Ulrich Bogdahn

Bio: Ulrich Bogdahn is an academic researcher from University of Regensburg. The author has contributed to research in topics: Neural stem cell & Neurogenesis. The author has an hindex of 67, co-authored 344 publications receiving 32279 citations. Previous affiliations of Ulrich Bogdahn include Hoffmann-La Roche & Volkswagen Foundation.

TGF-β2 Signaling in High-Grade Gliomas

Abstract: High-grade gliomas are the most common primary tumors in the central nervous system (CNS) in adults. Despite efforts to improve treatment by combination therapies (neurosurgery, radio- and chemotherapy), high-grade glioma patients still have a grim prognosis, indicating an urgent need for new therapeutic approaches. The molecular processes of gliomagenesis are being unraveled, and novel targeted therapeutic strategies to defy high-grade gliomas are emerging. Transforming growth factor-beta (TGF-β), in particular the TGF-β2 isoform, has been identified as a key factor in the progression of malignant gliomas. TGF-β2, originally described as "glioblastoma-derived T-cell suppressor factor", is associated with the immuno-suppressed status of patients with glioblastoma, and is therefore responsible for loss of tumor immune surveillance. Elevated TGF-β2 levels in tumors and in the plasma of patients have been associated with advanced disease stage and poor prognosis. Consequently, a targeted strategy to modulate TGF-β2 signaling is highly promising. The antisense oligonucleotide trabedersen (AP 12009) that specifically blocks TGF-β2 mRNA will be the main focus of this review. In three phase I/II studies and a randomized, active-controlled dose-finding phase IIb study, trabedersen treatment of high-grade glioma patients with recurrent or refractory tumor disease led to long-lasting tumor responses and so far promising survival data. On the basis of these data the currently ongoing phase III study SAPHIRRE was initiated.

Ocular color-coded sonography - a promising tool for neurologists and intensive care physicians.

Abstract: Ocular color-coded duplex sonography (OCCS), when performed within the safety limits of diagnostic ultrasonography, is an easy noninvasive technique with high potential for diagnosis and therapy in diseases with raised intracranial pressure and vascular diseases affecting the eye. Despite the capabilities of modern ultrasound systems and its scientific validation, OCCS has not gained widespread use in neurological practice. In this review, the authors describe the technique and main parameter settings of OCCS systems to reduce potential risks as thermal or cavitational effects for sensitive orbital structures. Applications of OCCS are the determination of intracranial pressure in emergency medicine, and follow-up evaluations of idiopathic intracranial hypertension and ventricular shunting by measuring the optic nerve sheath diameter. A diameter of 5.7 – 6.0 mm corresponds well with symptomatically increased intracranial pressure (> 20 cmH2O). OCCS also helps to discriminate between different etiologies of central retinal artery occlusion – by visualization of a “spot sign” and Doppler flow analysis of the central retinal artery – and aids the differential diagnosis of papilledema. At the end perspectives are illustrated that combine established ultrasound methods such as transcranial color-coded sonography with OCCS.

Diabetes, use of antidiabetic drugs, and the risk of glioma

Abstract: BACKGROUND Prior epidemiologic studies suggest inverse relations between diabetes and glioma risk, but the underlying mechanisms, including use of antidiabetic drugs, are unknown. METHODS We therefore performed a matched case-control analysis using the Clinical Practice Research Datalink (CPRD). We identified incident glioma cases diagnosed between 1995 and 2012 and matched each case with 10 controls on age, gender, calendar time, general practice, and years of active history in the CPRD. We performed conditional logistic regression to estimate odds ratios (ORs) with 95% CIs, adjusted for body mass index and smoking. RESULTS We identified 2005 cases and 20 050 controls. Diabetes was associated with decreased risk of glioma (OR = 0.74; 95% CI = 0.60-0.93), particularly glioblastoma (OR = 0.69; 95% CI = 0.51-0.94). Glioblastoma risk reduction was markedly pronounced among diabetic men (OR = 0.60; 95% CI = 0.40-0.90), most apparently for those with diabetes of long-term duration (OR for >5 vs 0 y = 0.46; 95% CI = 0.26-0.82) or poor glycemic control (OR for HbA1c ≥8 vs <6.5% = 0.20; 95% CI = 0.06-0.70). In contrast, the effect of diabetes on glioblastoma risk was absent among women (OR = 0.85; 95% CI = 0.53-1.36). No significant associations with glioma were found for use of metformin (OR for ≥30 vs 0 prescriptions = 0.72; 95% CI = 0.38-1.39), sulfonylureas (OR = 0.71; 95% CI = 0.39-1.30), or insulin (OR = 0.79; 95% CI = 0.37-1.69). CONCLUSIONS Antidiabetic treatment appears to be unrelated to glioma, but long-term diabetes duration and increased HbA1c both show decreased glioma risk. Stronger findings in men than women suggest low androgen levels concurrent with diabetes as a biologic mechanism.

Novel POMGnT1 mutations define broader phenotypic spectrum of muscle-eye-brain disease.

