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.

Multislice CT angiography in the selection of patients with ruptured intracranial aneurysms suitable for clipping or coiling.

INTRODUCTION: We sought to establish whether CT angiography (CTA) can be applied to the planning and performance of clipping or coiling in ruptured intracranial aneurysms without recourse to intraarterial digital subtraction angiography (IA-DSA). METHODS: Over the period April 2003 to January 2006 in all patients presenting with a subarachnoid haemorrhage CTA was performed primarily. If CTA demonstrated an aneurysm, coiling or clipping was undertaken. IA-DSA was limited to patients with negative or inconclusive CTA findings. We compared CTA images with findings at surgery or coiling in patients with positive CTA findings and in patients with negative and inconclusive findings in whom IA-DSA had been performed. RESULTS: In this study, 224 consecutive patients (mean age 52.7 years, 135 women) were included. In 133 patients (59%) CTA demonstrated an aneurysm, and CTA was followed directly by neurosurgical (n = 55) or endovascular treatment (n = 78). In 31 patients (14%) CTA findings were categorized as inconclusive, and in 60 (27%) CTA findings were negative. One patient received surgical treatment on the basis of false-positive CTA findings. In 17 patients in whom CTA findings were inconclusive, IA-DSA provided further diagnostic information required for correct patient selection for any therapy. Five ruptured aneurysms in patients with a nonperimesencephalic SAH were negative on CTA, and four of these were also false-negative on IA-DSA. On a patient basis the positive predictive value, negative predictive value, sensitivity, specificity and accuracy of CTA for symptomatic aneurysms were 99%, 90%, 96%, 98% and 96%, respectively. CONCLUSION: CTA should be used as the first diagnostic modality in the selection of patients for surgical or endovascular treatment of ruptured intracranial aneurysms. If CTA renders inconclusive results, IA-DSA should be performed. With negative CTA results the complementary value of IA-DSA is marginal. IA-DSA is not needed in patients with negative CTA and classic perimesencephalic SAH. Repeat IA-DSA or CTA should still be performed in patients with a nonperimesencephalic SAH.

Long-term evaluation of treatment of chronic, therapeutically refractory tinnitus by neurostimulation.

OBJECTIVE: Long-term evaluation of treatment of chronic, therapeutically refractory tinnitus by means of chronic electrical stimulation of the vestibulocochlear nerve. PATIENTS: Inclusion criteria were severe, chronic, therapeutically refractory, unilateral tinnitus and severe hearing loss at the ipsilateral site. Out of 6 patients, 4 patients were selected for long-term evaluation. Two patients were not evaluated because of premature dropout. MATERIAL AND METHODS: A stimulation electrode was placed around the vestibulocochlear nerve through a retrosigmoid approach and connected to a subcutaneously positioned pulse generator via an extension cable. Follow-up was performed 3 months and 42.5 months after implantation. Three measures for treatment outcome were used. First, effect sizes were determined by means of the total Tinnitus Handicap Inventory (THI) score using Cohen's formula. Second, general and tinnitus-specific audiometric tests were performed in on and off conditions of the neurostimulation system. Third, recordings were noted for tinnitus severity and treatment success on a visual analogue scale. RESULTS: All 4 patients reported successful treatment with neurostimulation. The effect size after 3 months was 0.7, indicating an average effect, while the effect size measured during long-term follow-up was 1.75, indicating a substantial effect with major clinical implications. No changes in hearing level for both ears were measured. The neurostimulation system did not change the tinnitus pitch in any of the patients, and resulted in a minimal reduction of tinnitus loudness in only 2 patients. In all 4 patients the original tinnitus sound was replaced by another, pleasantly perceived sound. The average VAS score of perceived tinnitus severity was reduced from 8 to 3.25. The average VAS score for treatment success was 7.25. CONCLUSIONS: The long-term follow-up of neurostimulation treatment for chronic tinnitus shows promising results. Long-term results were better than those determined after a 3-month follow-up. In all patients the tinnitus was replaced by another sound, which was perceived as pleasant. Further studies are needed before accepting neurostimulation as a treatment modality for chronic, therapeutically refractory tinnitus.

Improvement after treatment of hydrocephalus in aneurysmal subarachnoid haemorrhage: implications for grading and prognosis.

Two patients with aneurysmal subarachnoid haemorrhage and hydrocephalus are presented. On admission they scored E1M4V1 and E1M3Vtube on the Glasgow Coma Scale. The first patient recovered to E3M5Vtube after treatment of hydrocpehalus by extraventricular drainage. The second recovered to E2M5Vtube and later E4M6V4 after treatment of hydrocephalus with lumbar drainage. Based on the literature it is argued that these cases are no exception as to the improvement after treatment of hydrocephalus. The prognosis of patients with hydrocephalus after a subarachnoid haemorrhage, improves in parallel with the Glasgow Coma Scale after treatment of hydrocephalus. Therefore decision making on whether or not to treat a patient with a subarachnoid haemorrhage should be postponed until after treatment of hydrocephalus, if present.

