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Background: Nails contain genomic DNA that can be used for genetic analyses, which is attractive for large epidemiologic studies that have collected or are planning to collect nail clippings. Study participants will more readily participate in a study when asked to provide nail samples than when asked to provide a blood sample. In addition, nails are easy and cheap to obtain and store compared with other tissues. Methods: We describe our findings on toenail DNA in terms of yield, quality, genotyping a limited set of SNPs with the Sequenom MassARRAY iPLEX platform and high-density genotyping with the Illumina HumanCytoSNP_FFPE-12 DNA array (>262,000 markers). We discuss our findings together with other studies on nail DNA and we compare nails and other frequently used tissue samples as DNA sources. Results: Although nail DNA is considerably degraded, genotyping a limited set of SNPs with the Sequenom MassARRAY iPLEX platform (average sample call rate, 97.1%) and high-density genotyping with the Illumina HumanCytoSNP_FFPE chip (average sample call rate, 93.8%) were successful. Conclusions: Nails are a suitable source of DNA for genotyping in large-scale epidemiologic studies, provided that methods are used that are suitable or optimized for degraded DNA. For genotyping through (next generation) sequencing where DNA degradation is less of an issue, nails may be an even more attractive DNA source, because it surpasses other sources in terms of ease and costs of obtaining and storing the samples. Impact: It is worthwhile to consider nails as a source of DNA for genotyping in large-scale epidemiologic studies. See all the articles in this CEBP Focus section, “Biomarkers, Biospecimens, and New Technologies in Molecular Epidemiology.” Cancer Epidemiol Biomarkers Prev; 23(12); 2703–12. ©2014 AACR.

ObjectiveThe objective of this study was to review the current anatomic indications for and early results of aortouni-iliac (AUI) devices for endovascular aneurysm repair.MethodsA total of 128 patients receiving an Endurant (Medtronic Inc, Minneapolis, Minn) AUI device in the U.S. Investigational Device Exemption trial (44 patients) or the Endurant Stent Graft Natural Selection Global Postmarket Registry (84 patients) were reviewed. Preoperative computed tomography imaging of patients in the Investigational Device Exemption trial and case report forms of Registry patients were used to determine anatomic indications. Baseline characteristics and early results were compared with those of 1305 patients receiving a bifurcated (BIF) device in sister studies.ResultsThe indication for the AUI device was unclear from case report forms in two Registry cases. The remaining 126 patients had a unilateral iliac occlusion in 30 (23%), a severely narrowed aortic segment in 58 (45%), severe iliac occlusive disease in 28 (22%), severe iliac tortuosity in 29 (23%), or complex iliac aneurysms in 19 (15%). Two patients had a previous aortobifemoral graft; 38 patients (30%) had multiple indications. The AUI cohort included more women than the BIF group did (19% vs 10%; P < .01) and had more severe comorbidities. Successful deployment was achieved in all AUI cases. The 30-day mortality was 2% (BIF cohort, 1%; P = .21). More AUI patients underwent repair under general anesthesia (81% vs 64%; P < .01), and procedures were longer (110.9 ± 54.9 minutes vs 99.2 ± 44.3 minutes; P = .02). Except for longer intensive care unit stays (19.6 ± 80.0 hours vs 9.0 ± 34.8 hours; P = .01) and higher myocardial infarction rates (4% vs 1%; P < .01), outcomes of the AUI cohort were similar to those of the BIF cohort. There were no migrations, ruptures, fractures, or open conversions at up to 1-year follow-up.ConclusionsThe AUI configuration extends endovascular aneurysm repair feasibility to several hostile anatomic conditions. Despite increased comorbidities in the recipient patient population and associated higher rates of postoperative myocardial infarction and respiratory complications, early outcomes with the new generation of AUI devices are acceptable and comparable to those after treatment with BIF configurations.

Background: Basal cell carcinoma (BCC) is the most common form of cancer among Caucasians and its incidence continues to rise. Surgical excision (SE) is considered standard treatment, though randomised trials with long-term follow-up are rare. We now report the long-term results of a randomised trial comparing surgical excision with Mohs' micrographic surgery (MMS) for facial BCC.Methods: 408 facial, high risk (diameter at least 1 cm, H-zone location or aggressive histological subtype) primary BCCs (pBCCs) and 204 facial recurrent BCCs (rBCCs) were randomly allocated to treatment with either SE or MMS between 5th October 1999 and 27th February 2002. The primary outcome was recurrence of carcinoma. A modified intention to treat analysis was performed.Findings: For primary BCC, the 10-year cumulative probabilities of recurrence were 4.4% after MMS and 12.2% after SE (Log-rank test chi(2) 2.704, p = 0.100). For recurrent BCC, cumulative 10-year recurrence probabilities were 3.9% and 13.5% for MMS and SE, respectively (Log-rank chi(2) 5.166, p = 0.023). A substantial proportion of recurrences occurred after more than 5 years post-treatment: 56% for pBCC and 14% for rBCC.Interpretation: Fewer recurrences occurred after treatment of high risk facial BCC with MMS compared to treatment with SE. The proportion of recurrences occurring more than 5 years post-treatment was especially high for pBCC, stressing the need for long-term follow-up in patients with high risk facial pBCC. (C) 2014 Elsevier Ltd. All rights reserved.

WHAT THIS PAPER ADDS The aim of this study was to perform a cost-analysis of a recommended but largely underutilized SET first treatment strategy in intermittent claudication (IC). Until now no study has been performed to investigate the overall economic consequences of a nationwide SET first approach (stepped care). As the study used a large database (3.4 million people), daily practice is reflected well in the results. Implementation of a stepped care treatment for patients with IC may lead to significant savings of healthcare resources. These findings may be generalizable to other European healthcare systems. Objectives: International guidelines recommend supervised exercise therapy (SET) as primary treatment for intermittent claudication (IC). The aim of this study was to calculate treatment costs in patients with IC and to estimate nationwide annual savings if a stepped care model (SCM, primary SET treatment followed by revascularization in case of SET failure) was followed. Methods: Invoice data of all patients with IC in 2009 were obtained from a Dutch health insurance company (3.4 millionmembers).Patientsweredividedintothreegroupsbasedoninitialtreatmentafterdiagnosis(t0).TheSETgroup receivedSETinitiatedatanytimebetween12monthsbeforeandupto3monthsaftert0.Theinterventiongroup(INT) underwentendovascularoropenrevascularizationbetweent0andtþ 3m onths.Thethirdgroup(REST)receivedneither SET nor any intervention. All peripheral arterial disease related invoices were recorded during 2 years and average costs per patient were calculated. Savings following use of a SCM were calculated for three scenarios. Results: Data on 4954 patients were analyzed. Initial treatment was SET (n ¼ 701, 14.1%), INT (n ¼ 1363, 27.5%), or REST (n ¼ 2890, 58.3%). Within 2 years from t0, invasive revascularization in the SET group was performed in 45 patients (6.4%). Additional interventions (primary at other location and/or re-interventions) were performed in 480 INT patients (35.2%). Some 431 REST patients received additional SET (n ¼ 299, 10.3%) or an intervention (n ¼ 132, 4.5%). Mean total IC related costs per patient were V2,191, V9851 and V824 for SET, INT, and REST, respectively. Based on a hypothetical worst, moderate, and best case scenario, some 3.8, 20.6, or 33.0 million euros would have been saved per annum if SCM was implemented in the Dutch healthcare system. Conclusion: Implementation of a SCM treatment for patients with IC may lead to significant savings of health care resources.

Objective Guidelines for complex regional pain syndrome (CRPS) 1 advocate several substance classes to reduce pain and support physical rehabilitation, but guidance about which agent should be prioritized when designing a therapeutic regimen is not provided. Using a network meta-analytic approach, we examined the efficacy of all agent classes investigated in randomized clinical trials of CRPS 1 and provide a rank order of various substances stratified by length of illness duration. Design In this study a network meta-analysis was conducted. Patients The participants of this study were patients with CRPS 1. Method Searches in electronic, previous systematic reviews, conference abstracts, book chapters, and the reference lists of relevant articles were performed. Eligible studies were randomized controlled trials comparing at least one analgesic agent with placebo or with another analgesic and reporting efficacy in reducing pain. Summary efficacy stratified by symptom duration and length of follow-up was computed across all substance classes. Two authors independently extracted data. Results In total, 16 studies were included in the analysis. Bisphosphonates appear to be the treatment of choice in early stages of CRPS 1. The effects of calcitonin surpass that of bisphosphonates and other substances as a short-term medication in more chronic stages of the illness. While most medications showed some efficacy on short-term follow-up, only bisphosphonates, NMDA analogs, and vasodilators showed better long-term pain reduction than placebo. Limitation For some drug classes, only a few studies were available and many studies included a small group of patients. Insufficient data were available to analyze efficacy on disability. Conclusion This network meta-analysis indicates that a rational pharmacological treatment strategy of pain management should consider bisphosphonates in early CRPS 1 and a short-term course of calcitonin in later stages. While most medications showed some efficacy on short-term follow-up, only bisphosphonates, NMDA analogs and vasodilators showed better long-term pain reduction than placebo.

