Updated investigations of cancer excesses in individuals born or resident in the vicinity of Sellafield and Dounreay.

BACKGROUND: Earlier studies have shown raised risks of leukaemia and non-Hodgkin lymphoma in children, teenagers and young adults resident either at birth or diagnosis in Seascale. Some increases in cancer risk in these age groups have also been noted among those living around Dounreay. We aimed to update previous analyses relating to areas close to these nuclear installations by considering data from an additional 16 years of follow-up. METHODS: Cross-sectional analyses compared cancer incidence rates for 1963-2006 among those aged 0-24 years at diagnosis living in geographically specified areas around either Sellafield or Dounreay with general population rates. Cancer incidence for the period 1971-2006 among the cohort of Cumbrian births between 1950 and 2006 was compared to national incidence for 1971-2006 using person-years analysis. Cancer among those born in the postcode sector closest to Dounreay was compared with that among those born in the three adjoining postcode sectors. Analyses considered both cancer overall and ICD-O-3 defined diagnostic subgroups including leukaemia, central nervous system tumours and other malignancies. RESULTS: Apart from previously reported raised risks, no new significantly increased risks for cancer overall or any diagnostic subgroup were found among children or teenagers and young adults living around either nuclear installation. Individuals born close to the installations from 1950 to 2006 were not shown to be at any increased risk of cancer during the period 1971 to date. CONCLUSIONS: Analysis of recent data suggests that children, teenagers and young adults currently living close to Sellafield and Dounreay are not at an increased risk of developing cancer. Equally, there is no evidence of any increased cancer risk later in life among those resident in these areas at birth.

Does referral to specialist paediatric palliative care services reduce hospital admissions in oncology patients at the end of life?

BACKGROUND: Despite advances in the treatment of childhood cancer, some children continue to die from their disease. This study aimed to assess the impact of specialist paediatric palliative care services (SPPCSs) on the number of hospital admissions in children who subsequently died from cancer in Yorkshire, UK. METHODS: An extract of patients aged 0-19 years from the Yorkshire Specialist Register of Cancer in Children and Young People (YSRCCYP) diagnosed from 1990 to 2009 were linked to inpatient hospital episodes data and a SPPCS database. Deaths were included if they occurred before 31 August 2011. Differences in hospital admission patterns were assessed using negative binomial regression and presented as incidence rate ratios (IRRs). RESULTS: Of 2508 children on the YSRCCYP, 657 (26%) had died by the censoring date. A total of 211 children had been referred to the local SPPCS, of whom 182 (86%) had subsequently died. Referral to SPPCS was associated with a significant reduction in the rate of planned hospital admissions (IRR=0.60, 95% CI 0.43-0.85). Central nervous system tumours showed significant decreases for all planned and emergency admissions compared with all other diagnostic groups. CONCLUSION: Referral to SPPCS significantly reduced the number of planned hospital admissions for children and young people with cancer before their death, which are often integral to paediatric oncology treatment regimens. Overall, our findings show that SPPCS have a role in reducing hospital admissions during end of life care of paediatric cancer patients with potential personal, social and economic benefits.

Insulin VNTR allele-specific effect in type 1 diabetes depends on identity of untransmitted paternal allele. The IMDIAB Group.

The IDDM2 type 1 diabetes susceptibility locus was mapped to and identified as allelic variation at the insulin gene (INS) VNTR regulatory polymorphism. In Caucasians, INS VNTR alleles divide into two discrete size classes. Class I alleles (26 to 63 repeats) predispose in a recessive way to type 1 diabetes, while class III alleles (140 to more than 200 repeats) are dominantly protective. The protective effect may be explained by higher levels of class III VNTR-associated INS mRNA in thymus such that elevated levels of preproinsulin protein enhance immune tolerance to preproinsulin, a key autoantigen in type 1 diabetes pathogenesis. The mode of action of IDDM2 is complicated, however, by parent-of-origin effects and possible allelic heterogeneity within the two defined allele classes. We have now analysed transmission of specific VNTR alleles in 1,316 families and demonstrate that a particular class I allele does not predispose to disease when paternally inherited, suggestive of polymorphic imprinting. But this paternal effect is observed only when the father's untransmitted allele is a class III. This allelic interaction is reminiscent of epigenetic phenomena observed in plants (for example, paramutation; ref. 17) and in yeast (for example, trans-inactivation; ref. 18). If untransmitted chromosomes can have functional effects on the biological properties of transmitted chromosomes, the implications for human genetics and disease are potentially considerable.

