Esophageal Columnar Metaplasia in Childhood: A Population-Based Case Series Analysis.

BACKGROUND: Adults with Barrett's esophagus (BE) are often entered into surveillance for esophageal adenocarcinoma (EAC), although cancer risk is relatively low. BE can be detected in children (< 16 years). Little is known about the epidemiology of pediatric BE, and it is unclear what the optimal surveillance regimes are in children. AIM: To evaluate the demographic and clinical characteristics, and future neoplastic progression risk in all pediatric BE patients diagnosed in Northern Ireland between 1993 and 2010. METHODS: Data from the population-based Northern Ireland BE register were matched to the Northern Ireland Cancer Registry for EAC outcomes until end 2013. Age-adjusted incidence of pediatric BE was calculated, and characteristics between pediatric and adult BE patients compared using Chi-square tests. RESULTS: Over 18 years, 42 pediatric BE patients (< 16 years) were identified, equivalent to an age-adjusted incidence of < 2 per 100,000 children. There was a clear age differential, with BE incidence increasing with age within the pediatric population. The majority (85.7%) of patients were male, a significantly higher male/female ratio than adult BE patients (p < 0.001). No pediatric BE patients progressed to high-grade dysplasia (HGD) or EAC, although the eldest patient was aged 34 years by the end of follow-up. CONCLUSIONS: This is the largest series of pediatric BE ever reported. It demonstrates that pediatric BE is rare. The male preponderance of this condition is more apparent in childhood compared with adult cases. No children developed HGD/EAC during follow-up, suggesting that regular surveillance is not required, at least until adulthood.

Fusobacterium nucleatum in the Colorectum and Its Association with Cancer Risk and Survival: A Systematic Review and Meta-analysis.

BACKGROUND: The gut microbiome, in particular Fusobacterium nucleatum, has been reported to play a role in colorectal cancer development and in patient prognosis. We aimed to perform a systematic review and meta-analysis of published studies to assess the prevalence of F. nucleatum in colorectal tumors and evaluate the association between F. nucleatum and colorectal cancer development and prognosis. METHODS: MEDLINE, EMBASE, and Web of Science databases were systematically searched for studies published until January 2019. Random effects meta-analyses were used to assess the prevalence of F. nucleatum in patients with colorectal cancer or tissues relative to controls and survival in F. nucleatum-positive versus -negative patients. RESULTS: Forty-five relevant articles were identified. Meta-analyses indicated higher odds of F. nucleatum being present in colorectal tissue samples from patients with colorectal cancer [n = 6 studies, pooled OR = 10.06; 95% confidence intervals (CI), 4.48-22.58] and individuals with colorectal polyps (n = 5 studies, pooled OR = 1.83; 95% CI, 1.07-3.16) compared with healthy controls. Similar results were apparent in fecal samples, and when comparing tumor with adjacent normal tissue. Meta-analyses indicated poorer survival in patients with colorectal cancer with high versus low F. nucleatum abundance (n = 5 studies, pooled HR = 1.87; 95% CI, 1.12-3.11). CONCLUSIONS: A consistent increase in the prevalence and/or abundance of F. nucleatum in colorectal cancer tissue and fecal samples compared with controls was apparent. High abundance of F. nucleatum in colorectal tumors was also associated with poorer overall survival. IMPACT: F. nucleatum could be useful as a diagnostic and prognostic marker for colorectal cancer or as a treatment target.

The association between self-reported poor oral health and gastrointestinal cancer risk in the UK Biobank: A large prospective cohort study.

