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Objective: The aim of this study is to identify risk factors for readmission after elective esophagogastric cancer surgery and characterize the impact of readmission on long-term survival. The study will also identify whether the location of readmission to either the hospital that performed the primary surgery (index hospital) or another institution (nonindex hospital) has an impact on postoperative mortality. Background: Over the past decade, the center-volume relationship has driven the centralization of major cancer surgery, which has led to improvements in perioperative mortality. However, the impact of readmission, especially to nonindex centers, on long-term mortality remains unclear. Methods: This was a national population-based cohort study using Hospital Episode Statistics of adult patients undergoing esophagectomy and gastrectomy in England between January 2008 and December 2019. Results: This study included 27,592 patients, of which overall readmission rates were 25.1% (index 15.3% and nonindex 9.8%). The primary cause of readmission to an index hospital was surgical in 45.2% and 23.7% in nonindex readmissions. Patients with no readmissions had significantly longer survival than those with readmissions (median: 4.5 vs 3.8 years; P < 0.001). Patients readmitted to their index hospital had significantly improved survival as compared to nonindex readmissions (median: 3.3 vs 4.7 years; P < 0.001). Minimally invasive surgery and surgery performed in high-volume centers had improved 90-day mortality (odds ratio, 0.75; P < 0.001; odds ratio, 0.60; P < 0.001). Conclusion: Patients requiring readmission to the hospital after surgery have an increased risk of mortality, which is worsened by readmission to a nonindex institution. Patients requiring readmission to the hospital should be assessed and admitted, if required, to their index institution.
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BACKGROUND : Missing upper gastrointestinal cancer (UGIC) at endoscopy may prevent curative treatment. We have developed a root cause analysis system for potentially missed UGICs at endoscopy (post-endoscopy UGIC [PEUGIC]) to establish the most plausible explanations. METHODS : The electronic records of patients with UGIC at two National Health Service providers were examined. PEUGICs were defined as UGICs diagnosed 6-36 months after an endoscopy that did not diagnose cancer. An algorithm based on the World Endoscopy Organization post-colonoscopy colorectal cancer algorithm was developed to categorize and identify potentially avoidable PEUGICs. RESULTS : Of 1327 UGICs studied, 89 (6.7â%) were PEUGICs (patient median [IQR] age at endoscopy 73.5 (63.5-81.0); 60.7â% men). Of the PEUGICs, 40â% were diagnosed in patients with Barrett's esophagus. PEUGICs were categorized as: A - lesion detected, adequate assessment and decision-making, but PEUGIC occurred (16.9â%); B - lesion detected, inadequate assessment or decision-making (34.8â%); C - possible missed lesion, endoscopy and decision-making adequate (8.9â%); D - possible missed lesion, endoscopy or decision-making inadequate (33.7â%); E - deviated from management pathway but appropriate (5.6â%); F - deviated inappropriately from management pathway (3.4â%). The majority of PEUGICs (71â%) were potentially avoidable and in 45â% the cancer outcome could have been different if it had been diagnosed on the initial endoscopy. There was a negative correlation between endoscopists' mean annual number of endoscopies and the technically attributable PEUGIC rate (correlation coefficient -0.57; Pâ=â0.004). CONCLUSION : Missed opportunities to avoid PEUGIC were identified in 71â% of cases. Root cause analysis can standardize future investigation of PEUGIC and guide quality improvement efforts.
