Andrew H. Kaye

The EGFRvIII variant in glioblastoma multiforme

Glioblastoma multiforme (GBM) is the most common brain tumour and has the worst prognosis. Epidermal growth factor receptor (EGFR) gene amplification, mutation and re-arrangement (all of which enhance tumour growth, survival, progression and resistance to therapy) are frequently observed in primary GBM. The most common EGFR variant in GBM, the EGFRvIII, is characterised by a deletion of 267 amino acids in the extracellular domain, leading to a receptor which is unable to bind ligand yet is constitutively active. Together with its impaired internalisation and degradation, the EGFRvIII enhances the tumourigenic potential of GBM by activating and sustaining mitogenic, anti-apoptotic and pro-invasive signalling pathways. This EGFRvIII-mediated enhanced tumourigenicity combined with the lack of EGFRvIII expression in normal tissue makes it an ideal candidate for targeted therapy. This review summarizes the current knowledge about the role of EGFRvIII in GBM and discusses therapeutic agents targeting EGFRvIII that are being evaluated as treatments for GBM.

Invadopodia: At the cutting edge of tumour invasion

Invasion of tissues by malignant tumours is facilitated by tumour cell migration and degradation of extracellular matrix (ECM) barriers. Several invasive neoplasms, including head and neck squamous cell carcinoma, breast carcinoma, melanoma and glioma, contain tumour cells that can form actin-rich protrusions with ECM proteolytic activity called invadopodia. These dynamic organelle-like structures adhere to, and digest, collagens, laminins and fibronectin. Invadopodia are dependent on multiple transmembrane, cytoplasmic and secreted proteins engaged in cell adhesion, signal transduction, actin assembly, membrane regulation and ECM proteolysis. Strategies aimed at disrupting invadopodia could form the basis of novel anti-invasive therapies for treating patients. Here we review the molecular basis of invadopodia formation with particular emphasis on the intracellular signaling networks that are essential for invadopodia activity and examine the potential role of these structures in glioma invasion.

Photodynamic therapy of high grade glioma - long term survival

Haemetaporphyrin derivative (HpD) mediated photodynamic therapy (PDT) has been investigated as an adjuvant treatment for cerebral glioma. This study records the survival of patients at the Royal Melbourne Hospital with residences in the State of Victoria, utilizing the Victorian Cancer Registry database for patients treated with adjuvant PDT following surgical resection of the tumour. For primary (newly diagnosed) tumours, median survival from initial diagnosis was 76.5 months for anaplastic astrocytoma (AA) and 14.3 months for glioblastoma multiforme (GBM). Seventy-three percent of patients with AA and 25% with GBM survived longer than 36 months. For recurrent tumour, median survival from the time of surgery was 66.6 months for AA and 13.5 months for GBM. Fifty-seven percent of patients with recurrent AA and 41% of patients with recurrent GBM survived longer than 36 months. Older age at the time of diagnosis was associated with poorer prognosis. Laser light doses above the sample median of 230 J/cm2 were associated with better prognosis in the 136 patients studied (primary tumour patients - (HR=0.50[0.27,0.95],p=0.033); recurrent tumour patients (HR=0.75[0.42,1.31],p=0.312). There was no mortality directly associated with the therapy, three patients had increased cerebral oedema thought to be related to photodynamic therapy that was controlled with conventional therapies.

Onset seizures independently predict poor outcome after subarachnoid hemorrhage

Objective: To determine whether onset seizures after subarachnoid hemorrhage (SAH) carry independent prognostic information and to investigate the risk factors for late seizures after SAH. Background: Modern management of SAH, including early operation, has substantially reduced mortality. No study has adequately assessed the importance of onset seizures in a contemporary SAH cohort. Methods: The authors analyzed the records and initial CT scans of 412 consecutive patients with aneurysmal or nonaneurysmal SAH admitted to the Royal Melbourne Hospital from 1990 to 1996. Each patient with an onset seizure (n = 32, 7.8% of cohort) was age and sex matched to two nonseizure patients of the same cohort. Each patient with a late seizure (n = 17, 5.1% of cohort) was matched to five control subjects of the same cohort. Results: With use of logistic regression analysis, onset seizures correlated with the sum score of blood on initial CT scan (OR = 1.1, p = 0.05), but there was no significant correlation with duration of loss of consciousness at onset, Glasgow Coma Score (GCS), presence of aneurysm, or past history of hypertension or epilepsy. Disability 6 weeks after SAH according to the Glasgow Outcome Scale was independently predicted by initial GCS of <6 (OR = 13.7, p < 0.01) and onset seizure (OR = 7.8, p = 0.04). Late seizures within the first 6 weeks were independently related to rebleeding (OR = 94, p < 0.01) and onset seizures (OR = 27, p < 0.01) but not to other onset variables, development of hydrocephalus, or vasospasm. Conclusion: In this single-institution cohort of patients with SAH, onset seizures were an independent risk factor for late seizures and a predictor of poor outcome.

Integrins: Molecular determinants of glioma invasion

Gliomas, the most common form of brain tumour are characterised by a capacity to invade throughout normal brain tissue. This infiltrative nature is the hallmark of poor prognosis. A greater understanding of the molecular determinants that drive invasion may lead to improved therapy. Integrins are a large family of cell surface receptors that mediate interaction between a cell and the extracellular matrix. Integrins facilitate extracellular matrix dependent organization of the cytoskeleton and activation of intracellular signalling that is required for the regulation of cell adhesion and migration. Since integrins are key regulators of these processes, the role these receptors play in tumour invasion is a field of intense research.

