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1. Breast cancer mortality in 500 000 women with early invasive breast cancer in England, 1993-2015: population based observational cohort study

Author

Taylor, C, McGale, P, Probert, J, Broggio, J, Charman, J, Darby, SC, Kerr, AJ, Whelan, T, Cutter, DJ, Mannu, G, and Dodwell, D

Abstract

Objectives To describe long term breast cancer mortality among women with a diagnosis of breast cancer in the past and estimate absolute breast cancer mortality risks for groups of patients with a recent diagnosis. Design Population based observational cohort study. Setting Routinely collected data from the National Cancer Registration and Analysis Service. Participants All 512 447 women registered with early invasive breast cancer (involving only breast and possibly axillary nodes) in England during January 1993 to December 2015, with follow-up to December 2020. Main outcome measures Annual breast cancer mortality rates and cumulative risks by time since diagnosis, calendar period of diagnosis, and nine characteristics of patients and tumours. Results For women with a diagnosis made within each of the calendar periods 1993-99, 2000-04, 2005-09, and 2010-15, the crude annual breast cancer mortality rate was highest during the five years after diagnosis and then declined. For any given time since diagnosis, crude annual breast cancer mortality rates and risks decreased with increasing calendar period. Crude five year breast cancer mortality risk was 14.4% (95% confidence interval 14.2% to 14.6%) for women with a diagnosis made during 1993-99 and 4.9% (4.8% to 5.0%) for women with a diagnosis made during 2010-15. Adjusted annual breast cancer mortality rates also decreased with increasing calendar period in nearly every patient group, by a factor of about three in oestrogen receptor positive disease and about two in oestrogen receptor negative disease. Considering just the women with a diagnosis made during 2010-15, cumulative five year breast cancer mortality risk varied substantially between women with different characteristics: it was Conclusions These five year breast cancer mortality risks for patients with a recent diagnosis may be used to estimate breast cancer mortality risks for patients today. The prognosis for women with early invasive breast cancer has improved substantially since the 1990s. Most can expect to become long term cancer survivors, although for a few the risk remains appreciable.

Published
2023
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2. Radiation Dose-Response for Risk of Myocardial Infarction in Breast Cancer Survivors

Author

Jacobse, JN, Duane, FK, Boekel, NB, Schaapveld, M, Hauptmann, M, Hooning, Maartje, Seynaeve, Caroline, Baaijens, Margreet, Gietema, JA, Darby, SC, van Leeuwen, FE, Aleman, BMP, Taylor, CW, Jacobse, JN, Duane, FK, Boekel, NB, Schaapveld, M, Hauptmann, M, Hooning, Maartje, Seynaeve, Caroline, Baaijens, Margreet, Gietema, JA, Darby, SC, van Leeuwen, FE, Aleman, BMP, and Taylor, CW

Published
2019

3. Cardiovascular disease incidence after internal mammary chain irradiation and anthracycline-based chemotherapy for breast cancer

Author

Boekel, NB, Jacobse, JN, Schaapveld, M, Hooning, Maartje, Gietema, JA, Duane, FK, Taylor, CW, Darby, SC, Hauptmann, M, Seynaeve, Caroline, Baaijens, Margreet, Sonke, GS, Rutgers, EJT, Russell, NS, Aleman, BMP, van Leeuwen, FE, Boekel, NB, Jacobse, JN, Schaapveld, M, Hooning, Maartje, Gietema, JA, Duane, FK, Taylor, CW, Darby, SC, Hauptmann, M, Seynaeve, Caroline, Baaijens, Margreet, Sonke, GS, Rutgers, EJT, Russell, NS, Aleman, BMP, and van Leeuwen, FE

Published
2018

4. A cardiac contouring atlas for radiotherapy

Author

Duane, F, Aznar, MC, Cutter, DJ, Darby, SC, Jagsi, R, Lorenzen, EL, McArdle, O, McGale, P, Myerson, S, Rahimi, K, Vivekanandan, S, Warren, S, and Taylor, CW

Abstract

Background and Purpose: The heart is a complex anatomical organ and contouring the cardiac substructures is challenging. This study presents a reproducible method for contouring left ventricular and coronary arterial segments on radiotherapy CT-planning scans. Material and Methods: Segments were defined from cardiology models and agreed by two cardiologists. Reference atlas contours were delineated and written guidelines prepared. Six radiation oncologists tested the atlas. Spatial variation was assessed using the DICE similarity coefficient (DSC) and the directed Hausdorff average distance (𝑑⃗𝐻,𝑎𝑣𝑔). The effect of spatial variation on doses was assessed using six different breast cancer regimens. Results: The atlas enabled contouring of 15 cardiac segments. Inter-observer contour overlap (mean DSC) was 0.60-0.73 for five left ventricular segments and 0.10-0.53 for ten coronary arterial segments. Inter-observer contour separation (mean 𝑑⃗𝐻,𝑎𝑣𝑔 ) was 1.5-2.2 mm for left ventricular segments and 1.3-5.1 mm for coronary artery segments. This spatial variation resulted in Conclusions: This cardiac atlas enables reproducible contouring of segments of the left ventricle and main coronary arteries to facilitate future studies relating cardiac radiation doses to clinical outcomes.

Published
2017

7. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015

Author

Hay, S, Gething, PW, Cooper, C, Darby, SC, Ali, RI, Bennett, DA, Jha, V, and Kazem, R

Abstract

Background Improving survival and extending the longevity of life for all populations requires timely, robust evidence on local mortality levels and trends. The Global Burden of Disease 2015 Study (GBD 2015) provides a comprehensive assessment of all-cause and cause-specifi c mortality for 249 causes in 195 countries and territories from 1980 to 2015. These results informed an in-depth investigation of observed and expected mortality patterns based on sociodemographic measures. Methods We estimated all-cause mortality by age, sex, geography, and year using an improved analytical approach originally developed for GBD 2013 and GBD 2010. Improvements included refi nements to the estimation of child and adult mortality and corresponding uncertainty, parameter selection for under-5 mortality synthesis by spatiotemporal Gaussian process regression, and sibling history data processing. We also expanded the database of vital registration, survey, and census data to 14 294 geography–year datapoints. For GBD 2015, eight causes, including Ebola virus disease, were added to the previous GBD cause list for mortality. We used six modelling approaches to assess causespecific mortality, with the Cause of Death Ensemble Model (CODEm) generating estimates for most causes. We used a series of novel analyses to systematically quantify the drivers of trends in mortality across geographies. First, we assessed observed and expected levels and trends of cause-specifi c mortality as they relate to the Socio-demographic Index (SDI), a summary indicator derived from measures of income per capita, educational attainment, and fertility. Second, we examined factors aff ecting total mortality patterns through a series of counterfactual scenarios, testing the magnitude by which population growth, population age structures, and epidemiological changes contributed to shifts in mortality. Finally, we attributed changes in life expectancy to changes in cause of death. We documented each step of the GBD 2015 estimation processes, as well as data sources, in accordance with Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER). Findings Globally, life expectancy from birth increased from 61·7 years (95% uncertainty interval 61·4–61·9) in 1980 to 71·8 years (71·5–72·2) in 2015. Several countries in sub-Saharan Africa had very large gains in life expectancy from 2005 to 2015, rebounding from an era of exceedingly high loss of life due to HIV/AIDS. At the same time, many geographies saw life expectancy stagnate or decline, particularly for men and in countries with rising mortality from war or interpersonal violence. From 2005 to 2015, male life expectancy in Syria dropped by 11·3 years (3·7–17·4), to 62·6 years (56·5–70·2). Total deaths increased by 4·1% (2·6–5·6) from 2005 to 2015, rising to 55·8 million (54·9 million to 56·6 million) in 2015, but age-standardised death rates fell by 17·0% (15·8–18·1) during this time, underscoring changes in population growth and shifts in global age structures. The result was similar for noncommunicable diseases (NCDs), with total deaths from these causes increasing by 14·1% (12·6–16·0) to 39·8 million (39·2 million to 40·5 million) in 2015, whereas age-standardised rates decreased by 13·1% (11·9–14·3). Globally, this mortality pattern emerged for several NCDs, including several types of cancer, ischaemic heart disease, cirrhosis, and Alzheimer’s disease and other dementias. By contrast, both total deaths and age-standardised death rates due to communicable, maternal, neonatal, and nutritional conditions significantly declined from 2005 to 2015, gains largely attributable to decreases in mortality rates due to HIV/AIDS (42·1%, 39·1–44·6), malaria (43·1%, 34·7–51·8), neonatal preterm birth complications (29·8%, 24·8–34·9), and maternal disorders (29·1%, 19·3–37·1). Progress was slower for several causes, such as lower respiratory infections and nutritional defi ciencies, whereas deaths increased for others, including dengue and drug use disorders. Age-standardised death rates due to injuries significantly declined from 2005 to 2015, yet interpersonal violence and war claimed increasingly more lives in some regions, particularly in the Middle East. In 2015, rotaviral enteritis (rotavirus) was the leading cause of under-5 deaths due to diarrhoea (146 000 deaths, 118 000–183 000) and pneumococcal pneumonia was the leading cause of under-5 deaths due to lower respiratory infections (393 000 deaths, 228 000–532 000), although pathogen-specifi c mortality varied by region. Globally, the eff ects of population growth, ageing, and changes in age-standardised death rates substantially differed by cause. Our analyses on the expected associations between cause-specifi c mortality and SDI show the regular shifts in cause of death composition and population age structure with rising SDI. Country patterns of premature mortality (measured as years of life lost [YLLs]) and how they diff er from the level expected on the basis of SDI alone revealed distinct but highly heterogeneous patterns by region and country or territory. Ischaemic heart disease, stroke, and diabetes were among the leading causes of YLLs in most regions, but in many cases, intraregional results sharply diverged for ratios of observed and expected YLLs based on SDI. Communicable, maternal, neonatal, and nutritional diseases caused the most YLLs throughout sub-Saharan Africa, with observed YLLs far exceeding expected YLLs for countries in which malaria or HIV/AIDS remained the leading causes of early death. Interpretation At the global scale, age-specific mortality has steadily improved over the past 35 years; this pattern of general progress continued in the past decade. Progress has been faster in most countries than expected on the basis of development measured by the SDI. Against this background of progress, some countries have seen falls in life expectancy, and age-standardised death rates for some causes are increasing. Despite progress in reducing agestandardised death rates, population growth and ageing mean that the number of deaths from most noncommunicable causes are increasing in most countries, putting increased demands on health systems.

Published
2016

13. Adjuvant chemotherapy in oestrogen-receptor-poor breast cancer: patient-level meta-analysis of randomised trials

Author

Clarke M, Coates AS, Darby SC, Davies C, Gelber RD, Godwin J, Goldhirsch A, Gray R, Peto R, Pritchard KI, Wood WC, Early Breast Cancer Trialists' Collaborative Group, DE LAURENTIIS, MICHELINO, DE PLACIDO, SABINO, Clarke, M, Coates, A, Darby, S, Davies, C, Gelber, R, Godwin, J, Goldhirsch, A, Gray, R, Peto, R, Pritchard, K, Wood, W, Darby, Sc, Gelber, Rd, Pritchard, Ki, Wood, Wc, Early Breast Cancer Trialists' Collaborative, Group, DE LAURENTIIS, Michelino, and DE PLACIDO, Sabino

Subjects
Oncology, medicine.medical_specialty, medicine.medical_treatment, Breast Neoplasms, Disease, Breast cancer, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Adjuvant therapy, Medicine, Humans, Multicenter Studies as Topic, Aged, Randomized Controlled Trials as Topic, Chemotherapy, business.industry, General Medicine, Middle Aged, medicine.disease, Clinical trial, Receptors, Estrogen, Chemotherapy, Adjuvant, Meta-analysis, Female, Neoplasm Recurrence, Local, business, Adjuvant, Tamoxifen, medicine.drug
Abstract

Background The long-term effects of adjuvant polychemotherapy regimens in oestrogen-receptor-poor (ER-poor) breast cancer, and the extent to which these effects are modified by age or tamoxifen use, can be assessed by an updated meta-analysis of individual patient data from randomised trials. Methods Collaborative meta-analyses of individual patient data for about 6000 women with ER-poor breast cancer in 46 trials of polychemotherapy versus not (non-taxane-based polychemotherapy, typically about six cycles; trial start dates 1975–96, median 1984) and about 14 000 women with ER-poor breast cancer in 50 trials of tamoxifen versus not (some trials in the presence and some in the absence of polychemotherapy; trial start dates 1972–93, median 1982). Findings In women with ER-poor breast cancer, polychemotherapy significantly reduced recurrence, breast cancer mortality, and death from any cause, in those younger than 50 years and those aged 50–69 years at entry into trials of polychemotherapy versus not. In those aged younger than 50 years (1907 women, 15% node-positive), the 10-year risks were: recurrence 33% versus 45% (ratio of 10-year risks 0·73, 2p Interpretation In women who had ER-poor breast cancer, and were either younger than 50 years or between 50 and 69 years, these older adjuvant polychemotherapy regimens were safe (ie, had little effect on mortality from causes other than breast cancer) and produced substantial and definite reductions in the 10-year risks of recurrence and death. Current and future chemotherapy regimens could well yield larger proportional reductions in breast cancer mortality.

Published
2008

14. Risk for Valvular Heart Disease After Treatment for Hodgkin Lymphoma

Author

Cutter, DJ, Schaapveld, M, Darby, SC, Hauptmann, M (Michael), van Nimwegen, FA, Krol, ADG, Janus, Cecile, van Leeuwen, FE, Aleman, BMP, Cutter, DJ, Schaapveld, M, Darby, SC, Hauptmann, M (Michael), van Nimwegen, FA, Krol, ADG, Janus, Cecile, van Leeuwen, FE, and Aleman, BMP

Abstract

Background: Hodgkin lymphoma (HL) survivors are at increased risk for developing valvular heart disease (VHD). We evaluated the determinants of the risk and the radiation dose-response. Methods: A case-control study was nested in a cohort of 1852 five-year HL survivors diagnosed at ages 15 to 41 years and treated between 1965 and 1995. Case patients had VHD of at least moderate severity as their first cardiovascular diagnosis following HL treatment. Control patients were matched to case patients for age, gender, and HL diagnosis date. Treatment and follow-up data were abstracted from medical records. Radiation doses to heart valves were estimated by reconstruction of individual treatments on representative computed tomography datasets. All statistical tests were two-sided. Results: Eighty-nine case patients with VHD were identified (66 severe or life-threatening) and 200 control patients. Aortic (n = 63) and mitral valves (n = 42) were most frequently affected. Risks increased more than linearly with radiation dose. For doses to the affected valve(s) of less than or equal to 30, 31-35, 36-40, and more than 40 Gy, VHD rates increased by factors of 1.4, 3.1, 5.4, and 11.8, respectively (P-trend < .001). Approximate 30-year cumulative risks were 3.0%, 6.4%, 9.3%, and 12.4% for the same dose categories. VHD rate increased with splenectomy by a factor of 2.3 (P = .02). Conclusions: Radiation dose to the heart valves can increase the risk for clinically significant VHD, especially at doses above 30 Gy. However, for patients with mediastinal involvement treated today with 20 or 30 Gy, the 30-year risk will be increased by only about 1.4%. These findings may be useful for patients and doctors both before treatment and during follow-up.

Published
2015

15. Secondhand smoke exposure in adulthood and risk of lung cancer among never smokers: a pooled analysis of two large studies

Author

Brennan, P, Bluffer, Pa, Reynolds, P, Wu, Ah, Wichmann, He, Agudo, A, Pershagen, G, Joeckel, Kh, Benhamou, S, Greenberg, Rs, Merletti, F, Winck, C, Fontham, Eth, Kreuzer, M, Darby, Sc, Forastiere, F, Simonato, Lorenzo, Boffetta, P., Brennan, P., Buffler, P.A., Reynolds, P., Wu, A.H., Wichmann, H.E., Agudo, A., Pershagen, G., Jöckel, K.-H., Benhamou, S., Greenberg, R.S., Merlett, F., Winck, C., Fontham, E.T.H., Kreuzer, M., Darby, S.C., Forastiere, F., Simonato, L., and Boffetta, P.

