Review: on TRAIL for malignant glioma therapy?

Glioblastoma (GBM) is a devastating cancer with a median survival of around 15 months. Significant advances in treatment have not been achieved yet, even with a host of new therapeutics under investigation. Therefore, the quest for a cure for GBM remains as intense as ever. Of particular interest for GBM therapy is the selective induction of apoptosis using the pro-apoptotic tumour necrosis factor-related apoptosis-inducing ligand (TRAIL). TRAIL signals apoptosis via its two agonistic receptors TRAIL-R1 and TRAIL-R2. TRAIL is normally present as homotrimeric transmembrane protein, but can also be processed into a soluble trimeric form (sTRAIL). Recombinant sTRAIL has strong tumouricidal activity towards GBM cells, with no or minimal toxicity towards normal human cells. Unfortunately, GBM is a very heterogeneous tumour, with multiple genetically aberrant clones within one tumour. Consequently, any single agent therapy is likely to be not effective enough. However, the anti-GBM activity of TRAIL can be synergistically enhanced by a variety of conventional and novel targeted therapies, making TRAIL an ideal candidate for combinatorial strategies. Here we will, after briefly detailing the biology of TRAIL/TRAIL receptor signalling, focus on the promises and pitfalls of recombinant TRAIL as a therapeutic agent alone and in combinatorial therapeutic approaches for GBM.

The role of CXC chemokine ligand (CXCL)12-CXC chemokine receptor (CXCR)4 signalling in the migration of neural stem cells towards a brain tumour.

AIMS: It has been shown that neural stem cells (NSCs) migrate towards areas of brain injury or brain tumours and that NSCs have the capacity to track infiltrating tumour cells. The possible mechanism behind the migratory behaviour of NSCs is not yet completely understood. As chemokines are involved in the migration of immune cells in the injured brain, they may also be involved in chemoattraction of NSCs towards a brain tumour. METHODS: The expression profile of various chemokine receptors in NSCs, harvested from the subventricular zone of adult mice, was investigated by reverse transcriptase- polymerase chain reaction analysis. Furthermore, the functionality of the chemokine receptors was assessed in in vitro chemotaxis assays and calcium signalling experiments. To test the in vivo migration of NSCs, a syngeneic mouse model was developed, whereby a B16F10 melanoma cell line was grafted into one hemisphere and later NSCs were grafted in the contralateral hemisphere. Furthermore, the expression of chemokines in this melanoma cell line was investigated. RESULTS AND CONCLUSIONS: Adult mouse NSCs functionally express various chemokine receptors of which CXC chemokine receptor (CXCR)4 shows the highest mRNA levels and most pronounced functional responses in vitro. CXC chemokine ligand (CXCL)12, the ligand for CXCR4, is expressed by the melanoma cell line. In this mouse model for metastatic brain tumours, it is shown that NSCs express CXCR4 at their cell membranes while they migrate towards the tumour, which produces CXCL12. It is therefore suggested that the CXCR4/CXCL12 pathway plays a role in the mechanism underlying tumour-mediated attraction of NSCs.

CME for neurosurgeons in the Netherlands: the "quality" conferences.

In 1993 the Netherlands Society for Neurosurgery started a yearly event, a "Quality Conference", specifically devoted to continuous medical education (CME). These conferences differ from "normal" scientific meetings, in the choice for specific topics, in the preparation with inquiries among all the Dutch neurosurgical centres, and in the way the results of these inquiries are discussed, preceded by lectures concerning the chosen topic by guest faculty and Dutch neurosurgeons. Each year's principal guest delivers the "Beks Lecture", named after the former professor in Neurosurgery in Groningen, Jan Beks. On several occasions, the foreign guests suggested to present this format for a larger neurosurgical forum. Therefore, it was decided to describe the various aspects of this format for CME in the Netherlands in a paper for Acta Neurochirugica. Examples of topics are given, a summary of two recent inquiries are presented and discussed, and the way of organizing such a conference including finance and the obligatory character are described.