WHAT THIS PAPER ADDS The aim of the study was to validate a tri-axial activity monitor to measure daily activities and walking steps (physical activity) in patients with intermittent claudication. A clear call in vascular research for alternative tests to determine walking capacity or walking behaviour in patients with peripheral arterial disease (PAD) has been made. This study validated an activity monitor to measure these types of outcome variables, which may offer a valuable contribution to the research armamentarium of PAD and could therefore support future PAD research. Objectives: The daily life physical activity (PA) of patients with peripheral arterial disease (PAD) may be severely hampered by intermittent claudication (IC). From a therapeutic, as well as research, point of view, it may be more relevant to determine improvement in PA as an outcome measure in IC. The aim of this study was to validate daily activities using a novel type of tri-axial accelerometer (Dynaport MoveMonitor) in patients with IC. Methods: Patients with IC were studied during a hospital visit. Standard activities (locomotion, lying, sitting, standing, shuffling, number of steps and “not worn” detection) were video recorded and compared with activities scored by the MoveMonitor. Inter-rater reliability (expressed in intraclass correlation coefficients [ICC]), sensitivity, specificity, and positive predictive values (PPV) were calculated for each activity. Results: Twenty-eight hours of video observation were analysed (n ¼ 21). Our video annotation method (the gold standard method) appeared to be accurate for most postures (ICC > 0.97), except for shuffling (ICC ¼ 0.38). The MoveMonitor showed a high sensitivity (>86%), specificity (>91%), and PPV (>88%) for locomotion, lying, sitting, and “not worn” detection. Moderate accuracy was found for standing (46%), while shuffling appeared to be undetectable (18%). A strong correlation was found between video recordings and the MoveMonitor with regard to the calculation of the “number of steps” (ICC ¼ 0.90). Conclusions: The MoveMonitor provides accurate information on a diverse set of postures, daily activities, and number of steps in IC patients. However, the detection of low amplitude movements, such as shuffling and “sitting to standing” transfers, is a matter of concern. This tool is useful in assessing the role of PA as a novel, clinically relevant outcome parameter in IC.

OBJECTIVE The objective of this study was to determine whether treatment with metformin in patients with renal impairment is associated with a higher risk of lactic acidosis or elevated lactate concentrations compared with users of a noninsulin antidiabetic drug (NIAD) who had never used metformin. RESEARCH DESIGN AND METHODS A cohort of 223,968 metformin users and 34,571 diabetic patients who had never used metformin were identified from the Clinical Practice Research Datalink (CPRD).The primary outcome was defined as either a CPRD READ code lactic acidosis or a record of a plasma lactate concentration >5 mmol/L. The associations between renal impairment, dose of metformin, and the risk of lactic acidosis or elevated lactate concentrations were determined with time-dependent Cox models and expressed as hazard ratios (HRs). RESULTS The crude incidence of lactic acidosis or elevated lactate concentrations in current metformin users was 7.4 per 100,000 person-years (vs. 2.2 per 100,000 person-years in nonusers). Compared with nonusers, risk of lactic acidosis or elevated lactate concentrations in current metformin users was significantly associated with a renal function 2 g) of metformin (adjusted HR 13.0 [95% CI 2.36–72.0]). CONCLUSIONS Our study is consistent with current recommendations that the renal function of metformin users should be adequately monitored and that the dose of metformin should be adjusted, if necessary, if renal function falls below 60 mL/min/1.73 m2.

Introduction: Women with former preeclampsia (exPE) develop chronic hypertension 4 times more often than healthy parous controls. Women, destined to develop remote chronic hypertension, had increased left ventricular mass index (LVMI) and diastolic blood pressure (BP) prior to the onset of hypertension as compared to those remaining normotensive. However, longitudinal data on the progress of this increased LVMI in women destined to develop hypertension are lacking. Methods: We included 20 women with exPE and 8 parous controls. At both 1- and 14-year postpartum (pp), we performed cardiac ultrasound and determined circulating levels of the metabolic syndrome variables. Of 14-year pp, 7 (35%) former patients had developed chronic hypertension. We compared these 7 former patients with both the 13 former patients who remained normotensive and the 8 parous controls using the Mann-Whitney U test and Kruskal-Wallis analysis. Results: Women with hypertensive exPE differed from their normotensive counterparts by a higher incidence of early-onset preeclampsia (PE) in their index pregnancy and a higher rate of recurrence in next pregnancies. At 1-year pp, they also had high/normal BP and higher fasting insulin levels. At 14 years pp, the relative left ventricular wall thickness was higher, and the E/A ratio was lower, in the hypertensive group relative to those remaining normotensive. Conclusion: Women with exPE are at increased risk of developing chronic hypertension, when (1) the PE in the index pregnancy had an early-onset and/or recurred in next pregnancies and (2) the 1-year pp. Blood pressure was high normal. We also noticed that at 14 years pp, the hypertensive group showed signs of concentric left ventricular remodeling along with a decreased E/A ratio.

Objectives The evidence for an association between occupational asbestos exposure and pharyngeal cancer (PhC) is limited, while for oral cavity cancer (OCC) the literature is even sparser. We studied OCC and PhC risk both separately and combined (OCPC) in relation to occupational asbestos exposure, specifically addressing the influence of potential confounders, the existence of an exposure-response relation, and the presence of interaction between asbestos and smoking. Methods Using the prospective Netherlands Cohort Study (N=58 279 men, aged 55-69 years), we estimated asbestos exposure by linkage to a general population job-exposure matrix (DOMJEM) and a Finnish job-exposure matrix (FINJEM). After 17.3 years of follow-up, 58 OCC and 53 PhC cases were available for analysis. Results No association between asbestos and risk of OCC was observed for either JEM. Hazard ratios (HR) of PhC and OCPC increased after adjusting for confounders, particularly alcohol consumption and socioeconomic status. For PhC, a multivariable-adjusted increased HR was observed for "ever" versus "never" exposed to asbestos [HR 2.20, 95% confidence interval (95% CI) 1.08-4.49] when using FINJEM, but a trend of increased risks with higher cumulative exposure could not be demonstrated for either JEM. Results for OCPC showed patterns similar to those observed for PhC. None of the cancers showed a significant interaction between asbestos and smoking. Conclusions This prospective population-based study showed no convincing evidence of an association between asbestos and risk of OCC, PhC, and OCPC as an exposure-response relation was lacking, and results were not robust against the use of different JEM. However, the potentially increased HR of PhC and OCPC observed in this and previous studies warrant further research. Chemicals/CAS: asbestos, 1332-21-4. This work is licensed under a Creative Commons Attribution 4.0 International License.

Purpose: Drug utilization studies have applied different methods to various data types to describe medication use, which hampers comparisons across populations. The aim of this study was to describe the time trends in antidepressant prescribing in the last decade and the variation in the prevalence, calculated in a uniform manner, in seven European electronic healthcare databases. Methods: Annual prevalence per 10,000 person-years (PYs) was calculated for 2001-2009 in databases from Spain, Germany, Denmark, the United Kingdom (UK), and the Netherlands. Prevalence data were stratified according to age, sex, antidepressant type (selective serotonin re-uptake inhibitors [SSRIs] or tricyclic antidepressants [TCAs]) and major indications. Results: The age- and sex-standardized prevalence was lowest in the two Dutch (391 and 429 users per 10,000 PYs) and highest in the two UK (913 and 936 users per 10,000 PYs) populations in 2008. The prevalence in the Danish, German, and Spanish populations was 637, 618, and 644 users per 10,000 PY respectively. Antidepressants were prescribed most often in 20- to 60-year-olds in the two UK populations compared with the others. SSRIs were prescribed more often than TCAs in all except the German population. In the majority of countries we observed an increasing trend of antidepressant prescribing over time. Two different methods identifying recorded indications yielded different ranges of proportions of patients recorded with the specific indication (15-57 % and 39-69 % for depression respectively). Conclusion: Despite applying uniform methods, variations in the prevalence of antidepressant prescribing were obvious in the different populations. Database characteristics and clinical factors may both explain these variations. © 2014 Springer-Verlag.

IMPORTANCE Combined anticoagulant and aspirin therapy is associated with increased bleeding risk in patients with atrial fibrillation, but the bleeding risk of combined use of anticoagulant and nonsteroidal anti-inflammatory drugs (NSAIDs) is poorly documented.OBJECTIVE To estimate the bleeding risk of combined anticoagulant (rivaroxaban or enoxaparin-vitamin K antagonist [VKA]) and NSAID or aspirin therapy in patients with venous thromboembolism.DESIGN, SETTING, AND PARTICIPANTS Prospective analysis of observational data from the EINSTEIN deep vein thrombosis and pulmonary embolism clinical trials comparing rivaroxaban with enoxaparin-VKA treatment, trials performed in hospitals and clinics in 8246 patients enrolled from 2007 to 2009.EXPOSURE Bleeding event rates during exposure to NSAID and aspirin therapy were compared to time without exposure.MAIN OUTCOMES AND MEASURES Days of NSAID or aspirin use and nonuse, clinically relevant bleeding event and major bleeding event rates by patient-years, and hazard ratios.RESULTS During NSAID-anticoagulant concomitant treatment, clinically relevant bleeding occurred with an event rate of 37.5 per 100 patient-years vs 16.6 per 100 patient-years during anticoagulant use only (hazard ratio [HR], 1.77 [95% CI, 1.46-2.14]). Major bleeding during NSAID-anticoagulant treatment occurred with an event rate of 6.5 per 100 patient-years, compared to 2.0 per 100 patient-years during nonuse (HR, 2.37 [95% CI, 1.51-3.75]). For aspirin-anticoagulant concomitant treatment, clinically relevant bleeding occurred with an event rate of 36.6 per 100 patient-years, compared to 16.9 per 100 patient-years during aspirin nonuse (HR, 1.70 [95% CI, 1.38-2.11]). Major bleeding in aspirin-anticoagulant-treated patients occurred with an event rate of 4.8 per 100 patient-years, compared to 2.2 per 100 patient-years during aspirin nonuse (HR, 1.50 [95% CI, 0.86-2.62]). Increases in risk for clinically relevant and major bleeding were similar for rivaroxaban and enoxaparin-VKA anticoagulation regimens.CONCLUSIONS AND RELEVANCE Among patients with venous thromboembolism receiving anticoagulant therapy, concomitant use of an NSAID or aspirin is associated with an increased risk of clinically relevant and major bleeding.

