Factors associated with interobserver variation amongst pathologists in the diagnosis of endometrial hyperplasia: A systematic review.

OBJECTIVE: Reproducible diagnoses of endometrial hyperplasia (EH) remains challenging and has potential implications for patient management. This systematic review aimed to identify pathologist-specific factors associated with interobserver variation in the diagnosis and reporting of EH. METHODS: Three electronic databases, namely MEDLINE, Embase and Web of Science, were searched from 1st January 2000 to 25th March 2023, using relevant key words and subject headings. Eligible studies reported on pathologist-specific factors or working practices influencing interobserver variation in the diagnosis of EH, using either the World Health Organisation (WHO) 2014 or 2020 classification or the endometrioid intraepithelial neoplasia (EIN) classification system. Quality assessment was undertaken using the QUADAS-2 tool, and findings were narratively synthesised. RESULTS: Eight studies were identified. Interobserver variation was shown to be significant even amongst specialist gynaecological pathologists in most studies. Few studies investigated pathologist-specific characteristics, but pathologists were shown to have different diagnostic styles, with some more likely to under-diagnose and others likely to over-diagnose EH. Some novel working practices were identified, such as grading the "degree" of nuclear atypia and the incorporation of objective methods of diagnosis such as semi-automated quantitative image analysis/deep learning models. CONCLUSIONS: This review highlighted the impact of pathologist-specific factors and working practices in the accurate diagnosis of EH, although few studies have been conducted. Further research is warranted in the development of more objective criteria that could improve reproducibility in EH diagnostic reporting, as well as determining the applicability of novel methods such as grading the degree of nuclear atypia in clinical settings.

Cancer-specific mortality in breast cancer patients with hypothyroidism: a UK population-based study.

PURPOSE: Epidemiological studies have indicated a higher prevalence of hypothyroidism in breast cancer patients, possibly related to shared risk factors and breast cancer treatments. However, few studies have evaluated how hypothyroidism impacts survival outcomes in breast cancer patients. We aimed to determine the association between hypothyroidism and breast cancer-specific and all-cause mortality. METHODS: We conducted a population-based study using the Scottish Cancer Registry to identify women diagnosed with breast cancer between 2010 and 2017. A matched comparison cohort of breast cancer-free women was also identified. Using hospital diagnoses and dispensed prescriptions for levothyroxine, we identified hypothyroidism diagnosed before and after breast cancer diagnosis and determined associations with breast cancer-specific and all-cause mortality. Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) adjusted for potential confounders. RESULTS: A total of 33,500 breast cancer patients were identified, of which 3,802 had hypothyroidism before breast cancer diagnosis and 565 patients went on to develop hypothyroidism after. Breast cancer patients had higher rates of hypothyroidism compared with cancer-free controls (HR 1.14, 95% CI 1.01-1.30). Among breast cancer patients, we found no association between hypothyroidism (diagnosed before or after) and cancer-specific mortality (before: HR 0.99, 95% CI 0.88-1.12, after: HR 0.97, 95% CI 0.63-1.49). Similar associations were seen for all-cause mortality. CONCLUSION: In a large contemporary breast cancer cohort, there was little evidence that hypothyroidism, either at diagnosis or diagnosed after breast cancer, was associated with cancer-specific or all-cause mortality.

Survival outcomes in endometrial cancer patients according to diabetes: a systematic review and meta-analysis.

BACKGROUND: Diabetes is an established risk factor for endometrial cancer development but its impact on prognosis is unclear and epidemiological studies to date have produced inconsistent results. We aimed to conduct the first systematic review and meta-analysis to compare survival outcomes in endometrial cancer patients with and without pre-existing diabetes. METHODS: We conducted a systematic search of MEDLINE, EMBASE and Web of Science databases up to February 2022 for observational studies that investigated the association between pre-existing diabetes and cancer-specific survival in endometrial cancer patients. Secondary outcomes included overall survival and progression or recurrence-free survival. Quality assessment of included studies was undertaken using the Newcastle-Ottawa Scale and a random-effects model was used to produce pooled hazard ratios (HRs) and 95% confidence intervals (CIs). (PROSPERO 2020 CRD42020196088). RESULTS: In total, 31 studies were identified comprising 55,475 endometrial cancer patients. Pooled results suggested a worse cancer-specific survival in patients with compared to patients without diabetes (n = 17 studies, HR 1.15, 95% CI 1.00-1.32, I2 = 62%). Similar results were observed for progression or recurrence-free survival (n = 6 studies, HR 1.23, 95% CI 1.02-1.47, I2 = 0%) and for overall survival (n = 24 studies, HR 1.42, 95% CI 1.31-1.54, I2 = 46%). CONCLUSION: In this systematic review and meta-analysis, we show that diabetes is associated with a worse cancer-specific and overall survival in endometrial cancer patients.