Background: Controversy remains as to whether poor oral health is independently associated with gastrointestinal cancers, due to potential confounding by smoking, alcohol and poor nutrition. The aim of this study was to investigate the association between oral health conditions and gastrointestinal cancer risk. Methods: Data from the large, prospective UK Biobank cohort, which includes n = 475,766 participants, were analysed. Cox proportional hazard models were applied to estimate the relationship between gastrointestinal cancer risk and self-reported poor oral health (defined as painful gums, bleeding gums and/or having loose teeth), adjusting for confounders. Results: During an average six years of follow-up, n = 4069 gastrointestinal cancer cases were detected, of which 13% self-reported poor oral health. Overall, there was no association between self-reported poor oral health and risk of gastrointestinal cancer detected (hazard ratio 0.97, 95% confidence interval 0.88-1.07). In site-specific analysis, an increased risk of hepatobiliary cancers was observed in those with self-reported poor oral health (hazard ratio 1.32, 95% confidence interval 0.95-1.80), which was stronger for hepatocellular carcinoma (hazard ratio 1.75, 95% confidence interval 1.04-2.92). Conclusion: Overall there was no association between self-reported poor oral health and gastrointestinal cancer risk. However, there was a suggestion of an increased risk of hepatobiliary cancer, specifically hepatocellular carcinoma.

Diabetes in relation to Barrett's esophagus and adenocarcinomas of the esophagus: A pooled study from the International Barrett's and Esophageal Adenocarcinoma Consortium.

BACKGROUND: Diabetes is positively associated with various cancers, but its relationship with tumors of the esophagus/esophagogastric junction remains unclear. METHODS: Data were harmonized across 13 studies in the International Barrett's and Esophageal Adenocarcinoma Consortium, comprising 2309 esophageal adenocarcinoma (EA) cases, 1938 esophagogastric junction adenocarcinoma (EGJA) cases, 1728 Barrett's esophagus (BE) cases, and 16,354 controls. Logistic regression was used to estimate study-specific odds ratios (ORs) and 95% CIs for self-reported diabetes in association with EA, EGJA, and BE. Adjusted ORs were then combined using random-effects meta-analysis. RESULTS: Diabetes was associated with a 34% increased risk of EA (OR, 1.34; 95% CI, 1.00-1.80; I2  = 48.8% [where 0% indicates no heterogeneity, and larger values indicate increasing heterogeneity between studies]), 27% for EGJA (OR, 1.27; 95% CI, 1.05-1.55; I2  = 0.0%), and 30% for EA/EGJA combined (OR, 1.30; 95% CI, 1.06-1.58; I2  = 34.9%). Regurgitation symptoms modified the diabetes-EA/EGJA association (P for interaction = .04) with a 63% increased risk among participants with regurgitation (OR, 1.63; 95% CI, 1.19-2.22), but not among those without regurgitation (OR, 1.03; 95% CI, 0.74-1.43). No consistent association was found between diabetes and BE. CONCLUSIONS: Diabetes was associated with increased EA and EGJA risk, which was confined to individuals with regurgitation symptoms. Lack of an association between diabetes and BE suggests that diabetes may influence progression of BE to cancer.

'Missed' oesophageal adenocarcinoma and high-grade dysplasia in Barrett's oesophagus patients: A large population-based study.

BACKGROUND: A systematic review suggests that 25% of oesophageal adenocarcinomas (OAC) are 'missed' at index endoscopy for Barrett's oesophagus (BO); however, this included few population-based studies and may be an overestimate. OBJECTIVE: The objective of this article is to quantify the 'missed' rates of high-grade dysplasia (HGD) and OAC at index BO endoscopy. METHODS: Patients from the Northern Ireland BO register diagnosed between 1993 and 2010 (n = 13,159) were linked to the Northern Ireland Cancer Registry to identify patients who developed OAC or HGD. Logistic regression analysis compared characteristics of 'missed' vs 'incident' HGD/OAC, defined as diagnoses within 3-12 months vs >1 year after incident BO, respectively. RESULTS: A total of 267 patients were diagnosed with HGD/OAC ≥3 months after BO diagnosis, of whom 34 (12.7%) were potentially 'missed'. The proportion of 'missed' HGD/OAC was 25% among BO patients with low-grade dysplasia (LGD) and 9% among non-dysplastic BO patients. Older age and BO-LGD carried a higher risk of 'missed' HGD/OAC. Non-dysplastic BO patients were more often diagnosed with a 'missed' OAC (rather than HGD; 89%), compared with BO-LGD patients (40%). CONCLUSIONS: Approximately one in 10 HGD/OAC cases are 'missed' at incident BO diagnosis, which is significant but lower than previous reports. However, 'missed' HGD/OAC cases represent only 0.26% of all BO patients.

