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1.  Variability in Tuberculosis Granuloma T Cell Responses Exists, but a Balance of Pro- and Anti-inflammatory Cytokines Is Associated with Sterilization 
PLoS Pathogens  2015;11(1):e1004603.
Lung granulomas are the pathologic hallmark of tuberculosis (TB). T cells are a major cellular component of TB lung granulomas and are known to play an important role in containment of Mycobacterium tuberculosis (Mtb) infection. We used cynomolgus macaques, a non-human primate model that recapitulates human TB with clinically active disease, latent infection or early infection, to understand functional characteristics and dynamics of T cells in individual granulomas. We sought to correlate T cell cytokine response and bacterial burden of each granuloma, as well as granuloma and systemic responses in individual animals. Our results support that each granuloma within an individual host is independent with respect to total cell numbers, proportion of T cells, pattern of cytokine response, and bacterial burden. The spectrum of these components overlaps greatly amongst animals with different clinical status, indicating that a diversity of granulomas exists within an individual host. On average only about 8% of T cells from granulomas respond with cytokine production after stimulation with Mtb specific antigens, and few “multi-functional” T cells were observed. However, granulomas were found to be “multi-functional” with respect to the combinations of functional T cells that were identified among lesions from individual animals. Although the responses generally overlapped, sterile granulomas had modestly higher frequencies of T cells making IL-17, TNF and any of T-1 (IFN-γ, IL-2, or TNF) and/or T-17 (IL-17) cytokines than non-sterile granulomas. An inverse correlation was observed between bacterial burden with TNF and T-1/T-17 responses in individual granulomas, and a combinatorial analysis of pair-wise cytokine responses indicated that granulomas with T cells producing both pro- and anti-inflammatory cytokines (e.g. IL-10 and IL-17) were associated with clearance of Mtb. Preliminary evaluation suggests that systemic responses in the blood do not accurately reflect local T cell responses within granulomas.
Author Summary
The characteristic feature of Mycobacterium tuberculosis (Mtb) infection is the formation of lesions, which are organized structures of immune cells in the lungs called granulomas, which contain the bacteria. When the granuloma functions effectively, it can kill the bacteria. T cells (a type of immune cell, also present in granulomas) are known to play an important role in control of tuberculosis. However, functions of T cells at individual granuloma levels are unknown. Here, we studied the functional characteristics of T cells, which are defined by the production of chemical messengers (cytokines) at the granuloma level in a non-human primate model. We compared the relationship between cytokine response and the number of bacteria (Mtb) in each granuloma. Each granuloma was found to be unique, suggesting different types exist within an animal. Only a small proportion of T cells produced any cytokine, but different types of cytokines were observed within each granuloma. A balance between different types of cytokine was associated with more killing of bacteria in granulomas. Understanding how to improve the T cell responses to obtain killing of bacteria in the granuloma will be important for vaccine development.
doi:10.1371/journal.ppat.1004603
PMCID: PMC4303275  PMID: 25611466
2.  Early Changes by 18Fluorodeoxyglucose Positron Emission Tomography Coregistered with Computed Tomography Predict Outcome after Mycobacterium tuberculosis Infection in Cynomolgus Macaques 
Infection and Immunity  2014;82(6):2400-2404.
Cynomolgus macaques infected with low-dose Mycobacterium tuberculosis develop both active tuberculosis and latent infection similar to those of humans, providing an opportunity to study the clinically silent early events in infection. 18Fluorodeoxyglucose radiotracer with positron emission tomography coregistered with computed tomography (FDG PET/CT) provides a noninvasive method to measure disease progression. We sought to determine temporal patterns of granuloma evolution that distinguished active-disease and latent outcomes. Macaques (n = 10) were infected with low-dose M. tuberculosis with FDG PET/CT performed during infection. At 24 weeks postinfection, animals were classified as having active disease (n = 3) or latent infection (n = 6), with one “percolator” monkey. Imaging characteristics (e.g., lesion number, metabolic activity, size, mineralization, and distribution of lesions) were compared among active and latent groups. As early as 3 weeks postinfection, more pulmonary granulomas were observed in animals that would later develop active disease than in those that would develop latent infection. Over time, new lesions developed in active-disease animals but not in latent animals. Granulomas and mediastinal lymph nodes from active-disease but not latent animals consistently increased in metabolic activity at early time points. The presence of fewer lesions at 3 weeks and the lack of new lesion development in animals with latent infection suggest that innate and rapid adaptive responses are critical to preventing active tuberculosis. A greater emphasis on innate responses and/or rapid recruitment of adaptive responses, especially in the airway, should be emphasized in newer vaccine strategies.