Hormone therapy use and the risk of acute kidney injury in patients with prostate cancer: a population-based cohort study.

BACKGROUND: Hormone therapy is widely used in prostate cancer. However, studies have raised concerns that hormone therapy, particularly the use of gonadotropin-releasing hormone agonists, could increase the risk of acute kidney injury. METHODS: Men newly diagnosed with non-metastatic prostate cancer, from 2012 to 2017, were identified from the Scottish Cancer Registry. A matched comparison cohort of prostate cancer-free men was also identified. Hormone therapy use was determined from the Prescribing Information System in Scotland. The primary outcome was hospitalisations with acute kidney injury taken from Scottish hospital records (SMR01) up to June 2019. Time-dependent Cox regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for acute kidney injury by hormone therapy use. RESULTS: The prostate cancer cohort contained 10,751 patients followed for 41,997 person years, during which there were 618 hospitalisations with acute kidney injury. Prostate cancer patients had higher rates of acute kidney injury compared with cancer-free controls (adjusted HR = 1.47 95% CI 1.29, 1.69). However, prostate cancer patients currently using hormone therapy (adjusted HR = 1.14 95% CI 0.92, 1.41), including gonadotropin-releasing hormone (GnRH) agonists (adjusted HR = 1.13 95% CI 0.90, 1.40), did not appear to have a marked increase in acute kidney injury compared with prostate cancer patients not using hormone therapy after adjusting for potential confounders. CONCLUSIONS: In our cohort, there was little evidence that gonadotropin-releasing hormone agonists were associated with marked increases in acute kidney injury.

Circulating Sex Hormones Are Associated With Gastric and Colorectal Cancers but Not Esophageal Adenocarcinoma in the UK Biobank.

INTRODUCTION: Gastrointestinal cancers show an unexplained male predominance, but few prospective studies have investigated sex hormones and gastrointestinal cancer risk. This study aimed to determine the impact of circulating sex hormones on risk of esophageal, gastric, and colorectal cancers in men and women. METHODS: We included 219,425 men and 147,180 women from the UK Biobank. Sex hormones were quantified using chemiluminescent immunoassay. Gastrointestinal cancers were identified from cancer registry linkages. Sex hormone concentrations and risk of gastrointestinal cancers were investigated using Cox proportional hazards regression. RESULTS: During the 10 years of follow-up, 376 esophageal adenocarcinoma, 108 esophageal squamous cell carcinoma, and 333 gastric and 2,868 colorectal cancer cases were identified. Increased hazard ratios (HRs) were found for sex hormone-binding globulin (SHBG) and risk of gastric cancer in men (Q4 vs Q1 HR 1.43, 95% confidence interval [CI] 0.95-2.17, Ptrend = 0.01). Free testosterone was inversely associated with esophageal squamous cell carcinoma in women (Q4 vs Q1 HR 0.32, 95% CI 0.11-0.98, Ptrend = 0.05). For colorectal cancer, SHBG was associated with a reduced risk among men (Q4 vs Q1 HR 0.89, 95% CI 0.77-1.03, Ptrend = 0.04) and free testosterone concentrations was associated with a reduction in risk among women (Q4 vs Q1 HR 0.80, 95% CI 0.66-0.97, Ptrend = 0.01). No associations were found for esophageal adenocarcinoma. DISCUSSION: In this large prospective investigation of prediagnostic sex hormones and risk of gastrointestinal cancers, men with higher SHBG concentrations had higher gastric, yet lower colorectal, cancer risks, whereas women with higher free testosterone levels had a lower risk of esophageal squamous cell carcinoma and colorectal cancer.

