Jonathon F. Parkinson

IQGAP1 and IGFBP2: Valuable Biomarkers for Determining Prognosis in Glioma Patients

Abstract Clinical treatment decisions and the survival outcomes of patients with gliomas are directly impacted by accurate tumor classification. New and more reliable prognostic markers are needed to better identify the variable duration of survival among histologically defined glioma grades. Microarray expression analysis and immunohistochemistry were used to identify biomarkers associated with gliomas with more aggressive biologic behaviors. The protein expression of IQGAP1 and IGFBP2, when used in conjunction with the World Health Organization grading system, readily identified and defined a subgroup of patients with grade III gliomas whose prognosis was poor. In addition, in patients with glioblastoma multiforme, in whom IQGAP1 and IGFBP2 were absent, long-term survival of more than 3 years was observed. The use of these markers confirmed a nonuniform distribution of survival in those with World Health Organization grade III and IV tumors. Thus, IQGAP1 and IGFBP2 immunostaining supplements current histologic grading by offering additional prognostic and predictive information.

Molecular heterogeneity in glioblastoma: potential clinical implications.

Glioblastomas, (grade 4 astrocytomas), are aggressive primary brain tumors characterized by histopathological heterogeneity. High-resolution sequencing technologies have shown that these tumors also feature significant inter-tumoral molecular heterogeneity. Molecular subtyping of these tumors has revealed several predictive and prognostic biomarkers. However, intra-tumoral heterogeneity may undermine the use of single biopsy analysis for determining tumor genotype and has implications for potential targeted therapies. The clinical relevance and theories of tumoral molecular heterogeneity in glioblastoma are discussed.

Intratumoral heterogeneity identified at the epigenetic, genetic and transcriptional level in glioblastoma.

Heterogeneity is a hallmark of glioblastoma with intratumoral heterogeneity contributing to variability in responses and resistance to standard treatments. Promoter methylation status of the DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT) is the most important clinical biomarker in glioblastoma, predicting for therapeutic response. However, it does not always correlate with response. This may be due to intratumoral heterogeneity, with a single biopsy unlikely to represent the entire lesion. Aberrations in other DNA repair mechanisms may also contribute. This study investigated intratumoral heterogeneity in multiple glioblastoma tumors with a particular focus on the DNA repair pathways. Transcriptional intratumoral heterogeneity was identified in 40% of cases with variability in MGMT methylation status found in 14% of cases. As well as identifying intratumoral heterogeneity at the transcriptional and epigenetic levels, targeted next generation sequencing identified between 1 and 37 unique sequence variants per specimen. In-silico tools were then able to identify deleterious variants in both the base excision repair and the mismatch repair pathways that may contribute to therapeutic response. As these pathways have roles in temozolomide response, these findings may confound patient management and highlight the importance of assessing multiple tumor biopsies.

Contribution of DNA repair mechanisms to determining chemotherapy response in high-grade glioma

Despite the existence of a well described, succinct pathological grading system for gliomas, tumour behaviour between individual patients varies widely. In addition, predictors of response to treatment in glioblastoma multiforme are lacking. The majority of chemotherapeutic agents currently employed exert their effect on DNA. As our understanding of DNA repair mechanisms improves and predictive markers are elucidated, this may allow treating clinicians to individualise treatment based on molecular markers. This review examines important DNA repair mechanisms and their application to glioblastoma multiforme. By improving understanding of these mechanisms, and particularly the variations that occur between tumours and individuals, it may be possible to adapt treatment to maximise effectiveness and minimise toxicity.

Loss of prostaglandin D2 synthase: a key molecular event in the transition of a low-grade astrocytoma to an anaplastic astrocytoma

Reduction in the mRNA and protein expression of lipocalin-like prostaglandin D2 (PGD2) synthase (PGDS), the main arachidonic acid metabolite produced in neurons and glial cells of the central nervous system, is a significant biological event involved in the malignant progression of astrocytomas and is predictive of poor survival. In vitro, the addition of the main PGDS metabolite, PGD2, to A172 glioblastoma cells devoid of PGDS resulted in antiproliferative activity and cell death. In vitro PGD2 substitution also enhanced the efficacy of cyclo-oxygenase-2 inhibitors. This finding has exciting implications for early interventional efforts for the grade 2 and 3 astrocytomas. [Mol Cancer Ther 2008;7(10):3420–8]

Surgical management of spinal epidural abscess: selection of approach based on MRI appearance.

Spinal epidural abscess (SEA) is associated with considerable morbidity and mortality despite its infrequent occurrence. The evolution of magnetic resonance imaging has allowed for easier diagnosis of this potentially devastating condition. It is also possible to predict the intraoperative appearance of each individual case of SEA prior to the procedure, based on the MR findings. Surgical treatment of SEA usually involves extensive decompressive laminectomy, predisposing the patient to the development of spinal instability and deformity. Recent advances in surgical approach to SEA have seen the institution of less invasive techniques to manage this condition, including washout of the epidural space with catheters introduced via laminotomy. Our three cases illustrate the ability to predict the intraoperative findings in patients with SEA, and accordingly adjust the surgical approach to minimize the extensiveness of potentially destabilizing procedures, without impinging on the effectiveness of treatment.

The impact of molecular and clinical factors on patient outcome in oligodendroglioma from 20 years' experience at a single centre.

