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1.  Survival of patients with small cell lung cancer undergoing lung resection in England, 1998–2009 
Thorax  2013;69(3):269-273.
Introduction
Chemotherapy or chemoradiotherapy is the recommended treatment for small cell lung cancer (SCLC), except in stage I disease where clinical guidelines state there may be a role for surgery based on favourable outcomes in case series. Evidence supporting adjuvant chemotherapy in resected SCLC is limited but this is widely offered.
Methods
Data on 359 873 patients who were diagnosed with a first primary lung cancer in England between 1998 and 2009 were grouped according to histology (SCLC or non-SCLC (NSCLC)) and whether they underwent a surgical resection. We explored their survival using Kaplan–Meier analysis and Cox regression, adjusting for age, sex, comorbidity and socioeconomic status.
Results
The survival of 465 patients with resected SCLC was lower than patients with resected NSCLC (5-year survival 31% and 45%, respectively), but much higher than patients of either group who were not resected (3%). The difference between resected SCLC and NSCLC diminished with time after surgery. Survival was superior for the subgroup of 198 ‘elective’ SCLC cases where the diagnosis was most likely known before resection than for the subgroup of 267 ‘incidental’ cases where the SCLC diagnosis was likely to have been made after resection.
Conclusions
These data serve as a natural experiment testing the survival after surgical management of SCLC according to NSCLC principles. Patients with SCLC treated surgically for early stage disease may have survival outcomes that approach those of NSCLC, supporting the emerging clinical practice of offering surgical resection to selected patients with SCLC.
doi:10.1136/thoraxjnl-2013-203884
PMCID: PMC3932952  PMID: 24172710
Lung Cancer; Small Cell Lung Cancer
2.  A cohort study on mental disorders, stage of cancer at diagnosis and subsequent survival 
BMJ Open  2014;4(1):e004295.
Objectives
To assess the stage at cancer diagnosis and survival after cancer diagnosis among people served by secondary mental health services, compared with other local people.
Setting
Using the anonymised linkage between a regional monopoly secondary mental health service provider in southeast London of four London boroughs, Croydon, Lambeth, Lewisham and Southwark, and a population-based cancer register, a historical cohort study was constructed.
Participants
A total of 28 477 cancer cases aged 15+ years with stage of cancer recorded at diagnosis were identified. Among these, 2206 participants had been previously assessed or treated in secondary mental healthcare before their cancer diagnosis and 125 for severe mental illness (schizophrenia, schizoaffective or bipolar disorders).
Primary and secondary outcome measures
Stage when cancer was diagnosed and all-cause mortality after cancer diagnosis among cancer cases registered in the geographical area of southeast London.
Results
Comparisons between people with and without specific psychiatric diagnosis in the same residence area for risks of advanced stage of cancer at diagnosis and general survival after cancer diagnosed were analysed using logistic and Cox models. No associations were found between specific mental disorder diagnoses and beyond local spread of cancer at presentation. However, people with severe mental disorders, depression, dementia and substance use disorders had significantly worse survival after cancer diagnosis, independent of cancer stage at diagnosis and other potential confounders.
Conclusions
Previous findings of associations between mental disorders and cancer mortality are more likely to be accounted for by differences in survival after cancer diagnosis rather than by delayed diagnosis.
doi:10.1136/bmjopen-2013-004295
PMCID: PMC3913023  PMID: 24477317
Cancer Stage at Diagnosis; Case Register Linkage; Severe Mental Illness; Survival
3.  An improved prognostic model for stage T1a and T1b prostate cancer by assessments of cancer extent 
Treatment decisions on prostate cancer diagnosed by trans-urethral resection (TURP) of the prostate are difficult. The current TNM staging system for pT1 prostate cancer has not been re-evaluated for 25 years. Our objective was to optimise the predictive power of tumor extent measurements in TURP of the prostate specimens. A total of 914 patients diagnosed by TURP of the prostate between 1990 and 1996, managed conservatively were identified. The clinical end point was death from prostate cancer. Diagnostic serum prostate-specific antigen (PSA) and contemporary Gleason grading was available. Cancer extent was measured by the percentage of chips infiltrated by cancer. Death rates were compared by univariate and multivariate proportional hazards models, including baseline PSA and Gleason score. The percentage of positive chips was highly predictive of prostate cancer death when assessed as a continuous variable or as a grouped variable on the basis of and including the quintiles, quartiles, tertiles and median groups. In the univariate model, the most informative variable was a four group-split (≤ 10%, >10–25%, > 25–75% and > 75%); (HR = 2.08, 95% CI = 1.8–2.4, P < 0.0001). The same was true in a multivariate model (ΔX2 (1 d.f.) = 15.0, P = 0.0001). The current cutoff used by TNM (< = 5%) was sub-optimal (ΔX2 (1 d.f.) = 4.8, P = 0.023). The current TNM staging results in substantial loss of information. Staging by a four-group subdivision would substantially improve prognostication in patients with early stage disease and also may help to refine management decisions in patients who would do well with conservative treatments.
doi:10.1038/modpathol.2010.182
PMCID: PMC3853363  PMID: 20834240
conservative treatment; prostate cancer; stage; trans-urethral resection of prostate; watchful waiting
4.  Measurements of cancer extent in a conservatively treated prostate cancer biopsy cohort 
Virchows Archiv : an international journal of pathology  2010;457(5):10.1007/s00428-010-0971-z.
