corresponding PAR (95% CI) increased from 15% (13% to 16%) to 51% (17% to 74%) for proximal colon cancer and from 47% (45% to 50%) to 75% (61% to 84%) for distal CRC. Results were similar for CRC mortality. A limitation of our study is that our study participants are all health professionals and predominantly whites, which may not be representative of the general population.Conclusions: Our study suggests that healthy lifestyle is associated with lower CRC incidence and mortality independent of endoscopic screening. An integration of healthy lifestyle with endoscopic screening may substantially enhance prevention for CRC, particularly for proximal colon cancer, compared to endoscopic screening alone. [ABSTRACT FROM AUTHOR]

Serrated polyps (SPs) and conventional adenomas represent 2 distinct groups of colorectal premalignancy. The influence of early life adiposity on risk of these precursors remains unclear. Within the Nurses' Health Study, the Nurses' Health Study 2, and the Health Professionals Follow‐up Study, we assessed body fatness during childhood using 9‐level somatotype and obtained weight and body mass index (BMI) in adulthood. We used multivariable‐adjusted logistic regression to examine the association of SPs and conventional adenomas with body fatness in early childhood (age 5), late childhood (age 10), early adulthood (age 18/21) and middle adulthood (baseline) and weight change during early‐to‐middle adulthood. During 18–20 years of follow‐up, we documented 8,697 SPs and 10,219 conventional adenomas in 132,514 women; 2,403 SPs and 4,495 conventional adenomas in 29,207 men. We found a modest positive association of adiposity in early and late childhood with risk of SPs and conventional adenomas, with odds ratios ranging from 1.12 to 1.18 for comparison of extreme somatotypes groups. The associations were attenuated after adjusting for adulthood BMI but remained significant for conventional adenomas. No association with early life body fatness was found in men. Adulthood body fatness and weight change during early‐to‐middle adulthood showed positive relationships with SPs and conventional adenomas in both women and men, with stronger associations observed for SPs (pheterogeneity < 0.0001). Our findings indicated a potential role in development of colorectal cancer precursors of childhood body fatness in women, and early‐to‐middle adulthood weight gain and attained adiposity in both sexes. What's new? Being overweight in childhood may increase the risk of colon cancer in adulthood. Here, the authors set out to quantify the effect of childhood adiposity on the risk of 2 different colorectal cancer precursors, serrated polyps and conventional adenomas. They collected data on body mass from various points throughout people's lifetime. Excess fat in early and late childhood had a small positive association with risk of serrated polyps and conventional adenomas in women, with odds ratios between 1.12‐1.28. These findings suggest that childhood obesity could lay the groundwork for the formation of colorectal cancer precursors. [ABSTRACT FROM AUTHOR]

Anthropometric measurements, such as body mass index (BMI), waist circumference, and body fat percentage, have been used as indicators of obesity. Despite evidence that excess body fat is a risk factor for colorectal carcinoma (CRC), the magnitude of the association of BMI and other obesity indicators with the long‐term risk of CRC remains unclear. Utilizing a Cox proportional hazards regression model, we examined differential associations between predicted body fat percentage and BMI with the risk of CRC (n = 2,017). The associations between CRC incidence and different adiposity measurements were also assessed. Predicted body fat percentage had a similar increased risk of CRC risk as BMI. In multivariable‐adjusted analyses, the hazard ratio for CRC in the second to fifth quintiles (compared to the first quintile) of predicted body fat percentage were 1.32, 1.31, 1.53 and 2.09 for men (ptrend < 0.001) and 0.91, 0.90, 0.98 and 1.15 for women (ptrend = 0.03). Among various anthropometric measurements, predicted fat mass and waist circumference were slightly more strongly associated with CRC risk than BMI. In conclusion, the novel anthropometric prediction equations provided further evidence that a greater amount of body fat might contribute to CRC risk in both sexes. An innovative approach enabled us to estimate the susceptibilities of specific body composition with CRC risk, in an inexpensive and minimally invasive manner. Furthermore, the typically used measures of BMI and waist circumference are robust measures of adiposity to predict cancer risk in a relatively healthy population. What's new? While excess body fat is linked to increased colorectal cancer (CRC) risk, the degree to which specific factors, such as body mass index (BMI) and waist circumference, predict long‐term CRC risk is unclear. In this investigation, data from two U.S. prospective cohorts and novel anthropometric prediction equations highly correlated with dual‐energy X‐ray absorptiometry measures were used to examine the long‐term influence of specific body composition on CRC risk. Analyses show that predicted body fat percentage and BMI share similar associations with CRC risk in both sexes. Hence, no marked heterogeneity was observed in CRC risk estimation across adiposity measures. [ABSTRACT FROM AUTHOR]