Subjects
Male, Risk, Lung Neoplasms, Dose-Response Relationship, Drug, Smoking, Environmental Exposure, Middle Aged, United States, Europe, lung cancer, secondhand smoke, Case-Control Studies, Odds Ratio, Humans, Female, Tobacco Smoke Pollution, Lung cancer, secondhand smoke, Aged
Abstract

The interpretation of the evidence linking exposure to secondhand smoke with lung cancer is constrained by the imprecision of risk estimates. The objective of the study was to obtain precise and valid estimates of the risk of lung cancer in never smokers following exposure to secondhand smoke, including adjustment for potential confounders and exposure misclassification. Pooled analysis of data from 2 previously reported large case-control studies was used. Subjects included 1,263 never smoking lung cancer patients and 2,740 population and hospital controls recruited during 1985-1994 from 5 metropolitan areas in the United States, 11 areas in Germany, Italy, Sweden, United Kingdom, France, Spain and Portugal. Odds ratios (ORs) of lung cancer were calculated for ever exposure and duration of exposure to secondhand smoke from spouse, workplace and social sources. The OR for ever exposure to spousal smoking was 1.18 (95% CI = 1.01-1.37) and for long-term exposure was 1.23 (95% CI = 1.01-1.51). After exclusion of proxy interviews, the OR for ever exposure from the workplace was 1.16 (95% CI = 0.99-1.36) and for long-term exposure was 1.27 (95% CI = 1.03-1.57). Similar results were obtained for exposure from social settings and for exposure from combined sources. A dose-response relationship was present with increasing duration of exposure to secondhand smoke for all 3 sources, with an OR of 1.32 (95% CI = 1.10-1.79) for the long-term exposure from all sources. There was no evidence of confounding by employment in high-risk occupations, education or low vegetable intake. Sensitivity analysis for the effects of misclassification (both positive and negative) indicated that the observed risks are likely to underestimate the true risk. Clear dose-response relationships consistent with a causal association were observed between exposure to secondhand smoke from spousal, workplace and social sources and the development of lung cancer among never smokers. © 2003 Wiley-Liss, Inc.

Published
2004

16. Risk of Ischemic Heart Disease in Women after Radiotherapy for Breast Cancer

Author

Darby, SC, Ewertz, M, McGale, P, Bennet, AM, Blom-Goldman, U, Bronnum, D, Correa, C, Cutter, D, Gagliardi, G, Gigante, B, Jensen, M-B, Nisbet, A, Peto, R, Rahimi, K, Taylor, C, Hall, P, Darby, SC, Ewertz, M, McGale, P, Bennet, AM, Blom-Goldman, U, Bronnum, D, Correa, C, Cutter, D, Gagliardi, G, Gigante, B, Jensen, M-B, Nisbet, A, Peto, R, Rahimi, K, Taylor, C, and Hall, P

Published
2013

17. Cancer risk in 680 000 people exposed to computed tomography scans in childhood or adolescence: data linkage study of 11 million Australians

Author

Mathews, JD, Forsythe, AV, Brady, Z, Butler, MW, Goergen, SK, Byrnes, GB, Giles, GG, Wallace, AB, Anderson, PR, Guiver, TA, McGale, P, Cain, TM, Dowty, JG, Bickerstaffe, AC, Darby, SC, Mathews, JD, Forsythe, AV, Brady, Z, Butler, MW, Goergen, SK, Byrnes, GB, Giles, GG, Wallace, AB, Anderson, PR, Guiver, TA, McGale, P, Cain, TM, Dowty, JG, Bickerstaffe, AC, and Darby, SC

Abstract

OBJECTIVE: To assess the cancer risk in children and adolescents following exposure to low dose ionising radiation from diagnostic computed tomography (CT) scans. DESIGN: Population based, cohort, data linkage study in Australia. COHORT MEMBERS: 10.9 million people identified from Australian Medicare records, aged 0-19 years on 1 January 1985 or born between 1 January 1985 and 31 December 2005; all exposures to CT scans funded by Medicare during 1985-2005 were identified for this cohort. Cancers diagnosed in cohort members up to 31 December 2007 were obtained through linkage to national cancer records. MAIN OUTCOME: Cancer incidence rates in individuals exposed to a CT scan more than one year before any cancer diagnosis, compared with cancer incidence rates in unexposed individuals. RESULTS: 60,674 cancers were recorded, including 3150 in 680,211 people exposed to a CT scan at least one year before any cancer diagnosis. The mean duration of follow-up after exposure was 9.5 years. Overall cancer incidence was 24% greater for exposed than for unexposed people, after accounting for age, sex, and year of birth (incidence rate ratio (IRR) 1.24 (95% confidence interval 1.20 to 1.29); P<0.001). We saw a dose-response relation, and the IRR increased by 0.16 (0.13 to 0.19) for each additional CT scan. The IRR was greater after exposure at younger ages (P<0.001 for trend). At 1-4, 5-9, 10-14, and 15 or more years since first exposure, IRRs were 1.35 (1.25 to 1.45), 1.25 (1.17 to 1.34), 1.14 (1.06 to 1.22), and 1.24 (1.14 to 1.34), respectively. The IRR increased significantly for many types of solid cancer (digestive organs, melanoma, soft tissue, female genital, urinary tract, brain, and thyroid); leukaemia, myelodysplasia, and some other lymphoid cancers. There was an excess of 608 cancers in people exposed to CT scans (147 brain, 356 other solid, 48 leukaemia or myelodysplasia, and 57 other lymphoid). The absolute excess incidence rate for all cancers combined was 9.38 per

Published
2013

19. Long-term mortality from heart disease and lung cancer after radiotherapy for early breast cancer: prospective cohort study of about 300,000 women in US SEER cancer registries.

Author

Darby SC, McGale P, Taylor CW, Peto R, Darby, Sarah C, McGale, Paul, Taylor, Carolyn W, and Peto, Richard

Abstract

Background: Radiotherapy for early breast cancer can decrease breast cancer mortality but increase other mortality, mainly from heart disease and lung cancer. The mean cardiac dose from irradiation of a left-sided breast cancer can be two or three times that for a right-sided breast cancer. The mean ipsilateral (ie, on the same side as the breast cancer) lung dose can also be two or three times the mean contralateral lung dose. Particularly during the 1970s, when typical heart and lung exposures were greater than now, the laterality of an irradiated breast cancer could measurably affect cardiac mortality and mortality from cancer of the right or the left lung decades later. This study aimed to assess the hazards in the general US population from routine cancer-registry and death-certificate data.Methods: We analysed data for 308 861 US women with early breast cancer of known laterality (left-sided or right-sided) who were registered in the US Surveillance Epidemiology and End Results (SEER) cancer registries during 1973-2001 and followed prospectively for cause-specific mortality until Jan 1, 2002.Findings: 115 165 (37%) received radiotherapy. Among those who did not, tumour laterality was of little relevance to subsequent mortality. For women diagnosed during 1973-82 and irradiated, the cardiac mortality ratio (left versus right tumour laterality) was 1.20 (95% CI 1.04-1.38) less than 10 years afterwards, 1.42 (1.11-1.82) 10-14 years afterwards, and 1.58 (1.29-1.95) after 15 years or more (trend: 2p=0.03). For women diagnosed during 1983-92 and irradiated, the cardiac mortality ratio was 1.04 (0.91-1.18) less than 10 years afterwards and 1.27 (0.99-1.63) 10 or more years afterwards. For women diagnosed during 1993-2001 and irradiated the cardiac mortality ratio was 0.96 (0.82-1.12), with none yet followed for 10 years. Among women irradiated for breast cancer who subsequently developed an ipsilateral or contralateral lung cancer, the lung cancer mortality ratio (ipsilateral versus contralateral) for women diagnosed during 1973-82 and irradiated was 1.17 (0.62-2.19), 2.00 (1.00-4.00), and 2.71 (1.65-4.48), respectively, less than 10 years, 10-14 years, and 15 or more years afterwards (trend: 2p=0.04). For women irradiated after 1982 there is, as yet, little information on lung cancer risks more than 10 years afterwards.Interpretation: US breast cancer radiotherapy regimens of the 1970s and early 1980s appreciably increased mortality from heart disease and lung cancer 10-20 years afterwards with, as yet, little direct evidence on the hazards after more than 20 years. Since the early 1980s, improvements in radiotherapy planning should have reduced such risks, but the long-term hazards in the general populations of various countries still need to be monitored directly. [ABSTRACT FROM AUTHOR]

Published
2005
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21. Importance of age at infection with HIV-1 for survival and development of AIDS in UK haemophilia population. UK Haemophilia Centre Directors' Organisation.

Author

Darby SC, Ewart DW, Giangrande PLF, Spooner RJD, Rizza CR, UK Haemophilia Centre Directors' Organisation, Darby, S C, Ewart, D W, Giangrande, P L, Spooner, R J, and Rizza, C R

Abstract

Background: Greater age at infection with HIV-1 is known to be associated with shorter time to development of AIDS, but the size of the differences between people infected in infancy and those infected in old age has not been examined in a single large population of patients with death as an endpoint. We, therefore, investigated the role of age at seroconversion in the entire UK population of haemophiliacs.Methods: We studied 1216 HIV-1-infected haemophilia patients in the UK who were registered with the National Haemophilia Register and were alive on Jan 1, 1985. Their estimated ages at HIV-1 seroconversion ranged from 8 months to 79 years.Findings: 10 years after seroconversion 67% (95% Cl 64-69) of the population were still alive. Survival was strongly related to age at seroconversion (86% [82-90], 72% [68-76], 45% [39-51], and 12% [5-21] at 10 years among those patients who seroconverted at ages < 15, 15-34, 35-54, and > or = 55). This steep age-gradient in survival was not explained by deaths expected in the absence of HIV infection or by confounding with other factors such as haemophilia type or severity. The age-gradient was steeper for survival (ie, time from HIV-1 infection to death) than for time to diagnosis of AIDS, partly because survival after an AIDS diagnosis was poorer in older patients, and there was also a substantial increase in mortality among HIV-infected patients who did not satisfy the formal AIDS definition and this increase was greater in older patients.Interpretation: Age at infection with HIV-1 is a more important determinant of survival than has previously been appreciated. Age should, therefore, be considered in future studies of disease progression, and studies that compare people infected at different ages should provide insight into the biology of the immune response to HIV-1. [ABSTRACT FROM AUTHOR]

Published
1996
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25. Multicenter case-control study of exposure to environmental tobacco smoke and lung cancer in Europe.

Author

Boffetta P, Agudo A, Ahrens W, Benhamou E, Benhamou S, Darby SC, Ferro G, Fortes C, Gonzalez CA, Jockel K, Krauss M, Kreienbrock L, Kreuzer M, Mendes A, Merletti F, Nyberg F, Pershagen G, Pohlabeln H, Riboli E, and Schmid G

Abstract

Background: An association between exposure to environmental tobacco smoke (ETS) and lung cancer risk has been suggested. To evaluate this possible association better, researchers need more precise estimates of risk, the relative contribution of different sources of ETS, and the effect of ETS exposure on different histologic types of lung cancer. To address these issues, we have conducted a case-control study of lung cancer and exposure to ETS in 12 centers from seven European countries.Methods: A total of 650 patients with lung cancer and 1542 control subjects up to 74 years of age were interviewed about exposure to ETS. Neither case subjects nor control subjects had smoked more than 400 cigarettes in their lifetime.Results: ETS exposure during childhood was not associated with an increased risk of lung cancer (odds ratio [OR] for ever exposure = 0.78; 95% confidence interval [CI] = 0.64-0.96). The OR for ever exposure to spousal ETS was 1.16 (95% CI = 0.93-1.44). No clear dose-response relationship could be demonstrated for cumulative spousal ETS exposure. The OR for ever exposure to workplace ETS was 1.17 (95% CI = 0.94-1.45), with possible evidence of increasing risk for increasing duration of exposure. No increase in risk was detected in subjects whose exposure to spousal or workplace ETS ended more than 15 years earlier. Ever exposure to ETS from other sources was not associated with lung cancer risk. Risks from combined exposure to spousal and workplace ETS were higher for squamous cell carcinoma and small-cell carcinoma than for adenocarcinoma, but the differences were not statistically significant.Conclusions: Our results indicate no association between childhood exposure to ETS and lung cancer risk. We did find weak evidence of a dose-response relationship between risk of lung cancer and exposure to spousal and workplace ETS. There was no detectable risk after cessation of exposure. [ABSTRACT FROM AUTHOR]

Published
1998
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26. A Bayesian approach to parallel line bioassay

Author

Darby, SC and Armitage, P

Abstract

This thesis considers parallel line bioassay from a Bayesian point of view along the lines laid about Lindley (1972) and de Finetti (1975). The mathematical model used for the analysis is a non-linear one in which the log potency appears explicitly as a parameter. This enables prior knowledge about the log potency ratio to be incorporated straightforwardly in the analysis. The method of analysis follows closely the ideas of Lindley and Smith (1972) for the linear model. Extended models in which experimental design features such as randomized blocks and Latin squares are accounted for are also considered, and a method for the use of prior information to design an assay is given. In addition to the analysis of a single essay the problem of combining information from several assays is considered and two different models which combine such information are discussed.

28. Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017

Author

Stanaway, Jeffrey D., Afshin, Ashkan, Gakidou, Emmanuela, Lim, Stephen S., Abate, Degu, Abate, Kalkidan Hassen, Abbafati, Cristiana, Abbasi, Nooshin, Abbastabar, Hedayat, Abd-Allah, Foad, Abdela, Jemal, Abdelalim, Ahmed, Abdollahpour, Ibrahim, Abdulkader, Rizwan Suliankatchi, Abebe, Molla, Abebe, Zegeye, Abera, Semaw F., Abil, Olifan Zewdie, Abraha, Haftom Niguse, Abrham, Aklilu Roba, Abu-Raddad, Laith Jamal, Abu-Rmeileh, Niveen ME, Accrombessi, Manfred Mario Kokou, Acharya, Dilaram, Acharya, Pawan, Adamu, Abdu A., Adane, Akilew Awoke, Adebayo, Oladimeji M., Adedoyin, Rufus Adesoji, Adekanmbi, Victor, Ademi, Zanfina, Adetokunboh, Olatunji O., Adib, Mina G., Admasie, Amha, Adsuar, Jose C., Afanvi, Kossivi Agbelenko, Afarideh, Mohsen, Agarwal, Gina, Aggarwal, Anju, Aghayan, Sargis Aghasi, Agrawal, Anurag, Agrawal, Sutapa, Ahmadi, Alireza, Ahmadi, Mehdi, Ahmadieh, Hamid, Ahmed, Muktar Beshir, Aichour, Amani Nidhal, Aichour, Ibtihel, Aichour, Miloud Taki Eddine, Akbari, Mohammad Esmaeil, Akinyemiju, Tomi, Akseer, Nadia, Al-Aly, Ziyad, Al-Eyadhy, Ayman, Al-Mekhlafi, Hesham M., Alahdab, Fares, Alam, Khurshid, Alam, Samiah, Alam, Tahiya, Alashi, Alaa, Alavian, Seyed Moayed, Alene, Kefyalew Addis, Ali, Komal, Ali, Syed Mustafa, Alijanzadeh, Mehran, Alizadeh-Navaei, Reza, Aljunid, Syed Mohamed, Alkerwi, Ala'a, Alla, François, Alsharif, Ubai, Altirkawi, Khalid, Alvis-Guzman, Nelson, Amare, Azmeraw T., Ammar, Walid, Anber, Nahla Hamed, Anderson, Jason A., Andrei, Catalina Liliana, Androudi, Sofia, Animut, Megbaru Debalkie, Anjomshoa, Mina, Ansha, Mustafa Geleto, Antó, Josep M., Antonio, Carl Abelardo T., Anwari, Palwasha, Appiah, Lambert Tetteh, Appiah, Seth Christopher Yaw, Arabloo, Jalal, Aremu, Olatunde, Ärnlöv, Johan, Artaman, Al, Aryal, Krishna K., Asayesh, Hamid, Ataro, Zerihun, Ausloos, Marcel, Avokpaho, Euripide F.G.A., Awasthi, Ashish, Ayala Quintanilla, Beatriz Paulina, Ayer, Rakesh, Ayuk, Tambe B., Azzopardi, Peter S., Babazadeh, Arefeh, Badali, Hamid, Badawi, Alaa, Balakrishnan, Kalpana, Bali, Ayele Geleto, Ball, Kylie, Ballew, Shoshana H., Banach, Maciej, Banoub, Joseph Adel Mattar, Barac, Aleksandra, Barker-Collo, Suzanne Lyn, Bärnighausen, Till Winfried, Barrero, Lope H., Basu, Sanjay, Baune, Bernhard T., Bazargan-Hejazi, Shahrzad, Bedi, Neeraj, Beghi, Ettore, Behzadifar, Masoud, Behzadifar, Meysam, Béjot, Yannick, Bekele, Bayu Begashaw, Bekru, Eyasu Tamru, Belay, Ezra, Belay, Yihalem Abebe, Bell, Michelle L., Bello, Aminu K., Bennett, Derrick A., Bensenor, Isabela M., Bergeron, Gilles, Berhane, Adugnaw, Bernabe, Eduardo, Bernstein, Robert S., Beuran, Mircea, Beyranvand, Tina, Bhala, Neeraj, Bhalla, Ashish, Bhattarai, Suraj, Bhutta, Zulfiqar A., Biadgo, Belete, Bijani, Ali, Bikbov, Boris, Bilano, Ver, Bililign, Nigus, Bin Sayeed, Muhammad Shahdaat, Bisanzio, Donal, Biswas, Tuhin, Bjørge, Tone, Blacker, Brigette F., Bleyer, Archie, Borschmann, Rohan, Bou-Orm, Ibrahim R., Boufous, Soufiane, Bourne, Rupert, Brady, Oliver J., Brauer, Michael, Brazinova, Alexandra, Breitborde, Nicholas J.K., Brenner, Hermann, Briko, Andrey Nikolaevich, Britton, Gabrielle, Brugha, Traolach, Buchbinder, Rachelle, Burnett, Richard T., Busse, Reinhard, Butt, Zahid A., Cahill, Leah E., Cahuana-Hurtado, Lucero, Campos-Nonato, Ismael R., Cárdenas, Rosario, Carreras, Giulia, Carrero, Juan J., Carvalho, Félix, Castañeda-Orjuela, Carlos A., Castillo Rivas, Jacqueline, Castro, Franz, Catalá-López, Ferrán, Causey, Kate, Cercy, Kelly M., Cerin, Ester, Chaiah, Yazan, Chang, Hsing Yi, Chang, Jung Chen, Chang, Kai Lan, Charlson, Fiona J., Chattopadhyay, Aparajita, Chattu, Vijay Kumar, Chee, Miao Li, Cheng, Ching Yu, Chew, Adrienne, Chiang, Peggy Pei Chia, Chimed-Ochir, Odgerel, Chin, Ken Lee, Chitheer, Abdulaal, Choi, Jee Young J., Chowdhury, Rajiv, Christensen, Hanne, Christopher, Devasahayam J., Chung, Sheng Chia, Cicuttini, Flavia M., Cirillo, Massimo, Cohen, Aaron J., Collado-Mateo, Daniel, Cooper, Cyrus, Cooper, Owen R., Coresh, Josef, Cornaby, Leslie, Cortesi, Paolo Angelo, Cortinovis, Monica, Costa, Megan, Cousin, Ewerton, Criqui, Michael H., Cromwell, Elizabeth A., Cundiff, David K., Daba, Alemneh Kabeta, Dachew, Berihun Assefa, Dadi, Abel Fekadu, Damasceno, Albertino Antonio Moura, Dandona, Lalit, Dandona, Rakhi, Darby, Sarah C., Dargan, Paul I., Daryani, Ahmad, Das Gupta, Rajat, Das Neves, José, Dasa, Tamirat Tesfaye, Dash, Aditya Prasad, Davitoiu, Dragos Virgil, Davletov, Kairat, De la Cruz-Góngora, Vanessa, De La Hoz, Fernando Pio, De Leo, Diego, De Neve, Jan Walter, Degenhardt, Louisa, Deiparine, Selina, Dellavalle, Robert P., Demoz, Gebre Teklemariam, Denova-Gutiérrez, Edgar, Deribe, Kebede, Dervenis, Nikolaos, Deshpande, Aniruddha, Des Jarlais, Don C., Dessie, Getenet Ayalew, Deveber, Gabrielle Aline, Dey, Subhojit, Dharmaratne, Samath Dhamminda, Dhimal, Meghnath, Dinberu, Mesfin Tadese, Ding, Eric L., Diro, Helen Derara, Djalalinia, Shirin, Do, Huyen Phuc, Dokova, Klara, Doku, David Teye, Doyle, Kerrie E., Driscoll, Tim R., Dubey, Manisha, Dubljanin, Eleonora, Duken, Eyasu Ejeta, Duncan, Bruce B., Duraes, Andre R., Ebert, Natalie, Ebrahimi, Hedyeh, Ebrahimpour, Soheil, Edvardsson, David, Effiong, Andem, Eggen, Anne Elise, El Bcheraoui, Charbel, El-Khatib, Ziad, Elyazar, Iqbal Rf, Enayati, Ahmadali, Endries, Aman Yesuf, Er, Benjamin, Erskine, Holly E., Eskandarieh, Sharareh, Esteghamati, Alireza, Estep, Kara, Fakhim, Hamed, Faramarzi, Mahbobeh, Fareed, Mohammad, Farid, Talha A., Farinha, Carla Sofia E.sá, Farioli, Andrea, Faro, Andre, Farvid, Maryam S., Farzaei, Mohammad Hosein, Fatima, Batool, Fay, Kairsten A., Fazaeli, Ali Akbar, Feigin, Valery L., Feigl, Andrea B., Fereshtehnejad, Seyed Mohammad, Fernandes, Eduarda, Fernandes, Joao C., Ferrara, Giannina, Ferrari, Alize J., Ferreira, Manuela L., Filip, Irina, Finger, Jonas David, Fischer, Florian, Foigt, Nataliya A., Foreman, Kyle J., Fukumoto, Takeshi, Fullman, Nancy, Fürst, Thomas, Furtado, João M., Futran, Neal D., Gall, Seana, Gallus, Silvano, Gamkrelidze, Amiran, Ganji, Morsaleh, Garcia-Basteiro, Alberto L., Gardner, William M., Gebre, Abadi Kahsu, Gebremedhin, Amanuel Tesfay, Gebremichael, Teklu Gebrehiwo, Gelano, Tilayie Feto, Geleijnse, Johanna M., Geramo, Yilma Chisha Dea, Gething, Peter W., Gezae, Kebede Embaye, Ghadimi, Reza, Ghadiri, Keyghobad, Ghasemi Falavarjani, Khalil, Ghasemi-Kasman, Maryam, Ghimire, Mamata, Ghosh, Rakesh, Ghoshal, Aloke Gopal, Giampaoli, Simona, Gill, Paramjit Singh, Gill, Tiffany K., Gillum, Richard F., Ginawi, Ibrahim Abdelmageed, Giussani, Giorgia, Gnedovskaya, Elena V., Godwin, William W., Goli, Srinivas, Gómez-Dantés, Hector, Gona, Philimon N., Gopalani, Sameer Vali, Goulart, Alessandra C., Grada, Ayman, Grams, Morgan E., Grosso, Giuseppe, Gugnani, Harish Chander, Guo, Yuming, Gupta, Rahul, Gupta, Rajeev, Gupta, Tanush, Gutiérrez, Reyna Alma, Gutiérrez-Torres, Daniela S., Haagsma, Juanita A., Habtewold, Tesfa Dejenie, Hachinski, Vladimir, Hafezi-Nejad, Nima, Hagos, Tekleberhan B., Hailegiyorgis, Tewodros Tesfa, Hailu, Gessessew Bugssa, Haj-Mirzaian, Arvin, Haj-Mirzaian, Arya, Hamadeh, Randah R., Hamidi, Samer, Handal, Alexis J., Hankey, Graeme J., Hao, Yuantao, Harb, Hilda L., Harikrishnan, Sivadasanpillai, Haro, Josep Maria, Hassankhani, Hadi, Hassen, Hamid Yimam, Havmoeller, Rasmus, Hawley, Caitlin N., Hay, Simon I., Hedayatizadeh-Omran, Akbar, Heibati, Behzad, Heidari, Behnam, Heidari, Mohsen, Hendrie, Delia, Henok, Andualem, Heredia-Pi, Ileana, Herteliu, Claudiu, Heydarpour, Fatemeh, Heydarpour, Sousan, Hibstu, Desalegn T., Higazi, Tarig B., Hilawe, Esayas Haregot, Hoek, Hans W., Hoffman, Howard J., Hole, Michael K., Homaie Rad, Enayatollah, Hoogar, Praveen, Hosgood, H. Dean, Hosseini, Seyed Mostafa, Hosseinzadeh, Mehdi, Hostiuc, Mihaela, Hostiuc, Sorin, Hoy, Damian G., Hsairi, Mohamed, Hsiao, Thomas, Hu, Guoqing, Hu, Howard, Huang, John J., Hussen, Mamusha Aman, Huynh, Chantal K., Iburg, Kim Moesgaard, Ikeda, Nayu, Ilesanmi, Olayinka Stephen, Iqbal, Usman, Irvani, Seyed Sina Naghibi, Irvine, Caleb Mackay Salpeter, Islam, Sheikh Mohammed Shariful, Islami, Farhad, Jackson, Maria D., Jacobsen, Kathryn H., Jahangiry, Leila, Jahanmehr, Nader, Jain, Sudhir Kumar, Jakovljevic, Mihajlo, James, Spencer L., Jassal, Simerjot K., Jayatilleke, Achala Upendra, Jeemon, Panniyammakal, Jha, Ravi Prakash, Jha, Vivekanand, Ji, John S., Jonas, Jost B., Jonnagaddala, Jitendra, Jorjoran Shushtari, Zahra, Joshi, Ankur, Jozwiak, Jacek Jerzy, Jürisson, Mikk, Kabir, Zubair, Kahsay, Amaha, Kalani, Rizwan, Kanchan, Tanuj, Kant, Surya, Kar, Chittaranjan, Karami, Manoochehr, Karami Matin, Behzad, Karch, André, Karema, Corine, Karimi, Narges, Karimi, Seyed M., Kasaeian, Amir, Kassa, Dessalegn H., Kassa, Getachew Mullu, Kassa, Tesfaye Dessale, Kassebaum, Nicholas J., Katikireddi, Srinivasa Vittal, Kaul, Anil, Kawakami, Norito, Kazemi, Zhila, Karyani, Ali Kazemi, Kefale, Adane Teshome, Keiyoro, Peter Njenga, Kemp, Grant Rodgers, Kengne, Andre Pascal, Keren, Andre, Kesavachandran, Chandrasekharan Nair, Khader, Yousef Saleh, Khafaei, Behzad, Khafaie, Morteza Abdullatif, Khajavi, Alireza, Khalid, Nauman, Khalil, Ibrahim A., Khan, Gulfaraz, Khan, Muhammad Shahzeb, Khan, Muhammad Ali, Khang, Young Ho, Khater, Mona M., Khazaei, Mohammad, Khazaie, Habibolah, Khoja, Abdullah T., Khosravi, Ardeshir, Khosravi, Mohammad Hossein, Kiadaliri, Aliasghar A., Kiirithio, Daniel N., Kim, Cho Il, Kim, Daniel, Kim, Young Eun, Kim, Yun Jin, Kimokoti, Ruth W., Kinfu, Yohannes, Kisa, Adnan, Kissimova-Skarbek, Katarzyna, Kivimäki, Mika, Knibbs, Luke D., Knudsen, Ann Kristin Skrindo, Kochhar, Sonali, Kokubo, Yoshihiro, Kolola, Tufa, Kopec, Jacek A., Kosen, Soewarta, Koul, Parvaiz A., Koyanagi, Ai, Kravchenko, Michael A., Krishan, Kewal, Krohn, Kristopher J., Kromhout, Hans, Kuate Defo, Barthelemy, Kucuk Bicer, Burcu, Kumar, G. Anil, Kumar, Manasi, Kuzin, Igor, Kyu, Hmwe Hmwe, Lachat, Carl, Lad, Deepesh P., Lad, Sheetal D., Lafranconi, Alessandra, Lalloo, Ratilal, Lallukka, Tea, Lami, Faris Hasan, Lang, Justin J., Lansingh, Van C., Larson, Samantha Leigh, Latifi, Arman, Lazarus, Jeffrey V., Lee, Paul H., Leigh, James, Leili, Mostafa, Leshargie, Cheru Tesema, Leung, Janni, Levi, Miriam, Lewycka, Sonia, Li, Shanshan, Li, Yichong, Liang, Juan, Liang, Xiaofeng, Liao, Yu, Liben, Misgan Legesse, Lim, Lee Ling, Linn, Shai, Liu, Shiwei, Lodha, Rakesh, Logroscino, Giancarlo, Lopez, Alan D., Lorkowski, Stefan, Lotufo, Paulo A., Lozano, Rafael, Lucas, Tim C.D., Lunevicius, Raimundas, Ma, Stefan, Macarayan, Erlyn Rachelle King, Machado, Ísis Eloah, Madotto, Fabiana, Mai, Hue Thi, Majdan, Marek, Majdzadeh, Reza, Majeed, Azeem, Malekzadeh, Reza, Malta, Deborah Carvalho, Mamun, Abdullah A., Manda, Ana Laura, Manguerra, Helena, Mansournia, Mohammad Ali, Mantovani, Lorenzo Giovanni, Maravilla, Joemer C., Marcenes, Wagner, Marks, Ashley, Martin, Randall V., Martins, Sheila C.O., Martins-Melo, Francisco Rogerlândio, März, Winfried, Marzan, Melvin B., Massenburg, Benjamin Ballard, Mathur, Manu Raj, Mathur, Prashant, Matsushita, Kunihiro, Maulik, Pallab K., Mazidi, Mohsen, McAlinden, Colm, McGrath, John J., McKee, Martin, Mehrotra, Ravi, Mehta, Kala M., Mehta, Varshil, Meier, Toni, Mekonnen, Fantahun Ayenew, Melaku, Yohannes A., Melese, Addisu, Melku, Mulugeta, Memiah, Peter T.N., Memish, Ziad A., Mendoza, Walter, Mengistu, Desalegn Tadese, Mensah, George A., Mensink, Gert B.M., Mereta, Seid Tiku, Meretoja, Atte, Meretoja, Tuomo J., Mestrovic, Tomislav, Mezgebe, Haftay Berhane, Miazgowski, Bartosz, Miazgowski, Tomasz, Millear, Anoushka I., Miller, Ted R., Miller-Petrie, Molly Katherine, Mini, G. K., Mirarefin, Mojde, Mirica, Andreea, Mirrakhimov, Erkin M., Misganaw, Awoke Temesgen, Mitiku, Habtamu, Moazen, Babak, Mohajer, Bahram, Mohammad, Karzan Abdulmuhsin, Mohammadi, Moslem, Mohammadifard, Noushin, Mohammadnia-Afrouzi, Mousa, Mohammed, Shafiu, Mohebi, Farnam, Mokdad, Ali H., Molokhia, Mariam, Momeniha, Fatemeh, Monasta, Lorenzo, Moodley, Yoshan, Moradi, Ghobad, Moradi-Lakeh, Maziar, Moradinazar, Mehdi, Moraga, Paula, Morawska, Lidia, Morgado-Da-Costa, Joana, Morrison, Shane Douglas, Moschos, Marilita M., Mouodi, Simin, Mousavi, Seyyed Meysam, Mozaffarian, Dariush, Mruts, Kalayu Brhane, Muche, Achenef Asmamaw, Muchie, Kindie Fentahun, Mueller, Ulrich Otto, Muhammed, Oumer Sada, Mukhopadhyay, Satinath, Muller, Kate, Musa, Kamarul Imran, Mustafa, Ghulam, Nabhan, Ashraf F., Naghavi, Mohsen, Naheed, Aliya, Nahvijou, Azin, Naik, Gurudatta, Naik, Nitish, Najafi, Farid, Nangia, Vinay, Nansseu, Jobert Richie, Nascimento, Bruno Ramos, Neal, Bruce, Neamati, Nahid, Negoi, Ionut, Negoi, Ruxandra Irina, Neupane, Subas, Newton, Charles Richard James, Ngunjiri, Josephine W., Nguyen, Anh Quynh, Nguyen, Grant, Nguyen, Ha Thu, Nguyen, Huong Lan Thi, Nguyen, Huong Thanh, Nguyen, Minh, Nguyen, Nam Ba, Nichols, Emma, Nie, Jing, Ningrum, Dina Nur Anggraini, Nirayo, Yirga Legesse, Nishi, Nobuo, Nixon, Molly R., Nojomi, Marzieh, Nomura, Shuhei, Norheim, Ole F., Noroozi, Mehdi, Norrving, Bo, Noubiap, Jean Jacques, Nouri, Hamid Reza, Nourollahpour Shiadeh, Malihe, Nowroozi, Mohammad Reza, Nsoesie, Elaine O., Nyasulu, Peter S., Obermeyer, Carla M., Odell, Christopher M., Ofori-Asenso, Richard, Ogbo, Felix Akpojene, Oh, In Hwan, Oladimeji, Olanrewaju, Olagunju, Andrew T., Olagunju, Tinuke O., Olivares, Pedro R., Olsen, Helen Elizabeth, Olusanya, Bolajoko Olubukunola, Olusanya, Jacob Olusegun, Ong, Kanyin L., Ong, Sok King, Oren, Eyal, Orpana, Heather M., Ortiz, Alberto, Ota, Erika, Otstavnov, Stanislav S., Øverland, Simon, Owolabi, Mayowa Ojo, P A, Mahesh, Pacella, Rosana, Pakhare, Abhijit P., Pakpour, Amir H., Pana, Adrian, Panda-Jonas, Songhomitra, Park, Eun Kee, Parry, Charles D.H., Parsian, Hadi, Patel, Shanti, Pati, Sanghamitra, Patil, Snehal T., Patle, Ajay, Patton, George C., Paudel, Deepak, Paulson, Katherine R., Paz Ballesteros, Wayra Citlali, Pearce, Neil, Pereira, Alexandre, Pereira, David M., Perico, Norberto, Pesudovs, Konrad, Petzold, Max, Pham, Hai Quang, Phillips, Michael R., Pillay, Julian David, Piradov, Michael A., Pirsaheb, Meghdad, Pischon, Tobias, Pishgar, Farhad, Plana-Ripoll, Oleguer, Plass, Dietrich, Polinder, Suzanne, Polkinghorne, Kevan R., Postma, Maarten J., Poulton, Richie, Pourshams, Akram, Poustchi, Hossein, Prabhakaran, Dorairaj, Prakash, Swayam, Prasad, Narayan, Purcell, Caroline A., Purwar, Manorama B., Qorbani, Mostafa, Radfar, Amir, Rafay, Anwar, Rafiei, Alireza, Rahim, Fakher, Rahimi, Zohreh, Rahimi-Movaghar, Afarin, Rahimi-Movaghar, Vafa, Rahman, Mahfuzar, Rahman, Mohammad Hifz ur, Rahman, Muhammad Aziz, Rai, Rajesh Kumar, Rajati, Fatemeh, Rajsic, Sasa, Raju, Sree Bhushan, Ram, Usha, Ranabhat, Chhabi Lal, Ranjan, Prabhat, Rath, Goura Kishor, Rawaf, David Laith, Rawaf, Salman, Reddy, K. Srinath, Rehm, Colin D., Rehm, Jürgen, Reiner, Robert C., Reitsma, Marissa B., Remuzzi, Giuseppe, Renzaho, Andre M.N., Resnikoff, Serge, Reynales-Shigematsu, Luz Myriam, Rezaei, Satar, Ribeiro, Antonio Luiz P., Rivera, Juan A., Roba, Kedir Teji, Rodríguez-Ramírez, Sonia, Roever, Leonardo, Román, Yesenia, Ronfani, Luca, Roshandel, Gholamreza, Rostami, Ali, Roth, Gregory A., Rothenbacher, Dietrich, Roy, Ambuj, Rubagotti, Enrico, Rushton, Lesley, Sabanayagam, Charumathi, Sachdev, Perminder S., Saddik, Basema, Sadeghi, Ehsan, Saeedi Moghaddam, Sahar, Safari, Hosein, Safari, Yahya, Safari-Faramani, Roya, Safdarian, Mahdi, Safi, Sare, Safiri, Saeid, Sagar, Rajesh, Sahebkar, Amirhossein, Sahraian, Mohammad Ali, Sajadi, Haniye Sadat, Salam, Nasir, Salamati, Payman, Saleem, Zikria, Salimi, Yahya, Salimzadeh, Hamideh, Salomon, Joshua A., Salvi, Devashri Digvijay, Salz, Inbal, Samy, Abdallah M., Sanabria, Juan, Sanchez-Niño, Maria Dolores, Sánchez-Pimienta, Tania G., Sanders, Taren, Sang, Yingying, Santomauro, Damian Francesco, Santos, Itamar S., Santos, João Vasco, Santric Milicevic, Milena M., Sao Jose, Bruno Piassi, Sardana, Mayank, Sarker, Abdur