Abstract: Muscle–eye–brain disease (MEB, OMIM 253280) is an autosomal recessive disorder characterized by a distinct triad of congenital muscular dystrophy, structural eye abnormalities, and cobblestone lissencephaly. Clinically, MEB patients present with early onset muscular hypotonia, severely compromised motor development, and mental retardation. Magnetic resonance imaging reveals a lissencephaly type II with hypoplasia of the brainstem and cerebellum. MEB is associated with mutations in the gene for protein O-mannose beta-1,2-N-acetylglucosaminyltransferase (POMGnT1, OMIM 606822). In this paper, we report the clinical findings of nine MEB patients from eight families. Eight of the nine patients presented typical features of MEB. However, a broad phenotypic variability was observed, ranging from two patients with severe autistic features to another patient with an unusually mild phenotype, initially diagnosed as congenital muscular dystrophy. Furthermore, severe hydrocephalus was reported in two families during a previous pregnancy, emphasizing the phenotypic overlap with Walker–Warburg syndrome. In addition to three previously reported mutations, we identified six novel POMGnT1 mutations (one missense, five truncating) in the present patient cohort. Our data suggest mutational hotspots within the minimal catalytic domain at arginine residue 442 (exon 16) and in intron 17. It is interesting to note that all mutations analyzed so far result in a complete loss of enzyme activity. Therefore, we conclude that the type and position of the POMGnT1 mutations are not of predictive value for the clinical severity. This supports the notion that additional environmental and/or genetic factors may contribute to the observed broad spectrum of POMGnT1-associated phenotypes.

Guidelines for the Early Management of Patients With Acute Ischemic Stroke A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association

Abstract: Background and Purpose—The authors present an overview of the current evidence and management recommendations for evaluation and treatment of adults with acute ischemic stroke. The intended audienc...

Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition

Abstract: The 3rd edition of the International Classification of Headache Disorders (ICHD-3) may be reproduced freely for scientific, educational or clinical uses by institutions, societies or individuals. Otherwise, copyright belongs exclusively to the International Headache Society. Reproduction of any part or parts in any manner for commercial uses requires the Society’s permission, which will be granted on payment of a fee. Please contact the publisher at the address below. International Headache Society 2013–2018. Applications for copyright permissions should be submitted to Sage Publications Ltd, 1 Oliver’s Yard, 55 City Road, London EC1Y 1SP, United Kingdom (tel: þ44 (0) 207 324 8500; fax: þ44 (0) 207 324 8600; permissions@sagepub.co.uk) (www.uk.sagepub.com). Translations

Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial

Abstract: BACKGROUND: In 2004, a randomised phase III trial by the European Organisation for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada Clinical Trials Group (NCIC) reported improved median and 2-year survival for patients with glioblastoma treated with concomitant and adjuvant temozolomide and radiotherapy. We report the final results with a median follow-up of more than 5 years. METHODS: Adult patients with newly diagnosed glioblastoma were randomly assigned to receive either standard radiotherapy or identical radiotherapy with concomitant temozolomide followed by up to six cycles of adjuvant temozolomide. The methylation status of the methyl-guanine methyl transferase gene, MGMT, was determined retrospectively from the tumour tissue of 206 patients. The primary endpoint was overall survival. Analyses were by intention to treat. This trial is registered with Clinicaltrials.gov, number NCT00006353. FINDINGS: Between Aug 17, 2000, and March 22, 2002, 573 patients were assigned to treatment. 278 (97%) of 286 patients in the radiotherapy alone group and 254 (89%) of 287 in the combined-treatment group died during 5 years of follow-up. Overall survival was 27.2% (95% CI 22.2-32.5) at 2 years, 16.0% (12.0-20.6) at 3 years, 12.1% (8.5-16.4) at 4 years, and 9.8% (6.4-14.0) at 5 years with temozolomide, versus 10.9% (7.6-14.8), 4.4% (2.4-7.2), 3.0% (1.4-5.7), and 1.9% (0.6-4.4) with radiotherapy alone (hazard ratio 0.6, 95% CI 0.5-0.7; p<0.0001). A benefit of combined therapy was recorded in all clinical prognostic subgroups, including patients aged 60-70 years. Methylation of the MGMT promoter was the strongest predictor for outcome and benefit from temozolomide chemotherapy. INTERPRETATION: Benefits of adjuvant temozolomide with radiotherapy lasted throughout 5 years of follow-up. A few patients in favourable prognostic categories survive longer than 5 years. MGMT methylation status identifies patients most likely to benefit from the addition of temozolomide. FUNDING: EORTC, NCIC, Nelia and Amadeo Barletta Foundation, Schering-Plough.

MGMT Gene Silencing and Benefit from Temozolomide in Glioblastoma

Abstract: background Epigenetic silencing of the MGMT (O 6 -methylguanine–DNA methyltransferase) DNArepair gene by promoter methylation compromises DNA repair and has been associated with longer survival in patients with glioblastoma who receive alkylating agents. methods We tested the relationship between MGMT silencing in the tumor and the survival of patients who were enrolled in a randomized trial comparing radiotherapy alone with radiotherapy combined with concomitant and adjuvant treatment with temozolomide. The methylation status of the MGMT promoter was determined by methylation-specific polymerase-chain-reaction analysis. results The MGMT promoter was methylated in 45 percent of 206 assessable cases. Irrespective of treatment, MGMT promoter methylation was an independent favorable prognostic factor (P<0.001 by the log-rank test; hazard ratio, 0.45; 95 percent confidence interval, 0.32 to 0.61). Among patients whose tumor contained a methylated MGMT promoter, a survival benefit was observed in patients treated with temozolomide and radiotherapy; their median survival was 21.7 months (95 percent confidence interval, 17.4 to 30.4), as compared with 15.3 months (95 percent confidence interval, 13.0 to 20.9) among those who were assigned to only radiotherapy (P=0.007 by the log-rank test). In the absence of methylation of the MGMT promoter, there was a smaller and statistically insignificant difference in survival between the treatment groups. conclusions Patients with glioblastoma containing a methylated MGMT promoter benefited from temozolomide, whereas those who did not have a methylated MGMT promoter did not have such a benefit.