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

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.

Low-dose aspirin use and survival in colorectal cancer: results from a population-based cohort study.

BACKGROUND: Aspirin has been proposed as a novel adjuvant agent in colorectal cancer (CRC). Six observational studies have reported CRC-specific survival outcomes in patients using aspirin after CRC diagnosis but the results from these studies have been conflicting. Using a population-based cohort design this study aimed to assess if low-dose aspirin use after diagnosis reduced CRC-specific mortality. METHODS: A cohort of 8391 patients with Dukes' A-C CRC (2009-2012) was identified from the Scottish Cancer Registry and linked to national prescribing and death records. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for CRC-specific mortality were calculated using time-dependent Cox regression. RESULTS: There were 1064 CRC-specific deaths after a median follow-up of 3.6 years. Post-diagnostic low-dose aspirin use was not associated with a reduction in CRC-specific mortality either before or after adjustment for confounders (adjusted HR = 1.17, 95% CI 1.00-1.36). In sensitivity analysis pre-diagnostic low-dose aspirin was also not associated with reduced CRC-specific mortality (adjusted HR = 0.96, 95% CI 0.88-1.05). CONCLUSION: Low-dose aspirin use, either before or after diagnosis, did not prolong survival in this population-based CRC cohort.

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, ß2 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 ß2 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 ß2 agonists. This increased cancer risk in ß2 agonist users merits further investigation.

Association between circulating levels of sex steroid hormones and esophageal adenocarcinoma in the FINBAR Study.

BACKGROUND: Esophageal adenocarcinoma (EA) is characterized by a strong male predominance. Sex steroid hormones have been hypothesized to underlie this sex disparity, but no population-based study to date has examined this potential association. METHODS: Using mass spectrometry and ELISA, we quantitated sex steroid hormones and sex hormone binding globulin, respectively, in plasma from males- 172 EA cases and 185 controls-within the Factors Influencing the Barrett/Adenocarcinoma Relationship (FINBAR) Study, a case-control investigation conducted in Northern Ireland and Ireland. Multivariable adjusted logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between circulating hormones and EA. RESULTS: Higher androgen:estrogen ratio metrics were associated with increased odds of EA (e.g., testosterone:estradiol ratio ORQ4 v. Q1 = 2.58, 95%CI = 1.23-5.43; Ptrend = 0.009). All estrogens and androgens were associated with significant decreased odds of EA. When restricted to individuals with minimal to no decrease in body mass index, the size of association for the androgen:estrogen ratio was not greatly altered. CONCLUSIONS: This first study of sex steroid hormones and EA provides tentative evidence that androgen:estrogen balance may be a factor related to EA. Replication of these findings in prospective studies is needed to enhance confidence in the causality of this effect.

Blood biomarkers for early diagnosis of oesophageal cancer: a systematic review.