The goals in clinical and cohort studies often include evaluation of the association of a time-dependent binary treatment or exposure with a survival outcome. Recently, several impactful studies targeted the association between initiation of aspirin and survival following colorectal cancer (CRC) diagnosis. The value of this exposure is zero at baseline and may change its value to one at some time point. Estimating this association is complicated by having only intermittent measurements on aspirin-taking. Commonly used methods can lead to substantial bias. We present a class of calibration models for the distribution of the time of status change of the binary covariate. Estimates obtained from these models are then incorporated into the proportional hazard partial likelihood in a natural way. We develop non-parametric, semiparametric, and parametric calibration models, and derive asymptotic theory for the methods that we implement in the aspirin and CRC study. We further develop a risk-set calibration approach that is more useful in settings in which the association between the binary covariate and survival is strong. [ABSTRACT FROM AUTHOR]

Background: Increasing evidence suggests that conventional adenomas (CAs) and serrated polyps (SPs) represent two distinct groups of precursor lesions for colorectal cancer (CRC). The influence of common genetic variants on risk of CAs and SPs remain largely unknown.Methods: Among 27 426 participants within three prospective cohort studies, we created a weighted genetic risk score (GRS) based on 40 CRC-related single nucleotide polymorphisms (SNPs) identified in previous genome-wide association studies; and we examined the association of GRS (per one standard deviation increment) with risk of CAs, SPs and synchronous CAs and SPs, by multivariable logistic regression. We also analysed individual variants in the secondary analysis.Results: During 18-20 years of follow-up, we documented 2952 CAs, 1585 SPs and 794 synchronous CAs and SPs. Higher GRS was associated with increased risk of CAs [odds ratio (OR) = 1.17, 95% confidence interval (CI): 1.12-1.21] and SPs (OR = 1.09, 95% CI: 1.03-1.14), with a stronger association for CAs than SPs (Pheterogeneity=0.01). An even stronger association was found for patients with synchronous CAs and SPs (OR = 1.32), advanced CAs (OR = 1.22) and multiple CAs (OR = 1.25). Different sets of variants were associated with CAs and SPs, with a Spearman correlation coefficient of 0.02 between the ORs associating the 40 SNPs with the two lesions. After correcting for multiple testing, three variants were associated with CAs (rs3802842, rs6983267 and rs7136702) and two with SPs (rs16892766 and rs4779584).Conclusions: Common genetic variants play a potential role in the conventional and serrated pathways of CRC. Different sets of variants are identified for the two pathways, further supporting the aetiological heterogeneity of CRC. [ABSTRACT FROM AUTHOR]

Mitochondrial DNA (mtDNA) is susceptible to oxidative stress and mutation. Few epidemiological studies have assessed the relationship between mtDNA copy number (mtDNAcn) and risk of colorectal cancer (CRC), with inconsistent findings. In this study, we examined the association between pre-diagnostic leukocyte mtDNAcn and CRC risk in a case–control study of 324 female cases and 658 matched controls nested within the Nurses' Health Study (NHS). Relative mtDNAcn in peripheral blood leukocytes was measured by quantitative polymerase chain reaction-based assay. Conditional logistic regression models were applied to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) for the association of interest. Results showed lower log-mtDNAcn was significantly associated with increased risk of CRC, in a dose-dependent relationship (P for trend < 0.0001). Compared to the fourth quartile, multivariable-adjusted OR [95% confidence interval (CI)] was 1.10 (0.69, 1.76) for the third quartile, 1.40 (0.89, 2.19) for the second quartile and 2.19 (1.43, 3.35) for the first quartile. In analysis by anatomic subsite of CRC, we found a significant inverse association for proximal colon cancer [lowest versus highest quartile, multivariable-adjusted OR (95% CI) = 3.31 (1.70, 6.45), P for trend = 0.0003]. Additionally, stratified analysis according to the follow-up time since blood collection showed that the inverse association between mtDNAcn and CRC remained significant among individuals with ≥ 5 years' follow-up, and marginally significant among those with ≥ 10 years' follow-up since mtDNAcn testing, suggesting that mtDNAcn may serve as a long-term predictor for risk of CRC. In conclusion, pre-diagnostic leukocyte mtDNAcn was inversely associated with CRC risk. Further basic experimental studies are needed to explore the underlying biological mechanisms linking mtDNAcn to CRC carcinogenesis. [ABSTRACT FROM AUTHOR]