doi:10.1128/IAI.01599-13
PMCID: PMC4019174  PMID: 24664509
3.  Sterilization of granulomas is common in both active and latent tuberculosis despite extensive within-host variability in bacterial killing 
Nature medicine  2013;20(1):75-79.
Over 30% of the world’s population is infected with Mycobacterium tuberculosis (Mtb), yet only ~5–10% will develop clinical disease1. Despite considerable effort, we understand little about what distinguishes individuals who progress to active tuberculosis (TB) from those who remain latent for decades. The variable course of disease is recapitulated in cynomolgus macaques infected with Mtb2. Active disease in macaques is defined by clinical, microbiologic and immunologic signs and occurs in ~45% of animals, while the remaining are clinically asymptomatic2,3. Here, we use barcoded Mtb isolates and quantitative measures of culturable and cumulative bacterial burden to show that most lesions are likely founded by a single bacterium and reach similar maximum burdens. Despite common origins, the fate of individual lesions varies substantially within the same host. Strikingly, in active disease, the host sterilizes some lesions even while others progress. Our data suggest that lesional heterogeneity arises, in part, through differential killing of bacteria after the onset of adaptive immunity. Thus, individual lesions follow diverse and overlapping trajectories, suggesting critical responses occur at a lesional level to ultimately determine the clinical outcome of infection. Defining the local factors that dictate outcome will be important in developing effective interventions to prevent active TB.
doi:10.1038/nm.3412
PMCID: PMC3947310  PMID: 24336248
4.  Breast cancer survival and stage at diagnosis in Australia, Canada, Denmark, Norway, Sweden and the UK, 2000-2007: a population-based study 
British Journal of Cancer  2013;108(5):1195-1208.
Background:
We investigate whether differences in breast cancer survival in six high-income countries can be explained by differences in stage at diagnosis using routine data from population-based cancer registries.
Methods:
We analysed the data on 257 362 women diagnosed with breast cancer during 2000–7 and registered in 13 population-based cancer registries in Australia, Canada, Denmark, Norway, Sweden and the UK. Flexible parametric hazard models were used to estimate net survival and the excess hazard of dying from breast cancer up to 3 years after diagnosis.
Results:
Age-standardised 3-year net survival was 87–89% in the UK and Denmark, and 91–94% in the other four countries. Stage at diagnosis was relatively advanced in Denmark: only 30% of women had Tumour, Nodes, Metastasis (TNM) stage I disease, compared with 42–45% elsewhere. Women in the UK had low survival for TNM stage III–IV disease compared with other countries.
Conclusion:
International differences in breast cancer survival are partly explained by differences in stage at diagnosis, and partly by differences in stage-specific survival. Low overall survival arises if the stage distribution is adverse (e.g. Denmark) but stage-specific survival is normal; or if the stage distribution is typical but stage-specific survival is low (e.g. UK). International differences in staging diagnostics and stage-specific cancer therapies should be investigated.
doi:10.1038/bjc.2013.6
PMCID: PMC3619080  PMID: 23449362
breast cancer; survival; stage; population-based
5.  Differential Virulence and Disease Progression following Mycobacterium tuberculosis Complex Infection of the Common Marmoset (Callithrix jacchus) 
Infection and Immunity  2013;81(8):2909-2919.
