Smoking Behavior and Prognosis After Colorectal Cancer Diagnosis: A Pooled Analysis of 11 Studies.

Background: Smoking has been associated with colorectal cancer (CRC) incidence and mortality in previous studies, but current evidence on smoking in association with survival after CRC diagnosis is limited. Methods: We pooled data from 12 345 patients with stage I-IV CRC from 11 epidemiologic studies in the International Survival Analysis in Colorectal Cancer Consortium. Cox proportional hazards regression models were used to evaluate the associations of prediagnostic smoking behavior with overall, CRC-specific, and non-CRC-specific survival. Results: Among 12 345 patients with CRC, 4379 (35.5%) died (2515 from CRC) over a median follow-up time of 7.5 years. Smoking was strongly associated with worse survival in stage I-III patients, whereas no association was observed among stage IV patients. Among stage I-III patients, clear dose-response relationships with all survival outcomes were seen for current smokers. For example, current smokers with 40 or more pack-years had statistically significantly worse overall, CRC-specific, and non-CRC-specific survival compared with never smokers (hazard ratio [HR] =1.94, 95% confidence interval [CI] =1.68 to 2.25; HR = 1.41, 95% CI = 1.12 to 1.78; and HR = 2.67, 95% CI = 2.19 to 3.26, respectively). Similar associations with all survival outcomes were observed for former smokers who had quit for less than 10 years, but only a weak association with non-CRC-specific survival was seen among former smokers who had quit for more than 10 years. Conclusions: This large consortium of CRC patient studies provides compelling evidence that smoking is strongly associated with worse survival of stage I-III CRC patients in a clear dose-response manner. The detrimental effect of smoking was primarily related to noncolorectal cancer events, but current heavy smoking also showed an association with CRC-specific survival.

Physical Activity and Long-term Quality of Life among Colorectal Cancer Survivors-A Population-based Prospective Study.

Evidence suggests that physical activity (PA) is positively associated with (health-related) quality of life (QOL) in colorectal cancer survivors. However, little is known regarding long-term effects of PA on QOL and if prediagnosis PA is associated with QOL in the years after diagnosis. Our study aimed to investigate the association of prediagnosis and postdiagnosis PA with long-term QOL in colorectal cancer survivors.This study is based on a population-based cohort from Germany of 1,781 newly diagnosed colorectal cancer survivors over a 5-year period. PA was assessed at diagnosis and at 5-year follow-up (5YFU). Quality of life was assessed by the European Organisation for Research and Treatment of Cancer C Quality of Life Questionnaire QLQ-C30 at 5YFU. Multivariable linear regression was used to explore associations between prediagnosis and postdiagnosis PA and QOL at 5YFU.No evidence of a positive association between higher levels of prediagnosis PA and better long-term QOL was found. Higher levels of prediagnosis work-related PA and vigorous PA were even associated with decreased QOL in domains such as cognitive [Beta(ß) = -2.52, 95% confidence interval (CI) = -3.77, -1.27; ß = -1.92, CI = -3.17, -0.67) and emotional functioning (ß = -2.52, CI = -3.84, -1.19; ß = -2.12, CI = -3.44, -0.80). In cross-sectional analyses, higher postdiagnosis PA was strongly associated with higher QOL. Survivors physically active at both prediagnosis and postdiagnosis as well as survivors who increased their PA between prediagnosis and postdiagnosis reported significantly higher long-term QOL compared with survivors who remained inactive at prediagnosis and postdiagnosis. In this study, higher prediagnosis PA does not appear to be associated with higher QOL among long-term colorectal cancer survivors but our results support the importance of ongoing PA throughout survivorship.

Magnitude of the Age-Advancement Effect of Comorbidities in Colorectal Cancer Prognosis.