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Esófago de Barrett , Neoplasias Esofágicas , Neoplasias Gastrointestinales , Masculino , Humanos , Femenino , Análisis de Causa Raíz , Medicina Estatal , Esófago de Barrett/patología , Endoscopía Gastrointestinal , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/etiología , Neoplasias Esofágicas/patología , Neoplasias Gastrointestinales/diagnóstico , Neoplasias Gastrointestinales/etiologíaRESUMEN
BACKGROUND AND AIMS: PEG has been associated with poor case selection and high mortality. We examined indications, 30-day mortality, and 7-day adverse events in a national cohort undergoing PEG tube insertion. METHODS: Adult patients undergoing their first PEG tube insertion from 2007 to 2019 were identified in the Hospital Episode Statistics database. Indications and adverse events were identified using International Statistical Classification of Diseases and Related Health Problems, 10th Revision codes. Multivariable logistic regression modeling examined factors associated with mortality. RESULTS: Of 87,682 patients identified, 58% were men and median age was 69 years (interquartile range, 57-79). The number of patients with dementia or stroke as the indication for PEG fell from 2007 to 2019 (dementia, from 147 to 28 [P < .001]; stroke, from 2851 to 1781 [P < .001]). The median interval from stroke admission to PEG tube insertion increased from 21 (interquartile range, 12-36) to 28 (interquartile range, 13-45) days (P < .001). Aspiration pneumonia within 7 days of PEG fell from 10.2% to 8.6% (P = .04). Thirty-day mortality fell from 13.2% to 5.3% (P < .001), with associated factors of increasing age (≥82 years quintile odds ratio [OR], 4.44; 95% confidence interval [CI], 4.01-4.92), PEG tube insertion during emergency admission (OR, 2.10; 95% CI, 1.97-2.25), Charlson comorbidity score ≥5 (OR, 1.67; 95% CI, 1.53-1.82), and dementia (OR, 1.46; 95% CI, 1.26-1.71). Female sex (OR, .81; 95% CI, .77-.85), least-deprived quintile (OR, .88; 95% CI, .81-.95), and more recent years of PEG tube insertion (2019; OR, .44; 95% CI, .39-.51) were negatively associated with mortality. CONCLUSIONS: Thirty-day mortality after PEG tube insertion has fallen 60% over 13 years. Dementia or stroke as an indication for PEG fell, and the time interval from stroke to PEG tube insertion increased. These findings may be attributable to improved patient selection and timing for PEG tube insertion.
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Trastornos de Deglución , Demencia , Accidente Cerebrovascular , Humanos , Adulto , Masculino , Femenino , Anciano , Anciano de 80 o más Años , Estudios Retrospectivos , Nutrición Enteral , Trastornos de Deglución/etiología , Gastrostomía/efectos adversos , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/complicaciones , Estudios de CohortesRESUMEN
BACKGROUND : Data are limited regarding pancreatic cancer diagnosed following a pancreaticobiliary endoscopic ultrasound (EUS) that does not diagnose pancreatic cancer. We have studied the frequency of, and factors associated with, post-EUS pancreatic cancer (PEPC) and 1-year mortality. METHODS : Between 2010 and 2017, patients with pancreatic cancer and a preceding pancreaticobiliary EUS were identified in a national cohort using Hospital Episode Statistics. Patients with a pancreaticobiliary EUS 6-18 months before a later pancreatic cancer diagnosis were the PEPC cases; controls were those with pancreatic cancer diagnosed within 6 months of pancreaticobiliary EUS. Multivariable logistic regression models examined the factors associated with PEPC and a Cox regression model examined factors associated with 1-year cumulative mortality. RESULTS : 9363 pancreatic cancer patients were studied; 93.5â% identified as controls (men 53.2â%; median age 68 [interquartile range (IQR) 61-75]); 6.5â% as PEPC cases (men 58.2â%; median age 69 [IQR 61-77]). PEPC was associated with older age (≥â75 years compared with <â65 years, odds ratio [OR] 1.42, 95â%CI 1.15-1.76), increasing co-morbidity (Charlson co-morbidity score >â5, OR 1.90, 95â%CI 1.49-2.43), chronic pancreatitis (OR 3.13, 95â%CI 2.50-3.92), and diabetes mellitus (OR 1.58, 95â%CI 1.31-1.90). Metal biliary stents (OR 0.57, 95â%CI 0.38-0.86) and EUS-FNA (OR 0.49, 95â%CI 0.41-0.58) were inversely associated with PEPC. PEPC was associated with a higher cumulative mortality at 1 year (hazard ratio 1.12, 95â%CI 1.02-1.24), with only 14â% of PEPC patients (95â%CI 12â%-17â%) having a surgical resection, compared with 21â% (95â%CI 20â%-22â%) of controls. CONCLUSIONS : PEPC occurred in 6.5â% of patients and was associated with chronic pancreatitis, older age, more co-morbidities, and specifically diabetes mellitus. PEPC was associated with a worse prognosis and lower surgical resection rates.