Existing small-animal models of tuberculosis (TB) rarely develop cavitary disease, limiting their value for assessing the biology and dynamics of this highly important feature of human disease. To develop a smaller primate model with pathology similar to that seen in humans, we experimentally infected the common marmoset (Callithrix jacchus) with diverse strains of Mycobacterium tuberculosis of various pathogenic potentials. These included recent isolates of the modern Beijing lineage, the Euro-American X lineage, and M. africanum. All three strains produced fulminant disease in this animal with a spectrum of progression rates and clinical sequelae that could be monitored in real time using 2-deoxy-2-[18F]fluoro-d-glucose (FDG) positron emission tomography (PET)/computed tomography (CT). Lesion pathology at sacrifice revealed the entire spectrum of lesions observed in human TB patients. The three strains produced different rates of progression to disease, various extents of extrapulmonary dissemination, and various degrees of cavitation. The majority of live births in this species are twins, and comparison of results from siblings with different infecting strains allowed us to establish that the infection was highly reproducible and that the differential virulence of strains was not simply host variation. Quantitative assessment of disease burden by FDG-PET/CT provided an accurate reflection of the pathology findings at necropsy. These results suggest that the marmoset offers an attractive small-animal model of human disease that recapitulates both the complex pathology and spectrum of disease observed in humans infected with various M. tuberculosis strain clades.
doi:10.1128/IAI.00632-13
PMCID: PMC3719573  PMID: 23716617
6.  Gravity and the Evolution of Cardiopulmonary Morphology in Snakes 
Physiological investigations of snakes have established the importance of heart position and pulmonary structure in contexts of gravity effects on blood circulation. Here we investigate morphological correlates of cardiopulmonary physiology in contexts related to ecology, behavior and evolution. We analyze data for heart position and length of vascular lung in 154 species of snakes that exhibit a broad range of characteristic behaviors and habitat associations. We construct a composite phylogeny for these species, and we codify gravitational stress according to species habitat and behavior. We use conventional regression and phylogenetically independent contrasts to evaluate whether trait diversity is correlated with gravitational habitat related to evolutionary transitions within the composite tree topology. We demonstrate that snake species living in arboreal habitats, or which express strongly climbing behaviors, possess relatively short blood columns between the heart and the head, as well as relatively short vascular lungs, compared to terrestrial species. Aquatic species, which experience little or no gravity stress in water, show the reverse – significantly longer heart–head distance and longer vascular lungs. These phylogenetic differences complement the results of physiological studies and are reflected in multiple habitat transitions during the evolutionary histories of these snake lineages, providing strong evidence that heart–to–head distance and length of vascular lung are co–adaptive cardiopulmonary features of snakes.
doi:10.1016/j.cbpa.2011.10.029
PMCID: PMC3242868  PMID: 22079804
heart; lung; circulation; phylogeny; hydrostatic pressure; aquatic; arboreal
7.  Erythrocyte Antioxidant Protection of Rose Hips (Rosa spp.) 
Rose hips are popular in health promoting products as the fruits contain high content of bioactive compounds. The aim of this study was to investigate whether health benefits are attributable to ascorbic acid, phenols, or other rose-hip-derived compounds. Freeze-dried powder of rose hips was preextracted with metaphosphoric acid and the sample was then sequentially eluted on a C18 column. The degree of amelioration of oxidative damage was determined in an erythrocyte in vitro bioassay by comparing the effects of a reducing agent on erythrocytes alone or on erythrocytes pretreated with berry extracts. The maximum protection against oxidative stress, 59.4 ± 4.0% (mean ± standard deviation), was achieved when incubating the cells with the first eluted meta-phosphoric extract. Removal of ascorbic acid from this extract increased the protection against oxidative stress to 67.9 ± 1.9%. The protection from the 20% and 100% methanol extracts was 20.8 ± 8.2% and 5.0 ± 3.2%, respectively. Antioxidant uptake was confirmed by measurement of catechin by HPLC-ESI-MS in the 20% methanol extract. The fact that all sequentially eluted extracts studied contributed to protective effects on the erythrocytes indicates that rose hips contain a promising level of clinically relevant antioxidant protection.
doi:10.1155/2012/621579
PMCID: PMC3399354  PMID: 22829958
8.  Socioeconomic inequalities in cancer survival in England after the NHS cancer plan 
British Journal of Cancer  2010;103(4):446-453.
Background:
Socioeconomic inequalities in survival were observed for many cancers in England during 1981–1999. The NHS Cancer Plan (2000) aimed to improve survival and reduce these inequalities. This study examines trends in the deprivation gap in cancer survival after implementation of the Plan.
