Poisoning from lead gunshot: still a threat to wild waterbirds in Britain

Lead is a highly toxic metal known to be an important cause of morbidity and mortality in waterbirds and terrestrial birds worldwide. The risk to birds of poisoning from lead has resulted in the introduction of legislation in many countries, such as UK restrictions on the use of lead in angling weights and lead gunshot. In this study, we examined data on current and historical trends in lead poisoning in British waterbirds and related these to the introduction of legislation restricting the use of lead. Our results indicate that lead poisoning has continued to affect a wide range of British waterbirds long after legal restrictions were introduced. Elevated levels of lead (i.e. > 20.0 mu g/dL) were found in the blood of 34 % (n = 285) of waterbirds tested at four sites in Britain during the 2010/2011 winter and accounted for the deaths of at least 10.6 % (n = 2,365) of waterbirds recovered across Britain between 1971 and 2010 and 8.1 % (n = 1,051) between 2000 and 2010, with lead gunshot being the most likely source of poisoning. The proportion of birds dying from lead poisoning in England did not vary significantly after the introduction of legislation, accounting for 13.7 % of non-infectious causes of death between 1971 and 1987 (n = 204), 20.8 % (n = 360) between 1988 and 1999 and 11.8 % (n = 423) between 2000 and 2010, despite a significant change in lead-related mortality in mute swans found during the same time period, 25 % (n = 12) between 1971 and 1987, 4.6 % (n = 65) between 1988 and 1999 and 2 % (n = 100) between 2000 and 2010. Existing legislation needs review and extension to ensure the delivery of international commitments and a broad-scale transition to the use of non-toxic shot and angling materials in all environments.

Oncofetal gene SALL4 in aggressive hepatocellular carcinoma

Hepatocellular carcinoma is the third leading cause of cancer-related deaths worldwide. In the heterogeneous group of hepatocellular carcinomas, those with characteristics of embryonic stem-cell and progenitor-cell gene expression are associated with the worst prognosis. The oncofetal gene SALL4, a marker of a subtype of hepatocellular carcinoma with progenitor-like features, is associated with a poor prognosis and is a potential target for treatment.

A morpho-molecular prognostic model for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the third common cause of cancer-related deaths and its prognostication is still suboptimal. The aim of this study was to establish a new prognostication algorithm for HCC.

Worked to Death? A census-based longitudinal study of the relationship between the numbers of hours spent working and mortality risk

Background There has been an increasing interest in the health effects of long
working hours, but little empirical evidence to substantiate early
10 case series suggesting an increased mortality risk. The aim of the
current study is to quantify the mortality risk associated with long
working hours and to see if this varies by employment relations and
conditions of occupation.
Methods A census-based longitudinal study of 414 949 people aged 20-59/64
15 years, working at least 35 h/week, subdivided into four occupational
classes (managerial/professional, intermediate, own account workers,
workers in routine occupations) with linkage to deaths records
over the following 8.7 years. Cox proportional hazards models were
used to examine all-cause and cause-specific mortality risk.
20 Results Overall 9.4% of the cohort worked 55 or more h/week, but this
proportion was greater in the senior management and professional
occupations and in those who were self-employed. Analysis of 4447
male and 1143 female deaths showed that hours worked were
associated with an increased risk of all-cause mortality only for
25 men working for more than 55 or more h/week in routine/semiroutine
occupations [adjusted hazard ratios (adjHR) 1.31: 95%
confidence intervals (CIs) 1.11, 1.55)] compared with their peers
working 35–40 h/week. Their equivalent risk of death from cardiovascular
disease was (adjHR 1.49: 95% CIs 1.10, 2.00).
30 Conclusions These findings substantiate and add to the earlier studies indicating
the deleterious impact of long working hours but also suggest that
the effects are moderated by employment relations or conditions of
occupation. The policy implications of these findings are discussed.

Smoking is a major cause of premature death worldwide

Question. How many deaths were attributable to smoking in 2000 worldwide? Study design. Statistical extrapolation of epidemiological and clinical data. Main results. In the year 2000, about 12% of adults died prematurely from smoking (estimated 4.83 million uncertainty range 3.94-5.93 million). Leading causes of death attributable to smoking were cardiovascular diseases (1.69 million deaths), chronic obstructive pulmonary disease (0.97 million deaths) and lung cancer (0.85 million deaths; 71% of lung cancers were smoking related). Smoking related deaths in men were about 3 times more common than women in industrial countries, and about 7 times more common in developing countries. Authors' conclusions. Smoking was a major cause of death worldwide in 2000. © 2004 Elsevier Ltd. All rights reserved.

High population prevalence of cardiac troponin I measured by a high-sensitivity assay and cardiovascular risk estimation: the MORGAM Biomarker Project Scottish Cohort

Aims
Our aim was to test the prediction and clinical applicability of high-sensitivity assayed troponin I for incident cardiovascular events in a general middle-aged European population.