BACKGROUND: Oesophageal cancer prognosis remains poor owing to the inability to detect the disease at an early stage. Nontissue (serum, urinary or salivary) biomarkers potentially offer less invasive methods to aid early detection of oesophageal cancer. We aimed to systematically review studies assessing the relationship between nontissue biomarkers and subsequent development of oesophageal cancer. METHODS: Using terms for biomarkers and oesophageal cancer, Medline, EMBASE and Web of Science were systematically searched for longitudinal studies, published until April 2016, which assessed the association between nontissue biomarkers and subsequent oesophageal cancer risk. Random effects meta-analyses were used to calculate pooled relative risk (RR) and 95% confidence intervals (CIs), where possible. RESULTS: A total of 39 studies were included. Lower serum pepsinogen I concentrations were associated with an increased risk of oesophageal squamous cell carcinoma (n=3 studies, pooled RR=2.20, 95% CI: 1.31-3.70). However, the association for the pepsinogen I : II ratio was not statistically significant (n=3 studies, pooled RR=2.22, 95% CI: 0.77-6.40), with a large degree of heterogeneity observed (I=68.0%). Higher serum glucose concentrations were associated with a modestly increased risk of total oesophageal cancer (n=3 studies, pooled RR=1.27, 95% CI: 1.02-1.57). No association was observed for total cholesterol and total oesophageal cancer risk (n=3 studies, pooled RR=0.95, 95% CI: 0.58-1.54). Very few studies have assessed other biomarkers for meta-analyses. CONCLUSION: Serum pepsinogen I concentrations could aid early detection of oesophageal squamous cell carcinoma. More prospective studies are needed to determine the use of other nontissue biomarkers in the early detection of oesophageal cancer.

Adenocarcinoma risk in gastric atrophy and intestinal metaplasia: a systematic review.

BACKGROUND: Gastric cancer (GC) has a poor prognosis with wide variation in survival rates across the world. Several studies have shown premalignant lesions gastric atrophy (GA) and intestinal metaplasia (IM) influence gastric cancer risk. This systematic review examines all available evidence of the risk of GC in patients with GA or IM and explores the geographical variation between countries. METHODS: EMBASE, MEDLINE, Web of Science and the Cochrane Library were searched for relevant articles published to June 2016 investigating the risk of GC in individuals with GA or IM. Analysis was performed to determine variation based on geographical location. Study quality was assessed using the Newcastle-Ottawa Scale and heterogeneity between studies was also evaluated. RESULTS: Fifteen relevant articles were identified, in which there were eight studies of GC incidence in GA and nine in IM cohorts (two articles investigated both GA and IM). The incidence rate of GC in patients with GA ranged from 0.53 to 15.24 per 1000 person years, whereas there was more variation in GC incidence in patients with IM (0.38 to 17.08 per 1000 person years). The greatest GC incidence rates were in Asian countries, for patients with GA, and the USA for those with IM (15.24 and 17.08 per 1000 person years, respectively). The largest studies (four over 25,000 person years) had an incidence rate range of 1.0-2.5 per 1000 person years, however, in general, study quality was poor and there was marked heterogeneity. CONCLUSION: Overall there is a wide variation in annual incidence rate of GC from premalignant lesions. With the recent introduction of surveillance guidelines for gastric atrophy and intestinal metaplasia in the Western world, future assessment of this risk should be performed. Furthermore, substantial heterogeneity supports the need for more robust studies in order to pool results and determine the overall incidence rate of gastric cancer for patients with these premalignant lesions.

QuPath: Open source software for digital pathology image analysis.

QuPath is new bioimage analysis software designed to meet the growing need for a user-friendly, extensible, open-source solution for digital pathology and whole slide image analysis. In addition to offering a comprehensive panel of tumor identification and high-throughput biomarker evaluation tools, QuPath provides researchers with powerful batch-processing and scripting functionality, and an extensible platform with which to develop and share new algorithms to analyze complex tissue images. Furthermore, QuPath's flexible design makes it suitable for a wide range of additional image analysis applications across biomedical research.

Commonly used medications and endometrial cancer survival: a population-based cohort study.

