Matthew J. Grainge

Aspirin for the Chemoprevention of Colorectal Adenomas: Meta-analysis of the Randomized Trials

BACKGROUND Multiple lines of evidence indicate that aspirin has an antineoplastic effect in the large bowel. Randomized clinical trials have been conducted to evaluate the effectiveness of aspirin for reducing the risk of colorectal adenomas. A meta-analysis of these trials will provide more precise estimates of the aspirin effect, both overall and in subgroups. METHODS We combined data from all randomized double-blind placebo-controlled trials that evaluated aspirin for the prevention of colorectal adenomas. We used random-effects meta-analysis to estimate risk ratios and 95% confidence intervals (CIs) for the effect of aspirin on the occurrence of adenomas and of advanced lesions (ie, tubulovillous adenomas, villous adenomas, adenomas >or=1 cm in diameter, adenomas with high-grade dysplasia, or invasive cancer). All statistical tests were two-sided. RESULTS We identified four clinical trials with 2967 randomly assigned participants. Each trial evaluated aspirin for the secondary prevention of colorectal adenomas. Doses of aspirin tested ranged from 81 to 325 mg/d. The average age of participants at baseline was 58 years, and 60% were male. Median follow-up was 33 months. A total of 2698 participants underwent colonoscopic follow-up and were included in the analysis of adenoma occurrence and advanced-lesion occurrence after randomization. Among these participants, adenomas were found in 424 (37%) of the 1156 participants allocated to placebo and in 507 (33%) of the 1542 participants allocated to any dose of aspirin. Advanced lesions were found in 12% of participants in the placebo group and in 9% of participants allocated to any dose of aspirin. The pooled risk ratio of any adenoma for any dose of aspirin vs placebo was 0.83 (95% CI = 0.72 to 0.96). This corresponded to an absolute risk reduction of 6.7% (95% CI = 3.2% to 10.2%). For any advanced lesion, the pooled risk ratio was 0.72 (95% CI = 0.57 to 0.90). We found no statistically significant effect modification for any of the baseline factors studied. CONCLUSION Aspirin is effective for the prevention of colorectal adenomas in individuals with a history of these lesions.

Venous thromboembolism during active disease and remission in inflammatory bowel disease: a cohort study.

BACKGROUND Patients with inflammatory bowel disease who develop deep vein thrombosis or pulmonary embolism often have active disease at the time of thromboembolism. We therefore aimed to quantify the risk of venous thromboembolism prospectively during different activity phases of inflammatory bowel disease. METHODS From the General Practice Research Database, we matched patients with prospectively recorded inflammatory bowel disease from November, 1987, until July, 2001 with up to five controls by age, sex, and general practice. A flare was defined as the period 120 days after a new corticosteroid prescription. We used Cox regression analysis with time-varying covariates to accommodate changes in the state of inflammatory bowel disease, and whether patients were at high risk of venous thromboembolism after hospitalisation. FINDINGS 13 756 patients with inflammatory bowel disease and 71 672 matched controls were included in the analysis, and of these 139 patients and 165 controls developed venous thromboembolism. Overall, patients with inflammatory bowel disease had a higher risk of venous thromboembolism than did controls (hazard ratio 3.4, 95% CI 2.7-4.3; p<0.0001; absolute risk 2.6 per 1000 per person-years). At the time of a flare, however, this increase in risk was much more prominent (8.4, 5.5-12.8; p<0.0001; 9.0 per 1000 person-years). This relative risk at the time of a flare was higher during non-hospitalised periods (15.8, 9.8-25.5; p<0.0001; 6.4 per 1000 person-years) than during hospitalised periods (3.2, 1.7-6.3; p=0.0006; 37.5 per 1000 person-years). INTERPRETATION Trials of primary prophylaxis of venous thromboembolism are warranted to find out whether this important complication can be prevented. FUNDING National Association for Colitis and Crohns Disease.

Prognostic Significance of Nottingham Histologic Grade in Invasive Breast Carcinoma

PURPOSE The three strongest prognostic determinants in operable breast cancer used in routine clinical practice are lymph node (LN) stage, primary tumor size, and histologic grade. However, grade is not included in the recent revision of the TNM staging system of breast cancer as its value is questioned in certain settings. MATERIALS AND METHODS This study is based on a large and well-characterized consecutive series of operable breast cancer (2,219 cases), treated according to standard protocols in a single institution, with a long-term follow-up (median, 111 months) to assess the prognostic value of routine assessment of histologic grade using Nottingham histologic grading system. RESULTS Histologic grade is strongly associated with both breast cancer-specific survival (BCSS) and disease-free survival (DFS) in the whole series as well as in different subgroups based on tumor size (pT1a, pT1b, pT1c, and pT2) and LN stages (pN0 and pN1 and pN2). Differences in survival were also noted between different individual grades (1, 2, and 3). Multivariate analyses showed that histologic grade is an independent predictor of both BCSS and DFS in operable breast cancer as a whole as well as in all studied subgroups. CONCLUSION Histologic grade, as assessed by the Nottingham grading system, provides a strong predictor of outcome in patients with invasive breast cancer and should be incorporated in breast cancer staging systems.

