Andrew T. Kunzmann

Low-Dose Aspirin Use After Diagnosis of Colorectal Cancer Does Not Increase Survival: A Case–Control Analysis of a Population-Based Cohort

BACKGROUND & AIMS Individuals who began taking low-dose aspirin before they were diagnosed with colorectal cancer were reported to have longer survival times than patients who did not take this drug. We investigated survival times of patients who begin taking low-dose aspirin after a diagnosis of colorectal cancer in a large population-based cohort study. METHODS We performed a nested case-control analysis using a cohort of 4794 patients diagnosed with colorectal cancer from 1998 through 2007, identified from the UK Clinical Practice Research Datalink and confirmed by cancer registries. There were 1559 colorectal cancer-specific deaths, recorded by the Office of National Statistics; these were each matched with up to 5 risk-set controls. Conditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI), based on practitioner-recorded aspirin usage. RESULTS Overall, low-dose aspirin use after a diagnosis of colorectal cancer was not associated with colorectal cancer-specific mortality (adjusted OR = 1.06; 95% CI: 0.92-1.24) or all-cause mortality (adjusted OR = 1.06; 95% CI: 0.94-1.19). A dose-response association was not apparent; for example, low-dose aspirin use for more than 1 year after diagnosis was not associated with colorectal cancer-specific mortality (adjusted OR = 0.98; 95% CI: 0.82-1.19). There was also no association between low-dose aspirin usage and colon cancer-specific mortality (adjusted OR = 1.02; 95% CI: 0.83-1.25) or rectal cancer-specific mortality (adjusted OR = 1.10; 95% CI: 0.88-1.38). CONCLUSIONS In a large population-based cohort, low-dose aspirin usage after diagnosis of colorectal cancer did not increase survival time.

Prior Autoimmune Disease and Risk of Monoclonal Gammopathy of Undetermined Significance and Multiple Myeloma: A Systematic Review

Background: Several observational studies have investigated autoimmune disease and subsequent risk of monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma. Findings have been largely inconsistent and hindered by the rarity and heterogeneity of the autoimmune disorders investigated. A systematic review of the literature was undertaken to evaluate the strength of the evidence linking prior autoimmune disease and risk of MGUS/multiple myeloma. Methods: A broad search strategy using key terms for MGUS, multiple myeloma, and 50 autoimmune diseases was used to search four electronic databases (PubMed, Medline, Embase, and Web of Science) from inception through November 2011. Results: A total of 52 studies met the inclusion criteria, of which 32 were suitably comparable to perform a meta-analysis. “Any autoimmune disorder” was associated with an increased risk of both MGUS [n = 760 patients; pooled relative risk (RR) 1.42; 95% confidence interval (CI), 1.14–1.75] and multiple myeloma (n>2,530 patients; RR 1.13, 95% CI, 1.04–1.22). This risk was disease dependent with only pernicious anemia showing an increased risk of both MGUS (RR 1.67; 95% CI, 1.21–2.31) and multiple myeloma (RR 1.50; 95% CI, 1.25–1.80). Conclusions: Our findings, based on the largest number of autoimmune disorders and patients with MGUS/multiple myeloma reported to date, suggest that autoimmune diseases and/or their treatment may be important in the etiology of MGUS/multiple myeloma. The strong associations observed for pernicious anemia suggest that anemia seen in plasma cell dyscrasias may be of autoimmune origin. Impact: Underlying mechanisms of autoimmune diseases, general immune dysfunction, and/or treatment of autoimmune diseases may be important in the pathogenesis of MGUS/multiple myeloma. Cancer Epidemiol Biomarkers Prev; 23(2); 332–42. ©2014 AACR.