The increased chemosensitivity of oligodendroglial tumours has been associated with loss of heterozygosity (LOH) of the p arm of chromosome 1 and the q arm of chromosome 19 (LOH 1p/19q). Other clinical and molecular factors have also been identified as being prognostic and predictive of treatment outcome. We reviewed 105 patients with oligodendroglioma treated at a single centre over 20 years. Median survival in oligodendroglioma patients with LOH 1p/19q was significantly longer (10.9 vs. 2.0 years). In the anaplastic oligodendroglioma group, univariate analysis demonstrated decreased patient age, presentation with seizures, use of adjuvant chemotherapy and LOH 1p/19q as predictors of improved survival. Multivariate analysis confirmed LOH 1p/19q as a significant predictor of improved survival (hazard ratio, 3.4; p=0.015). Median survival in patients with anaplastic oligodendroglioma with LOH 1p/19q was 15.4 years vs. 1.2 years for those without LOH 1p/19q. This study confirms the utility of LOH 1p/19q as a prognostic marker in oligodendroglioma.

Etoposide-mediated glioblastoma cell death: dependent or independent on the expression of its target, topoisomerase II alpha?

BackgroundTreatments which significantly improve progression-free and overall survival for patients with relapsed glioblastoma (GBM) after the standard therapy are lacking. The Topoisomerase II (TopoII) enzyme is a key target of anticancer agents because of the important role it plays in transcription regulation and chromatin remodeling. A drug with strong topoisomerase-mediated anticancer activity is etoposide that is used in combination with carboplatin in patients with relapsed GBM. We hypothesized that tumors harboring high expression of TopoII alpha (TopoIIa) would be more sensitive to etoposide treatment.MethodsThe relative expression levels of TopoIIa protein were measured in a panel of GBM cell lines using Western blot analysis and in a cohort of GBM using immunohistochemistry. Expression levels of TopoIIa in the cell lines were correlated with relative sensitivity to treatment with etoposide. To ascertain the role TopoIIa plays in mediating response to etoposide, expression was reduced with a siRNA targeted to TopoIIa.ResultsProtein expression of TopoIIa, although high in the cell lines, was very low in patient specimens. Correlations between TopoIIa protein expression and sensitivity to etoposide were evident. The IC50 for the low-TopoIIa-expressing cell line, T98G, was almost 50 times higher than M059K (high TopoIIa). Inhibition of TopoIIa in MO59K cells with siRNA significantly altered the IC50, increasing the resistance to etoposide. Interestingly, the expression of TopoIIa was not decreased after treatment with etoposide, indicating other mechanisms underplay treatment response.ConclusionsIn vitro, the levels of TopoIIa protein expression correlate with response to etoposide but also multiple molecular events namely DNA-PK and MDR also play a role in cell sensitivity to etoposide. That we did not find a high expression of TopoIIa in clinical specimens further suggests the mechanisms underlying treatment response are complex.

Idiopathic intradural dorsal thoracic arachnoid cysts: A case series and review of the literature

BACKGROUND Spinal intradural arachnoid cysts (SIAC) are cerebrospinal fluid (CSF) filled sacs formed by arachnoid membranes and may be either idiopathic or acquired. Idiopathic cysts represent a separate entity and their aetiology remains uncertain. By far the most difficult differential diagnosis is distinguishing between idiopathic anterior spinal cord herniation (IASCH) and dorsal thoracic intradural arachnoid cysts (TIAC), due to their similarity in radiological appearance. Cine-mode (SSFP) is emerging as a novel technique in the diagnosis and operative planning of SIAC. METHOD Retrospective analysis of patients with idiopathic TIACs that were surgically managed at Royal North Shore Hospital and North Shore Private Hospital between November 2000 and November 2015. RESULTS Ten patients were included in this study. Age ranged from 20 to 77years with a mean age of 60years and a female preponderance. The most common clinical features were progressive gait ataxia and lower limb myelopathy. Radicular pain tends to improve following surgery, however gait ataxia may not. DISCUSSION While there are circumstances in which the distinction between dorsal thoracic intradural arachnoid cysts and idiopathic anterior spinal cord herniation are radiologically obvious, in cases where the appearances are less clear, cine-mode SSFP MRI imaging can provide an invaluable tool to differentiate these pathologies and lead the clinician towards the correct diagnosis and management. The mainstay of surgical management for dorsal TIACs is laminectomy and cyst excision or fenestration. Surgery for gait ataxia should be aimed towards preventing deterioration, while maintaining the potential for symptomatic improvement, whereas surgery for radicular pain should be curative.

The role of 18F-fluoro-ethyl-tyrosine (FET) PET in the investigation and management of suspected gliomas

BACKGROUND This study aims to investigate the utility of 18F-fluoro-ethyl-tyrosine (18F-FET) positron emission tomography in surgical decision making in suspected glioma. METHODS A retrospective review of patients undergoing 18F-FET positron emission tomography was performed. Previously published thresholds for maximum tumor background ratios (TBRs) were used for quantitative analysis. Forty-seven patients were included in the study, of whom 15 had confirmed glioma and 7 had a confirmed alternative diagnosis. RESULTS 18F-FET showed significantly higher uptake in high-grade glioma than in nonglioma. CONCLUSIONS Lesions with TBRmax >2.5 should be considered suspicious for glioma and biopsy considered. Threshold TBRmax >3.0 is useful for differentiating high-grade glioma from low-grade glioma. This may be a particularly useful tool for directing management in eloquent areas, such as brainstem glioma.