Elevated ASCL1 activity creates de novo regulatory elements associated with neuronal differentiation.

BACKGROUND: The pro-neural transcription factor ASCL1 is a master regulator of neurogenesis and a key factor necessary for the reprogramming of permissive cell types to neurons. Endogenously, ASCL1 expression is often associated with neuroblast stem-ness. Moreover, ASCL1-mediated reprogramming of fibroblasts to differentiated neurons is commonly achieved using artificially high levels of ASCL1 protein, where ASCL1 acts as an "on-target" pioneer factor. However, the genome-wide effects of enhancing ASCL1 activity in a permissive neurogenic environment has not been thoroughly investigated. Here, we overexpressed ASCL1 in the neuronally-permissive context of neuroblastoma (NB) cells where modest endogenous ASCL1 supports the neuroblast programme. RESULTS: Increasing ASCL1 in neuroblastoma cells both enhances binding at existing ASCL1 sites and also leads to creation of numerous additional, lower affinity binding sites. These extensive genome-wide changes in ASCL1 binding result in significant reprogramming of the NB transcriptome, redirecting it from a proliferative neuroblastic state towards one favouring neuronal differentiation. Mechanistically, ASCL1-mediated cell cycle exit and differentiation can be increased further by preventing its multi-site phosphorylation, which is associated with additional changes in genome-wide binding and gene activation profiles. CONCLUSIONS: Our findings show that enhancing ASCL1 activity in a neurogenic environment both increases binding at endogenous ASCL1 sites and also results in additional binding to new low affinity sites that favours neuronal differentiation over the proliferating neuroblast programme supported by the endogenous protein. These findings have important implications for controlling processes of neurogenesis in cancer and cellular reprogramming.

An investigation of cancer survival inequalities associated with individual-level socio-economic status, area-level deprivation, and contextual effects, in a cancer patient cohort in England and Wales.

BACKGROUND: People living in more deprived areas of high-income countries have lower cancer survival than those in less deprived areas. However, associations between individual-level socio-economic circumstances and cancer survival are relatively poorly understood. Moreover, few studies have addressed contextual effects, where associations between individual-level socio-economic status and cancer survival vary depending on area-based deprivation. METHODS: Using 9276 individual-level observations from a longitudinal study in England and Wales, we examined the association with cancer survival of area-level deprivation and individual-level occupation, education, and income, for colorectal, prostate and breast cancer patients aged 20-99 at diagnosis. With flexible parametric excess hazard models, we estimated excess mortality across individual-level and area-level socio-economic variables and investigated contextual effects. RESULTS: For colorectal cancers, we found evidence of an association between education and cancer survival in men with Excess Hazard Ratio (EHR) = 0.80, 95% Confidence Interval (CI) = 0.60;1.08 comparing "degree-level qualification and higher" to "no qualification" and EHR = 0.74 [0.56;0.97] comparing "apprenticeships and vocational qualification" to "no qualification", adjusted on occupation and income; and between occupation and cancer survival for women with EHR = 0.77 [0.54;1.10] comparing "managerial/professional occupations" to "manual/technical," and EHR = 0.81 [0.63;1.06] comparing "intermediate" to "manual/technical", adjusted on education and income. For breast cancer in women, we found evidence of an association with income (EHR = 0.52 [0.29;0.95] for the highest income quintile compared to the lowest, adjusted on education and occupation), while for prostate cancer, all three individual-level socio-economic variables were associated to some extent with cancer survival. We found contextual effects of area-level deprivation on survival inequalities between occupation types for breast and prostate cancers, suggesting wider individual-level inequalities in more deprived areas compared to least deprived areas. Individual-level income inequalities for breast cancer were more evident than an area-level differential, suggesting that area-level deprivation might not be the most effective measure of inequality for this cancer. For colorectal cancer in both sexes, we found evidence suggesting area- and individual-level inequalities, but no evidence of contextual effects. CONCLUSIONS: Findings highlight that both individual and contextual effects contribute to inequalities in cancer outcomes. These insights provide potential avenues for more effective policy and practice.