Current management of acoustic neuromas: review of surgical approaches and outcomes

The management options for patients with acoustic neuromas is discussed with a review of 164 patients assessed and treated between 1994 and 1998. Twenty-one patients have neurofibromatosis type II. In 33 cases initial observation was undertaken with repeated imaging. Surgical removal of 122 tumours was performed in 121 patients. Eleven of these patients have NF2, of whom three underwent Auditory Brainstem Implantation. Hearing preservation tumour removal was attempted in 37 and was successful in 20 (54%). The middle cranial fossa approach was used in ten cases with 100% successful hearing preservation. The retrosigmoid approach was used in 27 cases with 36% successful hearing preservation. Non-hearing preservation tumour removal was performed in 85 cases where hearing was poor or the tumour measured more than 2 cm within the cerebellopontine angle. The translabyrinthine approach was used in 80 of these patients. Postoperative facial nerve outcome was dependent on tumour size. All 38 patients with tumours </= 1.5 cm have normal (Grade 1) facial function. For all sized tumours, 90% of patients have good facial function (82% Grade 1, 8% Grade 2), 7% of patients have moderate function (6% Grade 3 and 1% Grade 4) and only 3% of patients have poor function (2% Grade 5, 1% Grade 6). Lasting complications were minimal with no operative mortality and eight patients (6.4%) suffering CSF fistulae. Seven patients in this series have had stereotactic radiation with variable outcome. The radiobiology of both single dose and fractionated stereotactic radiation is described and the current role of stereotactic radiation in the management of acoustic neuromas is discussed. Surgical tumour removal by an experienced multi-disciplinary team remains the primary treatment modality for acoustic neuromas. The middle cranial fossa approach is recommended for management of intracanalicular tumours. The translabyrinthine approach facilitates facial nerve preservation, particularly in patients with large tumours.

SUBCELLULAR LOCALIZATION OF PORPHYRINS USING CONFOCAL LASER SCANNING MICROSCOPY

The in vitro subcellular distribution patterns of 10 porphyrins, varying in hydrophobicity and charge, were studied using confocal laser scanning microscopy on two cell lines (V79 and C6 glioma cells) for incubation times up to 24 h. All of the porphyrins were taken up rapidly by both cell lines and distinct classes of subcellular distribution patterns were observed: general cytoplasmic staining; localization in lysosomes (usually associated with general cytoplasmic staining); localization in mitochondria (and general cytoplasmic staining); localization in mitochondria with subsequent uptake into lysosomes. Structure‐localization relationships which have emerged are that porphyrins with dominantly cationic side chains localize in mitochondria, whereas those with a more anionic character tend to localize in lysosomes.

Epilepsy Surgery for Pathologically Proven Hippocampal Sclerosis Provides Long‐term Seizure Control and Improved Quality of Life

Summary:  Purpose: To examine long‐term seizure and quality‐of‐life outcome in a homogeneous group of patients after temporal lobectomy with pathologically proven hippocampal sclerosis (HS). Previous research has had limited follow‐up (generally <2 years) and has grouped patients across multiple pathologies.

Targeting malignant glioma survival signalling to improve clinical outcomes

Malignant gliomas are common and aggressive brain tumours in adults. Current treatments for glioblastoma multiforme result in a poor median survival of less than 12 months. The blood-brain barrier restricts the delivery of many chemotherapies to the central nervous system, contributing to the failure of treatment. PI3K/Akt and Ras/MAPK pathways have been identified as important oncogenic pathways in these tumours. The PI3K/Akt pathway mediates cell survival and growth, whereas the Ras/MAPK pathway signals cell differentiation, proliferation and anti-apoptosis. Modern targeted therapies include antibodies to circulating growth factors and cell surface receptors, as well as inhibitors of receptor tyrosine kinases and specific intracellular signalling proteins. Monotherapy with most targeted therapies produces only modest efficacy. Better results are achieved in combination with cytotoxic chemotherapies. Future therapeutics should focus on combination therapy with small lipophilic molecules.

EGF receptor modifies cellular responses to hyaluronan in glioblastoma cell lines.

Cell contact with the extracellular matrix component, hyaluronan, plays a pivotal role in glioma cell invasion and proliferation. Although it is well established that glioma cells can bind hyaluronan to their surface via the expression of CD44, the cellular responses following ligand-receptor interaction remain poorly understood. Given that a large proportion of human high grade gliomas over express the epidermal growth factor receptor (EGFR) and ErbB2, this study aimed to investigate whether an interaction exists between CD44 and these receptor tyrosine kinases. Here we present evidence that CD44 co-immunoprecipitates with EGFR and ErbB2 in the glioma cell lines U87MG and SMA560. Hyaluronan treatment mediated the rapid and transient phosphorylation of extracellular signal regulated kinases 1 and 2 (ERK1 and ERK2) in glioma cell lines. This response to hyaluronan was augmented by the co-expression of EGFR. EGFR also differentially modified the hyaluronan induced expression of a number of genes associated with cellular invasion and proliferation. Northern blot analysis demonstrated that genes encoding urokinase type plasminogen activator (uPA), urokinase type plasminogen activator receptor (uPAR), plasminogen activator inhibitor-1 (PAI-1), tissue inhibitor of metalloproteinases (TIMP-1) and c- myc were up-regulated in response to hyaluronan. Furthermore, zymographic analysis revealed increased levels of uPA in the conditioned medium of hyaluronan stimulated cells. These results indicate a novel functional relationship between CD44 and EGFR in glioma cell lines. The capacity of CD44 to form stable complexes with receptor tyrosine kinases may provide a versatile system for the regulation of cellular invasion and proliferation that allows hyaluronan to activate signal transduction pathways and modulate gene expression via an EGFR-dependent manner. These findings provide new insights into the mode by which hyaluronan regulates the malignant phenotype and also suggest a role for EGFR-CD44 interactions in glial tumorigenesis.