Sex difference in risk of second but not of first venous thrombosis: paradox explained.

BACKGROUND: The risk of recurrent venous thrombosis is 2-fold higher in men than in women. In contrast, no such sex difference in the risk of first venous thrombosis has been reported. We hypothesized that, for a first event, a risk difference between the sexes is masked by female exposure to reproductive factors (oral contraception, pregnancy/puerperium, and postmenopausal hormone therapy). METHODS AND RESULTS: From the Multiple Environmental and Genetic Assessment of Risk Factors for Venous Thrombosis (MEGA) study, a population-based case-control study on risk factors for venous thrombosis, 2915 patients with a first venous thrombosis and their partners as control subjects were included. Odds ratios and 95% confidence intervals for first venous thrombosis were assessed in men compared with women without reproductive risk factors by use of conditional logistic regression. Analyses were stratified in 10-year age categories to account for the variation in exposure to reproductive risk factors over different age groups and adjusted for body mass index and smoking. Overall, men had a 2.1-fold (95% confidence interval, 1.9-2.4) increased risk of first venous thrombosis compared with women without reproductive risk factors. Similar results were found when 10-year age categories were viewed separately. Adjustment for body mass index and smoking and exclusion of cancer patients did not materially affect the results. CONCLUSIONS: When female reproductive risk factors are taken into account, the risk of a first venous thrombosis is twice as high in men as in women. These findings are in line with previous studies on recurrent venous thrombosis and may have implications for future treatment and prevention strategies.

Increased risk of CVD after VT is determined by common etiologic factors.

Patients with venous thrombosis (VT) have an increased risk of subsequent CVD (CVD), but the underlying pathophysiology is unclear. Using data from the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis follow-up study, 4480 patients with VT, 2926 partner control participants, and 2638 random digit dialing (RDD) control participants were followed-up between 1999 and 2008. Incidence rates and hazard ratios with 95% confidence intervals (95% CIs) of CVD (defined as myocardial infarction or ischemic stroke) were calculated for patients vs controls. Measurable confounders (age, sex, body mass index, smoking, chronic disease, malignancy, genetic thrombophilia, and procoagulant markers) were adjusted for when comparing patients with RDD controls. Unmeasured lifestyle-related factors were also considered by comparing patients with their partners. During a median follow-up time of 5 years, 124 CVD events occurred. Incidence of CVD per 1000 person-years was 3.2 (95% CI, 2.5-4.0) in patients, 2.2 (95% CI, 1.5-3.0) in partners, and 1.6 (95% CI, 0.9-2.6) in RDD controls. Crude hazard ratio was 2.2 (95% CI, 1.2-3.8) in patients compared with RDD controls and 1.5 (95% CI, 1.0-2.3) in patients compared with partners. After adjustment for all confounders, these risks attenuated to 1.8 (95% CI, 0.8-4.2) and 1.3 (95% CI, 0.7-2.5) for patients compared with RDD control participants and partners, respectively. In conclusion, individuals with VT had an increased risk of CVD. This could be explained by common etiologic factors.

The risk of venous thrombosis in individuals with a history of superficial vein thrombosis and acquired venous thrombotic risk factors.

Superficial vein thrombosis (SVT) increases the risk of venous thrombosis fourfold to sixfold. As most individuals with SVT do not develop venous thrombosis, additional risk factors may explain the risk of developing a venous thrombosis. In the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis study, we assessed the risk of venous thrombosis in individuals with previous SVT and a mild thrombotic risk factor (smoking or overweight/obesity), a strong risk factor (surgery, hospitalization, plaster cast immobilization, or malignancy), or a reproductive factor in women (oral contraception, postmenopausal hormone therapy, or pregnancy/puerperium). Individuals with previous SVT alone had a 5.5-fold (95% confidence interval [CI], 4.4-6.8) increased risk of venous thrombosis. This was 9.3 (95% CI, 7.2-12.1) combined with a mild thrombotic risk factor, 31.4 (95% CI, 14.6-67.5) with a strong risk factor, and 34.9 (95% CI, 19.1-63.8) in women with a reproductive risk factor. The highest separate risk estimates were found for SVT with surgery (42.5; 95% CI, 10.2-177.6), hospitalization (49.8; 95% CI, 11.9-209.2), or oral contraception (43.0; 95% CI, 15.5-119.3 in women). In conclusion, the risk of venous thrombosis is markedly increased in individuals with previous SVT who have an acquired thrombotic risk factor.

