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.

Compost: its role, mechanism and impact on reducing soil-borne plant diseases.

Soil-borne plant pathogens are responsible for causing many crop plant diseases, resulting in significant economic losses. Compost application to agricultural fields is an excellent natural approach, which can be taken to fight against plant pathogens. The application of organic waste products is also an environmentally friendly alternative to chemical use, which unfortunately is the most common approach in agriculture today. This review analyses pioneering and recent compost research, and also the mechanisms and mode of action of compost microbial communities for reducing the activity of plant pathogens in agricultural crops. In addition, an approach for improving the quality of composts through the microbial communities already present in the compost is presented. Future agricultural practices will almost definitely require integrated research strategies to help combat plant diseases.

Archaeal community dynamics and abiotic characteristics in a mesophilic anaerobic co-digestion process treating fruit and vegetable processing waste sludge with chopped fresh artichoke waste.

This study evaluated the feasibility of obtaining methane in anaerobic digestion (AD) from the waste products generated by the processing of fruit and vegetables. During the first phase (0-55 d) of the AD using sludge from fruit and vegetable processing, an average value of 244±88 L kg(-1) dry matter d(-1)of biogas production was obtained, and methane content reached 65% of the biogas. Co-digestion with chopped fresh artichoke wastes in a second phase (55-71 d) enhanced biogas production, and resulted in an average value of 354±68 L kg(-1) dry matter d(-1), with higher methane content (more than 70%). The archaeal community involved in methane production was studied using the ANAEROCHIP microarray and real-time PCR. Results indicated that species of Methanosaeta and Methanosarcina were important during the AD process. Methanosarcina numbers increased after the addition of chopped fresh artichoke, while Methanosaeta numbers decreased.

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.

The impact of systemic fungal infection in patients with perforated oesophagus.

INTRODUCTION: Perforated oesophagus is a surgical emergency with significant morbidity and mortality. Systemic fungal infection represents a poor response to the magnitude of the insult, which adds significantly to the risk of morbidity and mortality in these patients. We reviewed our experience with this group of patients over a six-year period in a tertiary referral centre. METHODS: A retrospective clinical review was conducted of patients who were admitted following a ruptured oesophagus over a period of six years (January 2002 - January 2008). RESULTS: We had 27 admissions (18 men and 9 women) following an isolated perforated oesophagus to our unit. The median patient age was 65 years (range: 22-87 years). The majority (n=24, 89%) presented with spontaneous perforations (Boerhaave's syndrome) and three (11%) were iatrogenic. Fungal organisms, predominantly Candida albicans, were positively cultured in pleural or blood samples in 16 (59%) of the 27 patients. Fourteen patients grew yeasts within the first seven days while two showed a delayed growth after ten days. Overall mortality was 5 out of 27 patients (19%). There was no mortality among the group that did not grow yeasts in their blood/pleural fluid while mortality was 31% (5/16) in the group with systemic fungal infection (p<0.001). A positive fungal culture was also associated with increase ventilation time, intensive care unit stay and inpatient hospital stay but not an increased rate of complications. CONCLUSIONS: Systemic fungal infection in patients with a ruptured oesophagus affects a significant proportion of these patients and carries a poor prognosis despite advanced critical care interventions. It may represent a general marker of poor host response to a major insult but can add to mortality and morbidity. It is worth considering adding antifungal therapy empirically at an early stage to antimicrobials in patients with an established diagnosis of a perforated oesophagus.

Microbiological community analysis of vermicompost tea and its influence on the growth of vegetables and cereals.

Vermicompost, the digestion product of organic material by earthworms, has been widely reported to have a more positive effect on plant growth and plant health than conventional compost. A study was conducted to investigate the effects of different vermicompost elutriates (aerated compost teas) on soils and plant growth. The teas were analyzed by chemical, microbiological, and molecular methods accompanied by plant growth tests at laboratory and field scale. The number of microorganisms in the teas increased during the extraction process and was affected by substrate addition. The vermicompost tea found to increase plant growth best under laboratory tests was applied to cereals (wheat and barley) and vegetables (Raphanus sativus, Rucola selvatica, and Pisum sativum) in a field study. The results revealed no effects of tea application on plant yield; however, sensoric tests indicated an improvement in crop quality. The soils from laboratory and field studies were investigated to detect possible microbial or chemical changes. The results indicated that minor changes to the soil microbial community occurred following tea application by foliar spray in both the laboratory-scale and field-scale experiments.

Investigation of the relationship between transcranial impedance and intracranial pressure.

Studies on piglets have shown that cranial bioimpedance (Z) measurements correlate well with invasively measured intracranial pressure (ICP). We have tested the feasibility of collecting transcranial impedance from a clinical device for measuring whole-body water content (ImpediMed SFB7). In the clinical study, 50 normal healthy volunteers had transcranial impedance measured using nine different head montages (forehead to mastoid (left/right), temporal to mastoid (left/right), forehead to temporal (left/right), forehead to occipital (left/right) and temporal to temporal). Impedance was measured 20 times over a frequency range per montage and ANOVA used to test for effects of electrode position upon recorded value. For the experimental study, five sedated and ventilated Marino sheep were instrumented for intraventricular ICP and transcranial impedance measurement. Measures of ICP were recorded while ICP was increased from baseline to greater than 50 mmHg in five steps using an intraventricular infusion of mock CSF. There is a significant effect of electrode position and gender upon transcranial impedance (p < 0.001). The temporal-mastoid electrode position had significantly lower impedance values in keeping with its shorter path length. ICP correlated with craniospinal compliance measurements and Impedance vs Freq by ICP step shows a clear ICP dependence (p = 0.007) across the sheep.

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%).

Effect of biowaste sludge maturation on the diversity of thermophilic bacteria and archaea in an anaerobic reactor.

Prokaryotic diversity was investigated near the inlet and outlet of a plug-flow reactor. After analyzing 800 clones, 50 bacterial and 3 archaeal phylogenetic groups were defined. Clostridia (>92%) dominated among bacteria and Methanoculleus (>90%) among archaea. Significant changes in pH and volatile fatty acids did not invoke a major shift in the phylogenetic groups. We suggest that the environmental filter imposed by the saline conditions (20 g liter(-1)) selected a stable community of halotolerant and halophilic prokaryotes.

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.

Assessment of factors affecting MRI measurement of intracranial volume changes and elastance index.

Non-invasive measurement of cerebral hydrodynamic parameters may be of great use in the study and treatment of conditions involving abnormal intracranial pressure (ICP). ICP can be assessed indirectly in humans by calculation of intracranial volume changes and elastance using MRI. These two hydrodynamic parameters are derived from mathematical analysis of the relationships between blood flow to and from the brain, CSF flow and heart rate. This paper examines the variability in these three critical subject specific parameters. Three healthy adult males had measurements of blood and CSF flow to and from the brain made on three occasions. Inter-individual variation in vasculature and intra-individual variation in heart rates led to modest repeatability (defined as standard deviation divided by the mean) of intracranial volume change and elastance index in two subjects and poor repeatability in the third. Particular care is required in the selection of image planes and the blood vessels to include, and the analysis is very sensitive to differences in heart-rate. Because of these difficulties, caution is required in the interpretation of results obtained from a single examination. Techniques and methods that may reduce the variability in the derived hydrodynamic parameters are discussed.