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Summary Background Beta-blockers have potential antiangiogenic and antimigratory activity. Studies have demonstrated a survival benefit in patients with malignant melanoma treated with beta-blockers. Objectives To investigate the association between postdiagnostic beta-blocker usage and risk of melanoma-specific mortality in a population-based cohort of patients with malignant melanoma. Methods Patients with incident malignant melanoma diagnosed between 1998 and 2010 were identified within the U.K. Clinical Practice Research Datalink and confirmed using cancer registry data. Patients with malignant melanoma with a melanoma-specific death (cases) recorded by the Office of National Statistics were matched on year of diagnosis, age and sex to four malignant melanoma controls (who lived at least as long after diagnosis as their matched case). A nested case–control approach was used to investigate the association between postdiagnostic beta-blocker usage and melanoma-specific death and all-cause mortality. Conditional logistic regression was applied to generate odds ratios (ORs) and 95% confidence intervals (CIs) for beta-blocker use determined from general practitioner prescribing. Results Beta-blocker medications were prescribed after malignant melanoma diagnosis to 20·2% of 242 patients who died from malignant melanoma (cases) and 20·3% of 886 matched controls. Consequently, there was no association between beta-blocker use postdiagnosis and cancer-specific death (OR 0·99, 95% CI 0·68–1·42), which did not markedly alter after adjustment for confounders including stage (OR 0·87, 95% CI 0·56–1·34). No significant associations were detected for individual beta-blocker types, by defined daily doses of use or for all-cause mortality. Conclusions Contrary to some previous studies, beta-blocker use after malignant melanoma diagnosis was not associated with reduced risk of death from melanoma in this U.K. population-based study.

Aspirin use is associated with reduced risk of, and death from, prostate cancer. Our aim was to determine whether low-dose aspirin use after a prostate cancer diagnosis was associated with reduced prostate cancer-specific mortality. A cohort of newly diagnosed prostate cancer patients (1998–2006) was identified in the UK Clinical Practice Research Datalink (confirmed by cancer registry linkage). A nested case–control analysis was conducted using conditional logistic regression to compare aspirin usage in cases (prostate cancer deaths) with up to three controls (matched by age and year of diagnosis). Post-diagnostic low-dose aspirin use was identified in 52 % of 1,184 prostate cancer-specific deaths and 39 % of 3,531 matched controls (unadjusted OR 1.51, 95 % CI 1.19, 1.90; p

Background Epidemiological and laboratory studies suggest that β-blockers may reduce cancer progression in various cancer sites. The aim of this study was to conduct the first epidemiological investigation of the effect of post-diagnostic β-blocker usage on colorectal cancer-specific mortality in a large population-based colorectal cancer patient cohort. Patients and methods: A nested case–control analysis was conducted within a cohort of 4794 colorectal cancer patients diagnosed between 1998 and 2007. Patients were identified from the UK Clinical Practice Research Datalink and confirmed using cancer registry data. Patients with a colorectal cancer- specific death (data from the Office of National Statistics death registration system) were matched to five controls. Conditional logistic regression was applied to calculate odds ratios (OR) and 95% confidence intervals (95% CIs) according to β-blocker usage (data from GP-prescribing records). Results Post-diagnostic β-blocker use was identified in 21.4% of 1559 colorectal cancer-specific deaths and 23.7% of their 7531 matched controls, with little evidence of an association (OR = 0.89 95% CI 0.78–1.02). Similar associations were found when analysing drug frequency, β-blocker type or specific drugs such as propranolol. There was some evidence of a weak reduction in all-cause mortality in β-blocker users (adjusted OR = 0.88; 95% CI 0.77–1.00; P = 0.04) which was in part due to the marked effect of atenolol on cardiovascular mortality (adjusted OR = 0.62; 95% CI 0.40–0.97; P = 0.04). Conclusions In this novel, large UK population-based cohort of colorectal cancer patients, there was no evidence of an association between post-diagnostic β-blocker use and colorectal cancer-specific mortality. Clinical Trials number NCT00888797.