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Neoplasias Pancreáticas , Pancreatitis Crónica , Anciano , Humanos , Masculino , Biopsia por Aspiración con Aguja Fina Guiada por Ultrasonido Endoscópico , Endosonografía , Neoplasias Pancreáticas/diagnóstico por imagen , Neoplasias Pancreáticas/complicaciones , Pancreatitis Crónica/complicaciones , Estudios Retrospectivos , Femenino , Persona de Mediana Edad , Neoplasias PancreáticasRESUMEN
Background and study aims Population-level data on the outcomes of pancreaticobiliary endoscopic ultrasound (PB-EUS) are limited. We examined national PB-EUS and fine-needle aspiration (FNA) activity, its relation to pancreatic cancer therapy, associated mortality and adverse events. Patients and methods Adults undergoing PB-EUS in England from 2007-2016 were identified in Hospital Episode Statistics. A pancreatic cancer cohort diagnosed within 6 months of PB-EUS were studied separately. Multivariable logistic regression models examined associations with 30-day mortality and therapies for pancreatic cancer. Results 79,269 PB-EUS in 68,908 subjects were identified. Annual numbers increased from 2,874 (28â% FNA) to 12,752 (35â% FNA) from 2007 to 2016. 8,840 subjects (13â%) were diagnosed with pancreatic cancer. Sedation related adverse events were coded in 0.5â% and emergency admission with acute pancreatitis in 0.2â% within 48 hours of PB-EUS.â1.5â% of subjects died within 30 days of PB-EUS.âFactors associated with 30-day mortality included increasing age (odds ratio 1.03 [95â% CI 1.03-1.04]); male sex (1.38 [1.24-1.56]); increasing comorbidity (1.49 [1.27-1.74]); EUS-FNA (2.26 [1.98-2.57]); pancreatic cancer (1.39 [1.19-1.62]); increasing deprivation (least deprived quintile 0.76 [0.62-0.93]) and lower provider PB-EUS volume (2.83 [2.15-3.73]). Factors associated with surgical resection in the pancreatic cancer cohort included lower provider PB-EUS volume (0.44 [0.26-0.74]) and the least deprived subjects (1.33 [1.12-1.57]). 33â% of pancreatic cancer subjects who underwent EUS, did not subsequently receive active cancer treatment. Conclusions Lower provider PB-EUS volume was associated with higher 30-day mortality and reduced rates of both pancreatic cancer surgery and chemotherapy. These results suggest potential issues with case selection in lower-volume EUS providers.
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AIM: The clinical consequences of readmission following major surgery in the English National Health Service are unknown. This study aimed to determine differences in outcome between patients readmitted to index vs non-index trusts after major surgery. METHOD: Adult patients who underwent colorectal resection in England in April 2006 to March 2017 were identified in the national Hospital Episodes Statistics dataset. Patients were included if they were readmitted as emergencies within 30 days of initial discharge. The primary outcome measure was all-cause mortality within 90 days of readmission. Comparisons between patients readmitted to index vs non-index trusts were adjusted for confounders using multivariable logistic regression. Rectal resection patients were a planned subgroup. RESULTS: The readmission rate following colorectal resection was 15.1% (54 680/364 481), with 7.1% (3905/54 680) readmitted to a non-index trust. The 90-day mortality following readmission was 7.1% (3874/54 680) overall and 3.9% (652/16 736) in the rectal resection subgroup. The reoperation rate was 19.2% (10 498/54 680) overall and 23.1% (3859/16 736) after rectal resection. Mortality was significantly higher in non-index [10.9% (427/3905)] vs index trusts [6.8% (3447/507 75), adjusted OR 1.50, 95% CI 1.34-1.68, P < 0.001]. There was an annual average of 14.7 excess deaths in non-index trusts; only 1.9 of these followed surgical reoperation. In patients who underwent rectal resection, only 0.3 of the total 1.9 excess deaths each year in non-index trusts followed surgical reoperation. CONCLUSION: Despite a statistical difference, the absolute number of excess deaths attributable to readmission to a non-index trust is very low, particularly amongst patients requiring reoperation.
