Impact of surgeon volume on outcomes of rectal cancer surgery: a systematic review and meta-analysis.

AIM: To clarify the relationship between surgeon caseload and patient outcomes for patients undergoing rectal cancer surgery in order to inform debate about organisation of services. METHODS: We searched Medline and Embase for articles published up to March 2010, and included studies examining surgeon caseload and outcomes in rectal cancer patients treated after 1990. Outcomes considered were 30-day mortality, overall survival, anastomotic leak, local recurrence, permanent stoma and abdominoperineal excision rates. We assessed the risk of bias in included studies and performed random effects meta-analyses based on both unadjusted and casemix adjusted data. RESULTS: Eleven included studies enrolled 18,301 rectal cancer patients undergoing resective surgery. Unadjusted meta-analysis showed a statistically significant benefit in favour of high volume surgeons for 30-day postoperative mortality (OR = 0.57, 95% CI: 0.43-0.77; based on three studies, 4809 patients) and overall survival (HR = 0.76, 95% CI 0.63-0.90; based on two studies, 1376 patients), although the former relationship was attenuated and non-significant when based on two studies (9685 patients) that adjusted for casemix (OR = 0.79, 95% CI: 0.59-1.06). Pooling of three studies (2202 patients) showed no significant relationship between surgeon volume and anastomotic leak rate. Permanent stoma formation was less likely for high volume surgeons (adjusted OR = 0.75, 95% CI: 0.64 to 0.88; based on two studies, 9685 patients) and APER rates were lower for high volume surgeons (unadjusted OR = 0.58, 95% CI: 0.45 to 0.76); based on six studies, 3921 participants. CONCLUSIONS: This review gives evidence that higher surgeon volume is associated with better overall survival, lower permanent stoma and APER rates.

Pain in children with cerebral palsy: a cross-sectional multicentre European study.

AIM: To determine the prevalence and associations of self-reported and parent-reported pain in children with cerebral palsy (CP) of all severities. METHOD: Cross-sectional design using a questionnaire; analysis using ordinal regression. Children aged 8-12 years were randomly selected from population-based registers of children with CP in eight European regions; a further region recruited 75 children from multiple sources. Outcome measures were pain in the previous week among children who could self-report and parents' perception of their child's pain in the previous 4 weeks. RESULTS: Data on pain were available from 490 children who could self-report and parents of 806 children (those who could and could not self-report). The estimated population prevalence of self-reported pain in the previous week was 60% (95% CI: 54-65%) and that of parent-reported pain in the previous 4 weeks was 73% (95% CI: 69-76%). In self-reporting children, older children reported more pain but pain was not significantly associated with severity of impairment. In parent reports, severity of child impairment, seizures and parental unemployment were associated with more frequent and severe pain. CONCLUSION: Pain in children with CP is common. Clinicians should enquire about pain and consider appropriate physical, therapeutic or psychological management.

Cardioprotective interventions for cancer patients receiving anthracyclines.

BACKGROUND: Anthracyclines are among the most effective chemotherapeutic agents in the treatment of numerous malignancies. Unfortunately, their use is limited by a dose-dependent cardiotoxicity. In an effort to prevent this cardiotoxicity, different cardioprotective agents have been studied. OBJECTIVES: The objective of this review was to assess the efficacy of different cardioprotective agents in preventing heart damage in cancer patients treated with anthracyclines. SEARCH STRATEGY: We searched the databases of the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 2, 2007), MEDLINE (1966 to April 2007) and EMBASE (1980 to April 2007). In addition, we handsearched reference lists and conference proceedings of the SIOP and ASCO meetings (1998 to 2006). SELECTION CRITERIA: Randomised controlled trials (RCTs) in which any cardioprotective agent was compared to no additional or placebo therapy in cancer patients (children and adults) receiving anthracyclines. DATA COLLECTION AND ANALYSIS: Two review authors independently performed the study selection, quality assessment and data-extraction including adverse effects. MAIN RESULTS: We identified RCTs for seven cardioprotective agents: N-acetylcysteine, phenetylamines, coenzyme Q10, combination of vitamins E and C and N-acetylcysteine, L-carnitine, carvedilol and dexrazoxane (mostly adults with advanced breast cancer). All studies had methodological limitations. For the first six agents, there were too few studies to allow pooling of results. None of the individual studies showed a cardioprotective effect. The nine included studies of dexrazoxane enrolled 1403 patients. The meta-analysis of dexrazoxane showed a statistically significant benefit in favour of dexrazoxane for the occurrence of heart failure (Relative Risk (RR) 0.29, 95% CI 0.20 to 0.41). No evidence was found for a difference in response rate or survival between the dexrazoxane and control group. Only for one adverse effect (abnormal white blood cell count at nadir) a difference in favour of the control group was identified. AUTHORS' CONCLUSIONS: For cardioprotective agents for which pooling was impossible, no definitive conclusions can be made about their efficacy. Dexrazoxane prevents heart damage and no evidence for a difference in response rate or survival between the dexrazoxane and control group was identified. Only for an abnormal white blood cell count at nadir a clearly significant difference in favour of the control group was identified. We conclude that if the risk of cardiac damage is expected to be high, it might be justified to use dexrazoxane in patients with cancer treated with anthracyclines. However, for each individual patient clinicians should weigh the cardioprotective effect of dexrazoxane against the possible risk of adverse effects.