Epidemiologic evidence relating fiber intake to colorectal cancer (CRC) remains inconclusive and data are limited on different food sources of fiber and heterogeneity by tumor subsite and molecular profile. We prospectively followed for CRC incidence 90,869 women from the Nurses' Health Study (1980–2012) and 47,924 men from the Health Professionals Follow‐up Study (1986–2012), who completed a validated food frequency questionnaire every 4 years. Cox proportional hazards regression was used to examine the associations with CRC risk for total, cereal, fruit and vegetable fiber and whole grains. We also assessed the associations according to tumor subsites (proximal colon, distal colon and rectum) and molecular markers (microsatellite instability, BRAF mutation, CpG island methylator phenotype and KRAS mutation). We documented 3,178 CRC cases during 3,685,903 person‐years of follow‐up in the NHS and HPFS. Intake of total dietary fiber was not associated with CRC risk after multivariable adjustment in either women (hazard ratio [HR] comparing extreme deciles, 1.17; 95% CI, 0.92–1.48, ptrend = 0.55) or men (HR, 0.90; 95% CI, 0.67–1.21, ptrend = 0.47). Higher intake of cereal fiber and whole grains was associated with lower CRC risk in men with an HR of 0.75 (95% CI, 0.57–1.00) and 0.72 (95% CI, 0.54–0.96), respectively. No heterogeneity was detected by tumor subsite or molecular markers (pheterogeneity > 0.05). Higher intake of total dietary fiber within the range of a typical American diet is unlikely to substantially reduce CRC risk. The potential benefit of cereal fiber and whole grains in men warrants further confirmation. What's new? Epidemiologic evidence relating fiber intake to colorectal cancer (CRC) remains inconclusive and data are still limited on different food sources and heterogeneity by tumor subsite and molecular profile. Here, total dietary fiber intake within the range of a typical American diet was not found to be associated with CRC risk after adjusting for other dietary and lifestyle factors. Higher intake of cereal fiber and whole grains was associated with lower CRC risk in men. Associations of dietary fiber and CRC did not vary by tumor subsites and molecular markers (microsatellite instability, BRAF mutation, CpG island methylator phenotype, and KRAS mutation). [ABSTRACT FROM AUTHOR]

Background: Individuals with a family history of cancer may be at increased risk of pancreatic cancer. Ashkenazi Jewish (AJ) individuals carry increased risk for pancreatic cancer and other cancer types.Methods: We examined the association between family history of cancer, AJ heritage, and incident pancreatic cancer in 49 410 male participants of the prospective Health Professionals Follow-up Study. Hazard ratios (HRs) were estimated using multivariable-adjusted Cox proportional hazards models.Results: During 1.1 million person-years (1986-2016), 452 participants developed pancreatic cancer. Increased risk of pancreatic cancer was observed in individuals with a family history of pancreatic (HR, 2.79; 95% confidence interval [CI], 1.28-6.07) or breast cancer (HR, 1.40; 95% CI, 1.01-1.94). There was a trend towards higher risk of pancreatic cancer in relation to a family history of colorectal cancer (HR, 1.21; 95% CI, 0.95-1.55) or AJ heritage (HR, 1.29; 95% CI, 0.94-1.77). The risk was highly elevated among AJ men with a family history of breast or colorectal cancer (HR, 2.61 [95% CI, 1.41-4.82] and 1.92 [95% CI, 1.05-3.49], respectively).Conclusion: Family history of pancreatic cancer was associated with increased risk of this malignancy. Family history of breast or colorectal cancer was associated with the increased risk among AJ men. [ABSTRACT FROM AUTHOR]

Background: Evidence suggests that diets inducing postprandial hyperinsulinemia may be associated with increased cancer-related mortality. The goal of this study was to assess the influence of postdiagnosis dietary insulin load and dietary insulin index on outcomes of stage III colon cancer patients.Methods: We conducted a prospective observational study of 1023 patients with resected stage III colon cancer enrolled in an adjuvant chemotherapy trial who reported dietary intake halfway through and six months after chemotherapy. We evaluated the association of dietary insulin load and dietary insulin index with cancer recurrence and survival using Cox proportional hazards regression adjusted for potential confounders; statistical tests were two-sided.Results: High dietary insulin load had a statistically significant association with worse disease-free survival (DFS), comparing the highest vs lowest quintile (adjusted hazard ratio [HR] = 2.77, 95% confidence interval [CI] = 1.90 to 4.02, Ptrend < .001). High dietary insulin index was also associated with worse DFS (highest vs lowest quintile, HR = 1.75, 95% CI = 1.22 to 2.51, Ptrend= .01). The association between higher dietary insulin load and worse DFS differed by body mass index and was strongest among patients with obesity (HR = 3.66, 95% CI = 1.88 to 7.12, Pinteraction = .04). The influence of dietary insulin load on cancer outcomes did not differ by mutation status of KRAS, BRAF, PIK3CA, TP53, or microsatellite instability.Conclusions: Patients with resected stage III colon cancer who consumed a high-insulinogenic diet were at increased risk of recurrence and mortality. These findings support the importance of dietary management following resection of colon cancer, and future research into underlying mechanisms of action is warranted. [ABSTRACT FROM AUTHOR]

