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.

Survival from teenage and young adult cancer in Northern England, 1968-2008.

BACKGROUND: Although cancer is relatively rare in teenagers and young adults (TYAs) aged 15-24 years, it is a major cause of death in this age group. This study investigated survival trends in TYA cancer diagnosed in Northern England, 1968-2008. METHODS: Five-year survival was analyzed using Kaplan-Meier estimation for four successive time periods. Cox regression analysis was used to investigate associations with demographic factors. RESULTS: The study included 2,987 cases (1,634 males, 1,353 females). Five-year survival for all patients with cancer improved greatly from 46% in 1968-1977 to 84% in 1998-2008 (P < 0.001), for patients with leukemia from 2% to 71% (P < 0.001), lymphoma from 66% to 86% (P < 0.001), central nervous system tumors from 53% to 84% (P < 0.001), bone tumors from 29% to 72% (P < 0.001), germ cell tumors from 39% to 94% (P < 0.001), melanoma and skin cancer from 64% to 100% (P < 0.001), and carcinomas from 48% to 80% (P < 0.001). Cox analysis showed that for all patients with cancer, survival was better for females than males (HR = 0.83; 95% CI 0.74-0.94, P < 0.001), for patients aged 20-24 years compared with those aged 15-19 years (HR = 0.84; 95% CI 0.75-0.94, P = 0.002), but survival was worse for patients who resided in more deprived areas (HR = 1.06; 95% CI 1.01-1.11, P = 0.025). CONCLUSION: There have been large improvements in TYA cancer survival in Northern England over the last four decades. Future work should determine factors that could lead to even better survival, including possible links with delayed diagnosis.

Development of a database of organ doses for paediatric and young adult CT scans in the United Kingdom.

Despite great potential benefits, there are concerns about the possible harm from medical imaging including the risk of radiation-related cancer. There are particular concerns about computed tomography (CT) scans in children because both radiation dose and sensitivity to radiation for children are typically higher than for adults undergoing equivalent procedures. As direct empirical data on the cancer risks from CT scans are lacking, the authors are conducting a retrospective cohort study of over 240,000 children in the UK who underwent CT scans. The main objective of the study is to quantify the magnitude of the cancer risk in relation to the radiation dose from CT scans. In this paper, the methods used to estimate typical organ-specific doses delivered by CT scans to children are described. An organ dose database from Monte Carlo radiation transport-based computer simulations using a series of computational human phantoms from newborn to adults for both male and female was established. Organ doses vary with patient size and sex, examination types and CT technical settings. Therefore, information on patient age, sex and examination type from electronic radiology information systems and technical settings obtained from two national surveys in the UK were used to estimate radiation dose. Absorbed doses to the brain, thyroid, breast and red bone marrow were calculated for reference male and female individuals with the ages of newborns, 1, 5, 10, 15 and 20 y for a total of 17 different scan types in the pre- and post-2001 time periods. In general, estimated organ doses were slightly higher for females than males which might be attributed to the smaller body size of the females. The younger children received higher doses in pre-2001 period when adult CT settings were typically used for children. Paediatric-specific adjustments were assumed to be used more frequently after 2001, since then radiation doses to children have often been smaller than those to adults. The database here is the first detailed organ-specific paediatric CT scan database for the UK. As well as forming the basis for the UK study, the results and description of the methods will also serve as a key resource for paediatric CT scan studies currently underway in other countries.

Survival from childhood cancer in northern England, 1968-2005.

BACKGROUND: Cancer is the second most common cause of death in children in the developed world. The study investigated patterns and trends in survival from childhood cancer in patients from northern England diagnosed 1968-2005. METHODS: Five-year survival was analysed using Kaplan-Meier estimation for four successive time periods. Cox regression analysis was used to explore associations with age and demographic factors. RESULTS: The study included 2958 cases (1659 males and 1299 females). Five-year survival for all cancers improved significantly from 39% in 1968-1977 to 79% in 1998-2005 (P<0.001). Five-year survival for leukaemia increased from 24% to 81% (P<0.001), lymphoma from 46% to 87% (P<0.001), central nervous system tumours from 43% to 73% (P<0.001), bone tumours from 21% to 75% (P<0.001), soft tissue sarcoma from 30% to 58% (P<0.001) and germ cell tumours from 59% to 97% (P<0.001). Survival was worse for cases of acute lymphoblastic leukaemia (P<0.001) and astrocytoma (P<0.001) aged 10-14 years compared with 0-4-year olds. CONCLUSION: There were marked improvements in survival over a 38-year time span. Future work should examine factors that could influence further improvement in survival such as diagnosis delays.

