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Utrecht, Netherlands

Van Den Bent M.J.,Be430a | Erdem-Eraslan L.,Be430a | Spliet W.G.M.,UMCU | Den Dunnen W.F.A.,UMCG | And 6 more authors.
Clinical Cancer Research | Year: 2013

Purpose: The long-term follow-up results from the EORTC-26951 trial showed that the addition of procarbazine, CCNU, and vincristine (PCV) after radiotherapy increases survival in anaplastic oligodendrogliomas/ oligoastrocytomas (AOD/AOA). However, some patients appeared to benefit more from PCV treatment than others. Experimental Design:Weconducted genome-wide methylation profiling of 115 samples included in the EORTC-26951 trial and extracted theCpGisland hypermethylated phenotype (CIMP) andMGMTpromoter methylation (MGMT-STP27) status. Results: We first show that methylation profiling can be conducted on archival tissues with a performance that is similar to snap-frozen tissue samples. We then conducted methylation profiling on EORTC-26951 clinical trial samples. Univariate analysis indicated that CIMP? or MGMT-STP27 methylated tumors had an improved survival compared with CIMP- and/or MGMT-STP27 unmethylated tumors [median overall survival (OS), 1.05 vs. 6.46 years and 1.06 vs. 3.8 years, both P < 0.0001 for CIMP and MGMT-STP27 status, respectively]. Multivariable analysis indicates that CIMP and MGMT-STP27 are significant prognostic factors for survival in presence of age, sex, performance score, and reviewdiagnosis in themodel. CIMP?andMGMTSTP27methylated tumors showed a clear benefit fromadjuvantPCVchemotherapy: themedianOSof CIMP? samples in the RT and RT-PCV arms was 3.27 and 9.51 years, respectively (P = 0.0033); for MGMT-STP27 methylated samples, it was 1.98 and 8.65 years. There was no such benefit for CIMP- or for MGMT-STP27 unmethylated tumors. MGMT-STP27 status remained significant in an interaction test (P = 0.003). Statistical analysis of microarray (SAM) identified 259 novel CpGs associated with treatment response. Conclusions:MGMT-STP27 may be used to guide treatment decisions in this tumor type. © 2013 American Association for Cancer Research. Source


Van Santvoort H.C.,UMCU
Nederlands Tijdschrift voor Geneeskunde | Year: 2013

A recent meta-analysis of 57 studies investigated the diagnostic accuracy of imaging techniques in acute cholecystitis. The main findings were that abdominal ultrasound has a sensitivity of 81% and a specificity of 83%, that ultrasound seems comparable to magnetic resonance imaging (MRI), that cholescintigraphy has a sensitivity of 96% and a specificity of 90%, and that there are insufficient studies to evaluate the role of computed tomography (CT). In daily practice, ultrasound is the preferred modality as it is safe, widely available and cheap. MRI and cholescintigraphy are less available and have additional disadvantages. Patients with a negative or inconclusive ultrasound examination should undergo CT as this is in line with the general diagnostic strategy for acute abdominal pain that results in the highest sensitivity for urgent conditions and lowest exposure to radiation. Patients with clinical suspicion of acute cholecystitis but negative imaging findings should undergo prompt diagnostic laparoscopy and potentially cholecystectomy. Source


