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Wirz S.,Abteilung fur Anasthesie | Nadstawek J.,Universitatskliniken Bonn | Kuhn K.U.,Universitatsklinikum des Saarlandes | Vater S.,Universitatskliniken Bonn | And 2 more authors.
Schmerz | Year: 2010

Aim: The authors conducted an open-label investigation examining the effects of modafinil in reducing fatigue in patients with cancer, undergoing cancer treatment, and receiving opioid therapy. Methods: After approval by the local Ethics Committee and informed consent cancer patients who reported fatigue - defined as persistent tiredness interfering with usual functioning - were enrolled in the study. Once daily, patients received 100 mg open-label modafinil. The Fatigue Severity Scale (FSS), Epworth Sleepiness Scale (ESS), and a visual analogue scale (VAS, 0-10) were performed at baseline (t1), day 7 (t2), and day 28 (t3). Further assessment comprised the d2 Test of Attention (d2), the Hamilton Depression Scale (HAMD), the Eastern Cooperative Oncology Group-Score (ECOG), side effects, and patients' satisfaction with modafinil treatment. Results: Of the 37 patients who were enrolled, 29 completed all assessments in the study. Modafinil had a significant effect on the FSS (t1 44.612.2, t2 3912.4, t3 35.313.8 (p=0.015), on the VAS (t1 63.1), t2 4.52.8, t3 3.72.8 (p=0.005), and an insignificant effect on d2 parameters of neurophysiological functioning and ESS. No differences were seen for ECOG and patients' satisfaction. No severe adverse effects were detected. Conclusion: Modafinil improved alertness and cognitive skills in patients receiving cancer pain treatment by enhancing vigilance and cognitive performance. Although confirmation of this preliminary result is needed, these findings suggest that modafinil may improve quality of life in this patient population. However, in Germany the use of modafinil for fatigue is off-label and careful assessment of fatigue is needed prior to treatment. Randomized controlled trials are needed to confirm this evidence. © 2010 Springer-Verlag. Source


Kandenwein J.A.,Universitatskliniken Bonn | Park-Simon T.-W.,Klinik fur Frauenheilkunde und Geburtshilfe | Schramm J.,Universitatskliniken Bonn | Simon M.,Universitatskliniken Bonn
Journal of Neuro-Oncology | Year: 2011

The extent of resection and the intrinsic biological aggressiveness of the tumor have been repeatedly identified as the primary determinants of meningioma recurrence. Invasive growth limits the resectability of meningiomas. Tumor invasion is mediated by matrix metalloproteases and their inhibitors such as uPA and PAI-1. In some cancers uPA expression is controlled in part by promoter methylation. In the work reported in this paper we investigated the role of uPA/PAI-1 expression and methylation of the uPA promoter in meningiomas. Sixty-five tumor tissue samples (WHO grade I: 26, grade II: 27, grade III: 12) from 58 patients were analyzed for uPA and PAI-1 protein content using a commercially available ELISA kit. For uPA promoter methylation analysis, a 365-bp promoter fragment was amplified by PCR after bisulfite treatment and subjected to a methylation-sensitive restriction digest with AciI. Pertinent clinical data were retrieved from the patients' charts. uPA and PAI-1 protein expression correlated significantly with WHO grade (uPA: P < 0.033, PAI-1: P < 0.001). High (>6 ng/ml = median) PAI-1 levels were seen more frequently in tumors with brain invasion (P = 0.006) and proved a significant predictor of the patients' prognosis (Kaplan-Meier estimates of progression-free survival: P = 0.004). Increased methylation of the uPA promoter was found to correlate significantly with lower levels of uPA expression. Our data suggest PAI-1 (and possibly to a lesser degree uPA) as potential prognostic markers in meningiomas. uPA expression in meningiomas might, in part, be controlled by promoter methylation. © 2010 Springer Science+Business Media, LLC. Source


Dobbins S.E.,Institute of Cancer Research | Broderick P.,Institute of Cancer Research | Melin B.,Umea University | Feychting M.,Karolinska Institutet | And 25 more authors.
Nature Genetics | Year: 2011