Summary Background Idrabiotaparinux, a long-acting inhibitor of factor Xa, was shown to be effective in the treatment of patients with venous thromboembolism. Objective To assess non-inferiority for the efficacy of idrabiotaparinux versus warfarin in patients with atrial fibrillation (AF) at risk of stroke and systemic embolism. Bleeding was also assessed. Methods This randomized, double-blind trial enrolled patients with electrocardiogram-documented AF. Idrabiotaparinux was administered weekly via subcutaneous injection, and warfarin was administered daily with dose adjustment to maintain the international normalized ratio between 2.0 and 3.0. Each idrabiotaparinux injection was 3 mg for the first 7 weeks, followed by 2 mg thereafter, except in patients with a creatinine clearance of 30–50 mL min−1 or aged ≥ 75 years. The patients received 1.5 mg after the first 7 weeks. The efficacy outcome was the composite of all fatal or non-fatal strokes and systemic embolism. The safety outcome was clinically relevant bleeding (major and clinically relevant non-major bleeding). Results The study was terminated prematurely by the sponsor for strategic/commercial, not scientific, reasons, with 39% of the planned number of patients included and an average duration of treatment of 240 days. Of the 1886 idrabiotaparinux recipients, 20 developed stroke or systemic embolism (1.5% per year), whereas this occurred in 22 of the 1887 warfarin patients (1.6% per year, hazard ratio 0.98, 95% confidence interval 0.49–1.66). The annual incidence of bleeding was 6.1% in the idrabiotaparinux and 10.0% in the warfarin group (hazard ratio 0.61, 95% confidence interval 0.46–0.81). Conclusion If anything, despite its early termination, the idrabiotaparinux regimen studied suggested a comparable efficacy to dose-adjusted warfarin, with a lower bleeding risk.

INTRODUCTION: The value of diagnostic strategies in patients with clinically suspected recurrent pulmonary embolism (PE) has not been established. The aim was to determine the safety of a simple diagnostic strategy using the Wells clinical decision rule (CDR), quantitative D-dimer testing and computed tomography pulmonary angiography (CTPA) in patients with clinically suspected acute recurrent PE.MATERIALS AND METHODS: Multicenter clinical outcome study in 516 consecutive patients with clinically suspected acute recurrent PE without using anticoagulants.RESULTS: An unlikely clinical probability (Wells rule 4 points or less) was found in 182 of 516 patients (35%), and the combination of an unlikely CDR-score and normal D-dimer result excluded PE in 88 of 516 patients (17%), without recurrent venous thromboembolism (VTE) during 3month follow-up (0%; 95% CI 0.0-3.4%). CTPA was performed in all other patients and confirmed recurrent PE in 172 patients (overall prevalence of PE 33%) and excluded PE in the remaining 253 patients (49%). During follow-up, seven of these 253 patients returned with recurrent VTE (2.8%; 95% CI 1.2-5.5%), of which in one was fatal (0.4 %; 95 % CI 0.02-1.9%). The diagnostic algorithm was feasible in 98% of patients.CONCLUSIONS: A diagnostic algorithm consisting of a clinical decision rule, D-dimer test and CTPA is effective in the management of patients with clinically suspected acute recurrent PE. CTPA provides reasonable safety in excluding acute recurrent PE in patients with a likely clinical probability or an elevated D-dimer test for recurrent PE, with a low risk for fatal PE at follow-up.

Item does not contain fulltext BACKGROUND: Post-partum haemorrhage (PPH) causes rapidly developing deficiencies in clotting factors and contributes to substantial maternal morbidity and mortality. Rotational thromboelastometry (ROTEM((R))) is increasingly used as a point of care coagulation monitoring device in patients with massive haemorrhage; however, there are limited data on reference ranges in the peri-partum period. These are required due to the haemostatic changes in pregnancy. METHODS: In a Dutch multi-centre trial, 161 subjects were included; blood samples were obtained during labour (T1) and within 1 h of delivery (T2). Reference ranges of ROTEM((R)) INTEM, EXTEM, FIBTEM, and APTEM were set and correlation with laboratory results was investigated using the guidelines of the International Federation of Clinical Chemistry. RESULTS: Reference ranges were obtained for clotting time (CT), clot formation time (CFT), alpha-angle, clot firmness at 10 and 20 min (A10, A20), maximum clot firmness (MCF), and maximum lysis (ML). These were comparable from centre to centre, and between T1 and T2. Reference ranges T1: EXTEM: CT 31-63 s, CFT 41-120 s, and MCF 42-78 mm. INTEM: CT 109-225 s, CFT 40-103, and MCF 63-78 mm. FIBTEM: CT 31-79 s and MCF 13-45 mm. APTEM: CT 33-62 s, CFT 42-118, and MCF 61-79 mm. CONCLUSIONS: Reference values for ROTEM((R)) parameters are reported. The previously published correlation between FIBTEM parameters and plasma fibrinogen levels by the Clauss method is confirmed. Further research is needed to define threshold values for haemostatic therapy in the course of PPH. Clinical trial registration NTR 2515 (http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2515).

INTRODUCTION: We have recently described epitope detection in macrophages (EDIM) by flow cytometry. This is a promising tool for the diagnosis and follow-up of malignancies. However, biological and technical validation is warranted before clinical applicability can be explored. METHODS: The pre-analytic and analytic phases were investigated. Five different aspects were assessed: blood sample stability, intra-individual variability in healthy persons, intra-assay variation, inter-assay variation and assay transferability. The post-analytic phase was already partly standardized and described in an earlier study. RESULTS: The outcomes in the pre-analytic phase showed that samples are stable for 24h after venipuncture. Biological variation over time was similar to that of serum tumor marker assays; each patient has a baseline value. Intra-assay variation showed good reproducibility, while inter-assay variation showed reproducibility similar to that of to established serum tumor marker assays. Furthermore, the assay showed excellent transferability between analyzers. CONCLUSION: Under optimal analytic conditions the EDIM method is technically stable, reproducible and transferable. Biological variation over time needs further assessment in future work.

The phase III EINSTEIN DVT and EINSTEIN PE trials demonstrated the potential of oral rivaroxaban for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE). The length of initial hospitalization in patients presenting with either symptomatic DVT or PE was assessed using hospitalization records from these trials.Analyses were carried out in the intention-to-treat population, using non-parametric and parametric statistical methods.Overall, 52% (1781/3434) of EINSTEIN DVT patients and 90% (4328/4821) of EINSTEIN PE patients were admitted to hospital. The proportion of hospitalized patients with a length of stay of five or fewer days receiving rivaroxaban was 54% compared with 31% for enoxaparin/vitamin K antagonist (VKA) in patients with DVT. For patients with PE, the corresponding values were 45% and 33%. Stays of 6-10 days were observed in 29% of rivaroxaban-treated patients compared with 45% of enoxaparin/VKA-treated patients for DVT. For patients with PE, these values were 39% and 46% in the rivaroxaban and enoxaparin/VKA groups, respectively. Overall, length of stay was significantly shorter in the rivaroxaban group, compared with the enoxaparin/VKA group across all analyses performed (p 0.0001). Across regions, the observed admission rates and length of stay duration varied greatly: Asia had the longest overall hospitalization rates, whereas the lowest rates were reported in North America, Australia and New Zealand. Nevertheless, a consistent trend was observed: length of hospital stay in patients with DVT or PE receiving rivaroxaban was shorter than, or at least similar to, patients receiving enoxaparin/VKA.A single-drug regimen with rivaroxaban may reduce the burden on healthcare systems and patients, and provides effective and well tolerated treatment. The studies shared an open-label design that allowed comparison of initial hospitalization, but limitations include the well monitored clinical trial setting in which decisions on admission and discharge could vary from real-world management.

Background: The annual prevalence of antiepileptic drug (AED) prescribing reported in the literature differs considerably among European countries; this may be due to differences in type of data sources, time periods, population distributions, and methodology. Objectives: To assess the prevalence of AED prescribing across seven European routine health care databases in Spain, Denmark, the Netherlands, the UK, and Germany using standardised methodology and to investigate sources of variation. Methods: We used data from the Spanish Base de Datos para la Investigacion Farmacoepidemiologica en Atencion Primaria (BIFAP), the Danish national registries, the Dutch Mondriaan project (AHC, NPCRD), The Health Improvement Network (THIN) and the Clinical Practice Research Datalink (CPRD) from the UK, and the German Bavarian claims database (KVB). Analyses on annual prevalence of AEDs over the study period of 2001–2009 were stratified by sex, age, and AED type (‘old’ vs. ‘new’ depending registration year for marketing). Overall prevalences were standardised to the European 2008 reference population. Results: Prevalence of any AED varied from 79 per 10,000 persons in the Netherlands to 147 per 10,000 persons in Spain in 2001. After standardisation this range decreased to 88 per 10,000 persons in the Netherlands to 144 per 10,000 in Spain and Denmark. In all databases prevalence increased yearly since 2001 with 6% in Denmark to 15% in Spain. This increase could be entirely attributed to an increase in prescribing of ‘new’ AEDs. AED use increased with age for both females and males up to ages of 80–89 years-old and tended to be somewhat higher in females between 40 and 70 years-old. We did not find differences across databases in the number of AEDs concomitantly used. Conclusions: During the study period of 2001–2009, AED prescribing increased in all five EU countries which was mainly due to newer AEDs. Using a standardised methodology showed consistent trends across databases and countries over time. Differences in age and sex distribution explained part of the variation between countries.

