Olaf M. Dekkers

Mediastinoscopy vs endosonography for mediastinal nodal staging of lung cancer: a randomized trial.

CONTEXT Mediastinal nodal staging is recommended for patients with resectable non-small cell lung cancer (NSCLC). Surgical staging has limitations, which results in the performance of unnecessary thoracotomies. Current guidelines acknowledge minimally invasive endosonography followed by surgical staging (if no nodal metastases are found by endosonography) as an alternative to immediate surgical staging. OBJECTIVE To compare the 2 recommended lung cancer staging strategies. DESIGN, SETTING, AND PATIENTS Randomized controlled multicenter trial (Ghent, Leiden, Leuven, Papworth) conducted between February 2007 and April 2009 in 241 patients with resectable (suspected) NSCLC in whom mediastinal staging was indicated based on computed or positron emission tomography. INTERVENTION Either surgical staging or endosonography (combined transesophageal and endobronchial ultrasound [EUS-FNA and EBUS-TBNA]) followed by surgical staging in case no nodal metastases were found at endosonography. Thoracotomy with lymph node dissection was performed when there was no evidence of mediastinal tumor spread. MAIN OUTCOME MEASURES The primary outcome was sensitivity for mediastinal nodal (N2/N3) metastases. The reference standard was surgical pathological staging. Secondary outcomes were rates of unnecessary thoracotomy and complications. RESULTS Two hundred forty-one patients were randomized, 118 to surgical staging and 123 to endosonography, of whom 65 also underwent surgical staging. Nodal metastases were found in 41 patients (35%; 95% confidence interval [CI], 27%-44%) by surgical staging vs 56 patients (46%; 95% CI, 37%-54%) by endosonography (P = .11) and in 62 patients (50%; 95% CI, 42%-59%) by endosonography followed by surgical staging (P = .02). This corresponded to sensitivities of 79% (41/52; 95% CI, 66%-88%) vs 85% (56/66; 95% CI, 74%-92%) (P = .47) and 94% (62/66; 95% CI, 85%-98%) (P = .02). Thoracotomy was unnecessary in 21 patients (18%; 95% CI, 12%-26%) in the mediastinoscopy group vs 9 (7%; 95% CI, 4%-13%) in the endosonography group (P = .02). The complication rate was similar in both groups. CONCLUSIONS Among patients with (suspected) NSCLC, a staging strategy combining endosonography and surgical staging compared with surgical staging alone resulted in greater sensitivity for mediastinal nodal metastases and fewer unnecessary thoracotomies. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00432640.

European Society of Clinical Microbiology and Infectious Diseases (ESCMID): Data review and recommendations for diagnosing Clostridium difficile-infection (CDI)

The aim of the present systematic review was to evaluate the available evidence on laboratory diagnosis of CDI and to formulate recommendations to optimize CDI testing. In comparison with cell culture cytotoxicity assay (CCA) and toxigenic culture (TC) of stools, we analyzed the test characteristics of 13 commercial available enzyme immunoasssays (EIA) detecting toxins A and/or B, 4 EIAs detecting Clostridium difficile glutamate dehydrogenase (GDH), and a real-time PCR for C. difficile toxin B gene. In comparison with CCA and TCA and assuming a prevalence of CDI of 5%, PPV and NPV varied between 0.28-0.77, 0.12-0.65 and 0.98-1.00, 0.97-1.00, respectively. Only if the tests were performed in a population with a CDI prevalence of 50 percent, would PPVs be acceptable (ranging from 0.71 to 1.00).To overcome the problem of a low PPV, we propose a two step approach, with a second test or a reference method in case of a positive first test. Further reducing the number of false negative results would require either retesting of all subjects with a negative first test, or re-testing all subjects with a negative second test, after an initially positive test. This approach resulted in non-significant improvements, and emphasizes the need for better diagnostic tests. Further studies to validate the applicability of two-step testing, including assessment of clinical features, are required.

