Randomized controlled trials: who fails run-in?

Background: Early identification of participants at risk of run-in failure (RIF) may present opportunities to improve trial efficiency and generalizability. Methods: We conducted a partial factorial-design, randomized, controlled trial of calcium and vitamin D to prevent colorectal adenoma recurrence at 11 centers in the United States. At baseline, participants completed two self-administered questionnaires (SAQs) and a questionnaire administered by staff. Participants in the full factorial randomization (calcium, vitamin D, both, or neither) received a placebo during a 3-month single-blinded run-in; women electing to take calcium enrolled in a two-group randomization (calcium with vitamin D, or calcium alone) and received calcium during the run-in. Using logistic regression models, we examined baseline factors associated with RIF in three subgroups: men (N = 1606) and women (N = 301) in the full factorial randomization and women in the two-group randomization (N = 666). Results: Overall, 314/2573 (12 %) participants failed run-in; 211 (67 %) took fewer than 80 % of their tablets (poor adherence), and 103 (33 %) withdrew or were uncooperative. In multivariable models, 8- to 13-fold variation was seen by study center in odds of RIF risk in the two largest groups. In men, RIF decreased with age (adjusted odds ratio [OR] per 5 years 0.85 [95 % confidence interval, CI; 0.76-0.96]) and was associated with being single (OR 1.65 [95 % CI; 1.10-2.47]), not graduating from high school (OR 2.77 [95 % CI; 1.58-4.85]), and missing SAQ data (OR 1.97 [1.40-2.76]). Among women, RIF was associated primarily with health-related factors; RIF risk was lower with higher physical health score (OR 0.73 [95 % CI; 0.62-0.86]) and baseline multivitamin use (OR 0.44 [95 % CI; 0.26-0.75]). Women in the 5-year colonoscopy surveillance interval were at greater risk of RIF than those with 3-year follow-up (OR 1.91 [95 % CI; 1.08-3. 37]), and the number of prescription medicines taken was also positively correlated with RIF (p = 0.03). Perceived toxicities during run-in were associated with 12- to 29-fold significantly increased odds of RIF. Conclusions: There were few common baseline predictors of run-in failure in the three randomization groups. However, heterogeneity in run-in failure associated with study center, and missing SAQ data reflect potential opportunities for intervention to improve trial efficiency and retention

Multiple functional risk variants in a SMAD7 enhancer implicate a colorectal cancer risk haplotype

Genome-wide association studies (GWAS) of colorectal cancer (CRC) have led to the identification of a number of common variants associated with modest risk. Several risk variants map within the vicinity of TGFβ/BMP signaling pathway genes, including rs4939827 within an intron of SMAD7 at 18q21.1. A previous study implicated a novel SNP (novel 1 or rs58920878) as a functional variant within an enhancer element in SMAD7 intron 4. In this study, we show that four SNPs including novel 1 (rs6507874, rs6507875, rs8085824, and rs58920878) in linkage disequilibrium (LD) with the index SNP rs4939827 demonstrate allele-specific enhancer effects in a large, multi-component enhancer of SMAD7. All four SNPs demonstrate allele-specific protein binding to nuclear extracts of CRC cell lines. Furthermore, some of the risk-associated alleles correlate with increased expression of SMAD7 in normal colon tissues. Finally, we show that the enhancer is responsive to BMP4 stimulation. Taken together, we propose that the associated CRC risk at 18q21.1 is due to four functional variants that regulate SMAD7 expression and potentially perturb a BMP negative feedback loop in TGFβ/BMP signaling pathways

Association between adenoma location and risk of recurrence

The biological environment varies across the colorectum and may therefore differently affect neoplastic growth in the proximal and distal colon. The aim of the study was to evaluate the risk for recurrent adenomas and their anatomic location based on adenoma location at baseline colonoscopy

Associations of Height With the Risks of Colorectal and Endometrial Cancer in Persons With Lynch Syndrome

People with Lynch syndrome (LS), who carry a pathogenic mutation in a DNA mismatch repair gene, have increased risks of colorectal cancer (CRC) and endometrial cancer (EC). A high reported variability in cancer risk suggests the existence of factors that modify cancer risk for persons with LS. We aimed to investigate the associations between height and CRC and EC risk for persons with LS using data from 2 large studies. Information on 1,115 men and 1,553 women with LS from the Colon Cancer Family Registry (1998-2007) and the GEOLynch Cohort Study (2006-2017) was harmonized. We used weighted Cox proportional hazards regression models with age on the time axis to estimate adjusted hazard ratios and 95% confidence intervals for each 5-cm increment in self-reported height. CRC was diagnosed in 947 persons during 65,369 person-years of observation, and 171 women were diagnosed with EC during 39,227 person-years. Height was not associated with CRC for either men (per 5-cm increment, hazard ratio (HR) = 1.00, 95% confidence interval (CI): 0.91, 1.11) or women (per 5-cm increment, HR = 1.01, 95% CI: 0.92, 1.11), nor was height associated with EC (per 5-cm increment, HR = 1.08, 95% CI: 0.94, 1.24). Hence, we observed no evidence for an association of height with either CRC or EC among persons with LS.</p