BACKGROUND: Comorbidities and old age independently compromise prognosis of patients with colorectal cancer (CRC). The impact of comorbidities could thus be considered as conveying worse prognosis already at younger ages, but evidence is lacking on how much worsening of prognosis with age is advanced to younger ages in comorbid versus noncomorbid patients. We aimed to quantify, for the first time, the impact of comorbidities on CRC prognosis in "age advancement" of worse prognosis. METHODS: A total of 4,602 patients aged ≥30 years who were diagnosed with CRC in 2003 through 2014 were recruited into a population-based study in the Rhine-Neckar region of Germany and observed over a median period of 5.1 years. Overall comorbidity was quantified using the Charlson comorbidity index (CCI). Hazard ratios and age advancement periods (AAPs) for comorbidities were calculated from multivariable Cox proportional hazards models for relevant survival outcomes. RESULTS: Hazard ratios for CCI scores 1, 2, and ≥3 compared with CCI 0 were 1.25, 1.53, and 2.30 (P<.001) for overall survival and 1.20, 1.48, and 2.03 (P<.001) for disease-free survival, respectively. Corresponding AAP estimates for CCI scores 1, 2, and ≥3 were 5.0 (95% CI, 1.9-8.1), 9.7 (95% CI, 6.1-13.3), and 18.9 years (95% CI, 14.4-23.3) for overall survival and 5.5 (95% CI, 1.5-9.5), 11.7 (95% CI, 7.0-16.4), and 21.0 years (95% CI, 15.1-26.9) for disease-free survival. Particularly pronounced effects of comorbidity on CRC prognosis were observed in patients with stage I-III CRC. CONCLUSIONS: Comorbidities advance the commonly observed deterioration of prognosis with age by many years, meaning that at substantially younger ages, comorbid patients with CRC experience survival rates comparable to those of older patients without comorbidity. This first derivation of AAPs may enhance the empirical basis for treatment decisions in patients with comorbidities and highlight the need to incorporate comorbidities into prognostic nomograms for CRC.

Treatment selection bias for chemotherapy persists in colorectal cancer patient cohort studies even in comprehensive propensity score analyses.

INTRODUCTION: Propensity score methods are increasingly used to address confounding related to treatment selection in observational studies. Studies estimating the effect of chemotherapy in colon cancer (CC) patients, however, often lacked information on pertinent comorbidities and functional status (FS). We assessed to what extent comorbidities and FS impact treatment decisions in colorectal cancer patients and explain the benefit of chemotherapy in stage III CC patients. METHODS: Stage II-III colorectal cancer patients diagnosed in 2003-2014 and recruited into a population-based study were included (N=1102). Associations of comorbidity and FS with treatment patterns were examined with multivariable logistic regression. The contribution of lower comorbidity and higher FS to the benefit of chemotherapy was estimated with propensity score weighted Cox models in 430 stage III CC patients who were followed over a median time of 4.7 years. RESULTS: In stage II (high-risk) and III CC patients, Charlson comorbidity scores 1, 2 and 3+ were associated with 57%, 66% and 70% lower odds of chemotherapy use, respectively. In combination with older age and poor FS, comorbidity was associated with 97% and 83% decreased odds of adjuvant chemotherapy use in CC and rectal cancer patients, respectively. In stage III CC patients, lower comorbidity and higher FS explained 38% and 24% of the overall and disease-specific survival benefits of chemotherapy, respectively. Selection bias was observed even in the comprehensive models, as chemotherapy was still associated with substantially higher non-disease-specific survival (hazard ratio (HR): 0.66; 95% confidence interval (CI): 0.46-0.92), especially in patients <75 years (HR: 0.33; 95% CI: 0.17-0.63). CONCLUSION: Lower comorbidity and higher FS of recipients of chemotherapy explain approximately 40% of the benefits of chemotherapy in stage III CC patients. Regardless of how comprehensive propensity score analyses might be in observational studies, treatment selection bias might persist and affect estimates of treatment effects.

Decreasing Use of Chemotherapy in Older Patients With Stage III Colon Cancer Irrespective of Comorbidities.