PTGS2 (Cyclooxygenase-2) Expression and Survival among Colorectal Cancer Patients: A Systematic Review

Background: Studies have examined whether tumor expression of PTGS2 (also known as COX-2), an enzyme inhibited by nonsteroidal anti-inflammatory drugs such as aspirin, is associated with prognosis in patients with colorectal cancer. However, results to date have been mixed. Methods: Using terms for PTGS2 and colorectal cancer, the Medline, Embase, and Web of Science databases were systematically searched for studies published, in any language, until December 2011. Random effects meta-analyses were used to calculate pooled HRs [95% confidence intervals (CI)] for the association between PTGS2 expression and tumor recurrence, colorectal cancer–specific survival, and overall survival. Results: In total, 29 studies, which had prognostic data on 5,648 patients, met the inclusion criteria. PTGS2-positive patients were at an increased risk of tumor recurrence (n = 9 studies; HR, 2.79; 95% CI, 1.76–4.41; P < 0.001) and had poorer colorectal cancer–specific survival (n = 7; HR, 1.36; 95% CI, 1.02–1.82; P = 0.04). However, there was funnel plot asymmetry, possibly due to publication bias, for the association with cancer-specific survival but less so for recurrence. PTGS2 expression was not associated with overall survival [(n = 16; pooled unadjusted HR, 1.30; 95% CI, 0.94–1.79; P = 0.11) and (n = 9; pooled adjusted HR, 1.02; 95% CI, 0.72–1.45; P = 0.91)]. Conclusions: PTGS2 expression was associated with an increased risk of tumor recurrence and poorer colorectal cancer–specific survival but not overall survival among patients with colorectal cancer. However, confounding by tumor characteristics such as tumor stage seems likely. Impact: There is insufficient evidence to recommend PTGS2 expression as a prognostic marker in patients with colorectal cancer. Furthermore, studies providing adjusted results are required. Cancer Epidemiol Biomarkers Prev; 22(9); 1490–7. ©2013 AACR.

Fruit and vegetable intakes and risk of colorectal cancer and incident and recurrent adenomas in the PLCO cancer screening trial.

The roles of fruits and vegetables in colorectal cancer development are unclear. Few prospective studies have assessed the association with adenoma, a known precursor to colorectal cancer. Our aim was to evaluate the association between fruit and vegetable intake and colorectal cancer development by evaluating the risk of incident and recurrent colorectal adenoma and colorectal cancer. Study participants were identified from the intervention arm of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Fruit and vegetable intake was measured using a self‐reported dietary questionnaire. Total fruit and vegetable intake was not associated with reduced incident or recurrent adenoma risk overall, but a protective association was observed for multiple adenomas (Odds ratio 3rd tertile vs. 1st tertile = 0.61, 95% confidence interval (CI): 0.38, 1.00). Higher fruit and vegetable intakes were associated with a borderline reduced risk of colorectal cancer (Hazard ratio (HR) 3rd tertile vs. 1st tertile = 0.82, 95% CI: 0.67, 1.01), which reached significance amongst individuals with high processed meat intakes (HR = 0.74, 95% CI: 0.55, 0.99). Our results suggest that increased fruit and vegetable intake may protect against multiple adenoma development and may reduce the detrimental effects of high processed meat intakes on colorectal cancer risk.

The prevalence of viral agents in esophageal adenocarcinoma and Barrett’s esophagus: A systematic review

Background and aims Human papilloma virus (HPV), which may reach the esophagus through orogenital transmission, has been postulated to be associated with esophageal adenocarcinoma (EAC). A systematic review of the literature investigating the prevalence of infectious agents in EAC and Barrett’s esophagus (BE) was carried out. Methods Using terms for viruses and EAC, the Medline, Embase, and Web of Science databases were systematically searched for studies published, in any language, until June 2016 that assessed the prevalence of viral agents in EAC or BE. Random-effects meta-analyses of proportions were carried out to calculate the pooled prevalence and 95% confidence intervals (CIs) of infections in EAC and BE. Results A total of 30 studies were included. The pooled prevalence of HPV in EAC tumor samples was 13% (n=19 studies, 95% CI: 2–29%) and 26% (n=6 studies, 95% CI: 3–59%) in BE samples. HPV prevalence was higher in EAC tissue than in esophageal tissue from healthy controls (n=5 studies, pooled odds ratio=3.31, 95% CI: 1.15–9.50). The prevalence of Epstein–Barr virus (EBV) in EAC was 6% (n=5, 95% CI: 0–27%). Few studies have assessed other infectious agents. For each of the analyses, considerable between-study variation was observed (I2=84–96%); however, sensitivity analyses did not show any major sources of heterogeneity. Conclusion The prevalence of HPV and EBV in EAC is low compared with other viral-associated cancers, but may have been hampered by small sample sizes and detection methods susceptible to fixation processes. Additional research with adequate sample sizes and high-quality detection methods is required.