Are socio-economic inequalities in breast cancer survival explained by peri-diagnostic factors?

BACKGROUND: Patients living in more deprived localities have lower cancer survival in England, but the role of individual health status at diagnosis and the utilisation of primary health care in explaining these differentials has not been widely considered. We set out to evaluate whether pre-existing individual health status at diagnosis and primary care consultation history (peri-diagnostic factors) could explain socio-economic differentials in survival amongst women diagnosed with breast cancer. METHODS: We conducted a retrospective cohort study of women aged 15-99 years diagnosed in England using linked routine data. Ecologically-derived measures of income deprivation were combined with individually-linked data from the English National Cancer Registry, Clinical Practice Research Datalink (CPRD) and Hospital Episodes Statistics (HES) databases. Smoking status, alcohol consumption, BMI, comorbidity, and consultation histories were derived for all patients. Time to breast surgery was derived for women diagnosed after 2005. We estimated net survival and modelled the excess hazard ratio of breast cancer death using flexible parametric models. We accounted for missing data using multiple imputation. RESULTS: Net survival was lower amongst more deprived women, with a single unit increase in deprivation quintile inferring a 4.4% (95% CI 1.4-8.8) increase in excess mortality. Peri-diagnostic co-variables varied by deprivation but did not explain the differentials in multivariable analyses. CONCLUSIONS: These data show that socio-economic inequalities in survival cannot be explained by consultation history or by pre-existing individual health status, as measured in primary care. Differentials in the effectiveness of treatment, beyond those measuring the inclusion of breast surgery and the timing of surgery, should be considered as part of the wider effort to reduce inequalities in premature mortality.

Life tables for global surveillance of cancer survival (the CONCORD programme): data sources and methods.

BACKGROUND: We set out to estimate net survival trends for 10 common cancers in 279 cancer registry populations in 67 countries around the world, as part of the CONCORD-2 study. Net survival can be interpreted as the proportion of cancer patients who survive up to a given time, after eliminating the impact of mortality from other causes (background mortality). Background mortality varies widely between populations and over time. It was therefore necessary to construct robust life tables that accurately reflected the background mortality in each of the registry populations. METHODS: Life tables of all-cause mortality rates by single year of age and sex were constructed by calendar year for each population and, when possible, by racial or ethnic sub-groups. We used three different approaches, based on the type of mortality data available from each registry. With death and population counts, we adopted a flexible multivariable modelling approach. With unsmoothed mortality rates, we used the Ewbank relational method. Where no data were available from the registry or a national statistical office, we used the abridged UN Population Division life tables and interpolated these using the Elandt-Johnson method. We also investigated the impact of using state- and race-specific life tables versus national race-specific life tables on estimates of net survival from four adult cancers in the United States (US). RESULTS: We constructed 6,514 life tables covering 327 populations. Wide variations in life expectancy at birth and mortality by age were observed, even within countries. During 1995-99, life expectancy was lowest in Nigeria and highest in Japan, ranging from 47 to 84 years among females and 46 to 78 years among males. During 2005-09, life expectancy was lowest in Lesotho and again highest in Japan, ranging from 45 to 86 years among females and 45 to 80 years among males. For the US, estimates of net survival differed by up to 4% if background mortality was fully controlled with state- and race-specific life tables, rather than with national race-specific life tables. CONCLUSIONS: Background mortality varies worldwide. This emphasises the importance of using population-specific life tables for geographic and international comparisons of net survival.

Synthesis and Biological Evaluation of 7-Deoxy-Epothilone Analogues.