To identify susceptibility loci for meningioma, we conducted a genome-wide association study of 859 affected individuals (cases) and 704 controls with validation in two independent sample sets totaling 774 cases and 1,764 controls. We identified a new susceptibility locus for meningioma at 10p12.31 (MLLT10, rs11012732, odds ratio = 1.46, P combined = 1.88 ×10-14). This finding advances our understanding of the genetic basis of meningioma development. © 2011 Nature America, Inc. All rights reserved. Source


Simon M.,Universitatskliniken Bonn | Hosking F.J.,Institute of Cancer Research | Marie Y.,University Pierre and Marie Curie | Gousias K.,Universitatskliniken Bonn | And 13 more authors.
Clinical Cancer Research | Year: 2010

Purpose: Genome-wide association studies have recently identified single-nucleotide polymorphisms (SNP) in five loci at 5p15.33 (rs2736100, TERT), 8q24.21 (rs4295627, CCDC26), 9p21.3 (rs4977756, CDKN2A/CDKN2B), 20q13.33 (rs6010620, RTEL1), and 11q23.3 (rs498872, PHLDB1) to be associated with glioma risk. Because gliomas are heterogeneous in histology, molecular alterations, and clinical behavior, we have investigated these polymorphisms for potential correlations with tumor histology and patient survival. Experimental Design: We studied the relationship between SNPs and glioma subtype in two large patient cohorts from France and Germany, totaling 1,577 patients, as well as the relationship between SNP genotype and overall survival. Results: In both cohorts, the frequencies of rs2736100 and rs6010620 risk genotypes were highly correlated with high-grade disease (P < 0.001), whereas rs4295627 and rs498872 risk genotypes were inversely related to tumor grade (P < 0.001). These data show that genetic variations at these loci have subtype-specific effects on the risk of developing glioma. In contrast, the rs4977756 genotype was not correlated with tumor grade, consistent with the causal variant having a generic influence on glioma development. None of the five SNPs was associated with prognosis independent of tumor grade. Conclusions: Our findings provide novel insight into etiologic pathways in the different glioma subtypes. ©2010 AACR. Source


Kurzwelly D.,Universitatskliniken Bonn | Herrlinger U.,Universitatskliniken Bonn | Simon M.,Universitatskliniken Bonn
Advances and technical standards in neurosurgery | Year: 2010

Seizures complicate the clinical course of > 80% of patients with low-grade gliomas. Patients with some tumor variants almost always have epilepsy. Diffuse low-grade gliomas (LGG) are believed to cause epilepsy through partial deafferentiation of nearby brain cortex (denervation hypersensitivity). Glioneural tumors may interfere with local neurotransmitter levels and are sometimes associated with structural abnormalities of the brain which may produce seizures. The severity of tumor associated epilepsy varies considerably between patients. Some cases may present with a first seizure. Others suffer from long-standing pharmacoresistant epilepsy. Seizure control rates of > 70-80% can be expected after complete tumor resections. Patients with drug-resistant epilepsy require a comprehensive preoperative epileptological work-up which may include the placement of subdural (and intraparenchymal) electrodes or intraoperative electrocorticography (ECoG) for the delineation of extratumoral seizure foci. Partial and subtotal tumor resections are helpful in selected cases, i.e. for gliomas involving the insula. In one series, 40% of patients presented for surgery with uncontrolled seizures, i.e. medical therapy alone often fails to control tumor-related epilepsy. Use of the newer (second generation) non-enzyme inducing antiepileptic drugs (non-EIAED) is encouraged since they seem to have lesser interactions with other medications (e.g. chemotherapy). Chemotherapy and irradiation may have some minor beneficial effects on the patients' seizure disorder. Overall 60-70% of patients may experience recurrent epilepsy during long-term follow-up. Recurrent seizures (not infrequently heralding tumor recurrence) after surgery continue to pose significant clinical problems. Source

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