Breast cancer mortality is frequently associated with metastatic disease. Metastasis models have shown adrenoceptor (AR) stimulation induces cell migration which is inhibited by adrenoceptor antagonist drugs. We investigated adrenoceptor protein expression in clinical breast tumours and its association with disease progression and prognosis. Immunohistochemistry on tissue microarrays was used to characterise α1b, α2c and β22 adrenoceptor protein expression in operable breast tumours. Associations with tumour-relevant biological markers and clinical outcome were statistically assessed. Strong α1b expression occurred in large high grade (P

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. [Cancer Res 2009;69(9):3802–9]

The Nottingham prognostic index plus (NPI+) is based on the assessment of biological class combined with established clinicopathologic prognostic variables providing improved patient outcome stratification for breast cancer superior to the traditional NPI. This study aimed to determine prognostic capability of the NPI+ in predicting risk of development of distant disease. A well-characterised series of 1073 primary early-stage BC cases treated in Nottingham and 251 cases from Budapest were immunohistochemically assessed for cytokeratin (Ck)5/6, Ck18, EGFR, oestrogen receptor (ER), progesterone receptor, HER2, HER3, HER4, Mucin 1 and p53 expression. NPI+ biological class and prognostic scores were assigned using individual algorithms for each biological class incorporating clinicopathologic parameters and investigated in terms of prediction of distant metastases-free survival (MFS). The NPI+ identified distinct prognostic groups (PG) within each molecular class which were predictive of MFS providing improved patient outcome stratification superior to the traditional NPI. NPI+ PGs, between series, were comparable in predicting patient outcome between series in luminal A, basal p53 altered and HER2+/ER+ (p 0.01) tumours. The low-risk groups were similarly validated in luminal B, luminal N, basal p53 normal tumours (p 0.01). Due to small patient numbers the remaining PGs could not be validated. NPI+ was additionally able to predict a higher risk of metastases at certain distant sites. This study may indicate the NPI+ as a useful tool in predicting the risk of metastases. The NPI+ provides accurate risk stratification allowing improved individualised clinical decision making for breast cancer.

Background To investigate the association between post-diagnostic beta-blocker usage and risk of cancer-specific mortality in a large population-based cohort of female breast cancer patients. Methods A nested case-control study was conducted within a cohort of breast cancer patients identified from cancer registries in England(using the National Cancer Data repository) and diagnosed between 1998 and 2007. Patients who had a breast cancer-specific death(ascertained from Office of National Statistics death registration data) were each matched to four alive controls by year and age at diagnosis. Prescription data for these patients were available through the Clinical Practice Research Datalink. Conditional logistic regression models were used to investigate the association between breast cancer-specific death and beta-blocker usage. Results Post-diagnostic use of beta-blockers was identified in 18.9% of 1435 breast cancer-specific deaths and 19.4% of their 5697 matched controls,indicating little evidence of association between beta-blocker use and breast cancer-specific mortality [odds ratio (OR) = 0.97,95% confidence interval (CI) 0.83, 1.13]. There was also little evidence of an association when analyses were restricted to cardio non-selective beta-blockers (OR = 0.90, 95% CI 0.69, 1.17). Similar results were observed in analyses of drug dosage frequency and duration, and beta-blocker type. Conclusions In this large UK population-based cohort of breast cancer patients,there was little evidence of an association between post-diagnostic beta-blocker usage and breast cancer progression. Further studies which include information on tumour receptor status are warranted to determine whether response to beta-blockers varies by tumour subtypes.