Combined oral contraceptives: the risk of myocardial infarction and ischemic stroke.

BACKGROUND: Combined oral contraceptives (COCs) have been associated with an increased risk of arterial thrombosis, i.e. myocardial infarction or ischemic stroke. However, as these diseases are rare in young women and as many types of combined oral contraception exist, the magnitude of the risk and the effect of different hormonal contents of COC preparations remain unclear. OBJECTIVES: To estimate the risk of myocardial infarction or ischemic stroke in users compared with non-users of different types, doses and generations of combined oral contraception. SEARCH METHODS: We searched electronic databases (MEDLINE (1966 to July 08, 2015), EMBASE (1980 to July 08, 2015), Popline (1970 to July 08, 2015) and LILACS (1985 to July 08, 2015) for eligible studies, without language restrictions. SELECTION CRITERIA: We included observational studies that recruited women in the reproductive age group (18 to 50 years) and compared the risk of myocardial infarction or ischemic stroke between users and non-users of COCs. DATA COLLECTION AND ANALYSIS: Two review authors independently selected relevant studies and extracted data. We pooled relative risks ()(combined odds ratios and one incidence rate ratio) and 95% confidence intervals (CIs) for myocardial infarction or ischemic stroke in users versus non-users of COCs.We combined the outcomes of myocardial infarction and ischemic stroke and also analysed these outcomes separately. Analyses were stratified according to estrogen dose and progestagen type. MAIN RESULTS: In total, we identified 1298 publications through the search strategy. We included 28 publications reporting on 24 studies. COC users were at increased risk of myocardial infarction or ischemic stroke compared with non-users: relative risk (RR) 1.6 (95% CI 1.3-1.9).These RRs were similar for myocardial infarction (1.6, 95% CI 1.2 to 2.1) and ischemic stroke (1.7, 95% CI 1.5 to 1.9). The risks did not vary clearly according to the generation of progestagen or according to progestagen type. When we stratified preparations according to estrogen dose, the risk of myocardial infarction or ischemic stroke seemed to increase with higher doses of estrogen. AUTHORS' CONCLUSIONS: This meta-analysis showed that the risk of myocardial infarction or ischemic stroke was 1.6-fold increased in women using COCs . The risk was highest for pills with > 50 microgram estrogen. When combined with the results of studies on the risk of venous thrombosis in COC users, it seems that the COC pill containing levonorgestrel and 30 µg of estrogen is the safest oral form of hormonal contraception.

[Atypical presentation of male breast cancer]. / Atypische presentatie van borstkanker bij een man.

BACKGROUND: Approximately 1% of all breast cancers occur in men. With an annual incidence of 130 cases in the Netherlands, the occurrence of male breast cancer is rare. CASE DESCRIPTION: We report the case of a 72-year-old male who was referred to a breast outpatient clinic for the evaluation of a multinodular skin lesion of the nipple. The nipple lesion was found to be an invasive carcinoma of the breast with neuroendocrine differentiation. Retrospectively, a breast abnormality could be detected on radiologic imaging 2 years prior to cancer diagnosis. CONCLUSION: Breast cancer in men is associated with an increased diagnostic delay compared to women and is subsequently diagnosed at a later stage. Studies on the survival of breast cancer report worse survival in men compared to women. Health care professionals should be alerted to the presence of a malignancy when dealing with abnormalities of the male breast.

Recommendations for the Optimal Radiation Dose in Patients With Primary Cutaneous Anaplastic Large Cell Lymphoma: A Report of the Dutch Cutaneous Lymphoma Group.