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Colectomía/mortalidad , Hospitales/estadística & datos numéricos , Readmisión del Paciente/estadística & datos numéricos , Proctectomía/mortalidad , Reoperación/mortalidad , Anciano , Inglaterra/epidemiología , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Medicina Estatal , Resultado del TratamientoRESUMEN
INTRODUCTION: Achalasia is a disorder characterised by failed relaxation of the lower oesophageal sphincter. The aim of this study was to examine, at a national level, the long-term outcomes of achalasia therapies. METHODS: Hospital Episode Statistics include diagnostic and procedural data for all English National Health Service-funded hospital admissions. Subjects with a code for achalasia who had their initial treatment between January 2006 and December 2015 were grouped by treatment; pneumatic dilatation (PD) or surgical Heller's myotomy (HM). Procedural failure was defined as time to a further episode of the same therapy or a change to a different therapy. Up to three PDs were permitted without being considered a therapy failure. RESULTS: 6938 subjects were included; 3619 (52.2%) were men and median age at diagnosis was 59 (IQR 43-75) years. 4748 (68.4%) initially received PD and 2190 (31.6%) HM. The perforation rate following PD was 1.6%. Mortality at 30 days was 0.0% for HM and 1.9% for PD, and <8% after perforation following PD. Factors associated with increased mortality after PD included age quintile 66-77 (OR 4.55 (95% CI 2.00 to 10.38), p<0.001), >77 (9.78 (4.33 to 22.06), p<0.001); Charlson comorbidity score >4 (2.87 (2.08 to 3.95), p<0.001); previous HM (2.47 (1.33 to 4.62), p<0.001); and repeat PD 1-3 (1.58 (1.15 to 2.16), p=0.005), >3 (1.97 (1.21 to 3.19), p=0.006). Durability of up to 3 PD and HM over 10 years of follow-up was 86.2% and 81.9%, respectively (p<0.001). DISCUSSION: The efficacy of PD for achalasia appears to be greater than HM over 10 years. There was no mortality associated with HM, but 1.9% of subjects died within 30 days of PD. Mortality was associated with increasing age, comorbidity, previous HM and repeat PD.
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Dilatación/estadística & datos numéricos , Acalasia del Esófago/cirugía , Miotomía de Heller/estadística & datos numéricos , Complicaciones Posoperatorias/epidemiología , Adulto , Anciano , Dilatación/efectos adversos , Inglaterra/epidemiología , Acalasia del Esófago/etiología , Acalasia del Esófago/mortalidad , Esfínter Esofágico Inferior , Femenino , Miotomía de Heller/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Achalasia is an uncommon condition characterised by failed lower oesophageal sphincter relaxation. Data regarding its incidence, prevalence, disease associations and long-term outcomes are very limited. METHODS: Hospital Episode Statistics (HES) include demographic and diagnostic data for all English hospital attendances. The Health Improvement Network (THIN) includes the primary care records of 4.5 million UK subjects, representative of national demographics. Both were searched for incident cases between 2006 and 2016 and THIN for prevalent cases. Subjects with achalasia in THIN were compared with age, sex, deprivation tand smoking status matched controls for important comorbidities and mortality. RESULTS: There were 10 509 and 711 new achalasia diagnoses identified in HES and THIN, respectively. The mean incidence per 100 000 people in HES was 1.99 (95% CI 1.87 to 2.11) and 1.53 (1.42 to 1.64) per 100 000 person-years in THIN. The prevalence in THIN was 27.1 (25.4 to 28.9) per 100 000 population. Incidence rate ratios (IRRs) were significantly higher in subjects with achalasia (n=2369) compared with controls (n=3865) for: oesophageal cancer (IRR 5.22 (95% CI: 1.88 to 14.45), p<0.001), aspiration pneumonia (13.38 (1.66 to 107.79), p=0.015), lower respiratory tract infection (1.33 (1.05 to 1.70), p=0.02) and mortality (1.33 (1.17 to 1.51), p<0.001). The median time from achalasia diagnosis to oesophageal cancer diagnosis was 15.5 (IQR 20.4) years. CONCLUSION: The incidence of achalasia is 1.99 per 100 000 population in secondary care data and 1.53 per 100 000 person-years in primary care data. Subjects with achalasia have an increased incidence of oesophageal cancer, aspiration pneumonia, lower respiratory tract infections and higher mortality. Clinicians treating patients with achalasia should be made aware of these associated morbidities and its increased mortality.