Razzaque, Sarmiento-Suárez, Rodrigo, Sarrafzadegan, Nizal, Sartorius, Benn, Sarvi, Shahabeddin, Sathian, Brijesh, Satpathy, Maheswar, Sawant, Arundhati R., Sawhney, Monika, Saylan, Mete, Sayyah, Mehdi, Schaeffner, Elke, Schmidt, Maria Inês, Schneider, Ione J.C., Schöttker, Ben, Schutte, Aletta Elisabeth, Schwebel, David C., Schwendicke, Falk, Scott, James G., Seedat, Soraya, Sekerija, Mario, Sepanlou, Sadaf G., Serre, Marc L., Serván-Mori, Edson, Seyedmousavi, Seyedmojtaba, Shabaninejad, Hosein, Shaddick, Gavin, Shafieesabet, Azadeh, Shahbazi, Mehdi, Shaheen, Amira A., Shaikh, Masood Ali, Shamah Levy, Teresa, Shams-Beyranvand, Mehran, Shamsi, Mohammadbagher, Sharafi, Heidar, Sharafi, Kiomars, Sharif, Mehdi, Sharif-Alhoseini, Mahdi, Sharifi, Hamid, Sharma, Jayendra, Sharma, Meenakshi, Sharma, Rajesh, She, Jun, Sheikh, Aziz, Shi, Peilin, Shibuya, Kenji, Shiferaw, Mekonnen Sisay, Shigematsu, Mika, Shin, Min Jeong, Shiri, Rahman, Shirkoohi, Reza, Shiue, Ivy, Shokraneh, Farhad, Shoman, Haitham, Shrime, Mark G., Shupler, Matthew S., Si, Si, Siabani, Soraya, Sibai, Abla Mehio, Siddiqi, Tariq J., Sigfusdottir, Inga Dora, Sigurvinsdottir, Rannveig, Silva, Diego Augusto Santos, Silva, João Pedro, Silveira, Dayane Gabriele Alves, Singh, Jasvinder A., Singh, Narinder Pal, Singh, Virendra, Sinha, Dhirendra Narain, Skiadaresi, Eirini, Skirbekk, Vegard, Smith, David L., Smith, Mari, Sobaih, Badr Hasan, Sobhani, Soheila, Somayaji, Ranjani, Soofi, Moslem, Sorensen, Reed J.D., Soriano, Joan B., Soyiri, Ireneous N., Spinelli, Angela, Sposato, Luciano A., Sreeramareddy, Chandrashekhar T., Srinivasan, Vinay, Starodubov, Vladimir I., Steckling, Nadine, Stein, Dan J., Stein, Murray B., Stevanovic, Goran, Stockfelt, Leo, Stokes, Mark A., Sturua, Lela, Subart, Michelle L., Sudaryanto, Agus, Sufiyan, Mu'awiyyah Babale, Sulo, Gerhard, Sunguya, Bruno F., Sur, Patrick John, Sykes, Bryan L., Szoeke, Cassandra E.I., Tabarés-Seisdedos, Rafael, Tabuchi, Takahiro, Tadakamadla, Santosh Kumar, Takahashi, Ken, Tandon, Nikhil, Tassew, Segen Gebremeskel, Tavakkoli, Mohammad, Taveira, Nuno, Tehrani-Banihashemi, Arash, Tekalign, Tigist Gashaw, Tekelemedhin, Shishay Wahdey, Tekle, Merhawi Gebremedhin, Temesgen, Habtamu, Temsah, Mohamad Hani, Temsah, Omar, Terkawi, Abdullah Sulieman, Tessema, Belay, Teweldemedhin, Mebrahtu, Thankappan, Kavumpurathu Raman, Theis, Andrew, Thirunavukkarasu, Sathish, Thomas, Hannah J., Thomas, Matthew Lloyd, Thomas, Nihal, Thurston, George D., Tilahun, Binyam, Tillmann, Taavi, To, Quyen G., Tobollik, Myriam, Tonelli, Marcello, Topor-Madry, Roman, Torre, Anna E., Tortajada-Girbés, Miguel, Touvier, Mathilde, Tovani-Palone, Marcos Roberto, Towbin, Jeffrey A., Tran, Bach Xuan, Tran, Khanh Bao, Truelsen, Thomas Clement, Truong, Nu Thi, Tsadik, Afewerki Gebremeskel, Tudor Car, Lorainne, Tuzcu, E. Murat, Tymeson, Hayley D., Tyrovolas, Stefanos, Ukwaja, Kingsley N., Ullah, Irfan, Updike, Rachel L., Usman, Muhammad Shariq, Uthman, Olalekan A., Vaduganathan, Muthiah, Vaezi, Afsane, Valdez, Pascual R., Van Donkelaar, Aaron, Varavikova, Elena, Varughese, Santosh, Vasankari, Tommi Juhani, Venkateswaran, Vidhya, Venketasubramanian, Narayanaswamy, Villafaina, Santos, Violante, Francesco S., Vladimirov, Sergey Konstantinovitch, Vlassov, Vasily, Vollset, Stein Emil, Vos, Theo, Vosoughi, Kia, Vu, Giang Thu, Vujcic, Isidora S., Wagnew, Fasil Shiferaw, Waheed, Yasir, Waller, Stephen G., Walson, Judd L., Wang, Yafeng, Wang, Yanping, Wang, Yuan Pang, Weiderpass, Elisabete, Weintraub, Robert G., Weldegebreal, Fitsum, Werdecker, Andrea, Werkneh, Adhena Ayaliew, West, J. 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Hsiao, Thoma, Hu, Guoqing, Hu, Howard, Huang, John J, Hussen, Mamusha Aman, Huynh, Chantal K, Iburg, Kim Moesgaard, Ikeda, Nayu, Ilesanmi, Olayinka Stephen, Iqbal, Usman, Irvani, Seyed Sina Naghibi, Irvine, Caleb Mackay Salpeter, Islam, Sheikh Mohammed Shariful, Islami, Farhad, Jackson, Maria D, Jacobsen, Kathryn H, Jahangiry, Leila, Jahanmehr, Nader, Jain, Sudhir Kumar, Jakovljevic, Mihajlo, James, Spencer L, Jassal, Simerjot K, Jayatilleke, Achala Upendra, Jeemon, Panniyammakal, Jha, Ravi Prakash, Jha, Vivekanand, Ji, John S, Jonas, Jost B, Jonnagaddala, Jitendra, Jorjoran Shushtari, Zahra, Joshi, Ankur, Jozwiak, Jacek Jerzy, Jürisson, Mikk, Kabir, Zubair, Kahsay, Amaha, Kalani, Rizwan, Kanchan, Tanuj, Kant, Surya, Kar, Chittaranjan, Karami, Manoochehr, Karami Matin, Behzad, Karch, André, Karema, Corine, Karimi, Narge, Karimi, Seyed M, Kasaeian, Amir, Kassa, Dessalegn H, Kassa, Getachew Mullu, Kassa, Tesfaye Dessale, Kassebaum, Nicholas J, Katikireddi, Srinivasa Vittal, Kaul, Anil, Kawakami, Norito, Kazemi, Zhila, Karyani, Ali Kazemi, Kefale, Adane Teshome, Keiyoro, Peter Njenga, Kemp, Grant Rodger, Kengne, Andre Pascal, Keren, Andre, Kesavachandran, Chandrasekharan Nair, Khader, Yousef Saleh, Khafaei, Behzad, Khafaie, Morteza Abdullatif, Khajavi, Alireza, Khalid, Nauman, Khalil, Ibrahim A, Khan, Gulfaraz, Khan, Muhammad Shahzeb, Khan, Muhammad Ali, Khang, Young-Ho, Khater, Mona M, Khazaei, Mohammad, Khazaie, Habibolah, Khoja, Abdullah T, Khosravi, Ardeshir, Khosravi, Mohammad Hossein, Kiadaliri, Aliasghar A, Kiirithio, Daniel N, Kim, Cho-Il, Kim, Daniel, Kim, Young-Eun, Kim, Yun Jin, Kimokoti, Ruth W, Kinfu, Yohanne, Kisa, Adnan, Kissimova-Skarbek, Katarzyna, Kivimäki, Mika, Knibbs, Luke D, Knudsen, Ann Kristin Skrindo, Kochhar, Sonali, Kokubo, Yoshihiro, Kolola, Tufa, Kopec, Jacek A, Kosen, Soewarta, Koul, Parvaiz A, Koyanagi, Ai, Kravchenko, Michael A, Krishan, Kewal, Krohn, Kristopher J, Kromhout, Han, Kuate Defo, Barthelemy, Kucuk Bicer, Burcu, Kumar, G Anil, Kumar, Manasi, Kuzin, Igor, Kyu, Hmwe Hmwe, Lachat, Carl, Lad, Deepesh P, Lad, Sheetal D, Lafranconi, Alessandra, Lalloo, Ratilal, Lallukka, Tea, Lami, Faris Hasan, Lang, Justin J, Lansingh, Van C, Larson, Samantha Leigh, Latifi, Arman, Lazarus, Jeffrey V, Lee, Paul H, Leigh, Jame, Leili, Mostafa, Leshargie, Cheru Tesema, Leung, Janni, Levi, Miriam, Lewycka, Sonia, Li, Shanshan, Li, Yichong, Liang, Juan, Liang, Xiaofeng, Liao, Yu, Liben, Misgan Legesse, Lim, Lee-Ling, Linn, Shai, Liu, Shiwei, Lodha, Rakesh, Logroscino, Giancarlo, Lopez, Alan D, Lorkowski, Stefan, Lotufo, Paulo A, Lozano, Rafael, Lucas, Tim C D, Lunevicius, Raimunda, Ma, Stefan, Macarayan, Erlyn Rachelle King, Machado, Ísis Eloah, Madotto, Fabiana, Mai, Hue Thi, Majdan, Marek, Majdzadeh, Reza, Majeed, Azeem, Malekzadeh, Reza, Malta, Deborah Carvalho, Mamun, Abdullah A, Manda, Ana-Laura, Manguerra, Helena, Mansournia, Mohammad Ali, Mantovani, Lorenzo Giovanni, Maravilla, Joemer C, Marcenes, Wagner, Marks, Ashley, Martin, Randall V, Martins, Sheila C O, Martins-Melo, Francisco Rogerlândio, März, Winfried, Marzan, Melvin B, Massenburg, Benjamin Ballard, Mathur, Manu Raj, Mathur, Prashant, Matsushita, Kunihiro, Maulik, Pallab K, Mazidi, Mohsen, McAlinden, Colm, McGrath, John J, McKee, Martin, Mehrotra, Ravi, Mehta, Kala M, Mehta, Varshil, Meier, Toni, Mekonnen, Fantahun Ayenew, Melaku, Yohannes A, Melese, Addisu, Melku, Mulugeta, Memiah, Peter T N, Memish, Ziad A, Mendoza, Walter, Mengistu, Desalegn Tadese, Mensah, George A, Mensink, Gert B M, Mereta, Seid Tiku, Meretoja, Atte, Meretoja, Tuomo J, Mestrovic, Tomislav, Mezgebe, Haftay Berhane, Miazgowski, Bartosz, Miazgowski, Tomasz, Millear, Anoushka I, Miller, Ted R, Miller-Petrie, Molly Katherine, Mini, G.K., Mirarefin, Mojde, Mirica, Andreea, Mirrakhimov, Erkin M, Misganaw, Awoke Temesgen, Mitiku, Habtamu, Moazen, Babak, Mohajer, Bahram, Mohammad, Karzan Abdulmuhsin, Mohammadi, Moslem, Mohammadifard, Noushin, Mohammadnia-Afrouzi, Mousa, Mohammed, Shafiu, Mohebi, Farnam, Mokdad, Ali H, Molokhia, Mariam, Momeniha, Fatemeh, Monasta, Lorenzo, Moodley, Yoshan, Moradi, Ghobad, Moradi-Lakeh, Maziar, Moradinazar, Mehdi, Moraga, Paula, Morawska, Lidia, Morgado-Da-Costa, Joana, Morrison, Shane Dougla, Moschos, Marilita M, Mouodi, Simin, Mousavi, Seyyed Meysam, Mozaffarian, Dariush, Mruts, Kalayu Brhane, Muche, Achenef Asmamaw, Muchie, Kindie Fentahun, Mueller, Ulrich Otto, Muhammed, Oumer Sada, Mukhopadhyay, Satinath, Muller, Kate, Musa, Kamarul Imran, Mustafa, Ghulam, Nabhan, Ashraf F, Naghavi, Mohsen, Naheed, Aliya, Nahvijou, Azin, Naik, Gurudatta, Naik, Nitish, Najafi, Farid, Nangia, Vinay, Nansseu, Jobert Richie, Nascimento, Bruno Ramo, Neal, Bruce, Neamati, Nahid, Negoi, Ionut, Negoi, Ruxandra Irina, Neupane, Suba, Newton, Charles Richard Jame, Ngunjiri, Josephine W, Nguyen, Anh Quynh, Nguyen, Grant, Nguyen, Ha Thu, Nguyen, Huong Lan Thi, Nguyen, Huong Thanh, Nguyen, Minh, Nguyen, Nam Ba, Nichols, Emma, Nie, Jing, Ningrum, Dina Nur Anggraini, Nirayo, Yirga Legesse, Nishi, Nobuo, Nixon, Molly R, Nojomi, Marzieh, Nomura, Shuhei, Norheim, Ole F, Noroozi, Mehdi, Norrving, Bo, Noubiap, Jean Jacque, Nouri, Hamid Reza, Nourollahpour Shiadeh, Malihe, Nowroozi, Mohammad Reza, Nsoesie, Elaine O, Nyasulu, Peter S, Obermeyer, Carla M, Odell, Christopher M, Ofori-Asenso, Richard, Ogbo, Felix Akpojene, Oh, In-Hwan, Oladimeji, Olanrewaju, Olagunju, Andrew T, Olagunju, Tinuke O, Olivares, Pedro R, Olsen, Helen Elizabeth, Olusanya, Bolajoko Olubukunola, Olusanya, Jacob Olusegun, Ong, Kanyin L, Ong, Sok King, Oren, Eyal, Orpana, Heather M, Ortiz, Alberto, Ota, Erika, Otstavnov, Stanislav S, Øverland, Simon, Owolabi, Mayowa Ojo, P A, Mahesh, Pacella, Rosana, Pakhare, Abhijit P, Pakpour, Amir H, Pana, Adrian, Panda-Jonas, Songhomitra, Park, Eun-Kee, Parry, Charles D H, Parsian, Hadi, Patel, Shanti, Pati, Sanghamitra, Patil, Snehal T, Patle, Ajay, Patton, George C, Paudel, Deepak, Paulson, Katherine R, Paz Ballesteros, Wayra Citlali, Pearce, Neil, Pereira, Alexandre, Pereira, David M, Perico, Norberto, Pesudovs, Konrad, Petzold, Max, Pham, Hai Quang, Phillips, Michael R, Pillay, Julian David, Piradov, Michael A, Pirsaheb, Meghdad, Pischon, Tobia, Pishgar, Farhad, Plana-Ripoll, Oleguer, Plass, Dietrich, Polinder, Suzanne, Polkinghorne, Kevan R, Postma, Maarten J, Poulton, Richie, Pourshams, Akram, Poustchi, Hossein, Prabhakaran, Dorairaj, Prakash, Swayam, Prasad, Narayan, Purcell, Caroline A, Purwar, Manorama B, Qorbani, Mostafa, Radfar, Amir, Rafay, Anwar, Rafiei, Alireza, Rahim, Fakher, Rahimi, Zohreh, Rahimi-Movaghar, Afarin, Rahimi-Movaghar, Vafa, Rahman, Mahfuzar, Rahman, Mohammad Hifz ur, Rahman, Muhammad Aziz, Rai, Rajesh Kumar, Rajati, Fatemeh, Rajsic, Sasa, Raju, Sree Bhushan, Ram, Usha, Ranabhat, Chhabi Lal, Ranjan, Prabhat, Rath, Goura Kishor, Rawaf, David Laith, Rawaf, Salman, Reddy, K Srinath, Rehm, Colin D, Rehm, Jürgen, Reiner, Robert C, Reitsma, Marissa B, Remuzzi, Giuseppe, Renzaho, Andre M N, Resnikoff, Serge, Reynales-Shigematsu, Luz Myriam, Rezaei, Satar, Ribeiro, Antonio Luiz P, Rivera, Juan A, Roba, Kedir Teji, Rodríguez-Ramírez, Sonia, Roever, Leonardo, Román, Yesenia, Ronfani, Luca, Roshandel, Gholamreza, Rostami, Ali, Roth, Gregory A, Rothenbacher, Dietrich, Roy, Ambuj, Rubagotti, Enrico, Rushton, Lesley, Sabanayagam, Charumathi, Sachdev, Perminder S, Saddik, Basema, Sadeghi, Ehsan, Saeedi Moghaddam, Sahar, Safari, Hosein, Safari, Yahya, Safari-Faramani, Roya, Safdarian, Mahdi, Safi, Sare, Safiri, Saeid, Sagar, Rajesh, Sahebkar, Amirhossein, Sahraian, Mohammad Ali, Sajadi, Haniye Sadat, Salam, Nasir, Salamati, Payman, Saleem, Zikria, Salimi, Yahya, Salimzadeh, Hamideh, Salomon, Joshua A, Salvi, Devashri Digvijay, Salz, Inbal, Samy, Abdallah M, Sanabria, Juan, Sanchez-Niño, Maria Dolore, Sánchez-Pimienta, Tania G, Sanders, Taren, Sang, Yingying, Santomauro, Damian Francesco, Santos, Itamar S, Santos, João Vasco, Santric Milicevic, Milena M, Sao Jose, Bruno Piassi, Sardana, Mayank, Sarker, Abdur Razzaque, Sarmiento-Suárez, Rodrigo, Sarrafzadegan, Nizal, Sartorius, Benn, Sarvi, Shahabeddin, Sathian, Brijesh, Satpathy, Maheswar, Sawant, Arundhati R, Sawhney, Monika, Saylan, Mete, Sayyah, Mehdi, Schaeffner, Elke, Schmidt, Maria Inê, Schneider, Ione J C, Schöttker, Ben, Schutte, Aletta Elisabeth, Schwebel, David C, Schwendicke, Falk, Scott, James G, Seedat, Soraya, Sekerija, Mario, Sepanlou, Sadaf G, Serre, Marc L, Serván-Mori, Edson, Seyedmousavi, Seyedmojtaba, Shabaninejad, Hosein, Shaddick, Gavin, Shafieesabet, Azadeh, Shahbazi, Mehdi, Shaheen, Amira A, Shaikh, Masood Ali, Shamah Levy, Teresa, Shams-Beyranvand, Mehran, Shamsi, Mohammadbagher, Sharafi, Heidar, Sharafi, Kiomar, Sharif, Mehdi, Sharif-Alhoseini, Mahdi, Sharifi, Hamid, Sharma, Jayendra, Sharma, Meenakshi, Sharma, Rajesh, She, Jun, Sheikh, Aziz, Shi, Peilin, Shibuya, Kenji, Shiferaw, Mekonnen Sisay, Shigematsu, Mika, Shin, Min-Jeong, Shiri, Rahman, Shirkoohi, Reza, Shiue, Ivy, Shokraneh, Farhad, Shoman, Haitham, Shrime, Mark G, Shupler, Matthew S, Si, Si, Siabani, Soraya, Sibai, Abla Mehio, Siddiqi, Tariq J, Sigfusdottir, Inga Dora, Sigurvinsdottir, Rannveig, Silva, Diego Augusto Santo, Silva, João Pedro, Silveira, Dayane Gabriele Alve, Singh, Jasvinder A, Singh, Narinder Pal, Singh, Virendra, Sinha, Dhirendra Narain, Skiadaresi, Eirini, Skirbekk, Vegard, Smith, David L, Smith, Mari, Sobaih, Badr Hasan, Sobhani, Soheila, Somayaji, Ranjani, Soofi, Moslem, Sorensen, Reed J D, Soriano, Joan B, Soyiri, Ireneous N, Spinelli, Angela, Sposato, Luciano A, Sreeramareddy, Chandrashekhar T, Srinivasan, Vinay, Starodubov, Vladimir I, Steckling, Nadine, Stein, Dan J, Stein, Murray B, Stevanovic, Goran, Stockfelt, Leo, Stokes, Mark A, Sturua, Lela, Subart, Michelle L, Sudaryanto, Agu, Sufiyan, Mu'awiyyah Babale, Sulo, Gerhard, Sunguya, Bruno F, Sur, Patrick John, Sykes, Bryan L, Szoeke, Cassandra E I, Tabarés-Seisdedos, Rafael, Tabuchi, Takahiro, Tadakamadla, Santosh Kumar, Takahashi, Ken, Tandon, Nikhil, Tassew, Segen Gebremeskel, Tavakkoli, Mohammad, Taveira, Nuno, Tehrani-Banihashemi, Arash, Tekalign, Tigist Gashaw, Tekelemedhin, Shishay Wahdey, Tekle, Merhawi Gebremedhin, Temesgen, Habtamu, Temsah, Mohamad-Hani, Temsah, Omar, Terkawi, Abdullah Sulieman, Tessema, Belay, Teweldemedhin, Mebrahtu, Thankappan, Kavumpurathu Raman, Theis, Andrew, Thirunavukkarasu, Sathish, Thomas, Hannah J, Thomas, Matthew Lloyd, Thomas, Nihal, Thurston, George D, Tilahun, Binyam, Tillmann, Taavi, To, Quyen G, Tobollik, Myriam, Tonelli, Marcello, Topor-Madry, Roman, Torre, Anna E, Tortajada-Girbés, Miguel, Touvier, Mathilde, Tovani-Palone, Marcos Roberto, Towbin, Jeffrey A, Tran, Bach Xuan, Tran, Khanh Bao, Truelsen, Thomas Clement, Truong, Nu Thi, Tsadik, Afewerki Gebremeskel, Tudor Car, Lorainne, Tuzcu, E Murat, Tymeson, Hayley D, Tyrovolas, Stefano, Ukwaja, Kingsley N, Ullah, Irfan, Updike, Rachel L, Usman, Muhammad Shariq, Uthman, Olalekan A, Vaduganathan, Muthiah, Vaezi, Afsane, Valdez, Pascual R, Van Donkelaar, Aaron, Varavikova, Elena, Varughese, Santosh, Vasankari, Tommi Juhani, Venkateswaran, Vidhya, Venketasubramanian, Narayanaswamy, Villafaina, Santo, Violante, Francesco S, Vladimirov, Sergey Konstantinovitch, Vlassov, Vasily, Vollset, Stein Emil, Vos, Theo, Vosoughi, Kia, Vu, Giang Thu, Vujcic, Isidora S, Wagnew, Fasil Shiferaw, Waheed, Yasir, Waller, Stephen G, Walson, Judd L, Wang, Yafeng, Wang, Yanping, Wang, Yuan-Pang, Weiderpass, Elisabete, Weintraub, Robert G, Weldegebreal, Fitsum, Werdecker, Andrea, Werkneh, Adhena Ayaliew, West, J Jason, Westerman, Ronny, Whiteford, Harvey A, Widecka, Justyna, Wijeratne, Tissa, Winkler, Andrea Sylvia, Wiyeh, Alison B, Wiysonge, Charles Shey, Wolfe, Charles D A, Wong, Tien Yin, Wu, Shouling, Xavier, Deni, Xu, Gelin, Yadgir, Simon, Yadollahpour, Ali, Yahyazadeh Jabbari, Seyed Hossein, Yamada, Tomohide, Yan, Lijing L, Yano, Yuichiro, Yaseri, Mehdi, Yasin, Yasin Jemal, Yeshaneh, Alex, Yimer, Ebrahim M, Yip, Paul, Yisma, Engida, Yonemoto, Naohiro, Yoon, Seok-Jun, Yotebieng, Marcel, Younis, Mustafa Z, Yousefifard, Mahmoud, Yu, Chuanhua, Zaidi, Zoubida, Zaman, Sojib Bin, Zamani, Mohammad, Zavala-Arciniega, Lui, Zhang, Anthony Lin, Zhang, Hao, Zhang, Kai, Zhou, Maigeng, Zimsen, Stephanie R M, Zodpey, Sanjay, and Murray, Christopher J L