Purpose: Observational studies have demonstrated increased colon cancer recurrence and mortality in states of excess energy balance, as denoted by factors including sedentary lifestyle, diabetes, increased dietary glycemic load, and increased intake of sugar-sweetened beverages. Nonetheless, the relation between artificially sweetened beverages, a popular alternative for sugar-sweetened beverages, and colon cancer recurrence and survival is unknown. Methods: We analyzed data from 1,018 patients with stage III colon cancer who prospectively reported dietary intake during and after chemotherapy while enrolled in a National Cancer Institute-sponsored trial of adjuvant chemotherapy. Using Cox proportional hazards regressions, we assessed associations of artificially sweetened beverage intake with cancer recurrence and mortality. Results: Patients consuming one or more 12-ounce servings of artificially sweetened beverages per day experienced an adjusted hazard ratio for cancer recurrence or mortality of 0.54 (95% confidence interval, 0.36 to 0.80) when compared to those who largely abstained (Ptrend = .004). Similarly, increasing artificially sweetened beverage intake was also associated with a significant improvement in both recurrence-free survival (Ptrend = .005) and overall survival (Ptrend = .02). Substitution models demonstrated that replacing a 12-ounce serving of a sugar-sweetened beverage with an isovolumetric serving of an artificially sweetened beverage per day was associated with a 23% lower risk of cancer recurrence and mortality (relative risk, 0.77; 95% confidence interval, 0.63 to 0.95; P = .02). Conclusion: Higher artificially sweetened beverage consumption may be associated with significantly reduced cancer recurrence and death in patients with stage III colon cancer. This association may be mediated by substitution for sugar-sweetened alternatives. Further studies are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

We expanded and updated our colon cancer risk model to evaluate colorectal cancer (CRC) and whether subsite-specific risk models are warranted. Using data from 1980-2010 for 90,286 women enrolled in the Nurses' Health Study, we performed competing-risks regression and tests for subsite heterogeneity (proximal colon: n = 821 ; distal colon: n = 521 ; rectum: n = 376). Risk factors for CRC were consistent with those in our colon cancer model. Processed meat consumption was associated with a higher risk of distal (hazard ratio (HR) = 1.45; P = 0.02) but not proximal (HR = 0.95; P = 0.72) colon cancer. Smoking was associated with both colon (HR = 1.21) and rectal (HR = 1.27) cancer and was more strongly associated with proximal (HR = 1.31) than with distal (HR = 1.04) colon cancer (P = 0.029). We observed a significant trend of cancer risk for smoking in subsites from the cecum (HR = 1.41) to the proximal colon (excluding the cecum; HR = 1.27) to the distal colon (HR = 1.04; P for trend = 0.040). The C statistics for colorectal (C = 0.607), colon (C = 0.603), and rectal (C = 0.639) cancer were similar, although C was slightly higher for rectal cancer. Despite evidence for site-specific differences for several risk factors, overall our findings support the application of risk prediction models for colon cancer to CRC. [ABSTRACT FROM AUTHOR]

Periodontal diseases including tooth loss might increase systemic inflammation, lead to immune dysregulation and alter gut microbiota, thereby possibly influencing colorectal carcinogenesis. Few epidemiological studies have examined the association between periodontal diseases and colorectal cancer (CRC) risk. We collected information on the periodontal disease (defined as history of periodontal bone loss) and number of natural teeth in the Nurses' Health Study. A total of 77,443 women were followed since 1992. We used Cox proportional hazard models to calculate multivariable hazard ratios (HRs) and 95% confidence intervals (95% CIs) after adjustment for smoking and other known risk factors for CRC. We documented 1,165 incident CRC through 2010. Compared to women with 25-32 teeth, the multivariable HR (95% CI) for CRC for women with <17 teeth was 1.20 (1.04-1.39). With regard to tumor site, the HRs (95% CIs) for the same comparison were 1.23 (1.01-1.51) for proximal colon cancer, 1.03 (0.76-1.38) for distal colon cancer and 1.48 (1.07-2.05) for rectal cancer. In addition, compared to those without periodontal disease, HRs for CRC were 0.91 (95% CI 0.74-1.12) for periodontal disease, and 1.22 (95% CI 0.91-1.63) when limited to moderate to severe periodontal disease. The results were not modified by smoking status, body mass index or alcohol consumption. Women with fewer teeth, possibly moderate or severe periodontal disease, might be at a modest increased risk of developing CRC, suggesting a potential role of oral health in colorectal carcinogenesis. [ABSTRACT FROM AUTHOR]