The synthesis of two deoxygenated analogues of potent epothilones is reported in an effort to analyze the relative importance of molecular conformation and ligand-target interactions to biological activity. 7-deoxy-epothilone D and 7-deoxy-(S)-14-methoxy-epothilone D were prepared through total synthesis and shown to maintain the conformational preferences of their biologically active parent congeners through computer modeling and nuclear magnetic resonance (NMR) studies. The significant decrease in observed potency for each compound suggests that a hydrogen bond between the C7-hydroxyl group and the tubulin binding site plays a critical role in the energetics of binding in the epothilone class of polyketides.

Impact of deprivation on breast cancer survival among women eligible for mammographic screening in the West Midlands (UK) and New South Wales (Australia): Women diagnosed 1997-2006.

Women diagnosed with breast cancer in the UK display marked differences in survival between categories defined by socio-economic deprivation. Timeliness of diagnosis is one of the possible explanations for these patterns. Women whose cancer is screen-detected are more likely to be diagnosed at an earlier stage. We examined deprivation and screening-specific survival in order to evaluate the role of early diagnosis upon deprivation-specific survival differences in the West Midlands (UK) and New South Wales (Australia). We estimated net survival for women aged 50-65 years at diagnosis and whom had been continuously eligible for screening from the age of 50. Records for 5,628 women in West Midlands (98.5% of those eligible, mean age at diagnosis 53.7 years) and 6,396 women in New South Wales (99.9% of those eligible, mean age at diagnosis 53.8 years). In New South Wales, survival was similar amongst affluent and deprived women, regardless of whether their cancer was screen-detected or not. In the West Midlands, there were large and persistent differences in survival between affluent and deprived women. Deprivation differences were similar between the screen-detected and non-screen detected groups. These differences are unlikely to be solely explained by artefact, or by patient or tumour factors. Further investigations into the timeliness and appropriateness of the treatments received by women with breast cancer across the social spectrum in the UK are warranted.

Are international differences in breast cancer survival between Australia and the UK present amongst both screen-detected women and non-screen-detected women? survival estimates for women diagnosed in West Midlands and New South Wales 1997-2006.

We examined survival in screened-detected and non-screen-detected women diagnosed in the West Midlands (UK) and New South Wales (Australia) in order to evaluate whether international differences in survival are related to early diagnosis, or to other factors relating to the healthcare women receive. Data for women aged 50 - 65 years who had been eligible for screening from 50 years were examined. Data for 5,628 women in West Midlands and 6,396 women in New South Wales were linked to screening service records (mean age at diagnosis 53.7 years). We estimated net survival and modelled the excess hazard ratio of breast cancer death by screening status. Survival was lower for women in the West Midlands than in New South Wales (5-year net survival 90.9% [95% CI 89.9%-91.7%] compared with 93.4% [95% CI 92.6%-94.1%], respectively). The difference was greater between the two populations of non-screen-detected women (4.9%) compared to between screen-detected women, (1.8% after adjustment for lead-time and over-diagnosis). The adjusted excess hazard ratio of breast cancer death for West Midlands compared with New South Wales was greater in the non-screen-detected group (EHR 2.00, 95% CI 1.70 - 2.31) but not significantly different to that for women whose cancer had been screen-detected (EHR 1.72, 95% CI 0.87 - 2.56). In this study more than one in three breast cancer deaths in the West Midlands would have been avoided if survival had been the same as in New South Wales. The possibility that women in the UK receive poorer treatment is an important potential explanation which should be examined with care.

Multivariable flexible modelling for estimating complete, smoothed life tables for sub-national populations.