Parenteral anticoagulation for prolonging survival in patients with cancer who have no other indication for anticoagulation.

BACKGROUND: Basic research and clinical studies have generated the hypothesis that anticoagulation may improve survival in patients with cancer through an antitumour effect in addition to the antithrombotic effect. OBJECTIVES: To evaluate the efficacy and safety of heparin (including unfractionated heparin (UFH) and low molecular weight heparin (LMWH)) and fondaparinux to improve survival of patients with cancer. SEARCH STRATEGY: A comprehensive search for studies of anticoagulation in cancer patients including (1) A January 2007 electronic search of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and ISI the Web of Science; (2) Hand search of the American Society of Clinical Oncology and of the American Society of Hematology; (3) Checking of references of included studies; and (4) Use of "related article" feature in PubMed. SELECTION CRITERIA: We included randomized controlled trials (RCTs) in cancer patients without clinical evidence of venous thromboembolism comparing UFH, LMWH or fondaparinux to no intervention or placebo and RCTs comparing two of the three agents of interest. DATA COLLECTION AND ANALYSIS: Using a standardized form we extracted in duplicate data on methodological quality, participants, interventions and outcomes of interest including all cause mortality, venous thrombosis, symptomatic pulmonary embolism, major bleeding and minor bleeding. MAIN RESULTS: Of 3986 identified citations five RCTs fulfilled the inclusion criteria. In all included RCTs the intervention consisted of heparin ( either UFH or LMWH). The overall methodological quality of the included studies was acceptable. Overall, heparin therapy was associated with a statistically and clinically significant survival benefit (hazard ratio (HR) = 0.77; 95% CI: 0.65 to 0.91). In subgroup analyses, patients with limited small cell lung cancer experienced a clear survival benefit (HR = 0.56; 95% CI: 0.38 to 0.83). The survival benefit was not statistically significant for either patients with extensive small cell lung cancer (HR = 0.80; 95% CI: 0.60 to 1.06) or patients with advanced cancer (HR = 0.84; 95%: 0.68 to 1.03). The increased risk of bleeding with heparin was not statistically significant (RR = 1.78; 95% CI: 0.73 to 4.38). AUTHORS' CONCLUSIONS: Heparin has a survival benefit in cancer patients in general, and in patients with limited small cell lung cancer in particular. Heparin might be particularly beneficial in cancer patients with limited cancer or a longer life expectancy. Future research should investigate the survival benefit of different types of anticoagulants (in different dosing, schedules and duration of therapy) in patients with different types and stages of cancers.

Effectiveness of brief alcohol interventions in primary care populations.

BACKGROUND: Many trials reported that brief interventions are effective in reducing excessive drinking. However, some trials have been criticised for being clinically unrepresentative and unable to inform clinical practice. OBJECTIVES: To assess the effectiveness of brief intervention, delivered in general practice or based primary care, to reduce alcohol consumption SEARCH STRATEGY: We searched the Cochrane Drug and Alcohol Group specialised register (February 2006), MEDLINE (1966 to February 2006), EMBASE (1980 to February 2006), CINAHL (1982 to February 2006), PsycINFO (1840 to February 2006), Science Citation Index (1970 to February 2006), Social Science Citation Index (1970 to February 2006), Alcohol and Alcohol Problems Science Database (1972 to 2003), reference lists of articles. SELECTION CRITERIA: Randomised controlled trials, patients presenting to primary care not specifically for alcohol treatment; brief intervention of up to four sessions. DATA COLLECTION AND ANALYSIS: Two authors independently abstracted data and assessed trial quality. Random effects meta-analyses, sub-group, sensitivity analyses, and meta-regression were conducted. MAIN RESULTS: The meta-analysis included 21 RCTs (7,286 participants), showing that participants receiving brief intervention reduced their alcohol consumption compared to the control group (mean difference: -41 grams/week, 95% CI: -57 to -25), although there was substantial heterogeneity between trials (I2 = 52%). Sub-group analysis (8 studies, 2307 participants) confirmed the benefit of brief intervention in men (mean difference: -57 grams/week, 95% CI: -89 to -25, I2 = 56%), but not in women (mean difference: -10 grams/week, 95% CI: -48 to 29, I2 = 45%). Meta-regression showed a non-significant trend of an increased reduction in alcohol consumption of 1.1, 95%CI: -0.05 to 2.2 grams/week, p=0.06, for each extra minute of treatment exposure, but no relationship between the reduction in alcohol consumption and the efficacy score of the trial. Extended intervention when compared with brief intervention was associated with a non-significantly greater reduction in alcohol consumption (mean difference = -28, 95%CI: -62 to 6 grams/week, I2 = 0%) AUTHORS' CONCLUSIONS: Brief interventions consistently produced reductions in alcohol consumption. When data were available by gender, the effect was clear in men at one year of follow up, but unproven in women. Longer duration of counselling probably has little additional effect. The lack of differences in outcomes between efficacy and effectiveness trials suggests that the current literature had clear relevance to routine primary care. Future trials should focus on women and on delineating the most effective components of interventions.

