A systematic review and meta-analysis of gene therapy in animal models of cerebral glioma: why did promise not translate to human therapy?

BACKGROUND: The development of therapeutics is often characterized by promising animal research that fails to translate into clinical efficacy; this holds for the development of gene therapy in glioma. We tested the hypothesis that this is because of limitations in the internal and external validity of studies reporting the use of gene therapy in experimental glioma. METHOD: We systematically identified studies testing gene therapy in rodent glioma models by searching three online databases. The number of animals treated and median survival were extracted and studies graded using a quality checklist. We calculated median survival ratios and used random effects meta-analysis to estimate efficacy. We explored effects of study design and quality and searched for evidence of publication bias. RESULTS: We identified 193 publications using gene therapy in experimental glioma, including 6,366 animals. Overall, gene therapy improved median survival by a factor of 1.60 (95% CI 1.53-1.67). Study quality was low and the type of gene therapy did not account for differences in outcome. Study design characteristics accounted for a significant proportion of between-study heterogeneity. We observed similar findings in a data subset limited to the most common gene therapy. CONCLUSION: As the dysregulation of key molecular pathways is characteristic of gliomas, gene therapy remains a promising treatment for glioma. Nevertheless, we have identified areas for improvement in conduct and reporting of studies, and we provide a basis for sample size calculations. Further work should focus on genes of interest in paradigms recapitulating human disease. This might improve the translation of such therapies into the clinic.

Systematic review and meta-analysis of temozolomide in animal models of glioma: was clinical efficacy predicted?

BACKGROUND: Malignant glioma is an aggressive tumour commonly associated with a dismal outcome despite optimal surgical and radio-chemotherapy. Since 2005 temozolomide has been established as first-line chemotherapy. We investigate the role of in vivo glioma models in predicting clinical efficacy. METHODS: We searched three online databases to systematically identify publications testing temozolomide in animal models of glioma. Median survival and number of animals treated were extracted and quality was assessed using a 12-point scale; random effects meta-analysis was used to estimate efficacy. We analysed the impact of study design and quality and looked for evidence of publication bias. RESULTS: We identified 60 publications using temozolomide in models of glioma, comprising 2443 animals. Temozolomide prolonged survival by a factor of 1.88 (95% CI 1.74-2.03) and reduced tumour volume by 50.4% (41.8-58.9) compared with untreated controls. Study design characteristics accounted for a significant proportion of between-study heterogeneity, and there was evidence of a significant publication bias. CONCLUSION: These data reflect those from clinical trials in that temozolomide improves survival and reduces tumour volume, even after accounting for publication bias. Experimental in vivo glioma studies of temozolomide differ from those of other glioma therapies in their consistent efficacy and successful translation into clinical medicine.

Recognition of mental incapacity when consenting patients with intracranial tumours for surgery: how well are we doing?

INTRODUCTION: Many patients with intracranial tumours have cognitive deficits that might affect their mental capacity to give valid consent to neurosurgical treatment. The aim of this study was to determine the incidence of mental incapacity, as assessed by neurosurgeons, in patients with intracranial tumours undergoing neurosurgery. METHODS: The case notes of successive patients undergoing brain tumour surgery between 16 October 2008 and 16 October 2010 were reviewed. The frequency of use of standard consent forms and Certificates of Incapacity was recorded. In addition, the frequency and scores of pre-operative cognitive assessments were recorded. RESULTS: Case notes of 247 of 262 patients undergoing surgery for intracranial tumours were reviewed since there was no record of either a standard consent form or a Certificate of Incapacity in the case notes for 15 patients. Nine of 247 brain tumour patients were issued with a Certificate of Incapacity (3.6%, 95% CI 1.6-6.8%), while 238 (96.4%) signed a standard consent form. Seven of these nine had high-grade gliomas, for an incidence of incapacity of 5.9% (95% CI 2.8-11.8%), while the remaining two Certificates of Incapacity were issued for patients with meningiomas (incidence 3%; 95% CI 0.04-10.4%). Fifty of the 262 patients (19%) had some form of pre-operative cognitive assessment documented, but only three of these were issued with a Certificate of Incapacity. All three patients issued with a Certificate of Incapacity had Mini-Mental State Examination scores suggestive of cognitive impairment. CONCLUSIONS: Incapacity to consent to brain tumour surgery, as assessed by neurosurgeons, is uncommon. The incidence of incapacity is less than might be expected given the level of cognitive impairment known in this population. Decisions about capacity by neurosurgeons are often made in the absence of any documented assessment of cognition or other objective evidence that could support their decision in the event of dispute.