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Acalasia del Esófago/epidemiología , Adulto , Anciano , Inglaterra/epidemiología , Acalasia del Esófago/complicaciones , Acalasia del Esófago/diagnóstico , Femenino , Hospitalización/estadística & datos numéricos , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Morbilidad , Prevalencia , Atención Primaria de Salud/estadística & datos numéricos , Tasa de SupervivenciaRESUMEN
BACKGROUND: Epidemiological studies have provided strong evidence for a role of endogenous sex steroids in the etiology of breast cancer. Our aim was to identify common variants in genes involved in sex steroid synthesis or metabolism that are associated with hormone levels and the risk of breast cancer in premenopausal women. METHODS: We measured urinary levels of estrone glucuronide (E1G) using a protocol specifically developed to account for cyclic variation in hormone levels during the menstrual cycle in 729 healthy premenopausal women. We genotyped 642 single-nucleotide polymorphisms (SNPs) in these women; a single SNP, rs10273424, was further tested for association with the risk of breast cancer using data from 10 551 breast cancer case patients and 17 535 control subjects. All statistical tests were two-sided. RESULTS: rs10273424, which maps approximately 50 kb centromeric to the cytochrome P450 3A (CYP3A) gene cluster at chromosome 7q22.1, was associated with a 21.8% reduction in E1G levels (95% confidence interval [CI] = 27.8% to 15.3% reduction; P = 2.7 × 10(-9)) and a modest reduction in the risk of breast cancer in case patients who were diagnosed at or before age 50 years (odds ratio [OR] = 0.91, 95% CI = 0.83 to 0.99; P = .03) but not in those diagnosed after age 50 years (OR = 1.01, 95% CI = 0.93 to 1.10; P = .82). CONCLUSIONS: Genetic variation in noncoding sequences flanking the CYP3A locus contributes to variance in premenopausal E1G levels and is associated with the risk of breast cancer in younger patients. This association may have wider implications given that the most predominantly expressed CYP3A gene, CYP3A4, is responsible for metabolism of endogenous and exogenous hormones and hormonal agents used in the treatment of breast cancer.
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Neoplasias de la Mama/enzimología , Neoplasias de la Mama/genética , Citocromo P-450 CYP3A/genética , Estrona/orina , Glucurónidos/orina , Mamografía , Polimorfismo de Nucleótido Simple , Premenopausia , Globulina de Unión a Hormona Sexual/genética , Adulto , Factores de Edad , Andrógenos/sangre , Neoplasias de la Mama/sangre , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/orina , Estudios de Casos y Controles , Estudios Transversales , Citocromo P-450 CYP3A/metabolismo , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Estilo de Vida , Desequilibrio de Ligamiento , Ciclo Menstrual/orina , Oportunidad Relativa , Valor Predictivo de las Pruebas , Pregnanodiol/orina , Historia Reproductiva , Medición de Riesgo , Factores de Riesgo , Globulina de Unión a Hormona Sexual/metabolismo , Reino Unido/epidemiología , Población Blanca/genéticaRESUMEN
BACKGROUND: Genome-wide association studies have identified several common genetic variants associated with breast cancer risk. It is likely, however, that a substantial proportion of such loci have not yet been discovered. METHODS: We compared 296,114 tagging single-nucleotide polymorphisms in 1694 breast cancer case subjects (92% with two primary cancers or at least two affected first-degree relatives) and 2365 control subjects, with validation in three independent series totaling 11,880 case subjects and 12,487 control subjects. Odds ratios (ORs) and associated 95% confidence intervals (CIs) in each stage and all stages combined were calculated using unconditional logistic regression. Heterogeneity was evaluated with Cochran Q and I(2) statistics. All statistical tests were two-sided. RESULTS: We identified a novel risk locus for breast cancer at 9q31.2 (rs865686: OR = 0.89, 95% CI = 0.85 to 0.92, P = 1.75 × 10(-10)). This single-nucleotide polymorphism maps to a gene desert, the nearest genes being Kruppel-like factor 4 (KLF4, 636 kb centromeric), RAD23 homolog B (RAD23B, 794 kb centromeric), and actin-like 7A (ACTL7A, 736 kb telomeric). We also identified two variants (rs3734805 and rs9383938) mapping to 6q25.1 estrogen receptor 1 (ESR1), which were associated with breast cancer in subjects of northern European ancestry (rs3734805: OR = 1.19, 95% CI = 1.11 to 1.27, P = 1.35 × 10(-7); rs9383938: OR = 1.18, 95% CI = 1.11 to 1.26, P = 1.41 × 10(-7)). A variant mapping to 10q26.13, approximately 300 kb telomeric to the established risk locus within the second intron of FGFR2, was also associated with breast cancer risk, although not at genome-wide statistical significance (rs10510102: OR = 1.12, 95% CI = 1.07 to 1.17, P = 1.58 × 10(-6)). CONCLUSIONS: These findings provide further evidence on the role of genetic variation in the etiology of breast cancer. Fine mapping will be needed to identify causal variants and to determine their functional effects.
