Non-targeted effects of ionising radiation-Implications for low dose risk

Non-DNA targeted effects of ionising radiation, which include genomic instability, and a variety of bystander effects including abscopal effects and bystander mediated adaptive response, have raised concerns about the magnitude of low-dose radiation risk. Genomic instability, bystander effects and adaptive responses are powered by fundamental, but not clearly understood systems that maintain tissue homeostasis. Despite excellent research in this field by various groups, there are still gaps in our understandfng of the likely mechanisms associated with non-DNA targeted effects, particularly with respect to systemic (human health) consequences at low and intermediate doses of ionising radiation. Other outstanding questions include links between the different non-targeted responses and the variations. in response observed between individuals and cell lines, possibly a function of genetic background. Furthermore, it is still not known what the initial target and early interactions in cells are that give rise to non-targeted responses in neighbouring or descendant cells. This paper provides a commentary on the current state of the field as a result of the non-targeted effects of ionising radiation (NOTE) Integrated Project funded by the European Union. Here we critically examine the evidence for non-targeted effects, discuss apparently contradictory results and consider implications for low-dose radiation health effects. (C) 2012 Elsevier B.V. All rights reserved.

Incidence trends for childhood type 1 diabetes in Europe during 1989-2003 and predicted new cases 2005-20: a multicentre prospective registration study

Background: The incidence of type 1 diabetes in children younger than 15 years is increasing. Prediction of future incidence of this disease will enable adequate fund allocation for delivery of care to be planned. We aimed to establish 15-year incidence trends for childhood type 1 diabetes in European centres, and thereby predict the future burden of childhood diabetes in Europe.
Methods: 20 population-based EURODIAB registers in 17 countries registered 29 311 new cases of type 1 diabetes, diagnosed in children before their 15th birthday during a 15-year period, 1989–2003. Age-specific log linear rates of increase were estimated in five geographical regions, and used in conjunction with published incidence rates and population projections to predict numbers of new cases throughout Europe in 2005, 2010, 2015, and 2020.
Findings: Ascertainment was better than 90% in most registers. All but two registers showed significant yearly increases in incidence, ranging from 0·6% to 9·3%. The overall annual increase was 3·9% (95% CI 3·6–4·2), and the increases in the age groups 0–4 years, 5–9 years, and 10–14 years were 5·4% (4·8–6·1), 4·3% (3·8–4·8), and 2·9% (2·5–3·3), respectively. The number of new cases in Europe in 2005, is estimated as 15 000, divided between the 0–4 year, 5–9 year, and 10–14 year age-groups in the ratio 24%, 35%, and 41%, respectively. In 2020, the predicted number of new cases is 24 000, with a doubling in numbers in children younger than 5 years and a more even distribution across age-groups than at present (29%, 37%, and 34%, respectively). Prevalence under age 15 years is predicted to rise from 94 000 in 2005, to 160 000 in 2020.
Interpretation: If present trends continue, doubling of new cases of type 1 diabetes in European children younger than 5 years is predicted between 2005 and 2020, and prevalent cases younger than 15 years will rise by 70%. Adequate health-care resources to meet these children’s needs should be made available.

Trends in childhood type 1 diabetes incidence in Europe during 1989-2008: evidence of non-uniformity over time in rates of increase

AIMS/HYPOTHESIS:

The aim of the study was to describe 20-year incidence trends for childhood type 1 diabetes in 23 EURODIAB centres and compare rates of increase in the first (1989-1998) and second (1999-2008) halves of the period.

METHODS:

All registers operate in geographically defined regions and are based on a clinical diagnosis. Completeness of registration is assessed by capture-recapture methodology. Twenty-three centres in 19 countries registered 49,969 new cases of type 1 diabetes in individuals diagnosed before their 15th birthday during the period studied.

RESULTS:

Ascertainment exceeded 90% in most registers. During the 20-year period, all but one register showed statistically significant changes in incidence, with rates universally increasing. When estimated separately for the first and second halves of the period, the median rates of increase were similar: 3.4% per annum and 3.3% per annum, respectively. However, rates of increase differed significantly between the first half and the second half for nine of the 21 registers with adequate coverage of both periods; five registers showed significantly higher rates of increase in the first half, and four significantly higher rates in the second half.