Subjects
Science & Technology, GBD, risks, risk factors, comparative risk assesment, Dalys, Medicine (all), CHOLESTEROL, BLOOD-PRESSURE, 11 Medical And Health Sciences, ILLNESS, TRENDS, humanities, Medicine, General & Internal, TOBACCO CONTROL, General & Internal Medicine, parasitic diseases, Medicine and Health Sciences, CARDIOVASCULAR-DISEASES, TRIAL, Human medicine, Life Sciences & Biomedicine, METAANALYSIS
Abstract

Background The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 comparative risk assessment (CRA) is a comprehensive approach to risk factor quantification that offers a useful tool for synthesising evidence on risks and risk–outcome associations. With each annual GBD study, we update the GBD CRA to incorporate improved methods, new risks and risk–outcome pairs, and new data on risk exposure levels and risk– outcome associations. Methods We used the CRA framework developed for previous iterations of GBD to estimate levels and trends in exposure, attributable deaths, and attributable disability-adjusted life-years (DALYs), by age group, sex, year, and location for 84 behavioural, environmental and occupational, and metabolic risks or groups of risks from 1990 to 2017. This study included 476 risk–outcome pairs that met the GBD study criteria for convincing or probable evidence of causation. We extracted relative risk and exposure estimates from 46 749 randomised controlled trials, cohort studies, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. Using the counterfactual scenario of theoretical minimum risk exposure level (TMREL), we estimated the portion of deaths and DALYs that could be attributed to a given risk. We explored the relationship between development and risk exposure by modelling the relationship between the Socio-demographic Index (SDI) and risk-weighted exposure prevalence and estimated expected levels of exposure and risk-attributable burden by SDI. Finally, we explored temporal changes in risk-attributable DALYs by decomposing those changes into six main component drivers of change as follows: (1) population growth; (2) changes in population age structures; (3) changes in exposure to environmental and occupational risks; (4) changes in exposure to behavioural risks; (5) changes in exposure to metabolic risks; and (6) changes due to all other factors, approximated as the risk-deleted death and DALY rates, where the risk-deleted rate is the rate that would be observed had we reduced the exposure levels to the TMREL for all risk factors included in GBD 2017. Findings In 2017, 34·1 million (95% uncertainty interval [UI] 33·3–35·0) deaths and 1·21 billion (1·14–1·28) DALYs were attributable to GBD risk factors. Globally, 61·0% (59·6–62·4) of deaths and 48·3% (46·3–50·2) of DALYs were attributed to the GBD 2017 risk factors. When ranked by risk-attributable DALYs, high systolic blood pressure (SBP) was the leading risk factor, accounting for 10·4 million (9·39–11·5) deaths and 218 million (198–237) DALYs, followed by smoking (7·10 million [6·83–7·37] deaths and 182 million [173–193] DALYs), high fasting plasma glucose (6·53 million [5·23–8·23] deaths and 171 million [144–201] DALYs), high body-mass index (BMI; 4·72 million [2·99–6·70] deaths and 148 million [98·6–202] DALYs), and short gestation for birthweight (1·43 million [1·36–1·51] deaths and 139 million [131–147] DALYs). In total, risk-attributable DALYs declined by 4·9% (3·3–6·5) between 2007 and 2017. In the absence of demographic changes (ie, population growth and ageing), changes in risk exposure and risk-deleted DALYs would have led to a 23·5% decline in DALYs during that period. Conversely, in the absence of changes in risk exposure and risk-deleted DALYs, demographic changes would have led to an 18·6% increase in DALYs during that period. The ratios of observed risk exposure levels to exposure levels expected based on SDI (O/E ratios) increased globally for unsafe drinking water and household air pollution between 1990 and 2017. This result suggests that development is occurring more rapidly than are changes in the underlying risk structure in a population. Conversely, nearly universal declines in O/E ratios for smoking and alcohol use indicate that, for a given SDI, exposure to these risks is declining. In 2017, the leading Level 4 risk factor for age-standardised DALY rates was high SBP in four super-regions: central Europe, eastern Europe, and central Asia; north Africa and Middle East; south Asia; and southeast Asia, east Asia, and Oceania. The leading risk factor in the high-income super-region was smoking, in Latin America and Caribbean was high BMI, and in sub-Saharan Africa was unsafe sex. O/E ratios for unsafe sex in sub-Saharan Africa were notably high, and those for alcohol use in north Africa and the Middle East were notably low. Lancet 2018; 392: 1923–94 *Collaborators listed at the end of the paper Correspondence to: Prof Christopher J L Murray, Institute for Health Metrics and Evalution, Seattle, WA 98121, USA cjlm@uw.edu Global Health Metrics 1924 www.thelancet.com Vol 392 November 10, 2018 Interpretation By quantifying levels and trends in exposures to risk factors and the resulting disease burden, this assessment offers insight into where past policy and programme efforts might have been successful and highlights current priorities for public health action. Decreases in behavioural, environmental, and occupational risks have largely offset the effects of population growth and ageing, in relation to trends in absolute burden. Conversely, the combination of increasing metabolic risks and population ageing will probably continue to drive the increasing trends in non-communicable diseases at the global level, which presents both a public health challenge and opportunity. We see considerable spatiotemporal heterogeneity in levels of risk exposure and risk-attributable burden. Although levels of development underlie some of this heterogeneity, O/E ratios show risks for which countries are overperforming or underperforming relative to their level of development. As such, these ratios provide a benchmarking tool to help to focus local decision making. Our findings reinforce the importance of both risk exposure monitoring and epidemiological research to assess causal connections between risks and health outcomes, and they highlight the usefulness of the GBD study in synthesising data to draw comprehensive and robust conclusions that help to inform good policy and strategic health planning.