BACKGROUND: Chemotherapy underuse in elderly patients (aged ≥75 years) with colon cancer has been reported in previous studies. However, these studies were mostly registry-based and limited in their potential to consider underlying reasons of such undertreatment. This study aimed to evaluate patient and hospital determinants of chemotherapeutic treatment in patients with stage III colon cancer, with a particular focus on age and underlying reasons for nontreatment of elderly patients. METHODS: A total of 629 patients with stage III colon cancer who were diagnosed in 2003 through 2012 and recruited into a population-based study in the Rhine-Neckar region of Germany were included. Information on sociodemographic and lifestyle factors, comorbidities, and treatment was collected from patient interviews and physicians. Patient (with an emphasis on age) and hospital factors were evaluated for their associations with administration of adjuvant chemotherapy overall and of oxaliplatin specifically using multivariable logistic regression. RESULTS: Administration of chemotherapy decreased from 94% in patients aged 30 to 64 years to 51% in those aged ≥75 years. A very strong decline in chemotherapy use with age persisted even after comprehensive adjustment for multiple patient factors-including comorbidities-and hospital factors and was also seen among patients without any major comorbidities. Between 2005 and 2008, and 2009 and 2012, chemotherapy administration in patients aged ≥75 years decreased from 60% to 41%. Among chemotherapy recipients, old age was also strongly associated with higher odds of nonadministration of oxaliplatin. The 2 most commonly reported reasons for chemotherapy nonreceipt among the study population were patient refusal (30%) and old age (24%). CONCLUSIONS: Age was the strongest predictor of chemotherapy underuse, irrespective of comorbidities and even in patients without comorbidities. Such underuse due just to older age in otherwise healthy patients deserves increased attention in clinical practice to ensure that elderly patients also get the best possible care. Patients' refusal as the most frequent reason for chemotherapy nonreceipt also warrants further investigation to exclude misinformation as underlying cause.

A prognostic CpG score derived from epigenome-wide profiling of tumor tissue was independently associated with colorectal cancer survival.

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

External validation of molecular subtype classifications of colorectal cancer based on microsatellite instability, CIMP, BRAF and KRAS.

BACKGROUND: Competing molecular classification systems have been proposed to complement the TNM staging system for a better prediction of survival in colorectal cancer (CRC). However, validation studies are so far lacking. The aim of this study was to validate and extend previously published molecular classifications of CRC in a large independent cohort of CRC patients. METHODS: CRC patients were recruited into a population-based cohort study (DACHS). Molecular subtypes were categorized based on three previously published classifications. Cox-proportional hazard models, based on the same set of patients and using the same confounders as reported by the original studies, were used to determine overall, cancer-specific, or relapse-free survival for each subtype. Hazard ratios and confidence intervals, as well as Kaplan-Meier plots were compared to those reported by the original studies. RESULTS: We observed similar patterns of worse survival for the microsatellite stable (MSS)/BRAF-mutated and MSS/KRAS-mutated subtypes in our validation analyses, which were included in two of the validated classifications. Of the two MSI subtypes, one defined by additional presence of CIMP-high and BRAF-mutation and the other by tumors negative for CIMP, BRAF and KRAS-mutations, we could not confirm associations with better prognosis as suggested by one of the classifications. For two of the published classifications, we were able to provide results for additional subgroups not included in the original studies (men, other disease stages, other locations). CONCLUSIONS: External validation of three previously proposed classifications confirmed findings of worse survival for CRC patients with MSS subtypes and BRAF or KRAS mutations. Regarding MSI subtypes, other patient characteristics such as stage of the tumor, may influence the potential survival benefit. Further integration of methylation, genetic, and immunological information is needed to develop and validate a comprehensive classification that will have relevance for use in clinical practice.

An individual participant data meta-analysis on metabolomics profiles for obesity and insulin resistance in European children.

Childhood obesity prevalence is rising in countries worldwide. A variety of etiologic factors contribute to childhood obesity but little is known about underlying biochemical mechanisms. We performed an individual participant meta-analysis including 1,020 pre-pubertal children from three European studies and investigated the associations of 285 metabolites measured by LC/MS-MS with BMI z-score, height, weight, HOMA, and lipoprotein concentrations. Seventeen metabolites were significantly associated with BMI z-score. Sphingomyelin (SM) 32:2 showed the strongest association with BMI z-score (P = 4.68 × 10-23) and was also closely related to weight, and less strongly to height and LDL, but not to HOMA. Mass spectrometric analyses identified SM 32:2 as myristic acid containing SM d18:2/14:0. Thirty-five metabolites were significantly associated to HOMA index. Alanine showed the strongest positive association with HOMA (P = 9.77 × 10-16), while acylcarnitines and non-esterified fatty acids were negatively associated with HOMA. SM d18:2/14:0 is a powerful marker for molecular changes in childhood obesity. Tracing back the origin of SM 32:2 to dietary source in combination with genetic predisposition will path the way for early intervention programs. Metabolic profiling might facilitate risk prediction and personalized interventions in overweight children.