Role of medical history and medication use in the aetiology of upper aerodigestive tract cancers in Europe: the ARCAGE study.

BACKGROUND: The study aimed to investigate the role of medical history (skin warts, Candida albicans, herpetic lesions, heartburn, regurgitation) and medication use (for heartburn; for regurgitation; aspirin) in the aetiology of upper aerodigestive tract (UADT) cancer. METHODS: A multicentre (10 European countries) case-control study [Alcohol-Related CAncers and GEnetic susceptibility (ARCAGE) project]. RESULTS: There were 1779 cases of UADT cancer and 1993 controls. History of warts or C. albicans infection was associated with a reduced risk [odds ratio (OR) 0.80, 95% confidence interval (CI) 0.68-0.94 and OR 0.73, 95% CI 0.60-0.89, respectively] but there was no association with herpetic lesions, heartburn, regurgitation or medication for related symptoms. Regurgitation was associated with an increased risk for cancer of the oesophagus (OR 1.47, 95% CI 0.98-2.21). Regular aspirin use was not associated with risk of UADT cancer overall but was associated with a reduced risk for cancer of oesophagus (OR 0.51, 95% CI 0.28-0.96), hypopharynx (OR 0.53, 95% CI 0.28-1.02) and larynx (OR 0.74, 95% CI 0.54-1.01). CONCLUSIONS: A history of some infections appears to be a marker for decreased risk of UADT cancer. The role of medical history and medication use varied by UADT subsites with aspirin use associated with a decreased risk of oesophageal cancer and suggestive of a decreased risk of hypopharyngeal and laryngeal cancers.

Incidence rate trends in childhood type 1 diabetes in Yorkshire, UK 1978-2007: effects of deprivation and age at diagnosis in the South Asian and non-South Asian populations.

AIMS: Incidence of Type 1 diabetes in children is increasing worldwide. Earlier studies suggest that UK south Asian immigrants develop similar rates to the overall UK population, although incidence is lower in their country of origin. This study examines incidence rate trends of childhood Type 1 diabetes in Yorkshire 1978-2007, focusing on differences between south Asians and non-south Asians. METHODS: Data from the population-based Yorkshire Register of Diabetes in Children and Young People were used to estimate incidence (per 100,000 childhood population < 15 years per year) of Type 1 diabetes, stratified by sex, age and ethnicity validated using two name-recognition programs. Age-sex standardized rates were calculated for 1978-2007 and assessed by ethnic-group and deprivation for 1990-2007. We used Poisson regression to assess incidence trends and predict rates until 2020. RESULTS: From 1978-2007, 3912 children were diagnosed. Overall incidence was 18.1 per 100,000 childhood population (< 15 years) per year (95% CI17.6-18.7) and increased significantly over time: 13.2 (1978-1987) to 17.3 (1988-1997) to 24.2 (1998-2007). Average annual percentage change was 2.8% (2.5-3.2). Incidence for non-south Asians (21.5; 20.7-22.4) was significantly higher than for south Asians (14.7; 12.4-17.1). Average annual percentage change increased significantly over 18 years (1990-2007) in non-south Asians (3.4%; 2.7-4.2) compared with a non-significant rise of 1.5% (-1.5 to 4.6) in south Asians. Deprivation score did not affect overall incidence. CONCLUSIONS: Type 1 diabetes incidence rose almost uniformly for non-south Asians, but not for south Asians, contrary to previous studies. Overall rates are predicted to rise by 52% from 2007 to 2020 to 39.0 per 100,000 per year.

Cancer incidence among the south Asian and non-south Asian population under 30 years of age in Yorkshire, UK.

