Co-Planar Stereotaxic Atlas of the Human Brain—3-Dimensional Proportional System: An Approach to Cerebral Imaging, J. Talairach, P. Tournoux. Georg Thieme Verlag, New York (1988), 122 pp., 130 figs. DM 268

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...

/pdf/guidelines-for-the-early-management-of-patients-with-acute-19udbft6e7.pdf

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

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

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

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.

https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(09)70025-7.pdf

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

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.

/pdf/mgmt-gene-silencing-and-benefit-from-temozolomide-in-24olu5dmi6.pdf

MGMT Gene Silencing and Benefit from Temozolomide in Glioblastoma

Das Medulloblastom ist der haufigste
maligne Hirntumor im Kindes- und Jugendalter. Medulloblastome
bei Erwachsenen sind relativ selten und stellen nur einen Anteil
von 1% aller Hirntumoren des Erwachsenenalters. Die Inzidenz bei
Erwachsenen wird um 0,5/Mio./Jahr angegeben [11, 26], betragt
jedoch in der Altersgruppe von 15–19 Jahren um 2,33/Mio./Jahr
und nimmt dann mit steigendem Alter kontinuierlich ab [26]. Der
Beginn des Erwachsenenalters wird in der Literatur
unterschiedlich definiert. Die meisten der klinischen Studien
schliesen diesbezuglich Patienten >15 Jahre
ein.
 Die Gruppe der sog. embryonalen
Tumoren reprasentieren im Kindesalter mit einem Anteil von 25%
unter den Hirntumoren die zweithaufigste Entitat. Sie entstehen
wahrscheinlich aus unreifen neuralen Progenitorzellen des ZNS.
Am haufigsten ist ein primitiv neuroektodermaler Tumor (PNET),
der zu 85% vom Kleinhirn ausgeht und dann Medulloblastom genannt
wird [24]. Nach der WHO-Klassifikation fur zentralnervose
Tumoren sollte der Begriff PNET ausschlieslich solchen Tumoren
vorbehalten sein, die Eigenschaften eines primitiv
neuroektodermalen Zelltyps im engeren Sinn auspragen
[53].

Medulloblastome im erwachsenenalter

The capability of the adult central nervous system to self-repair/regenerate was demonstrated repeatedly throughout the last decades but remains in debate. Reduced neurogenic niche activity paralleled by a profound neuronal loss represents fundamental hallmarks in the disease course of neurodegenerative disorders. We and others have demonstrated the endogenous TGFβ system to represent a potential pathogenic participant in disease progression, of amyotrophic lateral sclerosis (ALS) in particular, by generating and promoting a disequilibrium of neurodegenerative and neuroregenerative processes. The novel human/primate specific LNA Gapmer Antisense Oligonucleotide “NVP-13”, targeting TGFBR2, effectively reduced its expression and lowered TGFβ signal transduction in vitro and in vivo, paralleled by boosting neurogenic niche activity in human neuronal progenitor cells and nonhuman primate central nervous system. Here, we investigated NVP-13 in vivo pharmacology, safety, and tolerability following repeated intrathecal injections in nonhuman primate cynomolgus monkeys for 13 weeks in a GLP-toxicology study approach. NVP-13 was administered intrathecally with 1, 2, or 4 mg NVP-13/animal within 3 months on days 1, 15, 29, 43, 57, 71, and 85 in the initial 13 weeks. We were able to demonstrate an excellent local and systemic tolerability, and no adverse events in physiological, hematological, clinical chemistry, and microscopic findings in female and male Cynomolgus Monkeys. Under the conditions of this study, the no observed adverse effect level (NOAEL) is at least 4 mg/animal NVP-13.