BACKGROUND: Different studies have reported an association between HIV infection, antiretroviral therapies, and impaired bone metabolism, but data on their impact on fracture risk are scarce. We studied the association between a clinical diagnosis of HIV infection and fracture risk. METHODS: We conducted a case-control study using data from the Danish National Health Service registries, including 124,655 fracture cases and 373,962 age- and gender-matched controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression. RESULTS: A total of 50 (0.40/1000) patients in the fracture group and 52 (0.14/1000) controls had an HIV diagnosis. The risk of any fracture was thus significantly increased among HIV-infected patients (age- and gender-matched OR = 2.89, 95% CI: 1.99 to 4.18). Similarly, significant increases in the risk of hip (OR = 8.99, 95% CI: 1.39 to 58.0), forearm (OR = 3.50, 95% CI: 1.26 to 9.72), and spine fractures (OR = 9.00, 95% CI: 1.39 to 58.1) were observed. CONCLUSIONS: HIV infection is associated with an almost 3-fold increase in fracture risk compared with that of age- and gender-matched uninfected patients. HIV patients are also at an almost 9-fold higher risk of hip fracture. © 2013 by Lippincott Williams and Wilkins.

Age-related macular degeneration (AMD) is a blinding disease placing considerable burden on society due to blindness-associated costs. Intravitreal anti-vascular endothelial growth factors (anti-VEGFs) are effective in reducing the incidence of blindness, but at potentially high costs, depending on the cost of the drug used. Aflibercept has been introduced as an anti-VEGF equally effective to ranibizumab, but less costly. For this new drug, new cost-effectiveness analyses are needed, and AMD models used today give biased results. We investigated the cost-effectiveness of aflibercept compared to bevacizumab, ranibizumab, and no treatment and studied the influence of commonly used model parameters.A patient-level, visual acuity-based, 2-eye model was developed. Data on effectiveness were derived from randomized controlled trials evaluating the outcomes of aflibercept, bevacizumab, and ranibizumab. Utility and resource utilization were assessed in interviews with AMD patients. Costs were based on standard health care cost prices. Time horizons were two and five years. A societal perspective was employed.Over five years, costs associated with aflibercept treatment were a,not sign36,030, with 2.15 QALYs. Costs associated with the bevacizumab regimens, ABC study as-needed (PRN); CATT study PRN; and CATT study 1x/month, were a,not sign19,367; a,not sign26,746; and a,not sign30,520, with 2.16; 2.17; and 2.15 QALYs, respectively. Costs associated with ranibizumab PRN and 1x/month were a,not sign45,491 and a,not sign74,837 with 2.16 and 2.15 QALYs, respectively. 'No treatment' was associated with a,not sign9530 and 1.96 QALYs. The incremental cost-effectiveness ratios versus 'no treatment' were: aflibercept-a,not sign140,274; bevacizumab-a,not sign51,062 (ABC PRN), a,not sign83,256 (CATT PRN) and a,not sign110,361 (1x/month); ranibizumab-a,not sign181,667 (PRN) and a,not sign349,773 (1x/month). Results were highly dependent on whether only one or both eyes were included, length of time horizon, and whether the costs of blindness and low-vision were included in the analysis.Aflibercept is a cost-effective treatment for AMD over ranibizumab. However, aflibercept is not a cost-effective treatment when compared to bevacizumab. Application of inappropriate model assumptions leads to a biased cost-saving estimate of the cost-effectiveness of aflibercept. Therefore, cost-effectiveness analyses should be conducted with appropriate models.

Objectives: In the present study, the authors have investigated whether rotational thromboelastometry (ROTEM) could predict thrombocytopenia and hypofibrinogenemia in cardiac surgery using the clot amplitude after 5 minutes (A5). Another parameter, PLTEM, in which the contribution of fibrinogen is eliminated by subtracting a fibrin-specific ROTEM test (FIBTEM) from an extrinsically-activated ROTEM test (EXTEM), was investigated. Furthermore, the turnaround time of ROTEM was compared to conventional laboratory tests.Design: Prospective cohort study.Setting: Single academic medical center.Participants: Ninety-seven patients undergoing cardiac surgery between July 2011 until August 2012.Interventions: The correlations between EXTEM/FIBTEM A5, A10, and maximal clot formation (MCF), EXTEM/PLTEM (A5/A10, and MCF) and platelet count, and FIBTEM (A5/A10, and MCF) and fibrinogen were evaluated using the Pearson's correlation coefficient and receiver-operating characteristic curves. Turnaround times of ROTEM tests and conventional laboratory tests were assessed in the central laboratory.Measurements and Main Results: EXTEM AS and FIBTEM A5 showed an excellent correlation with A10 (R:0.99/1.00) and MCF (R:0.97/0.99). The correlation between EXTEM AS and platelet count (R:0.74) was comparable with the correlation of A10 (R:0.73) and MCF (R:0.70) with platelet count. FIBTEM AS predicted fibrinogen levels (R:0.87) as well as A10 (R:0.86) and MCF (R:0.87). PLTEM AS (R:0.85) correlated better with platelet count than EXTEM A5 (R:0.74; p = 0.04) and showed significantly better area under the curve values than EXTEM for predicting thrombocytopenia (A5 p = 0.012, A10 p = 0.019). Turnaround time for ROTEM tests, 12 minutes, was comparable with emergency requests for platelet count, 13 minutes, and shorter than emergency requests for fibrinogen levels, 37 minutes.Conclusions: Implementation of PLTEM and FIBTEM AS in ROTEM-guided transfusion protocols may improve transfusion management.

Item does not contain fulltext OBJECTIVE: Current stroke risk schemes need improvement of predictive value in patients with atrial fibrillation. Transoesophageal echocardiography (TEE) may facilitate stroke risk assessment in such patients and guide antithrombotic treatment. METHODS: We randomised 238 patients with non-valvular atrial fibrillation and a moderate stroke risk to aspirin or adjusted vitamin K antagonist therapy after TEE had ruled out thrombogenic features in the atria and aorta. The primary outcome was a composite of stroke, major bleeding, peripheral embolism and all-cause mortality. RESULTS: Mean CHA2DS2-VASc score was 2.1+/-1.1. The incidences of the composite primary outcome at a mean follow-up of 1.6 years were 3.2% (2.02% per year) in the aspirin group compared to 6.1% (3.84% per year) in the vitamin K antagonists group with an absolute advantage of 2.9 percentage points. Aspirin was non-inferior to vitamin K antagonists (p

Background: The ankle-brachial index (ABI) obtained after a treadmill challenge is often used to confirm the diagnosis of intermittent claudication (IC). However, some patients fail treadmill testing due to (temporary) orthopedic or neurologic comorbidity or fear of falling. The aim of this study was to evaluate the role of bicycle testing as an alternative for treadmill testing. It was hypothesized that ABIs obtained after bicycle tests were not different compared with values after standard treadmill testing. Methods: In this validation study, newly diagnosed IC patients (Rutherford 1-3) underwent a standard treadmill test (TT, "gold standard") and two bicycle protocols, one with a continuous resistance submaximal character (submaximal bicycle test, SBT) and a second with an incremental ramp form having a maximal character (maximal bicycle test, MBT). ABIs of both legs were obtained before and twice after each of these three different exercise tests. Healthy individuals matched for age and gender served as controls. Results: The study population consisted of 32 patients (68 +/- 11 years, 21 men). ABIs of each leg (n = 64) obtained after TT correlated significantly with values obtained after either bicycle test (TT vs. SBT: r = 0.90, P < 0.001; TT vs. MBT: r = 0.88, P < 0.001). Drops in ABI after both types of exercise were significantly correlated (TT vs. SBT: r = 0.66, P < 0.001; TT vs. MBT: r = 0.32, P < 0.01). A 98% sensitivity and 86% specificity for diagnosis of IC was observed after the SBT. After the MBT, these values were 98% and 43%, respectively. Healthy controls (n = 13) demonstrated ABI values >0.9 after cycling in all tests. Conclusions: Both submaximal and a maximal bicycle tests may serve as alternative noninvasive tools for detecting intermittent claudication. Bicycle tests can potentially be used for patients unable to perform a treadmill test.

Improved prognostic stratification of patients with TNM stage II colorectal cancer (CRC) is desired, since 20–30% of high-risk stage II patients may die within five years of diagnosis. This study was conducted to investigate REarranged during Transfection ( RET ) gene promoter CpG island methylation as a possible prognostic marker for TNM stage II CRC patients. The utility of RET promoter CpG island methylation in tumors of stage II CRC patients as a prognostic biomarker for CRC related death was studied in three independent series (including 233, 231, and 294 TNM stage II patients, respectively) by using MSP and pyrosequencing. The prognostic value of RET promoter CpG island methylation was analyzed by using Cox regression analysis. In the first series, analyzed by MSP, CRC stage II patients ( n = 233) with RET methylated tumors had a significantly worse overall survival as compared to those with unmethylated tumors (HR multivariable = 2.51, 95%-CI: 1.42–4.43). Despite a significant prognostic effect of RET methylation in stage III patients of a second series, analyzed by MSP, the prognostic effect in stage II patients ( n = 231) was not statistically significant (HR multivariable = 1.16, 95%-CI 0.71–1.92). The third series ( n = 294), analyzed by pyrosequencing, confirmed a statistically significant association between RET methylation and poor overall survival in stage II patients (HR multivariable = 1.91, 95%-CI: 1.04–3.53). Our results show that RET promoter CpG island methylation, analyzed by two different techniques, is associated with a poor prognosis in stage II CRC in two independent series and a poor prognosis in stage III CRC in one series. RET methylation may serve as a useful and robust tool for clinical practice to identify high-risk stage II CRC patients with a poor prognosis. This merits further investigation.