CONCLUSIONS/INTERPRETATION:

The incidence rate of childhood type 1 diabetes continues to rise across Europe by an average of approximately 3-4% per annum, but the increase is not necessarily uniform, showing periods of less rapid and more rapid increase in incidence in some registers. This pattern of change suggests that important risk exposures differ over time in different European countries. Further time trend analysis and comparison of the patterns in defined regions is warranted.

Incidence of Type 1 Diabetes in Sweden Among Individuals Aged 0–34 Years, 1983–2007:An analysis of time trends

OBJECTIVE: To clarify whether the increase in childhood type 1 diabetes is mirrored by a decrease in older age-groups, resulting in younger age at diagnosis.
RESEARCH DESIGN AND METHODS: We used data from two prospective research registers, the Swedish Childhood Diabetes Register, which included case subjects aged 0-14.9 years at diagnosis, and the Diabetes in Sweden Study, which included case subjects aged 15-34.9 years at diagnosis, covering birth cohorts between 1948 and 2007. The total database included 20,249 individuals with diabetes diagnosed between 1983 and 2007. Incidence rates over time were analyzed using Poisson regression models.
RESULTS: The overall yearly incidence rose to a peak of 42.3 per 100,000 person-years in male subjects aged 10-14 years and to a peak of 37.1 per 100,000 person-years in female subjects aged 5-9 years and decreased thereafter. There was a significant increase by calendar year in both sexes in the three age-groups <15 years; however, there were significant decreases in the older age-groups (25- to 29-years and 30- to 34-years age-groups). Poisson regression analyses showed that a cohort effect seemed to dominate over a time-period effect.
CONCLUSIONS: Twenty-five years of prospective nationwide incidence registration demonstrates a clear shift to younger age at onset rather than a uniform increase in incidence rates across all age-groups. The dominance of cohort effects over period effects suggests that exposures affecting young children may be responsible for the increasing incidence in the younger age-groups.

EURODIAB childhood type 1 diabetes incidence registers - results from the first 20 years. Oral presentation at the 47th EASD Annual Meeting, Lisbon, Portugal.

Background and aims: In 1989 a number of registers in Europe began recording new cases of type 1 diabetes diagnosed in children aged under 15 years using a common protocol. Trends in incidence rate during the 20 year period 1989-2008 are described.
Materials and methods: All registers operate in geographically defined regions and are based on a clinical diagnosis. When possible, completeness of registration in each register is assessed using capture-recapture methodology by identifying primary and secondary sources of ascertainment. The completeness estimate is obtained by identifying the numbers of cases identified by the primary source only, by the secondary source only and by both the primary and the secondary sources.
Results: Other registers have joined the Group since 1989, and 21 registers in 15 countries continue to submit registration data. In the first five years (1989-93) incidence rates varied from 3.2 per 100,000 in the Former Yugoslav Republic of Macedonia to 25.8 per 100,000 in the Stockholm area of Sweden. In the last five years (2004-2008) these same two registers again had the lowest and highest incidence, but rates had increased to 5.8 per 100,000 and 36.6 per 100,000, respectively. During the 20 year period all but two of the 21 registers showed statistically significant rates of increase (median rate of increase 4% per annum), and similar figures were obtained when this median rate of increase was estimated for the first half of the period (1989-98) and for the second half (1999-2008) . However, rates of increase differed significantly between the first half and the second half of the period for eight of the 17 registers with adequate coverage of both periods; four registers showing significantly higher rates of increase in the first half and four significantly higher rates in the second half.
Conclusion: The childhood type 1 diabetes incidence rate continues to rise across Europe by approximately 4% per annum, but the increase within a register is not necessarily uniform with periods of less rapid and more rapid increase in incidence occurring in some registers. This pattern of change suggests that important risk exposures differ over time in different European countries. Further time trend analysis and comparison of the patterns in defined regions are warranted.