Materials and method:
We examined relative survival among adults diagnosed with 1 of 21 common cancers in England during 1996–2006, followed up to 31 December 2007. Three periods were defined: 1996–2000 (before the Cancer Plan), 2001–2003 (initialisation) and 2004–2006 (implementation). We estimated the difference in survival between the most deprived and most affluent groups (deprivation gap) at 1 and 3 years after diagnosis, and the change in the deprivation gap both within and between these periods.
Results:
Survival improved for most cancers, but inequalities in survival were still wide for many cancers in 2006. Only the deprivation gap in 1-year survival narrowed slightly over time. A majority of the socioeconomic disparities in survival occurred soon after a cancer diagnosis, regardless of the cancer prognosis.
Conclusion:
The recently observed reduction in the deprivation gap was minor and limited to 1-year survival, suggesting that, so far, the Cancer Plan has little effect on those inequalities. Our findings highlight that earlier diagnosis and rapid access to optimal treatment should be ensured for all socioeconomic groups.
doi:10.1038/sj.bjc.6605752
PMCID: PMC2939774  PMID: 20588275
relative survival; deprivation; socioeconomic inequalities; health policy
9.  Cancer mortality in ethnic South Asian migrants in England and Wales (1993–2003): patterns in the overall population and in first and subsequent generations 
British Journal of Cancer  2010;102(9):1438-1443.
Background:
Cancer mortality has been examined among ethnic South Asian migrants in England and Wales, but not by generation of migration.
Methods:
Using South Asian mortality records, identified by a name-recognition algorithm, and census information, age-standardised rates among South Asians, and South Asian vs non-South Asian rate ratios, were calculated.
Results and conclusions:
All-cancer rates in ethnic South Asians were half of those in non-South Asians in first-generation (all-cancer-standardised mortality ratio (SMR) in males 0.51 and in females 0.56) and subsequent-generation South Asians (SMR in males 0.43 and in females 0.36). The higher mortality in first-generation South Asians for liver (both sexes), oral cavity and gallbladder cancer (females), particularly marked among Bangladeshis, was reduced in subsequent generations.
doi:10.1038/sj.bjc.6605645
PMCID: PMC2865755  PMID: 20424619
cancer mortality; migrants: England and Wales; Asian continental ancestry group; health transition
10.  Characterisation of a dendritic cell subset in synovial tissue which strongly expresses Jak/STAT transcription factors from patients with rheumatoid arthritis 
Annals of the Rheumatic Diseases  2007;66(8):992-999.
Objectives
To characterise the phenotype of the putative dendritic cells strongly expressing Jak3 and STAT4, which have been previously identified in the synovial tissue of patients with active rheumatoid arthritis (RA).
Methods
Synovial biopsy specimens were obtained at arthroscopy from 30 patients with active RA (42 synovial biopsies). Immunohistological analysis was performed using monoclonal antibodies to detect dendritic cell subsets, including activation markers and cytokines relevant to dendritic cell function. Co‐localisation of cell surface markers and cytokines was assessed primarily using sequential sections, with results confirmed by dual immunohistochemistry and immunofluorescence with confocal microscopy.
Results
The dendritic cells identified in RA synovial tissue that strongly express Jak3 also strongly express STAT4 and STAT 6 and are correlated with the presence of serum rheumatoid factor. These cells are not confined to a single dendritic cell subset, with cells having phenotypes consistent with both myeloid‐ and plasmacytoid‐type dendritic cells. The activation status of these dendritic cells suggests that they are maturing or mature dendritic cells. These dendritic cells produce IL12 as well as interferon α and γ.
Conclusions
The close correlation of these dendritic cells with the presence of serum rheumatoid factor, a prognostic factor for worse disease outcome, and the strong expression by these cells of components of the Jak/STAT transcription factor pathway suggest a potential therapeutic target for the treatment of RA.
doi:10.1136/ard.2006.060822
PMCID: PMC1954703  PMID: 17223651
rheumatoid arthritis; myeloid dendritic cells; plasmacytoid dendritic cells; IL12; interferon alpha; interferon gamma
11.  No socioeconomic inequalities in colorectal cancer survival within a randomised clinical trial 
British Journal of Cancer  2008;99(11):1923-1928.
