Subsequent cancers within 5 years from initial diagnosis of childhood cancer. Patterns and risks in the population of Great Britain.

BACKGROUND: Patterns and risks of subsequent primary tumours (SPTs) among long-term survivors of childhood cancer have been extensively described, but much less is known about early SPTs (ESPTs) occurring within 5 years after initial diagnosis. PROCEDURE: We carried out a population-based study of ESPTs following childhood cancer throughout Britain, using the National Registry of Childhood Tumours. The full study series comprised all ESPTs occurring among 56,620 children whose initial cancer diagnosis was in the period 1971-2010. Frequencies of ESPT were calculated for the entire cohort. For analyses of risk, follow-up began 92 days after initial diagnosis. RESULTS: ESPT developed in 0.4% of children overall, 0.52% of those initially diagnosed at age less than 1 year and 0.38% of those diagnosed at age 1-14 years. Standardised incidence ratio (SIR) was 7.7 (95% confidence interval [CI]: 6.7-8.9), overall 9.5 (95% CI: 7.1-12.5) for children initially diagnosed in 1981-1990 and 6.5-7.5 for those from earlier and later decades. SIR by type of first cancer ranged from 4.4 (95% CI: 1.8-9.1) for Wilms tumour to 13.1 (95% CI: 7.7-21.0) for non-Hodgkin lymphoma. SIR by type of ESPT ranged from 2.0 (95% CI: 1.0-3.4) for acute lymphoblastic leukaemia to 66.6 (95% CI: 52.3-83.6) for acute myeloid leukaemia. Predisposition syndromes were known to be implicated in 21% of children with ESPT and suspected in another 5%. CONCLUSIONS: This study provides an overview of the patterns and risks of ESPTs in a large population where many children received therapy that is still in widespread use. Further research will be needed to monitor and understand changes in risk as childhood cancer treatment continues to evolve.

Case-control study of paternal occupational exposures and childhood bone tumours and soft-tissue sarcomas in Great Britain, 1962-2010.

BACKGROUND: This nationwide study investigated associations between paternal occupational exposure and childhood bone tumours and soft- tissue sarcomas. METHODS: The UK National Registry of Childhood Tumours provided cases of childhood sarcomas born and diagnosed in Great Britain, 1962-2010. Control births, unaffected by childhood cancer, were matched on sex, birth period and birth registration sub-district. Fathers' occupations were assigned to one or more of 33 exposure groups and coded for occupational social class. RESULTS: We analysed 5,369 childhood sarcoma cases and 5380 controls. Total bone tumours, total soft-tissue sarcomas and the subgroups osteosarcoma, rhabdomyosarcoma and Ewing Sarcoma Family of Tumours (ESFT) were considered separately. Significant positive associations were seen between rhabdomyosarcoma and paternal exposure to EMFs (odds ratio = 1.67, CI = 1.22-2.28) and also for ESFT and textile dust (1.93, 1.01-3.63). There were putative protective effects on total bone tumours of paternal dermal exposure to hydrocarbons, metal, metal working or oil mists. CONCLUSIONS: Despite the large size and freedom from bias of this study, our results should be interpreted with caution. Many significance tests were undertaken, and chance findings are to be expected. Nevertheless, our finding of associations between ESFT and paternal exposure to textile dust may support related suggestions in the literature.

One-year outcomes of infants born with congenital diaphragmatic hernia: a national population cohort study.

OBJECTIVE: To report outcomes to 1 year, in infants born with congenital diaphragmatic hernia (CDH), explore factors associated with infant mortality and examine the relationship between surgical techniques and postoperative morbidity. DESIGN: Prospective national population cohort study. SETTING: Paediatric surgical centres in the UK and Ireland. METHOD: Data were collected to 1 year for infants with CDH live-born between 1 April 2009 to 30 September 2010. Factors associated with infant mortality are explored using logistic regression. Postoperative morbidity following patch versus primary closure, minimally invasive versus open surgery and biological versus synthetic patch material is described. Data are presented as n (%) and median (IQR). RESULTS: Overall known survival to 1 year was 75%, 95% CI 68% to 81% (138/184) and postoperative survival 93%, 95% CI 88% to 97% (138/148). Female sex, antenatal diagnosis, use of vasodilators or inotropes, being small for gestational age, patch repair and use of surfactant were all associated with infant death. Infants undergoing patch repair had a high incidence of postoperative chylothorax (11/54 vs 2/96 in infants undergoing primary closure) and a long length of hospital stay (41 days, IQR 24-68 vs 16 days, IQR 10-25 in primary closure group). Infants managed with synthetic patch material had a high incidence of chylothorax (11/34 vs 0/19 with biological patch). CONCLUSION: The majority of infant deaths in babies born with CDH occur before surgical correction. Female sex, being born small for gestational age, surfactant use, patch repair and receipt of cardiovascular support were associated with a higher risk of death. The optimum surgical approach, timing of operation and choice of patch material to achieve lowest morbidity warrants further evaluation.