Neurostimulation as a new treatment for severe tinnitus: a pilot study.

BACKGROUND: Tinnitus is an uncomfortable symptom for the patient and an embarrassing one for the consulted physician. So far, there is no treatment that can be considered well established in terms of providing long-term reduction of tinnitus in excess of placebo effects. There is considerable evidence of pathophysiological similarity between tinnitus and chronic pain. Some forms of chronic pain can be treated by neurostimulation. OBJECTIVE: This study was designed to investigate the feasibility of neurostimulation of the cochlear nerve in order to reduce tinnitus. STUDY DESIGN: Pilot study. SETTING: Tertiary referral center. PATIENTS: Five patients with therapeutically refractory tinnitus were selected for this study. INTERVENTION: Placing a stimulation lead around the cochlear nerve through the suboccipital approach and connecting the stimulation lead to a pulse generator. MAIN OUTCOME MEASURES: The patients experienced 1) an absence of major or minor complications, such as death, meningitis, cranial nerve deficit, and vestibular problems; 2) tolerance of the procedure as considered by the patient; 3) relief of tinnitus in at least one patient. RESULTS: Implantation of the neurostimulation system was accomplished in each patient without any difficulty. None of the patients considered the treatment unbearable. No major or minor complications occurred in this study. Subjective tinnitus reduction was accomplished in four patients. CONCLUSION: Our preliminary data show that neurostimulation of the cochlear nerve is feasible, is bearable for the patient, and is a safe treatment modality without major complications. The effects on tinnitus are promising.

High frequency of TP53 mutations in juvenile pilocytic astrocytomas indicates role of TP53 in the development of these tumors.

In adults, the TP53 tumor suppressor gene is frequently mutated in astrocytic brain tumors which is supposed to represent an early event in their development. In juvenile pilocytic and low-grade astrocytomas, however, TP53 mutations have until now been reported as rare, which has led to the suggestion that these tumors may follow a different molecular pathogenesis with an involvement of genes other than TP53. Our analysis of 20 pilocytic and two low-grade astrocytomas of childhood, based on a comprehensive denaturing gradient gel electrophoresis (DGGE) mutation detection assay of the entire coding region, including all splice site junctions of TP53, showed mutations considered as causative in 7 of the 20 (35%) pilocytic astrocytomas and in one of the two low-grade astrocytomas. Our finding is significantly different from the mutation frequency of 1.3% (2/155) previously reported for these tumor types. This may be attributed to the mutation detection system used, which also detects mutations occurring outside the evolutionary conserved region of TP53. Our results suggest that, contrary to the present notion, TP53 mutations may well play a role in the development of juvenile astrocytomas. Furthermore, no mutations were found in tumors of patients with progression of residual tumor after postoperative follow-up. This suggests that TP53 mutations may be associated with less aggressive forms of juvenile astrocytomas, analogous to the situation in adult astrocytomas.

Influence of chloride and sodium pump activity on carbachol- and acetylaholine-induced depolarizations in denervated rat diphragm.

The effect was measured of low chloride medium and ouabain on carbachol- and acetylcholine-induced depolarizations in denervated rat diaphragm. Membrane potentials were measured in rat diaphragm muscle fibers 10-14 days after denervation. Depolarizations induced by carbachol and acetycholine were increased when the extracellular chloride concentration was diminished from 110 to 40 or 10 mM. Sodium pump inhibition by ouabain (10(-4) M) dramatically enhanced the carbachol depolarizations. In 40 mM Cl- solutions, dose-response relations were determineed with ACh in the absence of presence of dTc. For ACh a pD2 value of 5.2 was found; the pA2 value for dTC appeared to be about 6.4. Therefore, the binding properties of the post-denervational receptors do not appear to be influenced by the chloride gradient. It was concluded that drug-induced depolarizations of the denervated rat diaphragm are short-circuited by chloride ions and counteracted by sodium pumping.