The optimal method for measuring cancer extent in prostate biopsy specimens is unknown. Seven hundred forty-four patients diagnosed between 1990 and 1996 with prostate cancer and managed conservatively were identified. The clinical end point was death from prostate cancer. The extent of cancer was measured in terms of number of cancer cores (NCC), percentage of cores with cancer (PCC), total length of cancer (LCC) and percentage length of cancer in the cores (PLC). These were correlated with prostate cancer mortality, in univariate and multivariate analysis including Gleason score and prostate-specific antigen (PSA). All extent of cancer variables were significant predictors of prostate cancer death on univariate analysis: NCC, hazard ration (HR)=1.15, 95% confidence interval (CI)=1.04–1.28, P=0.011; PPC, HR=1.01, 95% CI=1.01–1.02, P<0.0001; LCC, HR=1.02, 95% CI=1.01–1.03, P=0.002; PLC, HR=1.01, 95% CI=1.01–1.02, P=0.0001. In multivariate analysis including Gleason score and baseline PSA, PCC and PLC were both independently significant P=0.004 and P=0.012, respectively, and added further information to that provided by PSA and Gleason score, whereas NNC and LCC were no longer significant (P=0.5 and P=0.3 respectively). In a final model, including both extent of cancer variables, PCC was the stronger, adding more value than PLC (χ2 (1df)=7.8, P=0.005, χ2 (1df)=0.5, P=0.48 respectively). Measurements of disease burden in needle biopsy specimens are significant predictors of prostate-cancer-related death. The percentage of positive cores appeared the strongest predictor and was stronger than percentage length of cancer in the cores.
doi:10.1007/s00428-010-0971-z
PMCID: PMC3853376  PMID: 20827488
Prostate biopsy; Prostate cancer; Biopsy; prognostic factors; Tumour extent
5.  Are alarm symptoms predictive of cancer survival? 
The British Journal of General Practice  2013;63(617):e807-e812.
Background
Alarm symptom presentations are predictive of cancer diagnosis but may also be associated with cancer survival.
Aim
To evaluate diagnostic time intervals, and consultation patterns after presentation with alarm symptoms, and their association with cancer diagnosis and survival.
Design and setting
Cohort study using the Clinical Practice Research Database, with linked Cancer Registry data, in 158 general practices.
Method
Participants included those with haematuria, haemoptysis, dysphagia, and rectal bleeding or urinary tract cancer, lung cancer, gastro-oesophageal cancer, and colorectal cancer.
Results
The median (interquartile range) interval in days from first symptom presentation to the corresponding cancer diagnosis was: haematuria and urinary tract cancer, 59 (28–109); haemoptysis and lung cancer, 35 (18–89); dysphagia and gastro-oesophageal cancer, 25 (12–48); rectal bleeding and colorectal cancer, 49 (20–157). Three or more alarm symptom consultations were associated with increased odds of diagnosis of urinary tract cancer (odds ratio [OR] 1.84, 95% CI = 1.50 to 2.27), lung cancer (OR = 1.76, 95% CI = 1.07 to 2.90) and gastro-oesophageal cancer (OR = 2.17, 95% CI = 1.48 to 3.19). Longer diagnostic intervals were associated with increased mortality only for urinary tract cancer (hazard ratio 2.23, 95% CI = 1.35 to 3.69). Patients with no preceding alarm symptom had shorter survival from diagnosis of urinary tract, lung or colorectal cancer than those presenting with a relevant alarm symptom.
Conclusion
After alarm symptom presentation, repeat consultations are associated with cancer diagnoses. Longer diagnostic intervals appeared to be associated with a worse prognosis for urinary tract cancer only. Mortality is higher when cancer is diagnosed in the absence of alarm symptoms.
doi:10.3399/bjgp13X675197
PMCID: PMC3839389  PMID: 24351496
alarm symptom; colorectal cancer; gastro-oesophageal cancer; general practice; primary care; survival
6.  A model for generating several adaptive phenotypes from a single genetic event 
Microbial populations adapt to environmental fluctuations through random switching of fitness-related traits in individual cells. This increases the likelihood that a subpopulation will be adaptive in a future milieu. However, populations are particularly challenged when several environment factors change simultaneously. We suggest that a population can rapidly adapt to multiple environmental changes if individual members stochastically flip a hub-switch that controls a set of adaptive phenotypes in a single event. This mechanism of coupling phenotypic outcomes via a hub-switch can protect a population against large fluctuations in size. Here we report that the general amino acid transporter Gap1 is a potential hub-switch. The GAP1 gene is flanked by two direct repeats that can lead to GAP1 deletions (∆gap1) and a self-replicating GAP1 circle. Thus, an isogenic GAP1 population can differentiate into two variant, reversible genotypes, ∆gap1 or GAP1circle. These subpopulations have different phenotypic advantages. A ∆gap1 population has a selective advantage on allantoin or ammonium as a nitrogen source and high stress tolerance. Advantages of the GAP1 population include amino acid uptake, fast energy recruitment by trehalose mobilization, and in some cases, adherent biofilm growth. Our proposed model of a hub-switch locus enhances the bet-hedging model of population dynamics.
doi:10.4161/cib.23933
PMCID: PMC3656021  PMID: 23713139
DNA circle; fitness; social; extrachromosomal element; hub-switch; Gap1; evolution; biological adaptation; population dynamics
7.  Pulmonary metastasectomy for sarcoma: a systematic review of reported outcomes in the context of Thames Cancer Registry data 
BMJ Open  2012;2(5):e001736.
Objectives
Sarcoma has a predilection to metastasis to the lungs. Surgical excision of these metastases (pulmonary metastasectomy) when possible has become standard practice. We reviewed the published selection and outcome data.
Design
Systematic review of published reports that include survival rates or any other outcome data. Survival data were put in the context of those in a cancer registry.
Setting
Specialist thoracic surgical centres reporting the selection and outcome for pulmonary metastasectomy in 18 follow-up studies published 1991–2010.
Participants
Patients having one or more of 1357 pulmonary metastasectomy operations performed between 1980 and 2006.
Interventions
All patients had surgical pulmonary metastasectomy. A first operation was reported in 1196 patients. Of 1357 patients, 43% had subsequent metastasectomy, some having 10 or more thoracotomies. Three studies were confined to patients having repeated pulmonary metastasectomy.