There is strong evidence that colorectal cancer survival differs between socioeconomic groups. We analysed data on 2481 patients diagnosed during 1989–1997 and recruited to a randomised controlled clinical trial (AXIS, ISRCTN32414363) of chemotherapy and radiotherapy for colorectal cancer. Crude and relative survival at 1 and 5 years was estimated in five categories of socioeconomic deprivation. Multiple imputation was used to account for missing data on tumour stage. A multivariable fractional polynomial model was fitted to estimate the excess hazard of death in each deprivation category, adjusting for the confounding effects of age, stage, cancer site (colon, rectum) and sex, using generalised linear models. Relative survival in the trial patients was higher than in the general population of England and Wales. The socioeconomic gradient in survival was much smaller than that seen for colorectal cancer patients in the general population, both at 1 year −3.2% (95% CI −7.3 to 1.0%, P=0.14) and at 5 years −1.7% (95% CI −8.3 to 4.9%, P=0.61). Given equal treatment, colorectal cancer survival in England and Wales does not appear to depend on socioeconomic status, suggesting that the socioeconomic gradient in survival in the general population could well be due to health-care system factors.
doi:10.1038/sj.bjc.6604743
PMCID: PMC2600684  PMID: 19034284
colorectal cancer; rectum cancer; cancer survival; deprivation; cancer registries
12.  Changes in synovial tissue Jak‐STAT expression in rheumatoid arthritis in response to successful DMARD treatment 
Annals of the Rheumatic Diseases  2006;65(12):1558-1564.
Background
Modulation of Jak‐STAT signalling may provide an effective therapeutic strategy in inflammatory arthritis (IA).
Objective
To examine the effect of successful disease‐modifying antirheumatic drug (DMARD) treatment on the expression of Jak‐STAT in a cohort of patients with active rheumatoid arthritis.
Methods
Synovial tissue biopsy specimens from 16 patients with active rheumatoid arthritis, taken before and after initiation of DMARD treatment, were examined for the presence of janus kinase (Jak)3, signal transducer and activator of transcription (STAT)1, STAT4 and STAT6 expression using immunohistochemistry.
Results
Successful treatment with DMARDs results in reduction in STAT1 expression in the lining, and STAT1 and STAT6 in the sublining of rheumatoid arthritis synovial tissue. Although the overall expression of STAT4 and Jak3 was not significantly altered by DMARD treatment, there was a significant reduction in the expression of the STAT4 and Jak3 bright cells, thought to be an activated dendritic cell subpopulation.
Conclusion
Results show that Jak3, STAT1, STAT4 expression and STAT6 sublining expression decrease in response to successful treatment of rheumatoid arthritis with standard DMARDs. Therefore, altering the expression of these pathways may represent an alternative treatment option, either through promoting up‐regulation of inhibitory pathways, or suppressing inflammatory paths.
doi:10.1136/ard.2005.050385
PMCID: PMC1798468  PMID: 16760256
13.  Combined PET and low-dose, noncontrast CT scanning obviates the need for additional diagnostic contrast-enhanced CT scans in patients undergoing staging or restaging for lymphoma 
Annals of Oncology  2008;19(10):1770-1773.
Background: Positron emission tomography (PET) is more accurate than computed tomography (CT) in staging and restaging of lymphoma, but both are considered necessary. Increasingly, PET is carried out with a low-dose CT scan. Many patients undergo both PET/CT and standard diagnostic CT. The clinical utility of performing both studies in patients with lymphoma was evaluated.
Patients and methods: Patients with lymphoma who underwent concurrent PET/CT and diagnostic CT (a scan pair) were identified, and findings detected in either scan but not both were documented. Discrepancies were considered significant if they were related to either lymphoma or another disease process which potentially required intervention.
Results: Eighty-seven scan pairs were identified. PET/CT detected additional lesions over diagnostic CT in 30 patients, of which 11 demonstrated increased clinical stage. Lymphoma therapy changed based on PET/CT in two patients, and one occult rectal cancer was detected. In contrast, diagnostic CT detected five relevant findings, including two incidental findings (venous thrombosis) and three patients with splenic lesions, none of which could be confirmed as lymphoma. No patient had change of stage or lymphoma therapy based on diagnostic CT.