EURODIAB childhood type 1 diabetes incidence registers - results from the first 20 years

Background and aims: In 1989 a number of registers in Europe began recording new cases of type 1 diabetes diagnosed in children aged under 15 years using a common protocol. Trends in incidence rate during the 20 year period 1989-2008 are described.
Materials and methods: All registers operate in geographically defined regions and are based on a clinical diagnosis. When possible, completeness of registration in each register is assessed using capture-recapture methodology by identifying primary and secondary sources of ascertainment. The completeness estimate is obtained by identifying the numbers of cases identified by the primary source only, by the secondary source only and by both the primary and the secondary sources.
Results: Other registers have joined the Group since 1989, and 21 registers in 15 countries continue to submit registration data. In the first five years (1989-93) incidence rates varied from 3.2 per 100,000 in the Former Yugoslav Republic of Macedonia to 25.8 per 100,000 in the Stockholm area of Sweden. In the last five years (2004-2008) these same two registers again had the lowest and highest incidence, but rates had increased to 5.8 per 100,000 and 36.6 per 100,000, respectively. During the 20 year period all but two of the 21 registers showed statistically significant rates of increase (median rate of increase 4% per annum), and similar figures were obtained when this median rate of increase was estimated for the first half of the period (1989-98) and for the second half (1999-2008) . However, rates of increase differed significantly between the first half and the second half of the period for eight of the 17 registers with adequate coverage of both periods; four registers showing significantly higher rates of increase in the first half and four significantly higher rates in the second half.
Conclusion: The childhood type 1 diabetes incidence rate continues to rise across Europe by approximately 4% per annum, but the increase within a register is not necessarily uniform with periods of less rapid and more rapid increase in incidence occurring in some registers. This pattern of change suggests that important risk exposures differ over time in different European countries. Further time trend analysis and comparison of the patterns in defined regions are warranted.

Trends in skin cancer knowledge, sun protection practices and behaviours in the Northern Ireland population

Background: Sun exposure increases risk of skin cancer, especially melanoma, incidence of which continues to rise. Reported skin cancer knowledge and trends in sun care behaviours are documented in a UK region where there has been 20 years of sun-related health promotion campaigns. Methods: In 2000, 2004 and 2008, a 'care in the sun' module was included in the Northern Ireland (NI) Omnibus survey. Randomly selected subjects were asked to complete a sun-related questionnaire and proportions of respondents analysed by demographic and socio-economic factors, with differences tested using z-tests and the chi-squared test. Results: Around 3623 persons responded. Skin cancer knowledge was high (97). Sun avoidance decreased with time and was lowest among younger age groups and males. Sunscreen use was high (70), unchanged over 8 years, and more likely among younger age groups, females, those in paid employment, and those with tertiary level education. Use of sunscreen with minimum Sun Protection Factor (SPF) 15 (a campaign message) increased from 45 to 70 (P

Minimal residual disease detection in childhood acute lymphoblastic leukaemia patients at multiple time-points reveals high levels of concordance between molecular and immunophenotypic approaches

In this single centre study of childhood acute lymphoblastic leukaemia (ALL) patients treated on the Medical Research Council UKALL 97/99 protocols, it was determined that minimal residual disease (MRD) detected by real time quantitative polymerase chain reaction (RQ-PCR) and 3-colour flow cytometry (FC) displayed high levels of qualitative concordance when evaluated at multiple time-points during treatment (93.38%), and a combined use of both approaches allowed a multi time-point evaluation of MRD kinetics for 90% (53/59) of the initial cohort. At diagnosis, MRD markers with sensitivity of at least 0.01% were identified by RQ-PCR detection of fusion gene transcripts, IGH/TRG rearrangements, and FC. Using a combined RQ-PCR and FC approach, the evaluation of 367 follow-up BM samples revealed that the detection of MRD >1% at Day 15 (P = 0.04), >0.01% at the end of induction (P = 0.02), >0.01% at the end of consolidation (P = 0.01), >0.01% prior to the first delayed intensification (P = 0.01), and >0.1% prior to the second delayed intensification and continued maintenance (P = 0.001) were all associated with relapse and, based on early time-points (end of induction and consolidation) a significant log-rank trend (P = 0.0091) was noted between survival curves for patients stratified into high, intermediate and low-risk MRD groups.