BACKGROUND: Few studies have examined epidemiological differences between ethnic groups for children and young adults with cancer. METHODS: Subjects aged 0-29 years, diagnosed between 1990 and 2005 in the former Yorkshire Regional Health Authority, were included in the analysis. Ethnicity (south Asian or not) was assigned using name analysis program and Hospital Episode Statistics data. Differences in incidence (per 1,000,000 person-years) rates and trends were analysed using joinpoint and Poisson regression analysis. RESULTS: Overall cancer incidence was similar for south Asians (12.1, 95% CI: 10.7-13.5; n=275) and non-south Asians (12.6, 95% CI: 12.2-13.1; n=3259). Annual incidence rates increased significantly by 1.9% per year on average (95% CI: 1.2-2.6%), especially for south Asians (7.0%; 95% CI: 4.2-9.9%). CONCLUSION: If present trends continue, the higher rate of increase seen among south Asians aged 0-29 years in Yorkshire will result in three times higher cancer incidence than non-south Asians by 2020.

Dietary acrylamide intake and risk of breast cancer in the UK women's cohort.

BACKGROUND: No studies to date have demonstrated a clear association with breast cancer risk and dietary exposure to acrylamide. METHODS: A 217-item food frequency questionnaire was used to estimate dietary acrylamide intake in 33,731 women aged 35-69 years from the UK Women's Cohort Study followed up for a median of 11 years. RESULTS: In all, 1084 incident breast cancers occurred during follow-up. There was no evidence of an overall association between acrylamide intake and breast cancer (hazard ratio=1.08 per 10 µg day(-1), 95% CI: 0.98-1.18, P(trend)=0.1). There was a suggestion of a possible weak positive association between dietary acrylamide intake and premenopausal breast cancer after adjustment for potential confounders (hazard ratio=1.2, 95% CI: 1.0-1.3, P(trend)=0.008). There was no suggestion of any association for postmenopausal breast cancer (hazard ratio=1.0, 95% CI: 0.9-1.1, P(trend)=0.99). CONCLUSIONS: There is no evidence of an association between dietary acrylamide intake and breast cancer. A weak association may exist with premenopausal breast cancer, but requires further investigation.

Life course social mobility and risk of upper aerodigestive tract cancer in men.

The aim of this study was to explore associations between social mobility and tumours of the upper aero-digestive tract (UADT), focussing on life-course transitions in social prestige (SP) based on occupational history. 1,796 cases diagnosed between 1993 and 2005 in ten European countries were compared with 1585 controls. SP was classified by the Standard International Occupational Prestige Scale (SIOPS) based on job histories. SIOPS was categorised in high (H), medium (M) and low (L). Time weighted average achieved and transitions between SP with nine trajectories: H --> H, H --> M, H --> L, M --> H, M --> M, M --> L, L --> H, L --> M and L --> L were analysed. Odds ratios (ORs) and 95%-confidence intervals [95%-CIs] were estimated with logistic regression models including age, consumption of fruits/vegetables, study centre, smoking and alcohol consumption. The adjusted OR for the lowest versus the highest of three categories (time weighted average of SP) was 1.28 [1.04-1.56]. The distance of SP widened between cases and controls during working life. The downward trajectory H --> L gave an OR of 1.71 [0.75-3.87] as compared to H --> H. Subjects with M --> M and L --> L trajectories ORs were also elevated relative to subjects with H --> H trajectories. The association between SP and UADT is not fully explained by confounding factors. Downward social trajectory during the life course may be an independent risk factor for UADT cancers.

Incidence and survival of childhood bone cancer in northern England and the West Midlands, 1981-2002.

There is a paucity of population-based studies examining incidence and survival trends in childhood bone tumours. We used high quality data from four population-based registries in England. Incidence patterns and trends were described using Poisson regression. Survival trends were analysed using Cox regression. There were 374 cases of childhood (ages 0-14 years) bone tumours (206 osteosarcomas, 144 Ewing sarcomas, 16 chondrosarcomas, 8 other bone tumours) registered in the period 1981-2002. Overall incidence (per million person years) rates were 2.63 (95% confidence interval (CI) 2.27-2.99) for osteosarcoma, 1.90 (1.58-2.21) for Ewing sarcoma and 0.21 (0.11-0.31) for chondrosarcoma. Incidence of Ewing sarcoma declined at an average rate of 3.1% (95% CI 0.6-5.6) per annum (P=0.04), which may be due to tumour reclassification, but there was no change in osteosarcoma incidence. Survival showed marked improvement over the 20 years (1981-2000) for Ewing sarcoma (hazard ratio (HR) per annum=0.95 95% CI 0.91-0.99; P=0.02). However, no improvement was seen for osteosarcoma patients (HR per annum=1.02 95% CI 0.98-1.05; P=0.35) over this time period. Reasons for failure to improve survival including potential delays in diagnosis, accrual to trials, adherence to therapy and lack of improvement in treatment strategies all need to be considered.