Conclusion: In our series, diagnostic CT did not add value to staging or restaging of lymphoma when carried out concurrently with PET/CT.
doi:10.1093/annonc/mdn282
PMCID: PMC2735066  PMID: 18550578
lymphoma; PET/CT; staging
14.  Childhood leukaemia: long-term excess mortality and the proportion ‘cured' 
British Journal of Cancer  2008;99(1):219-223.
Survival from childhood leukaemia has increased, but the proportion of children cured is unknown. The proportion ‘cured' is defined as the proportion of survivors for whom, as a group, there is no longer excess mortality compared to the general population. Average time to cure is defined as the time since diagnosis at which the excess mortality rate has declined to or below a predetermined small value. Data on children diagnosed with leukaemia during 1971–2000 in Great Britain were used to estimate trends in survival, the proportion cured and the average time to cure. Five-year survival for all types of leukaemia combined rose from 33 to 79% by 2000. The percentage cured rose from 25 to 68% by 1995; it is predicted to increase to 73% for those diagnosed more recently. Average time to cure increased from 12 years (95% confidence interval (CI): 11–14) to 19 years (95% CI: 14–26) for lymphoid leukaemia (average annual increase of 0.3 years; P<0.001), but remained at about 5 years for acute nonlymphoblastic leukaemia. The proportion of children cured of leukaemia has risen dramatically, but the period of excess mortality associated with lymphoid leukaemia has also increased, possibly because of late relapse, secondary malignancy and toxicity from treatment.
doi:10.1038/sj.bjc.6604466
PMCID: PMC2453011  PMID: 18594545
survival; cure; childhood leukaemia; trends
15.  Expression of Jak3, STAT1, STAT4, and STAT6 in inflammatory arthritis: unique Jak3 and STAT4 expression in dendritic cells in seropositive rheumatoid arthritis 
Annals of the Rheumatic Diseases  2005;65(2):149-156.
Background
Modulation of Jak‐STAT signalling may provide an effective therapeutic strategy in inflammatory arthritis.
Objective
To document Jak‐STAT expression in a cohort of patients with active rheumatoid arthritis (RA), spondyloarthritis (SpA), and osteoarthritis (OA) and compare these subsets with normal synovial tissue.
Methods
Synovial tissue biopsy specimens from patients with RA, OA, and SpA and histologically normal tissue (n = 10 in each arthritis group) were examined for the presence of Jak3, STAT1, STAT4, and STAT6 expression using immunohistochemistry. Phenotyping was performed using immunohistochemistry and immunofluorescence. Clinical and serological characteristics of patients with RA expressing Jak3‐STAT4 were assessed.
Results
STAT1, STAT4, and Jak3 protein expression was generally increased in inflammatory arthritis. In contrast, STAT6 expression was relatively heterogeneous. A subpopulation of CD1a positive dendritic cells unique to seropositive patients with RA was detected. These cells showed intense protein expression for Jak3, STAT4, and STAT6.
Conclusion
CD1a positive dendritic cells intensely express Jak3, STAT4, and STAT6 in seropositive RA tissue and may be an alternative marker for dendritic cells in their early stages of activation as well as providing a tool for identifying RA at the level of the synovium. Jak3 inhibition may be a potential therapeutic target to prevent dendritic cell maturation in RA. STAT1 expression is increased in inflammatory arthritis, suggesting that its pro‐apoptotic and anti‐inflammatory effects cannot effectively counteract inflammation. STAT6 expression is heterogeneous in synovium, suggesting a possible homoeostatic role in addition to any anti‐inflammatory effects.
doi:10.1136/ard.2005.037929
PMCID: PMC1798020  PMID: 16096332
dendritic cells; rheumatoid arthritis; transcription factors
16.  Increasing incidence of childhood leukaemia: a controversy re-examined 
British Journal of Cancer  2007;97(7):1009-1012.
We provide evidence of a gradual increase in the incidence of childhood leukaemia over the twentieth century from examination of trends in both incidence and mortality in England and Wales. We conclude that much of the recorded increase is likely to be real.
doi:10.1038/sj.bjc.6603946
PMCID: PMC2360402  PMID: 17712312
childhood leukaemia; incidence; mortality; trends
17.  Socioeconomic inequalities in cancer survival in Scotland 1986–2000 
British Journal of Cancer  2007;97(7):999-1004.