Case-control study of paternal occupational exposures and childhood lymphoma in Great Britain, 1962-2010.

BACKGROUND: This nationwide study investigates associations between paternal occupational exposure and childhood lymphoma. METHODS: The UK National Registry of Childhood Tumours provided cases of childhood lymphoma born and diagnosed in Great Britain 1962-2010. Control births, unaffected by childhood cancer, were matched on sex, birth period and birth registration sub-district. Fathers' occupations were assigned to one or more of 33 exposure groups and also coded for occupational social class. RESULTS: We analysed 5033 childhood lymphoma cases and 4990 controls. Total lymphoma and the subgroups Hodgkin, Burkitt and non-Hodgkin lymphoma were considered separately. No one exposure was significantly associated with increased risk within all subgroups and for total lymphoma. However, exposure to "ceramics and glass" was significantly associated with increased risk of total lymphoma, Hodgkin and non-Hodgkin lymphoma. Paternal lead exposure was associated with Burkitt lymphoma and exposure to metal fumes was associated with Hodgkin lymphoma. CONCLUSIONS: This study provides no support for previous suggestions of an association between childhood lymphoma and paternal occupational exposure to pesticides, solvents/hydrocarbons or infections potentially transmitted by father's social contacts. An association with exposure to "ceramics and glass" was noted for the two major lymphoma subtypes together comprising 80% of total lymphoma.

Childhood cancer research in oxford III: The work of CCRG on ionising radiation.

BACKGROUND: High doses of ionising radiation are a known cause of childhood cancer and great public and professional interest attaches to possible links between childhood cancer and lower doses, particularly of man-made radiation. This paper describes work done by the Childhood Cancer Research Group (CCRG) on this topic METHODS: Most UK investigations have made use of the National Registry of Childhood Tumours and associated controls. Epidemiological investigations have included national incidence and mortality analyses, geographical investigations, record linkage and case-control studies. Dosimetric studies use biokinetic and dosimetric modelling. RESULTS: This paper reviews the work of the CCRG on the association between exposure to ionising radiation and childhood cancer, 1975-2014. CONCLUSION: The work of CCRG has been influential in developing understanding of the causes of 'clusters' of childhood cancer and the risks arising from exposure to ionising radiation both natural and man-made. Some clusters around nuclear installations have certainly been observed, but ionising radiation does not seem to be a plausible cause. The group's work has also been instrumental in discounting the hypothesis that paternal preconception irradiation was a cause of childhood cancers and has demonstrated an increased leukaemia risk for children exposed to higher levels of natural gamma-ray radiation.

Childhood cancer research in Oxford II: The Childhood Cancer Research Group.

BACKGROUND: We summarise the work of the Childhood Cancer Research Group, particularly in relation to the UK National Registry of Childhood Tumours (NRCT). METHODS: The Group was responsible for setting up and maintaining the NRCT. This registry was based on notifications from regional cancer registries, specialist children's tumour registries, paediatric oncologists and clinical trials organisers. For a large sample of cases, data on controls matched by date and place of birth were also collected. RESULTS: Significant achievements of the Group include: studies of aetiology and of genetic epidemiology; proposals for, and participation in, international comparative studies of these diseases and on a classification system specifically for childhood cancer; the initial development of, and major contributions to, follow-up studies of the health of long-term survivors; the enhancement of cancer registration records by the addition of clinical data and of birth records. The Group made substantial contributions to the UK government's Committee on Medical Aspects of Radiation in the Environment. CONCLUSION: An important part of the ethos of the Group was to work in collaboration with many other organisations and individuals, both nationally and internationally: many of the Group's achievements described here were the result of such collaborations.

Risks of ovarian, breast, and corpus uteri cancer in women treated with assisted reproductive technology in Great Britain, 1991-2010: data linkage study including 2.2 million person years of observation.