Effectiveness and safety of novel oral anticoagulants as compared with vitamin K antagonists in the treatment of acute symptomatic venous thromboembolism: a systematic review and meta‐analysis

New direct oral anticoagulants (NOACs) constitute a novel treatment option for acute venous thromboembolism (VTE), with practical advantages. Individual studies have demonstrated comparable efficacy to that of vitamin K antagonists (VKAs) and have suggested a more favorable safety profile . We performed a meta‐analysis to determine the efficacy and safety of NOACs as compared with those of VKAs in patients with acute VTE.

PCOS, coronary heart disease, stroke and the influence of obesity: a systematic review and meta-analysis

BACKGROUND Patients with polycystic ovary syndrome (PCOS) are at risk of arterial disease. We examined the risk of (non)fatal coronary heart disease (CHD) or stroke in patients with PCOS and ovulatory women without PCOS, and assessed whether obesity might explain a higher risk of CHD or stroke. METHODS We performed a systematic review and meta-analysis of controlled observational studies. Four definitions of PCOS were considered: World Health Organization type II anovulation, National Institutes of Health criteria, Rotterdam consensus and Androgen-excess criteria. Obesity was defined as BMI > 30 kg/m(2) and/or waist circumference >88 cm. Study quality was assessed using the Newcastle-Ottawa Scale. Primary outcome was fatal/non-fatal CHD or stroke. Definitions of CHD and stroke were based on criteria used by the various authors. The effect measure was the pooled relative risk in a random effects model. Risk ratios and rate ratios were combined here. RESULTS After identifying 1340 articles, 5 follow-up studies published between 2000 and 2008 were included. The studies showed heterogeneity in design, definitions and quality. In a random effects model the relative risk for CHD or stroke were 2.02 comparing women with PCOS to women without PCOS (95% confidence interval 1.47, 2.76). Pooling the two studies with risk estimates adjusted for BMI showed a relative risk of 1.55 (1.27, 1.89). CONCLUSIONS This meta-analysis showed a 2-fold risk of arterial disease for patients with PCOS relative to women without PCOS. BMI adjustment did not affect this finding, suggesting the increased risk for cardiovascular events in PCOS is not completely related to a higher BMI in patients with PCOS.

Time interval of increased risk for Clostridium difficile infection after exposure to antibiotics

BACKGROUND Clostridium difficile infections (CDIs) are common in developed countries and affect >250,000 hospitalized patients annually in the USA. The most important risk factor for the disease is antibiotic therapy. METHODS To determine the period at risk for CDI after cessation of antibiotics, we performed a multicentre case-control study in the Netherlands between March 2006 and May 2009. Three hundred and thirty-seven hospitalized patients with diarrhoea and a positive toxin test were compared with 337 patients without diarrhoea. Additionally, a control group of patients with diarrhoea due to a cause other than CDI (n=227) was included. RESULTS In the month prior to the date of inclusion, CDI patients more frequently used an antibiotic compared with non-diarrhoeal patients (77% versus 49%). During antibiotic therapy and in the first month after cessation of the therapy, patients had a 7-10-fold increased risk for CDI (OR 6.7-10.4). This risk declined in the period between 1 and 3 months after the antibiotic was stopped (OR 2.7). Similar results were observed when the second control group was used. All antibiotic classes, except first-generation cephalosporins and macrolides, were associated with CDI. Second- and third-generation cephalosporins (OR 3.3 and 5.3, respectively) and carbapenems (OR 4.7) were the strongest risk factors for CDI. Patients with CDI used more antibiotic classes and more defined daily doses, compared with non-diarrhoeal patients. CONCLUSIONS Antibiotic use increases the risk for CDI during therapy and in the period of 3 months after cessation of antibiotic therapy. The highest risk for CDI was found during and in the first month after antibiotic use. Our study will aid clinicians to identify high-risk patients.