Infectious exposure in the first year of life and risk of central nervous system tumors in children: analysis of day care, social contact, and overcrowding.

Little is known regarding the aetiology of central nervous system tumors in children. Recent studies have speculated on a potential infectious aetiology, but no clear associations have been found. This article uses parent reported questionnaire data from the UK Childhood Cancer Study (UKCCS), a population-based case-control study, to examine the relationship between the infectious exposure in the first year of life and the likelihood of developing a CNS tumor. The variables representing infectious exposure were social contact (including social contact with other infants and attendance at informal and formal day care), sharing a bedroom with another child, birth order, and exposure to a school-age child within the home. Children reported to have had no social contact with other infants in the first year of life displayed an increased risk of developing a CNS tumor when compared to those who had (OR 1.37, 95% CI 1.08-1.75). This effect was most prominent in the primitive neuroectodermal tumor/medulloblastoma subgroup (OR 1.78, 95% CI 1.12-2.83). Those who had attended informal (OR 0.86, 95% CI 0.68-1.09) or formal day care (OR 0.93, 95% CI 0.68-1.26) showed slightly non-statistically significant reduced risks when compared to those reporting social contact only. No association with any of the other variables was observed. Overall, the inconsistent findings by variable and tumor subtype suggest that an early exposure to infections is not strongly implicated in the aetiology of CNS tumors. However, the effect for social contact outside the home, particularly for PNET/medulloblastomas warrants further investigation.

Autoantibodies and associated T-cell responses to determinants within the 831-860 region of the autoantigen IA-2 in Type 1 diabetes.

B-cells influence T-cell reactivity by facilitating antigen presentation, but the role of autoantibody-secreting B-cells in regulating T-cell responses in Type 1 diabetes is poorly defined. The aims of this study were to characterise epitopes on the IA-2 autoantigen for three monoclonal antibodies from diabetic patients by amino acid substitutions of selected residues of IA-2, establish contributions of these epitopes to binding of serum antibodies in Type 1 diabetes and relate B- and T-cell responses to overlapping determinants on IA-2. The monoclonal antibodies recognised overlapping epitopes, with residues within the 831-860 region of IA-2 contributing to binding; substitution of Glu836 inhibited binding of all three antibodies. Monoclonal antibody Fab fragments and substitution of residues within the 831-836 region blocked serum antibody binding to an IA-2 643-937 construct. IL-10-secreting T-cells responding to peptides within the 831-860 region were detected by cytokine-specific ELISPOT in diabetic patients and responses to 841-860 peptide were associated with antibodies to the region of IA-2 recognised by the monoclonal antibodies. The study identifies a region of IA-2 frequently recognised by antibodies in Type 1 diabetes and demonstrates that these responses are associated with T-cells secreting IL-10 in response to a neighbouring determinant.

Occupational exposure of UK adults to extremely low frequency magnetic fields.

BACKGROUND: Occupational exposure to extremely low frequency (ELF) magnetic fields (MF) in the UK general population is poorly documented. AIMS: To assess levels of occupational exposure to ELF MF in the UK and evaluate the use of a rigid job-exposure matrix (JEM) to assign exposures to subjects in the UK Adult Brain Tumour Study (UKABTS). METHODS: Personal ELF MF measurements were carried out. Exposure traces were divided into occupational, travel and elsewhere periods, under differing exposure metrics. Exposure was classified by Standard Occupational Classification (2000), Standard Industrial Classification (1997), and a combined occupation-industry classification. Statistical analyses (mixed effects model) determined the contribution of occupational exposure to the 24 h cumulative exposure and the contribution of occupation and industry to total variance. RESULTS: Data were obtained from 317 individuals, comprising UKABTS subjects (n = 192), occupational proxies for UKABTS subjects (n = 101) and "interest" readings (n = 24). 236 individuals provided occupational data covering 117 different occupations. Average exposure was significantly higher at work than at home. Elevated average occupational exposure was found for welding trades, printers, telephonists and filing and other records assistants. The discrimination of a rigid JEM based on occupation can be improved by linking the classification with industry and by the use of contextual information. CONCLUSIONS: This report substantially expands information on adult exposure to ELF MF in the UK. The accuracy of exposure assessments based solely on job codes is improved by linking with either industry code or contextual knowledge of equipment and of power lines or substations in the work environment.