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Neoplasias de la Mama/genética , Cromosomas Humanos Par 9 , Polimorfismo de Nucleótido Simple , Población Blanca/genética , Actinas/genética , Adulto , Anciano , Neoplasias de la Mama/etnología , Estudios de Casos y Controles , Cromosomas Humanos Par 10 , Cromosomas Humanos Par 6 , Enzimas Reparadoras del ADN/genética , Proteínas de Unión al ADN/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Factor 4 Similar a Kruppel , Factores de Transcripción de Tipo Kruppel/genética , Desequilibrio de Ligamiento , Modelos Logísticos , Persona de Mediana Edad , Oportunidad Relativa , Control de Calidad , Factores de Riesgo , Encuestas y Cuestionarios , Reino UnidoRESUMEN
Mammographic density is strongly associated with breast cancer risk, and endogenous hormones, which are risk factors for breast cancer, may be involved in the mechanism. This cross-sectional study of 494 premenopausal women is the first to account for cyclic variations in estrogen levels, by measuring urinary estrone glucuronide (E1G) in the periovulatory and luteal phases of the menstrual cycle, and to assess the role of androgens. Computer-assisted density readings were obtained from digitized mammograms. Mean ovulatory E1G level and daily E1G load were both positively associated with percent density before adjustment for body mass index (BMI), with women in the top fourth having 10.2% (95% CI: 2.9%, 18.1%) and 8.9% (1.7%, 16.7%), respectively, higher density than those in the bottom fourth (Ptrend before/after BMI adjustment=0.006/0.11 and 0.01/0.13, respectively). Neither the peak nor luteal E1G levels were predictive of density after adjustment for E1G levels at other points in the cycle. The plasma androgens testosterone, androstenedione, and dehydroepiandrosterone sulfate were negatively associated with density. In mutually adjusted analyses, density was positively associated with insulin-like growth factor (IGF)-I and negatively with IGF-II (Ptrend=0.006 for both) but not with IGF binding protein-3. There was also weak evidence of a positive association of prolactin with density. The study supports the hypothesis that endogenous hormones affect density in premenopausal women; in particular, it shows a positive association between estrogen levels and density and suggests that the mean level throughout the cycle is the most biologically relevant measure. Most of these hormone-density associations were attenuated with further adjustment for BMI.
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Hormonas Esteroides Gonadales/sangre , Mamografía , Ciclo Menstrual/sangre , Premenopausia/fisiología , Prolactina/sangre , Somatomedinas/análisis , Adulto , Índice de Masa Corporal , Calibración , Estudios Transversales , Femenino , Humanos , Interpretación de Imagen Asistida por Computador , Glándulas Mamarias Humanas/anatomía & histología , Mamografía/normas , Ciclo Menstrual/metabolismo , Persona de Mediana Edad , Premenopausia/sangre , Premenopausia/metabolismo , Somatomedinas/metabolismoRESUMEN
INTRODUCTION: Sex steroids, insulin-like growth factors (IGFs) and prolactin are breast cancer risk factors but whether their effects are mediated through mammographic density, one of the strongest risk factors for breast cancer, is unknown. If such a hormonal basis of mammographic density exists, hormones may underlie ethnic differences in both mammographic density and breast cancer incidence rates. METHODS: In a cross-sectional study of 270 postmenopausal Caucasian and Afro-Caribbean women attending a population-based breast screening service in London, UK, we investigated whether plasma biomarkers (oestradiol, oestrone, sex hormone binding globulin (SHBG), testosterone, prolactin, leptin, IGF-I, IGF-II and IGF binding protein 3 (IGFBP3)) were related to and explained ethnic differences in mammographic percent density, dense area and nondense area, measured in Cumulus using the threshold method. RESULTS: Mean levels of oestrogens, leptin and IGF-I:IGFBP3 were higher whereas SHBG and IGF-II:IGFBP3 were lower in Afro-Caribbean women compared with Caucasian women after adjustment for higher mean body mass index (BMI) in the former group (by 3.2 kg/m(2) (95% confidence interval (CI): 1.8, 4.5)). Age-adjusted percent density was lower in Afro-Caribbean compared with Caucasian women by 5.4% (absolute difference), but was attenuated to 2.5% (95% CI: -0.2, 5.1) upon BMI adjustment. Despite ethnic differences in biomarkers and in percent density, strong ethnic-age-adjusted inverse associations of oestradiol, leptin and testosterone with percent density were completely attenuated upon adjustment for BMI. There were no associations of IGF-I, IGF-II or IGFBP3 with percent density or dense area. We found weak evidence that a twofold increase in prolactin and oestrone levels were associated, respectively, with an increase (by 1.7% (95% CI: -0.3, 3.7)) and a decrease (by 2.0% (95% CI: 0, 4.1)) in density after adjustment for BMI. CONCLUSIONS: These findings suggest that sex hormone and IGF levels are not associated with BMI-adjusted percent mammographic density in cross-sectional analyses of postmenopausal women and thus do not explain ethnic differences in density. Mammographic density may still, however, be influenced by much higher premenopausal hormone levels.