/pdf/safe-and-effective-cynomolgus-monkey-glp-tox-study-with-2vtk9dlc.pdf

Safe and Effective Cynomolgus Monkey GLP—Tox Study with Repetitive Intrathecal Application of a TGFBR2 Targeting LNA-Gapmer Antisense Oligonucleotide as Treatment Candidate for Neurodegenerative Disorders

OBJECTIVE: G-CSF may compensate rapid neuronal loss in ALS. Therefore we initiated long-term compassionate use of G-CSF in ALS patients.
 BACKGROUND: Granulocyte-colony-stimulating factor (G-CSF) is a long-term established and safe hematopoietic growth factor. It is neuroprotective, increases neurogenesis and induces neuronal differentiation. Despite evidence for efficacy in ALS animal models, multiple small trials with G-CSF in patients delivered inconclusive results. Functional improvement might have been missed due to inadequate application and duration of treatment with short follow up.
 DESIGN/METHODS: 23 ALS patients (15 male, 8 female, mean age 51,4 yrs. (±13.2), mean ALS-FRS-r at start 36.75 (± 6.84)) were treated with G-CSF 5-10 μg/kg BW s.c. plus standard treatment incl. Riluzole. Application modes were individually adapted with (1) G-CSF for five consecutive days every four weeks (mean: 26.3 treatment months (8 - 49)) or (2) G-CSF twice a week (mean 23.2 treatment months (8 - 31)). Monthly control visits with clinical exams, ALSFRS-r, clinical chemistry, blood smears, bone marrow function were performed.
 RESULTS: Compliance was excellent, aside from mild to moderate bone pain in all patients, application modes were well tolerated.
Both modes of delivery resulted in hematopoietic stem cell mobilization and biomarker modulation. We found no evidence of premalignant changes in bone marrow differentiation. In retrospective analysis a significant decrease in ALS progression rate - ALS-FRS-r - and clinical relevant prolongation of overall survival in comparison to the current Pro-ACT database, indicate high safety of prolonged G-CSF treatment.
 CONCLUSIONS: Long-term administration of G-CSF in ALS patients is safe and feasible. Compliance of outpatient regimens is excellent. A prospective trial is very urgently needed. Disclosure: Dr. Khomenko has nothing to disclose. Dr. Baldaranov has nothing to disclose. Dr. Johannesen has nothing to disclose. Dr. Kobor has nothing to disclose. Dr. Blume has nothing to disclose. Dr. Bruun has nothing to disclose. Dr. Grassinger has nothing to disclose. Dr. Kammermaier has nothing to disclose. Dr. Ludolph has nothing to disclose. Dr. Deppe has nothing to disclose. Dr. Schuierer has nothing to disclose. Dr. Schulte-Mattler has nothing to disclose. Dr. Friede has nothing to disclose. Dr. Laage has nothing to disclose. Dr. Schneider has nothing to disclose. Dr. Bogdahn has nothing to disclose.

Safety and Feasibility of G-CSF Compassionate use in ALS Patients (P6.009)

A 49-year-old man with no significant medical history was seen by a neurologic consultant in eastern Bavaria, Germany, after he developed weakness of both arms. A few days earlier he had been referred to the internal medicine department with flu-like symptoms lasting for 2 weeks, which improved only transiently with trimethoprim/sulfamethoxazole for suspected urinary tract infection. The neurologic examination revealed an alert and oriented patient who was febrile (39.8°C, 103.6°F) but without meningeal signs or headache. He had normal cranial nerves and weakness of the shoulder girdle and both proximal arms. He had no sensory deficits, was hyporeflexic, and had flexor plantar responses. Gait was unsteady. Bladder function was reportedly normal. The patient was a passionate mushroom hunter and had no sick contacts.

The authors thank the patient, Dr. G. Schuierer for providing the MRI, and Dr. L. Walter for comments on the manuscript.

https://n.neurology.org/content/neurology/82/8/e65.full.pdf

Ulrich Bogdahn

Papers

Medulloblastome im erwachsenenalter

Safe and Effective Cynomolgus Monkey GLP—Tox Study with Repetitive Intrathecal Application of a TGFBR2 Targeting LNA-Gapmer Antisense Oligonucleotide as Treatment Candidate for Neurodegenerative Disorders

Safety and Feasibility of G-CSF Compassionate use in ALS Patients (P6.009)

Clinical reasoning: a 49-year-old man with fever and proximal weakness of his arms.

Deuterium enthaltende pharmazeutische zusammensetzung zur abtötung von tumoren