Primary and secondary outcome measures
Survival data to various time points usually 5 years and sometimes 3 or 10 years. No symptomatic or quality of life data were reported.
Results
About 34% and 25% of patients were alive 5 years after a first metastasectomy operation for bone or soft tissues sarcoma respectively. Better survival was reported with fewer metastases and longer intervals between diagnosis and the appearance of metastases. In the Thames Cancer Registry for 1985–1994 and 1995–2004 5 year survival rates for all patients with metastatic sarcoma were 20% and 25% for bone, and for soft tissue sarcoma 13% and 15%.
Conclusions
The 5 year survival rate among sarcoma patients who are selected to have pulmonary metastasectomy is higher than that observed among unselected registry data for patients with any metastatic disease at diagnosis. There is no evidence that survival difference is attributable to metastasectomy. No data were found on respiratory or any other symptomatic benefit. Given the certain harm associated with thoracotomy, often repeated, better evidence is required.
doi:10.1136/bmjopen-2012-001736
PMCID: PMC3488730  PMID: 23048062
8.  Nomogram incorporating PSA level to predict cancer-specific survival for men with clinically localized prostate cancer managed without curative intent 
Cancer  2008;112(1):69-74.
Introduction
The prognosis of men with clinically localized prostate cancer is highly variable, and it is difficult to counsel a man who may be considering avoiding, or delaying, aggressive therapy. After collecting data on a large cohort of men who received no initial active prostate cancer therapy, we sought to develop, and to internally validate, a nomogram for prediction of disease-specific survival.
Methods
Working with 6 cancer registries within England and numerous hospitals in the region, we constructed a population-based cohort of men diagnosed with prostate cancer between 1990 and 1996. All men had baseline serum prostate specific antigen (PSA) measurements, centralized pathologic grading, and centralized review of clinical stage assignment. Based upon the clinical and pathological data from 1,911 men, we developed and validated a statistical model that served as the basis for the nomogram. The discrimination and calibration of the nomogram were assessed with use of one third of the men, who were omitted from modeling and used as a test sample.
Results
The median age of the included men was 70.4 years. The 25th and 75th percentiles of PSA were 7.3 and 32.6 ng/ml respectively, and the median was 15.4 ng/ml. Forty-two percent of the men had high grade disease. The nomogram predicted well with a concordance index of 0.73 and had good calibration.
Conclusions
We have developed an accurate tool for predicting the probability that a man with clinically localized prostate cancer will survive his disease for 120 months if the cancer is not treated with curative intent immediately. The tool should be helpful for patient counseling and clinical trial design.
doi:10.1002/cncr.23106
PMCID: PMC3390682  PMID: 18000803
9.  Social differences in lung cancer management and survival in South East England: a cohort study 
BMJ Open  2012;2(3):e001048.
Objective
To examine possible social variations in lung cancer survival and assess if any such gradients can be attributed to social differences in comorbidity, stage at diagnosis or treatment.
Design
Population-based cohort identified in the Thames Cancer Registry.
Setting
South East England.
Participants
15 582 lung cancer patients diagnosed between 2006 and 2008.
Main outcome measures
Stage at diagnosis, surgery, radiotherapy, chemotherapy and survival.
Results
The likelihood of being diagnosed as having early-stage disease did not vary by socioeconomic quintiles (p=0.58). In early-stage non-small-cell lung cancer, the likelihood of undergoing surgery was lowest in the most deprived group. There were no socioeconomic differences in the likelihood of receiving radiotherapy in stage III disease, while in advanced disease and in small-cell lung cancer, receipt of chemotherapy differed over socioeconomic quintiles (p<0.01). In early-stage disease and following adjustment for confounders, the HR between the most deprived and the most affluent group was 1.24 (95% CI 0.98 to 1.56). Corresponding estimates in stage III and advanced disease or small-cell lung cancer were 1.16 (95% CI 1.01 to 1.34) and 1.12 (95% CI 1.05 to 1.20), respectively. In early-stage disease, the crude HR between the most deprived and the most affluent group was approximately 1.4 and constant through follow-up, while in patients with advanced disease or small-cell lung cancer, no difference was detectable after 3 months.
Conclusion
We observed socioeconomic variations in management and survival in patients diagnosed as having lung cancer in South East England between 2006 and 2008, differences which could not fully be explained by social differences in stage at diagnosis, co-morbidity and treatment. The survival observed in the most affluent group should set the target for what is achievable for all lung cancer patients, managed in the same healthcare system.
Article summary
Article focus
Social differences in management and survival in lung cancer patients.
Particular focus on possible social variations in lung cancer survival and assess if any such gradients can be attributed to social differences in co-morbidity, stage at diagnosis or treatment.
Key messages
There were no detectable socioeconomic differences in stage at diagnosis among lung cancer patients in South East England between 2006 and 2008.
Socioeconomic differences in lung cancer management and survival existed. The observed inequalities in survival could not fully be explained by social differences in stage at diagnosis, co-morbidity and treatment factors.
In early-stage disease, social gradients in survival existed throughout follow-up, whereas in advanced disease, variations in survival were confined to the period immediately after diagnosis.
Strengths and limitations of this study
Strengths included the population-based cohort design. The material at hand allowed analyses that accounted for co-morbidity, stage at diagnosis and treatment factors.