PURPOSE: To determine the optimal radiation dose for treatment of primary cutaneous anaplastic large cell lymphoma (C-ALCL) with solitary or localized, multifocal or recurrent skin lesions. METHODS AND MATERIALS: In this multicenter study, patients with C-ALCL who had been treated with radiation therapy (RT) between 1984 and 2016 were retrieved from the Dutch registry of cutaneous lymphomas. Distinction was made between patients first presenting with solitary or localized lesions (n=63), with multifocal skin lesions (n=6), and patients with a skin relapse (n=22). Radiation doses, treatment response, and follow-up were evaluated. Radiation doses were categorized as low-dose (≤20 Gy), intermediate-dose (21-39 Gy), and high-dose (≥40 Gy) RT. RESULTS: Of 63 patients presenting with solitary or localized skin lesions, 61 (97%) showed a complete response (CR). There were no differences in CR between low-dose (16 of 17), intermediate-dose (15 of 15), and high-dose RT (30 of 31). After a median follow-up of 46 months, 30 of 63 patients (48%) had a relapse, but in-field relapses were never observed. Six of 6 patients (100%) initially presenting with multifocal skin lesions showed a CR (3 of 3 low-dose, 2 of 2 intermediate-dose, 1 of 1 high-dose RT). After a median follow-up of 27 months, 3 of 6 patients had a relapse. Treatment of 33 skin relapses in 22 patients showed no differences in CR between low-dose (18 of 19), intermediate-dose (6 of 6), and high-dose RT (8 of 8). In the last 10 years there has been a decrease in radiation dose used in the treatment of C-ALCL. Treatment of multifocal and recurrent lesions with a dose of 8 Gy (2 × 4 Gy) resulted in CR of 17 of 18 lesions. CONCLUSIONS: Our results show that a radiation dose of 20 Gy (8 × 2.5 Gy) is effective in patients presenting with solitary or localized skin lesions. For patients with multifocal skin lesions and patients with a skin relapse, a dose of 8 Gy (2 × 4 Gy) may be sufficient.

Clinical Staging and Prognostic Factors in Folliculotropic Mycosis Fungoides.

IMPORTANCE: Large case series suggest that patients with folliculotropic mycosis fungoides (FMF) have a worse prognosis than patients with classic mycosis fungoides (MF). However, recent studies described a subgroup of patients with FMF with a more favorable prognosis. Distinction between indolent and aggressive FMF may have important therapeutic consequences but is hampered by the inability of the current tumor-node-metastasis-blood (TNMB) staging system to classify patients with FMF in a clinically meaningful way. OBJECTIVE: To differentiate between indolent and aggressive FMF using clinicopathological criteria and to define prognostic factors in patients with FMF. DESIGN, SETTING, AND PARTICIPANTS: In this prospective cohort study, we followed 203 patients with FMF, included in the Dutch Cutaneous Lymphoma Registry between October 1985 and May 2014 at a tertiary referral center hosting the Dutch Cutaneous Lymphoma Registry. Overall, 220 patients with FMF had been registered, but 17 patients with incomplete follow-up data or a history of classic MF were excluded. MAIN OUTCOMES AND MEASURES: Main outcomes included clinical and histological characteristics, disease progression, and survival. Prognostic factors were investigated using Cox proportional hazard regression analysis. Distinction between early plaque-stage FMF and advanced plaque-stage FMF was made by a blinded review of skin biopsy specimens from patients presenting with plaques. RESULTS: In a cohort of 147 men and 56 women (median [range] age, 59 [15-93] years), patients with histologically early plaque-stage FMF had a very similar overall survival (OS) rate to patients with only patches and/or follicular papules (10-year OS, 71% vs 80%), while the survival rate of patients with histologically advanced plaque-stage FMF was almost identical to that of patients presenting with tumors (10-year OS, 25% vs 27%). Subsequently, 3 clinical subgroups with significantly different survival data were distinguished: early skin-limited FMF (group A; n = 84; 5-year and 10-year OS, 92% and 72%); advanced skin-limited FMF (group B; n = 102; 5-year and 10-year OS, 55% and 28%); and FMF presenting with extracutaneous disease (group C; n = 17; 5-year and 10-year OS, 23% and 2%). Age at diagnosis, large cell transformation and secondary bacterial infection were independent risk factors for disease progression and/or poor survival. CONCLUSIONS AND RELEVANCE: The results of this study provide useful criteria to differentiate between indolent and aggressive FMF and confirm the existence of a subgroup of FMF with a favorable prognosis.

Thrombin generation and low-molecular-weight heparin prophylaxis in pregnant women with thrombophilia.