Background: Diagnosing epilepsy is a lengthy and burdensome process for patients and their family. Although the need for a more patient-centered approach in clinical practice is widely acknowledged, empirical evidence regarding patient preferences for diagnostic modalities in epilepsy is missing. The objectives of this study were 1) to identify to what extent important attributes of diagnostic procedures in epilepsy affect preferences for a procedure, 2) to determine the relative importance of these attributes, and 3) to calculate overall utility scores for routine electroencephalography (EEG) and magnetoencephalography (MEG) recordings.Methods: A discrete choice experiment was performed to determine patients' preferences, which involved presentation of pairwise choice tasks regarding hypothetical scenarios. Scenarios varied along six attributes: "way of measuring brain activity", "duration", "freedom of movement", "travel time", "type of additional examination", and "chance of additional examination". Choice tasks were constructed using a statistically efficient design, and the questionnaire contained 15 unique unlabeled choice tasks. Mixed multinomial logistic regression was used to estimate patients' preferences.Results: A total of 289 questionnaires were included in the analysis. McFadden's pseudo R-2 showed a model fit of 0.28, and all attributes were statistically significant. Heterogeneity in preferences was present for all attributes. "Freedom of movement" and "Chance of additional examination" were perceived as the most important attributes. Overall utility scores did not substantially differ between routine EEG and MEG.Conclusion: This study suggests that the identified attributes are important in determining patients' preference for epilepsy diagnostics. It can be concluded that MEG is not necessarily more patient-friendly than a routine EEG in primary diagnostics and, regarding additional diagnostics, patients have a strong preference for long-term 24-h EEG over EEG after sleep deprivation. Furthermore, barring substantial heterogeneity within the parameters in mind, our study suggests that it is important to take individual preferences into account in medical decision-making. (C) 2013 Elsevier Inc. All rights reserved.

Acrylamide, a probable human carcinogen, is present in heat-treated carbohydrate-rich foods. Epidemiological studies have not shown a clear association between acrylamide intake and colorectal cancer (CRC) risk. This may be due to the molecular heterogeneity in colorectal tumors, which was not taken into consideration before. Since the acrylamide metabolite glycidamide induces specific DNA mutations in rodents, we investigated whether acrylamide is associated with CRC risk characterized by mutations in Kirsten-ras (KRAS) and adenomatous polyposis coli (APC); key genes in colorectal carcinogenesis. This case-cohort analysis, within the Netherlands Cohort Study on diet and cancer, was based on 7.3 years of follow-up. Acrylamide intake was assessed with a food frequency questionnaire. Mutation analysis of codons 1286-1520 in exon 15 in APC and codons 12 and 13 in exon 1 in KRAS was performed on tumor tissue of 733 cases. Hazard ratios (HR) were calculated using Cox proportional hazards analysis. Among men, acrylamide intake was statistically significantly associated with an increased risk of particularly tumors with an activating KRAS mutation {HR fourth versus first quartile: 2.12 [95% confidence interval (CI): 1.16-3.87], P trend: 0.01}. Among women, acrylamide intake was statistically significantly associated with a decreased risk of particularly tumors with a truncating APC mutation (fourth versus first quartile: 0.47 (95% CI: 0.23-0.94), P trend: 0.02), but only in the highest quartile of intake. This is the first study to show that acrylamide might be associated with CRC with specific somatic mutations, differentially in men and women. More research is needed to corroborate or refute these findings.

Item does not contain fulltext OBJECTIVE: To develop and internally validate a model that predicts the outcome of an intended vaginal birth after caesarean (VBAC) for a Western European population that can be used to personalise counselling for deliveries at term. DESIGN: Registration-based retrospective cohort study. SETTING: Five university teaching hospitals, seven non-university teaching hospitals, and five non-university non-teaching hospitals in the Netherlands. POPULATION: A cohort of 515 women with a history of one caesarean section and a viable singleton pregnancy, without a contraindication for intended VBAC, who delivered at term. METHODS: Potential predictors for a vaginal delivery after caesarean section were chosen based on literature and expert opinions. We internally validated the prediction model using bootstrapping techniques. MAIN OUTCOME MEASURES: Predictors for VBAC. For model validation, the area under the receiver operating characteristic curve (AUC) for discriminative capacity and calibration-per-risk-quantile for accuracy were calculated. RESULTS: A total of 371 out of 515 women had a VBAC (72%). Variables included in the model were: estimated fetal weight greater than the 90(th) percentile in the third trimester; previous non-progressive labour; previous vaginal delivery; induction of labour; pre-pregnancy body mass index; and ethnicity. The AUC was 71% (95% confidence interval, 95% CI = 69-73%), indicating a good discriminative ability. The calibration plot shows that the predicted probabilities are well calibrated, especially from 65% up, which accounts for 77% of the total study population. CONCLUSION: We developed an appropriate Western European population-based prediction model that is aimed to personalise counselling for term deliveries.

Aim : To compare the health related quality of life (HRQOL) of long-term breast cancer survivors with and without breast cancer related lymphedema (BCRL) treated in the sentinel lymph node biopsy (SLNB) era. Methods : HRQOL was assessed as subject of a secondary analysis of data gathered for a study evaluating the prevalence of BCRL in long-term breast cancer survivors. The 145 women in this study cohort had undergone SLNB and or axillary, lymph node dissection (ALND) according to Dutch Breast cancer treatment guidelines. HRQOL was assessed using two questionnaires : the European Organization for Research and Treatment of Cancer Quality (QLQ-C30) and the Breast Cancer-specific Quality of life questionnaire (QLQ-BR23). Results : Twenty-six women, of whom 5 only underwent SLNB, were identified with objectively measured lymphedema and/or self-perceived arm swelling. Patients with BCRL scored significantly lower on the social (p = 0.000) functioning scale after adjustment for BMI and age compared to women without BCRL. Compared to normative data, women with BCRL scored significantly lower on social- (p

Background This population-based study aimed to evaluate trends in surgical approach for screen-detected cancer versus interval breast cancer, and to determine the factors associated with positive resection margins. Methods Screening mammograms of women aged 50–75 years, who underwent biennial screening in a Dutch breast-screening region between 1997 and 2011, were included. Patient and tumour characteristics were compared between women who underwent mastectomy or breast-conserving surgery (BCS) for screen-detected or interval cancer, and women with a negative or positive resection margin after BCS. Results Some 417 013 consecutive screening mammograms were included. A total of 2224 screen-detected and 825 interval cancers were diagnosed. The BCS rate remained stable (mean 6·1 per 1000 screened women; P = 0·099), whereas mastectomy rates increased significantly during the study from 0·9 (1997–1998) to 1·9 (2009–2010) per 1000 screened women (P < 0·001). The proportion of positive resection margins for invasive cancer was 19·6 and 7·6 per cent in 1997–1998 and 2009–2010 respectively (P < 0·001), with significant variation between hospitals. Dense breasts, preoperative magnetic resonance imaging, microcalcifications, architectural distortion, tumour size over 20 mm, axillary lymph node metastasis and treating hospital were independent risk factors for mastectomy. Interval cancer, image-guided tumour localization, microcalcifications, breast parenchyma asymmetry, tumour size greater than 20 mm, lobular tumour histology, low tumour grade, extensive invasive component and treating hospital were independent risk factors for positive resection margins. Conclusion Mastectomy rates doubled during a 14-year period of screening mammography and the proportion of positive resection margins decreased, with variation among hospitals. The latter observation stresses the importance of quality control programmes for hospitals treating women with breast cancer.

Background Between 20% and 42% of patients with clinically node-positive breast cancer achieve a pathologic complete response (pCR) of axillary lymph nodes after neoadjuvant chemotherapy or immunotherapy, or both, (chemo[immuno]therapy). Hypothetically, axillary lymph node dissection (ALND) may be safely omitted in these patients. This study aimed to develop a model for predicting axillary pCR in these patients. Patients and Methods We retrospectively identified patients with clinically node-positive breast cancer who were treated with neoadjuvant chemo(immuno)therapy and ALND between 2005 and 2012 in 5 hospitals. Patient and tumor characteristics, neoadjuvant chemo(immuno)therapy regimens, and pathology reports were extracted. Binary logistic regression analysis was used to predict axillary pCR with the following variables: age, tumor stage and type, hormone receptor and human epidermal growth factor receptor 2 (HER2) status, and administration of taxane and trastuzumab. The model was internally validated by bootstrap resampling. The overall performance of the model was assessed by the Brier score and the discriminative performance by receiver operating characteristic (ROC) curve analysis. Results A model was developed based on 291 patients and was internally validated with a scaled Brier score of 0.14. The area under the ROC curve of this model was 0.77 (95% confidence interval [CI], 0.71-0.82). At a cutoff value of predicted probability ≥ 0.50, the model demonstrated specificity of 88%, sensitivity of 43%, positive predictive value (PPV) of 65%, and negative predictive value (NPV) of 75%. Conclusion This prediction model shows reasonable accuracy for predicting axillary pCR. However, omitting axillary treatment based solely on the nomogram score is not justified. Further research is warranted to noninvasively identify patients with axillary pCR.

AimThe therapeutic options available to treat neonatal pain are limited, and one alternative for nonopioid systemic treatment is paracetamol. However, pharmacokinetic data from prolonged administration of intravenous paracetamol in neonates are limited. The aim of this study was to present pharmacokinetics after multiple dose of intravenous paracetamol in very preterm infants of

There is convincing evidence from both human and animal studies suggesting that the infant intestinal microbiota plays an important role in regulating immune responses associated with the development of allergic diseases. To date there are, however, still no definite bacterial taxa or particular subsets of the microbiota that have been consistently associated with allergic diseases, which is mainly attributable to the methodological dissimilarities between studies. As such there is a need to apply different methodological concepts to enhance a deeper and more refined understanding of the relationship between the gut microbiota and allergies. Within our recent studies we reported that colonization by clostridia in early infancy increased the risk of atopic dermatitis. Using subsequent mediation analysis, we demonstrated that birth mode and having older siblings strongly impacted the infant microbiota which in turn affected the risk of atopic dermatitis. The results of these mediation analyses contributed stronger evidence for a causal link of birth mode and birth order on allergy risk through modulation of the microbiota composition.