Limitations included the absence of data on performance status, forced expiratory volume, smoking history and lifestyle factors.
doi:10.1136/bmjopen-2012-001048
PMCID: PMC3367157  PMID: 22637374
10.  Evaluation of Prediagnostic Prostate-Specific Antigen Dynamics as Predictors of Death from Prostate Cancer in Patients Treated Conservatively 
Prostate-specific antigen (PSA) dynamics have been proposed to predict outcome in men with prostate cancer. We assessed the value of PSA velocity (PSAV) and doubling time (PSADT) for predicting prostate-cancer–specific mortality (PCSM) in men with clinically localized prostate cancer undergoing conservative management or early hormonal therapy. From 1990 to 1996, 2333 patients were identified, of whom 594 had two or more PSA values before diagnosis. We examined 12 definitions for PSADT and 10 for PSAV. Because each definition required PSA measurements at particular intervals, the number of patients eligible for each definition varied from 40 to 594 and number of events from 10 to 119. Four PSAV definitions, but no PSADT, were significantly associated with PCSM after adjustment for PSA in multivariable Cox proportional hazards regression. All 4 could be calculated only for a proportion of events, and the enhancements in predictive accuracy associated with PSAV had very wide confidence intervals. There was no clear benefit of PSAV in men with low PSA and Gleason grade 6 or less. Although evidence that certain PSAV definitions help predict PCSM in the cohort exist, the value of incorporating PSAV in predictive models to assist in determining eligibility for conservative management is, at best, uncertain.
doi:10.1002/ijc.25570
PMCID: PMC2988082  PMID: 20658531
prostate-specific antigen; prostate-specific antigen velocity; prostate-specific antigen doubling time; watchful waiting; prediction
11.  Tea drinking habits and oesophageal cancer in a high risk area in northern Iran: population based case-control study 
Objective To investigate the association between tea drinking habits in Golestan province, northern Iran, and risk of oesophageal squamous cell carcinoma.
Design Population based case-control study. In addition, patterns of tea drinking and temperature at which tea was drunk were measured among healthy participants in a cohort study.
Setting Golestan province, northern Iran, an area with a high incidence of oesophageal squamous cell carcinoma.
Participants 300 histologically proved cases of oesophageal squamous cell carcinoma and 571 matched neighbourhood controls in the case-control study and 48 582 participants in the cohort study.
Main outcome measure Odds ratio of oesophageal squamous cell carcinoma associated with drinking hot tea.
Results Nearly all (98%) of the cohort participants drank black tea regularly, with a mean volume consumed of over one litre a day. 39.0% of participants drank their tea at temperatures less than 60°C, 38.9% at 60-64°C, and 22.0% at 65°C or higher. A moderate agreement was found between reported tea drinking temperature and actual temperature measurements (weighted κ 0.49). The results of the case-control study showed that compared with drinking lukewarm or warm tea, drinking hot tea (odds ratio 2.07, 95% confidence interval 1.28 to 3.35) or very hot tea (8.16, 3.93 to 16.9) was associated with an increased risk of oesophageal cancer. Likewise, compared with drinking tea four or more minutes after being poured, drinking tea 2-3 minutes after pouring (2.49, 1.62 to 3.83) or less than two minutes after pouring (5.41, 2.63 to 11.1) was associated with a significantly increased risk. A strong agreement was found between responses to the questions on temperature at which tea was drunk and interval from tea being poured to being drunk (weighted κ 0.68).
Conclusion Drinking hot tea, a habit common in Golestan province, was strongly associated with a higher risk of oesophageal cancer.
doi:10.1136/bmj.b929
PMCID: PMC3269898  PMID: 19325180
12.  Incidence and survival of oesophageal and gastric cancer in England between 1998 and 2007, a population-based study 
BMC Cancer  2012;12:11.
Background
Major changes in the incidence of oesophageal and gastric cancers have been reported internationally. This study describes recent trends in incidence and survival of subgroups of oesophageal and gastric cancer in England between 1998 and 2007 and considers the implications for cancer services and policy.
Methods
Data on 133,804 English patients diagnosed with oesophageal and gastric cancer between 1998 and 2007 were extracted from the National Cancer Data Repository. Using information on anatomical site and tumour morphology, data were divided into six groups; upper and middle oesophagus, lower oesophagus, oesophagus with an unspecified anatomical site, cardia, non-cardia stomach, and stomach with an unspecified anatomical site. Age-standardised incidence rates (per 100,000 European standard population) were calculated for each group by year of diagnosis and by socioeconomic deprivation. Survival was estimated using the Kaplan-Meier method.
Results
The majority of oesophageal cancers were in the lower third of the oesophagus (58%). Stomach with an unspecified anatomical site was the largest gastric cancer group (53%). The incidence of lower oesophageal cancer increased between 1998 and 2002 and remained stable thereafter. The incidence of cancer of the cardia, non-cardia stomach, and stomach with an unspecified anatomical site declined over the 10 year period. Both lower oesophageal and cardia cancers had a much higher incidence in males compared with females (M:F 4:1). The incidence was also higher in the most deprived quintiles for all six cancer groups. Survival was poor in all sub-groups with 1 year survival ranging from 14.8-40.8% and 5 year survival ranging from 3.7-15.6%.
Conclusions
An increased focus on prevention and early diagnosis, especially in deprived areas and in males, is required to improve outcomes for these cancers. Improved recording of tumour site, stage and morphology and the evaluation of focused early diagnosis programmes are also needed. The poor long-term survival reinforces the need for early detection and multidisciplinary care.
doi:10.1186/1471-2407-12-11
PMCID: PMC3274437  PMID: 22239958
13.  Prognostic value of an RNA expression signature derived from cell cycle proliferation genes for recurrence and death from prostate cancer: A retrospective study in two cohorts 
The lancet oncology  2011;12(3):245-255.
SUMMARY
Background
Optimal management of clinically localized prostate cancer presents unique challenges because of its highly variable and often indolent natural history. To predict disease aggressiveness, clinicians combine clinical parameters to create prognostic models, but the accuracy of current models is very limited. There is significant clinical need for biomarkers that improve our ability to predict disease outcome.
