Nijmegen, Netherlands
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Beckers M.M.,University of Groningen | Huls G.,University of Groningen | Huls G.,University Medical Center Nijmegen
European Journal of Haematology | Year: 2013

The prognosis of therapy refractory angioimmunoblastic lymphoma (AITL) is very poor. In this report we describe a patient with AITL refractory to 2 lines of chemotherapy. He was treated with lenalidomide 15 mg continuously and prednisone. After 2 yr follow-up, the patient has no detectable disease. Lenalidomide was well tolerated without side-effects. Lenalidomide even in lower dosed combined with steroids can induce complete responses in patients with refractory AITL. © 2012 John Wiley & Sons A/S.


Vincken W.,UZ Brussel | Dekhuijzen R.,University Medical Center Nijmegen | Barnes P.,UK National Heart and Lung Institute
Primary Care Respiratory Journal | Year: 2010

For patients with COPD, inhalation is the preferred route of administration of respiratory drugs for both maintenance and acute treatment. Numerous inhaler types and devices have been developed, each with their own particularities, advantages and disadvantages. Nevertheless, published COPD management guidelines pay little attention to the optimal choice of inhaler devices for COPD patients. Although efficacy and safety are the primary factors determining the choice of an inhaler device, randomised controlled trials (RCTs) directly comparing the efficacy and safety of different inhalers in COPD patients are scarce. Systematic reviews on this subject failed to find significant differences between devices for any of the clinical outcomes studied. When selecting a device for the delivery of inhaled drugs in 'real life' patients with COPD, other factors should be considered. These include availability and affordability of the inhaled drugs and inhaler devices, the uniformity of inhaler devices when several drugs are to be inhaled, the ability of patients to handle correctly the selected device - in particular taking into account the advanced age of the average COPD patient, and finally the patient's preference. The prescribing clinician's task is to provide comprehensive instructions for correct handling of the device and to review regularly the patient's inhalation technique. © 2010 Primary Care Respiratory Society UK. All rights reserved.


Kotsovilis S.,National and Kapodistrian University of Athens | Markou N.,National and Kapodistrian University of Athens | Pepelassi E.,National and Kapodistrian University of Athens | Nikolidakis D.,University Medical Center Nijmegen
Journal of Periodontal Research | Year: 2010

Objective: The evidence for the efficacy of the adjunctive use of platelet-rich plasma (PRP) in periodontal intraosseous defects has not been systematically evaluated. The objective of this review was to address the focused question, 'What is the efficacy, with respect to clinical, radiographical and patient-centred outcomes, of combinations of PRP with other therapeutic bioactive agents/procedures, compared with the efficacy of the same agents/procedures without the adjunctive use of PRP in the therapy of periodontal intraosseous defects in patients with chronic periodontitis and without systemic diseases that could potentially influence the outcome of periodontal therapy?' by performing a systematic review of randomized controlled clinical trials (RCTs) published in the dental literature in any language, up to and including September 2008. Material and Methods: Data sources principally included electronic databases, manually searched journals and contact with experts. In the first phase of study selection, the titles and abstracts, and in the second phase, full papers were screened independently and in duplicate by two reviewers. Results: In the first phase, 6124 potentially relevant titles and abstracts were examined. In the second phase, the full text of 20 publications was thoroughly evaluated. Eventually, 10 RCTs were selected. Conclusion: Diverse outcomes (positive and negative) have been reported for the efficacy of PRP combined with various therapeutic bioactive agents/procedures, reflecting the limited and heterogeneous data available and possibly suggesting that the specific selection of agents/procedures combined with PRP could be important. Additional research on the efficacy of each specific combination of PRP is necessary. © 2009 The Authors. Journal compilation © 2009 Blackwell Munksgaard.