Background Over 50% of patients presenting to pain clinic with neck pain have the cervical facet joints as the source of pain. Radiofrequency (RF) treatment of the medial branch, innervating the facet joint, is a therapeutic option. The objectives of this study were to evaluate the therapeutic effect and its duration of RF treatment, using the single posterior-lateral approach in patients suffering from facet joint degeneration and to identify predictors for a long-term effect. Methods Of the 130 consecutive patients with axial neck pain referred to the University Pain Center Maastricht, 67 fulfilled the inclusion criteria. The therapeutic effect was measured using the Patients' Global Impression of Change (PGIC) scale. Retrospective data were made complete using newly collected PGIC follow-up data. A Kaplan–Meier curve evaluated the long-term therapeutic effect. Possible predictors of outcome were evaluated. Results Two patients refused to participate and in the remaining 65 patients, overall pain relief was reported in 55.4% at 2-month follow-up. Moderately, important change of improvement and substantial change of improvement were seen in 50.8% of patients. At 3-year follow-up, 30% still reported pain reduction. Spinal treatment level was the only predictor found. Conclusions Radiofrequency treatment of the cervical facet joints using a single posterior-lateral approach is a promising technique in patients with chronic neck pain due to facet degeneration. The short-term and long-term therapeutic effects of this intervention justify a randomized controlled trial to estimate the efficacy of cervical facet joint RF treatment in a chronic neck pain population.

In their Review, Roelof van Leeuwen and colleagues1 recommend various dose adjustments during concomitant use of tyrosine-kinase inhibitors and drugs that inhibit or induce cytochrome P450 3A4 (CYP3A4).1 Most information is taken from the US Food and Drug Administration (FDA)'s drug label or the European Medicines Agency (EMA)'s Summary of Product Characteristics. However, we could not find support for their advice regarding concomitant use of pazopanib and strong CYP3A4 inducers such as carbamazepine. They suggested to gradually increase the pazopanib dose in 200 mg steps depending on patient's tolerance,1 whereas both the FDA and EMA recommend that concomitant use should be avoided, and that the dose of pazopanib should not exceed 800 mg.2 and 3 We are unaware of clinical evidence for safety and efficacy of dose enhancement. By contrast, concomitant use and enhancement might result in carbamazepine toxic effects, because pazopanib can also act as a CYP3A4 inhibitor,2, 3 and 4 whereas carbamazepine is not only a CYP3A4 inducer, but also a CYP3A4 substrate with a narrow therapeutic index. We wonder which evidence supports the dosing guidelines that have been recommended by the authors.1 The Department of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences (employers of FV) has received unrestricted research funding from the Netherlands Organisation for Health Research and Development, the Dutch Health Insurance Board, the Royal Dutch Association for the Advancement of Pharmacy, the private–public funded Top Institute Pharma (EU Innovative Medicines Initiative, EU 7th Framework Program), the Dutch Medicines Evaluation Board, the Dutch Ministry of Health, and industry (GlaxoSmithKline, Pfizer, and others).

Objectives: The impact of postoperative complications after Major Abdominal Surgery (MAS) is substantial, especially when socio-economical aspects are taken into account. This systematic review focuses on the effects of preoperative exercise therapy (PEXT) on physical fitness prior to MAS, length of hospital admission and postoperative complications in patients eligible for MAS, and on what is known about the most effective kind of exercise regime. Methods: A systematic search identified randomised controlled trials on exercise therapy and pulmonary physiotherapy prior to MAS. The methodological quality of the included studies was rated using the 'Delphi List For Quality Assessment of Randomised Clinical Trials'. The level of agreement between the two reviewers was estimated with Cohen's kappa. Results: A total of 6 studies were included, whose methodological quality ranged from moderate to good. Cohen's kappa was 0.90. Three studies reported on improving physical fitness prior to MAS with the aid of PEXT. Two studies reported on the effect of training on postoperative complications, showing contradictory results. Three studies focused on the effect of preoperative chest physiotherapy on postoperative lung function parameters after MAS. While the effects seem positive, the optimal training regime is still unclear. Conclusion: Preoperative exercise therapy might be effective in improving the physical fitness of patients prior to major abdominal surgery, and preoperative chest physiotherapy seems effective in reducing pulmonary complications. However consensus on training method is lacking. Future research should focus on the method and effect of PEXT before high-risk surgical procedures. (C) 2013 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.

Introduction: Diabetic macular edema (DME) is a vision-threatening complication of diabetic retinopathy. The current practice of management is a" trial and error "method of using intravitreal antivascular endothelial growth factor (VEGF)'' or steroids to treat the patient and watch the response. However, if the patient's genetic profile helps us choose appropriate medicine, it would help customize treatment option for each patient. This forms the basis of our study. Materials and Methods: A case-control, prospective, observational series, where DME patients were treated with bevacizumab and subclassified as treatment naive, treatment responders, and treatment nonresponders. Blood samples of 20 subjects were studied, with five patients in each of the groups (nondiabetic-group 1, treatment naive-group 2, treatment responder-group 3, and treatment nonresponder-group 4). Whole blood RNA extraction followed by labeling, amplification and hybridization was done, and microarray data analyzed. Genes were classified based on functional category and pathways. Results: The total number of genes upregulated among all three experimental groups was 5, whereas 105 genes were downregulated. There were no common genes upregulated between the responders and nonresponders. There was only one gene upregulated between the diabetic and diabetic responders posttreatment. There were 19 genes upregulated and 8 genes downregulated in the inflammatory pathway in group 2 versus group 1. There were no downregulated genes detected in vascular angiogenesis and transcription group. There were identical numbers of genes up-and downregulated in the inflammatory pathway. Seventeen genes were upreguated and 11 genes downregulated in receptor activity, which remained the predominant group in the group classification. Discussion: In summary, this study would provide an insight into the probable signaling mechanisms for disease pathogenesis as well as progression. This type of study eventually would aid in developing or improvising existing treatment modules with a rational approach towards personalized medicine, in future addressing the differential responses to treatment.

Epicardial adipose tissue (EAT) is emerging as a risk factor for coronary artery disease (CAD).The aim of this study was to determine the applicability and efficiency of automated EAT quantification.EAT volume was assessed both manually and automatically in 157 patients undergoing coronary CT angiography. Manual assessment consisted of a short-axis-based manual measurement, whereas automated assessment on both contrast and non-contrast-enhanced data sets was achieved through novel prototype software. Duration of both quantification methods was recorded, and EAT volumes were compared with paired samples t test. Correlation of volumes was determined with intraclass correlation coefficient; agreement was tested with Bland-Altman analysis. The association between EAT and CAD was estimated with logistic regression.Automated quantification was significantly less time consuming than automated quantification (17 ? 2 seconds vs 280 ? 78 seconds; P

Item does not contain fulltext OBJECTIVE: To externally validate two models from the USA (entry-to-care [ETC] and close-to-delivery [CTD]) that predict successful intended vaginal birth after caesarean (VBAC) for the Dutch population. DESIGN: A nationwide registration-based cohort study. SETTING: Seventeen hospitals in the Netherlands. POPULATION: Seven hundred and sixty-three pregnant women, each with one previous caesarean section and a viable singleton cephalic pregnancy without a contraindication for an intended VBAC. METHODS: The ETC model comprises the variables maternal age, prepregnancy body mass index (BMI), ethnicity, previous vaginal delivery, previous VBAC and previous nonprogressive labour. The CTD model replaces prepregnancy BMI with third-trimester BMI and adds estimated gestational age at delivery, hypertensive disease of pregnancy, cervical examination and induction of labour. We included consecutive medical records of eligible women who delivered in 2010. For validation, individual probabilities of women who had an intended VBAC were calculated. MAIN OUTCOME MEASURES: Discriminative performance was assessed with the area under the curve (AUC) of the receiver operating characteristic and predictive performance was assessed with calibration plots and the Hosmer-Lemeshow (H-L) statistic. RESULTS: Five hundred and fifteen (67%) of the 763 women had an intended VBAC; 72% of these (371) had an actual VBAC. The AUCs of the ETC and CTD models were 68% (95% CI 63-72%) and 72% (95% CI 67-76%), respectively. The H-L statistic showed a P-value of 0.167 for the ETC model and P = 0.356 for the CTD model, indicating no lack of fit. CONCLUSION: External validation of two predictive models developed in the USA revealed an adequate performance within the Dutch population.