C-reactive Protein and Risk of Colorectal Adenomas or Serrated Polyps: A Prospective Study

Serum C-reactive protein (CRP) is a sensitive marker of systemic inflammation. Since there is a well-recognized relationship between local inflammation and colorectal cancer, we aimed to evaluate whether serum CRP levels were associated with the occurrence of colorectal adenomas and serrated polyps using data from a large adenoma prevention trial. 930 participants with a history of colorectal adenomas were enrolled in a randomized trial of calcium supplementation (1200 mg/day) for the prevention of colorectal adenomas. Outcomes in this analysis are metachronous adenomas (and advanced neoplasms specifically), and serrated polyps at follow-up colonoscopy. High sensitivity CRP levels were measured 1 year following baseline colonoscopy. Multivariate analysis was performed to estimate risk ratios (RR) using Poisson regression, controlling for potential confounders. We measured serum CRP levels in 689 participants(mean CRP 3.62mg/L ± 5.72). There was no difference in CRP levels with respect to calcium vs. placebo treatment assignment (p=0.99). After adjustment for potential confounders, we found no association between CRP level and risk of recurrent adenoma or advanced lesion (Quartile 4 vs. Quartile 1: RR (95% CI) = 0.99 (0.73, 1.34) and 0.92 (0.49, 1.75) respectively). Similarly, no association was seen between CRP levels and riskof serrated polypsor proximal serrated polyps(Quartile 4 vs. Quartile 1: RR (95% CI) = 1.32 (0.85, 2.03) and 1.19 (0.54, 2.58) respectively. In conclusion, this large prospective colorectal adenoma chemoprevention study found no significant relationship between CRP levels and occurrence of adenomas, advanced neoplasms, or serrated polyps

Risk Factors for Hemorrhoids on Screening Colonoscopy

BackgroundConstipation, a low fiber diet, sedentary lifestyle and gravidity are commonly assumed to increase the risk of hemorrhoids. However, evidence regarding these factors is limited. We examined the association between commonly cited risk factors and the prevalence of hemorrhoids.MethodsWe performed a cross sectional study of participants who underwent a colonoscopy in a colorectal adenoma prevention trial and who had a detailed assessment of bowel habits, diet and activity. The presence of hemorrhoids was extracted from the subjects’ colonoscopy reports. We used logistic regression to estimate odds ratios and 95% confidence intervals while adjusting for age and sex.ResultsThe study included 2,813 participants. Of these, 1,074 had hemorrhoids recorded. Constipation was associated with an increased prevalence of hemorrhoids (OR 1.43, 95% CI 1.11, 1.86). Of the fiber subtypes, high grain fiber intake was associated with a reduced risk (OR for quartile 4 versus quartile 1 = 0.78, 95% CI 0.62, 0.98). We found no association when comparing gravid and nulligravida women (OR 0.93, 95% CI 0.62–1.40). Sedentary behavior was associated with a reduced risk (OR 0.80, 95% CI 0.65–0.98), but not physical activity (OR 0.83, 95% CI 0.66–1.03). Neither being overweight nor obese was associated with the presence of hemorrhoids (OR 0.89, 95% CI 0.72–1.09 and OR 0.86, 95% CI 0.70–1.06).ConclusionsConstipation is associated with an increased risk of hemorrhoids. Gravidity and physical activity do not appear to be associated. High grain fiber intake and sedentary behavior are associated with a decreased risk of hemorrhoids

Urinary Metabolites of Prostanoids and Risk of Recurrent Colorectal Adenomas in the Aspirin/Folate Polyp Prevention Study (AFPPS)

Aspirin has been shown to protect against colorectal neoplasms, however the optimal chemopreventive dose and underlying mechanisms are unclear. We aimed to study the relationship between prostanoid metabolites and aspirin’s effect on adenoma occurrence. We used data from the Aspirin/Folate Polyp Prevention Study, in which 1,121 participants with a recent adenoma were randomized to placebo or two doses of aspirin (81 or 325 mg/d) to be taken until the next surveillance colonoscopy, anticipated about 3 years later. Urinary metabolites of prostanoids (PGE-M, PGI-M, and dTxB2) were measured using LC/MS or GC/NICI-MS in 876 participants near the end of treatment follow-up. Poisson regression with a robust error variance was used to calculate relative risks and 95% confidence intervals. PGE-M, PGI-M, and dTxB2 levels were 28%, 37%, and 60% proportionately lower, respectively, in individuals who took 325 mg of aspirin compared to individuals who took placebo (all P<0.001). Similarly, among individuals who took 81 mg of aspirin, PGE-M, PGI-M, and dTxB2 were, respectively, 18%, 30%, and 57% proportionally lower compared to placebo (all P<0.005). None of the metabolites or their ratios were statistically significantly associated with the risk of adenoma occurrence. The effect of aspirin in reducing adenoma risk was independent of prostanoid levels. Aspirin use is associated with lower levels of urinary prostanoid metabolites. However, our findings do not support the hypothesis that these metabolites are associated with adenoma occurrence, suggesting that COX-dependent mechanisms may not completely explain the chemopreventive effect of aspirin on colorectal neoplasms

