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.

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.

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.

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.

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.

Calculation of sample size in trials of screening for early diagnosis of disease.

The calculation of the sample sizes required for trials of screening for disease with the aim of reducing mortality involves the estimation of both the mortality in the control group at intervals after the start of the trial, and the potential reduction due to screening. Since at the start of a screening trial the population is selected to be free of the disease in question, the mortality rate in the control group will differ from that in the general population. A method of estimating this mortality rate using published incidence and survival data is described. The expected reduction in mortality due to screening depends both on the number of, and intervals between, screens and on parameters concerning the natural history of the disease; the means by which these parameters can be estimated are discussed. A trial of screening for colorectal cancer by a faecal occult blood test is used to illustrate these calculations.

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.

Apparent association between benzene and childhood leukaemia: methodological doubts concerning a report by Knox.

A recent study by Knox concludes that cases and "clusters" of two or more cases of childhood leukaemia and non-Hodgkin's lymphoma occur closer to many kinds of industrial installation than to supposedly comparable control locations. It is argued that these findings could be largely or entirely artefactual, the apparent differences arising out of the inappropriateness of the control data. Knox used randomly selected postcode units as controls, a procedure that leads to the comparison of individuals located in areas with typically quite different population densities from those for the cases. The resulting potential for bias is explored and the arguments are exemplified by analysing household data based on postcodes.

Occupations of fathers of children dying from neoplasms.

It has been suggested in a number of recent reports that there is a possible relationship between parental occupation and malignant disease in children. A proportional mortality analysis relating deaths among children in England and Wales in 1959-63 and 1970-72 to occupation of father as stated on the child's death certificate has not shown any convincing evidence for such associations. Earlier papers published on the subject are reviewed. Although there is some slight evidence for associations between childhood tumours and certain parental occupations there is little consistency between the results reported by different authors. A previously reported association between higher social class and deaths from neoplasms was found also in this study. The explanation for this finding is unknown, and it remains possible that it is an artefact.

The Inter-Regional Epidemiological Study of Childhood Cancer (IRESCC): past medical history in children with cancer.

The Inter-Regional Epidemiological Study of Childhood Cancer (IRESCC) collected interview and medical information relating to the child's past medical experiences from parents of 555 children diagnosed with cancer and parents of 1110 unaffected matched controls. No significant associations emerged overall for ante-natal care, place and mode of delivery, length of gestation, birth weight, condition at birth, special care, neonatal procedures or breast-feeding. Few risk factors relating to previous illnesses and medication were found, although increasing numbers of illnesses appeared to be associated with an increased risk of childhood cancer, particularly acute lymphoblastic leukaemia. A highly significant excess of case children had not been immunised (p = 0.005). In general, these results indicate that past medical experiences have little influence on the development of cancer in children.

Retinoblastoma in Great Britain 1969-80: incidence, treatment, and survival.

Patients with retinoblastoma diagnosed from 1969 to 1980 have been followed up for periods of up to 17 years. Data from a previous study of patients diagnosed from 1962 to 1968 have been included for analysis of incidence and second primary tumours, and for study of trends in treatment. The registration rate in Britain (which may be about 10% less than the true incidence) is about one in 23,000 live births, approximately 40% of cases being known to be genetic. There is no apparent trend in incidence during the period covered by these two studies. The three-year survival rate in 88%. Patients with bilateral tumours have a better survival rate than those with unilateral tumours for the first few years, but their long-term survival rate is worse because of later deaths from ectopic intracranial retinoblastoma or second primary neoplasms. Older children tend to have a worse prognosis, which is related to the fact that their tumours are diagnosed at a more advanced stage. There is a significantly higher survival rate for boys than for girls; this is partly accounted for by difference in age and stage at diagnosis between the sexes. Children referred to units specialising in the treatment of retinoblastoma have a higher three-year survival rate than those treated at other hospitals. Comparing methods of treatment between the periods 1962-8 and 1969-80, we find there has been a trend towards more conservative treatment. The use of chemotherapy is now usually reserved for recurrences and metastases and for palliative treatment in terminal retinoblastoma.

The risk of diagnostic radiation of the newborn.

The amount of diagnostic radiation received by neonates at a large maternity hospital in 1982 was calculated. The risk of inducing neoplasia is unlikely to be greater than one in 280,000 for each radiograph of chest or abdomen. Provided that the exposure of the newborn to radiation at the John Radcliffe Hospital is typical of the rest of the country, and excluding cardiac catheterisation and computed tomography, we estimate that at most one to two cases of malignant disease per year may be caused by diagnostic radiation in the United Kingdom. Genetic risks appear to be negligible. The risks of not using radiography in newborn patients outweigh the risks of inducing malignant or genetic disease.

