Childhood cancer research in Oxford I: the Oxford Survey of Childhood Cancers.

BACKGROUND: Significant research on the epidemiology and natural history of childhood cancer took place in the Universities of Oxford and Birmingham over sixty years. This is the first of three papers recording this work and describes the Oxford Survey of Childhood Cancers (OSCC), the largest case-control survey of childhood cancer ever undertaken. METHODS: The OSCC studied deaths in Britain from 1953 to 1981. Parents were interviewed and medical records from ante-natal clinics and treatment centres were followed up and abstracted. The survey left Oxford in 1975 and was run subsequently from Birmingham. The data are now being documented and archived to make them available for future study. RESULTS: Many papers have resulted from this survey, most notably those relating to the association first reported therein between childhood cancer and ante-natal X-raying. This paper is a historical review of the OSCC. CONCLUSIONS: In spite of many analyses of the study, this historic data set has continuing value because of the large number of examples of some very rare tumours and the detailed clinical and family history data that are available; and also because of the possibility of carrying out new analyses to investigate emerging research issues.

A contextualisation approach to health promotion guideline development in South Africa.

BACKGROUND: Risk factors for chronic illness contribute significantly to the disease burden in South Africa. The National Department of Health (NDoH) commissioned the development of a toolkit of health promotion guidelines for use by healthcare professionals working in the primary care setting to address this burden. OBJECTIVES: To (i) demonstrate the contextualisation approach to evidence-based health promotion recommendations; and (ii) present the development process of a contextually sensitive and illustrated fit-for-purpose product. METHODS: A contextualised approach was used whereby evidence from rigorous guidelines produced elsewhere was tailored to local conditions. The scope of the toolkit included five risk factors and 22 conditions identified by the NDoH and was underpinned by the Theory of Planned Behaviour. Potential health promotion messages relevant to risks, conditions or both were formulated as population, intervention, comparison and outcome (PICO) questions. The team searched for and selected evidence for each PICO question in a stepwise hierarchical manner and categorised sources as: (i) World Health Organization (WHO) guidelines; (ii) Cochrane systematic reviews; and (iii) non-Cochrane systematic reviews. Those messages supported by source-based evidence were included in the toolkit with culturally appropriate illustrations. Regular engagement with stakeholders included an initial health department stakeholder consultation, a focus group with national programme managers on the appearance and content of a draft toolkit, and a presentation of the final draft at a forum of provincial managers. Final approval of the toolkit rested with programme representatives. RESULTS: A total of 152 PICO questions were formulated. Supporting evidence was identified from 42 current WHO guidelines and 45 Cochrane systematic reviews to answer 147 PICO questions with several guidelines relevant to more than one risk or condition. Evidence for a further five PICO questions was obtained from non-Cochrane systematic reviews. Six additional service delivery messages and four 'no harm' messages were included to align the toolkit with current national guidelines. The illustrated toolkit was well received by stakeholders nationally and provincially, with programme managers expressing a high degree of willingness to adopt a preventive approach in the primary care clinic setting. CONCLUSIONS: Use of a tailored contextualised approach to health promotion guidelines resulted in a culturally appropriate tool based on evidence gathered from rigorous sources and probably reduced development time and costs. Adherence to a robust framework to identify evidence ensured that the toolkit conforms to international guideline development standards.

Solution phase synthesis and intense pulsed light sintering and reduction of a copper oxide ink with an encapsulating nickel oxide barrier.