Time-of-flight magnetic resonance angiography in the follow-up of intracranial aneurysms treated with Guglielmi detachable coils.

The purpose of this study was to evaluate time-of-flight magnetic resonance angiography (MRA) in the follow-up of intracranial aneurysms treated with Guglielmi detachable coils (GDCs). From January 1998 to January 2002 27 MRA and intra-arterial digital subtraction angiography (IADSA) examinations were analyzed for residual aneurysms and arterial patency following GDC placement. A total number of 33 intracranial aneurysms was analyzed, including 18 located in the posterior circulation. The MRA analysis was based on source images in combination with maximum intensity projections. The IADSA was used as the reference standard. Two aneurysms were excluded from evaluation, because of susceptibility artefacts from other aneurysms, which were clipped. Sensitivity and positive predictive values of MRA in revealing residual aneurysms were, respectively, 89% and 80%. Specificity in ruling out remnant necks and residual flow around coils was, respectively, 91% and 97%, with a negative predictive value of, respectively, 95% and 100%. Specificity and negative predictive value of MRA for arterial occlusion were, respectively, 87% and 100% for the parent arteries and, respectively, 85% and 100% for the adjacent arteries. MRA is a reliable diagnostic tool in the follow-up of GDC treatment, and it may replace IADSA in excluding residual flow around coils and aneurysmal necks and in ruling out arterial occlusion.

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.

Magnetic resonance angiography in the selection of patients suitable for neurosurgical intervention of ruptured intracranial aneurysms.

This study was aimed at establishing whether magnetic resonance angiography (MRA) can be applied to planning and performing surgery on ruptured intracranial aneurysms, especially in the early phase, without recourse to intra-arterial digital subtraction angiography (IA-DSA). From February 1998 to August 2001, in all patients presenting with a subarachnoid hemorrhage, MRA was performed first. A three-dimensional time-of-flight MRA protocol with T2-weighted coronal and axial images was used. If MRA demonstrated an aneurysm, surgery was undertaken. IA-DSA was limited to patients with negative or inconclusive MRA findings. We compared MRA images with operative findings in positive patients and with IA-DSA in negatives. IA-DSA was considered the gold standard when MRA findings were inconclusive. In this study, 205 consecutive patients (mean age 52.7 years, 69% women) were included. In 133 patients (64.9%) MRA demonstrated an aneurysm, directly followed by neurosurgical intervention. In 33 patients (16.1%) MRA findings were categorized as inconclusive. In 39 patients (19.0%) MRA results were negative. No false-negative ruptured aneurysms were selected by MRA. In only one patient surgical intervention was performed based on false-positive MRA findings. MRA can replace IA-DSA as a first diagnostic modality in the selection of patients suitable for surgical treatment of ruptured intracranial aneurysms.

[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.

Effect of radiotherapy and other treatment-related factors on mid-term to long-term cognitive sequelae in low-grade gliomas: a comparative study.

BACKGROUND: Because survival benefits of treatment with radiotherapy are questionable and such treatment can cause substantial damage to the brain over time, the optimum management strategy for low-grade gliomas remains controversial. We aimed to identify the specific effects of radiotherapy on objective and self-reported cognitive function, and on cognitive deterioration over time, in patients with low-grade gliomas treated with early radiotherapy. METHODS: 195 patients with low-grade glioma (of whom 104 had received radiotherapy 1-22 years previously) were compared with 100 low-grade haematological patients and 195 healthy controls. Our analyses aimed to differentiate between the effects of the tumour (eg, disease duration, lateralisation) and treatment effects (neurosurgery, radiotherapy, antiepileptic drugs) on cognitive function and on relative risk of cognitive disability. FINDINGS: Low-grade glioma patients had lower ability in all cognitive domains than did low-grade haematological patients, and did even less well by comparison with healthy controls. Use of radiotherapy was associated with poorer cognitive function; however, cognitive disability in the memory domain was found only in radiotherapy patients who received fraction doses exceeding 2 Gy. Antiepileptic drug use was strongly associated with disability in attentional and executive function. INTERPRETATION: Our findings suggest that the tumour itself has the most deleterious effect on cognitive function and that radiotherapy mainly results in additional long-term cognitive disability when high fraction doses are used. Additionally, the effects of other medical factors, especially antiepileptic drug use, on cognitive function in glioma patients deserve attention.

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.

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.