Published
2018

29. Epidemiology of ductal carcinoma in situ

Author

Mannu, GS, Darby, SC, and Hamdy, F

Subjects
Epidemiology
Abstract

Introduction: Almost 7,000 people are diagnosed with ductal carcinoma in situ (DCIS) in the United Kingdom each year, but there remains uncertainty regarding its natural history and optimal management. The aim of this thesis was to evaluate factors contributing to the epidemiology of DCIS and its outcomes. Methods: 1) A cohort study comparing risk factors for DCIS and invasive breast cancer (IBC) using UK Biobank; 2) A cohort study examining the accuracy of preoperative biopsy in DCIS using clinical records from the Netherlands Cancer Institute; 3) A cohort study examining the rate of invasive breast cancer following treatment for screen-detected DCIS in England using the National Health Service Breast Screening Programme (NHSBSP) audit; 4) A methodological study to develop an algorithm to identify invasive breast cancer recurrences, which in the future may used to identify DCIS recurrences, using all relevant routinely collected data stored within Public Health England (PHE). Results: (1) For both DCIS and IBC, postmenopausal BMI was associated with an increased risk of developing disease, and the number of live births was associated with a decreased risk of developing disease. However, the magnitude of the effect differed between DCIS and IBC. The increased risk from postmenopausal BMI &GE;35 kg/m2 was larger for DCIS than for IBC (RR 2.35, 95% CI 1.14 – 4.82), and the trend of reduction in risk with each additional live birth was greater for DCIS than for IBC (p for trend = 0.03). (2) Consideration of mammographic lesion size and the absence of necrosis on biopsy may be helpful in selecting low-risk women for non-operative management of DCIS in the future, as may use of the 9G vacuum-assisted method of biopsy. (3) The cumulative risks of IBC at 5, 10 and 15 years after screen-detected DCIS in England were 3.5%, 7.1%, and 9.4% respectively. Women with clear surgical margins of 1 – 2 mm had a higher IBC rate than women with clear margins of 5+ mm (RR 1.85, 95% CI 1.20 – 2.84). Women given breast-conserving surgery (BCS) without radiotherapy had a higher ipsilateral IBC rate than women given BCS with radiotherapy (RR 1.63, 95% CI 1.27 – 2.10). Women given hormone therapy had a lower rate of any IBC compared with oestrogen receptor (ER) positive women not given hormone therapy (RR 0.76, 95% CI 0.63 – 0.93). (4) There was good agreement between the number of recurrences indicated by the developed algorithm using routinely collected data sources and the number of recurrences recorded in the test dataset. This finding supports the potential value of compiling recurrence information on a nationwide basis from routinely collected data, for use in future descriptive and epidemiological studies and in follow-up for randomised trials. Conclusions: Using a variety of methods these studies have all succeeded in adding to knowledge about the epidemiology of DCIS. This knowledge can be used to help the future management of women with DCIS. In addition, each of the studies has planned extensions and will continue to contribute further knowledge periodically into the future.

Published
2018

30. Invasive breast cancer and breast cancer death after non-screen detected ductal carcinoma in situ from 1990 to 2018 in England: population based cohort study.

Author

Mannu GS, Wang Z, Dodwell D, Broggio J, Charman J, and Darby SC

Subjects
Humans, Female, Cohort Studies, Mastectomy, England epidemiology, Breast Neoplasms, Carcinoma, Intraductal, Noninfiltrating epidemiology
Abstract

Objectives: To evaluate the long term risks of invasive breast cancer and death related to breast cancer after non-screen detected ductal carcinoma in situ. Risks for women in the general population and for women diagnosed with ductal carcinoma in situ via the screening programme were compared., Design: Population based cohort study., Setting: Data from the National Disease Registration Service., Participants: All 27 543 women in England who were diagnosed with ductal carcinoma in situ, outside the NHS breast screening programme, during 1990 to 2018., Main Outcome Measures: Incident invasive breast cancer and death caused by breast cancer., Results: By 31 December 2018, 3651 women with non-screen detected ductal carcinoma in situ had developed invasive breast cancer, more than four times higher than expected from national cancer incidence rates (ratio of observed to expected rate was 4.21 (95% conference interval 4.07 to 4.35)). The ratio of observed to expected rate of developing invasive breast cancer remained increased throughout follow-up among women aged <45-70 years. The 25 year cumulative risks of invasive breast cancer by age at diagnosis of ductal carcinoma in situ were 27.3% for <45 years, 25.2% for 45-49 years, 21.7% for 50-59 years, and 20.8% for 60-70 years. 908 women died of breast cancer, almost four times higher than that expected from breast cancer death rates in the general population (ratio of observed to expected rate 3.83 (3.59 to 4.09)). The ratio of observed to expected rate of mortality attributed to breast cancer remained increased throughout follow-up. The 25 year cumulative risks of breast cancer death by age at ductal carcinoma in situ diagnosis were 7.6% for <45 years, 5.8% for 45-49 years, 5.9% for 50-59 years, and 6.2% for 60-70 years. Among women aged 50-64 years, and therefore eligible for breast screening by the NHS, the ratio of observed to expected rate of invasive breast cancer in women with non-screen detected compared with screen detected ductal carcinoma in situ was 1.26 (95% conference interval 1.17 to 1.35), while the ratio for mortality from breast cancer was 1.37 (1.17 to 1.60). Among 22 753 women with unilateral ductal carcinoma in situ undergoing surgery, those who had mastectomy rather than breast conserving surgery had a lower 25 year cumulative rate of ipsilateral invasive breast cancer (mastectomy 8.2% (95% conference interval 7.0% to 9.4%), breast conserving surgery with radiotherapy 19.8% (16.2% to 23.4%), and breast conserving surgery with no radiotherapy recorded 20.6% (18.7% to 22.4%)). However, reductions did not translate into a lower 25 year cumulative rate of deaths attributable to breast cancer (mastectomy 6.5% (4.9% to 10.9%), breast conserving surgery with radiotherapy 8.6% (5.9% to 15.5%), breast conserving surgery with no radiotherapy recorded 7.8% (6.3% to 11.5%))., Conclusions: For at least 25 years after their diagnosis, women with non-screen detected ductal carcinoma in situ had higher long term risks of invasive breast cancer and breast cancer death than women in the general population. Additionally, they had higher long term risks than women with screen detected ductal carcinoma in situ. Mastectomy was associated with lower risks of invasive breast cancer than breast conserving surgery, even when accompanied by radiotherapy. However, risks of breast cancer death appeared similar for mastectomy, breast conserving surgery with radiotherapy, and breast conserving surgery with no radiotherapy recorded., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest and declare: funding from Cancer Research UK, Cancer Research UK Clinician Scientist Fellowship, the National Institute for Health Research Biomedical Research Centre, and the University of Oxford; no support from any organisation for the submitted work other than salaries from their employing institutions and the funding listed in the section above; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; and no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2024
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31. Cardiovascular disease incidence rates: a study using routinely collected health data.

Author

Ramroth J, Shakir R, Darby SC, Cutter DJ, and Kuan V

Abstract

Background: There is substantial evidence that systemic anticancer therapies and radiotherapy can increase the long-term risk of cardiovascular disease (CVD). Optimal management decisions for cancer patients therefore need to take into account the likely risks from a proposed treatment option, as well as its likely benefits. For CVD, the magnitude of the risk depends on the incidence of the disease in the general population to which the patient belongs, including variation with age and sex, as well as on the treatment option under consideration. The aim of this paper is to provide estimates of CVD incidence rates in the general population of England for use in cardio-oncology and in other relevant clinical, research and health policy contexts., Methods: We studied a population-based representative cohort, consisting of 2,633,472 individuals, derived by electronic linkage of records from primary care with those of admitted-patient care in England during April 1, 2010, to April 1, 2015. From 38 individual CVDs available via the linked dataset we identified five relevant categories of CVD whose risk may be increased by cancer treatments: four of heart disease and one of stroke., Results: We calculated incidence rates by age-group and sex for all relevant CVD categories combined, for the four relevant categories of heart disease combined, and for the five relevant CVD categories separately. We present separate incidence rates for all 38 individual CVDs available via the linked dataset. We also illustrate how our data can be used to estimate absolute CVD risks in a range of people with Hodgkin lymphoma treated with chemotherapy and radiotherapy., Conclusions: Our results provide population-based CVD incidence rates for a variety of uses, including the estimation of absolute risks of CVD from cancer treatments, thus helping patients and clinicians to make appropriate individualized cancer treatment decisions. Graphical Abstract: Cardiovascular incidence rates for use in cardio-oncology and elsewhere: A presentation of age- and sex-specific cardiovascular disease (CVD) incidence rates for use in calculation of absolute cardiovascular risks of cancer treatments, and in other clinical, research and health policy contexts. Abbreviations - CVD: cardiovascular disease; y: years., (© 2023. The Author(s).)

Published
2023
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32. Proton Beam Therapy for Early Breast Cancer: A Systematic Review and Meta-analysis of Clinical Outcomes.

Author

Holt F, Probert J, Darby SC, Haviland JS, Coles CE, Kirby AM, Liu Z, Dodwell D, Ntentas G, Duane F, and Taylor C

Subjects
Humans, Female, Breast Neoplasms radiotherapy, Breast Neoplasms surgery, Breast Neoplasms etiology, Proton Therapy adverse effects, Proton Therapy methods
Abstract

Purpose: Adjuvant proton beam therapy (PBT) is increasingly available to patients with breast cancer. It achieves better planned dose distributions than standard photon radiation therapy and therefore may reduce the risks. However, clinical evidence is lacking., Methods and Materials: A systematic review of clinical outcomes from studies of adjuvant PBT for early breast cancer published in 2000 to 2022 was undertaken. Early breast cancer was defined as when all detected invasive cancer cells are in the breast or nearby lymph nodes and can be removed surgically. Adverse outcomes were summarized quantitatively, and the prevalence of the most common ones were estimated using meta-analysis., Results: Thirty-two studies (1452 patients) reported clinical outcomes after adjuvant PBT for early breast cancer. Median follow-up ranged from 2 to 59 months. There were no published randomized trials comparing PBT with photon radiation therapy. Scattering PBT was delivered in 7 studies (258 patients) starting 2003 to 2015 and scanning PBT in 22 studies (1041 patients) starting 2000 to 2019. Two studies (123 patients) starting 2011 used both PBT types. For 1 study (30 patients), PBT type was unspecified. Adverse events were less severe after scanning than after scattering PBT. They also varied by clinical target. For partial breast PBT, 498 adverse events were reported (8 studies, 358 patients). None were categorized as severe after scanning PBT. For whole breast or chest wall ± regional lymph nodes PBT, 1344 adverse events were reported (19 studies, 933 patients). After scanning PBT, 4% (44/1026) of events were severe. The most prevalent severe outcome after scanning PBT was dermatitis, which occurred in 5.7% (95% confidence interval, 4.2-7.6) of patients. Other severe adverse outcomes included infection, pain, and pneumonitis (each ≤1%). Of the 141 reconstruction events reported (13 studies, 459 patients), the most prevalent after scanning PBT was prosthetic implant removal (34/181, 19%)., Conclusions: This is a quantitative summary of all published clinical outcomes after adjuvant PBT for early breast cancer. Ongoing randomized trials will provide information on its longer-term safety compared with standard photon radiation therapy., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2023
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34. Ki67 and breast cancer mortality in women with invasive breast cancer.

Author

Probert J, Dodwell D, Broggio J, Charman J, Dowsett M, Kerr A, McGale P, Taylor C, Darby SC, and Mannu GS

Subjects
Female, Humans, Ki-67 Antigen analysis, Biomarkers, Tumor analysis, Cohort Studies, Receptors, Estrogen analysis, Kaplan-Meier Estimate, Breast Neoplasms pathology
Abstract

Background: The percentage of cells staining positive for Ki67 is sometimes used for decision-making in patients with early invasive breast cancer (IBC). However, there is uncertainty regarding the most appropriate Ki67 cut points and the influence of interlaboratory measurement variability. We examined the relationship between breast cancer mortality and Ki67 both before and after accounting for interlaboratory variability and 8 patient and tumor characteristics., Methods: A multicenter cohort study of women with early IBC diagnosed during 2009-2016 in more than 20 NHS hospitals in England and followed until December 31, 2020., Results: Ki67 was strongly prognostic of breast cancer mortality in 8212 women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative early IBC (Ptrend < .001). This relationship remained strong after adjustment for patient and tumor characteristics (Ptrend < .001). Standardization for interlaboratory variability did little to alter these results. For women with Ki67 scores of 0%-5%, 6%-10%, 11%-19%, and 20%-29% the corresponding 8-year adjusted cumulative breast cancer mortality risks were 3.3% (95% confidence interval [CI] = 2.8% to 4.0%), 3.7% (95% CI = 3.0% to 4.4%), 3.4% (95% CI = 2.8% to 4.1%), and 3.4% (95% CI = 2.8% to 4.1%), whereas for women with Ki67 scores of 30%-39% and 40%-100%, these risks were higher, at 5.1% (95% CI = 4.3% to 6.2%) and 7.7% (95% CI = 6.6% to 9.1) (Ptrend < .001). Similar results were obtained when the adjusted analysis was repeated with omission of pathological information about tumor size and nodal involvement, which would not be available preoperatively for patients being considered for neoadjuvant therapy., Conclusion: Our findings confirm the prognostic value of Ki67 scores of 30% or more in women with ER-positive, HER2-negative early IBC, irrespective of interlaboratory variability. These results also suggest that Ki67 may be useful to aid decision-making in the neoadjuvant setting., (© The Author(s) 2023. Published by Oxford University Press.)

Published
2023
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35. Temporal trends in the incidence of malignant and nonmalignant primary brain and central nervous system tumors by the method of diagnosis in England, 1993-2017.

Author

Ali UM, Withrow DR, Judge AD, Plaha P, and Darby SC

Subjects
Humans, Incidence, Registries, England epidemiology, Brain, State Medicine, Central Nervous System Neoplasms diagnostic imaging, Central Nervous System Neoplasms epidemiology
Abstract

Background: Several studies report increases in the incidences of primary central nervous system (CNS) tumors. The reasons for this are unclear., Methods: Data on all 188 340 individuals diagnosed with a primary CNS tumor in England (1993-2017) were obtained from the National Cancer Registration and Analysis Service. Data on all computerized tomography (CT) head and magnetic resonance imaging (MRI) brain scans in England (2013-2017) were obtained from the National Health Service Digital. Age-sex-standardized annual incidence rates per 100 000 population (ASR) were calculated by calendar year, tumor behavior, tumor location, and method of diagnosis. Temporal trends were quantified using average annual percent change (AAPC)., Results: The ASR for all CNS tumors increased from 13.0 in 1993 to 18.6 in 2017 (AAPC: +1.5%, 95% CI: 1.3, 1.7). The ASR for malignant tumors (52% overall) remained stable (AAPC: +0.5%, 95% CI: -0.2, 1.3), while benign tumors (37% overall) increased (AAPC: +2.6%, 95% CI: 1.2, 4.0). Among the 66% of benign tumors that were microscopically confirmed, the ASR increased modestly (AAPC: +1.3%, 95% CI: 0.5, 2.1). However, among the 25% of benign tumors that were radiographically confirmed, the ASR increased substantially (AAPC: 10.2%, 95% CI: 7.9, 12.5), principally driven by large increases in those who are aged 65+ years. The rate of CT head scans in Accident & Emergency (A&E) increased during 2013-2017, with especially large increases in 65-84 and 85+-year-olds (AAPCs: +18.4% and +22.5%)., Conclusions: Increases in CNS tumor incidence in England are largely attributable to the greater detection of benign tumors. This could be the result of the increasing use of neuroimaging, particularly CT head scans in A&E in people who are aged 65+ years., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Published
2023
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36. Association of Radiation and Procarbazine Dose With Risk of Colorectal Cancer Among Survivors of Hodgkin Lymphoma.