BACKGROUND: Increasing incidence and new indications for existing drugs make it important to identify new adjuvant therapies for endometrial cancer (EC). METHODS: This is a prospective cohort study of 3058 newly diagnosed EC cases from 1998 to 2010, identified through record linkages between the UK Clinical Practice Research Datalink, the National Cancer Research Datalink and death registrations from the Office of National Statistics. Using Cox regression models, unadjusted and adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for EC-specific survival. RESULTS: Over a mean 6.1 (range 1-16) years of follow-up, there were 394 EC-specific deaths. There was no evidence of a significant association between post-diagnostic use of statins (adjusted HR 0.83, 95% CI 0.64, 1.08), ß-blockers (adjusted HR 0.86, 95% CI 0.65, 1.13) or low-dose aspirin (adjusted HR 0.91, 95% CI 0.69, 1.20) and EC survival before or after adjustment for confounders. There were also no evidence of a dose-response association between these drug groups and EC survival. CONCLUSIONS: In this large UK population-based study, no significant associations were observed for post-diagnostic use of statins, ß-blockers or low-dose aspirin and EC survival.

Dietary inflammatory index and risk of reflux oesophagitis, Barrett's oesophagus and oesophageal adenocarcinoma: a population-based case-control study.

The dietary inflammatory index (DIITM) is a novel composite score based on a range of nutrients and foods known to be associated with inflammation. DII scores have been linked to the risk of a number of cancers, including oesophageal squamous cell cancer and oesophageal adenocarcinoma (OAC). Given that OAC stems from acid reflux and that the oesophageal epithelium undergoes a metaplasia-dysplasia transition from the resulting inflammation, it is plausible that a high DII score (indicating a pro-inflammatory diet) may exacerbate risk of OAC and its precursor conditions. The aim of this analytical study was to explore the association between energy-adjusted dietary inflammatory index (E-DIITM) in relation to risk of reflux oesophagitis, Barrett's oesophagus and OAC. Between 2002 and 2005, reflux oesophagitis (n 219), Barrett's oesophagus (n 220) and OAC (n 224) patients, and population-based controls (n 256), were recruited to the Factors influencing the Barrett's Adenocarcinoma Relationship study in Northern Ireland and the Republic of Ireland. E-DII scores were derived from a 101-item FFQ. Unconditional logistic regression analysis was applied to determine odds of oesophageal lesions according to E-DII intakes, adjusting for potential confounders. High E-DII scores were associated with borderline increase in odds of reflux oesophagitis (OR 1·87; 95 % CI 0·93, 3·73), and significantly increased odds of Barrett's oesophagus (OR 2·05; 95 % CI 1·22, 3·47), and OAC (OR 2·29; 95 % CI 1·32, 3·96), when comparing the highest with the lowest tertiles of E-DII scores. In conclusion, a pro-inflammatory diet may exacerbate the risk of the inflammation-metaplasia-adenocarcinoma pathway in oesophageal carcinogenesis.

Statin use after esophageal cancer diagnosis and survival: A population based cohort study.

BACKGROUND: A recent epidemiological study of esophageal cancer patients concluded statin use post-diagnosis was associated with large (38%) and significant reductions in cancer-specific mortality. We investigated statin use and cancer-specific mortality in a large population-based cohort of esophageal cancer patients. METHODS: Newly diagnosed [2009-2012] esophageal cancer patients were identified from the Scottish Cancer Registry and linked with the Prescribing Information System and Scotland Death Records (to January 2015). Time-dependent Cox regression models were used to calculate hazard ratios (HR) for cancer-specific mortality and 95% confidence intervals (CIs) by post-diagnostic statin use (using a 6 month lag to reduce reverse causation) and to adjust these HRs for potential confounders. RESULTS: 1921 esophageal cancer patients were included in the main analysis, of whom 651 (34%) used statins after diagnosis. There was little evidence of a reduction in esophageal cancer-specific mortality in statin users compared with non-users after diagnosis (adjusted HR=0.93, 95% CI, 0.81, 1.07) and no dose response associations were seen. However, statin users compared with non-users in the year before diagnosis had a weak reduction in esophageal cancer-specific mortality (adjusted HR=0.88, 95% CI, 0.79, 0.99). CONCLUSIONS: In this large population-based esophageal cancer cohort, there was little evidence of a reduction in esophageal cancer-specific mortality with statin use after diagnosis.