Patterns of care and survival for patients aged under 40 years with bone sarcoma in Britain, 1980-1994.

The purpose of the study was to calculate population-based survival rates for osteosarcoma (OS) and Ewing's sarcoma (ES) in Great Britain during 1980-1994, determine proportions of patients treated at specialist centres or entered in national and international clinical trials, and investigate effects of these factors on survival. Data on a population-based series of 1349 patients with OS and 849 with ES were compiled from regional and national cancer registries, UK Children's Cancer Study Group, regional bone tumour registries and clinical trials. Follow-up was through population registers. Survival was analysed by actuarial analysis with log-rank tests and by Cox's proportional hazards analysis. Five-year survival rates during 1980-1984, 1985-1989 and 1990-1994 were 42% (95% CI: 37, 46), 54% (95% CI: 50, 59) and 53% (95% CI: 48, 57), respectively, for OS and 31% (95% CI: 26, 37), 46% (95% CI: 40, 51) and 51% (95% CI: 45, 57) for ES. Proportions of patients treated at a supraregional bone tumour centre or a paediatric oncology centre in the three quinquennia were 36, 56 and 67% for OS and 41, 60 and 69% for ES. In 1983-1992, 48% of OS patients were entered in a national trial; for ES, 27% were entered in 1980-1986 and 54% in 1987-1994. Survival was similar for trial and nontrial patients with OS. For ES, trial patients had consistently higher 5-year survival than nontrial patients: 1980-1986, 42 vs 30%; 1987-1992, 59 vs 42%; 1993-1994, 54 vs 43%. During 1985-1994, patients with OS or ES whose main treatment centre was a nonteaching hospital had lower survival rates. In multivariate analyses of patients diagnosed during 1985-1994 that also included age, sex, primary site, surgical treatment centre, the results relating to main treatment centre for both OS and ES retained significance but the survival advantage of trial entry for ES became nonsignificant. For both OS and ES diagnosed since 1985, patients whose main treatment centre was a nonspecialist hospital had a lower survival rate.

Analysis of the binding of monoclonal and polyclonal antibodies to the glycoproteins of antigenic variants of human respiratory syncytial virus by surface plasmon resonance.

The surface glycoproteins of human respiratory syncytial virus (hRSV), F and G, are the major protective antigens of the virus. Both are antigenically variable, although to different degrees, but the role of antigenic variation in the pathogenesis of hRSV disease has not been fully evaluated. Assessment of immunity to different virus strains is difficult with conventional antibody assays where differing properties of the virus antigens, other than antigenicity, may influence the outcome of the assay. Here, we have developed BIAcore surface plasmon resonance based assays for antibodies to the glycoproteins of hRSV which allow valid comparison of antibody titres against multiple hRSV strains. Glycoproteins from a number of lineages of hRSV sub-group A were captured from lysates of infected cells onto the dextran coated surface of a BIAcore sensor chip via primary monoclonal antibodies (MAbs) to conserved epitopes. For the G glycoprotein, primary MAbs were conjugated directly to the dextran of the sensor chip via free amide groups. For the F glycoprotein, direct conjugation was found to inactivate the MAb and primary MAb was immobilised on the chip via rabbit anti-mouse Fc antibody fragments in an indirect system. Using monoclonal antibodies as secondary MAbs, the glycoproteins in both systems were shown to exhibit a sub-set of conserved and variable epitopes, with some epitopes of both sorts being unavailable, presumably blocked by the primary antibody. Polyclonal anti-hRSV sera raised against viruses of different genotype bound equally to both F and G glycoproteins from homologous and heterologous viruses suggesting that mice immunised systemically with lysates of cells infected with recent isolates of virus do not respond well to genotype specific epitopes.

Doxorubicin and cisplatin chemotherapy in high-grade spindle cell sarcomas of the bone, other than osteosarcoma or malignant fibrous histiocytoma: a European Osteosarcoma Intergroup Study.