Substantial inter-observer variability in screening mammography interpretation has been reported at single reading. However, screening results of pairs of screening radiologists have not yet been published. We determined variations in screening performances among pairs of screening radiologists at non-blinded double reading. We included pairs of screening radiologists with at least 7,500 screening examinations per pair, obtained between 1997 and 2011. During 2-year follow-up, breast imaging reports, surgical reports and pathology results were collected of all referred women and interval cancers. Referral rate, cancer detection rate, positive predictive value and sensitivity were calculated for each pair. A total of 310,906 screening mammograms, read by 26 pairs of screening radiologists, were included for analysis. The referral rate ranged from 1.0 % (95 % CI 0.8 %–1.2 %) to 1.5 % (95 % CI 1.3 %–1.8 %), the cancer detection rate from 4.0 (95 % CI 2.8–5.2) to 6.3 (95 % CI 4.5–8.0) per 1,000 screens. The programme sensitivity and positive predictive value of referral ranged from 55.1 % (95 % CI 45.1 %–65.1 %) to 81.5 % (95 % CI 73.4 %–89.6 %) and from 28.7 % (95 % CI 20.8 %–36.6 %) to 49.5 % (95 % CI 39.7 %–59.3 %), respectively. We found significant variations in screening outcomes among pairs of screening radiologists at non-blinded double reading. This stresses the importance of monitoring screening results on a local scale. • Substantial inter-observer variability in screening mammography interpretation is known at single reading • Population-based study showed significant variations in outcomes among pairs of screening radiologists • Local monitoring and regular feedback are important to optimise screening outcome

Background: Strong opioids in the home setting after ambulatory surgery have rarely been studied for fear of hazardous adverse effects such as respiratory depression. Objectives: We compared the efficacy of paracetamol/controlled-release (CR) oxycodone and paracetamol/naproxen for treatment of acute postoperative pain at home after ambulatory surgery. Secondary outcomes were adverse effects of study medication, treatment satisfaction, and postoperative analgesic compliance. Methods: Patients undergoing ambulatory knee arthroscopy or inguinal hernia repair surgery (n = 105) were randomized into 3 groups: Group1 paracetamol/naproxen (n = 35), Group 2 paracetamol/CR oxycodone for 24 hours (n = 35), and Group 3 paracetamol/CR oxycodone for 48 hours (n = 35). Pain intensity at movement and at rest using a visual analog scale as well as satisfaction with postoperative analgesia and side effects were recorded for up to 48 hours postoperatively. Compliance with study medication was also assessed. Results: For pain at movement and at rest, no significant differences were found between the paracetamol/naproxen group and either the paracetamol/CR oxycodone for 24 hours group (β = 2.6 [4.9]; P = 0.597) or the paracetamol/CR oxycodone for 48 hours (β = –1.7 [5.1]; P = 0.736). No major adverse effects of study medication were registered and satisfaction with postoperative pain treatment was high in all groups. Compliance was comparable across the groups. Despite clear instructions, 8 patients with the lowest pain scores did not use any of the prescribed pain medication. Conclusions: Paracetamol/CR oxycodone and paracetamol/naproxen are equally effective in treatment of acute postoperative pain at home after ambulatory surgery with comparable patient satisfaction level. We suggest paracetamol/CR oxycodone to be a valuable alternative for the current paracetamol/naproxen gold standard, particularly in patients with a contraindication for nonsteroidal anti-inflammatory drugs. ClinicalTrials.gov identifier: NCT02152592.

Purpose: To investigate the stability in position of the Baerveldt glaucoma drainage tube over time and to study movement of the drainage tube in the anterior chamber (AC) under varying light conditions.Methods: This prospective study included 70 eyes with implantation of a Baerveldt glaucoma drainage tube in the anterior chamber. Anterior segment optical coherence tomography (AS-OCT) images were made preoperatively to quantify AC depth. AS-OCT images were made twice under photopic and twice under scotopic conditions, in the angle parallel to the Baerveldt tube to quantify drainage tube position, at 3, 6, 12, and 24 months postoperatively. Tube-corneal (T-C) and tube-iris (T-I) distances were measured. Additionally, the central AC depth and the peripheral angle opening (AOD 500) were determined. Two subgroups were distinguished according to tube position: free in the AC (group 1, n = 48) and transiridal (group 2, n = 22).Results: After 24 months of follow-up, the drainage tube was found to move statistically significantly closer (0.12 mm) to the corneal endothelium in group 1 (pConclusions: The Baerveldt glaucoma drainage tube remained in a stable position when a transiridal implantation was performed, whereas the tube moved closer to the endothelium when placed free into the AC. Transiridal implantation of the Baerveldt tube seems a safe alternative for tube implantation with respect to tube motility.

There is controversy on the preferred mode of delivery (vaginal delivery (VD) versus caesarean section (CS)) in preterm breech delivery in relation to neonatal outcome. While CS is supposed to be safer for the fetus, arguments against CS can be the increased risk of maternal morbidity, risks for future pregnancies, and costs. Moreover, neonatal respiratory distress syndrome occurs more frequently after CS compared to VD.In the past, several RCTs have been started on this subject, but they were all preliminary and stopped due to recruitment difficulties. As the Cochrane review of these RCT's reported on 116 women only, knowledge on the effectiveness of CS and VD can at present only be obtained from non-randomized studies.We performed a systematic review and meta-analysis of non-randomized studies that assessed the association between mode of delivery and neonatal mortality in women with preterm breech presentation. We searched Pubmed, Embase and the Cochrane library for articles comparing neonatal mortality after VD versus CS in preterm breech presentation (gestational age 25(+0) till 36(+6) weeks). Seven studies, involving a total of 3557 women, met the eligibility criteria and were included in this systematic review. The weighted risk of neonatal mortality was 3.8% in the CS group and 11.5% in the VD group (pooled RR 0.63 (95% CI 0.48-0.81)). We conclude that cohort studies indicate that CS reduces neonatal mortality as compared to (C). 2013 Elsevier Ireland Ltd. All rights reserved.

Background: We investigated body size, physical activity, and early-life energy restriction in relation to colorectal tumors with and without methylated insulin-like growth factor–binding protein (IGFBP) genes, which are putative tumor-suppressor genes. Methods: We determined IGFBP2, IGFBP3, and IGFBP7 promoter CpG island hypermethylation in tumors of 733 colorectal cancer cases from the Netherlands Cohort Study (N = 120,852). Participants self-reported lifestyle and dietary factors at baseline in 1986. Using a case–cohort approach (N subcohort = 5,000), we estimated hazard ratios (HR) for colorectal cancer by extent of IGFBP methylation. Results: Comparison of the highest versus lowest sex-specific tertiles of adult body mass index (BMI) gave multivariable-adjusted HRs [95% confidence intervals (CI)] for colorectal cancers with 0 (18.7%), 1 (29.5%), 2 (32.4%), and 3 (19.5%) methylated genes of 1.39 (0.88–2.19), 1.11 (0.77–1.62), 1.67 (1.17–2.38), and 2.07 (1.29–3.33), respectively. Other anthropometric measures and physical activity were not associated with colorectal cancer risk by extent of IGFBP methylation, except height in sex-specific analyses for women. Exposure to energy restriction during the Dutch Hunger Winter versus nonexposure gave HRs (95% CIs) for colorectal cancers with 0, 1, 2, and 3 methylated genes of 1.01 (0.67–1.53), 1.03 (0.74–1.44), 0.72 (0.52–0.99), and 0.50 (0.32–0.78), respectively. Conclusions: Adult BMI, height (in women only), and early-life energy restriction were associated with the risk of having a colorectal tumor characterized by IGFBP methylation. Impact: Body size may particularly increase the risk of IGFBP gene–methylated colorectal tumors; this finding might facilitate more targeted approaches to prevent obesity-related colorectal cancers. Cancer Epidemiol Biomarkers Prev; 23(9); 1852–62. ©2014 AACR.

Background: Coinciding with the relatively good and improving prognosis for patients with stage I-III breast cancer, late recurrences, new primary tumours and late side-effects of treatment may occur. We gained insight into prognosis for long-term breast cancer survivors.Patients and methods: Data on all 205 827 females aged 15-89 diagnosed with stage I-III breast cancer during 1989-2008 were derived from the Netherlands Cancer Registry. Conditional 5-year relative survival was calculated for every subsequent year from diagnosis up to 15 years.Results: For stage I, conditional 5-year relative survival remained similar to 95% up to 15 years after diagnosis (a stable 5-year excess mortality rate of 5%). For stage II, excess mortality remained 10% for those aged 15-44 or 45-59 and 15% for those aged 60-74. For stage III, excess mortality decreased from 35% at diagnosis to 10% at 15 years for those aged 15-44 or 45-59, and from similar to 40% to 30% for those aged >= 60.Conclusions: Patients with stage I or II breast cancer had a (very) good long-term prognosis, albeit exhibiting a small but significant excess mortality at least up to 15 years after diagnosis. Improvements albeit from a lower level were mainly seen for patients who had been diagnosed with stage III disease. Caregivers can use this information to better inform (especially disease-free) cancer survivors about their actual prognosis.

Background A recent noninferiority randomized trial showed that in terms of clinical effectiveness imiquimod was superior and topical fluorouracil noninferior to methylaminolaevulinate photodynamic therapy (MAL-PDT) for treatment of superficial basal-cell carcinoma (sBCC). Although it was expected that MAL-PDT would be more costly than either cream, a full cost-effectiveness analysis is necessary to determine the balance between effectiveness and costs.Objective To determine whether imiquimod or topical fluorouracil are cost-effective treatments for sBCC compared with MAL-PDT.Methods An economic evaluation was performed from a healthcare perspective. Data on resource use and costs were collected alongside the randomized clinical trial. The incremental cost-effectiveness ratio was expressed as the incremental costs per additional patient free of tumour recurrence.Results At 12 months follow-up, the total mean costs for MAL-PDT were (sic)680, for imiquimod cream (sic)526 and for topical fluorouracil cream (sic)388. Both imiquimod and topical fluorouracil were cost-effective treatments compared with MAL-PDT. Comparing costs and effectiveness of both creams led to a incremental investment of (sic)4451 to achieve an additional patient free of tumour recurrence. The acceptability curve showed that, for a threshold value of _ 4451, the probability of imiquimod being more cost-effective than topical fluorouracil was 50%.Conclusion Based on the 12 months follow-up results, imiquimod and topical fluorouracil cream are more cost-effective than MAL-PDT for treatment of sBCC. Hence, substituting MAL-PDT with either imiquimod or topical fluorouracil results in cost savings; these savings will be larger for topical fluorouracil. Longterm follow-up effectiveness data are necessary to confirm the cost-effectiveness of imiquimod vs. topical 5-fluorouracil cream.