Dinarello C.A.,University of Colorado at Denver | Dinarello C.A.,University Medical Center Nijmegen | Bufler P.,Ludwig Maximilians University of Munich
Seminars in Immunology | Year: 2013

IL-37 was formerly termed IL-1 family member 7. The cytokine was discovered by in silico research of human databases. Although there are no genes in the databases with an open reading frame for a murine homologue for IL-37, human IL-37 is functional in the mouse. Like others members of the IL-1 family, IL-37 lacks a signal peptide. The precursor form of IL-37 has a caspase-1 site, but the role of caspase-1 in the processing and secretion of IL-37 has not been documented with certainty. IL-37 is similar to IL-1α and IL-33, in that the cytokine is found in the nucleus where, like IL-1α and IL-33, functions in transcription. Translocation of IL-37 to the nucleus likely involves SMAD3, which is a component of the TGFβ anti-inflammatory signaling pathway. Also similar to IL-1α and IL-33, with loss of membrane integrity upon cell death, the IL-37 precursor exits from the cell where it binds to the IL-18 receptor alpha chain. However, this binding results in reduced inflammation. Without a murine form of IL-37, deletion studies were carried out with specific siRNA. In human monocytes deficient in IL-37, LPS and IL-1β induced cytokines increased 2-3 fold, suggesting that endogenous IL-37 serves as a break on inflammation. Indeed, in mice expressing human IL-37, inflammation is reduced in models of LPS shock, chemical colitis, cardiac ischemia and contact dermatitis. © 2013.


Novick D.,Weizmann Institute of Science | Kim S.,Konkuk University | Kaplanski G.,Aix - Marseille University | Dinarello C.A.,University of Colorado at Denver | Dinarello C.A.,University Medical Center Nijmegen
Seminars in Immunology | Year: 2013

Together with IL-12 or IL-15, interleukin-18 (IL-18) plays a major role in the production of interferon-γ from T-cells and natural killer cells; thus, IL-18 is considered to have a major role in the Th1 response. However, without IL-12, IL-18 is proinflammatory in an IFNγ independent manner. IL-18 is a member of the IL-1 family of cytokines and similar to IL-1β, the cytokine is synthesized as an inactive precursor requiring processing by caspase-1 into an active cytokine. IL-18 is also present as an integral membrane protein but requires caspase-1 for full activity in order to induce IFNγ. Uniquely, unlike IL-1β, the IL-18 precursor is constitutively present in nearly all cells in healthy humans and animals. The activity of IL-18 is balanced by the presence of a high-affinity, naturally occurring IL-18 binding protein (IL-18BP). In humans, increased disease severity can be associated with an imbalance of IL-18 to IL-18BP such that the levels of free IL-18 are elevated in the circulation. Increasing number of studies have expanded the role of IL-18 in mediating inflammation in animal models of disease using the IL-18BP, IL-18 deficient mice, neutralization of IL-18 or deficiency in the IL-18 receptor alpha chain. A role for IL-18 has been implicated in several autoimmune diseases, myocardial function, emphysema, metabolic syndromes, psoriasis, inflammatory bowel disease, macrophage activation syndrome, sepsis and acute kidney injury, although paradoxically, in some models of disease, IL-18 is protective. The IL-18BP has been used safely in humans and clinical trials of IL-18BP as well as neutralizing anti-IL-18 antibodies are being tested in various diseases. © 2013 Elsevier Ltd.


Dinarello C.A.,University of Colorado at Denver | Dinarello C.A.,University Medical Center Nijmegen | Novick D.,Weizmann Institute of Science | Kim S.,Konkuk University | Kaplanski G.,Aix - Marseille University
Frontiers in Immunology | Year: 2013

Interleukin-18 (IL-18) is a member of the IL-1 family of cytokines. Similar to IL-1ß, IL-18 is synthesized as an inactive precursor requiring processing by caspase-1 into an active cytokine but unlike IL-1ß, the IL-18 precursor is constitutively present in nearly all cells in healthy humans and animals. The activity of IL-18 is balanced by the presence of a high affinity, naturally occurring IL-18 binding protein (IL-18BP). In humans, increased disease severity can be associated with an imbalance of IL-18 to IL-18BP such that the levels of free IL-18 are elevated in the circulation. Increasing number of studies have expanded the role of IL-18 in mediating inflammation in animal models of disease using the IL-18BP, IL-18-deficient mice, neutralization of IL-18, or deficiency in the IL-18 receptor alpha chain. A role for IL-18 has been implicated in several autoimmune diseases, myocardial function, emphysema, metabolic syndromes, psoriasis, inflammatory bowel disease, hemophagocytic syndromes, macrophage activation syndrome, sepsis, and acute kidney injury, although in some models of disease, IL-18 is protective. IL-18 plays a major role in the production of interferon-γ from T-cells and natural killer cells. The IL-18BP has been used safely in humans and clinical trials of IL-18BP as well as neutralizing anti-IL-18 antibodies are in clinical trials. This review updates the biology of IL-18 as well as its role in human disease. © 2013 Dinarello, Novick, Kim and Kaplanski.