Global surveillance of cancer survival 1995–2009: analysis of individual data for 25 676 887 patients from 279 population-based registries in 67 countries (CONCORD-2)

BACKGROUND: Worldwide data for cancer survival are scarce. We aimed to initiate worldwide surveillance of cancer survival by central analysis of population-based registry data, as a metric of the effectiveness of health systems, and to inform global policy on cancer control.

METHODS: Individual tumour records were submitted by 279 population-based cancer registries in 67 countries for 25·7 million adults (age 15-99 years) and 75,000 children (age 0-14 years) diagnosed with cancer during 1995-2009 and followed up to Dec 31, 2009, or later. We looked at cancers of the stomach, colon, rectum, liver, lung, breast (women), cervix, ovary, and prostate in adults, and adult and childhood leukaemia. Standardised quality control procedures were applied; errors were corrected by the registry concerned. We estimated 5-year net survival, adjusted for background mortality in every country or region by age (single year), sex, and calendar year, and by race or ethnic origin in some countries. Estimates were age-standardised with the International Cancer Survival Standard weights.

FINDINGS: 5-year survival from colon, rectal, and breast cancers has increased steadily in most developed countries. For patients diagnosed during 2005-09, survival for colon and rectal cancer reached 60% or more in 22 countries around the world; for breast cancer, 5-year survival rose to 85% or higher in 17 countries worldwide. Liver and lung cancer remain lethal in all nations: for both cancers, 5-year survival is below 20% everywhere in Europe, in the range 15-19% in North America, and as low as 7-9% in Mongolia and Thailand. Striking rises in 5-year survival from prostate cancer have occurred in many countries: survival rose by 10-20% between 1995-99 and 2005-09 in 22 countries in South America, Asia, and Europe, but survival still varies widely around the world, from less than 60% in Bulgaria and Thailand to 95% or more in Brazil, Puerto Rico, and the USA. For cervical cancer, national estimates of 5-year survival range from less than 50% to more than 70%; regional variations are much wider, and improvements between 1995-99 and 2005-09 have generally been slight. For women diagnosed with ovarian cancer in 2005-09, 5-year survival was 40% or higher only in Ecuador, the USA, and 17 countries in Asia and Europe. 5-year survival for stomach cancer in 2005-09 was high (54-58%) in Japan and South Korea, compared with less than 40% in other countries. By contrast, 5-year survival from adult leukaemia in Japan and South Korea (18-23%) is lower than in most other countries. 5-year survival from childhood acute lymphoblastic leukaemia is less than 60% in several countries, but as high as 90% in Canada and four European countries, which suggests major deficiencies in the management of a largely curable disease.

INTERPRETATION: International comparison of survival trends reveals very wide differences that are likely to be attributable to differences in access to early diagnosis and optimum treatment. Continuous worldwide surveillance of cancer survival should become an indispensable source of information for cancer patients and researchers and a stimulus for politicians to improve health policy and health-care systems.

Is childhood type 1 diabetes a wealth-related disease? An ecological analysis of European incidence rates

Aims/Hypothesis: To describe the epidemiology of childhood-onset Type 1 (insulin-dependent) diabetes in Europe, the EURODIAB collaborative group has established prospective, geographically-defined registers of children diagnosed under 15 years. A total of 16,362 cases were registered by 44 centres during the period 1989-1994. The registers cover a population of approximately 28 million children with most European countries represented. Methods In most centres a primary and a secondary source of ascertainment were used so that the completeness of registration could be assessed by the capture-recapture method. Ecological correlation and regression analyses were used to study the relationship between incidence and various environmental, health and economic indicators. Findings: The standardised average annual incidence rate during the period 1989-94 ranged from 3.2 cases per 100,000 per annum in the Former Yugoslavian Republic of Macedonia to 40.2 cases per 100,000 per annum in Finland. Indicators of national prosperity such as infant mortality (r= -0.64) and gross domestic product (r= 0.58) were most strongly and significantly correlated with incidence rate, and previously-reported associations with coffee consumption (r= 0.51), milk consumption (r= 0.58) and latitude (r= 0.40) were also observed. Conclusion/Interpretation: The wide variation in childhood type 1 diabetes incidence rates within Europe could be partially explained by indicators of national prosperity. These indicators could reflect differences in environmental risk factors such as nutrition or lifestyle that are important in determining a country's incidence rate.