There are limited data that define the role of chemotherapy in the treatment of high-grade spindle cell sarcomas of bone, other than osteosarcoma or malignant fibrous histiocytoma (MFH-B). This prospective study evaluates the effect of doxorubicin and cisplatin on these tumours. Thirty-seven patients, age 65 years, with spindle cell sarcoma of bone, except osteosarcoma or MFH-B, were included. Chemotherapy consisted of doxorubicin and cisplatin every 3 weeks for six cycles. Resection was performed after three cycles. In 15 patients with metastases, response assessment showed three complete responses (CR), four stable disease (SD), five progression; three were not evaluable. Median time to progression was 30 months (95% Confidence Interval (CI), 8-51 months) for the operable non-metastatic patients; median survival 41 months (95% CI, 16-82 months). Median time to progression in the metastatic group was 10 months (95% CI, 0-18 months) and median survival was 14 months (95% CI, 4-45 months). This study suggests a limited role for doxorubicin and cisplatin in metastatic high-grade spindle cell sarcoma of bone, other than osteosarcoma or MFH-B cases.

Detection of human respiratory syncytial virus genotype specific antibody responses in infants.

Infection and reinfection of infants with human respiratory syncytial virus (HRSV) occur despite the presence of serum anti-viral glycoprotein antibodies similar to those, which afford protection in animal models of infection. Antigenic variation of the viral glycoproteins between different genotypes of the virus which co-circulate in the population may contribute to the ability of the virus to escape from antibody-mediated protection. In this study, we have investigated whether human infants infected with HRSV produced antibody responses recognising the antigenic differences between different contemporary genotypes of virus. Acute and convalescent sera from 26 infants were analysed for antibody responses to the glycoproteins of the virus isolated from their respiratory tract and to representative viruses of homologous and heterologous genotypes. All infants developed antibodies with similar reactivity for viruses of all contemporary isolates and genotypes when measured in an immunofluorescence assay against unfixed virus infected cells. However, when antibody responses to the individual glycoproteins were measured in a surace plasmon resonance (SPR) assay, although all infants developed genotype cross-reactive antibodies to the F glycoprotein, anti-G antibodies were detectable in only half of the infants and in all cases these were genotype specific. Possession of no or only genotype specific antibodies to the G glycoprotein may contribute to the susceptibility of infants to reinfection. In both assays, reactivity of anti-glycoprotein antibodies with the sub-group A archetypal strain, A2, was markedly lower than with any contemporary virus tested indicating that this strain alone is unsuitable for accurate assessment of infant antibody responses. .

Establishing long-term survival and cure in young patients with Ewing's sarcoma.

This paper investigates the potential for long-term survivorship for young patients diagnosed with Ewing's sarcoma. Data are examined from two successive UKCCSG Ewing's Tumour studies (ET-1 and ET-2). Patients have been followed for up to 20 years. These studies had suggested that better 5-year survival with ET-2 over the earlier ET-1 was achieved by replacing cyclophosphamide by ifosfamide and increasing the dose of doxorubicin in a four-drug chemotherapy regimen. The updated hazard ratio, stratified for metastatic status at diagnosis, of 0.39 (95% confidence interval 0.12-0.61) confirmed the advantage of the ET-2 regimen in terms of overall survival. Cure models, based on the Weibull distribution, suggested that factors for long-term survival in addition to presence of metastases were age, primary site of tumour and study. Modelling identified the proportion cured with the ET-2 protocol as best at 70% in those who are under 10 years with a nonpelvic primary site and without metastatic disease. This contrasts to only 13% cure in those with the corresponding adverse prognostic indicators. Additionally, the risk of death remains greatest but relatively constant over the first 2 years postdiagnosis, and then declines to a lower but constant value for the next 3 years before reaching the 'cure plateau' at about 5 years. This investigation suggests that 'cure' is possible for patients with Ewing's sarcoma. This is established at approximately 5 years post diagnosis and the proportion cured depends on the presence of metastases, pelvic site and age at diagnosis.

Measurement of antibody against contemporary virus lineages of human respiratory syncytial virus sub-group A in infants and their mothers.