Methods and results
High-sensitivity assayed troponin I was measured in the Scottish Heart Health Extended Cohort (n = 15 340) with 2171 cardiovascular events (including acute coronary heart disease and probable ischaemic strokes), 714 coronary deaths (25% of all deaths), 1980 myocardial infarctions, and 797 strokes of all kinds during an average of 20 years follow-up. Detection rate above the limit of detection (LoD) was 74.8% in the overall population and 82.6% in men and 67.0% in women. Troponin I assayed by the high-sensitivity method was associated with future cardiovascular risk after full adjustment such as that individuals in the fourth category had 2.5 times the risk compared with those without detectable troponin I (P < 0.0001). These associations remained significant even for those individuals in whom levels of contemporary-sensitivity troponin I measures were not detectable. Addition of troponin I levels to clinical variables led to significant increases in risk prediction with significant improvement of the c-statistic (P < 0.0001) and net reclassification (P < 0.0001). A threshold of 4.7 pg/mL in women and 7.0 pg/mL in men is suggested to detect individuals at high risk for future cardiovascular events.

Conclusion
Troponin I, measured with a high-sensitivity assay, is an independent predictor of cardiovascular events and might support selection of at risk individuals.

Inclusion of chemotherapy in addition to anthracycline in the treatment of acute promyelocytic leukaemia does not improve outcomes:results of the MRC AML15 trial

Two hundred eighty-five patients, median age 42, with PML-RARa-positive acute promyelocytic leukaemia were randomised to Ara-C-containing 'Medical Research Council (MRC) Chemotherapy'+ATRA (All-trans-retinoic acid) or anthracycline+ATRA (modified 'Spanish') therapy. MRC treatment comprised four courses with ATRA in courses 1-2. Spanish treatment comprised four anthracycline-based courses with ATRA in courses 1-3. In course 3 patients were randomised to gemtuzumab ozogamicin (GO) or not. The Spanish arm received 24-month maintenance. Patients were sequentially molecularly monitored. Quality of life was assessed at baseline, 3, 6, 9, 12, 24 months. Remission rates were similar in both arms (93%): cumulative incidence of haematological relapse (CIHR) was 6% at 5 years; 5 patients relapsed molecularly. Survival post relapse was 80%. There were more deaths in remission in the MRC arm (4% vs 10%: P=0.2). The overall 5-year relapse-free and overall survival was similar between arms (81% vs 82% and 84% vs 83%, respectively). More supportive care and hospitalisation (81.8 vs 63 days, P10 × 10(9)/l) was not prognostic overall, or within treatment arms. Both approaches deliver similar results with minor differences in quality of life. MRC treatment required more hospitalisation. This suggests that additional chemotherapy, Ara-C in particular, is not required.

Prognostic and therapeutic relevance of FLIP and procaspase-8 overexpression in non-small cell lung cancer

Non-small cell lung carcinoma remains by far the leading cause of cancer-related deaths worldwide. Overexpression of FLIP, which blocks the extrinsic apoptotic pathway by inhibiting caspase-8 activation, has been identified in various cancers. We investigated FLIP and procaspase-8 expression in NSCLC and the effect of HDAC inhibitors on FLIP expression, activation of caspase-8 and drug resistance in NSCLC and normal lung cell line models. Immunohistochemical analysis of cytoplasmic and nuclear FLIP and procaspase-8 protein expression was carried out using a novel digital pathology approach. Both FLIP and procaspase-8 were found to be significantly overexpressed in tumours, and importantly, high cytoplasmic expression of FLIP significantly correlated with shorter overall survival. Treatment with HDAC inhibitors targeting HDAC1-3 downregulated FLIP expression predominantly via post-transcriptional mechanisms, and this resulted in death receptor- and caspase-8-dependent apoptosis in NSCLC cells, but not normal lung cells. In addition, HDAC inhibitors synergized with TRAIL and cisplatin in NSCLC cells in a FLIP- and caspase-8-dependent manner. Thus, FLIP and procaspase-8 are overexpressed in NSCLC, and high cytoplasmic FLIP expression is indicative of poor prognosis. Targeting high FLIP expression using HDAC1-3 selective inhibitors such as entinostat to exploit high procaspase-8 expression in NSCLC has promising therapeutic potential, particularly when used in combination with TRAIL receptor-targeted agents.

Drugs affecting the renin-angiotensin system and survival from cancer: a population based study of breast, colorectal and prostate cancer patient cohorts

Background: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) are commonly prescribed to the growing number of cancer patients (more than two million in the UK alone) often to treat hypertension. However, increased fatal cancer in ARB users in a randomized trial and increased breast cancer recurrence rates in ACEI users in a recent observational study have raised concerns about their safety in cancer patients. We investigated whether ACEI or ARB use after breast, colorectal or prostate cancer diagnosis was associated with increased risk of cancer-specific mortality.