Author

Geurts YM, Shakir R, Ntentas G, Roberti S, Aznar MC, John KM, Ramroth J, Janus CPM, Krol ADG, Roesink JM, van der Maazen RWM, Zijlstra JM, Darby SC, Aleman BMP, van Leeuwen FE, Cutter DJ, and Schaapveld M

Subjects
Male, Humans, Child, Female, Procarbazine adverse effects, Case-Control Studies, Survivors, Hodgkin Disease drug therapy, Hodgkin Disease epidemiology, Hodgkin Disease radiotherapy, Colorectal Neoplasms epidemiology, Colorectal Neoplasms diagnosis
Abstract

Importance: Hodgkin lymphoma (HL) survivors have higher rates of colorectal cancer, which may be associated with subdiaphragmatic radiation therapy and/or alkylating chemotherapy. Although radiation dose-response associations with breast, lung, stomach, pancreatic, and esophageal cancer after HL have been demonstrated, the association of radiation therapy with colorectal cancer remains unclear., Objective: To quantify the rate of colorectal cancer according to radiation dose to the large bowel and procarbazine dose among HL survivors., Design, Setting, and Participants: A nested case-control study examined 5-year HL survivors at 5 hospital centers in the Netherlands. Participants had been diagnosed with HL in 1964 to 2000, when they were 15 to 50 years of age, and were followed for a median of approximately 26 years. Survivors of HL who developed colorectal cancer and survivors who were selected as controls were individually matched on sex, age at HL diagnosis, and date of HL diagnosis. Data were analyzed from July 2021 to October 2022., Exposures: Mean radiation doses to the large bowel were estimated by reconstructing individual radiation therapy treatments on representative computed tomography data sets., Main Outcomes and Measures: Excess rate ratios (ERRs) were modeled to evaluate the excess risk associated with each 1-gray increase in radiation dose, and potential effect modification by procarbazine was explored., Results: The study population included 316 participants (mean [SD] age at HL diagnosis, 33.0 [9.8] years; 221 [69.9%] men), 78 of whom were HL survivors who developed colorectal cancer (cases) and 238 who did not (controls). The median (IQR) interval between HL and colorectal cancer was 25.7 (18.2-31.6) years. Increased colorectal cancer rates were seen for patients who received subdiaphragmatic radiation therapy (rate ratio [RR], 2.4; 95% CI, 1.4-4.1) and those who received more than 8.4 g/m2 procarbazine (RR, 2.5; 95% CI, 1.3-5.0). Overall, colorectal cancer rate increased linearly with mean radiation dose to the whole large bowel and dose to the affected bowel segment. The association between radiation dose and colorectal cancer rate became stronger with increasing procarbazine dose: the ERR per gray to the whole bowel was 3.5% (95% CI, 0.4%-12.6%) for patients who did not receive procarbazine, and increased 1.2-fold (95% CI, 1.1-1.3) for each 1-g/m2 increase in procarbazine dose., Conclusions and Relevance: This nested case-control study of 5-year HL survivors found a dose-response association between radiation therapy and colorectal cancer risk, and modification of this association by procarbazine. These findings may enable individualized colorectal cancer risk estimations, identification of high-risk survivors for subsequent screening, and optimization of treatment strategies.

Published
2023
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37. Exposure of the heart and cardiac valves in women irradiated for breast cancer 1970-2009.

Author

Duane FK, Boekel NB, Jacobse JN, Wang Z, Aleman BMP, Darby SC, Schaapveld M, van Leeuwen FE, Baaijens MHA, Warren S, and Taylor CW

Abstract

Purpose: To describe cardiac exposure from breast cancer radiotherapy regimens used during 1970-2009 for the development of dose-response relationships and to consider the associated radiation-risks using existing dose-response relationships., Material and Methods: Radiotherapy charts for 771 women in the Netherlands selected for case control studies of heart disease after breast cancer radiotherapy were used to reconstruct 44 regimens on a typical CT-dataset. Doses were estimated for the whole heart (WH), left ventricle (LV) and cardiac valves., Results: For breast/chest wall radiotherapy average WH doses decreased during 1970-2009. For internal mammary chain (IMC) radiotherapy WH doses were highest during the 1980s and 1990s when direct anterior fields were used and reduced in the 2000s when oblique fields were introduced. Average doses varied substantially for IMC regimens (WH 2-33 Gy, LV < 1-23 Gy). For cardiac valves, at least one valve received >30 Gy from most regimens., Conclusions: Radiation-risks of IHD from breast/chest wall regimens likely reduced during 1970-2009. Direct anterior IMC regimens likely increased the risks of IHD and VHD over this time period but the use of oblique IMC fields from 2003 may have lowered these risks. These data provide a unique opportunity to develop dose-response relationships., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Warren reports non-financial support from Raystation UK Users Meeting May 2019, outside the submitted work., (© 2022 The Author(s).)

Published
2022
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38. Adjuvant and neoadjuvant breast cancer treatments: A systematic review of their effects on mortality.

Author

Kerr AJ, Dodwell D, McGale P, Holt F, Duane F, Mannu G, Darby SC, and Taylor CW

Subjects
Chemotherapy, Adjuvant, Female, Humans, Mastectomy, Neoadjuvant Therapy, Tamoxifen therapeutic use, Breast Neoplasms drug therapy, Breast Neoplasms pathology
Abstract

Background: Adjuvant and neoadjuvant breast cancer treatments can reduce breast cancer mortality but may increase mortality from other causes. Information regarding treatment benefits and risks is scattered widely through the literature. To inform clinical practice we collated and reviewed the highest quality evidence., Methods: Guidelines were searched to identify adjuvant or neoadjuvant treatment options recommended in early invasive breast cancer. For each option, systematic literature searches identified the highest-ranking evidence. For radiotherapy risks, searches for dose-response relationships and modern organ doses were also undertaken., Results: Treatment options recommended in the USA and elsewhere included chemotherapy (anthracycline, taxane, platinum, capecitabine), anti-human epidermal growth factor 2 therapy (trastuzumab, pertuzumab, trastuzumab emtansine, neratinib), endocrine therapy (tamoxifen, aromatase inhibitor, ovarian ablation/suppression) and bisphosphonates. Radiotherapy options were after breast conserving surgery (whole breast, partial breast, tumour bed boost, regional nodes) and after mastectomy (chest wall, regional nodes). Treatment options were supported by randomised evidence, including > 10,000 women for eight treatment comparisons, 1,000-10,000 for fifteen and < 1,000 for one. Most treatment comparisons reduced breast cancer mortality or recurrence by 10-25%, with no increase in non-breast-cancer death. Anthracycline chemotherapy and radiotherapy increased overall non-breast-cancer mortality. Anthracycline risk was from heart disease and leukaemia. Radiation-risks were mainly from heart disease, lung cancer and oesophageal cancer, and increased with increasing heart, lung and oesophagus radiation doses respectively. Taxanes increased leukaemia risk., Conclusions: These benefits and risks inform treatment decisions for individuals and recommendations for groups of women., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Published
2022
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39. Proton Therapy in Supradiaphragmatic Lymphoma: Predicting Treatment-Related Mortality to Help Optimize Patient Selection.

Author

Ntentas G, Dedeckova K, Andrlik M, Aznar MC, Shakir R, Ramroth J, Begum R, Kubeš J, Darby SC, Mikhaeel NG, and Cutter DJ

Subjects
Humans, Patient Selection, Radiotherapy Dosage, Smoking, Hodgkin Disease drug therapy, Hodgkin Disease radiotherapy, Proton Therapy adverse effects, Proton Therapy methods
Abstract

Purpose: In some patients with Hodgkin lymphoma (HL), proton beam therapy (PBT) may reduce the risk of radiation-related cardiovascular disease (CVD) and second cancers (SC) compared with photon radiation therapy (RT). Our aim was to identify patients who benefit the most from PBT in terms of predicted 30-year absolute mortality risks (AMR 30 ) from CVD and SC, taking into account individual background, chemotherapy, radiation, and smoking-related risks., Methods and Materials: Eighty patients with supradiaphragmatic HL treated with PBT between 2015 and 2019 were replanned using optimal photon RT. To identify patients predicted to derive the greatest benefit from PBT compared with photon RT, doses and AMR 30 from CVD and SC of the lung, breast, and esophagus were compared for all patients and across patient subgroups., Results: For patients with mediastinal disease below the origin of the left main coronary artery (n = 66; 82%), PBT reduced the mean dose to the heart, left ventricle, and heart valves by 1.0, 2.7, and 3.6 Gy, respectively. Based on U.S. mortality rates, PBT reduced CVD AMR 30 by 0.2%, from 5.9% to 5.7%. The benefit was larger if the mediastinal disease overlapped longitudinally with the heart by ≥40% (n = 23; 29%). PBT reduced the mean dose to the heart, left ventricle, and heart valves by 3.2, 5.6, and 5.1 Gy, respectively, and reduced CVD AMR 30 by 0.8%, from 7.0% to 6.2%. For patients with axillary disease (n = 25; 31%), PBT reduced the mean lung dose by 2.8 Gy and lung cancer AMR 30 by 0.6%, from 2.7% to 2.1%. Breast and esophageal doses were also lower with PBT, but the effects on AMR 30 were negligible. The effect of smoking on CVD and lung cancer AMR 30 was much larger than radiation and chemotherapy and the differences between radiation modalities., Conclusions: The predicted benefit of PBT is not universal and limited to certain categories of patients with lymphoma and lower mediastinal or axillary disease. Smoking cessation should be strongly encouraged in smokers who require thoracic RT., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Published
2022
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40. Predicted Risks of Cardiovascular Disease Following Chemotherapy and Radiotherapy in the UK NCRI RAPID Trial of Positron Emission Tomography-Directed Therapy for Early-Stage Hodgkin Lymphoma.

Author

Cutter DJ, Ramroth J, Diez P, Buckle A, Ntentas G, Popova B, Clifton-Hadley L, Hoskin PJ, Darby SC, Radford J, and Illidge T

Subjects
Adolescent, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols adverse effects, Bleomycin therapeutic use, Cardiovascular Diseases diagnostic imaging, Cardiovascular Diseases mortality, Clinical Decision-Making, Dacarbazine therapeutic use, Doxorubicin therapeutic use, Female, Heart Disease Risk Factors, Hodgkin Disease diagnostic imaging, Hodgkin Disease mortality, Hodgkin Disease pathology, Humans, Incidence, Male, Middle Aged, Neoplasm Staging, Predictive Value of Tests, Radiation Dosage, Radiation Injuries diagnostic imaging, Radiation Injuries mortality, Risk Assessment, Time Factors, Treatment Outcome, United Kingdom epidemiology, Vinblastine therapeutic use, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cardiovascular Diseases epidemiology, Chemoradiotherapy adverse effects, Chemoradiotherapy mortality, Hodgkin Disease therapy, Positron-Emission Tomography, Radiation Injuries epidemiology
Abstract

Purpose: The contemporary management of early-stage Hodgkin lymphoma (ES-HL) involves balancing the risk of late adverse effects of radiotherapy against the increased risk of relapse if radiotherapy is omitted. This study provides information on the risk of radiation-related cardiovascular disease to help personalize the delivery of radiotherapy in ES-HL., Methods: We predicted 30-year absolute cardiovascular risk from chemotherapy and involved field radiotherapy in patients who were positron emission tomography (PET)-negative following three cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine chemotherapy within a UK randomized trial of PET-directed therapy for ES-HL. Cardiac and carotid radiation doses and chemotherapy exposure were combined with established dose-response relationships and population-based mortality and incidence rates., Results: Average mean heart dose was 4.0 Gy (range 0.1-24.0 Gy) and average bilateral common carotid artery dose was 21.5 Gy (range 0.6-38.1 Gy), based on individualized cardiovascular dosimetry for 144 PET-negative patients receiving involved field radiotherapy. The average predicted 30-year radiation-related absolute excess overall cardiovascular mortality was 0.56% (range 0.01%-6.79%; < 0.5% in 67% of patients and > 1% in 15%), whereas average predicted 30-year excess incidence was 6.24% (range 0.31%-31.09%; < 5% in 58% of patients and > 10% in 24%). For cardiac disease, the average predicted 30-year radiation-related absolute excess mortality was 0.42% (0.79% with mediastinal involvement and 0.05% without) and for stroke, it was 0.14%., Conclusion: Predicted excess cardiovascular risk is small for most patients, so radiotherapy may provide net benefit. However, for a minority of patients receiving high doses of radiation to cardiovascular structures, it may be preferable to consider advanced radiotherapy techniques to reduce doses or to omit radiotherapy and accept the increased relapse risk. Individual assessment of cardiovascular and other risks before treatment would allow personalized decision making about radiotherapy in ES-HL., Competing Interests: Johanna RamrothEmployment: Gilead Sciences (I)Stock and Other Ownership Interests: Gilead Sciences Laura Clifton-HadleyResearch Funding: Various pharmaceutical companies Peter J. HoskinResearch Funding: Varian Medical Systems, Astellas Pharma, Bayer, Roche, Pfizer, Elekta John RadfordStock and Other Ownership Interests: AstraZeneca, ADC TherapeuticsHonoraria: Takeda, ADC TherapeuticsConsulting or Advisory Role: Takeda, Seattle Genetics, NovartisSpeakers' Bureau: Takeda, Seattle Genetics, NovartisResearch Funding: TakedaTravel, Accommodations, Expenses: Takeda, ADC Therapeutics Tim IllidgeConsulting or Advisory Role: Takeda, Nordic NanovectorSpeakers' Bureau: Takeda, Bristol Myers Squibb, RocheResearch Funding: AstraZeneca/MedImmune, MSD OncologyTravel, Accommodations, Expenses: RocheNo other potential conflicts of interest were reported.

Published
2021
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41. Exposure of the oesophagus in breast cancer radiotherapy: A systematic review of oesophagus doses published 2010-2020.

Author

Duane FK, Kerr A, Wang Z, Darby SC, Ntentas G, Aznar MC, and Taylor CW

Subjects
Breast, Esophagus, Female, Humans, Radiotherapy Dosage, Radiotherapy Planning, Computer-Assisted, Breast Neoplasms radiotherapy, Radiotherapy, Intensity-Modulated, Thoracic Wall
Abstract

Background and Purpose: Breast cancer radiotherapy can increase the risk of subsequent primary oesophageal cancer, with risk increasing according to oesophagus radiation dose. We describe oesophagus exposure from modern breast cancer regimens and discuss the risks of oesophageal cancer for women irradiated recently., Materials and Methods: A systematic review was undertaken of oesophagus doses from breast cancer radiotherapy regimens published during 2010-2020. Mean and maximum oesophagus doses were described for different target regions irradiated and different radiotherapy techniques., Results: In 112 published regimens from 18 countries, oesophagus doses varied with target region. For partial breast irradiation, average mean oesophagus dose was 0.2 Gy (range 0.1-0.4) in four regimens; maximum dose was not reported. For breast or chest wall radiotherapy, average oesophagus doses were mean 1.8 Gy (range 0.1-10.4) in 24 regimens and maximum 6.7 Gy (range 0.4-14.3) in seven regimens. For radiotherapy including a nodal region, average oesophagus doses were higher: mean 11.4 Gy (range <0.1-29.3) in 61 regimens and maximum 34.4 Gy (range 3.4-51.3) in 55 regimens. Average mean oesophagus doses were >10 Gy for intensity modulated nodal radiotherapy, but lower for other node techniques., Conclusions: Mean oesophagus doses from partial breast and breast/chest wall regimens were usually less than 2 Gy, hence radiation-risks will be very small. However, for radiotherapy including lymph nodes, average mean oesophagus dose of 11.4 Gy may nearly double oesophageal cancer risk. Consideration of oesophageal exposure during nodal radiotherapy planning may reduce the risks of radiation-related oesophageal cancer for women irradiated today., Competing Interests: Conflicts of interest None., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Published
2021
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42. Dose-response relationships for radiation-related heart disease: Impact of uncertainties in cardiac dose reconstruction.

Author

Ntentas G, Darby SC, Aznar MC, Hodgson DC, Howell RM, Maraldo MV, Ahmed S, Ng A, Aleman BMP, and Cutter DJ

Subjects
Child, Dose-Response Relationship, Radiation, Heart, Humans, Uncertainty, Heart Diseases etiology, Radiation Injuries epidemiology, Radiation Injuries etiology
Abstract

Background and Purpose: Radiation-related heart disease (RRHD) can occur many decades after thoracic radiotherapy for Hodgkin lymphoma (HL) or childhood cancer (CC). To quantify the likely risk of RRHD for patients treated today, dose-response relationships derived from patients treated in previous decades are used. Publications presenting these dose-response relationships usually include estimates of uncertainties in the risks but ignore the effect of uncertainties in the reconstructed cardiac doses., Materials/methods: We assessed the systematic and random uncertainties in the reconstructed doses for published dose-response relationships for RRHD risk in survivors of HL or CC. Using the same reconstruction methods as were used in the original publications, we reconstructed mean heart doses and, wherever possible, mean left-ventricular doses for an independent case-series of test patients. These patients had known, CT-based, cardiac doses which were compared with the reconstructed doses to estimate the magnitude of the uncertainties and their effect on the dose-response relationships., Results: For all five reconstruction methods the relationship between reconstructed and CT-based doses was linear. For all but the simplest reconstruction method, the dose uncertainties were moderate, the effect of the systematic uncertainty on the dose-response relationships was less than 10%, and the effects of random uncertainty were small except at the highest doses., Conclusions: These results increase confidence in the published dose-response relationships for the risk of RRHD in HL and CC survivors. This may encourage doctors to use these dose-response relationships when estimating individualised risks for patients-an important aspect of personalising radiotherapy treatments today., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Published
2020
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43. Cardiac mortality after radiotherapy, chemotherapy and endocrine therapy for breast cancer: Cohort study of 2 million women from 57 cancer registries in 22 countries.