Effectiveness and acceptability of non-pharmacological interventions to reduce wandering in dementia: a systematic review.

BACKGROUND: Wandering occurs in 15-60% of people with dementia. Psychosocial interventions rather than pharmacological methods are recommended, but evidence for their effectiveness is limited and there are ethical concerns associated with some non-pharmacological approaches, such as electronic tracking devices. OBJECTIVE: To determine the clinical and cost effectiveness and acceptability of non-pharmacological interventions to reduce wandering in dementia. DESIGN: A systematic review to evaluate effectiveness of the interventions and to assess acceptability and ethical issues associated with their use. The search and review strategy, data extraction and analysis followed recommended guidance. Papers of relevance to effectiveness, acceptability and ethical issues were sought. RESULTS: (i) Clinical effectiveness. Eleven studies, including eight randomised controlled trials, of a variety of interventions, met the inclusion criteria. There was no robust evidence to recommend any intervention, although there was some weak evidence for exercise. No relevant studies to determine cost effectiveness met the inclusion criteria. (ii) Acceptability/ethical issues. None of the acceptability papers reported directly the views of people with dementia. Exercise and music therapy were the most acceptable interventions and raised no ethical concerns. Tracking and tagging devices were acceptable to carers but generated considerable ethical debate. Physical restraints were considered unacceptable. CONCLUSIONS: In order to reduce unsafe wandering high quality research is needed to determine the effectiveness of non-pharmacological interventions that are practically and ethically acceptable to users. It is important to establish the views of people with dementia on the acceptability of such interventions prior to evaluating their effectiveness through complex randomised controlled trials.

Magnesium supplementation for the management of essential hypertension in adults.

BACKGROUND: Epidemiological evidence on the effects of magnesium on blood pressure is inconsistent. Metabolic and experimental studies suggest that magnesium may have a role in the regulation of blood pressure. OBJECTIVES: To evaluate the effects of magnesium supplementation as treatment for primary hypertension in adults. SEARCH STRATEGY: We searched the Cochrane Library, MEDLINE, EMBASE, Science Citation Index, ISI Proceedings, ClinicalTrials.gov, Current Controlled Trials, CAB abstracts, and reference lists of systematic reviews, meta-analyses and randomised controlled trials (RCTs) included in the review. SELECTION CRITERIA: Inclusion criteria were: 1) RCTs of a parallel or crossover design comparing oral magnesium supplementation with placebo, no treatment, or usual care; 2) treatment and follow-up >/=8 weeks; 3) participants over 18 years old, with raised systolic blood pressure (SBP) >/=140 mmHg or diastolic blood pressure (DBP) >/=85 mmHg; 4) SBP and DBP reported at end of follow-up. We excluded trials where: participants were pregnant; received antihypertensive medication which changed during the study; or magnesium supplementation was combined with other interventions. DATA COLLECTION AND ANALYSIS: Two reviewers independently abstracted data and assessed trial quality. Disagreements were resolved by discussion or a third reviewer. Random effects meta-analyses and sensitivity analyses were conducted. MAIN RESULTS: Twelve RCTs (n=545) with eight to 26 weeks follow-up met our inclusion criteria. The results of the individual trials were heterogeneous. Combining all trials, participants receiving magnesium supplements as compared to control did not significantly reduce SBP (mean difference: -1.3 mmHg, 95% CI: -4.0 to 1.5, I(2)=67%), but did statistically significantly reduce DBP (mean difference: -2.2 mmHg, 95% CI: -3.4 to -0.9, I(2)=47%). Sensitivity analyses excluding poor quality trials yielded similar results. Sub-group analyses and meta-regression indicated that heterogeneity between trials could not be explained by dose of magnesium, baseline blood pressure or the proportion of males among the participants. AUTHORS' CONCLUSIONS: In view of the poor quality of included trials and the heterogeneity between trials, the evidence in favour of a causal association between magnesium supplementation and blood pressure reduction is weak and is probably due to bias. This is because poor quality studies generally tend to over-estimate the effects of treatment. Larger, longer duration and better quality double-blind placebo controlled trials are needed to assess the effect of magnesium supplementation on blood pressure and cardiovascular outcomes.