BACKGROUND: The methods currently available to estimate age- and sex-specific mortality rates for sub-populations are subject to a number of important limitations. We propose two alternative multivariable approaches: a relational model and a Poisson model both using restricted cubic splines. METHODS: We evaluated a flexible Poisson and flexible relational model against the Elandt-Johnson approach in a simulation study using 100 random samples of population and death counts, with different sampling proportions and data arrangements. Estimated rates were compared to the original mortality rates using goodness-of-fit measures and life expectancy. We further investigated an approach for determining optimal knot locations in the Poisson model. RESULTS: The flexible Poisson model outperformed the flexible relational and Elandt-Johnson methods with the smallest sample of data (1%). With the largest sample of data (20%), the flexible Poisson and flexible relational models performed comparably, though the flexible Poisson model displayed a slight advantage. Both approaches tended to underestimate infant mortality and thereby overestimate life expectancy at birth. The flexible Poisson model performed much better at young ages when knots were fixed a priori. For ages 30 and above, results were similar to the model with no fixed knots. CONCLUSIONS: The flexible Poisson model is recommended because it derives robust and unbiased estimates for sub-populations without making strong assumptions about age-specific mortality profiles. Fixing knots a priori in the final model greatly improves fit at the young ages.

Cancer incidence, survival and mortality: explaining the concepts.

Cancer incidence, survival and mortality are essential population-based indicators for public health and cancer control. Confusion and misunderstanding still surround the estimation and interpretation of these indicators. Recurring controversies over the use and misuse of population-based cancer statistics in health policy suggests the need for further clarification. In our article, we describe the concepts that underlie the measures of incidence, survival and mortality, and illustrate the synergy between these measures of the cancer burden. We demonstrate the relationships between trends in incidence, survival and mortality, using real data for cancers of the lung and breast from England and Sweden. Finally, we discuss the importance of using all three measures in combination when interpreting overall progress in cancer control, and we offer some recommendations for their use.

Risk factors for early-onset pancreatic ductal adenocarcinoma: A systematic literature review.

BACKGROUND: Emerging cancer trends suggest an increase in pancreatic cancer incidence in individuals younger than its typical age of onset, potentially reflecting changes in population exposures and lifestyles. PATIENTS AND METHODS: We conducted a PRISMA-standard systematic literature review to identify non-heritable risk factors for early-onset pancreatic ductal adenocarcinoma (PDAC) (PROSPERO number: CRD42022299397). Systematic searches of MEDLINE and Embase bibliographic databases were performed (January 2022), and publications were screened against predetermined eligibility criteria; data were extracted using standardised data fields. The STROBE checklist was used to assess the completeness of reporting as a proxy for publication quality. Data were categorised by risk factor and analysed descriptively. RESULTS: In total, 24 publications were included. All publications reported observational study data; thresholds for age group comparisons ranged between 40 and 65 years. Lifestyle factors investigated included smoking, alcohol consumption, obesity, physical inactivity, meat intake, socioeconomic status and geographical residence. Clinical factors investigated included pancreatitis, diabetes/insulin resistance, prior cancer and cancer stage at diagnosis, hepatitis B infection, metabolic syndrome and long-term proton pump inhibitor exposure. Publication STROBE scores were 6-21 (maximum, 22). Eight studies reported results adjusted for confounders. Potential non-heritable risk factors for early-onset PDAC that warrant further investigation included smoking, alcohol consumption, pancreatitis and hepatitis B infection. CONCLUSION: Evidence for non-heritable risk factors for early-onset PDAC is heterogeneous, but four factors were identified that might aid the identification of at-risk individuals who may benefit from screening and risk reduction strategies.

Palbociclib releases the latent differentiation capacity of neuroblastoma cells.

Neuroblastoma is the most common extracranial solid tumor in infants, arising from developmentally stalled neural crest-derived cells. Driving tumor differentiation is a promising therapeutic approach for this devastating disease. Here, we show that the CDK4/6 inhibitor palbociclib not only inhibits proliferation but induces extensive neuronal differentiation of adrenergic neuroblastoma cells. Palbociclib-mediated differentiation is manifested by extensive phenotypic and transcriptional changes accompanied by the establishment of an epigenetic program driving expression of mature neuronal features. In vivo palbociclib significantly inhibits tumor growth in mouse neuroblastoma models. Furthermore, dual treatment with retinoic acid resets the oncogenic adrenergic core regulatory circuit of neuroblastoma cells, further suppresses proliferation, and can enhance differentiation, altering gene expression in ways that significantly correlate with improved patient survival. We therefore identify palbociclib as a therapeutic approach to dramatically enhance neuroblastoma differentiation efficacy that could be used in combination with retinoic acid to improve patient outcomes.