Pregnancy is associated with increased risk of venous thromboembolism, especially in the presence of thrombophilia. However, there is no consensus on the optimal approach for thromboprophylaxis in this population. Recent evidence suggests that thrombin generation correlates with the overall procoagulant state of the plasma. Our aim was to evaluate thrombin generation in a prospective cohort of thrombophilic pregnant women, and investigate the effectiveness of low-molecular-weight heparin (LMWH) prophylaxis in pregnancy. Women with severe (n=8), mild (n=47) and no (n=15) thrombophilia were followed throughout their pregnancies. Thrombin generation was evaluated in each trimester as well as five days and eight weeks postpartum (as a reference category). In women undergoing LMWH prophylaxis, thrombin generation and anti-Factor-Xa activity were measured just before and 4 hours after administration (peak effect). Thrombin generation was determined using Technothrombin TGA assay system. For the analysis, median peak thrombin and endogenous thrombin potential were used. Peak thrombin and endogenous thrombin potential were increased during pregnancy compared to the non-pregnant state with the highest results in the severe thrombophilia group. In women receiving LMWH prophylaxis a decrease was observed in thrombin generation at peak effect but over the progression of pregnancy the extent of this decrease reduced in a stepwise fashion. Our results show that thrombin generation demonstrates the hypercoagulable state in thrombophilic pregnancies. In addition, we found the effect of LMWH prophylaxis to progressively decrease with advancing stages of pregnancy.

[Case-crossover studies. Research into risk factors with the patient as his or her own control]. / Patiënt-cross-overstudies. Observationeel onderzoek naar risicofactoren met de patiënt als zijn eigen controlepersoon.

The case-crossover study is a relatively unknown way of identifying short-term transient risk factors for acute-onset diseases. In patients with the disease of interest, the frequency of exposure to a certain risk factor is compared between two time periods. If the exposure is more common in the period directly preceding disease onset than in an earlier period, the control period, it is likely that the exposure contributes to the development of the disease. The problem of confounding is minimized in case-crossover studies since the patient serves as his or her own control. A potential disadvantage is that sufficient biological knowledge of the clinical picture is needed to provide a good estimate of the risk period. As administrative databases are now commonly used for research purposes, future use of case-crossover methods is likely to increase. We illustrate the case-crossover study with the question of whether antibiotic use increases the risk of unwanted pregnancy in women who use the contraceptive pill.

[Drug-promoting advertisements in the Dutch Journal of Medicine and Pharmaceutical Weekly: not always evidence based]. / Geneesmiddeladvertenties in het NTvG en het Pharmaceutisch Weekblad: niet altijd evidencebased.

OBJECTIVE: To determine and compare the foundation of claims in drug-promoting advertisements in a Dutch journal for physicians and a Dutch journal for pharmacists. DESIGN: A cross-sectional study. METHOD: We included all the drug-promoting advertisements referring to a randomized controlled trial (RCT) we could find on Medline from 2 volumes of the Dutch Journal of Medicine (Nederlands Tijdschrift voor Geneeskunde; NTvG) and the (also Dutch) Pharmaceutical Weekly (Pharmaceutisch Weekblad; PW). The validity of the advertisements (n = 54) and the methodological quality of the referenced RCTs (n = 150) were independently scored by 250 medical students using 2 standardised questionnaires. The advertisements' sources were concealed from the students. Per journal, the percentage of drug-promoting advertisements having a valid claim and the percentage of high-quality RCT references were determined. Average scores on quality and validity were compared between the 2 journals. RESULTS: On a scale of 0-18 points, the mean quality scores of the RCTs differed 0.3 (95% CI: -0.1-0.7) between the NTvG (score: 14.8; SD: 2.2) and the PW (score: 14.5; SD: 2.6). The difference between the validity scores of drug-promoting advertisements in the NTvG (score: 5.8; SD: 3.3) and the PW (score: 5.6; SD: 3.6) was 0.3 (95% CI: -0.3-0.9) on a scale of 0-10 points. For both journals, an average of 15% of drug-promoting advertisements was valid (defined as a validity score of > 8 points); 35% of the RCTs referred to was of good methodological quality (defined as a quality score of > 16 points). CONCLUSION: The substantiation of many claims in drug-promoting advertisements in the NTvG and the PW was mediocre. There was no difference between the 2 journals.