Copper oxide nanoparticle inks sintered and reduced by intense pulsed light (IPL) are an inexpensive means to produce conductive patterns on a number of substrates. However, the oxidation and diffusion characteristics of copper are issues that must be resolved before it can be considered as a viable solution. Nickel can provide a degree of oxidation protection and act as a barrier for the diffusion of copper. In the present study we have for the first time synthesized copper oxide with an encapsulating nickel oxide nanostructure using a solution phase synthesis process in the presence of a surfactant at room temperature. The room temperature process enables us to easily prevent the formation of alloys at the copper-nickel interface. The synthesis results in a simple technique (easily commercializable, tested at a 10 g scale) with highly controllable layer thicknesses on a 20 nm copper oxide nanoparticle. These Cu(2)O@NiO dispersions were then directly deposited onto substrates and sintered/reduced using an IPL source. The sintering technique produces a highly conductive film with very short processing times. Films have been deposited onto silicon, and the copper-nickel structure has shown a lower copper diffusion. The nanostructures and resulting films were characterized using electron and x-ray spectroscopy, and the films' resistivity was measured.

Second and subsequent tumours among 1927 retinoblastoma patients diagnosed in Britain 1951-2004.

BACKGROUND: Retinoblastoma is an eye tumour of childhood that occurs in heritable and non-heritable forms. In the heritable form, there is a predisposition to the development of non-ocular subsequent primary tumours (SPTs). METHODS: This study included 1927 retinoblastoma patients diagnosed in Britain from 1951 to 2004. Ascertainment was through the (UK) National Registry of Childhood Tumours; cases were followed-up for the occurrence of SPTs. Standardised incidence ratios (SIRs) were calculated. RESULTS: We identified 169 SPTs in 152 patients. The SIR analysis included 145 SPTs with cancer registrations from the years 1971 to 2009. These tumours occurred in 132 patients: 112 of the 781 heritable and 20 of the 1075 (presumed) non-heritable cases under surveillance at the start of this period developed at least one registered SPT. The SIRs for all tumours combined were 13.7 (95% confidence interval 11.3-16.5) in heritable cases and 1.5 (0.9-2.3) in non-heritable cases. The main types of SPT in the heritable cases were leiomyosarcoma, (31 cases; SIR 1018.7 (692.2-1446.0)), osteosarcoma (26 cases; SIR 444.6 (290.4-651.4)), and skin melanoma (12 cases; SIR 18.6 (9.6-32.4)). CONCLUSION: The risk of SPTs in heritable retinoblastoma is extremely high. This has important implications for the clinical follow-up and counselling of survivors and their families.

Hip fractures among indigenous Western Australians from 1999 to 2009.

BACKGROUND: Minimal trauma hip fractures are prevalent in Australia. The incidence rate and trend of hip fractures in Indigenous Western Australians have not been formally reported. AIMS: To evaluate incidence rates and trend of minimal trauma hip fractures in Indigenous and other Western Australians aged 40 years and over in 1999-2009 METHODS: Hip fracture data were obtained from an administrative database for all hospitalisations in Western Australia. Age-standardised incidence rates were calculated using direct standardisation, and standardised rate ratios were calculated using the indirect method. Trend in incidence rates were calculated using Poisson regression. RESULTS: In 1999-2009, 11,844 admissions for minimal trauma hip fractures were reported among Western Australians aged 40 years and over, of which 201 were recorded as indigenous. The age-standardised hip fracture rate was 273.0 (95% confidence interval (CI) 230.7-315.4) per 100,000 person-years for indigenous adults and 148.8 (95% CI 146.1-151.5) per 100,000 person-years for non-indigenous adults. The standardised morbidity ratio was 2.2 (95% CI 1.9-2.5). Over this period, age-standardised rates increased by an average of 7.2% per year among indigenous adults (P = 0.006), whereas non-indigenous rates fell by an average of 3.4% per year (P < 0.001). The relatively higher rates among indigenous adults were more evident in the younger age groups. CONCLUSION: There is a widening gap in minimal trauma hip fracture rates between indigenous and other Western Australians. This study demonstrates a need for public health review and management strategies to reduce falls and hip fracture in the indigenous community.

Childhood cancer and magnetic fields from high-voltage power lines in England and Wales: a case-control study.