Potassium supplementation for the management of primary hypertension in adults.

BACKGROUND: Epidemiological evidence on the effects of potassium on blood pressure is inconsistent. OBJECTIVES: To evaluate the effects of potassium supplementation on health outcomes and blood pressure in people with elevated blood pressure. SEARCH STRATEGY: We searched the Cochrane Library, MEDLINE, EMBASE, Science Citation Index, ISI Proceedings, ClinicalTrials.gov, Current Controlled Trials, CAB abstracts, and reference lists of systematic reviews, meta-analyses and randomised controlled trials (RCTs) included in the review. SELECTION CRITERIA: Inclusion criteria were: 1) RCTs of a parallel or crossover design comparing oral potassium supplements with placebo, no treatment, or usual care; 2) treatment and follow-up >=8 weeks; 3) participants over 18 years, with raised systolic blood pressure (SBP) >=140 mmHg or diastolic blood pressure (DBP) >=85 mmHg); 4) SBP and DBP reported at end of follow-up. We excluded trials where: participants were pregnant; received antihypertensive medication which changed during the study; or potassium supplementation was combined with other interventions. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed trial quality. Disagreements were resolved by discussion or a third reviewer. Random effects meta-analyses and sensitivity analyses were conducted. MAIN RESULTS: Six RCT's (n=483), with eight to 16 weeks follow-up, met our inclusion criteria. Meta-analysis of five trials (n=425) with adequate data indicated that potassium supplementation compared to control resulted in a large but statistically non-significant reductions in SBP (mean difference: -11.2, 95% CI: -25.2 to 2.7) and DBP (mean difference: -5.0, 95% CI: -12.5 to 2.4). The substantial heterogeneity between trials was not explained by potassium dose, quality of trials or baseline blood pressure. Excluding one trial in an African population with very high baseline blood pressure resulted in smaller overall reductions in blood pressure (SBP mean difference: -3.9, 95% CI: -8.6 to 0.8; DBP mean difference: -1.5, 95% CI: -6.2 to 3.1). Further sensitivity analysis restricted to two high quality trials (n=138) also found non-significant reductions in blood pressure (SBP mean difference: -7.1, 95% CI: -19.9 to 5.7; DBP mean difference: -5.5, 95% CI: -14.5 to 3.5). AUTHORS' CONCLUSIONS: This systematic review found no statistically significant effect of potassium supplementation on blood pressure. Because of the small number of participants in the two high quality trials, the short duration of follow-up, and the unexplained heterogeneity between trials, the evidence about the effect of potassium supplementation on blood pressure is not conclusive. Further high quality RCTs of longer duration are required to clarify whether potassium supplementation can reduce blood pressure and improve health outcomes.

Combined calcium, magnesium and potassium supplementation for the management of primary hypertension in adults.