Infections in early life and childhood leukaemia risk: a UK case-control study of general practitioner records.

We investigated infections in early life (diagnosed in general practice) and subsequent risk of childhood leukaemia in the UK General Practice Research Database (GPRD). All children born at GPRD practices and subsequently diagnosed with leukaemia were identified as cases and were individually matched (on year of birth, sex and practice) to up to 20 controls. The final analysis included 162 leukaemia cases and 2215 matched controls. Conditional logistic regression demonstrated no evidence that children with one or more recorded infection in the first year of life had a reduced risk of leukaemia (OR=1.05, 95%CI 0.69, 1.59; P=0.83) or acute lymphoblastic leukaemia (ALL; OR=1.05, 95%CI 0.64-1.74; P=0.84). Our study provides no support for the Greaves hypothesis, which proposes that reduced or delayed exposure to infections in early life increases the risk of childhood ALL.

Atopic dysfunction and risk of central nervous system tumours in children.

Risk factors for central nervous system (CNS) tumours in children remain largely unknown. Evidence of an inverse relationship between atopy and tumour development exists in adults but little is known about childhood tumours. This study aims to examine the risk of childhood CNS tumours given a history of eczema and asthma. Cases of children diagnosed with CNS tumours (n=575) and controls (n=6292) from the UK Childhood Cancer Study (UKCCS) were analysed using conditional logistic regression comparing reported histories of allergic disease. Asthma was statistically significantly and negatively associated with all CNS tumours (odds ratios, OR 0.75, confidence of interval, CI(95%): 0.58-0.97), though this was not observed for eczema (OR 0.94, CI(95%): 0.74-1.18). Individuals who had suffered both asthma and eczema showed the most significant reduction in risk (OR 0.48, CI(95%): 0.28-0.81). Analysis by tumour subtype showed the strongest effect for the medulloblastoma/PNET group. These results may have a biological explanation with raised immunosurveillance in atopic individuals protecting against the development of brain tumours. Alternative explanations might include bias, reverse causality or confounding.

Children and young people with diabetes in Yorkshire: a population-based clinical audit of patient data 2005/2006.

AIMS: To provide a population-based clinical audit of children and young people with diabetes, reporting outcomes, including glycaemic control, for named individual units. METHODS: Clinical audit data on care processes and glycated haemoglobin (HbA(1c)) were collected for 1742 children and young people treated in 16 paediatric units in Yorkshire, from January 2005 to March 2006. The Yorkshire Register of Diabetes in Children and Young People provided information technology support and validation that enhanced data quality. Multi-level linear regression modelling investigated factors affecting glycaemic control. RESULTS: An HbA(1c) measure was recorded for 91.6% of patients. The National Institute for Clinical Excellence-recommended target level for HbA(1c) of < 7.5% was achieved for 14.7% of patients. HbA(1c) was positively associated with duration of diabetes and later age at diagnosis. Patients living in deprived areas had significantly poorer control compared with those from affluent areas. Significant between-unit variation in HbA(1c) was not reflected by any association with unit size. CONCLUSIONS: Our population-based clinical audit of children with diabetes is the product of an effective collaboration between those who deliver care and health services researchers. High levels of recording the key care process measuring diabetes control, compared with national figures, suggests collaboration has translated into improved services. The interesting association between poor diabetes control and higher deprivation is noteworthy and requires further investigation. Future audits require recording of clinical management and clinic structures, in addition to resources to record, assemble and analyse data.

Assigning exposure to pesticides and solvents from self-reports collected by a computer assisted personal interview and expert assessment of job codes: the UK Adult Brain Tumour Study.