The masking role of the sodium pump and chloride ions on the effect of carbachol in- and outside the endplate region of rat diaphragm muscle.

The effect of carbachol (10(-3)M) on the membrane potential of rat diaphragm muscle fibres near and remote from the endplate has been investigated by means of a microelectrode technique. In the endplate region a rather slow depolarization was observed followed by spontaneous repolarization. Outside the endplate region similar, but smaller, responses could be measured. In a muscle part separated from the endplate zone, carbachol had no depolarizing effect. Inhibition of the sodium pump by ouabain (10(-4)M) or potassium-free medium not changing the membrane potential itself, allowed carbachol to exert a depolarizing effect on this endplate-free membrane, while in endplate-free regions continuous with the endplate-zone the depolarizations already observed were enhanced. In low chloride solutions carbachol also had a depolarizing effect on endplate-free muscle membrane. It is concluded from these experiments that a direct effect of cholinergic drugs on endplate-free muscle membrane of rat diaphragm is counteracted by the sodium pump in combination with passive chloride movements. The results are discussed in the context of known receptor densities and chloride effects.

Somatosensory evoked potential monitoring of temporary middle cerebral artery occlusion during aneurysm operation.

Somatosensory evoked potentials (SEPs) in response to median nerve stimulation were used as a guide to cortical function during temporary occlusion of the distal M1 segment of the middle cerebral artery (MCA) in the surgical treatment of five large aneurysms of the MCA bifurcation. MCA occlusion times ranged from 8 to 19 minutes under moderate hypothermia at 28.8 degrees to 30.3 degrees C. SEPs were preserved for variable times during MCA occlusion, ranging from no increase in latency after 13 minutes of occlusion to severe deterioration after 6 minutes. In no case was MCA occlusion maintained for longer than 3 minutes in the presence of a severely disturbed SEP. Recovery of the SEP to its preoperative relationship with that of the nonoperated hemisphere was seen in all cases before the end of operation. All patients were awake after rewarming at the end of operation without any neurological deficit. Monitoring the SEP pertaining to the territory of a cerebral artery during its temporary occlusion can help avoid ischemic damage and will allow the surgeon to take advantage of the several benefits of this technique in aneurysm surgery.

The acoustic detection of intracranial aneurysms: a clinical study.

A new recording method for the acoustical detection of intracranial aneurysms is presented. A study examining the capability of the method to discriminate between patients with an aneurysm and control patients by a simple, objective parameter is reported. Sound signals were recorded over the eyes, and a real-time spectral analysis was performed on these signals. For this study, recordings performed on 26 patients with an aneurysm were compared with recordings on 26 age- and sex-matched control patients without intracerebral abnormalities. As a result of measures taken to reduce artifacts and to improve the signal-to-noise ratio, the measurements were performed reliably, with little inconvenience for the patients; all measurements could be used for analysis. The power spectra measured in the control patients showed a typical, smoothly descending pattern; those measured in the aneurysm patients clearly differed from this pattern, showing peaks of varying width, height, and dominant frequency. For the objective judgment of the power spectra, the power median is introduced. The sensitivity and specificity of this parameter were determined. Possible methods to improve the results will be discussed.

Hemifacial spasm: intraoperative electromyographic monitoring as a guide for microvascular decompression.