BACKGROUND: Epidemiological evidence suggests that chronic low-intensity extremely-low-frequency magnetic-field exposure is associated with increased risk of childhood leukaemia; it is not certain the association is causal. METHODS: We report a national case-control study relating childhood cancer risk to the average magnetic field from high-voltage overhead power lines at the child's home address at birth during the year of birth, estimated using National Grid records. From the National Registry of Childhood Tumours, we obtained records of 28,968 children born in England and Wales during 1962-1995 and diagnosed in Britain under age 15. We selected controls from birth registers, matching individually by sex, period of birth, and birth registration district. No participation by cases or controls was required. RESULTS: The estimated relative risk for each 0.2 µT increase in magnetic field was 1.14 (95% confidence interval 0.57 to 2.32) for leukaemia, 0.80 (0.43-1.51) for CNS/brain tumours, and 1.34 (0.84-2.15) for other cancers. CONCLUSION: Although not statistically significant, the estimate for childhood leukaemia resembles results of comparable studies. Assuming causality, the estimated attributable risk is below one case per year. Magnetic-field exposure during the year of birth is unlikely to be the whole cause of the association with distance from overhead power lines that we previously reported.

Pooled analysis of recent studies on magnetic fields and childhood leukaemia.

BACKGROUND: Previous pooled analyses have reported an association between magnetic fields and childhood leukaemia. We present a pooled analysis based on primary data from studies on residential magnetic fields and childhood leukaemia published after 2000. METHODS: Seven studies with a total of 10,865 cases and 12,853 controls were included. The main analysis focused on 24-h magnetic field measurements or calculated fields in residences. RESULTS: In the combined results, risk increased with increase in exposure, but the estimates were imprecise. The odds ratios for exposure categories of 0.1-0.2 µT, 0.2-0.3 µT and ≥0.3 µT, compared with <0.1 µT, were 1.07 (95% CI 0.81-1.41), 1.16 (0.69-1.93) and 1.44 (0.88-2.36), respectively. Without the most influential study from Brazil, the odds ratios increased somewhat. An increasing trend was also suggested by a nonparametric analysis conducted using a generalised additive model. CONCLUSIONS: Our results are in line with previous pooled analyses showing an association between magnetic fields and childhood leukaemia. Overall, the association is weaker in the most recently conducted studies, but these studies are small and lack methodological improvements needed to resolve the apparent association. We conclude that recent studies on magnetic fields and childhood leukaemia do not alter the previous assessment that magnetic fields are possibly carcinogenic.

Non-ocular tumours following retinoblastoma in Great Britain 1951 to 2004.

BACKGROUND: Retinoblastoma occurs in both a heritable and a non-heritable form. In the heritable form, there is a predisposition to the development of non-ocular tumours. OBJECTIVES: To identify the types of non-ocular tumour occurring in retinoblastoma survivors and to produce estimates of risk for these tumours. METHODS: We carried out a cohort study that included 1927 cases of retinoblastoma diagnosed in Great Britain between 1951 and 2004. Cases were ascertained through the National Registry of Childhood Tumours and followed up for the occurrence of non-ocular tumours using the routine notification system based on the National Health Service Central Registers in Britain. RESULTS: Of the 1927 cases, 809 were known to have the heritable form of the disease and 1118 assumed to have the non-heritable form. 102 of the heritable and 13 of those classified as non-heritable developed a non-ocular tumour. The cumulative risk of developing such a tumour 50 years after retinoblastoma diagnosis was 48.3% (95% confidence interval: 38.1 to 59.7%) in the heritable and 4.9% (1.9 to 12.4%) in the non-heritable cases. The main categories of non-ocular tumours observed in the heritable cases were soft-tissue sarcomas (36 of which 21 were leiomyosarcoma), osteosarcoma (32), carcinoma (13), brain and central nervous system tumours (10), melanoma (9), leukaemia (4) and others (4). There were a total of 108 non-ocular tumours in 102 cases. CONCLUSIONS: There is a high risk of non-ocular tumours occurring in survivors of heritable retinoblastoma. These results have important implications for the clinical follow-up and counselling of survivors.