OBJECTIVES: To compare assignment of occupational pesticide and solvent exposure using self-reported data collected by a computer assisted personal interview (CAPI) with exposure based on expert assessment of job codes. To discuss the advantages and disadvantages of using a CAPI to collect individual occupational exposure data. METHODS: Between 2001 and 2004, 1495 participants were interviewed using a CAPI for a case-control study of adult brain tumours and acoustic neuromas. Two types of occupational data were collected: (1) a full history, including job title from which a job code was assigned from the Standard Occupational Classification; and (2) specific details on pesticide and solvent exposure reported by participants. Study members' experiences of using the CAPI were recorded and advantages and disadvantages summarised. RESULTS: Of 7192 jobs recorded, the prevalence of self-reported exposure was 1.3% for pesticides and 11.5% for solvents. Comparing this with exposure expertly assessed from job titles showed 53.6% and 45.8% concordance for pesticides and solvents respectively. Advantages of the CAPI include no data entry stage, automatic input validation, and a reduction in interviewer bias. Disadvantages include an adverse effect on study implementation as a consequence of resources required for programming and difficulties encountered with data management prior to analysis. CONCLUSIONS: Different methods of exposure assessment derive different exposure levels for pesticide and solvent exposure at work. Agreement between self-reported and expert assessment of exposure was greater for pesticides compared to solvents. The advantages of using a CAPI for the collection of complex data outweigh the disadvantages for interviewers and data quality but using such a method requires extra resources at the study outset.

Validation of short term recall of mobile phone use for the Interphone study.

AIM: To validate short term recall of mobile phone use within Interphone, an international collaborative case control study of tumours of the brain, acoustic nerve, and salivary glands related to mobile telephone use. METHODS: Mobile phone use of 672 volunteers in 11 countries was recorded by operators or through the use of software modified phones, and compared to use recalled six months later using the Interphone study questionnaire. Agreement between recalled and actual phone use was analysed using both categorical and continuous measures of number and duration of phone calls. RESULTS: Correlations between recalled and actual phone use were moderate to high (ranging from 0.5 to 0.8 across countries) and of the same order for number and duration of calls. The kappa statistic demonstrated fair to moderate agreement for both number and duration of calls (weighted kappa ranging from 0.20 to 0.60 across countries). On average, subjects underestimated the number of calls per month (geometric mean ratio of recalled to actual = 0.92, 95% CI 0.85 to 0.99), whereas duration of calls was overestimated (geometric mean ratio = 1.42, 95% CI 1.29 to 1.56). The ratio of recalled to actual use increased with level of use, showing underestimation in light users and overestimation in heavy users. There was substantial heterogeneity in this ratio between countries. Inter-individual variation was also large, and increased with level of use. CONCLUSIONS: Volunteer subjects recalled their recent phone use with moderate systematic error and substantial random error. This large random error can be expected to reduce the power of the Interphone study to detect an increase in risk of brain, acoustic nerve, and parotid gland tumours with increasing mobile phone use, if one exists.

Leukaemia Research Fund Data Collection Survey: descriptive epidemiology of chronic myeloid leukaemia.

This paper describes the recent epidemiology of chronic myeloid leukaemia occurring in selected parts of England and Wales. The overall rates for the pooled sexes is 1.0/10(5) per year and the geographical distributions described in this paper show remarkable homogeneity at county, district and electoral ward level. The implication of these observations is discussed.

Acute myeloid leukemia in adults: a case-control study in Yorkshire.

This paper reports the results of a case-control analysis of 161 cases of acute myeloid leukemia and 310 matched hospital controls. The patients were interviewed between 1982 and 1986. The study shows a weak association for cases with previous malignant disease. Furnace workers show excess risks. Urticaria and vertigo are in excess, as well as some aspects of family medical histories, including multiple sclerosis and cases of leukemia/lymphoma in blood relations.

Acute lymphoblastic leukaemia incidence in the UK by immunophenotype.

The incidence of acute lymphoblastic leukaemia (ALL) is described for both children and adults for the three major immunophenotypes: null, CD10-positive (CD+) which includes both common and pre-B types, and T-cell (including pre-T variants). The data are derived from a population-based specialist registry of leukaemias and lymphomas covering approximately one-half of England and Wales. Null ALL predominates in those under 1 year old and CD10+ ALL in the 1-7 year olds. There is a male excess at all ages for T-cell disease, which is particularly prominent in adolescents and young adults. The effect of socioeconomic levels is seen most clearly for CD10+ ALL in the childhood peak, where B-cell precursor disease occurs more frequently in areas of higher socioeconomic status.