Methods: Population-based cohorts of 9,814 breast, 4,762 colorectal and 6,339 prostate cancer patients newly diagnosed from 1998 to 2006 were identified in the UK Clinical Practice Research Datalink and confirmed by cancer registry linkage. Cancer-specific and all-cause mortality were identified from Office of National Statistics mortality data in 2011 (allowing up to 13 years of follow-up). A nested case–control analysis was conducted to compare ACEI/ARB use (from general practitioner prescription records) in cancer patients dying from cancer with up to five controls (not dying from cancer). Conditional logistic regression estimated the risk of cancer-specific, and all-cause, death in ACEI/ARB users compared with non-users.

Results: The main analysis included 1,435 breast, 1,511 colorectal and 1,184 prostate cancer-specific deaths (and 7,106 breast, 7,291 colorectal and 5,849 prostate cancer controls). There was no increase in cancer-specific mortality in patients using ARBs after diagnosis of breast (adjusted odds ratio (OR) = 1.06 95% confidence interval (CI) 0.84, 1.35), colorectal (adjusted OR = 0.82 95% CI 0.64, 1.07) or prostate cancer (adjusted OR = 0.79 95% CI 0.61, 1.03). There was also no evidence of increases in cancer-specific mortality with ACEI use for breast (adjusted OR = 1.06 95% CI 0.89, 1.27), colorectal (adjusted OR = 0.78 95% CI 0.66, 0.92) or prostate cancer (adjusted OR = 0.78 95% CI 0.66, 0.92).

Conclusions: Overall, we found no evidence of increased risks of cancer-specific mortality in breast, colorectal or prostate cancer patients who used ACEI or ARBs after diagnosis. These results provide some reassurance that these medications are safe in patients diagnosed with these cancers.

Keywords: Colorectal cancer; Breast cancer; Prostate cancer; Mortality; Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers

Beta-blocker usage and breast cancer survival: a nested case-control study within a UK clinical practice research datalink cohort.

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.

Low-dose aspirin and survival in men with prostate cancer: a study using the UK Clinical Practice Research Datalink

Purpose: 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.

Methods: 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).

Results: 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 < 0.001). After adjustment for confounders including treatment and comorbidities, this association was attenuated (adjusted OR 1.02 95 % CI 0.78, 1.34; p = 0.86). Adjustment for estrogen therapy accounted for the majority of this attenuation. There was also no evidence of dose–response association after adjustments. Compared with no use, patients with 1–11 prescriptions and 12 or more prescriptions had adjusted ORs of 1.07 (95 % CI 0.78, 1.47; p = 0.66) and 0.97 (95 % CI 0.69, 1.37; p = 0.88), respectively. There was no evidence of a protective association between low-dose aspirin use in the year prior to diagnosis and prostate cancer-specific mortality (adjusted OR 1.04 95 % CI 0.89, 1.22; p = 0.60).

Conclusion: We found no evidence of an association between low-dose aspirin use before or after diagnosis and risk of prostate cancer-specific mortality, after potential confounders were accounted for, in UK prostate cancer patients.

Beta-blocker usage and prostate cancer survival:A nested case-control study in the UK Clinical Practice Research Datalink cohort

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.

Children drawing their own conclusions: Children’s perceptions of a ‘post-conflict’ society

In societies emerging from conflict/war, sustained occurrence of violence appears to be a common feature. In Northern Ireland, while incidents of violent deaths and injuries specifically related to the political conflict have decreased dramatically since 1998, regular riots and paramilitary activity confirm continuing division and conflict. The study described here explored children’s perceptions of their own lives and their predecessors’ lives in the country, through a draw-and-tell technique (n=179). While multiple positive elements of peace/hope were depicted by the majority of children, especially in the pictures portraying the present, negative elements and violent references mostly appeared in the pictures representing the past. Violence was more likely to be portrayed by boys, older children, and those attending segregated education.

Towards optimal clinical and epidemiological registration of haematological malignancies: Guidelines for recording progressions, transformations and multiple diagnoses

Haematological malignancies (HM) represent over 6% of the total cancer incidence in Europe and affect all ages, ranging between 45% of all cancers in children and 7% in the elderly. Thirty per cent of childhood cancer deaths are due to HM, 8% in the elderly. Their registration presents specific challenges, mainly because HM may transform or progress in the course of the disease into other types of HM. In the context of cancer registration decisions have to be made about classifying subsequent notifications on the same patient as the same tumour (progression), a transformation or a new tumour registration. Allocation of incidence date and method of diagnosis must also be standardised. We developed European Network of Cancer Registries (ENCR) recommendations providing specific advice for cancer registries to use haematology and molecular laboratories as data sources, conserve the original date of incidence in case of change of diagnosis, make provision for recording both the original as well as transformed tumour and to apply precise rules for recording and counting multiple diagnoses. A reference table advising on codes which reflect a potential transformation or a new tumour is included. This work will help to improve comparability of data produced by population-based cancer registries, which are indispensable for aetiological research, health care planning and clinical research, an increasing important area with the application of targeted therapies.

Post-diagnostic prescriptions for low-dose aspirin and breast cancer-specific survival: a nested case-control study in a breast cancer cohort from the UK Clinical Practice Research Datalink

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.