Author

Henson KE, McGale P, Darby SC, Parkin M, Wang Y, and Taylor CW

Subjects
Antineoplastic Agents, Hormonal therapeutic use, Cardiotoxicity, Cohort Studies, Drug Therapy, Female, Heart Diseases etiology, Humans, Middle Aged, Mortality trends, Patient Selection, Radiotherapy, Registries, Unilateral Breast Neoplasms epidemiology, Unilateral Breast Neoplasms therapy, Breast Neoplasms epidemiology, Breast Neoplasms therapy, Heart Diseases mortality
Abstract

Comparisons of patients receiving different cancer treatments reflect the effects of both treatment and patient selection. In breast cancer, however, if radiotherapy decisions are unrelated to laterality, comparisons of left-sided and right-sided cancers can demonstrate the causal effects of higher-versus-lower cardiac radiation dose. Cardiac mortality was analysed using individual patient data for 1,934,248 women with breast cancer in 22 countries. The median date of diagnosis was 1996 and the interquartile range was 1987-2002. A total of 1,018,505 women were recorded as irradiated, 223,077 as receiving chemotherapy, 317,619 as receiving endocrine therapy and 55,264 died of cardiac disease. Analyses were stratified by time since breast cancer diagnosis, age at diagnosis, calendar year of diagnosis and country. Patient-selection effects were evident for all three treatments. For radiotherapy, there was also evidence of selection according to laterality in women irradiated 1990 or later. In patients irradiated before 1990, there was no such selection and cardiac mortality was higher in left-sided than right-sided cancer (rate ratio [RR]: 1.13, 95% confidence interval 1.09-1.17). Left-versus-right cardiac mortality RRs were greater among younger women (1.46, 1.19, 1.20, 1.09 and 1.08 after cancer diagnoses at ages <40, 40-49, 50-59, 60-69 and 70+ years, 2p trend =0.003). Left-versus-right RRs also increased with time since cancer diagnosis (1.03, 1.11, 1.19 and 1.21 during 0-4, 5-14, 15-24 and 25+ years, 2p trend =0.002) while for women who also received chemotherapy, the left-versus-right RR was 1.42 (95% confidence interval 1.13-1.77), compared to 1.10 (1.05-1.16) for women who did not (2p difference = 0.03). These results show that the relative increase in cardiac mortality from cardiac exposure during breast cancer radiotherapy given in the past was greater in younger women, lasted into the third decade after exposure and was greater when chemotherapy was also given., (© 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Published
2020
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45. Heart failure after treatment for breast cancer.

Author

Boekel NB, Duane FK, Jacobse JN, Hauptmann M, Schaapveld M, Sonke GS, Gietema JA, Hooning MJ, Seynaeve CM, Maas AHEM, Darby SC, Aleman BMP, Taylor CW, and van Leeuwen FE

Subjects
Adult, Aged, Case-Control Studies, Female, Humans, Mastectomy, Middle Aged, Anthracyclines adverse effects, Breast Neoplasms drug therapy, Breast Neoplasms epidemiology, Breast Neoplasms radiotherapy, Heart Failure epidemiology, Trastuzumab adverse effects
Abstract

Background: We aimed to develop dose-response relationships for heart failure (HF) following radiation and anthracyclines in breast cancer treatment, and to assess HF associations with trastuzumab and endocrine therapies., Methods and Results: A case-control study was performed within a cohort of breast cancer survivors treated during 1980-2009. Cases (n = 102) had HF as first cardiovascular diagnosis and were matched 1:3 on age and date of diagnosis. Individual cardiac radiation doses were estimated, and anthracycline doses and use of trastuzumab and endocrine therapy were abstracted from oncology notes. For HF cases who received radiotherapy, the estimated median mean heart dose (MHD) was 6.8 Gy [interquartile range (IQR) 0.9-13.7]. MHD was not associated with HF risk overall [excess rate ratio (ERR) = 1%/Gy, 95% confidence interval (CI) -2 to 10]. In patients treated with anthracyclines, exposure of ≥20% of the heart to ≥20 Gy was associated with a rate ratio of 5.7 (95% CI 1.7-21.7) compared to <10% exposed to ≥20 Gy. For cases who received radiotherapy, median cumulative anthracycline dose was 247 mg/m 2 (IQR 240-319). A dose-dependent increase was observed after anthracycline without trastuzumab (ERR = 1.5% per mg/m 2 , 95% CI 0.5-4.1). After anthracycline and trastuzumab, the rate ratio was 34.9 (95% CI 11.1-110.1) compared to no chemotherapy., Conclusions: In absence of anthracyclines, breast cancer radiotherapy was not associated with increased HF risk. Strongly elevated HF risks were observed after treatment with anthracyclines and also after treatment with trastuzumab. The benefits of these systemic treatments usually exceed the risks of HF, but our results emphasize the need to support ongoing efforts to evaluate preventative strategies., (© 2019 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Published
2020
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46. Reliability of preoperative breast biopsies showing ductal carcinoma in situ and implications for non-operative treatment: a cohort study.

Author

Mannu GS, Groen EJ, Wang Z, Schaapveld M, Lips EH, Chung M, Joore I, van Leeuwen FE, Teertstra HJ, Winter-Warnars GAO, Darby SC, and Wesseling J

Subjects
Adult, Aged, Biopsy methods, Biopsy standards, Cohort Studies, Combined Modality Therapy, Disease Management, Female, Humans, Middle Aged, Neoplasm Grading, Netherlands, Preoperative Care, Randomized Controlled Trials as Topic, Registries, Young Adult, Breast Neoplasms diagnosis, Breast Neoplasms surgery, Carcinoma, Intraductal, Noninfiltrating diagnosis, Carcinoma, Intraductal, Noninfiltrating surgery
Abstract

Purpose: The future of non-operative management of DCIS relies on distinguishing lesions requiring treatment from those needing only active surveillance. More accurate preoperative staging and grading of DCIS would be helpful. We identified determinants of upstaging preoperative breast biopsies showing ductal carcinoma in situ (DCIS) to invasive breast cancer (IBC), or of upgrading them to higher-grade DCIS, following examination of the surgically excised specimen., Methods: We studied all women with DCIS at preoperative biopsy in a large specialist cancer centre during 2000-2014. Information from clinical records, mammography, and pathology specimens from both preoperative biopsy and excised specimen were abstracted. Women suspected of having IBC during biopsy were excluded., Results: Among 606 preoperative biopsies showing DCIS, 15.0% (95% confidence interval 12.3-18.1) were upstaged to IBC and a further 14.6% (11.3-18.4) upgraded to higher-grade DCIS. The risk of upstaging increased with presence of a palpable lump (21.1% vs 13.0%, p difference  = 0.04), while the risk of upgrading increased with presence of necrosis on biopsy (33.0% vs 9.5%, p difference  < 0.001) and with use of 14G core-needle rather than 9G vacuum-assisted biopsy (22.8% vs 7.0%, p difference  < 0.001). Larger mammographic size increased the risk of both upgrading (p heterogeneity  = 0.01) and upstaging (p heterogeneity  = 0.004)., Conclusions: The risk of upstaging of DCIS in preoperative biopsies is lower than previously estimated and justifies conducting randomized clinical trials testing the safety of active surveillance for lower grade DCIS. Selection of women with low grade DCIS for such trials, or for active surveillance, may be improved by consideration of the additional factors identified in this study.

Published
2019
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47. Endocrine therapy in the years following a diagnosis of breast cancer: A proof of concept study using the primary care prescription database linked to cancer registration data.

Author

Emanuel G, Henson KE, Broggio J, Charman J, Horgan K, Dodwell D, and Darby SC

Subjects
Adolescent, Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Hormonal pharmacology, Female, Humans, Middle Aged, Primary Health Care, Registries, Young Adult, Antineoplastic Agents, Hormonal therapeutic use, Breast Neoplasms drug therapy, Proof of Concept Study
Abstract

Introduction: National cancer registration data were linked to the Primary Care Prescription Database (PCPD) in England. The level of endocrine therapy (ET) prescribed in women after a diagnosis of breast cancer was studied., Materials and Methods: Cancer registrations for women diagnosed with breast cancer during 1995-2015, who survived to 31st March 2015, were linked to ET prescriptions issued during April-July 2015., Results: Among 369 277 survivors of breast cancer diagnosed during 1995-2015, 37% were prescribed ET during April-July 2015. Among women whose breast cancer diagnosis was after 31st July 2010, 81% of those recorded with oestrogen receptor positive (ER+ve) disease were prescribed ET compared with only 6% of those with ER-ve disease. Younger women usually received tamoxifen and older women usually received aromatase inhibitors., Discussion: The pattern of ET use observed in these data corresponds to that expected. This provides confidence in the potential of the PCPD for epidemiological research., (Crown Copyright © 2019. Published by Elsevier Ltd. All rights reserved.)

Published
2019
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48. International Variation in Criteria for Internal Mammary Chain Radiotherapy.

Author

Duane FK, McGale P, Teoh S, Mortimer C, Broggio J, Darby SC, Dodwell D, Lavery B, Oliveros S, Vallis KA, and Taylor CW

Subjects
Adult, Aged, Aged, 80 and over, Female, Humans, Lymph Nodes pathology, Middle Aged, Breast pathology, Breast Neoplasms radiotherapy, Lymph Nodes radiation effects, Radiotherapy, Adjuvant methods
Abstract

Aims: Evidence has emerged that internal mammary chain (IMC) radiotherapy reduces breast cancer mortality, leading to changes in treatment guidelines. This study investigated current IMC radiotherapy criteria and the percentages of patients irradiated for breast cancer in England who fulfilled them., Materials and Methods: A systematic search was undertaken for national guidelines published in English during 2013-2018 presenting criteria for 'consideration of' or 'recommendation for' IMC radiotherapy. Patient and tumour variables were collected for patients who received breast cancer radiotherapy in England during 2012-2016. The percentages of patients fulfilling criteria stipulated in each set of guidelines were calculated., Results: In total, 111 729 women were recorded as receiving adjuvant breast cancer radiotherapy in England during 2012-2016 and full data were available on 48 095 of them. Percentages of patients fulfilling IMC radiotherapy criteria in various national guidelines were: UK Royal College of Radiologists 13% (6035/48 095), UK National Institute for Health and Care Excellence 18% (8816/48 095), Germany 32% (15 646/48 095), Ireland 56% (26 846/48 095) and USA 59% (28 373/48 095). Differences between countries occurred because in Ireland and the USA, treatment may be considered in some node-negative patients, whereas in the UK, treatment is considered if at least four axillary nodes are involved or for high-risk patients with one to three positive nodes. In Germany, treatment may be considered for all node-positive patients., Conclusions: There is substantial variability between countries in criteria for consideration of IMC radiotherapy, despite guidelines being based on the same evidence. This will probably lead to large variations in practice and resource needs worldwide., (Copyright © 2019 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Published
2019
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49. Cardiac Structure Doses in Women Irradiated for Breast Cancer in the Past and Their Use in Epidemiological Studies.

Author

Duane FK, McGale P, Brønnum D, Cutter DJ, Darby SC, Ewertz M, Hackett S, Hall P, Lorenzen EL, Rahimi K, Wang Z, Warren S, and Taylor CW

Subjects
Dose-Response Relationship, Radiation, Epidemiologic Studies, Female, Humans, Organs at Risk, Radiotherapy Dosage, Radiotherapy Planning, Computer-Assisted methods, Tomography, X-Ray Computed, Breast Neoplasms radiotherapy, Heart radiation effects, Radiation Injuries etiology, Radiotherapy Planning, Computer-Assisted adverse effects
Abstract

Purpose: Incidental cardiac exposure during radiation therapy may cause heart disease. Dose-response relationships for cardiac structures (segments) may show which ones are most sensitive to radiation. Radiation-related cardiac injury can take years to develop; thus, studies need to involve women treated using 2-dimensional planning, with segment doses estimated using a typical computed tomography (CT) scan. We assessed whether such segment doses are accurate enough to use in dose-response relationships using the radiation therapy charts of women with known segment injury. We estimated interregimen and interpatient segment dose variability and segment dose correlations., Methods and Materials: The radiation therapy charts of 470 women with cardiac segment injury after breast cancer radiation therapy were examined, and 41 regimens were identified. Regimens were reconstructed on a typical CT scan. Doses were estimated for 5 left ventricle (LV) and 10 coronary artery segments. Correlations between cardiac segments were estimated. Interpatient dose variation was assessed in 10 randomly selected CT scans for left regimens and in 5 for right regimens., Results: For the typical CT scan, interregimen segment dose variation was substantial (range, LV segments <1-39 Gy; coronary artery segments <1-48 Gy). In 10 CT scans, interpatient segment dose variation was higher for segments near field borders (range, 3-47 Gy) than other segments (range, <2 Gy). Doses to different left-anterior descending coronary artery (LADCA) segments were highly correlated with each other, as were doses to different LV segments. Also, LADCA segment doses were highly correlated with doses to LV segments usually supplied by the LADCA. For individual regimens there was consistency in hotspot location and segment ranking of higher-versus-lower dose., Conclusions: The scope for developing quantitative cardiac segment dose-response relationships in patients who had 2-dimensional planning is limited because different segment doses are often highly correlated, and segment-specific dose uncertainties are not independent of each other. However, segment-specific doses may be reliably used to rank segments according to higher-versus-lower doses., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2019
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50. Clinical Intensity Modulated Proton Therapy for Hodgkin Lymphoma: Which Patients Benefit the Most?

Author

Ntentas G, Dedeckova K, Andrlik M, Aznar MC, George B, Kubeš J, Darby SC, and Cutter DJ

Subjects
Adolescent, Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Female, Hodgkin Disease drug therapy, Humans, Male, Middle Aged, Organs at Risk, Proton Therapy adverse effects, Radiation Injuries etiology, Radiotherapy Dosage, Radiotherapy Planning, Computer-Assisted methods, Radiotherapy, Conformal methods, Radiotherapy, Intensity-Modulated methods, Treatment Outcome, Hodgkin Disease radiotherapy, Proton Therapy methods
Abstract

Purpose: Radiation therapy (RT) improves control of Hodgkin lymphoma (HL), but patients who undergo RT are at risk for late effects, including cardiovascular disease and second cancers, because of radiation doses to organs at risk (OARs). Proton therapy (PT) can reduce OAR doses compared with conventional photon RT. However, access to PT is currently limited, so referrals must be appropriately selective. We aimed to identify subgroups of patients with HL who could benefit the most dosimetrically from RT with PT based on the prechemotherapy disease characteristics., Methods and Materials: Normal tissue radiation doses were calculated for 21 patients with HL who were treated with deep-inspiration breath-hold pencil-beam scanning (PBS) PT and compared with doses from 3-dimensional conformal (3D-CRT) and partial arc volumetric modulated (PartArc) photon RT. Prechemotherapy disease characteristics associated with significant dosimetric benefits from PBS compared with photon RT were identified., Results: Treatment with PBS was well tolerated and provided with good local control. PBS provided dosimetric advantages for patients whose clinical treatment volume extended below the seventh thoracic level and for female patients with axillary disease. In addition, an increasing dosimetric benefit for some OARs was observed for increasing target volume. PBS significantly reduced the mean dose to the heart, breast, lungs, spinal cord, and esophagus. Dose homogeneity and conformity within the target volume were also superior with PBS, but some high-dose measures and hot spots were increased with PBS compared with partial arc volumetric modulated photon RT., Conclusions: PBS gives good target coverage and local control while providing reductions in radiation dose to OARs for individuals who receive RT for HL compared with advanced photon RT. Our findings highlight groups of patients who would be expected to gain more dosimetric benefit from PBS. These findings facilitate the selection of patients who should be considered a priority for PT., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2019
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