The concepts, diagnosis and management of early imaging changes after therapy for glioblastomas.

Since postoperative radiotherapy plus concomitant temozolomide followed by adjuvant temozolomide has become standard treatment for glioblastoma, the phenomenon of early post-treatment enlargement of the imaged tumour volume, usually without clinical deterioration, has become widely recognised. The term pseudoprogression has been used to describe a poorly understood pathophysiological process. In this review, the pathophysiological concepts, relevance, diagnosis and management of patients with 'pseudoprogression' and 'pseudoresponse' are discussed. Guidelines are given with respect to radiological imaging modality, mode and frequency. Further biological and clinical insights into these phenomena require carefully designed prospective studies.

Trends in classification, referral and treatment and the effect on outcome of patients with glioma: a 20 year cohort.

This retrospective audit was conducted to examine the changes in patient characteristics, referral, treatment and outcome over a 20-year period in a large regional neuro-oncology centre, focusing on the impact of the changes in pathological classification of gliomas. Using the Edinburgh Cancer Centre (ECC) database all cases of glioma were identified and patient, tumour and treatment characteristics noted. Survival was calculated from date of surgery or, if no operation was performed, the date of referral. Comparison was made between four periods 1988-1992 (c1), 1993-1997(c2), 1998-2002(c3) and 2003-2007 (c4). During the 20 years, 1175 patients with a glioma were referred to ECC. The median age increased from 53 years to 57 years (p < 0.001) but the proportion without pathology remained unchanged (10%). The distribution of pathological grades changed over time Grade I-II: 24, 6, 6, and 6%, Grade III: 42, 27, 17, and 13% and Grade IV: 24, 61, 68, and 68% in c1, c2, c3 and c4, respectively (p < 0.001). Immediate RT was given to 68% (c1), 70% (c2), 78% (c3) and 79% (c4). Median interval from resection to RT reduced from 43 days (c1) to 36 days (c4) (p < 0.001). 5-year overall survival for patients with Grade III lesions increased: 21% (c1), 35% (c2), 37% (c3), 33% (c4) as did 1-year overall survival for Grade IV lesions: 18% (c1), 26% (c2), 29% (c3), 27% (c4)). This improvement probably reflects the change in pathological classification rather than a change in management. Proportional hazards analysis of grade IV 1993-2007 only (to reduce pathological variation) showed that younger age, frontal lesions, excision, higher RT dose had reduced hazard of death. Interval from surgery to RT had no impact on survival in this series.

Proximal migration of a lumbo-peritoneal shunt into a cerebellar peduncle.

We present dramatic images of a lumbo-peritoneal (LP) shunt that has migrated into the posterior fossa. We discuss its successful revision, and review previous reports of LP shunt migration.

Proteomic data in meningiomas: post-proteomic analysis can reveal novel pathophysiological pathways.

Meningiomas account for approximately 20% of adult primary intracranial tumours. WHO I meningiomas are the most common and are generally benign, but can progress, recur or transform to WHO II or WHO III grades over many years. A systematic review of multiple independent shotgun proteomic analyses of meningioma was performed to provide insight into underlying disease pathways. Shotgun proteomics has been conducted in seven meningioma related studies but there is considerable variation in aims, methodology, statistical power and the use of control tissue between these studies. Fifteen proteins which are different between WHO I and WHO II meningiomas and nine proteins which are different between WHO II and WHO III meningiomas have been described but without a view of their biological significance. Network analysis of proteins different between WHO I and WHO II meningiomas provided a coherent hypothesis for the involvement of these proteins in meningioma. Western blot analyses of meningioma tissue provided a measure of support for a core component in the network (involving VDAC2, APOA1 and HNF4α) but highlighted intrinsic difficulty of proteomic and biochemical analysis of meningiomas (as a consequence of gross alterations in tissue composition). Systematic review of shotgun proteomics and network analysis provides insight into meningioma pathophysiology despite the many barriers and difficulties that are inherent to this type of study.

What is the place of conservative management for adult supratentorial low-grade glioma?