OBJECTIVE: To investigate the risks of ovarian, breast, and corpus uteri cancer in women who have had assisted reproduction. DESIGN: Large, population based, data linkage cohort study. SETTING AND PARTICIPANTS: All women who had assisted reproduction in Great Britain, 1991-2010, as recorded by the Human Fertilisation and Embryology Authority (HFEA). INTERVENTIONS: HFEA fertility records for cohort members were linked to national cancer registrations. MAIN OUTCOME MEASURES: Observed first diagnosis of ovarian, breast, and corpus uteri cancer in cohort members were compared with age, sex, and period specific expectation. Standardised incidence ratios (SIRs) were calculated by use of age, sex, and period specific national incidence rates. RESULTS: 255 786 women contributed 2 257 789 person years' follow-up. No significant increased risk of corpus uteri cancer (164 cancers observed v 146.9 cancers expected; SIR 1.12, 95% confidence interval 0.95 to 1.30) was found during an average of 8.8 years' follow-up. This study found no significantly increased risks of breast cancer overall (2578 v 2641.2; SIR 0.98, 0.94 to 1.01) or invasive breast cancer (2272 v 2371.4; SIR 0.96, 0.92 to 1.00). An increased risk of in situ breast cancer (291 v 253.5; SIR 1.15, 1.02 to 1.29; absolute excess risk (AER) 1.7 cases per 100 000 person years, 95% confidence interval 0.2 to 3.2) was detected, associated with an increasing number of treatment cycles (P=0.03). There was an increased risk of ovarian cancer (405 v 291.82; SIR 1.39, 1.26 to 1.53; AER 5.0 cases per 100 000 person years, 3.3 to 6.9), both invasive (264 v 188.1; SIR 1.40, 1.24 to 1.58; AER 3.4 cases per 100 000 person years, 2.0 to 4.9) and borderline (141 v 103.7; SIR 1.36, 1.15 to 1.60; AER 1.7 cases per 100 000 person years, 0.7 to 2.8). Increased risks of ovarian tumours were limited to women with endometriosis, low parity, or both. This study found no increased risk of any ovarian tumour in women treated because of only male factor or unexplained infertility. CONCLUSIONS: No increased risk of corpus uteri or invasive breast cancer was detected in women who had had assisted reproduction, but increased risks of in situ breast cancer and invasive and borderline ovarian tumours were found in this study. Our results suggest that ovarian tumour risks could be due to patient characteristics, rather than assisted reproduction itself, although both surveillance bias and the effect of treatment are also possibilities. Ongoing monitoring of this population is essential.

Proximity to overhead power lines and childhood leukaemia: an international pooled analysis.

BACKGROUND: Although studies have consistently found an association between childhood leukaemia risk and magnetic fields, the associations between childhood leukaemia and distance to overhead power lines have been inconsistent. We pooled data from multiple studies to assess the association with distance and evaluate whether it is due to magnetic fields or other factors associated with distance from lines. METHODS: We present a pooled analysis combining individual-level data (29,049 cases and 68,231 controls) from 11 record-based studies. RESULTS: There was no material association between childhood leukaemia and distance to nearest overhead power line of any voltage. Among children living < 50 m from 200 + kV power lines, the adjusted odds ratio for childhood leukaemia was 1.33 (95% CI: 0.92-1.93). The odds ratio was higher among children diagnosed before age 5 years. There was no association with calculated magnetic fields. Odds ratios remained unchanged with adjustment for potential confounders. CONCLUSIONS: In this first comprehensive pooled analysis of childhood leukaemia and distance to power lines, we found a small and imprecise risk for residences < 50 m of 200 + kV lines that was not explained by high magnetic fields. Reasons for the increased risk, found in this and many other studies, remains to be elucidated.

Early population-based outcomes of infants born with congenital diaphragmatic hernia.

PURPOSE: This study aims to describe short-term outcomes of live-born infants with congenital diaphragmatic hernia (CDH) and to identify prognostic factors associated with early mortality. DESIGN: A prospective population cohort study was undertaken between April 2009 and September 2010, collecting data on live-born infants with CDH from all 28 paediatric surgical centres in the UK and Ireland using an established surgical surveillance system. Management and outcomes are described. Prognostic factors associated with death before surgery are explored. RESULTS: Two hundred and nineteen live-born infants with CDH were reported within the data collection period. There were 1.5 times more boys than girls (n=133, 61%). Thirty-five infants (16%) died without an operation. This adverse outcome was associated with female sex (adjusted OR (aOR) 3.96, 95% CI 1.66 to 9.47), prenatal diagnosis (aOR 4.99, 95% CI 1.31 to 18.98), and the need for physiological support in the form of inotropes (aOR 9.96, 95% CI 1.19 to 83.25) or pulmonary vasodilators (aOR 4.09, 95% CI 1.53 to 10.93). Significant variation in practice existed among centres, and some therapies potentially detrimental to infant outcomes were used, including pulmonary surfactant in 45 antenatally diagnosed infants (34%). Utilisation of extracorporeal membrane oxygenation was very low compared with published international studies (n=9/219, 4%). Postoperative 30-day survival was 98% for 182 infants with CDH who were adequately physiologically stabilised and underwent surgery. CONCLUSION: This is the first British Isles population-based study reporting outcome metrics for infants born with CDH. 16% of babies did not survive to undergo surgery. Factors associated with poor outcome included female sex and prenatal diagnosis. Early postoperative survival in those who underwent surgical repair was excellent.