Cancer in the offspring of female radiation workers: a record linkage study.

This study uses record linkage between the National Registry of Childhood Tumours (NRCT) and the National Registry for Radiation Workers to re-assess our earlier finding that the offspring of women radiation workers exposed to ionising radiation before the child's conception may be at an increased risk of childhood cancer. An additional 16,964 childhood cancer patients taken from the NRCT, together with the same number of matched controls, are included. Pooled analyses, based on the new and original datasets, include 52,612 cases and their matched controls. Relative risks (RRs) for maternal employment as a radiation worker, maternal exposure or not during the relevant pregnancy and pattern of employment relative to conception and diagnosis dates were calculated.The new data provide no evidence of an increased risk of childhood cancer associated with maternal preconception radiation work and thus do not support our earlier finding of a raised risk in the offspring of female radiation workers. Considering the pooled data, a weak association was found between maternal radiation work during pregnancy and childhood cancer in offspring although the evidence is limited by the small numbers of linked cases and controls.

Retinoblastoma in Great Britain 1963-2002.

AIM: This paper describes the epidemiology and family history status of 1601 children with retinoblastoma in Great Britain diagnosed 1963-2002 and summarises the practical consequences for diagnosis and counselling of developments in molecular genetics. METHODS: Incidence rates were analysed according to year of diagnosis and tumour laterality. Cases were classified as heritable or non-heritable on the basis of laterality and family history of the disease. RESULTS: There were 998 unilateral cases, 581 bilateral and 22 of unknown laterality. Bilateral cases tended to be diagnosed at a younger age than unilateral. All bilateral cases are regarded as heritable, and 35% had a family history of the disease. 7% of the unilateral cases had a family history and are therefore heritable. Thus, at least (41%) of our cases are heritable. This is an underestimate, since these data on family history are incomplete. For unilateral cases aged below 1 year, the reported incidence rate increased significantly (p<0.0001) by about 2.5% per year; for the age group 1-4 years, the average increase was about 0.5% per year (not significant).

Retinoblastoma: treatment and survival in Great Britain 1963 to 2002.

AIM: This paper describes the treatment and survival of 1576 children with retinoblastoma in Great Britain diagnosed 1963-2002. METHODS: Survival rates were analysed according to period of diagnosis and tumour laterality. RESULTS: Survival was calculated by calendar period of diagnosis, 1963-1982 and 1983-2002. For both unilateral and bilateral retinoblastoma, survival improved between the two periods. The survival curves for the two periods were significantly different: for unilateral retinoblastoma p<0.00001, for bilateral p<0.01. For unilateral cases, the estimated 5-year survival rates rose from 85% for those diagnosed in 1963-1967 to 97% for those diagnosed in 1998-2002. The equivalent rates for bilateral cases were 88% and 100%. CONCLUSION: Survival rates were already high at the start of the study period. They increased with changes in treatment regimens.

Retinoblastoma incidence and survival in European children (1978-1997). Report from the Automated Childhood Cancer Information System project.

Based on 2283 cases of retinoblastoma diagnosed in children aged 0-14 years, incidence and survival in Europe during the period 1978-1997 are described. Data were provided to the Automated Childhood Cancer Information System (ACCIS) from 60 paediatric and general cancer registries. During 1988-1997, the cumulative incidence of retinoblastoma in the ACCIS regions was found to be between 44.2 and 67.9 per million births. The highest incidence was seen in the first year of life. The age-standardised (World standard) incidence rate for the age-range 0-14 years was 4.1 per million. Approximately one-third of cases had bilateral tumours. Overall incidence increased over the period 1978-1997 by 1% per year, as derived from a model adjusted for sex, age group and type of registry (general or paediatric). The 5-year survival rate improved from 89% to 95% during the period covered by the study. This improvement was seen in both unilateral and bilateral cases but was significant only for the unilateral tumours. Survival was lower in the East region, although smaller differences were also observed between the other four regions (British Isles, North, South and West). Availability and quality of registration data on retinoblastoma need to be improved for effective evaluation of incidence and survival.