To invade and metastasize, carcinomas must penetrate or lose their epithelial basement membrane (EBM), and then penetrate basement membranes (BMs) surrounding blood vessels, lymphatics, nerves and muscle cells. Knowledge of the composition of different BMs is necessary, so that appropriate antibodies and DNA probes are used to analyse these events. Laminin and type IV collagen are the principal BM components. However, recent studies show these two proteins exist in various isoforms, each of which is a heterotrimer of different subunit polypeptides. In this study, we analysed the distribution of laminin subunits, alpha 1 (lam), alpha 2 (lam), beta 1(lam), beta 2(lam) and gamma 1 (lam), and collagen IV subunits, alpha 1(IV), alpha 3(IV), alpha 4(IV) and alpha 5 (IV), in normal and neoplastic tissues of colorectum and breast. Subunits alpha 1(IV), alpha 1(lam), beta 1(lam) and gamma 1(lam) were detected in all BMs, while the distribution of alpha 3(IV), alpha 4(IV), alpha 5(IV) and alpha 2(lam) was much more restricted. In carcinomas, EBM staining for all subunits was invariably discontinuous or absent, consistent with the presence of complete EBM breaks. Use of antibody to alpha 1(lam) selectively stained the EBMs of carcinomas. Strong vascular staining for alpha 1(lam), beta 1(lam), gamma 1(lam) and alpha 1(IV) suggests an abundance of BM proteins in vessel walls, which may aid tumour cell attachment before vascular invasion. Within carcinomas, vascular BM staining for beta 2(lam) was clearly weaker than in normal tissues, which may reflect incomplete maturation of these vessels. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5

Background Recent laboratory and epidemiological evidence suggests that beta-blockers could inhibit prostate cancer progression. Methods : We investigated the effect of beta-blockers on prostate cancer-specific mortality in a cohort of prostate cancer patients. Prostate cancer patients diagnosed between 1998 and 2006 were identified from the UK Clinical Practice Research Database and confirmed by cancer registries. Patients were followed up to 2011 with deaths identified by the Office of National Statistics. A nested case–control analysis compared patients dying from prostate cancer (cases) with up to three controls alive at the time of their death, matched by age and year of diagnosis. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional logistic regression. Results : Post-diagnostic beta-blocker use was identified in 25% of 1184 prostate cancer-specific deaths and 26% of 3531 matched controls. There was little evidence ( P =0.40) of a reduction in the risk of cancer-specific death in beta-blocker users compared with non-users (OR=0.94 95% CI 0.81, 1.09). Similar results were observed after adjustments for confounders, in analyses by beta-blocker frequency, duration, type and for all-cause mortality. Conclusions : Beta-blocker usage after diagnosis was not associated with cancer-specific or all-cause mortality in prostate cancer patients in this large UK study.

Many previous qualitative studies have shown that tumours are less vascular in the centre, and that host tissues become more vascular in close proximity to tumours. However, quantitative findings presented here for human colorectal cancer reveal some significant differences. Sections from 20 colorectal carcinomas (ten moderately and ten poorly differentiated) were immunostained with the QB/end/10 monoclonal to demonstrate blood vessels. These were measured by interactive morphometry and vascular volume density, surface density (Sv) and length density were recorded. In poorly differentiated carcinomas, the tumour centre was significantly less vascular than the periphery for all three parameters (P = 0.008 for Sv). However, no significant difference was seen for moderately differentiated tumours, which constitute the majority of colorectal cancers. Surrounding host tissues did not show a general increase in vascular density close to tumours. Furthermore, when total viable tissue was considered, the vascular density of carcinomas was not markedly different from normal mucosa. In the centre of moderately differentiated carcinomas for example, the mean value for Sv was only 1.4 times higher than the mean value for normal mucosa. These findings suggest that colorectal cancers may elicit a relatively weak angiogenic response, consistent with their exceptionally slow growth rate. Images Figure 1 Figure 2 Figure 3