Wijkstra J.,UMCU
The Cochrane database of systematic reviews | Year: 2013

Evidence is limited regarding the most effective pharmacological treatment for psychotic depression: combination of an antidepressant plus an antipsychotic, monotherapy with an antidepressant or monotherapy with an antipsychotic. This is an update of a review first published in 2005 and last updated in 2009. 1. To compare the clinical efficacy of pharmacological treatments for patients with an acute psychotic depression: antidepressant monotherapy, antipsychotic monotherapy and the combination of an antidepressant plus an antipsychotic, compared with each other and/or with placebo.2. To assess whether differences in response to treatment in the current episode are related to non-response to prior treatment. A search of the Cochrane Central Register of Controlled Trials and the Cochrane Depression, Anxiety and Neurosis Group Register (CCDANCTR) was carried out (to 12 April 2013). These registers include reports of randomised controlled trials from the following bibliographic databases: EMBASE (1970-), MEDLINE (1950-) and PsycINFO (1960-). Reference lists of all studies and related reviews were screened and key authors contacted. All randomised controlled trials (RCTs) that included participants with acute major depression with psychotic features, as well as RCTs consisting of participants with acute major depression with or without psychotic features, that reported separately on the subgroup of participants with psychotic features. Two review authors independently extracted data and assessed risk of bias in the included studies, according to the criteria of the Cochrane Handbook for Systematic Reviews of Interventions. Data were entered into RevMan 5.1. We used intention-to-treat data. For dichotomous efficacy outcomes, the risk ratio (RR) with 95% confidence intervals (CIs) was calculated. For continuously distributed outcomes, it was not possible to extract data from the RCTs. Regarding the primary outcome of harm, only overall dropout rates were available for all studies. The search identified 3659 abstracts, but only 12 RCTs with a total of 929 participants could be included in the review. Because of clinical heterogeneity, few meta-analyses were possible. The main outcome was reduction of severity (response) of depression, not of psychosis.We found no evidence for the efficacy of monotherapy with an antidepressant or an antipsychotic.However, evidence suggests that the combination of an antidepressant plus an antipsychotic is more effective than antidepressant monotherapy (three RCTs; RR 1.49, 95% CI 1.12 to 1.98, P = 0.006), more effective than antipsychotic monotherapy (four RCTs; RR 1.83, 95% CI 1.40 to 2.38, P = 0.00001) and more effective than placebo (two identical RCTs; RR 1.86, 95% CI 1.23 to 2.82, P = 0.003).Risk of bias is considerable: there were differences between studies with regard to diagnosis, uncertainties around randomisation and allocation concealment, differences in treatment interventions (pharmacological differences between the various antidepressants and antipsychotics) and different outcome criteria. Psychotic depression is heavily understudied, limiting confidence in the conclusions drawn. Some evidence indicates that combination therapy with an antidepressant plus an antipsychotic is more effective than either treatment alone or placebo. Evidence is limited for treatment with an antidepressant alone or with an antipsychotic alone. Source


van Santvoort H.C.,UMCU
Nederlands tijdschrift voor geneeskunde | Year: 2013

A recent meta-analysis of 57 studies investigated the diagnostic accuracy of imaging techniques in acute cholecystitis. The main findings were that abdominal ultrasound has a sensitivity of 81% and a specificity of 83%, that ultrasound seems comparable to magnetic resonance imaging (MRI), that cholescintigraphy has a sensitivity of 96% and a specificity of 90%, and that there are insufficient studies to evaluate the role of computed tomography (CT). In daily practice, ultrasound is the preferred modality as it is safe, widely available and cheap. MRI and cholescintigraphy are less available and have additional disadvantages. Patients with a negative or inconclusive ultrasound examination should undergo CT as this is in line with the general diagnostic strategy for acute abdominal pain that results in the highest sensitivity for urgent conditions and lowest exposure to radiation. Patients with clinical suspicion of acute cholecystitis but negative imaging findings should undergo prompt diagnostic laparoscopy and potentially cholecystectomy. Source


Van der Heyden M.A.G.,UMCU | Stary-Weinzinger A.,University of Vienna | Sanchez-Chapula J.A.,University of Colima
Current Molecular Medicine | Year: 2013

Cardiac inward rectifier channels belong to three different classes of the KIR channel protein family. The KIR2.x proteins generate the classical inward rectifier current, IK1, while KIR3 and KIR6 members are responsible for the acetylcholine responsive and ATP sensitive inward rectifier currents IKAch and IKATP, respectively. Aberrant function of these channels has been correlated with severe cardiac arrhythmias, indicating their significant contribution to normal cardiac electrophysiology. A common feature of inward rectifier channels is their dependence on the lipid phosphatidyl-4,5-bisphospate (PIP2) interaction for functional activity. Cationic amphiphilic drugs (CADs) are one of the largest classes of pharmaceutical compounds. Several widely used CADs have been associated with inward rectifier current disturbances, and recent evidence points to interference of the channel-PIP2 interaction as the underlying mechanism of action. we will review how six of these well known drugs, used for treatment in various different conditions, interfere in cardiac inward rectifier functioning. In contrast, KIR channel inhibition by the anionic anesthetic thiopental is achieved by a different mechanism of channel-PIP2 interference. We will discuss the latest basic science insights of functional inward rectifier current characteristics, recently derived KIR channel structures and specific PIP2-receptor interactions at the molecular level and provide insight in how these drugs interfere in the structure-function relationships. © 2013 Bentham Science Publishers. Source

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