Genome-wide DNA methylation analysis reveals a prognostic classifier for non-metastatic colorectal cancer (ProMCol classifier).

OBJECTIVE: Pathological staging used for the prediction of patient survival in colorectal cancer (CRC) provides only limited information. DESIGN: Here, a genome-wide study of DNA methylation was conducted for two cohorts of patients with non-metastatic CRC (screening cohort (n=572) and validation cohort (n=274)). A variable screening for prognostic CpG sites was performed in the screening cohort using marginal testing based on a Cox model and subsequent adjustment of the p-values via independent hypothesis weighting using the methylation difference between 34 pairs of tumour and normal mucosa tissue as auxiliary covariate. From the 1000 CpG sites with the smallest adjusted p-value, 20 CpG sites with the smallest Brier score for overall survival (OS) were selected. Applying principal component analysis, we derived a prognostic methylation-based classifier for patients with non-metastatic CRC (ProMCol classifier). RESULTS: This classifier was associated with OS in the screening (HR 0.51, 95% CI 0.41 to 0.63, p=6.2E-10) and the validation cohort (HR 0.61, 95% CI 0.45 to 0.82, p=0.001). The independent validation of the ProMCol classifier revealed a reduction of the prediction error for 3-year OS from 0.127, calculated only with standard clinical variables, to 0.120 combining the clinical variables with the classifier and for 4-year OS from 0.153 to 0.140. All results were confirmed for disease-specific survival. CONCLUSION: The ProMCol classifier could improve the prognostic accuracy for patients with non-metastatic CRC.

The Association Between Mutations in BRAF and Colorectal Cancer-Specific Survival Depends on Microsatellite Status and Tumor Stage.

BACKGROUND & AIMS: Colorectal tumors with mutations in BRAF and microsatellite stability (MSS) have been associated with adverse outcomes of patients. Combined tests for microsatellite instability-high (MSI-H) and BRAF mutations might therefore be used in risk assessment, particularly for patients with stage II tumors. We investigate the stage-specific prognostic value of combined testing for MSI-H and BRAF for patients with colorectal cancer. METHODS: We performed a retrospective analysis of colorectal tumor samples collected from 1995 patients at 22 hospitals in Germany, between 2003 and 2010. Samples were analyzed for MSI-H using an established mononucleotide marker panel; BRAF mutations (BRAFV600E) were detected by Sanger sequencing or in tissue microarray blocks using immunohistochemistry. Cancers were assigned to categories of having MSS without mutations in BRAF, MSS with mutant BRAF, MSI-H without mutations in BRAF, and MSI-H with mutant BRAF. We investigated the association between tumor categories with clinical and pathologic features and patient's overall, disease-specific, and recurrence-free survival (median follow-up time, 5.1 y). RESULTS: Tumors were stage I in 364 (18%), stage II in 678 (34%), stage III in 673 (34%), and stage IV (14%) in 280 patients. Sixty-three percent of tumors were located in the colon and 37% in the rectum. Most tumors (85%) had MSS without mutations in BRAF, 3% had MSS with mutant BRAF, 7% had MSI-H without mutations in BRAF, and 5% had MSI-H with mutant BRAF. In patients whose tumors were MSI-H, mutation of BRAF did not significantly affect survival time. Patients whose tumors had MSS with mutant BRAF had significantly reduced overall survival (hazard ratio [HR], 2.16; 95% CI, 1.54-3.04; P < .001), disease-specific survival (HR, 2.59; 95% CI, 1.77-3.79; P < .001), and recurrence-free survival (HR, 2.45; 95% CI, 1.70-3.52; P < .001) than patients whose tumors had MSS without BRAF mutation. Although BRAF mutations in tumors with MSS were associated with disease-specific survival of patients with stage III or IV tumors (P < .001), these features did not affect survival of patients with stage II tumors (P = .639). CONCLUSIONS: In an analysis of almost 2000 patients with colorectal cancer, we found BRAF mutations to reduce survival of patients in stage III or IV (but not stage II) tumors with MSS. These findings do not support testing stage I or II colorectal tumors for BRAF mutations, although additional large studies are needed.