Background Results in breast cancer research are reported using study endpoints. Most are composite endpoints (such as locoregional recurrence), consisting of several components (for example local recurrence) that are in turn composed of specific events (such as skin recurrence). Inconsistent endpoint selection and definition might lead to unjustified conclusions when comparing study outcomes. This study aimed to determine which locoregional endpoints are used in breast cancer studies, and how these endpoints and their components are defined. Methods PubMed was searched for breast cancer studies published in nine leading journals in 2011. Articles using endpoints with a local or regional component were included and definitions were compared. Results Twenty-three different endpoints with a local or regional component were extracted from 44 articles. Most frequently used were disease-free survival (25 articles), recurrence-free survival (7), local control (4), locoregional recurrence-free survival (3) and event-free survival (3). Different endpoints were used for similar outcomes. Of 23 endpoints, five were not defined and 18 were defined only partially. Of these, 16 contained a local and 13 a regional component. Included events were not specified in 33 of 57 (local) and 27 of 50 (regional) cases. Definitions of local components inconsistently included carcinoma in situ and skin and chest wall recurrences. Regional components inconsistently included specific nodal sites and skin and chest wall recurrences. Conclusion Breast cancer studies use many different endpoints with a locoregional component. Definitions of endpoints and events are either not provided or vary between trials. To improve transparency, facilitate trial comparison and avoid unjustified conclusions, authors should report detailed definitions of all endpoints.

International audience; IMPORTANCE: D-dimer measurement is an important step in the diagnostic strategy of clinically suspected acute pulmonary embolism (PE), but its clinical usefulness is limited in elderly patients. OBJECTIVE: To prospectively validate whether an age-adjusted D-dimer cutoff, defined as age × 10 in patients 50 years or older, is associated with an increased diagnostic yield of D-dimer in elderly patients with suspected PE. DESIGN, SETTINGS, AND PATIENTS: A multicenter, multinational, prospective management outcome study in 19 centers in Belgium, France, the Netherlands, and Switzerland between January 1, 2010, and February 28, 2013. INTERVENTIONS: All consecutive outpatients who presented to the emergency department with clinically suspected PE were assessed by a sequential diagnostic strategy based on the clinical probability assessed using either the simplified, revised Geneva score or the 2-level Wells score for PE; highly sensitive D-dimer measurement; and computed tomography pulmonary angiography (CTPA). Patients with a D-dimer value between the conventional cutoff of 500 µg/L and their age-adjusted cutoff did not undergo CTPA and were left untreated and formally followed-up for a 3-month period. MAIN OUTCOMES AND MEASURES: The primary outcome was the failure rate of the diagnostic strategy, defined as adjudicated thromboembolic events during the 3-month follow-up period among patients not treated with anticoagulants on the basis of a negative age-adjusted D-dimer cutoff result. RESULTS: Of the 3346 patients with suspected PE included, the prevalence of PE was 19%. Among the 2898 patients with a nonhigh or an unlikely clinical probability, 817 patients (28.2%) had a D-dimer level lower than 500 µg/L (95% CI, 26.6%-29.9%) and 337 patients (11.6%) had a D-dimer between 500 µg/L and their age-adjusted cutoff (95% CI, 10.5%-12.9%). The 3-month failure rate in patients with a D-dimer level higher than 500 µg/L but below the age-adjusted cutoff was 1 of 331 patients (0.3% [95% CI, 0.1%-1.7%]). Among the 766 patients 75 years or older, of whom 673 had a nonhigh clinical probability, using the age-adjusted cutoff instead of the 500 µg/L cutoff increased the proportion of patients in whom PE could be excluded on the basis of D-dimer from 43 of 673 patients (6.4% [95% CI, 4.8%-8.5%) to 200 of 673 patients (29.7% [95% CI, 26.4%-33.3%), without any additional false-negative findings. CONCLUSIONS AND RELEVANCE: Compared with a fixed D-dimer cutoff of 500 µg/L, the combination of pretest clinical probability assessment with age-adjusted D-dimer cutoff was associated with a larger number of patients in whom PE could be considered ruled out with a low likelihood of subsequent clinical venous thromboembolism. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01134068.

Objective: To investigate whether an adverse body composition is associated with endothelial dysfunction (ED) and the extent to which any such association could be explained by low-grade inflammation (LGI) and/or insulin resistance (HOMA2-IR). Methods: We studied 475 individuals from the Hoorn Study [mean (range) age, 68.9 (60-87) years, 245 women). Body composition was assessed by whole body dual-energy absorptiometry. Endothelial dysfunction was measured functionally, by flow-mediated dilation (FMD) and by circulating biomarkers. Associations were examined with multiple linear regression models and mediation analyses according to the ab product of coefficients method. Results: After adjustment for age, sex, glucose metabolism status, prior cardiovascular disease and lifestyle factors, total and central fat mass were positively associated with the ED score [beta = 0.16 (95% CI 0.04-0.29) and b 0.18 (0.05-0.31), respectively] and inversely, although not statistically significantly, with FMD. Peripheral fat mass was not associated with the ED score or FMD. There was a significant favourable association between peripheral lean mass and FMD [beta = 0.13 (0.00-0.26)], but not with the ED score. The association between total and central fat mass and the ED score was, to a great extent, mediated by LGI and HOMA2-IR. In contrast, LGI or HOMA2-IR did not mediate the association between peripheral lean mass and FMD. Conclusion: Higher levels of central, but not peripheral fat mass were adversely associated with ED, which was attributable to body composition-related LGI and insulin resistance. In contrast, peripheral lean mass was beneficially associated with ED, but this seemed to be unrelated to LGI or insulin resistance. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

Item does not contain fulltext Responsiveness to tumour necrosis factor (TNF) inhibitors has been associated with the TNF-alpha G-308A polymorphism in rheumatoid arthritis. The aim of this study was to examine the association between the presence of this polymorphism and the response to TNF inhibitors in patients with refractory sarcoidosis. Patients (n=111) who started TNF-inhibitor treatment (76 infliximab, 35 adalimumab) were followed for at least 1 year. The main symptoms in these patients were fatigue (n=100, 90.1%), small fibre neuropathy (n=91, 82.0%), pulmonary involvement (n=69, 62.2%), and/or uveitis (n=31, 27.9%). Patients were additionally genotyped for the presence of the TNF-alpha G-308A polymorphism. Treatment response was assessed using clinical outcome measures and questionnaires. Three-quarters (n=83, 74.8%) of the patients responded well. Of the patients without the variant A-allele 93.6% (73 out of 78, p

Summary The histopathology of premalignant laryngeal lesions does not provide reliable information on the risk of malignant transformation, hence we examined new molecular markers which can easily be implemented in clinical practice. Dual-target fluorescence in situ hybridisation (FISH) for chromosome 1 and 7 centromeres was performed on tissue sections of laryngeal premalignancies in 69 patients. Chromosome instability was indicated by numerical imbalances and/or polysomy for chromosomes 1 and 7. Additionally immuno-stainings for p53, Cyclin D1 and (p)FADD expression were evaluated. Malignant progression was recorded. Eighteen patients with carcinoma in situ (CIS) were treated after diagnosis and excluded from follow-up. Chromosome instability was strongly associated with a high risk of malignant transformation, especially in lower grade lesions (hyperplasia, mild and moderate dysplasia; odds ratio = 8.4, p = 0.004). Patients with lesions containing chromosome instability showed a significantly worse 5-year progression-free survival than those with premalignancies without chromosome instability ( p = 0.002). Neither histopathology nor the protein markers predicted progression in univariate analysis, although histo-pathological diagnosis, p53 and FADD contributed positively to chromosome instability in multivariate analysis. Chromosome instability is associated with malignant progression of laryngeal premalignancies, especially in lower grade lesions. These results may contribute to better risk counselling, provided that they can be validated in a larger patient set.

IntroductionIn most breast screening programmes screen-film mammography (SFM) has been replaced by full-field digital mammography (FFDM). We compared interval cancer characteristics at SFM and FFDM screening mammography.Patients and methodsWe included all 297 screen-detected and 104 interval cancers in 60,770 SFM examinations and 427 screen-detected and 124 interval cancers in 63,182 FFDM examinations, in women screened in the period 2008–2010. Breast imaging reports, biopsy results and surgical reports of all cancers were collected. Two radiologists reviewed prior and diagnostic mammograms of all interval cancers. They determined breast density, described mammographic abnormalities and classified interval cancers as missed, showing a minimal sign abnormality or true negative.ResultsThe referral rate and cancer detection at SFM were 1.5% and 4.9‰ respectively, compared to 3.0% (p < 0.001) and 6.6‰ (p < 0.001) at FFDM. Screening sensitivity was 74.1% at SFM (297/401, 95% confidence interval (CI) = 69.8–78.4%) and 77.5% at FFDM (427/551, 95% CI = 74.0–81.0%). Significantly more interval cancers were true negative at prior FFDM than at prior SFM screening mammography (65.3% (81/124) versus 47.1% (49/104), p = 0.02). For interval cancers following SFM or FFDM screening mammography, no significant differences were observed in breast density or mammographic abnormalities at the prior screen, tumour size, lymph node status, receptor status, Nottingham tumour grade or surgical treatment (mastectomy versus breast conserving therapy).ConclusionFFDM resulted in a significantly higher cancer detection rate, but sensitivity was similar for SFM and FFDM. Interval cancers are more likely to be true negative at prior FFDM than at prior SFM screening mammography, whereas their tumour characteristics and type of surgical treatment are comparable.Keywords: Breast cancer, Digital mammography, Interval cancer, Referral rate, Screening mammography, Sensitivity