BACKGROUND: Previous research suggests that increasing dietary intakes of calcium, potassium or magnesium separately may reduce BP to a small degree over the short term. It is unclear whether increasing intakes of a combination of these minerals produces a larger reduction in BP. OBJECTIVES: To evaluate the effects of combined mineral supplementation as a treatment for primary hypertension in adults. SEARCH STRATEGY: We searched the Cochrane Library, MEDLINE, EMBASE, Science Citation Index, ISI Proceedings, ClinicalTrials.gov, Current Controlled Trials, CAB abstracts, and reference lists of systematic reviews, meta-analyses and randomised controlled trials (RCTs) included in the review. The search was unrestricted by language or publication status. SELECTION CRITERIA: Inclusion criteria were: 1) RCTs of a parallel or crossover design comparing oral supplements comprising a combination of potassium, and/or calcium, and/or magnesium with placebo, no treatment, or usual care; 2) treatment and follow-up >=8 weeks; 3) participants over 18 years old, with raised systolic blood pressure (SBP) >=140 mmHg or diastolic blood pressure (DBP) >=85 mmHg with no known primary cause; 4) SBP and DBP reported at end of follow-up. We excluded trials where participants were pregnant, or received antihypertensive medication which changed during the study. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed trial quality. Disagreements were resolved by discussion or a third reviewer. Random effects meta-analyses and sensitivity analyses were conducted. MAIN RESULTS: We included three RCTs (n=277) with between 24 and 28 weeks follow-up. Three combinations of minerals were investigated: potassium & magnesium, calcium & magnesium, and calcium & potassium. One trial investigated combinations of calcium & magnesium and of calcium & potassium, and for each found a statistically non-significant increase in both SBP and DBP. All three trials investigated the combination of potassium & magnesium. None of the trials provided data on mortality or morbidity. The combination of potassium & magnesium compared to control resulted in statistically non-significant reductions in both SBP (mean difference = -4.6 mmHg, 95% CI: -9.9 to 0.7) and DBP (mean difference = -3.8 mmHg, 95% CI: -9.5 to 1.8), although the results were heterogeneous (I(2)=68% and 85% for SBP and DBP respectively).A sensitivity analysis using alternative reported values which accounted for missing data had very little effect on DBP but resulted in a larger, statistically significant reduction in SBP (mean difference = -5.8 mmHg, 95% CI: -10.5 to -1.0). The quality of the trials was not well reported. AUTHORS' CONCLUSIONS: We found no robust evidence that supplements of any combination of potassium, magnesium or calcium reduce mortality, morbidity or BP in adults. More trials are needed to investigate whether the combination of potassium & magnesium is effective.

Calcium supplementation for the management of primary hypertension in adults.

BACKGROUND: Metabolic studies suggest calcium may have a role in the regulation of blood pressure. Some epidemiological studies have reported that people with a higher intake of calcium tend to have lower blood pressure. Previous systematic reviews and meta-analyses have reached conflicting conclusions about whether oral calcium supplementation can reduce blood pressure. OBJECTIVES: To evaluate the effects of oral calcium supplementation as a treatment for primary hypertension in adults. SEARCH STRATEGY: We searched the Cochrane Library, MEDLINE, EMBASE, Science Citation Index, ISI Proceedings, ClinicalTrials.gov, Current Controlled Trials, CAB abstracts, and reference lists of systematic reviews, meta-analyses and randomised controlled trials (RCTs) included in the review. SELECTION CRITERIA: Inclusion criteria were: 1) RCTs comparing oral calcium supplementation with placebo, no treatment, or usual care; 2) treatment and follow-up >/=8 weeks; 3) participants over 18 years old, with raised systolic blood pressure (SBP) >/=140 mmHg or diastolic blood pressure (DBP) >/=85 mmHg; 4) SBP and DBP reported at end of follow-up. We excluded trials where: participants were pregnant; received antihypertensive medication which changed during the study; or calcium supplementation was combined with other interventions. DATA COLLECTION AND ANALYSIS: Two reviewers independently abstracted data and assessed trial quality. Disagreements were resolved by discussion or a third reviewer. Random effects meta-analyses and sensitivity analyses were conducted. MAIN RESULTS: We included 13 RCTs (n=485), with between eight and 15 weeks follow-up. The results of the individual trials were heterogeneous. Combining all trials, participants receiving calcium supplementation as compared to control had a statistically significant reduction in SBP (mean difference: -2.5 mmHg, 95% CI: -4.5 to -0.6, I(2 )= 42%), but not DBP (mean difference: -0.8 mmHg, 95% CI: -2.1 to 0.4, I(2) = 48%). Sub-group analyses indicated that heterogeneity between trials could not be explained by dose of calcium or baseline blood pressure. Heterogeneity was reduced when poor quality trials were excluded. The one trial reporting adequate concealment of allocation and the one trial reporting adequate blinding yielded results consistent with the primary meta-analysis. AUTHORS' CONCLUSIONS: In view of the poor quality of included trials and the heterogeneity between trials, the evidence in favour of causal association between calcium supplementation and blood pressure reduction is weak and is probably due to bias. This is because poor quality studies generally tend to over-estimate the effects of treatment. Larger, longer duration and better quality double-blind placebo controlled trials are needed to assess the effect of calcium supplementation on blood pressure and cardiovascular outcomes.

Cardioprotective interventions for cancer patients receiving anthracyclines.