Association of Aspirin and Nonsteroidal Anti-Inflammatory Drugs With Colorectal Cancer Risk by Molecular Subtypes.

BACKGROUND: Regular use of aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) for a longer period has been inversely associated with colorectal cancer (CRC) risk. However, CRC is a heterogenic disease, and little is known regarding the associations with molecular pathological subtypes. METHODS: Analyses included 2444 cases with a first diagnosis of CRC and 3130 healthy controls from a German population-based case control study. Tumor tissue samples were analyzed for major molecular pathological features: microsatellite instability (MSI), CpG island methylator phenotype, B-Raf proto-oncogene serine/threonine kinase (BRAF) mutation, and Kirsten rat sarcoma viral oncogene homolog gene (KRAS) mutation. Information on past and current use of NSAIDs, including aspirin, was obtained by standardized interviews. Multinomial logistic regression models were used to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). All statistical tests were two-sided. RESULTS: Regular use of NSAIDs was associated with a reduced CRC risk if tumors were MSS (OR = 0.66, 95% CI = 0.57 to 0.77), BRAF wildtype (OR = 0.67, 95% CI = 0.58 to 0.78), or KRAS wildtype (OR = 0.68, 95% CI = 0.58 to 0.80). Regular NSAID use was less clearly and mostly not statistically significantly associated with CRC risk reduction for MSI-high, BRAF-mutated, or KRAS-mutated CRC. In more specific analyses on MSI-high CRC, regular use of NSAIDs was associated with much stronger risk reduction in the absence of BRAF or KRAS mutations (OR = 0.34, 95% CI = 0.18 to 0.65) but not with KRAS- or BRAF-mutated MSI-high CRC (Pheterogeneity < .001). Results for just aspirin use were similar. CONCLUSION: Our study suggests variation in risk reduction of CRC subtypes following regular use of NSAIDs and aspirin. Regular use of NSAIDs and aspirin may be more strongly associated with risk reduction of MSI-high CRC without KRAS or BRAF mutation.

Association Between Intake of Red and Processed Meat and Survival in Patients With Colorectal Cancer in a Pooled Analysis.

BACKGROUND & AIMS: Red and processed meat intake is associated with colorectal cancer (CRC) incidence, but it is not clear if intake is associated with patient survival after diagnosis. METHODS: We pooled data from 7627 patients with stage I-IV CRC from 10 studies in the International Survival Analysis in Colorectal Cancer Consortium. Cox proportional hazards regression models were used to evaluate the associations of intake of red and processed meat before diagnosis with overall and CRC-specific survival. RESULTS: Among 7627 patients with CRC, 2338 died, including 1576 from CRC, over a median follow-up time of 5.1 years. In multivariable-adjusted analyses, higher intake of red or processed meat was not associated with overall survival of patients with stage I-III CRC: Q4 vs Q1 red meat hazard ratio [HR], 1.08 (95% CI, 0.93-1.26) and Q4 vs Q1 processed meat HR, 1.10 (95% CI, 0.93-1.32) or with CRC-specific survival: Q4 vs Q1 red meat HR, 1.09 (95% CI, 0.89-1.33) and Q4 vs Q1 processed meat HR, 1.11 (95% CI, 0.87-1.42). Results were similar for patients with stage IV CRC. However, patients with stage I-III CRC who reported an intake of processed meat above the study-specific medians had a higher risk of death from any cause (HR, 1.12; 95% CI, 1.01-1.25) than patients who reported eating at or less than the median. CONCLUSION: In this large consortium of CRC patient cohorts, intake of red and processed meat before a diagnosis of CRC was not associated with shorter survival time after diagnosis, although a possible weak adverse association cannot be excluded. Studies that evaluate dietary data from several time points before and after cancer diagnosis are required to confirm these findings.

Healthy Lifestyle Factors Associated With Lower Risk of Colorectal Cancer Irrespective of Genetic Risk.