Methods
Using quantitative RT-PCR on RNA from formalin fixed paraffin-embedded tumour samples, we measured the expression level of 31 genes involved in cell cycle progression (CCP genes), created a predefined score and evaluated its ability to predict disease outcome. The signature was tested in a retrospective cohort of 366 patients from the U.S. who had undergone radical prostatectomy, and in a retrospective cohort of 337 men with clinically localized prostate cancer diagnosed by a transurethral resection (TURP) in the UK and managed conservatively.
Findings
The cell cycle progression signature was a highly significant predictor of outcome in both cohorts. After prostatectomy the CCP score predicted biochemical recurrence in univariate (Hazard ratio (HR) for a one unit change in CCP (doubling) = 1.89; 95% CI (1.54, 2.31) χ2 = 34·0, 1df, p = 5·6 × 10−9) and multivariate analysis (HR = 1.74; 95% CI (1.39, 2.17) χ2 = 21·65, 1df, p = 3·3 ×10−6). The CCP score and PSA were the dominant variables in the best predictive model and were much more significant than any other clinical measure. In the TURP cohort, the CCP score was the dominant variable for predicting death from prostate cancer in both univariate (HR= 2.92; 95% CI (2.38, 3.57) χ2 = 92·7, 1df, p = 6.1 × 10−22) and multivariate analyses (χ2 = 42·2, p = 8·2 × 10−11), where it was much stronger than all other prognostic factors. In no case 4 was there significant evidence for heterogeneity in the hazard ratio for the CCP score across any clinical parameter.
Interpretation
The CCP score provides a substantial amount of independent information about the risk of recurrence after radical prostatectomy and the risk of death in conservatively managed prostate cancer diagnosed by TURP. Taken together, these studies provide strong evidence that the CCP score is a highly robust prognostic marker which, after additional validation, could have a central role in determining appropriate treatment for prostate cancer patients.
Funding
Study funded by Cancer Research UK, the Orchid Appeal, US National Institutes of Health (SPORE CA92629), and the Koch Foundation. Molecular testing performed at Myriad Genetics.
doi:10.1016/S1470-2045(10)70295-3
PMCID: PMC3091030  PMID: 21310658
Prostate cancer; predictive model; Cell cycle progression genes
14.  NIR Monitoring of Ammonia in Anaerobic Digesters Using a Diffuse Reflectance Probe 
Sensors (Basel, Switzerland)  2012;12(2):2340-2350.
The feasibility of using a diffuse reflectance probe attached to a near infrared spectrometer to monitor the total ammonia nitrogen (TAN) content in an anaerobic digester run on cattle manure was investigated; as a previous study has indicated that this probe can be easily attached to an anaerobic digester. Multivariate modelling techniques such as partial least squares regression and interval partial least squares methods were used to build models. Various data pre-treatments were applied to improve the models. The TAN concentrations measured were in the range of 1.5 to 5.5 g/L. An R2 of 0.91 with an RMSEP of 0.32 was obtained implying that the probe could be used for monitoring and screening purposes.
doi:10.3390/s120202340
PMCID: PMC3304169  PMID: 22438767
NIRS; biogas; ammonia; inhibition; monitoring; manure; PLS; iPLS
15.  Exposure to Polycyclic Aromatic Hydrocarbons Among Never Smokers in Golestan Province, Iran, an Area of High Incidence of Esophageal Cancer – a Cross-Sectional Study with Repeated Measurement of Urinary 1-OHPG in Two Seasons 
Studies have suggested a possible role of polycyclic aromatic hydrocarbons (PAHs) in the etiology of esophageal cancer in Golestan Province, Iran, where incidence of this cancer is very high. In order to investigate the patterns of non-smoking related exposure to PAHs in Golestan, we conducted a cross-sectional study collecting questionnaire data, genotyping polymorphisms related to PAH metabolism, and measuring levels of 1-hydroxypyrene glucuronide (1-OHPG), a PAH metabolite, in urine samples collected in two seasons from the same group of 111 randomly selected never-smoking women. Beta-coefficients for correlations between 1-OHPG as dependent variable and other variables were calculated using linear regression models. The creatinine-adjusted 1-OHPG levels in both winter and summer samples were approximately 110 μmol/molCr (P for seasonal difference = 0.40). In winter, red meat intake (β = 0.208; P = 0.03), processed meat intake (β = 0.218; P = 0.02), and GSTT1-02 polymorphism (“null” genotype: β = 0.228; P = 0.02) showed associations with 1-OHPG levels, while CYP1B1-07 polymorphism (GG versus AA + GA genotypes: β = –0.256; P = 0.008) showed an inverse association. In summer, making bread at home (> weekly versus never: β = 0.203; P = 0.04), second-hand smoke (exposure to ≥3 cigarettes versus no exposure: β = 0.254; P = 0.01), and GSTM1-02 “null” genotype (β = 0.198; P = 0.04) showed associations with 1-OHPG levels, but GSTP1-02 polymorphism (CT + TT versus CC: β = –0.218; P = 0.03) showed an inverse association. This study confirms high exposure of the general population in Golestan to PAHs and suggests that certain foods, cooking methods, and genetic polymorphisms increase exposure to PAHs.
doi:10.3389/fonc.2012.00014
PMCID: PMC3356003  PMID: 22655262
1-hydroxypyrene glucuronide; esophageal cancer; frying; red meat; polycyclic aromatic hydrocarbon; polymorphism
16.  Predictors of early death in female patients with breast cancer in the UK: a cohort study 
BMJ Open  2011;1(2):e000247.
Objective
To identify factors predicting early death in women with breast cancer.
Design
Cohort study.
Setting
29 trusts across seven cancer networks in the North Thames area.
Participants
15 037 women with primary breast cancer diagnosed between January 1996 and December 2005.
Methods
Logistic regression analyses to determine predictors of early death and factors associated with lack of surgical treatment.
