Marianne Tang Severinsen

Body Size and Risk of Prostate Cancer in the European Prospective Investigation into Cancer and Nutrition

Background: Body size has been hypothesized to influence the risk of prostate cancer; however, most epidemiologic studies have relied on body mass index (BMI) to assess adiposity, whereas only a few studies have examined whether body fat distribution predicts prostate cancer. Methods: We examined the association of height, BMI, waist and hip circumference, and waist-hip ratio with prostate cancer risk among 129,502 men without cancer at baseline from 8 countries of the European Prospective Investigation into Cancer and Nutrition (EPIC), using Cox regression, with age as time metric, stratifying by study center and age at recruitment, and adjusting for education, smoking status, alcohol consumption, and physical activity. Results: During a mean follow-up of 8.5 years, 2,446 men developed prostate cancer. Waist circumference and waist-hip ratio were positively associated with risk of advanced disease. The relative risk of advanced prostate cancer was 1.06 (95% confidence interval, 1.01-1.1) per 5-cm-higher waist circumference and 1.21 (95% confidence interval, 1.04-1.39) per 0.1-unit-higher waist-hip ratio. When stratified by BMI, waist circumference and waist-hip ratio were positively related to risk of total, advanced, and high-grade prostate cancer among men with lower but not among those with higher BMI (Pinteraction for waist with BMI, 0.25, 0.02, and 0.05, respectively; Pinteraction for waist-hip ratio with BMI, 0.27, 0.22, and 0.14; respectively). Conclusions: These data suggest that abdominal adiposity may be associated with an increased risk of advanced prostate cancer. This association may be stronger among individuals with lower BMI; however, this finding needs confirmation in future studies. (Cancer Epidemiol Biomarkers Prev 2008;17(11):3252–61)

Smoking and venous thromboembolism: a Danish follow‐up study

Summary.  Background: Large‐scale prospective studies are needed to assess whether smoking is associated with venous thromboembolism (VTE) (i.e. deep venous thrombosis and pulmonary embolism) independently of established risk factors. Objective: To investigate the association between smoking and the risk of VTE among middle‐aged men and women. Methods: From 1993 to 1997, 27 178 men and 29 875 women, aged 50–64 years and born in Denmark, were recruited into the Danish prospective study ‘Diet, Cancer and Health’. During follow‐up, VTE cases were identified in the Danish National Patient Registry. Medical records were reviewed and only verified VTE cases were included in the study. Baseline data on smoking and potential confounders were included in gender stratified Cox proportional hazard models to asses the association between smoking and the risk of VTE. The analyses were adjusted for alcohol intake, body mass index, physical activity, and in women also for use of hormone replacement therapy. Results: During follow‐up, 641 incident cases of VTE were verified. We found a positive association between current smoking and VTE, with a hazard ratio of 1.52 (95% CI, 1.15–2.00) for smoking women and 1.32 (95% CI, 1.00–1.74) for smoking men, and a positive dose‐response relationship. Former smokers had the same hazard as never smokers. Conclusions: Smoking was an independent risk factor for VTE among middle‐aged men and women. Former smokers have the same risk of VTE as never smokers, indicating acute effects of smoking, and underscoring the potential benefits of smoking cessation.

Cigarette smoking, environmental tobacco smoke exposure and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition

Cigarette smoking is an established risk factor for pancreatic cancer. However, prospective data for most European countries are lacking, and epidemiologic studies on exposure to environmental tobacco smoke (ETS) in relation to pancreatic cancer risk are scarce. We examined the association of cigarette smoking and exposure to ETS with pancreatic cancer risk within the European Prospective Investigation into Cancer and Nutrition (EPIC). This analysis was based on 465,910 participants, including 524 first incident pancreatic cancer cases diagnosed after a median follow‐up of 8.9 years. Estimates of risk were obtained by Cox proportional hazard models and adjusted for weight, height, and history of diabetes mellitus. An increased risk of pancreatic cancer was found for current cigarette smokers compared with never smokers (HR = 1.71, 95% CI = 1.36–2.15), and risk increased with greater intensity and pack‐years. Former cigarette smokers who quit for less than 5 years were at increased risk of pancreatic cancer (HR = 1.78, 95% CI = 1.23–2.56), but risk was comparable to never smokers after quitting for 5 years or more. Pancreatic cancer risk was increased among never smokers daily exposed to ETS (for many hours) during childhood (HR = 2.61, 95% CI = 0.96–7.10) and exposed to ETS at home and/or work (HR = 1.54, 95% CI = 1.00–2.39). These results suggest that both active cigarette smoking, as well as exposure to ETS, is associated with increased risk of pancreatic cancer and that risk is reduced to levels of never smokers within 5 years of quitting.