BACKGROUND & AIMS: The combined effects of healthy lifestyle factors on colorectal cancer (CRC) risk are unclear. We aimed to develop a healthy lifestyle score, to investigate the joint effects of modifiable lifestyle factors on reduction of CRC risk and determine whether associations differ with genetic risk. METHODS: We collected data from a large population-based case-control study in Germany and used multiple logistic regression analyses to examine associations between the healthy lifestyle score (derived from 5 modifiable lifestyle factors: smoking, alcohol consumption, diet, physical activity, and body fatness) and CRC risk. We created a genetic risk score, based on 53 risk variants, to investigate the association of the healthy lifestyle score and risk of CRC, stratified by genetic risk. RESULTS: We included 4092 patients with CRC and 3032 individuals without CRC (controls) in our analysis. In adjusted models, compared with participants with 0 or 1 healthy lifestyle factor, participants with 2 (odds ratio [OR] 0.85; 95% confidence interval [CI] 0.67-1.06), 3 (OR 0.62; 95% CI 0.50-0.77), 4 (OR 0.53; 95% CI 0.42-0.66), or 5 (OR 0.33; 95% CI 0.26-0.43) healthy lifestyle factors had increasingly lower risks of CRC (P trend <.0001). We found no differences among subgroups stratified by genetic risk score, history of colonoscopy, or family history of CRC. Overall, 45% of CRC cases (95% CI 34%-53%) could be attributed to nonadherence to all 5 healthy lifestyle behaviors. CONCLUSIONS: In a large population-based case-control study, we identified a combination of lifestyle factors that appears to reduce risk of CRC, regardless of the patient's genetic profile. These results reinforce the importance of primary prevention of CRC.

Potential determinants of physical inactivity among long-term colorectal cancer survivors.

PURPOSE: Since physical activity (PA) has been shown to be associated with better prognosis and quality of life (QOL) in colorectal cancer (CRC) patients, this study focuses on the barriers of PA among CRC survivors. METHODS: This study is based on a population-based study from Germany of 1343 women and men, diagnosed with CRC between 2003 and 2008 and being alive five years later. Multivariable logistic regression was used to explore associations between baseline as well as five-year follow-up (5YFU) characteristics and physical inactivity (PIA) at 5YFU. Quartiles were calculated based on metabolic equivalent hours per week of PA at baseline and at 5YFU. Participants in quartile 1 were defined as physically inactive, and patients in quartile 2 to quartile 4 were defined as physically active. RESULTS: Cancer-specific factors such as having a stoma (odds ratio (OR) = 1.51, 95% confidence interval (CI) = 1.12-2.04), demographic factors such as living in a small town or city (OR = 1.46, 95% CI = 1.05-2.02; OR = 1.42, 95% CI = 1.01-2.02), older age (OR = 1.44, 95% CI = 0.80-2.58), or being divorced (OR = 1.72, 95% CI = 0.96-3.07), as well as lifestyle factors such as being a current smoker (OR = 1.54, 95% CI = 1.04-2.29) or being obese (OR = 1.43, 95% CI = 0.96-2.13) were associated with PIA at 5YFU. Subgroup analyses showed that the association between body mass index  and PIA was stronger in women than in men. Baseline PA was identified as a strong predictor of PIA at 5YFU. CONCLUSIONS: Findings suggest that predominately patients with a stoma, patients living in a more populated area, being older, divorced, a current smoker, or obese were more likely to be physically inactive and therefore could be targeted to be more physically active. IMPLICATIONS FOR CANCER SURVIVORS: Addressing barriers for PA might help to develop specific, individually tailored PA interventions to overcome PIA and improve the long-term outcome of CRC survivors.

Association between Blood 25-Hydroxyvitamin D Levels and Survival in Colorectal Cancer Patients: An Updated Systematic Review and Meta-Analysis.

Previous meta-analyses have shown an improved survival with higher blood 25-hydroxyvitamin D (25(OH)D) concentrations in patients with colorectal cancer (CRC). However, a number of much larger studies have been published since then. We provide an updated meta-analysis to synthesize current evidence. PubMed and Web of Science databases were systematically searched for eligible studies. The dose-response relationships and pooled hazard ratios for overall and CRC-specific survival comparing the highest versus the lowest categories of blood 25(OH)D concentrations were assessed. Subgroup analyses based on study geographic location, year of publication, sample size, length of follow-up time and stage were conducted to explore potential sources of heterogeneity. Overall, 11 original studies with a total of 7718 CRC patients were included. The dose-response meta-analysis showed an improvement in survival outcomes with increasing blood 25(OH)D concentrations. Pooled hazard ratios (95% confidence intervals) comparing highest versus lowest categories were 0.68 (0.55⁻0.85) and 0.67 (0.57⁻0.78) for overall and CRC-specific survival, respectively. Associations were more prominent among studies conducted in Europe, with larger sample sizes, and including stage I⁻IV patients. This updated meta-analysis reveals robust evidence of an association between higher blood 25(OH)D concentrations and better survival in CRC patients. The potential for enhancing prognosis of CRC patients by vitamin D supplementation should be explored by randomized trials.