Adult supratentorial low-grade gliomas (LGG) cover a spectrum of neuropathologies that invariably present with seizure disorders. Following neuroradiological diagnosis management strategy will be determined by prognostic indicators such as patient age, lesion size, lesion location, clinical performance status and radiological differential diagnosis. Conservative management, characterised by a "watch and wait" policy, with serial neuroimaging and clinical observation, may form an integral part of overall Multi-Disciplinary Team management strategy in many patients. Conservative management may include the periods following radiological diagnosis to primary surgery, and from the time of surgery to timing of radiotherapy or chemotherapy. Results from randomised controlled clinical trials in LGG, recent findings following microsurgical excision, findings from serial observations using volumetric MRI, and recent findings following chemotherapy and tumour genotyping have helped in defining the place of conservative management in individual cases. These recent findings have moved conservative management from a 'controversial' legacy of a bygone era to a more objectively based coherent management component that is understood by both medical and surgical neuro-oncologists. However there is still no evidence from randomised controlled trials to either support or indict the role of conservative management, prior to primary intervention, in LGG. Informing patients of the uncertainties in both interventional strategies and the place of conservative management in LGG is essential in optimising patient outcomes and satisfaction.

The incidence of seizures following Deep Brain Stimulating electrode implantation for movement disorders, pain and psychiatric conditions.

Deep Brain Stimulation (DBS) for neuromodulation is now commonplace. However little is known about the incidence of either procedural related seizures or epilepsy following chronic DBS. This study aims to provide estimates of these complications for movement disorders, pain and psychiatric conditions. A literature review was performed. Because searches using the terms seizure, epilepsy, and deep brain stimulation revealed only papers dealing with experimental and clinical application of DBS to treat chronic seizures disorders, a search strategy trawling through papers that described clinical case series of DBS was used. Thirty-two papers were reviewed that described stereotactic placement of DBS electrodes for movement disorders, pain syndromes and psychiatric conditions with cohorts of n > 5. Sixteen of these papers describing at least 1418 DBS electrode placements in 1254 patients did not mention seizures as a complication (i.e., it was not possible to know whether seizures had or had not occurred). In 16 papers, describing at least 2101 electrode placements in 1555 patients, seizures were described in 42 patients (incidence 2.7%). The range of seizure incidence varied from 0% (three series encompassing 317 patients and 576 electrode placements) up to 10% (n = 130) and 13% (n = 15). The reasons for this variance were not obvious. At least 74% of seizures occurred around the time of electrode implantation and many of these patients also suffered intracranial hemorrhage. Follow up times were variable (range 6 mths to 5 years). The analysis was complicated by multiple publications from some centres with duplication of some data. The quality of literature on seizures following DBS insertion for neuromodulation is highly variable. Analysis of the available data, after making corrections for publication of duplicate data, suggests strongly that the risk of seizures associated with DBS placement is probably lower than 2.4% (95% CI 1.7 to 3.3 %). The risk of postprocedural seizures associated with chronic deep brain stimulation is even lower with best estimates around 0.5% (95% CI .02 to 1.0%).

What is the translational efficacy of chemotherapeutic drug research in neuro-oncology? A systematic review and meta-analysis of the efficacy of BCNU and CCNU in animal models of glioma.

INTRODUCTION: The translational value of experimental therapeutic neuroscience research to clinical practice is highly variable. This has been particularly well demonstrated in the field of neuroprotective agents following either head injury or stroke. In this study we evaluate the efficacy of systemic BCNU and CCNU in experimental glioma models and how the experimental data has translated into clinical practice. METHODS: A systematic review of the efficacy of BCNU and CCNU, against experimental rodent and murine in vivo glioma models was conducted. Selected articles were graded on a 15 point scale for scientific methodology. A stratified meta-analysis based on median-survival data and effect sizes was performed to generate global-efficacy estimates for BCNU and CCNU, and to produce 'weighted-mean effect-sizes' for individual sub-categories of selected study-characteristics. RESULTS: Fourteen papers satisfied search criteria and encompassed 231 treatment comparisons in 2256 animals. The median methodology score was 9 (range 7-12/15). Global-efficacy estimates were BCNU 0.194 (95% CI -0.538 to 0.927) and CCNU 0.432 (95% CI -0.392 to 1.256), with CCNU being significantly more effective than BCNU. Because of these wide confidence intervals a beneficial or detrimental effect of either agent could not be confirmed. Most selected study-design characteristics (e.g. glioma cell line, drug dosage, drug scheduling, mode of drug administration, timing of therapy after glioma implantation but not animal used) significantly influenced the efficacy-results obtained. The methodological score did not influence efficacy-estimate. CONCLUSION: This review has found (i) experimental-design influenced the efficacy-data obtained and (ii) that there is highly variable outcome data for the efficacy of both BCNU and CCNU in experimental in vivo rodent and murine glioma models. In many ways these findings are analagous to the use of nitrosoureas in human malignant glioma. The statistically significant small beneficial effect of nitrosoureas in combination with other chemotherapeutic agents in human glioma was only noted after a meta-analysis of human randomized controlled trials.

