Concurrent MEK targeted therapy prevents MAPK pathway reactivation during BRAFV600E targeted inhibition in a novel syngeneic murine glioma model.

Inhibitors of BRAFV600E kinase are currently under investigations in preclinical and clinical studies involving BRAFV600E glioma. Studies demonstrated clinical response to such individualized therapy in the majority of patients whereas in some patients tumors continue to grow despite treatment. To study resistance mechanisms, which include feedback activation of mitogen-activated protein kinase (MAPK) signaling in melanoma, we developed a luciferase-modified cell line (2341luc) from a BrafV600E mutant and Cdkn2a- deficient murine high-grade glioma, and analyzed its molecular responses to BRAFV600E- and MAPK kinase (MEK)-targeted inhibition. Immunocompetent, syngeneic FVB/N mice with intracranial grafts of 2341luc were tested for effects of BRAFV600E and MEK inhibitor treatments, with bioluminescence imaging up to 14-days after start of treatment and survival analysis as primary indicators of inhibitor activity. Intracranial injected tumor cells consistently generated high-grade glioma-like tumors in syngeneic mice. Intraperitoneal daily delivery of BRAFV600E inhibitor dabrafenib only transiently suppressed MAPK signaling, and rather increased Akt signaling and failed to extend survival for mice with intracranial 2341luc tumor. MEK inhibitor trametinib delivered by oral gavage daily suppressed MAPK pathway more effectively and had a more durable anti-growth effect than dabrafenib as well as a significant survival benefit. Compared with either agent alone, combined BRAFV600E and MEK inhibitor treatment was more effective in reducing tumor growth and extending animal subject survival, as corresponding to sustained MAPK pathway inhibition. Results derived from the 2341luc engraftment model application have clinical implications for the management of BRAFV600E glioma.

Detection of Cerebral Vasospasm Following Aneurysmal Subarachnoid Hemorrhage Using Motor Evoked Potentials.

BACKGROUND: Early detection of vasospasm (VS) following aneurysmal subarachnoid hemorrhage (aSAH) is vital to trigger therapy and to prevent infarction and subsequent permanent neurological deficit. Although motor evoked potentials (MEPs) are a well-established method for intraoperative detection of cerebral VS and cerebral ischemia during aneurysm surgery, there are no studies investigating the diagnostic value of MEPs for detecting delayed VS following aSAH in an intensive care unit. OBJECTIVE: A prospective study was conceived to assess the diagnostic accuracy of MEPs in comparison with digital subtraction angiography. METHODS: MEP threshold changes were determined in patients both with and without angiographic VS following high-grade aSAHs. Sensitivity, specificity, and the positive and negative predictive values of significant MEP threshold increases, which indicate angiographic VS, were calculated. RESULTS: In all patients experiencing VS of the arteries supplying cerebral motor areas, a minimal MEP threshold increase of 50 mA (mean 66.25 mA) was observed, whereas a maximum MEP threshold increase of 30 mA was observed in patients without VS. Therefore, an increase from a baseline of ≥50 mA was considered significant and resulted in a sensitivity of 0.83, a specificity of 0.92, a positive predictive value of 0.83, and a negative predictive value of 0.92. CONCLUSION: VS following aSAH can be detected accurately by using MEPs. MEPs are a feasible bedside tool for online VS detection in an intensive care unit and, therefore, may complement existing diagnostic tools.

Targeting a Plk1-Controlled Polarity Checkpoint in Therapy-Resistant Glioblastoma-Propagating Cells.

The treatment of glioblastoma (GBM) remains challenging in part due to the presence of stem-like tumor-propagating cells that are resistant to standard therapies consisting of radiation and temozolomide. Among the novel and targeted agents under evaluation for the treatment of GBM are BRAF/MAPK inhibitors, but their effects on tumor-propagating cells are unclear. Here, we characterized the behaviors of CD133(+) tumor-propagating cells isolated from primary GBM cell lines. We show that CD133(+) cells exhibited decreased sensitivity to the antiproliferative effects of BRAF/MAPK inhibition compared to CD133(-) cells. Furthermore, CD133(+) cells exhibited an extended G2-M phase and increased polarized asymmetric cell divisions. At the molecular level, we observed that polo-like kinase (PLK) 1 activity was elevated in CD133(+) cells, prompting our investigation of BRAF/PLK1 combination treatment effects in an orthotopic GBM xenograft model. Combined inhibition of BRAF and PLK1 resulted in significantly greater antiproliferative and proapoptotic effects beyond those achieved by monotherapy (P < 0.05). We propose that PLK1 activity controls a polarity checkpoint and compensates for BRAF/MAPK inhibition in CD133(+) cells, suggesting the need for concurrent PLK1 inhibition to improve antitumor activity against a therapy-resistant cell compartment.