Main exposures
Age at diagnosis, mode of presentation, ethnicity, disease severity, comorbidities, treatment and period of diagnosis in relation to the Cancer Plan (the NHS's strategy in 2000 for investment in and reform of cancer services).
Main outcome measures
Death from any cause within 1 year of diagnosis, and receipt of surgical treatment.
Results
By 31 December 2006, 4765 women had died, 980 in the year after diagnosis. Older age and disease severity independently predicted early death. Women over 80 were more likely to die early than women under 50 (OR 8.05, 95% CI 5.96 to 10.88). Presence of distant metastases on diagnosis increased the odds of early death more than eightfold (OR 8.41, 95% CI 6.49 to 10.89). Two or more recorded comorbidities were associated with a nearly fourfold increase. There was a significant decrease in odds associated with surgery (OR 0.29, 95% CI 0.24 to 0.35). Independently of disease severity and comorbidities, women over 70 were less likely than those under 50 to be treated surgically and this was even more pronounced in those aged over 80 (OR 0.09, 95% CI 0.07 to 0.10). Other factors independently associated with a reduced likelihood of surgery included a non-screening presentation, non-white ethnicity and additional comorbidities.
Conclusions
These findings may partially explain the survival discrepancies between the UK and other European countries in female patients with breast cancer. The study identifies a group of women with a particularly poor prognosis for whom interventions aiming at early detection may be targeted.
Article summary
Article focus
Several studies have shown that the UK has lower survival for breast cancer than some other European countries with a similar expenditure on healthcare.
Differences have been shown to occur mainly in older patients and in the first year after diagnosis.
Several reasons/explanations have been proposed.
Key messages
This study shows that patients with breast cancer dying in the first year after diagnosis are more likely to be older and have more advanced disease and existing comorbidities.
Surgical treatment and (to a lesser extent) radiotherapy and tamoxifen usage were associated with a reduced risk of early death.
The likelihood of receiving surgery was inversely related to age, independently of comorbidity and disease severity.
These findings suggest that early detection, management of comorbidities and optimisation of treatment of older patients are important target areas to improve outcomes.
Strengths and limitations of this study
This is a large cohort of women with a diagnosis of breast cancer, and the results may be generalisable to women treated for breast cancer in the UK during the same time period.
Many variables that may be related to both risk factors and outcomes have not been assessed in this study. However, their correlation with death within a year would have to be very strong to explain the strong associations seen in our data.
doi:10.1136/bmjopen-2011-000247
PMCID: PMC3227804  PMID: 22123920
17.  High level of SOX9 in the prostate contributes to increased proliferation and can cooperate with PTEN loss to accelerate neoplasia formation 
Cancer research  2010;70(3):979-987.
Developmental pathways have been shown to be important in the initiation and progression of cancer in various tissues. We showed that the transcription factor SOX9 is expressed in the epithelia of the mouse embryonic prostate and is required for proper prostate development. We have performed an in vivo investigation into the role of SOX9 in prostate cancer in mouse and human. Studies on Pten and Nkx3.1 mutant mice show that cells with an increased level of SOX9 appear within the epithelia at the early stages of prostate neoplasia and this high expression correlates with all stages of neoplastic progression. Using genetically modified mice we show that overexpression of SOX9 in prostate epithelia leads to an increase in cell proliferation without inducing hyperplasia. In mice that were heterozygous for the conditional mutant allele of Pten, overexpression of SOX9 gave rise to an earlier induction of high-grade prostate intraepithelial neoplasia. Consistent with this role, loss of Sox9 in prostate epithelia led to a decrease in proliferating cells in normal and in homozygous Pten mutant mice with prostate neoplasia. Analysis of a cohort of 880 human prostate cancer samples showed that SOX9 expression is associated with increasing Gleason grades and higher Ki67 staining. These studies identify SOX9 as part of a developmental pathway that is reactivated in prostate neoplasia where it is involved in regulating proliferation and suggests it can contribute to carcinogenesis in specific genetic contexts.
doi:10.1158/0008-5472.CAN-09-2370
PMCID: PMC3083842  PMID: 20103652
18.  Rapid Assessment of Mineral Concentration in Meadow Grasses by Near Infrared Reflectance Spectroscopy 
Sensors (Basel, Switzerland)  2011;11(5):4830-4839.
A near infrared reflectance spectroscopy (NIRS) method for rapid determination of nitrogen, phosphorous and potassium in diverse meadow grasses was developed with a view towards utilizing this material for biogas production and organic fertilizer. NIRS spectra between 12,000 cm−1 and 4,000 cm−1 were used. When validated on samples from different years to those used for the calibration set, the NIRS prediction of nitrogen was considered moderately useful with R2 = 0.77, ratio of standard error of prediction to reference data range (RER) of 9.32 and ratio of standard error of prediction to standard deviation of reference data (RPD) of 2.33. Prediction of potassium was less accurate, with R2 = 0.77, RER of 6.56 and RPD of 1.45, whilst prediction of phosphorous was not considered accurate enough to be of any practical use. This work is of interest from the point of view of both the removal of excess nutrients from formerly intensively farmed areas and also for assessing the plant biomass suitability for conversion into carbon neutral energy through biogas production.
doi:10.3390/s110504830
PMCID: PMC3231399  PMID: 22163878
minerals; grassland; NIR; biogas; eutrophication
19.  Socio-economic status and oesophageal cancer: results from a population-based case–control study in a high-risk area 
Background Cancer registries in the 1970s showed that parts of Golestan Province in Iran had the highest rate of oesophageal squamous cell carcinoma (OSCC) in the world. More recent studies have shown that while rates are still high, they are approximately half of what they were before, which might be attributable to improved socio-economic status (SES) and living conditions in this area. We examined a wide range of SES indicators to investigate the association between different SES components and risk of OSCC in the region.