Exogenous hormone use, reproductive factors and risk of intrahepatic cholangiocarcinoma among women: results from cohort studies in the Liver Cancer Pooling Project and the UK Biobank.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) arises from cholangiocytes in the intrahepatic bile duct and is the second most common type of liver cancer. Cholangiocytes express both oestrogen receptor-α and -ß, and oestrogens positively modulate cholangiocyte proliferation. Studies in women and men have reported higher circulating oestradiol is associated with increased ICC risk, further supporting a hormonal aetiology. However, no observational studies have examined the associations between exogenous hormone use and reproductive factors, as proxies of endogenous hormone levels, and risk of ICC. METHODS: We harmonised data from 1,107,498 women who enroled in 12 North American-based cohort studies (in the Liver Cancer Pooling Project, LCPP) and the UK Biobank between 1980-1998 and 2006-2010, respectively. Cox proportional hazards regression models were used to generate hazard ratios (HR) and 95% confidence internals (CI). Then, meta-analytic techniques were used to combine the estimates from the LCPP (n = 180 cases) and the UK Biobank (n = 57 cases). RESULTS: Hysterectomy was associated with a doubling of ICC risk (HR = 1.98, 95% CI: 1.27-3.09), compared to women aged 50-54 at natural menopause. Long-term oral contraceptive use (9+ years) was associated with a 62% increased ICC risk (HR = 1.62, 95% CI: 1.03-2.55). There was no association between ICC risk and other exogenous hormone use or reproductive factors. CONCLUSIONS: This study suggests that hysterectomy and long-term oral contraceptive use may be associated with an increased ICC risk.

Use of proton pump inhibitors and histamine-2 receptor antagonists and risk of gastric cancer in two population-based studies.

BACKGROUND: Studies have shown increased gastric cancer risk in users of proton pump inhibitors (PPI) and histamine-2 receptor antagonists, questioning the safety of gastric acid suppression. Therefore, we conducted a case-control study within the Scottish Primary Care Clinical Informatics Unit (PCCIU) database and a cohort study in the UK Biobank. METHODS: In PCCIU, five controls were matched to cases diagnosed in 1999-2011, and medications were determined from GP records. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional logistic regression. In the UK Biobank, medications were self-reported at cohort entry 2006-2010, and gastric cancer ascertained from cancer registries until 2014. Hazard ratios (HR) were calculated using Cox regression. RESULTS: PCCIU contained 1119 cases and 5394 controls. UK Biobank contained 250 cases in 471,779 participants. PPI users had a higher gastric cancer risk in PCCIU and UK Biobank when applying a 1-year lag (adjusted OR = 1.49, 95% CI 1.24, 1.80; adjusted HR = 1.28, 95% CI 0.86, 1.90, respectively), but these associations were attenuated when using a 2-year lag (adjusted OR = 1.13, 95% CI 0.91, 1.40; adjusted HR = 1.15, 95% CI 0.73, 1.82, respectively). CONCLUSIONS: Overall, we observed little consistent evidence of an increased risk of gastric cancer with PPI use.

Concurrent and future risk of endometrial cancer in women with endometrial hyperplasia: A systematic review and meta-analysis.

BACKGROUND: To inform treatment decisions in women diagnosed with endometrial hyperplasia, quantification of the potential for concurrent endometrial cancer and the future risk of progression to cancer is required. METHODS: We identified studies up to September 2018 that reported on the prevalence of concurrent cancer (within three months of endometrial hyperplasia diagnosis), or the incidence of cancer, identified at least three months after hyperplasia diagnosis. Random-effects meta-analyses produced pooled estimates and 95% confidence intervals (CIs). RESULTS: A total of 36 articles were identified; 15 investigating concurrent and 21 progression to cancer. In pooled analysis of 11 studies of atypical hyperplasia, the pooled prevalence of concurrent endometrial cancer was 32.6% (95% CI: 24.1%, 42.4%) while no studies evaluated concurrent cancer in non-atypical hyperplasia. The risk of progression to cancer was high in atypical hyperplasia (n = 5 studies, annual incidence rate = 8.2%, 95% CI 3.9%, 17.3%) and only one study reported on non-atypical hyperplasia (annual incidence rate = 2.6%, 95% CI: 0.6%, 10.6%). CONCLUSIONS: Overall, a third of women with atypical hyperplasia had concurrent endometrial cancer, although the number of studies, especially population-based, is small. Progression to cancer in atypical hyperplasia was high, but few studies were identified. Population-based estimates are required, in both atypical and non-atypical hyperplasia patients to better inform treatment strategies.