Different combined oral contraceptives and the risk of venous thrombosis: systematic review and network meta-analysis

Objective To provide a comprehensive overview of the risk of venous thrombosis in women using different combined oral contraceptives. Design Systematic review and network meta-analysis. Data sources PubMed, Embase, Web of Science, Cochrane, Cumulative Index to Nursing and Allied Health Literature, Academic Search Premier, and ScienceDirect up to 22 April 2013. Review methods Observational studies that assessed the effect of combined oral contraceptives on venous thrombosis in healthy women. The primary outcome of interest was a fatal or non-fatal first event of venous thrombosis with the main focus on deep venous thrombosis or pulmonary embolism. Publications with at least 10 events in total were eligible. The network meta-analysis was performed using an extension of frequentist random effects models for mixed multiple treatment comparisons. Unadjusted relative risks with 95% confidence intervals were reported. The requirement for crude numbers did not allow adjustment for potential confounding variables. Results 3110 publications were retrieved through a search strategy; 25 publications reporting on 26 studies were included. Incidence of venous thrombosis in non-users from two included cohorts was 1.9 and 3.7 per 10 000 woman years, in line with previously reported incidences of 1-6 per 10 000 woman years. Use of combined oral contraceptives increased the risk of venous thrombosis compared with non-use (relative risk 3.5, 95% confidence interval 2.9 to 4.3). The relative risk of venous thrombosis for combined oral contraceptives with 30-35 µg ethinylestradiol and gestodene, desogestrel, cyproterone acetate, or drospirenone were similar and about 50-80% higher than for combined oral contraceptives with levonorgestrel. A dose related effect of ethinylestradiol was observed for gestodene, desogestrel, and levonorgestrel, with higher doses being associated with higher thrombosis risk. Conclusion All combined oral contraceptives investigated in this analysis were associated with an increased risk of venous thrombosis. The effect size depended both on the progestogen used and the dose of ethinylestradiol.

Risk of Recurrent Venous Thromboembolism and Mortality in Patients With Cancer Incidentally Diagnosed With Pulmonary Embolism: A Comparison With Symptomatic Patients

PURPOSE The routine use of modern computed tomography scanners has led to an increased detection of incidental pulmonary embolism (PE), in particular in patients with cancer. The clinical relevance of these incidental findings is unknown. PATIENTS AND METHODS In this retrospective cohort study, oncology patients in whom PE was objectively proven between 2004 and 2010 and anticoagulant treatment was started, were included. Fifty-one patients with incidental PE and 144 with symptomatic PE were observed for 1 year to compare the risks of recurrent venous thromboembolism (VTE), bleeding complications, and mortality. Kaplan-Meier and Cox survival analyses were performed. RESULTS Incidental and symptomatic patients did not differ with respect to mean age, sex, cancer type and stage, and risk factors for VTE. As a result from evolving treatment guidelines, approximately half of the patients in both groups received long-term treatment with vitamin K antagonists in stead of currently recommended low-molecular-weight heparin. The 12-month cumulative incidence of recurrent VTE was 13.3% in the incidental group versus 16.9% in the symptomatic group (P = .77). Notably, 20% VTE events recurred after premature termination of anticoagulant therapy. The risk of major bleeding complications was also comparable in the two groups (12.5% for incidental patients and 8.6% for symptomatic patients; P = .5). The respective 12-month mortality risks were 52.9% and 53.3% (P = .7). CONCLUSION Our findings suggest that oncology patients diagnosed with and treated for incidental PE, have similar high rates of recurrent VTE, bleeding complications, and mortality, as compared with oncology patients who develop symptomatic PE.

Atypical fractures and bisphosphonate therapy: A cohort study of patients with femoral fracture with radiographic adjudication of fracture site and features

Atypical subtrochanteric/femoral shaft (ST/FS) fractures are increasingly reported in patients on long-term treatment with bisphosphonates (BPs). We estimated the frequency of atypical fractures and their association to BP use in patients aged ≥ 50 years consecutively admitted to a single center with a new femoral fracture. All individual radiographs were examined and fracture site confirmed. A case-control study of patients with low-energy ST/FS fractures, age- and sex-matched with patients with hip fractures (1:2 ratio), was performed. Patients with atypical ST/FS fractures were further compared with those with ordinary ST/FS fractures. Cortical thickness (CT) was measured in radiographs of cases and controls. Ninety-six of 906 patients (10.6%) had a ST/FS fracture. Of these, 63 with low-energy fractures were individually matched with 126 controls with hip fracture. BPs were used by 9.5% of cases and by 8.7% of controls (OR, 1.10; 95% CI, 0.39-3.06) with comparable duration of therapy between groups (54 ± 35 vs. 54 ± 52 months, P=0.53). CT was comparable between cases and controls, BP users and non-users, and was not related to treatment duration. Atypical fractures were observed in 10/63 ST/FS cases (15.9%). Compared to patients with ordinary ST/FS fractures, those with atypical fractures were using more frequently BPs (OR, 17.0; 95% CI, 2.6-113.3) and glucocorticoids (OR, 5.3; 95% CI, 0.9-28.6). Among patients with atypical fractures, CT was comparable between BP users and non-users. In conclusion, atypical femoral fractures have a low prevalence (1.1% of all femoral fractures), compared to ordinary ST/FS fractures are more frequent in bisphosphonate users, but equally occur in patients never treated with bisphosphonates.