Methods Data were obtained from a population-based case–control study conducted between 2003 and 2007 with 300 histologically proven OSCC cases and 571 matched neighbourhood controls. We used conditional logistic regression to compare cases and controls for individual SES indicators, for a composite wealth score constructed using multiple correspondence analysis, and for factors obtained from factors analysis.
Results We found that various dimensions of SES, such as education, wealth and being married were all inversely related to OSCC. The strongest inverse association was found with education. Compared with no education, the adjusted odds ratios (95% confidence intervals) for primary education and high school or beyond were 0.52 (0.27–0.98) and 0.20 (0.06–0.65), respectively.
Conclusions The strong association of SES with OSCC after adjustment for known risk factors implies the presence of yet unidentified risk factors that are correlated with our SES measures; identification of these factors could be the target of future studies. Our results also emphasize the importance of using multiple SES measures in epidemiological studies.
doi:10.1093/ije/dyp195
PMCID: PMC2720396  PMID: 19416955
Oesophageal cancer; socio-economic status; case–control; epidemiology; Iran; factor analysis; correspondence analysis
20.  Metastasis-Inducing S100A4 and RANTES Cooperate in Promoting Tumor Progression in Mice 
PLoS ONE  2010;5(4):e10374.
Background
The tumor microenvironment has been described as a critical milieu determining tumor growth and metastases. A pivotal role of metastasis-inducing S100A4 in the development of tumor stroma has been proven in animal models and verified in human breast cancer biopsies. Expression and release of S100A4 has been shown in various types of stroma composing cells, including fibroblasts and immune cells. However, the events implicated in upstream and downstream pathways regulating the activity of the extracellular S100A4 protein in the tumor milieu remain unsolved.
Methodology/Principal Findings
We studied the interplay between the tumor cell-derived cytokine regulated-upon-activation, normal T-cell expressed and secreted (RANTES; CCL5) and S100A4 which were shown to be critical factors in tumor progression. We found that RANTES stimulates the externalization of S100A4 via microparticle shedding from the plasma membrane of tumor and stroma cells. Conversely, the released S100A4 protein induces the upregulation of fibronectin (FN) in fibroblasts and a number of cytokines, including RANTES in tumor cells as well as stimulates cell motility in a wound healing assay. Importantly, using wild type and S100A4-deficient mouse models, we demonstrated a substantial influence of tumor cell-derived RANTES on S100A4 release into blood circulation which ultimately increases the metastatic burden in mice.
Conclusions/Significance
Altogether, the data presented strongly validate the pro-metastatic function of S100A4 in the tumor microenvironment and define how the tumor cell-derived cytokine RANTES acts as a critical regulator of S100A4-dependent tumor cell dissemination. Additionally, for the first time we demonstrated the mechanism of S100A4 release associated with plasma membrane microparticle shedding from various cells types.
doi:10.1371/journal.pone.0010374
PMCID: PMC2860983  PMID: 20442771
21.  Estimating attendance for breast cancer screening in ethnic groups in London 
BMC Public Health  2010;10:157.
Background
Breast screening uptake in London is below the Government's target of 70% and we investigate whether ethnicity affects this. Information on the ethnicity for the individual women invited is unavailable, so we use an area-based method similar to that routinely used to derive a geographical measure for socioeconomic deprivation.
Methods
We extracted 742,786 observations on attendance for routine appointments between 2004 and 2007 collected by the London Quality Assurance Reference Centre. Each woman was assigned to a lower super output (LSOA) based on her postcode of residence. The proportions of the ethnic groups within each LSOA are known, so that the likelihood of a woman belonging to White, Black and Asian groups can be assigned. We investigated screening attendance by age group, socioeconomic deprivation using the Index of Deprivation 2004 income quintile, invitation type and breast screening service. Using logistic regression analysis we calculated odds ratios for attendance based on ethnic composition of the population, adjusting for age, socioeconomic status, the invitation type and screening service.
Results
The unadjusted attendance odds ratios were high for the White population (OR: 3.34 95% CI [3.26-3.42]) and low for the Black population (0.13 [0.12-0.13]) and the Asian population (0.55 [0.53-0.56]). Multivariate adjustment reduced the differences, but the Black population remained below unity (0.47 [0.44-0.50]); while the White (1.30 [1.26-1.35]) and Asian populations (1.10 [1.05-1.15]) were higher. There was little difference in the attendance between age groups. Attendance was highest for the most affluent group and fell sharply with increasing deprivation. For invitation type, the routine recall was higher than the first call. There were wide variations in the attendance for different ethnic groups between the individual screening services.
Conclusions
Overall breast screening attendance is low in communities with large Black populations, suggesting the need to improve participation of Black women. Variations in attendance for the Asian population require further investigation at an individual screening service level.
doi:10.1186/1471-2458-10-157
PMCID: PMC2850886  PMID: 20334699
22.  Trends in the incidence and survival of multiple myeloma in South East England 1985-2004 
BMC Cancer  2010;10:74.
Background
Multiple myeloma is an uncommon cancer with a poor prognosis. Its incidence is expected to increase due to ageing populations and better diagnosis, and new treatments have been developed to improve survival. Our objective was to investigate trends in the epidemiology and survival of multiple myeloma for South East England.
Methods
Data on 15,010 patients diagnosed with multiple myeloma between 1985 and 2004 was extracted from the Thames Cancer Registry database. We calculated the yearly age-standardised incidence rates for males and females and age-specific incidence rates in 10-year age groups for both sexes combined. We also explored geographical variation in incidence across primary care trusts. We then used period analysis to calculate trends in 1- and 5-year relative survival over the 15 years 1990-2004, comparing survival by sex and by age group 59 years and below versus 60 years and above. Finally, we investigated 5-year relative survival for the period 2000-2004 by socio-economic deprivation, assigning patients to quintiles of deprivation using the Income Domain of the Index of Multiple Deprivation 2004 based on postcode of residence.