Statin use, candidate mevalonate pathway biomarkers, and colon cancer survival in a population-based cohort study.

BACKGROUND: Statin use after colorectal cancer diagnosis may improve survival but evidence from observational studies is conflicting. The anti-cancer effect of statins may be restricted to certain molecular subgroups. In this population-based cohort study, the interaction between p53 and 3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMGCR) expression, KRAS mutations, and the association between statin use and colon cancer survival was assessed. METHODS: The cohort consisted of 740 stage II and III colon cancer patients diagnosed between 2004 and 2008. Statin use was determined through clinical note review. Tissue blocks were retrieved to determine immunohistochemical expression of p53 and HMGCR in tissue microarrays and the presence of KRAS mutations in extracted DNA. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for colorectal cancer-specific and overall survival. RESULTS: Statin use was not associated with improved cancer-specific survival in this cohort (HR=0.91, 95% CI 0.64-1.28). Statin use was also not associated with improved survival when the analyses were stratified by tumour p53 (wild-type HR=1.31, 95% CI 0.67-2.56 vs aberrant HR=0.80, 95% CI 0.52-1.24), HMGCR (HMGCR-high HR=0.69, 95% CI 0.40-1.18 vs HMGCR-low HR=1.10, 95% CI 0.66-1.84), and KRAS (wild-type HR=0.73, 95% CI 0.44-1.19 vs mutant HR=1.21, 95% CI 0.70-2.21) status. CONCLUSIONS: Statin use was not associated with improved survival either independently or when stratified by potential mevalonate pathway biomarkers in this population-based cohort of colon cancer patients.

Evaluation of PTGS2 Expression, PIK3CA Mutation, Aspirin Use and Colon Cancer Survival in a Population-Based Cohort Study.

OBJECTIVES: The association between aspirin use and improved survival after colorectal cancer diagnosis may be more pronounced in tumors that have PIK3CA mutations or high PTGS2 expression. However, the evidence of a difference in association by biomarker status lacks consistency. In this population-based colon cancer cohort study the interaction between these biomarkers, aspirin use, and survival was assessed. METHODS: The cohort consisted of 740 stage II and III colon cancer patients diagnosed between 2004 and 2008. Aspirin use was determined through clinical note review. Tissue blocks were retrieved to determine immunohistochemical assessment of PTGS2 expression and the presence of PIK3CA mutations. Cox proportional hazards models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for colorectal cancer-specific and overall survival. RESULTS: In this cohort aspirin use was associated with a 31% improvement in cancer-specific survival compared to non-use (adjusted HR=0.69, 95% CI 0.47-0.98). This effect was more pronounced in tumors with high PTGS2 expression (PTGS2-high adjusted HR=0.55, 95% CI 0.32-0.96) compared to those with low PTGS2 expression (PTGS2-low adjusted HR=1.19, 95% CI 0.68-2.07, P for interaction=0.09). The aspirin by PTGS2 interaction was significant for overall survival (PTGS2-high adjusted HR=0.64, 95% CI 0.42-0.98 vs. PTGS2-low adjusted HR=1.28, 95% CI 0.80-2.03, P for interaction=0.04). However, no interaction was observed between aspirin use and PIK3CA mutation status for colorectal cancer-specific or overall survival. CONCLUSIONS: Aspirin use was associated with improved survival outcomes in this population-based cohort of colon cancer patients. This association differed according to PTGS2 expression but not PIK3CA mutation status. Limiting adjuvant aspirin trials to PIK3CA-mutant colorectal cancer may be too restrictive.

Oral bisphosphonates and colorectal cancer.

