The impact of eliminating age inequalities in stage at diagnosis on breast cancer survival for older women.

BACKGROUND: Older women with breast cancer have poorer relative survival outcomes, but whether achieving earlier stage at diagnosis would translate to substantial reductions in mortality is uncertain. METHODS: We analysed data on East of England women with breast cancer (2006-2010) aged 70+ years. We estimated survival for different stage-deprivation-age group strata using both the observed and a hypothetical stage distribution (assuming that all women aged 75+ years acquired the stage distribution of those aged 70-74 years). We subsequently estimated deaths that could be postponed beyond 5 years from diagnosis if women aged 75+ years had the hypothetical stage distribution. We projected findings to the English population using appropriate age and socioeconomic group weights. RESULTS: For a typically sized annual cohort in the East of England, 27 deaths in women with breast cancer aged 75+ years can be postponed within 5 years from diagnosis if their stage distribution matched that of the women aged 70-74 years (4.8% of all 566 deaths within 5 years post diagnosis in this population). Under assumptions, we estimate that the respective number for England would be 280 deaths (5.0% of all deaths within 5 years post diagnosis in this population). CONCLUSIONS: The findings support ongoing development of targeted campaigns aimed at encouraging prompt presentation in older women.This article is an independent research supported by different funding bodies, beyond the authors’ own employing organisations. MJR was partially funded by a Cancer Research UK Postdoctoral Fellowship (CRUK_A13275). GL is supported by a Postdoctoral Fellowship award by the National Institute for Health Research (NIHR PDF-2011-04-047) to end of 2014 and a Cancer Research UK Clinician Scientist Fellowship award (A18180) from 2015. We thank all staff at the National Cancer Registration Service, Public Health England, Eastern Office who helped collect and code data used in this study. We particularly acknowledge the help of Dr Clement H Brown and Dr Brian A Rous who were responsible for staging.This is the final published version. It first appeared at http://www.nature.com/bjc/journal/v112/n1s/full/bjc201551a.html#ack

Missing data and chance variation in public reporting of cancer stage at diagnosis: Cross-sectional analysis of population-based data in England

This is the final published version. Available from Elsevier via the DOI in this record.Background: The percentage of cancer patients diagnosed at an early stage is reported publicly for geographically-defined populations corresponding to healthcare commissioning organisations in England, and linked to pay-for-performance targets. Given that stage is incompletely recorded, we investigated the extent to which this indicator reflects underlying organisational differences rather than differences in stage completeness and chance variation. Methods We used population-based data on patients diagnosed with one of ten cancer sites in 2013 (bladder, breast, colorectal, endometrial, lung, ovarian, prostate, renal, NHL, and melanoma). We assessed the degree of bias in CCG (Clinical Commissioning Group) indicators introduced by missing-is-late and complete-case specifications compared with an imputed ‘gold standard’. We estimated the Spearman-Brown (organisation-level) reliability of the complete-case specification. We assessed probable misclassification rates against current pay-for-performance targets. Results Under the missing-is-late approach, bias in estimated CCG percentage of tumours diagnosed at an early stage ranged from −2 to −30 percentage points, while bias under the complete-case approach ranged from −2 to +7 percentage points. Using an annual reporting period, indicators based on the least biased complete-case approach would have poor reliability, misclassifying 27/209 (13%) CCGs against a pay-for-performance target in current use; only half (53%) of CCGs apparently exceeding the target would be correctly classified in terms of their underlying performance. Conclusions Current public reporting schemes for cancer stage at diagnosis in England should use a complete-case specification (i.e. the number of staged cases forming the denominator) and be based on three-year reporting periods. Early stage indicators for the studied geographies should not be used in pay-for-performance schemes.Cancer Research U

Envelope Determinants of Equine Lentiviral Vaccine Protection

Lentiviral envelope (Env) antigenic variation and associated immune evasion present major obstacles to vaccine development. The concept that Env is a critical determinant for vaccine efficacy is well accepted, however defined correlates of protection associated with Env variation have yet to be determined. We reported an attenuated equine infectious anemia virus (EIAV) vaccine study that directly examined the effect of lentiviral Env sequence variation on vaccine efficacy. The study identified a significant, inverse, linear correlation between vaccine efficacy and increasing divergence of the challenge virus Env gp90 protein compared to the vaccine virus gp90. The report demonstrated approximately 100% protection of immunized ponies from disease after challenge by virus with a homologous gp90 (EV0), and roughly 40% protection against challenge by virus (EV13) with a gp90 13% divergent from the vaccine strain. In the current study we examine whether the protection observed when challenging with the EV0 strain could be conferred to animals via chimeric challenge viruses between the EV0 and EV13 strains, allowing for mapping of protection to specific Env sequences. Viruses containing the EV13 proviral backbone and selected domains of the EV0 gp90 were constructed and in vitro and in vivo infectivity examined. Vaccine efficacy studies indicated that homology between the vaccine strain gp90 and the N-terminus of the challenge strain gp90 was capable of inducing immunity that resulted in significantly lower levels of post-challenge virus and significantly delayed the onset of disease. However, a homologous N-terminal region alone inserted in the EV13 backbone could not impart the 100% protection observed with the EV0 strain. Data presented here denote the complicated and potentially contradictory relationship between in vitro virulence and in vivo pathogenicity. The study highlights the importance of structural conformation for immunogens and emphasizes the need for antibody binding, not neutralizing, assays that correlate with vaccine protection. © 2013 Craigo et al