Full dates (day, month, year) should be used in population-based cancer survival studies.

Accurate survival estimates are essential for monitoring cancer survival trends, for health care planning and for resource allocation. To obtain precise estimates of survival, full dates (day, month and year) rather than partial dates (month and year) are required. In some jurisdictions, however, cancer registries are constrained from providing full dates on the grounds of confidentiality. The bias resulting from the use of partial dates in the estimation and comparison of survival makes it impossible to determine precisely the differences in the risk of death from cancer between population groups or in successive calendar periods. Important operational arguments also exist against the use of incomplete dates for survival analysis, including increased workload for cancer registry staff and the introduction of avoidable complexity for quality control of survival data. Cancer survival is one of the most widely known outputs produced by population-based cancer registries, and it is a crucial metric for the comparative effectiveness of health services. The bodies that set data access guidelines must take a more balanced view of the risks and benefits of using full dates for the estimation of cancer survival.

Are deprivation-specific cancer survival patterns similar according to individual-based and area-based measures? A cohort study of patients diagnosed with five malignancies in England and Wales, 2008-2016.

OBJECTIVE: To investigate if measured inequalities in cancer survival differ when using individual-based ('person') compared with area-based ('place') measures of deprivation for three socioeconomic dimensions: income, deprivation and occupation. DESIGN: Cohort study. SETTING: Data from the Office for National Statistics Longitudinal Study of England and Wales, UK, linked to the National Cancer Registration Database. PARTICIPANTS: Patients diagnosed with cancers of the colorectum, breast, prostate, bladder or with non-Hodgkin's lymphoma during the period 2008-2016. PRIMARY AND SECONDARY OUTCOME MEASURES: Differentials in net survival between groups defined by individual wage, occupation and education compared with those obtained from corresponding area-level metrics using the English and Welsh Indices of Multiple Deprivation. RESULTS: Survival was negatively associated with area-based deprivation irrespective of the type analysed, although a trend from least to most deprived was not always observed. Socioeconomic differences were present according to individually-measured socioeconomic groups although there was an absence of a consistent 'gradient' in survival. The magnitude of differentials was similar for area-based and individually-derived measures of deprivation, which was unexpected. CONCLUSION: These unique data suggest that the socioeconomic influence of 'person' is different to that of 'place' with respect to cancer outcomes. This has implications for health policy aimed at reducing inequalities. Further research could consider the separate and additional influence of area-based deprivation over individual-level characteristics (contextual effects) as well as investigate the geographic, socioeconomic and healthcare-related characteristics of areas with poor outcomes in order to inform policy intervention.

The proneural transcription factor ASCL1 regulates cell proliferation and primes for differentiation in neuroblastoma.