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Neoplasias de la Mama/etnología , Neoplasias de la Mama/metabolismo , Mamografía/métodos , Esteroides/metabolismo , Anciano , Población Negra , Índice de Masa Corporal , Neoplasias de la Mama/diagnóstico por imagen , Región del Caribe , Estudios Transversales , Estrógenos/metabolismo , Femenino , Hormonas/metabolismo , Humanos , Persona de Mediana Edad , Posmenopausia , Somatomedinas/metabolismo , Reino Unido , Población BlancaRESUMEN
Recent whole genome association studies of prostate, breast, and colorectal cancer have identified susceptibility loci on 8q24. We genotyped three variants associated with prostate cancer (rs10090154, rs13254738, and rs7000448), one associated with both prostate and colorectal cancer (rs6983267), and one associated with breast cancer (rs13281615) in a series of 1,499 breast cancer cases and 1,390 controls. 1,267 (85%) of the cases had two primary breast cancers. Our analysis provides further evidence of the relationship between rs13281615 and risk of breast cancer, with heterozygote odds ratio (OR) 1.30 95% confidence interval (CI) 1.09-1.54 and homozygote OR 1.52 (95% CI, 1.22-1.89; P trend = 0.00003), and confirms the prediction that the risk is substantially higher in this genetically enriched series (OR per allele, 1.24; 95% CI, 1.12-1.38) than in a large series of mainly unselected cases (reported OR per allele, 1.08; 95% CI, 1.05-1.11). We observed a protective effect of rs13254738 for breast cancer (allelic OR, 0.88; 95% CI, 0.78-0.98; P = 0.02), which is supported by the Cancer Genetic Markers of Susceptibility data (pooled allelic OR, 0.88; 95% CI, 0.81-0.96; P = 0.003). None of the other three single nucleotide polymorphisms, two associated with prostate (rs10090154 and rs7000448) and one with both prostate and colorectal cancers (rs6583267), was associated with breast cancer risk in our study. This evidence of a protective effect for breast cancer of one variant (rs13254738) that has been associated previously with a 1.25-fold increased risk of prostate cancer, with no effect for the two other variants, indicates that the effects of the risk alleles clustered at 8q24 are cancer site specific.
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Neoplasias de la Mama/genética , Cromosomas Humanos Par 8 , Variación Genética , Adulto , Anciano , Alelos , Neoplasias de la Mama/epidemiología , Estudios de Casos y Controles , Inglaterra/epidemiología , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Modelos Logísticos , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Sistema de Registros , Riesgo , Escocia/epidemiologíaRESUMEN
An important class of genetic variants that affect disease susceptibility may lie within regulatory elements that influence gene expression. Regulatory sequences are difficult to identify and may be distant from the genes they regulate, but many lie within evolutionarily conserved regions (ECRs). We used comparative genomics to identify 12 ECRs up to 75 kb 5' to and within introns of IGF1. These were screened by high-resolution melting curve analysis, and 18 single-nucleotide polymorphisms (SNPs) were identified, including five novel variants. We analysed two large population-based series of healthy women to test the nine SNPs with minor allele frequency (MAF) >1% within ECRs. Three of the nine SNPs within ECRs (rs35455143, rs35765817 and rs3839984) were significantly associated with circulating IGF1 levels in a multivariate analysis (P