The association of lifetime alcohol use with mortality and cancer risk in older adults: A cohort study

Background While current research is largely consistent as to the harms of heavy drinking in terms of both cancer incidence and mortality, there are disparate messages regarding the safety of light-moderate alcohol consumption, which may confuse public health messages. We aimed to evaluate the association between average lifetime alcohol intakes and risk of both cancer incidence and mortality. Methods and findings We report a population-based cohort study using data from 99,654 adults (68.7% female), aged 55–74 years, participating in the U.S. Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Cox proportional hazards models assessed the risk of overall and cause-specific mortality, cancer incidence (excluding nonmelanoma skin cancer), and combined risk of cancer and death across categories of self-reported average lifetime alcohol intakes, with adjustment for potential confounders. During 836,740 person-years of follow-up (median 8.9 years), 9,599 deaths and 12,763 primary cancers occurred. Positive linear associations were observed between lifetime alcohol consumption and cancer-related mortality and total cancer incidence. J-shaped associations were observed between average lifetime alcohol consumption and overall mortality, cardiovascular-related mortality, and combined risk of death or cancer. In comparison to lifetime light alcohol drinkers (1–3 drinks per week), lifetime never or infrequent drinkers (<1 drink/week), as well as heavy (2–<3 drinks/day) and very heavy drinkers (3+ drinks/day) had increased overall mortality and combined risk of cancer or death. Corresponding hazard ratios (HRs) and 95% confidence intervals (CIs) for combined risk of cancer or death, respectively, were 1.09 (1.01–1.13) for never drinkers, 1.08 (1.03–1.13) for infrequent drinkers, 1.10 (1.02–1.18) for heavy drinkers, and 1.21 (1.13–1.30) for very heavy drinkers. This analysis is limited to older adults, and residual confounding by socioeconomic factors is possible. Conclusions The study supports a J-shaped association between alcohol and mortality in older adults, which remains after adjustment for cancer risk. The results indicate that intakes below 1 drink per day were associated with the lowest risk of death. Trial registration NCT00339495 (ClinicalTrials.gov).

Physical activity, sedentary behaviour and risk of oesophago-gastric cancer: a prospective cohort study within UK Biobank

Background Few observational studies have assessed the role of physical activity in oesophago-gastric cancer risk. Objective This prospective cohort study aimed to assess the association between physical activity and risk of oesophageal or gastric cancer. Methods A cohort of 359,033 adults aged 40–69 years were identified from the UK Biobank, which recruited participants between 2006 and 2010. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between self-reported levels of physical activity and screen-based sedentary behaviour and risk of oesophageal and gastric cancer were calculated using Cox proportional hazards models. Results During eight years of follow-up (mean = 5.5), 294 oesophageal cancer and 217 gastric cancer cases were identified. Physical activity and screen-based sedentary behaviour levels were not associated with overall oesophago-gastric cancer risk. However, when compared with low levels, high physical activity levels were associated with a significantly reduced risk of gastric non-cardia cancer (HR 0.58, 95% CI 0.37–0.95). Moderate physical activity levels were associated with a 38% reduced risk of oesophageal adenocarcinoma (HR 0.62, 95% CI 0.43–0.89), although no dose-response association was apparent. Conclusion Moderate, rather than high, physical activity levels were associated with the strongest reductions in oesophageal adenocarcinoma risk in this large UK prospective cohort.