Neuroblastoma is believed to arise from sympathetic neuroblast precursors that fail to engage the neuronal differentiation programme, but instead become locked in a pro-proliferative developmental state. Achaete-scute homolog 1 (ASCL1) is a proneural master regulator of transcription which modulates both proliferation and differentiation of sympathetic neuroblast precursor cells during development, while its expression has been implicated in the maintenance of an oncogenic programme in MYCN-amplified neuroblastoma. However, the role of ASCL1 expression in neuroblastoma is not clear, especially as its levels vary considerably in different neuroblastoma cell lines. Here, we have investigated the role of ASCL1 in maintaining proliferation and controlling differentiation in both MYCN amplified and Anaplastic Lymphoma Kinase (ALK)-driven neuroblastoma cells. Using CRISPR deletion, we generated neuroblastoma cell lines lacking ASCL1 expression, and these grew more slowly than parental cells, indicating that ASCL1 contributes to rapid proliferation of MYCN amplified and non-amplified neuroblastoma cells. Genome-wide analysis after ASCL1 deletion revealed reduced expression of genes associated with neuronal differentiation, while chromatin accessibility at regulatory regions associated with differentiation genes was also attenuated by ASCL1 knock-out. In neuroblastoma, ASCL1 has been described as part of a core regulatory circuit of developmental regulators whose high expression is maintained by mutual cross-activation of a network of super enhancers and is further augmented by the activity of MYC/MYCN. Surprisingly, ASCL1 deletion had little effect on the transcription of CRC gene transcripts in these neuroblastoma cell lines, but the ability of MYC/MYCN and CRC component proteins, PHOX2B and GATA3, to bind to chromatin was compromised. Taken together, our results demonstrate several roles for endogenous ASCL1 in neuroblastoma cells: maintaining a highly proliferative phenotype, regulating DNA binding of the core regulatory circuit genes to chromatin, while also controlling accessibility and transcription of differentiation targets. Thus, we propose a model where ASCL1, a key developmental regulator of sympathetic neurogenesis, plays a pivotal role in maintaining proliferation while simultaneously priming cells for differentiation in neuroblastoma.

Super-enhancer associated core regulatory circuits mediate susceptibility to retinoic acid in neuroblastoma cells.

Neuroblastoma is a pediatric tumour that accounts for more than 15% of cancer-related deaths in children. High-risk tumours are often difficult to treat, and patients' survival chances are less than 50%. Retinoic acid treatment is part of the maintenance therapy given to neuroblastoma patients; however, not all tumours differentiate in response to retinoic acid. Within neuroblastoma tumors, two phenotypically distinct cell types have been identified based on their super-enhancer landscape and transcriptional core regulatory circuitries: adrenergic (ADRN) and mesenchymal (MES). We hypothesized that the distinct super-enhancers in these different tumour cells mediate differential response to retinoic acid. To this end, three different neuroblastoma cell lines, ADRN (MYCN amplified and non-amplified) and MES cells, were treated with retinoic acid, and changes in the super-enhancer landscape upon treatment and after subsequent removal of retinoic acid was studied. Using ChIP-seq for the active histone mark H3K27ac, paired with RNA-seq, we compared the super-enhancer landscape in cells that undergo neuronal differentiation in response to retinoic acid versus those that fail to differentiate and identified unique super-enhancers associated with neuronal differentiation. Among the ADRN cells that respond to treatment, MYCN-amplified cells remain differentiated upon removal of retinoic acid, whereas MYCN non-amplified cells revert to an undifferentiated state, allowing for the identification of super-enhancers responsible for maintaining differentiation. This study identifies key super-enhancers that are crucial for retinoic acid-mediated differentiation.

Can we screen for pancreatic cancer? Identifying a sub-population of patients at high risk of subsequent diagnosis using machine learning techniques applied to primary care data.

BACKGROUND: Pancreatic cancer (PC) represents a substantial public health burden. Pancreatic cancer patients have very low survival due to the difficulty of identifying cancers early when the tumour is localised to the site of origin and treatable. Recent progress has been made in identifying biomarkers for PC in the blood and urine, but these cannot be used for population-based screening as this would be prohibitively expensive and potentially harmful. METHODS: We conducted a case-control study using prospectively-collected electronic health records from primary care individually-linked to cancer registrations. Our cases were comprised of 1,139 patients, aged 15-99 years, diagnosed with pancreatic cancer between January 1, 2005 and June 30, 2009. Each case was age-, sex- and diagnosis time-matched to four non-pancreatic (cancer patient) controls. Disease and prescription codes for the 24 months prior to diagnosis were used to identify 57 individual symptoms. Using a machine learning approach, we trained a logistic regression model on 75% of the data to predict patients who later developed PC and tested the model's performance on the remaining 25%. RESULTS: We were able to identify 41.3% of patients < = 60 years at 'high risk' of developing pancreatic cancer up to 20 months prior to diagnosis with 72.5% sensitivity, 59% specificity and, 66% AUC. 43.2% of patients >60 years were similarly identified at 17 months, with 65% sensitivity, 57% specificity and, 61% AUC. We estimate that combining our algorithm with currently available biomarker tests could result in 30 older and 400 younger patients per cancer being identified as 'potential patients', and the earlier diagnosis of around 60% of tumours. CONCLUSION: After further work this approach could be applied in the primary care setting and has the potential to be used alongside a non-invasive biomarker test to increase earlier diagnosis. This would result in a greater number of patients surviving this devastating disease.