We analysed trends in 5-year survival of the 18 commonest cancers in Scotland diagnosed between 1986 and 2000 and followed up to 2004 in each of five deprivation groups based on patients postcode of residence at diagnosis. We estimated relative survival up to 5 years after diagnosis, adjusting for the different background mortality in each deprivation group by age, sex and calendar period. We estimated trends in overall survival and in the deprivation gap in survival up to 2004. Five-year survival improved for all malignancies except bladder cancer and was associated with a widening in the deprivation gap in survival. For 25 of 30 cancer–sex combinations examined, 5-year survival was lower among more deprived patients diagnosed during 1996–2000, and the deprivation gap in survival had widened since 1986–1990 for 15 of these 25 cancers, similar to the trends seen in England and Wales.
doi:10.1038/sj.bjc.6603980
PMCID: PMC2360415  PMID: 17876331
deprivation; socioeconomic inequalities; relative survival; Scotland
18.  Measuring the quality of referral letters about patients with upper gastrointestinal symptoms 
Postgraduate Medical Journal  2005;81(957):467-469.
Background: General practitioners state the reason for referring patients in referral letters. The paucity of information in these letters has been the source of criticism from specialist colleagues.
Objective: To invite general practitioners to set standards for referral letters to gastroenterologists and to apply these standards to actual referral letters to one specialist gastroenterology unit.
Methods: A scoring schedule was designed based on the responses to a questionnaire survey of a large sample of all general practitioners in one locality. Altogether 350 consecutive letters to a district general hospital about patients referred for an upper gastrointestinal specialist opinion were subsequently scored using the schedule.
Results: 102 practitioners responded to the survey. Their responses imply that colleagues assess and record findings on 18 potential features of upper bowel disease. In practice most referral letters address fewer than six features of upper bowel disease. The mean number of positive features of upper gastrointestinal disease reported in each letter was one.
Conclusions: This study reported a failure to meet "peer defined" standards for the content of referral letters set by colleagues in one locality. Referral letters serve many purposes, however, encouraging full documentation of specific clinical findings may serve to increase the pre-referral assessments performed in practice.
doi:10.1136/pgmj.2004.027516
PMCID: PMC1743314  PMID: 15998825
19.  Breast cancer survival in South Asian women in England and Wales 
Study objectives: To estimate ethnic and socioeconomic differences in breast cancer incidence and survival between South Asians and non-South Asians in England and Wales, and to provide a baseline for surveillance of cancer survival in South Asians, the largest ethnic minority.
Setting: 115 712 women diagnosed with first primary invasive breast cancer in England and Wales during 1986–90 and followed up to 1995.
Methods/design: Ethnic group was ascribed by a computer algorithm on the basis of the name. Incidence rates were derived from 1991 census population denominators for each ethnic group. One and five year relative survival rates were estimated by age, quintile of material deprivation, and ethnic group, using national mortality rates to estimate expected survival.
Main results: Age standardised incidence was 29% lower among South Asian women (40.5 per 100 000 per year) than among all other women (57.4 per 100 000). Five year age standardised relative survival was 70.3% (95%CI 65.2 to 75.4) for South Asian women and 66.7% (66.4 to 67.0) for other women. For both ethnic groups, survival was 8%–9% higher for women in the most affluent group than those in the most deprived group. In each deprivation category, however, survival was 3%–8% higher for South Asian women than other women.
Conclusions: This national study confirms that breast cancer incidence is substantially lower in South Asians than other women in England and Wales. It also provides some evidence that South Asian women diagnosed up to 1990 had higher breast cancer survival than other women in England and Wales, both overall and in each category of deprivation.
doi:10.1136/jech.2004.030965
PMCID: PMC1733081  PMID: 15831690
20.  Predicted trends in long-term breast cancer survival in England and Wales 
British Journal of Cancer  2007;96(7):1135-1138.
Trends in long-term relative survival from breast cancer are examined for women diagnosed in England and Wales up to 2001, using both period and hybrid approaches. Large improvements in long-term survival are predicted. Women with breast cancer still experience persistent excess mortality up to at least 20 years after diagnosis.
doi:10.1038/sj.bjc.6603668
PMCID: PMC2360119  PMID: 17406350
breast cancer; women; relative survival; long-term; trends; England and Wales
23.  Geographical variation in life expectancy at birth in England and Wales is largely explained by deprivation 
Study objective: To describe the population mortality profile of England and Wales by deprivation and in each government office region (GOR) during 1998, and to quantify the influence of geography and deprivation in determining life expectancy.