OBJECTIVE: Microvascular decompression is the logical and well-accepted treatment of choice for hemifacial spasm (HFS). In experienced hands, good to excellent results can be obtained. However, sometimes the exact site of the vascular compression is unclear. The aim of this study was to analyze whether intraoperative monitoring by stimulated electromyography of the facial nerve may help to improve the results of vascular decompression for HFS. METHODS: In a series of 74 patients operated for HFS, the impact of intraoperative facial nerve monitoring on the surgical procedure was analyzed by use of the clinical and operative patient records. The role of this type of monitoring, with assessment of the so-called abnormal muscle response, was broken down into four categories: a guiding, a confirming, an indirect confirming, or an inconclusive role. The relationship between abnormal muscle response monitoring results and final surgical outcome was analyzed. RESULTS: The overall cure rate was 87.8%, including patients who had previously undergone unsuccessful operations. Complications were minor, and hearing impairment was found in 2.7% of patients. A guiding role of intraoperative monitoring was apparent in 33.8% of patients, and a confirming role was demonstrated in 52.7% of patients, which resulted in a positive contribution of approximately 87% for intraoperative facial monitoring in microvascular decompression for HFS. In patients defined as guiding cases, the cure rate was 92%. CONCLUSION: This study demonstrates the applicability and usefulness of intraoperative facial nerve monitoring in microvascular decompression operations for HFS.

Follow-up of 13 patients with surgical treatment of cerebral cavernous malformations: effect on epilepsy and patient disability.

OBJECTIVE: We report a series of 13 patients with surgical treatment of cerebral cavernous malformation (CM). The aim of this study was to investigate postoperative patient disability and seizure control in patients with CM in order to clarify indications for neurosurgical removal. In our series we emphasize the beneficial effect of excision of CMs. We also give an overview of the current literature covering options for treatment in surgically inaccessible CMs. METHODS: In this retrospective study we describe the clinical outcomes of neurosurgical intervention in 13 patients with a CM. Seven patients had epilepsy at presentation and six had focal neurological deficits due to intracerebral haemorrhage (five patients) or mass effect due to the CM (one patient). The modified Rankin scale was used to define patient disability pre- and postoperatively. An overview of the indications for surgery and postoperative outcome with follow up periods of 1-6 years (mean: 3.3 years) are provided. RESULTS: In all patients presenting with epilepsy a reduction in seizure frequency was seen. Four of them became seizure-free postoperatively. The six patients with neurological deficits due to intracerebral haemorrhage or mass effect due to the CM showed clinical improvement postoperatively, two of them made full recoveries. Improvement of the postoperative Rankin score was seen in six of 13 patients. CONCLUSION: Improvement in seizure control and reduction in patient disability warrants surgical intervention in symptomatic CMs.

Design and application of sensor for recording sounds over human eye and nose.

The recording of sounds over the orbit of the eye has been found to be useful in the detection of intracranial aneurysms. A hydrophone for auscultation over the eye has been developed and is tested under controlled conditions. The tests consist of measurement over the eyes in three healthy volunteers at rest, during voluntary breathing, during eyeball movements and during sustained orbicular muscular contractions. Furthermore, measurements are performed at the side of the nose. Major features of the hydrophonic transducer are high sensitivity to physiological sounds and a high degree of insensitivity to environmental sounds propagated through the air. It can be concluded that the hydrophone may be useful for the early detection of intracranial aneurysms and also for apnoea detection.

[Hemifacial spasms caused by neurovascular compression]. / Hemifaciale spasmen door neurovasculaire compressie.

Three patients, one woman aged 52 years and two men aged 63 and 71 years, respectively, had involuntary movement on one side of their face due to hemifacial spasms. The first patient's spasms were misdiagnosed as a tic, the second patient had received injections of botulinum A toxin which gave no improvement and the third patient suffered from persistent symptoms after a first neurovascular decompression without intraoperative EMG monitoring. All three patients underwent microvascular decompression of the facial nerve with intraoperative EMG monitoring. All three patients were cured. Hemifacial spasm is a curable illness if appropriately diagnosed and treated. Oral medications have no effect on the disease. Local injection of botulinum A toxin is indicated when the spasm is mild or when surgery is contraindicated. The primary causative factor is vascular compression of the facial nerve at its exit zone. Therefore, decompressive surgery is the logical treatment, and the best results are obtained with intraoperative EMG monitoring.