Caveolin-1 (CAV1) and caveolin 2 (CAV2) are the principal structural proteins of caveolae, sphingolipid and cholesterol-rich invaginations of the plasma membrane involved in vesicular trafficking and signal transduction. Over the recent years there has been controversy about their role in breast cancer and their suitability as markers of basal-like phenotype. Caveolin-1 and CAV2 protein expression was assessed on a tissue microarray containing 880 unselected invasive breast cancer cases, by means of immunohistochemistry. Caveolin-1 and CAV2 expression was observed in 13.4 and 5.9% of all breast cancer, respectively. Their expression was strongly associated with high histological grade, lack of steroid hormone receptor positivity (ER and PR), and expression of basal markers (basal cytokeratins, P63, P-cadherin). Furthermore, there was a significant association between CAV1 and CAV2 expression and basal-like phenotype. On univariate analysis only CAV2 had a prognostic impact on breast cancer-specific survival; however, this was not independent from other traditional markers on multivariate analysis. Our results demonstrate that both CAV1 and CAV2 are associated with basal-like phenotype. Further studies are warranted to determine whether they play an oncogenic role in basal-like/triple-negative breast cancer development or are just surrogate markers for this subgroup.

This study investigated sonic hedgehog (Shh) signalling in gastric metaplasia in the insulin-gastrin (InsGas) hypergastrinaemic mouse +/− Helicobacter felis (H. felis) infection. Sonic hedgehog gene and protein expression was reduced in pre-metaplastic lesions from non-infected mice (90% gene reduction, P

Background The identification of antigens that distinguish cancer cells from normal cells is of major importance for the definition of therapeutic targets in human malignancies. Using sera from cancer patients, we have previously reported on the identification of immunologically recognized proteins that belong to the family of cancer testis antigens (CTAs). Methods A normal testicular cDNA library was screened with pooled allogeneic sera from patients with prostate cancer using a modified SEREX approach. Subsequently we have identified and characterized a novel antigen, T21, with an expression pattern similar to that of CTAs. mRNA expression of T21 was determined using a panel of whole tissues and prostate cell lines using Q-RT-PCR. For laser microdissection, fresh prostate cancer and benign tissue was obtained using our novel validated harvesting technique. Protein expression and cellular localization of T21 were assessed in prostate cell lines using Western blotting, confocal microscopy and flow cytometry. Results T21 showed tissue-restricted mRNA expression in gastric, kidney and prostate cancers, and in normal testis and prostate tissues. Following laser microdissection, T21 was significantly over-expressed in malignant compared to benign prostatic epithelium. We have demonstrated expression of T21 at the protein level and confocal microscopy on PC3 cells probed with a T21-monospecific antibody revealed cytoplasmic localization of T21 protein. Conclusions The highly restricted expression pattern of T21 makes it an attractive vaccine target for prostate cancer. Several CTAs reportedly induce cytotoxic T-lymphocyte responses, therefore it is reasonable to assume that T21 will be a valuable target for cancer immunotherapy. Prostate 67:274–287, 2007. © 2006 Wiley-Liss, Inc.

Prognostic signatures in breast cancer derived from microarray expression profiling have been reported by two independent groups. These signatures, however, have not been validated in external studies, making clinical application problematic. We performed microarray expression profiling of 135 early-stage tumors, from a cohort representative of the demographics of breast cancer. Using a recently proposed semisupervised method, we identified a prognostic signature of 70 genes that significantly correlated with survival (hazard ratio (HR): 5.97, 95% confidence interval: 3.0-11.9, P = 2.7e-07). In multivariate analysis, the signature performed independently of other standard prognostic classifiers such as the Nottingham Prognostic Index and the 'Adjuvant!' software. Using two different prognostic classification schemes and measures, nearest centroid (HR) and risk ordering (D-index), the 70-gene classifier was also found to be prognostic in two independent external data sets. Overall, the 70-gene set was prognostic in our study and the two external studies which collectively include 715 patients. In contrast, we found that the two previously described prognostic gene sets performed less optimally in external validation. Finally, a common prognostic module of 29 genes that associated with survival in both our cohort and the two external data sets was identified. In spite of these results, further studies that profile larger cohorts using a single microarray platform, will be needed before prospective clinical use of molecular classifiers can be contemplated.