BACKGROUND: Human respiratory syncytial virus (hRSV) infects the majority of infants in their first year of life. Maternal antibodies offer some protection although a small proportion of infected infants develop bronchiolitis and require admission to hospital. A number of lineages of the virus co-circulate in the population and the prevalent virus lineage changes from epidemic to epidemic. The effect of antigenic variation between virus lineages upon the protection offered by maternal antibodies has not been assessed. OBJECTIVES: To explore the possibility that infants may develop bronchiolitis because of a virus lineage-specific deficiency in their maternal antibodies. STUDY DESIGN: Virus isolates from infants admitted to hospital in Newcastle upon Tyne with hRSV infection during two consecutive winter epidemics were classified into lineages by genotypic analysis. Antibodies to the surface glycoproteins of contemporary sub-group A lineages and to the A2 virus strain were assayed in the acute sera of infected infants, in a group of uninfected infants and in the mothers of both groups. RESULTS: Four lineages of sub-group A hRSV were found circulating during the study period. Antibody titres measured against all virus lineages in the acute serum of infants with hRSV bronchiolitis were similar. In the uninfected infants and in the mothers of both infected and uninfected groups antibody titres to all four contemporary virus lineages were also similar. However, in these groups antibodies to the A2 virus strain were four-fold lower than those to contemporary isolates. CONCLUSIONS: Infants admitted to hospital with hRSV bronchiolitis exhibited no apparent selective deficiency in maternal antibodies to the viral glycoproteins of the infecting virus strain or lineage.

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

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

Outcome after relapse in an unselected cohort of children and adolescents with Ewing sarcoma.

BACKGROUND: Survival after relapse in patients with Ewing sarcoma is very poor and this retrospective study attempts to identify of prognostic factors predicting survival after relapse. PROCEDURE: A total of 191 patients with localised Ewing sarcoma were registered in the ET-2 trial of the United Kingdom Children's Cancer Study Group (UKCCSG). All patients received standardised primary treatment with chemotherapy and surgery and or radiotherapy as local modality treatment. Sixty-four patients who relapsed are included in this report. Treatment at relapse was variable and included chemotherapy, surgery, radiotherapy and high dose therapy (HDT) or megatherapy with peripheral stem cell transplantation (PBSCT) or autologous bone marrow transplantation (ABMT) in various combinations. A subgroup of patients had only non-specific symptomatic treatment at relapse. Both univariate and multivariate methods were used to investigate variables affecting survival after relapse. RESULTS: The overall actuarial median survival from relapse for all patients was 14 months (95% CI 11-16 months). Univariate analysis showed that males had a longer survival (median, 16 months vs. 11 months); patients who relapsed while on treatment did worse (median, 3 months vs. 16 months) and patients who had a longer disease-free interval (DFI) prior to relapse had a better outcome (DFI <1 year, median survival = 3 months; DFI 1-2 years, survival = 8 months; DFI > 2 years, median survival = 24 months, P < 0.001). Multivariate analysis confirmed that duration of first remission was the only factor associated with longer survival after relapse. CONCLUSIONS: These data suggest that although aggressive therapy may delay disease progression after relapse for some children, the course of the disease after relapse is usually fatal. International co-operative studies are needed to evaluate new strategies.

Nephrotoxicity in survivors of Wilms' tumours in the North of England.

One aspect of concern for survivors of Wilms' tumour has been the late outcome in terms of renal function. Previous studies have documented low glomerular filtration rate and high blood pressure in some patients. Furthermore, disorders in tubular function (especially urinary concentration defects) have been suggested but not confirmed in small studies. The aim of this study was to determine the prevalence and nature of subclinical and overt glomerular, proximal and distal renal tubular toxicity in a population based cohort of survivors of Wilms' tumour. Forty patients (24 female) with a median age of 4.3 years (3 months-11.8 years) at diagnosis were studied. Median follow-up was 8.8 (range 0.06-27.5) years. Glomerular filtration rate was measured by (51)Cr-EDTA plasma clearance, proximal tubular function by electrolyte fractional excretions, urine excretion of low molecular weight proteins (retinol-binding protein) and renal tubular enzymes (alanine aminopeptidase; N-acetylglucosaminidase) and distal tubular function by the osmolality of the first two urines of the day on 3 consecutive days. Renal size (ultrasound) and blood pressure were also measured. Mean (range) glomerular filtration rate was 100 (61-150) ml min(-1) 1.73 m(-2). Nine were below the reference range for healthy individuals with two kidneys. Most serum electrolyte concentrations (sodium, potassium, chloride, calcium, magnesium and phosphate) fell within the normal range for age, as did the fractional excretions. The values that fell outside the normal range were only marginally abnormal. Subclinical measures of tubular toxicity (retinal-binding protein, alanine aminopeptidase, N-acetylglucosaminidase) were abnormal in only four patients. Thirty-seven patients achieved maximal urine osmolalities > or =800 mOsm kg(-1), but three failed to achieve this value even after DDAVP administration. Two patients had evidence of increased urinary albumin excretion. Compensatory renal hypertrophy was seen in all but two patients, but blood pressure was within normal limits in all patients. Current and past treatment for Wilms' tumour does not have any clinically important nephrotoxic effect in the majority of patients. This finding will enable paediatric oncologists to reassure patients and parents that treatment for Wilms' tumour rarely causes long-term renal impairment.

