Rosalind L. Jeffree

Aminolevulinic acid (ALA)–protoporphyrin IX fluorescence guided tumour resection. Part 1: Clinical, radiological and pathological studies

The intraoperative identification and resection of glioma is a significant and important challenge in neurosurgery. Complete resection of the enhancing tumour increases the median survival time in glioblastoma compared to partial glioma resection; however, it is achieved in fewer than half of eligible patients when conventional tumour identification methods are used. Increasing the incidence of complete resection, without causing excess morbidity, requires new methods to accurately identify neoplastic tissue intraoperatively, such as use of the drug 5-amino-levulinic acid (ALA). After ALA ingestion, the fluorescent molecule protoporphyrin IX (PpIX) accumulates in high grade glioma, allowing the neurosurgeon to more easily detect and accurately resect tumour. The utility of ALA has been demonstrated in a large, multicentre phase III randomised control trial of 243 patients with high grade glioma. ALA use led to a significant increase in the incidence of complete resection (65% compared to 36%), improved progression-free survival at 6 months (41% compared to 21%), fewer reinterventions, and delayed onset of neurological deterioration. This review provides a broad assessment of ALA-PpIX fluorescence-guided resection, with Part 1 focusing on its clinical efficacy, and correlations with imaging and histology. The theoretical, biochemical and practical aspects of ALA use are reviewed in Part 2.

Aminolevulinic acid (ALA)-protoporphyrin IX fluorescence guided tumour resection. Part 2: Theoretical, biochemical and practical aspects

The importance of the extent of resection for gliomas, and the utility of aminolevulinic acid (ALA) and protoporphyrin IX fluorescence in increasing the extent of resection, has become increasingly evident over the past decade. This review continues from Part 1 and focuses on the biochemical mechanisms by which ALA ingestion leads to tumour fluorescence, and discusses practicalities of the equipment and techniques needed to introduce ALA and fluorescence guided resection into neurosurgical practice.

Colloid cyst of the third ventricle: a clinical review of 39 cases

This paper is a retrospective review of all patients treated for a colloid cyst of the third ventricle at Royal Prince Alfred Hospital over an 18-year consecutive period. Our experience is fairly typical compared with other published series. Colloid cys ts made up 1.6% of tumours treated by the neurosurgical unit. Patients presented with non-specific neurological symptoms and signs, commonly suggestive of raised intracranial pressure. Microsurgical excision was carried out via the transcallosal route in 34 cases and the transfrontal approach in four cases. There was no apparent difference in results from the different surgical approaches. In 86% of patients reviewed after more than 6 months good long term outcome was achieved. These benign tumours can be safely cured if the diagnosis is made early and the cyst removed by careful microsurgical techniques.

Postnatal Development of Arteriovenous Malformations

Background: Arteriovenous malformations (AVMs) are commonly thought to be congenital malformations; however, patients usually present in adolescence or adulthood. This study was carried out to better understand the development of AVMs between birth and presentation. Methods: A retrospective review was performed of the medical records of all patients under 25 presenting to a single institution with an AVM or spontaneous intracerebral hemorrhage from 2000 to 2007. Results: Out of a total of 34 cases, 3 children were identified with delayed de novo appearance of an AVM after an intracerebral hemorrhage and normal initial angiography. The clinical and angiographic features are presented for these 3 patients and for an additional patient with AVM recurrence after complete surgical excision. Conclusions: In the light of these cases and a review of the literature, we suggest a hypothesis that AVMs develop postnatally, undergoing a period of growth in childhood or early adulthood, and that they may become symptomatic from the time of their earliest development. The trigger to growth may be shear stress stimulating growth factor expression by endothelial cells lining an arteriovenous fistula. Alternative stimuli, such as venous hypertension, cannot be ruled out.

Integrated genomic and transcriptomic analysis of human brain metastases identifies alterations of potential clinical significance

Treatment options for patients with brain metastases (BMs) have limited efficacy and the mortality rate is virtually 100%. Targeted therapy is critically under‐utilized, and our understanding of mechanisms underpinning metastatic outgrowth in the brain is limited. To address these deficiencies, we investigated the genomic and transcriptomic landscapes of 36 BMs from breast, lung, melanoma and oesophageal cancers, using DNA copy‐number analysis and exome‐ and RNA‐sequencing. The key findings were as follows. (a) Identification of novel candidates with possible roles in BM development, including the significantly mutated genes DSC2, ST7, PIK3R1 and SMC5, and the DNA repair, ERBB–HER signalling, axon guidance and protein kinase‐A signalling pathways. (b) Mutational signature analysis was applied to successfully identify the primary cancer type for two BMs with unknown origins. (c) Actionable genomic alterations were identified in 31/36 BMs (86%); in one case we retrospectively identified ERBB2 amplification representing apparent HER2 status conversion, then confirmed progressive enrichment for HER2‐positivity across four consecutive metastatic deposits by IHC and SISH, resulting in the deployment of HER2‐targeted therapy for the patient. (d) In the ERBB/HER pathway, ERBB2 expression correlated with ERBB3 (r2 = 0.496; p < 0.0001) and HER3 and HER4 were frequently activated in an independent cohort of 167 archival BM from seven primary cancer types: 57.6% and 52.6% of cases were phospho‐HER3Y1222 or phospho‐HER4Y1162 membrane‐positive, respectively. The HER3 ligands NRG1/2 were barely detectable by RNAseq, with NRG1 (8p12) genomic loss in 63.6% breast cancer‐BMs, suggesting a microenvironmental source of ligand. In summary, this is the first study to characterize the genomic landscapes of BM. The data revealed novel candidates, potential clinical applications for genomic profiling of resectable BMs, and highlighted the possibility of therapeutically targeting HER3, which is broadly over‐expressed and activated in BMs, independent of primary site and systemic therapy. Copyright