Anthropometry, Body Fat, and Venous Thromboembolism A Danish Follow-Up Study

Background— Obesity, measured as body mass index, is associated with venous thromboembolism (VTE). Body mass index is a marker of excess weight and correlates well with body fat content in adults; however, it fails to consider the distribution of body fat. We assessed the association between anthropometric variables and VTE. Methods and Results— From 1993 to 1997, 27 178 men and 29 876 women 50 to 64 years of age were recruited into a Danish prospective study (Diet, Cancer, and Health). During 10 years of follow-up, the outcome of VTE events was identified in the Danish National Patient Registry and verified by review of medical records. Body weight, body mass index, waist circumference, hip circumference, and total body fat were measured at baseline. We used Cox proportional hazard models to assess the association between anthropometry and VTE. Age was used as a time axis, with further adjustment for smoking, physical activity, height, hypertension, diabetes mellitus, cholesterol, and, among women, use of hormone replacement therapy. We verified 641 incident VTE events and found monotonic dose-response relationships between VTE and all anthropometric measurements in both sexes. In mutually adjusted analyses of waist and hip circumference, we found that hip circumference was positively associated with VTE in women but not in men, whereas waist circumference was positively associated with VTE in men but not in women. Conclusions— All measurements of obesity are predictors of the risk for VTE. Positive associations were found between VTE and body weight, body mass index, waist circumference, hip circumference, and total body fat mass.

Risk of venous thromboembolism in patients with primary chronic immune thrombocytopenia: a Danish population‐based cohort study

from a ‘small-cell variant’ of ALCL. Leukemia, 18, 1693–1698. Lamant, L., de Reyniès, A., Duplantier, M.-M., Rickman, D., Sabourdy, F., Giuriato, S., Brugières, L., Gaulard, P., Espinos, E. & Delsol, G. (2007) Gene-expression profiling of systemic anaplastic large-cell lymphoma reveals differences based on ALK status and two distinct morphologic ALK+ subtypes. Blood, 109, 2156–2164. Menten, P., Wuyts, A. & Van Damme, J. (2002) Macrophage inflammatory protein-1. Cytokine & Growth Factor Reviews, 6, 455–481. Peiretti, F., Fossat, C., Anfosso, F., Alessi, M.C., Henry, M., Juhan-Vague, I. & Nalbone, G. (1996) Increase in cytosolic calcium upregulates the synthesis of type 1 plasminogen activator inhibitor in the human histiocyte cell line U937. Blood, 87, 162–173. Swerdlow, S.H., Campo, E., Harris, N.L., Jaffe, E., Pileri, S., Stein, H., Thiele, J. & Vardiman, J. (2008) WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. IARC Press, Lyon.

Anthropometric measures and epithelial ovarian cancer risk in the European Prospective Investigation into Cancer and Nutrition

We examined the associations of measured anthropometric factors, including general and central adiposity and height, with ovarian cancer risk. We also investigated these associations by menopausal status and for specific histological subtypes. Among 226,798 women in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, there were 611 incident cases of primary, malignant, epithelial ovarian cancer diagnosed during a mean 8.9 years of follow‐up. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), adjusted for potential confounders. Compared to women with body mass index (BMI) < 25 kg/m2, obesity (BMI ≥ 30 kg/m2) was associated with excess ovarian cancer risk for all women combined (HR = 1.33, 95% CI = 1.05–1.68; ptrend = 0.02) and postmenopausal women (HR = 1.59, 95% CI = 1.20–2.10; ptrend = 0.001), but the association was weaker for premenopausal women (HR = 1.16, 95% CI = 0.65–2.06; ptrend = 0.65). Neither height or weight gain, nor BMI‐adjusted measures of fat distribution assessed by waist circumference, waist–hip ratio (WHR) or hip circumference were associated with overall risk. WHR was related to increased risk of mucinous tumors (BMI‐adjusted HR per 0.05 unit increment = 1.17, 95% CI = 1.00–1.38). For all women combined, no other significant associations with risk were observed for specific histological subtypes. This large, prospective study provides evidence that obesity is an important modifiable risk factor for epithelial ovarian cancer, particularly among postmenopausal women.

Epidemiology and Clinical Significance of Secondary and Therapy-Related Acute Myeloid Leukemia: A National Population-Based Cohort Study

PURPOSE Secondary and therapy-related acute myeloid leukemia (sAML and tAML, respectively) remain therapeutic challenges. Still, it is unclear whether their inferior outcome compared with de novo acute myeloid leukemia (AML) varies as a result of previous hematologic disease or can be explained by differences in karyotype and/or age. PATIENTS AND METHODS In a Danish national population-based study of 3,055 unselected patients with AML diagnosed from 2000 to 2013, we compared the frequencies and characteristics of tAML, myelodysplastic syndrome (MDS) -sAML, and non-MDS-sAML (chronic myelomonocytic leukemia and myeloproliferative neoplasia) versus de novo AML. Limited to intensive therapy patients, we compared chance of complete remission by logistic regression analysis and used a pseudo-value approach to compare relative risk (RR) of death at 90 days, 1 year, and 3 years, overall and stratified by age and karyotype. Results were given crude and adjusted with 95% CIs. RESULTS Overall, frequencies of sAML and tAML were 19.8% and 6.6%, respectively. sAML, but not tAML, was associated with low likelihood of receiving intensive treatment. Among intensive therapy patients (n = 1,567), antecedent myeloid disorder or prior cytotoxic exposure was associated with decreased complete remission rates and inferior survival (3-year adjusted RR for MDS-sAML, non-MDS-sAML, and tAML: RR, 1.14; 95% CI, 1.02 to 1.32; RR, 1.27; 95% CI, 1.16 to 1.34; and RR, 1.16; 95% CI, 1.03 to 1.32, respectively) compared with de novo AML. Among patients ≥ 60 years old and patients with adverse karyotype, previous MDS or tAML did not impact overall outcomes, whereas non-MDS-sAML was associated with inferior survival across age and cytogenetic risk groups (adverse risk cytogenetics: 1-year adjusted RR, 1.47; 95% CI, 1.23 to 1.76; patients ≥ 60 years old: 1-year adjusted RR, 1.31; 95% CI, 1.06 to 1.61). CONCLUSION Our results support that de novo AML, sAML, and tAML are biologically and prognostically distinct subtypes of AML. Patients with non-MDS-sAML have dismal outcomes, independent of age and cytogenetics. Previous myeloid disorder, age, and cytogenetics are crucial determinants of outcomes and should be integrated in treatment recommendations for these patients.