Aluwini S.,Netherlands Cancer Institute | Pos F.,Netherlands Cancer Institute | Schimmel E.,Institute for Radiation Oncology Arnhem | van Lin E.,University Medical Center Nijmegen | And 7 more authors.
The Lancet Oncology | Year: 2015

Background: In 2007, we began the randomised phase 3 multicentre HYPRO trial to investigate the effect of hypofractionated radiotherapy compared with conventionally fractionated radiotherapy on relapse-free survival in patients with prostate cancer. Here, we examine whether patients experience differences in acute gastrointestinal and genitourinary adverse effects. Methods: In this randomised non-inferiority phase 3 trial, done in seven radiotherapy centres in the Netherlands, we enrolled intermediate-risk or high-risk patients aged between 44 and 85 years with histologically confirmed stage T1b-T4 NX-0MX-0 prostate cancer, a PSA concentration of 60 ng/mL or lower, and WHO performance status of 0-2. A web-based application was used to randomly assign (1:1) patients to receive either standard fractionation with 39 fractions of 2 Gy in 8 weeks (five fractions per week) or hypofractionation with 19 fractions of 3·4 Gy in 6·5 weeks (three fractions per week). Randomisation was done with minimisation procedure, stratified by treatment centre and risk group. The primary endpoint is 5-year relapse-free survival. Here we report data for the acute toxicity outcomes: the cumulative incidence of grade 2 or worse acute and late genitourinary and gastrointestinal toxicity. Non-inferiority of hypofractionation was tested separately for genitourinary and gastrointestinal acute toxic effects, with a null hypothesis that cumulative incidences of each type of adverse event were not more than 8% higher in the hypofractionation group than in the standard fractionation group. We scored acute genitourinary and gastrointestinal toxic effects according to RTOG-EORTC criteria from both case report forms and patients' self-assessment questionnaires, at baseline, twice during radiotherapy, and 3 months after completion of radiotherapy. Analyses were done in the intention-to-treat population. Patient recruitment has been completed. This study is registered with www.controlled-trials.com, number ISRCTN85138529. Findings: Between March 19, 2007, and Dec 3, 2010, 820 patients were randomly assigned to treatment with standard fractionation (n=410) or hypofractionation (n=410). 3 months after radiotherapy, 73 (22%) patients in the standard fractionation group and 75 (23%) patients in the hypofractionation group reported grade 2 or worse genitourinary toxicity; grade 2 or worse gastrointestinal toxicity was noted in 43 (13%) patients in the standard fractionation group and in 42 (13%) in the hypofractionation group. Grade 4 acute genitourinary toxicity was reported for two patients, one (<1%) in each group. No grade 4 acute gastrointestinal toxicities were observed. We noted no significant difference in cumulative incidence by 120 days after radiotherapy of grade 2 or worse acute genitourinary toxicity (57·8% [95% CI 52·9-62·7] in the standard fractionation group vs 60·5% (55·8-65·3) in the hypofractionation group; difference 2·7%, 90% CI -2·99 to 8·48; odds ratio [OR] 1·12, 95% CI 0·84-1·49; p=0·43). The cumulative incidence of grade 2 or worse acute gastrointestinal toxicity by 120 days after radiotherapy was higher in patients given hypofractionation (31·2% [95% CI 26·6-35·8] in the standard fractionation group vs 42·0% [37·2-46·9] in the hypofractionation group; difference 10·8%, 90% CI 5·25-16·43; OR 1·6; p=0·0015; non-inferiority not confirmed). Interpretation: Hypofractionated radiotherapy was not non-inferior to standard fractionated radiotherapy in terms of acute genitourinary and gastrointestinal toxicity for men with intermediate-risk and high-risk prostate cancer. In fact, the cumulative incidence of grade 2 or worse acute gastrointestinal toxicity was significantly higher in patients given hypofractionation than in those given standard fractionated radiotherapy. Patients remain in follow-up for efficacy endpoints. Funding: The Dutch Cancer Society. © 2015 Elsevier Ltd.