Smoking-associated risks of conventional adenomas and serrated polyps in the colorectum

PurposePrior studies suggest cigarette smoking is associated with 1.5- to twofold increased risk of colorectal adenomas and possibly a higher risk of serrated polyps. Further clarification of risk differences between adenomas and serrated polyps is needed with regard to co-occurrence and polyp location.Methods We conducted a combined analysis of conventional adenoma and serrated polyp occurrence using individual-level data from 2,915 patients participating in three colonoscopy-based clinical trials. All participants had ≥1 adenomas removed at baseline and were followed for up to 4years. Smoking habits and other lifestyle factors were collected at baseline using questionnaires. We used generalized linear regression to estimate risk ratios and 95% confidence intervals.ResultsSmokers were at slightly increased risk of adenomas compared to never smokers [current: RR 1.29 (95% CI 1.11–1.49) and former: RR 1.18 (1.05–1.32)]. Smoking was associated with greater risk of serrated polyps [current: RR 2.01 (1.66–2.44); former: RR 1.42 (1.20–1.68)], particularly in the left colorectum. Associations between current smoking and occurrence of serrated polyps only [RR 2.33 (1.76–3.07)] and both adenomas and serrated polyps [RR 2.27 (1.68–3.06)] were more pronounced than for adenomas only [RR 1.31 (1.08–1.58)]. Results were similar for other smoking variables and did not differ by gender or for advanced adenomas.ConclusionsCigarette smoking has only a weak association with adenomas, but is associated with a significantly increased risk of serrated polyps, particularly in the left colorectum. Since a minority of left-sided serrated polyps is thought to have malignant potential, the role of smoking in initiation phases of carcinogenesis is uncertain

Smoking-associated risks of conventional adenomas and serrated polyps in the colorectum

PurposePrior studies suggest cigarette smoking is associated with 1.5- to twofold increased risk of colorectal adenomas and possibly a higher risk of serrated polyps. Further clarification of risk differences between adenomas and serrated polyps is needed with regard to co-occurrence and polyp location.Methods We conducted a combined analysis of conventional adenoma and serrated polyp occurrence using individual-level data from 2,915 patients participating in three colonoscopy-based clinical trials. All participants had ≥1 adenomas removed at baseline and were followed for up to 4years. Smoking habits and other lifestyle factors were collected at baseline using questionnaires. We used generalized linear regression to estimate risk ratios and 95% confidence intervals.ResultsSmokers were at slightly increased risk of adenomas compared to never smokers [current: RR 1.29 (95% CI 1.11–1.49) and former: RR 1.18 (1.05–1.32)]. Smoking was associated with greater risk of serrated polyps [current: RR 2.01 (1.66–2.44); former: RR 1.42 (1.20–1.68)], particularly in the left colorectum. Associations between current smoking and occurrence of serrated polyps only [RR 2.33 (1.76–3.07)] and both adenomas and serrated polyps [RR 2.27 (1.68–3.06)] were more pronounced than for adenomas only [RR 1.31 (1.08–1.58)]. Results were similar for other smoking variables and did not differ by gender or for advanced adenomas.ConclusionsCigarette smoking has only a weak association with adenomas, but is associated with a significantly increased risk of serrated polyps, particularly in the left colorectum. Since a minority of left-sided serrated polyps is thought to have malignant potential, the role of smoking in initiation phases of carcinogenesis is uncertain

Older patients' attitudes towards and experiences of patient-physician end-of-life communication: a secondary analysis of interviews from British, Dutch and Belgian patients

<p>Abstract</p> <p>Background</p> <p>Older patients often experience sub-standard communication in the palliative phase of illness. Due to the importance of good communication in patient-centred end-of-life care, it is essential to understand the factors which influence older patients’ communication with physicians. This study examines older patients’ attitudes towards, and experiences of, patient-physician end-of-life (EoL) communication in three European countries.</p> <p>Methods</p> <p>A secondary analysis of interviews from British, Dutch and Belgian patients over the age of 60 with a progressive terminal illness was conducted. Cross-cutting themes were identified using a thematic approach.</p> <p>Results</p> <p>Themes from 30 interviews (Male n = 20, Median age 78.5) included: confidence and trust; disclosure and awareness; and participation in decision-making. Confidence and trust were reinforced by physicians’ availability, time and genuine attention and hindered by misdiagnoses and poor communication style. Most participants preferred full disclosure, though some remained deliberately ill-informed to avoid distress. Patients expressed a variety of preferences for and experiences of involvement in medical EoL decision-making and a few complained that information was only provided about the physician's preferred treatment.</p> <p>Conclusions</p> <p>A variety of experiences and attitudes regarding disclosure and participation in decision-making were reported from each country, suggesting that communication preferences are highly individual. It is important that physicians are sensitive to this diversity and avoid stereotyping. In regard to communication style, physicians are advised to provide clear explanations, avoid jargon, and continually check understanding. Both the ‘informed’ and the ‘shared’ patient-physician decision-making models assume patients make rational choices based on a clear understanding of treatment options. This idealized situation was often not reflected in patients’ experiences.</p