Variation with socioeconomic status of indoor radon levels in Great Britain: The less affluent have less radon.

We demonstrate a strong correlation between domestic radon levels and socio-economic status (SES) in Great Britain, so that radon levels in homes of people with lower SES are, on average, only about two thirds of those of the more affluent. This trend is apparent using small area measures of SES and also using individual social classes. The reasons for these differences are not known with certainty, but may be connected with greater underpressure in warmer and better-sealed dwellings. There is also a variation of indoor radon levels with the design of the house (detached, terraced, etc.). In part this is probably an effect of SES, but it appears to have other causes as well. Data from other countries are also reviewed, and broadly similar effects seen in the United States for SES, and in other European countries for detached vs other types of housing. Because of correlations with smoking, this tendency for the lower SES groups to experience lower radon levels may underlie the negative association between radon levels and lung cancer rates in a well-known ecological study based on US Counties. Those conducting epidemiological studies of radon should be alert for this effect and control adequately for SES.

Infant birthweight and risk of childhood cancer: international population-based case control studies of 40 000 cases.

BACKGROUND: High birthweight is an established risk factor for childhood leukaemia. Its association with other childhood cancers is less clear, with studies hampered by low case numbers. METHODS: We used two large independent datasets to explore risk associations between birthweight and all subtypes of childhood cancer. Data for 16 554 cases and 53 716 controls were obtained by linkage of birth to cancer registration records across five US states, and 23 772 cases and 33 206 controls were obtained from the UK National Registry of Childhood Tumours. US, but not UK, data were adjusted for gestational age, birth order, plurality, and maternal age and race/ethnicity. RESULTS: Risk associations were found between birthweight and several childhood cancers, with strikingly similar results between datasets. Total cancer risk increased linearly with each 0.5 kg increase in birthweight in both the US [odds ratio 1.06 (95% confidence interval 1.04, 1.08)] and UK [1.06 (1.05, 1.08)] datasets. Risk was strongest for leukaemia [USA: 1.10 (1.06, 1.13), UK: 1.07 (1.04, 1.10)], tumours of the central nervous system [USA: 1.05 (1.01, 1.08), UK: 1.07 (1.04, 1.10)], renal tumours [USA: 1.17 (1.10, 1.24), UK: 1.12 (1.06, 1.19)] and soft tissue sarcomas [USA: 1.12 (1.05, 1.20), UK: 1.07 (1.00, 1.13)]. In contrast, increasing birthweight decreased the risk of hepatic tumours [USA: 0.77 (0.69, 0.85), UK: 0.79 (0.71, 0.89) per 0.5 kg increase]. Associations were also observed between high birthweight and risk of neuroblastoma, lymphomas, germ cell tumours and malignant melanomas. For some cancer subtypes, risk associations with birthweight were non-linear. We observed no association between birthweight and risk of retinoblastoma or bone tumours. CONCLUSIONS: Approximately half of all childhood cancers exhibit associations with birthweight. The apparent independence from other factors indicates the importance of intrauterine growth regulation in the aetiology of these diseases.

Cancer risk among children born after assisted conception.

BACKGROUND: Accurate population-based data are needed on the incidence of cancer in children born after assisted conception. METHODS: We linked data on all children born in Britain between 1992 and 2008 after assisted conception without donor involvement with data from the United Kingdom National Registry of Childhood Tumours to determine the number of children in whom cancer developed before 15 years of age. Cohort cancer rates were compared with population-based rates in Britain over the same period, with stratification for potential mediating and moderating factors, including sex, age at diagnosis, birth weight, singleton versus multiple birth, parity, parental age, type of assisted conception, and cause of parental infertility. RESULTS: The cohort consisted of 106,013 children born after assisted conception (700,705 person-years of observation). The average duration of follow-up was 6.6 years. Overall, 108 cancers were identified, as compared with 109.7 expected cancers (standardized incidence ratio, 0.98; 95% confidence interval [CI], 0.81 to 1.19; P=0.87). Assisted conception was not associated with an increased risk of leukemia, neuroblastoma, retinoblastoma, central nervous system tumors, or renal or germ-cell tumors. It was associated with an increased risk of hepatoblastoma (standardized incidence ratio, 3.64; 95% CI, 1.34 to 7.93; P=0.02; absolute excess risk, 6.21 cases per 1 million person-years) and rhabdomyosarcoma (standardized incidence ratio, 2.62; 95% CI, 1.26 to 4.82; P=0.02; absolute excess risk, 8.82 cases per 1 million person-years), with hepatoblastoma developing in 6 children and rhabdomyosarcoma in 10 children. The excess risk of hepatoblastoma was associated with low birth weight. CONCLUSIONS: There was no increase in the overall risk of cancer among British children born after assisted conception during the 17-year study period. Increased risks of hepatoblastoma and rhabdomyosarcoma were detected, but the absolute risks were small. (Funded by Cancer Research UK and others.).