The Risk of Cardiovascular Disease in Prostate Cancer Patients Receiving Androgen Deprivation Therapies.

BACKGROUND: Androgen deprivation therapy (ADT), with a proven role in prostate cancer management, has been associated with various cardiovascular diseases. However, few studies have investigated these associations by type of ADT, particularly for newer ADTs such as the gonadotropin-releasing hormone (GnRH) antagonist degarelix. We investigated the risk of cardiovascular disease by type of ADT in a real-world setting. METHODS: We identified men newly diagnosed with prostate cancer, from 2009 to 2015, from the Scottish Cancer Registry and ADTs from the nationwide Prescribing Information System. Cardiovascular events were based upon hospitalization (from hospital records) or death from cardiovascular disease (from death records). We used Cox regression to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for cardiovascular events with time-varying ADT exposure, comparing ADT users with untreated patients, after adjusting for potential confounders, including prior cardiovascular disease. RESULTS: The cohort contained 20,216 prostate cancer patients, followed for 73,570 person-years, during which there were 3,853 cardiovascular events. ADT was associated with a 30% increase in cardiovascular events (adjusted HR = 1.3; 95% CI = 1.2, 1.4). This reflected increases in cardiovascular events associated with GnRH agonists (adjusted HR = 1.3; 95% CI = 1.2, 1.4), degarelix (adjusted HR = 1.5; 95% CI = 1.2, 1.9), but not bicalutamide monotherapy (adjusted HR = 1.0; 95% CI = 0.82, 1.3). CONCLUSIONS: There were increased risks of cardiovascular disease with the use of GnRH agonists and degarelix, but not with bicalutamide monotherapy. This is the first study to observe increased cardiovascular risks with degarelix, but the cause of this association is unclear and merits further investigation.

Statin use and risk of liver cancer: Evidence from two population-based studies.

Epidemiological studies of statin use and liver cancer risk have produced conflicting results. We examined the association between statin use and risk of primary liver cancer in two large independent study populations taking account of important covariates and main indications of statins such as high cholesterol and chronic liver disease. We performed a nested case-control study within the Scottish Primary Care Clinical Informatics Unit (PCCIU) database. Five controls were matched to cases with primary liver cancer and we used conditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for associations with statin use. We also conducted a prospective cohort study within the UK Biobank using self-reported statin use and cancer-registry recorded primary liver cancer outcomes. Cox regression was used to calculate hazard ratios (HRs) and 95% CIs. In the PCCIU case-control analysis, 434 liver cancer cases were matched to 2,103 controls. In the UK Biobank cohort, 182 out of 475,768 participants developed incident liver cancer. Statin use was associated with 39% lower risk of liver cancer in the PCCIU (adjusted OR 0.61, 95% CI 0.43-0.87). When we examined specific subtypes of liver cancer in the UK Biobank, statin use was associated with lower risk of hepatocellular carcinoma (HCC; adjusted HR, 0.48; 95% CI, 0.24-0.94) but not intrahepatic bile duct carcinoma (IBDC; adjusted HR, 1.09; 95% CI, 0.45-2.64). In conclusion, we found a consistent inverse relationship between statin use and risk of primary liver cancer which was only seen for HCC but not IBDC.

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.

Furosemide use and survival in patients with esophageal or gastric cancer: a population-based cohort study.