Intrathecal baclofen therapy for neurological disorders: a sound knowledge base but many challenges remain.

Continuous infusion of intrathecal baclofen (ITB) via a subcutaneously implanted pump has developed over the last 20 years as a powerful tool in the management of spasticity in various adult and paediatric neurological conditions. Acting more focally on spinal GABA receptors, ITB causes fewer systemic side effects than orally administered baclofen. The result is facilitation of daily caring, and symptomatic relief from painful spasm. With increasing experience of ITB use, novel applications and indications are emerging. These include the management of dystonia and chronic neuropathic pain. However, despite some recent authoritative reviews, there is still uncertainty about optimal use and evaluation of this therapy. Many challenges remain. How can efficacy of therapy best be assessed both at primary testing and after pump implantation? What is the precise mechanism of baclofen action in different brain and spinal disorders associated with spasticity and dystonia? Does placement of the spinal catheter tip influence efficacy? What is the cranio-caudal gradient of CSF baclofen levels at given pump flow rates and does this matter? What CSF baclofen levels are efficacious in various conditions? Why do some patients with the same primary condition require large differences in ITB dose? What are the relative merits of programmable versus constant infusion rate pumps? What are the implications of setting up multidisciplinary teams for long term follow up? This review evaluates these questions and highlights other areas for further investigation.

Randomized Phase III controlled trials of therapy in malignant glioma: where are we after 40 years?

The objective of this study was to review the results of randomized Phase III controlled trials (RCTs) that involve initial treatments of malignant glioma and determine changes in median survival times (MST) over the last 40 years. An electronic database search identified RCTs for patients undergoing initial treatment for supratentorial high-grade malignant glioma. MSTs were analysed with respect to the date that patient accrual to the trial started, to identify the time course of changes in MST. Linear regression was used for statistical analysis. The review included 44 clinical trials that recruited patients between 1966 and 2004. Overall, there was a steady significant improvement in MST for the novel treatment cohorts over this period (r(2) = 0.43, p < 0.001), with MST increasing from around 8 to 15 months. There was also consistent improvement in the MST of the control cohorts, from around 7 months to 14 months, that reached statistical significance (r(2) = 0.41, p < 0.001). However, analysis including a quadratic term revealed a trend towards the rate of improvement in MST decreasing in the last two decades in the control, but not novel treatment, groups. The differences, either positive or negative, in MSTs between the control and novel treatment cohorts, and number of trials performed have all decreased with time. Subgroup analysis of the three most recent clinical trials report statistically significant better outcomes in MST after either >90% or 'complete' tumour resection. Despite tremendous advances in both the understanding of the biology of malignant gliomas and treatments in neuro-oncology, the prognosis for patients with malignant gliomas, although improved, remains very poor. The limitations of this type of analysis, including how trial design can bias outcomes and militate against comparison of trials are discussed.

Idiopathic intracranial hypertension: can studies of obesity provide the key to understanding pathogenesis?

The pathogenesis of idiopathic intracranial hypertension (IIH) is poorly understood. Several mechanisms have been suggested, but no one mechanism has been able to account for all manifestations of the disease. Although IIH predominantly affects obese, premenopausal women, little is known about whether or how the obesity contributes to the IIH. Obesity is a heterogeneous condition, consisting of different phenotypes that are influenced by the regional distribution of adipose tissue. This review explores the literature to integrate current knowledge on the relationships between obesity and IIH. The review evaluates the hypotheses that dysregulation of insulin, glucose metabolism, sex hormones, adipokines, glucocorticoids, lipids and free fatty acids in obesity could predispose to IIH. One potential common pathway linking metabolic disorders to the pathogenesis of IHH is a thrombotic tendency due to dysregulation of haemostatic risk factors. This could cause either occult cerebral sinus thrombosis or partial thrombosis of the parasagittal venous lacunae, with subsequent impaired resorption of cerebrospinal fluid and venous hypertension. Investigations that evaluate obesity, fat metabolism, endocrinological dysregulation and thrombotic tendency in patients with IIH are required so that pathogenic mechanisms can be clarified and management strategies in IIH can be improved.