Screen Time, Physical Activity and Self-Esteem in Children: The Ulm Birth Cohort Study.

Screen time is a central activity of children’s daily life and jeopardizes mental health. However, results appear inconclusive and are often based on small cross-sectional studies. We aimed to investigate the temporal sequence of the association between screen time and self-esteem taking into account further indirect effects through family or friendship relationship. In our population-based birth cohort study (baseline November 2000⁻November 2001, Ulm, Germany), these relationships were explored in n = 519 11- and 13-year-old children and their parents who both provided information on children’s screen time: time spent watching television or videos (TV), time spent on computers, video game consoles, mobile devices, or cell phones; so called “other screen time”, and children’s self-esteem (KINDL-R). Time watching TV (self-reported) at age 11 was negatively associated with girls’ self-esteem at the same age but positively with an increase of self-esteem between age 11 and 13. However, the latter association was restricted to low to moderate TV viewers. In boys, a higher increase of other screen time between age 11 and age 13 was associated with lower self-reported self-esteem at age 13. Additionally, friendship relationship mediated the association between watching TV and self-esteem in girls. For parental reports similar associations were observed. These findings indicate that time sequence and potential mediators need further investigation in cohort studies with multiple assessments of screen time and self-esteem.

Dose-Response Relationship between Serum Retinol Levels and Survival in Patients with Colorectal Cancer: Results from the DACHS Study.

Current knowledge on the role of retinol in the prognosis of patients with colorectal cancer (CRC) is very limited. We investigated the association of serum retinol levels with survival outcomes in a large cohort of 2908 CRC patients from Germany. Retinol concentrations were determined in serum collected shortly after diagnosis by mass spectrometry. Associations between serum retinol levels and survival outcomes were assessed using multivariable Cox regression and dose-response analyses. The joint association of serum retinol and serum 25-hydroxyvitamin D3 (25(OH)D3) with survival outcomes was also examined. During a median follow-up of 4.8 years, 787 deaths occurred, 573 of which were due to CRC. Dose-response curves showed an inverse relationship between serum retinol levels and survival endpoints in the range of <2.4 µmol/L, but no associations at higher levels. Low (<1.2 µmol/L) versus high (≥2.4 µmol/L) serum retinol levels were associated with poorer overall survival (Hazard ratio (HR) = 1.46, 95% confidence interval (CI) = 1.19⁻1.78, P-trend = 0.0003) and CRC-specific survival (HR = 1.69, 95% CI = 1.33⁻2.15, P-trend < 0.0001). Joint presence of low serum retinol (<1.2 µmol/L) and low 25(OH)D3 (<30 nmol/L) was associated with a particularly strong decrease in overall and CRC-specific survival. Low serum retinol levels were identified as a predictor of poor survival in CRC patients, in particular when co-occurring with low serum concentrations of 25(OH)D3. The clinical implications of these findings require further investigation.

Impact of comorbidity and frailty on prognosis in colorectal cancer patients: A systematic review and meta-analysis.