Cancer in the offspring of radiation workers: an investigation of employment timing and a reanalysis using updated dose information.

An earlier case-control study found no evidence of paternal preconceptional irradiation (PPI) as a cause of childhood leukaemia and non-Hodgkin's lymphoma (LNHL). Although fathers of children with LNHL were more likely to have been radiation workers, the risk was most marked in those with doses below the level of detection. The timing of paternal employment as a radiation worker has now been examined. The previously reported elevated risk of LNHL in the children of male radiation workers was limited to those whose fathers were still radiation workers at conception or whose employment also continued until diagnosis. Children whose fathers stopped radiation work prior to their conception were found to have no excess risk of LNHL. It was not possible to distinguish between the risks associated with paternal radiation work at conception and at the time of diagnosis. A reanalysis of the original study hypothesis incorporating updated dosimetric information gave similar results to those obtained previously. In particular, the risks of LNHL did not show an association with radiation doses received by the father before conception. It seems likely that the increased risk of LNHL among the children of male radiation workers is associated with an increased exposure to some infective agent consequent on high levels of population mixing.

Vitamin K and childhood cancer: analysis of individual patient data from six case-control studies.

To investigate the hypothesis that neonates who receive intramuscular vitamin K are at an increased risk of developing cancer, particularly leukaemia, a pooled analysis of individual patient data from six case-control studies conducted in Great Britain and Germany has been undertaken. Subjects comprised 2431 case children diagnosed with cancer before 15 years of age and 6338 control children. The retrospective assessment of whether or not an individual baby received vitamin K is not straightforward. In many cases no record was found in stored medical notes and two types of analysis were therefore conducted; in the first it was assumed that where no written record of vitamin K was found it had not been given, and in the second, where no written record of administration was found, information on hospital policy and perinatal morbidity was used to 'impute' whether or not vitamin K had been given. In the first analysis, no association was found between neonatal administration of intramuscular. vitamin K and childhood cancer: odds ratios adjusted for mode of delivery, admission to special care baby unit and low birth weight were 1.09 (95% confidence interval 0.92-1.28) for leukaemia and 1.05 (0.92-1.20) for other cancers. In the second analysis, the adjusted odds ratios increased to 1.21 (1.02-1.44) for leukaemia and 1.10 (0.95-1.26) for other cancers. This shift did not occur in all studies, and when data from the hypothesis generating Bristol study were excluded, the adjusted odds ratios for leukaemia became 1.06 (0.89-1.25) in the first analysis and 1.16 (0.97-1.39) when data on prophylaxis imputed from hospital policy and perinatal morbidity were used. We conclude that whilst the broad nature of the diagnostic groups and the poor quality of some of the vitamin K data mean that small effects cannot be entirely ruled out, our analysis provides no convincing evidence that intramuscular vitamin K is associated with childhood leukaemia.

Case-control study of parental age, parity and socioeconomic level in relation to childhood cancers.