BACKGROUND: Anthracyclines are among the most effective chemotherapeutic agents in the treatment of numerous malignancies. Unfortunately, their use is limited by a dose-dependent cardiotoxicity. In an effort to prevent this cardiotoxicity, different cardioprotective agents have been studied. OBJECTIVES: The objective of this review was to assess the efficacy of different cardioprotective agents in preventing heart damage in cancer patients treated with anthracyclines. SEARCH STRATEGY: We searched the databases of CENTRAL (The Cochrane Library, Issue 3, 2002), MEDLINE (1966 to August 2002) and EMBASE (1980 to August 2002). In addition, we handsearched reference lists and conference proceedings of the International Society for Paediatric Oncology (SIOP) and the American Society of Clinical Oncology (ASCO) (1998 to 2002). SELECTION CRITERIA: Randomised controlled trials (RCTs) in which any cardioprotective agent was compared to no additional or placebo therapy in cancer patients (children and adults) receiving anthracyclines. DATA COLLECTION AND ANALYSIS: Two reviewers independently performed the study selection, quality assessment and data-extraction including adverse effects. MAIN RESULTS: We identified RCTs for 5 cardioprotective agents: N-acetylcysteine (1 study; 54 patients), phenetylamines (2 studies; 100 patients), coenzyme Q10 (1 study; 20 patients), combination of vitamin E, vitamin C and N-acetylcysteine (1 study; 14 patients) and dexrazoxane (6 studies; 1013 patients). All studies had methodological limitations. Due to the insufficient number of studies, for the first four mentioned cardioprotective agents pooling of the results was impossible. None of the individual studies showed a cardioprotective effect. The meta-analysis of the dexrazoxane-studies showed a statistically significant benefit in favour of dexrazoxane for the occurrence of heart failure (Relative Risk (RR) = 0.28, 95% Confidence Interval (CI) 0.18 to 0.42, P < 0.00001). No statistically significant difference in response rate between the dexrazoxane and control group was found (RR = 0.88, 95% CI 0.77 to 1.01, P = 0.06), but there was some suggestion that patients treated with dexrazoxane might have a lower anti-tumour response rate. Our meta-analysis of survival showed no significant difference between the dexrazoxane and control group. For adverse effects pooling was impossible. However, no important differences in the occurrence of side effects were found. The majority of the patients included in this meta-analysis were adults with advanced breast cancer. AUTHORS' CONCLUSIONS: For cardioprotective agents for which pooling was impossible no high quality evidence was available and therefore, no definitive conclusions can be made about their efficacy. Dexrazoxane prevents heart damage, however there was some suggestion that patients treated with dexrazoxane might have a lower anti-tumour response rate. There was no significant difference in survival between the dexrazoxane and control group. We conclude that if the risk of cardiac damage is expected to be high, it might be justified to use dexrazoxane in patients with cancer treated with anthracyclines. However, for each individual patient clinicians should weigh the cardioprotective effect of dexrazoxane against the possible risk of a lower response rate.

Childhood solid tumours in relation to population mixing around the time of birth.

In a retrospective cohort study of 673 787 live births in the Northern Region of England, 1975-1994, we investigated whether a higher level of population mixing around birth was a risk factor for solid tumours, by diagnostic group (Hodgkin's disease, brain and spinal tumours, neuroblastoma, other solid tumours), diagnosed during 1975-2001 under age 15 years. Logistic regression was used to relate risk to population mixing, based on (i) all movers and (ii) incomers from outside the region. Both ward and county district level analyses were performed. There was a decreased risk of brain and spinal tumours with increasing population mixing based on incomers from outside the region (OR for trend across three categories=0.79, 95% CI: 0.66-0.95, P=0.01 in the ward level analysis). Although this may be because of chance, it is consistent with a role of exposure to infection and immunological response in the aetiology of these tumours. For other tumour groups, there was no consistent evidence of an association between risk and population mixing.

A lifecourse study of risk for hyperinsulinaemia, dyslipidaemia and obesity (the central metabolic syndrome) at age 49-51 years.

AIMS: Suboptimal maternal nutrition and catch-up growth in early childhood predispose to insulin resistance and other components of metabolic syndrome in later life. A central metabolic syndrome (CMS) has been identified comprising obesity, dyslipidaemia and insulin resistance. This study was designed to investigate determinants of risk for CMS. METHODS: Persons born in Newcastle in May and June 1947 (n = 358) were followed to 1996-1998. A lifecourse approach was used to estimate the proportion of variance in a summary measure of CMS at age 49-51 years accounted for by factors operating at different stages of life. RESULTS: After adjustment for other early life variables, childhood catch-up growth in men accounted for significant variation in the CMS score independent of adult lifestyle. In adulthood, exercise level in men and smoking in both genders were independently associated with CMS. Over two-thirds of explained variation in the CMS score in women, and almost half in men, was accounted for exclusively by factors measured in adulthood. CONCLUSIONS: While risk for CMS in men is compounded by early life disadvantage, promotion of a healthier adult lifestyle and a reduction in the number of people taking up smoking would appear to be the public health interventions most likely to reduce the prevalence of CMS in middle age.