Describing socio-economic variation in life expectancy according to an individual's education, occupation and wage in England and Wales: An analysis of the ONS Longitudinal Study.

People who live in more deprived areas have poorer health outcomes, and this inequality is a major driver of health and social policy. Many interventions targeting these disparities implicitly assume that poorer health is predominantly associated with area-level factors, and that these inequalities are the same for men and women. However, health differentials due to individual socio-economic status (SES) of men and women are less well documented. We used census data linked to the ONS Longitudinal Study to derive individual-level SES in terms of occupation, education and estimated wage, and examined differences in adult mortality and life expectancy. We modelled age-, sex- and SES-specific mortality using Poisson regression, and summarised mortality differences using life expectancy at age 20. We compared the results to those calculated using area-level deprivation metrics. Wide inequalities in life expectancy between SES groups were observed, although differences across SES groups were smaller for women than for men. The widest inequalities were found across men's education (7.2-year (95% CI: 3.0-10.1) difference in life expectancy between groups) and wage (7.0-year (95% CI: 3.5-9.8) difference), and women's education (5.4-year (95% CI: 2.2-8.1) difference). Men with no qualifications had the lowest life expectancy of all groups. In terms of the number of years' difference in life expectancy, the inequalities measured here with individual-level data were of a similar magnitude to inequalities identified previously using area-level deprivation metrics. These data show that health inequalities are as strongly related to individual SES as to area-level deprivation, highlighting the complementary usefulness of these different metrics. Indeed, poor outcomes are likely to be a product of both community and individual influences. Current policy which bases health spending decisions on evidence of inequalities between geographical areas may overlook individual-level SES inequalities for those living in affluent areas, as well as missing important sex differences.

Survival from twenty adult cancers in the UK and Republic of Ireland in the late twentieth century.

BACKGROUND: International studies have shown that cancer survival was generally low in the UK and the Republic of Ireland compared to western and northern European countries, but no systematic comparative analysis has been performed between the UK countries and the Republic of Ireland. METHODS: Population-based survival for 20 adult malignancies was estimated for the UK and the Republic of Ireland. Data on adults (15-99 years) diagnosed between 1991 and 1999 in England, Scotland, Wales, Northern Ireland (1993-99) and the Republic of Ireland (1994-99) were analysed. All cases were followed up until the end of 2001. Relative survival was estimated by sex, period of diagnosis and country, and for the nine regions of England. Predicted survival was estimated using the hybrid approach. RESULTS: Overall, cancer survival in UK and Republic of Ireland improved during the 1990s, but there was geographic variation in survival across the UK and Republic of Ireland. Survival was generally highest in Ireland and Northern Ireland and lowest in England and Wales. Survival tended to be higher in Scotland for cancers for which early detection methods were in place. In England, survival tended to be lower in the north and higher in the south. CONCLUSIONS: The geographic variations in survival seen across the UK and Republic of Ireland are narrower than between these countries and comparable European countries. Artefact is likely to explain some, but not all of the differences across the UK and Republic of Ireland. Geographic differences in stage at diagnosis, co-morbidity and other clinical factors may also be relevant.