The role of endothelin in the cerebrovascular response following intracerebral haemorrhage: experimental studies using the endothelin antagonist SB209670.

Primary intracerebral haemorrhage (ICH) is associated with considerable morbidity and mortality. Local endothelin release following ICH may contribute to the pathophysiology of perilesional ischaemia. In diabetics, endothelin release can be enhanced by hyperglycaemia and cerebrovascular dilation may be inhibited by vascular endothelial dysfunction. To examine the effects of endothelin-mediated vasoconstriction after spontaneous ICH in the normal and diabetic brain, regional cerebral blood flow (rCBF) was examined in insulin dependent BB-rats and non-diabetic BB control rats. These experiments were performed 24 h following experimental ICH in both groups of animals that were either given the endothelin antagonist SB209670 or saline. Perilesional oligaemia was similar in control and SB209670 treated diabetic rats, but SB209670 reduced perilesional oligaemia in normal rats. In brain contralateral to the experimental ICH, rCBF was increased by SB209670 in diabetic rats, but not in non-diabetic rats. These studies show that there are differences in the cerebrovascular effects of endothelin in perilesional and contralateral brain in non-diabetic and diabetic rats following ICH.

Posterior fossa surgery complicated by a pseudomeningocele, bilateral subdural hygromata and cerebellar cognitive affective syndrome.

We report the case of a 51-year-old woman who underwent excision of a left postero-inferior, para-vermian cerebellar hemangioblastoma and foramen magnum decompression for an associated acquired Chiari I malformation. Two weeks postoperatively she developed a pseudomeningocele, bilateral supra- and infratentorial subdural hygromata, and a clinical disorder compatible with the cerebellar cognitive affective syndrome. There was no response to drainage of the left supratentorial collection. CSF aspiration from a pseudomeningocele lead to resolution of her syndrome and the subdural effusions. The relationships between the subdural hygromas, pseudomeningocele, location of the lesion within the cerebellum, cerebellar oedema, and the cause of her cognitive-affective syndrome are discussed.

Proteomic analysis of gliomas.

Primary malignant brain tumours (anaplastic glioma and glioblastoma) display heterogenous histopathology and diverse genetic abnormalities. These tumours remain incurable with no significant improvement in median survival times in the last 20 years, despite significant technological advances in surgery and radiotherapy, and mechanistic insights into their aetiology. Recent clinical trials suggest molecular characterization of tumours is essential in guiding both therapy and predicting prognosis. Genetic insight into tumour biology and increasingly proteomic technology has opened new avenues for novel applied clinical research. Protein expression in human malignant glioma and matched normal brain tissues can now be reliably analysed using quantitative proteomic techniques, the most accessible of which is two-dimensional gel electrophoresis (2DGE) and matrix-assisted laser desorption ionization time of flight (MALDI-TOF) mass spectrometry from which differentially expressed proteins can be identified and characterized. The potential of using differential proteomic profiling in gliomas to identify prognostic markers and to gain insight into tumour biology is currently being investigated. The current status of proteomic technology, its application to gliomas and the utility of such translational studies is reviewed.

Information processing in patients with intracranial tumours: A preliminary evaluation of the clinical utility of inspection time.

Psychomotor slowing is a common feature in many patients with intracranial tumours. We therefore performed a preliminary study to determine if inspection time, a measure of the efficiency of the brain's information processing, was impaired in patients with intracranial tumours. Inspection time, and some other neuropsychological and functional tests, were compared in 23 people with intracranial tumours and 24 spinal surgery controls prior to surgery. Groups were matched for sex, age and education. Inspection time scores were poorer in the brain tumour group (p < 0.003) and the effect size was moderate (eta2 = 0.197). The brain tumour group also had lower scores on the Boston Aphasia Severity Rating Scale, more anxiety on the Hospital Anxiety Depression Scales, but better Karnovsky Performance scores. Other cognitive and functional tests showed no significant differences between the groups, although group sizes were small. There were no significant changes in inspection time after spinal surgery; however, after intracranial tumour surgery, approximately 30% of patients showed no change, 30% deteriorated and 40% improved. This preliminary study suggests that recording inspection time, in a neuro-oncological setting, may prove informative and practically useful in assessing non-motor processing speed in people with brain tumours.