The Formation and Evolution of the First Massive Black Holes

The first massive astrophysical black holes likely formed at high redshifts (z>10) at the centers of low mass (~10^6 Msun) dark matter concentrations. These black holes grow by mergers and gas accretion, evolve into the population of bright quasars observed at lower redshifts, and eventually leave the supermassive black hole remnants that are ubiquitous at the centers of galaxies in the nearby universe. The astrophysical processes responsible for the formation of the earliest seed black holes are poorly understood. The purpose of this review is threefold: (1) to describe theoretical expectations for the formation and growth of the earliest black holes within the general paradigm of hierarchical cold dark matter cosmologies, (2) to summarize several relevant recent observations that have implications for the formation of the earliest black holes, and (3) to look into the future and assess the power of forthcoming observations to probe the physics of the first active galactic nuclei.Comment: 39 pages, review for "Supermassive Black Holes in the Distant Universe", Ed. A. J. Barger, Kluwer Academic Publisher

The impact of eliminating age inequalities in stage at diagnosis on breast cancer survival for older women

This is the final published version. Available from Springer Nature via the DOI in this record.BACKGROUND: Older women with breast cancer have poorer relative survival outcomes, but whether achieving earlier stage at diagnosis would translate to substantial reductions in mortality is uncertain.METHODS: We analysed data on East of England women with breast cancer (2006-2010) aged 70+ years. We estimated survival for different stage-deprivation-age group strata using both the observed and a hypothetical stage distribution (assuming that all women aged 75+ years acquired the stage distribution of those aged 70-74 years). We subsequently estimated deaths that could be postponed beyond 5 years from diagnosis if women aged 75+ years had the hypothetical stage distribution. We projected findings to the English population using appropriate age and socioeconomic group weights.RESULTS: For a typically sized annual cohort in the East of England, 27 deaths in women with breast cancer aged 75+ years can be postponed within 5 years from diagnosis if their stage distribution matched that of the women aged 70-74 years (4.8% of all 566 deaths within 5 years post diagnosis in this population). Under assumptions, we estimate that the respective number for England would be 280 deaths (5.0% of all deaths within 5 years post diagnosis in this population).CONCLUSIONS: The findings support ongoing development of targeted campaigns aimed at encouraging prompt presentation in older women.Cancer Research UKCancer Research UKNational Institute for Health Research (NIHR

The influence of patient case mix on public health area statistics for cancer stage at diagnosis: a cross-sectional study

This is the final version. Available on open access from OUP via the DOI in this recordBACKGROUND: statistics comparing the stage at diagnosis of geographically defined populations of cancer patients are increasingly used in public reporting to monitor geographical inequalities but may be confounded by patient case mix. We explore the impact of case-mix adjustment on a publicly reported measure of early stage at diagnosis in England. METHODS: We analyzed data used for publicly reported statistics about the stage of patients diagnosed with 1 of 11 solid tumours in 2015 in England, including information on cancer site (bladder, breast, colon, rectum, kidney, lung, melanoma, non-Hodgkin lymphoma, ovarian, prostate, endometrial), age, gender, income deprivation and population-based commissioning organization. We investigated how cancer site and other patient characteristics influence organizational comparisons and attainment of early-stage targets (≥60% of all cases diagnosed in TNM stages I-II). RESULTS: Adjusting for patient case mix reduced between-organization variance by more than 50%, resulting in appreciable discordance in organizational ranks (Kendall's tau = 0.53), with 18% (37/207) of organizations being reclassified as meeting/failing the early-stage target due to case mix. CONCLUSION: Summary statistics on stage of cancer diagnosis for geographical populations currently used as public health surveillance tools to monitor organizational inequalities need to account for patient sociodemographic characteristics and cancer site case mix.Cancer Research U