Population-based cancer survival trends in England and Wales up to 2007: an assessment of the NHS cancer plan for England.

BACKGROUND: The National Health Service (NHS) cancer plan for England was published in 2000, with the aim of improving the survival of patients with cancer. By contrast, a formal cancer strategy was not implemented in Wales until late 2006. National data on cancer patient survival in England and Wales up to 2007 thus offer the opportunity for a first formal assessment of the cancer plan in England, by comparing survival trends in England with those in Wales before, during, and after the implementation of the plan. METHODS: We analysed population-based survival in 2.2 million adults diagnosed with one of 21 common cancers in England and Wales during 1996-2006 and followed up to Dec 31, 2007. We defined three calendar periods: 1996-2000 (before the cancer plan), 2001-03 (initialisation), and 2004-06 (implementation). We estimated year-on-year trends in 1-year relative survival for patients diagnosed during each period, and changes in those trends between successive periods in England and separately in Wales. Changes between successive periods in mean survival up to 5 years after diagnosis were analysed by country and by government office region of England. Life tables for single year of age, sex, calendar year, deprivation category, and government office region were used to control for background mortality in all analyses. FINDINGS: 1-year survival in England and Wales improved for most cancers in men and women diagnosed during 1996-2006 and followed until 2007, although not all trends were significant. Annual trends were generally higher in Wales than in England during 1996-2000 and 2001-03, but higher in England than in Wales during 2004-06. 1-year survival for patients diagnosed in 2006 was over 60% for 12 of 17 cancers in men and 13 of 18 cancers in women. Differences in 3-year survival trends between England and Wales were less marked than the differences in 1-year survival. North-South differences in survival trends for the four most common cancers were not striking, but the North West region and Wales showed the smallest improvements during 2001-03 and 2004-06. INTERPRETATION: The findings indicate slightly faster improvement in 1-year survival in England than in Wales during 2004-06, whereas the opposite was true during 2001-03. This reversal of survival trends in 2001-03 and 2004-06 between England and Wales is much less obvious for 3-year survival. These different patterns of survival suggest some beneficial effect of the NHS cancer plan for England, although the data do not so far provide a definitive assessment of the effectiveness of the plan.

Assessment of the concordance between individual-level and area-level measures of socio-economic deprivation in a cancer patient cohort in England and Wales.

OBJECTIVES: Most research on health inequalities uses aggregated deprivation scores assigned to the small area where the patient lives; however, the concordance between aggregate area-level deprivation measures and personal deprivation experienced by individuals living in the area is poorly understood. Our objective was to examine the agreement between individual and ecological deprivation. We tested the concordance between metrics of income, occupation and education at individual and area levels, and assessed the reliability of area-based deprivation measures to predict individual deprivation circumstances. SETTING: England and Wales. PARTICIPANTS: A cancer patient cohort of 9547 individuals extracted from the Office for National Statistics Longitudinal Study. OUTCOMES: We quantified the concordance between measures of income, occupation and education at individual and area level. In addition, we used ROC (receiver operating characteristic) curves and the area under the curve (AUC) to assess the reliability of area-based deprivation measures to predict individual deprivation circumstances. RESULTS: We found low concordance between individual-level and area-level indicators of deprivation (Cramer's V statistics range between 0.07 and 0.20). The most commonly used indicator in health inequalities research, area-based income deprivation, was a poor predictor of individual income status (AUC between 0.56 and 0.59), whereas education and occupation were slightly better predictors (AUC between 0.62 and 0.65). The results were consistent across sexes and across six major cancer types. CONCLUSIONS: Our results indicate that ecological deprivation measures capture only part of the relationship between deprivation and health outcomes, especially with respect to income measurement. This has important implications for our understanding of the relationship between deprivation and health, and, as a consequence, healthcare policy. The results have a wide-reaching impact for the way in which we measure and monitor inequalities, and in turn, fund and organise current UK healthcare policy aimed at reducing them.