Use of oral bisphosphonates has been associated with a decreased risk of colorectal cancer (CRC), but the association may be related to residual confounding by healthy lifestyle or body mass index (BMI). Therefore, we conducted a prospective nested case-control study within the Kaiser Permanente, Northern California health system cohort. In total, 12,505 CRC cases were individually matched to 599,534 controls. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional logistic regression models with adjustment for important covariates extracted from the database. Participants who had ever used oral bisphosphonates were less likely than non-users to be diagnosed with CRC (OR 0.82; 95% CI: 0.74, 0.89). Colon and rectum site-specific associations were similar to the overall association. A stronger inverse association for ever use of bisphosphonates was observed for men (OR 0.63; 95% CI: 0.47, 0.85), however when stratified by previous lower endoscopy, the association was only observed in the participants who did not have a previous lower endoscopy (OR 0.73 (0.64, 0.83)). In conclusion, we found that oral bisphosphonate use was associated with a decreased odds of CRC, however this association may be due to residual confounding by BMI or another confounder.

Low-dose aspirin use and survival in breast cancer patients: A nationwide cohort study.

BACKGROUND: Preclinical evidence from breast cancer cell lines and animal models suggest that aspirin could have anti-cancer properties. In a large breast cancer patient cohort, we investigated whether post-diagnostic low-dose aspirin use was associated with a reduction in the risk of breast cancer-specific mortality. METHODS: We identified 15,140 newly diagnosed breast cancer patients within the Scottish Cancer Registry. Linkages to the Scottish Prescribing Information System provided data on dispensed medications and breast cancer-specific deaths were identified from National Records of Scotland Death Records. Time-dependent Cox regression models were used to calculate hazard ratios (HR) and 95% CIs for breast cancer-specific and all-cause mortality by post-diagnostic low-dose aspirin use. HRs were adjusted for a range of potential confounders including age at diagnosis, year of diagnosis, cancer stage, grade, cancer treatments received, comorbidities, socioeconomic status and use of statins. Secondary analysis investigated the association between pre-diagnostic low-dose aspirin use and breast cancer-specific and all-cause mortality. RESULTS: Post-diagnostic users of low-dose aspirin appeared to have increased breast cancer-specific mortality compared with non-users (HR 1.44, 95% CI 1.26, 1.65) but this association was entirely attenuated after adjustment for potential confounders (adjusted HR 0.92, 95% CI 0.75, 1.14). Findings were similar in analysis by increasing duration of use and in analysis of pre-diagnostic low-dose aspirin use. CONCLUSION: In this large nationwide study of breast cancer patients, we found little evidence of an association between post-diagnostic low-dose aspirin use and cancer-specific mortality.

Cardiac glycosides and breast cancer risk: A systematic review and meta-analysis of observational studies.

Cardiac glycosides are phytoestrogens and have been linked to the risk of estrogen sensitive cancers such as uterus cancer. However, the association between use of cardiac glycosides and risk of breast cancer remains unclear. We investigated the association between cardiac glycosides use and the risk of breast cancer by systematically reviewing the published literature and performing meta-analyses. A comprehensive literature search was performed using MEDLINE, EMBASE, Web of Science and SCOPUS to identify all relevant articles published up to November 2015. Risk estimates, and accompanying standard errors, for the association between cardiac glycoside use and breast cancer were extracted from identified studies. Meta-analysis models were used to calculate a combined hazard ratio (HR), and 95% confidence interval (CI), and to investigate heterogeneity between studies. In total, nine studies were identified investigating cardiac glycosides use and risk of developing breast cancer. Overall, there was evidence to suggest an association between cardiac glycosides use and breast cancer risk (HR = 1.34; 95% CI 1.25, 1.44; p < 0.001) with little variation in the association between studies (I2 = 16%, p for heterogeneity = 0.30). Results were little altered when analysis was restricted to studies with high quality scores or cohort studies. Overall, there was a 34% increase in breast risk with use of cardiac glycosides but it is unclear whether this association reflects confounding or is causal. Further observational studies are required to examine this association particularly for estrogen receptor positive breast cancer and to explore the role of potential confounding variables.