Implications of childhood obesity for adult health: findings from thousand families cohort study.

OBJECTIVE: To determine whether being overweight in childhood increases adult obesity and risk of disease. DESIGN: Prospective cohort study. SETTING: City of Newcastle upon Tyne. PARTICIPANTS: 932 members of thousand families 1947 birth cohort, of whom 412 attended for clinical examination age 50. MAIN OUTCOME MEASURES: Blood pressure; carotid artery intima-media thickness; fibrinogen concentration; total, low density lipoprotein, and high density lipoprotein cholesterol concentrations; triglyceride concentration; fasting insulin and 2 hour glucose concentrations; body mass index; and percentage body fat. RESULTS: Body mass index at age 9 years was significantly correlated with body mass index age 50 (r=0.24, P<0.001) but not with percentage body fat age 50 (r=0.10, P=0.07). After adult body mass index had been adjusted for, body mass index at age 9 showed a significant inverse association with measures of lipid and glucose metabolism in both sexes and with blood pressure in women. However, after adjustment for adult percentage fat instead of body mass index, only the inverse associations with triglycerides (regression coefficient= -0.21, P<0.01) and total cholesterol (-0.17, P<0.05) in women remained significant. CONCLUSIONS: Little tracking from childhood overweight to adulthood obesity was found when using a measure of fatness that was independent of build. Only children who were obese at 13 showed an increased risk of obesity as adults. No excess adult health risk from childhood or teenage overweight was found. Being thin in childhood offered no protection against adult fatness, and the thinnest children tended to have the highest adult risk at every level of adult obesity.

Neuroblastoma: changing incidence and survival in young people aged 0-24 years. A report from the North of England Young Persons' Malignant Disease Registry.

BACKGROUND AND PROCEDURE: Population based data for neuroblastoma in children and young adults under 25 years at diagnosis were ascertained from the Northern Region Young Persons' Malignant Disease Registry for the period 1968-1995. Age-standardised incidence rates were calculated (ASR) and changes in incidence and survival were investigated. Over the study period 144 patients were registered, of these 136 were children under 15 years at diagnosis (median age: 2.2 years, ASR: 8.6 cases per million children per year), and 8 were 15-24 years (ASR 0.6). RESULTS AND CONCLUSIONS: Incidence of childhood neuroblastoma in the North of England increased significantly over time; ASRs were 5.8 for 1968-1981 and 9.5 for 1982-1995 (rate ratio: 1.6, 95%; CI 1.2-2.3). The increase in incidence was seen in both infants and older children, and in both low stage and advanced disease. Overall 5 year survival was 15% for 1968-1981 and 40% for 1982-1995 (P < 0.0001). Significant improvements in survival were documented across different stage and age-groups, including those over 1 with stage 4 disease (0% versus 18%, P < 0.0001). Further research is needed to investigate the reasons for the increasing incidence of neuroblastoma.

Survival of children with bone sarcoma in Europe since 1978: results from the EUROCARE study.

Malignant bone tumours in children are rare, accounting for approximately 5% of all childhood cancers in European countries. In the EUROCARE childhood cancer study, there were 1785 registrations from 16 countries for bone cancers in patients aged 0--14 years during 1978--1989. Of this total, almost three-quarters were contributed by childhood cancer registries in Germany and the UK. Estimated 5-year survival rates were 52% for osteosarcoma and 50% for Ewing's sarcoma over the entire study period and 60% for both diagnostic groups in 1985--1989. For osteosarcoma, survival rates increased substantially until about 1985, but then showed no further improvement. For Ewing's sarcoma, there was a steady increase throughout the study period. Improvements in survival which had previously been reported from individual countries and in clinical series are confirmed as having taken place throughout much of Europe on a population basis.