Outpatient treatment in patients with acute pulmonary embolism: the Hestia Study

Summary.  Background: Traditionally, patients with pulmonary embolism (PE) are initially treated in the hospital with low molecular weight heparin (LMWH). The results of a few small non‐randomized studies suggest that, in selected patients with proven PE, outpatient treatment is potentially feasible and safe. Objective: To evaluate the efficacy and safety of outpatient treatment according to predefined criteria in patients with acute PE. Patients and Methods: A prospective cohort study of patients with objectively proven acute PE was conducted in 12 hospitals in The Netherlands between 2008 and 2010. Patients with acute PE were triaged with the predefined criteria for eligibility for outpatient treatment, with LMWH (nadroparin) followed by vitamin K antagonists. All patients eligible for outpatient treatment were sent home either immediately or within 24 h after PE was objectively diagnosed. Outpatient treatment was evaluated with respect to recurrent venous thromboembolism (VTE), including PE or deep vein thrombosis (DVT), major hemorrhage and total mortality during 3 months of follow‐up. Results: Of 297 included patients, who all completed the follow‐up, six (2.0%; 95% confidence interval [CI] 0.8–4.3) had recurrent VTE (five PE [1.7%] and one DVT [0.3%]). Three patients (1.0%, 95% CI 0.2–2.9) died during the 3 months of follow‐up, none of fatal PE. Two patients had a major bleeding event, one of which was fatal intracranial bleeding (0.7%, 95% CI 0.08–2.4). Conclusion: Patients with PE selected for outpatient treatment with predefined criteria can be treated with anticoagulants on an outpatient basis. (Dutch Trial Register No 1319; http://www.trialregister.nl/trialreg/index.asp).

Genetic associations in diabetic nephropathy: a meta-analysis

Aims/hypothesisThis meta-analysis assessed the pooled effect of each genetic variant reproducibly associated with diabetic nephropathy.MethodsPubMed, EMBASE and Web of Science were searched for articles assessing the association between genes and diabetic nephropathy. All genetic variants statistically associated with diabetic nephropathy in an initial study, then independently reproduced in at least one additional study, were selected. Subsequently, all studies assessing these variants were included. The association between these variants and diabetic nephropathy (defined as macroalbuminuria/proteinuria or end-stage renal disease [ESRD]) was calculated at the allele level and the main measure of effect was a pooled odds ratio. Pre-specified subgroup analyses were performed, stratifying for type 1/type 2 diabetes mellitus, proteinuria/ESRD and ethnic group.ResultsThe literature search yielded 3,455 citations, of which 671 were genetic association studies investigating diabetic nephropathy. We identified 34 replicated genetic variants. Of these, 21 remained significantly associated with diabetic nephropathy in a random-effects meta-analysis. These variants were in or near the following genes: ACE, AKR1B1 (two variants), APOC1, APOE, EPO, NOS3 (two variants), HSPG2, VEGFA, FRMD3 (two variants), CARS (two variants), UNC13B, CPVL and CHN2, and GREM1, plus four variants not near genes. The odds ratios of associated genetic variants ranged from 0.48 to 1.70. Additional variants were detected in subgroup analyses: ELMO1 (Asians), CCR5 (Asians) and CNDP1 (type 2 diabetes).Conclusions/interpretationThis meta-analysis found 24 genetic variants associated with diabetic nephropathy. The relative contribution and relevance of the identified genes in the pathogenesis of diabetic nephropathy should be the focus of future studies.