Global Histone Modifications in Breast Cancer Correlate with Tumor Phenotypes, Prognostic Factors, and Patient Outcome

Post-translational histone modifications are known to be altered in cancer cells, and loss of selected histone acetylation and methylation marks has recently been shown to predict patient outcome in human carcinoma. Immunohistochemistry was used to detect a series of histone lysine acetylation (H3K9ac, H3K18ac, H4K12ac, and H4K16ac), lysine methylation (H3K4me2 and H4K20me3), and arginine methylation (H4R3me2) marks in a well-characterized series of human breast carcinomas (n = 880). Tissue staining intensities were assessed using blinded semiquantitative scoring. Validation studies were done using immunofluorescence staining and Western blotting. Our analyses revealed low or absent H4K16ac in the majority of breast cancer cases (78.9%), suggesting that this alteration may represent an early sign of breast cancer. There was a highly significant correlation between histone modifications status, tumor biomarker phenotype, and clinical outcome, where high relative levels of global histone acetylation and methylation were associated with a favorable prognosis and detected almost exclusively in luminal-like breast tumors (93%). Moderate to low levels of lysine acetylation (H3K9ac, H3K18ac, and H4K12ac), lysine (H3K4me2 and H4K20me3), and arginine methylation (H4R3me2) were observed in carcinomas of poorer prognostic subtypes, including basal carcinomas and HER-2-positive tumors. Clustering analysis identified three groups of histone displaying distinct pattern in breast cancer, which have distinct relationships to known prognostic factors and clinical outcome. This study identifies the presence of variations in global levels of histone marks in different grades, morphologic types, and phenotype classes of invasive breast cancer and shows that these differences have clinical significance.

Rising burden of gout in the UK but continuing suboptimal management: a nationwide population study

Objectives To describe trends in the epidemiology of gout and patterns of urate-lowering treatment (ULT) in the UK general population from 1997 to 2012. Methods We used the Clinical Practice Research Datalink to estimate the prevalence and incidence of gout for each calendar year from 1997 to 2012. We also investigated the pattern of gout management for both prevalent and incident gout patients. Results In 2012, the prevalence of gout was 2.49% (95% CI 2.48% to 2.51%) and the incidence was 1.77 (95% CI 1.73 to 1.81) per 1000 person-years. Prevalence and incidence both were significantly higher in 2012 than in 1997, with a 63.9% increase in prevalence and 29.6% increase in incidence over this period. Regions with highest prevalence and incidence were the North East and Wales. Among prevalent gout patients in 2012, only 48.48% (95% CI 48.08% to 48.89%) were being consulted specifically for gout or treated with ULT and of these 37.63% (95% CI 37.28% to 38.99%) received ULT. In addition, only 18.6% (95% CI 17.6% to 19.6%) of incident gout patients received ULT within 6 months and 27.3% (95% CI 26.1% to 28.5%) within 12 months of diagnosis. The management of prevalent and incident gout patients remained essentially the same during the study period, although the percentage of adherent patients improved from 28.28% (95% CI 27.33% to 29.26%) in 1997 to 39.66% (95% CI 39.11% to 40.22%) in 2012. Conclusions In recent years, both the prevalence and incidence of gout have increased significantly in the UK. Suboptimal use of ULT has not changed between 1997 and 2012. Patient adherence has improved during the study period, but it remains poor.

FGFR1 amplification in breast carcinomas: a chromogenic in situ hybridisation analysis

BackgroundThe amplicon on 8p11.2 is reported to be found in up to 10% of breast carcinomas. It has been demonstrated recently that this amplicon has four separate cores. The second core encompasses important oncogene candidates, including the fibroblast growth factor receptor 1 (FGFR1) gene. Recent studies have demonstrated that specific FGFR1 amplification correlates with gene expression and that FGFR1 activity is required for the survival of a FGFR1 amplified breast cancer cell line.MethodsFGFR1 amplification was analysed in tissue microarrays comprising a cohort of 880 unselected breast tumours by means of chromogenic in situ hybridisation using inhouse-generated FGFR1-specific probes. Chromogenic in situ hybridisation signals were counted in a minimum 30 morphologically unequivocal neoplastic cells. Amplification was defined as >5 signals per nucleus in more than 50% of cancer cells or when large gene copy clusters were seen.ResultsFGFR1 amplification was observed in 8.7% of the tumours and was significantly more prevalent in patients >50 years of age and in tumours that lacked HER2 expression. No association was found with other histological parameters. Survival analysis revealed FGFR1 amplification as an independent prognostic factor for overall survival in the whole cohort. Subgroup analysis demonstrated that the independent prognostic impact of FGFR1 amplification was only seen in patients with oestrogen-receptor-positive tumours, where FGFR1 amplification was the strongest independent predictor of poor outcome.ConclusionGiven that up to 8.7% of all breast cancers harbour FGFR1 amplification and that this amplification is an independent predictor of overall survival, further studies analysing the FGFR1 as a potential therapeutic target for breast cancer patients are warranted.