Familial aggregation of childhood and adult cancer in the Utah genealogy.

A small proportion of childhood cancer is attributable to known hereditary syndromes, but whether there is any familial component to the remainder remains uncertain. We explored familial aggregation of cancer in a population-based case-control study using genealogical record linkage and designed to overcome limitations of previous studies. Subjects were selected from the Utah Population Database. We compared risk of cancer in adult first-degree relatives of children who were diagnosed with cancer with the risk in relatives of children who had not had a cancer diagnosed. We identified 1,894 childhood cancer cases and 3,788 controls; 7,467 relatives of cases and 14,498 relatives of controls were included in the analysis. Relatives of children with cancer had a higher risk of cancer in adulthood than relatives of children without cancer [odds ratio (OR) 1.31, 95% confidence interval (CI) 1.11-1.56]; this was restricted to mothers and siblings and was not evident in fathers. Familial aggregation appeared stronger among relatives of cases diagnosed before 5 years of age (OR 1.48, 95% CI 1.13-1.95) than among relatives of cases who were older when diagnosed (OR 1.22, 95% CI 0.98-1.51). These findings provide evidence of a generalized excess of cancer in the mothers and siblings of children with cancer. The tendency for risk to be higher in the relatives of children who were younger at cancer diagnosis should be investigated in other large data sets. The excesses of thyroid cancer in parents of children with cancer and of any cancer in relatives of children with leukemia merit further investigation.

Intrauterine growth and childhood leukemia and lymphoma risk.

Leukemias and lymphomas account for nearly half of all childhood cancers. Although there have been major advances in the treatment of these diseases, what causes them remains largely unknown. There is strong evidence to suggest that leukemia originates in utero, and early life factors may play a role in its etiology. A series of reports illustrate a convincing link between the rate of intrauterine growth and the risk of childhood leukemia. Some studies suggest that this risk relationship also extends to non-Hodgkin lymphoma in children, although, overall, the association with childhood lymphoma is less clear. This review discusses the intricacies of these risk relationships and explores potential explanations of how the rate of fetal growth may influence cancer risk.

Immunophenotype and cytogenetic characteristics in the relationship between birth weight and childhood leukemia.

BACKGROUND: High birth weight increases the risk of childhood acute lymphoid leukemia (ALL) through unknown mechanisms. Whether this risk is specific to ALL subtypes is unknown, and low case numbers have prevented investigation of the rarer leukemias. Here we address these associations using a large population-based dataset. PROCEDURE: Using the National Registry of Childhood Tumors, birth weights of 7,826 leukemia cases, defined by immunophenotype and cytogenetic subgroup, were compared with those of 10,785 controls born in England and Wales between 1980 and 2007. RESULTS: The risk for overall leukemia increases 7% with each 0.5 kg increase in birth weight (OR 1.07, 95%CI 1.04-1.10). This risk is limited to the lymphoid leukemias (OR 1.08, 95%CI 1.05-1.12) diagnosed between 1 and 9 years of age. Analysis by cytogenetic feature reveals that there appears to be association with specific chromosomal abnormality: the risk of tumors with high hyperdiploid karyotypes increases 12% per 0.5 kg increase in birth weight (OR 1.12, 95%CI 1.05-1.20), and t(1;19) tumors show an increased risk of 41% per 0.5 kg increase (OR 1.41, 95%CI 1.09-1.84). The risk of acute myeloid leukemia is elevated in high and low birth weight babies. There is no significant risk relationship to other leukemias or myeloproliferative diseases. CONCLUSIONS: Birth weight is a risk factor for ALL and AML. Other subtypes of the disease are not significantly affected. There appears to be association with specific chromosomal abnormality, which may aid our understanding of the development of childhood leukemia in utero.