Epidermal growth factor receptor overexpression is common and not correlated to gene copy number in ependymoma.

PURPOSE: The aim of this study was to investigate the epidermal growth factor receptor (EGFR) status in ependymoma specimens, as there is a need for new prognostic and druggable targets in this disease. METHODS: Ependymomas (WHO grade II, n = 40; WHO grade III, n = 15) located spinal (n = 35), infratentorial (n = 14), and supratentorial (n = 6) of 53 patients with a median age of 40 (range, 2-79) years were analyzed for Ki-67, p53, and EGFR expression by immunohistochemistry using a tissue microarray and for EGFR gene copy number alterations/mutations. Results were correlated to clinical data. RESULTS: EGFR overexpression was found in 30/60% of ependymomas depending on the antibody used and was more pronounced in WHO grade III. High EGFR gene copy number gains were found in 6 (11%) ependymomas with half of them being amplifications. EGFR amplified ependymomas displayed an EGFR overexpression with both antibodies in two of three cases. A missense mutation in exon 20 of EGFR (S768I) was detected in one amplified case. CONCLUSIONS: EGFR is frequently overexpressed in ependymomas. Other mechanisms than amplification of the EGFR gene appear to contribute to EGFR overexpression in most cases. EGFR mutations may be present in a small subset of ependymomas.

Impaired coagulation is a risk factor for clinical and radiologic deterioration in patients with traumatic brain injury and isolated traumatic subarachnoid hemorrhage.

BACKGROUND: Isolated traumatic subarachnoid hemorrhage (itSAH) is found in approximately 25% of all patients with mild traumatic brain injury (TBI). The aim of this study was to analyze the clinical course and identify risk factors for potential clinical and radiologic deterioration in consideration of impaired coagulation in patients with itSAH. METHODS: A retrospective analysis of 735 patients with TBI resulting in a pathologic computer-assisted tomography (CAT) was performed. Only those patients with itSAH and Glasgow Coma Scale (GCS) of greater than 8 points and follow-up CAT scan were included. Patients with hemorrhage in any other brain compartment (subdural, epidural, and intracerebral) were excluded. Impaired coagulation was operationally defined. RESULTS: Of the 735 patients, 89 met the inclusion criteria. The majority of these patients experienced mild TBI. The rate of radiologic expansion or conversion of the SAH was 28.1%. The rate of clinical deterioration was 6.7%. Neither the initial pattern of itSAH on different intracranial localizations nor the number of sulci involved in the itSAH was associated with clinical worsening. The rate of patients with impaired coagulation was 38%; 17.9% of all patients showed elevated international normalized ratio (INR). Radiologic and clinical deterioration was significantly associated with elevated INR. INR was shown to be independent of age in a logistic regression analysis. CONCLUSION: TBI patients with itSAH and impaired coagulation especially those who showed elevated INR are at risk of clinical and radiologic deterioration. Despite coagulation status, routine repetition of cranial CAT scan is advised in patients with itSAH to detect potential radiologic worsening, which if occurring should result in close clinical monitoring. LEVEL OF EVIDENCE: Therapeutic study, level IV; prognostic study, level III.

Monoamines block kainate- and carbachol-induced gamma-oscillations but augment stimulus-induced gamma-oscillations in rat hippocampus in vitro.

Monoamines are implicated in a cognitive processes in a variety of brain regions, including the hippocampal formation, where storage and retrieval of information are facilitated by synchronous network activities. We have investigated the effects of norepinephrine, serotonin, and dopamine on carbachol-, kainate-, and stimulus-induced hippocampal gamma-oscillations employing combined extra- and intracellular recordings. Monoamines dose-dependently and reversibly suppressed kainate- and carbachol-induced gamma-oscillations while increasing the frequency. The effect of serotonin was mimicked by fenfluramine, which releases serotonin from presynaptic terminals. Forskolin also suppressed kainate- and carbachol-induced gamma-oscillations. This effect was mimicked by 8-Br-cAMP and isoproterenol, an agonist of noradrenergic beta-receptor suggesting that the monoamines-mediated suppression of these oscillations could involve intracellular cyclic adenosine 3',5'-cyclic monophosphate (AMP). By contrast, stimulus-induced gamma-oscillations were dose-dependently augmented in power and duration after monoamines application. Intracellular recordings from pyramidal cells revealed that monoamines prolonged the stimulus-induced depolarization and membrane potential oscillations. Stimulus-induced gamma-oscillations were also suppressed by isoproterenol, the D1 agonist SKF-38393 forskolin, and 8-Br-cAMP. This suggests that the augmentation of stimulus-induced gamma-oscillations by monoamines involves--at least in part-different classes of cells than in case of carbachol- and kainate-induced gamma-oscillations.

Induction of sharp wave-ripple complexes in vitro and reorganization of hippocampal networks.

Hippocampal sharp wave-ripple complexes (SPW-Rs) occur during slow-wave sleep and behavioral immobility and are thought to represent stored information that is transferred to the neocortex during memory consolidation. Here we show that stimuli that induce long-term potentiation (LTP), a neurophysiological correlate of learning and memory, can lead to the generation of SPW-Rs in rat hippocampal slices. The induced SPW-Rs have properties that are identical to spontaneously generated SPW-Rs: they originate in CA3, propagate to CA1 and subiculum and require AMPA/kainate receptors. Their induction is dependent on NMDA receptors and involves changes in interactions between clusters of neurons in the CA3 network. Their expression is blocked by low-frequency stimulation but not by NMDA receptor antagonists. These data indicate that induction of LTP in the recurrent CA3 network may facilitate the generation of SPW-Rs.