Warfarin related intracranial haemorrhage: A case-controlled study of anticoagulation monitoring prior to spontaneous subdural or intracerebral haemorrhage

We present a retrospective, case-controlled study of the degree of over-warfarinisation and the frequency of International Normalized Ratio (INR) monitoring in patients with spontaneous intracranial haemorrhage (ICH) compared with a control group without ICH. A higher proportion of patients with ICH were taking warfarin than patients in the control group (33/221 [15%] versus 16/201 [8%], p<0.05). There was no significant difference between the ICH group and the controls in the mean INR of warfarinised patients on presentation, the mean INR when last measured prior to presentation, or in the number of days since the INR was last tested. There was no correlation between the time since the INR was last measured and the INR on presentation. Only 2 (6%) of patients were excessively anticoagulated at the time of ICH. Thus, in this study, warfarin use was associated with an increased risk of ICH despite appropriate community INR monitoring and therapeutic anticoagulation.

Current strategies in the surgical management of cerebral metastases: an evidence-based review

Metastatic tumours are the most common form of cerebral neoplasm, occurring in up to 40% of patients with systemic cancer. Although the presence of metastatic disease portends limited survival, aggressive management of cerebral metastases is vital to preventing death from neurological causes and prolonging functional independence. Due to advancement in neurosurgical techniques and the advent of stereotactic radiosurgery as a non-operative alternative, current decision making for selecting the appropriate local treatment often results in clinical equipoise. In addition, the traditional blanket application of whole brain radiation has come under scrutiny as new evidence regarding the deleterious neurocognitive effects of ionizing radiation emerges. The completion of a series of randomized studies comparing the efficacy of surgery, radiosurgery, whole brain radiotherapy and various combined approaches for cerebral metastases in recent years has shed important light on addressing some of these issues. The focus of this review is to summarize the key findings and outline a practical approach for the management of cerebral metastases.

Glioma surgical aspirate: a viable source of tumor tissue for experimental research

Brain cancer research has been hampered by a paucity of viable clinical tissue of sufficient quality and quantity for experimental research. This has driven researchers to rely heavily on long term cultured cells which no longer represent the cancers from which they were derived. Resection of brain tumors, particularly at the interface between normal and tumorigenic tissue, can be carried out using an ultrasonic surgical aspirator (CUSA) that deposits liquid (blood and irrigation fluid) and resected tissue into a sterile bottle for disposal. To determine the utility of CUSA-derived glioma tissue for experimental research, we collected 48 CUSA specimen bottles from glioma patients and analyzed both the solid tissue fragments and dissociated tumor cells suspended in the liquid waste fraction. We investigated if these fractions would be useful for analyzing tumor heterogeneity, using IHC and multi-parameter flow cytometry; we also assessed culture generation and orthotopic xenograft potential. Both cell sources proved to be an abundant, highly viable source of live tumor cells for cytometric analysis, animal studies and in-vitro studies. Our findings demonstrate that CUSA tissue represents an abundant viable source to conduct experimental research and to carry out diagnostic analyses by flow cytometry or other molecular diagnostic procedures.

STA-MCA bypass for symptomatic carotid occlusion and haemodynamic impairment

Patients with carotid artery occlusion and haemodynamic insufficiency have a high risk of stroke. Cerebral revascularization surgery improves cerebral blood flow, but it remains unclear whether this reduces the risk of stroke. This study assesses the long-term outcome of patients undergoing superficial temporal artery to middle cerebral artery (STA-MCA) bypass for symptomatic carotid occlusion. The long-term clinical follow-up and haemodynamic reserve, measured by (99)Technetium single photon emission computed tomography (Tc99 SPECT) scan with acetazolamide challenge, were reviewed for 19 consecutive patients before and after STA-MCA bypass. The stroke rate after bypass surgery was 8% per year. In patients waiting for surgery, the stroke rate was 18% per year. Cerebral perfusion assessed with SPECT scan improved in 88% of patients. These results are consistent with the high risks of haemodynamic infarction in untreated patients and a benefit from revascularization surgery. The percentage annual stroke risk compares favourably with an 18% rate reported for patients with internal carotid artery occlusion and impaired cerebrovascular reserve.

Using the apparent diffusion coefficient to identifying MGMT promoter methylation status early in glioblastoma: importance of analytical method.

Accurate knowledge of O6‐methylguanine methyltransferase (MGMT) gene promoter subtype in patients with glioblastoma (GBM) is important for treatment. However, this test is not always available. Pre‐operative diffusion MRI (dMRI) can be used to probe tumour biology using the apparent diffusion coefficient (ADC); however, its ability to act as a surrogate to predict MGMT status has shown mixed results. We investigated whether this was due to variations in the method used to analyse ADC.