Anthropometric characteristics and non-Hodgkin’s lymphoma and multiple myeloma risk in the European Prospective Investigation into Cancer and Nutrition (EPIC)

The incidences of non-Hodgkin’s lymphoma and multiple myeloma are increasing steadily. It has been hypothesized that this may be due, in part, to the parallel rising prevalence of obesity. This European Prospective Investigation into Cancer and Nutrition (EPIC) study supports an association between height and overall non-Hodgkin’s lymphoma and multiple myeloma among women. Background The incidences of non-Hodgkin’s lymphoma and multiple myeloma are increasing steadily. It has been hypothesized that this may be due, in part, to the parallel rising prevalence of obesity. It is biologically plausible that anthropometric characteristics can infuence the risk of non-Hodgkin’s lymphoma and multiple myeloma. Design and Methods In the context of the European Prospective Investigation into Cancer and Nutrition (EPIC), anthropometric characteristics were assessed in 371,983 cancer-free individuals at baseline. During the 8.5 years of follow-up, 1,219 histologically confirmed incident cases of non-Hodgkin’s lymphoma and multiple myeloma occurred in 609 men and 610 women. Gender-specific proportional hazards models were used to estimate relative risks and 95% confidence intervals (95% CI) of development of non-Hodgkin’s lymphoma and multiple myeloma in relation to the anthropometric characteristics. Results Height was associated with overall non-Hodgkin’s lymphoma and multiple myeloma in women (RR 1.50, 95% CI 1.14–1.98) for highest versus lowest quartile; p-trend < 0.01) but not in men. Neither obesity (weight and body mass index) nor abdominal fat (waist-to-hip ratio, waist or hip circumference) measures were positively associated with overall non-Hodgkin’s lymphoma and multiple myeloma. Relative risks for highest versus lowest body mass index quartile were 1.09 (95% CI 0.85–1.38) and 0.92 (95% CI 0.71–1.19) for men and women, respectively. Women in the upper body mass index quartile were at greater risk of diffuse large B-cell lymphoma (RR 2.18, 95% CI 1.05–4.53) and taller women had an elevated risk of follicular lymphoma (RR 1.25, 95% CI 0.59–2.62). Among men, height and body mass index were non-significantly, positively related to follicular lymphoma. Multiple myeloma risk alone was elevated for taller women (RR 2.34, 95% CI 1.29–4.21) and heavier men (RR 1.77, 95% CI 1.02–3.05). Conclusions The EPIC analyses support an association between height and overall non-Hodgkin’s lymphoma and multiple myeloma among women and suggest heterogeneous subtype associations. This is one of the first prospective studies focusing on central adiposity and non-Hodgkin’s lymphoma subtypes.

Genetic susceptibility, smoking, obesity and risk of venous thromboembolism.

The F5 G1691A (Factor V Leiden) and F2 G20210A (prothrombin) mutations are linked to an increase in the incidence rate of venous thromboembolism (VTE), but their effects are highly variable. We investigated whether the effects of smoking and obesity might explain this variability. In a case‐cohort study including the participants of the Danish Diet, Cancer and Health study, we computed incidence rates and Cox proportional hazard ratios for VTE in individuals with and without the mutations, categorized by weight and tobacco consumption. The sole effect of heavy smoking was 128 extra VTE events per 100 000 person years in individuals with the F5 G1691A mutation versus 59 in individuals without. The sole effect of obesity was 222 extra VTE events per 100 000 person years in individuals with the F5 G1691A mutation, versus 103 in individuals without this mutation; and 705 extra VTE events per 100 000 person years in individuals with the F2 G20210A mutation versus 107 in individuals without this mutation. The F5 G1691A and F2 G20210A mutations conferred increased susceptibility to the unfavourable effects of smoking and obesity on the risk for VTE. Thus, individuals with genetic risk factors for VTE might benefit from maintaining a healthy lifestyle.

Risk of arterial thrombosis in patients with primary chronic immune thrombocytopenia: a Danish population-based cohort study

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