BACKGROUND: Pre-clinical studies have shown that furosemide slows cancer cell growth by acting on the Na-K-2Cl transporter, particularly for gastric cancer cells. However, epidemiological studies have not investigated furosemide use and mortality in gastroesophageal cancer patients. Consequently, we conducted a population-based study to investigate whether furosemide use is associated with reduced cancer-specific mortality in esophageal/gastric cancer patients. METHODS: A cohort of patients newly diagnosed with esophageal or gastric cancer between 1998 and 2013 were identified from English cancer registries and linked to the Clinical Practice Research Datalink to provide prescription records and the Office of National Statistics to provide death data up to September 2015. Time-dependant Cox-regression models were used to calculate hazard ratios (HRs) comparing cancer-specific mortality in furosemide users with non-users. Analyses were repeated restricting to patients with common furosemide indications (heart failure, myocardial infarction, edema or hypertension) to reduce potential confounding. RESULTS: The cohort contained 2708 esophageal cancer patients and 2377 gastric cancer patients, amongst whom 1844 and 1467 cancer-specific deaths occurred, respectively. Furosemide use was not associated with reduced cancer-specific mortality overall (adjusted HR in esophageal cancer = 1.28, 95% CI 1.10, 1.50 and in gastric cancer = 1.27, 95% CI 1.08, 1.50) or when restricted to patients with furosemide indications before cancer diagnosis (adjusted HR in esophageal cancer = 1.07, 95% CI 0.88, 1.30 and in gastric cancer = 1.18, 95% CI 0.96, 1.46). CONCLUSIONS: In this large population-based cohort study, furosemide was not associated with reduced cancer-specific mortality in patients with esophageal or gastric cancer.

Coffee consumption by type and risk of digestive cancer: a large prospective cohort study.

BACKGROUND: Inverse associations have been observed between coffee consumption and liver cancer, but associations for other digestive cancers are unclear. Few previous studies have investigated coffee type (specifically instant or ground coffee) or a range of digestive cancer types within one cohort. We therefore investigated coffee consumption by type and digestive cancer risks in a population-based cohort. METHODS: The UK Biobank captured self-reported coffee consumption and cancer-registry recorded incident digestive cancers. Hazard ratios (HRs) and 95% CIs were calculated using Cox regression. The risk of every type of digestive cancer was investigated in association with coffee consumption by dose-response and by coffee type (decaffeinated, instant and ground). RESULTS: Over 7.5 years of follow-up, 3567 developed digestive cancer among 471,779 participants. There were 88 cases of hepatocellular carcinoma and a marked association was observed for hepatocellular carcinoma in coffee drinkers (HR 0.50, 95% CI 0.29, 0.87), which was similar for instant (HR 0.51, 95% CI 0.28, 0.93) and ground coffee (HR 0.47, 95% CI 0.20, 1.08). We did not observe significant consistently reduced risks of other individual digestive cancers amongst coffee drinkers. CONCLUSIONS: We found some evidence that coffee consumption was inversely associated with hepatocellular carcinoma which was similar by coffee type.

Information on Genetic Variants Does Not Increase Identification of Individuals at Risk of Esophageal Adenocarcinoma Compared to Clinical Risk Factors.

We previously developed a tool that identified individuals who later developed esophageal adenocarcinoma (based on age, sex, body mass index, smoking status, and prior esophageal conditions) with an area under the curve of 0.80. In this study, we collected data from 329,463 individuals in the UK Biobank cohort who were tested for genetic susceptibility to esophageal adenocarcinoma (a polygenic risk score based on 18 recognized genetic variants). We found that after inclusion of this genetic information, the area under the curve for identification of individuals who developed esophageal adenocarcinoma remained at 0.80. Testing for genetic variants associated with esophageal adenocarcinoma therefore seems unlikely to improve identification of individuals at risk of esophageal adenocarcinoma.

Sex hormone receptor expression and survival in esophageal adenocarcinoma: a prospective cohort study.