Adverse pregnancy outcomes around incinerators and crematoriums in Cumbria, north west England, 1956-93.

STUDY OBJECTIVE: To investigate the risk of stillbirth, neonatal death, and lethal congenital anomaly among babies of mothers living close to incinerators and crematoriums in Cumbria, north west England, 1956-93. DESIGN: Retrospective cohort study. Logistic regression was used to investigate the risk of each outcome in relation to proximity at birth to incinerators and crematoriums, adjusting for social class, year of birth, birth order, and multiple births. Continuous odds ratios for trend with proximity to sites were estimated. SETTING: All 3234 stillbirths, 2663 neonatal deaths, and 1569 lethal congenital anomalies among the 244 758 births to mothers living in Cumbria, 1956-1993. MAIN RESULTS: After adjustment for social class, year of birth, birth order, and multiple births, there was an increased risk of lethal congenital anomaly, in particular spina bifida (odds ratio 1.17, 95% CI: 1.07 to 1.28) and heart defects (odds ratio 1.12, 95% CI: 1.03 to 1.22) around incinerators and an increased risk of stillbirth (odds ratio 1.04, 95% CI: 1.01 to 1.07) and anencephalus (odds ratio 1.05, 95% CI: 1.00 to 1.10) around crematoriums. CONCLUSIONS: The authors cannot infer a causal effect from the statistical associations reported in this study. However, as there are few published studies with which to compare our results, the risk of spina bifida, heart defects, stillbirth, and anencephalus in relation to proximity to incinerators and crematoriums should be investigated further, in particular because of the increased use of incineration as a method of waste disposal.

Childhood leukaemia and non-Hodgkin's lymphoma in relation to proximity to railways.

We investigated whether living close to railway lines is a risk factor for childhood leukaemia and non-Hodgkin's lymphoma in electoral wards in England and Wales, 1966-1987. The national rail network, 1966-1987, was digitised and the numbers of cases in each ward were related to two measures of environmental exposure to railways: a proximity and a density function, contributions to these functions being weighted by the frequency of use and time in use of each stretch of railway. Poisson regression was used to derive rate ratios in relation to these measures of exposure to railways, both unadjusted and adjusted for population mixing. We found no association between risk of leukaemia and railway proximity (unadjusted rate ratio for trend from the lowest to the median value=1.006, 95% CI: 0.998 - 1.013, P=0.14) and a very small association with railway density, of marginal statistical significance (rate ratio for trend=1.001, 95% CI: 1.000 - 1.003, P=0.05). This effect depended on two deprived, urban wards with high railway density and high population mixing and became nonsignificant (P=0.09) after allowing for population mixing. The very weak association between railway density and risk of childhood leukaemia is likely to be a consequence of the association between population mixing and proximity to railways in very deprived, urban wards.

Comparison of Health and Safety Executive and Cumbrian birth cohort studies of risk of leukaemia/non-Hodgkin's lymphoma in relation to paternal preconceptional irradiation.

In 1993, a case-control study by the Health and Safety Executive (HSE) assessed the risk of leukaemia and non-Hodgkin's lymphoma (LNHL) among children of fathers employed at the Sellafield nuclear installation in relation to paternal preconceptional irradiation (PPI). It concluded that the statistical association between risk of LNHL and PPI was confined to children born in the village of Seascale, where the dose-response was extremely high and very significant. In contrast, in 2002, a Cumbrian birth cohort study, investigating largely the same cases, concluded that this statistical association was not significantly different among children born inside and outside Seascale and estimated the dose-response inside Seascale to be much lower. This review makes a detailed comparison of the two studies, considering their design, data and analyses. The differences between their findings are due to: (i) differences in the distribution of offspring-years which are differential with respect to dose category and Seascale birth status, (ii) a non-Seascale high-dose case included in the Cumbrian but not the HSE study, (iii) differences between analyses using categorical and continuous PPI dose and (iv) the presence of Seascale controls with PPI over 200 mSv in the Cumbrian but not the HSE study.

Childhood solid tumours in relation to infections in the community in Cumbria during pregnancy and around the time of birth.

In a retrospective cohort study of all 99 976 live births in Cumbria, 1975-1992, we investigated whether higher levels of community infections during the mother's pregnancy and in early life were risk factors for solid tumours (brain/spinal and other tumours), diagnosed 1975-1993 under age 15 years. Logistic regression was used to relate risk to incidence of community infections in three prenatal and two postnatal quarters. There was an increased risk of brain/spinal tumours among children exposed around or soon after birth to higher levels of community infections, in particular measles (OR for trend=2.1, 95%CI : 1.3-3.6, P=0.008) and influenza (OR for exposure=3.3, 95%CI : 1.5-7.4, P=0.005). There was some evidence of an association between exposure to infections around and soon after birth and risk of other tumours, but this may have been a chance finding. The findings are consistent with other recent epidemiological studies suggesting brain tumours may be associated with perinatal exposure to infections.