An overview of reports and current research concerning childhood leukaemia and cancer around nuclear installations in the UK.

Studies around UK nuclear installations suggest that it is possible that the incidence of leukaemia in young persons may be increased in the vicinity of such installations. However, the results of these studies are inconsistent and the cause or causes of the apparent increases are unknown; they may be at least in part attributable to chance variations in incidence, to selection factors, or to variations in completeness of recording. The cluster in Seascale, the village closest to the Sellafield reprocessing plant, may be the result of germ cell mutations in the fathers of the affected children.

Case-control studies of relation between childhood cancer and neonatal vitamin K administration.

OBJECTIVE: To investigate the possible link between neonatal administration of intramuscular vitamin K and childhood cancer. DESIGN: Matched case-control study. SETTING: Selected large maternity units in England and Wales. SUBJECTS: Children with cancer born 1968-85, diagnosed 1969-86; controls matched for sex, month of birth, and hospital of birth. MAIN EXPOSURE MEASURES: Neonatal administration of vitamin K, length of gestation, birth weight, type of delivery, admission to special care baby unit. RESULTS: After exclusion of cases with missing notes or unknown hospital vitamin K policy, 597 cases and matched controls were studied. Written records on the use of vitamin K were available for only about 40% of these, and to avoid possible bias from selective recording it was assumed that the stated hospital policy was followed. The association between cancer generally and intramuscular vitamin K was of borderline significance (odds ratio 1.44, P = 0.05); the association was strongest for leukaemia. There was, however, also an effect of abnormal delivery, which could explain some of the findings. CONCLUSIONS: The lack of consistency between the various studies so far published, including this one, and the low relative risks found in most of them suggest that the risk, if any, attributable to the use of vitamin K cannot be large, but the possibility that there is some risk cannot be excluded. A comparison of the predicted consequences of various policies shows that even a 10% increase would imply that prophylaxis using the commonly recommended 1 mg intramuscular dose should be restricted to babies at particularly high risk of vitamin K deficiency bleeding; alternatively a lower dose might be given to a larger proportion of those at risk.

Ecological studies of relation between hospital policies on neonatal vitamin K administration and subsequent occurrence of childhood cancer.

OBJECTIVE: To investigate the possible link between neonatal administration of intramuscular vitamin K and childhood cancer. DESIGN: Ecological studies comparing incidence of cancer in groups of children classified by the vitamin K policy in operation at their hospital of birth. SETTING: Selected large maternity units in England, Scotland, and Wales. SUBJECTS: Children born in these units in varying periods between 1966 and 1991. MAIN OUTCOME MEASURES: Cancer occurring among these children before age 15 years identified by using the National Registry of Childhood Tumours. Ratios of observed to expected numbers of these conditions calculated for hospitals where the policy was to give all babies intramuscular vitamin K (non-selective) and where the policy was to use this treatment only for a selected minority of babies at increased risk of vitamin K deficiency bleeding (selective). RESULTS: These ratios were calculated for children born in 94 hospitals with varying vitamin K policies. A raised risk was occasionally associated with vitamin K, but the overall results were not significant, and there was no evidence to support the previously suggested doubling of the risk of childhood cancer. CONCLUSIONS: On the basis of the results reported here it is unlikely that there is a greatly increased risk of childhood cancer attributable to intramuscular vitamin K given to newborns, if indeed there is any.

Distribution of childhood leukaemias and non-Hodgkin's lymphomas near nuclear installations in England and Wales.

OBJECTIVE: To examine the relation between the risk of childhood leukaemia and non-Hodgkin's lymphoma and proximity of residence to nuclear installations in England and Wales. DESIGN: Observed and expected numbers of cases were calculated and analysed by standard methods based on ratios of observed to expected counts and by a new statistical test, the linear risk score test, based on ranks and designed to be sensitive to excess incidence in close proximity to a putative source of risk. SETTING: Electoral wards within 25 km of 23 nuclear installations and six control sites that had been investigated for suitability for generating stations but never used. SUBJECTS: Children below age 15 in England and Wales, 1966-87. MAIN OUTCOME MEASURE: Registration of any leukaemia or non-Hodgkin's lymphoma. RESULTS: In none of the 25 km circles around the installations was the incidence ratio significantly greater than 1.0. The only significant results for the linear risk score test were for Sellafield (P = 0.00002) and Burghfield (P = 0.031). The circles for Aldermaston and Burghfield overlap; the incidence ratio was 1.10 in each. One of the control sites gave a significant linear risk score test result (P = 0.020). All the tests carried out were one sided with P values estimated by simulation. CONCLUSION: There is no evidence of a general increase of childhood leukaemia or non-Hodgkin's lymphoma around nuclear installations. Apart from Sellafield, the evidence for distance related risk is very weak.