INTRODUCTION: A striking epidemiological feature of esophageal adenocarcinoma (EAC) is its strong, unexplained male predominance but few studies have evaluated the prevalence of sex hormone receptor expression in EAC. RESULTS: A low proportion of EAC tumors stained positive for ERα (4%) and AR (3%) while approximately one third stained positive for ERß (31%). After a mean follow-up of 3 years (max 9 years), no significant associations were seen for ERα, ERß or AR expression and EAC recurrence or survival. A non-significant reduction in mortality was observed for positive ERß tumor expression, when restricting to patients with gastro-esophageal junctional (GEJ) cancer (HR 0.58, 95% CI 0.33, 1.03, p = 0.06). MATERIALS AND METHODS: We identified all EAC patients who underwent neo-adjuvant chemotherapy prior to surgical resection between 2004-2012 in the Northern Ireland Cancer Centre. Immunohistochemical expression of ERα, ERß and AR was scored on triplicate cores to generate H-scores. Cox proportional hazards regression was used to evaluate the association between sex hormone receptor expression and overall, cancer-specific and recurrence-free survival. CONCLUSION: We found little evidence of ERα or AR expression in EAC. A moderate proportion expressed ERß and there was suggestive evidence that its expression was associated with improved survival in GEJ cancer patients.

Vitamin D receptor as a marker of prognosis in oesophageal adenocarcinoma: a prospective cohort study.

AIMS: Vitamin D receptor (VDR) expression has been associated with survival in several cancer sites. This study aims to evaluate the association between VDR expression and prognosis in oesophageal adenocarcinoma patients. RESULTS: During a median of 2.5 (maximum 9) years of follow-up, 75 patients died. In analysis adjusted for confounders, higher VDR expression was associated with an improved overall survival (HR 0.49 95% CI 0.25-0.96) and disease-specific survival (HR 0.50 95% CI 0.26-0.99), when comparing the highest with the lowest tertile of expression. These associations were strongest in sensitivity analysis restricted to junctional tumours. CONCLUSIONS: This study is the first to demonstrate that patients with higher VDR expression in oesophageal adenocarcinoma have a more favourable prognosis. Further work is needed to validate these findings, and to define the role of VDR in the aetiology, progression and management of oesophageal adenocarcinoma. METHODS: Oesophageal adenocarcinoma specimens and clinical data were collected from 130 patients treated with neo-adjuvant chemotherapy prior to surgical resection at the Northern Ireland Cancer Centre between 2004 and 2012. Tissue microarrays were created and immunohistochemical staining for VDR was performed on triplicate tumour cores from each resection specimen. Cox proportional hazards models were applied to evaluate associations between VDR, according to tertiles of expression, and survival outcomes.

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.

Model for Identifying Individuals at Risk for Esophageal Adenocarcinoma.

BACKGROUND & AIMS: The prognosis for most patients with esophageal adenocarcinoma (EAC) is poor because they present with advanced disease. Models developed to identify patients at risk for EAC and increase early detection have been developed based on data from case-control studies. We analyzed data from a prospective study to identify factors available to clinicians that identify individuals with a high absolute risk of EAC. METHODS: We collected data from 355,034 individuals (all older than 50 years) without a prior history of cancer enrolled in the UK Biobank prospective cohort study from 2006 through 2010; clinical data were collected through September 2014. We identified demographic, lifestyle, and medical factors, measured at baseline, that associated with development of EAC within 5 years using logistic regression analysis. We used these data to create a model to identify individuals at risk for EAC. Model performance was assessed using area under the receiver operating characteristics curve (AUROC), sensitivity, and specificity analyses. RESULTS: Within up to 5 years of follow up, 220 individuals developed EAC. Age, sex, smoking, body mass index, and history of esophageal conditions or treatments identified individuals who developed EAC (AUROC, 0.80; 95% CI, 0.77-0.82). We used these factors to develop a scoring system and identified a point cut off that 104,723 individuals (29.5%), including 170 of the 220 cases with EAC, were above. The scoring system identified individuals who developed EAC with 77.4% sensitivity and 70.5% specificity. The 5-year risk of EAC was 0.16% for individuals with scores above the threshold and 0.02% for individuals with scores below the threshold. CONCLUSION: We combined data on several well-established risk factors that are available to clinicians to develop a system to identify individuals with a higher absolute risk of EAC within 5 years. Studies are needed to evaluate the utility of these factors in a multi-stage, triaged, screening program.

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.