INTRODUCTION: Colorectal cancer (CRC) is largely diagnosed at old age, when comorbidities and frailty are common and might be important prognostic factors of CRC. We aimed to systematically review epidemiological evidence on the prognostic role of comorbidity and frailty in CRC patients. METHODS: We systematically searched the PubMed and Web of Science databases up to August 08, 2017 for observational studies that used a standardized index to assess comorbidity or frailty, investigated and reported odds ratios (OR) or hazard ratios (HR) of their associations with any of the following CRC prognostic outcomes: thirty-day, overall or CRC-specific mortality and disease-free or recurrence-free survival. The study was conducted using standard meta-analysis methodology. RESULTS: Thirty-seven cohort studies were identified and included in this review: 35 on comorbidity and 2 on frailty. Of the 35 studies, 13 with comparable methodology were eligible for a meta-analysis. Compared to CRC patients without comorbidity, those with mild/moderate and severe comorbidity had, respectively, a higher risk of 30-day (OR = 1.71; 95% confidence interval (CI): 1.26-2.31 and OR = 2.62; 95% CI: 1.97-3.47), overall (HR = 1.41; 95% CI: 1.23-1.62 and HR = 2.03; 95% CI: 1.76-2.34), and CRC-specific mortality (HR = 1.06; 95% CI: 1.02-1.10 and HR = 1.14; 95% CI: 1.04-1.23). Frail CRC patients showed higher overall mortality than non-frail patients (HRrange: 2.60-3.39). CONCLUSIONS: Comorbidity and frailty are strong prognostic factors of survival in CRC patients apart from the commonly considered sociodemographic and tumor characteristics. Comprehensive geriatric assessment might help to optimize care of CRC patients, by improving early identification and management of comorbidities and geriatric syndromes.

Relationship of very low serum 25-hydroxyvitamin D3 levels with long-term survival in a large cohort of colorectal cancer patients from Germany.

To investigate the association of serum 25-hydroxyvitamin D (25(OH)D3) with survival in a large prospective cohort study of colorectal cancer (CRC) patients. The study population consisted of 2,910 patients diagnosed with CRC between 2003 and 2010 who participated in the DACHS study, a multicenter study from Germany with comprehensive long-term follow-up. 25(OH)D3 was determined in serum samples collected shortly after cancer diagnosis by High Performance Liquid Chromatography-Electro Spray Ionization-Mass Spectrometry. Analyses of survival outcomes were performed using Cox regression with comprehensive adjustment for relevant confounders. The majority (59%) of CRC patients were vitamin D deficient (serum 25(OH)D3 levels <30 nmol/L). During a median follow-up of 4.8 years, 787 deaths occurred, 573 of which were due to CRC. Compared to patients in the highest 25(OH)D3 quintile (>45.20 nmol/L), those in the lowest 25(OH)D3 quintile (<11.83 nmol/L) had a strongly increased mortality. Adjusted hazard ratios (95% Confidence Interval) were 1.78 (1.39-2.27), 1.65 (1.24-2.21), 1.32 (1.03-1.71) and 1.48 (1.18-1.85) for all-cause mortality, CRC-specific mortality, recurrence-free and disease-free survival, respectively. Subgroup analyses did not show any significant effect modification across strata defined by sex, age, stage, body mass index, or the late entry. Dose-response analyses showed a strong inverse relationship between serum 25(OH)D3 levels and survival endpoints at 25(OH)D3 levels <30 nmol/L, and no association with mortality at higher 25(OH)D3 levels. Vitamin D deficiency is highly prevalent in CRC patients and a strong independent predictor of poor prognosis. The possibility of enhancing CRC prognosis by vitamin D supplementation, ideally combined with outdoor physical activity, should be evaluated by randomized controlled trials focusing on patients with vitamin D deficiency.

Prediction of BMI at age 11 in a longitudinal sample of the Ulm Birth Cohort Study.

Obesity is one of the greatest public health challenges in the world with childhood prevalence rates between 20-26% and numerous associated health risks. The aim of the current study was to analyze the 11-year follow-up data of the Ulm Birth Cohort Study (UBCS), to identify whether abnormal eating behavior patterns, especially restrained eating, predict body mass index (BMI) at 11 years of age and to explore other factors known to be longitudinally associated with it. Of the original UBCS, n = 422 children (~ 40% of the original sample) and their parents participated in the 11-year follow-up. BMI at age 8 and 11 as well as information on restrained eating, psychological problems, depressive symptoms, lifestyle, and IQ at age 8 were assessed. Partial Least Squares Structural Equation Modeling (PLS-SEM) was used to predict children's BMI scores at age 11. PLS-SEM explained 68% of the variance of BMI at age 11, with BMI at age 8 being the most important predictor. Restrained eating, via BMI at age 8 as well as parental BMI, had further weak associations with BMI at age 11; no other predictor was statistically significant. Since established overweight at age 8 already predicts BMI scores at age 11 longitudinally, obesity interventions should be implemented in early childhood.