Results
The incidence of multiple myeloma was higher in males than in females and in patients over 70, throughout the period 1985-2004. No obvious geographical pattern of incidence by primary care trust emerged. The 1- and 5-year relative survival of male and female patients increased in both age groups and was statistically significant in males aged over 60. There was a tendency for better survival in patients resident in the most affluent areas, but this did not reach statistical significance.
Conclusions
The trends in incidence of multiple myeloma in males and females are similar to that reported from other western populations. Relative survival was higher for younger patients although we found significant improvements in 1-year relative survival for male patients over 60 years old. The improved survival demonstrated for patients of all ages is likely to reflect increased detection, earlier diagnosis and the introduction of new treatments. Future studies should investigate the influence of ethnicity on incidence and survival, and the effect of specific treatments on survival and quality of life.
doi:10.1186/1471-2407-10-74
PMCID: PMC2837016  PMID: 20193064
23.  Local Progression among Men with Conservatively Treated Localized Prostate Cancer: Results from the Transatlantic Prostate Group 
European urology  2007;53(2):347-354.
Objectives
Men with clinically detected localized prostate cancer treated without curative intent are at risk of complications from local tumor growth. We investigated rates of local progression and need for local therapy among such men.
Methods
Men diagnosed with prostate cancer during 1990–1996 were identified from cancer registries throughout the United Kingdom. Inclusion criteria were age ≤76 yr at diagnosis, PSA level ≤100 ng/ml, and, within 6 mo after diagnosis, no radiation therapy, radical prostatectomy, evidence of metastatic disease, or death. Local progression was defined as increase in clinical stage from T1/2 to T3/T4 disease, T3 to T4 disease, and/or need for transurethral resection of the prostate (TURP) to relieve symptoms >6 mo after cancer diagnosis.
Results
The study included 2333 men with median follow-up of 85 mo (range: 6–174). Diagnosis was by TURP in 1255 men (54%), needle biopsy in 1039 (45%), and unspecified in 39 (2%). Only 29% were treated with hormonal therapy within 6 mo of diagnosis. Local progression occurred in 335 men, including 212 undergoing TURP. Factors most predictive of local progression on multivariable analysis were PSA at diagnosis and Gleason score of the diagnostic tissue (detrimental), and early hormonal therapy (protective). We present a nomogram that predicts the likelihood of local progression within 120 mo after diagnosis.
Conclusions
Men with clinically detected localized prostate cancer managed without curative intent have an approximately 15% risk for local progression within 10 yr of diagnosis. Among those with progression, the need for treatment is common, even among men diagnosed by TURP. When counseling men who are candidates for management without curative intent, the likelihood of symptoms from local progression must be considered.
doi:10.1016/j.eururo.2007.05.015
PMCID: PMC2646888  PMID: 17544572
Cancer progression; Conservative management; Nomograms; Prostate cancer; Retrospective study; Risk factors; Transurethral resection of the prostate; Treatment outcome; Watchful waiting
24.  Inequalities in the incidence of cervical cancer in South East England 2001–2005: an investigation of population risk factors 
BMC Public Health  2009;9:62.
Background
The incidence of cervical cancer varies dramatically, both globally and within individual countries. The age-standardised incidence of cervical cancer was compared across primary care trusts (PCTs) in South East England, taking into account the prevalence of known behavioural risk factors, screening coverage and the deprivation of the area.
Methods
Data on 2,231 cases diagnosed between 2001 and 2005 were extracted from the Thames Cancer Registry, and data on risk factors and screening coverage were collated from publicly available sources. Age-standardised incidence rates were calculated for each PCT using cases of squamous cell carcinoma in the screening age group (25–64 years).
Results
The age-standardised incidence rate for cervical cancer in South East England was 6.7 per 100,000 population (European standard) but varied 3.1 fold between individual PCTs. Correlations between the age-standardised incidence rate and smoking prevalence, teenage conception rates, and deprivation were highly significant at the PCT level (p < 0.001). However, screening coverage was not associated with the incidence of cervical cancer at the PCT level. Poisson regression indicated that these variables were all highly correlated and could not determine the level of independent contribution at a population level.
Conclusion
There is excess disease burden within South East England. Significant public health gains can be made by reducing exposure to known risk factors at a population level.
doi:10.1186/1471-2458-9-62
PMCID: PMC2650689  PMID: 19232085
25.  Certified causes of death in patients with mesothelioma in South East England 
BMC Cancer  2009;9:28.
Background
Mesothelioma is a highly fatal cancer that is caused by exposure to asbestos fibres. In many populations, the occurrence of mesothelioma is monitored with the use of mortality data from death certification. We examine certified causes of death of patients who have been diagnosed with mesothelioma, and assess the validity of death certification data as a proxy for mesothelioma incidence.
Methods
We extracted mesothelioma registrations in the South East of England area between 2000 and 2004 from the Thames Cancer Registry database. We retained for analysis 2200 patients who had died at the time of analysis, after having excluded seven dead cases where the causes of death were not known to the cancer registry. The 2200 deaths were classified hierarchically to identify (1) mesothelioma deaths, (2) deaths certified as lung cancer deaths or (3) deaths from unspecified cancer, and (4) deaths from other causes.
Results
87% of the patients had mesothelioma mentioned on the death certificate. 6% had no mention of mesothelioma but included lung cancer as a cause of death. Another 6% had no mention of mesothelioma or lung cancer, but included an unspecified cancer as a cause of death. Lastly, 2% had other causes of death specified on the death certificate.
Conclusion
This analysis suggests that official mortality data may underestimate the true occurrence of mesothelioma by around 10%.
doi:10.1186/1471-2407-9-28
PMCID: PMC2639607  PMID: 19166594

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