Variation in advanced stage at diagnosis of lung and female breast cancer in an English region 2006-2009

This is the final published version. Available from Springer Nature via the DOI in this record.Background: Understanding variation in stage at diagnosis can inform interventions to improve the timeliness of diagnosis for patients with different cancers and characteristics. Methods: We analysed population-based data on 17 836 and 13 286 East of England residents diagnosed with (female) breast and lung cancer during 2006-2009, with stage information on 16 460 (92%) and 10 435 (79%) patients, respectively. Odds ratios (ORs) of advanced stage at diagnosis adjusted for patient and tumour characteristics were derived using logistic regression. Results :We present adjusted ORs of diagnosis in stages III/IV compared with diagnosis in stages I/II. For breast cancer, the frequency of advanced stage at diagnosis increased stepwise among old women (ORs: 1.21, 1.46, 1.68 and 1.78 for women aged 70-74, 75-79, 80-84 and ≥85, respectively, compared with those aged 65-69, P<0.001). In contrast, for lung cancer advanced stage at diagnosis was less frequent in old patients (ORs: 0.82, 0.74, 0.73 and 0.66, P<0.001). Advanced stage at diagnosis was more frequent in more deprived women with breast cancer (OR: 1.23 for most compared with least deprived, P=0.002), and in men with lung cancer (OR: 1.14, P=0.011). The observed patterns were robust to sensitivity analyses approaches for handling missing stage data under different assumptions. Conclusion: Interventions to help improve the timeliness of diagnosis of different cancers should be targeted at specific age groups. © 2012 Cancer Research UK All rights reserved

Socio-demographic inequalities in stage of cancer diagnosis: Evidence from patients with female breast,lung, colon, rectal, prostate, renal, bladder, melanoma, ovarian and endometrial cancer

This is the final published version. Available from Oxford University Press via the DOI in this record.Background: Understanding socio-demographic inequalities in stage at diagnosis can inform priorities for cancer control. Patients and methods: We analysed data on the stage at diagnosis of East of England patients diagnosed with any of 10 common cancers, 2006-2010. Stage information was available on 88 657 of 98 942 tumours (89.6%). Results: Substantial socio-demographic inequalities in advanced stage at diagnosis (i.e. stage III/IV) existed for seven cancers, but their magnitude and direction varied greatly by cancer: advanced stage at diagnosis was more likely for older patients with melanoma but less likely for older patients with lung cancer [odds ratios for 75-79 versus 65-69 1.60 (1.38-1.86) and 0.83 (0.77-0.89), respectively]. Deprived patients were more likely to be diagnosed in advanced stage for melanoma, prostate, endometrial and (female) breast cancer: odds ratios (most versus least deprived quintile) from 2.24 (1.66-3.03) for melanoma to 1.31 (1.15-1.49) for breast cancer. In England, elimination of sociodemographic inequalities in stage at diagnosis could decrease the number of patients with cancer diagnosed in advanced stage by 5600 annually. Conclusions: There are substantial socio-demographic inequalities in stage at diagnosis for most cancers. Earlier detection interventions and policies can be targeted on patients at higher risk of advanced stage diagnosis. ©The Author 2012.National Institute for Health Research (NIHR

Hypernovae and Other Black-Hole-Forming Supernovae

During the last few years, a number of exceptional core-collapse supernovae (SNe) have been discovered. Their kinetic energy of the explosions are larger by more than an order of magnitude than the typical values for this type of SNe, so that these SNe have been called `Hypernovae'. We first describe how the basic properties of hypernovae can be derived from observations and modeling. These hypernovae seem to come from rather massive stars, thus forming black holes. On the other hand, there are some examples of massive SNe with only a small kinetic energy. We suggest that stars with non-rotating black holes are likely to collapse "quietly" ejecting a small amount of heavy elements (Faint supernovae). In contrast, stars with rotating black holes are likely to give rise to very energetic supernovae (Hypernovae). We present distinct nucleosynthesis features of these two types of "black-hole-forming" supernovae. Hypernova nucleosynthesis is characterized by larger abundance ratios (Zn,Co,V,Ti)/Fe and smaller (Mn,Cr)/Fe. Nucleosynthesis in Faint supernovae is characterized by a large amount of fall-back. We show that the abundance pattern of the most Fe deficient star, HE0107-5240, and other extremely metal-poor carbon-rich stars are in good accord with those of black-hole-forming supernovae, but not pair-instability supernovae. This suggests that black-hole-forming supernovae made important contributions to the early Galactic (and cosmic) chemical evolution.Comment: 49 pages, to be published in "Stellar Collapse" (Astrophysics and Space Science; Kluwer) ed. C. L. Fryer (2003