Risk of venous thromboembolism in patients with cancer: a systematic review and meta-analysis

Venous thromboembolism in patients with cancer is common, but precise incidence rates in different cancers are not known, making it difficult to target prevention strategies. This study summarizes the existing literature to determine the risk of venous thromboembolism in high- and average-risk groups of patients with different cancers.

Incidence of venous thromboembolism in patients with cancer – A cohort study using linked United Kingdom databases

BACKGROUND Accurate population-based data are needed on the incidence of venous thromboembolism (VTE) in patients with different cancers in order to inform guidelines on which hospitalised and ambulatory cancer patients should receive VTE prophylaxis. METHODS We conducted a cohort study using data from the Clinical Practice Research Datalink, linked to Hospital Episode Statistics, Cancer Registry data and Office for National Statistics cause of death data. We determined the incidence rates (cases per 1000 person-years) of VTE separately for 24 cancer sites. To determine relative risk, incidence rates were compared to frequency-matched controls (by age) with no record of cancer. FINDINGS We identified 83,203 cancer patients and 577,207 controls. New cases of VTE were diagnosed in 3352 cancer patients, and 6353 controls. The absolute rate of VTE in all cancers was 13.9 per 1000 person-years (95% confidence interval [CI] 13.4-14.4), corresponding to an age, sex and calendar year adjusted hazard-ratio of 4.7 (CI 4.5-4.9) between cancer patients and the general population. Rates varied greatly by cancer site (range; 98 (CI 80-119) in pancreatic cancer to 3.1 (CI 1.5-6.5) in thyroid cancer), age (range; 16.9 for patients over 80 years to 4.9 for those under 30 years) and time from diagnosis (range; 75 in the first three months to 8.4, >1 year after diagnosis). INTERPRETATION VTE is strongly linked to cancer, but the annual rate varies greatly by cancer site, proximity to diagnosis and age. Prophylaxis guidelines should take account of cancer site and such intervention should also be targeted towards the three months following diagnosis.

Risk factors for first venous thromboembolism around pregnancy: a population-based cohort study from the United Kingdom

Knowledge of the absolute risk (AR) for venous thromboembolism (VTE) in women around pregnancy and how potential risk factors modify this risk is crucial in identifying women who would benefit most from thromboprophylaxis. We examined a large primary care database containing 376 154 pregnancies ending in live birth or stillbirth from women aged 15 to 44 years between 1995 and 2009 and assessed the effect of risk factors on the incidence of antepartum and postpartum VTE in terms of ARs and incidence rate ratios (IRR), using Poisson regression. During antepartum, varicose veins, inflammatory bowel disease (IBD), urinary tract infection, and preexisting diabetes were associated with an increased risk for VTE (ARs, ≥139/100 000 person-years; IRRs, ≥1.8/100 000 person-years). Postpartum, the strongest risk factor was stillbirth (AR, 2444/100 000 person-years; IRR, 6.2/100 000 person-years), followed by medical comorbidities (including varicose veins, IBD, or cardiac disease), a body mass index (BMI) of 30 kg/m(2) or higher, obstetric hemorrhage, preterm delivery, and caesarean section (ARs, ≥637/100 000 person-years; IRRs, ≥1.9/100 000 person-years). Our findings suggest that VTE risk varies modestly by recognized factors during antepartum; however, women with stillbirths, preterm births, obstetric hemorrhage, caesarean section delivery, medical comorbidities, or a BMI of 30 kg/m(2) or higher are at much higher risk for VTE after delivery. These risk factors should receive careful consideration when assessing the potential need for thromboprophylaxis during the postpartum period.

Cigarette Smoking, Alcohol and Caffeine Consumption, and Bone Mineral Density in Postmenopausal Women

Abstract: The aim of this analysis was to compare the effects of different measures of cigarette, alcohol and caffeine consumption upon bone mineral density (BMD). Five hundred and eighty postmenopausal women aged 45–59 years at recruitment completed a risk factor questionnaire that contained detailed sections on cigarette, alcohol and caffeine consumption. BMD was measured using dual-energy X-ray absorptiometry. Measurements taken at five bone sites were used: anterior-posterior spine, femoral neck, greater trochanter, radius/ulna and whole body. The data were analyzed using multiple linear regression, adjusting for a number of established BMD risk factors. BMD was more strongly related to the number of months spent smoking than to pack-years of smoking at all five sites (p <0.05 at four of the five sites). There were significant reductions in BMD when comparing smokers with non-smokers at ages 20, 30 and 40 years, but not for current smoking. Lifetime alcohol consumption and current alcohol consumption did not have an independent association with BMD. However, the heaviest beer drinkers in the sample had a particularly low bone density. Caffeine consumption at various ages was not associated with BMD. The results of these analyses suggest that for predicting BMD a simple history of smoking duration is as good as trying to obtain more detailed smoking information, but that only 25% of the variation in BMD is explained by personal characteristics, family history and lifestyle factors.