Risk Factors (Excluding Hormone Replacement Therapy) for Endometrial Hyperplasia: a Systematic Review

Objective: To conduct a systematic review of risk factors associated with the development of Endometrial Hyperplasia (EH). Data sources: Ovid MEDLINE, EMBASE and Web of Science databases were searched from inception to 30 June 2015. Study eligibility: Fifteen observational studies that reported on EH risk in relation to lifestyle factors (n=14), medical history (n=11), reproductive and menstrual history (n=9) and measures of socio-economic status (n=2) were identified. Pooled relative risk estimates and corresponding 95% confidence intervals (CI) were able to be derived for EH and Body Mass Index (BMI), smoking, diabetes and hypertension, using random effects models comparing high versus low categories. Results: The pooled relative risk for EH when comparing women with the highest versus lowest BMI was 1.82 (95% CI 1.22–2.71; n=7 studies, I2=90.4%). No significant associations were observed for EH risk for smokers compared with non-smokers (RR 0.88, 95% CI 0.66-1.17; n=3, I2=0.0%), hypertensive versus normotensive women (RR 1.51, 95% CI 0.72–3.15; n=5 studies, I2=79.1%), or diabetic versus non-diabetic women (RR 1.77, 95% CI 0.79–3.96; n=5 studies, I2=31.8%) respectively although the number of included studies was limited. There were mixed reports on the relationship between age and risk of EH. Too few studies reported on other factors to reach any conclusions in relation to EH risk. Conclusions: A high BMI was associated with an increased risk of EH, providing additional rationale for women to maintain a normal body weight. No significant associations were detected for other factors and EH risk, however relatively few studies have been conducted and few of the available studies adequately adjusted for relevant confounders. Therefore, further aetiological studies of endometrial hyperplasia are warranted.

Hormonal and reproductive factors and risk of upper gastrointestinal cancers in men: A prospective cohort study within the UK Biobank: Hormonal and reproductive factors and upper gastrointestinal cancers in men

Incidence of upper gastrointestinal cancers of the oesophagus and stomach show a strong unexplained male predominance. Hormonal and reproductive factors have been associated with upper gastrointestinal cancers in women but there is little available data on men. To investigate this, we included 219,425 men enrolled in the UK Biobank in 2006–2010. Baseline assessments provided information on hormonal and reproductive factors (specifically hair baldness, number of children fathered, relative age at first facial hair and relative age voice broke) and incident oesophageal or gastric cancers were identified through linkage to U.K. cancer registries. Unadjusted and adjusted hazard ratios (HR) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. During 8 years of follow‐up, 309 oesophageal 210 gastric cancers occurred. There was some evidence that male pattern baldness, was associated with gastric cancer risk (adjusted HR 1.35, 95% CI 0.97, 1.88), particularly for frontal male pattern baldness (adjusted HR 1.52, 95% CI 1.02, 2.28). There was little evidence of association between other hormonal and reproductive factors and risk of oesophageal or gastric cancer, overall or by histological subtype. In the first study of a range of male hormonal and reproductive factors and gastric cancer, there was a suggestion that male pattern baldness, often used as a proxy of sex hormone levels, may be associated with gastric cancer. Future prospective studies that directly test circulating sex steroid hormone levels in relation to upper gastrointestinal cancer risk are warranted.

Medications that relax the lower oesophageal sphincter and risk of oesophageal cancer: an analysis of two independent population-based databases

Excessive lower oesophageal sphincter relaxation increases gastro‐oesophageal acid reflux, an oesophageal adenocarcinoma risk factor. Medications that relax this sphincter (benzodiazepines, calcium channel blockers, nitrates, β2 agonists and xanthines) could promote cancer. These medications were investigated in two independent datasets. In the Scottish Primary Care Clinical Informatics Unit (PCCIU) database, a nested case–control study of oesophageal cancer was performed using GP prescription records. Conditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CIs) for medication use and oesophageal cancer. In UK Biobank, a cohort study was conducted using self‐reported medication use. Cox regression was used to calculate hazard ratios (HRs) and 95% CIs for medication use and oesophageal cancer, and by tumour subtype. Overall, 1,979 oesophageal cancer patients were matched to 9,543 controls in PCCIU, and 355 of 475,768 participants developed oesophageal cancer in UK Biobank. None of the medications investigated were significantly associated with oesophageal cancer risk apart from β2 agonists, which were associated with increased oesophageal cancer risk in PCCIU (adjusted OR 1.38, 95% CI 1.12, 1.70) but not in UK Biobank (adjusted HR 1.21, 95% CI 0.70, 2.08). Medications that relax the lower oesophageal sphincter were not associated with oesophageal cancer, apart from β2 agonists. This increased cancer risk in β2 agonist users merits further investigation.