Design: Construction of life tables describing age specific mortality rates and life expectancy at birth from death registrations and estimated population counts. Life tables were created for (a) quintiles of income deprivation based on the income domain score of the index of multiple deprivation 2000, (b) each GOR and Wales, and (c) every combination of deprivation and geography.
Setting: England and Wales.
Patients/participants: Residents of England and Wales, 1998.
Main results: Life expectancy at birth varies with deprivation quintile and is highest in the most affluent groups. The differences are mainly attributable to differences in mortality rates under 75 years of age. Regional life expectancies display a clear north-south gradient. Linear regression analysis shows that deprivation explains most of the geographical variation in life expectancy.
Conclusions: Geographical patterns of life expectancy identified within these data for England and Wales in 1998 are mainly attributable to variations in deprivation status as defined by the IMD 2000 income domain score.
doi:10.1136/jech.2003.013003
PMCID: PMC1733001  PMID: 15650142
24.  Survival differences between European and US patients with colorectal cancer: role of stage at diagnosis and surgery 
Gut  2005;54(2):268-273.
Background: Population based colorectal cancer survival among patients diagnosed in 1985–89 was lower in Europe than in the USA (45% v 59% five year relative survival).
Aims: To explain this difference in survival using a new analytic approach for patients diagnosed between 1990 and 1991.
Subjects: A total of 2492 European and 11 191 US colorectal adenocarcinoma patients registered by 10 European and nine US cancer registries.
Methods: We obtained clinical information on disease stage, number of lymph nodes examined, and surgical treatment. We analysed three year relative survival, calculating relative excess risks of death (RERs, referent category US patients) adjusted for age, sex, site, surgery, stage, and number of nodes examined, using a new multivariable approach.
Results: We found that 85% of European patients and 92% of US patients underwent surgical resection. Three year relative survival was 69% for US patients and 57% for European patients. After adjustment for age, sex, and site, the RER was significantly high in all 10 European populations, ranging from 1.07 (95% confidence interval 0.86–1.32) (Modena, Italy) to 2.22 (1.79–2.76) (Thames, UK). After further adjustment for stage, surgical resection, and number of nodes examined (a determinant of stage), RERs ranged from 0.77 (0.62–0.96) to 1.59 (1.28–1.97). For some European registries the excess risk was small and not statistically significant.
Conclusions: US-Europe survival differences in colorectal cancer are large but seem to be mostly attributable to differences in stage at diagnosis. There are wide variations in diagnostic and surgical practice between Europe and the USA.
doi:10.1136/gut.2004.044214
PMCID: PMC1774819  PMID: 15647193
colorectal cancer; population based cancer registries; surgery; lymph nodes; survival; USA; Europe
25.  Survival trends for small intestinal cancer in England and Wales, 1971–1990: national population-based study 
British Journal of Cancer  2006;95(9):1296-1300.
This population-based study examines prognostic factors and survival trends among adults (15–99 years) diagnosed with small intestinal cancer in England and Wales during 1971–1990 and followed up to 1995. During this period, the 1- and 5-year age-standardised relative survival rates for small intestinal cancers combined were 42% and 23%, respectively. Duodenal tumours, adenocarcinomas, men, patients with advanced age and the most deprived patients had the poorest prognosis. For all small bowel tumours combined, the excess risk of death fell significantly by 6–9% every 4 years over the 20-year period (adjusted excess hazard ratio (EHR) 0.91 at 1 year after diagnosis, 0.94 at 5 years). For duodenal tumours, the EHR fell by about 14% (95% CI 5–22%) every 4 years between 1979 and 1990, and a similar trend for jejunal tumours was of borderline significance. Further population-based investigations linking survival data to individual data on diagnostic methods and types of treatment are needed.
doi:10.1038/sj.bjc.6603417
PMCID: PMC2360562  PMID: 17031398
small intestinal cancers; relative survival; trends; prognostic factors; population-based

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