Van de Groes S.,University Medical Center Nijmegen | De Waal-Malefijt M.,University Medical Center Nijmegen | Verdonschot N.,University Medical Center Nijmegen | Verdonschot N.,University of Twente
Knee | Year: 2014

Background: Some follow-up studies of high flexion total knee arthoplasties report disturbingly high incidences of femoral component loosening. Femoral implant fixation is dependant on two interfaces: the cement-implant and the cement-bone interface. The present finite-element model (FEM) is the first to analyse both the cement-implant interface and cement-bone interface. The cement-bone interface is divided into cement-cancellous and cement-cortical bone interfaces, each having their own strength values. The research questions were: (1) which of the two interfaces is more prone to failure? and (2) what is the effect of different surgical preparation techniques for cortical bone on the risk of early failure.? Methods: FEM was used in which the posterior-stabilized PFC Sigma RP-F (DePuy) TKA components were incorporated. A full weight-bearing squatting cycle was simulated (ROM. = 50°-155°). An interface failure index (FI) was calculated for both interfaces. Results: The cement-bone interface is more prone to failure than the cement implant interface. When drilling holes through the cortex behind the anterior flange instead of unprepared cortical bone, the area prone to early interface failure can be reduced from 31.3% to 2.6%. Conclusion: The results clearly demonstrate high risk of early failure at the cement-bone interface. This risk can be reduced by some simple preparation techniques of the cortex behind the anterior flange. Clinical relevance: High-flexion TKA is currently being introduced. Some reports show high failure rates. FEM can be helpful in understanding failure of implants. © 2013 Elsevier B.V.


Jira P.,University Medical Center Nijmegen
Handbook of Clinical Neurology | Year: 2013

Genetic defects in enzymes responsible for cholesterol biosynthesis have emerged as important causes of congenital dysmorphology and retardation syndromes. Cholesterol is an important constituent of the cell membrane of most eukaryotic cells, in myelin formation in the brain, spinal cord, and peripheral nervous system, and acts as the precursor for steroid hormones and bile acids. Finally, cholesterol has important interactions with proteins, which control embryonic development. To date, eight distinct inherited disorders have been linked to different defects in cholesterol biosynthesis. Two result from an enzyme defect in the pre-squalene segment of the pathway: the classical form of mevalonic aciduria and the hyperimmunoglobulinemia D syndrome, also known as Dutch-type periodic fever. Six defects in the post-squalene segment of the pathway include: Smith-Lemli-Opitz syndrome, two X-linked dominant inherited and male-lethal disorders, Conradi-Hünermann-Happle syndrome and congenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD), and at least three extremely rare autosomal recessive disorders, Greenberg skeletal dysplasia, lathosterolosis, and desmosterolosis. All these inborn errors known to date have been linked to deficiency of specific enzymes on the basis of elevated levels of specific sterol intermediates in tissues of affected patients followed by demonstrating disease-causing mutations in the encoding genes. These cholesterol deficiency multiple malformation-retardation syndromes have clinical overlap. Besides psychomotor retardation, developmental delay, structural brain malformations, multiple congenital anomalies, microcephaly, and cataract, impaired cholesterol biosynthesis is associated with autism and other behavioral disorders. © 2013 Elsevier B.V.


Schoenberg P.L.A.,Radboud University Nijmegen | Schoenberg P.L.A.,University Medical Center Nijmegen | Schoenberg P.L.A.,Netherlands Institute for Advanced Study
Biological Psychology | Year: 2014

Major depressive disorder (MDD) ensues reduced goal-directed cognition and behaviour. Cognitive and emotional flexibility to disengage and adapt future responses was examined in the error processing system (error-related negativity/ERN, error-positivity/Pe event-related potentials) of 58 depressed patients (21 current, 37 remitted) vs. 27 controls undergoing cognitive and affective Go/NoGo paradigms. ERN was equivalent between patient and controls for the cognitive task, albeit amplitude attenuated in patients during the affective task. Blunted ERN amplitudes were evident between patients and controls in males compared to females, plausibly underpinned by disparities in dopaminergic pathways. Patients displayed enhanced Pe amplitudes for both cognitive and affective tasks. Abberations in cortical error processing in MDD appear specific to affective systems for the pre-attentive ERN, opposed to cognitive and affective processing for the consciously-integrated Pe. Heightened Pe, observed in both current and remitted patients, advocates the possibility of the Pe waveform as a candidate intermediate phenotype of depression. © 2014 Elsevier B.V.

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