Behavioral disorders and cognitive impairment associated with cerebellar lesions.

In the last decade evidence has accumulated that suggests that the cerebellum is involved not only in motor but also in behavioral and cognitive functions. A myriad of anatomical, clinical and imaging studies support that assumption. The lengthened survival of patients with cerebellar tumors has also brought an increased awareness of neurocognitive deficits to the neurooncological community. Although evidence from neurosurgical case series exists that clearly demonstrates that patients afflicted from posterior fossa tumors are at high risk for long-term cognitive or adaptive deficits, there is still a lack of systematic translational review on this issue. Accordingly a systematic review was conducted to summarize the impact of cerebellar lesions on behavior and cognition. The findings and clinical implications are discussed in the light of the recent advances in neuroimaging techniques.

Intraoperative somatosensory evoked potential recovery following opening of the fourth ventricle during posterior fossa decompression in Chiari malformation: case report.

The most appropriate surgical technique for posterior fossa decompression in Chiari malformation (CM) remains a matter of debate. Intraoperative electrophysiological studies during posterior fossa decompression of Type I CM (CM-I) aim to shed light on the entity's pathomechanism as well as on the ideal extent of decompression. The existing reports on this issue state that significant improvement in conduction occurs after craniotomy in all cases, but additional durotomy contributes a further improvement in only a minority of cases. This implies that craniotomy alone might suffice for clinical improvement without the need of duraplasty or even subarachnoid manipulation at the level of the craniocervical junction. In contrast to published data, the authors describe the case of a 32-year-old woman who underwent surgery for CM associated with extensive cervicothoracic syringomyelia and whose intraoperative somatosensory evoked potentials (SSEPs) did not notably improve after craniotomy or following durotomy; rather, they only improved after opening of the fourth ventricle and restoration of CSF flow through the foramen of Magendie. Postoperatively, the patient recovered completely from her preoperative neurological deficits. To the authors' knowledge, this is the first report of significant SSEP recovery after opening the fourth ventricle in the decompression of a CM-I. The electrophysiological and operative techniques are described in detail and the findings are discussed in the light of available literature. The authors conclude that there might be a subset of CM-I patients who require subarachnoid dissection at the level of the craniocervical junction to benefit clinically. Prospective studies with detailed electrophysiological analyses seem warranted to answer the question regarding the best surgical approach in CM-I decompression.

Repetitive long-term hyperbaric oxygen treatment (HBOT) administered after experimental traumatic brain injury in rats induces significant remyelination and a recovery of sensorimotor function.

Cells in the central nervous system rely almost exclusively on aerobic metabolism. Oxygen deprivation, such as injury-associated ischemia, results in detrimental apoptotic and necrotic cell loss. There is evidence that repetitive hyperbaric oxygen therapy (HBOT) improves outcomes in traumatic brain-injured patients. However, there are no experimental studies investigating the mechanism of repetitive long-term HBOT treatment-associated protective effects. We have therefore analysed the effect of long-term repetitive HBOT treatment on brain trauma-associated cerebral modulations using the lateral fluid percussion model for rats. Trauma-associated neurological impairment regressed significantly in the group of HBO-treated animals within three weeks post trauma. Evaluation of somatosensory-evoked potentials indicated a possible remyelination of neurons in the injured hemisphere following HBOT. This presumption was confirmed by a pronounced increase in myelin basic protein isoforms, PLP expression as well as an increase in myelin following three weeks of repetitive HBO treatment. Our results indicate that protective long-term HBOT effects following brain injury is mediated by a pronounced remyelination in the ipsilateral injured cortex as substantiated by the associated recovery of sensorimotor function.

Intraoperative neurophysiology of the motor system in children: a tailored approach.

INTRODUCTION: Intraoperative neurophysiology has moved giant steps forward over the past 15 years thanks to the advent of techniques aimed to reliably assess the functional integrity of motor areas and pathways. INTRAOPERATIVE NEUROPHYSIOLOGICAL TECHNIQUES: Motor evoked potentials recorded from the muscles and/or the spinal cord (D-wave) after transcranial electrical stimulation allow to preserve the integrity of descending pathways, especially the corticospinal tract (CT), during brain and spinal cord surgery. Mapping techniques allow to identify the motor cortex through direct cortical stimulation and to localize the CT at subcortical levels during brain and brainstem surgery. These techniques are extensively used in adult neurosurgery and, in their principles, can be applied to children. However, especially in younger children, the motor system is still under development, making both mapping and monitoring techniques more challenging. In this paper, we review intraoperative neurophysiological techniques commonly used in adult neurosurgery and discuss their application to pediatric neurosurgery, in the light of preliminary experience from our and other centers. The principles of development and maturation of the motor system, and especially of the CT, are reviewed focusing on clinical studies with transcranial magnetical stimulation.