INTRODUCTION: Recent observational studies indicate that post-diagnostic use of aspirin in breast cancer patients may protect against cancer progression perhaps by inhibiting cyclooxygenase-2 dependent mechanisms. Evidence also supports a crucial role for interactions between tumour cells and circulating platelets in cancer growth and dissemination, therefore, use of low-dose aspirin may reduce the risk of death from cancer in breast cancer patients.METHODS: A cohort of newly diagnosed breast cancer patients (1998 to 2006) were identified in the UK Clinical Practice Research Datalink (and confirmed by cancer registry linkage). Cancer-specific deaths were identified up to 2011 from Office for National Statistics mortality data. A nested case-control analysis was conducted using conditional logistic regression to compare post-diagnostic aspirin exposure using General Practice prescription data in 1,435 cases (breast cancer deaths) with 5,697 controls (matched by age and year of diagnosis).RESULTS: After breast cancer diagnosis, 18.3% of cancer-specific deaths and 18.5% of matched controls received at least one prescription for low-dose aspirin, corresponding to an odds ratio (OR) of 0.98 (95% CI 0.83, 1.15). Adjustment for potential confounders (including stage and grade) had little impact on this estimate. No dose response relationship was observed when the number of tablets was investigated and no associations were seen when analyses were stratified by receipt of prescriptions for aspirin in the pre-diagnostic period, by stage at diagnosis or by receipt of prescriptions for hormone therapy.CONCLUSIONS: Overall, in this large population-based cohort of breast cancer patients, there was little evidence of an association between receipt of post-diagnostic prescriptions for low-dose aspirin and breast cancer-specific death. However, information was not available on medication compliance or over-the-counter use of aspirin, which may have contributed to the null findings.

breast cancer series prepared as tissue microarray (n = 1858) using IHC (HercepTest, DakoCytomation) and chromogenic ISH (CISH; DuoCISH, DakoCytomation) in order to identify relationships with clinico-pathological variables and patient outcome. None of these cases have received anti-HER2 therapy. There was excellent overall concordance between HercepTest negative (scores 0/1+) and positive (3+) with CISH positive/negative (defined as HER2/Chr17 copy number ratio of P2; p < 0.001). Twelve percent of cases were identified as HER2 positive (those with 3+ HercepTest scores or 2+ with gene amplification). Of the 74 borderline HercepTest 2+ cases, 44 cases (59%) showed HER2 gene amplification. We identified that HercepTest 2+ non-amplified cases were not significantly different from those amplified 2+ or 3+ cases with respect to their clinical outcome (BCSS and DFS). The overall concordance between HercepTest and CISH analysis for HER2 status was excellent. All HercepTest 2+ cases identified were observed to have poor outcomes similar to those HercepTest 3+ cases regardless of gene amplification status. In the current clinical environment, cases exhibiting IHC 2+ with non-amplified HER2 gene status are not offered targeted HER2 therapy but do exhibit aggressive clinical behavioural characteristics and therefore optimal treatment strategies for these patients need to be determined.

Axillary nodal (LN) stage is the most important prognostic factor in early-stage breast cancer (BC) which has risen as a result of widespread BC screening. However, surgical procedures for LN staging carry the risk of early and long-term postoperative morbidity. Therefore, reliable predictors of nodal status are needed to reduce the extent of axillary surgery and its consequences.

ity in MCF-7 and MDA-MB-231 cells (P < 0.05). An array of 84 genes identified 5 genes decreased in resistant cells whose expression was upregulated after decitabine and TSA treatment (P < 0.05). Western analysis confirmed expression changes in only one gene, SERPINE1, in docetaxel-resistant cells. Conclusions: Docetaxel resistance is associated with changes in the DNA methylation machinery. Inhibiting DNA methylation and histone deacetylation, in combination, overcomes resistance of breast cancer cells to docetaxel. Our findings indicate that decreased SERPINE1 expression is associated with docetaxel resistance.