Paternal preconceptional irradiation, population mixing and solid tumors in the children of radiation workers (England).

OBJECTIVE: To investigate whether there was an increased incidence of solid tumors among offspring of male radiation workers at the Sellafield nuclear installation in Cumbria, northwest England and whether paternal preconceptional irradiation was associated with the risk of solid tumors. METHODS: A cohort study of 266,710 live births in Cumbria, 1950-1991, followed up to age 25 years on the end of 1991. RESULTS: Children of radiation workers had a non-significantly increased risk of solid tumors (RR= 1.5, 95% CI: 0.9-2.4, p = 0.09), determined largely by an increased risk of cancers excluding leukemias, lymphomas, brain, spinal and gender-specific tumors (RR= 1.9, 95% CI: 1.0-3.3, p = 0.05), which was partly explained by differing patterns of parental migration (adjusted RR= 1.7, 95% Cl: 0.8-3.2, p = 0.50). Within children of radiation workers there was no evidence of an increased risk with increasing paternal preconception dose of external radiation (hazard ratio per 100 mSv for all solid tumors=0.6, 95% CI: 0.1-1.8, p = 0.52). CONCLUSIONS: Any observed excess of solid tumors in children of radiation workers may be partly explained by population mixing. Fathers' occupational exposure to radiation before conception was not found to be risk factor for solid tumors in their children.

Seasonality of birth for cancer in Northern England, UK.

Environmental factors operating around the time of birth may influence the subsequent development of childhood cancer, particularly leukaemia. Certain factors may vary with season (e.g. infections), and we therefore investigated whether there was any evidence of seasonality of month of birth, based on data from 4199 children diagnosed with cancer under the age of 15 years. We extracted details of (i) children born 1960-95 and diagnosed 1968-95 from two population-based registries, covering the Northern (n = 2053) and Yorkshire (n = 1977) Regional Health Authority and (ii) children born in Cumbria 1950-93 and diagnosed anywhere in the UK before 1994 from a birth cohort database (n = 397). The following diagnostic categories were analysed: 0-14 years--all cancers, leukaemias, acute lymphoblastic leukaemias, central nervous system tumours, all other solid tumours; 1-6 years--leukaemias, acute lymphoblastic leukaemias. Seasonal variation was tested using Walter and Elwood's test, and logistic regression analysis allowing for cyclical variation in month of birth. No evidence of seasonality was present for any group except acute lymphoblastic leukaemia diagnosed among 1- to 6-year-olds. Seasonal trends varied by region: in the Northern and Cumbrian datasets, seasonality patterns were significant and similar (P < 0.05) with a predicted peak in early spring, whereas in Yorkshire there was less strong evidence of seasonality (P = 0.08) with a peak predicted in late summer. These findings suggest that local seasonal environmental factors operating around the time of birth are not associated with the totality of childhood cancer, but possible links with acute lymphoblastic leukaemia are supportive of a hypothesis of an infectious aetiology.

How complete and accurate are cancer registrations notified by the National Health Service Central Register for England and Wales?

STUDY OBJECTIVE: To assess the completeness and accuracy of notification of cancers by the National Health Service Central Register (NHSCR) for England and Wales. DESIGN: Comparison of 720 cancer registrations ascertained from NHSCR up to May 1999 with those ascertained for the same cohort from six other sources and a pathology review of the NHSCR cancer registrations. PARTICIPANTS: People born in Cumbria, north west England, 1950-89, and diagnosed with cancer throughout the UK, 1971-1989. MAIN RESULTS: Cancer diagnoses notified by NHSCR differed substantially from those determined by this pathology review for 47 of the 688 notified cases reviewed (7%; 95% CI 5%, 9%). Over one third of these discrepancies were attributable to failures in data capture or coding by the cancer registration system and almost half to changes in diagnosis; 26 of the 47 discrepant cases were reclassified as non-malignant and 21 as malignancies but with a substantially different diagnosis. The 694 confirmed malignancies represented 94% (95%CI 92%, 95%) of the 740 cancers ascertained from all sources. CONCLUSIONS: It is estimated that the cancer registration system missed at least 10% (95%CI 6%, 15%) of all incident cases of malignant disease. Without additional ascertainment from multiple sources and diagnostic review, it would be incautious to use NHSCR cancer registrations as the sole basis of an epidemiological study.