BACKGROUND: Parental ages, parity, and social class have been found in some studies to be associated with particular childhood cancers. Further investigation is warranted because of conflicting findings, biases, and the need to test specific hypotheses. METHODS: A case-control study was conducted (England and Wales, ages 0-14 years). Cases were ascertained from the National Registry of Childhood Tumours, and were born and diagnosed during 1968-1986. Birth record controls were matched 1:1 to cases on date of birth, sex and area. Information on variables of interest for both groups came from birth records. In all, 10 162 pairs could contribute to matched analyses. RESULTS: The odds ratio (OR) for retinoblastoma resulting from assumed new germ cell mutations among children of fathers aged > or =45 years was 3.0 (95% CI : 0.2-41.7). The risk of childhood acute lymphoblastic leukaemia (ALL) was significantly higher among children of older mothers and fathers, and significant trends with increasing mothers' (P < 0.001) and fathers' (P = 0.002) ages were found. There was a strong and significant protective effect of increasing parity on risk of childhood ALL. The adjusted OR for parity of > or =5 (versus 0) was 0.5 (95% CI : 0.3-0.8). Children in more deprived communities had a lower risk of ALL; but this was not significant after confounders were allowed for. There was no significant effect of social class based on parental occupation on ALL risk, but the numbers were small in those analyses. CONCLUSIONS: The associations between ALL and parental ages did not disappear when children with Down syndrome were excluded, suggesting an additional explanation beyond known links. The strong ALL association with parity may be because of an unknown environmental risk factor.

Constraining the Late Mesozoic and Early Tertiary Tectonic Evolution of Southern Mexico: Structure and Deformation History of the Tierra Caliente Region.

We analyze the structure and assess the deformation history of the Tierra Caliente Metamorphic Complex (TCMC) of southern Mexico, where Laramide accretion of exotic terranes is in debate. The TCMC consists of a south-plunging antiform fault that is bounded on both its eastern and western flanks. Tierra Caliente Metamorphic Complex rocks show at least two phases of compressional deformation. The first and most prominent records a mean tectonic transport direction of 068 degrees. This phase is responsible for east-verging asymmetrical folding and thrusting of both metamorphic and superjacent sedimentary rocks. The second phase has an average transport direction of 232 degrees and is restricted to the western portion of the TCMC. A third phase is responsible for normal faulting. Lack of discernible deformation before Late Cretaceous time indicates that the main deformation phase is coincident with Laramide orogenesis elsewhere in the North American Cordillera. The stratigraphy, structure, and deformational history of the TCMC do not require accretion of exotic terranes. We explain the Mesozoic tectonostratigraphic evolution of the TCMC in terms of deposition and deformation of Mesozoic volcanic and sedimentary strata over the attenuated continental crust of the North American plate.

All major regions of FtsK are required for resolution of chromosome dimers.

Resolution of chromosome dimers, by site-specific recombination between dif sites, is carried out in Escherichia coli by XerCD recombinase in association with the FtsK protein. We show here that a variety of altered FtsK polypeptides, consisting of the N-terminal (cell division) domain alone or with deletions in the proline-glutamine-rich part of the protein, or polypeptides consisting of the C-terminal domain alone are all unable to carry out dif recombination. Alteration of the putative nucleotide-binding site also abolishes the ability of FtsK to carry out recombination between dif sites.

Uranium-235 and childhood leukaemia around Greenham Common airfield.

There has been considerable publicity recently concerning the possible release of enriched uranium from the Greenham Common USAF base near Newbury in Berkshire. Evidence for the release relies on an internal report of the Atomic Weapons Research Establishment at Aldermaston, the authors of which postulated that it resulted from a fire in 1958 involving a B47 bomber standing on the runway. Their report contained a much publicised contour map of excess 235U levels estimated from the ratio of 235U to 238U in 26 evergreen leaf samples examined. The current concern of the inhabitants of Newbury centres mostly on the incidence of leukaemia, which was known beforehand to be slightly elevated in parts of West Berkshire, at least for young children. A number of cases have received considerable press publicity, with suggestions that their homes are located close to the base or the flight-path. The reports are, however, anecdotal and are not based on a complete register of cases. We have examined the evidence for this putative association by re-analysing the uranium data and determining the spatial relationship to the base of cases of childhood leukaemia diagnosed in the years 1966-87. We conclude that, although the excess uranium found has a non-random distribution, it does not support the pattern depicted by the contours and bears no relation to the incidence of childhood leukaemia for the period we examined. In any case, the increase in level of environmental radiation as a result of the putative release must be very small and is at variance with the reporting in some of the national press.